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Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents

Drug Interactions

Drug Interactions between Integrase Inhibitors and Other Drugs

(Last updated:2/12/2013; last reviewed:2/12/2013)

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Raltegravir (RAL) is expected to have fewer drug interactions than elvitegravir/cobicistat (EVG/COBI) (see Drug Interactions text). In the following table, where RAL is not listed, no data currently exists and there is either no dosage recommendation or no dosage adjustment is necessary when RAL is used with the concomitant medication.

Table 15d. Drug Interactions between Integrase Inhibitors and Other Drugs
Concomitant Drug
Class/Name 
Integrase Inhibitor Effect on Integrase Inhibitor or Concomitant Drug Concentrations Dosing Recommendations and Clinical Comments 
Acid Reducers
Antacids EVG/COBI/TDF/FTC EVG AUC ↓ 15%−20% if given 2 hours before or after antacid;

←→with 4-hour interval
 Separate EVG/COBI/FTC/TDF and antacid administration by more than 2 hours
H2-Receptor Antagonists EVG/COBI/TDF/FTC No significant effect No dosage adjustment necessary.
Proton Pump Inhibitors EVG/COBI/TDF/FTC No significant effect No dosage adjustment necessary.
RAL RAL AUC ↑ 212%, Cmax 315%, and Cmin ↑ 46% No dosage adjustment necessary.
Anticoagulants
Warfarin EVG/COBI/TDF/FTC No data: but warfarin levels may be affected Monitor INR and adjust warfarin dose accordingly.
Anticonvulsants
Carbamazepine
Oxcarbazepine
Phenobarbital
Phenytoin
EVG/COBI/TDF/FTC ↑ carbamazepine possible
↓ EVG possible
↓ COBI possible
Consider alternative anticonvulsant.
Ethosuximide EVG/COBI/TDF/FTC ↑ ethosuximide possible Clinically monitor for ethosuxamide toxicities.
Antidepressants
Selective Serotonin Reuptake Inhibitors (SSRIs) EVG/COBI/TDF/FTC ↑ SSRI possible Initiate with lowest dose of SSRI and titrate dose carefully based on antidepressant response.
Tricyclic Antidepressants (TCAs)
   Amitriptyline
   Desipramine
   Imipramine
   Nortriptyline
EVG/COBI/TDF/FTC Desipramine AUC ↑ 65% Initiate with lowest dose and titrate dose of TCA carefully.
Trazodone EVG/COBI/TDF/FTC ↑ trazodone possible Initiate with lowest dose and titrate dose of trazodone carefully.
Antifungals
Itraconazole EVG/COBI/TDF/FTC ↑ itraconazole expected
↑ EVG and COBI possible
Consider monitoring itraconazole level to guide dosage adjustments. High doses (>200 mg/day) are not recommended unless dose is guided by itraconazole levels.
Posaconazole EVG/COBI/TDF/FTC ↑ EVG and COBI possible
↑ posaconazole possible
Monitor posaconazole concentrations with co-administration.
Voriconazole EVG/COBI/TDF/FTC ↑ voriconazole expecte
↑ EVG and COBI possible
Risk/benefit ratio should be assessed to justify use of voriconazole. If administered, consider monitoring voriconazole level. Adjust dose accordingly.
Antimycobacterials
Clarithromycin EVG/COBI/TDF/FTC ↑ clarithromycin possible
↑ COBI possible
CrCl ≥60 mL/min: No dose adjustment necessary
CrCl 50−60 mL/min: Reduce clarithromycin dose by 50%
CrCl <50 mL/min: EVG/COBI/TDF/FTC is not recommended.
Rifabutin EVG/COBI/TDF/FTC Rifabutin (150 mg every other day):
No significant change in rifabutin AUC;
For 25-O-desacetyl-rifabutin, AUC ↑ 625% compared with rifabutin (300 mg daily) administered alone


EVG AUC ↓ 21%, Cmin ↓ 67%
Do not co-administer.
RAL RAL AUC ↑ 19%, Cmax ↑ 39%, and Cmin ↓ 20% No dosage adjustment necessary.
Rifampin EVG/COBI/TDF/FTC Significant ↓ EVG and COBI expected Do not co-administer.
RAL RAL 400 mg: RAL AUC ↓ 40% and Cmin ↓ 61%

Rifampin with RAL 800 mg BID compared with RAL 400 mg BID alone: RAL AUC ↑ 27% and Cmin ↓ 53%
Dose: RAL 800 mg BID
Monitor closely for virologic response or consider using rifabutin as an alternative rifamycin
Rifapentine EVG/COBI/TDF/FTC Significant ↓ EVG and COBI expected Do not co-administer.
Benzodiazepines
Clonazepam
Clorazepate
Diazepam
Estazolam
Flurazepam
EVG/COBI/TDF/FTC ↑ benzodiazepines possible Dose reduction of benzodiazepine may be necessary. Initiate with low dose and clinically monitor. Consider alternative benzodiazepines to diazepam, such as lorazepam, oxazepam, or temazepam.
Midazolam
Triazolam
EVG/COBI/TDF/FTC ↑ midazolam expected
↑ triazolam expected
Do not co-administer triazolam or oral midazolam and EVG/COBI. Parenteral midazolam can be used with caution in a closely monitored setting. Consider dose reduction, especially if >1 dose is administered.
Cardiac Medications
Anti-Arrhythmics
(amiodarone, bepridil, digoxin, disopyramide, dronedarone, flecainide, systemic lidocaine, mexilitine, propafenone, quinidine)
EVG/COBI/TDF/FTC ↑ anti-arrhythmics possible

digoxin Cmax ↑ 41%, AUC no significant change
Use anti-arrhythmics with caution. Therapeutic drug monitoring, if available, is recommended for anti arrhythmics.
Bosentan EVG/COBI/TDF/FTC ↑ bosentan possible In patients on EVG/COBI/FTC/TDF ≥10 days: start bosentan at 62.5 mg once daily or every other day based on individual tolerability. In patients on bosentan who require EVG/COBI/FTC/TDF: stop bosentan ≥36 hours before EVG/COBI/FTC/TDF initiation. After at least 10 days following initiation of EVG/COBI/FTC/TDF, resume bosentan at 62.5 mg once daily or every other day based on individual tolerability.
Beta-blockers EVG/COBI/TDF/FTC ↑ beta-blockers possible Adjust beta-blockers according to clinical response. Beta-blocker dose may need to be decreased. Some beta-blockers are metabolized via CYP450 pathway (e.g., metoprolol, timolol). Consider using other beta-blockers (e.g., atenolol, labetalol, nadolol, sotalol) as these agents are not metabolized by CYP450 enzymes.
Dihydropyridine and Non-Dihydropyridine Calcium Channel Blockers EVG/COBI/TDF/FTC ↑ CCBs possible Co-administer with caution. Monitor for CCB efficacy and toxicities.
Corticosteroids
Dexamethasone EVG/COBI/TDF/FTC ↓ EVG and COBI possible Co-administer with caution, monitor HIV virologic response
Fluticasone (inhaled/intranasal) EVG/COBI/TDF/FTC ↑ fluticasone possible Use alternative inhaled corticosteroid, particularly for long-term use
Hepatitis C NS3/4A—Protease Inhibitors
Boceprevir EVG/COBI/TDF/FTC No data Do not co-administer.
RAL No significant effect No dosage adjustment necessary.
Telaprevir EVG/COBI/TDF/FTC No data Do not co-administer.
RAL RAL AUC ↑ 31%
Telaprevir ←→
No dosage adjustment necessary.
Hormonal Contraceptives
Hormonal contraceptives RAL No clinically significant effect Safe to use in combination
Norgestimate/ethinyl estradiol EVG/COBI/TDF/FTC Norgestimate AUC, Cmax, Cmin ↑ >2-fold

Ethinyl estradiol AUC ↓ 25%, Cmin ↓ 44%
The effects of increases in progestin (norgestimate) are not fully known and can include insulin resistance, dyslipidemia, acne, and venous thrombosis. Weigh the risks and benefits of the drug, and consider alternative contraceptive method.
HMG-CoA Reductase Inhibitors
Atorvastatin EVG/COBI/TDF/FTC ↑ atorvastatin possible Titrate statin dose slowly and use the lowest dose possible.
Lovastatin EVG/COBI/TDF/FTC Significant ↑ lovastatin expected Contraindicated. Do not co-administer.
Pitavastatin
Pravastatin
EVG/COBI/TDF/FTC No data No dosage recommendation
Rosuvastatin EVG/COBI/TDF/FTC Rosuvastatin AUC ↑ 38% and Cmax ↑ 89% Titrate statin dose slowly and use the lowest dose possible.
Simvastatin EVG/COBI/TDF/FTC Significant ↑ simvastatin expected Contraindicated. Do not co-administer.
Immunosuppressants
Cyclosporine
Sirolimus
Tacrolimus
EVG/COBI/TDF/FTC ↑ immunosuppressant possible Initiate with an adjusted immunosuppressant dose to account for potential increased concentrations and monitor for toxicities. Therapeutic drug monitoring of immunosuppressant is recommended. Consult with specialist as necessary.
Narcotics/Treatment for Opioid Dependence
Buprenorphine EVG/COBI/TDF/FTC Buprenorphine: AUC ↑ 35%, Cmax ↑ 12%, Cmin ↑ 66%

Norbuprenorphine: AUC ↑ 42%,
Cmax ↑ 24%, Cmin ↑ 57%
No dosage adjustment necessary. Clinical monitoring is recommended.
RAL No significant effect No dosage adjustment necessary.
Methadone EVG/COBI/TDF/FTC No significant effect No dosage adjustment necessary.
 RAL No significant effect No dosage adjustment necessary.
Neuroleptics
Perphenazine
Risperidone
Thioridazine
EVG/COBI/TDF/FTC ↑ neuroleptic possible Initiate neuroleptic at low dose. Decrease in neuroleptic dose may be necessary.
Phosphodiesterase Type 5 (PDE5) Inhibitors
Avanafil EVG/COBI/TDF/FTC No data Co-administration is not recommended.
Sildenafil EVG/COBI/TDF/FTC ↑ sildenafil expected For treatment of erectile dysfunction:
Start with sildenafil 25 mg every 48 hours and monitor for adverse effects of sildenafil.
For treatment of PAH:

Contraindicated
Tadalafil EVG/COBI/TDF/FTC ↑ tadalafil expected For treatment of erectile dysfunction
Start with tadalafil 5-mg dose and do not exceed a single dose of 10 mg every 72 hours. Monitor for adverse effects of tadalafil.
For treatment of PAH
In patients on a EVG/COBI >7 days:
Start with tadalafil 20 mg once daily and increase to 40 mg once daily based on tolerability.
In patients on tadalafil who require EVG/COBI:
Stop tadalafil ≥24 hours before EVG/COBI initiation. Seven days after EVG/COBI initiation restart tadalafil at 20 mg once daily, and increase to 40 mg once daily based on tolerability.
Vardenafil EVG/COBI/TDF/FTC ↑ vardenafil expected Start with vardenafil 2.5 mg every 72 hours and monitor for adverse effects of vardenafil.
Sedatives/Hypnotics
Buspirone EVG/COBI/TDF/FTC ↑ buspirone possible Initiate buspirone at a low dose. Dose reduction may be necessary.
Zolpidem EVG/COBI/TDF/FTC ↑ zolpidem possible Initiate zolpidem at a low dose. Dose reduction may be necessary.
Miscellaneous Interactions
Colchicine EVG/COBI/TDF/FTC ↑ colchicine expected Do not co-administer in patients with hepatic or renal impairment. For treatment of gout flares:
Colchicine 0.6 mg x 1 dose, followed by 0.3 mg 1 hour later. Do not repeat dose for at least 3 days.
For prophylaxis of gout flares:
If original regimen was colchicine 0.6 mg BID, the regimen should be decreased to 0.3 mg once daily. If regimen was 0.6 mg once daily, the regimen should be decreased to 0.3 mg every other day.
For treatment of familial Mediterranean fever:
Do not exceed colchicine 0.6 mg once daily or 0.3 mg BID.
Salmeterol EVG/COBI/TDF/FTC ↑ salmeterol possible Do not co-administer because of potential increased risk of salmeterol-associated cardiovascular events.

Key to Abbreviations: AUC = area under the curve, BID = twice daily, CCB = calcium channel blocker, COBI = cobicistat, Cmax = maximum plasma concentration, Cmin = minimum plasma concentration, EVG = elvitegravir, PAH = pulmonary arterial hypertension, RAL = raltegravir