Diltiazem Drug Diltiazem Drug Interactions:Interactions:

A Quality Assessment of GeneMedRxA Quality Assessment of GeneMedRx

Shannon C. O’Hara, Pharm.D. Candidate (2007)Shannon C. O’Hara, Pharm.D. Candidate (2007)University of Washington School of PharmacyUniversity of Washington School of Pharmacy

Genelex CorporationGenelex CorporationSeattle, WASeattle, WA

February 22, 2007February 22, 2007

Objectives for this projectObjectives for this project

Research known pharmacokinetic and Research known pharmacokinetic and pharmacodynamic interactions between pharmacodynamic interactions between diltiazem and other drugs/drug classesdiltiazem and other drugs/drug classes

Compare list of diltiazem drug Compare list of diltiazem drug interactions with information already in interactions with information already in GeneMedRxGeneMedRx

Enter new notes for interactions not Enter new notes for interactions not found in GeneMedRx; revise existing found in GeneMedRx; revise existing notes with new information/referencesnotes with new information/references

Use new information to measure Use new information to measure effectiveness of GeneMedRx algorithm at effectiveness of GeneMedRx algorithm at predicting interactionspredicting interactions

Diltiazem: a non-Diltiazem: a non-dihydropyridine calcium dihydropyridine calcium channel blockerchannel blocker

Like other CCBs… Like other CCBs… blocks slow response blocks slow response (L-type) calcium (L-type) calcium channels in plasma channels in plasma membrane of heart membrane of heart and vascular smooth and vascular smooth muscle muscle vasodilation vasodilation

Unlike most other Unlike most other CCBs… CCBs… may cause AV may cause AV block, hypotension, block, hypotension, bradycardiabradycardia

The “kinder, gentler The “kinder, gentler verapamil”verapamil”

Don’t trust everything you Don’t trust everything you read in the product insert…read in the product insert… RescriptorRescriptor®® (delaviridine) and diltiazem (delaviridine) and diltiazem11

– Prescribing information for delaviridine (Pfizer) Prescribing information for delaviridine (Pfizer) mentions interactions with dihydropyridines onlymentions interactions with dihydropyridines only

– Diltiazem erroneously included in this listDiltiazem erroneously included in this list KaletraKaletra®® (lopinavir/ritonavir) and diltiazem (lopinavir/ritonavir) and diltiazem22

– Prescribing information notes that Kaletra Prescribing information notes that Kaletra increases levels of dihydropyridinesincreases levels of dihydropyridines

– Diltiazem is Diltiazem is not not mentioned in this listmentioned in this list Easy to assume that diltiazem does not Easy to assume that diltiazem does not

interact with either of these medications, interact with either of these medications, when in fact it doeswhen in fact it does

1 Pfizer Corporation, Rescriptor prescribing information, Feb. 2006. 1 Pfizer Corporation, Rescriptor prescribing information, Feb. 2006. Available at: Available at: http://www.pfizer.com/pfizer/download/uspi_rescriptor.pdf. . Accessed on 2/15/07.Accessed on 2/15/07.2 Abbott Laboratories, Kaletra prescribing information, Oct. 2005. 2 Abbott Laboratories, Kaletra prescribing information, Oct. 2005. Available at: Available at: http://www.rxabbott.com/pdf/kaletratabpi.pdf. Accessed on . Accessed on 2/11/07.2/11/07.

Diltiazem has three Diltiazem has three indicationsindications

1. Hypertension1. Hypertension: not usually 1: not usually 1stst line, but may be useful in the line, but may be useful in the following groups:following groups:– Compelling indications for diabetes Compelling indications for diabetes

or high coronary disease risk or high coronary disease risk (NORDIL Study, 2003)(NORDIL Study, 2003)33

– AsthmaAsthma– African-AmericansAfrican-Americans33 Saseen JJ, MacLaughlin EJ, Westfall JM. Treatment of uncomplicated Saseen JJ, MacLaughlin EJ, Westfall JM. Treatment of uncomplicated

hypertension: are ACE inhibitors and calcium channel blockers as hypertension: are ACE inhibitors and calcium channel blockers as effective as diuretics and beta blockers? effective as diuretics and beta blockers? J Am Board Fam Pract J Am Board Fam Pract 2003;289:2073-2082.2003;289:2073-2082.

Diltiazem indications, Diltiazem indications, cont’d.cont’d.2.2. AnginaAngina

– Alternative to beta blockersAlternative to beta blockers AsthmaAsthma Prinzmetal’s (variant) anginaPrinzmetal’s (variant) angina

– Increases oxygen supplyIncreases oxygen supply ↑ ↑ coronary blood flow*coronary blood flow* ↑ ↑ regional flow distributionregional flow distribution

– Decreases oxygen demandDecreases oxygen demand ↓ ↓ HR**HR** ↓ ↓ contractility**contractility** ↓↓ afterload*afterload*

* * In contrast to beta blockersIn contrast to beta blockers

** ** In contrast to dihydropyridine CCBsIn contrast to dihydropyridine CCBs

Diltiazem indications, Diltiazem indications, cont’d.cont’d.

3. Supraventricular arrhythmias3. Supraventricular arrhythmias– Class IV antiarrhythmic (Vaughn-Class IV antiarrhythmic (Vaughn-

Williams)Williams)– ↓ ↓ SA/AV nodal automaticitySA/AV nodal automaticity– ↓ ↓ AV node refractory periodAV node refractory period– Acute and long-term therapy for:Acute and long-term therapy for:

Atrial fibrillation/flutterAtrial fibrillation/flutter Supraventricular tachycardiasSupraventricular tachycardias

Diltiazem is involved in a Diltiazem is involved in a variety of drug interactionsvariety of drug interactions

PharmacokineticPharmacokinetic– CYP3A4 substrateCYP3A4 substrate– CYP3A4 inhibitorCYP3A4 inhibitor

Pharmacodynamic (various)Pharmacodynamic (various)

BothBoth

Diltiazem is vulnerable to Diltiazem is vulnerable to 3A4 inhibitors/inducers3A4 inhibitors/inducers

3A4 INHIBITION 3A4 INHIBITION

(EX: erythromycin, (EX: erythromycin, PI’s)PI’s)

↓↓POTENTIATED EFFECT POTENTIATED EFFECT

OF DILTIAZEMOF DILTIAZEM

↓↓

HypotensionHypotension

BradycardiaBradycardia

AV blockAV block

3A4 INDUCTION 3A4 INDUCTION

(EX: rifampin, CBZ)(EX: rifampin, CBZ)

↓↓LOSS OF EFFECT LOSS OF EFFECT

OF DILTIAZEMOF DILTIAZEM

↓↓

HypertensionHypertension

Chest painChest pain

SVARsSVARs

3A4 inhibition 3A4 inhibition byby diltiazem is diltiazem is notnot always clinically always clinically significantsignificant

3A4 substrate3A4 substrate ↓ ↓ CL with CL with diltiazemdiltiazem

Suggested Suggested dose dose

adjustmenadjustmentt

CilostazolCilostazol 30%30% ↓ ↓ 50%50%

DutasterideDutasteride 44%44% NoneNone

Is IV diltiazem less likely to Is IV diltiazem less likely to inhibit CYP3A4?inhibit CYP3A4? Some 3A4 interactions may involve first-pass Some 3A4 interactions may involve first-pass

effecteffect Randomized, 2-way crossover trial with 10 Randomized, 2-way crossover trial with 10

healthy volunteers (2000)healthy volunteers (2000)44

– Lovastatin, 20mg/day alone vs. following 60 min after Lovastatin, 20mg/day alone vs. following 60 min after IV loading dose of diltiazem followed by continuous IV loading dose of diltiazem followed by continuous infusioninfusion

– IV diltiazem did not significantly affect oral AUC, IV diltiazem did not significantly affect oral AUC, Cmax, or t ½ of lovastatinCmax, or t ½ of lovastatin

– Needed a third arm: lovastatin + PO dilt to measure Needed a third arm: lovastatin + PO dilt to measure differencedifference

Moral: Drug interactions may not become Moral: Drug interactions may not become apparent until a patient switches from IVapparent until a patient switches from IV PO PO

44 Masica AL, Azie NE, Brater DC, Hall SD, Jones DR. Intravenous Masica AL, Azie NE, Brater DC, Hall SD, Jones DR. Intravenous diltiazem and CYP3A-mediated metabolism. diltiazem and CYP3A-mediated metabolism. Br J Pharmacol Br J Pharmacol 2000 2000 Sep;50(3):273-276.Sep;50(3):273-276.

3A4 inhibition by diltiazem 3A4 inhibition by diltiazem has been exploited on has been exploited on occasionoccasion Post-transplant immunosuppression Post-transplant immunosuppression

(cyclosprorine, tacrolimus, sirolimus)(cyclosprorine, tacrolimus, sirolimus) Cyclosporine dose reduced 20-50%Cyclosporine dose reduced 20-50% AdvantagesAdvantages

– Saves moneySaves money– Fewer adverse effects (esp. renal)Fewer adverse effects (esp. renal)

Disadvantages:Disadvantages:– Interpatient variabilityInterpatient variability– Variability depending on organ Variability depending on organ

transplantedtransplanted– Increased pill burden?Increased pill burden?

Diltiazem is also subject to Diltiazem is also subject to numerous pharmacological numerous pharmacological drug interactionsdrug interactions1.1. Calcium channel blockade (amiodarone, lithium; Calcium channel blockade (amiodarone, lithium;

calcium supplements)calcium supplements)2.2. Negative inotropes (beta blockers)Negative inotropes (beta blockers)3.3. Anti-hypertensive medications (sometimes Anti-hypertensive medications (sometimes

desirable)desirable)4.4. Drugs with anti-hypertensive side effects Drugs with anti-hypertensive side effects

(anesthetics, antipsychotics; alprostadil, (anesthetics, antipsychotics; alprostadil, aldesleukin, baclofen)aldesleukin, baclofen)

5.5. Antagonism from drugs that increase blood Antagonism from drugs that increase blood pressure (corticosteroids, estrogens, ma huang, pressure (corticosteroids, estrogens, ma huang, yohimbineyohimbine

6.6. Barriers to absorption (bile acid sequestrants)Barriers to absorption (bile acid sequestrants)

Pharmacokinetic and Pharmacokinetic and pharmacodynamic pharmacodynamic interactions may occur interactions may occur simultaneouslysimultaneouslyDRUGDRUG PKPK PDPDAmiodaroneAmiodarone Dual 3A4 Dual 3A4

substrate/ substrate/ inhibitioninhibition

Calcium channel Calcium channel blockadeblockade

Metoprolol, Metoprolol, Propranolol, Propranolol, TimololTimolol

3A4 substrates3A4 substrates Negative Negative inotropy, inotropy,

hypotension, AV hypotension, AV blockblock

Opioid analgesicsOpioid analgesics 3A4 substrates3A4 substrates HypotensionHypotension

Diltiazem drug interactions Diltiazem drug interactions may occur at any timemay occur at any time

When the dose of one drug When the dose of one drug changeschanges– Dose dependent increase in Dose dependent increase in

ranolazine levels when diltiazem is ranolazine levels when diltiazem is increasedincreased

When one drug is stoppedWhen one drug is stopped– Recurrence of seizures on Recurrence of seizures on

carbamazepine when diltiazem carbamazepine when diltiazem discontinued. discontinued.

Updating GeneMedRxUpdating GeneMedRx

Sources consulted for this Sources consulted for this projectproject

Online drug databasesOnline drug databases– British National FormularyBritish National Formulary– Facts & ComparisonsFacts & Comparisons– Lexi-CompLexi-Comp– MicromedexMicromedex

PubMedPubMed Prescribing information (product Prescribing information (product

inserts)inserts) Misc. reference booksMisc. reference books

123 drug-drug, drug-class, and 123 drug-drug, drug-class, and class-class interactions foundclass-class interactions found

87

10

26Predicted by GeneMed Rx

Not Predicted

Needed changes

GeneMedRx algorithm had a GeneMedRx algorithm had a 79% prediction rate79% prediction rate

71%

8%

21%

0%10%20%30%40%50%60%70%80%90%

100%

Total

Not already entered

Entered but changed

Already entered

Updating GeneMedRxUpdating GeneMedRx

BEFORE: 36 interactions locatedBEFORE: 36 interactions located– 31 intxns under “diltiazem”31 intxns under “diltiazem”– 5 intxns under “calcium channel blockers”5 intxns under “calcium channel blockers”

AFTER: 95 interactionsAFTER: 95 interactions– 33 new drug-drug interactions33 new drug-drug interactions– 16 new drug-class interactions16 new drug-class interactions– 10 new class-class interactions10 new class-class interactions– 22 existing notes updated22 existing notes updated– Almost 150 references addedAlmost 150 references added

HighlightsHighlights

Xanthines (theophylline, aminophylline): Xanthines (theophylline, aminophylline): decreased CL with diltiazemdecreased CL with diltiazem

Nafcillin: a potent 3A4 inducerNafcillin: a potent 3A4 inducer Telithromycin: hypotension and Telithromycin: hypotension and

bradyarrhythmiabradyarrhythmia Antipsychotics: orthostatic hypotension may Antipsychotics: orthostatic hypotension may

be exacerbatedbe exacerbated Cardiac glycosides: conflicting evidenceCardiac glycosides: conflicting evidence Atorvastatin: case reports of rhabomyolysisAtorvastatin: case reports of rhabomyolysis Bile acid sequestrants: decrease absorptionBile acid sequestrants: decrease absorption Aspirin: prolonged bleedingAspirin: prolonged bleeding Lithium: neurotoxicity, increased maniaLithium: neurotoxicity, increased mania

Strengths of this Strengths of this assessmentassessment

Numerous sources were consulted to Numerous sources were consulted to provide a thorough list of drug provide a thorough list of drug interactions with diltiazem, including drug-interactions with diltiazem, including drug-class and class-class interactionsclass and class-class interactions

Pharmacokinetic and pharmacodynamic Pharmacokinetic and pharmacodynamic interactions were given equal importanceinteractions were given equal importance

Evidence-based literature from case Evidence-based literature from case reports and clinical trials tended to reports and clinical trials tended to broadly validate the GeneMedRx broadly validate the GeneMedRx algorithmalgorithm

Limitations of this Limitations of this assessmentassessment Some interactions had to be entered multiple Some interactions had to be entered multiple

times due to separations among categories in times due to separations among categories in GeneMedRxGeneMedRx– ““Anti-hypertensives, Central” vs. “Anti-Anti-hypertensives, Central” vs. “Anti-

hypertensives/Cardiac Medications”hypertensives/Cardiac Medications”– ““Antipsychotics” vs. “Antipsychotics-Atypical”Antipsychotics” vs. “Antipsychotics-Atypical”

Data entry system is designed to identify a Data entry system is designed to identify a “victim” and a “culprit” in a drug interaction; “victim” and a “culprit” in a drug interaction; this may not always be easy to identifythis may not always be easy to identify– Carbamazepine may decrease diltiazem levels via Carbamazepine may decrease diltiazem levels via

3A4 induction while diltiazem may increase 3A4 induction while diltiazem may increase carbamazepine levels via 3A4 inhibitioncarbamazepine levels via 3A4 inhibition

– Pharmacodynamic interactionsPharmacodynamic interactions

SummarySummary

Because of its pharmacokinetic and pharmacodynamic Because of its pharmacokinetic and pharmacodynamic properties, diltiazem is prone to numerous drug properties, diltiazem is prone to numerous drug interactionsinteractions

As with all drugs, interactions may occur at any time. As with all drugs, interactions may occur at any time. Prescribers should be alert to possible interactions not Prescribers should be alert to possible interactions not only when dilitazem or an interacting drug is intiated, only when dilitazem or an interacting drug is intiated, but also following dosing changes in either drug, but also following dosing changes in either drug, whenever one drug is discontinued, and possibly when whenever one drug is discontinued, and possibly when diltiazem is given by a different route.diltiazem is given by a different route.

Some of these interactions may be exploited in the Some of these interactions may be exploited in the patient’s best interest (antihypertensives, patient’s best interest (antihypertensives, immunosuppressants)immunosuppressants)

The GeneMedRx algorithm was able to broadly predict The GeneMedRx algorithm was able to broadly predict pharmacokinetic interactions between diltiazem and pharmacokinetic interactions between diltiazem and many other drugs with good accuracy.many other drugs with good accuracy.

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