Publications: A Guide to the Clinical Care of Women with HIV/AIDS, 2005 edition

Table 14-6a: Drug Interactions of Antiretrovirals (NRTIs)
Table 14-6b: Drug Interactions of Antiretrovirals (N+RTIs)
Table 14-6c: Drug Interactions of Antiretrovirals (NNRTIs)
Table 14-6d: Drug Interactions of Antiretrovirals (PIs)
Table 14-6e: Drug Interactions of Antiretrovirals (Fosamprenavir)
Table 14-6f: Drug Interactions of Antiretrovirals (FIs)

 

Table 14-6a: Drug Interactions of Antiretrovirals (NRTIs)  TOP
Primary Drug Interacting Drug Mechanism of Interaction Effect Time course Severity Comments / management recommendation
Drug Interactions with Nucleoside Reverse Transcriptase Inhibitors
AZT (Zidovudine) (Retrovir®) Ganciclovir/ Valganciclovir

Pharmacodynamic interaction/Additive toxicity

 Enhanced bone marrow toxicity Delayed Moderate Monitor CBC frequently. May require switch to alternative antiretroviral or use concomitant G-CSF.
AZT Acetaminophen Competitive inhibition of glucuronidation May rarely result in granulocytopenia and hepatotoxicity Delayed Minor Intermittent use of acetaminophen is considered safe. Adverse effects not consistently reported.
AZT Stavudine In vitro and in vivo antagonism Decreased antiviral efficacy Immediate Major Concomitant administration not recommended.
AZT Rifampin Enzymatic induction resulting in increased glucuronidation of AZT Increased clearance of AZT  Delayed Moderate Clinical significance unknown.
AZT Ribavirin In vitro ribavirin inhibits phosphorylation of AZT
Pharmacodynamic interaction		 Antagonism in vitro but not in vivo
Additive anemia		 Immediate
 
Delayed		  
 
Moderate/ Severe 		Avoid combination if possible or closely monotor virologic response.
Anemia may be severe. May require treatment or change in drugs.
AZT Doxorubicin Pharmacodynamic interaction Additive bone marrow suppression Delayed Moderate Additive bone marrow suppression. Consider alternative to AZT or support with G-CSF.
AZT Zalcitabine Low potency combination Non-responsive regimen Delayed Moderate Avoid combination.
AZT Myelosuppressive drugs (e.g., interferon, pyrimethamine) Pharmacodynamic interaction Additive bone marrow suppression Delayed Moderate Use with caution.
Monitor for bone marrow suppression.
AZT Atovaquone Inhibition of AZT glucuronidation AZT: AUC increased 31% decreased clearance  Immediate Moderate Clinical significance unknown. Use standard dose.
ddI (Didanosine) (Videx®) Ganciclovir/ Valganciclovir Unknown ddI AUC increased by >100% with concomitant dosing (or when oral ganciclovir is administered 2 hours after ddI); ganciclovir AUC decreased 21% Delayed Moderate Monitor for ddI toxicity (i.e. peripheral neuropathy, pancreatitis). Appropriate doses for combination of ddI and ganciclovir not established. Dose adjustment may be required.
ddI Tenofovir Unknown ddI AUC increased by 40–60%. Suboptimal response in 91% of patients with ddI/TDF/3TC only Delayed Major May increase rate of peripheral neuropathy and pancreatitis. Lower dose of ddI EC to 250 mg qd with TDF co-administration for pts >60kg. Dose for pts <60kg 200 mg qd.
ddI Indinavir Ritonavir Delavirdine Increase in gastric pH due to the buffer in ddI formulation Decreased absorption of indinavir, ritonavir, and delavirdine Immediate Moderate Separate administration time by at least 2 hours or use ddI EC formulation.
ddI Dapsone Increase in gastric pH due to the buffer in ddI formulation No significant interaction Immediate Mild Use standard dose.
ddI Itraconazole Ketoconazole Increase in gastric pH due to the buffer in ddI formulation Decreased absorption of antifungal agent Immediate Major Separate administration time by at least 2 hours or use ddI EC formulation. Fluconazole may be preferred as an alternative azole antifungal.
ddI Fluoroquinolones, Tetracyclines Chelation of fluoroquinolones and tetracyclines by the divalent cation in DDI formulation Significant decrease in antibiotic absorption resulting in sub-therapeutic levels Immediate Major Administer quinolones or tetracyclines 2 hours before or 6 hours after DDI administration or use ddI EC formulation.
ddI Pentamidine IV Ethambutol Pharmacodynamic interaction / additive toxicity May increase the risk of pancreatitis Delayed Moderate Should avoid in patients with current alcohol use. Use caution when administering to patients with a history of alcoholism.
ddI Atazanavir Decreased absorption of ATV due to buffer in ddI formulation ATV AUC decreased 87% with buffered ddI given simultaneously; no significant interaction expected with ddI EC Immediate Severe buffered ddI: Take ATV with food 2 hr before or 1 hr after ddI (if this timing of dosing not followed, 90% reduction in ATV level); ddI EC: take at different times (ATV with food and ddI on empty stomach).
ddI ddC,hydroxyurea, INH, cisplatin, disulfiram, thalidomide, vincristine, gold, hydralazine, and long-term metronidazole Pharmacodynamic interaction/ Additive toxicity May increase the risk of peripheral neuropathy Delayed Moderate Avoid co-administration or give with careful monitoring for symptoms of peripheral neuropathy. Incidence of peripheral neuropathy increases with low CD4 count.
ddI d4T Pharmacodynamic interaction/ Additive toxicity Increased risk lactic acidosis in pregnant women. Peripheral neuropathy and pancreatitis also reported with this combination Delayed Major Avoid co-administration especially during pregnancy, unless no other antiretroviral options are available and potential benefits outweigh risks.
ddI Methadone Unknown buffered ddI AUC decreased by 63%, methadone levels remains unchanged. No interaction with ddI EC Delayed Moderate Consider using ddI EC. May consider buffered ddI increase.
ddI Allopurinol Unknown ddI levels increased by 120% Immediate Moderate Avoid co-administration.
ddI Ribavirin Inhibition of mitochondrial DNA polymerase gamma ddI intracellular triphosphate levels increased Delayed Major Increased of risk of pancreatitis and lactic acidosis. Avoid co-administration.
ddC (Zalcitabine) (Hivid®) ddI, d4T, INH, cisplatin, disulfiram, thalidomide, vincristine, gold, hydralazine, pyridoxine, and long-term metronidazole Pharmacodynamic interaction/ Additive toxicity May increase the risk of peripheral neuropathy Delayed Moderate Avoid or give with careful monitoring of symptoms of peripheral neuropathy. Risk of peripheral neuropathy increases with total exposure and low CD4 count.
ddC Lamivudine Pharmacodynamic interaction Non-suppresive regimen Delayed Moderate To be avoided.
ddC Al or mg containing antacid Interference with absorption ddC absorption decreased by 25% Immediate Moderate Do not take simultaneously.
ddC Pentamidine I.V. Pharmacodynamic interaction Additive toxicity Delayed Moderate May increase the risk of development of fulminant pancreatitis.
ddC Probenecid Inhibition of tubular secretion May decrease elimination of ddC. ddC AUC increased by 54% Delayed Moderate Monitor signs of toxicity.
d4T (Stavudine) (Zerit®) ddC, INH, cisplatin, disulfiram, thalidomide, vincristine, gold, hydralazine, pyridoxine, and long-term metronidazole Pharmacodynamic interaction/Additive toxicity May increase the risk of peripheral neuropathy Delayed Moderate Avoid or give with careful monitoring of symptoms of peripheral neuropathy. Peripheral neuropathy increases with total exposure and low CD4 count.
d4T ddl Pharmacodynamic interaction/ Additive toxicity Increased risk lactic acidosis in pregnant women. Peripheral neuropathy and pancreatitis also reported with this combination Delayed Major Avoid coadministration use during pregnancy, unless no other antiretroviral options are available and potential benefits outweigh risks.
d4T Methadone Unknown d4T drug levels decreased by 23%. Methadone levels unchanged Delayed Mild Clinical significance unknown, no dose adjustment needed (unlikely to be significant).
d4T Zidovudine In vitro and in vivo antagonism Decreased efficacy of the combination therapy Immediate Major Concomitant administration not recommended due to antagonism.
d4T Ribavirin In vitro ribavirin interacts with thymidine-phosphorylated nucleoside analogs Antagonism in vitro but not in vivo Immediate Minor Not clinically significant.
3TC (Lamivudine) (Epivir®)
 Bactrim Trimethoprim competitively inhibits renal tubular secretion AUC of lamivudine increased by 44% Immediate Minor No dosage adjustment required due to the safety profile of 3TC (not clinically significant).
3TC Abacavir + tenofovir Pharmacodynamic interaction Non-suppressive regimen Delayed Major Avoid use of this combination without an NNRTI or a PI.
3TC Emtricitabine Overlapping resistance profile Non-suppressive regimen Delayed Major Avoid use together.
3TC Tenofovir + didanosine Pharmacodynamic interaction Non-suppressive regimen Delayed Major Avoid use of this combination without an NNRTI or a PI.
3TC Zalcitabine Pharmacodynamic interaction Non-suppressive regimen Delayed Moderate Consider alternative combination.
FTC (Emtricitabine) (Emtriva®) –         In vitro data suggest potential for CYP450-mediated interactions involving emtricitabine with other agents is low; in human studies, no significant PK changes in either drug with tenofovir, indinavir, famciclovir, or stavudine.
FTC Lamivudine Overlapping resistance profile Non-suppressive regimen Delayed Major Avoid.
Abacavir (Ziagen®) Alcohol Unknown Alcohol increases ABC levels by 41%. No effect on alcohol levels Immediate Minor Clinical significance unknown. No dose adjustment recommended.
Abacavir Tenofovir + didanosine Pharmacodynamic interaction Non-suppressive regimen Delayed Major Avoid us of this combination without an NNRTI or a PI.

AUC= Area Under the Concentration Time Curve
Cmax = Peak serum concentration
Cmin = Trough serum concentration
CrCl = Creatinine clearance
TDM = Therapeutic drug monitoring

Time course:

Delayed = maximal interaction occurring at 14 days
Immediate = interaction occurring immediately

Severity:

Major = Do not co-administer; contraindicated.
Moderate = Can be co-administered with caution and possible dose adjustment.
Minor = Can be co-administered.

Table 14-6b: Drug Interactions of Antiretrovirals (N+RTIs)  TOP
Primary Drug Interacting Drug Mechanism of Interaction Effect Time course Severity Comments / management recommendation
Drug Interactions with Nucleotide Reverse Transcriptase Inhibitors
Tenofovir (Viread®) Atazanavir Possible interference with absorption Atazanavir AUC decreased by 25%; decreased Cmin by 23% Immediate Moderate Clinical significance unknown. Consider dosing tenofovir 2 hours before atazanavir or “boosting” with RTV dose: (ATV 300 mg + RTV 100 mg).
Tenofovir ddI Unknown
Low potency combination		 ddI AUC increased by 40–60% Delayed Major May increase rate of peripheral neuropathy and pancreatitis. Lower dose of ddI to 250 mg qd with TDF co-administration for pts >60kg. Dose adjustments for pts <60kg 200 mg qd. Preliminary data shows low potency.
Tenofovir Cidofovir, ganciclovir, valganciclovir Possible competition for active tubular secretion May increase concentration of TDF or these drugs Immediate Moderate Monitor for dose-related toxicities.
Tenofovir Lamivudine + Abacavir Pharmacodynamic interaction Non-suppressive regimen Delayed Major Avoid use of this combination without an NNRTI or a PI.
Tenofovir Lamivudine + didanosine Pharmacodynamic interaction Non-suppressive regimen Delayed Major Avoid use of this combination without an NNRTI or a PI.
Tenofovir Didanosine Increased ddI serum level ddI AUC increased by 44% may result in increased toxicity Immediate Major Monitor for ddl associated toxicities for patients ≥ 60 kg, decrease ddl EC dose 250 mg qd for patients < 60 kg.

AUC= Area Under the Concentration Time Curve
Cmax = Peak serum concentration
Cmin = Trough serum concentration
CrCl = Creatinine clearance
TDM = Therapeutic drug monitoring

Time course:

Delayed = maximal interaction occurring at 14 days
Immediate = interaction occurring immediately

Severity:

Major = Do not co-administer; contraindicated.
Moderate = Can be co-administered with caution and possible dose adjustment.
Minor = Can be co-administered.

Table 14-6c: Drug Interactions of Antiretrovirals (NNRTIs)  TOP
Primary Drug Interacting Drug Mechanism of Interaction Effect Time course Severity Comments / management recommendation
Drug Interactions with Non-Nucleoside Reverse Transcriptase Inhibitors
Nevirapine (Viramune®) (NVP) Ethinyl estradiol (Oral contraceptives) Induction of hepatic metabolism Ethinyl estradiol AUC decreased by 23% Delayed Major Patients should be aware of the potential interaction. Alternative or additional birth control method should be recommended.
NVP Methadone Induction of hepatic metabolism Substantially decreased methadone AUC by 46% Delayed Moderate Opiate withdraw may occur. May need to increase dose of methadone by 15–25% (some patients may required doses of greater than 150 mg per day).
NVP Ketoconazole Induction of hepatic metabolism by nevirapine. Inhibition of hepatic metabolism by ketoconazole Ketoconazole levels decreased by 72%. Nevirapine levels increased by 15–30% Delayed Moderate Co-administration not recommended. Ketoconazole dose may need to be increased. Fluconazole may be preferred as alternative azole agent.
NVP Rifampin/ Rifabutin Induction of hepatic metabolism Nevirapine levels decreased by 37% with rifampin and 16% with rifabutin Delayed Major Co-administration not recommended with rifampin. Rifabutin is the preferred alternative agent.
NVP Phenobarbital, phenytoin, and carbamazepine Induction of hepatic metabolism by both NVP and anticonvulsants May decrease serum levels of NVP and anticonvulsants Delayed Moderate Consider alternative anticonvulsants (i.e valproic acid, levetiracetam, or topiramate).
NVP Clarithromycin Induction of hepatic metabolism by nevirapine Clarithromycin AUC decreased by 30%, but active hydroxy-metabolite is increased Delayed Minor No dose modification needed. Use standard doses of nevirapine and clarithromycin.
NVP   Inhibition of hepatic metabolism by clarithromycin Nevirapine AUC increased by 26% Immediate Minor  
NVP St. John’s wort Induction of hepatic metabolism by St. John’s wort NVP clearance increased by 35% Delayed Major Co-administration is contraindicated.
NVP Saquinavir Induction of hepatic metabolism Saquinavir AUC decreased by 38%. NVP level not affected Delayed Moderate Avoid concurrent use unless saquinavir is “boosted” with ritonavir (SQV 1000 mg/ RTV 100 mg bid.
NVP Ritonavir Induction of hepatic metabolism Ritonavir AUC decreased by 11%. NVP level not affected Delayed Minor Use standard doses.
NVP Indinavir Induction of hepatic metabolism Indinavir AUC decreased by 28%. NVP level not affected Delayed Minor Clinical trials demonstrated good efficacy with standard dose. Consider increasing IDV to 1000 mg q8h (or IDV 800 mg/RTV 100 mg q12h) with NVP coadministration.
NVP Nelfinavir Induction of hepatic metabolism Nelfinavir levels increase by 10%. NVP level not affected Delayed Minor Use standard doses.
NVP Lopinavir/r Induction of hepatic metabolism LPV/r AUC decreased by 22%. Cmin decreased by 55%. NVP level not affected Delayed Major Dose: LPV/r 533 mg/133 mg (4 caps) bid with food (NVP standard dose).
NVP Efavirenz Induction of hepatic metabolism EFV AUC decreased by 22%. NVP AUC not affected Delayed Moderate Though pharmacokinetic data exist, co-administration is not recommended due to overlapping resistance.
NVP Atazanavir No Data       Consider using ATV 300 mg/ RTV 100 mg qd.
NVP Fluconozole Inhibition of NVP metabolism May increase NVP serum level Immediate Moderate Monitor NVP-associated side effec
NVP Voriconozole Potential for bi-directional inhibition May significantly decrease voriconazole serum level Delayed Moderate/ Severe Monitor frequently for toxicites and voriconazole efficacy. Dose adjustment may be needed.
NVP Norethindrone Induction of northindrone metabolism May decrease norethindrone Delayed Major Use additional method of contraception.
NVP Rifapentine Induction of NVP metabolism May significantly decrease NVP serum level Delayed Major Avoid use together; consider rifabutin.
Delavirdine (Rescriptor®) (DLV) Indinavir Induction of hepatic metabolism Indinavir AUC increased by 40%. DLV no change Immediate Moderate May reduce indinavir dose to 600 mg q8h. DLV standard dose.
DLV Nelfinavir Inhibition of hepatic metabolism by delavirdine; Induction of hepatic metabolism by nelfinavir NFV AUC increased by 72%. DLV AUC decreased by 42% Cmin decreased by 52% Immediate;
delayed		 Moderate Do not co-administer.
DLV Ritonavir Inhibition of hepatic metabolism Ritonavir AUC increased by 61%. DLV no change Immediate Minor Standard doses likely (no data).
DLV Saquinavir Inhibition of hepatic metabolism Invirase® Cmin increased by 500%; DLV AUC decreased by 15% Delayed Minor A beneficial interaction. No dose adjustment necessary. Monitor transaminase levels.
DLV Amprenavir Inhibition of hepatic metabolism by DLV. Induction of hepatic metabolism by APV Amprenavir AUC increased by 125%. DLV AUC decreased by 60% Delayed Major Co-administration not recommended.
DLV Lopinavir/r Inhibition of hepatic metabolism LPV AUC increased by 8–134%. DLV no change Immediate Minor Limited data. No dose adjustment.
DLV ddI and antacid Decreased delavirdine absorption due to antacid content in DDI Delavirdine AUC decreased by 41% Immediate Moderate Separate administration by at least 1 hour or use ddI EC.
DLV Simvastatin/ Lovastatin Inhibition of hepatic metabolism Increased serum levels of simvastatin and lovastatin Immediate Moderate Avoid concurrent administration. Consider alternatives such as atorvastatin, pravastatin, fluvastatin. Monitor for adverse effects due to limited clinical data.
DLV H2 blockers, Proton pump inhibitors (i.e. omeprazole) Decreased delavirdine absorption due to antacid content in DDI May decrease delavirdine concentration Immediate Moderate Concurrent administration contraindicated.
DLV Terfenadine, Astemizole, Cisapride Inhibition of hepatic metabolism Increased levels of terfenadine, astemizole, cisapride Immediate Major Concurrent administration contraindicated due to potential for serious cardiac arrhythmias.
DLV Midazolam, Triazolam Inhibition of hepatic metabolism Midazolam and triazolam AUCs increased Immediate Major Concurrent administration contraindicated due to potential for prolonged sedation. Lorazepam and temazepam may be safe alternatives.
DLV Ergot alkaloid Inhibition of hepatic metabolism Possible acute ergot toxicity characterized by peripheral vasospasm and ischemia of extremities Immediate Major Concurrent administration contraindicated.
DLV St. John’s wort Induction of hepatic metabolism by St. John’s wort May decrease serum level of delavirdine Delayed Major Co-administration is contraindicated.
DLV Clarithromycin Inhibition of hepatic metabolism Clarithromycin levels increased by 100% and delavirdine levels increased by 44% Immediate Minor May require clarithromycin dose adjustment, based upon CrCl.
DLV Ethinyl estradiol Unknown Ethinyl estradiol levels decreased by 20% Delayed Major Patients should be aware of the potential interaction. Alternative or additional birth control method should be recommended.
DLV Quinidine Inhibition of hepatic metabolism May increase quinidine serum concentration Immediate Major No data. Use with caution with close EKG monitoring and serum levels of quinidine.
DLV Ketoconazole Inhibition of hepatic metabolism by delavirdine Ketoconazole AUC increased by 50% Immediate Minor Consider dose reduction of ketoconazole. DLV 200–400 mg tid.
DLV Rifampin Inhibition of hepatic metabolism Delavirdine Cmin decreased below the level of detection AUC decreased by 96% Delayed Major Concurrent administration contraindicated due to sub-therapeutic level of delavirdine.
DLV Rifabutin Inhibition of hepatic metabolism by delavirdine Rifabutin AUC increased by 100% Immediate Moderate Concurrent administration contraindicated due to sub-therapeutic level of delavirdine.
DLV Rifabutin Inhibition of hepatic metabolism by refabutin Delavirdine AUC decreased by 80% Delayed Major Concurrent administration contraindicated.
DLV Warfarin Potential inhibition of warfarin metabolism May increase warfarin Immediate Moderate Monitor INR.
DLV Voriconazole Potential for bi-directional inhibition May increase voriconazole and DLV serum level Immediate Moderate Monitor frequently for toxicities.
DLV Bepridil Potential inhibition of bepridil metabolism May increase bepridil serum level Immediate Moderate Use with caution; monitor for cardiac arrhythmias.
DLV Tadalafil Potential inhibition of tadalafil metabolism May substantially increase in tadalafil AUC and half life Immediate Moderate Start tadalafil 5 mg dose; do not exceed a single 10 mg dose of tadalafil in 72 hours.
DLV Vardenafil Potential inhibition of vardenafil metabolism May substantially increase vardenafil AUC     Start with a 2.5 mg dose; do not exceed a single 2.5 mg dose of vardenafil in 72 hours.
Efavirenz (Sustiva®) (EFV) Saquinavir Induction of hepatic metabolism Invirase® AUC decreased by 60%. Efavirenz AUC decreased by 12% Delayed Moderate Avoid using SQV as sole protease inhibitor with efavirenz. If RTV/SQV/efavirenz regimen used: dose SQV 1000 mg/RTV 100–200 mg bid plus EFV 600 mg qhs or RTV/SQV 400 mg/400 mg bid plus EFV 600 mg qhs.
EFV Nelfinavir Inhibition of hepatic metabolism Nelfinavir AUC increased by 21% Immediate Minor A beneficial pharmacokinetic interaction. No dose adjustment needed.
EFV Amprenavir Induction of hepatic metabolism Amprenavir AUC decreased by 36% Delayed Moderate Dose: APV 600 mg/ RTV 100 mg q12h + EFV 600 mg qhs.
EFV Indinavir Induction of hepatic metabolism Indinavir AUC decreased by 31% Delayed Moderate May need to increase indinavir dose to 1000 mg q8h or consider IDV “boosted” with 200 mg RTV.
EFV Ritonavir Dual inhibition of hepatic metabolism Efavirenz AUC increased by 21%. Ritonavir AUC increased by 17% Immediate Minor No adjustment needed.
EFV Lopinavir/r Induction of hepatic metabolism LPV AUC decreased by 19%. Cmin decreased by 39% Delayed Major Dose: LPV/r 533 mg/133 mg (4 caps) bid + EFV 600 mg qhs.
EFV Ergot alkaloid Induction of hepatic metabolism Potential acute ergot toxicity characterized by peripheral vasospasm and ischemia of extremities Immediate Major Concurrent administration contraindicated.
EFV Midazolam, Triazolam Induction of hepatic metabolism AUCs of midazolam and triazolam increased Immediate Major Concurrent administration contraindicated due to potential for prolonged sedation. Lorazepam and temazepam may be safe alternatives.
EFV Terfenadine, Astemizole, Cisapride Induction of hepatic metabolism Levels of terfenadine, astemizole, cisapride increased Immediate Major Concurrent administration contraindicated due to potential for serious cardiac arrhythmia.
EFV St. John’s wort Induction of hepatic metabolism by St. John’s wort May decrease efavirenz serum level Delayed Major Co-administration is contraindicated.
EFV Clarithromycin Induction of hepatic metabolism Clarithromycin AUC decreased by 39% Immediate Moderate Incidence of rash increased to 46% with concurrent administration. No interaction with azithromycin, a better alternative.
EFV Ethinyl estradiol Inhibition of hepatic metabolism Ethinyl estradiol AUC increased by 37% Immediate Minor No dose changes recommended. Clinical significance of interaction unknown. No data on progestin component of oral contraceptive available. Alternative or additional form of birth control recommended.
EFV Rifabutin Inhibition of hepatic metabolism Rifabutin AUC decreased by 35%. No effect on Efavirenz AUC Delayed Moderate If concurrent administration required, increase dose of rifabutin to 450 mg or 600 mg po qd.
EFV Rifampin Inhibition of hepatic metabolism Efavirenz AUC decreased by 26%. No change in rifampin levels Delayed Moderate Consider increasing EFV to 800 mg qhs with rifampin co-administration. An alternative is to use rifabutin dose adjusted to 450–600 mg qd (or 600 mg 3x/week) with standard dose EFV.
EFV Phenobarbital, phenytoin, and carbamazepine Induction of hepatic metabolism by both EFV and anticonvulsants May decrease serum levels of EFV and anticonvulsants Delayed Moderate Consider alternative anticonvulsants (i.e valproic acid, levetiracetam, or topiramate). Consider increasing EFV to 800 mg po qd with co-administration. Monitor anticonvulsant level.
EFV Nevirapine Induction of hepatic metabolism EFV AUC decreased by 22%. NVP AUC not affected Delayed Moderate Though pharmacokinetic data exist, co-administration is not recommended due to overlapping resistance.
EFV Methadone Induction of hepatic metabolism Decrease methadone AUC by 57% Delayed Moderate Opiate withdrawal may occur. May need to increase dose of methadone.
EFV Atazanavir Induction of hepatic metabolism ATV decreases AUC by 74% Delayed Major Use ATV 300 mg + RTV 100 mg qd with food. Standard EFV dose.
EFV Fosamprenavir Induction of hepatic metabolism fAPV Cmin decreases 36% when dosed at fAPV 1400 mg + RTV 250 mg qd Delayed Major Use fAPV 700 mg + RTV 100 mg bid,OR fAPV 1400 mg + RTV 300 mg with EFV co-administration.
EFV Indinavir Induction of hepatic metabolism IDV decreases 31% Delayed Major Increase IDV dose to 1000 mg q8h or consider IDV 800 mg + RTV 200 mg q12h.
EFV Warfarin Unknown Potential increase or decrease in warfarin levels Delayed Moderate Monitor INR.

AUC= Area Under the Concentration Time Curve
Cmax = Peak serum concentration
Cmin = Trough serum concentration
CrCl = Creatinine clearance
TDM = Therapeutic drug monitoring

Time course:

Delayed = maximal interaction occurring at 14 days
Immediate = interaction occurring immediately

Severity:

Major = Do not co-administer; contraindicated.
Moderate = Can be co-administered with caution and possible dose adjustment.
Minor = Can be co-administered.

Table 14-6d: Drug Interactions of Antiretrovirals (PIs)  TOP
Primary Drug Interacting Drug Mechanism of Interaction Effect Time course Severity Comments / management recommendation
Drug Interactions with Protease Inhibitors
Indinavir (Crixivan®) (IDV) ddI Impairment of indinavir absorption by DDI buffer Decreases absorption of indinavir Immediate Moderate Separate indinavir and ddI dosing by at least 2h or use ddI EC formulation.
IDV Simvastatin/ Lovastatin Inhibition of hepatic metabolism Increased serum levels of simvastatin and lovastatin Immediate Moderate Avoid concurrent administration. Possible alternative include atorvastatin, pravastatin, fluvastatin. Monitor for adverse effect due to limited clinical data with these agents.
IDV Rifabutin Inhibition of hepatic metabolism by indinavir Rifabutin AUC increased by 2 fold Immediate Moderate Decrease rifabutin dose by half (150 mg once a day) or 300 mg 3x/week.
IDV Rifabutin Induction of hepatic metabolism by rifabutin Indinavir AUC decreased by 32% Delayed Moderate May need to increase indinavir dose to 1000 mg tid. When IDV “boosted” with RTV, adjust rifabutin 150 mg qod.
IDV Rifampin Induction of hepatic metabolism Indinavir AUC decreased by 90% Immediate Major Concurrent administration contraindicated.
IDV Terfenadine, Astemizole, Cisapride Inhibition of hepatic metabolism Drug levels increased by 3-fold or greater Immediate Major Concurrent administration contraindicated due to potential for cardiac arrhythmias. Alternative antihistamines include loratidine, fexofenadine, or cetirizine. Alternative pro-kinetic agent includes metoclopramide.
IDV Ergot alkaloid Inhibition of hepatic metabolism Potential acute ergot toxicity characterized by peripheral vasospasm and ischemia of extremities Immediate Major Concurrent administration contraindicated.
IDV Ketoconazole, Itraconazole Inhibition of hepatic metabolism Indinavir AUC increased by 70% Immediate Moderate Dose Indinavir at 600 mg Q8h. No dose adjustment when “boosted” with RTV.
IDV Midazolam, Triazolam Inhibition of hepatic metabolism AUCs of midazolam and triazolam are increased Immediate Major Concurrent administration contraindicated due to potential for prolonged sedation.
IDV St. John’s wort Inhibition of hepatic metabolism by St. John's wort Indinavir AUC decreased by 57% Delayed Major Co-administration is contraindicated.
IDV Clarithromycin Inhibition of hepatic metabolism Clarithromycin AUC increased by 53% Immediate Minor No dose adjustment.
IDV Oral contraceptives Inhibition of hepatic metabolism Ethinyl estradiol AUC increased by 24% and norethindrone AUC increased by 26% Immediate Minor No dose adjustment.
IDV Phenobarbital, phenytoin, and carbamazepine Induction of hepatic metabolism May decrease serum levels of IDV. IDV may increase anticonvulsant serum level Delayed Moderate Consider alternative anticonvulsants (i.e valproic acid, levetiracetam, or topiramate). Monitor anticonvulsant level.
IDV Sildenafil Inhibition of hepatic metabolism Sildenafil AUC increased 3-fold Immediate Moderate The maximum dose of sildenafil is 25 mg/48h.
IDV Nelfinavir Inhibition of hepatic metabolism Indinavir AUC increased by 50% Nelfinavir AUC increased by 80% Immediate Minor Limited dosing data using IDV 1200 mg bid + NFV 1250 mg bid.
IDV Amprenavir Inhibition of hepatic metabolism Amprenavir AUC increased by 26%. Indinavir AUC increased by 38% Immediate Minor No dose adjustment recommended. Dose APV 800 mg tid /IDV 800 mg tid.
IDV Ritonavir Inhibition of hepatic metabolism Indinavir AUC increased by 2 to 5-fold Immediate Minor Interaction allows indinavir to be dosed twice a day. Dose: IDV 400 mg/RTV 400 mg or IDV 800 mg bid/RTV100 bid. IDV 1200 mg/RTV 400 mg qd (limited data).
IDV Lopinavir/r Inhibition of hepatic metabolism Indinavir AUC increased by 3-fold Immediate Moderate Dose: IDV 600 mg or 666 mg bid plus LPV/r 400 mg/100 mg bid.
IDV Saquinavir Inhibition of hepatic metabolism Saquinavir AUC increased 4 to 7 fold. No effect on Indinavir level Immediate Moderate In vitro antagonism. Avoid co-administration.
IDV Nevirapine Induction of hepatic metabolism Indinavir AUC decreased by 28%. NVP level not affected Delayed Minor Clinical trials demonstrated good efficacy with standard doses. Some experts recommend increasing the dose of IDV to 1000 mg q8h. When using “boosted” IDV consider RTV dose 200 mg bid.
IDV Efavirenz Induction of hepatic metabolism Indinavir AUC decreased by 31% Delayed Moderate May need to increase indinavir dose to 1000 mg q8h or IDV 800/ RTV 100 q12h.
IDV Delavirdine Inhibition of hepatic metabolism Indinavir AUC increased by 40%. DLV no change Immediate Moderate May reduce indinavir dose to 600 mg q8h. DLV standard dose.
IDV Methadone   No change in serum level     No interaction. Use standard dose.
IDV Voriconazole When IDV is boosted with RTV, potential for bi-directional interaction Voriconazole levels may be decreased with IDV/RTV Dealyed Moderate No interaction with IDV but voriconazole may be decreased with RTV co-administration. Monitor for toxicities and therapeutic efficacy.
IDV Tadalafil Inhibition of hepatic metabolism May substantially increase tadalafil AUC Immediate Moderate Start with 5 mg dose and do not exceed a single dose of 10 mg in 72 hrs.
IDV Vardenafil Inhibition of hepatic metabolism Vardenafil increases 16-fold IDV unboosted decreases 30% Immediate Moderate For unboosted IDV, consider using sildenafil instead; for IDV + RTV, do not exceed 2.5 mg vardenafil in 72 hrs.
IDV Atorvastatin Inhibition of hepatic metabolism Potential for atorvastatin AUC increase Immediate Moderate Use lowest possible starting dose of atorvastatin with careful monitoring or avoid use together.
Saquinavir (Invirase®) (Fortovase®) (SQV) Ritonavir Inhibition of hepatic metabolism Saquinavir AUC increased by 20-fold Immediate Minor Dual protease inhibitor combination with the most clinical experience. Recommended doses: RTV 400 mg bid plus SQV 400 mg bid. RTV 100 mg bid plus SQV 1000 mg bid. RTV 100 mg plus SQV 1600 mg qd.
SQV Indinavir Inhibition of hepatic metabolism Saquinavir AUC increased 4 to 7- fold No effect on Indinavir Immediate Moderate In vitro antagonism. Avoid co-administration.
SQV Nelfinavir Inhibition of hepatic metabolism Fortovase®AUC increased by 3 to 5-fold. Nelfinavir AUC increased by 20% Immediate Minor Recommended doses are nelfinavir 750 mg tid and Fortovase® 800 mg tid or 1200 mg bid.
SQV Amprenavir Induction of hepatic metabolism Saquinavir level decreased by 18%. Amprenavir level decreased by 36% Delayed Moderate Limited data: SQV (FTV) 800 mg tid plus APV 800 mg tid.
SQV Lopinavir/r Inhibition of hepatic metabolism Saquinavir Cmin increased by 3.6-fold Immediate Minor Dose: SQV 800–1000 mg bid plus LPV/r 400/100 mg bid.
SQV Ketoconazole Inhibition of hepatic metabolism Saquinavir level increased by 3-fold Immediate Minor Beneficial pharmacokinetic interaction. Use standard doses. If ketoconazole dose is >200 mg/da, monitor for GI side effects and adjust doses accordingly.
SQV Midazolam, Triazolam Inhibition of hepatic metabolism Midazolam and triazolam AUCs increased Immediate Major Concurrent administration contraindicated due to potential for prolonged sedation.
SQV Terfenadine, Astemizole, Cisapride Inhibition of hepatic metabolism Drug levels increased by 3-fold or greater Immediate Major Concurrent administration Contraindicated due to potential for cardiac arrhythmias. Alternative antihistamines include loratidine, fexofenadine, or cetirizine. Alternative pro-kinetic agent includes metoclopramide.
SQV Dexamethasone Induction of hepatic metabolism May decrease SQV serum levels Delayed Moderate Clinical significance unknown.
SQV Phenobarbital, phenytoin, and carbamazepine Induction of hepatic metabolism May decrease serum levels of SQV Delayed Moderate Consider alternative anticonvulsants (i.e valproic acid, levetiracetam, or topiramate). Monitor anticonvulsant level.
SQV Ergot alkaloid Inhibition of hepatic metabolism Acute ergot toxicity characterized by peripheral vasospasm and ischemia of extremities Immediate Major Concurrent administration contraindicated.
SQV Simvastatin/ Lovastatin Inhibition of hepatic metabolism Simvastatin and lovastatin serum level increased Immediate Moderate Avoid co-administration. Recommended alternatives include atorvastatin, pravastatin (but pravastatin AUC decreased by 50% with SQV/r), fluvastatin. Monitor for adverse effects due to limited clinical data with these agents.
SQV Clarithromycin Inhibition of hepatic metabolism Clarithromycin increases SQV AUC 177% and SQV increases clarithromycin AUC 45% Immediate Minor Beneficial pharmacokinetic interaction. Use standard doses.
SQV Rifabutin/ Rifampin Induction of hepatic metabolism Rifabutin and rifampin decrease AUC of saquinavir by 40% and 80% respectively Delayed Major Concurrent administration contraindicated unless using RTV/SQV. Consider RTV/SQV 400 mg/400 mg with rifabutin 150 mg 3x/week or rifampin 600 mg qd or 3x/week.
SQV Sildenafil Inhibition of hepatic metabolism Sildenafil AUC increased by 2-fold Immediate Moderate Caution with concurrent use, Do not exceed 25 mg of sildenafil in a 48-hour period.
SQV Oral contraceptives         No data.
SQV Methadone Induction of hepatic metabolism 8–10% reduction in methadone level Delayed Minor Insignificant interaction. No dose adjustment needed.
SQV St. John’s wort Inhibition of hepatic metabolism by St. John's wort May decrease SQV serum level Delayed Major Co-administration is contraindicated.
SQV Garlic supplement (3.5 mg bid) Unknown SQV Cmin decreased by 49% Delayed Moderate Avoid concurrent administration.
SQV Delavirdine Inhibition of hepatic metabolism SQV increases 5-fold Immediate Minor Decrease SQV-sgc dose to 800 mg tid, and monitor transaminase levels.
SQV Efavirenz Induction of hepatic metabolism SQV decreases 62%, EFV decreases 12% Delayed Moderate Use SQV-sgc 400 mg + RTV 400 mg.
SQV Nevirapine Inhibition of hepatic metabolism SQV decreases 25% Delayed Moderate SQV-sgc 400 + RTV 400 mg or SQV-sgc 1000 mg + RTV 100 mg bid or SQV-hgc 1000 mg + RTV 100 mg bid.
SQV Warfarin Unknown Increases or decreases warfarin Delayed Moderate Monitor INR.
SQV Amitryptiline Imipramine Inhibition of hepatic metabolism May increase tricyclics Immediate Minor Monitor tricyclic antidepressant concentration.
SQV Voricanazole Potential for bi-directional inhibition With SQV/RTV voriconazole serum level may be decreased Delayed Moderate Monitor for toxicities and therapeutic efficacy.
SQV Tadalafil Inhibition of hepatic metabolism May substantially increase tadalafil AUC Immediate Moderate Start with a 5 mg dose and do not exceed a single 10 mg dose of tadalafil in 72 hrs.
SQV Vardenafil Inhibition of hepatic metabolism Vardenafil AUC may increase substantially Immediate Moderate Start with a 2.5 mg dose, and do not exceed a single 2.5 mg dose in 72 hrs.
SQV Atorvastatin Inhibition of hepatic metabolism Atorvastatin increases 450% when combined with SQV/RTV Immediate Moderate Use lowest possible starting dose of atorvastatin with careful monitoring.
Ritonavir (Norvir®) (RTV) Metronidazole Alcohol in ritonavir liquid may precipitate a disulfiram-like reaction Unexpected nausea Immediate Moderate Warn patient of the alcohol content in ritonavir liquid.
RTV Voriconazole Hepatic induction Decreased voriconazole by 82% when administered with RTV 400 mg bid Delayed Major Do not co-administer with standard dose RTV 400 bid; no data with boosting doses of RTV.
RTV Oral contraceptives Induction and increase in glucuronosyl transferase activity Ethinyl estradiol level decreased by 40% Delayed Major Warn patient of interaction. Use alternative or additional method of contraception.
RTV Sildenafil Inhibition of hepatic metabolism Sildenafil AUC increased by 2 to 11-fold Immediate Major Caution with concurrent use, Do not exceed 25 mg of sildenafil in a 48-hour period.
RTV Theophylline Induction of glucuronosyl transferase activity Theophylline AUC decreased by 43% Delayed Moderate Monitor theophylline levels; dose may need to be increased if subtherapeutic.
RTV Ketoconazole Inhibition of hepatic metabolism Ketoconazole AUC increased by greater than 3-fold Immediate Moderate May need to decrease ketoconazole dose.
RTV Rifabutin Inhibition of hepatic metabolism Rifabutin AUC increased 4-fold Immediate Moderate Dose rifabutin 150 mg qod or 150 mg 3x/week with standard ritonavir.
RTV Rifampin Inhibition of hepatic metabolism Ritonavir AUC decreased by 35% Delayed Moderate There may be an increased risk of liver toxicity. Dose RTV 400 mg/ SQV 400 mg bid with rifampin 600 mg qd.
RTV Ergot alkaloid Inhibition of hepatic metabolism Acute ergot toxicity characterized by peripheral vasospasm and ischemia of extremities Immediate Major Concurrent administration contraindicated.
RTV Terfenadine, Astemizole, Cisapride Inhibition of hepatic metabolism Drug level increased by 3- fold or greater Immediate Major Concurrent administration contraindicated due to potential for cardiac arrhythmias. Alternative antihistamines include loratidine, fexofenadine, or cetirizine. Alternative pro-kinetic agent includes metoclopramide.
RTV St. John’s wort Inhibition of hepatic metabolism by St. John's wort May decrease RTV serum level Delayed Major Co-administration is contraindicated.
RTV Benzodiazepines Inhibition of hepatic metabolism Prolonged sedation due to accumulation of benzodiazepine Delayed Major Concurrent administration of midazolam and triazolam are contraindicated. Alternative benzodiazepines that can be used: Temazepam, oxazepam, and lorazepam.
RTV Antiarrhythmics Inhibition of hepatic metabolism AUC of antiarrhythmics increased Immediate Major Concurrent administration of propafenone, quinidine, flecainide, encainide, amiodarone, and bepridil are contraindicated.
RTV Methadone Induction of hepatic metabolism Methadone levels decreased by 37% Delayed Moderate Clinical significance unknown.
RTV Ketoconazole Inhibition of hepatic metabolism Ketoconazole levels increased by 3-fold Immediate Moderate Use with caution; do not exceed 200 mg ketoconazole per day.
RTV Phenobarbital, phenytoin, and carbamazepine Induction of hepatic metabolism May decrease serum levels of RTV. RTV may increase serum level of anticonvulsants Delayed Moderate Consider alternative anticonvulsants (i.e valproic acid, levetiracetam, or topiramate). Monitor anticonvulsant level. Carbamazepine toxicity has been reported.
RTV Antidepressant (TCAs: desipramine, amitriptyline) SSRIs, Bupropion Inhibition of hepatic metabolism Desipramine AUC increased by 145%.
Increased serum levels of SSRIs, bupropion		 Immediate Major Monitor desipramine levels. Consider citalopram, sertraline, or fluoxetine.
Monitor for increased effects from SSRIs, bupropion. Doses of RTV used in boosted PI regimens may have minimal effects.
RTV Antipsychotic (Olanzapine) Induction of hepatic metabolism Olanzapine AUC decreased by 50% Delayed Moderate Olanzapine dose may need to be increased.
RTV Antipsychotic (Pimozide) Inhibition of hepatic metabolism May significantly increase pimozide serum level resulting in QTc prolongation Immediate Major Concurrent administration of pimozide is contraindicated.
RTV Simvastatin/ Lovastatin Inhibition of hepatic metabolism Serum levels of simvastatin and lovastatin are increased Immediate Moderate Avoid co-administration, alternatives that may be used inlcude atorvastatin, pravastatin, fluvastatin. Monitor for adverse effects due to limited clinical data.
RTV Opioid analgesic Inhibition of hepatic metabolism Prolonged sedation and possible respiratory depression Immediate Major Avoid concurrent administration of meperidine, propoxyphene, and fentanyl. Morphine may be a safer alternative.
RTV Clarithromycin Inhibition of hepatic metabolism Clarithromycin AUC increased by 77% Immediate Minor Reduce clarithromycin dose for renal failure. Consider using azithromycin.
RTV Didanosine (buffered) Interference with absorption Decreased ritonavir absorption Immediate Major Consider using ddI EC or separate administration by >2 hours.
RTV Saquinavir Inhibition of hepatic metabolism Saquinavir AUC increased by 20-fold Immediate Minor Dual protease inhibitor with the most clinical experience. Recommended doses: ritonavir 400 mg bid and SQV (Fortovase® or Invirase®) 400 mg bid or SQV 1000 mg + RTV 100 mg bid or SQV 1600 mg + RTV 100 mg qd.
RTV Indinavir Inhibition of hepatic metabolism Indinavir AUC increased by 2 to 5-fold Immediate Minor Interaction allows indinavir to be dosed twice a day, which may reduce renal stones associated with higher dose indinavir. Dose: IDV 400 mg bid and RTV 400 mg bid or IDV 800 mg bid + RTV 100 bid.
RTV Nelfinavir Inhibition of hepatic metabolism Nelfinavir AUC increased by 2.5-fold Immediate Minor Only marginal PK benefit. Clinical trials have used ritonavir 400 mg bid and nelfinavir 500 mg or 750 mg bid.
RTV Amprenavir Inhibition of hepatic metabolism Amprenavir AUC increased by 2.5-fold Immediate Minor Dose: APV 600 mg bid plus RTV 100 mg bid or APV 1200 mg qd plus RTV 200 mg qd.
RTV Atazanavir Inhibition of hepatic metabolism ATV increases AUC by 238% Immediate Minor A beneficial PK interaction, use ATV 300 mg + RTV 100 mg qd.
RTV Fosamprenavir Inhibition of hepatic metabolism fAPV increases AUC by 100%, Cmin by 400% when combined with 200 mg RTV Immediate Minor A beneficial PK interaction, use RTV-boosted regimen (fAPV 700 mg + RTV 100 mg bid) in ARV-experienced patients.
Nelfinavir (Viracept®) (NFV) Ketoconazole Inhibition of hepatic metabolism Nelfinavir AUC increased by 35% Immediate Minor No dose adjustment needed.
NFV Fluconazole Inhibition of hepatic metabolism Nelfinavir AUC increased by 30% Immediate Minor May be beneficial. No dose adjustment needed.
NFV Simvastatin/ Lovastatin Inhibition of hepatic metabolism Increased serum level of simvastatin and lovastatin Immediate Moderate Avoid co-administration: Alternatives includes pravastatin (but pravastatin AUC decreased by 47%), and fluvastatin. Monitor for adverse effects due to limited clinical data. Atorvastatin levels increased by 74%.
NFV Methadone Induction of hepatic metabolism Decreased serum level of inactive methadone (S)-isomer. No change in active methadone (R)-isomer Delayed Minor Use standard dose. No withdrawal symptoms observed.
NFV Rifampin Induction of hepatic metabolism Nelfinavir AUC decreased by 82% Delayed Major Concurrent administration contraindicated.
NFV Rifabutin Induction of hepatic metabolism by rifabutin Nelfinavir AUC decreased by 32% Delayed Moderate If co-administration required, increase nelfinavir to 1000 mg po tid.
NFV   Inhibition of hepatic metabolism by nelfinavir Rifabutin levels increased by 2-fold Immediate Moderate If co-administration required, decrease rifabutin to 150 mg po qd or 300 mg 3x/week.
NFV Benzodiazepines Inhibition of hepatic metabolism Prolonged sedation due to accumulation of benzodiazepine Immediate Major Midazolam and triazolam are contraindicated. Alternative benzodiazepines include temazepam and lorazepam.
NFV Ergot alkaloid Inhibition of hepatic metabolism Acute ergot toxicity characterized by peripheral vasospasm and ischemia of extremities Immediate Major Concurrent administration contraindicated.
NFV Terfenadine, Astemizole, Cisapride Inhibition of hepatic metabolism Drug levels increased by 3- fold or greater Immediate Major Concurrent administration contraindicated due to potential cardiac arrhythmia. Recommended alternative antihistamine: loratidine, fexofenadine, or cetirizine. Alternative pro-kinetic agent: metoclopramide.
NFV St. John’s wort Induction of hepatic metabolism by St. John's wort May decrease NFV serum level Delayed Major Co-administration is contraindicated.
NFV Oral contraceptives Induction of hepatic metabolism Ethinyl estradiol AUC decreased by 47% Delayed Major Advise patient to use alternative or additional method of contraception.
NFV Sildenafil Inhibition of hepatic metabolism Sildenafil AUC increased by 2-11 fold Immediate Major Caution with concurrent use. Do not exceed 25 mg of sildenafil in a 48-hour period.
NFV Phenobarbital, phenytoin, and carbamazepine Induction of hepatic metabolism May decrease serum levels of NFV. NFV may increase serum levels of anticonvulsants Delayed Moderate Consider alternative anticonvulsants (i.e valproic acid, levetiracetam, or topiramate). Monitor anticonvulsant level.
NFV Indinavir Inhibition of hepatic metabolism Indinavir AUC increased by 50% Nelfinavir AUC increased by 80% Immediate Minor Limited data for dosing IDV 1200 mg bid + NFV 1250 mg bid.
NFV Saquinavir Inhibition of hepatic metabolism Fortovase® AUC increased by 3–5 fold. Nelfinavir AUC increased by 20% Immediate Moderate Dose nelfinavir 750 mg tid and Fortovase 800 mg tid or 1200 mg bid.
NFV Amprenavir Inhibition of hepatic metabolism Nelfinavir AUC increased by 15%, Amprenavir AUC increased by 50% Immediate Minor Limited data: NFV 1250 mg bid plus APV 1200 mg bid.
NFV Ritonavir Inhibition of hepatic metabolism Nelfinavir AUC increased by 1.5 fold. Increase in Nelfinavir metabolite Immediate Moderate Limited data: ritonavir 400 mg bid and nelfinavir 500 mg or 750 mg bid. Boosting with ritonavir will yield only minimal pharmacokinetic enhancement of nelfinavir serum concentration.
NFV Lopinavir/r Induction of hepatic metabolism by NFV. Inhibition of hepatic metabolism by LPV/r LPV decreased by 33%. NFV increased 25% Delayed Moderate Consider increasing LPV/r dose to 4 caps bid with NFV co-administration.
NFV Nevirapine         No significant drug interaction. Use standard dose.
NFV Delavirdine Induction of hepatic metabolism Delavirdine AUC decreased by 50%. NFV AUC increased by 2-fold Immediate Minor Consider increasing DLV dose to 600 mg tid with standard dose NFV 1250 mg bid (limited data).
NFV Efavirenz Inhibition of hepatic metabolism NFV AUC increased by 20%. EFV levels unchanged Immediate Minor No significant drug interaction. Use standard dose.
NFV Voriconazole Potential for bi-directional interaction NFV and voriconazole may be increased Immediate Moderate Monitor for toxicities.
Amprenavir
(Agenerase®)
(APV)		 Rifampin Induction of hepatic metabolism Amprenavir AUC decreased by 80% Delayed Major Amprenavir AUC decreased by 80%.
APV Rifabutin Induction of hepatic metabolism Amprenavir AUC decreased by 14%.
Rifabutin AUC increased by 204%		 Delayed Moderate Dose rifabutin 150 mg qd or 300 mg 3x/week. No change in amprenavir dose.
APV Ketoconazole Inhibition of hepatic metabolism Amprenavir AUC increased by 32%.
Ketoconazole AUC increased by 44%		 Immediate Minor May be beneficial. No dose adjustment needed.
APV Clarithromycin Inhibition of hepatic metabolism Amprenavir AUC increased by 18% Immediate Minor Amprenavir AUC increased by 18%.
APV Oral contraceptives Induction of hepatic metabolism Potential decreases in ethinyl estradiol level Delayed Major Advise patient of potential risk and the use of an alternative or additional method of contraception.
APV Sildenafil Inhibition of hepatic metabolism Sildenafil AUC increased by 2-11 fold Immediate Major Caution with concurrent use, Do not exceed 25 mg of sildenafil in a 48-hour period.
APV Simvastatin/ Lovastatin Inhibition of hepatic metabolism Simvastatin and lovastatin levels increased Immediate Moderate Avoid concurrent administration. Alternative agents include atorvastatin, pravastatin, fluvastatin. Monitor for adverse effects due to limited clinical data.
APV St. John’s wort Induction of hepatic metabolism by St. John's wort May decrease APV serum level Delayed Major Co-administration is contraindicated.
APV Saquinavir Induction of hepatic metabolism Saquinavir level decreased by 18%.
Amprenavir level decreased by 36%		 Delayed Minor No dose adjustment. Insufficient data for dose recommendation.
APV Indinavir Inhibition of hepatic metabolism Amprenavir AUC increased by 33%.
Indinavir AUC decreased by 38%		 Immediate Minor No dose adjustment. IDV 800 mg tid plus APV 800 mg tid.
APV Nelfinavir Inhibition of hepatic metabolism Nelfinavir AUC increased by 15%,
Amprenavir AUC increased by 50%		 Immediate Minor No dose adjustment. NFV 750 mg tid plus APV 800 mg tid.
APV Ritonavir Inhibition of hepatic metabolism Amprenavir AUC increased by 2.5-fold Immediate Minor Dose: APV 600 bid/RTV 100 bid or APV 1200 mg qd /RTV 200 mg qd.
APV Lopinavir/r Inhibition of hepatic metabolism by APV. Inhibition of hepatic metabolism by LPV/r APV Cmin increased 5-fold. LPV AUC decreased 30–50% Delayed Moderate Dose: LPV/r 533 mg/133 mg (4 caps) + APV 750 mg bid (+/- EFV).
APV Efavirenz Induction of hepatic metabolism Amprenavir AUC decreased by 36%.
Efavirenz AUC increased by 15%		 Delayed Moderate Dose: APV 600 mg/ RTV 100 mg bid + EFV 600 mg qHS.
APV Nevirapine Induction of hepatic metabolism APV level may be significantly decreased     No Data.
APV Delavirdine Induction of hepatic metabolism by APV. Inhibition of hepatic metabolism by DLV DLV AUC decreased by 60% and trough decreased by 90%. APV AUC increased by 25% Delayed Major Co-administration not recommended.
APV Methadone Induction of hepatic metabolism Decreased serum level of inactive methadone (S)-isomer. No change in active methadone (R)-isomer Delayed Minor Use standard dose. No withdrawal symptoms observed.
APV Ergot alkaloid Inhibition of hepatic metabolism Acute ergot toxicity characterized by peripheral vasospasm and ischemia of extremities Immediate Major Concurrent administration contraindicated.
APV Midazolam,
Triazolam		 Inhibition of hepatic metabolism AUC of midazolam and triazolam are increased Immediate Major Concurrent administration contraindicated due to potential for prolonged sedation. Lorazepam and temazepam may be safe alternatives.
APV Terfenadine
Astemizole
Cisapride		 Inhibition of hepatic metabolism Cardiotoxic drug level increased by 3-fold or greater Immediate Major Concurrent administration contraindicated due to potential for cardiac arrhythmias. Alternatives include loratidine, fexofenadine, or cetirizine. Alternative pro-kinetic agent includes metoclopramide.
APV Amiodarone, lidocaine (systemic), quinidine, and bepridil   May increase serum level of antiarrhythmics Immediate Moderate Use with caution. Monitor antiarrhythmic serum level.
APV Pimozide   May increase serum level of pimozide Immediate Major Contraindicated. Potential for life-threatening cardiac arrhythmia.
APV Calcium channel blocker   May increase serum level of calcium channel blocker Immediate Moderate Use with caution. Close monitoring recommended.
APV Dexamethasone   May decrease APV serum level Delayed Moderate Use with caution.
APV Cyclosporine, tacrolimus, rapamycin   May increase immunosuppressant serum level Immediate Moderate Therapeutic drug monitoring of immunosuppressant highly recommended.
APV Amitriptyline, imipramine, and desipramine   May increase TCA serum level Immediate Moderate Consider therapeutic drug monitoring or use SSRI (i.e. citalopram, sertraline, or fluoxetine).
APV Phenytoin, carbamazepine, and phenobarbital   May significantly decrease APV serum level Delayed Moderate Consider alternative anticonvulsant (i.e. valproic acid, levetiracetam, or topiramate). Monitor anticonvulsant level.
APV Didanosine May interfere with absorption APV serum level may be decreased Immediate Moderate Dosing should be separated by 1 hour.
APV Warfarin Unknown Increase or decrease in warfarin Immediate Moderate INR must be monitored.
APV Voriconazole Potential for bi-directional interaction (or induction with RTV co-administration) Voriconazole may be decreased with RTV co-administration. APV may be increased Immediate Moderate Monitor for toxicities and therapeutic efficacy.
APV Bepridil Inhibition of hepatic metabolism May increase bepridil Immediate Moderate Use with caution.
APV Tadalafil Inhibition of hepatic metabolism May substantially increase tadalafil AUC and half life Immediate Moderate Start with 5 mg dose; do not exceed a single 10 mg dose of tadalafil in 72 hrs.
APV Vardenafil Inhibition of hepatic metabolism May increase vardenafil AUC Immediate Moderate Start with a 2.5 mg dose; do not exceed a 2.5 mg dose of vardenafil in 72 hrs.
APV Atorvastatin Inhibition of hepatic metabolism May increase atorvastatin substantially Immediate Moderate Use lowest possible starting dose of atorvastatin with careful monitoring.

AUC= Area Under the Concentration Time Curve
Cmax = Peak serum concentration
Cmin = Trough serum concentration
CrCl = Creatinine clearance
TDM = Therapeutic drug monitoring

Time course:

Delayed = maximal interaction occurring at 14 days
Immediate = interaction occurring immediately

Severity:

Major = Do not co-administer; contraindicated.
Moderate = Can be co-administered with caution and possible dose adjustment.
Minor = Can be co-administered.

Table 14-6e: Drug Interactions of Antiretrovirals (Fosamprenavir)  TOP
Primary Drug Interacting Drug Mechanism of Interaction Effect Time course Severity Comments / management recommendation
Fosamprenavir drug-drug interactions
Since fosamprenavir is converted to amprenavir, all drug interaction data for “unboosted” amprenavir should also apply to “unboosted” fosamprenavir. However, there are some interactions that are more pronounced with fosamprenavir.
fAVP LPV/r Enzyme induction Significant decrease in levels of both LPV and APV Delayed Major Boosting with RTV still resulted in significant reduction of APV trough at standard dose. Best PK data with fAPV 1400 mg bid and LPV/r 533 mg/133 mg bid.
fAVP/r EFV Enzyme induction APV Cmin decreased by 17% (90% CI 4–29%) with bid vs. 36% (90% CI 8–56%) with qd fAPV dosing Delayed Moderate Recommended Dose: fAPV 700 mg bid/RTV 100 mg bid or fAPV 1400 mg qd/RTV 300 mg qd.
fAVP Atorvastatin Enzyme inhibition Atorvastatin AUC increased by 130% (with fAPV 1400 mg bid) and 150% (with fAPV 700 mg/RTV 100 mg bid). No change in APV AUC Immediate Moderate Close monitoring recommeded. Do not exceed 20 mg per day of atorvastatin.
fAVP/r Ritonavir Enzyme inhibition Amprenavir AUC increased by over 2-fold. Cmin increased by 4-fold with daily administration and 6-fold with twice daily administration compared to fAPV 1400 mg bid Immediate Minor Dose: fAPV 700 mg bid/RTV 100 mg bid or fAPV 1400 mg qd/RTV 200 mg qd.
Lopinavir/r Methadone Induction of hepatic metabolism Methadone AUC decreased by 53% Delayed Minor No withdrawal symptoms observed in 2 out of 3 studies. Standard dose recommended. Monitor and increase dose of methadone if needed.
LPV/r Rifampin Induction of hepatic metabolism LPV AUC decreased 75% Delayed Major Concurrent administration contraindicated. Consider using rifabutin with LPV/r.
LPV/r Rifabutin Inhibition of hepatic metabolism by LPV/r Rifabutin serum level increased by 3-fold. LPV serum level not affected Immediate Moderate

Dose: LPV/r 3 caps bid plus rifabutin 150 mg qod or
150mg 3x/week.
LPV/r Ergot alkaloid Inhibition of hepatic metabolism Acute ergot toxicity characterized by peripheral vasospasm and ischemia of extremities Immediate Major Concurrent administration contraindicated.
LPV/r Terfenadine
Astemizole
Cisapride		 Inhibition of hepatic metabolism Drug level increased by 3-fold or greater Immediate Major Concurrent administration contraindicated due to potential for cardiac arrhythmias. Alternative antihistamines include loratidine, fexofenadine, or cetirizine. Alternative pro-kinetic agent includes metoclopramide.
LPV/r St. John’s wort Induction of hepatic metabolism by St. John’s wort May decrease LPV serum level Delayed Major Co-administration is contraindicated.
LPV/r Benzodiazepines Inhibition of hepatic metabolism Prolonged sedation due to accumulation of benzodiazepine Delayed Major Concurrent administration of midazolam and triazolam are contraindicated. Alternative benzodiazepine that can be used: Temazepam, oxazepam, and lorazepam.
LPV/r Antidepressants (TCA, SSRIs, Bupropion) See RTV section        
LPV/r Antiarrhythmics Inhibition of hepatic metabolism AUC of antiarrhythmics increased Immediate Major Concurrent administration of propafenone, flecainide, and encainide are contraindicated.
LPV/r Antipsychotic (Pimozide) Inhibition of hepatic metabolism May significantly increase pimozide serum level resulting in QTc prolongation Immediate Major Concurrent administration of pimozide is contraindicated.
LPV/r Simvastatin/ Lovastatin Inhibition of hepatic metabolism Serum levels of simvastatin and lovastatin are increased Immediate Moderate Avoid co-administration, alternatives that may be used include pravastatin, fluvastatin. Monitor for adverse effects due to limited clinical data.
LPV/r Phenytoin
(also carbamazepine and phenobarbital)		 Induction of hepatic metabolism LPV decreased by 33%. Phenytoin decreased by 31% Delayed Major Consider alternative anticonvulsants. Consider TDM. Monitor anticonvulsant levels with co-administration.
LPV/r Atorvastatin Inhibition of hepatic metabolism Atorvastatin AUC increased by 6-fold Immediate Moderate Clinical significance unknown. Use with caution. Starting dose atorvastatin 10 mg qd.
LPV/r Indinavir Inhibition of hepatic metabolism Indinavir AUC increased by 3-fold Immediate Moderate Dose: IDV 600 mg or 666 mg bid plus LPV/r 400 mg/100 mg bid.
LPV/r Amprenavir Induction of hepatic metabolism by APV. Inhibition of hepatic metabolism by LPV/r APV Cmin increased 5-fold. LPV AUC decreased 30–50% Delayed Moderate Dose: LPV/r 533 mg/133 mg
(4 caps) + APV 750 mg bid.
LPV/r Efavirenz Induction of hepatic metabolism LPV AUC decreased by 40% Delayed Major Dose: LPV/r 533 mg/133 mg
(4 caps) bid + EFV 600 mg qhs.
LPV/r Delavirdine Inhibition of hepatic metabolism LPV AUC increased by 8–134%. DLV no change Immediate Minor Limited data. No dose adjustment.
LPV/r Nevirapine Induction of hepatic metabolism LPV Cmin decreased by 55%. NVP level not affected Delayed Major Dose: LPV/r 533 mg/133 mg
(4 caps) bid (NVP standard dose).
LPV/r Saquinavir Inhibition of hepatic metabolism Saquinavir Cmin increased by 3–6-fold Immediate Minor Dose: SQV 1000 mg bid plus LPV/r 400/100 mg bid.
LPV/r Nelfinavir Induction of hepatic metabolism LPV decreased by 33%. NFV increased 25% Delayed Moderate Consider increasing LPV/r dose to 4 caps bid with NFV co-administration.
LPV/r Itraconazole Inhibition of hepatic metabolism May increase itraconazole serum level Immediate Moderate Use with caution; do not exceed 200 mg itraconazole.
LPV/r Voriconazole Induction of hepatic metabolism May decrease voriconazole serum level Immediate Moderate Monitor for toxicities and therapeutic efficacy. Co-administration not recommended by manufacturer.
LPV/r Vardenafil Inhibition of hepatic metabolism May substantially increase vardenafil AUC Immediate Moderate Start with a 2.5 mg dose; do not exceed a 2.5 mg dose of vardenafil in 72 hrs.
LPV/r Ethinyl estradiol Induction of hepatic metabolism EE AUC decreases 42%     Use alternative or additional method.
Atazanavir (ATV) Clarithromycin Inhibition of hepatic metabolism ATV AUC increased by 28%.
Clarithromycin AUC increased by 94%. Clarithromycin hydroxy-metabolite AUC decreased by 30%		 Immediate Major QTc prolongation observed with co-administration. 50% of clarithromycin dose recommended.
ATV ddI (buffered) Interference with absorption No effect on ddI serum level. ATV AUC decreased by 87% Immediate

Major

 Administer ATV 400 mg one hour after ddI (buffered) administration. Consider ddI EC.
ATV EFV Induction of hepatic metabolism (Inhibition of hepatic metabolism with RTV boosting) ATV AUC decreased by 74%. EFV not measured
(ATV AUC increased by 39% with RTV boosting)		 Delayed
 
 
(Immediate)		 Major
 
 
(Minor) 		Co-administration of ATV as a sole PI with EFV is not recommended. Boosting ATV 300 mg with 100 mg RTV recommended with EFV co-administration (doubles total ATV exposure and increases ATV trough by 300%).
ATV Oral contraceptives Inhibition of glucuronidation Ethinyl estradiol AUC increased by 48%. Norethindrone AUC increased by 110%. ATV not measured Delayed Minor Clinical significance unknown. Monitor for adverse reactions with oral contraceptive; consider alternative method of contraception.
ATV Diltiazem Inhibition of hepatic metabolism Diltiazem AUC increased by 125%. Desacetyl diltiazem (active metabolite) AUC increased by 165%. ATV not affected Immediate Major Increase in PR interval observed.
Use with caution. Start with 50% of diltiazem dose and titrate slowly. Monitor BP and pulse.
ATV Atenolol Inhibition of hepatic metabolism Atenolol AUC increased by 25%. ATV not affected Immediate Moderate No effect on PR or QTc interval with co-administration.
Monitor BP and pulse.
ATV Rifabutin Inhibition of hepatic metabolism Rifabutin AUC increased. ATV not affected Immediate Moderate Dose: ATV 400 mg qd plus rifabutin 150 mg 3x/week.
ATV SQV Inhibition of hepatic metabolism SQV AUC increased by 5.5-fold. ATV not affected Immediate Minor Beneficial PK interactions which allows once-a-day administration of SQV 1200 mg.
ATV AZT/3TC No effect AZT and 3TC not affected. ATV not measured     Standard dose AZT/3TC with ATV.
ATV Ketoconazole No effect ATV not affected. Ketoconazole not measured     Standard dose ATV with ketoconazole co-administration.
ATV Tenofovir Interference with absorption ATV AUC decreased by 25%. TDF not measured Immediate Moderate Interaction likely to occur due to interference with absorption. ATV dose 300 mg qd + RTV 100 mg qd with co-administration.
ATV Rifampin Induction of hepatic metabolism ATV may be decreased Delayed Moderate Rifabutin may be a safer alternative. Dose: ATV 400 mg qd plus rifabutin 150 mg 3x/week.
ATV Ergot alkaloid Inhibition of hepatic metabolism Acute ergot toxicity characterized by peripheral vasospasm and ischemia of extremities may be observed Immediate Major Concurrent administration contraindicated until more data become available.
ATV Terfenadine
Astemizole
Cisapride		 Inhibition of hepatic metabolism Drug level may be increased by 3-fold or greater Immediate Major Concurrent administration contraindicated until more data become available.
ATV St. John’s wort Induction of hepatic metabolism by St. John’s wort May decrease ATV serum level Delayed Major Concurrent administration contraindicated until more data become available.
ATV Benzodiazepines Inhibition of hepatic metabolism May prolong sedation due to accumulation of benzodiazepine Delayed Major Concurrent administration of midazolam and triazolam are contraindicated until more data become available. Alternative benzodiazepine that can be used: Temazepam, oxazepam, and lorazepam.
ATV Antiarrhythmics Inhibition of hepatic metabolism AUC of antiarrhythmics increased Immediate Major Concurrent administration of propafenone, quinidine, flecainide, encainide, amiodarone, and bepridil are contraindicated until more data become available.
ATV Proton-pump inhibitors Decreased absorption ATV Significantly decreases ATV levels Immediate Major Avoid concomitant use.
ATV Phenobarbital, phenytoin, and carbamazepine Induction of hepatic metabolism May decrease serum levels of ATV. ATV may increase serum levels of anticonvulsants Delayed Moderate Consider alternative anticonvulsant (i.e. valproic acid, levetiracetam, or topiramate). Monitor anticonvulsant level. Carbamazepine toxicity has been reported.
ATV Methadone         No data.
ATV Nevirapine No Data       Consider using ATV 300 mg + RTV 100 mg qd.
ATV Ritonavir Induction of hepatic metabolism ATV AUC increases by 238% Immediate Minor Use ATV 300 mg + RTV 100 mg.
ATV Warfarin Unknown May increase in warfarin concentration Delayed Moderate Monitor INR.
ATV Amitryptiline Imipramine Inhibition of hepatic metabolism May increase tricyclic concentration Immediate Minor Monitor tricyclic antidepressant concentration.
ATV Voriconazole Potential for bi-directional inhibition and/or induction May decrease voriconazole serum level with RTV co-administration Delayed Moderate Monitor for toxicities and therapeutic efficacy.
ATV Sildenafil Inhibition of hepatic metabolism May increase sildenafil AUC Immediate Moderate Use with caution; start with reduced dose of 25 mg q48h and monitor for adverse affects.
ATV Tadalafil Inhibition of hepatic metabolism May substantially increase tadalafil AUC Immediate Moderate Start with 5 mg dose; do not exceed a single 10 mg dose of tadalafil in 72 hrs.
ATV Vardenafil Inhibition of hepatic metabolism May substantially increase vardenafil AUC Immediate Moderate Start with a 2.5 mg dose; do not exceed a 2.5 mg dose of vardenafil in 72 hrs.
ATV H2 receptor antagonist Interference with absorption May significantly decrease ATV concentration Immediate Moderate Separate ATV concentration by 12 hrs.
ATV Atorvastatin Inhibition of hepatic metabolism May increase atorvastatin substantially Immediate Moderate Use lowest possible starting dose (10 mg) of atorvastatin with careful monitoring.
Tipranavir/ ritonavir
(currently in Phase III trials)		 Efavirenz   No change in EFV PK, TPV PK (at 500/100 mg dose)     Phase II trials are currently using TPV500/200 mg with the co-administration of EFV (Roszko, 2003).
TPV/r AZT   AZT AUC decreased by 40%. No change in TPV PK   Minor Clinical significance unknown.
TPV/r ddI EC   No Interactions     Separate administration time by 4 hours due to potential interaction of self emulsifying drug delivery system (SEDDS) of TPV and the ddI EC outer coat.
TPV/r Tenofovir   TPV AUC decreased by 20% (with TPV 500 mg/100 mg)   Minor Reduction of TPV may be due to decrease in RTV. TPV 500 mg/200 mg should be considered.
TPV/r LPV/r   LPV AUC decreased by 49%   Major Do not co-administer.
TPV/r APV   APV AUC decreased by 45%   Major Do not co-administer.
TPV/r SQV   SQV AUC decreased by 70%   Major Do not co-administer.

AUC= Area Under the Concentration Time Curve
Cmax = Peak serum concentration
Cmin = Trough serum concentration
CrCl = Creatinine clearance
TDM = Therapeutic drug monitoring

Time course:

Delayed = maximal interaction occurring at 14 days
Immediate = interaction occurring immediately

Severity:

Major = Do not co-administer; contraindicated.
Moderate = Can be co-administered with caution and possible dose adjustment.
Minor = Can be co-administered.

Table 14-6f: Drug Interactions of Antiretrovirals (FIs)  TOP
Primary Drug Interacting Drug Mechanism of Interaction Effect Time course Severity Comments / management recommendation
Drug Interactions with Fusion Inhibitors
Fuseon No significant drug interactions          

AUC= Area Under the Concentration Time Curve
Cmax = Peak serum concentration
Cmin = Trough serum concentration
CrCl = Creatinine clearance
TDM = Therapeutic drug monitoring

Time course:

Delayed = maximal interaction occurring at 14 days
Immediate = interaction occurring immediately

Severity:

Major = Do not co-administer; contraindicated.
Moderate = Can be co-administered with caution and possible dose adjustment.
Minor = Can be co-administered.