Payers’Guide toNew FDA Approvals

MAY/JUNE 2011

VOLUME 4 I NUMBER 2 I SPECIAL FEATURE

THE PEER-REVIEWED FORUM FOR EVIDENCE IN BENEFIT DESIGN ™

FOR PAYERS, PURCHASERS, POLICYMAKERS, AND OTHER HEALTHCARE STAKEHOLDERS

Payers’ Guide to New FDA Approvals Special Feature

™

©2011 Engage Healthcare Communications, LLC www.AHDBonline.com

INDICATION %8!,'/ÂŽ TABLETS ARE AN EXTENDED RELEASE ORAL FORMULATION OF THE OPIOID AGONIST HYDROMORPHONE HYDROCHLORIDE THAT IS INDICATED FOR ONCE DAILY ADMINISTRATION FOR THE MANAGEMENT OF MODERATE TO SEVERE PAIN IN OPIOID TOLERANT PATIENTS REQUIRING CONTINUOUS AROUND THE CLOCK OPIOID ANALGESIA FOR AN EXTENDED PERIOD OF TIME IMPORTANT RISK INFORMATION WARNING: POTENTIAL FOR ABUSE, IMPORTANCE OF PROPER PATIENT SELECTION AND LIMITATIONS OF USE Potential for Abuse EXALGO contains hydromorphone, an opioid agonist and a Schedule II controlled substance with an abuse liability similar to other opioid analgesics. EXALGO can be abused in a manner similar to other opioid agonists, legal or illicit. These risks should be considered when administering, prescribing, or dispensing EXALGO in situations where the healthcare professional is concerned about increased risk of misuse, abuse, or diversion. Schedule II opioid substances which include hydromorphone, morphine, oxycodone, fentanyl, oxymorphone and methadone have the highest potential for abuse and risk of fatal overdose due to respiratory depression.

Proper Patient Selection EXALGO is an extended-release formulation of hydromorphone hydrochloride indicated for the management of moderate to severe pain in opioid tolerant patients when a continuous around-the-clock opioid analgesic is needed for an extended period of time.

Patients considered opioid tolerant are those who are taking at least 60 mg oral morphine per day, 25 mcg transdermal fentanyl/ hour, 30 mg oral oxycodone/day, 8 mg oral hydromorphone/day, 25 mg oral oxymorphone/day or an equianalgesic dose of another opioid, for a week or longer.

EXALGO is for use in opioid tolerant patients only.

Fatal respiratory depression could occur in patients who are not opioid tolerant.

Accidental consumption of EXALGO, especially in children, can result in a fatal overdose of hydromorphone.

Limitations of Use EXALGO is not indicated for the management of acute or postoperative pain.

EXALGO is not intended for use as an as-needed analgesic.

EXALGO tablets are to be swallowed whole and are not to be broken, chewed, dissolved, crushed or injected. Taking broken, chewed, dissolved or crushed EXALGO or its contents leads to rapid release and absorption of a potentially fatal dose of hydromorphone.

s %8!,'/ IS ALSO CONTRAINDICATED IN PATIENTS WHO NEED MANAGEMENT OF MILD PAIN OR PAIN NOT EXPECTED TO PERSIST HAVE SIGNIlCANT IMPAIRED RESPIRATORY FUNCTION INCLUDING THOSE WITH ACUTE OR SEVERE BRONCHIAL ASTHMA OR HYPERCARBIA HAVE OR ARE SUSPECTED TO HAVE PARALYTIC ILEUS HAVE NARROWED OR OBSTRUCTED GASTROINTESTINAL TRACT INCLUDING THOSE FROM PREVIOUS SURGERY OR hBLIND LOOPSv IN THE ') TRACT HAVE KNOWN HYPERSENSITIVITY TO ANY COMPONENTS INCLUDING HYDROMORPHONE HYDROCHLORIDE AND SULlTES s !VOID CONCURRENT USE OF ALCOHOL AND %8!,'/ #ONCURRENT USE OF %8!,'/ WITH #.3 DEPRESSANTS INCLUDING ALCOHOL INCREASES RISK OF RESPIRATORY DEPRESSION HYPOTENSION AND PROFOUND SEDATION

POTENTIALLY RESULTING IN COMA OR DEATH %8!,'/ MAY IMPAIR THE ABILITY TO DRIVE A CAR OR OPERATE MACHINERY s .OT INTENDED IN PATIENTS WHO HAVE RECEIVED -!/ INHIBITORS WITHIN DAYS OF STARTING %8!,'/ s 5SE WITH CAUTION AND IN REDUCED DOSES IN OLDER OR DEBILITATED PATIENTS AS WELL AS PATIENTS WITH RENAL OR HEPATIC INSUFlCIENCY

!DDISON S DISEASE DELIRIUM TREMENS MYXEDEMA OR HYPOTHYROIDISM

PROSTATIC HYPERTROPHY OR URETHRAL STRICTURE TOXIC PSYCHOSIS -AY AGGRAVATE CONVULSIONS IN PATIENTS WITH CONVULSIVE DISORDERS MAY INDUCE OR AGGRAVATE SEIZURES IN SOME CLINICAL SETTINGS #ONSIDER USE OF AN ALTERNATE ANALGESIC IN PATIENTS WITH SEVERE RENAL IMPAIRMENT s 2ESPIRATORY DEPRESSION WHICH OCCURS MORE FREQUENTLY IN ELDERLY OR DEBILITATED PATIENTS IS THE CHIEF HAZARD WITH %8!,'/ s 3ERIOUS ADVERSE EVENTS COULD ALSO INCLUDE HYPOTENSIVE EFFECTS

') EFFECTS CARDIAC ARREST FROM OVERDOSE AND PRECIPITATION OF WITHDRAWAL -OST COMMON ADVERSE EVENTS SEEN IN CLINICAL STUDIES . WERE CONSTIPATION NAUSEA

VOMITING SOMNOLENCE ASTHENIA AND DIZZINESS s 5SE %8!,'/ WITH EXTREME CAUTION IN PATIENTS SUSCEPTIBLE TO INTRACRANIAL EFFECTS OF #/ RETENTION s $O NOT ABRUPTLY DISCONTINUE %8!,'/ Please see brief summary of Full Prescribing Information, including boxed warning, on following pages. #/6)$)%. #/6)$)%. WITH LOGO AND #OVIDIEN LOGO ARE 5 3 AND INTERNATIONALLY REGISTERED TRADEMARKS OF #OVIDIEN !' %8!,'/ IS A REGISTERED TRADEMARK OF -ALLINCKRODT )NC ¥ -ALLINCKRODT )NC A #OVIDIEN COMPANY -+ -AY 0RINTED IN 53!

WHERE IS HER DAY HEADED WITHOUT A 24-HOUR PAIN MEDICATION? EXALGO® puts the power of hydromorphone into a once-daily dose, so your patients can worry less about their medicine wearing off.

To find out more, visit www.EXALGO.com.

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BRIEF SUMMARY - Consult full prescribing information before use.

EXALGOÂŽ (hydromorphone HCl) Extended-Release Tablets WARNING: POTENTIAL FOR ABUSE, IMPORTANCE OF PROPER PATIENT SELECTION AND LIMITATIONS OF USE Potential for Abuse EXALGO contains hydromorphone, an opioid agonist and a Schedule II controlled substance with an abuse liability similar to other opioid analgesics. EXALGO can be abused in a manner similar to other opioid agonists, legal or illicit. These risks should be considered when administering, prescribing, or dispensing EXALGO in situations where the healthcare professional is concerned about increased risk of misuse, abuse, or diversion. Schedule II opioid substances which include hydromorphone, morphine, oxycodone, fentanyl, oxymorphone and methadone have the highest potential for abuse and risk of fatal overdose due to respiratory depression [see Drug Abuse and Dependence (9)].

Proper Patient Selection EXALGO is an extended-release formulation of hydromorphone hydrochloride indicated for the management of moderate to severe pain in opioid tolerant patients when a continuous around-the-clock opioid analgesic is needed for an extended period of time. Patients considered opioid tolerant are those who are taking at least 60 mg oral morphine per day, 25 mcg transdermal fentanyl/hour, 30 mg of oral oxycodone/ day, 8 mg oral hydromorphone/day, 25 mg of oral oxymorphone/day or an equianalgesic dose of another opioid, for a week or longer [see Indications and Usage (1) and Dosage and Administration (2)].

EXALGO is for use in opioid tolerant patients only [see Indications and Usage (1) and Dosage and Administration (2)].

Fatal respiratory depression could occur in patients who are not opioid tolerant.

Accidental consumption of EXALGO, especially in children, can result in a fatal overdose of hydromorphone [see Warnings and Precautions (5.1)].

Limitations of Use EXALGO is not indicated for the management of acute or postoperative pain [see Indications and Usage (1)].

EXALGO is not intended for use as an as-needed analgesic [see Indications and Usage (1)].

EXALGO tablets are to be swallowed whole and are not to be broken, chewed, dissolved, crushed or injected. Taking broken, chewed, dissolved or crushed EXALGO or its contents leads to rapid release and absorption of a potentially fatal dose of hydromorphone [see Warnings and Precautions (5)].

CONTRAINDICATIONS Opioid Non-Tolerant Patients EXALGO is contraindicated in opioid non-tolerant patients. Fatal respiratory depression could occur in patients who are not opioid tolerant.

Impaired Pulmonary Function EXALGO is contraindicated in patients with significant respiratory depression, especially in the absence of resuscitative equipment or in unmonitored settings and in patients with acute or severe bronchial asthma or hypercarbia.

Paralytic Ileus EXALGO is contraindicated in patients who have or are suspected of having a paralytic ileus.

Preexisting Gastrointestinal (GI) Surgery or Narrowing of GI Tract EXALGO is contraindicated in patients who have had surgical procedures and/or underlying disease that would result in narrowing of the gastrointestinal tract, or have “blind loops� of the gastrointestinal tract or gastrointestinal obstruction.

Allergy or Hypersensitivity EXALGO is contraindicated in patients with known hypersensitivity to any of its components including the active agent, hydromorphone hydrochloride or known allergy to sulfite-containing medications [see Warnings and Precautions (5.8)].

WARNINGS AND PRECAUTIONS Information Essential for Safe Administration EXALGO tablets are to be swallowed whole, and are not to be broken, chewed, crushed, dissolved or injected. Taking broken, chewed, crushed, dissolved EXALGO or its contents leads to the rapid release and absorption of a potentially fatal dose of hydromorphone [see Boxed Warning].

EXALGO is for use only in opioid tolerant patients. Ingestion of EXALGO may cause fatal respiratory depression when administered to patients who are not opioid tolerant [see Boxed Warning].

EXALGO tablets must be kept in a secure place out of the reach of children. Accidental consumption of EXALGO, especially in children, can result in a fatal overdose of hydromorphone.

Misuse and Abuse EXALGO contains hydromorphone, an opioid agonist, and is a Schedule II controlled substance. Opioid agonists have the potential for being abused and are sought by drug abusers and people with addiction disorders and are subject to criminal diversion.

EXALGO can be abused in a manner similar to other opioid agonists, legal or illicit.

This should be considered when prescribing or dispensing EXALGO in situations where the healthcare professional is concerned about an increased risk of misuse, abuse, or diversion.

Breaking, crushing, chewing, or dissolving the contents of an EXALGO tablet results in the uncontrolled delivery of the opioid and poses a significant risk of overdose and death [see Drug Abuse and Dependence (9)].

If attempts are made to extract the drug from the hard outer shell for purposes of parenteral abuse, the injection of tablet excipients may be toxic and may result in lethal complications.

Concerns about abuse, addiction, and diversion should not prevent the proper management of pain. However, all patients treated with opioids, including EXALGO, require careful monitoring for signs of abuse and addiction, since use of opioid analgesic products carries the risk of addiction even under appropriate medical use.

Healthcare professionals should contact their State Professional Licensing Board or State Controlled Substances Authority for information on how to prevent and detect abuse or diversion of this product.

Respiratory Depression Respiratory depression is the chief hazard of EXALGO. Respiratory depression occurs more frequently in elderly or debilitated patients as well as those suffering from conditions accompanied by hypoxia or hypercapnia when even moderate therapeutic doses may dangerously decrease pulmonary ventilation, and when opioids are given in conjunction with other agents that depress respiration.

Use EXALGO with extreme caution in patients with conditions accompanied by hypoxia, hypercapnia, or decreased respiratory reserve such as asthma, chronic obstructive pulmonary disease or cor pulmonale, severe obesity, sleep apnea, myxedema, kyphoscoliosis or CNS depression. In these patients, even moderate therapeutic doses of hydromorphone may decrease respiratory drive while simultaneously increasing airway resistance to the point of apnea. In these patients, consider alternative non-opioid analgesics, and use EXALGO only under careful medical supervision at the lowest effective dose.

Interactions with Alcohol and Other CNS Depressants The concurrent use of EXALGO with other central nervous system (CNS) depressants, including but not limited to other opioids, illicit drugs, sedatives, hypnotics, general anesthetics, phenothiazines, muscle relaxants, other tranquilizers, and alcohol, increases the risk of respiratory depression, hypotension, and profound sedation, potentially resulting in coma or death. Use with caution and in reduced dosages in patients taking CNS depressants. Avoid concurrent use of alcohol and EXALGO [see Clinical Pharmacology (12.3)].

Head Injury and Increased Intracranial Pressure In the presence of head injury, intracranial lesions or a preexisting increase in intracranial pressure, the respiratory depressant effects of EXALGO and its potential to elevate cerebrospinal fluid pressure (resulting from vasodilation following CO2 retention) may be markedly exaggerated. Furthermore, EXALGO can produce effects on pupillary response and consciousness, which may obscure neurologic signs of further increases in intracranial pressure in patients with head injuries.

Hypotensive Effect EXALGO may cause severe hypotension. There is added risk to individuals whose ability to maintain blood pressure has been compromised by a depleted blood volume, or after concurrent administration with drugs such as phenothiazines, general anesthetics, or other agents that compromise vasomotor tone.

Administer EXALGO with caution to patients in circulatory shock, since vasodilation produced by the drug may further reduce cardiac output and blood pressure.

Gastrointestinal Effects Because the EXALGO tablet is nondeformable and does not appreciably change in shape in the GI tract, do not administer EXALGO to patients with preexisting severe gastrointestinal narrowing (pathologic or iatrogenic, for example: esophageal motility disorders small bowel inflammatory disease, “short gut� syndrome due to adhesions or decreased transit time, past history of peritonitis, cystic fibrosis, chronic intestinal pseudoobstruction, or Meckel’s diverticulum). There have been reports of obstructive symptoms in patients with known strictures or risk of strictures, such as previous GI surgery, in association with the ingestion of drugs in nondeformable extended-release formulations.

The administration of EXALGO may obscure the diagnosis or clinical course in patients with acute abdominal condition.

It is possible that EXALGO tablets may be visible on abdominal x-rays under certain circumstances, especially when digital enhancing techniques are utilized.

Sulfites EXALGO contains sodium metabisulfite, a sulfite that may cause allergic-type reactions including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people. The overall prevalence of sulfite sensitivity in the general population is unknown and probably low. Sulfite sensitivity is seen more frequently in asthmatic than in nonasthmatic people.

MAO Inhibitors EXALGO is not recommended for use in patients who have received MAO inhibitors within 14 days, because severe and unpredictable potentiation by MAO inhibitors has been reported with opioid analgesics.

Special Risk Groups EXALGO should be administered with caution in elderly (≼ 65 years) and debilitated patients and in patients who are known to be sensitive to central nervous system depressants, such as those with cardiovascular, pulmonary, renal, or hepatic disease [see Use in Specific Populations (8)].

EXALGO should also be used with caution in the following conditions: adrenocortical insufficiency (e.g., Addison’s disease); delirium tremens; myxedema or hypothyroidism; prostatic hypertrophy or urethral stricture; and, toxic psychosis.

EXALGO may aggravate convulsions in patients with convulsive disorders, and all opioids may induce or aggravate seizures in some clinical settings.

Use in Pancreatic/Biliary Tract Disease EXALGO can cause an increase in biliary tract pressure as a result of spasm in the sphincter of Oddi. Caution should be exercised in the administration of EXALGO to patients with inflammatory or obstructive bowel disorders, acute pancreatitis secondary to biliary tract disease and in patients about to undergo biliary surgery.

Driving and Operating Machinery EXALGO may impair the mental and/or physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery. Caution patients accordingly. Also warn patients about the potential combined effects of EXALGO with other CNS depressants, including other opioids, phenothiazines, sedative/hypnotics, and alcohol [see Drug Interactions (7)].

Precipitation of Withdrawal Mixed agonist/antagonist analgesics (i.e., pentazocine, nalbuphine, and butorphanol) should not be administered to patients who have received or are receiving a course of therapy with a pure opioid agonist analgesic, including EXALGO. In these patients, mixed agonists/antagonists analgesics may reduce the analgesic effect and/or may precipitate withdrawal symptoms. Do not abruptly discontinue EXALGO. Clinical conditions or medicinal products that cause a sudden and significant shortening of gastrointestinal transit time may result in decreased hydromorphone absorption with EXALGO and may potentially lead to withdrawal symptoms in patients with a physical dependence on opioids.

ADVERSE REACTIONS The following serious adverse reactions are discussed elsewhere in the labeling: K &3A>7@/B=@G 3>@3AA7=< [see Warnings and Precautions (5.3)] K Head Injury and Increased Intracranial Pressure [see Warnings and Precautions (5.5)] K G>=B3<A7D3 4431B [see Warnings and Precautions (5.6)] K /AB@=7<B3AB7</: 4431BA [see Warnings and Precautions (5.7)] K /@27/1 @@3AB [see Overdosage (10)] K %@317>7B/B7=< =4 +7B62@/E/: [see Warnings and Precautions (5.13)]

Clinical Studies Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

EXALGO was administered to a total of 2,524 patients in 15 controlled and uncontrolled clinical studies. Of these, 423 patients were exposed to EXALGO for greater than 6 months and 141 exposed for greater than one year.

The overall incidence of adverse reactions in patients greater than 65 years of age was higher, with a greater than 5% difference in rates for constipation and nausea when compared with younger patients. The overall incidence of adverse reactions in female patients was higher, with a greater than 5% difference in rates for nausea, vomiting, constipation and somnolence when compared with male patients.

A 12-week double-blind, placebo-controlled, randomized withdrawal study was conducted in opioid tolerant patients with moderate to severe low back pain [see Clinical Studies (14)]. A total of 447 patients were enrolled into the open-label titration phase with 268 patients randomized into the double-blind treatment phase. The adverse reactions that were reported in at least 2% of the patients are contained in Table 1.

Table 1.

Number (%) of Patients with Adverse Reactions Reported in â&#x2030;Ľ2% of Patients with Moderate to Severe Low Back Pain During the Open-Label Titration Phase or Double-Blind Treatment Phase by Preferred Term Preferred Term Open-Label Double-Blind Treatment Phase Titration Phase EXALGO (N=447) EXALGO (N=134) Placebo (N=134) Constipation 69 (15) 10 (7) 5 (4) Nausea 53 (12) 12 (9) 10 (7) Somnolence 39 (9) 1 (1) 0 (0) Headache 35 (8) 7 (5) 10 (7) Vomiting 29 (6) 8 (6) 6 (4) Drug Withdrawal Syndrome 22 (5) 13 (10) 16 (12) Pruritus 21 (5) 1 (1) 0 (0) Dizziness 17 (4) 3 (2) 2 (1) 16 (4) 2 (1) 6 (4) Asthenia a Insomnia 13 (3) 7 (5) 5 (4) Diarrhea 13 (3) 5 (4) 9 (7) Back Pain 13 (3) 6 (4) 8 (6) Dry Mouth 13 (3) 2 (1) 0 (0) Edema Peripheral 13 (3) 3 (2) 1 (1) Hyperhidrosis 13 (3) 2 (1) 2 (1) 10 (2) 2 (1) 0 (0) Anorexia b Arthralgia 9 (2) 8 (6) 3 (2) Anxiety 9 (2) 0 (0) 4 (3) 9 (2) 4 (3) 3 (2) Abdominal Pain c Muscle Spasms 5 (1) 3 (2) 1 (1) Weight Decreased 3 (1) 4 (3) 3 (2) a b c

Fatigue was grouped and reported with asthenia Decreased appetite was grouped and reported with anorexia Abdominal pain upper was grouped and reported with abdominal pain

The adverse reactions that were reported in at least 2% of the total treated patients (N=2,474) in the 14 chronic clinical trials are contained in Table 2.

Table 2.

Number (%) of Patients with Adverse Reactions Reported in â&#x2030;Ľ2% of Patients with Chronic Pain Receiving EXALGO in 14 Clinical Studies by Preferred Term Preferred Term All Patients (N=2,474) Constipation 765 (31) Nausea 684 (28) Vomiting 337 (14) Somnolence 367 (15) Headache 308 (12) Asthenia a 272 (11) Dizziness 262 (11) Diarrhea 201 (8) Pruritus 193 (8) Insomnia 161 (7) Hyperhidrosis 143 (6) Edema Peripheral 135 (5) Anorexia b 139 (6) Dry Mouth 121 (5) Abdominal Pain c 115 (5) Anxiety 95 (4) Back Pain 95 (4) Dyspepsia d 88 (4) Depression 81 (3) Dyspnea e 76 (3) Muscle Spasms 74 (3) Arthralgia 72 (3) Rash 64 (3) Pain in Extremity 63 (3) Pain 58 (2) Drug Withdrawal Syndrome 55 (2) Pyrexia 52 (2) Fall 51 (2) Chest Discomfort f 51 (2) a b c d e f

Fatigue was grouped and reported with asthenia Decreased appetite was grouped and reported with anorexia Abdominal pain upper was grouped and reported with abdominal pain Reflux esophagitis, gastroesophageal reflux disease and Barrettâ&#x20AC;&#x2122;s esophagus were grouped and reported with dyspepsia Dyspnea exacerbated and dyspnea exertional were grouped and reported with dyspnea Chest pain and non-cardiac chest pain were grouped and reported with chest discomfort

The following Adverse Reactions occurred in patients with an overall frequency of <2% and are listed in descending order within each System Organ Class: Cardiac disorders: palpitations, tachycardia, bradycardia, extrasystoles Ear and labyrinth disorders: vertigo, tinnitus Endocrine disorders: hypogonadism Eye disorders: vision blurred, diplopia, dry eye, miosis Gastrointestinal disorders: flatulence, dysphagia, hematochezia, abdominal distension, hemorrhoids, abnormal feces, intestinal obstruction, eructation, diverticulum, gastrointestinal motility disorder, large intestine perforation, anal fissure, bezoar, duodenitis, ileus, impaired gastric emptying, painful defecation General disorders and administration site conditions: chills, malaise, feeling abnormal, feeling hot and cold, feeling jittery, hangover, difficulty in walking, feeling drunk, hypothermia Infections and infestations: gastroenteritis, diverticulitis Injury, poisoning and procedural complications: contusion, overdose Investigations: weight decreased, hepatic enzyme increased, blood potassium decreased, blood amylase increased, blood testosterone decreased, oxygen saturation decreased Metabolism and nutrition disorders: dehydration, fluid retention, increased appetite, hyperuricemia Musculoskeletal and connective tissue disorders: myalgia Nervous system disorders: tremor, sedation, hypoesthesia, paraesthesia, disturbance in attention, memory impairment, dysarthria, syncope, balance disorder, dysgeusia, depressed level of consciousness, coordination abnormal, hyperesthesia, myoclonus, dyskinesia, hyperreflexia, encephalopathy, cognitive disorder, convulsion, psychomotor hyperactivity Psychiatric disorders: confusional state, nervousness, restlessness, abnormal dreams, mood altered, hallucination, panic attack, euphoric mood, paranoia, dysphoria, listless, crying, suicide ideation, libido decreased, aggression Renal and urinary disorders: dysuria, urinary retention, urinary frequency, urinary hesitation, micturition disorder Reproductive system and breast disorders: erectile dysfunction, sexual dysfunction Respiratory, thoracic and mediastinal disorders: rhinorrhoea, respiratory distress, hypoxia, bronchospasm, sneezing, hyperventilation, respiratory depression Skin and subcutaneous tissue disorders: erythema Vascular disorders: flushing, hypertension, hypotension DRUG INTERACTIONS CNS Depressants The concomitant use of EXALGO with central nervous system depressants such as hypnotics, sedatives, general anesthetics, antipsychotics and alcohol may cause additive depressant effects and respiratory depression. Additionally, hypotension and profound sedation or coma could occur. When this combination is indicated, the dose of one or both agents should be reduced. The concomitant use of alcohol should be avoided [see Clinical Pharmacology (12.3)].

Monoamine Oxidase (MAO) Inhibitors MAO inhibitors may cause CNS excitation or depression, hypotension or hypertension if co-administered with opioids including EXALGO. EXALGO is not intended for patients taking MAO inhibitors or within 14 days of stopping such treatment.

Mixed Agonist/Antagonist Opioid Analgesics The concomitant use of EXALGO with morphine agonist/antagonists (buprenorphone, nalbuphine, pentazocine) could lead to a reduction of the analgesic effect by competitive blocking of receptors, thus leading to risk of withdrawal symptoms. Therefore, this combination is not recommended.

Anticholinergics Anticholinergics or other medications with anticholinergic activity when used concurrently with EXALGO may result in increased risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.

Cytochrome P450 Enzymes In vitro data suggest that hydromorphone in clinically relevant concentrations has minimal potential to inhibit the activity of human hepatic CYP450 enzymes including CYP1A2, 2C9, 2C19, 2D6, 3A4, and 4A11.

USE IN SPECIFIC POPULATIONS Pregnancy Teratogenic Effects Pregnancy Category C: There are no adequate and well-controlled studies in pregnant women. Hydromorphone crosses the placenta. EXALGO should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus [see Use in Specific Populations (8.2)].

Hydromorphone was not teratogenic in pregnant rats given oral doses up to 6.25 mg/kg/day or in pregnant rabbits administered oral doses up to 25 mg/kg/day during the period of organogenesis (~1.2 times the human exposure following 32 mg/day).

Hydromorphone administration to pregnant Syrian hamsters and CF-1 mice during major organ development revealed teratogenicity likely the result of maternal toxicity associated with sedation and hypoxia. In Syrian hamsters given single subcutaneous doses from 14 to 258 mg/kg during organogenesis (gestation days 8 to 10), doses ≥ 19 mg/kg hydromorphone produced skull malformations (exencephaly and cranioschisis). Continuous infusion of hydromorphone (5 mg/kg, s.c.) via implanted osmotic mini pumps during organogenesis (gestation days 7 to 10) produced soft tissue malformations (cryptorchidism, cleft palate, malformed ventricals and retina), and skeletal variations (supraoccipital, checkerboard and split sternebrae, delayed ossification of the paws and ectopic ossification sites). The malformations and variations observed in the hamsters and mice were at doses approximately three-fold higher and <one-fold lower, respectively, than a 32 mg human daily oral dose on a body surface area basis.

Nonteratogenic Effects In the pre- and post-natal effects study in rats, neonatal viability was reduced at 6.25 mg/kg/day (~1.2 times the human exposure following 32 mg/day).

Neonates born to mothers who have been taking opioids regularly prior to delivery will be physically dependent. The withdrawal signs include irritability and excessive crying, tremors, hyperactive reflexes, increased respiratory rate, increased stools, sneezing, yawning, vomiting, and fever. The intensity of the syndrome does not always correlate with the duration of maternal opioid use or dose. There is no consensus on the best method of managing withdrawal.

Approaches to the treatment of the syndrome have included supportive care and, if indicated, drugs such as paregoric or phenobarbital.

Labor and Delivery EXALGO is not recommended for use in women during and immediately prior to labor and delivery. Administration of EXALGO to the mother shortly before delivery may result in some degree of respiratory depression in the neonate.

However, neonates whose mothers received opioid analgesics during labor should be observed closely for signs of respiratory depression.

Nursing Mothers Low concentrations of hydromorphone have been detected in human milk in clinical trials. Withdrawal symptoms can occur in breastfeeding infants when maternal administration of an opioid analgesic is stopped. Nursing should not be undertaken while a patient is receiving EXALGO since hydromorphone is excreted in the milk.

Pediatric Use The safety and effectiveness of EXALGO in pediatric patients 17 years of age and younger have not been established.

Geriatric Use Elderly patients have been shown to be more sensitive to the adverse effects of EXALGO compared to the younger population. Therefore, use extra caution when prescribing EXALGO in elderly patients and reduce the initial dose.

Neonatal Withdrawal Syndrome Chronic maternal use of opiates or opioids during pregnancy coexposes the fetus. The newborn may experience subsequent neonatal withdrawal syndrome (NWS). Manifestations of NWS include irritability, hyperactivity, abnormal sleep pattern, high-pitched cry, tremor, vomiting, diarrhea, weight loss, and failure to gain weight. The onset, duration, and severity of the disorder differ based on such factors as the addictive drug used, time and amount of mother’s last dose, and rate of elimination of the drug from the newborn. Approaches to the treatment of this syndrome have included supportive care and, when indicated, drugs such as paregoric or phenobarbital.

Hepatic Impairment In a study that used a single 4 mg oral dose of immediate-release hydromorphone tablets, four-fold increases in plasma levels of hydromorphone (Cmax and AUC0- ) were observed in patients with moderate hepatic impairment (Child-Pugh Group B). Start patients with moderate hepatic impairment on a reduced dose and closely monitored during dose titration.

The pharmacokinetics of hydromorphone in severe hepatic impairment patients have not been studied. Further increase in Cmax and AUC0- of hydromorphone in this group is expected, therefore, use an even more conservative starting dose [see Dosage and Administration (2.4)].

Renal Impairment Renal impairment affected the pharmacokinetics of hydromorphone and its metabolites following administration of a single 4 mg dose of immediate-release tablets. The effects of renal impairment on hydromorphone pharmacokinetics were two-fold and four-fold increases in plasma levels of hydromorphone (Cmax and AUC0-48h) in moderate (CLcr = 40 to 60 mL/min) and severe (CLcr < 30 mL/min) impairment, respectively. In addition, in patients with severe renal impairment hydromorphone appeared to be more slowly eliminated with longer terminal elimination half-life (40 hours) compared to subjects with normal renal function (15 hours). Start patients with moderate renal impairment on a reduced dose and closely monitored during dose titration. As EXALGO is only intended for once daily administration, consider use of an alternate analgesic that may permit more flexibility with the dosing interval in patients with severe renal impairment [see Dosage and Administration (2.4)].

DRUG ABUSE AND DEPENDENCE Controlled Substance EXALGO contains hydromorphone, a Schedule II controlled substance with a high potential for abuse similar to fentanyl, methadone, morphine, oxycodone, and oxymorphone. EXALGO can be abused and is subject to misuse, abuse, addiction, and criminal diversion [see Warnings and Precautions (5.2)]. The high drug content in the extended release formulation adds to the risk of adverse outcomes from abuse.

Abuse All patients treated with opioids, including EXALGO, require careful monitoring for signs of abuse and addiction, because use of opioid analgesic products carries the risk of addiction even under appropriate medical use.

Addiction is a primary, chronic, neurobiologic disease, with genetic, psychosocial, and environmental factors influencing its development and manifestations. It is characterized by behaviors that include one or more of the following: impaired control over drug use, compulsive use, continued use despite harm, and craving.

“Drug-seeking” behavior is very common to addicts and drug abusers. Drugseeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing or referral, repeated claims of loss of prescriptions, tampering with prescriptions and reluctance to provide prior medical records or contact information for other treating physician(s). “Doctor shopping” (visiting multiple prescribers) to obtain additional prescriptions is common among drug abusers, people suffering from untreated addiction and criminals seeking drugs to sell.

Abuse and addiction are separate and distinct from physical dependence and tolerance. Physicians should be aware that addiction may not be accompanied by concurrent tolerance and symptoms of physical dependence in all addicts.

In addition, abuse of opioids can occur in the absence of true addiction and is characterized by misuse for non-medical purposes, often in combination with other psychoactive substances. Since EXALGO may be diverted for non-medical use, careful record-keeping of prescribing information, including quantity, frequency, and renewal requests is strongly advised.

Proper assessment of the patient, proper prescribing practices, periodic re-evaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs.

EXALGO is intended for oral use only. Misuse or abuse by breaking, crushing, chewing, or dissolving EXALGO poses a hazard of overdose and death. This risk is increased with concurrent abuse of EXALGO with alcohol and other substances.

With intravenous abuse, the tablet excipients, especially polyethylene oxide, can be expected to result in necrosis and inflammation of cardiac tissues. In addition, parenteral drug abuse is commonly associated with transmission of infectious disease such as hepatitis and HIV. Healthcare professionals should contact their State Professional Licensing Board or State Controlled Substances Authority for information on how to prevent and detect abuse or diversion of this product.

Dependence Tolerance is a state of adaptation in which exposure to a drug induces changes that result in a diminution of one or more of the drug’s effects over time.

Tolerance could occur to both the desired and undesired effects of drugs, and may develop at different rates for different effects.

Physical dependence is a state of adaptation that is manifested by an opioid specific withdrawal syndrome that can be produced by abrupt cessation, rapid dose reduction, decreasing blood level of the drug, and/or administration of an antagonist. The opioid abstinence or withdrawal syndrome is characterized by some or all of the following: restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, piloerection, myalgia, mydriasis, irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, increased blood pressure, respiratory rate, or heart rate.

Infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal symptoms [see Use in Specific Populations (8.1, 8.2)].

OVERDOSAGE Symptoms Acute overdosage with opioids can be manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and sometimes bradycardia, hypotension and death. The extended release characteristics of EXALGO should also be taken into account when treating the overdose. Even in the face of improvement, continued medical monitoring is required because of the possibility of extended effects.

Deaths due to overdose could occur with abuse and misuse of EXALGO. Due to the delayed mean apparent peak plasma level of EXALGO occurring at 16 hours following administration as well as the 11 hour mean elimination half-life of EXALGO, patients who receive an overdose will require an extended period of monitoring and treatment that may go beyond 24 to 48 hours.

Treatment Give primary attention to the re-establishment of a patent airway and institution of assisted or controlled ventilation. Employ supportive measures (including oxygen and vasopressors) in the management of circulatory shock and pulmonary edema accompanying overdose as indicated. Cardiac arrest or arrhythmias will require advanced life support techniques.

The pure opioid antagonists, such as naloxone and naltrexone are specific antidotes to respiratory depression from opioid overdose. Since the duration of reversal would be expected to be less than the duration of action of hydromorphone in EXALGO, the patient must be carefully monitored until spontaneous respiration is reliably re-established. EXALGO will continue to release and add to the hydromorphone load for up to 24 hours after administration and the management of an overdose should be monitored accordingly, at least 24 to 48 hours beyond the overdose.

Only administer opioid antagonists in the presence of clinically significant respiratory or circulatory depression secondary to hydromorphone overdose. In patients who are physically dependent on any opioid agonist including EXALGO, an abrupt or complete reversal of opioid effects may precipitate an acute abstinence syndrome. The severity of the withdrawal syndrome produced will depend on the degree of physical dependence and the dose of the antagonist administered. Please see the prescribing information for the specific opioid antagonist for details of their proper use.

OROS is a registered trademark of ALZA Corporation.

EXALGO is a registered trademark of Mallinckrodt Inc. COVIDIEN, COVIDIEN with logo and Covidien logo are U.S. and/or internationally registered trademarks of Covidien AG. © 2010 Mallinckrodt Inc., a Covidien company Distributed by: Mallinckrodt Brand Pharmaceuticals, Inc. Hazelwood, MO 63042 USA Issued 11/2010

Mallinckrodt

MAY/JUNE 2011

VOLUME 4, NUMBER 2, SPECIAL FEATURE THE PEER-REVIEWED FORUM FOR EVIDENCE IN BENEFIT DESIGN ™

™

™

FOR PAYERS, PURCHASERS, POLICYMAKERS, AND OTHER HEALTHCARE STAKEHOLDERS

TABLE OF CONTENTS 7

INTRODUCTION New Drug Approvals in 2010: Another Difficult Year Gary M. Owens, MD

12

EXALGO® (hydromorphone HCl) Extended-Release Tablets, CII: A Once-Daily Extended-Release Option for the Management of Chronic Pain Stakeholder Perspective by Gary Rice, RPh, MS, MBA

22

FDA Approvals of Brand-Name Prescription Drugs in 2010

32

KAPVAY™: Clonidine Hydrochloride Extended-Release Tablets for the Treatment of Attention-Deficit/Hyperactivity Disorder Todd Parker, PhD, and Jillian Gee, PhD Stakeholder Perspectives Floyd R. Sallee, MD, PhD

41

48

The Current Drug Pipeline and New Approvals in 2011: A Managed Care Perspective Diana Papshev, PharmD; Chantell M. Reagan, PharmD FDA Approvals of Brand-Name Prescription Drugs, January-May 2011

Publisher’s note: The material presented in this supplement is intended to be a thorough, objective, balanced presentation of clinical information. The opinions expressed in this professional educational supplement are those of the authors, presenters, and/or panelists and do not necessarily reflect those of the Publisher, Editors, or Editorial Board of American Health & Drug Benefits, or the sponsor. Dosages, indications, and methods of use for products referred to in this professional educational supplement may reflect the clinical experience of the authors, presenters, and/or panelists or may be derived from the professional literature or other clinical sources and are not necessarily the same as indicated in the package insert for the product. This publication may contain or discuss off-label uses of commercial products or investigational uses not cleared for marketing. Readers are advised to consult the full prescribing information before administering any product. Neither the Editors nor the Publisher assume any responsibility for any injury and/or damage to persons or property arising out of or related to any use of the material mentioned in this publication.

American Health & Drug Benefits, ISSN 1942-2962 (print); ISSN 1942-2970 (online), is published 6 times a year by Engage Healthcare Communications, LLC, 241 Forsgate Drive, Suite 205A, Monroe Twp, NJ 08831. Copyright © 2011 by Engage Healthcare Communications, LLC. All rights reserved. American Health & Drug Benefits and The Peer-Reviewed Forum for Evidence in Benefit Design are trademarks of Engage Healthcare Communications, LLC. No part of this publication may be reproduced or transmitted in any form or by any means now or hereafter known, electronic or mechanical, including photocopy, recording, or any informational storage and retrieval system, without written permission from the Publisher. Printed in the United States of America.

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POSTMASTER: CORRESPONDENCE REGARDING SUBSCRIPTIONS OR CHANGE OF ADDRESS should be directed to CIRCULATION DIRECTOR, American Health & Drug Benefits, 241 Forsgate Drive, Suite 205A, Monroe Twp, NJ 08831. Fax: 732-992-1881.

The individual drug updates have been sponsored by their manufacturers. The drug manufacturers had editorial control over these articles.

Publisher Nicholas Englezos nick@engagehc.com 732-992-1884 Associate Publisher Maurice Nogueira maurice@engagehc.com 732-992-1895 Editorial Director Dalia Buffery dalia@AHDBonline.com 732-992-1889 Associate Editor Lara J. Reiman 732-992-1892 Editorial Assistant Jessica A. Smith Senior Production Manager Lynn Hamilton Quality Control Director Barbara Marino Business Manager Blanche Marchitto Founding Editor-in-Chief Robert E. Henry rhenry@AHDBonline.com

Mission Statement American Health & Drug Benefits is founded on the concept that health and drug benefits have undergone a transformation: the econometric value of a drug is of equal importance to clinical outcomes as it is to serving as the basis for securing coverage in formularies and benefit designs. Because benefit designs are greatly affected by clinical, business, and policy conditions, this journal offers a forum for stakeholder integration and collaboration toward the improvement of healthcare.

This publication further provides benefit design decision makers the integrated industry information they require to devise formularies and benefit designs that stand up to today’s special healthcare delivery and business needs.

Contact Information: For reprints, subscription information, and editorial queries, please contact: editorial@AHDBonline.com T: 732-992-1892 F: 732-992-1881 AHDB3911

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INTRODUCTION

New Drug Approvals in 2010: Another Difficult Year Gary M. Owens, MD President, Gary Owens Associates

T

he year 2010 represented another difficult period for the pharmaceutical industry. In a similar fashion to the 2 previous years, a relatively small number of new drugs were approved by the US Food and Drug Administration’s (FDA’s) Center for Drug Evaluation and Research (CDER). In total, there were 15 or 16 new molecular entities (NMEs) and between 6 and 13 biologic license applications (BLAs) approved, depending on whether one counts all entities, including vaccines, for example. (Different lists have different numbers, and it is not easy to reach a unanimous agreement on this, based on the FDA website.) Overall, these numbers represent less than the number of NMEs approved in either 2008 or 2009, but the same or more BLAs approved.

So far, FDA approvals in the past decade have been relatively modest, with only 2004 seeing more than 30 NMEs approved (Figure).1 It appears that the concept of looking to manufacture new drugs for use in large primary care markets is a thing of the past. We now infrequently see the launch of “blockbuster” drugs seen in the past, such as Pfizer’s Lipitor or Schering’s Claritin.

Rather, the focus is clearly turning toward specialty products and orphan drugs.

To this end, the approval of biologic entities represents close to half of all new agents approved in 2010. In the biologic space, 2010 saw entries into relatively crowded fields—including rheumatoid arthritis, with the launch of Roche’s Actemra (tocilizumab), and Novartis’ Gilenya (fingolimod), which is indicated for multiple sclerosis. However, there were also 6 new orphan drugs launched that targeted diverse conditions (Table 1).

New Drugs: The P&T Committee Perspective Although 2010 saw a small number of new medications reaching the market, Pharmacy & Therapeutics (P&T) Committees clearly had the basis for some very interesting discussions. In addition to the 6 orphan drugs in areas where previous therapies were either nonexistent or nonmedical (eg, surgery for Dupuytren’s contractures), there were 11 new drugs launched with requirements for the REMS (risk evaluation and mitigation

strategy) programs, as well as many new indications for previously approved drugs that require a REMS program.

Table 2 lists the total number of new drugs—NMEs and BLAs—approved in 2010.1 Of note, only 1 manufacturer had more than 1 drug on this list. That sole exception is Amgen’s denosumab, which was first approved as Prolia for osteoporosis, and was later approved under the brand name Xgeva for skeletal metastases.

As noted, several drugs have and will continue to generate considerable discussion with various P&T Committees as these new entities—molecular or biologic—come up for a P&T Committee review. For example, 2010 saw the approval of fingolimod for the treatment of multiple sclerosis. This approval represents the first oral therapy for multiple sclerosis, and this medication has a unique mechanism of action as a sphingosine 1-phosphate receptor modulator. P&T Committee discussions centered on the relative patient preference for an oral agent versus the injectable therapies, balanced by the known long-term data and outcomes for the injectables. Similarly, dalfampridine (Ampyra) became the first agent to be considered “addon” therapy to selected patients with multiple sclerosis to improve walking time. Concern about appropriate use of this drug, and how to measure its effects, dominated the discussions.

Probably some of the liveliest P&T Committee discussions centered on the launch of dabigatran (Pradaxa).

Dabigatran, which is indicated for stroke prevention in patients with atrial fibrillation, represents the first direct thrombin inhibitor to reach the market. This is the first new oral anticoagulant therapy to come to the market in more than 60 years. Warfarin (Coumadin) has been the gold standard for patients who need anticoagulation, but the narrow therapeutic window and significant potential for drug–drug interactions make warfarin a difficult drug to manage for patients and for physicians.

Discussions in this category attempted to balance the low cost of warfarin therapy versus the more expensive new anticoagulant agent. Considerations for laboratory monitoring of warfarin, bleeding complications,

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INTRODUCTION

Figure FDA Drug Approvals Since 1996 60

New molecular entities Biologic license applications

53

Number of drugs approved

50

39

40

35 31

30

30

27 24 21

20

21 18

17

10

7

6

16

7 5

3

3

19

18

6

5

4 2

2

15

2

6

6

2009

2010

3

0 1996

1997

1998

1999

2000

2001

2002

2003

2004

2005

2006

2007

2008

FDA indicates US Food and Drug Administration.

Reprinted with permission from Mullard A. Nat Rev Drug Discov. 2011;10:82-85.

and drug interactions had to be balanced with the cost of the new agent. In addition, the current drug pipeline contains at least 2 factor Xa inhibitors that are likely to be direct competitors for dabigatran and ultimately to warfarin. This caused many P&T Committee members to take a wait-and-see approach to this category.

Table 1 2010 Orphan Drugs Agent

Manufacturer

Ampyra (dalfampridine) Acorda

Condition Multiple sclerosis

Carbaglu (carglumic acid)

Orphan Europe Hyperammonemia resulting from NAGS deficiency

Krystexxa (pegloticase)

Savient

Gout

Lumizyme (alglucosidase alfa)

Genzyme

Noninfantile Pompe disease

Xiaflex (collagenase Auxilium clostridium histolyticum)

Dupuytrenâ&#x20AC;&#x2122;s contracture

NAGS indicates N-acetylglutamate synthase.

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Expect the oral anticoagulation category to be the subject of P&T Committee discussions well into 2011 and even 2012.

Amgenâ&#x20AC;&#x2122;s denosumab (Prolia), a first-in-class monoclonal antibody that is specific for receptor activator of nuclear factor kappa-B ligand (RANKL), was approved in June 2010 for the treatment of postmenopausal osteoporosis. A twice-yearly injectable medication for osteoporosis, this agent offers an attractive alternative to bisphosphonate therapy, which has long been the mainstay of osteoporosis therapy. Among the benefits of denosumab is that it is thought to act earlier to prevent bone destruction than the bisphosphonates. Again, P&T Committee discussions centered on the relative low cost of generic bisphosphonates such as alendronate (Fosamax), which is partially offset by the known low compliance rates for this category of drugs, balanced against the higher cost of denosumab, which has the potential to offer better compliance. To make things even more complex, later in the year denosumab also received approval under the brand name Xgeva for the prevention of skeletal-related events in patients with bone metastases from solid tumors.

INTRODUCTION

Table 2 FDA Approvals of NMEs and BLAs in 2010 Drug

Manufacturer

Indication

Class

Date

Dalfampridine (Ampyra)

Acorda Therapeutics

Improving walking in patients Potassium channel blocker with multiple sclerosis

Jan 22

Liraglutide (Victoza)

Novo Nordisk

Type 2 diabetes

Glucagon-like peptide 1 receptor agonist

Jan 25

Velaglucerase alfa (VPriv)

Shire

Gaucher disease

Recombinant human beta-glucocerebrosidase

Feb 26

Carglumic acid (Carbaglu) Orphan Europe

Acute hyperammonemia

Carbamoyl phosphate synthetase 1 activator

Mar 18

Polidocanol (Asclera)

Chemische Fabrik Kreussler

Uncomplicated spider veins and uncomplicated reticular veins

Sclerosing agent

Mar 30

Everolimus (Zortress)

Novartis

Prophylaxis of organ rejection Immunosuppressant in adults at low-to-moderate (macrolide) immunologic risk receiving a kidney transplant

Apr 22

Estradiol valerate and dienogest (Natazia)

Bayer

Contraception

Estrogen and progestin combination oral contraceptive

May 6

Cabazitaxel (Jevtana)

sanofi-aventis

Prostate cancer

Microtubule inhibitor

June 17

Alcaftadine (Lastacaft)

Vistakon Pharmaceuticals

Allergic conjunctivitis

H1 histamine receptor agonist

July 28

Ulipristal (Ella)

Lab HRA Pharma

Contraception

Progesterone receptor modulator

Aug 13

Fingolimod (Gilenya)

Novartis

Multiple sclerosis

Sphingosine 1-phosphate receptor modulator

Sept 21

Dabigatran (Pradaxa)

Boehringer Ingelheim Stroke prevention in atrial fibrillation

Direct thrombin inhibitor

Oct 10

Lurasidone (Latuda)

Sunovion

Schizophrenia

Atypical antipsychotic agent

Oct 28

Ceftaroline fosamil (Teflaro)

Cerexa

Skin and skin-structure infections, communityacquired pneumonia

Broad-spectrum cephalosporin antibiotic

Oct 29

Tesamorelin (Egrifta)

Theratechnologies

HIV lipodystrophy

Growth hormoneâ&#x20AC;&#x201C;releasing factor analog

Nov 10

Eribulin (Halaven)

Eisai

Breast cancer

Microtubule inhibitor

Nov 15

Tocilizumab (Actemra)

Genentech

Rheumatoid arthritis

Humanized mAb specific for the interleukin-6 receptor

Jan 8

Collagenase clostridium histolyticum (Xiaflex)

Auxilium

Dupuytrenâ&#x20AC;&#x2122;s contracture

Purified collagenase clostridium histolyticum

Feb 2

NMEs

BLAs

Continued May/June 2011

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INTRODUCTION

Table 2 FDA Approvals of NMEs and BLAs in 2010 (Continued) Drug a

Manufacturer

Indication

Class

Pneumococcal 13-valent conjugate vaccine (diphtheria CRM197 protein) (Prevnar 13)

Wyeth Pharmaceuticals

Immunization

Vaccine

Feb 24

Immune globulin subcutaneous [human], 20% liquid (Hizentra)

CSL Behring

Primary immunodeficiency

Immune globulin

Mar 4

Fibrin sealant patch (TachoSil)

Nycomed Danmark

Control of bleeding in cardiovascular surgery when standard surgical technique is ineffective or impractical

Hemostatic agent

Apr 2

Sipuleucel-T (Provenge)

Dendreon Corporation

Prostate cancer

Autologous cellular immunotherapy

Apr 29

Alglucosidase alfa (Lumizyme)

Genzyme

Pompe disease

Lysosomal glycogen-specific enzyme

May 24

Denosumab (Prolia)

Amgen

Postmenopausal osteoporosisb

Fully human mAb specific for RANKL

June 1

Alpha1-proteinase inhibitor [human] (Glassia)

Kamada

Emphysema resulting from congenital deficiency of alpha1-proteinase inhibitor

Alpha1-proteinase inhibitor

July 1

Incobotulinumtoxin-A (Xeomin)

Merz

Cervical dystonia and blepharospasm

Acetylcholine release inhibitor and neuromuscular blocking agent

July 30

Pegloticase (Krystexxa)

Savient

Gout

Pegylated uric acidâ&#x20AC;&#x201C;specific enzyme

Sept 14

Immunization

Bacterial vaccine

Nov 4

Meningococcal [groups A, Novartis C, Y, and W-135] oligosaccharide diphtheria CRM197 conjugate vaccine (Menveo)

Date

a

Listed in order of approval.

Denosumab was subsequently approved for the prevention of skeletal-related events in patients with bone metastases on November 18, for which it is marketed as Xgeva.

b

BLAs indicates biologic license applications; FDA, US Food and Drug Administration; mAb, monoclonal antibody; NMEs, new molecular entities; RANKL, nuclear factor kappa-B ligand.

The drugs mentioned above are only a few of the new drugs approved in 2010. Although there were relatively few drugs approved in 2010, P&T Committees continued to have very interesting discussions. As can be seen from these examples, the decisions P&T Committees are faced with are becoming increasingly complex, because new drugs often come to market with novel mechanisms of action.

Many of the agents approved in 2010 offer advantages

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either in efficacy or in safety, and sometimes in both.

However, in many cases there is a trade-off between efficacy and safety that must be openly discussed, and the evidence must therefore be weighed carefully when formulary decisions are made to adequately balance cost, quality, and access. â&#x2013;

Reference 1. Mullard A. 2010 FDA drug approvals. Nat Rev Drug Discov. 2011;10:82-85.

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Renal impairment is the leading microvascular complication associated with type 2 diabetes (over 40%), followed by retinopathy (28.5%) and neuropathy (19.4%)— it is important to recognize these complications as soon as possible1-4 Microalbuminuria (albumin in the urine *30 mg/day or *20 µg/min) is the earliest clinical evidence of renal disease6 Regular dilated eye examinations can be effective in detecting vision-threatening diabetic retinopathy6,7 Because diabetic neuropathy may be asymptomatic in about 50% of patients, it is important to conduct a physical examination of lower extremities and feet annually 6,8 It’s important to recognize and screen for microvascular complications in patients with type 2 diabetes as early as possible.7 Effective management of diabetes can help prevent or slow the progression of microvascular complications.

References: 1. Plantinga LC, Crews DC, Coresh J, et al; for the CDC CKD Surveillance Team. Prevalence of chronic kidney disease in US adults with undiagnosed diabetes or prediabetes. Clin J Am Soc Nephrol. 2010;5(4):673-682. 2. Parving H-H, Lewis JB, Ravid M, Remuzzi G, Hunsicker LG; for the DEMAND Investigators. Prevalence and risk factors for microalbuminuria in a referred cohort of type II diabetic patients: a global perspective. Kidney Int. 2006;69:2057-2063. 3. Zhang X, Saaddine JB, Chou C-F, et al. Prevalence of diabetic retinopathy in the United States, 2005-2008. JAMA. 2010;304(6):649-656. 4. Gregg EW, Gu Q, Williams D, et al. Prevalence of lower extremity diseases associated with normal glucose levels, impaired fasting glucose, and diabetes among U.S. adults aged 40 or older. Diabetes Res Clin Pract. 2007;77(3):485-488. 5. American Diabetes Association. Nephropathy in diabetes. Diabetes Care. 2004;27(suppl 1):S79-S83. 6. American Diabetes Association. Standards of medical care in diabetes—2011. Diabetes Care. 2011;34(suppl 1):S11-S61. 7. Fong DS,Ferris FL, Aiello LP, Klein R. Diabetic retinopathy. Diabetes Care. 2004;27(10):2540-2553.

8. Boulton AJM, Arezzo JC, Malik RZ, et al. Diabetic somatic neuropathies. Diabetes Care. 2004;27(6):1458-1486.

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EXALGO (hydromorphone HCl) Extended-Release Tablets, CII: A Once-Daily Extended-Release Option for the Management of Chronic Pain Burden and Impact of Chronic Pain In the United States, the estimated mean prevalence of chronic pain is a staggering 35.5%, with an estimated 105 million Americans reporting chronic pain.1,2 Untreated or inadequately controlled pain can significantly impact a person’s quality of life, including the ability to concentrate, perform a job, socialize, exercise, sleep restfully, perform chores, or participate in leisure activities.3 Findings from a recent survey of 27,035 adults (18 years of age or older) in the United States suggest that chronic pain imposes a substantial burden on our society.4 In fact, chronic pain was reported to occur in approximately one-third of the population, with lower back pain cited as the primary cause of pain, followed by osteoarthritis pain. The prevalence of chronic pain, defined as chronic, recurrent, or longlasting pain (lasting for at least 6 months) was higher for women (34.3%) than men (26.7%) and increased with age.4 According to the National Institute of Neurological Disorders and Stroke, low back pain is the most common cause of job-related disability and lost productivity, costing an estimated $50 billion per year in the United States.5 One study showed that employees who reported back pain or arthritis lost productive time of 5.2 hours per week.6 Back pain is the leading cause of disability in Americans under 45 years of age.7 Furthermore, as the prevalence of pain increases with age, pain in the elderly will rise over the next 2 decades as the baby boom generation (people born between 1946 and 1964) reaches the age of 65.8,9 Opioid Therapy for Chronic Pain Opioids are one of the most widely prescribed drug classes for the treatment of pain in the United States.

An estimated 4.3 million adults in this country take opioids regularly.10 However, many of these patients do not achieve acceptable pain relief. A survey of patients with chronic pain who were receiving opioids (N = 303) showed that only 23% reported their medications were “very effective.”11

One of the challenges of opioid therapy is consideration of the individual patient’s needs because no 2 patients are alike. Regimens must be carefully planned and titrated to an effective dose while opioid risks are managed; yet even with dose titration, adequate pain relief may not be achieved.12 In a study of 86 chronic pain sufferers, it took as many as 5 different extended-release opioids in succession to effectively treat 81% of the patients.13

Another Treatment Option for Chronic Pain Management Another therapeutic option for the management of chronic pain became available in March 2010, when EXALGO® (hydromorphone HCl) Extended-Release Tablets, CII, was approved by the Food and Drug Administration (FDA).14 EXALGO, an extended-release oral formulation of the opioid agonist hydromorphone hydrochloride, is indicated for the management of moderate to severe pain in opioid-tolerant patients requiring continuous around-the-clock opioid analgesia for an extended period of time.

EXALGO is not intended for use as an as-needed analgesic and is not indicated for the management of acute or postoperative pain.

EXALGO is the only extended-release formulation of hydromorphone available in the United States. The immediate-release formulation of hydromorphone has been used in this country for at least 80 years.15,16 Hydromorphone is classified as a Schedule II prescription opioid.17 Clinical Pharmacology Utilizing the OROS® Push-PullTM osmotic pump delivery system, EXALGO releases hydromorphone at a controlled rate over an extended period to achieve oncedaily dosing.17 With EXALGO, steady-state plasma concentrations are reached after 3 or 4 days and sustained throughout the 24-hour dosing interval.18 This OROS® Push-PullTM delivery system is a well-established technology that has been used in several marketed prescription and nonprescription products since 1989.17

See pages 20-21 for brief summary of Full Prescribing Information.

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Figure Mean Plasma Hydromorphone Concentrations Over Time after Administration of EXALGO q 24 h or Hydromorphone IR q 6 h HMIR 4 mg q 6 h EXALGO 16 mg q 24 h

Plasma hydromorphone (ng/mL)

4

3

2

1

0

Hour 6

Hour 12

Hour 18

Hour 24

Day 5 postdose

Time

Source: Reference 18.

EXALGOÂŽ (hydromorphone HCl) Extended-Release Tablets, CII, has a bioavailability comparable to immediate-release hydromorphone given 4 times daily, and produces steady-state concentrations of hydromorphone that comparably reduce the drugâ&#x20AC;&#x2122;s peaks and troughs (see Figure).18 Several studies conducted in healthy volunteers show that EXALGO continually releases hydromorphone resulting in consistent plasma levels over a 24-hour period.19-21 The once-daily formulation of EXALGO provides this 24-hour continual drug delivery with diminished peak-trough fluctuation compared with immediaterelease hydromorphone.22 Peak plasma concentrations are reached approximately 12-16 hours after administration.18 EXALGO has an apparent elimination half-life of 8-15 hours, and steady-state plasma concentrations are reached after 3-4 days of dosing.18 Its pharmacokinetics are not affected by food as indicated by bioequivalence when administered under fed and fasting conditions.18 Therefore, EXALGO may be administered without regard to meals.18 Based on a randomized, open-label, crossover study in healthy volunteers, EXALGO was shown to maintain steady-state plasma drug concentrations within the same range as the immediate-release formulation of hydromorphone, at the same total daily dose, with less peakto-trough fluctuation.23 The study participants (29 com-

pleted treatment) were randomly assigned to receive EXALGO 16 mg once daily and immediate-release hydromorphone 4 mg 4 times daily for 5 consecutive days.23 A washout period of 7-14 days separated the 2 treatments. The maximum measured plasma concentration during steady state (Cmaxss) of EXALGO was lower, and the time of Cmaxss (tmaxss) was longer, compared with the immediate-release formulation. Overall, systemic exposure to hydromorphone as assessed by the AUC0-24 was similar between both treatment formulations, with steady-state conditions attained by day 4. In addition, peak-to-trough fluctuations were significantly smaller with EXALGO compared with immediate-release hydromorphone (61% vs 172%).23 In a study measuring drug liking, single oral doses were compared with immediate-release hydromorphone in a double-blind, randomized, placebo-controlled, 2part crossover study (N = 30).24 When twice the dose of EXALGO (16 mg) was administered intact vs immediate-release hydromorphone (8 mg), the maximum drug liking (Emax) occurred later with EXALGO and was significantly lower, compared with immediate-release hydromorphone.24

Clinical Study Data The analgesic effect of EXALGO was demonstrated in multiple clinical studies. A double-blind, placebo-

See pages 20-21 for brief summary of Full Prescribing Information.

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13

controlled, randomized, withdrawal study of 268 opioidtolerant patients with moderate to severe low back pain for at least 6 months was conducted to evaluate the efficacy of EXALGO® (hydromorphone HCl) ExtendedRelease Tablets, CII.15 The study consisted of a screening visit, an open-label conversion/titration phase, and a double-blind treatment phase. All patients were on a stable dose of a different opioid before entering the study.

A total of 447 patients were enrolled into the open-label titration phase, with 268 patients randomized into the double-blind treatment phase; of the 110 patients who completed the double-blind phase, 49% of patients treated with EXALGO and 33% of those treated with placebo completed the 12-week treatment period.18 Significantly more patients in the placebo group were discontinued from the double-blind phase, compared with those in the EXALGO group (67% vs 50%). In the EXALGO and placebo groups, the most common reasons for discontinuation were insufficient analgesic efficacy (11.9% and 29.9%), noncompliance (8.2% and 8.2%), unacceptable rescue medication usage (6.0% and 9.0%), and adverse events (6.7% and 3.0%).25 During the conversion and titration phase of the study, all patients were titrated and converted to EXALGO. Patients in the EXALGO group and the placebo group had a 50% reduction in mean pain intensity score, from 6.4 at the screening visit to 3.2 in the week prior to randomization.25 In the double-blind treatment phase of the study, limited immediate-release hydromorphone was permitted as rescue medication.

Patients taking EXALGO had a significant reduction in pain intensity (measured on an 11-point numerical rating scale ranging from 0 for no pain to 10 for worst possible pain) at the 12-week study endpoint and throughout the study (P <0.001). The median change from baseline was 0.2 units for patients treated with EXALGO compared with 1.6 units for the placebo group.25 The analgesic efficacy of EXALGO was maintained in the long-term, based on an open-label extension trial of 388 patients (106 completed at least 1 year of therapy; 38 withdrew because of lack of efficacy; and 56 withdrew because of adverse events) with chronic cancer and non-cancer pain followed for 1 year.26 During this 12month study, analgesic efficacy was maintained with only moderate increases in daily dose.26 The most common adverse events included nausea (24%), constipation (19.3%), and vomiting (16.8%).

EXALGO was administered to a total of 2,524 patients in 15 controlled and uncontrolled clinical studies. Of these, 423 patients were exposed to EXALGO for greater than 6 months and 151 were exposed for greater than 1 year. The overall incidence of adverse reactions in patients greater than 65 years of age was higher, with a greater than 5% difference in rates for constipation and nausea when compared with younger patients. The overall incidence of adverse reactions in female patients was higher, with a greater than 5% difference in rates for nausea, vomiting, constipation, and somnolence when compared with male patients.18 EXALGO has the potential to induce severe respiratory depression. Other serious adverse events include increased intracranial pressure in the presence of a head injury, hypotensive effect, gastrointestinal effects, and cardiac arrest.18 For detailed Important Risk Information see below.

EXALGO has a reduced potential for certain drug interactions because it minimally interacts with the cytochrome P450 pathway and produces no active drug metabolites.18 Given this consideration, hydromorphone may be suitable for patients taking multiple medications.

The pharmacokinetic profile of EXALGO is not significantly affected by alcohol, and exhibits no evidence of “dose dumping” of hydromorphone.27 Therefore, consuming alcohol with EXALGO does not accelerate the release of hydromorphone into the bloodstream.

However, due to a central nervous system (CNS) depressant effect, patients should not consume alcohol while taking EXALGO.18

Safety Profile and Metabolic Properties The most common adverse reactions associated with EXALGO (>10%) include constipation (31%), nausea (28%), vomiting, somnolence, headache, and dizziness.18

Conversion in Opioid-Tolerant Patients No fixed conversion ratio is likely to be satisfactory in all patients, especially in patients receiving large opioid doses.18 In opioid-tolerant patients, patients should be

Once-Daily Dosing Available in several strengths for once-daily dosing, EXALGO is provided in 8 mg, 12 mg, and 16 mg tablets to facilitate conversion. For conversion to EXALGO in opioid-tolerant patients, the dose range of EXALGO studied in clinical trials was 8 mg to 64 mg. EXALGO tablets may be administered once every 24 hours with or without food. EXALGO is for use in opioid-tolerant patients only; no patient should receive EXALGO as the first opioid.18 Appropriate management of conversion and titration is crucial. The first time a patient takes EXALGO, hydromorphone levels gradually increase over 6-8 hours.28 Particularly during the initial transition period, other analgesics may be needed to treat breakthrough pain.

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Table Conversion Ratios from Various Opioids to EXALGOa Previous Opioid

Hydromorphone Codeine Hydrocodone Methadoneb Morphine Oxycodone Oxymorphone

Multiply the: Approximate daily equivalent oral dose

12 mg

200 mg

30 mg

20 mg

60 mg

30 mg

20 mg

1

0.06

0.4

0.6

0.2

0.4

0.6

By the: Oral conversion ratioc

• Select opioid • Sum the total daily dose • Multiply the dose by the conversion ratio to calculate the approximate oral hydromorphone equivalent • In general, start EXALGO therapy by administering 25%-50% of the calculated total daily dose of EXALGO every 24 hours • Dosing titration should occur gradually (25%-50%) every 3 to 4 days If EXALGO is discontinued, doses should also be tapered gradually (25%-50%) every 2 or 3 days a The conversion ratios and approximate doses in this conversion table are to be used only for the conversion from current opioid therapy to EXALGO. b It is extremely important to monitor all patients closely when converting from methadone to other opioid agonists. The ratio between methadone and other opioid agonists may vary widely as a function of previous dose exposure. Methadone has a long half-life and tends to accumulate in the plasma. c The ratio for conversion of oral opioid dose to approximate hydromorphone equivalent dose.

Source: References 18, 25, 30.

converted from prior opioid therapy to EXALGO® (hydromorphone HCl) Extended-Release Tablets, CII, using a simple conversion ratio of 5 to 1 (morphine equivalent to hydromorphone), because hydromorphone is approximately 5 times more potent than morphine.29 EXALGO treatment can be initiated 18 hours after removal of a fentanyl patch.18 For each 25 mcg/hour fentanyl transdermal dose, the equianalgesic dose of EXALGO is 12 mg every 24 hours.

Conversion ratios between other various opioids and EXALGO are shown in the Table. All other extendedrelease opioids must be discontinued when beginning EXALGO therapy. A stepwise manner is recommended when converting, starting in general, with an initial 25%-50% reduction of the calculated equianalgesic dose (see Table).18,25,30 Other key points regarding conversion include: • Increasing or decreasing the dose in the second step depends on the patient reassessment,30 which should be conducted every 3-4 days18 until a stable dose is reached.

• If reassessment indicates that the pain is severe,

dose increase is recommended; increase the dose gradually by 25%-50% every 3-4 days until a stable dose is reached.18 • If reassessment reveals moderate pain, mild confusion, and the use of multiple other drugs, it is judicious to reduce the dose by an additional 15%.30 In selecting the initial dose of EXALGO, attention should be given to the following18: • The daily dose, potency, and specific characteristics of the opioid the patient has been taking previously • The reliability of the relative potency estimate used to calculate the equivalent hydromorphone dose needed • The patient’s degree of opioid tolerance • The age, general condition, and medical status of the patient • The concurrent non-opioid analgesics and other medications, such as those with CNS activity • The type and severity of the patient’s pain • The balance between pain control and adverse effects • Risk factors for abuse, addiction, or diversion, including a history of abuse, addiction, or diversion.

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IMPORTANT RISK INFORMATION

WARNING: POTENTIAL FOR ABUSE, IMPORTANCE OF PROPER PATIENT SELECTION AND LIMITATIONS OF USE Potential for Abuse EXALGO contains hydromorphone, an opioid agonist and a Schedule II controlled substance with an abuse liability similar to other opioid analgesics. EXALGO can be abused in a manner similar to other opioid agonists, legal or illicit. These risks should be considered when administering, prescribing, or dispensing EXALGO in situations where the healthcare professional is concerned about increased risk of misuse, abuse, or diversion. Schedule II opioid substances which include hydromorphone, morphine, oxycodone, fentanyl, oxymorphone and methadone have the highest potential for abuse and risk of fatal overdose due to respiratory depression.

Proper Patient Selection EXALGO is an extended-release formulation of hydromorphone hydrochloride indicated for the management of moderate to severe pain in opioid tolerant patients when a continuous around-the-clock opioid analgesic is needed for an extended period of

• EXALGO® is also contraindicated in patients who: - need management of mild pain or pain not expected to persist - have significant impaired respiratory function including those with acute or severe bronchial asthma or hypercarbia - have or are suspected to have paralytic ileus - have narrowed or obstructed gastrointestinal tract including those from previous surgery or “blind loops” in the GI tract - have known hypersensitivity to any components including hydromorphone hydrochloride and sulfites.

• Avoid concurrent use of alcohol and EXALGO. Concurrent use of EXALGO with CNS depressants, including alcohol, increases risk of respiratory depression, hypotension, and profound sedation, potentially resulting in coma or death.

EXALGO may impair the ability to drive a car or operate machinery.

• Not intended in patients who have received MAO inhibitors within 14 days of starting EXALGO.

time. Patients considered opioid tolerant are those who are taking at least 60 mg oral morphine per day, 25 mcg transdermal fentanyl/hour, 30 mg oral oxycodone/day, 8 mg oral hydromorphone/day, 25 mg oral oxymorphone/ day or an equianalgesic dose of another opioid, for a week or longer.

EXALGO is for use in opioid tolerant patients only.

Fatal respiratory depression could occur in patients who are not opioid tolerant.

Accidental consumption of EXALGO, especially in children, can result in a fatal overdose of hydromorphone.

Limitations of Use EXALGO is not indicated for the management of acute or postoperative pain.

EXALGO is not intended for use as an as-needed analgesic.

EXALGO tablets are to be swallowed whole and are not to be broken, chewed, dissolved, crushed or injected.

Taking broken, chewed, dissolved or crushed EXALGO or its contents leads to rapid release and absorption of a potentially fatal dose of hydromorphone.

• Use with caution in reduced doses in older or debilitated patients, as well as patients with renal or hepatic insufficiency, Addison’s disease, delirium tremens, myxedema or hypothyroidism, prostatic hypertrophy or urethral stricture, toxic psychosis. May aggravate convulsions in patients with convulsive disorders; may induce or aggravate seizures in some clinical settings.

Consider use of an alternate analgesic in patients with severe renal impairment.

• Respiratory depression, which occurs more frequently in elderly or debilitated patients, is the chief hazard with EXALGO. • Serious adverse events could also include hypotensive effects, GI effects, cardiac arrest from overdose and precipitation of withdrawal. Most common adverse events (>10%) seen in clinical studies (N = 2474) were: constipation (31%), nausea (28%), vomiting, somnolence, headache, asthenia and dizziness.

• Use EXALGO with extreme caution in patients susceptible to intracranial effects of CO2 retention.

• Do not abruptly discontinue EXALGO.

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Risk Evaluation and Mitigation Strategy In February 2009, the FDA notified manufacturers of certain opioid drug products that a Risk Evaluation and Mitigation Strategy (REMS) for these drugs would be required to ensure that the benefits of the drug outweigh the risk to the patient.31 Effective March 25, 2008, as part of the Food and Drug Administration Amendments Act of 2007 (FDAAA), the FDA was given the authority to require certain drugs or biologics to have a REMS in place. This REMS requirement was enacted for those drugs that provide an important benefit to patients but may be especially dangerous if not used properly.31 In July 2010, the FDA presented a proposal for a class REMS for long-acting and extended-release opioid agents.32 An EXALGO REMS has been implemented in response to the FDA requirement. The REMS program provides education and training for patients and healthcare professionals designed to inform patients and healthcare professionals about the potential for abuse, misuse, overdose, and addiction of EXALGO, and about the safe use of EXALGO. It includes several elements to assure safe use, including a “dear healthcare professional letter,” full prescribing information, a medication guide, a prescribing brochure, and an essential information form. These REMS elements are available online at www.exalgorems.com.

Conclusion EXALGO® (hydromorphone HCl) Extended-Release Tablets, CII, a long-acting option for the management of moderate to severe pain in opioid-tolerant patients, provides consistent, prolonged analgesia in a convenient, once-daily formulation. Using the OROS® Push-Pull™ osmotic pump delivery system, EXALGO continually releases hydromorphone resulting in consistent plasma levels over a 24-hour period at steady state with diminished peak-trough fluctuation18,22 compared with immediate-release hydromorphone.

EXALGO is the only extended-release formulation of hydromorphone currently available in the United States.

EXALGO is provided in several strengths for once-daily dosing, including 8 mg, 12 mg, and 16 mg tablets, to facilitate conversion. The pharmacokinetic characteristics of EXALGO suggest that it may be well suited for the long-term management of chronic pain.22 As with other agents in the opioid class of drugs, appropriate patient selection and use are important considerations.

Funding Source Funding for this article was provided by Covidien.

References

1. Turk DC. Pain hurts—individuals, significant others, and society! Am Pain Soc Bull.

2006;16. www.ampainsoc.org/pub/bulletin/win06/pres1.htm. Accessed February 3, 2011.

2. Harstall C, Ospina M. How prevalent is chronic pain? Pain Clin Updates. 2003;11: 1-4. www.iasp-pain.org/AM/AMTemplate.cfm?Section=HOME,HOME&TEMPLATE= /CM/ContentDisplay.cfm&CONTENTID=7594&SECTION=HOME,HOME. Accessed February 3, 2011.

3. American Pain Society. Resources, chronic pain in America: roadblocks to relief, conclusions. www.ampainsoc.org/links/roadblocks/conclude_road.htm. Accessed February 4, 2011.

4. Johannes CB, Le TK, Zhou X, et al. The prevalence of chronic pain in United States adults: results of an internet-based survey. J Pain. 2010;11:1230-1239.

5. National Institute of Neurological Disorders and Stroke, National Institutes of Health. Low back pain—fact sheet. January 31, 2011. www.ninds.nih.gov/disorders/ backpain/detail_backpain.htm. Accessed January 31, 2011.

6. Stewart WF, Ricci JA, Chee E, et al. Lost productive time and cost due to common pain conditions in the US workforce. JAMA. 2003;290:2443-2454.

7. American Pain Society. APS press room—media backgrounder. www.ampainsoc. org/press/backgrounder.htm. Accessed February 3, 2011.

8. Vincent GK, Velkoff VA. The Next Four Decades, the Older Population in the United States: 2010 to 2050. Current Population Reports: 25-1138. US Census Bureau, Washington, DC: May 2010.

9. US Department of Health and Human Services, Administration on Aging. A profile of older Americans: 2007. www.agingcarefl.org/aging/AOA-2007profile.pdf. Accessed February 3, 2011.

10. Parsells Kelly J, Cook SF, Kaufman DW, et al. Prevalence and characteristics of opioid use in the US adult population. Pain. 2008;138:507-513.

11. David Michaelson & Company. Voices of chronic pain, a national study conducted for the American Pain Foundation. May 2006. www.painfoundation. org/media/resources/voices-survey-report.pdf. Accessed February 3, 2011.

12. Chou R, Fanciullo GJ, Fine PG, et al. Clinical guidelines for the use of chronic opioid therapy in chronic noncancer pain. J Pain. 2009;10:113-130.

13. Quang-Cantagrel ND, Wallace MS, Magnuson SK. Opioid substitution to improve the effectiveness of chronic noncancer pain control: a chart review. Anesth Analg. 2000;90:933-937.

14. FDA approves Exalgo™ extended-release tablets. Medical News Today. Press release.

March 4, 2010. www.medicalnewstoday.com/articles/181115.php. Accessed January 31, 2011.

15. Murray A, Hagen NA. Hydromorphone. J Pain Symptom Manage. 2005;29 (suppl 1):57-66.

16. Quigley C, Wiffen P. A systematic review of hydromorphone in acute and chronic pain. J Pain Symptom Manage. 2003;25:169-178.

17. Neuromed Pharmaceuticals. Exalgo™ (hydromorphone HCl) extended-release tablets CII. NDA 21-217. September 23, 2009.

18. Exalgo (hydromorphone HCl) prescribing information. Hazelwood, MO: Mallinckrodt, a Covidien company; 2010. www.fda.gov/downloads/Advisory Committees/CommitteesMeetingMaterials/Drugs/AnestheticAndLifeSupportDrugs Advisory Committee/UCM183035.pdf. Accessed February 3, 2011.

19. Drover DR, Angst MS, Valle M, et al. Input characteristics and bioavailability after administration of immediate and a new extended-release formulation of hydromorphone in healthy volunteers. Anesthesiology. 2002;97:827-836.

20. Angst MS, Drover DR, Lötsch J, et al. Pharmacodynamics of orally administered sustained-release hydromorphone in humans. Anesthesiology. 2001;94:67-73.

21. Sathyan G, Xu E, Thipphawong J, Gupta SK. Pharmacokinetic profile of a 24hour controlled-release OROS formulation of hydromorphone in the presence and absence of food. BC Clin Pharmacol. 2007;7:2.

22. Gupta S, Sathyan G. Advances in the long-term management of chronic pain: recent evidence with OROS® hydromorphone, a novel, once-daily, long-acting opioid analgesic, providing constant analgesia with OROS® hydromorphone. J Pain Symptom Manage. 2007;33(suppl 1):S19-S24.

23. Moore KT, St-Fleur D, Marricco NC, et al. Steady-state pharmacokinetics of extended-release hydromorphone (OROS hydromorphone): a randomized study in healthy volunteers. J Opioid Manag. 2007;6:351-358.

24. Shram MJ, Sathyan G, Khanna S, et al. Evaluation of the abuse potential of extended release hydromorphone versus immediate release hydromorphone. J Clin Psychopharmacol. 2010;30:25-33.

25. Hale M, Khan A, Kutch M, Li S. Once-daily OROS hydromorphone ER compared with placebo in opioid-tolerant patients with chronic low back pain. Curr Med Res Opin. 2010;26(6):1505-1518. Erratum in: Curr Med Res Opin. 2010;26:1505-1518.

26. Wallace M, Moulin DE, Rauck RL, et al. Long-term safety, tolerability, and efficacy of OROS hydromorphone in patients with chronic pain. J Opioid Manag. 2009;5:97-105.

27. Sathyan G, Sivakumar K, Thipphawong J. Pharmacokinetic profile of a 24-hour controlled-release OROS formulation of hydromorphone in the presence of alcohol.

Curr Med Res Opin. 2008;24:297-305.

28. Sathyan G, Xu E, Thipphawong J, Gupta SK. Pharmacokinetic investigation of dose proportionality with a 24-hour controlled-release formulation of hydromorphone. BMC Clin Pharmacol. 2007;7:3.

29. Palangio M, Northfelt DW, Portenoy RK, et al. Dose conversion and titration with a novel, once-daily, OROS osmotic technology, extended-release hydromorphone formulation in the treatment of chronic malignant or nonmalignant pain.

J Pain Symptom Manage. 2002;23:355-368.

30. Fine PG, Portenoy RK; Ad Hoc Expert Panel on Evidence Review and Guidelines for Opioid Rotation. Establishing “best practices” for opioid rotation: conclusions of an expert panel. J Pain Symptom Manage. 2009;38(3):418-425.

31. US Department of Health & Human Services, US Food and Drug Administration. Background on opioid REMS. November 20, 2009. www.fda.gov/Drugs/Drug Safety/InformationbyDrugClass/ucm187975.htm. Accessed February 4, 2011.

32. US Department of Health & Human Services, US Food and Drug Administration. Opioid drugs and risk evaluation and mitigation strategies (REMS). September 23, 2010. www.fda.gov/Drugs/DrugSafety/InformationbyDrugClass/ucm163647.htm.

Accessed February 4, 2011.

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STAKEHOLDER PERSPECTIVE

Extended-Release Formulation of Hydromorphone Available in the United States

By Gary Rice, RPh, MS, MBA Vice President of Operations, ITSRx, Houston, TX

A

t least 76 million individuals in the United States suffer from pain.1 The annual cost associated with chronic pain, including healthcare expenses, lost income, and lost productivity, in the United States is estimated to be $100 billion.2 When chronic pain is not adequately treated, it can have significant detrimental effects on one’s mood and social and occupational functions, and it can also increase the rate of comorbidities.2,3 Chronic pain also impairs quality of life and emotional well-being and is strongly correlated with psychiatric comorbidities, such as depression.3,4

Managed Care Organizations Although chronic pain is a common complaint among patients within managed care, pain management has not been a major focus of most health plans, in contrast to other chronic disorders, such as diabetes, asthma, cardiovascular disease, or hypertension.5,6 This is partly because of the inability of managed care organizations (MCOs) to quantify or classify chronic pain.7 This condition is difficult to track, because providers typically omit a pain diagnosis, although pain may be the patient’s primary reason for the office visit.7 In addition, it is difficult to code the severity of pain by standard International Classification of Diseases coding, even if a pain-related diagnosis is used as the primary code. Therefore, assessing the economic costs and therapies used for treating chronic pain has been challenging.8 The escalating cost of pain medications also poses a major challenge to pain treatment in managed care, because pain management medication options have changed from primarily lower-cost generic formulations to branded, more expensive formulations, including extended release, patches, and buccal dosage forms. Most MCOs restrict access to pain medications through the use of formularies, prior authorization (PA), and tiered copayment. Formulary restriction is the most common cost-control mechanism used in managed care.

Although tiered copayment systems may control the cost of more expensive new pain medications, there is no evidence that the total cost of pain care is controlled.

Considerable debate surrounds the usefulness of PA and drug utilization management in reducing the costs of pain

medications. Some MCOs indicate that these processes alienate physicians and are a source of dissatisfaction for patients.8 These processes can also be used by MCOs to educate physicians about appropriate utilization of pain medications, and often result in significant cost-savings.

Advocates of PA contend that by asking physicians to document the reasons for prescribing a particular pain medication, the physician learns appropriate clinical practice, while saving the cost of inappropriate prescribing.9 Formularies should include opioids that have been shown to manage pain most effectively, which will minimize long-term costs related to inadequate pain management.

New Drug Formulation Options The new drug formulation EXALGO® (hydromorphone HCl) Extended-Release Tablets, CII, is a once daily extended-release oral formulation indicated for once daily administration for the management of moderate to severe pain in opioid-tolerant patients who require continuous, around-the-clock opioid analgesia for an extended period of time.

The use of around-the-clock medication has been shown to be an effective approach for treating chronic pain. Guidelines issued by the American Pain Society as far back as 1999 state that, in most cases, the preferred route of opioid administration is oral, as a result of convenience, flexibility, and relative steadiness of the opioid concentrations in the blood. The advantages of aroundthe-clock therapy and an oral medication are some of the reasons for the development of controlled-release, oral formulations of opioids (eg, morphine, oxycodone, hydromorphone, and hydrocodone). The reduced dosing frequency makes the oral medication more convenient for patients, making it easier for them to comply with the dosing regimen.

Around-the-clock therapeutic coverage, and the possible increased compliance afforded by controlled-release formulations, can make opioids even more effective in the management of chronic pain.10 High-tech oral delivery systems such as the OROS® Push-PullTM osmotic pump delivery system produces steady-state concentrations of hydromorphone that comparably reduce the

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STAKEHOLDER PERSPECTIVE

drug’s peaks and troughs; once steady state is achieved, this should significantly reduce the need for additional analgesics for breakthrough pain.11

Conclusion The directive to “first, do not harm” is anything but simple in today’s pain therapy strategies, and nowhere is its complexity more evident than in treating chronic pain with opioids. Patients in pain who rely on opioids for their pain management and for improved function deserve access to safe and effective medications.

Depriving them of optimal pain relief does them harm.

These same life-restoring medications cause harm to patients who may be at risk for addiction and abuse.

Managed care navigates in a complex triad of clinical practice standards, population-based medicine, and patient variability to clinical responses. Chronic pain has no definitive solution, just a collection of clinical options for many patients. Extended-release forms of the opioid pain medication offer another option in the armamentarium of chronic pain therapy considerations. ■

Disclosure Statement Mr Rice reported no conflicts of interest in relation to this article.

References 1. Moskowitz MA. Advances in understanding chronic pain: mechanisms of pain modulation and relationship to treatment. Neurology. 2002;59(suppl 20):S1.

2. Gureje O, Von Korff M, Simon GE, Gater R. Persistent pain and well-being: a World Health Organization study in primary care. JAMA. 1998;280:147-151.

3. Stewart WF, Ricci JA, Chee E, et al. Lost productive time and cost due to common pain conditions in the US workforce. JAMA. 2003;290:2443-2454.

4. National Institutes of Health. NIH guide: new directions in pain research: I. Bethesda, MD: National Institutes of Health. September 4, 1998. http://grants.nih. gov/grants/guide/pa-files/PA-98-102.html. Accessed February 20, 2011.

5. Polatin PB, Mayer TG. Occupational disorders and the management of chronic pain. Orthop Clin North Am. 1996;27:881-890.

6. Liu AC, Byrne E. Cost of care for ambulatory patients with low back pain. J Fam Pract. 1995;40:449-455.

7. American Pain Society. Chronic pain in America: roadblocks to relief. www. ampainsoc.org/links/roadblocks. Accessed February 24, 2011.

8. Lande SD. The Problem of Pain in Managed Care. In: Lande SD, Kulich RJ, eds.

Managed Care and Pain. Glenview, IL: American Pain Society; 2000:15-36.

9. Zagari MJ, Mazonson PD, Longton WC. Pharmacoeconomics of chronic nonmalignant pain. Pharmacoeconomics. 1996;10:356-377.

10. Reder RF. Opioid formulations: tailoring to the needs in chronic pain. Eur J Pain.

2001;5(suppl A):109-111.

11. EXALGO (hydromorphone HCl) prescribing information. Hazelwood, MO: Mallinckrodt, a Covidien company; 2010.

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BRIEF SUMMARY - Consult full prescribing information before use.

EXALGOÂŽ (hydromorphone HCl) Extended-Release Tablets WARNING: POTENTIAL FOR ABUSE, IMPORTANCE OF PROPER PATIENT SELECTION AND LIMITATIONS OF USE Potential for Abuse EXALGO contains hydromorphone, an opioid agonist and a Schedule II controlled substance with an abuse liability similar to other opioid analgesics. EXALGO can be abused in a manner similar to other opioid agonists, legal or illicit. These risks should be considered when administering, prescribing, or dispensing EXALGO in situations where the healthcare professional is concerned about increased risk of misuse, abuse, or diversion. Schedule II opioid substances which include hydromorphone, morphine, oxycodone, fentanyl, oxymorphone and methadone have the highest potential for abuse and risk of fatal overdose due to respiratory depression [see Drug Abuse and Dependence (9)].

Proper Patient Selection EXALGO is an extended-release formulation of hydromorphone hydrochloride indicated for the management of moderate to severe pain in opioid tolerant patients when a continuous around-the-clock opioid analgesic is needed for an extended period of time. Patients considered opioid tolerant are those who are taking at least 60 mg oral morphine per day, 25 mcg transdermal fentanyl/hour, 30 mg of oral oxycodone/ day, 8 mg oral hydromorphone/day, 25 mg of oral oxymorphone/day or an equianalgesic dose of another opioid, for a week or longer [see Indications and Usage (1) and Dosage and Administration (2)].

EXALGO is for use in opioid tolerant patients only [see Indications and Usage (1) and Dosage and Administration (2)].

Fatal respiratory depression could occur in patients who are not opioid tolerant.

Accidental consumption of EXALGO, especially in children, can result in a fatal overdose of hydromorphone [see Warnings and Precautions (5.1)].

Limitations of Use EXALGO is not indicated for the management of acute or postoperative pain [see Indications and Usage (1)].

EXALGO is not intended for use as an as-needed analgesic [see Indications and Usage (1)].

EXALGO tablets are to be swallowed whole and are not to be broken, chewed, dissolved, crushed or injected. Taking broken, chewed, dissolved or crushed EXALGO or its contents leads to rapid release and absorption of a potentially fatal dose of hydromorphone [see Warnings and Precautions (5)].

CONTRAINDICATIONS Opioid Non-Tolerant Patients EXALGO is contraindicated in opioid non-tolerant patients. Fatal respiratory depression could occur in patients who are not opioid tolerant.

Impaired Pulmonary Function EXALGO is contraindicated in patients with significant respiratory depression, especially in the absence of resuscitative equipment or in unmonitored settings and in patients with acute or severe bronchial asthma or hypercarbia.

Paralytic Ileus EXALGO is contraindicated in patients who have or are suspected of having a paralytic ileus.

Preexisting Gastrointestinal (GI) Surgery or Narrowing of GI Tract EXALGO is contraindicated in patients who have had surgical procedures and/or underlying disease that would result in narrowing of the gastrointestinal tract, or have â&#x20AC;&#x153;blind loopsâ&#x20AC;? of the gastrointestinal tract or gastrointestinal obstruction.

Allergy or Hypersensitivity EXALGO is contraindicated in patients with known hypersensitivity to any of its components including the active agent, hydromorphone hydrochloride or known allergy to sulfite-containing medications [see Warnings and Precautions (5.8)].

WARNINGS AND PRECAUTIONS Information Essential for Safe Administration EXALGO tablets are to be swallowed whole, and are not to be broken, chewed, crushed, dissolved or injected. Taking broken, chewed, crushed, dissolved EXALGO or its contents leads to the rapid release and absorption of a potentially fatal dose of hydromorphone [see Boxed Warning].

EXALGO is for use only in opioid tolerant patients. Ingestion of EXALGO may cause fatal respiratory depression when administered to patients who are not opioid tolerant [see Boxed Warning].

EXALGO tablets must be kept in a secure place out of the reach of children. Accidental consumption of EXALGO, especially in children, can result in a fatal overdose of hydromorphone.

Misuse and Abuse EXALGO contains hydromorphone, an opioid agonist, and is a Schedule II controlled substance. Opioid agonists have the potential for being abused and are sought by drug abusers and people with addiction disorders and are subject to criminal diversion.

EXALGO can be abused in a manner similar to other opioid agonists, legal or illicit.

This should be considered when prescribing or dispensing EXALGO in situations where the healthcare professional is concerned about an increased risk of misuse, abuse, or diversion.

Breaking, crushing, chewing, or dissolving the contents of an EXALGO tablet results in the uncontrolled delivery of the opioid and poses a significant risk of overdose and death [see Drug Abuse and Dependence (9)].

If attempts are made to extract the drug from the hard outer shell for purposes of parenteral abuse, the injection of tablet excipients may be toxic and may result in lethal complications.

Concerns about abuse, addiction, and diversion should not prevent the proper management of pain. However, all patients treated with opioids, including EXALGO, require careful monitoring for signs of abuse and addiction, since use of opioid analgesic products carries the risk of addiction even under appropriate medical use.

Healthcare professionals should contact their State Professional Licensing Board or State Controlled Substances Authority for information on how to prevent and detect abuse or diversion of this product.

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Respiratory Depression Respiratory depression is the chief hazard of EXALGO. Respiratory depression occurs more frequently in elderly or debilitated patients as well as those suffering from conditions accompanied by hypoxia or hypercapnia when even moderate therapeutic doses may dangerously decrease pulmonary ventilation, and when opioids are given in conjunction with other agents that depress respiration.

Use EXALGO with extreme caution in patients with conditions accompanied by hypoxia, hypercapnia, or decreased respiratory reserve such as asthma, chronic obstructive pulmonary disease or cor pulmonale, severe obesity, sleep apnea, myxedema, kyphoscoliosis or CNS depression. In these patients, even moderate therapeutic doses of hydromorphone may decrease respiratory drive while simultaneously increasing airway resistance to the point of apnea. In these patients, consider alternative non-opioid analgesics, and use EXALGO only under careful medical supervision at the lowest effective dose.

Interactions with Alcohol and Other CNS Depressants The concurrent use of EXALGO with other central nervous system (CNS) depressants, including but not limited to other opioids, illicit drugs, sedatives, hypnotics, general anesthetics, phenothiazines, muscle relaxants, other tranquilizers, and alcohol, increases the risk of respiratory depression, hypotension, and profound sedation, potentially resulting in coma or death. Use with caution and in reduced dosages in patients taking CNS depressants. Avoid concurrent use of alcohol and EXALGO [see Clinical Pharmacology (12.3)].

Head Injury and Increased Intracranial Pressure In the presence of head injury, intracranial lesions or a preexisting increase in intracranial pressure, the respiratory depressant effects of EXALGO and its potential to elevate cerebrospinal fluid pressure (resulting from vasodilation following CO2 retention) may be markedly exaggerated. Furthermore, EXALGO can produce effects on pupillary response and consciousness, which may obscure neurologic signs of further increases in intracranial pressure in patients with head injuries.

Hypotensive Effect EXALGO may cause severe hypotension. There is added risk to individuals whose ability to maintain blood pressure has been compromised by a depleted blood volume, or after concurrent administration with drugs such as phenothiazines, general anesthetics, or other agents that compromise vasomotor tone.

Administer EXALGO with caution to patients in circulatory shock, since vasodilation produced by the drug may further reduce cardiac output and blood pressure.

Gastrointestinal Effects Because the EXALGO tablet is nondeformable and does not appreciably change in shape in the GI tract, do not administer EXALGO to patients with preexisting severe gastrointestinal narrowing (pathologic or iatrogenic, for example: esophageal motility disorders small bowel inflammatory disease, â&#x20AC;&#x153;short gutâ&#x20AC;? syndrome due to adhesions or decreased transit time, past history of peritonitis, cystic fibrosis, chronic intestinal pseudoobstruction, or Meckelâ&#x20AC;&#x2122;s diverticulum). There have been reports of obstructive symptoms in patients with known strictures or risk of strictures, such as previous GI surgery, in association with the ingestion of drugs in nondeformable extended-release formulations.

The administration of EXALGO may obscure the diagnosis or clinical course in patients with acute abdominal condition.

It is possible that EXALGO tablets may be visible on abdominal x-rays under certain circumstances, especially when digital enhancing techniques are utilized.

Sulfites EXALGO contains sodium metabisulfite, a sulfite that may cause allergic-type reactions including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people. The overall prevalence of sulfite sensitivity in the general population is unknown and probably low. Sulfite sensitivity is seen more frequently in asthmatic than in nonasthmatic people.

MAO Inhibitors EXALGO is not recommended for use in patients who have received MAO inhibitors within 14 days, because severe and unpredictable potentiation by MAO inhibitors has been reported with opioid analgesics.

Special Risk Groups EXALGO should be administered with caution in elderly (â&#x2030;Ľ 65 years) and debilitated patients and in patients who are known to be sensitive to central nervous system depressants, such as those with cardiovascular, pulmonary, renal, or hepatic disease [see Use in Specific Populations (8)].

EXALGO should also be used with caution in the following conditions: adrenocortical insufficiency (e.g., Addisonâ&#x20AC;&#x2122;s disease); delirium tremens; myxedema or hypothyroidism; prostatic hypertrophy or urethral stricture; and, toxic psychosis.

EXALGO may aggravate convulsions in patients with convulsive disorders, and all opioids may induce or aggravate seizures in some clinical settings.

Use in Pancreatic/Biliary Tract Disease EXALGO can cause an increase in biliary tract pressure as a result of spasm in the sphincter of Oddi. Caution should be exercised in the administration of EXALGO to patients with inflammatory or obstructive bowel disorders, acute pancreatitis secondary to biliary tract disease and in patients about to undergo biliary surgery.

Driving and Operating Machinery EXALGO may impair the mental and/or physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery. Caution patients accordingly. Also warn patients about the potential combined effects of EXALGO with other CNS depressants, including other opioids, phenothiazines, sedative/hypnotics, and alcohol [see Drug Interactions (7)].

Precipitation of Withdrawal Mixed agonist/antagonist analgesics (i.e., pentazocine, nalbuphine, and butorphanol) should not be administered to patients who have received or are receiving a course of therapy with a pure opioid agonist analgesic, including EXALGO. In these patients, mixed agonists/antagonists analgesics may reduce the analgesic effect and/or may precipitate withdrawal symptoms. Do not abruptly discontinue EXALGO. Clinical conditions or medicinal products that cause a sudden and significant shortening of gastrointestinal transit time may result in decreased hydromorphone absorption with EXALGO and may potentially lead to withdrawal symptoms in patients with a physical dependence on opioids.

ADVERSE REACTIONS The following serious adverse reactions are discussed elsewhere in the labeling: K &3A>7@/B=@G 3>@3AA7=< [see Warnings and Precautions (5.3)] K Head Injury and Increased Intracranial Pressure [see Warnings and Precautions (5.5)] K G>=B3<A7D3 4431B [see Warnings and Precautions (5.6)] K /AB@=7<B3AB7</: 4431BA [see Warnings and Precautions (5.7)] K /@27/1 @@3AB [see Overdosage (10)] K %@317>7B/B7=< =4 +7B62@/E/: [see Warnings and Precautions (5.13)]

Clinical Studies Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

EXALGO was administered to a total of 2,524 patients in 15 controlled and uncontrolled clinical studies. Of these, 423 patients were exposed to EXALGO for greater than 6 months and 141 exposed for greater than one year.

The overall incidence of adverse reactions in patients greater than 65 years of age was higher, with a greater than 5% difference in rates for constipation and nausea when compared with younger patients. The overall incidence of adverse reactions in female patients was higher, with a greater than 5% difference in rates for nausea, vomiting, constipation and somnolence when compared with male patients.

A 12-week double-blind, placebo-controlled, randomized withdrawal study was conducted in opioid tolerant patients with moderate to severe low back pain [see Clinical Studies (14)]. A total of 447 patients were enrolled into the open-label titration phase with 268 patients randomized into the double-blind treatment phase. The adverse reactions that were reported in at least 2% of the patients are contained in Table 1.

Table 1.

Number (%) of Patients with Adverse Reactions Reported in â&#x2030;Ľ2% of Patients with Moderate to Severe Low Back Pain During the Open-Label Titration Phase or Double-Blind Treatment Phase by Preferred Term Preferred Term Open-Label Double-Blind Treatment Phase Titration Phase EXALGO (N=447) EXALGO (N=134) Placebo (N=134) Constipation 69 (15) 10 (7) 5 (4) Nausea 53 (12) 12 (9) 10 (7) Somnolence 39 (9) 1 (1) 0 (0) Headache 35 (8) 7 (5) 10 (7) Vomiting 29 (6) 8 (6) 6 (4) Drug Withdrawal Syndrome 22 (5) 13 (10) 16 (12) Pruritus 21 (5) 1 (1) 0 (0) Dizziness 17 (4) 3 (2) 2 (1) 16 (4) 2 (1) 6 (4) Asthenia a Insomnia 13 (3) 7 (5) 5 (4) Diarrhea 13 (3) 5 (4) 9 (7) Back Pain 13 (3) 6 (4) 8 (6) Dry Mouth 13 (3) 2 (1) 0 (0) Edema Peripheral 13 (3) 3 (2) 1 (1) Hyperhidrosis 13 (3) 2 (1) 2 (1) 10 (2) 2 (1) 0 (0) Anorexia b Arthralgia 9 (2) 8 (6) 3 (2) Anxiety 9 (2) 0 (0) 4 (3) 9 (2) 4 (3) 3 (2) Abdominal Pain c Muscle Spasms 5 (1) 3 (2) 1 (1) Weight Decreased 3 (1) 4 (3) 3 (2) a b c

Fatigue was grouped and reported with asthenia Decreased appetite was grouped and reported with anorexia Abdominal pain upper was grouped and reported with abdominal pain

The adverse reactions that were reported in at least 2% of the total treated patients (N=2,474) in the 14 chronic clinical trials are contained in Table 2.

Table 2.

Number (%) of Patients with Adverse Reactions Reported in â&#x2030;Ľ2% of Patients with Chronic Pain Receiving EXALGO in 14 Clinical Studies by Preferred Term Preferred Term All Patients (N=2,474) Constipation 765 (31) Nausea 684 (28) Vomiting 337 (14) Somnolence 367 (15) Headache 308 (12) Asthenia a 272 (11) Dizziness 262 (11) Diarrhea 201 (8) Pruritus 193 (8) Insomnia 161 (7) Hyperhidrosis 143 (6) Edema Peripheral 135 (5) Anorexia b 139 (6) Dry Mouth 121 (5) Abdominal Pain c 115 (5) Anxiety 95 (4) Back Pain 95 (4) Dyspepsia d 88 (4) Depression 81 (3) Dyspnea e 76 (3) Muscle Spasms 74 (3) Arthralgia 72 (3) Rash 64 (3) Pain in Extremity 63 (3) Pain 58 (2) Drug Withdrawal Syndrome 55 (2) Pyrexia 52 (2) Fall 51 (2) Chest Discomfort f 51 (2) a b c d e f

Fatigue was grouped and reported with asthenia Decreased appetite was grouped and reported with anorexia Abdominal pain upper was grouped and reported with abdominal pain Reflux esophagitis, gastroesophageal reflux disease and Barrettâ&#x20AC;&#x2122;s esophagus were grouped and reported with dyspepsia Dyspnea exacerbated and dyspnea exertional were grouped and reported with dyspnea Chest pain and non-cardiac chest pain were grouped and reported with chest discomfort

The following Adverse Reactions occurred in patients with an overall frequency of <2% and are listed in descending order within each System Organ Class: Cardiac disorders: palpitations, tachycardia, bradycardia, extrasystoles Ear and labyrinth disorders: vertigo, tinnitus Endocrine disorders: hypogonadism Eye disorders: vision blurred, diplopia, dry eye, miosis Gastrointestinal disorders: flatulence, dysphagia, hematochezia, abdominal distension, hemorrhoids, abnormal feces, intestinal obstruction, eructation, diverticulum, gastrointestinal motility disorder, large intestine perforation, anal fissure, bezoar, duodenitis, ileus, impaired gastric emptying, painful defecation General disorders and administration site conditions: chills, malaise, feeling abnormal, feeling hot and cold, feeling jittery, hangover, difficulty in walking, feeling drunk, hypothermia Infections and infestations: gastroenteritis, diverticulitis Injury, poisoning and procedural complications: contusion, overdose Investigations: weight decreased, hepatic enzyme increased, blood potassium decreased, blood amylase increased, blood testosterone decreased, oxygen saturation decreased Metabolism and nutrition disorders: dehydration, fluid retention, increased appetite, hyperuricemia Musculoskeletal and connective tissue disorders: myalgia Nervous system disorders: tremor, sedation, hypoesthesia, paraesthesia, disturbance in attention, memory impairment, dysarthria, syncope, balance disorder, dysgeusia, depressed level of consciousness, coordination abnormal, hyperesthesia, myoclonus, dyskinesia, hyperreflexia, encephalopathy, cognitive disorder, convulsion, psychomotor hyperactivity Psychiatric disorders: confusional state, nervousness, restlessness, abnormal dreams, mood altered, hallucination, panic attack, euphoric mood, paranoia, dysphoria, listless, crying, suicide ideation, libido decreased, aggression Renal and urinary disorders: dysuria, urinary retention, urinary frequency, urinary hesitation, micturition disorder Reproductive system and breast disorders: erectile dysfunction, sexual dysfunction Respiratory, thoracic and mediastinal disorders: rhinorrhoea, respiratory distress, hypoxia, bronchospasm, sneezing, hyperventilation, respiratory depression Skin and subcutaneous tissue disorders: erythema Vascular disorders: flushing, hypertension, hypotension DRUG INTERACTIONS CNS Depressants The concomitant use of EXALGO with central nervous system depressants such as hypnotics, sedatives, general anesthetics, antipsychotics and alcohol may cause additive depressant effects and respiratory depression. Additionally, hypotension and profound sedation or coma could occur. When this combination is indicated, the dose of one or both agents should be reduced. The concomitant use of alcohol should be avoided [see Clinical Pharmacology (12.3)].

Monoamine Oxidase (MAO) Inhibitors MAO inhibitors may cause CNS excitation or depression, hypotension or hypertension if co-administered with opioids including EXALGO. EXALGO is not intended for patients taking MAO inhibitors or within 14 days of stopping such treatment.

Mixed Agonist/Antagonist Opioid Analgesics The concomitant use of EXALGO with morphine agonist/antagonists (buprenorphone, nalbuphine, pentazocine) could lead to a reduction of the analgesic effect by competitive blocking of receptors, thus leading to risk of withdrawal symptoms. Therefore, this combination is not recommended.

Anticholinergics Anticholinergics or other medications with anticholinergic activity when used concurrently with EXALGO may result in increased risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.

Cytochrome P450 Enzymes In vitro data suggest that hydromorphone in clinically relevant concentrations has minimal potential to inhibit the activity of human hepatic CYP450 enzymes including CYP1A2, 2C9, 2C19, 2D6, 3A4, and 4A11.

USE IN SPECIFIC POPULATIONS Pregnancy Teratogenic Effects Pregnancy Category C: There are no adequate and well-controlled studies in pregnant women. Hydromorphone crosses the placenta. EXALGO should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus [see Use in Specific Populations (8.2)].

Hydromorphone was not teratogenic in pregnant rats given oral doses up to 6.25 mg/kg/day or in pregnant rabbits administered oral doses up to 25 mg/kg/day during the period of organogenesis (~1.2 times the human exposure following 32 mg/day).

Hydromorphone administration to pregnant Syrian hamsters and CF-1 mice during major organ development revealed teratogenicity likely the result of maternal toxicity associated with sedation and hypoxia. In Syrian hamsters given single subcutaneous doses from 14 to 258 mg/kg during organogenesis (gestation days 8 to 10), doses ≥ 19 mg/kg hydromorphone produced skull malformations (exencephaly and cranioschisis). Continuous infusion of hydromorphone (5 mg/kg, s.c.) via implanted osmotic mini pumps during organogenesis (gestation days 7 to 10) produced soft tissue malformations (cryptorchidism, cleft palate, malformed ventricals and retina), and skeletal variations (supraoccipital, checkerboard and split sternebrae, delayed ossification of the paws and ectopic ossification sites). The malformations and variations observed in the hamsters and mice were at doses approximately three-fold higher and <one-fold lower, respectively, than a 32 mg human daily oral dose on a body surface area basis.

Nonteratogenic Effects In the pre- and post-natal effects study in rats, neonatal viability was reduced at 6.25 mg/kg/day (~1.2 times the human exposure following 32 mg/day).

Neonates born to mothers who have been taking opioids regularly prior to delivery will be physically dependent. The withdrawal signs include irritability and excessive crying, tremors, hyperactive reflexes, increased respiratory rate, increased stools, sneezing, yawning, vomiting, and fever. The intensity of the syndrome does not always correlate with the duration of maternal opioid use or dose. There is no consensus on the best method of managing withdrawal.

Approaches to the treatment of the syndrome have included supportive care and, if indicated, drugs such as paregoric or phenobarbital.

Labor and Delivery EXALGO is not recommended for use in women during and immediately prior to labor and delivery. Administration of EXALGO to the mother shortly before delivery may result in some degree of respiratory depression in the neonate.

However, neonates whose mothers received opioid analgesics during labor should be observed closely for signs of respiratory depression.

Nursing Mothers Low concentrations of hydromorphone have been detected in human milk in clinical trials. Withdrawal symptoms can occur in breastfeeding infants when maternal administration of an opioid analgesic is stopped. Nursing should not be undertaken while a patient is receiving EXALGO since hydromorphone is excreted in the milk.

Pediatric Use The safety and effectiveness of EXALGO in pediatric patients 17 years of age and younger have not been established.

Geriatric Use Elderly patients have been shown to be more sensitive to the adverse effects of EXALGO compared to the younger population. Therefore, use extra caution when prescribing EXALGO in elderly patients and reduce the initial dose.

Neonatal Withdrawal Syndrome Chronic maternal use of opiates or opioids during pregnancy coexposes the fetus. The newborn may experience subsequent neonatal withdrawal syndrome (NWS). Manifestations of NWS include irritability, hyperactivity, abnormal sleep pattern, high-pitched cry, tremor, vomiting, diarrhea, weight loss, and failure to gain weight. The onset, duration, and severity of the disorder differ based on such factors as the addictive drug used, time and amount of mother’s last dose, and rate of elimination of the drug from the newborn. Approaches to the treatment of this syndrome have included supportive care and, when indicated, drugs such as paregoric or phenobarbital.

Hepatic Impairment In a study that used a single 4 mg oral dose of immediate-release hydromorphone tablets, four-fold increases in plasma levels of hydromorphone (Cmax and AUC0- ) were observed in patients with moderate hepatic impairment (Child-Pugh Group B). Start patients with moderate hepatic impairment on a reduced dose and closely monitored during dose titration.

The pharmacokinetics of hydromorphone in severe hepatic impairment patients have not been studied. Further increase in Cmax and AUC0- of hydromorphone in this group is expected, therefore, use an even more conservative starting dose [see Dosage and Administration (2.4)].

Renal Impairment Renal impairment affected the pharmacokinetics of hydromorphone and its metabolites following administration of a single 4 mg dose of immediate-release tablets. The effects of renal impairment on hydromorphone pharmacokinetics were two-fold and four-fold increases in plasma levels of hydromorphone (Cmax and AUC0-48h) in moderate (CLcr = 40 to 60 mL/min) and severe (CLcr < 30 mL/min) impairment, respectively. In addition, in patients with severe renal impairment hydromorphone appeared to be more slowly eliminated with longer terminal elimination half-life (40 hours) compared to subjects with normal renal function (15 hours). Start patients with moderate renal impairment on a reduced dose and closely monitored during dose titration. As EXALGO is only intended for once daily administration, consider use of an alternate analgesic that may permit more flexibility with the dosing interval in patients with severe renal impairment [see Dosage and Administration (2.4)].

DRUG ABUSE AND DEPENDENCE Controlled Substance EXALGO contains hydromorphone, a Schedule II controlled substance with a high potential for abuse similar to fentanyl, methadone, morphine, oxycodone, and oxymorphone. EXALGO can be abused and is subject to misuse, abuse, addiction, and criminal diversion [see Warnings and Precautions (5.2)]. The high drug content in the extended release formulation adds to the risk of adverse outcomes from abuse.

Abuse All patients treated with opioids, including EXALGO, require careful monitoring for signs of abuse and addiction, because use of opioid analgesic products carries the risk of addiction even under appropriate medical use.

Addiction is a primary, chronic, neurobiologic disease, with genetic, psychosocial, and environmental factors influencing its development and manifestations. It is characterized by behaviors that include one or more of the following: impaired control over drug use, compulsive use, continued use despite harm, and craving.

“Drug-seeking” behavior is very common to addicts and drug abusers. Drugseeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing or referral, repeated claims of loss of prescriptions, tampering with prescriptions and reluctance to provide prior medical records or contact information for other treating physician(s). “Doctor shopping” (visiting multiple prescribers) to obtain additional prescriptions is common among drug abusers, people suffering from untreated addiction and criminals seeking drugs to sell.

Abuse and addiction are separate and distinct from physical dependence and tolerance. Physicians should be aware that addiction may not be accompanied by concurrent tolerance and symptoms of physical dependence in all addicts.

In addition, abuse of opioids can occur in the absence of true addiction and is characterized by misuse for non-medical purposes, often in combination with other psychoactive substances. Since EXALGO may be diverted for non-medical use, careful record-keeping of prescribing information, including quantity, frequency, and renewal requests is strongly advised.

Proper assessment of the patient, proper prescribing practices, periodic re-evaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs.

EXALGO is intended for oral use only. Misuse or abuse by breaking, crushing, chewing, or dissolving EXALGO poses a hazard of overdose and death. This risk is increased with concurrent abuse of EXALGO with alcohol and other substances.

With intravenous abuse, the tablet excipients, especially polyethylene oxide, can be expected to result in necrosis and inflammation of cardiac tissues. In addition, parenteral drug abuse is commonly associated with transmission of infectious disease such as hepatitis and HIV. Healthcare professionals should contact their State Professional Licensing Board or State Controlled Substances Authority for information on how to prevent and detect abuse or diversion of this product.

Dependence Tolerance is a state of adaptation in which exposure to a drug induces changes that result in a diminution of one or more of the drug’s effects over time.

Tolerance could occur to both the desired and undesired effects of drugs, and may develop at different rates for different effects.

Physical dependence is a state of adaptation that is manifested by an opioid specific withdrawal syndrome that can be produced by abrupt cessation, rapid dose reduction, decreasing blood level of the drug, and/or administration of an antagonist. The opioid abstinence or withdrawal syndrome is characterized by some or all of the following: restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, piloerection, myalgia, mydriasis, irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, increased blood pressure, respiratory rate, or heart rate.

Infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal symptoms [see Use in Specific Populations (8.1, 8.2)].

OVERDOSAGE Symptoms Acute overdosage with opioids can be manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and sometimes bradycardia, hypotension and death. The extended release characteristics of EXALGO should also be taken into account when treating the overdose. Even in the face of improvement, continued medical monitoring is required because of the possibility of extended effects.

Deaths due to overdose could occur with abuse and misuse of EXALGO. Due to the delayed mean apparent peak plasma level of EXALGO occurring at 16 hours following administration as well as the 11 hour mean elimination half-life of EXALGO, patients who receive an overdose will require an extended period of monitoring and treatment that may go beyond 24 to 48 hours.

Treatment Give primary attention to the re-establishment of a patent airway and institution of assisted or controlled ventilation. Employ supportive measures (including oxygen and vasopressors) in the management of circulatory shock and pulmonary edema accompanying overdose as indicated. Cardiac arrest or arrhythmias will require advanced life support techniques.

The pure opioid antagonists, such as naloxone and naltrexone are specific antidotes to respiratory depression from opioid overdose. Since the duration of reversal would be expected to be less than the duration of action of hydromorphone in EXALGO, the patient must be carefully monitored until spontaneous respiration is reliably re-established. EXALGO will continue to release and add to the hydromorphone load for up to 24 hours after administration and the management of an overdose should be monitored accordingly, at least 24 to 48 hours beyond the overdose.

Only administer opioid antagonists in the presence of clinically significant respiratory or circulatory depression secondary to hydromorphone overdose. In patients who are physically dependent on any opioid agonist including EXALGO, an abrupt or complete reversal of opioid effects may precipitate an acute abstinence syndrome. The severity of the withdrawal syndrome produced will depend on the degree of physical dependence and the dose of the antagonist administered. Please see the prescribing information for the specific opioid antagonist for details of their proper use.

OROS is a registered trademark of ALZA Corporation.

EXALGO is a registered trademark of Mallinckrodt Inc. COVIDIEN, COVIDIEN with logo and Covidien logo are U.S. and/or internationally registered trademarks of Covidien AG. © 2010 Mallinckrodt Inc., a Covidien company Distributed by: Mallinckrodt Brand Pharmaceuticals, Inc. Hazelwood, MO 63042 USA Issued 11/2010

Mallinckrodt

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FDA Approvals of Brand-Name Prescription Drugs in 2010 I. New Pharmaceuticals, NMEs, Biologics Ampyra (NME) (Dalfampridine; Acorda) Class: Potassium channel blocker Indication: To improve walking in patients with multiple sclerosis Approval considerations: Priority review, orphan drug, REMS Asclera (NME) (Polidocanol; Chemische Fabrik Kreussler) Class: Sclerosing agent Indication: Treatment of uncomplicated spider veins (varicose veins â&#x2030;¤1 mm in diameter) and uncomplicated reticular veins (varicose veins 1-3 mm in diameter) in the lower extremity Axiron (Testosterone; Eli Lilly) Class: Androgen, steroid (topical) Indication: Androgen replacement therapy in males for conditions associated with a deficiency or absence of endogenous testosterone Approval consideration: REMS Butrans (new formulation) (Buprenorphine; Purdue Pharma) Class: Opioid agonist Indication: Management of moderate-to-severe chronic pain in patients requiring a continuous, around-theclock opioid analgesic for an extended period of time Approval consideration: REMS Carbaglu (NME) (Carglumic acid; Orphan Europe) Class: Carbamoyl phosphate synthetase 1 activator Indication: Adjunctive therapy for the treatment of acute hyperammonemia resulting from the deficiency of the hepatic enzyme N-acetylglutamate synthase (NAGS) and maintenance therapy for the treatment of chronic hyperammonemia resulting from NAGS deficiency Approval considerations: Priority review, orphan drug Cysview (Hexaminolevulinate hydrochloride; Photocure ASA) Class: Optical imaging agent Indication: For cystoscopic detection of nonmuscle invasive papillary cancer of the bladder in patients suspected or known to have lesion(s) on the basis of a prior cysto-

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scopy; used with the Karl Storz D-Light C Photodynamic Diagnostic system to perform cystoscopy with the blue light setting (mode 2) as an adjunct to the white light setting (mode 1) Approval consideration: Priority review Egrifta (NME) (Tesamorelin acetate; Theratechnologies) Class: Growth hormoneâ&#x20AC;&#x201C;releasing factor analog Indication: Reduction of excess abdominal fat in HIVinfected patients with lipodystrophy Ella (NME) (Ulipristal acetate; Lab HRA Pharma) Class: Progesterone agonist/antagonist emergency contraception Indication: Prevention of pregnancy after unprotected intercourse or a known or suspected contraceptive failure; not intended for routine use as a contraceptive Exalgo (Hydromorphone hydrochloride; Covidien/Mallinckrodt) Class: Opioid agonist Indication: Management of moderate-to-severe pain in opioid-tolerant patients requiring continuous, aroundthe-clock opioid analgesia for an extended period of time Approval considerations: Priority review, REMS Gilenya (NME) (Fingolimod hydrochloride; Novartis) Class: Sphingosine 1-phosphate receptor modulator Indication: Treatment of patients with relapsing forms of multiple sclerosis to reduce the frequency of clinical exacerbations and to delay the accumulation of physical disability Approval considerations: Priority review, REMS Glassia (BLA) (Alpha1-proteinase inhibitor [human]; Kamada) Class: Alpha1-proteinase inhibitor Indication: Treatment of chronic augmentation and maintenance therapy in individuals with emphysema resulting from congenital deficiency of alpha1-proteinase inhibitor, also known as alpha1-antitrypsin Halaven (NME) (Eribulin mesylate; Eisai) Class: Microtubule inhibitor Indication: Treatment of patients with metastatic breast

2010 FDA Approvals of Brand-Name Drugs

cancer who have previously received at least 2 chemotherapeutic regimens for the treatment of metastatic disease; prior therapy should have included an anthracycline and a taxane in either the adjuvant or metastatic setting Approval consideration: Priority review Hizentra (BLA) (Immune globulin subcutaneous [human], 20% liquid; CSL Behring) Class: Immune globulin Indication: Treatment of primary immunodeficiency disease Jevtana (NME) (Cabazitaxel; sanofi-aventis) Class: Taxane antimicrotubule Indication: Treatment of patients with hormonerefractory metastatic prostate cancer previously treated with a docetaxel-containing treatment regimen Approval consideration: Priority review Kapvay (Clonidine hydrochloride; Shionogi) Class: Alpha2-adrenergic receptor agonist Indication: Treatment of attention-deficit/hyperactivity disorder in children and adolescents aged 6 to 17 years Krystexxa (BLA) (Pegloticase; Savient Pharmaceuticals) Class: Pegylated uric acidâ&#x20AC;&#x201C;specific enzyme Indication: Treatment of gout in adult patients who failed conventional gout therapy to control hyperuricemia and manage the signs and symptoms of gout Approval considerations: Priority review, orphan drug, REMS Lastacaft (NME) (Alcaftadine ophthalmic solution; Vistakon Pharmaceuticals) Class: H1 histamine receptor antagonist + mast-cell stabilizer Indication: Prevention of itching associated with allergic conjunctivitis Latuda (NME) (Lurasidone hydrochloride; Sunovion Pharmaceuticals) Class: Atypical antipsychotic Indication: Treatment of schizophrenia in adults Lumizyme (BLA) (Alglucosidase alfa; Genzyme Corporation) Class: Lysosomal glycogen-specific enzyme Indication: Treatment of patients aged â&#x2030;Ľ8 years with noninfantile Pompe disease who do not have evidence of cardiac hypertrophy Approval considerations: Priority review, orphan drug, REMS

Menveo (BLA) (Meningococcal [groups A, C, Y, and W-135] oligosaccharide diphtheria CRM197 conjugate vaccine; Novartis) Class: Bacterial vaccine Indication: For active immunization to prevent invasive meningococcal disease caused by Neisseria meningitidis serogroups A, C, Y, and W-135 when administered to individuals aged 2 through 55 years Moxeza (Moxifloxacin hydrochloride ophthalmic solution; Alcon Pharmaceuticals) Class: Topical fluoroquinolone Indication: Treatment of bacterial conjunctivitis caused by susceptible strains of the following organisms: Aerococcus viridans, Corynebacterium macginleyi, Enterococcus faecalis, Micrococcus luteus, Staphylococcus arlettae, S aureus, S capitis, S epidermidis, S haemolyticus, S hominis, S saprophyticus, S warneri, Streptococcus mitis, Streptococcus pneumoniae, Streptococcus parasanguinis, Escherichia coli, Haemophilus influenzae, Klebsiella pneumoniae, Propionibacterium acnes, and Chlamydia trachomatis Natazia (NME) (Estradiol valerate/dienogest; Bayer HealthCare) Class: Estrogen + progestin Indication: For the prevention of pregnancy Nuedexta (Dextromethorphan hydrobromide + quinidine sulfate; Avanir Pharmaceuticals) Class: Uncompetitive N-methyl-D-aspartate receptor antagonist/sigma-1 agonist plus a CYP450 2D6 inhibitor Indication: Treatment of pseudobulbar affect Approval consideration: Priority review Pradaxa (NME) (Dabigatran etexilate mesylate; Boehringer Ingelheim) Class: Direct thrombin inhibitor Indication: To reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation Approval consideration: Priority review Prevnar-13 (BLA) (Pneumococcal 13-valent conjugate vaccine [diphtheria CRM197 protein]; Wyeth) Class: Vaccine Indication: Active immunization for the prevention of invasive disease caused by Streptococcus pneumoniae serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, and 23F, for use in children aged 6 weeks through 5 years; for the prevention of otitis media caused by Streptococcus pneumoniae serotypes 4, 6B, 9V, 14, 18C, 19F, and 23F

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Prolia (BLA) (Denosumab; Amgen) Class: RANKL inhibitor Indication: Treatment of postmenopausal women with osteoporosis at high risk for fracture Approval consideration: REMS See also Xgeva Provenge (BLA) (Sipuleucel-T; Dendreon Corporation) Class: Autologous cellular immunotherapy Indication: Treatment of men with asymptomatic or minimally symptomatic metastatic castrate-resistant (hormone refractory) prostate cancer TachoSil (BLA) (Fibrin sealant patch; Nycomed Danmark) Class: Hemostatic agent (patch) Indication: Adjunct to hemostasis in cardiovascular surgery when control of bleeding by standard surgical techniques—such as suture, ligature, or cautery— is ineffective or impractical Teflaro (NME) (Ceftaroline fosamil; Cerexa) Class: Cephalosporin antibacterial Indication: Treatment of acute bacterial skin and skin-structure infections and community-acquired bacterial pneumonia Victoza (NME) (Liraglutide recombinant; Novo Nordisk) Class: Glucagon-like peptide-1 receptor agonist Indication: Adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus Approval consideration: REMS VPriv (NME) (Velaglucerase alfa; Shire Human Genetic Therapies)

Class: Hydrolytic lysosomal glucocerebroside-specific enzyme Indication: Long-term enzyme replacement therapy for pediatric and adult patients with type 1 Gaucher disease Approval considerations: Priority review, orphan drug Xeomin (BLA) (Incobotulinumtoxin-A; Merz Pharmaceuticals) Class: Acetylcholine release inhibitor + neuromuscular blocker Indication: Treatment of adults with cervical dystonia, to decrease the severity of abnormal head position and neck pain in both botulinum toxin–naïve and previously treated patients; treatment of blepharospasm in adults previously treated with onabotulinumtoxin-A Approval consideration: REMS Xgeva (BLA) (Denosumab; Amgen) Class: RANKL inhibitor Indication: To help prevent skeletal-related events in patients with bone metastases from solid tumors Approval consideration: REMS See also Prolia Xiaflex (BLA) (Collagenase clostridium histolyticum; Auxilium Pharmaceuticals) Class: Miscellaneous uncategorized agents Indication: Treatment of advanced Dupuytren’s contracture with a palpable cord Approval considerations: Priority review, orphan drug, REMS Zortress (NME) (Everolimus; Novartis) Class: Immunosuppressant (macrolide) Indication: Prophylaxis of organ rejection in adult patients at low-to-moderate immunologic risk receiving a kidney transplant Approval consideration: REMS

II. New Combinations, Formulations, Indications Actemra (new indication) (Tocilizumab; Genentech) Class: Interleukin-6 receptor inhibitor Indication: Treatment for reducing signs and symptoms in adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response to 1 or more tumor necrosis factor–antagonist therapies Approval consideration: REMS

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Alsuma (new formulation) (Sumatriptan succinate; King Pharmaceuticals) Class: 5-HT1B/1D receptor agonist Indication: Acute treatment of migraine attacks, with or without aura; acute treatment of cluster headache episodes Amturnide (new combination) (Aliskiren, amlodipine + hydrochlorothiazide; Novartis)

2010 FDA Approvals of Brand-Name Drugs

Class: Direct renin inhibitor + calcium channel blocker + diuretic Indication: Treatment of hypertension Aricept (new formulation) (Donepezil hydrochloride; Eisai) Class: Reversible acetylcholinesterase inhibitor (piperidine derivative) Indication: Treatment of dementia of the Alzheimer’s type Aridol/Aridol Kit (new formulation) (Mannitol; Pharmaxis) Class: Sugar alcohol Indication: Assessment of bronchial hyperresponsiveness in patients aged ≥6 years who do not have clinically apparent asthma Atelvia (new formulation) (Risedronate sodium; Warner Chilcott) Class: Bisphosphonate Indication: Treatment of osteoporosis in postmenopausal women Benicar (new indication) (Olmesartan medoxomil; Daiichi Sankyo) Class: Angiotensin II receptor blocker Indication: Treatment of hypertension, alone or with other antihypertensive agents, in adults and children aged 6 to 16 years Beyaz (new combination) (Drospirenone + ethinyl estradiol + levomefolate calcium; Bayer HealthCare) Class: Progestin + estrogen + folate combination oral contraceptive Indication: For prevention of pregnancy; treatment of symptoms of premenstrual dysphoric disorder for women who choose to use an oral contraceptive for contraception; treatment of moderate acne for women at least 14 years old only if the patient desires an oral contraceptive for birth control; to raise folate levels in women who choose to use an oral contraceptive Botox (new indication) (Onabotulinumtoxin-A; Allergan) Class: Acetylcholine release inhibitor + neuromuscular blocking agent Indication: Treatment of upper limb spasticity in adults, cervical dystonia in adults to reduce the severity of abnormal head position and neck pain, severe axillary hyperhidrosis that is inadequately managed with topical agents in adults, blepharospasm associated with dystonia in patients aged ≥12 years, strabismus in patients aged ≥12 years, chronic migraine

Bromday (new formulation) (Bromfenac ophthalmic solution; ISTA Pharmaceuticals) Class: Nonsteroidal anti-inflammatory drug Indication: Treatment of postoperative inflammation and reduction of ocular pain in patients who have undergone cataract extraction Carpine (new formulation) (Pilocarpine hydrochloride; Alcon) Class: Muscarinic cholinergic agonist Indication: Reduction of elevated intraocular pressure in patients with open-angle glaucoma or ocular hypertension; management of acute angle-closure glaucoma; prevention of postoperative elevated intraocular pressure associated with laser surgery; induction of miosis Approval consideration: Priority review Cayston (new formulation) (Aztreonam; Gilead) Class: Monobactam antibacterial Indication: Treatment of cystic fibrosis in patients known to have Pseudomonas aeruginosa in the lungs Cuvposa (new formulation) (Glycopyrrolate; Shionogi) Class: Acetylcholine receptor inhibitor Indication: Treatment of chronic severe drooling in patients aged 3 to 16 years with neurologic conditions associated with problem drooling (eg, cerebral palsy) Approval consideration: Priority review Cymbalta (new indication) (Duloxetine hydrochloride; Eli Lilly) Class: Serotonin + norepinephrine reuptake inhibitor Indication: Treatment of major depressive disorder, generalized anxiety disorder, diabetic peripheral neuropathic pain, fibromyalgia, chronic musculoskeletal pain Differin (new formulation) (Adapalene; Galderma Laboratories) Class: Retinoid Indication: Topical treatment of acne vulgaris in patients aged ≥12 years Dulera (new combination) (Formoterol fumarate dihydrate + mometasone furoate; Schering) Class: Corticosteroid + long-acting beta2-agonist Indication: Treatment of asthma in patients aged ≥12 years Approval consideration: REMS Fortesta (new formulation) (Testosterone; Endo Pharmaceuticals) Class: Steroid androgen Indication: Testosterone replacement therapy in males

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for primary hypogonadism (congenital or acquired) and hypogonadotrophic hypogonadism (congenital or acquired) associated with a deficiency or absence of endogenous testosterone Approval consideration: REMS Herceptin (new indication) (Trastuzumab; Genentech) Class: HER2/neu receptor antagonist Indication: Treatment of HER2-overexpressing cancer and treatment of HER2-overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma H.P. Acthar Gel (new indication) (Repository corticotropin; Questcor Pharmaceuticals) Class: Adrenocorticotropic hormone analog Indication: Monotherapy for infantile spasms in persons aged <2 years; treatment of exacerbations of multiple sclerosis in adults Approval consideration: REMS Jalyn (new combination) (Dutasteride + tamsulosin hydrochloride; GlaxoSmithKline) Class: Type I and II 5-alpha-reductase inhibitor + alpha1A-blocker Indication: Treatment of symptomatic benign prostatic hyperplasia in men with an enlarged prostate Kombiglyze XR (new combination) (Metformin hydrochloride + saxagliptin; Bristol-Myers Squibb) Class: Dipeptidyl peptidase-4 inhibitor + biguanide combination Indication: Adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus when treatment with both saxagliptin and metformin is appropriate Lamictal XR (new formulation) (Lamotrigine; GlaxoSmithKline) Class: Phenyltriazine (antiepileptic drug) Indication: Adjunctive therapy for primary generalized tonic-clonic seizures and partial-onset seizures with or without secondary generalization in patients aged â&#x2030;Ľ13 years Approval consideration: REMS Lamivudine, Nevirapine, and Stavudine (new combination) (Lamivudine + stavudine; Hetero Drugs) Class: Nucleoside analog (reverse transcriptase inhibitor) Indication: HIV-1 infection Lo Loestrin FE (new formulation) (Ethinyl estradiol + norethindrone acetate, ferrous fumarate; Warner Chilcott)

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Class: Progestin + estrogen combination oral contraceptive Indication: Use by women to prevent pregnancy Approval consideration: REMS Lumigan (new indication) (Bimatoprost; Allergan) Class: Prostaglandin analog Indication: Reduction of elevated intraocular pressure in patients with open-angle glaucoma or ocular hypertension Lyrica (new formulation) (Pregabalin; Pfizer) Class: Alpha2-delta ligand Indication: Neuropathic pain associated with diabetic peripheral neuropathy, postherpetic neuralgia, adjunctive therapy for adult patients with partial-onset seizures, fibromyalgia Approval consideration: REMS Namenda XR (new formulation) (Memantine hydrochloride; Forest Laboratories) Class: N-methyl-D-aspartate receptor antagonist Indication: Treatment of moderate-to-severe dementia of the Alzheimerâ&#x20AC;&#x2122;s type Norvir (new formulation) (Ritonavir; Abbott Laboratories) Class: HIV protease inhibitor Indication: Treatment of HIV-1 infection in combination with other antiretroviral agents Oleptro (new formulation) (Trazodone hydrochloride; Labopharm) Class: Triazolopyridine Indication: Major depressive disorder Approval consideration: REMS Orabloc (new combination) (Articaine hydrochloride + epinephrine bitartrate; Pierrel) Class: Amide local anesthetic Indication: Local, infiltrative, or conductive anesthesia in simple and complex dental procedures Oravig (new formulation) (Miconazole; Strativa Pharmaceuticals) Class: Azole antifungal Indication: Local treatment of oropharyngeal candidiasis in adults Ozurdex (new formulation) (Dexamethasone intravitreal implant; Allergan) Class: Corticosteroid Indication: Treatment of macular edema after branch

2010 FDA Approvals of Brand-Name Drugs

retinal vein occlusion or central retinal vein occlusion and noninfectious uveitis affecting the posterior segment of the eye Approval consideration: Priority review

Indication: Management of moderate-to-moderately severe chronic pain in adults who require around-theclock treatment of their pain for an extended period of time

Pennsaid (new formulation) (Diclofenac sodium; Covidien) Class: Nonsteroidal anti-inflammatory drug Indication: Treatment of signs and symptoms of osteoarthritis of the knee(s)

Trelstar (new formulation) (Triptorelin pamoate; Watson Laboratories) Class: Gonadotropin-releasing hormone agonist Indication: Palliative treatment of advanced prostate cancer

Silenor (new formulation) (Doxepin hydrochloride; Somaxon Pharmaceuticals) Class: H1 receptor antagonist Indication: Treatment of insomnia characterized by difficulties with sleep maintenance Approval consideration: REMS

Tribenzor (new combination) (Amlodipine besylate + hydrochlorothiazide + olmesartan medoxomil; Daiichi Sankyo) Class: Angiotensin II receptor blocker + dihydropyridine calcium channel blocker + thiazide diuretic Indication: Treatment of hypertension; not indicated for initial therapy

Sprix (new formulation) (Ketorolac tromethamine; Roxro Pharmaceuticals) Class: Nonsteroidal anti-inflammatory drug Indication: Short-term management (up to 5 days) of acute moderate-to-moderately severe pain Staxyn (new formulation) (Vardenafil hydrochloride; Bayer HealthCare) Class: Phosphodiesterase type 5 inhibitor (cGMPspecific) Indication: Treatment of erectile dysfunction Suboxone (new combination) (Buprenorphine + naloxone; Reckitt Benckiser) Class: Opioid (partial agonist-antagonist) + opioid antagonist Indication: Maintenance treatment of opioid dependence Approval consideration: REMS Suprep Bowel Prep Kit (new combination) (Magnesium sulfate anhydrous + potassium sulfate + sodium sulfate; Braintree Laboratories) Class: Osmotic bowel cleanser Indication: Cleansing of the colon in preparation for colonoscopy in adults Approval consideration: REMS Tekamlo (new combination) (Aliskiren hemifumarate + amlodipine besylate; Novartis) Class: Renin inhibitor + dihydropyridine calcium channel blocker Indication: Hypertension Tramadol hydrochloride (new formulation) (Tramadol hydrochloride; Cipher Pharmaceuticals) Class: Opioid agonist

Vimovo (new combination) (Esomeprazole magnesium + naproxen; AstraZeneca) Class: Nonsteroidal anti-inflammatory drug + proton pump inhibitor Indication: Relief of signs and symptoms of osteoarthritis, rheumatoid arthritis, and ankylosing spondylitis and to decrease the risk of developing gastric ulcers in patients at risk of developing nonsteroidal anti-inflammatory drug–associated gastric ulcers Vimpat (new formulation) (Lacosamide; UCB Pharma) Class: Sodium channel inactivator Indication: Adjunctive therapy in the treatment of partial-onset seizures in patients with epilepsy aged ≥17 years Approval consideration: REMS Vivitrol (new formulation) (Naltrexone; Alkermes) Class: Opioid antagonist Indication: Treatment of alcohol dependence in patients able to abstain from alcohol in an outpatient setting before initiation of treatment and for the prevention if relapse to opioid dependence after opioid detoxification Approval considerations: Priority review, REMS Xifaxan (new indication) (Rifaximin; Salix Pharmaceuticals) Class: Rifamycin antibacterial Indication: Treatment of patients (aged ≥12 years) with travelers’ diarrhea caused by noninvasive strains of Escherichia coli and reduction in risk of overt hepatic encephalopathy recurrence in patients aged ≥18 years Approval consideration: Priority review

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Zuplenz (new formulation) (Ondansetron; Strativa Pharmaceuticals/ Par Pharmaceutical Companies) Class: Selective 5-HT3 receptor antagonist Indication: Prevention of nausea and vomiting associated with highly emetogenic cancer chemotherapy; prevention of nausea and vomiting associated with initial and repeat courses of moderately emetogenic cancer chemotherapy; prevention of nausea and vomiting associated with radiotherapy in patients receiving total body irradiation, single high-dose fraction to abdomen, or daily fractions to the abdomen; prevention of postoperative nausea and/or vomiting

Zymaxid (new indication) (Gatifloxacin ophthalmic solution; Allergan) Class: Fluoroquinolone anti-infective Indication: Treatment of bacterial conjunctivitis caused by susceptible strains of Haemophilus influenzae, Staphylococcus aureus, S epidermidis, Streptococcus mitis group, Streptococcus oralis, and Streptococcus pneumoniae

III. Newly Approved Old Drugs Previously Marketed without FDA Approval (Drugs were available before the establishment of the FDA) Oxycodone Hydrochloride (Oxycodone hydrochloride; Lehigh Valley Technologies) Class: Opioid agonist Indication: Management of moderate-to-severe acute and chronic pain where the use of an opioid analgesic is appropriate Approval consideration: REMS

Pancreaze (Pancrelipase; Ortho-McNeil Janssen) Class: Digestive enzymes Indication: Treatment of exocrine pancreatic insufficiency resulting from cystic fibrosis or other conditions

BLA indicates biologic license application; NME, new molecular entity; REMS, risk evaluation and mitigation strategy.

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For patients who need more than metformin

Help grab type 2 diabetes by the roots.

Once-daily Victoza® provides powerful and sustained* reductions in A1C and:

Impacts beta-cell function to help regulate insulin secretion May reduce weight – Victoza® is not indicated for the management of obesity – Weight change was a secondary end point in clinical trials *Victoza® was evaluated in a 52-week monotherapy trial and in five 26-week, add-on combination trials.

Indications and usage Important safety information Victoza® is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

Because of the uncertain relevance of the rodent thyroid C-cell tumor findings to humans, prescribe Victoza® only to patients for whom the potential benefits are considered to outweigh the potential risk.

Victoza® is not recommended as first-line therapy for patients who have inadequate glycemic control on diet and exercise.

In clinical trials of Victoza®, there were more cases of pancreatitis with Victoza® than with comparators.

Victoza® has not been studied sufficiently in patients with a history of pancreatitis to determine whether these patients are at increased risk for pancreatitis while using Victoza®.

Use with caution in patients with a history of pancreatitis.

Victoza® is not a substitute for insulin. Victoza® should not be used in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis, as it would not be effective in these settings.

The concurrent use of Victoza® and insulin has not been studied.

Liraglutide causes dose-dependent and treatment-duration-dependent thyroid C-cell tumors at clinically relevant exposures in both genders of rats and mice. It is unknown whether Victoza® causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans, as human relevance could not be ruled out by clinical or nonclinical studies.

Victoza® is contraindicated in patients with a personal or family history of MTC and in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). Based on the findings in rodents, monitoring with serum calcitonin or thyroid ultrasound was performed during clinical trials, but this may have increased the number of unnecessary thyroid surgeries.

It is unknown whether monitoring with serum calcitonin or thyroid ultrasound will mitigate human risk of thyroid C-cell tumors. Patients should be counseled regarding the risk and symptoms of thyroid tumors.

If pancreatitis is suspected, Victoza® should be discontinued. Victoza® should not be re-initiated if pancreatitis is confirmed.

When Victoza® is used with an insulin secretagogue (e.g. a sulfonylurea) serious hypoglycemia can occur. Consider lowering the dose of the insulin secretagogue to reduce the risk of hypoglycemia.

There have been no studies establishing conclusive evidence of macrovascular risk reduction with Victoza® or any other antidiabetic drug.

The most common adverse reactions, reported in ≥5% of patients treated with Victoza® and more commonly than in patients treated with placebo, are headache, nausea, diarrhea, and anti-liraglutide antibody formation. Immunogenicity-related events, including urticaria, were more common among Victoza®-treated patients (0.8%) than among comparator-treated patients (0.4%) in clinical trials.

Victoza® has not been studied in type 2 diabetes patients below 18 years of age and is not recommended for use in pediatric patients.

Victoza® should be used with caution in patients with renal impairment and in patients with hepatic impairment.

Please see brief summary of Prescribing Information on adjacent page.

To learn how Victoza® can help your patients manage their type 2 diabetes, visit VictozaPro.com/Benefit.

Victoza® is a registered trademark and VictozaCare™ is a trademark of Novo Nordisk A/S. © 2011 Novo Nordisk 0311-00001944-1

April 2011

Victoza® (liraglutide [rDNA origin] injection) Rx Only BRIEF SUMMARY. Please consult package insert for full prescribing information.

WARNING: RISK OF THYROID C-CELL TUMORS: Liraglutide causes dose-dependent and treatment-duration-dependent thyroid C-cell tumors at clinically relevant exposures in both genders of rats and mice. It is unknown whether Victoza® causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans, as human relevance could not be ruled out by clinical or nonclinical studies. Victoza® is contraindicated in patients with a personal or family history of MTC and in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). Based on the findings in rodents, monitoring with serum calcitonin or thyroid ultrasound was performed during clinical trials, but this may have increased the number of unnecessary thyroid surgeries. It is unknown whether monitoring with serum calcitonin or thyroid ultrasound will mitigate human risk of thyroid C-cell tumors. Patients should be counseled regarding the risk and symptoms of thyroid tumors [see Contraindications and Warnings and Precautions].

INDICATIONS AND USAGE: Victoza® is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Important Limitations of Use: Because of the uncertain relevance of the rodent thyroid C-cell tumor findings to humans, prescribe Victoza® only to patients for whom the potential benefits are considered to outweigh the potential risk. Victoza® is not recommended as first-line therapy for patients who have inadequate glycemic control on diet and exercise. In clinical trials of Victoza®, there were more cases of pancreatitis with Victoza® than with comparators. Victoza® has not been studied sufficiently in patients with a history of pancreatitis to determine whether these patients are at increased risk for pancreatitis while using Victoza®. Use with caution in patients with a history of pancreatitis.

Victoza® is not a substitute for insulin. Victoza® should not be used in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis, as it would not be effective in these settings. The concurrent use of Victoza® and insulin has not been studied.

CONTRAINDICATIONS: Victoza® is contraindicated in patients with a personal or family history of medullary thyroid carcinoma (MTC) or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2).

WARNINGS AND PRECAUTIONS: Risk of Thyroid C-cell Tumors: Liraglutide causes dose-dependent and treatment-duration-dependent thyroid C-cell tumors (adenomas and/or carcinomas) at clinically relevant exposures in both genders of rats and mice. Malignant thyroid C-cell carcinomas were detected in rats and mice. A statistically significant increase in cancer was observed in rats receiving liraglutide at 8-times clinical exposure compared to controls. It is unknown whether Victoza® will cause thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans, as the human relevance of liraglutide-induced rodent thyroid C-cell tumors could not be determined by clinical or nonclinical studies [see Boxed Warning, Contraindications]. In the clinical trials, there have been 4 reported cases of thyroid C-cell hyperplasia among Victoza®-treated patients and 1 case in a comparator-treated patient (1.3 vs. 0.6 cases per 1000 patient-years). One additional case of thyroid C-cell hyperplasia in a Victoza®-treated patient and 1 case of MTC in a comparator-treated patient have subsequently been reported. This comparator-treated patient with MTC had pre-treatment serum calcitonin concentrations >1000 ng/L suggesting pre-existing disease. All of these cases were diagnosed after thyroidectomy, which was prompted by abnormal results on routine, protocol-specified measurements of serum calcitonin. Four of the five liraglutide-treated patients had elevated calcitonin concentrations at baseline and throughout the trial. One liraglutide and one non-liraglutide-treated patient developed elevated calcitonin concentrations while on treatment. Calcitonin, a biological marker of MTC, was measured throughout the clinical development program. The serum calcitonin assay used in the Victoza® clinical trials had a lower limit of quantification (LLOQ) of 0.7 ng/L and the upper limit of the reference range was 5.0 ng/L for women and 8.4 ng/L for men. At Weeks 26 and 52 in the clinical trials, adjusted mean serum calcitonin concentrations were higher in Victoza®treated patients compared to placebo-treated patients but not compared to patients receiving active comparator. At these timepoints, the adjusted mean serum calcitonin values (~ 1.0 ng/L) were just above the LLOQ with between-group differences in adjusted mean serum calcitonin values of approximately 0.1 ng/L or less. Among patients with pre-treatment serum calcitonin below the upper limit of the reference range, shifts to above the upper limit of the reference range which persisted in subsequent measurements occurred most frequently among patients treated with Victoza® 1.8 mg/day. In trials with on-treatment serum calcitonin measurements out to 5-6 months, 1.9% of patients treated with Victoza® 1.8 mg/day developed new and persistent calcitonin elevations above the upper limit of the reference range compared to 0.8-1.1% of patients treated with control medication or the 0.6 and 1.2 mg doses of Victoza®. In trials with on-treatment serum calcitonin measurements out to 12 months, 1.3% of patients treated with Victoza® 1.8 mg/day had new and persistent elevations of calcitonin from below or within the reference range to above the upper limit of the reference range, compared to 0.6%, 0% and 1.0% of patients treated with Victoza® 1.2 mg, placebo and active control, respectively. Otherwise, Victoza® did not produce consistent dose-dependent or time-dependent increases in serum calcitonin. Patients with MTC usually have calcitonin values >50 ng/L. In Victoza® clinical trials, among patients with pre-treatment serum calcitonin <50 ng/L, one Victoza®-treated patient and no comparator-treated patients developed serum calcitonin >50 ng/L. The Victoza®-treated patient who developed serum calcitonin >50 ng/L had an elevated pre-treatment serum calcitonin of 10.7 ng/L that increased to 30.7 ng/L at Week 12 and 53.5 ng/L at the end of the 6-month trial. Follow-up serum calcitonin was 22.3 ng/L more than 2.5 years after the last dose of Victoza®. The largest increase in serum calcitonin in a comparator-treated patient was seen with glimepiride in a patient whose serum calcitonin increased from 19.3 ng/L at baseline to 44.8 ng/L at Week 65 and 38.1 ng/L at Week 104. Among patients who began with serum calcitonin <20 ng/L, calcitonin elevations to >20 ng/L occurred in 0.7% of Victoza®-treated patients, 0.3% of placebo-treated patients, and 0.5% of active-comparator-treated patients, with an incidence of 1.1% among patients treated with 1.8 mg/day of Victoza®. The clinical significance of these findings is unknown. Counsel patients regarding the risk for MTC and the symptoms of thyroid tumors (e.g. a mass in the neck, dysphagia, dyspnea or persistent hoarseness). It is unknown whether monitoring with serum calcitonin or thyroid ultrasound will mitigate the potential risk of MTC, and such monitoring may increase the risk of unnecessary procedures, due to low test specificity for serum calcitonin and a high background incidence of thyroid disease. Patients with thyroid nodules noted on physical examination or neck imaging obtained for other reasons should be referred to an endocrinologist for further evaluation. Although routine monitoring of serum calcitonin is of uncertain value in patients treated with Victoza®, if serum calcitonin is measured and found to be elevated, the

patient should be referred to an endocrinologist for further evaluation. Pancreatitis: In clinical trials of Victoza®, there were 7 cases of pancreatitis among Victoza®-treated patients and 1 case among comparator-treated patients (2.2 vs. 0.6 cases per 1000 patient-years). Five cases with Victoza® were reported as acute pancreatitis and two cases with Victoza® were reported as chronic pancreatitis. In one case in a Victoza®-treated patient, pancreatitis, with necrosis, was observed and led to death; however clinical causality could not be established. One additional case of pancreatitis has subsequently been reported in a Victoza®-treated patient. Some patients had other risk factors for pancreatitis, such as a history of cholelithiasis or alcohol abuse. There are no conclusive data establishing a risk of pancreatitis with Victoza® treatment. After initiation of Victoza®, and after dose increases, observe patients carefully for signs and symptoms of pancreatitis (including persistent severe abdominal pain, sometimes radiating to the back and which may or may not be accompanied by vomiting). If pancreatitis is suspected, Victoza® and other potentially suspect medications should be discontinued promptly, confirmatory tests should be performed and appropriate management should be initiated. If pancreatitis is confirmed, Victoza® should not be restarted. Use with caution in patients with a history of pancreatitis. Use with Medications Known to Cause Hypoglycemia: Patients receiving Victoza® in combination with an insulin secretagogue (e.g., sulfonylurea) may have an increased risk of hypoglycemia. In the clinical trials of at least 26 weeks duration, hypoglycemia requiring the assistance of another person for treatment occurred in 7 Victoza®-treated patients and in two comparator-treated patients. Six of these 7 patients treated with Victoza® were also taking a sulfonylurea. The risk of hypoglycemia may be lowered by a reduction in the dose of sulfonylurea or other insulin secretagogues [see Adverse Reactions]. Macrovascular Outcomes: There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with Victoza® or any other antidiabetic drug.

ADVERSE REACTIONS: Clinical Trials Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of Victoza® was evaluated in a 52-week monotherapy trial and in five 26-week, add-on combination therapy trials. In the monotherapy trial, patients were treated with Victoza® 1.2 mg daily, Victoza® 1.8 mg daily, or glimepiride 8 mg daily. In the add-on to metformin trial, patients were treated with Victoza® 0.6 mg, Victoza® 1.2 mg, Victoza® 1.8 mg, placebo, or glimepiride 4 mg. In the add-on to glimepiride trial, patients were treated with Victoza® 0.6 mg, Victoza® 1.2 mg, Victoza® 1.8 mg, placebo, or rosiglitazone 4 mg. In the add-on to metformin + glimepiride trial, patients were treated with Victoza® 1.8 mg, placebo, or insulin glargine. In the add-on to metformin + rosiglitazone trial, patients were treated with Victoza® 1.2 mg, Victoza® 1.8 mg or placebo. Withdrawals: The incidence of withdrawal due to adverse events was 7.8% for Victoza®-treated patients and 3.4% for comparator-treated patients in the five controlled trials of 26 weeks duration or longer. This difference was driven by withdrawals due to gastrointestinal adverse reactions, which occurred in 5.0% of Victoza®-treated patients and 0.5% of comparator-treated patients. The most common adverse reactions leading to withdrawal for Victoza®-treated patients were nausea (2.8% versus 0% for comparator) and vomiting (1.5% versus 0.1% for comparator). Withdrawal due to gastrointestinal adverse events mainly occurred during the first 2-3 months of the trials. Tables 1, 2 and 3 summarize the adverse events reported in *5% of Victoza®-treated patients in the six controlled trials of 26 weeks duration or longer.

Table 1: Adverse events reported in *5% of Victoza®-treated patients or *5% of glimepiride-treated patients: 52-week monotherapy trial All Victoza® N = 497 Glimepiride N = 248 (%) (%) Adverse Event Term Nausea 28.4 8.5 Diarrhea 17.1 8.9 Vomiting 10.9 3.6 Constipation 9.9 4.8 Upper Respiratory Tract Infection 9.5 5.6 Headache 9.1 9.3 Influenza 7.4 3.6 Urinary Tract Infection 6.0 4.0 Dizziness 5.8 5.2 Sinusitis 5.6 6.0 Nasopharyngitis 5.2 5.2 Back Pain 5.0 4.4 Hypertension 3.0 6.0 Table 2: Adverse events reported in *5% of Victoza®-treated patients and occurring more frequently with Victoza® compared to placebo: 26-week combination therapy trials Add-on to Metformin Trial All Victoza® + Placebo + Glimepiride + Metformin N = 724 Metformin N = 121 Metformin N = 242 (%) (%) (%) Adverse Event Term Nausea 15.2 4.1 3.3 Diarrhea 10.9 4.1 3.7 Headache 9.0 6.6 9.5 Vomiting 6.5 0.8 0.4 Add-on to Glimepiride Trial All Victoza® + Placebo + Rosiglitazone + Glimepiride N = 695 Glimepiride N = 114 Glimepiride N = 231 (%) (%) (%) Adverse Event Term Nausea 7.5 1.8 2.6 Diarrhea 7.2 1.8 2.2 Constipation 5.3 0.9 1.7 Dyspepsia 5.2 0.9 2.6

Add-on to Metformin + Glimepiride Placebo + Metformin Glargine + Metformin Victoza® 1.8 + + Glimepiride + Glimepiride Metformin + N = 232 N = 114 Glimepiride N = 230 (%) (%) (%) Adverse Event Term Nausea 13.9 3.5 1.3 Diarrhea 10.0 5.3 1.3 Headache 9.6 7.9 5.6 Dyspepsia 6.5 0.9 1.7 6.5 3.5 0.4 Vomiting Add-on to Metformin + Rosiglitazone ® All Victoza + Metformin + Placebo + Metformin Rosiglitazone N = 355 + Rosiglitazone N = 175 (%) (%) Adverse Event Term Nausea 34.6 8.6 Diarrhea 14.1 6.3 Vomiting 12.4 2.9 Decreased Appetite 9.3 1.1 Anorexia 9.0 0.0 8.2 4.6 Headache Constipation 5.1 1.1 Fatigue 5.1 1.7 Table 3: Treatment-Emergent Adverse Events in 26 Week Open-Label Trial versus Exenatide (Adverse events with frequency *5% and occurring more frequently with Victoza® compared to exenatide are listed) Exenatide 10 mcg twice Victoza® 1.8 mg once daily + metformin and/or daily + metformin and/or sulfonylurea N = 232 sulfonylurea N = 235 (%) (%) Preferred Term Diarrhea 12.3 12.1 Dyspepsia 8.9 4.7 Constipation 5.1 2.6 Gastrointestinal adverse events: In the five clinical trials of 26 weeks duration or longer, gastrointestinal adverse events were reported in 41% of Victoza®-treated patients and were dose-related.

Gastrointestinal adverse events occurred in 17% of comparator-treated patients. Events that occurred more commonly among Victoza®-treated patients included nausea, vomiting, diarrhea, dyspepsia and constipation. In a 26-week study of Victoza® versus exenatide, both in combination with metformin and/or sulfonylurea overall gastrointestinal adverse event incidence rates, including nausea, were similar in patients treated with Victoza® and exenatide. In five clinical trials of 26 weeks duration or longer, the percentage of patients who reported nausea declined over time.

Approximately 13% of Victoza®-treated patients and 2% of comparator-treated patients reported nausea during the first 2 weeks of treatment. In a 26 week study of Victoza® versus exenatide, both in combination with metformin and/or sulfonylurea, the proportion of patients with nausea also declined over time. Immunogenicity: Consistent with the potentially immunogenic properties of protein and peptide pharmaceuticals, patients treated with Victoza® may develop anti-liraglutide antibodies. Approximately 50-70% of Victoza®-treated patients in the five clinical trials of 26 weeks duration or longer were tested for the presence of anti-liraglutide antibodies at the end of treatment. Low titers (concentrations not requiring dilution of serum) of anti-liraglutide antibodies were detected in 8.6% of these Victoza®-treated patients. Sampling was not performed uniformly across all patients in the clinical trials, and this may have resulted in an underestimate of the actual percentage of patients who developed antibodies. Cross-reacting anti-liraglutide antibodies to native glucagon-like peptide-1 (GLP-1) occurred in 6.9% of the Victoza®-treated patients in the 52-week monotherapy trial and in 4.8% of the Victoza®-treated patients in the 26-week add-on combination therapy trials. These cross-reacting antibodies were not tested for neutralizing effect against native GLP-1, and thus the potential for clinically significant neutralization of native GLP-1 was not assessed. Antibodies that had a neutralizing effect on liraglutide in an in vitro assay occurred in 2.3% of the Victoza®-treated patients in the 52-week monotherapy trial and in 1.0% of the Victoza®-treated patients in the 26-week add-on combination therapy trials.

Among Victoza®-treated patients who developed anti-liraglutide antibodies, the most common category of adverse events was that of infections, which occurred among 40% of these patients compared to 36%, 34% and 35% of antibody-negative Victoza®-treated, placebo-treated and active-control-treated patients, respectively. The specific infections which occurred with greater frequency among Victoza®-treated antibody-positive patients were primarily nonserious upper respiratory tract infections, which occurred among 11% of Victoza®-treated antibody-positive patients; and among 7%, 7% and 5% of antibody-negative Victoza®-treated, placebo-treated and active-control-treated patients, respectively. Among Victoza®-treated antibody-negative patients, the most common category of adverse events was that of gastrointestinal events, which occurred in 43%, 18% and 19% of antibody-negative Victoza®-treated, placebo-treated and active-control-treated patients, respectively. Antibody formation was not associated with reduced efficacy of Victoza® when comparing mean HbA1c of all antibody-positive and all antibody-negative patients.

However, the 3 patients with the highest titers of anti-liraglutide antibodies had no reduction in HbA1c with Victoza® treatment. In clinical trials of Victoza®, events from a composite of adverse events potentially related to immunogenicity (e.g. urticaria, angioedema) occurred among 0.8% of Victoza®-treated patients and among 0.4% of comparator-treated patients. Urticaria accounted for approximately one-half of the events in this composite for Victoza®-treated patients. Patients who developed anti-liraglutide antibodies were not more likely to develop events from the immunogenicity events composite than were patients who did not develop anti-liraglutide antibodies.

Injection site reactions: Injection site reactions (e.g., injection site rash, erythema) were reported in approximately 2% of Victoza®-treated patients in the five clinical trials of at least 26 weeks duration. Less than 0.2% of Victoza®-treated patients discontinued due to injection site reactions.

Papillary thyroid carcinoma: In clinical trials of Victoza®, there were 6 reported cases of papillary thyroid carcinoma in patients treated with Victoza® and 1 case in a comparator-treated patient (1.9 vs. 0.6 cases per 1000 patient-years). Most of these papillary thyroid carcinomas were <1 cm in greatest diameter and were diagnosed in surgical pathology specimens after thyroidectomy prompted by findings on protocol-specified screening with serum calcitonin or thyroid ultrasound. Hypoglycemia: In the clinical trials of at least 26 weeks duration, hypoglycemia requiring the assistance of another person for treatment occurred in 7 Victoza®-treated patients (2.6 cases per 1000 patient-years) and in two comparator-treated patients. Six of these 7 patients treated with Victoza® were also taking a sulfonylurea. One other patient was taking Victoza® in combination with metformin but had another likely explanation for the hypoglycemia (this event occurred during hospitalization and after insulin infusion) (Table 4). Two additional cases of hypoglycemia requiring the assistance of another person for treatment have subsequently been reported in patients who were not taking a concomitant sulfonylurea. Both patients were receiving Victoza®, one as monotherapy and the other in combination with metformin. Both patients had another likely explanation for the hypoglycemia (one received insulin during a frequently-sampled intravenous glucose tolerance test, and the other had intracranial hemorrhage and uncertain food intake).

Table 4: Incidence (%) and Rate (episodes/patient year) of Hypoglycemia in the 52-Week Monotherapy Trial and in the 26-Week Combination Therapy Trials Victoza® Active Placebo Treatment Comparator Comparator ® Monotherapy Victoza Glimepiride None (N = 497) (N = 248) Patient not able to self−treat 0 0 — Patient able to self−treat 9.7 (0.24) 25.0 (1.66) — 1.2 (0.03) 2.4 (0.04) — Not classified Placebo + Glimepiride + Add-on to Victoza® + Metformin Metformin Metformin Metformin (N = 121) (N = 242) (N = 724) Patient not able to self−treat 0.1 (0.001) 0 0 Patient able to self−treat 3.6 (0.05) 22.3 (0.87) 2.5 (0.06) ® Placebo + Add-on to Glimepiride Victoza + Rosiglitazone + Glimepiride Glimepiride Glimepiride (N = 114) (N = 231) (N = 695) Patient not able to self−treat 0.1 (0.003) 0 0 Patient able to self−treat 7.5 (0.38) 4.3 (0.12) 2.6 (0.17) Not classified 0.9 (0.05) 0.9 (0.02) 0 Victoza® + Placebo + Add-on to None Metformin + Metformin + Metformin + Rosiglitazone Rosiglitazone Rosiglitazone (N = 175) (N = 355) Patient not able to self−treat 0 — 0 Patient able to self−treat 7.9 (0.49) — 4.6 (0.15) Not classified 0.6 (0.01) — 1.1 (0.03) Placebo + Victoza® + Add-on to Insulin glargine Metformin + Metformin + + Metformin + Metformin + Glimepiride Glimepiride Glimepiride Glimepiride (N = 114) (N = 232) (N = 230) Patient not able to self−treat 2.2 (0.06) 0 0 Patient able to self−treat 27.4 (1.16) 28.9 (1.29) 16.7 (0.95) Not classified 0 1.7 (0.04) 0 In a pooled analysis of clinical trials, the incidence rate (per 1,000 patient-years) for malignant neoplasms (based on investigator-reported events, medical history, pathology reports, and surgical reports from both blinded and open-label study periods) was 10.9 for Victoza®, 6.3 for placebo, and 7.2 for active comparator. After excluding papillary thyroid carcinoma events [see Adverse Reactions], no particular cancer cell type predominated. Seven malignant neoplasm events were reported beyond 1 year of exposure to study medication, six events among Victoza®treated patients (4 colon, 1 prostate and 1 nasopharyngeal), no events with placebo and one event with active comparator (colon). Causality has not been established. Laboratory Tests: In the five clinical trials of at least 26 weeks duration, mildly elevated serum bilirubin concentrations (elevations to no more than twice the upper limit of the reference range) occurred in 4.0% of Victoza®-treated patients, 2.1% of placebo-treated patients and 3.5% of active-comparatortreated patients. This finding was not accompanied by abnormalities in other liver tests. The significance of this isolated finding is unknown.

OVERDOSAGE: In a clinical trial, one patient with type 2 diabetes experienced a single overdose of Victoza® 17.4 mg subcutaneous (10 times the maximum recommended dose). Effects of the overdose included severe nausea and vomiting requiring hospitalization. No hypoglycemia was reported. The patient recovered without complications. In the event of overdosage, appropriate supportive treatment should be initiated according to the patient’s clinical signs and symptoms.

More detailed information is available upon request.

For information about Victoza® contact: Novo Nordisk Inc., 100 College Road West, Princeton, New Jersey 08540, 1−877-484-2869 Date of Issue: December 22, 2010 Version: 2 Manufactured by: Novo Nordisk A/S, DK-2880 Bagsvaerd, Denmark Victoza® is a registered trademark of Novo Nordisk A/S. Victoza® is covered by US Patent Nos. 6,268,343; 6,458,924; and 7,235,627 and other patents pending. Victoza® Pen is covered by US Patent Nos. 6,004,297; 6,235,004; 6,582,404 and other patents pending. © 2011 Novo Nordisk 140586-R2 2/2011

™

KAPVAY : Clonidine Hydrochloride Extended-Release Tablets for the Treatment of Attention-Deficit/Hyperactivity Disorder Todd Parker, PhD, and Jillian Gee, PhD, MedThink SciCom, Inc

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ttention-deficit/hyperactivity disorder (ADHD) is characterized by a persistent pattern of inattention, impulsivity, and hyperactivity that is more frequently displayed and severe than is typically observed in peers. This disorder causes impairment of social, work, and academic functioning (eg, poor academic performance and increased use of school-based resources)1,2 and increases healthcare utilization, with annual costs associated with ADHD in children and adolescents in the United States estimated at more than $42 billion.3 The worldwide prevalence of ADHD in children and adolescents is estimated to be 5.3%.4 In the United States, approximately 2.4 million children (8.7%) aged 8 to 15 years are believed to have ADHD.5,6 The standard of care for patients with uncomplicated ADHD is psychostimulant monotherapy.7-9 However, some patients (up to 35%) have an inadequate clinical response to stimulants due to intolerable adverse events or suboptimal symptom relief.8,10 Thus, there is an unmet need for effective, well-tolerated therapies for the treatment of ADHD. Clonidine is an alpha2-adrenergic agonist, and immediate-release (IR) clonidine has been used off-label for the treatment of patients with ADHD either as a monotherapy or as part of a multimodal regimen with psychostimulants.11-14 However, IR clonidine is associated with widely fluctuating plasma drug concentrations and requires frequent dosing.15 These rapid fluctuations in the plasma concentration of clonidine may be associated with peak-and-trough–related side effects (eg, sedation, dry mouth),16 which can limit the therapeutic usefulness of IR clonidine. Furthermore, because IR clonidine is not indicated for the treatment of ADHD, it does not have labeling to provide dosing, safety, or other instructions and precautions for its use for ADHD. KAPVAY™ (clonidine hydrochloride extended-release tablets; Shionogi Inc, Florham Park, NJ) was approved by the US Food and Drug Administration in September 2010 for the treatment of ADHD as monotherapy or as adjunctive therapy to stimulant medications.17 KAPVAY is an extended-release formulation of clonidine that has a different pharmacokinetic profile than IR clonidine.

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The KAPVAY clinical development program included three phase 3 trials consisting of 2 randomized, multicenter, double-blind, placebo-controlled trials and an open-label, 12-month safety trial.

Clinical Pharmacology The novel formulation of KAPVAY provides a distinctly different pharmacokinetic profile compared with IR clonidine. A direct comparison of the pharmacokinetic profiles of KAPVAY and a marketed IR clonidine formulation (Catapres®; Boehringer Ingelheim Pharmaceuticals, Inc, Ridgefield, CT) in healthy adult volunteers (N = 15) demonstrated that KAPVAY provided extended release of clonidine.18 In this single-dose crossover study, peak plasma concentration (Cmax) with KAPVAY was reduced by approximately 50% (235 pg/mL vs 443 pg/mL for IR clonidine), and the mean time to reach the Cmax (Tmax) was extended by ~5 hours compared with IR clonidine (mean peak absorption within 7 hours for KAPVAY vs 2 hours for IR clonidine).

Thus, KAPVAY minimizes the peak-and-trough plasma concentrations observed with IR clonidine. The half-life of KAPVAY was similar to that of IR clonidine, and no food effects were observed. This pharmacokinetic profile suggested that this extended-release formulation of clonidine might overcome some of the limitations of IR clonidine. Three randomized-controlled phase 3 trials were subsequently initiated to evaluate the efficacy and safety of KAPVAY as a monotherapy for children and adolescents with ADHD and as adjunctive therapy for patients with an inadequate response to a stimulant regimen.

Monotherapy with KAPVAY The efficacy and safety of KAPVAY as a fixed-dose monotherapy for the treatment of ADHD was evaluated in a phase 3, multicenter, 8-week, randomized, doubleblind, placebo-controlled trial (NCT00556959; Table).

Patients aged 6 to 17 years who were diagnosed with either hyperactive- or combined-subtype ADHD according to DSM-IV-TR criteria (N = 236) were randomized to receive monotherapy with KAPVAY 0.1 mg twice daily (0.2 mg/d), 0.2 mg twice daily (0.4 mg/d), or a

Table Phase 3 Clinical Trials Evaluating KAPVAY for the Treatment of Attention-Deficit/Hyperactivity Disorder

KAPVAY Fixed-Dose Monotherapy for ADHD15,18-21 Study design

Population

Groups

End points

Key results

Phase 3, randomized, 8-week, multicenter, double-blind escalation study

Children and adolescents (aged 6-17 years) with hyperactiveor combined inattentive/ hyperactive– subtype ADHD

Placebo (n = 76)

Primary • Reduction in ADHD-RS-IV total score with KAPVAY vs placebo

Efficacy at week 5 (KAPVAY vs placebo) • Significant improvement in ADHD-RS-IV scores (P <0.0001 for both groups) • Significant improvement in ADHD-RS-IV inattention and hyperactivity/impulsivity subscale scores (P <0.002 for both groups) • Significant improvement in CPRS, CGI, HADS, and PGA

KAPVAY • 0.2 mg/d (n = 74) • 0.4 mg/d (n = 78)

Secondary • ADHD-RS-IV subscales • CPRS • CGI • PGA • HADS • Safety

Safety • Most common TEAEs were mild-to-moderate somnolence and fatigue • No discernible significant cardiac concerns

KAPVAY Flexible-Dose Combination Therapy for ADHD15,20-22 Study design

Population

Groups

End points

Key results

Phase 3, randomized, 8-week, multicenter, double-blind, dose-escalation study

Children and adolescents (aged 6-17 years) with hyperactive- or combined inattentive/ hyperactive– subtype ADHD with inadequate control of symptoms with a stable stimulant regimen

Placebo + stimulants (n = 96)a

Primary • Reduction in ADHD-RS-IV total score with KAPVAY + stimulants vs placebo + stimulants

Efficacy at week 5 (KAPVAY + stimulants vs placebo + stimulants) • Significant improvement in ADHD-RS-IV scores (P <0.0091) • Significant improvement in ADHD-RS-IV subscale scores, CPRS, CGI, and PGA

KAPVAY + stimulants (n = 102)

Secondary • ADHD-RS-IV subscales • CPRS • CGI • PGA • HADS • Safety

Safety • Most common TEAEs were headache, somnolence, and fatigue • Parameters were not affected by psychostimulant class used • No discernible significant cardiac concerns

a One patient in this group for whom there were no postbaseline assessments was not included in the intention-to-treat population.

ADHD indicates attention-deficit/hyperactivity disorder; ADHD-RS-IV, ADHD Rating Scale-IV; CGI, Clinical Global Impression; CPRS, Conners’ Parent Rating Scale; HADS, Horacek Adrenergic Dysregulation Scale; PGA, Parent Global Assessment; TEAEs, treatment-emergent adverse events.

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placebo.19 Doses of KAPVAY were initiated at 0.1 mg/d during the first week and escalated by 0.1 mg/d each week until patients reached their assigned dose during the initial 3 weeks. The target dose was maintained for at least 2 weeks through week 5, and during the last 3 weeks (ie, between weeks 5 and 8), the dose was tapered by 0.1 mg/d/week to 0.1 mg/d by week 8. Patients who could not tolerate their assigned doses were discontinued from the study. The primary efficacy end point was mean change in ADHD Rating Scale-IV (ADHD-RS-IV) total score from baseline to week 5; the last observation carried forward method was used for patients who discontinued earlier. Safety data collected from the safety population (ie, patients who received at least 1 dose; n = 230) included adverse events, vital signs, laboratory values, and electrocardiograms (ECGs).18 Baseline demographic characteristics were balanced between treatment groups.18 The mean improvement in ADHD-RS-IV total score from baseline to week 5 (ie, primary end point) was significantly greater in the KAPVAY 0.2-mg/d (–15.6) and 0.4-mg/d (–16.5) groups than in the placebo group (–7.5; P <0.0001 for both active treatment groups).19 Moreover, a statistically significant improvement in ADHD-RS-IV total score was observed by week 1 in the KAPVAY 0.2-mg/d group and week 2 in the KAPVAY 0.4-mg/d group compared with the placebo group. A post hoc analysis determined that the effect sizes were 0.713 (95% confidence interval [CI], 0.38 to 1.04) and 0.766 (95% CI, 0.44 to 1.09) for the KAPVAY 0.2-mg/d and 0.4-mg/d groups, respectively. In addition to improvement in ADHD-RS-IV total score, significant improvements in the KAPVAY groups were observed for secondary end points, such as the ADHD-RS-IV hyperactivity- and inattentionsubscale scores, Conners’ Parent Rating Scale (CPRS), Clinical Global Impression of Improvement (CGI-I), Clinical Global Impression of Severity (CGI-S), and Parent Global Assessment (PGA).

The most common treatment-emergent adverse events (TEAEs) associated with KAPVAY were somnolence and fatigue, which were also the most common TEAEs that led to discontinuation.19 Fourteen of 230 patients (6%) experienced a severe TEAE. No serious adverse events were reported. There were no clinically meaningful changes in chemistry or laboratory tests, and mean decreases in blood pressure and pulse rate were not clinically significant. Mean systolic and diastolic blood pressure were increased in the placebo group (1.1 and 0.3 mm Hg, respectively), unchanged or increased in the KAPVAY 0.2-mg/d group (0 and 0.6 mm Hg), and decreased in the KAPVAY 0.4-mg/d group (–5.8 and –4.6 mm Hg).20 Heart rate was increased in

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the placebo group (0.9 bpm), unchanged in the KAPVAY 0.2-mg/d group, and decreased in the KAPVAY 0.4-mg/d group (–4.3 bpm). Furthermore, there were no discontinuations due to bradycardia, and no patients had a QTc ≥500 msec.18-20 This study demonstrated that KAPVAY monotherapy significantly reduced symptoms of ADHD and was generally well tolerated.

Combination Therapy with KAPVAY In addition to the fixed-dose monotherapy trial, the efficacy and safety of KAPVAY as an adjunct to stimulant therapy was examined in a phase 3, 8-week, multicenter, randomized, double-blind, placebo-controlled trial (NCT00641329; Table). Patients aged 6-17 years with ADHD (N = 198) who had an inadequate response to stimulants after at least 4 weeks on a stable stimulant regimen were randomized to receive either KAPVAY (0.1-0.4 mg/d; doses >0.1 mg/d administered as 2 doses) added on to baseline stimulant medication or placebo plus baseline stimulant treatment.15,21,22 Both KAPVAY and stimulant doses were allowed to be adjusted to achieve an optimal efficacy and safety profile.22 As in the monotherapy trial, the primary efficacy end point was mean change in ADHD-RS-IV total score from baseline to week 5. Secondary end points included ADHD-RS-IV subscale scores, PGA, CGI-I, CGI-S, CPRS, and safety. In addition, a post hoc analysis of effect size was performed.

A total of 198 patients were randomized to receive either KAPVAY plus stimulants (n = 102) or placebo plus stimulants (n = 96).22 Demographics were similar between groups, and there were no differences in the use of concomitant medications (ie, stimulants or other approved non-ADHD medications). Statistically significant improvements in ADHD-RS-IV total score for the KAPVAY plus stimulants group were observed starting at week 2 and continuing through week 7. At week 5, the mean improvement in ADHD-RS-IV total score (ie, primary end point) was significantly greater in the KAPVAY plus stimulants group (–15.7) than in the placebo plus stimulants group (–11.5; P = 0.009).15 Significant improvements in ADHD subscale scores (ie, inattention and hyperactivity), CPRS, CGI-I, CGI-S, and PGA were also observed.22 Furthermore, when effect size with respect to ADHD-RS-IV total score was examined post hoc, the overall effect size for KAPVAY plus stimulants versus placebo plus stimulants was 0.34. These data demonstrate that KAPVAY provides an incremental benefit as an add-on therapy for those patients who have an inadequate response to stimulants alone.

The rates of TEAEs were similar between groups

(45% for KAPVAY plus stimulants and 41% for placebo plus stimulants).22 Common TEAEs occurring in ≥5% of patients in the KAPVAY plus stimulants group were headache, somnolence, fatigue, upper abdominal pain, nasal congestion, cough, irritability, pharyngolaryngeal pain, insomnia, increased body temperature, and dizziness. A total of 5 patients discontinued because of a TEAE (4 in the placebo plus stimulants group and 1 in the KAPVAY plus stimulants group).

Changes in ECGs were not considered clinically significant. Mean ECG changes were generally mild, with no significant changes to suggest a drug-related effect, and there were no incidents of symptomatic bradycardia or differences between groups in numbers of patients with an increase in QTc interval. These findings show that the addition of KAPVAY for 8 weeks to a stimulant regimen that did not achieve an adequate response was generally well tolerated and resulted in statistically significant ADHD symptom improvements.

12-Month Safety Study As part of the KAPVAY clinical development program, a prospectively designed open-label, 12-month extension study was conducted to examine the safety of a flexible dosing regimen of twice-daily KAPVAY (0.10.4 mg/d) when administered chronically under regular clinical conditions either as monotherapy or in combination with other ADHD medication(s). In this trial, patients who completed the monotherapy or combination-therapy trial or who discontinued for a reason other than safety were eligible to participate (NCT00723190).15 Patients (N = 303) received flexible dosing of KAPVAY (0.1-0.4 mg/d; doses >0.1 mg/d administered twice daily) as monotherapy or in combination with other ADHD medication(s), and doses of KAPVAY and other medications could have been titrated to optimize safety while maximizing efficacy.15,20 In addition to adverse events, data on vital signs and ECGs were obtained.20 At the time of a planned interim analysis (June 2, 2009), 14 of 215 patients (7%) had TEAEs leading to discontinuation.15 Somnolence (27%) and fatigue (11%) were among the most common TEAEs reported; the majority (96%) of TEAEs were mild to moderate. An in-depth analysis of cardiac data at the conclusion of the study indicated that, although 1 patient discontinued because of dizziness, there were no discontinuations due to bradycardia, and few patients had a prolonged QTc interval (≥450 msec).20 This study demonstrated that administration of KAPVAY (up to 0.4 mg/d) with or without other ADHD medications was well tolerated for up to 1 year with no significant cardiac TEAEs observed.

Conclusions In much the same way that the extended-release formulations of stimulants evolved, alpha2-adrenergic agonist formulations have evolved to address the limitations of currently marketed IR formulations. KAPVAY is a novel, extended-release oral formulation of clonidine that, when administered as directed, results in reduced peak plasma concentrations and extends the time necessary to reach the maximum plasma concentration compared with marketed IR clonidine. Because of differences in its pharmacokinetic profile, KAPVAY cannot be used interchangeably with the IR formulations of clonidine (ie, patients should be tapered off of IR clonidine before receiving KAPVAY).

Results from three phase 3 trials demonstrated that twice-daily treatment with KAPVAY (up to 0.4 mg/d) provides significant improvements in the core symptoms of ADHD for patients aged 6 to 17 years with ADHD when administered as monotherapy or as adjunctive therapy to those patients with an inadequate response to a stimulant regimen. The efficacy observed with KAPVAY was both statistically significant and clinically meaningful. Furthermore, the effect size of KAPVAY when administered as a monotherapy (ie, 0.713 and 0.766 for the 0.2-mg/d and 0.4-mg/d groups, respectively) is comparable to that observed with other nonstimulants for ADHD (eg, atomoxetine, guanfacine extended release).19 In addition, KAPVAY (up to 0.4 mg/d) was generally safe and well tolerated for up to 12 months of chronic use. As such, KAPVAY is an important new therapeutic option for the treatment of children and adolescents with ADHD alone or as part of a multimodal regimen in patients experiencing an inadequate response to stimulants. ■ Disclosure Statement Medical writing and editorial services were provided by MedThink SciCom, Inc, Raleigh, NC, with funding from Shionogi Inc, Florham Park, NJ.

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in children: a review. Clin Ther. 2008;30(5):942-957.

8. Pliszka S, and the AACAP Work Group on Quality Issues. Practice parameter for the assessment and treatment of children and adolescents with attentiondeficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry. 2007;46(7):894-921.

9. Clinical practice guideline: treatment of the school-aged child with attentiondeficit/hyperactivity disorder. Pediatrics. 2001;108(4):1033-1044.

10. Barbaresi WJ, Katusic SK, Colligan RC, et al. Long-term stimulant medication treatment of attention-deficit/hyperactivity disorder: results from a population-based study. J Dev Behav Pediatr. 2006;27(1):1-10.

11. Hazell PL, Stuart JE. A randomized controlled trial of clonidine added to psychostimulant medication for hyperactive and aggressive children. J Am Acad Child Adolesc Psychiatry. 2003;42(8):886-894.

12. Hunt RD, Minderaa RB, Cohen DJ. Clonidine benefits children with attention deficit disorder and hyperactivity: report of a double-blind placebo-crossover therapeutic trial. J Am Acad Child Psychiatry. 1985;24(5):617-629.

13. Schvehla TJ, Mandoki MW, Sumner GS. Clonidine therapy for comorbid attention deficit hyperactivity disorder and conduct disorder: preliminary findings in a children’s inpatient unit. South Med J. 1994;87(7):692-695.

14. Efron D, Hiscock H, Sewell JR, et al. Prescribing of psychotropic medications for children by Australian pediatricians and child psychiatrists. Pediatrics. 2003;111(2): 372-375.

15. Kollins S, Findling RL, Wigal SB, et al. Modified-release clonidine for the treatment of children/adolescents with ADHD. Poster presented at 56th Annual Meeting of the American Academy of Child and Adolescent Psychiatry. October 27November 1, 2009; Honolulu, HI.

16. Keränen A, Nykänen S, Taskinen J. Pharmacokinetics and side-effects of clonidine. Eur J Clin Pharmacol. 1978;13(2):97-101.

17. KAPVAY [package insert]. Florham Park, NJ: Shionogi Inc; 2010.

18. Jain R, Kollins S, Bailey C, et al. Developing a sustained release formulation of clonidine for the treatment of children and adolescents with attention deficit hyperactivity disorder (ADHD). Poster presented at 47th Annual Meeting of the American College of Neuropsychopharmacology; December 7-11, 2008; Scottsdale, AZ. 19. Jain R, Segal S, Kollins SH, Khayrallah M. Clonidine extended-release tablets for pediatric patients with attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry. 2011;50(2):171-179.

20. Jain R, Findling R, Kollins SH, Khayrallah M. Cardiac data from the use of clonidine hydrochloride extended-release tablets in children and adolescents with attention-deficit/hyperactivity disorder. Poster presented at 57th Annual Meeting of the American Academy of Child and Adolescent Psychiatry. October 26-31, 2010; New York, NY. 21. Findling R, Jain R, Kollins SH, Khayrallah M. Safety and efficacy of clonidine hydrochloride extended-release tablets by weight-adjusted dose in children and adolescents with attention-deficit/hyperactivity disorder. Poster presented at 57th Annual Meeting of the American Academy of Child and Adolescent Psychiatry.

October 26-31, 2010; New York, NY. 22. Forman N, Yoon M, Wang C, Cavanaugh P. An extended-release formulation of clonidine for the treatment of ADHD in children and adolescents with suboptimal response to stimulants. Poster presented at 22nd Annual International Conference on ADHD. November 11-13, 2010; Atlanta, GA.

STAKEHOLDER PERSPECTIVE

Alpha2-Adrenergic Agonists in Combination with Psychostimulants a Potential New Approach to ADHD Treatment

By Floyd R. Sallee, MD, PhD Professor of Psychiatry, University of Cincinnati, OH

A

ttention-deficit/hyperactivity disorder (ADHD) is a common psychiatric disorder that is recognized worldwide.1 The prevalence of ADHD in children has been estimated to be as high as 12%, making it one of the most common psychiatric disorders, afflicting 4.5 million children in the United States alone.2 The consequences of ADHD can be devastating over the lifespan of the individual, impacting academic- and work-related performance, as well as family and peer relations, and is also associated with high healthcare utilization.3-5 The presentation of ADHD can involve aspects of temperament (ie, impulsivity), motivation (ie, reward), behavior (ie, hyperactivity), and cognition (ie, inattention, working memory).6-8 The serious and impairing nature of ADHD coupled with its range of multidimensional symptoms, presents a therapeutic challenge for pharmacologic management.

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May/June 2011

The psychostimulant drug class has long been considered first-line pharmacotherapy for ADHD,9 offering substantial efficacy for most patients; however, we know that at least 25% to 35% of those afflicted with ADHD will not respond adequately to psychostimulant therapy.10,11 Hence, the need for an expansion of the kinds of treatments, both pharmaceutical and behavioral, that address the various symptom domains inherent in the disorder.

Lack of benefit from psychostimulants can encompass inadequate symptom relief, intolerable side effects, or nonadherence.4,12 This coupled with the fact that psychostimulants are contraindicated in many patients, including those with a history of drug abuse or symptomatic cardiovascular disease, makes the case for nonpsychostimulant options. Lingering concerns regarding the abuse, misuse, and diversion of the psychostimulant drug

STAKEHOLDER PERSPECTIVE

class have also contributed to the search for therapeutic alternatives such as the alpha2-adrenergic agonists.13,14 Prior to the systematic evaluation of alpha2-adrenergic agonists as possible treatments for ADHD, only atomoxetine was available as a nonpsychostimulant alternative for pharmacologic management. Although atomoxetine was a definite advance, offering long-duration symptom coverage and documented improvement in health-related quality of life, its drawbacks include significant lag time for therapeutic onset measured in weeks, and failure to meet or beat the efficacy associated with osmotically released methylphenidate or extended-release mixed amphetamine salts in direct comparator trials.15 Still, the search for nonstimulant ADHD treatment continues despite the lack of success demonstrated by some therapeutic drug class candidates, such as the novel neuronal nicotinic receptor partial agonist ABT-089.16 It is all the more remarkable that alpha2-adrenergic agonists, which had been used off-label to treat ADHD for more than two decades, should now be reformulated to take advantage of modern drug delivery technology, and thereby overcome limitations of rapid absorption and clearance as well as tolerability problems associated with their pharmacometric properties.17 New controlled release alpha2-adrenergic agonists have more gradual absorption profiles over older immediaterelease formulations, which has served to improve tolerability and safety for children and adolescents.18 At the same time, the extended-release aspect of these newer agents has overcome the need for multiple daily dosing when treating ADHD with immediate-release clonidine19 or guanfacine.

Recent large-scale randomized controlled trials have found clonidine extended-release, as well as guanfacine extended-release to be safe, tolerable, and effective for the treatment of ADHD in children and adolescents.17 Combination psychostimulant add-on studies have also been completed with these new reformulations (ie, guanfacine extended-release and clonidine extendedrelease) to demonstrate that the addition of alpha2adrenergic agonist to psychostimulant therapy can significantly enhance efficacy, without compromising safety.

Alpha2-adrenergic agonists offer the possibility of a new approach to ADHD treatment inherent in combination therapy with psychostimulants, to either reduce the side effect burden of the latter (ie, heart rate and blood pressure elevations) or to potentially work in an additive fashion to enhance therapeutic effectiveness.17 This combination therapy approach comes at a time

when the field is recognizing the importance of maximal ADHD symptom reduction, if not remission of symptoms, as a goal in ADHD treatment.20,21 What constitutes remission is controversial, but the preponderance of evidence would suggest that decreasing symptom burden is associated with improved functioning.20 Arguably, combination therapy of alpha2-adrenergic agonist added to a psychostimulant could be an effective strategy for many partial responders and may achieve the optimal functioning implicit in the concept of “remission” for ADHD patients generally.20 ■

References 1. Faraone SV, Sergeant J, Gillberg C, Biederman J. The worldwide prevalence of ADHD: is it an American condition? World Psychiatry. 2003;2:104-113.

2. Bloom B, Cohen RA, Freeman G. Summary health statistics for U.S. children: National Health Interview Survey, 2008. Vital Health Stat 10. 2009;244:1-81.

3. Barbaresi WJ, Katusic SK, Colligan RC, et al. Long-term school outcomes for children with attention-deficit/hyperactivity disorder: a population-based perspective. J Dev Behav Pediatr. 2007;28:265-273.

4. Biederman J, Faraone SV. Attention-deficit hyperactivity disorder. Lancet.

2005;366:237-248.

5. Cuffe SP, Moore CG, McKeown R. ADHD and health services utilization in the national health interview survey. J Atten Disord. 2009;12:330-340.

6. Castellanos FX, Tannock R. Neuroscience of attention-deficit/hyperactivity disorder. Nat Rev Neurosci. 2002;3:617-628.

7. Nigg JT. Neuropsychologic theory and findings in attention-deficit/hyperactivity disorder: the state of the field and salient challenges for the coming decade. Biol Psychiatry. 2005;57:1424-1435.

8. Sonuga-Barke EJ. Psychological heterogeneity in AD/HD—a dual pathway model of behaviour and cognition. Behav Brain Res. 2002;10:29-36.

9. Pliszka SR, Crismon ML, Hughes CW, et al., and the Texas Consensus Conference Panel on Pharmacotherapy of Childhood Attention-Deficit/ Hyperactivity Disorder.

The Texas Children’s Medication Algorithm Project: revision of the algorithm for pharmacotherapy of attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry. 2006;45:642-657.

10. Elia J, Ambrosini PJ, Rapoport JL. Treatment of attention-deficit-hyperactivity disorder. N Engl J Med. 1999;340:780-788.

11. Wood JG, Crager JL, Delap CM, Heiskell KD. Beyond methylphenidate: nonstimulant medications for youth with ADHD. J Atten Disord. 2007;11:341-350.

12. Wilens TE, Spencer TJ. The stimulants revisited. Child Adolesc Psychiatr Clin N Am. 2000;9:573-603.

13. Faraone SV, Wilens TE. Effect of stimulant medications for attentiondeficit/hyperactivity disorder on later substance use and the potential for stimulant misuse, abuse, and diversion. J Clin Psychiatry. 2007;68:15-22.

14. Wilens TE. A sobering fact: ADHD leads to substance abuse. J Am Acad Child Adolesc Psychiatry. 2011;50:6-8.

15. Garnock-Jones KP, Keating GM. Atomoxetine: a review of its use in attentiondeficit hyperactivity disorder in children and adolescents. Paediatr Drugs. 2009;11: 203-226.

16. Wilens TE, Gault LM, Childress A, et al. Safety and efficacy of ABT-089 in pediatric attention-deficit/hyperactivity disorder: results from two randomized placebo-controlled clinical trials. J Am Acad Child Adolesc Psychiatry. 2011; 50:73-84.

17. Sallee FR. The role of alpha2-adrenergic agonists in attention-deficit /hyperactivity disorder. Postgrad Med. 2010;122:78-87.

18. Daviss WB, Patel NC, Robb AS, et al. Clonidine for attention-deficit/hyperactivity disorder: II. ECG changes and adverse events analysis. J Am Acad Child Adolesc Psychiatry. 2008;47:189-198.

19. Palumbo DR, Sallee FR, Pelham WE Jr, et al., the CAT Study team. Clonidine for attention-deficit/hyperactivity disorder: I. Efficacy and tolerability outcomes.

J Am Acad Child Adolesc Psychiatry. 2008;47:180-188.

20. Ramos-Quiroga JA, Casas M. Achieving remission as a routine goal of pharmacotherapy in attention-deficit hyperactivity disorder. CNS Drugs. 2011;25:17-36.

21. Steele M, Jensen PS, Quinn DM. Remission versus response as the goal of therapy in ADHD: a new standard for the field? Clin Ther. 2006;28:1892-1908.

May/June 2011

www.AHDBonline.com

37

moving millimeters

NEW EDARBI: Head-to-head efficacy trials versus the highest marketed doses of DIOVAN® (320 mg) and BENICAR® (40 mg) EDARBI 80 mg was statistically superior to DIOVAN® 320 mg and BENICAR® 40 mg in reducing 24-hr mean ambulatory and clinic SBP1 REDUCTIONS IN 24-HR MEAN AMBULATORY SBP AT WEEK 61,2 ▼ Similar results were observed across two other comparator studies: Mean ambulatory baseline: Study 2 vs BENICAR 40 mg and Study 3 vs DIOVAN 320 mg Study 1=144.9 mm Hg ▼ Clinic SBP differences between EDARBI and active comparators STUDY 1 were consistent with mean ambulatory results Study 1 Design: A 6-week, randomized, double-blind, placebo-controlled, forced-titration study in patients (N = 1,291) with clinic SBP ≥150 mm Hg and ≤180 mm Hg and 24-hr mean SBP ≥130 mm Hg and ≤170 mm Hg. The primary endpoint was change in 24-hr mean ambulatory SBP. Placebo lowered 24-hr mean ambulatory SBP by 0.3 mm Hg. Data shown are placebo corrected.

IMPORTANT SAFETY INFORMATION WARNING: AVOID USE IN PREGNANCY

When pregnancy is detected, discontinue EDARBI as soon as possible. Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus.

DIOVAN 320 mg

-10.0 mm Hg BENICAR 40 mg

-11.7 mm Hg EDARBI 80 mg

-14.3 mm Hg P<0.001 vs DIOVAN 320 mg P=0.009 vs BENICAR 40 mg References: 1. EDARBI Prescribing Information. 2. White WB, Weber MA, Sica D, et al. Effects of the angiotensin receptor blocker azilsartan medoxomil versus olmesartan and valsartan on ambulatory and clinic blood pressure in patients with stages 1 and 2 hypertension. Hypertension.

2011;57:413-420.

▼ Avoid fetal or neonatal exposure. ▼ Correct volume or salt depletion prior to administration of EDARBI, or start treatment at 40 mg. ▼ Monitor for worsening renal function in patients with renal impairment. ▼ In patients with an activated renin-angiotensin system, as by volume or salt depletion, renin-angiotensin-aldosterone system (RAAS) blockers such as azilsartan medoxomil can cause excessive hypotension. In patients whose renal function may depend on the activity of the renin-angiotensin system, e.g., with renal artery stenosis, treatment with RAAS blockers has been associated with oliguria or progressive azotemia and rarely with acute renal failure and death. ▼ Monitor renal function periodically in patients receiving EDARBI and NSAIDs who are also elderly, volume-depleted, or who have compromised renal function. ▼ The most common adverse reaction in adults was diarrhea (2%).

For further information, please see adjacent Brief Summary of Prescribing Information.

INDICATION EDARBI is an angiotensin II receptor blocker (ARB) indicated for the treatment of hypertension, either alone or in combination with other antihypertensive agents.

EDARBI is a trademark of Takeda Pharmaceutical Company Limited registered with the U.S. Patent and Trademark Office and used under license by Takeda Pharmaceuticals America, Inc.

Trademarks are the property of their respective owners. ©2011 Takeda Pharmaceuticals North America, Inc. All rights reserved. LXA-00331 04/11

BRIEF SUMMARY OF FULL PRESCRIBING INFORMATION for Edarbi (azilsartan medoxomil) tablets WARNING: AVOID USE IN PREGNANCY When pregnancy is detected, discontinue Edarbi as soon as possible. Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus.

INDICATIONS AND USAGE Edarbi is an angiotensin II receptor blocker (ARB) indicated for the treatment of hypertension. It may be used alone or in combination with other antihypertensive agents.

CONTRAINDICATIONS None WARNINGS AND PRECAUTIONS Fetal/Neonatal Morbidity and Mortality Drugs that act directly on the renin-angiotensin system can cause fetal and neonatal morbidity and death when administered to pregnant women during the second and third trimester. When pregnancy is detected, Edarbi should be discontinued as soon as possible.

The use of drugs that act directly on the renin-angiotensin system during the second and third trimesters of pregnancy has been associated with fetal and neonatal injury, including hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure, and death. Oligohydramnios has also been reported, presumably resulting from decreased fetal renal function; oligohydramnios in this setting has been associated with fetal limb contractures, craniofacial deformation, and hypoplastic lung development.

Prematurity, intrauterine growth retardation, and patent ductus arteriosus have also been reported, although it is not clear whether these occurrences were due to exposure to the drug.

These adverse effects do not appear to have resulted from intrauterine drug exposure that has been limited to the first trimester. Mothers whose embryos and fetuses are exposed to an angiotensin II receptor antagonist only during the first trimester should be so informed. Nonetheless, when patients become pregnant, physicians should have the patient discontinue the use of Edarbi as soon as possible.

Rarely (probably less often than once in every thousand pregnancies), no alternative to a drug acting on the renin-angiotensin system is available. In these rare cases, the mother should be apprised of the potential hazards to the fetus and serial ultrasound examinations should be performed to assess the intra-amniotic environment.

If oligohydramnios is observed, Edarbi should be discontinued unless it is considered life-saving for the mother. Contraction stress testing, a nonstress test or biophysical profiling may be appropriate, depending upon the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury.

Infants with histories of in utero exposure to an angiotensin II receptor antagonist should be closely observed for hypotension, oliguria, and hyperkalemia. If oliguria occurs, attention should be directed toward support of blood pressure and renal perfusion. Exchange transfusion or dialysis may be required as a means of reversing hypotension and/or substituting for impaired renal function.

Hypotension in Volume- or Salt-Depleted Patients In patients with an activated renin-angiotensin system, such as volume- and/or saltdepleted patients (eg, those being treated with high doses of diuretics), symptomatic hypotension may occur after initiation of treatment with Edarbi. Correct volume or salt depletion prior to administration of Edarbi, or start treatment at 40 mg. If hypotension does occur, the patient should be placed in the supine position and, if necessary, given an intravenous infusion of normal saline. A transient hypotensive response is not a contraindication to further treatment, which usually can be continued without difficulty once the blood pressure has stabilized.

Impaired Renal Function As a consequence of inhibiting the renin-angiotensin system, changes in renal function may be anticipated in susceptible individuals treated with Edarbi. In patients whose renal function may depend on the activity of the renin-angiotensin system (e.g., patients with severe congestive heart failure, renal artery stenosis, or volume depletion), treatment with angiotensin-converting enzyme inhibitors and angiotensin receptor blockers has been associated with oliguria or progressive azotemia and rarely with acute renal failure and death. Similar results may be anticipated in patients treated with Edarbi.

In studies of ACE inhibitors in patients with unilateral or bilateral renal artery stenosis, increases in serum creatinine or blood urea nitrogen have been reported. There has been no long-term use of Edarbi in patients with unilateral or bilateral renal artery stenosis, but similar results may be expected.

ADVERSE REACTIONS Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

A total of 4814 patients were evaluated for safety when treated with Edarbi at doses of 20, 40 or 80 mg in clinical trials. This includes 1704 patients treated for at least 6 months; of these, 588 were treated for at least 1 year.

Treatment with Edarbi was well-tolerated with an overall incidence of adverse reactions similar to placebo. The rate of withdrawals due to adverse events in placebo-controlled monotherapy and combination therapy trials was 2.4% (19/801) for placebo, 2.2% (24/1072) for Edarbi 40 mg, and 2.7% (29/1074) for Edarbi 80 mg. The most common adverse event leading to discontinuation, hypotension/ orthostatic hypotension, was reported by 0.4% (8/2146) patients randomized to Edarbi 40 mg or 80 mg compared to 0% (0/801) patients randomized to placebo.

Generally, adverse reactions were mild, not dose related and similar regardless of age, gender and race.

In placebo controlled monotherapy trials, diarrhea was reported up to 2% in patients treated with Edarbi 80 mg daily compared with 0.5% of patients on placebo.

Other adverse reactions with a plausible relationship to treatment that have been reported with an incidence of â&#x2030;Ľ0.3% and greater than placebo in more than 3300 patients treated with Edarbi in controlled trials are listed below: Gastrointestinal Disorders: nausea General Disorders and Administration Site Conditions: asthenia, fatigue Musculoskeletal and Connective Tissue Disorders: muscle spasm Nervous System Disorders: dizziness, dizziness postural Respiratory, Thoracic and Mediastinal Disorders: cough Clinical Laboratory Findings In controlled clinical trials, clinically relevant changes in standard laboratory parameters were uncommon with administration of Edarbi.

Serum creatinine: Small reversible increases in serum creatinine are seen in patients receiving 80 mg of Edarbi. The increase may be larger when coadministered with chlorthalidone or hydrochlorothiazide.

In addition, patients taking Edarbi who had moderate to severe renal impairment at baseline or who were >75 years of age were more likely to report serum creatinine increases.

Hemoglobin/Hematocrit: Low hemoglobin, hematocrit, and RBC counts were observed in 0.2%, 0.4%, and 0.3% of Edarbi-treated subjects, respectively. None of these abnormalities were reported in the placebo group. Low and high markedly abnormal platelet and WBC counts were observed in <0.1% of subjects.

DRUG INTERACTIONS No clinically significant drug interactions have been observed in studies of azilsartan medoxomil or azilsartan given with amlodipine, antacids, chlorthalidone, digoxin, fluconazole, glyburide, ketoconazole, metformin, pioglitazone, and warfarin. Therefore, Edarbi may be used concomitantly with these medications.

Non-Steroidal Anti-Inflammatory Agents including Selective Cyclooxygenase-2 Inhibitors (COX-2 Inhibitors) In patients who are elderly, volume-depleted (including those on diuretic therapy), or who have compromised renal function, co-administration of NSAIDs, including selective COX-2 inhibitors, with angiotensin II receptor antagonists, including azilsartan, may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically in patients receiving azilsartan and NSAID therapy.

The antihypertensive effect of angiotensin II receptor antagonists, including azilsartan, may be attenuated by NSAIDs, including selective COX-2 inhibitors.

USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C (first trimester) and D (second and third trimesters). There is no clinical experience with the use of Edarbi in pregnant women.

Nursing Mothers It is not known if azilsartan is excreted in human milk, but azilsartan is excreted at low concentrations in the milk of lactating rats. Because of the potential for adverse effects on the nursing infant, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use Safety and effectiveness in pediatric patients under 18 years of age have not been established.

Geriatric Use No dose adjustment with Edarbi is necessary in elderly patients. Of the total patients in clinical studies with Edarbi, 26% were elderly (65 years of age and older); 5% were 75 years of age and older. Abnormally high serum creatinine values were more likely to be reported for patients age 75 or older. No other differences in safety or effectiveness were observed between elderly patients and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Renal Impairment Dose adjustment is not required in patients with mild-to-severe renal impairment or end-stage renal disease. Patients with moderate to severe renal impairment are more likely to report abnormally high serum creatinine values.

Hepatic Impairment No dose adjustment is necessary for subjects with mild or moderate hepatic impairment. Edarbi has not been studied in patients with severe hepatic impairment.

OVERDOSAGE Limited data are available related to overdosage in humans. During controlled clinical trials in healthy subjects, once daily doses up to 320 mg of Edarbi were administered for 7 days and were well tolerated. In the event of an overdose, supportive therapy should be instituted as dictated by the patientâ&#x20AC;&#x2122;s clinical status.

Azilsartan is not dialyzable.

CLINICAL PHARMACOLOGY Mechanism of Action Angiotensin II is formed from angiotensin I in a reaction catalyzed by angiotensinconverting enzymes (ACE, kinase II). Angiotensin II is the principal pressor agent of the renin-angiotensin system, with effects that include vasoconstriction, stimulation of synthesis and release of aldosterone, cardiac stimulation, and renal reabsorption of sodium. Azilsartan blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II by selectively blocking the binding of angiotensin II to the AT1 receptor in many tissues, such as vascular smooth muscle and the adrenal gland. Its action is, therefore, independent of the pathway for angiotensin II synthesis.

An AT2 receptor is also found in many tissues, but this receptor is not known to be associated with cardiovascular homeostasis. Azilsartan has more than a 10,000-fold greater affinity for the AT1 receptor than for the AT2 receptor.

Blockade of the renin-angiotensin system with ACE inhibitors, which inhibit the biosynthesis of angiotensin II from angiotensin I, is widely used in the treatment of hypertension. ACE inhibitors also inhibit the degradation of bradykinin, a reaction catalyzed by ACE. Because azilsartan does not inhibit ACE (kinase II), it should not affect bradykinin levels. Whether this difference has clinical relevance is not yet known. Azilsartan does not bind to or block other receptors or ion channels known to be important in cardiovascular regulation.

Blockade of the angiotensin II receptor inhibits the negative regulatory feedback of angiotensin II on renin secretion, but the resulting increased plasma renin activity and angiotensin II circulating levels do not overcome the effect of azilsartan on blood pressure.

Pharmacodynamics Azilsartan inhibits the pressor effects of an angiotensin II infusion in a dose-related manner. An azilsartan single dose equivalent to 32 mg azilsartan medoxomil inhibited the maximal pressor effect by approximately 90% at peak, and approximately 60% at 24 hours. Plasma angiotensin I and II concentrations and plasma renin activity increased while plasma aldosterone concentrations decreased after single and repeated administration of Edarbi to healthy subjects; no clinically significant effects on serum potassium or sodium were observed.

Effect on Cardiac Repolarization: A thorough QT/QTc study was conducted to assess the potential of azilsartan to prolong the QT/QTc interval in healthy subjects. There was no evidence of QT/QTc prolongation at a dose of 320 mg of Edarbi.

Pharmacokinetics Absorption: Azilsartan medoxomil is hydrolyzed to azilsartan, the active metabolite, in the gastrointestinal tract during absorption. Azilsartan medoxomil is not detected in plasma after oral administration. Dose proportionality in exposure was established for azilsartan in the azilsartan medoxomil dose range of 20 mg to 320 mg after single or multiple dosing.

The estimated absolute bioavailability of azilsartan following administration of azilsartan medoxomil is approximately 60%. After oral administration of azilsartan medoxomil, peak plasma concentrations (Cmax) of azilsartan are reached within 1.5 to 3 hours. Food does not affect the bioavailability of azilsartan.

Distribution: The volume of distribution of azilsartan is approximately 16L. Azilsartan is highly bound to human plasma proteins (>99%), mainly serum albumin. Protein binding is constant at azilsartan plasma concentrations well above the range achieved with recommended doses.

In rats, minimal azilsartan-associated radioactivity crossed the blood-brain barrier. Azilsartan passed across the placental barrier in pregnant rats and was distributed to the fetus.

Metabolism and Elimination: Azilsartan is metabolized to two primary metabolites. The major metabolite in plasma is formed by O-dealkylation, referred to as metabolite M-II, and the minor metabolite is formed by decarboxylation, referred to as metabolite M-I. Systemic exposures to the major and minor metabolites in humans were approximately 50% and less than 1% of azilsartan, respectively. M-I and M-II do not contribute to the pharmacologic activity of Edarbi. The major enzyme responsible for azilsartan metabolism is CYP2C9.

Following an oral dose of 14 C-labeled azilsartan medoxomil, approximately 55% of radioactivity was recovered in feces and approximately 42% in urine, with 15% of the dose excreted in urine as azilsartan. The elimination half-life of azilsartan is approximately 11 hours and renal clearance is approximately 2.3 mL/min. Steadystate levels of azilsartan are achieved within 5 days and no accumulation in plasma occurs with repeated once-daily dosing.

Special Populations The effect of demographic and functional factors on the pharmacokinetics of azilsartan was studied in single and multiple dose studies. Pharmacokinetic measures indicating the magnitude of the effect on azilsartan are presented in Figure 1 as change relative to reference (test/reference). Effects are modest and do not call for dosage adjustment.

Figure 1 Impact of intrinsic factors on the pharmacokinetics of azilsartan Population Description

PK

Fold Change and 90% CI

Recommendation

AGE >65y/18-45y

Cmax AUC

No dose adjustment

Cmax AUC

No dose adjustment

Cmax AUC

No dose adjustment

GENDER Females/Males RACE Whites/Blacks RENAL IMPAIRMENT Mild/Normal

Cmax AUC

No dose adjustment

Moderate/Normal

Cmax AUC

No dose adjustment

Severe/Normal

Cmax AUC

No dose adjustment

ESRD/Normal

Cmax AUC

No dose adjustment

Mild/Normal

Cmax AUC

No dose adjustment

Moderate/Normal

Cmax AUC

HEPATIC IMPAIRMENT

No dose adjustment

Severe/Normal

NO EXPERIENCE NO EXPERIENCE

PEDIATRIC

0.5

1.0

1.5

2.0

Change relative to reference

2.5

3.0

NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis: Azilsartan medoxomil was not carcinogenic when assessed in 26-week transgenic (Tg.rasH2) mouse and 2-year rat studies. The highest doses tested (450 mg azilsartan medoxomil/kg/day in the mouse and 600 mg azilsartan medoxomil/kg/day in the rat) produced exposures to azilsartan that are 12 (mice) and 27 (rats) times the average exposure to azilsartan in humans given the maximum recommended human dose (MRHD, 80 mg azilsartan medoxomil/day). M-II was not carcinogenic when assessed in 26-week Tg.rasH2 mouse and 2-year rat studies. The highest doses tested (approximately 8000 mg M-II/kg/day (males) and 11,000 mg M-II/kg/day (females) in the mouse and 1000 mg M-II/kg/day (males) and up to 3000 mg M-II/kg/day (females) in the rat) produced exposures that are, on average, about 30 (mice) and 7 (rats) times the average exposure to M-II in humans at the MRHD. Mutagenesis: Azilsartan medoxomil, azilsartan, and M-II were positive for structural aberrations in the Chinese Hamster Lung Cytogenetic Assay. In this assay, structural chromosomal aberrations were observed with the prodrug, azilsartan medoxomil, without metabolic activation. The active moiety, azilsartan was also positive in this assay both with and without metabolic activation. The major human metabolite, M-II was also positive in this assay during a 24 hr assay without metabolic activation.

Azilsartan medoxomil, azilsartan, and M-II were devoid of genotoxic potential in the Ames reverse mutation assay with Salmonella typhimurium and Escherichia coli, the in vitro Chinese Hamster Ovary Cell forward mutation assay, the in vitro mouse lymphoma (tk) gene mutation test, the ex vivo unscheduled DNA synthesis test, and the in vivo mouse and/or rat bone marrow micronucleus assay.

Impairment of Fertility: There was no effect of azilsartan medoxomil on the fertility of male or female rats at oral doses of up to 1000 mg azilsartan medoxomil/kg/day [6000 mg/m2 (approximately 122 times the MRHD of 80 mg azilsartan medoxomil/60 kg on a mg/m2 basis)]. Fertility of rats also was unaffected at doses of up to 3000 mg M-II/kg/day.

Animal Toxicology and/or Pharmacology Reproductive Toxicology: In peri- and postnatal rat development studies, adverse effects on pup viability, delayed incisor eruption and dilatation of the renal pelvis along with hydronephrosis were seen when azilsartan medoxomil was administered to pregnant and nursing rats at 1.2 times the MRHD on a mg/m2 basis. Reproductive toxicity studies indicated that azilsartan medoxomil was not teratogenic when administered at oral doses up to 1000 mg azilsartan medoxomil/kg/day to pregnant rats (122 times the MRHD on a mg/m2 basis) or up to 50 mg azilsartan medoxomil/ kg/day to pregnant rabbits (12 times the MRHD on a mg/m2 basis). M-II also was not teratogenic in rats or rabbits at doses up to 3000 mg M-II/kg/day. Azilsartan crossed the placenta and was found in the fetuses of pregnant rats and was excreted into the milk of lactating rats.

PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Patient Information).

General Information Pregnancy: Female patients of childbearing age should be told that use of drugs like Edarbi that act on the renin-angiotensin system during pregnancy can cause serious problems in the fetus and infant including low blood pressure, poor development of skull bones, kidney failure, and death. These consequences do not appear to have resulted from intrauterine drug exposure that has been limited to the first trimester.

Discuss other treatment options with female patients planning to become pregnant.

Women using Edarbi who become pregnant should notify their physicians as soon as possible.

Distributed by Takeda Pharmaceuticals America, Inc. Deerfield, IL 60015 Edarbi is a trademark of Takeda Pharmaceutical Company Limited registered with the U.S. Patent and Trademark Office and used under license by Takeda Pharmaceuticals America, Inc. Š2011 Takeda Pharmaceuticals America, Inc. For more detailed information, see the full prescribing information for Edarbi at www.edarbi.com or contact Takeda Pharmaceuticals America, Inc. at 1-877-825-3327.

AZL074 R1; February 2011 L-LXA-0211-2

The Current Drug Pipeline and New Approvals in 2011: A Managed Care Perspective Di ana Papshev, Phar mD, and Chant el l M. Reagan, Phar mD Dr Papshev is Partner and Dr Reagan is Managing Director, InformaCeutica, Yardley, PA

I

n 2010, the majority of the US Food and Drug Administration (FDA) drug approvals were focused on expanded indications and new dosing forms or formulations (Figure).1 According to the estimate reported by DrugManage mentForum.com (which is owned

by InformaCeutica), only 23 new Diana Papshev drugs and biologics were approved in 2010, including 21 new molecular entities (NMEs) approved by the FDA’s Center for Drug Evaluation and Research and 2 biologics approved by the Center for Biologics Evaluation and Research.1,2 This is substantially lower than was projected by these authors in 2010,3 primarily because of this unexpectedly low FDA approval rate. For example, of the 15 significant candidates in the pipeline that were highlighted last year,3 only 3 were actually approved in 2010. The FDA’s requests for new trials, additional data, or inclusion in the risk evaluation and mitigation strategy (REMS) program for the remaining 12 agents have resulted in drug development delays or program discontinuations.

New trials were requested for Bydureon (exenatide), Daliresp (roflumilast), Esbriet (pirfenidone), motavizumab, and Naproxcinod (nitronaproxen). Subsequently, roflumilast was approved in 2011 and development of motavizumab has been discontinued.

Additional information was also requested for belatacept, Brilinta (ticagrelor), Lorqess (lorcaserin), Neutroval (XM02), Qnexa (phentermine and topira-

InformaCeutica is a drug management information company focused on developing interactive tools for managed care decision makers. InformaCeutica’s offerings include Drug ManagementForum.com and DrugPipelineForecast.com.

DrugManagementForum.com allows managed care professionals to connect and share ideas on common issues and experiences in drug benefit management. DrugPipelineForecast.com offers a comprehensive tool for tracking late-phase drug pipeline developments from the managed care perspective.

mate), Replagal (agalsidase alfa), and Uplyso (taliglucerase alfa). For Qnexa, the FDA has also requested adjustments in the REMS program.

New FDA Approvals in 2011 Considering the 2010-2011 approval rate, and the number of new drug applications submitted Chantell M. Reagan to the FDA in 2010,4 approximately 20 to 25 new drugs are expected to be approved this year. The greatest impact of these approvals will concentrate in several categories, including: • Cardiovascular disease • Immunology-related conditions • Oncology • Antiviral agents for infectious diseases.

The following 22 drugs, biologics, and related devices have already been approved by the FDA as of May 23, 2011; 12 of these are classified as NMEs and 2 are new biologics5: • Abstral sublingual tablets CII (fentanyl; ProStrakan) • Adenovirus type 4 and type 7 vaccine, live, oral (Teva) • Benlysta (belimumab; HGS/GlaxoSmithKline) • Corifact (factor XIII concentrate, human; CSL Behring) • Daliresp (roflumilast; Forest/Nycomed) • Duexis (ibuprofen and famotidine; Horizon) • Edarbi (azilsartan; Takeda) • Edurant (rilpivirine; Tibotec) • Epicyn HydroGel (Oculus) • Gel-One (development code: Gel-200; Seikagaku) • Gralise tablets (gabapentin; Depomed/Abbott) • Horizant (gabapentin enacarbil extended-release; GlaxoSmithKline and Xenoport) • Incivek (telaprevir; Vertex) • Makena (hydroxyprogesterone caproate injection; KV Pharm/Hologic) • Natroba topical suspension 0.9% (spinosad; ParaPRO) • Phoslyra (calcium acetate 667 mg/5 mL; Fresenius) • Tradjenta (linagliptin; Boehringer Ingelheim) • Vandetanib tablets (AstraZeneca)

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Figure Significant Brand-Name Drugs Approved by the FDA in 2010 Antiinfectives

2

Antineoplastics

1

Cardiovascular 1

2

6

4

2

1

Central nervous system

18

Dermatology 1

7

4

Endocrine/diabetes

2

Enzyme replacements and modifiers

2

Gastrointestinal drugs

2

Hematologic drugs

2

Immunologic drugs and vaccines

New molecular entity New dosage/formulation New biologics Expanded indications

4

1

1

5 2

1 2

3

Obstetrics and gynecology 1

3

3

5

Ophthalmologic drugs 1

3

2

Orthopedic agents 1 2

Respiratory drugs

Transplant 1 2

Urologic agents 0

7.5

15

22.5

30

Adapted with permission from www.drugmanagementforum.com. Accessed February 10, 2011.

• Victrelis (boceprevir; Merck) • Viibryd (vilazodone; Trovis/Clinical Data) • Yervoy (ipilimumab injection for intravenous use; Bristol-Myers Squibb) • Zytiga (abiraterone; Centocor).

Benlysta, Yervoy, and Zytiga each represent a significant innovation in their respective therapeutic areas. All 3 are expected to reach blockbuster status.

In particular, 7 of these agents (Table 1) may be on the radar for health plans and pharmacy benefit managers.

Most attention is focused on the 2 drugs for hepatitis C virus (HCV) infection—telaprevir and boceprevir. These new HCV therapies are expected to change the standard of care for this condition and to have significant impact on drug utilization and cost. In clinical trials, both drugs have demonstrated an opportunity for shorter treatment

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duration and high efficacy rates in treatment-naïve patients with HCV and in those who were previously poor responders to other HCV therapies.

Benlysta, Yervoy, and Zytiga each represent a significant innovation in their respective therapeutic areas.

All 3 are expected to reach blockbuster status.

Makena, although not a novel treatment, has generated considerable controversy in the managed care community and the general public. At the center of this was the substantial increase in price in comparison with previously custom-compounded therapy (17P, hydroxyprogesterone caproate) and the threat of Makena’s market exclusivity. In an unprecedented move, the FDA publicly announced that it was not planning to take enforcement action against pharmacies compounding 17P. Since then, KV Pharmaceuticals, the manufacturer of Makena, lowered the price to $690 per injection (nearly 55%).

The 2011 Drug Pipeline The 10 other products that may be approved later in

The Current Drug Pipeline

Table 1 Significant FDA Approvals through May 23, 2011 Drug, formulation

Approval date

Indication

Estimated peak annual sales, $

Implications for managed care

Viibryd (vilazodone), oral tablet

1/2011

Major depressive disorder

1.7B

SSRI and 5-HT1A receptor agonist, positioned as having less impact on sexual dysfunction than traditional agents; will be entering crowded generic market

Makena (hydroxyprogesterone caproate), injection

2/2011

Preterm labor/delivery

413M

First drug approved for this indication; previously similar products were compounded

Benlysta (belimumab), IV infusion

3/2011

Immunology (SLE)

2.7B

First new drug approved for lupus treatment in 50 years

Yervoy (ipilimumab), IV infusion

3/2011

Immunology/ oncology (advanced melanoma)

2B

Zytiga (abiraterone), oral tablet

4/2011

Oncology (advanced prostate cancer [second/third-line])

1.5B

One of few agents to demonstrate prolonged survival (in patients who were previously treated with chemotherapy); expected to be evaluated in earlier stages of prostate cancer

Victrelis (boceprevir), oral tablet

5/2011

Antiviral (hepatitis C)

>1B

Novel mechanism of action—HCV protease inhibitor; showed superior efficacy in combination with pegylated interferon and ribavirin in treatmentnaïve and experienced patients (excluding null responders); depending on patient characteristics and treatment response, overall treatment duration can be reduced to 28 weeks (24 weeks for Victrelis); also being evaluated in patients coinfected with HIV; expected to compete with Incivek

Incivek (telaprevir) oral tablet

5/2011

Antiviral (hepatitis C)

3B-6B

Novel mechanism of action—HCV protease inhibitor; showed superior efficacy in combination with pegylated interferon and ribavirin in treatmentnaïve and experienced patients (including null responders); depending on patient characteristics and treatment response, overall treatment duration can be reduced to 24 weeks (12 weeks for Incivek); also being evaluated in patients coinfected with HIV; expected to compete with Victrelis

First-in-class CTL-4 inhibitor; first treatment that demonstrated prolonged survival; also being studied in prostate and lung cancers

5-HT1A indicates 5-hydroxytryptamine; B, billion; CTL-4, cytotoxic T-lymphocyte 4; HCV, hepatitis C virus; IV, intravenous; M, million; SLE, systemic lupus erythematosus; SSRI, selective serotonin reuptake inhibitor.

Sources: www.DrugManagementForum.com; EvaluatePharma. World Preview 2016. www.evaluatepharma.com/ EvaluatePharma_World_Preview_2016.aspx; EvaluatePharma. Weekly Market Movers, March 11, 2011. www.evaluatepharma.com.

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Table 2 Significant Nonspecialty Pipeline Candidates in 2011 (Starting 5/24/2011)

Drug

Estimated FDA approvala

Therapeutic Estimated peak category (investigated use) annual sales, $

Implications for managed care

Arcapta (indacaterol), inhalation

3Q 2011b

Respiratory (COPD)

>1B

Once-daily long-acting beta-agonist which showed superiority over twice-daily Serevent (salmeterol) and some clinical benefits over Spiriva (tiotropium); combination agents with mometasone and glycopyrronium are being developed; new trials were initiated after FDA concern regarding dosing regimens in 10/2009 and highest dose in 3/2011; FDA advisory board endorses “lowdose” in 3/2011

Brilinta (ticagrelor), oral

7/20/2011c

CV (ACS)

1.9B

Third antiplatelet drug to compete with Plavix (clopidogrel) and Effient (prasugrel); showed superiority to clopidogrel in CV events, without increased bleeding risk; unlikely to have black box warning for issues with CYP2C19 metabolism; FDA requested in 9/2010 additional analysis of the PLATO trial

Btripla (rilpivirine, emtricitabine, tenofovir), oral fixed dose

8/10/2011c

Antiviral (HIV)

1.1B

Expected to be successor to Atripla (efavirenz, emtricitabine, tenofovir), with an improved safety profile

Dapagliflozin, oral

10/28/2011c

Endocrine (type 2 diabetes)

>1B

First-in-class SGLT-2; showed additive effect in combination with Januvia (sitagliptin)

4Q 2011b

CV (AF, VTE)

1.6-3B

Direct factor Xa inhibitor; showed superiority to Lovenox (enoxaparin) in VTE prevention and warfarin in stroke prevention with no increase in intracranial bleeding; expected to compete with LMWHs and oral anticoagulants

Xarelto (rivaroxaban), oral

a

Estimated approval as of May 2011, subject to change.

Estimated approval time is based on publicly available information. c Estimated approval time is based on announced Prescription Drug User Fee Act date. b

ACS indicates acute coronary syndrome; AF, atrial fibrillation; B, billion; COPD, chronic obstructive pulmonary disease; CV, cardiovascular; LMWHs, low-molecular-weight heparins; Q, quarter; SGLT-2, sodium–glucose cotransporter type 2; VTE, venous thromboembolism.

Sources: www.DrugPipelineForecast.com; www.DrugManagementForum.com; EP Vantage. EvaluatePharma. World Preview 2016. www.evaluatepharma.com/EvaluatePharma_World_Preview_2016.aspx.

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The Current Drug Pipeline

Table 3 Significant Specialty Candidates in Drug Pipeline in 2011 (after 5/23/2011) Estimated FDA approvala

Therapeutic category (investigated use)

Nulogix (belatacept), IV

6/15/2011b

Immunology (renal transplant)

500M

First transplant drug approved in 13 years; novel mechanism of action; first selective costimulation blocker for prophylaxis of acute renal graft rejection; concerns with PML and kidney rejection; FDA requested additional data in 4/2010 from an ongoing phase 3 trial

VEGF Trap-Eye, (aflibercept), intravitreal injection

8/20/2011b

Ophthalmology (wet age-related macular degeneration)

870M

Fusion protein targeting VEGF-A and PIGF; expected to compete with Lucentis (ranibizumab) on the basis of noninferiority data and less frequent dosing (every 2 months); also being evaluated for central retinal vein occlusion, diabetic macular edema, and other eye diseases (IV form is also being studied in oncologic conditions)

Brentuximab, IV

8/30/2011b

Oncology (refractory lymphomas)

>250M

First-in-class antibody drug conjugate with anti-CD30 monoclonal antibody attached to monomethyl auristatin E; also being evaluated as first-line therapy in combination with chemotherapy (greater sales potential)

Crizotinib, oral

4Q 2011c

Oncology (advanced NSCLC)

755M

Oral agent, first-in-class ALK inhibitor for patients with ALK-positive advanced NSCLC

Neutroval (XM02), SC/IV

4Q 2011c

Hematology/ oncology (neutropenia)

N/A

First biosimilar granulocyte colonystimulating factor (with full BLA submission); likely to compete with filgrastim based on price and noninferiority data in head-to-head trials; FDA requested additional data in 10/2010, but no new trials were required

Drug, formulation

Estimated peak annual sales, $

Implications for managed care

a

Estimated approval time as of May 2011, subject to change.

Expected approval time is based on the announced Prescription Drug User Fee Act date. c Expected approval time is based on publicly available information. b

ALK indicates anaplastic lymphoma kinase; BLA, biologic license application; IV, intravenous; M, million; NSCLC, nonâ&#x20AC;&#x201C;small-cell lung cancer; PML, progressive multifocal leukoencephalopathy; Q, quarter; SC, subcutaneous; VEGF, vascular endothelial growth factor.

Sources: www.DrugPipelineForecast.com; www.DrugManagementForum.com; EP Vantage. EvaluatePharma World Preview 2016. www.evaluatepharma.com/EvaluatePharma_World_Preview_2016.aspx.

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2011 also have the potential to significantly impact drug utilization and trend: • Arcapta (indacaterol) • Brentuximab • Brilinta (ticagrelor) • Btripla (rilpivirine, emtricitabine, tenofovir) • Crizotinib • Dapagliflozin • Neutroval • Nulogix (belatacept) • VEGF Trap-Eye (aflibercept) • Xarelto (rivaroxaban).

Among 5 significant nonspecialty candidates in the drug pipeline (Table 2), Xarelto and Brilinta are particularly predicted to have moderate-to-significant impact on drug utilization.

Under the specialty category, pipeline agents with the greatest potential in 2011 have already been approved.

In addition, there are 5 other serious contenders (Table 3) likely to receive approval this year.

Of these agents, VEGF Trap-Eye is most likely to reach blockbuster sales. This ophthalmic product is also

of interest to managed care organizations, because it is expected to compete directly with Lucentis.

Unlike other specialty pipeline candidates, Neutroval is a follow-on biologic expected to be positioned against Neupogen (filgrastim). Neutroval has been available in Europe as a biosimilar, but in the United States it is being reviewed under a full biologic license application pathway. It will be interesting to see how the entry of Neutroval may affect the dynamics of the granulocyte colony-stimulating factor drug class. ■

References 1. Drug Management Forum. Significant brand approvals for 2010. www.drugmanage mentforum.com/forum/new-brand-drug-approvals-month/24780-significant-brandapprovals-2010-a.html. Accessed March 4, 2011.

2. US Food and Drug Administration. New molecular entities approved in 2010 by CDER. www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/HowDrugsare DevelopedandApproved/DrugandBiologicApprovalReports/UCM242677.pdf.

Accessed March 4, 2011.

3. Papshev D, Reagan CM. The new drug pipeline: what is on the horizon for managed care in 2010? Am Health Drug Benefits. 2010;3(3 suppl 10):S258-S264.

4. US Food and Drug Administration. Comparison of NMEs approved in 2010 to previous years. www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/How DrugsareDevelopedandApproved/DrugandBiologicApprovalReports/UCM242695. pdf. Accessed March 4, 2011.

5. Drug Management Forum. New brand drug approvals by month. www.drugmanage mentforum.com/forum/new-brand-drug-approvals-month/. Accessed March 4, 2011.

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AVBCC is the fastest growing national specialty organization dedicated to improving the care of cancer patients and their quality of life.

The organization was established to provide a network for payers and oncology healthcare professionals to interact and network in order to promote optimal care for patients and their families.

2011 REGIONAL MEETINGS September 24 Chicago, IL

October 1 San Francisco, CA

November 19 Tampa, FL

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Register online at

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FDA Approvals of Brand-Name Prescription Drugs, January-May 2011 Abstral (Fentanyl citrate; ProStrakan) Class: Opioid analgesic Indication: Management of breakthrough pain in cancer patients aged ≥18 years who are already receiving and are tolerant to opioid therapy for their underlying persistent cancer pain Approval consideration: REMS Benlysta (NME) (Belimumab; Human Genome Sciences/GlaxoSmithKline) Class: B-lymphocyte stimulator-specific inhibitor Indication: Treatment of adult patients with active, autoantibody-positive systemic lupus erythematosus Corifact (Factor XIII concentrate, human; CSL Behring) Class: Fibrin-stabilizing factor concentrate Indication: Routine prophylactic treatment of congenital factor XIII (FXIII) deficiency Daliresp (NME) (Roflumilast; Forest Research Institute) Class: Selective phosphodiesterase-4 inhibitor Indication: To reduce the risk of chronic obstructive pulmonary disease (COPD) exacerbations in patients with severe COPD and a history of exacerbations DaTscan (NME) (Ioflupane I123 injection; GE Healthcare) Class: Radiopharmaceutical Indication: To assist in the evaluation of adult patients with suspected Parkinsonian syndromes Approval consideration: Priority review Dificid (Fidaxomicin; Optimer Pharma) Class: Macrolide antibacterial Indication: Treatment of Clostridium difficile–associated diarrhea Duexis (Ibuprofen + famotidine; Horizon Pharma) Class: Nonsteroidal anti-inflammatory drug + histamine H2-receptor antagonist Indication: Relief of signs and symptoms of rheumatoid arthritis and osteoarthritis and to decrease the risk of developing upper gastrointestinal ulcers

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Edarbi (NME) (Azilsartan medoxomil; Takeda) Class: Angiotensin II receptor blocker Indication: Treatment of hypertension Edurant (NME) (Rilpivirine; Tibotec) Class: HIV type 1 specific, non-nucleoside reverse transcriptase inhibitor Indication: Treatment of HIV-1 infection in treatmentnaïve patients Gadavist (NME) (Gadobutrol; Bayer HealthCare) Class: Macrocyclic gadolinium-based contrast agent Indication: For intravenous use in diagnostic magnetic resonance imaging to visualize areas with disrupted blood-brain barrier and/or abnormal CNS vascularity Horizant (NME) (Gabapentin enacarbil; GlaxoSmithKline) Class: Gamma-aminobutyric acid analogs Indication: Treatment of moderate-to-severe primary restless legs syndrome Incivek (NME) (Telaprevir; Vertex Pharmaceuticals) Class: Hepatitis C virus NS3/4A protease inhibitor Indication: Treatment of genotype 1 chronic hepatitis C in adult patients with compensated liver disease Approval consideration: Priority review Makena (Hydroxyprogesterone caproate injection; Hologic) Class: Progestin Indication: To reduce the risk of preterm birth in women with a singleton pregnancy who have a history of singleton spontaneous preterm birth Natroba (NME) (Spinosad; ParaPRO) Class: Pediculicide Indication: Topical treatment of head lice infestations in patients aged ≥4 years Sylatron (NME) (Peginterferon alfa-2b; Merck) Class: Alpha interferon

2011 FDA Approvals of Brand-Name Drugs

Indication: Adjuvant treatment of melanoma with microscopic or gross nodal involvement within 84 days of definitive surgical resection Tradjenta (NME) (Linagliptin; Boehringer Ingelheim) Class: Dipeptidyl peptidase-4 inhibitor Indication: To improve glycemic control in adults with type 2 diabetes mellitus Vandetanib (NME) (Vandetanib; AstraZeneca) Class: Tyrosine kinase inhibitor Indication: Treatment of medullary thyroid cancer that cannot be removed by surgery or that has spread Approval considerations: Priority review, orphan drug, REMS Victrelis (NME) (Boceprevir; Schering) Class: Hepatitis C virus NS3/4A protease inhibitor Indication: Treatment of chronic hepatitis C genotype 1 infection Approval consideration: Priority review

Viibryd (NME) (Vilazodone hydrochloride; Forest Laboratories) Class: Antidepressant Indication: Treatment of major depressive disorder Approval consideration: REMS Yervoy (NME) (Ipilimumab; Bristol-Myers Squibb) Class: Human cytotoxic T-lymphocyte antigen 4â&#x20AC;&#x201C; blocking antibody Indication: For unresectable or metastatic melanoma Approval consideration: REMS Zytiga (NME) (Abiraterone acetate; Centocor Ortho Biotech) Class: CYP17 inhibitor Indication: Treatment of patients with metastatic castration-resistant prostate cancer who have received previous chemotherapy containing docetaxel Approval consideration: Priority review

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KAPVAY (clonidine hydrochloride) extended-release tablets, oral, Rx only INDICATIONS AND USAGE KAPVAY™ is a centrally acting alpha2-adrenergic agonist indicated for the treatment of attention deficit hyperactivity disorder (ADHD) as monotherapy or as adjunctive therapy to stimulant medications. (1) The efficacy of KAPVAY is based on the results of two clinical trials in children and adolescents.

(14) Maintenance efficacy has not been systematically evaluated, and patients who are continued on longer-term treatment require periodic reassessment. (1) This extended-release formulation of clonidine hydrochloride is also approved for the treatment of hypertension under the trade name JENLOGA. (1) CONTRAINDICATIONS KAPVAY should not be used in patients with known hypersensitivity to clonidine.

WARNINGS AND PRECAUTIONS Hypotension/Bradycardia Treatment with KAPVAY can cause dose related decreases in blood pressure and heart rate. In patients that completed 5 weeks of treatment in a controlled, fixed-dose monotherapy study in pediatric patients, during the treatment period the maximum placebo-subtracted mean change in systolic blood pressure was -4.0 mmHg on KAPVAY 0.2 mg/day and -8.8 mmHg on KAPVAY 0.4 mg/day. The maximum placebosubtracted mean change in diastolic blood pressure was -4.0 mmHg on KAPVAY 0.2 mg/day and -7.3 mmHg on KAPVAY 0.4 mg/day. The maximum placebo-subtracted mean change in heart rate was -4.0 beats per minute on KAPVAY 0.2 mg/day and -7.7 beats per minute on KAPVAY 0.4 mg/day.

During the taper period of the fixed-dose monotherapy study the maximum placebo-subtracted mean change in systolic blood pressure was +3.4 mmHg on KAPVAY 0.2 mg/day and -5.6 mmHg on KAPVAY 0.4 mg/day. The maximum placebo-subtracted mean change in diastolic blood pressure was +3.3 mmHg on KAPVAY 0.2 mg/day and -5.4 mmHg on KAPVAY 0.4 mg/day. The maximum placebosubtracted mean change in heart rate was -0.6 beats per minute on KAPVAY 0.2 mg/day and -3.0 beats per minute on KAPVAY 0.4 mg/day.

Measure heart rate and blood pressure prior to initiation of therapy, following dose increases, and periodically while on therapy. Use KAPVAY with caution in patients with a history of hypotension, heart block, bradycardia, or cardiovascular disease, because it can decrease blood pressure and heart rate.

Use caution in treating patients who have a history of syncope or may have a condition that predisposes them to syncope, such as hypotension, orthostatic hypotension, bradycardia, or dehydration. Use KAPVAY with caution in patients treated concomitantly with antihypertensives or other drugs that can reduce blood pressure or heart rate or increase the risk of syncope. Advise patients to avoid becoming dehydrated or overheated.

Sedation and Somnolence Somnolence and sedation were commonly reported adverse reactions in clinical studies. In patients that completed 5 weeks of therapy in a controlled fixed dose pediatric monotherapy study, 31% of patients treated with 0.4 mg/day and 38% treated with 0.2 mg/day vs 7% of placebo treated patients reported somnolence as an adverse event. In patients that completed 5 weeks of therapy in a controlled flexible dose pediatric adjunctive to stimulants study, 19% of patients treated with KAPVAY+stimulant vs 8% treated with placebo+stimulant reported somnolence. Before using KAPVAY with other centrally active depressants (such as phenothiazines, barbiturates, or benzodiazepines), consider the potential for additive sedative effects. Caution patients against operating heavy equipment or driving until they know how they respond to treatment with KAPVAY. Advise patients to avoid use with alcohol.

Abrupt Discontinuation No studies evaluating abrupt discontinuation of KAPVAY in children with ADHD have been conducted.

In children and adolescents with ADHD, physicians should gradually reduce the dose of KAPVAY in decrements of no more than 0.1 mg every 3 to 7 days. Patients should be instructed not to discontinue KAPVAY therapy without consulting their physician due to the potential risk of withdrawal effects.

In adults with hypertension, sudden cessation of clonidine hydrochloride extended-release formulation treatment in the 0.2 to 0.6 mg/day range resulted in reports of headache, tachycardia, nausea, flushing, warm feeling, brief lightheadedness, tightness in chest, and anxiety.

In adults with hypertension, sudden cessation of treatment with immediate-release clonidine has, in some cases, resulted in symptoms such as nervousness, agitation, headache, and tremor accompanied or followed by a rapid rise in blood pressure and elevated catecholamine concentrations in the plasma.

Allergic Reactions In patients who have developed localized contact sensitization to clonidine transdermal system, continuation of clonidine transdermal system or substitution of oral clonidine hydrochloride therapy may be associated with the development of a generalized skin rash.

In patients who develop an allergic reaction from clonidine transdermal system, substitution of oral clonidine hydrochloride may also elicit an allergic reaction (including generalized rash, urticaria, or angioedema).

Patients with Vascular Disease, Cardiac Conduction Disease, or Renal Failure Clonidine hydrochloride should be used with caution in patients with severe coronary insufficiency, conduction disturbances, recent myocardial infarction, cerebrovascular disease or chronic renal failure.

Other Clonidine-Containing Products Clonidine, the active ingredient in KAPVAY, is also approved as an antihypertensive. Do not use KAPVAY in patients concomitantly taking other clonidine-containing products, (e.g. Catapres®).

ADVERSE REACTIONS Clinical Trial Experience Two KAPVAY ADHD clinical studies evaluated 256 patients who received active therapy, in one of the two placebo-controlled studies (Studies 1 and 2) with primary efficacy end-points at 5-weeks.

Study 1: Fixed-dose KAPVAY Monotherapy Study 1 was a multi-center, randomized, double-blind, placebo-controlled study with primary efficacy endpoint at 5 weeks, of two fixed doses (0.2 mg/day or 0.4 mg/day) of KAPVAY in children and adolescents (6 to 17 years of age) who met DSM-IV criteria for ADHD hyperactive or combined inattentive/hyperactive subtypes.

Commonly observed adverse reactions (incidence of ≥ 2% in either active treatment group and greater than the rate on placebo) during the treatment period are listed in Table 2.

Table 2 Common Adverse Reactions in the Fixed-Dose Monotherapy Trial- Treatment period (Study 1) Percentage of Patients Reporting Event KAPVAY KAPVAY Preferred Term Placebo 0.2 mg/day 0.4 mg/day (N=76) N=76 N=78 Somnolence1 Headache Upper Abdominal Pain Fatigue2 Upper Respiratory Tract Infection Irritability Throat Pain Nausea Nightmare Dizziness Insomnia Emotional Disorder Constipation Dry Mouth Nasal Congestion Body Temperature Increased Gastrointestinal Viral Diarrhea Ear Pain Nasopharyngitis Abnormal Sleep-Related Event Aggression Asthma Bradycardia Enuresis Influenza like Illness Tearfulness Thirst Tremor Epistaxis Lower Respiratory Tract Infection Pollakiuria Sleep Terror

31% 19% 13% 13% 6% 6% 6% 8% 9% 3% 6% 5% 6% 5% 5% 1% 0% 1% 0 3% 1% 1% 1% 4% 4% 3% 3% 3% 3% 0 0

38% 29% 20% 16% 11% 9% 8% 5% 3% 7% 4% 4% 1% 0 3% 5% 7% 4% 5% 3% 3% 3% 3% 0 0 1% 1% 1% 1% 3% 3%

5% 18% 17% 1% 4% 3% 3% 4% 0 5% 1% 1% 0 1% 1% 3% 4% 3% 1% 1% 0 1% 1% 0 0 1% 0 0 0 0 1%

0 0

3% 3%

0 0

1. Somnolence includes the terms “somnolence” and “sedation”.

2. Fatigue includes the terms “fatigue” and “lethargy”.

Commonly observed adverse reactions (incidence of ≥ 2% in either active treatment group and greater than the rate on placebo) during the taper period are listed in Table 3.

Table 3 Common Adverse Reactions in the Fixed-Dose Monotherapy Trial- Taper period* (Study 1) Percentage of Patients Reporting Event KAPVAY KAPVAY Preferred Term Placebo 0.4 mg/day 0.2 mg/day (N=76) N=78 N=76 Abdominal Pain Upper Headache Gastrointestinal Viral Somnolence Heart Rate Increased Otitis Media Acute

6% 2% 5% 3% 3% 0

0 5% 0 2% 0 3%

3% 3% 0 0 0 0

*Taper Period: 0.2 mg dose, week 8; 0.4 mg dose, weeks 6-8; Placebo dose, weeks 6-8 Study 2: Flexible-dose KAPVAY as Adjunctive Therapy to Psychostimulants Study 2 was a multi-center, randomized, double-blind, placebo-controlled study, with primary efficacy endpoint at 5 weeks, of a flexible dose of KAPVAY as adjunctive therapy to a psychostimulant in children and adolescents (6 to 17 years) who met DSM-IV criteria for ADHD hyperactive or combined inattentive/hyperactive subtypes. KAPVAY was initiated at 0.1 mg/day and titrated up to 0.4 mg/day over a 3-week period. Most KAPVAY treated patients (75.5%) were escalated to the maximum dose of 0.4 mg/day.

Commonly observed adverse reactions (incidence of ≥ 2% in the treatment group and greater than the rate on placebo) during the treatment period are listed in Table 4.

Table 4 Common Adverse Reactions in the Flexible-Dose Adjunctive to Stimulant Therapy Trial- Treatment Period (Study 2) Preferred Term Somnolence1 Fatigue2 Abdominal Pain Upper Nasal Congestion Throat Pain Decreased Appetite Body Temperature Increased Dizziness Insomnia Epistaxis Rhinorrhea Abdominal Pain Anxiety Pain in Extremity

Percentage of Patients Reporting Event KAPVAY+STM PBO+STM (N=102) (N=96) 19% 8% 16% 4% 12% 7% 6% 5% 6% 3% 5% 4% 4% 2% 4% 2% 4% 2% 3% 0 3% 0 2% 1% 2% 0 2% 0

1. Somnolence includes the terms: “somnolence” and “sedation”.

2. Fatigue includes the terms “fatigue” and “lethargy”.

Commonly observed adverse reactions (incidence of ≥ 2% in the treatment group and greater than the rate on placebo) during the taper period are listed in Table 5.

Table 5 Common Adverse Reactions in the Flexible-Dose Adjunctive to Stimulant Therapy Trial- Taper Period* (Study 2)

Preferred Term

Percentage of Patients Reporting Event KAPVAY+STM PBO+STM (N=102) (N=96) 4% 2% 3% 1% 3% 2% 3% 1% 2% 0 2% 0

Nasal Congestion Headache Irritability Throat Pain Gastroenteritis Viral Rash *Taper Period: weeks 6-8.

Most common adverse reactions, defined as events that were reported in at least 5% of drugtreated patients and at least twice the rate as in placebo patients, during the treatment period were somnolence, fatigue, upper respiratory tract infection, irritability, throat pain, insomnia, nightmares, emotional disorder, constipation, nasal congestion, increased body temperature, dry mouth, and ear pain. The most common adverse reactions that were reported during the taper phase were upper abdominal pain and gastrointestinal virus.

Adverse Reactions Leading to Discontinuation Thirteen percent (13%) of patients receiving KAPVAY discontinued from the pediatric monotherapy study due to adverse events, compared to 1% in the placebo group. The most common adverse reactions leading to discontinuation of KAPVAY monotherapy treated patients were from somnolence/sedation (5%) and fatigue (4%). Less common adverse reactions leading to discontinuation (occurring in approximately 1% of patients) included: formication, vomiting, prolonged QT, increased heart rate, and rash. In the pediatric adjunctive treatment to stimulants study, one patient discontinued from KAPVAY + stimulant group because of bradyphrenia.

Effects on Laboratory Tests, Vital Signs, and Electrocardiograms KAPVAY treatment was not associated with any clinically important effects on any laboratory parameters in either of the placebo-controlled studies.

Mean decreases in blood pressure and heart rate were seen [see Warnings and Precautions (5.1)].

There were no changes on ECGs to suggest a drug-related effect.

DRUG INTERACTIONS No drug interaction studies have been conducted with KAPVAY in children. The following have been reported with other oral immediate release formulations of clonidine.

Interactions with CNS-depressant Drugs Clonidine may potentiate the CNS-depressive effects of alcohol, barbiturates or other sedating drugs.

Interactions with Tricyclic Antidepressants If a patient is receiving clonidine hydrochloride and also taking tricyclic antidepressants the hypotensive effects of clonidine may be reduced.

Interactions with Drugs Known to Affect Sinus Node Function or AV Nodal Conduction Due to a potential for additive effects such as bradycardia and AV block, caution is warranted in patients receiving clonidine concomitantly with agents known to affect sinus node function or AV nodal conduction (e.g., digitalis, calcium channel blockers and beta-blockers).

Use with other products containing clonidine Do not use KAPVAY concomitantly with other products containing clonidine (e.g. Catapres®).

Antihypertensive Drugs Use caution when KAPVAY is administered concomitantly with antihypertensive drugs, due to the potential for additive pharmacodynamic effects (e.g., hypotension, syncope) [see Warnings and Precautions (5.2)].

USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C: Oral administration of clonidine hydrochloride to pregnant rabbits during the period of embryo/fetal organogenesis at doses of up to 80 mcg/kg/day (approximately 3 times the oral maximum recommended daily dose [MRHD] of 0.4 mg/day on a mg/m2 basis) produced no evidence of teratogenic or embryotoxic potential. In pregnant rats, however, doses as low as 15 mcg/kg/day (1/3 the MRHD on a mg/m2 basis) were associated with increased resorptions in a study in which dams were treated continuously from 2 months prior to mating and throughout gestation. Increased resorptions were not associated with treatment at the same or at higher dose levels (up to 3 times the MRHD) when treatment of the dams was restricted to gestation days 6-15.

Increases in resorptions were observed in both rats and mice at 500 mcg/kg/day (10 and 5 times the MRHD in rats and mice, respectively) or higher when the animals were treated on gestation days 1-14; 500 mcg/kg/day was the lowest dose employed in this study. No adequate and wellcontrolled studies have been conducted in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should not be used during pregnancy unless clearly needed.

Nursing Mothers Since clonidine hydrochloride is excreted in human milk, caution should be exercised when KAPVAY is administered to a nursing woman.

Pediatric Use A study was conducted in which young rats were treated orally with clonidine hydrochloride from day 21 of age to adulthood at doses of up to 300 mcg/kg/day, which is approximately 3 times the maximum recommended human dose (MRHD) of 0.4 mg/day on a mg/m2 basis. A slight delay in onset of preputial separation was seen in males treated with the highest dose (with a no-effect dose of 100 mcg/kg/day, which is approximately equal to the MRHD), but there were no drug effects on fertility or on other measures of sexual or neurobehavioral development.

KAPVAY has not been studied in children with ADHD less than 6 years old.

Patients with Renal Impairment The impact of renal impairment on the pharmacokinetics of clonidine in children has not been assessed. The initial dosage of KAPVAY should be based on degree of impairment. Monitor patients carefully for hypotension and bradycardia, and titrate to higher doses cautiously. Since only a minimal amount of clonidine is removed during routine hemodialysis, there is no need to give supplemental KAPVAY following dialysis.

Adult Use in ADHD KAPVAY has not been studied in adult patients with ADHD. DRUG ABUSE AND DEPENDENCE Controlled Substance KAPVAY is not a controlled substance and has no known potential for abuse or dependence.

OVERDOSAGE Symptoms Clonidine overdose: hypertension may develop early and may be followed by hypotension, bradycardia, respiratory depression, hypothermia, drowsiness, decreased or absent reflexes, weakness, irritability and miosis. The frequency of CNS depression may be higher in children than adults. Large overdoses may result in reversible cardiac conduction defects or dysrhythmias, apnea, coma and seizures. Signs and symptoms of overdose generally occur within 30 minutes to two hours after exposure.

Treatment Consult with a Certified Poison Control Center for up-to-date guidance and advice. © 2010 Shionogi Pharma, Inc. Florham Park, NJ 07932 Last modified 10/2010

When you treat Attention Deficit/Hyperactivity Disorder (ADHD) with stimulants, for some patients, a question may be...

*Kapvay™ was FDA approved on September 28, 2010.

• When added to a stimulant, extended-release Kapvay™ demonstrated statistically significant improvement of ADHD symptoms compared with a stimulant alone at the end of 5 weeks of treatment, as measured by the ADHD RS-IV total score

Indication Kapvay™ (clonidine hydrochloride) extended-release tablets are indicated for the treatment of attention deficit/hyperactivity disorder (ADHD) as monotherapy or as adjunctive therapy to stimulant medications in children and adolescents ages 6-17. The efficacy of Kapvay™ is based on the results of 2 clinical trials in children and adolescents.

Kapvay™ is indicated as an integral part of a total treatment program for ADHD that may include other measures (psychological, educational, and social) for patients with this syndrome.

The effectiveness of Kapvay™ for longer-term use (more than 5 weeks) has not been systematically evaluated in controlled trials; therefore, the physician electing to use Kapvay™ for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient.

Important Safety Information • Kapvay™ should not be used in patients with known hypersensitivity to clonidine • Kapvay™ can cause dose-related decreases in blood pressure and heart rate. Use caution in treating patients who have a history of syncope or may have a condition that predisposes them to syncope, such as hypotension, orthostatic hypotension, bradycardia, or dehydration.

Use with caution in patients treated concomitantly with antihypertensives or other drugs that can reduce blood pressure or heart rate or increase the risk of syncope • Somnolence/Sedation were commonly reported adverse reactions in clinical studies with Kapvay™. Potential for additive sedative effects with CNS-depressant drugs. Advise patients to avoid use with alcohol. Caution patients against operating heavy equipment or driving until they know how they respond to Kapvay™ • Patients should be instructed not to discontinue Kapvay™ therapy without consulting their physician due to the potential risk of withdrawal effects.

Kapvay™ should be discontinued slowly in decrements of no more than 0.1 mg every 3 to 7 days • In patients who have developed localized contact sensitization or other allergic reaction to clonidine in a transdermal system, substitution of oral clonidine hydrochloride therapy may be associated with the development of a generalized skin rash, urticaria, or angioedema. Use cautiously in patients with vascular disease, cardiac conduction disease, or chronic renal failure: Monitor carefully and uptitrate slowly • Clonidine may potentiate the CNS-depressive effects of alcohol, barbiturates or other sedating drugs • Use caution when Kapvay™ is administered concomitantly with antihypertensive drugs, due to the additive pharmacodynamic effects (e.g., hypotension, syncope) • Kapvay™ should not be used during pregnancy unless clearly needed. Since clonidine hydrochloride is excreted in human milk, caution should be exercised when Kapvay™ is administered to a nursing woman • Caution is warranted in patients receiving clonidine concomitantly with agents known to affect sinus node function or AV nodal conduction (e.g., digitalis, calcium channel blockers and beta-blockers) due to a potential for additive effects, such as bradycardia and AV block • Clonidine, the active ingredient in Kapvay™, is also approved as an antihypertensive. Do not use Kapvay™ in patients concomitantly taking other clonidine-containing products, (e.g., Catapres® [clonidine hydrochloride], JENLOGA) • Common adverse reactions (incidence at least 5% and twice the rate of placebo) include: somnolence, fatigue, upper respiratory tract infection, irritability, throat pain, insomnia, nightmares, emotional disorder, constipation, nasal congestion, increased body temperature, dry mouth, and ear pain Kapvay™ is a trademark of Shionogi Pharma, Inc. Catapres® is a registered trademark of Boehringer Ingelheim.

Please see Brief Summary of full Prescribing Information on the adjacent page.

Extended-Release Formulation © 2011 Shionogi Pharma, Inc.

Atlanta, Georgia.

All rights reserved.

KAP10-PAD-002-00