Februaty/March 2009, Vol 2, No 2 Drug Update

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THE PEER-REVIEWED FORUM FOR EVIDENCE IN BENEFIT DESIGN ™ ADA MEETING HIGHLIGHTS FEBRUARY/MARCH 2009

VOLUME 2, NUMBER 2, SUPPLEMENT 3

SUPPLEMENT

Drug Update ™

A Complete Resource for New Drug Approvals and Indications in 2008

©2009 Engage Healthcare Communications, LLC www.AHDBonline.com

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One treatment, two targets...

SIMCOR— powerful dual-lipid management Impressive efficacy s ,OWERED ,$, # AND SIGNIlCANTLY RAISED ($, #1

Proven NCEP goal attainment s -AJORITY OF 3)-#/2 PATIENTS ATTAINED .#%0 OPTIMAL LIPID LEVELS2,3*†

Safety in clinical trials s OF 3)-#/2 PATIENTS DISCONTINUED THERAPY DUE TO mUSHING1 s /VER OF mUSHING EPISODES WERE MILD TO MODERATE3

A combination of two proven agents s 3IMVASTATIN AND NIACIN EXTENDED RELEASE EACH SUPPORTED WITH A COMPELLING BODY OF CLINICAL EVIDENCE

* OCEANS study was an open-label, randomized, multicenter study that evaluated the safety and efficacy of SIMCOR in adult patients (N=520) with mixed dyslipidemia.

Doses were titrated over an 8- or 12-week period to a maximum dose of SIMCOR 2000/40 mg. Targets were similar to NCEP goals/targets: LDL-C targets were CHD risk equivalent: <100 mg/dL; r2 risk factors: <130 mg/dL; b1 risk factor: <160 mg/dL. HDL-C target r40 mg/dL. TG target <150 mg/dL. Non-HDL-C targets were an additional 30 mg/dL to each LDL-C target. †

Included patients who were on treatment at 24 weeks and who were already at optimal lipid levels at baseline.

For more information, please visit www.simcortablets.com INDICATIONS AND IMPORTANT SAFETY INFORMATION Indications1 s Lipid-altering agents should be used in addition to a diet restricted in saturated fat and cholesterol when response to diet and other nonpharmacological measures alone has been inadequate. s SIMCOR (niacin extended-release/simvastatin) is indicated as an adjunct to diet to reduce total-C, LDL-C, Apo B, non-HDL-C, or TG, or to increase HDL-C in patients with primary hypercholesterolemia and mixed dyslipidemia (Fredrickson Types IIa and IIb) when treatment with simvastatin monotherapy or niacin extended-release monotherapy is considered inadequate. s SIMCOR is indicated to reduce TG in patients with hypertriglyceridemia (Fredrickson Type IV hyperlipidemia) when treatment with simvastatin monotherapy or niacin extended-release monotherapy is considered inadequate. s Limitations of use: No incremental benefit of SIMCOR on cardiovascular morbidity and mortality over and above that demonstrated for simvastatin monotherapy and niacin monotherapy has been established.

Important Safety Information s SIMCOR is contraindicated in patients with active liver disease or unexplained persistent elevations of serum transaminases, active peptic ulcer disease, arterial bleeding; in women who are pregnant or may become pregnant; in nursing mothers; and in patients with hypersensitivity to any product ingredient. s SIMCOR contains simvastatin, which occasionally causes myopathy manifested as muscle pain, tenderness, or weakness with CK levels above 10x ULN. Myopathy sometimes takes the form of rhabdomyolysis with or without acute renal failure secondary to myoglobinuria, and rare fatalities have occurred. The risk of myopathy/rhabdomyolysis is dose-related and is increased by high plasma concentrations of a statin. s Caution should be exercised when SIMCOR is administered to patients with renal disease. s The use of SIMCOR concomitantly with potent CYP3A4 inhibitors: itraconazole, ketoconazole and other antifungal azoles; erythromycin, clarithromycin and telithromycin; HIV protease inhibitors; nefazodone; and grapefruit juice in large quantities (>1 quart daily) should be avoided because of the increased risk of myopathy/rhabdomyolysis. Concomitant use of SIMCOR with cyclosporine, danazol, gemfibrozil, other fibrates, amiodarone, and verapamil should also be avoided because of increased risk of myopathy/rhabdomyolysis. s Myopathy and/or rhabdomyolysis have been reported when simvastatin is used in combination with lipid-altering doses (r1 g/day) of niacin. Patients on SIMCOR

Please see brief summary of complete Prescribing Information for SIMCOR on the following pages. ©2009 Abbott Laboratories Abbott Park, IL 60064 306-222358 February 2009 Printed in U.S.A.

should be monitored for muscle pain, tenderness or weakness, particularly during the initial month of treatment or during upward dose titration. Periodic CK determinations may be considered in such situations, but there is no assurance that such monitoring will prevent myopathy. SIMCOR therapy should be discontinued if CK levels above 10x ULN occur or if myopathy is diagnosed or suspected. s SIMCOR should not be substituted for equivalent doses of immediate-release niacin. Severe hepatic toxicity, including fulminant hepatic necrosis, has occurred in patients substituting sustained-release niacin for immediate-release niacin at equivalent doses. If switching from immediate-release niacin to SIMCOR, initiate with the lowest SIMCOR dose (500/20 mg) and titrate to the desired therapeutic response. Doses greater than 2000/40 mg are not recommended. s SIMCOR should be used with caution in patients who consume substantial quantities of alcohol and/or who have a past history of liver disease. s Liver function tests should be performed on all patients before treatment begins and every 12 weeks for the first 6 months, and periodically thereafter (eg, at approximately 6-month intervals). Should an increase in transaminase levels of more than 3x ULN persist, or if transaminase elevations are associated with symptoms of nausea, fever, and/or malaise, withdrawal of SIMCOR therapy is recommended. s Niacin treatment can increase fasting blood glucose. Glucose levels should be closely monitored in diabetic or potentially diabetic patients particularly during the first few months of use. Adjustment of diet and/or hypoglycemic therapy or discontinuation of SIMCOR may be necessary. s Niacin can reduce platelet count and phosphorus levels and increase uric acid levels. s In patients taking coumarin anticoagulants, monitor prothrombin time and INR before initiating SIMCOR and frequently after initiation or alteration of SIMCOR therapy until stable. s The most common adverse event with SIMCOR is flushing (warmth, redness, itching and/or tingling) which occurred in 59% of patients and resulted in study discontinuation for 6% of patients. Flushing may vary in severity and is more likely to occur with initiation of therapy or during dose increases. Spontaneous reports with niacin extended-release and clinical studies of SIMCOR suggest that flushing may be accompanied by symptoms of dizziness, syncope, tachycardia, palpitations, shortness of breath, sweating, chills and/or edema. s Other common adverse events occurring in r3% of patients treated with SIMCOR included headache, pruritus, nausea, back pain, and diarrhea.

References: 1. SIMCOR [package insert]. North Chicago, IL: Abbott Laboratories. 2. Karas RH, Kashyap ML, Knopp RH, et al., Long-term safety and efficacy of a combination of niacin extended release and simvastatin in patients with dyslipidemia: The OCEANS study. Am J Cardiovasc Drugs. 2008;8(2):69-81. 3. Data on file, Abbott Laboratories.

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Professional Brief Summary

5

306-222358

Simcor Niacin Extended-Release/Simvastatin

嗱 only

CONSULT PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE

5.1 Myopathy/Rhabdomyolysis Simvastatin

Therapy with lipid-altering agents should be only one component of multiple risk factor intervention in individuals at significantly increased risk for atherosclerotic vascular disease due to hypercholesterolemia. Drug therapy is indicated as an adjunct to diet when the response to a diet restricted in saturated fat and cholesterol and other nonpharmacologic measures alone has been inadequate.

Simvastatin, like other inhibitors of HMG-CoA reductase, occasionally causes myopathy manifested as muscle pain, tenderness or weakness with creatine kinase (CK) above ten times the upper limit of normal (ULN). Myopathy sometimes takes the form of rhabdomyolysis with or without acute renal failure secondary to myoglobinuria, and rare fatalities have occurred. The risk of myopathy is increased by high levels of HMG-CoA reductase inhibitory activity in plasma.

As with other HMG-CoA reductase inhibitors, the risk of myopathy/rhabdomyolysis is dose related. In a clinical trial database in which 41,050 patients were treated with simvastatin with 24,747 (approximately 60%) treated for at least 4 years, the incidence of myopathy was approximately 0.02%, 0.08%, and 0.53% at 20, 40, and 80 mg/day, respectively. In these trials, patients were carefully monitored and some interacting medicinal products were excluded.

Potent inhibitors of CYP3A4: The risk of myopathy appears to be increased by high levels of HMG-CoA reductase inhibitory activity in plasma. Simvastatin is metabolized by the cytochrome P450 isoform 3A4. Certain drugs which share this metabolic pathway can raise the plasma levels of simvastatin and may increase the risk of myopathy.

These include cyclosporine, itraconazole, ketoconazole, and other antifungal azoles, the macrolide antibiotics erythromycin and clarithromycin, and the ketolide antibiotic telithromycin, HIV protease inhibitors, the antidepressant nefazodone, or large quantities of grapefruit juice (> 1 quart daily).

The risk of myopathy/rhabdomyolysis is increased by concomitant use of simvastatin and, therefore, SIMCOR with the following: Potent inhibitors of cytochrome P-450 isoform, 3A4 (CYP 3A4): Itraconazole, ketoconazole, and other antifungal azoles Macrolide antibiotics erythromycin, clarithromycin, and telithromycin HIV protease inhibitors Antidepressant nefazodone Grapefruit juice in large quantities (> 1 quart daily) The use of SIMCOR concomitantly with these potent CYP3A4 inhibitors should be avoided. [See Drug Interactions (7.1)] Cyclosporine or Danazol: Simvastatin dose should not exceed 10 mg daily in combination with cyclosporine or danazol. Therefore, the combined used of SIMCOR with cyclosporine or danazol should be avoided. [See Drug Interactions (7.2)] Gemfibrozil: Simvastatin dose should not exceed 10 mg daily when concomitantly used with gemfibrozil. Therefore, the combined use of SIMCOR with gemfibrozil should be avoided. [See Drug Interactions (7.4)] Other Fibrates: Combined use of SIMCOR with drugs that cause myopathy/rhabdomyolysis when given alone, such as fibrates, should be avoided. [See Drug Interactions (7.4)] Amiodarone or Verapamil: The dose of the simvastatin component of SIMCOR should not exceed 20 mg in patients receiving amiodarone or verapamil concomitantly. The combined use of the simvastatin at doses higher than 20 mg daily with amiodarone or verapamil should be avoided unless the clinical benefit is likely to outweigh the increased risk of myopathy. [See Drug Interactions (7.3)]

1.1

Patients with Hypercholesterolemia Requiring Modifications of Lipid Profiles SIMCOR SIMCOR is indicated to reduce total-C, LDL-C, Apo B , non-HDL-C, or TG, or to increase HDL-C in patients with primary hypercholesterolemia and mixed dyslipidemia (Fredrickson type IIa and IIb) when treatment with simvastatin monotherapy or niacin extended-release monotherapy is considered inadequate.

SIMCOR is indicated to reduce TG in patients with hypertriglyceridemia (Fredrickson type IV hyperlipidemia) when treatment with simvastatin monotherapy or niacin extended-release monotherapy is considered inadequate.

Limitations of use No incremental benefit of SIMCOR on cardiovascular morbidity and mortality over and above that demonstrated for simvastatin monotherapy and niacin monotherapy has been established.

4

WARNINGS AND PRECAUTIONS

SIMCOR should not be substituted for equivalent doses of immediate-release (crystalline) niacin. For patients switching from immediate-release niacin to SIMCOR, therapy with SIMCOR should be initiated at 500/20 mg and appropriately titrated to the desired therapeutic response. Doses of SIMCOR greater than 2000/40 mg are not recommended.

®

CONTRAINDICATIONS

SIMCOR is contraindicated in the following conditions: • Active liver disease, which may include unexplained persistent elevations in hepatic transaminase levels [See Warnings and Precautions ( 5.2)] • Patients with active peptic ulcer disease • Patients with arterial bleeding • Women who are pregnant or may become pregnant. SIMCOR may cause fetal harm when administered to a pregnant woman. Serum cholesterol and triglycerides increase during normal pregnancy, and cholesterol or cholesterol derivatives are essential for fetal development. Atherosclerosis is a chronic process and discontinuation of lipid-lowering drugs during pregnancy should have little impact on long-term outcomes of primary hypercholesterolemia therapy. There are no adequate and well-controlled studies of SIMCOR use during pregnancy; however in rare reports congenital anomalies were observed following intrauterine exposure to HMG-CoA reductase inhibitors.

In rat and rabbit animal reproduction studies, simvastatin revealed no evidence of teratogenicity. There are no animal reproductive studies conducted with niacin. If SIMCOR is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. [See Use In Specific Populations (8.1)] • Nursing mothers. SIMCOR contains simvastatin and nicotinic acid.

Nicotinic acid is excreted into human milk and it is not known whether simvastatin is excreted into human milk; however a small amount of another drug in this class does pass into breast milk.

Because of the potential for serious adverse reactions in nursing infants, women who require SIMCOR treatment should not breastfeed their infants. [See Use In Specific Populations (8.3)] • Patients with a known hypersensitivity to any component of this product. Hypersensitivity reactions including one of more of the following adverse reactions have been reported for simvastatin and/or niacin extended-release: anaphylaxis, angioedema, urticaria, fever, dyspnea, tongue edema, larynx edema, face edema, peripheral edema, laryngismus, and flushing. [See Adverse Reactions (6.1)]

SIMCOR Myopathy and/or rhabdomyolysis have been reported when simvastatin is used in combination with lipid-altering doses (≥ 1 gram/day) of niacin. Physicians contemplating the use of SIMCOR, a combination of simvastatin and niacin, should weigh the potential benefits and risks, and should carefully monitor for any 1

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Increase in ProthrombinTime (PT): Niacin can cause small increases in PT . In a simvastatin-controlled, 24-week study with SIMCOR this effect was not seen.

Increase in Uric Acid: Elevated uric acid levels have occurred with niacin therapy. In a simvastatin-controlled, 24-week study with SIMCOR this effect was not seen. Nevertheless, in patients predisposed to gout, SIMCOR therapy should be used with caution.

Decrease in Phosphorus: Small dose-related reductions in phosphorous levels were seen in clinical studies with niacin. In a simvastatin-controlled, 24-week study with SIMCOR this effect was not seen.

signs and symptoms of muscle pain, tenderness, or weakness, particularly during the initial month of treatment or during any period of upward dosage titration of either drug. Periodic determination of serum creatine kinase (CK) determinations may be considered in such situations, but there is no assurance that such monitoring will prevent myopathy.

Patients starting therapy with SIMCOR should be advised of the risk of myopathy, and told to report promptly unexplained muscle pain, tenderness, or weakness. A CK level above 10 times ULN in a patient with unexplained muscle symptoms indicates myopathy. SIMCOR therapy should be discontinued if myopathy is diagnosed or suspected.

In patients with complicated medical histories predisposing to rhabdomyolysis, such as renal insufficiency, dose escalation requires caution. Also, as there are no known adverse consequences of brief interruption of therapy, treatment with SIMCOR should be stopped for a few days before elective major surgery and when any major acute medical or surgical condition supervenes (e.g., sepsis, hypotension, dehydration, major surgery, trauma, severe metabolic, endocrine, and electrolyte disorders, or uncontrolled seizures).

5.2

6

In a controlled clinical study, 14% of patients randomized to SIMCOR discontinued therapy due to an adverse event. Flushing episodes (i.e., warmth, redness, itching and/or tingling) were the most common treatment-emergent adverse reactions, occurring in up to 59% of patients treated with SIMCOR. Spontaneous reports with niacin extended-release and clinical studies of SIMCOR suggest that flushing may be accompanied by symptoms of dizziness or syncope, tachycardia, palpitations, shortness of breath, sweating, chills, and/or edema.

Liver Dysfunction

Cases of severe hepatic toxicity, including fulminant hepatic necrosis, have occurred in patients who have substituted sustained-release (modified-release, timed-release) niacin products for immediate-release (crystalline) niacin at equivalent doses. Patients previously receiving niacin products other than niacin extended-release should be started on SIMCOR at the lowest recommended starting dose.

SIMCOR should be used with caution in patients who consume substantial quantities of alcohol and/or have a past history of liver disease. Active liver disease or unexplained transaminase elevations are contraindications to the use of SIMCOR. [See Contraindications (4)] Niacin extended-release and simvastatin can cause abnormal liver tests. In a simvastatin-controlled, 24 week study with SIMCOR in 641 patients, there were no persistent increases (to more than 3x the ULN) in serum transaminases. In three placebo-controlled clinical studies of extended-release niacin there were no patients with normal serum transaminases levels at baseline who experienced elevations to more than 3x the ULN. Persistent increases (to more than 3x the ULN) in serum transaminases have occurred in approximately 1% of patients who received simvastatin in clinical studies. When drug treatment was interrupted or discontinued in these patients, the transaminases levels usually fell slowly to pretreatment levels. The increases were not associated with jaundice or other clinical signs or symptoms. There was no evidence of hypersensitivity.

Liver function tests should be performed on all patients during therapy with SIMCOR. It is recommended that liver function tests be performed before treatment begins, every 12 weeks for the first 6 months, and periodically thereafter (e.g., at approximately 6-month intervals). Patients who develop increased transaminase levels should be monitored with a second liver function evaluation to confirm the finding and be followed thereafter with frequent liver function tests until the abnormality returns to normal. Should an increase in transaminase levels of more than 3x ULN persist, or if transaminase elevations are associated with symptoms of nausea, fever, and/or malaise, withdrawal of SIMCOR therapy is recommended.

5.3

ADVERSE REACTIONS

Overview

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

The safety data described below reflect exposure to SIMCOR in 403 patients in a controlled study for a period of 6 months.

Flushing: Flushing (warmth, redness, itching and/or tingling) occurred in up to 59% of patients treated with SIMCOR. Flushing resulted in study discontinuation for 6.0% of patients.

More Common Adverse Reactions: In addition to flushing, adverse reactions occurring in â&#x2030;Ľ 3% of patients (irrespective of investigator causality) treated with SIMCOR are shown in Table 3 below: Table 3. Adverse Reactions Occurring in â&#x2030;Ľ 3% of Patients in a Controlled Clinical Trial Adverse Event SIMCOR overall * Simvastatin overall ** Total Number of Patients N=403 N=238 Headache 18 (4.5%) 11 (4.6%) Pruritus 13 (3.2%) 0 (0.0%) Nausea 13 (3.2%) 10 (4.2%) Back Pain 13 (3.2%) 5 (2.1%) Diarrhea 12 (3.0%) 7 (2.9%) *SIMCOR overall included all doses from 500/20 mg to 2000/40 mg ** Simvastatin overall included 20 mg, 40 mg, and 80 mg doses

Simvastatin In pre-marketing controlled clinical studies and their open extensions (2,423 patients with mean duration of follow-up of approximately 18 months) 1.4% of patients discontinued due to adverse reactions.

The most commonly reported adverse reactions (incidence > 1%) in simvastatin controlled clinical trials were: headache (3.5%), abdominal pain (3.5%), constipation (2.3%), upper respiratory infection (2.1%), diarrhea (1.9%), and flatulence (1.9%).

Laboratory Abnormalities

Increase in Blood Glucose: Niacin treatment can increase fasting blood glucose. In a simvastatin-controlled, 24-week study with SIMCOR the change from baseline in glycosylated hemoglobin levels was 0.2% for SIMCOR-treated patients and 0.2% for simvastatin-treated patients. Diabetic or potentially diabetic patients should be observed closely during treatment with SIMCOR, particularly during the first few months of therapy. Adjustment of diet and/or hypoglycemic therapy or discontinuation of SIMCOR may be necessary.

Reduction in platelet count: Niacin can reduce platelet count. In a simvastatin-controlled, 24-week study with SIMCOR the mean percent change from baseline for patients treated with 2000/40 mg daily was -5.6%.

Niacin Extended-Release In placebo-controlled clinical trials (n=245), flushing episodes were the most common treatment-emergent adverse events (up to 88% of patients) for niacin extended-release. Other adverse events occurring in 5% or greater of patients treated with niacin extended-release are headache (9%), diarrhea (7%), nausea (5%), rhinitis (5%), and dyspepsia (4%) at a maintenance dose of 1000mg daily.

Clinical Laboratory Abnormalities:

SIMCOR Chemistry Elevations in serum transaminases [See Warnings and Precautions (5.2)], CK, fasting glucose, uric acid, alkaline phosphatase, LDH, 2

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amylase, Îł-glutamyl transpeptidase, bilirubin, and reductions in phosphorus, and abnormal thyroid function tests.

Hematology Reductions in platelet counts and prolongation of PT. [See Warnings and Precautions (5.3)]

reductase inhibitors. The increase in AUC for simvastatin acid is presumably due, in part, to inhibition of CYP3A4. The risk of myopathy/rhabdomyolysis is increased by concomitant administration of cyclosporine or danazol particularly with higher doses of simvastatin. [See Warnings and Precautions (5.1)]

7.3

Postmarketing Experience Because the below reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

7.4

The following additional adverse reactions have been identified during postapproval use of simvastatin. Hypersensitivity reaction including one or more of the following features: anaphylaxis, angioedema, lupus erythematous-like syndrome, vasculitis, purpura, thrombocytopenia, leucopenia, hemolytic anemia, positive ANA, ESR increase, eosinophilia, arthritis, photosensitivity, chills, toxic epidermal necrolysis, erythema multiforme, Stevens-Johnson syndrome, urticaria, fever, dyspnea, and arthralgia; pancreatitis, hepatitis, hepatic failure, pruritus, cataracts, polymyositis, dermatomyositis, polymyalgia rheumatica, global amnesia, tendon rupture, peripheral neuropathy, memory impairment.

NIASPAN

7.5

The following additional adverse reactions have been identified during post-approval use of NIASPAN. Hypersensitivity reaction including one or more of the following features: anaphylaxis, angioedema, urticaria, flushing, dyspnea, tongue edema, larynx edema, face edema, peripheral edema, laryngismus, vesiculobullous rash, palpitations, syncope, hypotension, orthostasis, decreased glucose tolerance, gout, hepatitis, skin discoloration, rhabdomyolysis, amblyopia, and insomnia.

Propranolol

In healthy male volunteers there was a significant decrease in mean Cmax, but no change in AUC, for simvastatin total and active inhibitors with concomitant administration of single doses of simvastatin and propranolol. The clinical relevance of this finding is unclear. The pharmacokinetics of the enantiomers of propranolol were not affected.

7.6

DRUG INTERACTIONS

Digoxin

Concomitant administration of a single dose of digoxin in healthy male volunteers receiving simvastatin resulted in a slight elevation (less than 0.3 ng/mL) in digoxin concentrations in plasma (as measured by a radioimmunoassay) compared to concomitant administration of placebo and digoxin. Patients taking digoxin should be monitored appropriately when SIMCOR is initiated.

No drug interaction studies were conducted with SIMCOR. However, the following interactions have been noted with the individual components of SIMCOR:

Simvastatin 7.1 CYP3A4 Inhibitors

7.7 Coumarin Anticoagulants

Simvastatin, like several other inhibitors of HMG-CoA reductase, is a substrate of CYP3A4. Simvastatin is metabolized by CYP3A4 but has no CYP3A4 inhibitory activity; therefore it is not expected to affect the plasma concentrations of other drugs metabolized by CYP3A4.

Potent inhibitors of CYP3A4 include: Itraconazole, ketoconazole, and other antifungal azoles, Macrolide antibiotics erythromycin, clarithromycin, and telithromycin, HIV protease inhibitors, Antidepressant nefazodone, Grapefruit juice in large quantities (> 1 quart daily).

Potent inhibitors of CYP3A4 increase the risk of myopathy by reducing the elimination of simvastatin. Hence when simvastatin is used with a potent inhibitor of CYP3A4, elevated plasma levels of HMG-CoA reductase inhibitory activity can increase the risk of myopathy and rhabdomyolysis, particularly with higher doses of simvastatin. [See Warnings and Precautions (5.1)] Serious skeletal muscle disorder, e.g., rhabdomyolysis, have been reported during concomitant therapy of simvastatin or other HMG-CoA reductase inhibitors with cyclosporine, danazol, itraconazole, ketoconazole, gemfibrozil, niacin, erythromycin, clarithromycin, telithromycin, nefazodone or HIV protease inhibitors.

Concomitant use of drugs labeled as potent inhibitors of CYP3A4 should be avoided unless the benefits of combined therapy outweigh the increased risk. If treatment with itraconazole, ketoconazole, erythromycin, clarithromycin or telithromycin is unavoidable, therapy with SIMCOR should be suspended during the course of treatment.

7.2

Gemfibrozil and other Fibrates

Coadministration of gemfibrozil (600 mg twice daily for 3 days) with simvastatin (40 mg daily) resulted in clinically significant increases in simvastatin acid AUC (185%) and peak plasma concentration (Cmax,112%), possibly due to inhibition of simvastatin acid glucuronidation by gemfibrozil. The increase in simvastatin exposure increases the risk of myopathy when coadministred with gemfibrozil.

The combined use of SIMCOR with gemfibrozil should be avoided [See Warnings and Precautions (5.1)]. The risk of myopathy also increases to a lesser extent when simvastatin is used in combination with other fibrates. Coadministration of 160 mg fenofibrate daily with 80 mg simvastatin daily for 7 days had no effect on plasma AUC (and Cmax) of either total HMG-CoA reductase inhibitory activity or fenofibric acid; there was a modest reduction (approximately 35%) of simvastatin acid which was not considered clinically significant.

Simvastatin

7

Amiodarone or Verapamil

The risk of myopathy/rhabdomyolysis is increased by concomitant administration of amiodarone or verapamil with higher doses of simvastatin. [See Warnings and Precautions (5.1)]

In normal volunteers and hypercholesterolemic patients, simvastatin 20-40 mg/day modestly potentiated the effect of coumarin anticoagulants since the prothrombin time, reported as International Normalized Ratio (INR), increased from a baseline of 1.7 to 1.8 and from 2.6 to 3.4 in the volunteers and patients, respectively. With other reductase inhibitors, clinically evident bleeding and/or increased prothrombin time has been reported in a few patients taking coumarin anticoagulants concomitantly. In such patients, prothrombin time should be determined before starting SIMCOR and frequently enough during early therapy to ensure that no significant alteration of prothrombin time occurs. Once a stable prothrombin time has been documented, prothrombin times can be monitored at the intervals usually recommended for patients on coumarin anticoagulants. If the dose of SIMCOR is changed or discontinued, the same procedure should be repeated.

Niacin 7.8 Aspirin Concomitant use of aspirin may decrease the metabolic clearance of niacin. The clinical relevance of this finding is unclear.

7.9

Antihypertensive Therapy

Niacin may potentiate the effects of ganglionic blocking agents and vasoactive drugs resulting in postural hypotension.

7.10

Bile Acid Sequestrants

An in vitro study was carried out investigating the niacin-binding capacity of colestipol and cholestyramine. About 98% of available niacin was bound to colestipol, with 10 to 30% binding to cholestyramine. These results suggest that 4 to 6 hours, or as great an interval as possible, should elapse between the ingestion of bile acid-binding resins and the administration of SIMCOR.

Cyclosporine or Danazol

Although the mechanism is not fully understood, cyclosporine has been shown to increase the area under the curve (AUC) of HMG-CoA 3

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Other

8.6

Nutritional supplements containing large doses of niacin or related compounds may potentiate the adverse effects of SIMCOR.

8

USE IN SPECIFIC POPULATIONS

8.1

Pregnancy

8.7

Pregnancy Category X â&#x20AC;&#x201C; [See Contraindications (4)] SIMCOR is contraindicated in women who are or may become pregnant. Lipid lowering drugs offer no benefit during pregnancy, because cholesterol and cholesterol derivatives are needed for normal fetal development. Serum cholesterol and triglycerides increase during normal pregnancy. Atherosclerosis is a chronic process, and discontinuation of lipid-lowering drugs during pregnancy should have little impact on long-term outcomes of primary hypercholesterolemia therapy. There are no adequate and well-controlled studies of SIMCOR use during pregnancy; however, there are rare reports of congenital anomalies in infants exposed to HMG-CoA reductase inhibitors in utero. Animal reproduction studies of simvastatin in rats and rabbits showed no evidence of teratogenicity. SIMCOR may cause fetal harm when administered to a pregnant woman. If SIMCOR is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

SIMCOR contains simvastatin (a HMG-CoA reductase inhibitor) and niacin (nicotinic acid). There are rare reports of congenital anomalies following intrauterine exposure to HMG-CoA reductase inhibitors. In a review of approximately 100 prospectively followed pregnancies in women exposed to simvastatin or another structurally related HMG-CoA reductase inhibitor, the incidences of congenital anomalies, spontaneous abortions, and fetal deaths/stillbirths did not exceed those expected in the general population. However, the study was only able to exclude a 3- to 4-fold increased risk of congenital anomalies over the background rate. In 89% of these cases, drug treatment was initiated prior to pregnancy and was discontinued during the first trimester when pregnancy was identified. It is not known whether niacin at doses used for lipid disorders can cause fetal harm when administered to a pregnant woman.

Simvastatin was not teratogenic in rats or rabbits at doses that resulted in 3 times the human exposure based on mg/m2 surface area.

However, in studies with another structurally-related HMG-CoA reductase inhibitor, skeletal malformations were observed in rats and mice. Animal reproduction studies have not been conducted with niacin.

Women of childbearing potential, who require SIMCOR treatment for a lipid disorder, should use effective contraception. Patients trying to conceive should contact their prescriber to discuss stopping SIMCOR treatment. If pregnancy occurs, SIMCOR should be immediately discontinued.

8.3

8.8

Hepatic Impairment

No pharmacokinetic studies have been conducted in patients with hepatic insufficiency for SIMCOR. [See Warnings and Precautions (5.2)]

10

OVERDOSAGE

Supportive measures should be taken in the event of an overdose. The dialyzability of niacin, or of simvastatin and its metabolites, is not known.

A few cases of overdosage with simvastatin have been reported; the maximum dose taken was 3.6 g. All patients recovered without sequelae.

13

NONCLINICAL TOXICOLOGY

13.1

Carcinogenesis, Mutagenesis, Impairment of Fertility

No studies have been conducted with SIMCOR regarding carcinogenesis, mutagenesis, or impairment of fertility.

Niacin Niacin, administered to mice for a lifetime as a 1% solution in drinking water, was not carcinogenic. The mice in this study received approximately 6 to 8 times a human dose of 3000 mg/day as determined on a mg/m2 basis. Niacin was negative for mutagenicity in the Ames test. No studies on impairment of fertility have been performed.

Simvastatin In a 72-week carcinogenicity study, mice were administered daily doses of simvastatin of 25, 100, and 400 mg/kg body weight, which resulted in mean plasma drug levels approximately 1, 4, and 8 times higher than the mean human plasma drug level, respectively (as total inhibitory activity based on AUC) after an 80-mg oral dose. Liver carcinomas were significantly increased in high-dose females and mid- and high-dose males with a maximum incidence of 90% in males. The incidence of adenomas of the liver was significantly increased in mid- and high-dose females. Drug treatment also significantly increased the incidence of lung adenomas in mid- and high-dose males and females. Adenomas of the Harderian gland (a gland of the eye of rodents) were significantly higher in high-dose mice than in controls. No evidence of a tumorigenic effect was observed at 25 mg/kg/day.

In a separate 92-week carcinogenicity study in mice at doses up to 25 mg/kg/day, no evidence of a tumorigenic effect was observed (mean plasma drug levels were 1 times higher than humans given 80 mg simvastatin as measured by AUC). In a two-year study in rats at 25 mg/kg/day, there was a statistically significant increase in the incidence of thyroid follicular adenomas in female rats exposed to approximately 11 times higher levels of simvastatin than in humans given 80 mg simvastatin (as measured by AUC). A second two-year rat carcinogenicity study with doses of 50 and 100 mg/kg/day produced hepatocellular adenomas and carcinomas (in female rats at both doses and in males at 100 mg/kg/day). Thyroid follicular cell adenomas were increased in males and females at both doses; thyroid follicular cell carcinomas were increased in females at 100 mg/kg/day. The increased incidence of thyroid neoplasms appears to be consistent with findings from other HMG-CoA reductase inhibitors. These treatment levels represented plasma drug levels (AUC) of approximately 7 and 15 times (males) and 22 and 25 times (females) the mean human plasma drug exposure after an 80 milligram daily dose. No evidence of mutagenicity was observed in a

Nursing Mothers

Pediatric Use

The safety and effectiveness of SIMCOR in pediatric patients have not been established.

8.5

Renal Impairment

No pharmacokinetic studies have been conducted in patients with renal impairment for SIMCOR. Caution should be exercised when SIMCOR is administered to patients with renal disease. For patients with severe renal insufficiency, SIMCOR should not be started unless the patient has already tolerated treatment with simvastatin at a dose of 10 mg or higher. Caution should be exercised when SIMCOR is administered to these patients and they should be closely monitored.

It is not known whether simvastatin is excreted into human milk; however, a small amount of another drug in this class does pass into breast milk. Niacin is excreted into human milk but the actual infant dose or infant dose as a percent of the maternal dose is not known.

Because of the potential for serious adverse reactions in nursing infants, nursing mothers who require SIMCOR treatment should not breastfeed their infants. A decision should be made whether to discontinue nursing or discontinue drug, taking into account the importance of the drug to the mother. [see Contraindications (4)].

8.4

Gender

Data from the clinical trials suggest that women have a greater hypolipidemic response than men at equivalent doses of niacin extended-release. No consistent gender differences in efficacy and safety were observed in SIMCOR studies.

Geriatric Use

There were 281 (30.8%) patients aged 65 years and older treated with SIMCOR in Phase III clinical studies. No overall differences in safety and effectiveness were observed between these patients and younger patients, but greater sensitivity of some older individuals cannot be ruled out. A pharmacokinetic study with simvastatin showed the mean plasma level of HMG-CoA reductase inhibitory activity to be approximately 45% higher in elderly patients between 70-78 years of age compared with patients between 18-30 years of age.

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microbial mutagenicity (Ames) test with or without rat or mouse liver metabolic activation. In addition, no evidence of damage to genetic material was noted in an in vitro alkaline elution assay using rat hepatocytes, a V-79 mammalian cell forward mutation study, an in vitro chromosome aberration study in CHO cells, or an in vivo chromosomal aberration assay in mouse bone marrow. There was decreased fertility in male rats treated with simvastatin for 34 weeks at 25 mg/kg body weight (4 times the maximum human exposure level, based on AUC, in patients receiving 80 mg/day); however, this effect was not observed during a subsequent fertility study in which simvastatin was administered at this same dose level to male rats for 11 weeks (the entire cycle of spermatogenesis including epididymal maturation). No microscopic changes were observed in the testes of rats from either study. At 180 mg/kg/day, (which produces exposure levels 22 times higher than those in humans taking 80 mg/day based on surface area, mg/m2), seminiferous tubule degeneration (necrosis and loss of spermatogenic epithelium) was observed. In dogs, there was drug-related testicular atrophy, decreased spermatogenesis, spermatocytic degeneration and giant cell formation at 10 mg/kg/day, (approximately 2 times the human exposure, based on AUC, at 80 mg/day). The clinical significance of these findings is unclear.

17.3

17.4

Muscle Pain

To notify their physician of any unexplained muscle pain, tenderness, or weakness promptly. The risk of this occurring is increased when taking certain types of medication or consuming larger quantities of grapefruit juice. They should discuss all medication, both prescription and over the counter, with their physician.

17.5

Flushing

Flushing is a common side effect of niacin therapy that may subside after several weeks of consistent SIMCOR use. Flushing may vary in severity and is more likely to occur with initiation of therapy, or during dose increases. By dosing at bedtime, flushing will most likely occur during sleep. However, if awakened by flushing at night, the patient should get up slowly, especially if feeling dizzy, feeling faint, or taking blood pressure medications.

17.6

Use of Aspirin or other Non-Inflammatory Medication

Taking aspirin or non-steroidal anti-inflammatory medications (e.g., ibuprofen) approximately 30 minutes before dosing can minimize flushing.

No animal toxicology or pharmacology studies were done with SIMCOR.

Niacin

17.7

No animal toxicology or pharmacology studies were done with niacin extended-release.

Diet

To avoid ingestion of alcohol, hot beverages and spicy foods around the time of taking SIMCOR to minimize flushing.

Simvastatin

17.8

Optic nerve degeneration was seen in clinically normal dogs treated with simvastatin for 14 weeks at 180 mg/kg/day, a dose that produced mean plasma drug levels about 12 times higher than the mean plasma drug level in humans taking 80 mg/day. A chemically similar drug in this class also produced optic nerve degeneration (Wallerian degeneration of retinogeniculate fibers) in clinically normal dogs in a dose-dependent fashion starting at 60 mg/kg/day, a dose that produced mean plasma drug levels about 30 times higher than the mean plasma drug level in humans taking the highest recommended dose (as measured by total enzyme inhibitory activity). This same drug also produced vestibulocochlear Wallerian-like degeneration and retinal ganglion cell chromatolysis in dogs treated for 14 weeks at 180 mg/kg/day, a dose that resulted in a mean plasma drug level similar to that seen with the 60 mg/kg/day dose.

Central Nervous System (CNS) vascular lesions, characterized by perivascular hemorrhage and edema, mononuclear cell infiltration of perivascular spaces, perivascular fibrin deposits and necrosis of small vessels were seen in dogs treated with simvastatin at a dose of 360 mg/kg/day, a dose that produced mean plasma drug levels that were about 14 times higher than the mean plasma drug levels in humans taking 80 mg/day. Similar CNS vascular lesions have been observed with several other drugs of this class.

There were cataracts in female rats after two years of simvastatin treatment with 50 and 100 mg/kg/day (22 and 25 times the human AUC at 80 mg/day, respectively) and in dogs after three months at 90 mg/kg/day (19 times) and at two years at 50 mg/kg/day (5 times).

Reproductive Toxicology Studies Simvastatin was not teratogenic in rats at doses of 25 mg/kg/day or in rabbits at doses up to 10 mg/kg/day. These doses resulted in 3 times (rat) or 3 times (rabbit) the human exposure based on mg/m2 surface area. However, in studies with another structurally-related HMG-CoA reductase inhibitor, skeletal malformations were observed in rats and mice.

Supplements

To notify their physician if they are taking vitamins or other nutritional supplements containing niacin or nicotinamide.

17.9

Dizziness

To notify their physician if symptoms of dizziness occur.

17.10 Diabetics If diabetic, to notify their physician of changes in blood glucose.

17.11 Pregnancy Women of childbearing age should use an effective method of birth control to prevent pregnancy while using SIMCOR. Discuss future pregnancy plans with your healthcare professional, and discuss when to stop SIMCOR if you are trying to conceive. If you are pregnant, stop SIMCOR and call your healthcare professional.

17.12 Breastfeeding Women who are breastfeeding should not use SIMCOR. If you have a lipid disorder and are breastfeeding, speak with your healthcare professionals about your lipid disorder and whether or not you should breastfeed your infant.

Ref. 03-A138 Revised: August, 2008 306-193527 MASTER 306-222358

PATIENT COUNSELING INFORMATION

The patient should be informed of the following:

17.1

Dosing Interruption

If dosing is interrupted for any length of time, their physician should be contacted prior to re-starting therapy; re-titration is recommended.

13.2 Animal Toxicology and/or Pharmacology SIMCOR

17

Tablet Integrity

SIMCOR tablets should not be broken, crushed or chewed, but should be swallowed whole.

Dosing Time

SIMCOR tablets should be taken at bedtime, after a low-fat snack.

Administration on an empty stomach is not recommended.

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FEBRUARY/MARCH 2009

VOLUME 2, NUMBER 2, SUPPLEMENT 3

™

™

TABLE OF CONTENTS S97

S98

Publisher Nicholas Englezos nick@engagehc.com 732-992-1884

Introduction: Drug Approvals in 2008

Associate Publisher Maurice Nogueira maurice@engagehc.com 732-992-1895

Value-Based Drug Development Matthew Sarnes, PharmD

Editorial Director Dalia Buffery dalia@AHDBonline.com 732-992-1889 Associate Editor Dawn Lagrosa 732-992-1892

S100 2009 FDA’s NDA Decisions Calendar

Senior Production Manager Lynn Hamilton Business Manager Blanche Marchitto

S102 2008 FDA Prescription Drug Approvals

President Brian F. Tyburski brian@engagehc.com

S108 Patanase: Antihistamine in Long-Acting Nasal Spray Stakeholder Perspective by Jeff J. Guo, BPharm, PhD

Editor-in-Chief Robert E. Henry rhenry@AHDBonline.com 732-992-1885

Mission Statement S112 Trilipix: A New Fibrate Improves Lipids in Mixed Dyslipidemia

S115 Simcor: Simvastatin plus Niacin Working Together to Reduce the Risk of Coronary Heart Disease Stakeholder Perspective by Peter Alagona, MD, FACC

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. Benefit designs are greatly affected by clinical, business, and policy conditions.

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

Contact Information: For reprints, subscription information, and editorial queries, please contact: editorial@AHDBonline.com T: 732-992-1880 F: 732-992-1881

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INTRODUCTION

Drug Approvals in 2008

T

oward the end of 2008, the rate of new drug approvals by the US Foo d & Drug Admin istration (FDA) began to accelerate, potentially signaling a new direction in the FDA approval process, despite an almost universal perception of a risk-averse environment in Congress and in the FDA. The recent establishment of new drug safety measures by the FDA included postmarketing surveillance, as well as the in stitution of the Risk Evaluation and Mitigation Strategy (REMS) in 2008. Nevertheless, by the end of 2008, the number of new drugs approved by the FDA, including new molecular entities (NMEs) and new biologics; new indications; and new formulations far exceeded the rate of approvals in 2007. Compared with 2006, in which the FDA approved a total of 22 NMEs and biologics, the total NMEs and biologics approved in 2007 was only 18. That trend now appears to be changing. As illustrated in this supplement, the number of NMEs and biologics approved in 2008 jumped to 32—21 NMEs and 11 new biologics (pages S102-S107).

This increase in FDA approvals does not by any means signal a relaxing of the FDA ’s review process or regulations. Indeed, several of the biologics approved in 2008 will continue to be monitored by the FDA ’s Center for Drug Evaluation and Research. But the new requirements for postapproval surveillance and the

establishment of REMS may not slow down the approval process as was initially anticipated, as attested by the many new biologics and NMEs, as well as some new formulations that were approved in 2008 under the FDA’s priority review process.

Whether the long list of new drug applications (NDAs) to be reviewed by the FDA in 2009 listed in this supplement (pages S100-S101; the list does not include supplemental NDAs) suggests that the institution of more regulatory steps may actually make the FDA take bolder steps for moving the process forward rather than put more blocks in its way remains to be seen; but for now, the process seems to suggest a rather active FDA in 2009.

In addition to new drugs approved in 2008, this supplement is a goo d resource for a host of new therapeutic options, including novel indications approved in 2008 (page S107), such as an antidepressant—duloxetine hydrochloride (Cymbalta)—for the treatment of fibromyalgia and a protease inhibitor—bortezomib (Velcade)—for the treatment of patients with previously untreated multiple myeloma.

Finally, several drugs approved in 2008 are also featured in the supplement in special articles that include stakeholder perspectives by experts in the respective fields.

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Value-Based Drug Development Matthew Sarnes, PharmD Dr Sarnes is Vice President, Managed Markets Division, Xcenda, Collegeville, PA.

T

he pharmaceutical pipeline is a cornerstone of innovation in healthcare. Currently, more than 2700 drugs are in development in the United States, for nearly 4600 different indications. The pharmaceutical industry’s continued commitment to invest in research and development (R&D) in recent years is commendable, in light of the growing costs and resources required to navigate through the complexities of the current risk-averse healthcare environment.

It takes an estimated $1.3 billion and 10 to 15 years to bring a new drug from the laboratory to the pharmacy.1

The New R&D Environment The high cost of pro duct development is the result of several factors, including (but not limited to): • The increased scrutiny over the safety of new agents • A push toward measuring outcomes and events in clinical trials, along with comparative effectiveness research • A shift toward the development of biologics.

The requirement for stronger safety data and preference for measurement of “hard” clinical outcomes over “intermediate” or “surrogate” end points (eg, reduction in heart attacks rather than decrease in systolic bloo d pressure) has dramatically increased the length of follow-up time and the average sample size of clinical trials. These 2 factors contribute significantly to development costs and time. In addition, manufacturers are now required to invest in postmarketing surveillance for many of their pro ducts to ensure their safety once they are on the market. Finally , in an effort to continue to bring innovative products to market, much of the industry has shifted its focus from traditional, smallmolecule pro ducts to biologics. Because biologics are typically derived from human-based antibo dies, enzymes, or hormones, 2 their pro duction is generally more complex and costly.

To survive in this changing R&D environment, many pharmaceutical and biotech companies are breaking away from traditional development business models and practices, by setting up small research teams or drug performance units that will compete for funding from a global resource. 3 These small research

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pods foster an entrepreneurial spirit and help the company become more flexible and nimble.

In addition to such an internal shift, many of the larger pharmaceutical companies are moving more resources to evaluate licensing and acquisition opportunities. Given the high attrition rates in drug development seen in phase 3 trials during the past few years, larger companies are more willing to enter into risksharing agreements with smaller development companies. These types of arrangements may allow the larger pharmaceutical company to have a stake in more compounds with less investment up-front, in exchange for future royalties once a pro duct enters the market.

The Shift toward Biologics The regulatory process adds another layer to the pressures facing innovation in the pharmaceutical industry. Given the growing emphasis on biologics and specialty pharmaceuticals, and the rising costs of these agents, the regulatory process may change in the coming months or years. Since 2003 there has been a marked increase in the number of generics entering the market. Generics represented 51% of total prescriptions dispensed in the United States in 2003; by 2008 that percentage grew to 64%. 4 It will be important to follow whether biosimilar legislation will be enacted under President Obama’s administration.

With the more protected status of biologic products, the business side of pharmaceutical development is also moving toward specialty pro ducts. In 2005, there were more than 600 biologic pro ducts in the US pipeline, and that number is expected to continue to rise. The top 3 therapeutic areas for pipeline pro ducts are5,6: • Oncology—210 agents • Infectious diseases—50 agents • Autoimmune diseases—44 agents.

Biologic pro duct sales are expected to exceed $60 billion by 2010 and will likely account for 25% of all drug sales and 50% of new drug approvals. 7 But this growth in biologics will have a substantial financial impact to the healthcare system: the average daily cost of a biologic agent is $55, compared with only $2 for a traditional, small-molecule drug. 5,6

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Value-Based Drug Development

The Payer’s Role An important factor in the current healthcare system is the interaction between pharmaceutical development and managed care; pharmaceutical innovation cannot be sustained without the sanction of the payer , and the objective of managed care organizations (MCOs) is to provide the highest quality and most cost-effective care to their members. Thus, changes by manufacturers influence MCOs and, in turn, shifts in MCOs’ policies affect manufacturers.

Prior authorizations, adherence to clinical guidelines, variable reimbursements, and step therapy are all strategies that were used to help manage costs in 2008.8 The percentage of MCOs that will use at least 1 of these management strategies is expected to increase considerably in 2009. 8 There is also a defined shift to managing injectable products under the pharmacy benefit as quickly as possible. This shift to biologic coverage under the pharmacy provides access to richer data, better utilization monitoring, and prior authorizations—designed to help control costs.8

tion of payers and deliver or document that value proposition once on the market.

The New Value-Based Drug Development Bringing a product to market requires raising the bar across the spectrum. The current shift to value-based drug development requires a paradigm shift. Although critical to the success of a new pharmaceutical product, drug developers can no longer rely solely on traditional efficacy and safety data to feel confident that they have a “blockbuster” drug. Given the growing influence of payers and the demand for cost-effective therapies, health outcomes researchers, reimbursement specialists, and managed markets experts are playing a larger role in the development process. Therefore, experts from these various disciplines must work handin-hand with clinical and marketing teams to develop a cohesive market strategy for an emerging therapy .

An important take-away message for to day’s changing healthcare environment is the need to deliver on the brand-drug promise, or value proposition, that is being created during the drug development/planning process. Effective market value planning allows the manufacturer to not only evaluate which pro ducts to pursue based on their potential value proposition when entering the marketplace, but also to set the expecta-

References

Given the growing influence of payers and the demand for cost-effective therapies, health outcomes researchers, reimbursement specialists, and managed markets experts are playing a larger role in the development process.

With the growing focus on tracking outcomes and the progress in data-capturing systems (ie, electronic medical records, claims databases), the ability of the various stakeholders to evaluate the true value of new medical technologies will continue to increase.

Therefore, setting a defined and realistic value proposition—that can be proved or reinforced over time—for the pro duct during launch time will be a key characteristic of successful emerging therapies. ■ 1. America’s Pharmaceutical Research Companies. New drug approvals in 2007: pharmaceutical research companies receive approval for 26 new treatments in 2007. 2008. www.phrma.org/media/NDA2007.pdf. Accessed November 16, 2008.

2. US National Library of Medicine and the National Institutes of Health.

Medline Plus. One-quarter of biologic drugs have had safety issues. www . nlm.nih.gov/medlineplus/print/news/fullstory_70694.html. Accessed November 17, 2008.

3. Mauney E. Pipeline dreams: GSK’ s W itty outlines plans to lower phase II attrition. The Pink Sheet. 2008;70:10.

4. IMS Health. IMS Health reports annual global generics prescription sales growth of 3.6 percent, to $78 billion. December 10, 2008. www.ims health.com/portal/site/imshealth/menuitem.a46c6d4df3db4b3d88f6110 19418c22a/?vgnextoid=2943d52288d1e110VgnVCM100000ed152ca2 RCRD&vgnextchannel=41a67900b55a5110VgnVCM10000071812ca2 RCRD&vgnextfmt=default. Accessed January 1, 2009.

5. Grabowski H, Cockburn I, Long G. The market for follow-on biologics: how will it evolve? Health Aff (Millwood). 2006;25:1291-1301.

6. Miller S, Houts J. Potential savings of biogenerics in the US. Express Scripts. February 2007:1-8. www .express-scripts.com/industryresearch/ outcomes/onlinepublications/study/potentialSavingsBiogenericsUS.pdf.

Accessed December 2, 2008.

7. Schofield I. Getting biosimilars to market. RAJ Pharma. 2007;6:369-371.

8. Xcenda. Trends in injectable versus oral management practices survey.

Managed Care Network meeting. March 2008; Orlando, FL. The survey was conducted through Xcenda’ s Managed Care Network, an organization comprised of more than 100 medical and pharmacy directors from commercial managed care plans and pharmacy benefit managers from across the United States.

February/March 2009

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Date

New Drug Applications

January 31

Multaq (dronedarone) for atrial fibrillation (priority review)

February 3

Effient (prasugrel) for acute coronary syndrome

February 7

ATryn (recombinant human antithrombin) (BLA; priority review)

February 15

Embeda (morphine + naltrexone) designed to deter abuse and diversion

February 15

Byetta (exenatide) monotherapy for type 2 diabetes

February 25

Ampligen (poly I:poly C 12 U) for chronic fatigue syndrome (orphan status)

February 27

Metozolv (metoclopramide orally disintegrating tablets) for gastroesophageal reflux disease; gastroparesis

February 28

Silenor (doxepin) for treatment of insomnia (new indication)

February 28

Toremifene 80 mg for bone loss due to prostate cancer (priority review)

March 9

Everolimus for advanced kidney cancer (priority review)

March 23

DX-88 (ecallantide) for hereditary angioedema acute attacks (BLA; priority review)

March 29

Rezonic (casopitant) for chemotherapy-induced nausea, vomiting

April 2

Liraglutide for type 2 diabetes

April 13

Reloxin (botulinum toxin type A) for esthetic indications (BLA)

April 17

Surfaxin (lucinactant) for prevention of respiratory distress syndrome in premature infants

April 27

Golimumab (CNTO 148) for rheumatoid arthritis (BLA)

April 30

PolyHeme (human hemoglobin-based temporary oxygen-carrying red bloo d cell substitute) for life-threatening red blood cell loss (BLA; priority review)

April 30

Puricase (pegloticase) for treatment-failure gout patients (BLA; priority review)

April 30

Onglyza (saxagliptin, a dipeptidyl peptidase-4 enzyme inhibitor) for type 2 diabetes

April 30

Inhaled treprostinil for pulmonary arterial hypertension

April 30

Provenge (sipuleucel-T) for metastatic, androgen-independent prostate cancer (BLA)

May 15

Serdolect (sertindole) for treatment of schizophrenia

May 24

Tadalafil for treatment of pulmonary arterial hypertension

May 30

Xarelto (rivaroxaban) for treatment of deep vein thrombosis, pulmonary embolism

May 31

Gencaro (bucindolol) for chronic heart failure

June 15

Onsolis (BEMA fentanyl) for breakthrough cancer pain

June 23

Zentase (EUR-1008) for pancreatic enzyme replacement therapy

June 26

Alogliptin (SYR-322) for type 2 diabetes

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Date

New Drug Applications

July 18

Rapid-onset trazodone (DDS-04A) for treatment of major depressive disorder (new formulation)

July 23

Alogliptin + Actos (SYR-322 + pioglitazone, combination tablet) for treatment of diabetes type 2

July 30

Intermezzo (zolpidem sublingual lozenge) for use as needed for insomnia from middle-of-thenight awakenings

July 31

Adenovirus types 4 and 7 (live oral tablet vaccines) for prevention of acute respiratory disease (BLA)

August 1

Cethromycin for community-acquired pneumonia

August 22

Qutenza (NGX-4010, capsaicin skin patch) for postherpetic neuralgia nerve pain

August 24

Comfyde (carisbamate) for seizure control in epilepsy

September 12

Bepreve (bepotastine, eye drop) for ocular itching associated with allergic conjunctivitis

September 13

Trelstar (triptorelin) for palliative treatment of advanced prostate cancer (new 6-month formulation)

September 20

Trabectedin (tetrahydroisoquinoline alkaloid) in combination with Doxil (doxorubicin) for treatment of relapsed ovarian cancer

October 18

CorVue (cardiac imaging agent)

October 19

Denosumab (fully human monoclonal antibo dy) for postmenopausal osteoporosis; bone loss from prostate and breast cancer (BLA)

November 9

Solzira (gabapentin enacarbil) for treatment of mo derate to severe restless leg syndrome

November 26

Telavancin (once-daily antibiotic) for treatment of hospital-acquired pneumonia, including methicillin-resistant Staphylococcus aureus

BLA indicates biologic license approval.

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2008 FDA Prescription Drug Approvals New Pharmaceuticals/Formulations AdreView (NME)a,b (Iobenguane I 123, injection; GE Healthcare) Class Gamma-scintigraphy radiopharmaceutical iobenguane I 123 IV Indication Detection of primary/metastatic pheo chromocytomas or neuroblastoma Ak-Fluor (new formulation) (Fluorescein sodium 10%, 25%, IV; Akorn) Class Sterile ophthalmic solution Indication Aid in diagnostic fluorescein angiography/angiography of the retina and iris vasculature Aloxi (new formulation) (Palonosetron hydrochloride; MGI/Helsinn Healthcare) Class Antiemetic Indication Prevention of acute/delayed chemo therapy-induced nausea, vomiting Alvesco (new formulation) (Ciclesonide, inhalation aerosol; Nycomed) Class Inhaled corticosteroid with novel release properties Indication Maintenance/prophylactic therapy of asthma in patients ≥12 years Aplenzin (Bupropion hydrobromide, ER tablets; Biovail)

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Class Aminoketone antidepressant Indication Treatment of MDD in adults

Indication Adjunctive treatment for seizures associated with Lennox-Gastaut syndrome in patients ≥4 years

Apriso ER (new formulation) (Mesalamine, ER capsules; Salix) Class Antiinflammatory; 5-ASA Indication Maintenance of UC remission

Cefepime injection (new formulation) (Baxter Healthcare) Class Cephalosporin antibiotic Indication For various infections from susceptible strains

Aptivus (new formulation)a (Tipranavir; Boehringer Ingelheim) Class Protease inhibitor Indication HIV/AIDS treatment Arcalyst (BLA)a,b (Rilonacept, injection; Regeneron) Class Interleukin-1 blocker Indications For cryopyrin-associated periodic syndromes in patients ≥12 years: familial cold autoinflammatory syndrome; Muckle-Wells syndrome Artiss (BLA)c (Fibrin sealant [human]; Baxter Healthcare) Class Fibrin sealant Indication To adhere autologous skin grafts to surgically prepared wound beds resulting from burns Banzel (NME) (Rufinamide; Eisai) Class Anticonvulsant

February/March 2009

Cimzia (BLA) (Certolizumab pegol, subcutaneous injection; UCB) Class Tumor necrosis factor blocker Indication Treatment of moderate to severe Crohn’s disease when conventional treatment fails Cinryze (BLA)c (C1 inhibitor [human], IV freezedried powder; Lev) Class C1 inhibitor Indication Routine prophylaxis against angioede ma attacks in adolescents and adults with hereditary angioedema Claritin liqui-gel (new formulation) (Loratadine; Schering-Plough) Class Antihistamine Indication For allergy relief Cleviprex (NME) (Clevidipine butyrate, IV; The Medicines Co)

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Class Calcium channel blocker Indication Reduction of blood pressure when oral therapy is not feasible/ desirable Degarelix (NME) (Degarelix acetate, injection; Ferring) Class GnRH receptor antagonist Indication Treatment of advanced prostate cancer Docetaxel injectiond (Docetaxel; Hospira) Class Antineoplastic agent Indications For treatment of breast cancer; non–small-cell lung cancer; prostate cancer Durezol (NME)a (Difluprednate, ophthalmic emulsion; Sirion) Class Corticosteroid Indication For inflammation/pain associated with ocular surgery Entereg (NME) (Alvimopan, oral capsules; Adolor/GlaxoSmithKline) Class Peripherally acting µ-opioid receptor antagonist Indication To expedite GI recovery after partial large-/small-bowel resection surgery with primary anastomosis

Page S103

Indication Contrast agent for MRI of the liver in adults Epiduo gel (Adapalene + benzoyl peroxide, topical; Galderma) Class Retinoid (combination) Indication For treating acne vulgaris in patients ≥12 years Flo-Pred (new formulation) (Prednisolone acetate, oral suspension; Taro) Class Antiinflammatory/immunosup pressive Indications For treating allergic, dermatologic, GI tract, hematologic, ophthalmologic, CNS, renal, respiratory tract, and rheumatologic conditions; specific infections; conditions related to organ transplantation; certain endocrinologic conditions; palliation of certain neoplastic conditions Intelence (NME)a (Etravirine, tablets; Tibotec) Class NNRTI Indication Treatment of HIV-1 infection, in an antiretroviral regimen, in patients with evidence of viral replication and HIV-1 strains resistant to NNRTIs/other antiretrovirals

Class Vaccine Indication For immunization against DTaP, polio Lamivudine, Stavudined (Cipla) Class Antiretroviral regimen Indication HIV/AIDS treatment Lamivudine, Tenofovir disoproxil furamated (Matrix Labs) Class Antiretroviral regimen Indication HIV/AIDS treatment Lamivudine, Zidovudine, Nevirapined (Matrix Labs) Class Antiretroviral regimen Indication HIV/AIDS treatment Lexiscan (NME) (Regadenoson, IV injection; CV Therapeutics/Astellas) Class A2A adenosine receptor agonist (stress agent) Indication For radionuclide myocardial perfusion imaging in patients unable to undergo exercise stress

Liquadd (Dextroamphetamine sulfate, oral Keppra XR (new formulation) (Levetiracetam, ER capsules; UCB) solution; Auriga) Class Class CNS stimulant Antiepileptic Indication Indication Eovist (NME) For partial-onset seizures in patients Treatment of attention-deficit (Gadoxetate disodium, IV injection; ≥4 years disorder with hyperactivity Bayer HealthCare) Class LoSeasonique (new formulation) Kinrix (BLA)c (DTaP + inactivated polio virus, Organ-specific, gadolinium-based (Levonorgestrel + ethinyl estradiol vaccine; GlaxoSmithKline) MRI contrast agent 0.1 mg, tablets; Duramed)

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Class Oral contraceptive (combination) Indication Prevention of pregnancy Lusedra (NME) (Fospropofol disodium, solution, IV; Eisai) Class Sedative/hypnotic/anesthetic drug Indication To monitor anesthesia sedation in adults undergoing diagnostic/ therapeutic procedures Luvox CR (new formulation) (Fluvoxamine maleate; Jazz) Class SSRI antidepressant Indications Social anxiety disorder; OCD Mesalamine (new formulation) (Formerly Asacol; delayed-release tablets; Procter & Gamble) Class Antiinflammatory; 5-ASA Indications Treatment of mild to mo derate UC; maintenance of UC remission Morphine sulfatee (Immediate-release tablets; oral solution, concentrate; Roxane) Class Opioid Indication For severe, chronic pain in terminal disease

Class Hematopoietic stem-cell mobilizer Indication In combination with G-CSF, to mobilize hematopoietic stem cells to peripheral blood for collection/ subsequent autologous transplan tation in patients with nonHodgkinâ&#x20AC;&#x2122;s lymphoma and multiple myeloma Navstel (new formulation) (Hypromellose + dextrose + gluta thione, ophthalmic solution; Alcon) Class Intraocular irrigating agent (combination) Indication For ocular irrigation in surgical procedures involving perfusion of the eye Nexium (new formulation) (Esomeprazole magnesium, delayedrelease oral suspension; AstraZeneca) Class Proton pump inhibitor Indications Treatment of GERD; erosive esophagitis; NSAID-linked gastric ulcer prophylaxis

Nexterone (new formulation) (Amiodarone hydrochloride; Prism) Class Injectable antiarrhythmic agent Indications Treatment initiation/prophylaxis of frequent ventricular fibrillation and hemodynamically unstable ventricuMoxatag (new formulation) lar tachycardia in disease refractory (Amoxicillin, ER tablets; MiddleBrook) to other therapies Class Antibiotic NovoLog Mix 50/50 (new Indication formulation) Treatment of tonsillitis/pharyngitis (50% insulin aspart protamine secondary to Streptococcus pyogenes suspension/50% insulin aspart in patients >12 years recombinant; Novo Nordisk) Class Mozobil (NME)a,b Human insulin analog (Plerixafor, injection; Genzyme) (combination)

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Indication Adjunct to diet and exercise for gly cemic control in diabetes mellitus Nplate (BLA) (Romiplostim, subcutaneous injection; Amgen) Class Thrombopoietin receptor agonist Indication For adult chronic ITP in patients not responding well to steroids, immunoglobulin, splenectomy Omnitrope (new formulation) (Somatropin liquid, in 10-mg/1.5-mL cartridge, for injection; Sandoz) Class rhGH Indication For long-term treatment of growth failure in children/replacement therapy in adults (cartridge provides treatment flexibility at a reduced cost) OraVerse (new formulation) (Phentolamine mesylate; Novalar) Class Alpha-adrenergic blocker Indication For reversal of soft-tissue anesthesia/ functional deficits from local dental anesthetic Pantoprazole sodiumd (Pantoprazole sodium, IV; Teva Parenteral) Class Proton pump inhibitor Indications For 7- to 10-day treatment of GERD with a history of erosive esophagitis; treatment of pathological hypersecretory conditions associated with Zollinger-Ellison syndrome/other neoplastic conditions Patanase (Olopatadine hydrochloride, nasal spray, metered; Alcon)

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Class H1 receptor antagonist Indication For symptom relief of seasonal allergic rhinitis in patients ≥12 years PegIntron/Rebetol Combo Pack (BLA) (Peginterferon alpha-2b + ribavirin; Schering) Class Antiviral (combination) Indication For chronic hepatitis C treatment, in combination with ribavirin Pentacel (BLA)c (DTaP + inactivated polio virus and Hib/PRP-T, vaccine; sanofi pasteur) Class Vaccine Indication Immunization against DTaP and invasive disease cause by Haemophilus influenzae type B for children 6 weeks to 4 years PrandiMet (Repaglinide + metformin hydrochloride, tablets; Novo Nordisk) Class Insulin secretagogue, biguanide (combination) Indication Adjunct to diet/exercise for glycemic control in diabetes, when hyperglycemia is not controlled with meglitinide and metformin, or with either agent alone Prilosec (new formulation) (Omeprazole; AstraZeneca) Class Proton pump inhibitor Indication Treatment of GERD Pristiq (NME) (Desvenlafaxine succinate, tablets; Wyeth)

Class Selective SNRI antidepressant Indication For MDD treatment

Class Dopamine agonist Indication For idiopathic Parkinson’s disease

Promacta (NME)a,b (Eltrombopag olamine, tablets; GlaxoSmithKline) Class Thrombopoietin thyroid peroxidase receptor agonist Indication Treatment of thrombocytopenia in patients with chronic immune ITP not responding well to corticoste roids, immunoglobulin, splenectomy

Rotarix (BLA)c (Live attenuated rotavirus, oral vaccine; GlaxoSmithKline) Class Vaccine Indication Prevention of rotavirus gastroenteritis in infants (ages 6-24 weeks) administered as a 2-dose series

Recothrom (BLA)c (Thrombin topical [recombinant] powder for solution; ZymoGenetics) Class Serine protease Indication To aid hemostasis in bleeding/ oozing and minor bleeding from capillaries/small venules if surgical techniques are inadequate/ ineffective in adults

Sancuso (Granisetron hydrochloride, transdermal system; Strakan) Class Serotonin subtype 3 (5-HT) receptor agonist Indication Prevention of chemotherapyinduced nausea, vomiting

Requip XL (new formulation) (Ropinirole; GlaxoSmithKline)

Stavudine, Lamivudine, Nevirapine d (Strides Arcolab)

Salonpas (new formulation) (Methyl salicylate + menthol, Rapaflo (NME) patch; Hisamitsu) (Silodosin, oral capsules; Watson) Class Class Analgesic (combination) Alpha-1 adrenergic receptor antagonist Indication Indication Relief of muscle/joint pain, For benign prostatic hyperplasia particularly backache, arthritis, treatment strains, sprains, bruises

Simcor (Simvastatin 20 mg + niacin ER Relistor (NME) 500, 750, 1000 mg, tablets; Abbott) (Methylnaltrexone bromide, subcu- Class taneous injection; Progenics/Wyeth) HMG-CoA reductase inhibitor + Class nicotinic acid (combination) Peripherally acting µ-opioid Indication receptor antagonist To improve lipid profile by reducing LDL-C, triglycerides, and increasing Indication HDL-C in patients with primary Treatment of opioid-induced hypercholesterolemia and mixed constipation in advanced illness, dyslipidemia, when monotherapy when palliative/laxative therapy is inadequate is insufficient

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Class Indication Antiretroviral regimen (combination) Blood pressure reduction Indication HIV/AIDS treatment Toviaz (NME) (Fesoterodine fumarate, tablets; Pfizer) Stavzor (new formulation) Class (Valproic acid, delayed-release capsules; Banner Pharmacaps) Anticholinergic Class Indication Anticonvulsant, mood stabilizer Control of overactive bladder Indication syndrome Treatment of manic episodes of Treanda (NME)a,b bipolar disorder (Bendamustine hydrochloride, IV Synthetic Conjugated Estrogens A injection; Cephalon) Class (new formulation) Cytotoxic chemotherapy (Conjugated estrogens, vaginal Indications cream; Duramed/Barr) Treatment of chronic lymphocytic Class leukemia; indolent B-cell nonEstrogen Hodgkin’s lymphoma that has proIndication gressed during/within 6 months’ Treatment of moderate to severe vaginal dryness/dyspareunia treatment with rituximab/rituximabcontaining regimen Taclonex Scalp (new formulation) (Calcipotriene hydrate + beta meth- Treximet asone dipropionate, topical suspen- (Sumatriptan succinate + naproxen sion; Warner Chilcott/LEO Pharma) sodium; GlaxoSmithKline) Class Class Triptan + NSAID (combination) Vitamin D analog + corticosteroid Indication (combination) Treatment of acute migraine Indication Treatment of moderate to severe pso- with/without aura in adults riasis vulgaris of the scalp ( ≥18 years) Trilipix (Fenofibric acid, delayed-release Tapentadol HCl (NME) capsules; Abbott) (Tapentadol hydrochloride, immediate-release tablets; Class Johnson & Johnson) Fibrate Class Indications Treatment of mixed dyslipidemia, Analgesic monotherapy or with a statin; Indication adjunctive therapy to diet for severe Relief of moderate to severe hypertriglyceridemia; for primary acute pain in adults hyperlipidemia Tekturna HCT Trivaris (new formulation) (Aliskiren + hydrochlorothiazide, (Triamcinolone acetonide, tablets; Novartis) injectable suspension; Allergan) Class Class Renin-angiotensin-aldosterone Synthetic corticosteroid inhibitor

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Indications Treatment of psoriasis; other recal citrant skin conditions Vasovist (NME) (Gadofosveset trisodium, injection; EPIX) Class Gadolinium-based contrast agent (for magnetic resonance angiography) Indication For blood vessel imaging: to evaluate aortoiliac occlusive disease/narrowing of peripheral vascular disease Venlafaxine hydrochloride (new formulation) (ER tablets; Osmotica) Class SNRI antidepressant Indications Treatment of MDD; social anxiety disorder Vimpat (NME) (Lacosamide, IV/tablets; Schwarz Biosciences) Class Anticonvulsant Indication Adjunctive therapy for partial-onset seizures in patients ≥17 years Xenazine (NME)a,b (Tetrabenazine tablets; Prestwick) Class Centrally acting dopaminedepleting drug Indication Treatment of chorea of Huntington’s disease Xyntha (BLA)c (Antihemophilic factor [recombinant] plasma/albumin-free, IV freeze-dried powder; Wyeth) Class Antihemophilic recombinant factor III Indications To control/prevent bleeding

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episodes/surgical prophylaxis in patients with hemophilia A Xyzal (new formulation) (Levocetirizine dihydrochloride, oral suspension; UCB)

Class Antiallergen Indications For relief of indoor/outdoor allergies; chronic idiopathic urticaria in patients â&#x2030;Ľ6 years

Zolpimist (new formulation) (Zolpidem tartrate, oral spray; NovaDel) Class Nonbenzodiazepine hypnotic Indication For short-term treatment of insomnia

New Indications Kaposi sarcoma, after chemotherapy Indication failure/intolerance Treatment of hypotrichosis of the eyelashes (to increase their length, Gamunex thickness, darkness) (Immune globulin, 10% infusion; Talecris Biotherapeutics) Luvox Class (Fluvoxamine maleate; Jazz) Immune globulin Class Indications SSRI antidepressant Depakote ER (new population) Treatment of chronic inflammatory Indication (Divalproex sodium; Abbott) Class demyelinating polyneuropathy; pri- Long-term treatment of OCD Valproate mary humoral immunodeficiency Indications Prezista For pediatric use in: acute treatment Gleevec (Darunavir ethanolate; Tibotec) of manic/mixed episodes associated (Imatinib mesylate; Novartis) Class with bipolar disorder; complex par- Class Protease inhibitor tial seizures; simple/complex absence Kinase inhibitor Indication Indication seizures; migraine prophylaxis HIV infection, coadministration Kit (CD117) positive unresectable with ritonavir/other antiretroviral Doxil and/or metastatic malignant GI agents in patients â&#x2030;Ľ6 years (Doxorubicin hydrochloride; stromal tumors Ortho Biotech) Velcade Latisse (new formulation)a Class (Bortezomib; Millennium) (Bimatoprost, ophthalmic solution; Class Anthracycline topoisomerase Allergan) inhibitor Proteasome inhibitor Class Indication Indication Reformulation of prostaglandin analog Treatment of previously untreated Treatment of AIDS-associated multiple myeloma Cymbalta (Duloxetine hydrochloride, tablets; Eli Lilly) Class Selective SNRI antidepressant Indication Fibromyalgia

a

Priority review.

Orphan drug.

Continues to be reviewed postmarketing. d Tentative approval. e Previously marketed without FDA approval. b c

ASA indicates aminosalicylic acid; BLA, biologic license approval; CNS, central nervous system; DT aP, diphtheria and tetanus toxoids with acellular pertussis absorbed; ER, extended release; G-CSF, granulocyte-colony stimulating factor; GERD, gastroesophageal reflux disease; GI, gastrointestinal; GnRH, gonadotropin-releasing hormone; HDL-C, high-density lipoprotein cholesterol; Hib/PRP-T, haemophilus b conjugate [tetanus toxoid conjugate]; HMG-CoA, 3-hydroxy-3-methylglutaryl coenzyme A; ITP, idiopathic thrombocytopenia purpura; IV, intravenous; LDL-C, low-density lipoprotein cholesterol; MDD, major depressive disorder; MRI, magnetic resonance imaging; NME, new molecular entity; NNR TI, nonnucleoside reverse transcriptase inhibitor; NSAID, nonsteroidal antiinflammatory drug; rhGH, recombinant human growth hormone; O CD, obsessive-compulsive disorder; SNRI, serotonin-norepinephrine reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor; TNF, tumor necrosis factor; UC, ulcerative colitis.

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Patanase: Antihistamine in Long-Acting Nasal Spray

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easonal allergic rhinitis occurs in reaction to airborne substances, such as pollen, that invade the nose, throat, sinuses, ears, and eyes. The most common allergic disease is seasonal allergic rhinitis, also known as hay fever, which affects 20% of the population.1 The total direct and indirect costs of allergic rhinitis are estimated at $5.3 billion annually .2 Perennial allergic rhinitis is a similar allergy that affects those prone to it year-round. It is caused by a variety of allergens, from pet dander to dust mites. Allergic rhinitis is common in children and adolescents and affects up to 40% of children. The majority of cases occur by age 20. 2 When foreign microscopic substances invade the nose, the body produces antibodies in response, which in turn activate cells to release histamine. Histamine binds to receptors in the upper respiratory passages, making them swell and resulting in a complex of symptoms typical of hay fever , including itchy and watery eyes, frequent sneezing, nasal congestion and itching, rhinorrhea, coughing, and/or wheezing.

Inflammation of the mucous membranes is triggered by an immunoglobulin (Ig) E-mediated response to an invading substance or protein. IgE-mediated reactions to extrinsic allergens are transferred genetically . IgE coats the surface of mast cells of the nasal mucosa.

When an invading protein such as pollen is inhaled, it can bind to the IgE on the mast cells, leading to the release of mediators. The mediators (histamine, tryptase, chymase, kinins, and heparin) are released immediately, triggering the release of further mediators, including leukotrienes and prostaglandin D 2, which result in the symptoms of rhinorrhea—itchy nose, sneezing, and congestion. Over a perio d of hours, these mediators recruit inflammatory cells to the mucosa, which results in further congestion that can last hours or days. Systemic effects, such as fatigue and malaise, may also occur and negatively affect patients’ quality of life. 3-6 Although allergic rhinitis is not life-threatening, individuals who suffer from it are susceptible to other allergic respiratory disorders, such as asthma, eustachian tube dysfunction, acute sinusitis, or chronic sinusitis.7,8 In fact, 20% of individuals with allergic rhini tis also have symptoms of asthma, and uncontrolled

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allergic rhinitis can lead to worsening of asthma or atopic dermatitis.

Alcon Laboratories has recently developed olopatadine hydrochloride (Patanase) nasal spray 0.6%, which has been approved by the US Foo d and Drug Administration for the relief of symptoms of seasonal allergic rhinitis in patients aged 12 years or older . The drug offers relief within 30 minutes, with a 12-hour duration of effect. The 100-mL spray contains 665 µg of olopatadine, released in a metered-spray solution for intranasal administration. The active component of Patanase nasal spray—olopatadine—is a white, water soluble crystalline powder.

Clinical Pharmacology Olopatadine is an antihistamine with selective H 1receptor antagonist activity , principally mediated via inhibition of H 1 receptors. Olopatadine has shown linear pharmacokinetics across several routes: nasal, oral, intravenous, and topic ocular . Individual peak plasma concentrations were observed between 30 minutes and 1 hour after twice-daily administration of Patanase nasal spray. Protein binding of olopatadine was mo derate (55% in human serum) and independent of drug concentration at a range of 0.1 ng/mL to 1000 ng/mL. Olopatadine was not metabolized extensively and accounted for 77% of peak plasma total radioactivity and all metabolites (olopatadine N-oxide and Ndesmethyl olopatadine) of less than 6% combined. The plasma elimination half-life of olopatadine is between 8 and 2 hours. It is one of the few antiallergy drugs that is eliminated mainly through urinary excretion.

Clinical Trials Three randomized, double-blind, placebo-controlled, parallel-group, multicenter , 2-week studies were conducted to determine the safety and efficacy of olopatadine nasal spray for the treatment of seasonal allergic rhinitis.5,6,9 The studies were conducted in adult and adolescent patients aged 12 years or older with symptoms of seasonal allergic rhinitis. In all 3 trials, patients were treated with Patanase nasal spray (0.4% or 0.6%), 2 sprays per nostril, twice daily or placebo (a vehicle nasal spray). Efficacy was based on patient recording of

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4 nasal symptoms: nasal congestion, rhinorrhea, itchy nose, and sneezing. Instantaneous recording required patients to note the severity of symptoms at the time of recording, whereas reflective recordings note the severity of symptoms since the last dose. The primary efficacy end point was the total nasal symptom score (TNSS) from daily diaries. The superiority of olopatadine over placebo was significant for reducing the reflective and instantaneous assessments on the TNSS, and olopatadine’s safety profile was comparable to placebo. In these studies, adverse events were nonserious and infrequent in all treatment groups. Olopatadine afforded significant improvement in quality of life and the ability to perform work and conduct usual activities in patients with seasonal allergic rhinitis.

Drug Interactions and Safety Concerns Drug interaction studies have not been conducted for Patanase nasal spray. Interactions with inhibitors of liver enzymes are not anticipated, because olopatadine is eliminated predominantly by renal excretion. Drug interactions involving cytochrome (CY) P450 inhibition are also not expected because olopatadine did not inhibit the in-vitro metabolism of substrates specific for CYP1A2, CYP2C9, CYP2C19, CYP2CE1, and CYP3A4. Drug interactions through displacement from plasma proteins are not expected because of the modest protein-binding ability of olopatadine (55%).

Simultaneous use with alcohol and other central nervous system depressants should be avoided.

Adverse Reactions Use of Patanase nasal spray can result in epistaxis and nasal ulcerations. Other common adverse events include bitter taste, headache, pharyngolaryngeal pain, postnasal drip, and urinary tract infection. Some patients have reported somnolence. Thus, patients should be cautioned against engaging in occupations that require mental alertness and motor coordination, such as driving or operating machinery , after administration of Patanase nasal spray.

Dosing and Administration Patanase nasal spray is approved for intranasal use only. The recommended dose in patients 12 years of age or older is 2 sprays per nostril twice daily . The nasal spray applicator must be primed before initial use and when the spray has not been used for more than 7 days.

Each 100-mL spray delivers 665 µg of olopatadine hydrochloride. There are 240 spays in a 30.5-g bottle.

Physical Examination for Seasonal Allergic Rhinitis • Look for: ◆ Allergic shiners—dark circle around the eyes resulting from vasodilation or nasal congestion ◆ Nasal crease (allergic salute)—a horizontal crease across the lower half of the bridge of the nose caused by upward rubbing of the tip of the nose • Use a nasal speculum (rigid or flexible rhinolaryn goscope) to examine the nose • Assess the character and quantity of nasal mucus.

Thin and watery secretions are often associated with allergic rhinitis • Examine the nasal septum for deviation or septal perforation resulting from chronic rhinitis, granulomatous disease, decongestant abuse, or topical steroid overuse • Examine the nasal cavity for polyps or tumors • Perform otoscopy and look for tympanic mem brane retraction, air–fluid levels, or bubbles • Conduct an ocular examination for findings of injection and swelling of the palpebral conjunc tivae with excess tear pro duction • Check for tonsillar hypertrophy or cobblestoning (ie, streaks of lymphoid tissue on the posterior pharynx) • Examine the neck for evidence of lymphadenop athy or thyroid disease • Examine the lungs for findings of asthma • Evaluate the skin for possible atopic dermatitis • Look for evidence of systemic disease (eg, sarcoid osis, hypothyroidism, immuno deficiency, ciliary dyskinesia syndrome, or other connective tissue disease) that can cause rhinitis

Use in Specific Populations • No adequate or well-controlled studies have been conducted in pregnant women. Olopatadine can be used in pregnant women only if the potential benefit to the mother justifies the potential risk to the embryo or fetus • Similarly, it may only be used by nursing mothers if the potential benefit to the mother outweighs the potential risk to the infant • Olopatadine is safe and effective in adolescents aged

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12 years or older; its safety in patients younger than age 12 has not been established • Clinical studies did not include sufficient numbers of patients aged 65 years and older to determine if their response would differ from that of younger patients • Dose selection for elderly patients should be cautious, because of their decreased hepatic, renal, or cardiac function and because of the presence of concomitant disease and use of drug therapy.

ened psychomotor speed) and in the workplace (slower decision-making), allergic rhinitis exerts a tremendous negative influence on pro ductivity.5 The enhancement of quality of life in patients with seasonal allergic rhinitis who took olopatadine was significantly associated with a reduction of symptoms. 5 In a society that seeks immediate relief for its ailments, olopatadine can provide rapid improvement and relief of symptoms and, therefore, improved quality of life. ■

References

The enhancement of quality of life in patients with seasonal allergic rhinitis who took olopatadine was significantly associated with a reduction of symptoms.

Benefit Design Considerations Olopatadine has a rapid onset of action. It offers relief in minutes (30 minutes according to the prescribing information) in a convenient, steroid-free nasal spray, and it has a long duration of effect (12 hours).

Because of the high incidence of allergic rhinitis, its impact on quality of life, its year-round negative effects, the potential for the development of associated chronic disorders, attendant emotional and cognitive impairment in the classroom (worsened verbal learning, less-

1. Togias AG. Systemic immunologic and inflammatory aspects of allergic rhinitis. J Allergy Clin Immunol. 2000;106(5 suppl):S247-S250.

2. Sheikh J. Rhinitis, allergic. eMedicine Web site. www.emedicine.com/ MED/topic104.htm. Accessed December 1, 2008.

3. Blaiss MS. Quality of life in allergic rhinitis.

Ann Allergy Asthma Immunol. 1999;83:449-454.

4. Fairchild CJ, Meltzer EO, Roland PS, et al. Comprehensive report of the efficacy, safety, quality of life, and work impact of olopatadine 0.6% and olopatadine 0.4% treatment in patients with seasonal allergic rhinitis. Allergy Asthma Proc. 2007;28:716-723.

5. Hampel FC Jr , Ratner PH, Amar NJ, et al. Improved quality of life among seasonal allergic rhinitis patients treated with olopatadine HCl nasal spray 0.4% and olopatadine HCl nasal spray 0.6% compared with vehicle placebo. Allergy Asthma Proc. 2006;27:202-207.

6. Meltzer EO, Hampel FC, Ratner PH, et al. Safety and efficacy of olopatadine hydrochloride nasal spray for the treatment of seasonal allergic rhinitis. Ann Allergy Asthma Immunol. 2005;95:600-606.

7. Skoner DP. Complications of allergic rhinitis. J Allergy Clin Immunol.

2000;105(6 pt 2):S610-S615.

8. Nayak AS. The asthma and allergic rhinitis link. Allergy Asthma Proc.

2003;24:395-402.

9. Ratner PH, Hampel FC, Amar NJ, et al. Safety and efficacy of olopatadine hydrochloride nasal spray for the treatment of seasonal allergic rhinitis to mountain cedar. Ann Allergy Asthma Immunol. 2005;95: 474-479.

STAKEHOLDER PERSPECTIVE Innovative Medications Are Essential for Allergic Rhinitis Disease Management MEDICAL/PHARMACY DIRECTORS: Allergic rhinitis is a common inflammatory disease in the nasal mucous membrane that is usually caused by exposure to inhaled allergens. Both seasonal and perennial allergic rhinitis conditions are identified among patients. Traditional drug therapies involve these drug classes: 1. Histamine H1-receptor antagonists (eg, chlorpheniramine, diphenhydramine, clemastine, loratadine, fexofenadine, and cetirizine) that prevent histamine binding and action

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2. Decongestants (eg, pseudoephedrine, ephedrine, phenylephrine, naphazoline, tetrahydrozoline, oxymetazoline, and xylometazoline), which act on nasal mucosa to improve ventilation 3. Nasal glucocorticoids (eg, beclomethasone, budesonide, flunisolide, fluticasone, mometasone, and triamcinolone).

Although all those medications have been shown to be clinically useful and effective, disease management of allergic rhinitis remains a challenge in clinical practice.

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Epidemiologic studies show that inappropriate control of allergic rhinitis is one of the key risk factors for future asthma, a costly and serious upper airway disease.

Innovative medication is therefore critical for improving treatment and quality of life in patients with allergic rhinitis. Olopatadine (Patanase) nasal spray was approved by the US Foo d and Drug Administration (FDA) for allergic rhinitis in April 2008. Earlier , olopatadine 0.1% ophthalmic solution (Patanol), a topical antihistamine received FDA approval in December 1996, and 0.2% oncedaily ophthalmic formulation (Pataday) received FDA approval in December 2004.

Olopatadine nasal spray has some unique characteristics. Unlike other antihistamines, olopatadine is eliminated mainly by renal excretion. Many drug interactions involving inhibition of cytochrome (CY) P450 isoenzymes likely would be avoided.

As mentioned in the article, multiple randomized controlled clinical trials demonstrated that olopatadine nasal spray is superior to placebo in controlling symptoms, such as nasal congestion, rhinorrhea, itchy nose, and sneezing. 1-3 However, some adverse drug events, including epistaxis, pharyngolaryngeal pain, dysgeusia, and nasal ulceration, were reported with relatively low frequency.1,3 Based on drug utilization studies from other therapeutic areas, a new , innovative agent for allergic rhinitis likely would obtain a significant market share within a few years. 4 The critical success fac-

tors for a new drug must rely on scientifically sound research data about its cost-effectiveness and longterm safety profiles.

Because comparative studies between olopatadine and other antihistamine agents are limited, additional postmarketing pharmacoeconomic and epidemiologic evaluations should be available in the near future.

Understanding the cost-effectiveness and the safety profile for a new agent such as olopatadine is very important for drug formulary decision-making or for drug benefit design managers in the management of allergic rhinitis.

References 1. Fairchild CJ, Meltzer EO, Roland PS, et al. Comprehensive report of the efficacy, safety, quality of life, and work impact of olopatadine 0.6% and olopatadine 0.4% treatment in patients with seasonal allergic rhinitis. Allergy Asthma Proc. 2007;28:716-723.

2. Hampel FC Jr, Ratner PH, Amar NJ, et al. Improved quality of life among seasonal allergic rhinitis patients treated with olopatadine HCl nasal spray 0.4% and olopatadine HCl nasal spray 0.6% compared with vehicle placebo. Allergy Asthma Proc. 2006;27:202-207.

3. Meltzer EO, Hampel FC, Ratner PH, et al. Safety and efficacy of olopatadine hydrochloride nasal spray for the treatment of seasonal allergic rhinitis. Ann Allergy Asthma Immunol. 2005;95:600-606.

4. Guo JJ, Kelton CML, Pasquale MK, et al. Price and market-share competition of anti-ulcer gastric medications in the Ohio Medicaid market. Int J Pharm Med. 2004;18:271-282.

Jeff J. Guo, BPharm, PhD Associate Professor University of Cincinnati College of Pharmacy Cincinnati, OH

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Trilipix: A New Fibrate Improves Lipids in Mixed Dyslipidemia

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ince their introduction 20 years ago, statins have been used successfully to reduce low-density lipoprotein cholesterol (LDL-C) levels and to prevent the development of heart disease. In the past 10 years, however , extensive research has indicated that reduction of LDL-C is not sufficient. Controlling other lipids, particularly triglycerides and high-density lipoprotein cholesterol (HDL-C), is just as important. 1 A major development in understanding lipid control and preventing heart disease involves the characterization of the metabolic syndrome. In 2001, the Third Report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Bloo d Cholesterol in Adults highlighted the importance of treating patients with the metabolic syndrome to prevent heart disease.

Researchers analyzed data from the Third National Health and Nutrition Examination Survey (19881994), which was drawn from a large, representative 1 Among sample (n = 8814) of the US population. young participants (20-29 years), metabolic syndrome prevalence was only 6.7%, but the prevalence was 43.5% in those aged 60 to 69 and 42% in the elderly (≥70 years). 2 After adjusting for age, the overall metabolic syndrome prevalence in the United States was 23.7%, nearly one quarter of the US population. 2 A diagnosis of the metabolic syndrome is defined as having ≥3 of these 5 symptoms: (1) waist circumference >102 cm in men, >88 cm in women; (2) serum triglyceride ≥150 mg/dL; (3) HDL-C <40 mg/dL in men, 50 mg/dL in women; (4) bloo d pressure ≥130/85 mm Hg; (5) serum glucose ≥110 mg/dL.1 Therefore, any patient with mixed dyslipidemia— high LDL-C, low HDL-C, and high trigly cerides—is likely to have at least 2 of the symptoms of the metabolic syndrome, which, when combined with 1 of the other 3 symptoms, significantly increases the risk for heart disease or type 2 diabetes. 3 And although statins have been shown to be effective in reducing LDL-C levels by 18% to 55%, their impact on other lipids is not as significant; they reduce triglycerides by 7% to 30% and increase HDL-C levels by 5% to 15%. 4 By contrast, fenofibrates, which lower LDL-C levels by only 5% to 20%, reduce triglycerides

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by as much as 20% to 50% and raise HDL-C levels by 10% to 20%. 4 It would, therefore, appear that combining a statin plus a fenofibrate would be effective, but such therapy was off-label until recently . In December 2008, however, the US Foo d and Drug Administration (FDA) approved T rilipix, a delayed-release fenofibric acid, for use in combination with a statin. 5

Mechanism of Action Trilipix is available as a delayed-release capsule.

Each capsule contains choline fenofibrate equivalent to 45 mg or 135 mg of fenofibric acid, which is freely soluble in water. By activating peroxisome proliferatoractivated receptor α (PPARα), fenofibric acid increases lipolysis and the elimination of triglyceride-rich particles from plasma by activating lipoprotein lipase and reducing pro duction of Apo-CIII (an inhibitor of lipoprotein lipase). The reduction in triglycerides alters the size and composition of LDL-C from small, dense particles to large, buoyant particles, which in turn have a greater affinity for cholesterol receptors and are catabolized rapidly. When activated, PPARα increases synthesis of HDL-C. 6 Pharmacokinetics After oral administration of T rilipix, fenofibric acid is the only circulating pharmacologically active moiety in plasma. Plasma concentrations of fenofibric acid after administration of the 135-mg delayed-release capsule are equivalent to concentrations after a 200-mg capsule of micronized fenofibrate administered with foo d.

Fenofibric acid is well absorbed by the gastrointestinal tract, and its absolute availability is approximately 81%.6 After a single-dose administration of T rilipix under fasting conditions, peak plasma levels of fenofibric acid occur within 4 to 5 hours; exposure in plasma, as mea sured by maximum concentration of drug and area under the curve, is not significantly different whether a 135-mg dose is administered in fasting or nonfasting conditions.6 After multiple dosing of Trilipix, fenofibric acid concentrations reach steady state within 8 days, and at steady state are slightly more than double those after a single dose. Serum protein binding is nearly 99% in normal and in dyslipidemic subjects. 6

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Clinical Trials Three separate 12-week, phase 3, double-blind, ac tive-controlled trials evaluated combination therapy with T rilipix 135 mg/day . Participants in study 1 received rosuvastatin (10 mg/d and 20 mg/d) combined with T rilipix 135 mg/day 7; study 2 patients received simvastatin (20 mg/d and 40 mg/d) combined with Trilipix 135 mg/day 8; and patients in study 3 received atorvastatin (20 mg/d and 40 mg/d) combined with Trilipix 135 mg/day .9 Results of the simvastatin- and rosuvastatin-based trials have been published in peer reviewed journals.7,8 Study participants were enrolled for approximately 22 weeks, which comprised a 6-week diet run-in/ washout period, a 12-week treatment perio d, and a 30day safety follow-up period. Participants completing the 12-week treatment period were eligible to participate in a 52-week extension study.7-9 The primary end points were mean percent changes from baseline to end-of-study HDL-C, triglycerides, and LDL-C values. For each statin dose coadministered with Trilipix, there were 3 primary comparisons. For HDL-C and triglycerides, the combination therapy was compared with statin monotherapy at the corresponding dose; for LDL-C, the combination therapy was compared with Trilipix monotherapy.7-9 Trilipix combined with rosuvastatin 10 mg or 20 mg was superior to rosuvastatin monotherapy ( Table 1 ).7 No cases of rhabdomyolysis or unexpected hepatic, renal, or muscle safety signals were identified. 7 Trilipix combined with simvastatin 20 mg or 40 mg was superior to simvastatin monotherapy (Table 2).8 No cases of rhabdomyolysis were reported. 8 Adverse Reactions As with statins, myopathy and rhabdomyolysis have been reported in patients taking fenofibrates, and the risk is increased when fenofibrates are combined with statins. Patients who are elderly , have diabetes, renal failure, or hypothyroidism are more prone to myopathy and rhabdomyolysis.6 Trilipix can increase serum transaminases; therefore, liver tests should be conducted perio dically. T rilipix can reversibly increase serum creatinine levels; renal function should be monitored perio dically in patients with renal insufficiency. Because Trilipix raises cholesterol levels in the bile, there is an increased risk of cholelithiasis; if cholelithiasis is suspected, gallbladder studies are indicated. 6 Patients who have unexplained muscle pain, tenderness, or weakness should notify their healthcare pro -

Table 1 Trilipix plus Rosuvastatin Superior to Monotherapy Combination/Monotherapy HDL-C, % LDL-C, %a TG, % Trilipix + rosuvastatin 10 mg Rosuvastatin 10 mg monotherapy

20.3↑

37.2↓

8.5↑

Trilipix + rosuvastatin 20 mg

19.0↑

Rosuvastatin 20 mg monotherapy

10.3↑

47.1↓ 24.4↓

38.8↓

42.9↓ 25.6↓

aLDL-C was reduced by 6.5% with Trilipix monotherapy.

HDL-C indicates high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; TG, triglycerides.

Table 2 Trilipix plus Simvastatin Superior to Monotherapy Combination/Monotherapy HDL-C, % LDL-C, %a TG, % Trilipix + simvastatin 20 mg Simvastatin 20 mg Trilipix + simvastatin 40 mg Simvastatin 40 mg

17.8↑

24.0↓

7.2↑ 18.9↑

37.4↓ 14.2↓

25.3↓

8.5↑

42.7↓ 22.4↓

aLDL-C

was reduced by 4.0% with Trilipix monotherapy.

HDL-C indicates high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; TG, triglycerides.

viders immediately . Patients should also notify their healthcare providers if they experience abdominal pain, nausea, or vomiting while taking Trilipix.6 The most common adverse events reported in patients taking Trilipix are headache, back pain, naso pharyngitis, nausea, myalgia, diarrhea, and upper respiratory tract infection. 6

Dosing and Administration Trilipix should be taken once daily , with or without food ( Table 3 ) and is available in 45-mg and 135-mg delayed-release oral capsules. The capsule should be swallowed whole, and if coadministered with a statin, the 2 may be taken together. The daily dose should not exceed 135 mg, nor should T rilipix be taken with the maximum dose of a statin unless the benefits are expected to outweigh the risks. 6 Trilipix should not be used in the following situations—severe renal impairment, including dialysis; active liver disease, including those with primary biliary cirrhosis and unexplained persistent liver function abnormalities; preexisting gallbladder disease; nursing mothers; and hypersensitivity to fenofibric acid, choline fenofibrate, or fenofibrate. 6

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Table 3 Recommended Trilipix Dosing Indication Dose Mixed dyslipidemia 135 mg once daily Primary hyperlipidemia 135 mg once daily Severe hypertriglyceridemia 45–135 mg once daily Patients w/ mild to moderate renal disease 45 mg once daily NOTE: Maximum dose should not exceed 135 mg/day.

Source: Trilipix [package insert]. Chicago, IL: Abbott Laboratories; 2008.

Drug Interactions • Coumarin anticoagulants: Healthcare providers should exercise caution when administering concomitant treatment with oral coumarin anticoagulants. The dosage of the anticoagulant should be adjusted to maintain the prothrombin time/interna tional normalized ratio at the desired level to prevent bleeding complications.6 • Bile acid resins: Bile acid resins can bind other drugs used concurrently; therefore, patients should take Trilipix at least 1 hour before or 4 to 6 hours after taking a bile acid resin to avoid impeding absorption. 6 • Cyclosporine: Renal excretion is the primary elimination route of fibrates. Because cyclosporine can produce nephrotoxicity with decreases in creatinine clearance and increases in serum creatinine, there is a risk that interaction of cyclosporine and T rilipix will result in renal function decline. Healthcare providers should carefully weigh the benefits and risks of using Trilipix with cyclosporine, other immunosuppressants, and potentially with nephrotoxic agents. 6 Benefit Design Considerations Since FDA approval of lovastatin in August 1987, the benefits of lipid-lowering therapy in adults with dyslipidemia and underlying risk factors for coronary artery disease have been well documented. Statin therapy has also reduced the risk of myocardial infarction and cardiac death.10 Although managed care interventions by prescribers have increased the use of selected drugs such as statins, studies show that drugs indicated for lowering LDL-C and triglycerides and raising HDL-C are still underprescribed, particularly by employer-sponsored drug plans.

Researchers recently reported the results of a study that evaluated the use of statins and antihypertensives among 1181 patients aged 65 or older with type 2 diabetes selected from state-sponsored health plans, the Veterans Administration (V A), and employee-spon-

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sored health plans.11 Overall, 33% received a statin and an antihypertensive, 44% a statin or an antihypertensive, and 23% neither. After adjustment, VA and statesponsored drug benefits were most strongly associated with combined antihypertensive and statin use (relative risk = 4.83; 95% confidence interval, 2.24-10.4), followed by employer-sponsored coverage (relative risk = 2.60; 95% confidence interval, 1.67-4.03). 11 These results suggest that employer-sponsored plans should do more to encourage their employees to be proactive in preventing cardiovascular (CV) disease.

This prompts the question of whether aggressive pharmacotherapeutic intervention will confer economic benefits. Many studies have confirmed that intervention with lipid-regulating drugs will save money in the longterm. For example, researchers determined that the estimated number of members requiring drug interventions to prevent 1 major CV event was 220. 10 They then calculated the estimated CV event cost avoidance to be $12,323 per 220 members who received the intervention, after subtraction of program administrative costs and the cost of statin drug therapy.10 Therefore, an investment in statins and fibrates to lower LDL-C and triglycerides and raise HDL-C should reduce the risk of more expensive interventions later on. ■ References

1. Expert Panel on Detection, Evaluation, and T reatment of High Bloo d Cholesterol in Adults. Executive Summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and T reatment of High Bloo d Cholesterol in Adults (Adult Treatment Panel III). JAMA. 2001;285:2486-2497.

2. Ford ES, Giles WH, Dietz WH. Prevalence of the metabolic syndrome among US adults: findings from the third National Health and Nutrition Examination Survey. JAMA. 2002;287:356-359.

3. Robinson JG. Is a statin as part of a polypill the answer? Curr Atheroscler Rep. 2009;11:15-22.

4. National Heart, Lung, and Blood Institute. ATP III guidelines at-a-glance quick desk reference. May 2001. www .nhlbi.nih.gov/guidelines/cholesterol/ atglance.pdf. Accessed January 6, 2009.

5. WebMD Health News. FDA OKs new cholesterol drug T rilipix. www.webmd.com/cholesterol-management/news/20081215/fda-oks-newcholesterol-drug-trilipix. Accessed January 6, 2009.

6. Trilipix [package insert]. Chicago, IL: Abbott Laboratories; 2008.

7. Jones PH, Davidson MH, Kashyap ML, et al. Efficacy and safety of ABT 335 (fenofibric acid) in combination with rosuvastatin in patients with mixed dyslipidemia: a phase 3 study. Atherosclerosis. 2008 Oct 5. Epub ahead of print.

8. Mohiuddin SM, Pepine CJ, Kelly MT, et al. Efficacy and safety of ABT-335 (fenofibric acid) in combination with simvastatin in patients with mixed dyslipidemia: a phase 3, randomized, controlled study . Am Heart J. 2009;157: 195-203.

9. Goldberg AC, Bays HE, Ballantyne DM, et al. Efficacy and safety of ABT 335 (fenofibric acid) in combination with atorvastatin in patients with mixed dyslipidemia. Am J Cardiol. 22 Dec 2008. Epub ahead of print.

10. Stockl KM, Tjioe D, Gong S, et al. Effect of an intervention to increase statin use in Medicare members who qualified for a medication therapy management program. J Manag Care Pharm. 2008;14:532-540.

11. Tjia J, Briesacher BA. Prescription drug benefits and use of guideline recommended medications by elderly Medicare beneficiaries with diabetes mellitus. J Am Geriatr Soc. 2008;56:1879-1886.

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Simcor: Simvastatin plus Niacin Working Together to Reduce the Risk of Coronar y Heart Disease

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holesterol treatment generally has been directed at lowering elevated levels of low-density lipoprotein cholesterol (LDL-C) to slow the development of coronary heart disease (CHD). It has been shown that for every 1% reduction in LDL-C, there is a corresponding reduction in the risk of major cardiovascular (CV) events.1,2 Studies have shown that lowering LDL-C levels by 12% to 38% has resulted in a relative risk reduction of 19% to 35%. 3,4 However, approximately 40% of individuals with heart disease also have low levels of high-density lipoprotein cholesterol (HDL-C).5 Raising HDL-C can have as powerful an impact in reducing the risk of cardiac events as lowering LDL-C levels. Increases in HDL-C levels by increments of 1 mg/dL have been associated with 2% to 4% reductions in cardiac events, independent of LDL-C levels.6 Many large studies have attested to the ability of statins, the drug class used to reduce LDL-C, to lower cardiac event rates.

Statins also raise HDL-C levels but usually only to a small degree. Since the Framingham Heart Study , physicians have been taught to look for the ratio of total cholesterol to HDL-C levels. Patients with a ratio less than 3 have a low risk of developing CHD. Niacin tends to raise HDL-C levels, but it frequently causes flushing, a side effect that can be lessened if it is taken at night and with food. Like statins, it has been associated with reversible liver abnormalities. Niacin also raises blood sugar levels.

Evidence shows that combining statin therapy with niacin provides beneficial effects on a broad range of lipids and could result in an increased reduction in CHD.7 Although the benefits of each component are not surprising to most physicians, the degree of improvement associated with the combination is.

Simvastatin on its own reduces LDL-C, whereas niacin increases HDL-C levels. Combining the 2 therapies has been shown to reduce non–HDL-C, LDL-C, triglycerides, and the total cholesterol to HDL-C ratio by 50%, as well as to increase HDL-C levels by 25%. 7

Mechanism of Action Simcor is a combination of simvastatin and extendedrelease niacin. Simvastatin is a pro drug that is hydro -

lyzed to its active β-hydroxyacid form, simvastatin acid, after administration. It is a specific inhibitor of 3hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, the enzyme that catalyzes the conversion of HMG-CoA to mevalonate, an early rate-limiting step in the biosynthetic pathway for cholesterol. Simvastatin also reduces very LDL-C (VLDL-C) and triglycerides and increases HDL-C. Niacin functions in the bo dy after it has been converted to nicotinamide adenine dinucleotide (NAD) in the NAD coenzyme system. How it alters lipid profiles is not completely understoo d; it is believed to involve partial inhibition of the release of free fatty acids from adipose tissue and increased lipoprotein lipase activity, which may increase the rate of chylomicron triglyceride removal from plasma. Niacin decreases the rate of hepatic synthesis of VLDL-C and LDL-C.

Pharmacokinetics Niacin concentrations in the circulation are dosedependent and very variable. Peak steady-state concentrations after daily doses of 1000 mg, 1500 mg, and 2000 mg extended-release niacin (given as two 500-mg, two 750-mg, and two 1000-mg tablets) were 0.6 µg/mL, 4.9 µg/mL, and 15.5 µg/mL, respectively . Extendedrelease niacin should be taken with a low-fat meal or a snack to reduce gastrointestinal upset.

Simvastatin undergoes first-pass extraction in the liver; thus, the availability of the drug to the general circulation is low (<5%). Peak plasma concentrations of both the active and total inhibitors were attained within 1.3 hours to 2.4 hours postdose. The plasma profile of inhibitors was not affected when simvastatin was administered immediately before an American Heart Association–recommended low-fat meal.

Clinical Trials Several studies have shown that the combination of simvastatin plus niacin can slow and sometimes even reverse arterial damage associated with CHD. 7-9 The strength of the combination results not only from lowering LDL-C levels but also from raising HDL-C levels, which has an equal impact on reducing the risk of myocardial infarction (MI) and other CV events.

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Table 1 Recommended Extended-Release Niacin Dosing Initial titration schedule

Weeks

Dose, mg/d

1–4

500

5–8

1000

>8*

1500

>8*

2000

After week 8, titrate according to patient response and tolerance. If response to 1000 mg/day is inadequate, increase dose to 1500 mg/day; subsequently may increase dose to 2000 mg/day. Daily dose should not be increased by more than 500 mg in a 4-week perio d, and daily doses >2000 mg are not recommended.

Source: Simcor [package insert]. Chicago, IL: Abbott Laboratories; 2008.

*

Table 2 Simcor: Tablet Strengths Simcor Niacin ER equivalent, mg Simvastatin equivalent, mg

500 mg/ 20 mg 500

750 mg/ 20 mg 750

20

20

1000 mg/ 20 mg 1000 20

Source: Simcor [package insert]. Chicago, IL: Abbott Laboratories; 2008.

In the original HDL Atherosclerosis T reatment Study (HA TS), a 3-year , double-blind trial, 160 patients with coronary artery disease, low HDL-C levels, and normal LDL-C levels were randomized to 4 factorial combinations of antioxidant vitamins or their placebos and simvastatin plus niacin or their placebos.8 The end points were arteriographic evidence of a change in coronary stenosis and the occurrence of a first CV event (death, MI, stroke, or revascularization).

Mean levels of LDL-C and HDL-C did not change in patients randomized to the antioxidants or the placebo; however, these levels changed substantially in the simvastatin–niacin group: LDL-C levels were reduced by 42% and HDL-C levels increased by 26%. The combination significantly slowed the progression of stenosis.

The average stenosis progressed by 3.9% with the placebos, 1.8% with antioxidants, and 0.7% with simvastatin–niacin plus antioxidants ( P = .004). The stenoses actually regressed by 0.4% with the simvastatin–niacin combination ( P <.001). Clinically and angiographically, there were measurable benefits in patients randomized to simvastatin plus niacin. 8 In the safety and tolerability analysis of HA TS, glycemic control among 25 patients with diabetes declined mildly in the simvastatin–niacin group but returned to pretreatment levels at 8 months and remained stable for the rest of the study .9 The combination of simvastatin plus niacin was described by 91% of treated patients and 86% of placebo-treated subjects as “very easy” or “fairly easy” to take. The simvastatin

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plus niacin regimen was well tolerated and was found to be safe and effective in patients with and without diabetes mellitus.

Adverse Reactions Unexplained muscle weakness or pain could be a sign of rhabdomyolysis. This adverse effect is rare and should be reported to the physician immediately .

Simcor should not be taken with other lipid-lowering medications, called fibrates, or with niacin, because the combination increases the likelihoo d of this serious side effect.

Flushing (warmth, redness, itching, and/or tingling of the skin) is a common side effect with Simcor and varies in intensity; however , it usually becomes less frequent over time. T aking Simcor at bedtime will help limit flushing to occur during sleep. Patients should be cautioned to take their time when getting up, especially if they feel dizzy or are taking antihypertensive medications. Other symptoms may include rapid heartbeat, shortness of breath, sweating, chills, dizziness, fainting, and/or swelling, headache, nausea, back pain, and diarrhea.

Dosing and Administration Simcor should be taken as a single daily dose at bedtime, with a low-fat snack. Patients not currently taking extended-release niacin and patients currently using niacin pro ducts other than extended-release niacin should start Simcor at a single 500-mg/20-mg tablet daily at bedtime. The dose of extended-release niacin should not be increased by more than 500 mg every 4 weeks (Table 1). Simcor tablets are formulated for oral administration in 3 strength combinations ( Table 2).

Dosage in Specific Populations Simcor should not be used in patients with the following conditions: • Liver dysfunction or abnormalities • Peptic ulcer disease • Arterial bleeding • Other serious bleeding problems • Pregnancy • Nursing mothers • Allergy or hypersensitivity to any product ingredient.

Simcor can increase bloo d sugar levels. Patients with diabetes should report any changes in bloo d sugar levels to their healthcare provider.

Extended-release niacin should be prescribed with caution in individuals who consume substantial amounts of alcohol and/or have a history of liver dis-

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ease. Liver function tests should be performed on all patients during therapy with niacin.

Simcor should not be taken with any of the following medications: • Cyclosporine • Danazol • Other fibrates (eg, fenofibrate, gemfibrozil, clofibrate) • Azole antifungals (eg, itraconazole) • Mibefradil • Nefazodone • Ketolide antibiotics (eg, telithromycin) • Macrolide antibiotics (eg, clarithromycin).

Additional monitoring may be required for patients taking any of these agents: • Anticoagulants (eg, warfarin) • Protease inhibitors (eg, ritonavir) • Daptomycin • Digoxin • Blood pressure medications (eg, alpha blockers) • Other drugs that cause flushing (eg, isosorbide dinitrate) • Vitamin or dietary pro ducts that contain niacin or nicotinamide • Bosentan • Amiodarone, diltiazem, verapamil, rifampin • St. John’s wort • Carbamazepine • Ranolazine • Immunosuppressants (eg, tacrolimus) • Streptogramins (eg, quinupristin).

Benefit Design Considerations As baby boomers age, prospects for lipid-lowering drugs are very likely to increase. PricewaterhouseCoopers has reported that almost 40 million people in the United States have elevated cholesterol levels and 45% of them do not take appropriate medications; however , it predicted that a shift will occur from treatment to prevention.10 With drugs such as Simcor, the need to treat CHD could lessen. In addition, if the incidence of obe-

sity and metabolic syndrome can be lessened, the economic risks of living with elevated cholesterol and CHD will also be lessened. Lowering LDL-C levels and raising HDL-C levels with drugs such as Simcor , increased exercise, and low-fat diets should result in a decreased need for open heart surgery and lowered costs associated with postoperative drugs and medical care from stroke, congestive heart failure, and CHD. Simcor also presents a possible financial benefit for patients: combining a statin and a niacin in a single medication will reduce the overall copayment for the patient. ■

References

1. Wilson PR, Anderson KM, Castelli WP . Twelve-year incidence of coronary heart disease in middle-aged adults during the era of hypertensive therapy: the Framingham Offspring Study [published erratum appears in Am J Med. 1991;90:537]. Am J Med. 1991;90:11-16.

2. Assmann G, Cullen P, Schulte H. The Munster Heart Study (PROCAM): results of a follow-up at 8 years. Eur Heart J. 1998;19(suppl A): A2-A11.

3. Hennekens CH, Ridker PM, Buring JE, Manson MD, eds.

Clinical Trials in Cardiovascular Disease: A Companion to Braunwald’s Heart Disease.

Section 2. Treatment trials. Philadelphia, PA: W.B. Saunders; 1999:206.

4. The Long-term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. N Engl J Med. 1998;339:1349-1357.

5. Yale-New Haven Hospital HealthLINK. Simvastatin plus niacin lower heart attack risk [news release]. January 2002. www .ynhh.org/ healthlink/cardiac/cardiac_1_02.html. Accessed December 15, 2008.

6. Robins SJ, Collins D, W ittes JT, et al. Relation of gemfibrozil treatment and lipid levels with major coronary events: V A-HIT: a randomized controlled trial. JAMA. 2001;285:1585-1591.

7. Vo AN, Kashyap ML. Fixed-dose combination of extended-release niacin plus simvastatin for lipid disorders. Expert Rev Cardiovasc Ther.

2008;6:1303-1310.

8. Brown BG, Zhao XQ, Chait A, et al. Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease. N Engl J Med. 2001;345:1583-1592.

9. Zhao XQ, Morse JS, Dowdy AA, et al. Safety and tolerability of simvastatin plus niacin in patients with coronary artery disease and low high-density lipoprotein cholesterol (The HDL Atherosclerosis T reatment Study). Am J Cardiol. 2004;93:307-312.

10. PricewaterhouseCoopers. Pharma 2020: The vision. Which path will you take? www .pwc.com/extweb/pwcpublications.nsf/docid/91BF 330647FFA402852572F2005ECC22. Accessed December 16, 2008.

STAKEHOLDER PERSPECTIVE Simvastatin–Niacin Combination Enhances Lipid Profile MEDICAL/PHARMACY DIRECTORS: The development of statin drugs has revolutionized the care of patients with atherosclerotic disease; specifically ,

they help prevent cardiovascular (CV) events.

Clinical trials data reveal the benefits of lowering low-density lipoprotein cholesterol (LDL-C) levels Continued

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Continued by using statins, especially for secondary prevention of CV events. Lowering LDL-C is now considered the primary goal of pharmacologic treatment by all relevant professional societies and clinical guidelines and recommendations, including the National Cholesterol Education Program Adult T reatment Panel III (A TP III). Although the data supporting this goal appear strong and irrefutable, there is a consistently documented limitation to the use of statins to lower LDL-C. The majority of clinical trials achieved a 25% to 30% relative risk reduction for recurrent CV events with statin use. However , even in trials that used more intensive therapy (Pravastatin or Atorvastatin Evaluation and Infection Therapy—Thrombolysis in Myocardial Infarction 22 [PRO VE IT -TIMI 22], Incremental Decrease in Endpoints through Ag gressive Lipid Lowering, T reating to New T argets [TNT]), in which participants achieved the goal of LDL-C 70 mg/dL, significant residual risk of recurrent CV events in the treated groups remained. Evidence suggests that there is only mo dest benefit when lowering LDL-C from 100 mg/dL to 70 mg/dL, even in the secondary prevention group (number needed to treat >60). It appears that to reduce the instance of CV events even further , other known or potential risk factors need to be addressed.

CV risk is clearly multifactorial. Recent evidence suggests the important contribution of non–LDL-C factors, including triglycerides (TG) and decreased high-density lipoprotein cholesterol (HDL-C) levels.

More than one third of the adult population of the United States has elevated TG and low HDL-C levels, as defined by the A TP III. Several studies, including the Framingham Heart Study , revealed significantly decreased CV events with every 1-mg/dL increase in HDL-C in the population studied. The ATP III report noted that low HDL-C is a significant independent risk factor for coronary heart disease. Frequently , low HDL-C levels appear to accompany high levels of serum TG, and clinical data from the PRO VE IT and TNT studies reveal that high TG and low HDL-C levels remain significant risk factors even after aggressive lowering of LDL-C levels. Elevated TG levels are associated with increased levels of serum very low-density lipoprotein levels and increased numbers of apo B–con-

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taining atherogenic particles in the circulation. This is readily correlated with non–HDL-C (total cholesterol minus HDL-C), which can be tested in the nonfasting state and is a better risk predictor than LDL-C of the atherogenic burden.

Although statin therapy can often further decrease non–HDL-C, these factors can also be beneficially affected by niacin therapy . Niacin has been available in a variety of forms for many years, and the prescription form of extended-release niacin has been commercially available for a decade. There are significant data with regard to its efficacy and safety, both alone and in combination with other lipid-modifying treatments. A new product—Simcor—a combination of simvastatin and extended-release niacin is now available.

Clinical trial data that were submitted to the US Food and Drug Administration (FDA) reveal an outstanding safety profile and no significant increased liver muscle or toxicity compared with statin treatment, with excellent efficacy and lipid goal attainment using this combination pro duct. Niacin is the best pharmacologic treatment available to increase HDL-C, reduce TG to a similar level as fibric acid derivatives, and substantially lower non–HDL-C and C-reactive protein. A number of angiographic regression trials have shown significant benefit for the addition of niacin to other lipid-modifying therapies.

In fact, niacin has an FDA-approved indication for atherosclerosis regression, which only certain statins currently have.

When considering all available evidence addressing various lipid parameters and CV disease risk, lipid management in specific patients should not be limited to statin monotherapy . The benefits conferred by raising HDL-C levels with niacin appear additive to lowering LDL-C levels with statins. Several guidelines now suggest that in certain subsets of patients, combination therapy , including statins and niacin, may be necessary to achieve multiple lipid goals.

February/March 2009

Peter Alagona, MD, FACC Associate Professor of Medicine and Radiology Penn State College of Medicine Program Director, General Cardiology Penn State Heart and Vascular Institute Hershey, PA

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HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use PATANASEÂŽ Nasal Spray safely and effectively.

See full prescribing information for PATANASE Nasal Spray.

PATANASE (olopatadine hydrochloride) Nasal Spray Initial U.S. Approval: 1996 INDICATIONS AND USAGE PATANASE Nasal Spray is an H1 receptor antagonist indicated for the relief of the symptoms of seasonal allergic rhinitis in patients 12 years of age and older. (1) DOSAGE AND ADMINISTRATION For intranasal use only.

The recommended dose of PATANASE Nasal Spray in patients 12 years and older is two sprays per nostril twice daily. (2) Priming Information: Prime PATANASE Nasal Spray before initial use and when PATANASE Nasal Spray has not been used for more than 7 days. (2.2) DOSAGE FORMS AND STRENGTHS Nasal spray 0.6%: 665 mcg of olopatadine hydrochloride in each 100-microliter spray. (3) Supplied as a 30.5 g bottle containing 240 sprays.

CONTRAINDICATIONS None.

WARNINGS AND PRECAUTIONS s %PISTAXIS NASAL ULCERATION AND NASAL SEPTAL PERFORATION -ONITOR patients periodically for signs of adverse effects on the nasal mucosa. Avoid use in patients with nasal disease other than allergic rhinitis. (5.1) s !VOID ENGAGING IN HAZARDOUS OCCUPATIONS REQUIRING COMPLETE mental alertness such as driving or operating machinery when taking PATANASE Nasal Spray. (5.2) s !VOID CONCURRENT USE OF ALCOHOL OR OTHER CENTRAL NERVOUS SYSTEM depressants with PATANASE Nasal Spray. (5.2) ADVERSE REACTIONS 4HE MOST COMMON ADVERSE REACTIONS INCLUDED BITTER TASTE

HEADACHE EPISTAXIS PHARYNGOLARYNGEAL PAIN POST NASAL DRIP

COUGH AND URINARY TRACT INFECTION To report SUSPECTED ADVERSE REACTIONS, contact Alcon Laboratories, Inc. at 1-800-757-9195 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

References: 0ATEL $ 'ARADI 2 "RUBAKER - ET AL /NSET AND DURATION OF ACTION OF NASAL SPRAYS IN SEASONAL ALLERGIC rhinitis patients: olopatadine hydrochloride versus mometasone furoate monohydrate. Allergy Asthma Proc. 2007;28:592-599.

-ELTZER %/ (AMPEL &# 2ATNER 0( ET AL 3AFETY AND EFFICACY OF OLOPATADINE HYDROCHLORIDE NASAL SPRAY for the treatment of seasonal allergic rhinitis. Ann Allergy Asthma Immunol. 2005;95(6):600-606.

2ATNER 0( (AMPEL &# !MAR .* ET AL 3AFETY AND EFFICACY OF OLOPATADINE HYDROCHLORIDE NASAL SPRAY for the treatment of seasonal allergic rhinitis to mountain cedar. Ann Allergy Asthma Immunol. 2005; 95(5):474-479.

2OSENWASSER ,* / "RIEN 4 7EYNE * -AST CELL STABILIZATION AND anti-histamine effects of olopatadine ophthalmic solution: A REVIEW OF PRE CLINICAL AND CLINICAL RESEARCH #URR -ED 2ES /PIN 2005;21(9):1377-1387.

Š2008 Alcon, Inc.

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PTN08510JA

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How fast do noses demand seasonal allergy relief ?

Fast seasonal allergic rhinitis relief is here.

t The only nasal spray approved to work in 30 minutes1 t Sustained symptom relief over 2 weeks2,3 t Steroid-free1 t From a proven, potent H1 antagonist4 Prescribe the nasal spray that starts working ASAP. PATANASEÂŽ Nasal Spray is an H1 receptor antagonist indicated for the relief of symptoms of seasonal allergic rhinitis in patients 12 years of age or older.

The most common adverse reactions (>1%) included bitter taste, headache, epistaxis, pharyngolaryngeal pain, post-nasal drip, cough, and urinary tract infection. Nasal ulceration and nasal septal perforation occurred at a rate of <1%; patients should be monitored periodically for signs of adverse effects on the nasal mucosa. Avoid use in patients with nasal disease other than allergic rhinitis. Please see highlights of prescribing information on reverse page.

For full prescribing information, please visit www.patanase.com

Š2008 Alcon, Inc.

8/08

PTN08510JA