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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: May 1, 2014; last reviewed: May 1, 2014)

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Table 18d. Drug Interactions between Integrase Strand Transfer Inhibitors and Other Drugs
Concomitant Drug
Class/Name 
INSTI Effect on INSTI or Concomitant Drug Concentrations Dosing Recommendations and Clinical Comments 
Acid Reducers
Aluminium, Magnesium 
+/- 
Calcium Containing Antacids

Please refer to the Miscellaneous Interactions section below for recommendations on use with other polyvalent cation products (e.g., iron, calcium supplements, multivitamins).
DTG DTG AUC ↓ 74% if given simultaneously; DTG AUC ↓ 26% if given 2 hours before antacid  Give DTG at least 2 hours before or at least 6 hours after medications containing polyvalent cations.
EVG/cobi/TDF/FTC
EVG AUC ↓ 40% to 50% if given simultaneously, ↓ 15% to 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.
RAL Al-Mg Hydroxide Antacid
RAL Cmin ↓ 54% to 63% if given simultaneously or 2 hours before or after antacid

CaCO3 Antacid
RAL AUC ↓ 54%, Cmin ↓ 32%
Do not co-administer RAL and Al-Mg hydroxide antacids either simultaneously or within 2 hours.

No dosing separation necessary when co-administering RAL and CaCO3 antacids.
H2-Receptor Antagonists EVG/cobi/TDF/FTC No significant effect No dosage adjustment necessary.
Proton Pump Inhibitors DTG No significant effect
No dosage adjustment necessary.
EVG/cobi/TDF/FTC No significant effect No dosage adjustment necessary.
RAL RAL AUC ↑ 212%, 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
DTG DTG possible
Consider alternative anticonvulsant.
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
SSRIs EVG/cobiTDF/FTC ↑ SSRI possible Initiate with lowest dose of SSRI and titrate dose carefully based on antidepressant response.
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
If co-administered, monitor posaconazole concentrations 
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 is necessary.

CrCl 50−60 mL/min:
Reduce clarithromycin dose by 50%.

CrCl <50 mL/min:
EVG/cobi/TDF/FTC is not recommended.
Rifabutin DTG Rifabutin (300 mg once daily):
DTG AUC ↔, Cmin 30%
No dosage adjustment necessary.
EVG/cobi/TDF/FTC Compared with rifabutin (300 mg daily) administered alone, when rifabutin (150 mg every other day) administered with EVG/cobi/TDF/FTC, no significant change in rifabutin AUC; 

For 25-O-desacetyl-rifabutin, AUC ↑ 625% 

EVG AUC 21%, Cmin 67%
Do not co-administer.
RAL RAL AUC ↑ 19%, Cmin ↓ 20% No dosage adjustment necessary.
Rifampin DTG Rifampin with DTG 50 mg BID Compared with DTG 50 mg BID Alone
DTG AUC ↓ 54%, Cmin ↓ 72%

Rifampin with DTG 50 mg BID Compared with DTG 50 mg Once Daily Alone
DTG AUC ↑ 33%, Cmin ↑ 22%
Dose: DTG 50 mg BID (instead of 50 mg once daily) for patients without suspected or documented INSTI mutation. 

Avoid concomitant use in patients with certain suspected or determined INSTI-associated resistance substitutions. Consider using rifabutin.
EVG/cobi/TDF/FTC Significant ↓ EVG and cobi expected Do not co-administer.
RAL RAL 400 mg
RAL AUC ↓ 40%, Cmin ↓ 61% 

Compared with RAL 400 mg BID Alone, Rifampin with RAL 800 mg BID
RAL AUC ↑ 27%, 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
DTG DTG 25 mg
midazolam AUC ↔
No dosage adjustment necessary.
EVG/cobi/TDF/FTC ↑ midazolam expected
↑ triazolam expected
Do not co-administer triazolam or oral midazolam and EVG/cobi/TDF/FTC.

Parenteral midazolam can be used with caution in a closely monitored setting. Consider dose reduction, especially if more than one 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 (e.g., metoprolol, timolol) are metabolized via CYP450 pathway. Consider using other beta-blockers (e.g., atenolol, labetalol, nadolol, sotalol) as these agents are not metabolized by CYP450 enzymes.
Dofetilide
DTG ↑ dofetilide expected
Do not co-administer.
Dihydropyridine and Non-Dihydropyridine CCBs 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 Co-administration may result in adrenal insufficiency, including Cushing’s syndrome. Consider alternative therapy (e.g., beclomethasone), particularly for long-term use.
Methylprednisolone, Prednisolone, Triamcinolone 
Local injections, including intra-articular, epidural, intra-orbital
EVG/cobi/TDF/FTC
↑ glucocorticoids expected
Co-administration may result in adrenal insufficiency, including Cushing’s syndrome. Do not co-administer.

Consider alternative non-steroidal therapies. If intra-articular corticosteroid therapy required, change to alternative non-CYP3A-modulating ART (e.g., RAL, DTG).
Hepatitis C NS3/4A—PIs
Boceprevir DTG DTG AUC ↔
No dosage adjustment necessary.
EVG/cobi/TDF/FTC No data Do not co-administer.
RAL No significant effect No dosage adjustment necessary.
Simeprevir
EVG/cobi/TDF/FTC
↑ simeprevir expected
Co-administration is not recommended.
RAL No significant effect
No dosage adjustment necessary.
Telaprevir DTG DTG AUC ↑ 25%
No dosage adjustment necessary.
EVG/cobi/TDF/FTC EVG AUC ↓ 31%, Cmin ↑ 29%

Telaprevir AUC ↔
No dosage adjustment necessary.
RAL RAL AUC ↑ 31%
Telaprevir
No dosage adjustment necessary.
Herbal Products
St. John’s Wort
DTG ↓ DTG possible
Do not co-administer.
Hormonal Contraceptives
Hormonal Contraceptives RAL No clinically significant effect Safe to use in combination
Norgestimate/ethinyl estradiol DTG No significant effect
No dosage adjustment necessary.
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%, 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 DTG No significant effect
No dosage adjustment necessary.
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.
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 EVG/cobi/TDF/FTC >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/TDF/FTC:
Stop tadalafil ≥24 hours before EVG/cobi/TDF/FTC initiation. Seven days after EVG/cobi/TDF/FTC 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 for 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.
Metformin
DTG ↑ metformin possible
Monitor clinically when starting or stopping DTG. Dose adjustment of metformin may be necessary.
Polyvalent Cations 
Mg, Al, Fe, Ca, Zn, including multivitamins with minerals
All INSTIs
↓ INSTI possible if co-administered with these products
Give INSTI at least 2 hours before or at least 6 hours after medications containing polyvalent cations, including but not limited to the following products: cation-containing antacids or laxatives; iron, calcium, or magnesium supplements; and sucralfate. 

Many oral multivitamins also contain varying amounts of polyvalent cations. 

Exception: No dosing separation necessary when co-administering RAL and CaCO3 antacids.
Quetiapine
EVG/cobi/TDF/FTC
↑ quetiapine AUC expected. 
Initiation of Quetiapine in a Patient Receiving EVG/cobi/TDF/FTC:
Start quetiapine at the lowest dose and titrate up as needed. Monitor for quetiapine efficacy and adverse effects. 

Initiation of EVG/cobi/TDF/FTC in a Patient Receiving a Stable Dose of Quetiapine:
Reduce quetiapine dose to 1/6 of the original dose, and closely monitor for quetiapine efficacy and adverse effects.
Salmeterol EVG/cobi/TDF/FTC ↑ salmeterol possible Do not co-administer because of potential increased risk of salmeterol-associated cardiovascular events.

Key to Acronyms: Al = aluminum; ART = antiretroviral therapy; AUC = area under the curve; BID = twice daily; Ca = calcium; CaCO3 = calcium carbonate; CCB = calcium channel blocker; Cmax = maximum plasma concentration; Cmin = minimum plasma concentration; cobi = cobicistat; CrCl = creatinine clearance; DTG = dolutegravir; EVG = elvitegravir; Fe = iron; FTC = emtricitabine; INSTI = integrase strand transfer inhibitor; Mg = magnesium; PAH = pulmonary arterial hypertension; RAL = raltegravir; SSRI = selective serotonin reuptake inhibitor; TCA = tricyclic anti-depressants; TDF = tenofovir disoproxil fumarate; Zn = zinc

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