Comparison of Calcium Channel Blockers

Detail-Document #250414 This Detail-Document accompanies the related article published in PHARMACIST S LETTER / PRESCRIBER S LETTER April 2009 ~ Volume 25 ~ Number 250414 Comparison of Calcium Channel Blockers Calcium channel blockers (CCBs) are divided into two classes: the non-dihydropyridines (diltiazem [e.g., Cardizem, etc] and verapamil [e.g., Calan, etc]) and the dihydropyridines (all CCBs except verapamil and diltiazem). The following chart provides information on the pharmacology and therapeutic interchange for the CCBs in the U.S. Many states allow therapeutic interchange without prescriber approval of therapeutic equivalents as listed in the FDA s Orange Book. Therapeutic equivalents are drugs that demonstrate BOTH pharmaceutical equivalence (same active ingredient, dosage form, and strength) and bioequivalence (comparable rate and extent of absorption). (See our Detail-Document Generic Substitution for Commonly Prescribed Drugs for information about generic substitution of other drugs and for a chart of state substitution regulations). The chart below does not include authorized generics. Authorized generics are the exact same product as the brand name, but marketed as a generic (e.g., Pfizer s nifedipine ER is the same as Procardia XL). Abbreviations: A. fib-atrial fibrillation; A. flutter-atrial flutter; ER-extended release; HS-at bedtime; HTN-hypertension; IR-immediate release; mfrmanufacturer; SVT-supraventricular tachycardia DIHYDROPYRIDINES: Mechanism of action involves coronary and peripheral arteriolar vasodilation. This can lead to reflex tachycardia, headache, flushing, and peripheral edema. The dihydropyridines can impair myocardial contractility to varying degrees. 1 Dihydropyridines are CYP3A4 substrates. 2 Once-a-day (24 hour) Dihydropyridines Amlodipine (Norvasc) 2.5 mg, 5 mg, 10 mg s Amlodipine Actavis Totowa, Amneal, Apotex, Aurobindo, Caraco, Cobalt, Dr. Reddy s, Gedeon Richter, Invagen, Kali, Lek, Lupin, Matrix, Mylan, Ranbaxy, Roxane, Synthon, Teva, Torrent, Upsher Smith, Watson, Wockhardt, Zydus HTN: initial 5 mg QD (2.5 mg QD for small, frail, elderly, or hepatic insufficiency); max 10 mg QD CAD: 5 mg to 10 mg QD May be the safest choice if a CCB is needed in a patient with systolic heart failure. 1

(Detail-Document #250414: Page 2 of 10) Once-a-day (24 hour) Dihydropyridines, continued Felodipine ER (Plendil) 2.5 mg, 5 mg, 10 mg Felodipine ER Mutual, Mylan HTN: initial 5 mg QD (2.5 mg QD elderly); max 10 mg QD Isradipine ER (DynaCirc CR) 5 mg, 10 mg None c HTN: 5 mg QD; max 20 mg per day Patients may have more side effects with no additional benefit at doses >10 mg daily. Nifedipine ER (Adalat CC) 30 mg, 60 mg Nifedipine ER Actavis, Afeditab CR (Watson), Biovail (marketed by Teva as Nifediac CC) HTN: initial 30 mg QD; doses >90 mg not recommended Take on an empty stomach. 90 mg Biovail (marketed by Teva as Nifediac CC) Nifedipine ER (Afeditab CR) 30 mg, 60 mg Nifedipine ER Actavis, Adalat CC (Bayer), Biovail (marketed by Teva as Nifediac CC) HTN: initial 30 mg QD; doses >90 mg not recommended Take on an empty stomach. Nifedipine ER (Procardia XL) 30 mg, 60 mg Nifedipine ER Biovail (marketed by Teva as Nifedical XL), Osmotica 90 mg Nifedipine ER Osmotica HTN: initial 30-60 mg QD; max 120 mg QD Vasospastic or chronic stable angina: initial 30-60 mg QD; max 120 mg QD (limited experience with >90 mg QD)

(Detail-Document #250414: Page 3 of 10) Once-a-day (24 hour) Dihydropyridines, continued Nisoldipine ER (Sular) 8.5 mg, 17 mg, 25.5 mg, 34 mg None c HTN: initial 17 mg QD; max 34 mg QD Nisoldipine ER (generic only; brand to which it was equivalent has been reformulated) (Mylan) 20 mg, 30 mg, 40 mg None HTN: initial 20 mg QD; usual 20-40 mg QD; max 60 mg QD Increased risk of adverse effects over 40 mg. Twice Daily Dihydropyridines Isradipine (DynaCirc [brand discontinued], generics available) 2.5 mg, 5 mg Isradipine Actavis, Cobalt HTN: initial 2.5 mg BID; max daily dose 20 mg (given in divided doses) Patients may have more side effects with no additional benefit with >10 mg daily. Nicardipine ER (Cardene SR) 30 mg, 45 mg, 60 mg None c HTN: usual 30-60 mg twice daily Three Times Daily Dihydropyridines Nicardipine (Cardene [brand 20 mg, 30 mg discontinued], generics available) Nicardipine Amneal, Barr, Mylan, Teva, Watson HTN: initial 20 mg TID; usual 20-40 mg TID Chronic stable angina: initial 20 mg TID; usual 20-40 mg TID Start with 20 mg BID in hepatic insufficiency. Nifedipine IR (Procardia) 10 mg, 20 mg Nifedpine Actavis Elizabeth, Catalent, Inverness Vasospastic or chronic stable angina: initial 10 mg TID; usual 10-20 mg TID; max 60 mg TID Not to be used to treat acute blood pressure elevation or hypertension.

(Detail-Document #250414: Page 4 of 10) NON-DIHYDROPYRIDINES: Compared to the dihydropyridines, the non-dihydropyridines provide relatively less peripheral and coronary arteriolar vasodilation. They have significant negative inotropic and negative chronotropic effects, with verapamil having the most pronounced effect. The nondihydropyridines also slow cardiac conduction. 1 Diltiazem and verapamil are CYP3A4 substrates and CYP3A4 inhibitors. 2 Constipation is common with verapamil. 1 Once-a-day (24 hour) Non-dihydropyridine Products Diltiazem ER (Cardizem CD) 240 mg, 300 mg 360 mg None c Diltiazem ER Actavis Elizabeth, Biovail, Cartia XT (Watson Labs Florida), Dilt-CD (Torpharm) HTN: initial 180-240 mg QD; usual 240-360 mg QD; max 480 mg QD Vasospastic and chronic stable angina: 120-180 mg QD; max 480 mg QD Capsules can be opened for administration of the intact granules. 3 Some patients may respond to lower dose. Diltiazem ER (Cardizem LA) 240 mg, 300 mg, 360 mg, 420 mg None c HTN: initial 180-240 mg QD; max 540 mg QD Chronic stable angina: initial 180 mg QD; max 360 mg QD Some patients may respond to lower dose. Diltiazem ER (Cartia XT) 240 mg, 300 mg Diltiazem ER Actavis Elizabeth, Biovail, Cardizem CD (Biovail), Dilt-CD (Torpharm) HTN:initial 180-240 mg QD; usual 240-360 mg QD; max 480 mg QD Vasospastic and chronic stable angina: initial 120-180 mg QD; max 480 mg QD Some patients may respond to lower dose. Diltiazem ER (Dilacor XR) 240 mg Diltiazem ER Watson Labs Florida, Mylan, Torpharm HTN: initial 180-240 mg (elderly 120 mg QD); usual 180-480 mg QD; max 540 mg QD Chronic stable angina: initial 120 mg QD; max 480 mg QD

(Detail-Document #250414: Page 5 of 10) Once-a-day (24 hour) Non-dihydropyridine Products, continued Diltiazem ER (Dilt-CD) Diltiazem ER 240 mg, 300 mg Actavis Elizabeth, Biovail, Cardizem CD (Biovail), Cartia XT (Watson Labs Florida) HTN: initial 180-240 mg QD; usual 240-360 mg QD; max 480 mg QD Vasospastic and chronic stable angina: initial 120-180 mg QD; max 480 mg QD Some patients may respond to lower dose. Diltiazem ER (Diltzac) 240 mg, 300 mg, 360 mg Diltiazem ER KV Pharm, Taztia XT (Watson Labs Florida), Tiazac (Biovail) HTN: initial 120-240 mg QD; max 540 mg QD Chronic stable angina: initial 120-180 mg QD; max 540 mg QD May administer contents sprinkled on a spoonful of applesauce, followed by a glass of cool water; do not chew. Diltiazem ER (Taztia XT) 240 mg, 300 mg, 360 mg Diltiazem ER KV Pharm, Diltzac (Apotex), Tiazac (Biovail) HTN: initial 120-240 mg QD; max 540 mg QD Chronic stable angina: initial 120-180 mg QD; max 540 mg QD May administer contents sprinkled on a spoonful of applesauce, followed by a glass of cool water; do not chew. Diltiazem ER (Tiazac) 240 mg, 300 mg Diltiazem ER KV Pharm, Diltzac (Apotex), Taztia XT (Watson Labs Florida) 420 mg Diltiazem ER KV Pharm HTN: initial 120-240 mg QD; max 540 mg QD Chronic stable angina: initial 120-180 mg QD; max 540 mg QD May administer contents sprinkled on a spoonful of applesauce, followed by a glass of cool water; do not chew. Verapamil ER (Verelan) 240 mg 360 mg None Verapamil ER Mylan HTN: 240 mg QD (120 mg QD for small or elderly patients, or those with liver impairment); max 480 mg QD May administer contents sprinkled on a spoonful of applesauce, followed by a glass of cool water; do not chew.

(Detail-Document #250414: Page 6 of 10) Therapeutic Equivalents a Once-a-day (24 hour) Non-dihydropyridine Products, continued Verapamil ER (Verelan PM) 100 mg, Verapamil ER 200 mg, 300 mg Mylan HTN: 200 mg HS (100 mg HS for small or elderly patients, or renal or hepatic insufficiency); max 400 mg HS May administer contents sprinkled on a spoonful of applesauce, followed by a glass of cool water; do not chew. Taken HS, peak effect occurs in morning & early afternoon. Verapamil ER (Covera-HS) 180 mg, 240 mg None c HTN: initial 180 mg QD; max 480 mg QD Angina: initial 180 mg QD; max 540 mg QD Taken HS, peak verapamil plasma concentrations occur in the early morning hours. Twice-a-day (12 hour) Non-dihydropyridine Products Diltiazem ER (formerly Cardizem SR [discontinued]; generic available) 60 mg, 90 mg, 120 mg Diltiazem ER Mylan HTN: initial 60-120 mg BID; usual daily dose 240-360 mg (given in divided doses) Verapamil ER (Isoptin SR) 120 mg, 240 mg Ivax, Kali, Mylan 180 mg Ivax, Mylan HTN: initial 180 mg QD (consider 120 mg in small or elderly patients, or hepatic insufficiency); max 240 mg Q12 hrs

(Detail-Document #250414: Page 7 of 10) Three and Four times daily Non-dihydropyridine Products Diltiazem IR (Cardizem) 30 mg, 60 mg, Diltiazem IR 120 mg, 90 mg Clonmel, Mylan, Teva Vasospastic and chronic stable angina: initial 30 mg QID; average daily dose 180-360 mg (given in divided doses) Take before meals and at bedtime. Verapamil IR (Calan) 40 mg Verapamil IR Sandoz, Watson 80 mg, 120 mg Verapamil IR Actavis Elizabeth, Mylan, Sandoz, Watson HTN: initial 80 mg TID (consider 40 mg TID in small or elderly patients, or hepatic impairment); max daily dose 480 mg (given in divided doses)(no evidence of additional benefit beyond 360 mg) Vasospastic and chronic stable angina: usual 80-120 mg TID; consider initial dose of 40 mg TID in small or elderly, or hepatic impairment. A.fib, A.flutter: 80 mg TID to 80 mg QID (with digoxin) SVT: 80 mg TID to 120 mg QID (nondigitalized) Acute Care Calcium Channel Blockers Clevidipine (Cleviprex) 0.5 mg/ml emulsion None Blood pressure reduction: initial 1-2 mg/hour; usual 4-6 mg/hr Also see our Detail- Document: New Drug: Cleviprex (Clevidipine)

(Detail-Document #250414: Page 8 of 10) Acute Care Calcium Channel Blockers, continued Diltiazem (Cardizem) injection (brand discontinued, generic available) 5 mg/ml Diltiazem injection Apotex, Baxter, Bedford, Hospira, Intl Medication, Taylor, Teva 100 mg/15 ml Add-Vantage vial Diltiazem injection Hospira A. fib and A. flutter: 0.25 mg/kg (20 mg for average size patient) over 2 min; after 15 min., if needed, give 0.35 mg/kg (25 mg for average size patient); if needed give additional boluses or start continuous infusion of 10 mg/hour (range 5-15 mg/hour) for up to 24 hours Diltiazem exhibits dosedependent, non-linear kinetics, and may accumulate with infusion for more than 24 hours. SVT: 0.25 mg/kg (20 mg for average size patient) over 2 min; after 15 min., if needed, give 0.35 mg/kg (25 mg for average size patient); subsequent doses per patient need Nicardipine injection (Cardene) 2.5 mg/ml Nicardipine injection Teva 20 mg (0.1 mg/ml), 40 mg (0.2 mg/ml) premix Nicardipine injection EKR Therapeutics HTN: initial 5 mg/hour, max 15 mg/hour; decrease to 3 mg/hour when goal reached As a substitute for oral nicardipine: 20 mg Q8hrs=0.5 mg/hour; 30 mg Q8hrs=1.2 mg/hour; 40 mg Q8hrs=2.2 mg/hour Nimodipine (Nimotop [brand discontinued, generic available]) 30 mg s Nimodipine s Banner, Barr, Sun Subarachnoid hemorrhage: 60 mg Q4 hours for 21 days Can puncture on both ends and withdraw contents with 18-guage needle & administer through nasogastric tube followed by 30 ml of water. Label syringe Not for IV use.

(Detail-Document #250414: Page 9 of 10) Acute Care Calcium Channel Blockers, continued Verapamil injection (Calan [brand discontinued, generic available]) 2.5 mg/ml Verapamil injection Bedford, Hospira, Intl Medication, Luitpold SVT, A.fib., A.flutter: initial 5-10 mg (0.075-0.15 mg/kg) over 2 min; if needed, after 30 min., give 10 mg (0.15 mg/kg); optimal interval for subsequent doses not determined Infuse over at least 3 min. in elderly patients. a. From Electronic Orange Book. March 13, 2009. http://www.fda.gov/cder/ob/default.htm. (Accessed March 14, 2009). The manufacturers listed may differ from the company who markets or distributes the drug. Both the manufacturer and distributor are listed on the drug s product labeling. b. From U.S. prescribing information unless otherwise specified. c. Cost of 30-day supply (drugstore.com): Cardene SR 60 mg BID $125.99; Cardizem CD 360 mg QD $215.23; Cardizem LA 360 mg QD $133.78; Covera HS 240 mg HS $79.37; DynaCirc CR 10 mg QD $159.73; Sular 34 mg QD $92.38; Verelan 360 mg QD $191.20. Users of this document are cautioned to use their own professional judgment and consult any other necessary or appropriate sources prior to making clinical judgments based on the content of this document. Our editors have researched the information with input from experts, government agencies, and national organizations. Information and Internet links in this article were current as of the date of publication.

(Detail-Document #250414: Page 10 of 10) Project Leader in preparation of this Detail- Document: Melanie Cupp, Pharm.D., BCPS References 1. Saseen JJ, Carter BL. Essential hypertension. In: Koda-Kimble MA, Young LY, Kradjan WA, Gugliemo BJ, editors. Applied therapeutics: the clinical use of drugs. Philadelphia, PA: Lippincott Williams & Wilkins; 2005. 2. Cytochrome P450 drug interactions. Pharmacist's Letter/Prescriber's Letter 2006;22(2):220233. 3. Medications that should not be crushed. Pharmacist's Letter/Prescriber's Letter 2008;24(12):241204. 4. Product information for Norvasc. Pfizer Inc. NY, NY 10017. August 2006. 5. Product information for Plendil. AstraZeneca LP. Wilmington, DE 19850. November 2003. 6. Product information for DynaCirc CR. Reliant Pharmaceuticals, Inc. Liberty Corner, NJ 07938. August 2005. 7. Product information for Adalat CC. Schering Corporation. Kenilworth, NJ 07033. October 2004. 8. Product information for Afeditab CR. Watson Laboratories. Corona, CA 92880. September 2007. 9. Product information for Nifediac CC. Teva Pharmaceuticals USA. Sellersville, PA 18960. July 2003. 10. Product information for Nifedical XL. Teva Pharmaceuticals USA. Sellersville, PA 18960. September 2003. 11. Product information for Procardia XL. Pfizer Inc. NY, NY 10017. August 2003. 12. Product information for Sular. Sciele Pharma, Inc. Atlanta, GA 30328. January 2008. 13. Product information for nisoldipine. Mylan Pharmaceuticals Inc. Morgantown, WV 26505. June 2008. 14. Product information for isradipine. Cobalt Laboratories. Bonita Springs, FL 34134. May 2008. 15. Product information for Cardene SR. PDL BioPharma, Inc. Redwood City, CA 94063. January 2007. 16. Product information for nicardipine. Mylan Pharmaceuticals Inc. Morgantown, WV 26505. December 2004. 17. Product information for Procardia. Pfizer Inc. NY, NY 10017. March 2006. 18. Product information for Cardizem CD. Biovail Pharmaceuticals, Inc. Morrisville, NC 27560. August 2001. 19. Product information for Cardizem LA. Abbott Laboratories. North Chicago, IL 60064. September 2007. 20. Product information for Cartia XT. Watson Laboratories, Inc. Corona, CA 92880. December 2006. 21. Product information for Dilt-CD. Apotex Corp. Weston, FL 33326. May 2004. 22. Product information for Dilt-XT. Apotex Corp. Weston, FL 33326. September 2005. 23. Product information for Diltzac. Apotex Corp. Weston, FL 33326. July 2008. 24. Product information for Diltia XT. Watson Laboratories, Inc. Corona, CA 92889. July 2007. 25. Product information for Taztia XT. Watson Laboratories. Corona, CA 92880. December 2006. 26. Product information for Tiazac. Forest Pharmaceuticals, Inc. St. Louis, MO 63045. April 2006. 27. Product information for Verelan. Schwarz Pharma. Milwaukee, WI 53201. March 2005. 28. Product information for Verelan PM. Schwarz Pharma. Milwaukee, WI 53201. May 2004. 29. Product information for Covera-HS. Pfizer In. NY, NY 10017. March 2006. 30. Product information for diltiazem extended-release (twice-a-day dosage). Mylan Pharmaceuticals Inc. Morgantown, WV 26505. June 2006. 31. Product information for Isoptin SR. Ranbaxy Laboratories Inc. Jacksonville, FL 32257. July 2007. 32. Product information for Cardizem. Biovail Pharmaceuticals, Inc. Morrisville, NC 27560. August 2001. 33. Product information for Calan. Pfizer Inc. NY, NY 10017. May 2006. 34. Product information for Cleviprex. The Medicines Company. Parsippany, NJ 07054. August 2008. 35. Product information for diltiazem injection. Bedford Laboratories. Bedford, OH 44146. May 2005. 36. Product information for nicardipine injection. EKR Therapeutics, Inc. Bedminster, NJ 07921. May 2008. 37. Product information for nimodipine. Barr Laboratories, Inc. Pomona, NY 10970. February 2007. 38. Product information for verapamil injection. Hospira, Inc. Lake Forest, IL 60045. June 2005. Cite this Detail-Document as follows: Comparison of calcium channel blockers. Pharmacist s Letter/Prescriber s Letter 2009;25(4):250414. Evidence and Advice You Can Trust 3120 West March Lane, P.O. Box 8190, Stockton, CA 95208 ~ TEL (209) 472-2240 ~ FAX (209) 472-2249 Subscribers to Pharmacist s Letter and Prescriber s Letter can get Detail-Documents, like this one, on any topic covered in any issue by going to www.pharmacistsletter.com or www.prescribersletter.com