Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents Living with HIV

The information in the brief version is excerpted directly from the full-text guidelines. The brief version is a compilation of the tables and boxed recommendations.

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Drug-Drug Interactions

Drug Interactions between Integrase Inhibitors and Other Drugs

Last Updated: October 25, 2018; Last Reviewed: October 25, 2018

Table 19d. Drug Interactions Between Integrase Strand Transfer Inhibitors and Other Drugs

This table provides information on known or predicted PK interactions between INSTIs (BIC, DTG, EVG, or RAL) and non-ARV drugs. EVG is always coadministered with COBI. 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.

Table 19d. 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
Alpha-Adrenergic Antagonists for Benign Prostatic Hyperplasia
Alfuzosin BIC, DTG, RAL ↔ expected No dose adjustment necessary.
EVG/c ↑ alfuzosin expected Contraindicated.
Doxazosin BIC, DTG, RAL ↔ expected No dose adjustment necessary.
EVG/c ↑ doxazosin possible Initiate doxazosin at lowest dose and titrate while monitoring for clinical response/toxicity. Dose reduction may be necessary.
Tamsulosin BIC, DTG, RAL ↔ expected No dose adjustment necessary.
EVG/c ↑ tamsulosin expected Coadministration is not recommended. If coadministered, monitor for tamsulosin toxicities.
Terazosin BIC, DTG, RAL ↔ expected No dose adjustment necessary.
EVG/c ↑ terazosin possible Initiate terazosin at lowest dose and titrate while monitoring for clinical response/toxicity. Dose reduction may be necessary.
Silodosin BIC, DTG, RAL ↔ expected No dose adjustment necessary.
EVG/c ↑ silodosin expected Contraindicated.
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, Ca supplements, multivitamins).
BIC ↔ BIC AUC if antacid is given 2 hours after BIC and under fasting conditions

BIC AUC ↓ 79% if given simultaneously with antacid

BIC AUC ↓ 52% if antacid is given 2 hours before BIC
With Antacids Containing Al/Mg or Ca:
  • BIC can be taken under fasting conditions at least 2 hours before antacids containing Al/Mg or Ca.
Do not coadminister BIC simultaneously with, or 2 hours after, antacids containing Al/Mg or Ca.
DTG DTG AUC ↓ 74% if given simultaneously with antacid

DTG AUC ↓ 26% if given 2 hours before antacid
Give DTG at least 2 hours before or at least 6 hours after antacids containing polyvalent cations.
EVG/c EVG AUC ↓ 40% to 50% if given simultaneously with antacid

EVG AUC ↓ 15% to 20% if given 2 hours before or after antacid; ↔ with 4-hour interval
Separate EVG/c/TDF/FTC and antacid administration by >2 hours.
RAL Al/Mg Hydroxide Antacid:
  • RAL Cmin ↓ 49% to 63%
CaCO3 Antacid:
  • RAL (400 mg BID) Cmin ↓ 32%
  • RAL (1200 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 1200 mg once daily: Do not coadminister.
  • RAL 400 mg BID: No dose adjustment or separation necessary.
H2-Receptor Antagonists BIC, DTG, EVG/c No significant effect No dose adjustment necessary.
RAL RAL AUC ↑ 44% and Cmax ↑ 60% No dose adjustment necessary.
PPIs BIC, DTG, EVG/c No significant effect No dose adjustment necessary.
RAL RAL AUC ↑ 37% and Cmin ↑ 24% No dose adjustment necessary.
Anticoagulants and Antiplatelets
Apixaban BIC, DTG, RAL ↔ expected No dose adjustment necessary.
EVG/c ↑ apixaban expected In Patients Requiring Apixaban 2.5 mg Twice Daily:
  • Coadministration is not recommended.
In Patients Requiring Apixaban 5 mg or 10 mg Twice Daily:
  • Reduce apixaban dose by 50%.
Betrixaban BIC, DTG, RAL ↔ expected No dose adjustment necessary.
EVG/c ↑ betrixaban expected Administer initial single dose of betrixaban 80 mg, followed by betrixaban 40 mg once daily.
Dabigatran BIC, DTG, RAL ↔ expected No dose adjustment necessary.
EVG/c ↑ dabigatran expected

Dabigatran AUC ↑ 110% to 127% with COBI 150 mg alone
Dabigatran dosing recommendation depends on indication and renal function. Refer to dabigatran prescribing information for dosing instruction when used with P-gp inhibitors.
Edoxaban BIC, DTG, RAL ↔ expected No dose adjustment necessary.
EVG/c ↔ or ↑ edoxaban expected For Stroke Prevention in Nonvalvular Atrial Fibrillation:
  • No dose adjustment necessary.
For Deep Venous Thrombosis and Pulmonary Embolism:
  • Administer edoxaban 30 mg once daily.
Rivaroxaban BIC, DTG, RAL ↔ expected No dose adjustment necessary.
EVG/c ↑ rivaroxaban expected Coadministration is not recommended.
Ticagrelor BIC, DTG, RAL ↔ expected No dose adjustment necessary.
EVG/c ↑ ticagrelor expected Coadministration is not recommended.
Vorapaxar BIC, DTG, RAL ↔ expected No dose adjustment necessary.
EVG/c ↑ vorapaxar expected Coadministration is not recommended.
Warfarin BIC, DTG, RAL ↔ expected No dose adjustment necessary.
EVG/c ↑ or ↓ warfarin possible Monitor INR and adjust warfarin dose accordingly.
Anticonvulsants
Carbamazepine BIC ↓ BIC possible Consider using an alternative anticonvulsant or ARV.
DTG DTG AUC ↓ 49% Increase DTG dose to 50 mg BID in treatment-naive or treatment-experienced, INSTI-naive patients.

Use alternative anticonvulsant for 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 Coadministration is not recommended.
Eslicarbazepine All INSTIs ↓ INSTI possible

↓ COBI possible
Consider using an alternative anticonvulsant or ARV.
Ethosuximide BIC, DTG, RAL ↔ expected No dose adjustment necessary.
EVG/c ↑ ethosuximide possible Clinically monitor for ethosuximide toxicities.
Lamotrigine BIC, DTG, RAL ↔ expected No dose adjustment necessary.
EVG/c No data Monitor anticonvulsant level and adjust dose accordingly.
Oxcarbazepine All INSTIs ↓ INSTI possible

↓ COBI possible
Consider using an alternative anticonvulsant or ARV.
Phenobarbital
Phenytoin
BIC ↓ BIC possible Coadministration is not recommended.
DTG ↓ DTG possible Coadministration is not recommended.
EVG/c ↓ EVG/c expected Contraindicated.
RAL ↓ or ↔ RAL possible Coadministration is not recommended.
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 ↔ expected No dose adjustment necessary.
EVG/c ↑ aripiprazole expected Administer 25% of the usual aripiprazole dose. Titrate based on clinical monitoring for efficacy and toxicity. 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 ↔ expected No dose adjustment necessary.
EVG/c ↑ brexpiprazole expected Administer 25% of the usual brexpiprazole dose. Titrate based on clinical monitoring for efficacy/toxicity. 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 ↔ expected No dose adjustment necessary.
EVG/c ↑ bupropion possible Titrate bupropion dose based on clinical response.
Buspirone BIC, DTG, RAL ↔ expected No dose adjustment necessary.
EVG/c ↑ buspirone possible Initiate buspirone at a low dose. Dose reduction may be necessary.
Cariprazine BIC, DTG, RAL ↔ expected No dose adjustment necessary.
EVG/c ↑ cariprazine expected Starting Cariprazine in a Patient Already on 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 1.5 mg daily. 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 Already on 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.
Fluvoxamine BIC, DTG, RAL ↔ expected No dose adjustment necessary.
EVG/c ↑ or ↓ EVG possible Consider alternative antidepressant or ARV.
Lurasidone BIC, DTG, RAL ↔ expected No dose adjustment necessary.
EVG/c ↑ lurasidone expected Contraindicated.
Pimavanserin BIC, DTG, RAL ↔ expected Standard doses.
EVG/c ↑ pimavanserin expected Reduce pimavanserin dose by 50%. Titrate dose based on efficacy and toxicity.
Pimozide BIC, DTG, RAL ↔ expected No dose adjustment necessary.
EVG/c ↑ pimozide expected Contraindicated.
Quetiapine BIC, DTG, RAL ↔ expected No dose adjustment necessary.
EVG/c ↑ quetiapine AUC expected Initiation of Quetiapine in a Patient Receiving EVG/c:
  • Start quetiapine at the lowest dose and titrate up as needed. Monitor for quetiapine efficacy and adverse effects.
Initiation of EVG/c 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.
SSRIs
Citalopram, escitalopram, fluoxetine, paroxetine, sertraline
EVG/c ↔ EVG

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

↔ SSRI expected
No dose adjustment necessary.
TCAs
Amitriptyline, desipramine, doxepin, imipramine, nortriptyline
BIC, DTG, RAL ↔ expected No dose adjustment necessary.
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 levels.
Trazodone BIC, DTG, RAL ↔ expected No dose adjustment necessary.
EVG/c ↑ trazodone possible Initiate with lowest dose of trazodone and titrate dose carefully.
Other Antipsychotics
(CYP3A4 and/or CYP2D6 substrates)
EVG/c ↑ antipsychotic possible Initiate antipsychotic at a low dose. Decrease in antipsychotic dose may be necessary.
Antifungals
Isavuconazole BIC ↑ BIC possible No dose adjustment necessary.
EVG/c ↑ isavuconazole expected

↑ EVG and COBI possible
If coadministered, consider monitoring isavuconazole concentrations and assessing virologic response.
Itraconazole BIC ↑ BIC expected No dose adjustment necessary.
DTG, RAL ↔ expected No dose adjustment necessary.
EVG/c ↑ itraconazole expected

↑ EVG and COBI possible
Consider monitoring itraconazole level to guide dosage adjustments. High itraconazole doses (>200 mg/day) are not recommended unless dose is guided by itraconazole levels.
Posaconazole BIC ↑ BIC expected No dose adjustment necessary.
DTG, RAL ↔ expected No dose adjustment necessary.
EVG/c ↑ EVG and COBI possible

↑ posaconazole possible
If coadministered, monitor posaconazole concentrations.
Voriconazole BIC ↑ BIC possible No dose adjustment necessary.
DTG, RAL ↔ expected No dose adjustment necessary.
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 metformin adverse effects.
DTG DTG 50 mg Once Daily plus Metformin 500 mg BID:
  • Metformin AUC ↑ 79% and Cmax ↑ 66%
DTG 50 mg BID plus Metformin 500 mg BID:
  • Metformin AUC ↑ 2.4-fold and Cmax ↑ 2-fold
Start metformin at lowest dose and titrate based on glycemic control. Monitor for metformin adverse effects.

When starting/stopping DTG in patients on metformin, dose adjustment of metformin may be necessary to maintain optimal glycemic control and/or minimize adverse effects of metformin.
RAL ↔ expected No dose adjustment necessary.
Saxagliptin BIC, DTG, RAL ↔ expected No dose adjustment necessary.
EVG/c ↑ saxagliptin expected Limit saxagliptin dose to 2.5 mg once daily.
Dapagliflozin/
Saxagliptin
BIC, DTG, RAL ↔ expected No dose adjustment necessary.
EVG/c ↑ saxagliptin expected Do not coadminister, as this coformulated drug contains 5 mg of saxagliptin.
Antimycobacterials
Clarithromycin BIC, DTG, RAL ↔ expected No dose adjustment necessary.
EVG/c ↑ clarithromycin possible

↑ COBI possible
CrCl 50−60 mL/min:
  • Reduce clarithromycin dose by 50%.
CrCl <50 mL/min:
  • EVG/c is not recommended.
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 necessary.
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 necessary.
Rifampin BIC BIC AUC ↓ 75% Contraindicated.
DTG Rifampin with DTG 50 mg BID Compared to DTG 50 mg BID Alone:
  • DTG AUC ↓ 54% and Cmin ↓ 72%
Rifampin with DTG 50 mg BID Compared to DTG 50 mg Once Daily Alone:
  • DTG AUC ↑ 33% and Cmin ↑ 22%
    Dose:
    • DTG 50 mg BID (instead of 50 mg once daily) for patients without suspected or documented INSTI mutation.
    An alternative to rifampin should be used in patients with certain suspected or documented INSTI-associated resistance substitutions. Consider using rifabutin.
    EVG/c Significant ↓ EVG and COBI expected. Contraindicated.
    RAL RAL 400 mg:
    • RAL AUC ↓ 40% and Cmin ↓ 61%
    Rifampin with RAL 800 mg BID Compared to RAL 400 mg BID Alone:
    • RAL AUC ↑ 27% and Cmin ↓ 53%
    Dose:
    • RAL 800 mg BID, instead of 400 mg BID
    Do not coadminister RAL 1200 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, use standard RAL 400 mg BID doses.

    Do not coadminister with once-daily rifapentine.
    Cardiac Medications
    Antiarrhythmics
    Amiodarone, 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 necessary.

    Coadminister with caution. Clinical monitoring is recommended.
    RAL ↔ expected for the listed antiarrhythmics No dose adjustment necessary.
    EVG/c ↑ antiarrhythmics possible

    Digoxin Cmax ↑ 41% and no significant change in AUC
    Use antiarrhythmics with caution. TDM, if available, is recommended for antiarrhythmics.
    Bosentan BIC, DTG ↓ BIC, DTG possible Standard doses.
    RAL ↔ expected No dose adjustment necessary.
    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.
    Beta-Blockers
    (e.g., metoprolol, timolol)
    BIC, DTG, RAL ↔ expected No dose adjustment necessary.
    EVG/c ↑ beta-blockers possible Beta-blocker dose may need to be decreased; adjust dose based on clinical response.

    Consider using beta-blockers that are not metabolized by CYP450 enzymes (e.g., atenolol, labetalol, nadolol, sotalol).
    CCBs BIC ↑ BIC possible with diltiazem

    ↔ expected for all other CCBs
    No dose adjustment necessary.
    DTG, RAL ↔ expected No dose adjustment necessary.
    EVG/c ↑ CCBs possible Coadminister with caution. Titrate CCB dose and monitor for CCB efficacy and toxicities.

    Refer to Table 19a for diltiazem plus ATV/r recommendations.
    Dofetilide BIC, DTG ↑ dofetilide expected Contraindicated.
    RAL ↔ expected No dose adjustment necessary.
    EVG/c ↑ dofetilide possible Do not coadminister.
    Eplerenone BIC, DTG, RAL ↔ expected No dose adjustment necessary.
    EVG/c ↑ eplerenone expected Contraindicated.
    Ranolazine BIC, DTG, RAL ↔ expected No dose adjustment necessary.
    EVG/c ↑ ranolazine expected Contraindicated.
    Ivabradine BIC, DTG, RAL ↔ expected No dose adjustment necessary.
    EVG/c ↑ ivabradine expected Contraindicated.
    Corticosteroids
    Beclomethasone
    Inhaled or intranasal
    BIC, DTG, EVG/c, RAL ↔ expected No dose adjustment necessary.
    Budesonide, Ciclesonide, Fluticasone, Mometasone
    Inhaled or intranasal
    BIC, DTG, RAL ↔ expected No dose adjustment necessary.
    EVG/c ↑ glucocorticoid possible Coadministration can result in adrenal insufficiency and Cushing’s syndrome. Do not coadminister unless potential benefits of inhaled or intranasal corticosteroid outweigh the risks of systemic corticosteroid adverse effects. Consider using an alternative corticosteroid (e.g., beclomethasone).
    Betamethasone, Budesonide
    Systemic
    BIC, DTG, RAL ↔ expected No dose adjustment necessary.
    EVG/c ↑ glucocorticoids possible

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

    ↔ grazoprevir

    ↔ DTG
    No dose adjustment necessary.
    EVG/c ↑ elbasvir and ↑ grazoprevir expected Coadministration is not recommended.
    RAL ↔ elbasvir

    ↔ grazoprevir

    ↔ RAL with elbasvir

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

    Pibrentasvir AUC ↑ 57%

    EVG AUC ↑ 47%
    No dose adjustment necessary.
    Ledipasvir/ Sofosbuvir EVG/c/TDF/FTC ↑ TDF and ↑ ledipasvir expected Do not coadminister.
    EVG/c/TAF/FTC ↔ EVG/c/TAF/FTC expected No dose adjustment necessary.
    BIC, DTG, RAL ↔ DTG or RAL No dose adjustment necessary.
    Simeprevir BIC, DTG, RAL ↔ expected No dose adjustment necessary.
    EVG/c ↑ simeprevir expected Coadministration is not recommended.
    Sofosbuvir All INSTIs ↔ expected No dose adjustment necessary.
    Sofosbuvir/ Velpatasvir All INSTIs ↔ expected No dose adjustment necessary.
    Sofosbuvir/ Velpatasvir/ Voxilaprevir EVG/c When Given 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 necessary.
    BIC, DTG, RAL ↔ expected No dose adjustment necessary.
    Herbal Products
    St. John’s Wort BIC, DTG ↓ BIC and DTG possible Do not coadminister.
    EVG/c ↓ EVG and COBI possible Contraindicated.
    Hormonal Therapies
    Hormonal Contraceptives
    Oral
    BIC, DTG, RAL ↔ ethinyl estradiol, norgestimate, and DTG or RAL No dose adjustment necessary.
    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 can include insulin resistance, dyslipidemia, acne, and venous thrombosis. Weigh the risks and benefits of the drug and consider using an alternative contraceptive method.
    ↑ drospirenone possible Clinical monitoring is recommended, due to the potential for hyperkalemia.
    Hormonal 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 if oral drug-drug interaction data can be extrapolated beyond oral routes of administration.
    Menopausal Hormone Replacement Therapy BIC, DTG, RAL With Estradiol or Conjugated Estrogen (Equine and Synthetic):
    • ↔ estrogen expected
    ↔ drospirenone, medroxyprogesterone, or micronized progesterone expected
    No dose adjustment necessary.
    EVG/c ↓ estrogen expected

    ↑ drospirenone possible

    ↑ oral medroxyprogesterone possible

    ↑ oral micronized progesterone possible
    Adjust estrogen and progestin dose as needed based on clinical effects.
    Gender-Affirming Hormone Therapy BIC, DTG, RAL ↔ estrogen expected No dose adjustment necessary.
    BIC, DTG, EVG/c, RAL ↔ finasteride, goserelin, leuprolide acetate, spironolactone expected
    EVG/c ↓ estradiol expected

    ↑ dutasteride possible
    Adjust dutasteride dosage as needed based on clinical effects and endogenous hormone concentrations.
    EVG/c ↑ testosterone possible Monitor masculinizing effects of testosterone and for adverse effects. Adjust testosterone dose as necessary.
    BIC, DTG, RAL ↔ testosterone expected No dose adjustment necessary.
    HMG-CoA Reductase Inhibitors
    Atorvastatin BIC, DTG, RAL ↔ expected No dose adjustment necessary.
    EVG/c Atorvastatin AUC ↑ 2.6-fold and Cmax ↑ 2.3-fold Titrate statin dose carefully and use the lowest dose necessary while monitoring for toxicities. Do not exceed 20 mg atorvastatin daily.
    Lovastatin BIC, DTG, RAL ↔ expected No dose adjustment necessary.
    EVG/c Significant ↑ lovastatin expected Contraindicated.
    Pitavastatin, Pravastatin BIC, DTG, RAL ↔ expected No dose adjustment necessary.
    EVG/c No data No dose recommendation.
    Rosuvastatin BIC, DTG, RAL ↔ expected No dose adjustment necessary.
    EVG/c Rosuvastatin AUC ↑ 38% and Cmax ↑ 89% Titrate statin dose carefully and use the lowest dose necessary while monitoring for toxicities.;
    Simvastatin BIC, DTG, RAL ↔ expected No dose adjustment necessary.
    EVG/c Significant ↑ simvastatin expected Contraindicated.
    Immunosuppressants
    Cyclosporine, Everolimus, Sirolimus, Tacrolimus BIC, DTG, RAL ↔ expected No dose adjustment necessary.
    EVG/c ↑ immunosuppressant possible Initiate with an adjusted immunosuppressant dose to account for potential increased concentration and monitor for toxicities. Therapeutic drug monitoring of immunosuppressant is recommended. Consult with a specialist as necessary.
    Narcotics/Treatment for Opioid Dependence
    Buprenorphine
    Sublingual, buccal, or implant
    BIC, DTG ↔ expected No dose adjustment necessary.
    EVG/c Buprenorphine AUC ↑ 35% and Cmin ↑ 66%

    Norbuprenorphine AUC ↑ 42% and Cmin ↑ 57%
    No dose adjustment necessary. Clinical monitoring is recommended. When transferring buprenorphine from transmucosal administration to implantation, monitor to ensure buprenorphine effect is adequate and not excessive.
    RAL ↔ observed (sublingual)

    ↔ expected (implant)
    No dose adjustment necessary.
    Methadone All INSTIs No significant effect No dose adjustment necessary.
    PDE5 Inhibitors
    Avanafil BIC, DTG, RAL ↔ expected No dose adjustment necessary.
    EVG/c No data Coadministration is not recommended.
    Sildenafil BIC, DTG, RAL ↔ expected No dose adjustment necessary.
    EVG/c ↑ 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 BIC, DTG, RAL ↔ expected No dose adjustment necessary.
    EVG/c ↑ tadalafil expected For Treatment of Erectile Dysfunction:
    • Start with tadalafil 5-mg dose 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 ↔ expected No dose adjustment necessary.
    EVG/c ↑ vardenafil expected Start with vardenafil 2.5 mg every 72 hours and monitor for adverse effects of vardenafil.
    Sedative/Hypnotics
    Clonazepam, Clorazepate, Diazepam, Estazolam, Flurazepam BIC, DTG, RAL ↔ expected No dose adjustment necessary.
    EVG/c ↑ 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 BIC, RAL ↔ expected No dose adjustment necessary.
    DTG With DTG 25 mg:
    • ↔ Midazolam AUC
    No dose adjustment necessary.
    EVG/c ↑ midazolam expected

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

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

    For Treatment of Gout Flares:
    • Administer colchicine 0.6 mg for 1 dose, 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 BID, decrease to colchicine 0.3 mg once daily. If regimen 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 BID.
    Enzalutamide DTG ↓ DTG possible Monitor for ARV efficacy.
    BIC, EVG/c ↓ BIC, EVG/c expected Contraindicated.
    RAL ↔ expected No dose adjustment necessary.
    Ergot Derivatives BIC, DTG, RAL ↔ expected No dose adjustment necessary.
    EVG/c ↑ dihydroergotamine, ergotamine, methylergonovine expected Contraindicated.
    Dronabinol BIC, DTG, RAL ↔ expected No dose adjustment necessary.
    EVG/c ↑ dronabinol possible Monitor for dronabinol-related adverse effects.
    Eluxadoline BIC, DTG, RAL ↔ expected No dose adjustment necessary.
    EVG/c ↑ eluxadoline possible Monitor for eluxadoline-related adverse effects.
    Flibanserin BIC, DTG, RAL ↔ expected No dose adjustment necessary.
    EVG/c ↑ flibanserin expected Contraindicated.
    Mitotane BIC, EVG/c ↓ BIC and ↓ EVG/c expected Contraindicated.
    DTG ↓ DTG possible Monitor for ARV efficacy.
    RAL ↔ expected No dose adjustment necessary.
    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 given simultaneously with Fe or Ca and food

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

    BIC AUC ↓ 63% if given simultaneously with Fe under fasting conditions
    With Supplements that Contain Ca or Fe:
    • BIC and supplements containing Ca or Fe can be taken together with food.
    Do not coadminister BIC under fasting conditions simultaneously with, or 2 hours after, supplements containing Ca or Fe.
    DTG DTG AUC ↓ 39% if given simultaneously with calcium carbonate under fasting conditions

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

    ↔ DTG when administered with Ca or Fe supplement simultaneously with food
    With Supplements That Contain Ca or Fe:
    • DTG and supplements containing Ca or Fe can be taken together with food; alternately, 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 containing Ca or Fe.
    EVG/c, RAL ↓ INSTI possible If coadministration is necessary, give INSTI at least 2 hours before or at least 6 hours after supplements containing polyvalent cations, including but not limited to the following products: cation-containing laxatives; Fe, Ca, or Mg supplements; and sucralfate. Monitor for virologic efficacy.

    Many oral multivitamins also contain varying amounts of polyvalent cations; the extent and significance of chelation is unknown.
    Salmeterol BIC, DTG, RAL ↔ expected No dose adjustment necessary.
    EVG/c ↑ salmeterol possible Do not coadminister, due to potential increased risk of salmeterol-associated cardiovascular events.
    Key to Symbols:
    ↑ = increase
    ↓ = decrease
    ↔ = no change

    Key to Acronyms: Al = aluminum; ART = antiretroviral therapy; ARV = antiretroviral; ATV/r = atazanavir/ritonavir; AUC = area under the curve; BIC = bictegravir; 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; CYP = cytochrome P; DTG = dolutegravir; EVG = elvitegravir; EVG/c = elvitegravir/cobicistat; Fe = iron; FTC = emtricitabine; INR= international normalized ratio; INSTI = integrase strand transfer inhibitor; Mg = magnesium; PAH = pulmonary arterial hypertension; PI = protease inhibitor; PK = pharmacokinetic; PTH = parathyroid hormone; RAL = raltegravir; RTV = ritonavir; SSRI = selective serotonin reuptake inhibitors; TAF = tenofovir alafenamide; TCA = tricyclic antidepressants; TDF = tenofovir disoproxil fumarate; TDM = therapeutic drug monitoring; Zn = zinc

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