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Special Alerts
Clopidogrel (Plavix®) and Proton Pump Inhibitors (PPIs): Health Canada Issues Notice- August 2009
Health Canada, in conjunction with Sanofi-Aventis Canada Inc., and Bristol Myers Squibb Canada Co., has issued a Dear HealthCare Professional letter to Canadian practitioners regarding the potential interaction between clopidogrel (Plavix®) and proton pump inhibitors (PPIs). A similar notice had previously been issued in the U.S. by the Food and Drug Administration (FDA). Certain PPIs may inhibit the cytochrome enzyme (CYP2C19) which metabolizes clopidogrel to its active metabolite, thus potentially resulting in decreased clinical efficacy of clopidogrel.
Health Canada is recommending that healthcare providers continue to prescribe clopidogrel and patients continue taking clopidogrel as directed. Health Canada recommends against the use of drugs (including PPIs) which inhibit CYP2C19 in patients receiving clopidogrel. Prescribers should consider the risk-benefits of combination (PPI-clopidogrel) therapy as well as use of alternative gastroprotective agents. Health Canada is currently working with the manufacturers mentioned to update the Canadian product monograph with this important safety information.
Further information may be found at: http://www.hc-sc.gc.ca/dhp-mps/medeff/advisories-avis/prof/_2009/plavix_hpc-cps-eng.php
Clopidogrel (Plavix®) and Proton Pump Inhibitors (PPIs): Ongoing Safety Review - January 2009; Updated June 2009
The U.S. Food and Drug Administration (FDA) is communicating important information regarding an ongoing safety review of clopidogrel and its effectiveness when used with proton pump inhibitors (PPIs).
Clopidogrel is a prodrug requiring hepatic conversion via CYP3A4 and/or CYP2C19 to its active metabolite. Impaired clopidogrel conversion to its active metabolite may be due to either CYP450 polymorphisms or drug-drug interactions resulting in suboptimal antiplatelet activity.
A PPI is often prescribed with the combination of aspirin and clopidogrel to prevent gastrointestinal bleeding. A number of PPIs are available and include dexlansoprazole, esomeprazole, lansoprazole, omeprazole, pantoprazole, and rabeprazole. Several studies have reported greater clinical event rates (eg, myocardial infarction, death) or greater platelet reactivity associated with concurrent use of clopidogrel and a PPI (Ho, 2008; Pezella, 2008; Gilard, 2006). Similarly, a prospective, randomized, double-blind trial demonstrated a reduction in antiplatelet activity when omeprazole and clopidogrel are used concurrently (Gilard, 2008). Another controlled trial with the PPI lansoprazole also found evidence of a possible interaction resulting in less antiplatelet activity (Small, 2008). This interaction is thought to result from competitive inhibition of the CYP2C19-mediated activation of clopidogrel by omeprazole and other PPIs, which are all metabolized to at least some degree by CYP2C19. In contrast, one study with esomeprazole and pantoprazole did not find evidence of reduced antiplatelet activity when administered with clopidogrel (Siller-Matula, 2009), highlighting the need for additional studies to determine the degree to which individual PPIs may differ in their potential for interacting with clopidogrel.
The manufacturer of Plavix® has agreed to conduct further studies to better understand the effect of other drugs (including PPIs) and genetic factors on the effectiveness of clopidogrel. The FDA is recommending that healthcare providers continue to prescribe clopidogrel while reevaluating the need for prescription or over-the-counter (OTC) PPIs in patients taking clopidogrel. Patients should continue taking clopidogrel as directed. If taking a PPI with clopidogrel, patients should consult with their healthcare provider.
More recently, the Clopidogrel Medco Outcomes Study (Stanek, 2009) was presented at the Society for Cardiovascular Angiography and Interventions (SCAI) Annual Scientific Sessions. The study was a retrospective cohort analysis evaluating integrated medical and pharmacy claims. Patients included (n=16,718) were those who had a coronary stent procedure with a new clopidogrel prescription claim within 1 month of procedure. Patients were segregated according to PPI use; newer PPIs (ie, rabeprazole, dexlansoprazole) were not included in the analysis. Those who received a PPI demonstrated a 51% increase in the risk of cardiovascular events (MI, unstable angina, stroke, repeat coronary procedure) compared to those who did not receive a PPI (lansoprazole 24.3%; pantoprazole 29.2%; esomeprazole 24.9%; omeprazole 25.1% vs 17.9%). SCAI has urged healthcare providers to consider prescribing alternatives to PPI use, such as an antacid or H2 blocker (eg, famotidine, ranitidine, or cimetidine). Of note, cimetidine is a moderate CYP2C19 inhibitor. Although no documented interactions exist, theoretically cimetidine may also reduce conversion of clopidogrel to its active metabolite. In cases where gastrointestinal conditions require treatment, the patient's primary care provider or gastroenterologist should be contacted to discuss treatment options.
For more information, healthcare professionals may refer to the following websites:
http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/ucm079520.htm
http://www.scai.org/drlt1.aspx?PAGE_ID=5870
References:
Ho PM, Maddox TM, Wang L, et al, “Risk of Adverse Outcomes Associated With Concomitant Use of Clopidogrel and Proton Pump Inhibitors Following Acute Coronary Syndrome,” JAMA, 2009, 301(9):937-44.
Pezalla E, Day D, and Pulliadath I, “Initial Assessment of Clinical Impact of a Drug Interaction Between Clopidogrel and Proton Pump Inhibitors,” J Am Coll Cardiol, 2008, 52(12):1038-9.
Gilard M, Arnaud B, Le Gal G, et al, “Influence of Omeprazol on the Antiplatelet Action of Clopidogrel Associated to Aspirin,” J Thromb Haemost, 2006, 4(11):2508-9.
Gilard M, Arnaud B, Cornily JC, et al, “Influence of Omeprazole on the Antiplatelet Action of Clopidogrel Associated With Aspirin: The Randomized, Double-Blind Ocla (Omeprazole Clopidogrel Aspirin) Study,” J Am Coll Cardiol, 2008, 51(3):256-60.
Siller-Matula JM, Spiel AO, Lang IM, et al, “Effects of Pantoprazole and Esomeprazole on Platelet Inhibition by Clopidogrel,” Am Heart J, 2009, 157(1):148.e1-5.
Small DS, Farid NA, Payne CD, et al, “Effects of the Proton Pump Inhibitor Lansoprazole on the Pharmacokinetics and Pharmacodynamics of Prasugrel and Clopidogrel,” J Clin Pharmacol, 2008, 48(4):475-84.
Stanek EJ, Aubert RE, Flockhart DA, et al, “A National Study of the Effect of Individual Proton Pump Inhibitors on Cardiovascular Outcomes in Patients Treated With Clopidogrel Following Coronary Stenting: The Clopidogrel Medco Outcomes Study,” Society for Cardiovascular Angiography and Interventions 2009 Scientific Sessions; May 6, 2009; Las Vegas, NV.
Medication Safety Issues
Sound-alike/look-alike issues:
AcipHex® may be confused with Acephen®, Accupril®, Aricept®, pHisoHex®
Rabeprazole may be confused with aripiprazole,donepezil, lansoprazole, omeprazole, raloxifene
Pronunciation
(ra BEP ra zole)
U.S. Brand Names
Index Terms
Generic Available
No
Canadian Brand Names
Pharmacologic Category
Pharmacologic Category Synonyms
Use: Labeled Indications
Short-term (4-8 weeks) treatment and maintenance of erosive or ulcerative gastroesophageal reflux disease (GERD); symptomatic GERD; short-term (up to 4 weeks) treatment of duodenal ulcers; long-term treatment of pathological hypersecretory conditions, including Zollinger-Ellison syndrome; H. pylori eradication (in combination therapy)
Canadian labeling: Additional uses (not in U.S. labeling): Treatment of nonerosive reflux disease (NERD); treatment of gastric ulcers
Use: Unlabeled/Investigational
Maintenance of duodenal ulcer
Pregnancy Risk Factor
B
Pregnancy Considerations
Not shown to be teratogenic in animal studies, however, adequate and well-controlled studies have not been done in humans; use during pregnancy only if clearly needed
Lactation
Excretion in breast milk unknown/not recommended
Contraindications
Hypersensitivity to rabeprazole, substituted benzimidazoles (ie, esomeprazole, lansoprazole, omeprazole, pantoprazole), or any component of the formulation
Warnings/Precautions
Concerns related to adverse effects:
• Atrophic gastritis: Long-term omeprazole therapy has caused atrophic gastritis (by biopsy); this may also occur with rabeprazole.
• Carcinoma: No reports of enterochromaffin-like (ECL) cell carcinoids, dysplasia, or neoplasia has occurred.
Disease-related concerns:
• Gastric malignancy: Relief of symptoms does not preclude the presence of a gastric malignancy.
• Gastrointestinal infection (eg, Salmonella, Campylobacter): Use of proton pump inhibitors may increase risk of these infections.
• Hepatic impairment: Use caution in patients with severe hepatic impairment.
Special populations:
• Pediatrics: Safety and efficacy have not been established in children <12 years of age.
Other warnings/precautions:
• Appropriate use: Helicobacter pylori eradication: Short-term combination therapy (?7 days) has been associated with a higher incidence of treatment failure. The American College of Gastroenterology recommends 10-14 days of therapy (triple or quadruple) for eradication of H. pylori (Chey, 2007).
Adverse Reactions
1% to 10%:
Central nervous system: Pain (3%), headache (2% to 5%)
Gastrointestinal: Diarrhea (3%), flatulence (3%), constipation (2%), nausea (2%)
Respiratory: Pharyngitis (3%)
Miscellaneous: Infection (2%)
<1%, postmarketing, and/or case reports (limited to important or life-threatening): Abdomen enlarged, abdominal pain, abnormal stools, abnormal vision, agitation, agranulocytosis, albuminuria, allergic reaction, alopecia, amblyopia, anaphylaxis, anemia, angina pectoris, angioedema, anorexia, apnea, arrhythmia, arthralgia, arthritis, ascites, asthma, bloody diarrhea, bone pain, bradycardia, breast enlargement, bullous and other drug eruptions of skin, bundle branch block, bursitis, cataract, cellulitis, cerebral hemorrhage, chest pain substernal, cholangitis, cholecystitis, cholelithiasis, colitis, coma, contact dermatitis, convulsions, corneal opacity, CPK increased, cystitis, deafness, delirium, depression, diaphoresis, diabetes mellitus, diplopia, disorientation, dizziness, duodenitis, dysmenorrhea, dyspepsia, dysphagia, dyspnea, dysuria, edema, electrocardiogram abnormal, embolus, epistaxis, erythema multiforme, esophageal stenosis, esophagitis, extrapyramidal syndrome, eye hemorrhage, facial edema, fever, fungal dermatitis, gastritis, gastroenteritis, gastrointestinal hemorrhage, gingivitis, glaucoma, glossitis, gout, gynecomastia, hematuria, hemolytic anemia, hepatic encephalopathy, hepatic cirrhosis, hepatic enzymes increased, hepatitis, hepatoma, hernia, hyperammonemia, hypercholesteremia, hyperglycemia, hyperkinesia, hyperlipemia, hypertension, hyper-/hypothyroidism, hypertonia, hypokalemia, hyponatremia, hypoxia, impotence, injection site hemorrhage/pain/reaction, insomnia, interstitial nephritis, interstitial pneumonia, jaundice, kidney calculus, leukocytosis, leukopenia, leukorrhea, liver fatty deposit, lymphadenopathy, malaise, melena, menorrhagia, metrorrhagia, MI, migraine, myalgia, neck rigidity, nervousness, neuralgia, neuropathy, neutropenia, orchitis, palpitation, pancreatitis, pancytopenia, paresthesia, peripheral edema, photosensitivity, polycystic kidney, polyuria, proctitis, pruritus, PSA increased, psoriasis, pulmonary embolus, QTc prolongation, rash, rectal hemorrhage, retinal degeneration, rhabdomyolysis, salivary gland enlargement, sinus bradycardia, skin discoloration, somnolence, Stevens-Johnson syndrome, stomatitis, strabismus, sudden death, supraventricular tachycardia, syncope, tachycardia, taste abnormal, thrombocytopenia, thrombophlebitis, thrombosis, thirst (rare) tinnitus, toxic epidermal necrolysis, tremor, TSH increased, ulcerative colitis, urinary incontinence, urticaria, vasodilation, ventricular arrhythmias, vertigo, vomiting, weakness, weight gain/loss, xerostomia
Metabolism/Transport Effects
Substrate (major) of CYP2C19, 3A4; Inhibits CYP2C8 (moderate), 2C19 (moderate), 2DC (weak), 3A4 (weak)
Drug Interactions
Atazanavir: Proton Pump Inhibitors may decrease the absorption of Atazanavir. Risk D: Consider therapy modification
Clopidogrel: Proton Pump Inhibitors may diminish the therapeutic effect of Clopidogrel. This appears to be due to reduced formation of the active clopidogrel metabolite. Management: Due to the risk for impaired clopidogrel effectiveness, clinicians should carefully consider the need for proton pump inhibitor therapy in patients receiving clopidogrel. Other acid-lowering therapies do not appear to share this interaction. Risk D: Consider therapy modification
CYP2C19 Inducers (Strong): May increase the metabolism of CYP2C19 Substrates. Risk C: Monitor therapy
CYP2C19 Substrates: CYP2C19 Inhibitors (Moderate) may decrease the metabolism of CYP2C19 Substrates. Risk C: Monitor therapy
CYP2C8 Substrates (High risk): CYP2C8 Inhibitors (Moderate) may decrease the metabolism of CYP2C8 Substrates (High risk). Risk C: Monitor therapy
CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy
Dabigatran Etexilate: Proton Pump Inhibitors may decrease the serum concentration of Dabigatran Etexilate. Risk C: Monitor therapy
Dasatinib: Proton Pump Inhibitors may decrease the absorption of Dasatinib. Risk D: Consider therapy modification
Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy
Delavirdine: Proton Pump Inhibitors may decrease the serum concentration of Delavirdine. Management: Chronic therapy with proton pump inhibitors (PPIs) should be avoided in patients treated with delavirdine. The clinical significance of short-term PPI therapy with delavirdine is uncertain, but such therapy should be undertaken with caution. Risk X: Avoid combination
Erlotinib: Proton Pump Inhibitors may decrease the serum concentration of Erlotinib. Risk X: Avoid combination
Fluconazole: May increase the serum concentration of Proton Pump Inhibitors. Risk C: Monitor therapy
Herbs (CYP3A4 Inducers): May increase the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy
Indinavir: Proton Pump Inhibitors may decrease the serum concentration of Indinavir. Risk C: Monitor therapy
Iron Salts: Proton Pump Inhibitors may decrease the absorption of Iron Salts. Exceptions: Ferric Gluconate; Ferumoxytol; Iron Dextran Complex; Iron Sucrose. Risk C: Monitor therapy
Itraconazole: Proton Pump Inhibitors may decrease the serum concentration of Itraconazole. Risk D: Consider therapy modification
Ketoconazole: Proton Pump Inhibitors may decrease the serum concentration of Ketoconazole. Ketoconazole may increase the serum concentration of Proton Pump Inhibitors. Risk D: Consider therapy modification
Mesalamine: Proton Pump Inhibitors may diminish the therapeutic effect of Mesalamine. Proton pump inhibitor-mediated increases in gastrointestinal pH may cause the premature release of mesalamine from specific sustained-release mesalamine products. Management: Consider avoiding concurrent administration of high-dose proton pump inhibitors (PPIs) with sustained-release mesalamine products. Risk D: Consider therapy modification
Methotrexate: Proton Pump Inhibitors may decrease the excretion of Methotrexate. Antirheumatic doses of methotrexate probably hold minimal risk. Risk C: Monitor therapy
Mycophenolate: Proton Pump Inhibitors may decrease the serum concentration of Mycophenolate. Specifically, concentrations of the active mycophenolic acid may be reduced. Risk C: Monitor therapy
Nelfinavir: Proton Pump Inhibitors may decrease serum concentrations of the active metabolite(s) of Nelfinavir. Proton Pump Inhibitors may decrease the serum concentration of Nelfinavir. Risk X: Avoid combination
Posaconazole: Proton Pump Inhibitors may decrease the serum concentration of Posaconazole. Risk X: Avoid combination
Raltegravir: Proton Pump Inhibitors may increase the serum concentration of Raltegravir. Risk C: Monitor therapy
Saquinavir: Proton Pump Inhibitors may increase the serum concentration of Saquinavir. Risk C: Monitor therapy
Tacrolimus: Proton Pump Inhibitors may increase the serum concentration of Tacrolimus. Management: Tacrolimus dose adjustment may be required. Rabeprazole, pantoprazole, or selected H2-receptor antagonists (i.e., ranitidine or famotidine) may be less likely to interact. Genetic testing may predict patients at highest risk. Risk D: Consider therapy modification
Tipranavir: May decrease the serum concentration of Proton Pump Inhibitors. These data are derived from studies with Ritonavir-boosted Tipranavir. Risk C: Monitor therapy
Voriconazole: Proton Pump Inhibitors may increase the serum concentration of Voriconazole. Risk C: Monitor therapy
Ethanol/Nutrition/Herb Interactions
Ethanol: Avoid ethanol (may cause gastric mucosal irritation).
Food: High-fat meals may delay absorption, but Cmax and AUC are not altered.
Herb/Nutraceutical: St John's wort may increase the metabolism and thus decrease the levels/effects of rabeprazole.
Storage
Store at 25°C (77°F). Protect from moisture.
Mechanism of Action
Potent proton pump inhibitor; suppresses gastric acid secretion by inhibiting the parietal cell H+/K+ ATP pump
Pharmacodynamics/Kinetics
Onset of action: Within 1 hour
Duration: 24 hours
Absorption: Oral: Well absorbed within 1 hour
Protein binding, serum: ~96%
Metabolism: Hepatic via CYP3A and 2C19 to inactive metabolites
Bioavailability: Oral: ~52%
Half-life elimination (dose dependent): 1-2 hours
Time to peak, plasma: 2-5 hours
Excretion: Urine (90% primarily as thioether carboxylic acid metabolites); remainder in feces
Dosage
Oral:
Children ?12 years: U.S. labeling: Short-term treatment of GERD: 20 mg once daily for ?8 weeks
Adults >18 years and Elderly:
Erosive/ulcerative GERD: Treatment: 20 mg once daily for 4-8 weeks; if inadequate response, may repeat up to an additional 8 weeks; maintenance: 20 mg once daily
Canadian labeling: 20 mg once daily for 4 weeks; if inadequate response, may repeat for an additional 4 weeks (lack of symptom control after 4 weeks warrants further evaluation); maintenance: 10 mg once daily (maximum: 20 mg once daily)
Symptomatic GERD: Treatment: 20 mg once daily for 4 weeks; if inadequate response, may repeat for an additional 4 weeks
Canadian labeling: 10 mg once daily (maximum: 20 mg once daily) for 4 weeks; lack of symptom control after 4 weeks warrants further evaluation
Duodenal ulcer: 20 mg/day before breakfast for 4 weeks; additional therapy may be required for some patients
Gastric ulcers (Canadian labeling): 20 mg once daily up to 6 weeks; additional therapy may be required for some patients
Helicobacter pylori eradication:
Manufacturer labeling: 20 mg twice daily administered with amoxicillin 1000 mg and clarithromycin 500 mg twice daily for 7 days
American College of Gastroenterology guidelines (Chey, 2007):
Nonpenicillin allergy: 20 mg twice daily administered with amoxicillin 1000 mg and clarithromycin 500 mg twice daily for 10-14 days
Penicillin allergy: 20 mg twice daily administered with clarithromycin 500 mg and metronidazole 500 mg twice daily for 10-14 days or 20 mg once or twice daily administered with bismuth subsalicylate 525 mg and metronidazole 250 mg plus tetracycline 500 mg 4 times/day for 10-14 days
Hypersecretory conditions: 60 mg once daily; dose may need to be adjusted as necessary. Doses as high as 100 mg once daily and 60 mg twice daily have been used, and continued as long as necessary (up to 1 year in some patients).
NERD (Canadian labeling): Treatment: 10 mg (maximum: 20 mg once daily) for 4 weeks; lack of symptom control after 4 weeks warrants further evaluation
Dosage adjustment in renal impairment: No dosage adjustment required
Dosage adjustment in hepatic impairment:
Mild-to-moderate: Elimination decreased; no dosage adjustment required
Severe: Use caution
Administration: Oral
May be administered with or without food; best if taken before breakfast. Do not crush, split, or chew tablet. May be administered with an antacid.
Dietary Considerations
May be taken with or without food; best if taken before breakfast.
Patient Education
Take as directed. Swallow whole; do not crush, split, or chew. Follow recommended diet and activity instructions. Avoid alcohol. You may experience headache (use of mild analgesic may help) or other side effects. Report persistent abdominal pain or headaches to prescriber. Breast-feeding precaution: Breast-feeding is not recommended.
Geriatric Considerations
No difference in efficacy or safety was noted in elderly subjects as compared to younger subjects. No dosage adjustment is necessary in the elderly.
Dental Health: Effects on Dental Treatment
No significant effects or complications reported
Dental Health: Vasoconstrictor/Local Anesthetic Precautions
No information available to require special precautions
Mental Health: Effects on Mental Status
May cause insomnia, anxiety, dizziness, depression, nervousness, somnolence, vertigo, convulsions, abnormal dreams; may rarely cause agitation, amnesia, confusion, extrapyramidal syndrome
Mental Health: Effects on Psychiatric Treatment
None reported
Nursing: Physical Assessment/Monitoring
Assess other medications, especially those dependent on cytochrome P450 metabolism (eg, digoxin) and those requiring acid environment for absorption (eg, ketoconazole, ampicillin). Monitor therapeutic effectiveness (reduction in symptoms) and adverse reactions and toxicity. Assess knowledge/teach patient appropriate use, interventions to reduce side effects, and adverse reactions to report.
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [CAN] = Canadian brand name
Tablet, delayed release, enteric coated, as sodium:
AcipHex®: 20 mg
Pariet® [CAN]: 10 mg, 20 mg
Pricing: U.S. (www.drugstore.com)
Tablet, EC (Aciphex)
20 mg (30): $194.55
References
Chey WD, Wong BC, et al, “American College of Gastroenterology Guideline on the Management of Helicobacter pylori Infection,” Am J Gastroent, 2007, 102(8):1808-25.
Cockayne SE, Glet RJ, Gawkrodger DJ, et al, “Severe Erythrodermic Reactions to the Proton Pump Inhibitors Omeprazole and Lansoprazole,” Br J Dermatol,1999, 141(1):173-5.
Natsch S, Vinks MH, Voogt AK, et al, “Anaphylactic Reactions to Proton-Pump Inhibitors,” Ann Pharmacother, 2000, 34(4):474-6.
Paoluzi P, Iacopini F, Crispino P, et al, “2-Week Triple Therapy for Helicobacter pylori Infection is Better Than 1-Week in Clinical Practice: a Large Prospective Single-Center Randomized Study,” Helicobacter, 2006, 11(6):562-8.
Wolfe MM and Sachs G, “Acid Suppression: Optimizing Therapy for Gastroduodenal Ulcer Healing, Gastroesophageal Reflux Disease, and Stress-Related Erosive Syndrome,” Gastroenterology, 2000,118(2 Suppl 1):9-31.
International Brand Names
Lexi-Comp.com
Last full review/revision August 2009
Content last modified August 2009
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