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

Drug Interactions

Drug Interactions between Integrase Inhibitors and Other Drugs

(Last updated: April 8, 2015; last reviewed: April 8, 2015)

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

This table provides information on known or predicted PK interactions between INSTIs and non-ARV drugs. The table includes information on interactions with EVG, an INSTI that is available in two formulations:
  1. A fixed-dose combination tablet of EVG/c/TDF/FTC indicated for use as a single-tablet regimen
  2. A stand-alone tablet indicated for use with a RTV-boosted PI (PI/r) and other ARVs in ARV treatment-experienced patients.
In the table, the drug interactions with EVG/c/TDF/FTC and those with EVG plus (PI/r) are presented separately. For several interactions, no dose adjustment is necessary for EVG when given with a concomitant drug; however, since EVG should always be given with a PI/r, clinicians should refer to Table 19a for recommendations on the management of drug interactions resulting from the PI/r used with EVG.

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
Acid Reducers
Aluminium, Magnesium +/- Calcium Containing Antacids

Please refer to the Miscellaneous Drugs section of this table for recommendations on use with other polyvalent cation products (e.g., iron, calcium supplements, multivitamins).
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/TDF/FTC 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 more than 2 hours.
EVG plus (PI/r)
  • EVG AUC ↓ 40% to 50% if given simultaneously with antacid;
  • EVG AUC ↓ 15% to 20% if antacid given 2 hours before or after EVG; ↔ with 4-hour interval
Separate EVG and antacid administration by more than 2 hours.
RAL Al-Mg Hydroxide Antacid:
  • RAL Cmin ↓ 54% to 63%
CaCO3 Antacid:
  • RAL Cmin ↓ 32%
Do not coadminister RAL and Al-Mg hydroxide antacids. Use alternative acid reducing agent.

No dosing separation necessary when coadministering RAL and CaCO3 antacids.
H2-Receptor Antagonists EVG/c/TDF/FTC No significant effect No dosage adjustment necessary.
EVG plus (PI/r) ↔ EVG No dosage adjustment necessary for EVG. Refer to Table 19a for information on PI/r interactions.
 PPIs DTG No significant effect No dosage adjustment necessary.
EVG/c/TDF/FTC No significant effect No dosage adjustment necessary.
EVG plus (PI/r) ↔ EVG No dosage adjustment necessary for EVG. Refer to Table 19a for information on PI/r interactions.
RAL RAL AUC ↑ 212% and Cmin ↑ 46% No dosage adjustment necessary.
Anticoagulants and Antiplatelets
Apixaban
  • EVG/c/TDF/FTC
  • EVG plus (PI/r)
↑ apixaban expected Avoid concomitant use.
Dabigatran
  • EVG/c/TDF/FTC
  • EVG plus (PI/r)
↑ dabigatran possible No dosage adjustment for dabigatran if CrCl >50 mL/min. Avoid coadministration if CrCl <50 mL/min.
Rivaroxaban
  • EVG/c/TDF/FTC
  • EVG plus (PI/r)
↑ rivaroxaban expected Avoid concomitant use.
Ticagrelor
  • EVG/c/TDF/FTC
  • EVG plus (PI/r)
↑ ticagrelor expected Avoid concomitant use.
Vorapaxar
  • EVG/c/TDF/FTC
  • EVG plus (PI/r)
↑ vorapaxar expected Avoid concomitant use.
Warfarin
  • EVG/c/TDF/FTC
  • EVG plus (PI/r)
No data, but warfarin levels may be affected Monitor INR and adjust warfarin dose accordingly.
Anticonvulsants
Carbamazepine
Oxcarbazepine
Phenobarbital
Phenytoin
DTG ↓ DTG possible Consider alternative anticonvulsant.
EVG/c/TDF/FTC
  • ↑ carbamazepine possible
  • ↓ EVG possible
  • ↓ COBI possible
Consider alternative anticonvulsant.
EVG plus (PI/r) ↓ EVG Consider alternative anticonvulsant.
Ethosuximide
  • EVG/c/TDF/FTC
  • EVG plus (PI/r)
↑ ethosuximide possible Clinically monitor for ethosuxamide toxicities.
Antidepressants/Anxiolytics/Antipsychotics
Also see Sedative/Hypnotics section below.
Bupropion EVG/c/TDF/FTC ↑ or ↓ bupropion possible Titrate bupropion dose based on clinical response.
EVG plus (PI/r) ↓ bupropion possible Titrate bupropion dose based on clinical response.
Buspirone
  • EVG/c/TDF/FTC
  • EVG plus (PI/r)
↑ buspirone possible Initiate buspirone at a low dose. Dose reduction may be necessary.
Fluvoxamine
  • EVG/c/TDF/FTC
  • EVG plus (PI/r)
↑ or ↓ EVG possible Consider alternative antidepressant or ARV.
Quetiapine
  • EVG/c/TDF/FTC
  • EVG plus (PI/r)
↑ quetiapine AUC expected. Initiation of quetiapine in a patient receiving EVG/c/TDF/FTC:
  • Start quetiapine at the lowest dose and titrate up as needed. Monitor for quetiapine efficacy and adverse effects.
Initiation of EVG/c/TDF/FTC in a patient receiving a stable dose of quetiapine:
  • Reduce quetiapine dose to 1/6 of the original dose, and closely monitor for quetiapine efficacy and adverse effects.

SSRIs

Citalopram
Escitalopram
Fluoxetine
Paroxetine
Sertraline

EVG/c/TDF/FTC ↑ SSRI possible Initiate with lowest dose of SSRI and titrate dose carefully based on antidepressant response.
EVG plus (PI/r) ↑ or ↓ SSRI possible Titrate SSRI dose based on clinical response.
TCAs

Amitriptyline
Desipramine
Doxepin
Imipramine
Nortriptyline
EVG/c/TDF/FTC Desipramine AUC ↑ 65% Initiate with lowest dose of TCA and titrate dose carefully.
EVG plus (PI/r) ↑ TCA expected Initiate with lowest dose of TCA and titrate dose carefully based on antidepressant response and/or drug levels.
Trazodone
  • EVG/c/TDF/FTC
  • EVG plus (PI/r)
↑ trazodone possible Initiate with lowest dose of trazodone and titrate dose carefully.
Antifungals
Itraconazole EVG/c/TDF/FTC
  • ↑ 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.
EVG plus (PI/r) ↑ EVG possible Refer to Table 19a for PI recommendations.
Posaconazole EVG/c/TDF/FTC
  • ↑ EVG and COBI possible
  • ↑ posaconazole possible
If coadministered, monitor posaconazole concentrations.
EVG plus (PI/r) ↑ EVG possible Refer to Table 19a for PI recommendations.
Voriconazole EVG/c/TDF/FTC
  • ↑ voriconazole expected
  • ↑ EVG and COBI possible
Risk/benefit ratio should be assessed to justify use of voriconazole. If administered, consider monitoring voriconazole level. Adjust dose accordingly.
EVG plus (PI/r) Changes in voriconazole and EVG possible Refer to Table 19a for PI recommendations.
Antimycobacterials
Clarithromycin EVG/c/TDF/FTC
  • ↑ clarithromycin possible
  • ↑ COBI possible
CrCl 50−60 mL/min:
  • Reduce clarithromycin dose by 50%.
CrCl <50 mL/min:
  • EVG/c/TDF/FTC is not recommended.
Rifabutin  DTG Rifabutin (300 mg once daily):
  • DTG AUC ↔ and Cmin ↓ 30%
No dosage adjustment necessary.
EVG/c/TDF/FTC Rifabutin 150 mg every other day with EVG/c/TDF/FTC once daily compared to Rifabutin 300 mg once daily alone:
  • No significant change in rifabutin AUC
  • 25-O-desacetyl-rifabutin AUC ↑ 625%
  • EVG AUC ↓ 21% and Cmin ↓ 67%
Do not coadminister.
EVG plus (PI/r)
  • ↔ EVG
  • ↔ rifabutin AUC
  • 25-O-desacetyl-rifabutin AUC ↑ 951%
Refer to Table 19a for dosing recommendations for rifabutin with PI.
RAL RAL AUC ↑ 19% and Cmin ↓ 20% No dosage adjustment necessary.
Rifampin 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.
Alternative to rifampin should be used in patients with certain suspected or documented INSTI-associated resistance substitutions. Consider using rifabutin.
  • EVG/c/TDF/FTC
  • EVG plus (PI/r)
Significant ↓ EVG and COBI expected Do not coadminister.
RAL RAL 400 mg:
  • RAL AUC ↓ 40% and Cmin ↓ 61%
Compared with RAL 400 mg BID alone, Rifampin with RAL 800 mg BID:
  • RAL AUC ↑ 27% and Cmin ↓ 53%
Dose:
  • RAL 800 mg BID
Monitor closely for virologic response or consider using rifabutin as an alternative rifamycin.
Rifapentine DTG Significant ↓ DTG expected Do not coadminister.
  • EVG/c/TDF/FTC
  • EVG plus (PI/r)
Significant ↓ EVG and COBI expected Do not coadminister.
RAL RAL Cmin ↓ 41% Do not coadminister.
Cardiac Medications
Anti-Arrhythmics

Amiodarone
Bepridil
Digoxin
Disopyramide
Dronedarone
Flecainide
Systemic
lidocaine
Mexilitine
Propafenone
Quinidine
EVG/c/TDF/FTC
  • ↑ anti-arrhythmics possible
  • digoxin Cmax ↑ 41% and AUC no significant change
Use anti-arrhythmics with caution. Therapeutic drug monitoring, if available, is recommended for anti-arrhythmics.
EVG plus (PI/r) ↑ anti-arrhythmics possible Refer to Table 18 and 19a for use of anti-arrhythmics and PI/r
Bosentan EVG/c/TDF/FTC ↑ bosentan possible; In patients on EVG/c/TDF /FTC ≥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/TDF /FTC:
  • Stop bosentan ≥36 hours before EVG/c/FTC/TDF initiation. At least 10 days after initiation of EVG/c/TDF /FTC, resume bosentan at 62.5 mg once daily or every other day based on individual tolerability.
EVG plus (PI/r) ↑ bosentan possible Refer to Table 19a for recommendations on bosentan dosing when used with PI/r.
Beta-blockers (e.g., metoprolol, timolol)
  • EVG/c/TDF/FTC
  • EVG plus (PI/r)
↑ 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).
Dofetilide DTG ↑ dofetilide expected Do not coadminister.
CCBs  
  • EVG/c/TDF/FTC
  • EVG plus (PI/r)
 ↑ CCBs possible Coadminister with caution. Titrate CCB dose and monitor for CCB efficacy and toxicities. 

Refer to  Table 19a for diltiazem plus ATV/r and SQV/r recommendations.
 
Corticosteroids
Dexamethasone (systemic)
 
  • EVG/c/TDF/FTC
  • EVG plus (PI/r)
↓ EVG and COBI possible
↓ EVG possible
 
Use systemic dexamethasone with caution. Monitor virologic response to ART. Consider alternative corticosteroid.
Fluticasone 
Inhaled/Intranasal
 

 
  • EVG/c/TDF/FTC
  • EVG plus (PI/r)
↑ fluticasone possible Coadministration may result in adrenal insufficiency and Cushing’s syndrome. Consider alternative therapy (e.g., beclomethasone), particularly for long-term use.
Methylpredniso-lone, Prednisolone, Triamcinolone 

Local injections, including intra-articular, epidural, intra-orbital
 

 
  • EVG/c/TDF/FTC
  • EVG plus (PI/r)
↑ glucocorticoids expected
Coadministration may result in adrenal insufficiency and Cushing’s syndrome. Do not coadminister.
Hepatitis C Direct Acting Antivirals
Boceprevir
DTG
DTG AUC ↔
No dosage adjustment necessary.
EVG/c/TDF/FTC
No data
Do not coadminister.
EVG plus (PI/r)
↓ boceprevir
Do not coadminister.
RAL
No significant effect
No dosage adjustment necessary.
Dasabuvir 
plus 
Ombitasvir/
Paritaprevir/r

 

RAL RAL AUC ↑ 134%
No dosage adjustment necessary.
DTG No data
No dosing recommendations at this time.
  • EVG plus (PI/r)
  • EVG/c/TDF/FTC

No data
Do not coadminister.
Ledipasvir/
Sofosbuvir

 

EVG/c/TDF/FTC
↑ TDF and ↑ ledipasvir expected
Do not coadminister.
EVG plus (PI/r)
↔ EVG expected
Refer to Table 19a  for PI dosing recommendations.
Simeprevir
EVG/c/TDF/FTC
↑ simeprevir expected
Coadministration is not recommended.
EVG plus (PI/r)
↔ EVG expected
Coadministration is not recommended.
RAL
No significant effect
No dosage adjustment necessary.
Sofosbuvir
All INSTIs No significant effect expected No dosage adjustment necessary.
Herbal Products
St. John's Wort DTG ↓ DTG possible
Do not coadminister.
  • EVG/c/TDF/FTC
  • EVG plus (PI/r)

↓ EVG and COBI possible
Do not coadminister.
Hormonal Contraceptives
Hormonal Contraceptives RAL No clinically significant effect No dosage adjustment necessary.
Norgestimate/
Ethinyl Estradiol

 

DTG No significant effect
No dosage adjustment necessary.
EVG/c/TDF/FTC
  • 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 alternative contraceptive method.
EVG plus (PI/r) ↔EVG 
Refer to Table 19a  for recommendations when used with PI/r.
HMG-CoA Reductase Inhibitors
Atorvastatin 
EVG/c/TDF/FTC
↑ atorvastatin possible
Titrate statin dose slowly and use the lowest dose possible.
EVG plus (PI/r)
↔ EVG expected
Refer to Table 19a  for recommendations when used with PI/r.
Lovastatin
  • EVG/c/TDF/FTC
  • EVG plus (PI/r)
 
Significant ↑ lovastatin expected
Contraindicated. Do not coadminister.
Pitavastatin

Pravastatin

 

 EVG/c/TDF/FTC No data No dosage recommendation
EVG plus (PI/r)
↔ EVG expected
Refer to Table 19a  for recommendations when used with PI/r.
Rosuvastatin EVG/c/TDF/FTC
Rosuvastatin AUC ↑ 38% and Cmax ↑ 89%
Titrate statin dose slowly and use the lowest dose possible.
EVG plus (PI/r)
↔ EVG expected
Refer to Table 19a  for recommendations when used with PI/r.
Simvastatin
  • EVG/c/TDF/FTC
  • EVG plus (PI/r)

Significant ↑ simvastatin expected
Contraindicated. Do not coadminister.
Immunosuppressants
Cyclosporine

Everolimus

Sirolimus

Tacrolimus

 

 
  • EVG/c/TDF/FTC
  • EVG plus (PI/r)
  • ↑ 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 specialist as necessary.
    Narcotics/Treatment for Opioid Dependence
    Buprenorphine
    EVG/c/TDF/FTC
    • Buprenorphine AUC ↑ 35%, Cmax ↑ 12%, and Cmin ↑ 66%
    • Norbuprenorphine AUC ↑ 42%, Cmax ↑ 24%, and Cmin ↑ 57%
     
    No dosage adjustment necessary. Clinical monitoring is recommended. 
    EVG plus (PI/r)
    ↔ EVG expected
    Refer to Table 19a  for recommendations when used with PI/r.
    RAL
    No significant effect
    No dosage adjustment necessary.
    Methadone
    DTG No significant effect
    No dosage adjustment necessary.
    EVG/c/TDF/FTC No significant effect
    No dosage adjustment necessary.
    EVG plus (PI/r) ↓ methadone
    Opioid withdrawal unlikely but may occur. Dosage adjustment of methadone is not usually required. Monitor for opioid withdrawal and increase methadone dose as clinically indicated.
    RAL No significant effect
    No dosage adjustment necessary.
    Neuroleptics
    Perphenazine

    Risperidone

    Thioridazine

     

    EVG/c/TDF/FTC
    ↑ neuroleptic possible
    Initiate neuroleptic at a low dose. Decrease in neuroleptic dose may be necessary.
    PDE5 Inhibitors
    Avanafil
  • EVG/c/TDF/FTC
  • EVG plus (PI/r)

  • No data Coadministration is not recommended.
    Sildenafil  
  • EVG/c/TDF/FTC
  • EVG plus (PI/r)
  • ↑ sildenafil expected

    For treatment of erectile dysfunction:

    • Start with sildenafil 25 mg every 48 hours and monitor for adverse effects of sildenafil.

    For treatment of PAH:

    • Contraindicated
     

    Tadalafil
  • EVG/c/TDF/FTC
  • EVG plus (PI/r)

  • ↑ tadalafil expected

    For treatment of erectile dysfunction:

    • Start with tadalafil 5-mg dose and do not exceed a single dose of 10 mg every 72 hours. Monitor for adverse effects of tadalafil.

      For treatment of PAH
      In patients on EVG/c/TDF/FTC >7 days:
    • Start with tadalafil 20 mg once daily and increase to 40 mg once daily based on tolerability.

      In patients on tadalafil who require EVG/c/TDF/FTC:
    • Stop tadalafil ≥24 hours before EVG/c/TDF/FTC initiation. Seven days after EVG/c/TDF/FTC initiation restart tadalafil at 20 mg once daily, and increase to 40 mg once daily based on tolerability.
     

    Vardenafil 
  • EVG/c/TDF/FTC
  • EVG plus (PI/r)

  • ↑ 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

     

  • EVG/c/TDF/FTC
  • EVG plus (PI/r)

  • ↑ benzodiazepines possible
    Dose reduction of benzodiazepine may be necessary. Initiate with low dose and clinically monitor.

    Consider alternative benzodiazepines to diazepam, such as lorazepam, oxazepam, or temazepam.
     

    Midazolam

    Triazolam

     

    DTG

    With DTG 25 mg: 

    • midazolam AUC ↔
     

    No dosage adjustment necessary.
  • EVG/c/TDF/FTC
  • EVG plus (PI/r)

    • ↑ midazolam expected
    • ↑ triazolam expected
     
    Do not coadminister triazolam or oral midazolam and EVG/c/TDF/FTC or (EVG plus PI).

    Parenteral midazolam can be used with caution in a closely monitored setting. Consider dose reduction, especially if more than one dose is administered.
     

    Suvorexant
  • EVG/c/TDF/FTC
  • EVG plus (PI/r)

  • ↑ suvorexant expected
    Coadministration is not recommended.
    Zolpidem
  • EVG/c/TDF/FTC
  • EVG plus (PI/r)

  • ↑ zolpidem expected
    Initiate zolpidem at a low dose. Dose reduction may be necessary.
    Miscellaneous Drugs
    Colchicine
  • EVG/c/TDF/FTC
  • EVG plus (PI/r)

  • ↑ colchicine expected
    Do not coadminister in patients with hepatic or renal impairment.

    For treatment of gout flares:
    Colchicine 0.6 mg for 1 dose, followed by 0.3 mg 1 hour later. Do not repeat dose for at least 3 days.

    For prophylaxis of gout flares:
    If original 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.
     

    Metformin
    DTG

    DTG 50 mg once daily plus metformin: 

    • Metformin AUC ↑ 79%, Cmax ↑ 66%, and Cmin ↑ 9% 

    DTG 50 mg BID plus metformin: 

    • Metformin AUC↑ 2.4 fold, Cmax ↑ 2 fold, and Cmin ↑ 14%
     
    When starting metformin in patient on DTG, start at low metformin dose and titrate dose to achieve glycemic control and minimize GI symptoms.

    When starting/stopping DTG in patient on metformin, dose adjustment of metformin may be necessary to maintain optimal glycemic control and/or minimize GI symptoms.
     

    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.
     

    All INSTIs 
    • ↓ INSTI possible 
    • DTG ↔ when administered with Ca or Fe supplement simultaneously with food
     
    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.

    DTG and supplements containing Ca or Fe can be taken simultaneously with food.

    Many oral multivitamins also contain varying amounts of polyvalent cations; the extent and significance of chelation is unknown. 
     

    Salmeterol
  • EVG/c/TDF/FTC
  • EVG plus (PI/r)

  • ↑ salmeterol possible
    Do not coadminister because of potential increased risk of salmeterol-associated cardiovascular events.
    Key to Acronyms: Al = aluminum; ART = antiretroviral therapy; ARV = antiretroviral; ATV/r = atazanavir/ritonavir; AUC = area under the curve; BID = twice daily; Ca = calcium; CaCO3 = calcium carbonate; CCB = calcium channel blocker; Cmax = maximum plasma concentration; Cmin = minimum plasma concentration; COBI = cobicistat; CrCl = creatinine clearance; CYP: cytochrome P; DTG = dolutegravir; EVG = elvitegravir; EVG/c/TDF/FTC = elvitegravir/cobicistat/tenofovir disoproxil fumarate/emtricitabine; Fe = iron; GI = gastrointestinal; INR - international normalized ratio; INSTI = integrase strand transfer inhibitor; Mg = magnesium; PAH = pulmonary arterial hypertension; PI = protease inhibitor; PI/r = ritonavir-boosted protease inhibitor; PPI = proton pump inhibitor; RAL = raltegravir; SQV/r = saquanavir/ritonavir; SSRI = selective serotonin reuptake inhibitor; TCA = tricyclic anti-depressant; TDF = tenofovir disoproxil fumarate; Zn = zinc 

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