Updated
Reviewed
Dec. 18, 2019

Drug-Drug Interactions

Drug Interactions between Integrase Inhibitors and Other Drugs

Table 21d. Drug Interactions Between Integrase Strand Transfer Inhibitors and Other Drugs

This table provides information on the known or predicted interactions between INSTIs (BIC, DTG, EVG, or RAL) and non-ARV drugs. EVG is always coadministered with COBI. For information regarding interactions between INSTIs and other ARV drugs, including dosing recommendations, refer to Tables 21c, 22a, and 22b.

Recommendations for managing a particular drug interaction may differ depending on whether a new ARV drug is being initiated in a patient on a stable concomitant medication or whether a new concomitant medication is being initiated in a patient on a stable ARV regimen. The magnitude and significance of drug interactions are difficult to predict when several drugs with competing metabolic pathways are prescribed concomitantly. In cases where an interacting drug needs to be replaced with an alternative, providers should exercise their clinical judgement to select the most appropriate alternative medication to use.

Table 21d. Drug Interactions Between Integrase Strand Transfer Inhibitors and Other Drugs
Concomitant Drug INSTI Effect on INSTI or Concomitant Drug Concentrations Dosing Recommendations and Clinical Comments
Acid Reducers
Al, Mg, +/- Ca-Containing Antacids

Please refer to the Miscellaneous Drugs section of this table for recommendations on use with other polyvalent cation products (e.g., Fe and Ca supplements, multivitamins).		 BIC Al/Mg Hydroxide Antacid:
  • ↔ BIC AUC if antacid is administered 2 hours after BIC and under fasting conditions
  • BIC AUC ↓ 52% if antacid is administered 2 hours before BIC
  • BIC AUC ↓ 47% to 79% if administered simultaneously with antacid
CaCO3 Antacid:
  • ↔ BIC AUC if administered with food
  • BIC AUC ↓ 33% if administered under fasting conditions
 With Antacids That Contain Al/Mg:
  • Administer antacids that contain Al/Mg at least 2 hours after or 6 hours before BIC.
With Antacids That Contain Ca:
  • Administer BIC and antacids that contain Ca together with food.
  • Do not coadminister BIC simultaneously with antacids that contain Ca on an empty stomach.
DTG DTG AUC ↓ 74% if administered simultaneously with antacid

DTG AUC ↓ 26% if administered 2 hours before antacid		 Administer DTG at least 2 hours before or at least 6 hours after antacids that contain polyvalent cations.
EVG/c EVG AUC ↓ 40% to 50% if administered simultaneously with antacid

EVG AUC ↓ 15% to 20% if administered 2 hours before or after antacid; ↔ with 4-hour interval		 Separate EVG/c and antacid administration by more than 2 hours.
RAL Al/Mg Hydroxide Antacid:
  • RAL Cmin ↓ 49% to 63%
CaCO3 Antacid:
  • RAL 400 mg twice daily: Cmin ↓ 32%
  • RAL 1,200 mg once daily: Cmin ↓ 48% to 57%
 Do not coadminister RAL and Al/Mg hydroxide antacids. Use alternative acid-reducing agent.

With CaCO3 Antacids:
  • RAL 1,200 mg once daily: Do not coadminister.
  • RAL 400 mg twice daily: No dose adjustment or separation needed.
H2-Receptor Antagonists BIC, DTG, EVG/c ↔ INSTI No dose adjustment needed.
RAL RAL AUC ↑ 44% and Cmax ↑ 60% No dose adjustment needed.
Proton Pump Inhibitors BIC, DTG, EVG/c ↔ INSTI No dose adjustment needed.
RAL RAL AUC ↑ 37% and Cmin ↑ 24% No dose adjustment needed.
Alpha-Adrenergic Antagonists for Benign Prostatic Hyperplasia
Alfuzosin BIC, DTG, RAL ↔ alfuzosin expected No dose adjustment needed.
EVG/c ↑ alfuzosin expected Contraindicated.
Doxazosin BIC, DTG, RAL ↔ doxazosin expected No dose adjustment needed.
EVG/c ↑ doxazosin possible Initiate doxazosin at lowest dose and titrate based on doxazosin efficacy and adverse events. Doxazosin dose reduction may be needed.
Tamsulosin BIC, DTG, RAL ↔ tamsulosin expected No dose adjustment needed.
EVG/c ↑ tamsulosin expected Do not coadminister, unless benefits outweigh risks. If coadministered, monitor for tamsulosin-related adverse events.
Terazosin BIC, DTG, RAL ↔ terazosin expected No dose adjustment needed.
EVG/c ↑ terazosin possible Initiate terazosin at lowest dose and titrate based on terazosin efficacy and adverse events. Terazosin dose reduction may be necessary.
Silodosin BIC, DTG, RAL ↔ silodosin expected No dose adjustment needed.
EVG/c ↑ silodosin expected Contraindicated.
Antibacterials
Antimycobacterials
Rifabutin BIC Rifabutin 300 mg Once Daily:
  • BIC AUC ↓ 38% and Cmin ↓ 56%
 Do not coadminister.
DTG Rifabutin 300 mg Once Daily:
  • ↔ DTG AUC and Cmin ↓ 30%
 No dose adjustment needed.
EVG/c Rifabutin 150 mg Every Other Day with EVG/c Once Daily Compared to Rifabutin 300 mg Once Daily Alone:
  • ↔ rifabutin AUC
  • 25-O-desacetyl-rifabutin AUC ↑ 625%
  • EVG AUC ↓ 21% and Cmin ↓ 67%
 Do not coadminister.
RAL RAL AUC ↑ 19% and Cmin ↓ 20% No dose adjustment needed.
Rifampin BIC BIC AUC ↓ 75% Contraindicated.
DTG Rifampin with DTG 50 mg Twice Daily Compared to DTG 50 mg Twice Daily Alone:
  • DTG AUC ↓ 54% and Cmin ↓ 72%
Rifampin with DTG 50 mg Twice Daily Compared to DTG 50 mg Once Daily Alone:
  • DTG AUC ↑ 33% and Cmin ↑ 22%
 Use DTG 50 mg twice daily (instead of DTG 50 mg once daily) in patients without suspected or documented INSTI-associated resistance mutations.

Consider an alternative to rifampin, such as rifabutin, in patients with certain suspected or documented INSTI-associated resistance mutations.
EVG/c Significant ↓ EVG and COBI expected Contraindicated.
RAL RAL 400 mg:
  • RAL AUC ↓ 40% and Cmin ↓ 61%
Rifampin with RAL 800 mg Twice Daily Compared to RAL 400 mg Twice Daily Alone:
  • RAL AUC ↑ 27% and Cmin ↓ 53%
 Use RAL 800 mg twice daily instead of 400 mg twice daily.

Do not coadminister RAL 1,200 mg once daily with rifampin.

Monitor closely for virologic response, or consider using rifabutin as an alternative rifamycin.
Rifapentine BIC, DTG, EVG/c Significant ↓ BIC, DTG, EVG, and COBI expected Do not coadminister.
RAL Rifapentine 900 mg Once Weekly:
  • RAL AUC ↑ 71% and Cmin ↓ 12%
Rifapentine 600 mg Once Daily:
  • RAL Cmin ↓ 41%
 For once-weekly rifapentine and RAL 400 mg twice daily, no dose adjustment needed.

Do not coadminister with once-daily rifapentine.
Macrolides
Azithromycin All INSTIs ↔ azithromycin expected No dose adjustment needed.
Clarithromycin BIC ↑ BIC possible No dose adjustment needed.
DTG, RAL ↔ clarithromycin expected No dose adjustment needed.
EVG/c ↑ clarithromycin expected

↑ COBI possible		 Reduce clarithromycin dose by 50% in patients with CrCl 50 to 60 mL/min.

Do not coadminister in patients with CrCl <50 mL/min. Consider alternative ARV or use azithromycin.
Erythromycin BIC ↑ BIC possible No dose adjustment needed.
DTG, RAL ↔ INSTI expected

↔ erythromycin expected		 No dose adjustment needed.
EVG/c ↑ erythromycin expected

↑ COBI possible		 No data available for dose recommendation. Consider alternative ARV or use azithromycin.
Anticoagulants
Apixaban BIC, DTG, RAL ↔ apixaban expected No dose adjustment needed.
EVG/c ↑ apixaban expected Do not coadminister in patients who require apixaban 2.5 mg twice daily.

Reduce apixaban dose by 50% in patients who require apixaban 5 mg or 10 mg twice daily.
Betrixaban BIC, DTG, RAL ↔ betrixaban expected No dose adjustment needed.
EVG/c ↑ betrixaban expected Administer initial single dose of betrixaban 80 mg, followed by betrixaban 40 mg once daily.
Dabigatran BIC, DTG, RAL ↔ dabigatran expected No dose adjustment needed.
EVG/c ↑ dabigatran expected

With COBI 150 mg Alone:
  • Dabigatran AUC ↑ 110% to 127%
 Dabigatran dosing recommendation depends on indication and renal function. Refer to dabigatran prescribing information for dosing instructions when using dabigatran concomitantly with P-glycoprotein inhibitors.
Edoxaban BIC, DTG, RAL ↔ edoxaban expected No dose adjustment needed.
EVG/c ↔ or ↑ edoxaban expected Stroke Prevention in Nonvalvular Atrial Fibrillation:
  • No dose adjustment needed.
Deep Venous Thrombosis and Pulmonary Embolism:
  • Administer edoxaban 30 mg once daily.
Rivaroxaban BIC, DTG, RAL ↔ rivaroxaban expected No dose adjustment needed.
EVG/c ↑ rivaroxaban expected Do not coadminister.
Warfarin BIC, DTG, RAL ↔ warfarin expected No dose adjustment needed.
EVG/c ↑ or ↓ warfarin possible Monitor INR and adjust warfarin dose accordingly.
Anticonvulsants
Carbamazepine BIC ↓ BIC possible Do not coadminister.
DTG DTG AUC ↓ 49% Increase DTG dose to 50 mg twice daily in ART-naive or ART-experienced, INSTI-naive patients.

Do not coadminister in INSTI-experienced patients with known or suspected INSTI resistance.
EVG/c Carbamazepine AUC ↑ 43%

EVG AUC ↓ 69% and Cmin ↓ >99%

↓ COBI expected		 Contraindicated.
RAL ↓ or ↔ RAL possible Do not coadminister.
Eslicarbazepine All INSTIs ↓ INSTI possible

↓ COBI possible		 Consider alternative ARV or anticonvulsant.
Ethosuximide BIC, DTG, RAL ↔ ethosuximide expected No dose adjustment needed.
EVG/c ↑ ethosuximide possible Monitor for ethosuximide-related adverse events.
Lamotrigine BIC, DTG, RAL ↔ lamotrigine expected No dose adjustment needed.
EVG/c No data Monitor anticonvulsant concentrations and adjust dose accordingly.
Oxcarbazepine BIC, DTG ↓ BIC and DTG possible Do not coadminister.
EVG/c, RAL ↓ EVG/c and RAL possible Consider alternative ARV or anticonvulsant.
Phenobarbital Phenytoin BIC ↓ BIC possible Do not coadminister.
DTG ↓ DTG possible Do not coadminister.
EVG/c ↓ EVG/c expected Contraindicated.
RAL ↓ or ↔ RAL possible Do not coadminister.
Valproic Acid All INSTIs No data Monitor valproic acid concentration and virologic response.
Antidepressants, Anxiolytics, Antipsychotics
Also see Sedative/Hypnotics section below
Aripiprazole BIC, DTG, RAL ↔ aripiprazole expected No dose adjustment needed.
EVG/c ↑ aripiprazole expected Administer 25% of the usual aripiprazole dose. Titrate based on aripiprazole efficacy and adverse events. Refer to aripiprazole label for dosing recommendations in patients who are known to be CYP2D6 poor metabolizers or who have major depressive disorder.
Brexpiprazole BIC, DTG, RAL ↔ brexpiprazole expected No dose adjustment needed.
EVG/c ↑ brexpiprazole expected Administer 25% of the usual brexpiprazole dose. Titrate based on brexpiprazole efficacy and adverse events. Refer to brexpiprazole label for dosing recommendations in patients who are known to be CYP2D6 poor metabolizers or who have major depressive disorder.
Bupropion BIC, DTG, RAL ↔ bupropion expected No dose adjustment needed.
EVG/c ↑ bupropion possible Titrate bupropion dose based on clinical response.
Buspirone BIC, DTG, RAL ↔ buspirone expected No dose adjustment needed.
EVG/c ↑ buspirone possible Initiate buspirone at a low dose. Buspirone dose reduction may be needed.
Cariprazine BIC, DTG, RAL ↔ cariprazine expected No dose adjustment needed.
EVG/c ↑ cariprazine expected Starting Cariprazine in a Patient Who Is Already Receiving EVG/c:
  • Administer cariprazine 1.5 mg on Day 1 and Day 3, with no dose given on Day 2. From Day 4 onward, administer cariprazine 1.5 mg daily. Dose can be increased to a maximum dose of 3 mg daily. If EVG/c is withdrawn, cariprazine dose may need to be increased.
Starting EVG/c in a Patient Who is Already Receiving Cariprazine:
  • For patients receiving cariprazine 3 mg or 6 mg daily, reduce cariprazine dose by half. For patients taking cariprazine 4.5 mg daily, the dose should be reduced to 1.5 mg or 3 mg daily. For patients taking cariprazine 1.5 mg daily, change to 1.5 mg every other day. If EVG/c is withdrawn, cariprazine dose may need to be increased.
Iloperidone BIC, DTG, RAL ↔ iloperidone expected No dose adjustment needed.
EVG/c ↑ iloperidone expected Decrease iloperidone dose by 50%.
Lurasidone BIC, DTG, RAL ↔ lurasidone expected No dose adjustment needed.
EVG/c ↑ lurasidone expected Contraindicated.
Nefazodone BIC, DTG, RAL ↔ nefazodone expected No dose adjustment needed.
EVG/c ↑ nefazodone expected Consider alternative ARV or antidepressant.
Pimavanserin BIC, DTG, RAL ↔ pimavanserin expected No dose adjustment needed.
EVG/c ↑ pimavanserin expected Reduce pimavanserin dose to 10 mg.
Pimozide BIC, DTG, RAL ↔ pimozide expected No dose adjustment needed.
EVG/c ↑ pimozide expected Contraindicated.
Quetiapine BIC, DTG, RAL ↔ quetiapine expected No dose adjustment needed.
EVG/c ↑ quetiapine AUC expected Starting Quetiapine in a Patient Receiving EVG/c:
  • Start quetiapine at the lowest dose and titrate up as needed. Monitor for quetiapine efficacy and adverse events.
Starting EVG/c in a Patient Receiving a Stable Dose of Quetiapine:
  • Reduce quetiapine dose to 1/6 of the current dose, and closely monitor for quetiapine efficacy and adverse events.
Selective Serotonin Reuptake Inhibitors
Citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline		 EVG/c ↔ EVG

↔ sertraline
 		 No dose adjustment needed.
↑ other SSRIs possible Initiate with lowest dose of SSRI and titrate dose carefully based on antidepressant response.
BIC, DTG, RAL ↔ BIC, DTG and RAL expected

↔ SSRI expected		 No dose adjustment needed.
Tricyclic Antidepressants
Amitriptyline, desipramine, doxepin, imipramine, nortriptyline		 BIC, DTG, RAL ↔ TCA expected No dose adjustment needed.
EVG/c Desipramine AUC ↑ 65% Initiate with lowest dose of TCA and titrate dose carefully.
↑ TCA expected Initiate with lowest dose of TCA and titrate dose carefully based on antidepressant response and/or drug concentrations.
Trazodone BIC, DTG, RAL ↔ trazodone expected No dose adjustment needed.
EVG/c ↑ trazodone possible Initiate with lowest dose of trazodone and titrate dose carefully.
Ziprasidone BIC, DTG, RAL ↔ ziprasidone expected No dose adjustment needed.
EVG/c ↑ ziprasidone possible Monitor for ziprasidone-related adverse events.
Other Antipsychotics
CYP3A4 and/or CYP2D6 substrates (e.g., perphenazine, risperidone, thioridazine)		 EVG/c ↑ antipsychotic possible Initiate antipsychotic at a low dose. Antipsychotic dose reduction may be needed.
Antifungals
Isavuconazole BIC ↑ BIC possible No dose adjustment needed.
EVG/c ↑ isavuconazole expected

↑ or ↓ EVG and COBI possible		 If coadministered, consider monitoring isavuconazole concentrations and assessing virologic response.
Itraconazole BIC ↑ BIC expected No dose adjustment needed.
DTG, RAL ↔ INSTI expected

↔ itraconazole expected		 No dose adjustment needed.
EVG/c ↑ itraconazole expected

↑ EVG and COBI possible		 Consider monitoring itraconazole concentrations to guide dose adjustments. Do not coadminister with high itraconazole doses (>200 mg/day) unless guided by itraconazole concentrations.
Posaconazole BIC ↑ BIC expected No dose adjustment needed.
DTG, RAL ↔ INSTI expected

↔ posaconazole expected		 No dose adjustment needed.
EVG/c ↑ EVG and COBI possible

↑ posaconazole possible		 If coadministered, monitor posaconazole concentrations.
Voriconazole BIC ↑ BIC possible No dose adjustment needed.
DTG, RAL ↔ INSTI expected

↔ voriconazole expected		 No dose adjustment needed.
EVG/c ↑ voriconazole expected

↑ EVG and COBI possible		 Do not coadminister voriconazole and COBI unless benefit outweighs risk. If coadministered, consider monitoring voriconazole concentrations and adjust dose accordingly.
Antihyperglycemics
Metformin BIC Metformin AUC ↑ 39% Monitor for adverse events of metformin.
DTG DTG 50 mg Once Daily plus Metformin 500 mg Twice Daily:
  • Metformin AUC ↑ 79% and Cmax ↑ 66%
DTG 50 mg Twice Daily plus Metformin 500 mg Twice Daily:
  • Metformin AUC ↑ 2.4-fold and Cmax ↑ 2-fold
 Start metformin at lowest dose and titrate based on glycemic control. Monitor for adverse events of metformin.

When starting/stopping DTG in patients on metformin, dose adjustment of metformin may be necessary to maintain optimal glycemic control and/or minimize adverse events of metformin.
RAL ↔ metformin expected No dose adjustment needed.
Saxagliptin BIC, DTG, RAL ↔ saxagliptin expected No dose adjustment needed.
EVG/c ↑ saxagliptin expected Limit saxagliptin dose to 2.5 mg once daily.
Dapagliflozin/ Saxagliptin BIC, DTG, RAL ↔ dapagliflozin or saxagliptin expected No dose adjustment needed.
EVG/c ↑ saxagliptin expected Do not coadminister. Dapagliflozin is only available as a coformulated drug that contains 5 mg of saxagliptin. When coadministered with EVG/c, the dose of saxagliptin should not exceed 2.5 mg once daily; thus, this combination is not recommended.
Antiplatelets
Clopidogrel BIC, DTG, RAL ↔ clopidogrel expected No dose adjustment needed.
EVG/c ↓ clopidogrel active metabolite, with impaired platelet inhibition expected Do not coadminister.
Prasugrel BIC, DTG, RAL ↔ prasugrel expected No dose adjustment needed.
EVG/c ↓ prasugrel active metabolite, with no impairment of platelet inhibition expected Insufficient data to make a dose recommendation.
Ticagrelor BIC, DTG, RAL ↔ ticagrelor expected No dose adjustment needed.
EVG/c ↑ ticagrelor expected Do not coadminister.
Vorapaxar BIC, DTG, RAL ↔ vorapaxar expected No dose adjustment needed.
EVG/c ↑ vorapaxar expected Do not coadminister.
Beta-Agonists, Long-Acting Inhaled
Arformoterol, Formoterol All INSTIs ↔ arformoterol or formoterol expected No dose adjustment needed.
Indacaterol BIC, DTG, RAL ↔ indacaterol expected No dose adjustment needed.
EVG/c ↑ indacaterol expected No dose adjustment needed.
Olodaterol BIC, DTG, RAL ↔ olodaterol expected No dose adjustment needed.
EVG/c ↑ olodaterol expected No dose adjustment needed.
Salmeterol BIC, DTG, RAL ↔ salmeterol expected No dose adjustment needed.
EVG/c ↑ salmeterol possible Do not coadminister because of potential increased risk of salmeterol-associated cardiovascular events.
Cardiac Medications
Amiodarone BIC, DTG, RAL ↔ INSTI expected

↔ amiodarone expected		 No dose adjustment needed.
EVG/c ↑ INSTI possible

↑ amiodarone possible		 Do not coadminister, unless benefits outweigh risks. If coadministration is necessary, monitor for amiodarone-related adverse events and consider monitoring ECG and amiodarone concentrations.
Bepridil, Digoxin, Disopyramide, Dronedarone, Flecainide, Systemic Lidocaine, Mexilitine, Propafenone, Quinidine BIC, DTG ↔ expected for the listed antiarrhythmics, except for disopyramide

↑ disopyramide possible		 No dose adjustment needed.

Monitor for disopyramide-related adverse events.
RAL ↔ expected for the listed antiarrhythmics No dose adjustment needed.
EVG/c ↑ antiarrhythmics possible

Digoxin Cmax ↑ 41% and ↔ AUC		 Therapeutic drug monitoring for antiarrhythmics, if available, is recommended.
Beta-Blockers
(e.g., metoprolol, timolol)		 BIC, DTG, RAL ↔ beta-blocker expected No dose adjustment needed.
EVG/c ↑ beta-blocker possible Beta-blocker dose may need to be decreased; adjust dose based on clinical response.

Consider using an alternative ARV, or a beta-blocker that is not metabolized by CYP450 enzymes (e.g., atenolol, labetalol, nadolol, sotalol).
Bosentan BIC, DTG ↓ BIC and DTG possible No dose adjustment needed.
RAL ↔ bosentan expected No dose adjustment needed.
EVG/c ↑ bosentan possible In Patients on EVG/c ≥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/c:
  • Stop bosentan ≥36 hours before EVG/c initiation. At least 10 days after initiation of EVG/c, resume bosentan at 62.5 mg once daily or every other day based on individual tolerability.
Calcium Channel Blockers BIC ↑ BIC possible with diltiazem

↔ expected for all other CCBs		 No dose adjustment needed.
DTG, RAL ↔ INSTI expected

↔ CCB expected		 No dose adjustment needed.
EVG/c ↑ CCB possible Titrate CCB dose and monitor for CCB efficacy and adverse events.
Dofetilide BIC, DTG ↑ dofetilide expected Contraindicated.
RAL ↔ dofetilide expected No dose adjustment needed.
EVG/c ↑ dofetilide possible Do not coadminister.
Eplerenone BIC, DTG, RAL ↔ eplerenone expected No dose adjustment needed.
EVG/c ↑ eplerenone expected Contraindicated.
Ivabradine BIC, DTG, RAL ↔ ivabradine expected No dose adjustment needed.
EVG/c ↑ ivabradine expected Contraindicated.
Ranolazine BIC, DTG, RAL ↔ ranolazine expected No dose adjustment needed.
EVG/c ↑ ranolazine expected Contraindicated.
Corticosteroids
Beclomethasone
Inhaled or intranasal		 BIC, DTG, EVG/c, RAL ↔ glucocorticoid expected No dose adjustment needed.
Budesonide, Ciclesonide, Fluticasone, Mometasone
Inhaled or intranasal		 BIC, DTG, RAL ↔ glucocorticoid expected No dose adjustment needed.
EVG/c ↑ glucocorticoid possible Do not coadminister unless potential benefits of inhaled or intranasal corticosteroid outweigh the risks of systemic corticosteroid adverse effects. Coadministration can result in adrenal insufficiency and Cushing’s syndrome. Consider using an alternative corticosteroid (e.g., beclomethasone).
Betamethasone, Budesonide
Systemic		 BIC, DTG, RAL ↔ INSTI expected

↔ glucocorticoid expected		 No dose adjustment needed.
EVG/c ↑ glucocorticoids possible

↓ EVG possible		 Do not coadminister unless potential benefits of systemic budesonide outweigh the risks of systemic corticosteroid adverse effects. Coadministration can result in adrenal insufficiency and Cushing’s syndrome.
Dexamethasone
Systemic		 BIC ↓ BIC possible Consider alternative corticosteroid for long-term use or alternative ARV. If coadministration is necessary, monitor virologic response to ART.
DTG, RAL ↔ INSTI expected No dose adjustment needed.
EVG/c ↓ EVG and COBI possible Consider alternative corticosteroid for long-term use or alternative ARV. If coadministration is necessary, monitor virologic response to ART.
Prednisone, Prednisolone
Systemic		 BIC, DTG, RAL ↔ glucocorticoid expected No dose adjustment needed.
EVG/c ↑ prednisolone possible Coadministration may be considered if the potential benefits outweigh the risks of systemic corticosteroid adverse effects. If coadministration is necessary, monitor for adrenal insufficiency and Cushing’s syndrome.
Betamethasone, Methylprednisolone, Prednisolone, Triamcinolone
Local injections, including intra-articular, epidural, or intra-orbital		 BIC, DTG, RAL ↔ glucocorticoid expected No dose adjustment needed.
EVG/c ↑ glucocorticoid expected Do not coadminister. Coadministration may result in adrenal insufficiency and Cushing’s syndrome.
Hepatitis C Direct-Acting Antiviral Agents
Daclatasvir BIC, RAL No data No dose adjustment needed.
DTG ↔ daclatasvir No dose adjustment needed.
EVG/c ↑ daclatasvir Decrease daclatasvir dose to 30 mg once daily.
Dasabuvir plus Ombitasvir/ Paritaprevir/ RTV BIC, DTG No data No dose adjustment needed.
EVG/c No data Do not coadminister.
RAL RAL AUC ↑ 134% No dose adjustment needed.
Elbasvir/ Grazoprevir BIC ↔ BIC expected No dose adjustment needed.
DTG ↔ elbasvir

↔ grazoprevir

↔ DTG		 No dose adjustment needed.
EVG/c ↑ elbasvir expected

↑ grazoprevir expected		 Do not coadminister.
RAL ↔ elbasvir

↔ grazoprevir

↔ RAL with elbasvir

RAL AUC ↑ 43% with grazoprevir		 No dose adjustment needed.
Glecaprevir/ Pibrentasvir BIC ↔ BIC expected No dose adjustment needed.
DTG, RAL No significant effect No dose adjustment needed.
EVG/c Glecaprevir AUC ↑ 3-fold

Pibrentasvir AUC ↑ 57%

EVG AUC ↑ 47%		 No dose adjustment needed. If coadministered with TDF, monitor for TDF-related adverse events. Consider monitoring for hepatotoxicity if coadministered with TDF or TAF.
Ledipasvir/ Sofosbuvir BIC, DTG, RAL ↔ DTG and RAL No dose adjustment needed.
EVG/c/TDF/FTC ↑ TDF expected

↑ ledipasvir expected		 Do not coadminister.
EVG/c/TAF/FTC ↔ EVG/c/TAF/FTC expected No dose adjustment needed.
Sofosbuvir All INSTIs ↔ INSTI expected

↔ sofosbuvir expected		 No dose adjustment needed.
Sofosbuvir/ Velpatasvir All INSTIs ↔ INSTI expected

↔ sofosbuvir and velpatasvir expected		 No dose adjustment needed. If coadministered with TDF, monitor for TDF-related adverse events.
Sofosbuvir/ Velpatasvir/ Voxilaprevir EVG/c When Administered with Sofosbuvir/Velpatasvir/Voxilaprevir (400 mg/100 mg/100 mg) plus Voxilaprevir 100 mg:
  • Sofosbuvir AUC ↑ 22%
  • ↔ velpatasvir
  • Voxilaprevir AUC ↑ 2-fold
 No dose adjustment needed. If coadministered with TDF, monitor for TDF-related adverse events. Consider monitoring for hepatotoxicity if coadministered with TDF or TAF.
BIC, DTG, RAL ↔ INSTI expected

↔ sofosbuvir, velpatasvir, and voxilaprevir expected		 No dose adjustment needed.
Herbal Products
St. John’s Wort BIC, DTG ↓ BIC and DTG possible Do not coadminister.
EVG/c ↓ EVG and COBI expected Contraindicated.
Hormonal Therapies
Contraceptives: Non-Oral All INSTIs No data No drug-drug interaction studies have been conducted with INSTIs and non-oral routes of hormone administration. It is unclear whether drug-drug interaction data for oral drugs can be used to predict interactions for non-oral drugs.
Contraceptives – Oral BIC, DTG, RAL ↔ ethinyl estradiol and norgestimate

↔ INSTI		 No dose adjustment needed.
EVG/c Norgestimate AUC, Cmax, and Cmin ↑ >2-fold

Ethinyl estradiol AUC ↓ 25% and Cmin ↓ 44%		 The effects of increases in progestin (norgestimate) are not fully known and may include insulin resistance, dyslipidemia, acne, and venous thrombosis. Weigh the risks and benefits of using the drug and consider using an alternative ARV or contraceptive method.
↑ drospirenone possible Clinical monitoring is recommended, due to the potential for hyperkalemia. Consider using alternative ARV or contraceptive method.
Gender-Affirming Therapy BIC, DTG, EVG/c, RAL ↔ goserelin, leuprolide acetate, and spironolactone expected No dose adjustment needed.
BIC, DTG, RAL ↔ estrogen expected No dose adjustment needed.
↔ testosterone expected No dose adjustment needed.
EVG/c ↓ or ↑ estradiol possible

↑ dutasteride and finasteride possible		 Adjust dutasteride dose as needed based on clinical effects and endogenous hormone concentrations.
↑ testosterone possible Monitor masculinizing effects of testosterone and monitor for adverse effects. Adjust testosterone dose as necessary.
Menopausal Replacement Therapy BIC, DTG, RAL ↔ estrogen expected with estradiol or conjugated estrogen (equine and synthetic)

↔ drospirenone, medroxyprogesterone, and micronized progesterone expected		 No dose adjustment needed.
EVG/c ↓ or ↑ estrogen possible

↑ drospirenone possible

↑ oral medroxyprogesterone possible

↑ oral micronized progesterone possible		 Adjust estrogen and progestin dose as needed based on clinical effects.
Immunosuppressants
Cyclosporine, Everolimus, Sirolimus, Tacrolimus BIC, DTG, RAL ↔ immunosuppressant expected No dose adjustment needed.
EVG/c ↑ immunosuppressant possible Initiate with an adjusted dose of immunosuppressant to account for potential increased concentrations of the immunosuppressant and monitor for immunosuppressant-related adverse events. Therapeutic drug monitoring of immunosuppressant is recommended. Consult with a specialist as necessary.
Lipid-Modifying Agents
Atorvastatin BIC, DTG, RAL ↔ atorvastatin expected No dose adjustment needed.
EVG/c Atorvastatin AUC ↑ 2.6-fold and Cmax ↑ 2.3-fold Titrate statin dose carefully and administer the lowest effective dose while monitoring for adverse events. Do not exceed 20 mg atorvastatin daily.
Lomitapide BIC, DTG, RAL ↔ lomitapide expected No dose adjustment needed.
EVG/c ↑ lomitapide expected Contraindicated.
Lovastatin BIC, DTG, RAL ↔ lovastatin expected No dose adjustment needed.
EVG/c Significant ↑ lovastatin expected Contraindicated.
Pitavastatin, Pravastatin BIC, DTG, RAL ↔ statin expected No dose adjustment needed.
EVG/c No data No data available for dose recommendation.
Rosuvastatin BIC, DTG, RAL ↔ rosuvastatin expected No dose adjustment needed.
EVG/c Rosuvastatin AUC ↑ 38% and Cmax ↑ 89% Titrate statin dose carefully and use the lowest effective dose while monitoring for adverse events.
Simvastatin BIC, DTG, RAL ↔ simvastatin expected No dose adjustment needed.
EVG/c Significant ↑ simvastatin expected Contraindicated.
Narcotics and Treatment for Opioid Dependence
Buprenorphine
Sublingual, buccal, or implant		 BIC, DTG ↔ buprenorphine and norbuprenorphine (active metabolite) expected No dose adjustment needed.
EVG/c Buprenorphine AUC ↑ 35% and Cmin ↑ 66%

Norbuprenorphine (active metabolite) AUC ↑ 42% and Cmin ↑ 57%		 No dose adjustment needed. Monitor for adverse events of buprenorphine. When transferring buprenorphine from transmucosal administration to implantation, monitor to ensure buprenorphine effect is adequate and not excessive.
RAL ↔ buprenorphine and norbuprenorphine (active metabolite) (sublingual)

↔ buprenorphine or norbuprenorphine (active metabolite) expected (implant)		 No dose adjustment needed.
Fentanyl BIC, DTG, RAL ↔ fentanyl expected No dose adjustment needed.
EVG/c ↑ fentanyl Monitor for fentanyl efficacy and adverse events, including potentially fatal respiratory depression.
Lofexidine BIC, DTG, RAL ↔ lofexidine expected No dose adjustment needed.
EVG/c ↑ lofexidine possible Monitor for lofexidine-related adverse events, including symptoms of orthostasis and bradycardia.
Methadone All INSTIs ↔ methadone No dose adjustment needed.
Tramadol BIC, DTG, RAL ↔ tramadol and M1 (active metabolite) expected No dose adjustment needed.
EVG/c ↑ tramadol expected

↓ M1 (active metabolite) possible		 Tramadol dose adjustments may be necessary. Monitor for clinical response and tramadol-related adverse events.
PDE5 Inhibitors
Avanafil BIC, DTG, RAL ↔ avanafil expected No dose adjustment needed.
EVG/c No data Do not coadminister.
Sildenafil BIC, DTG, RAL ↔ sildenafil expected No dose adjustment needed.
EVG/c ↑ sildenafil expected For Treatment of Erectile Dysfunction:
  • Start with sildenafil 25 mg every 48 hours and monitor for adverse effects of sildenafil.

Contraindicated for treatment of PAH.
Tadalafil BIC, DTG, RAL ↔ tadalafil expected No dose adjustment needed.
EVG/c ↑ tadalafil expected For Treatment of Erectile Dysfunction:
  • Start with tadalafil 5 mg and do not exceed a single dose of tadalafil 10 mg every 72 hours. Monitor for adverse effects of tadalafil.

For Treatment of PAH
In Patients on EVG/c >7 Days:
  • Start with tadalafil 20 mg once daily and increase to tadalafil 40 mg once daily based on tolerability.
In Patients on Tadalafil who Require EVG/c:
  • Stop tadalafil ≥24 hours before EVG/c initiation. Seven days after EVG/c initiation, restart tadalafil at 20 mg once daily, and increase to tadalafil 40 mg once daily based on tolerability.
Vardenafil BIC, DTG, RAL ↔ vardenafil expected No dose adjustment needed.
EVG/c ↑ vardenafil expected Start with vardenafil 2.5 mg every 72 hours and monitor for adverse effects of vardenafil.
Sedative/Hypnotics
Buspirone BIC, DTG, RAL ↔ buspirone expected No dose adjustment needed.
EVG/c ↑ buspirone expected Initiate buspirone at a low dose. Dose reduction may be needed.
Clonazepam, Clorazepate, Diazepam, Estazolam, Flurazepam BIC, DTG, RAL ↔ benzodiazepine expected No dose adjustment needed.
EVG/c ↑ benzodiazepine possible Dose reduction of benzodiazepine may be necessary. Initiate with a low dose and monitor for benzodiazepine-related adverse events.

Consider using an alternative benzodiazepine, such as lorazepam, oxazepam, or temazepam.
Midazolam, Triazolam BIC, RAL ↔ benzodiazepine expected No dose adjustment needed.
DTG With DTG 25 mg:
  • ↔ midazolam AUC
 No dose adjustment needed.
EVG/c ↑ midazolam expected

↑ triazolam expected		 Contraindicated. Do not coadminister triazolam or oral midazolam and EVG/c.

Parenteral midazolam can be administered in a closely monitored setting. Consider dose reduction, especially if >1 dose is administered.
Suvorexant BIC, DTG, RAL ↔ suvorexant expected No dose adjustment needed.
EVG/c ↑ suvorexant expected Do not coadminister.
Zolpidem BIC, DTG, RAL ↔ zolpidem expected No dose adjustment needed.
EVG/c ↑ zolpidem expected Initiate zolpidem at a low dose. Dose reduction of zolpidem may be necessary.
Miscellaneous Drugs
Calcifediol BIC, DTG, RAL ↔ calcifediol expected No dose adjustment needed.
EVG/c ↑ calcifediol possible Dose adjustment of calcifediol may be required. Monitor serum 25-hydroxyvitamin D, intact PTH, and serum Ca concentrations.
Cisapride BIC, DTG, RAL ↔ cisapride expected No dose adjustment needed.
EVG/c ↑ cisapride expected Contraindicated.
Colchicine BIC, DTG, RAL ↔ colchicine expected No dose adjustment needed.
EVG/c ↑ colchicine expected Do not coadminister in patients with hepatic or renal impairment.

For Treatment of Gout Flares:
  • Administer a single dose of colchicine 0.6 mg, followed by colchicine 0.3 mg 1 hour later. Do not repeat dose for at least 3 days.
For Prophylaxis of Gout Flares:
  • If original dose was colchicine 0.6 mg twice daily, decrease to colchicine 0.3 mg once daily. If dose was 0.6 mg once daily, decrease 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 twice daily.
Dronabinol BIC, DTG, RAL ↔ dronabinol expected No dose adjustment needed.
EVG/c ↑ dronabinol possible Monitor for dronabinol-related adverse events.
Eluxadoline BIC, DTG, RAL ↔ eluxadoline expected No dose adjustment needed.
EVG/c ↑ eluxadoline possible Monitor for eluxadoline-related adverse events.
Ergot Derivatives BIC, DTG, RAL ↔ dihydroergotamine, ergotamine, and methylergonovine expected No dose adjustment needed.
EVG/c ↑ dihydroergotamine, ergotamine, and methylergonovine expected Contraindicated.
Flibanserin BIC, DTG, RAL ↔ flibanserin expected No dose adjustment needed.
EVG/c ↑ flibanserin expected Contraindicated.
Polyvalent Cation Supplements
Mg, Al, Fe, Ca, Zn, including multivitamins with minerals

Note: Please refer to the Acid Reducers section in this table for recommendations on use with Al-, Mg-, and Ca-containing antacids.		 BIC ↔ BIC AUC if administered simultaneously with Fe or Ca and food

BIC AUC ↓ 33% if administered simultaneously with CaCO3 under fasting conditions

BIC AUC ↓ 63% if administered simultaneously with Fe under fasting conditions		 With Supplements That Contain Ca or Fe:
  • Administer BIC and supplements that contain Ca or Fe together with food.

Do not coadminister BIC under fasting conditions simultaneously with, or 2 hours after, supplements that contain Ca or Fe.
DTG DTG AUC ↓ 39% if administered simultaneously with CaCO3 under fasting conditions

DTG AUC ↓ 54% if administered simultaneously with Fe under fasting conditions

↔ DTG when administered with Ca or Fe supplement simultaneously with food		 With Supplements That Contain Ca or Fe:
  • Administer DTG and supplements that contain Ca or Fe together with food, or administer DTG at least 2 hours before or at least 6 hours after supplement.

Do not coadminister DTG under fasting conditions simultaneously with, or 2 hours after, supplements that contain Ca or Fe.
EVG/c, RAL ↓ INSTI possible If coadministration is necessary, administer INSTI at least 2 hours before or at least 6 hours after supplements that contain polyvalent cations, including but not limited to the following products: cation-containing laxatives; Fe, Ca, or Mg supplements; and sucralfate. Monitor for virologic response.

Many oral multivitamins also contain varying amounts of polyvalent cations; the extent and significance of chelation is unknown.
Key to Symbols:
↑ = increase
↓ = decrease
↔ = no change

Key: Al = aluminum; ART = antiretroviral therapy; ARV = antiretroviral; AUC = area under the curve; BIC = bictegravir; Ca = calcium; CaCO3 = calcium carbonate; CCB = calcium channel blocker; Cmax = maximum plasma concentration; Cmin = minimum plasma concentration; COBI = cobicistat; CrCl = creatinine clearance; CYP = cytochrome P; DAA = direct-acting antiviral; DTG = dolutegravir; ECG = electrocardiogram; EVG = elvitegravir; EVG/c = elvitegravir/cobicistat; Fe = iron; FTC = emtricitabine; HCV = hepatitis C virus; INR= international normalized ratio; INSTI = integrase strand transfer inhibitor; Mg = magnesium; PAH = pulmonary arterial hypertension; PDE5 = Phosphodiesterase Type 5; PTH = parathyroid hormone; RAL = raltegravir; RTV = ritonavir; SSRI = selective serotonin reuptake inhibitors; TAF = tenofovir alafenamide; TCA = tricyclic antidepressants; TDF = tenofovir disoproxil fumarate; Zn = zinc

Drug-Drug Interactions

Drug Interactions between Integrase Inhibitors and Other Drugs

Table 21d. Drug Interactions Between Integrase Strand Transfer Inhibitors and Other Drugs

This table provides information on the known or predicted interactions between INSTIs (BIC, DTG, EVG, or RAL) and non-ARV drugs. EVG is always coadministered with COBI. For information regarding interactions between INSTIs and other ARV drugs, including dosing recommendations, refer to Tables 21c, 22a, and 22b.

Recommendations for managing a particular drug interaction may differ depending on whether a new ARV drug is being initiated in a patient on a stable concomitant medication or whether a new concomitant medication is being initiated in a patient on a stable ARV regimen. The magnitude and significance of drug interactions are difficult to predict when several drugs with competing metabolic pathways are prescribed concomitantly. In cases where an interacting drug needs to be replaced with an alternative, providers should exercise their clinical judgement to select the most appropriate alternative medication to use.

Table 21d. Drug Interactions Between Integrase Strand Transfer Inhibitors and Other Drugs
Concomitant Drug INSTI Effect on INSTI or Concomitant Drug Concentrations Dosing Recommendations and Clinical Comments
Acid Reducers
Al, Mg, +/- Ca-Containing Antacids

Please refer to the Miscellaneous Drugs section of this table for recommendations on use with other polyvalent cation products (e.g., Fe and Ca supplements, multivitamins).		 BIC Al/Mg Hydroxide Antacid:
  • ↔ BIC AUC if antacid is administered 2 hours after BIC and under fasting conditions
  • BIC AUC ↓ 52% if antacid is administered 2 hours before BIC
  • BIC AUC ↓ 47% to 79% if administered simultaneously with antacid
CaCO3 Antacid:
  • ↔ BIC AUC if administered with food
  • BIC AUC ↓ 33% if administered under fasting conditions
 With Antacids That Contain Al/Mg:
  • Administer antacids that contain Al/Mg at least 2 hours after or 6 hours before BIC.
With Antacids That Contain Ca:
  • Administer BIC and antacids that contain Ca together with food.
  • Do not coadminister BIC simultaneously with antacids that contain Ca on an empty stomach.
DTG DTG AUC ↓ 74% if administered simultaneously with antacid

DTG AUC ↓ 26% if administered 2 hours before antacid		 Administer DTG at least 2 hours before or at least 6 hours after antacids that contain polyvalent cations.
EVG/c EVG AUC ↓ 40% to 50% if administered simultaneously with antacid

EVG AUC ↓ 15% to 20% if administered 2 hours before or after antacid; ↔ with 4-hour interval		 Separate EVG/c and antacid administration by more than 2 hours.
RAL Al/Mg Hydroxide Antacid:
  • RAL Cmin ↓ 49% to 63%
CaCO3 Antacid:
  • RAL 400 mg twice daily: Cmin ↓ 32%
  • RAL 1,200 mg once daily: Cmin ↓ 48% to 57%
 Do not coadminister RAL and Al/Mg hydroxide antacids. Use alternative acid-reducing agent.

With CaCO3 Antacids:
  • RAL 1,200 mg once daily: Do not coadminister.
  • RAL 400 mg twice daily: No dose adjustment or separation needed.
H2-Receptor Antagonists BIC, DTG, EVG/c ↔ INSTI No dose adjustment needed.
RAL RAL AUC ↑ 44% and Cmax ↑ 60% No dose adjustment needed.
Proton Pump Inhibitors BIC, DTG, EVG/c ↔ INSTI No dose adjustment needed.
RAL RAL AUC ↑ 37% and Cmin ↑ 24% No dose adjustment needed.
Alpha-Adrenergic Antagonists for Benign Prostatic Hyperplasia
Alfuzosin BIC, DTG, RAL ↔ alfuzosin expected No dose adjustment needed.
EVG/c ↑ alfuzosin expected Contraindicated.
Doxazosin BIC, DTG, RAL ↔ doxazosin expected No dose adjustment needed.
EVG/c ↑ doxazosin possible Initiate doxazosin at lowest dose and titrate based on doxazosin efficacy and adverse events. Doxazosin dose reduction may be needed.
Tamsulosin BIC, DTG, RAL ↔ tamsulosin expected No dose adjustment needed.
EVG/c ↑ tamsulosin expected Do not coadminister, unless benefits outweigh risks. If coadministered, monitor for tamsulosin-related adverse events.
Terazosin BIC, DTG, RAL ↔ terazosin expected No dose adjustment needed.
EVG/c ↑ terazosin possible Initiate terazosin at lowest dose and titrate based on terazosin efficacy and adverse events. Terazosin dose reduction may be necessary.
Silodosin BIC, DTG, RAL ↔ silodosin expected No dose adjustment needed.
EVG/c ↑ silodosin expected Contraindicated.
Antibacterials
Antimycobacterials
Rifabutin BIC Rifabutin 300 mg Once Daily:
  • BIC AUC ↓ 38% and Cmin ↓ 56%
 Do not coadminister.
DTG Rifabutin 300 mg Once Daily:
  • ↔ DTG AUC and Cmin ↓ 30%
 No dose adjustment needed.
EVG/c Rifabutin 150 mg Every Other Day with EVG/c Once Daily Compared to Rifabutin 300 mg Once Daily Alone:
  • ↔ rifabutin AUC
  • 25-O-desacetyl-rifabutin AUC ↑ 625%
  • EVG AUC ↓ 21% and Cmin ↓ 67%
 Do not coadminister.
RAL RAL AUC ↑ 19% and Cmin ↓ 20% No dose adjustment needed.
Rifampin BIC BIC AUC ↓ 75% Contraindicated.
DTG Rifampin with DTG 50 mg Twice Daily Compared to DTG 50 mg Twice Daily Alone:
  • DTG AUC ↓ 54% and Cmin ↓ 72%
Rifampin with DTG 50 mg Twice Daily Compared to DTG 50 mg Once Daily Alone:
  • DTG AUC ↑ 33% and Cmin ↑ 22%
 Use DTG 50 mg twice daily (instead of DTG 50 mg once daily) in patients without suspected or documented INSTI-associated resistance mutations.

Consider an alternative to rifampin, such as rifabutin, in patients with certain suspected or documented INSTI-associated resistance mutations.
EVG/c Significant ↓ EVG and COBI expected Contraindicated.
RAL RAL 400 mg:
  • RAL AUC ↓ 40% and Cmin ↓ 61%
Rifampin with RAL 800 mg Twice Daily Compared to RAL 400 mg Twice Daily Alone:
  • RAL AUC ↑ 27% and Cmin ↓ 53%
 Use RAL 800 mg twice daily instead of 400 mg twice daily.

Do not coadminister RAL 1,200 mg once daily with rifampin.

Monitor closely for virologic response, or consider using rifabutin as an alternative rifamycin.
Rifapentine BIC, DTG, EVG/c Significant ↓ BIC, DTG, EVG, and COBI expected Do not coadminister.
RAL Rifapentine 900 mg Once Weekly:
  • RAL AUC ↑ 71% and Cmin ↓ 12%
Rifapentine 600 mg Once Daily:
  • RAL Cmin ↓ 41%
 For once-weekly rifapentine and RAL 400 mg twice daily, no dose adjustment needed.

Do not coadminister with once-daily rifapentine.
Macrolides
Azithromycin All INSTIs ↔ azithromycin expected No dose adjustment needed.
Clarithromycin BIC ↑ BIC possible No dose adjustment needed.
DTG, RAL ↔ clarithromycin expected No dose adjustment needed.
EVG/c ↑ clarithromycin expected

↑ COBI possible		 Reduce clarithromycin dose by 50% in patients with CrCl 50 to 60 mL/min.

Do not coadminister in patients with CrCl <50 mL/min. Consider alternative ARV or use azithromycin.
Erythromycin BIC ↑ BIC possible No dose adjustment needed.
DTG, RAL ↔ INSTI expected

↔ erythromycin expected		 No dose adjustment needed.
EVG/c ↑ erythromycin expected

↑ COBI possible		 No data available for dose recommendation. Consider alternative ARV or use azithromycin.
Anticoagulants
Apixaban BIC, DTG, RAL ↔ apixaban expected No dose adjustment needed.
EVG/c ↑ apixaban expected Do not coadminister in patients who require apixaban 2.5 mg twice daily.

Reduce apixaban dose by 50% in patients who require apixaban 5 mg or 10 mg twice daily.
Betrixaban BIC, DTG, RAL ↔ betrixaban expected No dose adjustment needed.
EVG/c ↑ betrixaban expected Administer initial single dose of betrixaban 80 mg, followed by betrixaban 40 mg once daily.
Dabigatran BIC, DTG, RAL ↔ dabigatran expected No dose adjustment needed.
EVG/c ↑ dabigatran expected

With COBI 150 mg Alone:
  • Dabigatran AUC ↑ 110% to 127%
 Dabigatran dosing recommendation depends on indication and renal function. Refer to dabigatran prescribing information for dosing instructions when using dabigatran concomitantly with P-glycoprotein inhibitors.
Edoxaban BIC, DTG, RAL ↔ edoxaban expected No dose adjustment needed.
EVG/c ↔ or ↑ edoxaban expected Stroke Prevention in Nonvalvular Atrial Fibrillation:
  • No dose adjustment needed.
Deep Venous Thrombosis and Pulmonary Embolism:
  • Administer edoxaban 30 mg once daily.
Rivaroxaban BIC, DTG, RAL ↔ rivaroxaban expected No dose adjustment needed.
EVG/c ↑ rivaroxaban expected Do not coadminister.
Warfarin BIC, DTG, RAL ↔ warfarin expected No dose adjustment needed.
EVG/c ↑ or ↓ warfarin possible Monitor INR and adjust warfarin dose accordingly.
Anticonvulsants
Carbamazepine BIC ↓ BIC possible Do not coadminister.
DTG DTG AUC ↓ 49% Increase DTG dose to 50 mg twice daily in ART-naive or ART-experienced, INSTI-naive patients.

Do not coadminister in INSTI-experienced patients with known or suspected INSTI resistance.
EVG/c Carbamazepine AUC ↑ 43%

EVG AUC ↓ 69% and Cmin ↓ >99%

↓ COBI expected		 Contraindicated.
RAL ↓ or ↔ RAL possible Do not coadminister.
Eslicarbazepine All INSTIs ↓ INSTI possible

↓ COBI possible		 Consider alternative ARV or anticonvulsant.
Ethosuximide BIC, DTG, RAL ↔ ethosuximide expected No dose adjustment needed.
EVG/c ↑ ethosuximide possible Monitor for ethosuximide-related adverse events.
Lamotrigine BIC, DTG, RAL ↔ lamotrigine expected No dose adjustment needed.
EVG/c No data Monitor anticonvulsant concentrations and adjust dose accordingly.
Oxcarbazepine BIC, DTG ↓ BIC and DTG possible Do not coadminister.
EVG/c, RAL ↓ EVG/c and RAL possible Consider alternative ARV or anticonvulsant.
Phenobarbital Phenytoin BIC ↓ BIC possible Do not coadminister.
DTG ↓ DTG possible Do not coadminister.
EVG/c ↓ EVG/c expected Contraindicated.
RAL ↓ or ↔ RAL possible Do not coadminister.
Valproic Acid All INSTIs No data Monitor valproic acid concentration and virologic response.
Antidepressants, Anxiolytics, Antipsychotics
Also see Sedative/Hypnotics section below
Aripiprazole BIC, DTG, RAL ↔ aripiprazole expected No dose adjustment needed.
EVG/c ↑ aripiprazole expected Administer 25% of the usual aripiprazole dose. Titrate based on aripiprazole efficacy and adverse events. Refer to aripiprazole label for dosing recommendations in patients who are known to be CYP2D6 poor metabolizers or who have major depressive disorder.
Brexpiprazole BIC, DTG, RAL ↔ brexpiprazole expected No dose adjustment needed.
EVG/c ↑ brexpiprazole expected Administer 25% of the usual brexpiprazole dose. Titrate based on brexpiprazole efficacy and adverse events. Refer to brexpiprazole label for dosing recommendations in patients who are known to be CYP2D6 poor metabolizers or who have major depressive disorder.
Bupropion BIC, DTG, RAL ↔ bupropion expected No dose adjustment needed.
EVG/c ↑ bupropion possible Titrate bupropion dose based on clinical response.
Buspirone BIC, DTG, RAL ↔ buspirone expected No dose adjustment needed.
EVG/c ↑ buspirone possible Initiate buspirone at a low dose. Buspirone dose reduction may be needed.
Cariprazine BIC, DTG, RAL ↔ cariprazine expected No dose adjustment needed.
EVG/c ↑ cariprazine expected Starting Cariprazine in a Patient Who Is Already Receiving EVG/c:
  • Administer cariprazine 1.5 mg on Day 1 and Day 3, with no dose given on Day 2. From Day 4 onward, administer cariprazine 1.5 mg daily. Dose can be increased to a maximum dose of 3 mg daily. If EVG/c is withdrawn, cariprazine dose may need to be increased.
Starting EVG/c in a Patient Who is Already Receiving Cariprazine:
  • For patients receiving cariprazine 3 mg or 6 mg daily, reduce cariprazine dose by half. For patients taking cariprazine 4.5 mg daily, the dose should be reduced to 1.5 mg or 3 mg daily. For patients taking cariprazine 1.5 mg daily, change to 1.5 mg every other day. If EVG/c is withdrawn, cariprazine dose may need to be increased.
Iloperidone BIC, DTG, RAL ↔ iloperidone expected No dose adjustment needed.
EVG/c ↑ iloperidone expected Decrease iloperidone dose by 50%.
Lurasidone BIC, DTG, RAL ↔ lurasidone expected No dose adjustment needed.
EVG/c ↑ lurasidone expected Contraindicated.
Nefazodone BIC, DTG, RAL ↔ nefazodone expected No dose adjustment needed.
EVG/c ↑ nefazodone expected Consider alternative ARV or antidepressant.
Pimavanserin BIC, DTG, RAL ↔ pimavanserin expected No dose adjustment needed.
EVG/c ↑ pimavanserin expected Reduce pimavanserin dose to 10 mg.
Pimozide BIC, DTG, RAL ↔ pimozide expected No dose adjustment needed.
EVG/c ↑ pimozide expected Contraindicated.
Quetiapine BIC, DTG, RAL ↔ quetiapine expected No dose adjustment needed.
EVG/c ↑ quetiapine AUC expected Starting Quetiapine in a Patient Receiving EVG/c:
  • Start quetiapine at the lowest dose and titrate up as needed. Monitor for quetiapine efficacy and adverse events.
Starting EVG/c in a Patient Receiving a Stable Dose of Quetiapine:
  • Reduce quetiapine dose to 1/6 of the current dose, and closely monitor for quetiapine efficacy and adverse events.
Selective Serotonin Reuptake Inhibitors
Citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline		 EVG/c ↔ EVG

↔ sertraline
 		 No dose adjustment needed.
↑ other SSRIs possible Initiate with lowest dose of SSRI and titrate dose carefully based on antidepressant response.
BIC, DTG, RAL ↔ BIC, DTG and RAL expected

↔ SSRI expected		 No dose adjustment needed.
Tricyclic Antidepressants
Amitriptyline, desipramine, doxepin, imipramine, nortriptyline		 BIC, DTG, RAL ↔ TCA expected No dose adjustment needed.
EVG/c Desipramine AUC ↑ 65% Initiate with lowest dose of TCA and titrate dose carefully.
↑ TCA expected Initiate with lowest dose of TCA and titrate dose carefully based on antidepressant response and/or drug concentrations.
Trazodone BIC, DTG, RAL ↔ trazodone expected No dose adjustment needed.
EVG/c ↑ trazodone possible Initiate with lowest dose of trazodone and titrate dose carefully.
Ziprasidone BIC, DTG, RAL ↔ ziprasidone expected No dose adjustment needed.
EVG/c ↑ ziprasidone possible Monitor for ziprasidone-related adverse events.
Other Antipsychotics
CYP3A4 and/or CYP2D6 substrates (e.g., perphenazine, risperidone, thioridazine)		 EVG/c ↑ antipsychotic possible Initiate antipsychotic at a low dose. Antipsychotic dose reduction may be needed.
Antifungals
Isavuconazole BIC ↑ BIC possible No dose adjustment needed.
EVG/c ↑ isavuconazole expected

↑ or ↓ EVG and COBI possible		 If coadministered, consider monitoring isavuconazole concentrations and assessing virologic response.
Itraconazole BIC ↑ BIC expected No dose adjustment needed.
DTG, RAL ↔ INSTI expected

↔ itraconazole expected		 No dose adjustment needed.
EVG/c ↑ itraconazole expected

↑ EVG and COBI possible		 Consider monitoring itraconazole concentrations to guide dose adjustments. Do not coadminister with high itraconazole doses (>200 mg/day) unless guided by itraconazole concentrations.
Posaconazole BIC ↑ BIC expected No dose adjustment needed.
DTG, RAL ↔ INSTI expected

↔ posaconazole expected		 No dose adjustment needed.
EVG/c ↑ EVG and COBI possible

↑ posaconazole possible		 If coadministered, monitor posaconazole concentrations.
Voriconazole BIC ↑ BIC possible No dose adjustment needed.
DTG, RAL ↔ INSTI expected

↔ voriconazole expected		 No dose adjustment needed.
EVG/c ↑ voriconazole expected

↑ EVG and COBI possible		 Do not coadminister voriconazole and COBI unless benefit outweighs risk. If coadministered, consider monitoring voriconazole concentrations and adjust dose accordingly.
Antihyperglycemics
Metformin BIC Metformin AUC ↑ 39% Monitor for adverse events of metformin.
DTG DTG 50 mg Once Daily plus Metformin 500 mg Twice Daily:
  • Metformin AUC ↑ 79% and Cmax ↑ 66%
DTG 50 mg Twice Daily plus Metformin 500 mg Twice Daily:
  • Metformin AUC ↑ 2.4-fold and Cmax ↑ 2-fold
 Start metformin at lowest dose and titrate based on glycemic control. Monitor for adverse events of metformin.

When starting/stopping DTG in patients on metformin, dose adjustment of metformin may be necessary to maintain optimal glycemic control and/or minimize adverse events of metformin.
RAL ↔ metformin expected No dose adjustment needed.
Saxagliptin BIC, DTG, RAL ↔ saxagliptin expected No dose adjustment needed.
EVG/c ↑ saxagliptin expected Limit saxagliptin dose to 2.5 mg once daily.
Dapagliflozin/ Saxagliptin BIC, DTG, RAL ↔ dapagliflozin or saxagliptin expected No dose adjustment needed.
EVG/c ↑ saxagliptin expected Do not coadminister. Dapagliflozin is only available as a coformulated drug that contains 5 mg of saxagliptin. When coadministered with EVG/c, the dose of saxagliptin should not exceed 2.5 mg once daily; thus, this combination is not recommended.
Antiplatelets
Clopidogrel BIC, DTG, RAL ↔ clopidogrel expected No dose adjustment needed.
EVG/c ↓ clopidogrel active metabolite, with impaired platelet inhibition expected Do not coadminister.
Prasugrel BIC, DTG, RAL ↔ prasugrel expected No dose adjustment needed.
EVG/c ↓ prasugrel active metabolite, with no impairment of platelet inhibition expected Insufficient data to make a dose recommendation.
Ticagrelor BIC, DTG, RAL ↔ ticagrelor expected No dose adjustment needed.
EVG/c ↑ ticagrelor expected Do not coadminister.
Vorapaxar BIC, DTG, RAL ↔ vorapaxar expected No dose adjustment needed.
EVG/c ↑ vorapaxar expected Do not coadminister.
Beta-Agonists, Long-Acting Inhaled
Arformoterol, Formoterol All INSTIs ↔ arformoterol or formoterol expected No dose adjustment needed.
Indacaterol BIC, DTG, RAL ↔ indacaterol expected No dose adjustment needed.
EVG/c ↑ indacaterol expected No dose adjustment needed.
Olodaterol BIC, DTG, RAL ↔ olodaterol expected No dose adjustment needed.
EVG/c ↑ olodaterol expected No dose adjustment needed.
Salmeterol BIC, DTG, RAL ↔ salmeterol expected No dose adjustment needed.
EVG/c ↑ salmeterol possible Do not coadminister because of potential increased risk of salmeterol-associated cardiovascular events.
Cardiac Medications
Amiodarone BIC, DTG, RAL ↔ INSTI expected

↔ amiodarone expected		 No dose adjustment needed.
EVG/c ↑ INSTI possible

↑ amiodarone possible		 Do not coadminister, unless benefits outweigh risks. If coadministration is necessary, monitor for amiodarone-related adverse events and consider monitoring ECG and amiodarone concentrations.
Bepridil, Digoxin, Disopyramide, Dronedarone, Flecainide, Systemic Lidocaine, Mexilitine, Propafenone, Quinidine BIC, DTG ↔ expected for the listed antiarrhythmics, except for disopyramide

↑ disopyramide possible		 No dose adjustment needed.

Monitor for disopyramide-related adverse events.
RAL ↔ expected for the listed antiarrhythmics No dose adjustment needed.
EVG/c ↑ antiarrhythmics possible

Digoxin Cmax ↑ 41% and ↔ AUC		 Therapeutic drug monitoring for antiarrhythmics, if available, is recommended.
Beta-Blockers
(e.g., metoprolol, timolol)		 BIC, DTG, RAL ↔ beta-blocker expected No dose adjustment needed.
EVG/c ↑ beta-blocker possible Beta-blocker dose may need to be decreased; adjust dose based on clinical response.

Consider using an alternative ARV, or a beta-blocker that is not metabolized by CYP450 enzymes (e.g., atenolol, labetalol, nadolol, sotalol).
Bosentan BIC, DTG ↓ BIC and DTG possible No dose adjustment needed.
RAL ↔ bosentan expected No dose adjustment needed.
EVG/c ↑ bosentan possible In Patients on EVG/c ≥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/c:
  • Stop bosentan ≥36 hours before EVG/c initiation. At least 10 days after initiation of EVG/c, resume bosentan at 62.5 mg once daily or every other day based on individual tolerability.
Calcium Channel Blockers BIC ↑ BIC possible with diltiazem

↔ expected for all other CCBs		 No dose adjustment needed.
DTG, RAL ↔ INSTI expected

↔ CCB expected		 No dose adjustment needed.
EVG/c ↑ CCB possible Titrate CCB dose and monitor for CCB efficacy and adverse events.
Dofetilide BIC, DTG ↑ dofetilide expected Contraindicated.
RAL ↔ dofetilide expected No dose adjustment needed.
EVG/c ↑ dofetilide possible Do not coadminister.
Eplerenone BIC, DTG, RAL ↔ eplerenone expected No dose adjustment needed.
EVG/c ↑ eplerenone expected Contraindicated.
Ivabradine BIC, DTG, RAL ↔ ivabradine expected No dose adjustment needed.
EVG/c ↑ ivabradine expected Contraindicated.
Ranolazine BIC, DTG, RAL ↔ ranolazine expected No dose adjustment needed.
EVG/c ↑ ranolazine expected Contraindicated.
Corticosteroids
Beclomethasone
Inhaled or intranasal		 BIC, DTG, EVG/c, RAL ↔ glucocorticoid expected No dose adjustment needed.
Budesonide, Ciclesonide, Fluticasone, Mometasone
Inhaled or intranasal		 BIC, DTG, RAL ↔ glucocorticoid expected No dose adjustment needed.
EVG/c ↑ glucocorticoid possible Do not coadminister unless potential benefits of inhaled or intranasal corticosteroid outweigh the risks of systemic corticosteroid adverse effects. Coadministration can result in adrenal insufficiency and Cushing’s syndrome. Consider using an alternative corticosteroid (e.g., beclomethasone).
Betamethasone, Budesonide
Systemic		 BIC, DTG, RAL ↔ INSTI expected

↔ glucocorticoid expected		 No dose adjustment needed.
EVG/c ↑ glucocorticoids possible

↓ EVG possible		 Do not coadminister unless potential benefits of systemic budesonide outweigh the risks of systemic corticosteroid adverse effects. Coadministration can result in adrenal insufficiency and Cushing’s syndrome.
Dexamethasone
Systemic		 BIC ↓ BIC possible Consider alternative corticosteroid for long-term use or alternative ARV. If coadministration is necessary, monitor virologic response to ART.
DTG, RAL ↔ INSTI expected No dose adjustment needed.
EVG/c ↓ EVG and COBI possible Consider alternative corticosteroid for long-term use or alternative ARV. If coadministration is necessary, monitor virologic response to ART.
Prednisone, Prednisolone
Systemic		 BIC, DTG, RAL ↔ glucocorticoid expected No dose adjustment needed.
EVG/c ↑ prednisolone possible Coadministration may be considered if the potential benefits outweigh the risks of systemic corticosteroid adverse effects. If coadministration is necessary, monitor for adrenal insufficiency and Cushing’s syndrome.
Betamethasone, Methylprednisolone, Prednisolone, Triamcinolone
Local injections, including intra-articular, epidural, or intra-orbital		 BIC, DTG, RAL ↔ glucocorticoid expected No dose adjustment needed.
EVG/c ↑ glucocorticoid expected Do not coadminister. Coadministration may result in adrenal insufficiency and Cushing’s syndrome.
Hepatitis C Direct-Acting Antiviral Agents
Daclatasvir BIC, RAL No data No dose adjustment needed.
DTG ↔ daclatasvir No dose adjustment needed.
EVG/c ↑ daclatasvir Decrease daclatasvir dose to 30 mg once daily.
Dasabuvir plus Ombitasvir/ Paritaprevir/ RTV BIC, DTG No data No dose adjustment needed.
EVG/c No data Do not coadminister.
RAL RAL AUC ↑ 134% No dose adjustment needed.
Elbasvir/ Grazoprevir BIC ↔ BIC expected No dose adjustment needed.
DTG ↔ elbasvir

↔ grazoprevir

↔ DTG		 No dose adjustment needed.
EVG/c ↑ elbasvir expected

↑ grazoprevir expected		 Do not coadminister.
RAL ↔ elbasvir

↔ grazoprevir

↔ RAL with elbasvir

RAL AUC ↑ 43% with grazoprevir		 No dose adjustment needed.
Glecaprevir/ Pibrentasvir BIC ↔ BIC expected No dose adjustment needed.
DTG, RAL No significant effect No dose adjustment needed.
EVG/c Glecaprevir AUC ↑ 3-fold

Pibrentasvir AUC ↑ 57%

EVG AUC ↑ 47%		 No dose adjustment needed. If coadministered with TDF, monitor for TDF-related adverse events. Consider monitoring for hepatotoxicity if coadministered with TDF or TAF.
Ledipasvir/ Sofosbuvir BIC, DTG, RAL ↔ DTG and RAL No dose adjustment needed.
EVG/c/TDF/FTC ↑ TDF expected

↑ ledipasvir expected		 Do not coadminister.
EVG/c/TAF/FTC ↔ EVG/c/TAF/FTC expected No dose adjustment needed.
Sofosbuvir All INSTIs ↔ INSTI expected

↔ sofosbuvir expected		 No dose adjustment needed.
Sofosbuvir/ Velpatasvir All INSTIs ↔ INSTI expected

↔ sofosbuvir and velpatasvir expected		 No dose adjustment needed. If coadministered with TDF, monitor for TDF-related adverse events.
Sofosbuvir/ Velpatasvir/ Voxilaprevir EVG/c When Administered with Sofosbuvir/Velpatasvir/Voxilaprevir (400 mg/100 mg/100 mg) plus Voxilaprevir 100 mg:
  • Sofosbuvir AUC ↑ 22%
  • ↔ velpatasvir
  • Voxilaprevir AUC ↑ 2-fold
 No dose adjustment needed. If coadministered with TDF, monitor for TDF-related adverse events. Consider monitoring for hepatotoxicity if coadministered with TDF or TAF.
BIC, DTG, RAL ↔ INSTI expected

↔ sofosbuvir, velpatasvir, and voxilaprevir expected		 No dose adjustment needed.
Herbal Products
St. John’s Wort BIC, DTG ↓ BIC and DTG possible Do not coadminister.
EVG/c ↓ EVG and COBI expected Contraindicated.
Hormonal Therapies
Contraceptives: Non-Oral All INSTIs No data No drug-drug interaction studies have been conducted with INSTIs and non-oral routes of hormone administration. It is unclear whether drug-drug interaction data for oral drugs can be used to predict interactions for non-oral drugs.
Contraceptives – Oral BIC, DTG, RAL ↔ ethinyl estradiol and norgestimate

↔ INSTI		 No dose adjustment needed.
EVG/c Norgestimate AUC, Cmax, and Cmin ↑ >2-fold

Ethinyl estradiol AUC ↓ 25% and Cmin ↓ 44%		 The effects of increases in progestin (norgestimate) are not fully known and may include insulin resistance, dyslipidemia, acne, and venous thrombosis. Weigh the risks and benefits of using the drug and consider using an alternative ARV or contraceptive method.
↑ drospirenone possible Clinical monitoring is recommended, due to the potential for hyperkalemia. Consider using alternative ARV or contraceptive method.
Gender-Affirming Therapy BIC, DTG, EVG/c, RAL ↔ goserelin, leuprolide acetate, and spironolactone expected No dose adjustment needed.
BIC, DTG, RAL ↔ estrogen expected No dose adjustment needed.
↔ testosterone expected No dose adjustment needed.
EVG/c ↓ or ↑ estradiol possible

↑ dutasteride and finasteride possible		 Adjust dutasteride dose as needed based on clinical effects and endogenous hormone concentrations.
↑ testosterone possible Monitor masculinizing effects of testosterone and monitor for adverse effects. Adjust testosterone dose as necessary.
Menopausal Replacement Therapy BIC, DTG, RAL ↔ estrogen expected with estradiol or conjugated estrogen (equine and synthetic)

↔ drospirenone, medroxyprogesterone, and micronized progesterone expected		 No dose adjustment needed.
EVG/c ↓ or ↑ estrogen possible

↑ drospirenone possible

↑ oral medroxyprogesterone possible

↑ oral micronized progesterone possible		 Adjust estrogen and progestin dose as needed based on clinical effects.
Immunosuppressants
Cyclosporine, Everolimus, Sirolimus, Tacrolimus BIC, DTG, RAL ↔ immunosuppressant expected No dose adjustment needed.
EVG/c ↑ immunosuppressant possible Initiate with an adjusted dose of immunosuppressant to account for potential increased concentrations of the immunosuppressant and monitor for immunosuppressant-related adverse events. Therapeutic drug monitoring of immunosuppressant is recommended. Consult with a specialist as necessary.
Lipid-Modifying Agents
Atorvastatin BIC, DTG, RAL ↔ atorvastatin expected No dose adjustment needed.
EVG/c Atorvastatin AUC ↑ 2.6-fold and Cmax ↑ 2.3-fold Titrate statin dose carefully and administer the lowest effective dose while monitoring for adverse events. Do not exceed 20 mg atorvastatin daily.
Lomitapide BIC, DTG, RAL ↔ lomitapide expected No dose adjustment needed.
EVG/c ↑ lomitapide expected Contraindicated.
Lovastatin BIC, DTG, RAL ↔ lovastatin expected No dose adjustment needed.
EVG/c Significant ↑ lovastatin expected Contraindicated.
Pitavastatin, Pravastatin BIC, DTG, RAL ↔ statin expected No dose adjustment needed.
EVG/c No data No data available for dose recommendation.
Rosuvastatin BIC, DTG, RAL ↔ rosuvastatin expected No dose adjustment needed.
EVG/c Rosuvastatin AUC ↑ 38% and Cmax ↑ 89% Titrate statin dose carefully and use the lowest effective dose while monitoring for adverse events.
Simvastatin BIC, DTG, RAL ↔ simvastatin expected No dose adjustment needed.
EVG/c Significant ↑ simvastatin expected Contraindicated.
Narcotics and Treatment for Opioid Dependence
Buprenorphine
Sublingual, buccal, or implant		 BIC, DTG ↔ buprenorphine and norbuprenorphine (active metabolite) expected No dose adjustment needed.
EVG/c Buprenorphine AUC ↑ 35% and Cmin ↑ 66%

Norbuprenorphine (active metabolite) AUC ↑ 42% and Cmin ↑ 57%		 No dose adjustment needed. Monitor for adverse events of buprenorphine. When transferring buprenorphine from transmucosal administration to implantation, monitor to ensure buprenorphine effect is adequate and not excessive.
RAL ↔ buprenorphine and norbuprenorphine (active metabolite) (sublingual)

↔ buprenorphine or norbuprenorphine (active metabolite) expected (implant)		 No dose adjustment needed.
Fentanyl BIC, DTG, RAL ↔ fentanyl expected No dose adjustment needed.
EVG/c ↑ fentanyl Monitor for fentanyl efficacy and adverse events, including potentially fatal respiratory depression.
Lofexidine BIC, DTG, RAL ↔ lofexidine expected No dose adjustment needed.
EVG/c ↑ lofexidine possible Monitor for lofexidine-related adverse events, including symptoms of orthostasis and bradycardia.
Methadone All INSTIs ↔ methadone No dose adjustment needed.
Tramadol BIC, DTG, RAL ↔ tramadol and M1 (active metabolite) expected No dose adjustment needed.
EVG/c ↑ tramadol expected

↓ M1 (active metabolite) possible		 Tramadol dose adjustments may be necessary. Monitor for clinical response and tramadol-related adverse events.
PDE5 Inhibitors
Avanafil BIC, DTG, RAL ↔ avanafil expected No dose adjustment needed.
EVG/c No data Do not coadminister.
Sildenafil BIC, DTG, RAL ↔ sildenafil expected No dose adjustment needed.
EVG/c ↑ sildenafil expected For Treatment of Erectile Dysfunction:
  • Start with sildenafil 25 mg every 48 hours and monitor for adverse effects of sildenafil.

Contraindicated for treatment of PAH.
Tadalafil BIC, DTG, RAL ↔ tadalafil expected No dose adjustment needed.
EVG/c ↑ tadalafil expected For Treatment of Erectile Dysfunction:
  • Start with tadalafil 5 mg and do not exceed a single dose of tadalafil 10 mg every 72 hours. Monitor for adverse effects of tadalafil.

For Treatment of PAH
In Patients on EVG/c >7 Days:
  • Start with tadalafil 20 mg once daily and increase to tadalafil 40 mg once daily based on tolerability.
In Patients on Tadalafil who Require EVG/c:
  • Stop tadalafil ≥24 hours before EVG/c initiation. Seven days after EVG/c initiation, restart tadalafil at 20 mg once daily, and increase to tadalafil 40 mg once daily based on tolerability.
Vardenafil BIC, DTG, RAL ↔ vardenafil expected No dose adjustment needed.
EVG/c ↑ vardenafil expected Start with vardenafil 2.5 mg every 72 hours and monitor for adverse effects of vardenafil.
Sedative/Hypnotics
Buspirone BIC, DTG, RAL ↔ buspirone expected No dose adjustment needed.
EVG/c ↑ buspirone expected Initiate buspirone at a low dose. Dose reduction may be needed.
Clonazepam, Clorazepate, Diazepam, Estazolam, Flurazepam BIC, DTG, RAL ↔ benzodiazepine expected No dose adjustment needed.
EVG/c ↑ benzodiazepine possible Dose reduction of benzodiazepine may be necessary. Initiate with a low dose and monitor for benzodiazepine-related adverse events.

Consider using an alternative benzodiazepine, such as lorazepam, oxazepam, or temazepam.
Midazolam, Triazolam BIC, RAL ↔ benzodiazepine expected No dose adjustment needed.
DTG With DTG 25 mg:
  • ↔ midazolam AUC
 No dose adjustment needed.
EVG/c ↑ midazolam expected

↑ triazolam expected		 Contraindicated. Do not coadminister triazolam or oral midazolam and EVG/c.

Parenteral midazolam can be administered in a closely monitored setting. Consider dose reduction, especially if >1 dose is administered.
Suvorexant BIC, DTG, RAL ↔ suvorexant expected No dose adjustment needed.
EVG/c ↑ suvorexant expected Do not coadminister.
Zolpidem BIC, DTG, RAL ↔ zolpidem expected No dose adjustment needed.
EVG/c ↑ zolpidem expected Initiate zolpidem at a low dose. Dose reduction of zolpidem may be necessary.
Miscellaneous Drugs
Calcifediol BIC, DTG, RAL ↔ calcifediol expected No dose adjustment needed.
EVG/c ↑ calcifediol possible Dose adjustment of calcifediol may be required. Monitor serum 25-hydroxyvitamin D, intact PTH, and serum Ca concentrations.
Cisapride BIC, DTG, RAL ↔ cisapride expected No dose adjustment needed.
EVG/c ↑ cisapride expected Contraindicated.
Colchicine BIC, DTG, RAL ↔ colchicine expected No dose adjustment needed.
EVG/c ↑ colchicine expected Do not coadminister in patients with hepatic or renal impairment.

For Treatment of Gout Flares:
  • Administer a single dose of colchicine 0.6 mg, followed by colchicine 0.3 mg 1 hour later. Do not repeat dose for at least 3 days.
For Prophylaxis of Gout Flares:
  • If original dose was colchicine 0.6 mg twice daily, decrease to colchicine 0.3 mg once daily. If dose was 0.6 mg once daily, decrease 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 twice daily.
Dronabinol BIC, DTG, RAL ↔ dronabinol expected No dose adjustment needed.
EVG/c ↑ dronabinol possible Monitor for dronabinol-related adverse events.
Eluxadoline BIC, DTG, RAL ↔ eluxadoline expected No dose adjustment needed.
EVG/c ↑ eluxadoline possible Monitor for eluxadoline-related adverse events.
Ergot Derivatives BIC, DTG, RAL ↔ dihydroergotamine, ergotamine, and methylergonovine expected No dose adjustment needed.
EVG/c ↑ dihydroergotamine, ergotamine, and methylergonovine expected Contraindicated.
Flibanserin BIC, DTG, RAL ↔ flibanserin expected No dose adjustment needed.
EVG/c ↑ flibanserin expected Contraindicated.
Polyvalent Cation Supplements
Mg, Al, Fe, Ca, Zn, including multivitamins with minerals

Note: Please refer to the Acid Reducers section in this table for recommendations on use with Al-, Mg-, and Ca-containing antacids.		 BIC ↔ BIC AUC if administered simultaneously with Fe or Ca and food

BIC AUC ↓ 33% if administered simultaneously with CaCO3 under fasting conditions

BIC AUC ↓ 63% if administered simultaneously with Fe under fasting conditions		 With Supplements That Contain Ca or Fe:
  • Administer BIC and supplements that contain Ca or Fe together with food.

Do not coadminister BIC under fasting conditions simultaneously with, or 2 hours after, supplements that contain Ca or Fe.
DTG DTG AUC ↓ 39% if administered simultaneously with CaCO3 under fasting conditions

DTG AUC ↓ 54% if administered simultaneously with Fe under fasting conditions

↔ DTG when administered with Ca or Fe supplement simultaneously with food		 With Supplements That Contain Ca or Fe:
  • Administer DTG and supplements that contain Ca or Fe together with food, or administer DTG at least 2 hours before or at least 6 hours after supplement.

Do not coadminister DTG under fasting conditions simultaneously with, or 2 hours after, supplements that contain Ca or Fe.
EVG/c, RAL ↓ INSTI possible If coadministration is necessary, administer INSTI at least 2 hours before or at least 6 hours after supplements that contain polyvalent cations, including but not limited to the following products: cation-containing laxatives; Fe, Ca, or Mg supplements; and sucralfate. Monitor for virologic response.

Many oral multivitamins also contain varying amounts of polyvalent cations; the extent and significance of chelation is unknown.
Key to Symbols:
↑ = increase
↓ = decrease
↔ = no change

Key: Al = aluminum; ART = antiretroviral therapy; ARV = antiretroviral; AUC = area under the curve; BIC = bictegravir; Ca = calcium; CaCO3 = calcium carbonate; CCB = calcium channel blocker; Cmax = maximum plasma concentration; Cmin = minimum plasma concentration; COBI = cobicistat; CrCl = creatinine clearance; CYP = cytochrome P; DAA = direct-acting antiviral; DTG = dolutegravir; ECG = electrocardiogram; EVG = elvitegravir; EVG/c = elvitegravir/cobicistat; Fe = iron; FTC = emtricitabine; HCV = hepatitis C virus; INR= international normalized ratio; INSTI = integrase strand transfer inhibitor; Mg = magnesium; PAH = pulmonary arterial hypertension; PDE5 = Phosphodiesterase Type 5; PTH = parathyroid hormone; RAL = raltegravir; RTV = ritonavir; SSRI = selective serotonin reuptake inhibitors; TAF = tenofovir alafenamide; TCA = tricyclic antidepressants; TDF = tenofovir disoproxil fumarate; Zn = zinc
 

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