Diltiazem Drug Interactions: A Quality Assessment of GeneMedRx

1. Diltiazem Drug Interactions:A Quality Assessment of GeneMedRx Shannon C. O’Hara, Pharm.D. Candidate (2007) University of Washington School of Pharmacy Genelex Corporation Seattle, WA February 22, 2007

2. Objectives for this project • Research known pharmacokinetic and pharmacodynamic interactions between diltiazem and other drugs/drug classes • Compare list of diltiazem drug interactions with information already in GeneMedRx • Enter new notes for interactions not found in GeneMedRx; revise existing notes with new information/references • Use new information to measure effectiveness of GeneMedRx algorithm at predicting interactions

3. Diltiazem: a non-dihydropyridine calcium channel blocker • Like other CCBs… blocks slow response (L-type) calcium channels in plasma membrane of heart and vascular smooth muscle  vasodilation • Unlike most other CCBs… may cause AV block, hypotension, bradycardia • The “kinder, gentler verapamil”

4. Don’t trust everything you read in the product insert… • Rescriptor® (delaviridine) and diltiazem1 • Prescribing information for delaviridine (Pfizer) mentions interactions with dihydropyridines only • Diltiazem erroneously included in this list • Kaletra® (lopinavir/ritonavir) and diltiazem2 • Prescribing information notes that Kaletra increases levels of dihydropyridines • Diltiazem is not mentioned in this list • Easy to assume that diltiazem does not interact with either of these medications, when in fact it does 1 Pfizer Corporation, Rescriptor prescribing information, Feb. 2006. Available at: http://www.pfizer.com/pfizer/download/uspi_rescriptor.pdf. Accessed on 2/15/07. 2 Abbott Laboratories, Kaletra prescribing information, Oct. 2005. Available at: http://www.rxabbott.com/pdf/kaletratabpi.pdf. Accessed on 2/11/07.

5. Diltiazem has three indications 1. Hypertension: not usually 1st line, but may be useful in the following groups: • Compelling indications for diabetes or high coronary disease risk (NORDIL Study, 2003)3 • Asthma • African-Americans 3Saseen JJ, MacLaughlin EJ, Westfall JM. Treatment of uncomplicated hypertension: are ACE inhibitors and calcium channel blockers as effective as diuretics and beta blockers? J Am Board Fam Pract 2003;289:2073-2082.

6. Diltiazem indications, cont’d. 2. Angina • Alternative to beta blockers • Asthma • Prinzmetal’s (variant) angina • Increases oxygen supply • ↑ coronary blood flow* • ↑ regional flow distribution • Decreases oxygen demand • ↓ HR** • ↓ contractility** • ↓ afterload* * In contrast to beta blockers ** In contrast to dihydropyridine CCBs

7. Diltiazem indications, cont’d. 3. Supraventricular arrhythmias • Class IV antiarrhythmic (Vaughn-Williams) • ↓ SA/AV nodal automaticity • ↓ AV node refractory period • Acute and long-term therapy for: • Atrial fibrillation/flutter • Supraventricular tachycardias

8. Diltiazem is involved in a variety of drug interactions • Pharmacokinetic • CYP3A4 substrate • CYP3A4 inhibitor • Pharmacodynamic (various) • Both

9. 3A4 INHIBITION (EX: erythromycin, PI’s) ↓ POTENTIATED EFFECT OF DILTIAZEM ↓ Hypotension Bradycardia AV block 3A4 INDUCTION (EX: rifampin, CBZ) ↓ LOSS OF EFFECT OF DILTIAZEM ↓ Hypertension Chest pain SVARs Diltiazem is vulnerable to 3A4 inhibitors/inducers

10. 3A4 inhibition by diltiazem is not always clinically significant

11. Is IV diltiazem less likely to inhibit CYP3A4? • Some 3A4 interactions may involve first-pass effect • Randomized, 2-way crossover trial with 10 healthy volunteers (2000)4 • Lovastatin, 20mg/day alone vs. following 60 min after IV loading dose of diltiazem followed by continuous infusion • IV diltiazem did not significantly affect oral AUC, Cmax, or t ½ of lovastatin • Needed a third arm: lovastatin + PO dilt to measure difference • Moral: Drug interactions may not become apparent until a patient switches from IV PO 4 Masica AL, Azie NE, Brater DC, Hall SD, Jones DR. Intravenous diltiazem and CYP3A-mediated metabolism. Br J Pharmacol 2000 Sep;50(3):273-276.

12. 3A4 inhibition by diltiazem has been exploited on occasion • Post-transplant immunosuppression (cyclosprorine, tacrolimus, sirolimus) • Cyclosporine dose reduced 20-50% • Advantages • Saves money • Fewer adverse effects (esp. renal) • Disadvantages: • Interpatient variability • Variability depending on organ transplanted • Increased pill burden?

13. Diltiazem is also subject to numerous pharmacological drug interactions 1. Calcium channel blockade (amiodarone, lithium; calcium supplements) 2. Negative inotropes (beta blockers) 3. Anti-hypertensive medications (sometimes desirable) 4. Drugs with anti-hypertensive side effects (anesthetics, antipsychotics; alprostadil, aldesleukin, baclofen) 5. Antagonism from drugs that increase blood pressure (corticosteroids, estrogens, ma huang, yohimbine 6. Barriers to absorption (bile acid sequestrants)

14. Pharmacokinetic and pharmacodynamic interactions may occur simultaneously

15. Diltiazem drug interactions may occur at any time • When the dose of one drug changes • Dose dependent increase in ranolazine levels when diltiazem is increased • When one drug is stopped • Recurrence of seizures on carbamazepine when diltiazem discontinued.

16. Updating GeneMedRx

17. Sources consulted for this project • Online drug databases • British National Formulary • Facts & Comparisons • Lexi-Comp • Micromedex • PubMed • Prescribing information (product inserts) • Misc. reference books

18. 123 drug-drug, drug-class, and class-class interactions found

19. GeneMedRx algorithm had a 79% prediction rate

20. Updating GeneMedRx • BEFORE: 36 interactions located • 31 intxns under “diltiazem” • 5 intxns under “calcium channel blockers” • AFTER: 95 interactions • 33 new drug-drug interactions • 16 new drug-class interactions • 10 new class-class interactions • 22 existing notes updated • Almost 150 references added

21. Highlights • Xanthines (theophylline, aminophylline): decreased CL with diltiazem • Nafcillin: a potent 3A4 inducer • Telithromycin: hypotension and bradyarrhythmia • Antipsychotics: orthostatic hypotension may be exacerbated • Cardiac glycosides: conflicting evidence • Atorvastatin: case reports of rhabomyolysis • Bile acid sequestrants: decrease absorption • Aspirin: prolonged bleeding • Lithium: neurotoxicity, increased mania

22. Strengths of this assessment • Numerous sources were consulted to provide a thorough list of drug interactions with diltiazem, including drug-class and class-class interactions • Pharmacokinetic and pharmacodynamic interactions were given equal importance • Evidence-based literature from case reports and clinical trials tended to broadly validate the GeneMedRx algorithm

23. Limitations of this assessment • Some interactions had to be entered multiple times due to separations among categories in GeneMedRx • “Anti-hypertensives, Central” vs. “Anti-hypertensives/Cardiac Medications” • “Antipsychotics” vs. “Antipsychotics-Atypical” • Data entry system is designed to identify a “victim” and a “culprit” in a drug interaction; this may not always be easy to identify • Carbamazepine may decrease diltiazem levels via 3A4 induction while diltiazem may increase carbamazepine levels via 3A4 inhibition • Pharmacodynamic interactions

24. Summary • Because of its pharmacokinetic and pharmacodynamic properties, diltiazem is prone to numerous drug interactions • As with all drugs, interactions may occur at any time. Prescribers should be alert to possible interactions not only when dilitazem or an interacting drug is intiated, but also following dosing changes in either drug, whenever one drug is discontinued, and possibly when diltiazem is given by a different route. • Some of these interactions may be exploited in the patient’s best interest (antihypertensives, immunosuppressants) • The GeneMedRx algorithm was able to broadly predict pharmacokinetic interactions between diltiazem and many other drugs with good accuracy.

25. References • Altman R, Scazziota A, Dujoune C. Diltiazem potentiates the inhibitory effect of aspirin on platelet aggregation. Clin Pharmacol Ther 1988;44:320-325. PMID 3416553. • Asberg A, Christiansen H, Hartmann A, et al. Pharmacokinetic interactions between microemulsion formulated cyclosporine A and diltiazem iin renal transplant recipients. Eur J Clin Pharmacol 1999 Jul;55(5):383-387. PMID 1045648. • Cozza KL, Armstrong SC, Oesterheld JR. Drug interaction principles for medical practice: cytochrome P450s, UGTs, P-glycoproteins. Second edition. Washington, DC: American Psychiatric Publishing, 2003. • David B-O & Yoel G. Calcium and calciferol antagonise effect of verapamil in atrial fibrillation. Br Med J 1981;282;1584-1585. PMID 6786574. • Foradori A, Mezzano S, Videla C et al. Modification of the pharmcokinetics of cyclosporine A and metabolites by concomitant use of Neoral and diltiazem or ketoconazole in stable adult kidney transplants. Transplant Proc 1998 Aug;30(5):1685-1687. PMID 9723244.

26. References, cont’d. • Gerónimo-Pardo M, Cuartero-del-Pozo AB, Jiménez-Vizuete J, et al. Clarithromycin-nifedipine interaction as possible cause of vasodilatory shock. Ann Pharmacother 2005 Mar; 39:538-542. PMID 15703161. • Glesby MJ, Aberg JA, Kendall MA et al. Pharmacokinetic interactions between indinavir plus ritonavir and calcium channel blockers. Clin Pharmacol Ther 2005 Aug;78(2):143-153. PMID 16084849. • Goldschmidt N, Azaz-Livshits T, Gotsman I et al. Compound cardiac toxicity of oral erythromycin and verapamil. Ann Pharmacother 2001 Nov; 35(11):1396-1399. PMID 11724091. • Hansten PD, Horn JR. The top 100 drug interactions: a guide to patient management. 2005 edition. Edmonds, WA: H&H Publications, 2005. • Jones TE, Morris RG. Pharmacokinetic interaction between tacrolimus and diltiazem: dose-response relationship in kidney and liver transplant recipients. Clin Pharmacokinet 2002;41(5):381-388. PMID 12036394. • Kaeser YA, Brunner F, Drewe J, & Haefeli WE. Severe hypotension and bradycardia associated with verapamil and clarithromycin. Am J Health System Pharm 1998 (Nov 15); 55:2417-2419. PMID 9023574.

27. References, cont’d. • Kothari J, Nash M, Zaltzman J, Ramesh Prasad GV. Diltiazem use in tacrolimus-treated renal patients. J Clin Pharm Ther. 2004 Oct;29(5): 425-430. PMID 15482385. • Masica AL, Azie NE, Brater DC, Hall SD, Jones DR. Intravenous diltiazem and CYP3A-mediated metabolism. Br J Phamacol 2000 Sep;50(3):273-276. PMID 10971313 • McCauley J, Ptachcinski R, Shapiro R. The cyclosporine-sparing effects of diltiazem in renal transplantation. Transplant Proc 1989;21:3955-3957. PMID 2609415. • McLachlan AJ & Tett SE. Effect of metabolic inhibitors on cyclosproine pharmacokinetics using a population approach. Ther Drug Monit 1998 Aug;20(4):390-395. PMID 9712463. • Neumayer HM & Wagner K. Diltiazem and economic use of cyclosporine. Lancet 1986;2:523. PMID 2875274. • Pea F & Furlanut M. Pharmacokinetic aspects of treating infections in the intensive care unit: focus on drug interactions. Clin Pharmacokinet 2001; 40(11):833-868. PMID 11735605.

28. References, cont’d. • Prenner JG, Lehle K, Eichinger H, Repprecht L. First-pass metabolism of cyclosporine A in human intestine: inhibition by diltiazem. Transplant Proc 1998 Sep;30(6):2545-2546. PMID 9745480. • Ray WA, Murray KT, Meredith S et al. Oral erythromycin and the risk of sudden death from cardiac causes. N Engl J Med 2004;351(11):1089-1096. PMID 15356306. • Reed M, Wall GC, Shah NP, et al. Verapamil toxicity resulting from a probable interaction with telithromycin. Ann Pharmacother 2005 Feb; 39(2):357-360. PMID 15598962. • Ring ME, Corrigan JJ Jr, Fenster PE. Effects of oral diltiazem on platelet function: alone and in combination with “low dose” aspirin. Thromb Res 1986;44:391-400. PMID 3798404. • Ring ME, Martin GV, Fenster PE: Clinically significant antiplatelet effects of calcium-channel blockers. J Clin Pharmacol 1986;26:719-720. PMID 3793966.

29. References, cont’d. • Saseen JJ, MacLaughlin EJ, Westfall JM. Treatment of uncomplicated hypertension: are ACE inhibitors and calcium channel blockers as effective as diuretics and beta blockers? J Am Board Fam Pract 2003;289:2073-2082. • Smith CL, Hampton EM, Pederson JA, et al. Clinical and medicoeconomic impact of the cyclosporine-diltiazem interaction in renal transplant patients. Pharmacotherapy 1994;14:471-481. PMID 7937285. • Valantine H, Keogh A, McIntosh N, et al. Cost containment: coadministration of diltiazem with cyclosporine after heart transplantation. J Heart Lung Transplant 1992;11:1-7. PMID 1540597.