CIPLADOC - AIDS Update - DRUG INTERACTIONS BETWEEN ANTIRETROVIRALS AND OTHER DRUGS

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DRUG INTERACTIONS IN HIV THERAPY
A Clinician's Guide

DRUG INTERACTIONS BETWEEN ANTIRETROVIRALS AND OTHER DRUGS

a) Protease inhibitors

Drug Interactions Requiring Dose Modifications or Cautious Use

Drug Affected	Indinavir (IDV)	Ritonavir** (RTV)	Saquinavir* (SQV)	Nelfinavir (NFV)	Amprenavir (APV)	Lopinavir (LPV)
ANTIFUNGALS
Ketoconazole	Levels: IDV h68% Dose: IDV	Levels: ketoh 3XDose: Use with caution; do not exceed 200 mg ketoconazole daily	Levels: SQVh 3X Dose: Standard	No dose adjustment necessary	Levels : APVh 31% Ketoh 44% Combination under investigation	Levels: LPV AUC i13% Ketoh 3-fold
ANTICONVULSANTS
Phenobar- bital, phenytoin, carbamaz- epine	Carbamaz- epine markedlyi IDV AUC. Consider alternative agent	Unknnown Use with caution Monitor anticonvuls-ant levels	Unknown but may decrease SQV levels substantially. Monitor anticonvu- lsant levels	Unknown but may decrease NFV levels substantially. Monitor anticonvu- lsant levels	Unknown but may decrease APV levels substantially. Monitor anticonvu- lsant levels	Unknown but may decrease LPV levels substantially. Monitor anticonvu- lsant levels
METHADONE
Methadone	No change in methadone levels	Methadonei h37% Monitor and titrate dose if needed. May requireh methadone dose	No data	NFV may decrease methadone levels, but minimal effect on maintenance dose. Monitor and titrate dose if needed. May requirei methadone dose	No data	Methadone AUCi53% Monitor and titrate dose if needed. May requirei methadone dose
MISCELLANEOUS
Miscellaneous	Grapefruit juicei IDV levels by 26% Sildenafil AUC h 2-11 fold. Do notexceed 25 mg in a 48hr. period	Desipramine h 145%,Reduce dose Theophyllinei 47%, monitor theo. levels. Many possible interactions Sildenafil AUCh 2-11 fold. Do not exceed 25 mg in a 48hr. period	Grapefruit juice increases SQV levels Dexamethasone decreases SQV levels Sildenafil AUC h 2-11 fold.Use a 25 mg starting dose of sildenafil.	Sildenafil AUC h 2-11 fold. Do not exceed 25 mg in a 48 hr. period	Sildenafil AUC h 2-11 fold. Do not exceed 25 mg in a 48 hr. period	Probable substantialh in sildenafil AUC. Do not exceed 25 mg in a 48 hr period

* Some drug interaction studies were conducted with saquinavir hard gel formulation; these may not necessarily apply for the soft gel formulation.
**Drugs for which plasma concentrations may be decreased by coadministration with Ritonavir; anticoagulants (warfarin), anticonvulsants (Phenytoin, divaproex, lamotrigine), antiparasitics (atovaquone)

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DRUG INTERACTIONS BETWEEN ANTIRETROVIRALS AND OTHER DRUGS

Drugs Affected	Indinavir (IDV)	Ritonavir **(RTV)	Saquina- vir *(SQV)	Nelfina-vir (NFV)	Ampren-avir (APV)	Lopinavir (LPV)
LIPID LOWERING AGENTS
Simvastatin, Lovastatin Atorvastatin, pravastatin	Levels: Potential for large increase in statin levels. Avoid concomitant use	Levels: Potential for large increase in statin levels. Avoid concomitant use	Levels: Potential for large increase in statin levels. Avoid concomitant use	Levels: Potential for large increase in statin levels. Avoid concomitant use Atorvastatin AUC h 74% - use with caution. Simvastatin AUC h 505% - not recommended. Potential for large increase in Lovastatin AUC -not recommended	Levels: Potential for large increase in statin levels. Avoid concomitant use with lovastatin and simvastatin	Levels: Potential for large increase in statin levels. Avoid concomitant use Atorvastatin AUC 5.88 fold. Use with caution and monitoring Pravastatin AUCh 33%; no dosage adjustment necessary
ANTIMYCOBACTERIALS
Rifampin	Levels: IDV 89% Contraindicated	Levels: RTV i35% Dose: No data Increased liver toxicity possible	Levels: SQV i 84% Contraindicated, unless using RTV + SQV, then use rifampin 600 mg qd or 2-3x/week	Levels 82% Contraidicated	Levels: APV AUCi 82% No change in rifampin AUC. Avoid concomitant use	Levels: LPV AUC i75% Avoid concomitant use
Rifabutin	Levels: IDV i32% Rifabutin h 2X Dose:i rifabutin to 150 mg qd or 300 mg 2-3 x/week IDV 1000 mg tid	Levels: Rifabutinh 4X Dose: h rifabutin to 150 mg qd Ordose 3x per week RTV: standard	Levels: SQV i 40% No dose adjustment unless using RTV + SQV, then use rifabutin 150 mg 2-3x/week	Levels: NFV i 32% Rifabutin h 2x Dose :i rifabutin to150mg or 300mg 2-3x/week hNFV dose to 1000 mg tid	Levels: APV AUC i15% Rifabutin h 193% Dose : No change in APV dose; Decrease rifa- butin to 150 mg qd or 300 mg 2-3 x/week	Levels: Ribafutin AUC h 3-fold 25-0 desacetyl metaboliteh 47.5 fold. Decrease rifabutin dose to150 mg qod. LPV/r: standard
Clarithromycin	Levels: Clari h53% No dose adjustment	Levels: Clari h77% Dose to be adjusted for renal insufficiency	Levels: Clari h 45% SQV 177% No dose adjustment	No data	Levels: APV AUC 18h % No change in Clari AUC. No dose adjustment	No data
ORAL CONTRACEPTIVES
Oral contraceptives	Levels: Norethindrone h26% Ethinylestradiol h 24% No dose adjustment	Levels: ethinylestradiol h40% Use alternative or additional method	No data	Levels: Norethindrone i18% } Ethinylestradiol i47% Use alternative or additional method	Levels: Potential for metabolic intractions; use alternative or additional method	Levels: Ethinyl estradioli 42% Use alternative or additional method

b) Non-nucleoside Reverse-transcriptase Inhibitors

Drug Interactions Requiring Dose Modifications or Cautious Use

Drugs Affected	Nevirapine (NVP)	Delavirdine (DLV)	Efavirenz (EFV)
ANTIFUNGALS
Ketoconazole	Levels: Keto.i 63% NVP h15-30% Dose: Not recommended	No data	No data
ANTIMYCOBACTERIALS
Rifampin	Levels: NVP i37% Not recommended	Levels: DLVi 96% Contraindicated	Levels: EFV i25% No dose adjustment
Rifabutin	Levels: NVP i16% No dose adjustment*	Rifabutin i100% Not recommended	unchanged; Rifabutin i35% Doseh rifabutin dose to 450-600 mg qd or 600 mg 2-3 times/week* EFV: Standard
Clarithromycin	Levels: h NVP 26%, clari. i 30% No dose adjustment	Levels: clari. h 100%, DLV h 44% Dose to be adjusted for renal failure	Levels: clari i39% Alternative recommended
ORAL CONTRACEPTIVES
	Levels: ethinyl estradiol i approximately 20%. Use alternative or additional methods	No data	Levels: Ethinyl estradiol 37%. No data on other component. Use alternative or additional methods
LIPID LOWERING AGENTS
Simvastatin, Lovastatin	No data	Levels: Potential for large increase in statin levels. Avoid concomitant use.	No data
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Drugs Affected Nevirapine (NVP) Delavirdine (DLV) Efavirenz (EFV)
ANTICONVULSANTS
Phenobarbital, phenytoin, carbamazepine	Unknown Use with caution Monitor anticonvulsant levels	Unknown but may decrease DLV levels substantially Monitor anticonvulsant levels	Unknown Use with caution Monitor anticonvulsant levels
METHADONE
	Levels: NVP unchanged, methadone i significantly. Titrate methadone dose to effect	No data	Levels: methadone i significantly. Titrate methadone dose to effect
MISCELLANEOUS
	No data	May increase levels of dapsone, warfarin and quinidine Sildenafil: Potential for increased concentrations and adverse effects. Do not exceed 25 mg in a 48hr. period	Monitor warfarin when used concomitantly
*These recommendations apply to regimens that do not include PIs, which can substantially increase rifabutin levels.

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C) Nucleoside/ Nucleotide Reverse Transcriptase Inhibitors (NRTIs)

Drug Interactions Requiring Dose Modifications or Cautious Use
Drugs Affected	Zidovudine (ZDV)	Stavudine (d4T)	Didanosine (ddI)	Tenofovir
Methadone	No data	Levels: d4T i 27%, methadone unchanged. No dose adjustment	Levels: ddI i 41%, methadone unchanged. Consider ddI dose increase.	No data
MISCELLANEOUS
Ribavirin	Ribavirin inhibits phosphorylation of ZDV; this combination should be avoided if possible	No data	Levels: methadone i significantly. Titrate methadone dose to effect	No data
Didanosine
Buffered tablets	No data	No data	No data	ddI AUC 44%, Cmax 28%. Monitor for associated toxicities
Cidofovir, Ganciclovir, Valganciclovir	No data	No data	No data	Possibly competes for active tubular secretion With tenofovir, may increase serum concent-ration of these drugs and/ or tenofovir. Monitor for dose-related toxicities

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