Diltiazem Drug Interactions: A Quality Assessment of GeneMedRx

1
Diltiazem Drug InteractionsA Quality Assessment
of GeneMedRx

• Shannon C. OHara, 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

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Dont 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_rescrip
tor.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.
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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

3 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 20032892073-2082.
6
Diltiazem indications, contd.

• 2. Angina
• Alternative to beta blockers
• Asthma
• Prinzmetals (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
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Diltiazem indications, contd.

• 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

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Diltiazem is involved in a variety of drug
interactions

• Pharmacokinetic
• CYP3A4 substrate
• CYP3A4 inhibitor
• Pharmacodynamic (various)
• Both

9
Diltiazem is vulnerable to 3A4 inhibitors/inducers

• 3A4 INHIBITION
• (EX erythromycin, PIs)
• ?
• POTENTIATED EFFECT
• OF DILTIAZEM
• ?
• Hypotension
• Bradycardia
• AV block

• 3A4 INDUCTION
• (EX rifampin, CBZ)
• ?
• LOSS OF EFFECT
• OF DILTIAZEM
• ?
• Hypertension
• Chest pain
• SVARs

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3A4 inhibition by diltiazem is not always
clinically significant
3A4 substrate ? CL with diltiazem Suggested dose adjustment
Cilostazol 30 ? 50
Dutasteride 44 None
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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
Sep50(3)273-276.
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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?

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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)

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Pharmacokinetic and pharmacodynamic interactions
may occur simultaneously
DRUG PK PD
Amiodarone Dual 3A4 substrate/ inhibition Calcium channel blockade
Metoprolol, Propranolol, Timolol 3A4 substrates Negative inotropy, hypotension, AV block
Opioid analgesics 3A4 substrates Hypotension
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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

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Sources consulted for this project

• Online drug databases
• British National Formulary
• Facts Comparisons
• Lexi-Comp
• Micromedex
• PubMed
• Prescribing information (product inserts)
• Misc. reference books

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123 drug-drug, drug-class, and class-class
interactions found
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GeneMedRx algorithm had a 79 prediction rate
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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

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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

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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

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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

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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 patients best interest (antihypertensives,
  immunosuppressants)
• The GeneMedRx algorithm was able to broadly
  predict pharmacokinetic interactions between
  diltiazem and many other drugs with good accuracy.

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References

• Altman R, Scazziota A, Dujoune C. Diltiazem
  potentiates the inhibitory effect of aspirin on
  platelet aggregation. Clin Pharmacol Ther
  198844320-325. 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 Jul55(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 19812821584-1585. 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
  Aug30(5)1685-1687. PMID 9723244.

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References, contd.

• Gerónimo-Pardo M, Cuartero-del-Pozo AB,
  Jiménez-Vizuete J, et al. Clarithromycin-nifedipin
  e interaction as possible cause of vasodilatory
  shock. Ann Pharmacother 2005 Mar 39538-542.
  PMID 15703161.
• Glesby MJ, Aberg JA, Kendall MA et al.
  Pharmacokinetic interactions between indinavir
  plus ritonavir and calcium channel blockers.
  Clin Pharmacol Ther 2005 Aug78(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 HH Publications,
  2005.
• Jones TE, Morris RG. Pharmacokinetic interaction
  between tacrolimus and diltiazem dose-response
  relationship in kidney and liver transplant
  recipients. Clin Pharmacokinet
  200241(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) 552417-2419. PMID
  9023574.

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References, contd.

• Kothari J, Nash M, Zaltzman J, Ramesh Prasad GV.
  Diltiazem use in tacrolimus-treated renal
  patients. J Clin Pharm Ther. 2004 Oct29(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
  Sep50(3)273-276. PMID 10971313
• McCauley J, Ptachcinski R, Shapiro R. The
  cyclosporine-sparing effects of diltiazem in
  renal transplantation. Transplant Proc
  1989213955-3957. PMID 2609415.
• McLachlan AJ Tett SE. Effect of metabolic
  inhibitors on cyclosproine pharmacokinetics using
  a population approach. Ther Drug Monit 1998
  Aug20(4)390-395. PMID 9712463.
• Neumayer HM Wagner K. Diltiazem and economic
  use of cyclosporine. Lancet 19862523. 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.

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References, contd.

• Prenner JG, Lehle K, Eichinger H, Repprecht L.
  First-pass metabolism of cyclosporine A in human
  intestine inhibition by diltiazem. Transplant
  Proc 1998 Sep30(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 2004351(11)1089-10
  96. 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
  198644391-400. PMID 3798404.
• Ring ME, Martin GV, Fenster PE Clinically
  significant antiplatelet effects of
  calcium-channel blockers. J Clin Pharmacol
  198626719-720. PMID 3793966.

29
References, contd.

• 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 20032892073-2082.
• Smith CL, Hampton EM, Pederson JA, et al.
  Clinical and medicoeconomic impact of the
  cyclosporine-diltiazem interaction in renal
  transplant patients. Pharmacotherapy
  199414471-481. PMID 7937285.
• Valantine H, Keogh A, McIntosh N, et al. Cost
  containment coadministration of diltiazem with
  cyclosporine after heart transplantation. J
  Heart Lung Transplant 1992111-7. PMID 1540597.