NSAIDs and Anti-inflammatories

NSAIDs and Anti-inflammatories Deborah A. Ward, PharmD., BCOP, BCPS

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Learning Objectives Describe the mechanism of action as it relates to both efficacy and toxicity Identify the clinical situations when use of an NSAID/Anti-inflammatory is front line therapy Identify ways to either ameliorate or reduce toxicities in the patient population(s) that may be at increased risk

OTC = SAFE + EFFECTIVE RIGHT?

FDA Public Service Announcement

fda.gov

FDA National Education Campaign Using Acetaminophen and Nonsteroidal Anti-inflammatory Drugs Safely  The Food and Drug Administration advises consumers to follow directions when using common pain and fever reducers. The active ingredients, acetaminophen and non-steroidal anti-inflammatory drugs (NSAIDs), are safe and effective when the labeling directions or the advice from a healthcare professional is followed. Using more than recommended can cause serious injury fda.gov

Label Warning IF USE IS NEEDED FOR MORE THAN 10 DAYS, CONSULT A PHYSICIAN

If total daily maximum is 8 tablets Then 80 tablets are needed So why do we buy 500 at a time?

Historical Background 1899: Aspirin (prototype) first synthesized 1938: 1st endoscopic evidence of Aspirin induced gastric mucosal damage 1970’s: “Safer” NSAIDs developed 1992: COX-2 discovered 1998: 1st COX-2 selective NSAID approved

National Ambulatory Medical Care Survey: 2002 Survey Results  Most frequent patient diagnoses – HTN, common cold, sore throat, diabetes, arthritis and joint disorders

 At ≈ 2/3 of doctor visits, patients were ordered, prescribed or administered one or more medications, totaling 1.3 billion drugs  The most frequent drugs prescribed – NSAIDS , Antidepressants, Antihistamines

 From 1995 to 2002, NSAID use ↑ by 10%, antihistamine use by 35%, and antidepressants by 48% http://www.cdc.gov/nchs/

How many non-selective NSAIDs are available by prescription?

A. B. C. D.

9 13 17 21

Of these, how many are available OTC? A. B. C. D.

4 7 1 9

An Enormous Array  COX-2 Selective NSAIDs – Celecoxib, Valdecoxib, Rofecoxib

 Non-selective NSAIDs Diclofenac

Diflunisal

Etodolac

Fenoprofen

Flurbiprofen

Ibuprofen*

Indomethacin

Ketoprofen*

Ketorolac

Mefanamic Acid

Meloxicam

Nabumetone

Naproxen*

Oxaprozin

Piroxicam

Sulindac

Tolmetin

* over-the-counter versions of these Rx meds available

Even More: The Steroids  Inhalant  Nasal  Ophthalmic  Otic  Rectal  Systemic

– Cortisone, Dexamethasone, Hydrocortisone, Fludrocortisone – Methylprednisolone, Prednisolone, Prednisone

 Topical

Mechanism of Action Toxicity and Efficacy

Mechanism of Action - Efficacy All nociceptors can be sensitized by prostaglandins  greatly enhances the receptor response to noxious stimuli NSAIDs inhibit prostaglandin synthesis by decreasing the activity of the enzyme cyclooxygenase (COX)  decreased formation of prostaglandin precursors End result is anti-inflammatory activity and analgesia

NSAIDs - Mechanism of Toxicity  COX-1 inhibition in vasculature/stomach/kidneys – Decreased (PG)12 and PGE2 concentrations • ↓ production of mucosa and bicarbonate • ↓ gastric blood flow • ↑ acid secretion within the GI tract • Vasoconstriction within renal arterioles

– Impaired platelet aggregation 2o to ↓ synthesis of thromboxane A2

 If selective for COX-2 should be safer?

Selective ≠ Safer  Clinical trial investigating new use of Celecoxib to prevent colon polyps was closed by NCI due to increased risk of CV events in patients receiving active drug versus placebo – 3.4 x increased risk 400 mg BID – 2.5 x increased risk 200 mg BID

 Average duration of therapy 33 months  FDA released Public Health Advisory in 2004

Boxed Warning FDA Alert [4/7/2005] Based on a review of available data from long-term placebo- and active-controlled clinical trials of non-steroidal anti-inflammatory drugs (NSAIDs), FDA has concluded that an increased risk of serious adverse cardiovascular (CV) events may be a class effect for NSAIDs (excluding aspirin). FDA has requested that the package insert for all NSAIDs be revised to include a boxed warning to highlight the potential increased risk of CV events and the well described risk of serious, and potentially life-threatening, GI bleeding. FDA has also requested that the package insert for all NSAIDs include a contraindication for use in patients immediately post-operative from coronary artery bypass graft (CABG) surgery www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders

COX-2 US Market Availability  Rofecoxib (Vioxx®) – 2004: Merck & Co voluntarily withdraws drugfrom the worldwide market

 Valdecoxib (Bextra®) – 2005: FDA asks Pfizer to remove drug from market

 Celecoxib (Celebrex®) – 2006: Receives additional approval for JRA with a 15 to 1 vote of the FDA’s Arthritis Advisory Committee

COX-2 International Market Availability  Etoricoxib – Oral administration

 Niflumic Acid – Oral and topical administration

 Nimesulide – Oral therapy for 15 days maximum

 Parecoxib – Injection for post-operative pain

COX-2 Inhibitors and CV Risk  > 1 decade ago, Rofecoxib and Celecoxib were shown to decrease the amount of PGI-M in urine, the major metabolite of PGI2  Yu et al demonstrated definitively that depletion of COX-2 in mouse vasculature – Resulted in decreased excretion of PGI-M – Resulted in depressed expression of endothelial NO synthase and consequent release of and function of Nitrous Oxide – Predisposed mice to hypertension and thrombosis Y Yu et al. Sci Transl Med 4, 132ra54 (2012)

Hypersensitivity Reactions  NSAIDs are the 2nd most common cause of drug-induced hypersensitivity reactions – 21 – 25% of reported ADRs

 Clinical manifestations – Bronchial asthma – Rhinosinusitis – Urticaria – Anaphylaxis

 Observed with all NSAIDs regardless of chemical structure and/or anti-inflammatory potency

Hypersensitivity Reactions (cont’d)

Allergy 66 (2011) 818-829 © 2011 John Wiley & Sons A/S

Is It Truly a Reaction?

Allergy 66 (2011) 818-829 Š 2011 John Wiley & Sons A/S

Steroid-induced Avascular Necrosis  Bone tissue death due to vascularization failure  Irreversible and extensive  Morbidity: progressive joint destruction leading to decreased range of motion, painful movements, and arthritis  Often involves weight-bearing joints, but may also include the shoulder, elbow, wrist, hand, and vertebral bodies  Due to either intermittent or continuous steroid treatment

Case Scenario  JT is a 22 yr old college student who occasionally binge-drinks on the weekends  Last weekend after partying with some friends, he developed a hangover, for which he took at least 2 – 3 extra strength acetaminophen tablets every few hours  When he was still not feeling better a few days later, he went to the Minor Med with c/o abdominal pain, nausea, and vomiting  H&P, physical exam, and chemistry panel obtained, which was significant for a critically elevated AST and ALT

Acetaminophen: A Serious Public Health Problem  Most frequent cause of drug-induced liver failure secondary to drug overdose – May result in need for transplant or even death – Most cases due to either excess single agent OTC product or concurrent use with combination Rx products – Alcohol consumption

 Acetaminophen Best Practices Task Group – Label consistency – Complete spelling of acetaminophen and all other active ingredients on pharmacy labels of all acetaminophen-containing Rx products – Standardize concomitant use and liver pharmacy warning label

 FDA seeks help of National Boards of Pharmacy fda.gov/drugs/drugsafety

Postulated Mechanism Of Acetaminophen-induced Hepatotoxicity

Š 2002 Society of Toxicology Toxicological Sciences Jaeschke H et al. Toxicol. Sci. 2002;65:166-176

Upcoming FDA-Mandated Changes To take effect January 2014 Based on the following decision –FDA states that limiting the amount of Acetaminophen may reduce the risk of severe liver injury from overdose –No more than 325 mg of Acetaminophen per dosage unit in Rx drug products, including opioids

One Drug Company’s Response  Abbott, manufacturer of Vicodin® introduced the following changes in third quarter of 2012 – Vicodin® 5 mg/300 mg from 5mg/500 mg • Not to exceed 8 tablets daily

– Vicodin® ES 7.5/300 mg from 7.5/750 mg • Not to exceed 6 tablets daily

– Vicodin® HP 10/300 mg from 10/660 mg • Not to exceed 6 tablets daily

 Immediate discontinuation of manufacturing and distribution of current formulations – Huge potential for dispensing errors

Therapeutic Uses

Patient Populations Range from Very Young to the Very Old –Neonates –Children –Young Adults –Older Adults

Otherwise healthy to the chronically ill

Therapeutic Uses Premenstrual syndrome and dysmenorrhea Osteoarthritis, rheumatoid arthritis, juvenile arthritis, and ankylosing spondylitis Headaches, migraine prevention and treatment Musculoskeletal pain to metastatic bone pain Minor aches and pains Fever Antineoplastic

Preventing And Ameliorating Toxicity

Gastrointestinal Toxicity  Complications include bleeding, perforation, and occlusion  Ulceration and symptoms are POOR predictors of severe reactions  Risk factors – High dose regimen – Age > 65 years – History of gastric or duodenal ulcer or GI bleeding – Alcohol and tobacco use – Concomitant use of any of the following: • Corticosteroids • Antiplatelets

Anticoagulants SSRIs

Prescrire Int 2011 Sept;20(119):216-9

Gastroprotection Misoprostol –A synthetic prostaglandin E1 analog with labeled indication for prevention of NSAID-induced ulcers –Dose 400 – 800 mcg/day –The only prophylactic agent documented to reduce ulcer complication

Double dose Histamine 2 receptors antagonists Proton pump inhibitors Cochrane Database Syst Review 2002;(4):CD002296

Case Scenario NL is a 68 yr old female who is quite active and enjoys gardening Her PMH is significant for HTN and DM, for which she receives Enalapril and Metformin Recently, she has been complaining of not being able to hold/handle her gardening tools as usual, and at times has mild to moderate pain Her PCP diagnoses her with RA

Nephrotoxicity  Inhibition of prostaglandin synthesis leads to impaired renal perfusion – Acute kidney injury – Chronic interstitial nephritis – Papillary necrosis – Electrolyte and fluid abnormalities

 Often reversible with drug withdrawal  Dose and duration of NSAID therapy determine nephrotoxic potential

Nephrotoxicity (cont’d)  Risk factors – Diabetes – Cardiovascular and hepatic disease – Underlying renal dysfunction – Elderly – Concurrent use of other nephrotoxic drugs • Aminoglycosides • ACEI

Diuretics ARBS

 IF NSAIDs are indicated, critically select patient and use an agent with a short half life

Cardiovascular Disease  Use is associated with an increased risk of

– Thrombotic events, including MI and stroke – New onset or worsening of pre-existing HTN

 Contraindication: perioperative pain in the setting of coronary artery bypass graft (CABG) surgery  Evaluate individual cardiac risk factors – Use with Caution: fluid retention or heart failure

 Lowest effective dose for shortest period of time, consistent with patient goals  Consider alternate therapies in high risk patients

Summary  Safe and Effective Use is Possible – Perform a comprehensive Medication Reconciliation • Document all OTC and Rx drugs • Identify indications and dosages • Quantitate duration of therapy

– Medical History • Identify co-morbidities that put patients at increased risk of NSAID-induced toxicity

– Always use the lowest effective dose for the shortest period of time