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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: July 14, 2016; last reviewed: July 14, 2016)

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

This table provides information on known or predicted pharamacokinetic interactions between INSTIs (DTG, EVG, or RAL) and non-ARV drugs. EVG is always coadministered with either COBI or RTV. In this table, the drug interactions with EVG/c products and those with EVG plus PI/r are presented separately. When EVG is given with a PI/r, clinicians should refer to Table 19a for recommendations on the management of drug interactions of concomitant medications and the specific 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 (eg, 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
EVG plus PI/r

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.
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 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 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
EVG plus PI/r
↑ apixaban expected Avoid concomitant use.
Dabigatran EVG/c
EVG plus PI/r
↑ dabigatran possible No dosage adjustment for dabigatran if CrCl >50 mL/min. Avoid coadministration if CrCl <50 mL/min.
Edoxaban EVG/c
EVG plus PI/r
↑ edoxaban expected Avoid concomitant use.
Rivaroxaban EVG/c
EVG plus PI/r
↑ rivaroxaban expected Avoid concomitant use.
Ticagrelor EVG/c
EVG plus PI/r
↑ ticagrelor expected Avoid concomitant use.
Vorapaxar EVG/c
EVG plus PI/r
↑ vorapaxar expected Avoid concomitant use.
Warfarin EVG/c
EVG plus PI/r
Warfarin levels may be affected Monitor INR and adjust warfarin dose accordingly.
Anticonvulsants
Carbamazepine
Phenobarbital
Phenytoin
DTG ↓ DTG possible Consider alternative anticonvulsant.
EVG/c

carbamazepine AUC ↑ 43%

EVG AUC ↓ 69% and Cmin ↓ >99%

↓ COBI expected

Contraindicated. Do not coadminister.
EVG plus PI/r ↓ EVG Consider alternative anticonvulsant.
Ethosuximide EVG/c
EVG plus PI/r
↑ ethosuximide possible Clinically monitor for ethosuxamide toxicities.
Oxcarbazepine DTG
EVG/c
EVG plus PI/r
↓ INSTI possible Consider alternative anticonvulsant.
Antidepressants/Anxiolytics/Antipsychotics
Also see Sedative/Hypnotics section below.
Bupropion EVG/c ↑ 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
EVG plus PI/r
↑ buspirone possible Initiate buspirone at a low dose. Dose reduction may be necessary.
Fluvoxamine EVG/c
EVG plus PI/r
↑ or ↓ EVG possible Consider alternative antidepressant or ARV.
Quetiapine EVG/c
EVG plus PI/r
↑ 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 ↑ 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.
RAL

↔ RAL

↔ citalopram

No dosage adjustment necessary.
TCAs

Amitriptyline
Desipramine
Doxepin
Imipramine
Nortriptyline
EVG/c 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
EVG plus PI/r
↑ trazodone possible Initiate with lowest dose of trazodone and titrate dose carefully.
Antifungals
Isavuconazole EVG/c

↑ isavuconazole expected

↑ EVG and COBI possible

If coadministered, consider monitoring isavuconazole concentrations and assess virologic response.
EVG plus PI/r Changes in isavuconazole and EVG possible Refer to Table 19a for PI recommendations.
Itraconazole 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.
EVG plus PI/r ↑ EVG possible Refer to Table 19a for PI recommendations.
Posaconazole EVG/c

↑ 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

↑ 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

↑ clarithromycin possible

↑ COBI possible

CrCl 50−60 mL/min:
  • Reduce clarithromycin dose by 50%.
CrCl <50 mL/min:
  • EVG/c is not recommended.
Rifabutin  DTG Rifabutin (300 mg once daily):
  • DTG AUC ↔ and Cmin ↓ 30%
No dosage 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%, 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%, Cmin ↓ 72%

Rifampin with DTG 50 mg BID compared to DTG 50 mg once daily alone:

DTG AUC ↑ 33%, Cmin ↑ 22%

Dose:

DTG 50 mg BID (instead of 50 mg once daily) for patients without suspected or documented INSTI mutation.

Alternative to rifampin should be used in patients with certain suspected or documented INSTI-associated resistance substitutions. Consider using rifabutin.
EVG/c
EVG plus PI/r
Significant ↓ EVG and COBI expected Do not coadminister.
RAL RAL 400 mg:

RAL AUC ↓ 40%, Cmin ↓ 61%

Compared with RAL 400 mg BID alone, Rifampin with RAL 800 mg BID:

RAL AUC ↑ 27%, Cmin ↓ 53%

Dose:

RAL 800 mg BID

Monitor closely for virologic response or consider using rifabutin as an alternative rifamycin.
Rifapentine DTG Significant ↓ DTG expected Do not coadminister.
EVG/c
EVG plus PI/r
Significant ↓ EVG and COBI expected Do not coadminister.
RAL Rifapentine 600 mg once daily:

RAL Cmin ↓ 41%

Rifapentine 900 mg once weekly:

RAL AUC ↑ 71%, Cmin ↓ 12%

Do not coadminister with once-daily rifapentine.

For once-weekly rifapentine, use standard doses.
Cardiac Medications
Antiarrhythmics

Amiodarone
Bepridil
Digoxin
Disopyramide
Dronedarone
Flecainide
Systemic
lidocaine
Mexilitine
Propafenone
Quinidine
EVG/c

↑ antiarrhythmics possible

digoxin Cmax ↑ 41% and AUC no significant change

Use antiarrhythmics with caution. Therapeutic drug monitoring, if available, is recommended for antiarrhythmics.
EVG plus PI/r ↑ antiarrhythmics possible Refer to Table 18 and 19a for use of antiarrhythmics and PI/r.
Bosentan 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.
EVG plus PI/r ↑ bosentan possible Refer to Table 19a for recommendations on bosentan dosing when used with PI/r.
Beta-blockers
(eg, metoprolol, timolol)
EVG/c
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 (eg, atenolol, labetalol, nadolol, sotalol).

CCBs EVG/c
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.
Dofetilide DTG ↑ dofetilide expected Do not coadminister.
Eplerenone EVG/c
EVG plus PI/r
↑ eplerenone expected Contraindicated. Do not coadminister.
Ivabradine EVG/c
EVG plus PI/r
↑ ivabradine expected Contraindicated. Do not coadminister.
Corticosteroids
Dexamethasone
(systemic)
EVG/c ↓ EVG and COBI possible
Use systemic dexamethasone with caution. Monitor virologic response to ART. Consider alternative corticosteroid.
EVG plus PI/r ↓ EVG possible
Fluticasone 
Inhaled/Intranasal
EVG/c
EVG plus PI/r
↑ fluticasone possible Coadministration may result in adrenal insufficiency and Cushing’s syndrome. Consider alternative therapy (eg, beclomethasone), particularly for long-term use.
Methylprednisolone, Prednisolone, Triamcinolone 

Local injections, including intra-articular, epidural, intra-orbital
EVG/c
EVG plus PI/r
↑ glucocorticoids expected
Coadministration may result in adrenal insufficiency and Cushing’s syndrome. Do not coadminister.
Hepatitis C Direct Acting Antivirals
Daclatasvir
DTG Daclatasvir ↔ No dosage adjustment necessary.
EVG/c ↑ Daclatasvir Decrease daclastavir dose to 30 mg once daily.
EVG plus PI/r ↑ Daclatasvir expected Decrease daclastavir dose to 30 mg once daily, regardless of which PI/r is used, except for TPV/r. Do not coadminister EVG plus TPV/r with daclastavir.
RAL No data No dosage adjustment necessary.
Dasabuvir plus
Ombitasvir/ Paritaprevir/r
DTG No data No dosing recommendations at this time.

EFG plus PI/r

EVG/c

No data Do not coadminister.
RAL RAL AUC ↑ 134% No dosage adjustment necessary.
Elbasvir/Grazoprevir DTG

Elbasvir ↔

Grazoprevir ↔

DTG ↔

No dosage adjustment necessary.
EVG plus PI/r Refer to Table 19a for PI dosing recommendations.
EVG/c ↑ elbasvir, grazoprevir expected Coadministration is not recommended.
RAL

Elbasvir ↔

Grazoprevir ↔

RAL ↔ with elbasvir

RAL AUC ↑ 43% with grazoprevir

No dosage 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 dosage adjustment necessary.
EVG plus PI/r ↔ EVG expected Refer to Table 19a for PI dosing recommendations.
DTG
RAL
↔ DTG or RAL No dosage adjustment necessary.
Simeprevir
DTG ↔ DTG expected No dosage adjustment necessary.
EVG/c
↑ 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
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

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
↑ atorvastatin possible
Titrate statin dose slowly and use the lowest dose possible.
EVG plus PI/r
↔ EVG expected
Refer to Table 19a  for dosing recommendations when used with PI/r.
Lovastatin
EVG/c
EVG plus PI/r
Significant ↑ lovastatin expected
Contraindicated. Do not coadminister.
Pitavastatin
Pravastatin
EVG/c No data No dosage recommendation
EVG plus PI/r
↔ EVG expected
Refer to Table 19a  for dosing recommendations when used with PI/r.
Rosuvastatin EVG/c
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 dosing recommendations when used with PI/r.
Simvastatin
EVG/c
EVG plus PI/r
Significant ↑ simvastatin expected
Contraindicated. Do not coadminister.
Immunosuppressants
Cyclosporine
Everolimus
Sirolimus
Tacrolimus

EVG/c
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
Sublingual/Buccal/Implant
EVG/c

Buprenorphine AUC ↑ 35%, Cmax ↑ 12%, and Cmin ↑ 66%

Norbuprenorphine AUC ↑ 42%, Cmax ↑ 24%, and Cmin ↑ 57%

No dosage adjustment necessary. Clinical monitoring is recommended.

When transferring buprenorphine from transmucosal to implantation, monitor to ensure buprenorphine effect is adequate and not excessive.
EVG plus PI/r
↔ EVG expected
Refer to Table 19a  for dosing recommendations when used with PI/r.
RAL
No significant effect observed (sublingual) or expected (implant) No dosage adjustment necessary.
Methadone
DTG No significant effect
No dosage adjustment necessary.
EVG/c 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
↑ neuroleptic possible
Initiate neuroleptic at a low dose. Decrease in neuroleptic dose may be necessary.
PDE5 Inhibitors
Avanafil
EVG/c
EVG plus PI/r
No data Coadministration is not recommended.
Sildenafil

EVG/c 

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
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 >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:
  • Stop tadalafil ≥24 hours before EVG/c initiation. Seven days after EVG/c initiation, restart tadalafil at 20 mg once daily, and increase to 40 mg once daily based on tolerability.
Vardenafil 
EVG/c
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
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
EVG plus PI/r

↑ midazolam expected

↑ triazolam expected

Do not coadminister triazolam or oral midazolam and EVG/c 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
EVG plus PI/r
↑ suvorexant expected
Coadministration is not recommended.
Zolpidem
EVG/c
EVG plus PI/r
↑ zolpidem expected
Initiate zolpidem at a low dose. Dose reduction may be necessary.
Miscellaneous Drugs
Colchicine
EVG/c
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.
Flibanserin EVG/c
EVG plus PI/r
↑ flibanserin expected Contraindicated. Do not coadminister.
Metformin
DTG DTG 50 mg once daily plus metformin 500 mg BID

Metformin AUC ↑ 79%, Cmax ↑ 66% 

DTG 50 mg BID plus metformin 500 mg BID:

Metformin AUC↑ 2.4 fold, Cmax ↑ 2 fold

Limit metformin dose to no more than 1,000 mg per day.

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
EVG plus PI/r
↑ salmeterol possible
Do not coadminister due to 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; c or COBI = cobicistat; CrCl = creatinine clearance; CYP = cytochrome P; DTG = dolutegravir; EVG = elvitegravir; EVG/c = elvitegravir/cobicistat; 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 antidepressant; Zn = zinc

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