Lead author: Joshua R. Sawyer, PharmD, AAHIVP, with the Medical Care Criteria Committee, reviewed February 2021
RECOMMENDATION |
|
Caveats: Many of the formal interaction studies involving ARVs are carried out in small samples of patients who do not have HIV or other known comorbid conditions. Although the results of such studies may be extrapolated to larger populations of patients with HIV, several important considerations should be kept in mind. The U.S. Food and Drug Administration has issued draft guidance on the design, analysis, and clinical implications of drug-drug interaction studies to aid in the interpretation of future interactions [FDA 2017].
Given the limited financial and clinical resources available to researchers, it is impossible to design and run randomized controlled trials to determine the effects of every possible drug-drug interaction. Therefore, many drug-drug interactions are theoretical—based not on evidence or data, but instead on what is known about the pharmacokinetic properties of the various individual agents. As a result, there is often an incomplete correlation between predicted drug-drug interactions and in vivo pharmacokinetics. There is also significant person-to-person variability in drug-drug interactions, and small sample sizes may not be adequate to identify the effects such an interaction may have on a specific patient.
Patients with HIV may be at greater risk of pharmacokinetic variability due to the nature of the infection itself or the drugs taken for antiretroviral therapy (ART). At the same time, both the medications and HIV itself may alter the physiologic processes of the liver, kidney, brain, gastrointestinal system, or other organ systems, which may affect absorption, distribution, metabolism, or elimination of pharmacologically active agents. Additionally, patients with HIV are at a greater risk of the effects of polypharmacy, and the effects of multiple drugs on the pharmacokinetic pathways or pharmacodynamic effects of a single agent are not well documented. Therefore, when treating patients who are taking several medications for multiple comorbid conditions, expert advice may be necessary and is often recommended to ensure appropriate management of drug-drug interactions.
ARVs can have complex interactions with other medications commonly used by patients with HIV. When questions arise regarding the management of drug-drug interactions not described here, a clinician cannot assume that no interaction exists. Several theoretical drug-drug interactions may exist given the unique nature of the pharmacokinetic and pharmacodynamic effects seen with each medication, and the clinical significance of these interactions is not always known. The interactions described here reflect medications used to treat comorbid conditions commonly seen in primary care or family health clinics.
Prescribers should become familiar with the potential for adverse effects and drug-drug interactions with all co-administered drugs they prescribe for their patients. Clinicians who manage the care of only a few patients with HIV may find it difficult to remember the potential mechanisms or effects of interactions between ARVs and other medications commonly seen in primary care settings, and drug-drug interactions may lead to symptoms attributed to ARV medications rather than the physiologic effect of an interaction. Consultation with a pharmacist or healthcare provider experienced in prescribing ART may assist in determining the true cause of symptoms and/or adverse effects. Adverse drug-drug interactions can be prevented when patients receive anticipatory guidance regarding possible interactions between prescribed medications and commonly available over-the-counter medications or supplements.
- Boosted Protease Inhibitor (PI) Drug-Drug Interactions
- Integrase Strand Transfer Inhibitor (INSTI) Drug-Drug Interactions
- Non-Nucleoside Reverse Transcriptase Inhibitor (NNRTI) Drug-Drug Interactions
- Nucleoside Reverse Transcriptase (NRTI) Drug-Drug Interactions
Reference
FDA. Clinical Drug Interaction Studies—Study Design, Data Analysis, and Clinical Implications. Guidance for Industry. 2017 Oct. https://www.fda.gov/drugs/drug-interactions-labeling/drug-interactions-relevant-regulatory-guidance-and-policy-documents [accessed 2019 Jan 9]
Boosted Protease Inhibitors (PIs): ATZ, DRV
Lead author: Joshua R. Sawyer, PharmD, AAHIVP, with the Medical Care Criteria Committee, updated February 2021
Table 2: Boosted Atazanavir (ATV) Interactions (also see drug package inserts) | ||
Print this table | ||
Class or Drug | Mechanism of Action | Clinical Comments |
Proton pump inhibitors (PPIs) |
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Histamine 2 receptor antagonist (H2RA) |
ATV requires an acidic gastric pH for absorption, and acid-reducing agents interfere with the absorption of ATV. |
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Antacids |
ATV requires an acidic gastric pH for absorption, and acid-reducing agents interfere with the absorption of ATV. | Give ATV 2 hours before or 1 to 2 hours after antacids (and all buffered medications). |
Simvastatin, lovastatin |
|
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Pravastatin |
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Use the lowest effective dose of pravastatin and monitor for adverse events, including myopathy and rhabdomyolysis. |
Atorvastatin |
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Rosuvastatin |
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Fluvastatin | Interaction has not been studied, but potential for moderate increase is possible. | Do not use, but if clinical use is desired, use the lowest effective dose; monitor closely for safety and efficacy before increasing statin dose. |
Pitavastatin, pravastatin | Although moderate increases are possible, low doses are considered safe when used with boosted PIs. | Use with lowest effective doses; dose adjustments are not necessary when using these statins with boosted EVG. |
Anticoagulants, factor Xa inhibitors |
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PY2-antagonists |
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Aliskiren | Boosted PIs inhibit P-gP, which may decrease aliskiren elimination, increasing risk of adverse events. | Do not coadminister. |
Atenolol | COBI-boosted PIs may increase atenolol concentrations via inhibition of MATE-1 elimination. Similar interaction is not seen with RTV-boosted PIs. | If atenolol must be used with boosted PIs, use RTV as the PK booster. |
Calcium channel blockers (CCBs) | Boosted PIs may increase CCB concentrations by as much as 50%. | Decrease original dose of CCB by as much as 50% when using with boosted PIs and slowly titrate to effect. |
Anti-arrhythmic drugs |
Boosted PIs inhibit anti-arrhythmic drug metabolism via CYP3A and CYP2D6. | Avoid concomitant use to avoid increased risk of QT prolongation and other adverse events of anti-arrhythmic drugs. |
Anti-mineral corticoid (eplerenone) |
ATV inhibits the hepatic CYP3A4 isoenzyme and can increase the serum concentrations of eplerenone. | Avoid concomitant use due to increased risk of hyperkalemia and hypotension. |
Glyburide | Drug is mainly metabolized via CYP3A, so concentrations are increased with boosted ARVs. | Use the lowest effective dose of glyburide and monitor for signs of hypoglycemia. |
Saxagliptin | Levels may be increased via inhibition of CYP3A. | Limit dose of saxagliptin to 2.5 mg once per day. |
Canagliflozin | Could lead to reduced canagliflozin exposure as a result of ATV’s induction of UGT enzymes. | With RTV-boosted ATV and inadequate glycemic control, consider increasing dose to 300 mg per day if patient is tolerating 100 mg and has GFR >60 ml/min/1.73 m2. |
GLP-1 agonists | Exenatide may inhibit gastric secretion, reducing absorption of ATV. | Consider taking ATV 4 hours before exenatide. |
Long-acting beta agonists | Inhibition of CYP3A increases plasma concentrations of these agents. |
|
Inhaled, intranasal, and injected corticosteroids |
Boosted PIs are strong inhibitors of CYP3A, and many corticosteroids are substrates of these enzymes. Risk of Cushing’s syndrome when coadministered with the following corticosteroids:
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Oral prednisone |
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Benzodiazepines |
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Antipsychotics |
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HCV PIs (“-previr” drugs) |
Inhibition of CYP3A4 and OATP1B1 by ATV may increase the plasma concentrations of other PIs. | Avoid concomitant use to avoid adverse events of NS3/4A PIs. |
Daclatasvir |
Boosted PIs inhibit daclatasvir metabolism via CYP3A4. | Decrease daclatasvir dose to 30 mg per day. |
Etravirine (ETR) |
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Sleep medications |
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Non-opioid pain medications |
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Other antiplatelet drugs |
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Antidiabetic drugs |
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Trazodone | May increase trazodone concentrations. | Monitor antidepressant and/or sedative effects. |
Anticonvulsants |
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Opioid analgesics | Complex mechanisms of metabolism and the formation of both active and inactive metabolites create interactions of unclear significance between these drugs and boosted PIs. | Monitor for signs of opiate toxicity and analgesic effect, and dose these analgesics accordingly. |
Tramadol | Tramadol exposure is increased with inhibition of CYP3A, but this reduces conversion to the more potent active metabolite seen when tramadol is metabolized by CYP2D6. | When tramadol is given with COBI or RTV, monitoring for tramadol-related side effects and for the analgesic effect may be required as clinically indicated; adjust tramadol dosage if needed. |
Hormonal contraceptives |
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Erectile and sexual dysfunction agents |
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Methadone, buprenorphine (BUP), naloxone (NLX) |
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Immunosuppressants |
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Rifabutin, rifampin |
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Abbreviations: ARV, antiretroviral; ATV, atazanavir; AUC, area under the curve; BUP, buprenorphine; COBI, cobicistat; CrCl, creatinine clearance; CYP, cytochrome P450; EVG, elvitegravir; GFR, glomerular filtration rate; GLP-1, glucagon-like peptide-1; HCV, hepatitis C virus; INR, international normalized ratio; MATE, multidrug and toxin extrusion; NLX, naloxone; NS3/4A, nonstructural protein 3/4A; PK, pharmacokinetic; OATP, organic anion transporting polypeptide; PDE-5, phosphodiesterase type 5; P-gP, P-glycoprotein; PI, protease inhibitor; RTV, ritonavir; TCA, tricyclic antidepressant; TFV, tenofovir; TZD, thiazolidinedione; UGT, uridine diphosphate glucuronosyltransferase. No significant interactions/no dose adjustments necessary: Common oral antibiotics; drugs used as antihypertensive medicines; asthma and allergy medications; tobacco and smoking cessation products; alcohol, disulfiram, and acamprosate; gender-affirming hormones. |
Table 3: Boosted Darunavir (DRV) Interactions (also see drug package inserts) | ||
Print this table | ||
Class or Drug | Mechanism of Action | Clinical Comments |
Simvastatin, lovastatin |
|
|
Pravastatin |
|
If pravastatin use is necessary, use the lowest effective dose and monitor for signs of toxicity. |
Atorvastatin |
|
|
Rosuvastatin |
|
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Fluvastatin | Interaction has not been studied, but potential for moderate increase is possible. | Do not use, but if clinical use is desired, use the lowest effective dose; monitor closely for safety and efficacy before increasing statin dose. |
Factor Xa inhibitors |
|
|
Antiplatelet drugs and PY2-antagonists |
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Atenolol | Eliminated via OCT2 and MATE1, which are inhibited by DTG and BIC; limited potential for atenolol levels to increase if given with these INSTIs. |
|
Calcium channel blockers (CCBs) | Boosted PIs may increase CCB concentrations by as much as 50%. | Decrease the original dose of CCB by as much as 50% when using with boosted PIs and slowly titrate to effect. |
Eplerenone |
DRV inhibits the hepatic CYP3A4 isoenzyme and can increase the serum concentrations of eplerenone. | Avoid concomitant use to avoid increased risk of hyperkalemia and hypotension. |
Antidiabetic drugs |
|
|
Long-acting beta-agonists | Inhibition of CYP3A increases plasma concentrations of these agents. |
|
Inhaled and injected corticosteroids |
Boosted PIs are strong inhibitors of CYP3A and many corticosteroids are substrates of these enzymes. Risk of Cushing’s syndrome when coadministered with the following corticosteroids:
|
|
Oral prednisone |
|
Avoid concomitant use unless risk outweighs benefits, because of increased risk of corticosteroid-related adverse events. |
Benzodiazepines |
|
|
Antipsychotics |
|
|
HCV PIs (“-previr” drugs) |
Inhibition of CYP3A4, P-gP, and OATP1B1 by boosted PIs may increase the plasma concentrations of other PIs. | Avoid concomitant use to avoid adverse events of NS3/4A PIs. |
Daclatasvir |
Boosted PIs inhibit daclatasvir metabolism via CYP3A4. | Decrease daclatasvir dose to 30 mg per day. |
Sleep medications |
|
|
Non-opioid pain medications |
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Omeprazole | No significant interactions noted. | Do not exceed omeprazole 40 mg per day. |
Trazadone | May increase trazodone concentrations. | Monitor antidepressant and/or sedative effects. |
Carbamazepine, oxcarbazepine, phenobarbital, phenytoin | Coadministration may significantly reduce concentrations of ARV agents through induction of CYP450 system. |
|
Zonisamide | Zonisamide concentrations may be increased through CYP3A4 inhibition. | Monitor efficacy and adverse effects; adjust dose as needed. |
Opioid analgesics | Complex mechanisms of metabolism and the formation of both active and inactive metabolites create interactions of unclear significance between these drugs and boosted PIs. | Monitor for signs of opiate toxicity and analgesic effect and dose these analgesics accordingly. |
Tramadol | Tramadol exposure is increased with inhibition of CYP3A, but this reduces conversion to the more potent active metabolite seen when tramadol is metabolized by CYP2D6. | When tramadol is given with COBI or RTV monitoring for tramadol-related side effects and for the analgesic effect may be required as clinically indicated; adjust tramadol dosage if needed. |
Hormonal contraceptives |
|
Norethindrone: Consider alternative or additional contraceptive method or alternative ARV agent. |
Erectile and sexual dysfunction agents |
|
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Methadone, buprenorphine (BUP), naloxone (NLX), and naltrexone |
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Immunosuppressants |
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Rifabutin, rifampin |
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Abbreviations: ARV, antiretroviral; BIC, bictegravir; BUP, buprenorphine; COBI, cobicistat; CYP, cytochrome P450; DTG, dolutegravir; GFR, glomerular filtration rate; GLP-1, glucagon-like peptide-1; HCV, hepatitis C virus; INR, international normalized ratio; INSTI: integrase strand transfer inhibitor; MATE, multidrug and toxin extrusion; NLX, naloxone; NS3/4A, nonstructural protein 3/4A; OATP, organic anion transporting polypeptide; OCT, organic cation transporter; P-gP, P-glycoprotein; PI, protease inhibitor; RTV, ritonavir; TCA, tricyclic antidepressant; UGT, uridine diphosphate glucuronosyltransferase. No significant interactions/no dose adjustments necessary: Common oral antibiotics; acid-reducing agents; polyvalent cations; asthma and allergy medications; tobacco and smoking cessation products; alcohol, disulfiram, and acamprosate; gender-affirming hormones. |
References
Aquilante CL, Kiser JJ, Anderson PL, et al. Influence of SLCO1B1 polymorphisms on the drug-drug interaction between darunavir/ritonavir and pravastatin. J Clin Pharmacol 2012;52(11):1725-1738. [PMID: 22174437]
Brooks KM, George JM, Kumar P. Drug interactions in HIV treatment: complementary & alternative medicines and over-the-counter products. Expert Rev Clin Pharmacol 2017;10(1):59-79. [PMID: 27715369]
Busti AJ, Bain AM, Hall RG, 2nd, et al. Effects of atazanavir/ritonavir or fosamprenavir/ritonavir on the pharmacokinetics of rosuvastatin. J Cardiovasc Pharmacol 2008;51(6):605-610. [PMID: 18520949]
Chauvin B, Drouot S, Barrail-Tran A, et al. Drug-drug interactions between HMG-CoA reductase inhibitors (statins) and antiviral protease inhibitors. Clin Pharmacokinet 2013;52(10):815-831. [PMID: 23703578]
Custodio J, Wang H, Hao J, et al. Pharmacokinetics of cobicistat boosted-elvitegravir administered in combination with rosuvastatin. J Clin Pharmacol 2014;54(6):649-656. [PMID: 24375014]
Daveluy A, Raignoux C, Miremont-Salame G, et al. Drug interactions between inhaled corticosteroids and enzymatic inhibitors. Eur J Clin Pharmacol 2009;65(7):743-745. [PMID: 19399485]
Egan G, Hughes CA, Ackman ML. Drug interactions between antiplatelet or novel oral anticoagulant medications and antiretroviral medications. Ann Pharmacother 2014;48(6):734-740. [PMID: 24615627]
Falcon RW, Kakuda TN. Drug interactions between HIV protease inhibitors and acid-reducing agents. Clin Pharmacokinet 2008;47(2):75-89. [PMID: 18193914]
Feinstein MJ, Achenbach CJ, Stone NJ, et al. A systematic review of the usefulness of statin therapy in HIV-infected patients. Am J Cardiol 2015;115(12):1760-1766. [PMID: 25907504]
Kakadiya PP, Higginson RT, Fulco PP. Ritonavir-boosted protease inhibitors but not cobicistat appear safe in HIV-positive patients ingesting dabigatran. Antimicrob Agents Chemother 2018;62(2). [PMID: 29133562]
Keating GM, Plosker GL. Eplerenone: A review of its use in left ventricular systolic dysfunction and heart failure after acute myocardial infarction. Drugs 2004;64(23):2689-2707. [PMID: 15537370]
Kellick KA, Bottorff M, Toth PP, et al. A clinician’s guide to statin drug-drug interactions. J Clin Lipidol 2014;8(3 Suppl):S30-46. [PMID: 24793440]
Kis O, Zastre JA, Hoque MT, et al. Role of drug efflux and uptake transporters in atazanavir intestinal permeability and drug-drug interactions. Pharm Res 2013;30(4):1050-1064. [PMID: 23224979]
Kiser JJ, Carten ML, Aquilante CL, et al. The effect of lopinavir/ritonavir on the renal clearance of tenofovir in HIV-infected patients. Clin Pharmacol Ther 2008;83(2):265-272. [PMID: 17597712]
Kishi T, Matsunaga S, Iwata N. Suvorexant for primary insomnia: A systematic review and meta-analysis of randomized placebo-controlled trials. PLoS One 2015;10(8):e0136910. [PMID: 26317363]
McKeage K, Perry CM, Keam SJ. Darunavir: a review of its use in the management of HIV infection in adults. Drugs 2009;69(4):477-503. [PMID: 19323590]
Orrell C, Felizarta F, Nell A, et al. Pharmacokinetics of etravirine combined with atazanavir/ritonavir and a nucleoside reverse transcriptase inhibitor in antiretroviral treatment-experienced, HIV-1-infected patients. AIDS Res Treat 2015;2015:938628. [PMID: 25664185]
Roden DM, Darbar D, Kannankeril PJ. Antiarrhythmic drugs. In: Willerson JT, Wellens HJ, Cohn JN et al., editors. Cardiovascular medicine. London: Springer London; 2007. 2085-2102.
Saberi P, Phengrasamy T, Nguyen DP. Inhaled corticosteroid use in HIV-positive individuals taking protease inhibitors: a review of pharmacokinetics, case reports and clinical management. HIV Med 2013;14(9):519-529. [PMID: 23590676]
Samineni D, Desai PB, Sallans L, et al. Steady-state pharmacokinetic interactions of darunavir/ritonavir with lipid-lowering agent rosuvastatin. J Clin Pharmacol 2012;52(6):922-931. [PMID: 21712498]
Soriano V, Labarga P, Fernandez-Montero JV, et al. Drug interactions in HIV-infected patients treated for hepatitis C. Expert Opin Drug Metab Toxicol 2017;13(8):807-816. [PMID: 28689442]
Teng R. Ticagrelor: Pharmacokinetic, pharmacodynamic and pharmacogenetic profile: An update. Clin Pharmacokinet 2015;54(11):1125-1138. [PMID: 26063049]
Vildhede A, Karlgren M, Svedberg EK, et al. Hepatic uptake of atorvastatin: influence of variability in transporter expression on uptake clearance and drug-drug interactions. Drug Metab Dispos 2014;42(7):1210-1218. [PMID: 24799396]
Wang X, Boffito M, Zhang J, et al. Effects of the H2-receptor antagonist famotidine on the pharmacokinetics of atazanavir-ritonavir with or without tenofovir in HIV-infected patients. AIDS Patient Care STDS 2011;25(9):509-515. [PMID: 21770762]
Integrase Strand Transfer Inhibitors (INSTIs): BIC, DTG, Boosted EVG, RAL
Lead author: Joshua R. Sawyer, PharmD, AAHIVP, with the Medical Care Criteria Committee, updated February 2021
Table 4: Bictegravir (BIC) Interactions (also see drug package inserts) | ||
Print this table | ||
Class or Drug | Mechanism of Action | Clinical Comments |
Antacids | BIC chelates with cations, forming insoluble compounds that inactivate both drugs. | Administer BIC 2 hours before or 6 hours after taking antacids containing polyvalent cations |
Other polyvalent cations | BIC chelates with cations, which can inactivate both drugs. | Calcium- or iron-containing supplements: If taken with food, BIC can be taken at the same time. If not taken with food, these supplements should be administered as with antacids. |
Dofetilide |
BIC inhibits renal OCT2 and MATE1, and these transporters eliminate dofetilide. | Avoid concomitant use (may cause QT prolongation or torsade de pointes). |
Metformin [Custodio, et al. 2017] |
BIC inhibits renal OCT2 and MATE1, which are involved in elimination of metformin. |
|
Atenolol | Atenolol is eliminated via OCT2 and MATE1, which are inhibited by BIC. Coadministration may increase levels of atenolol |
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Valproic acid | Coadministration may significantly decrease BIC concentrations. |
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Cyclosporine | May increase BIC concentrations to a modest degree via P-gP inhibition. | Monitor for BIC-related adverse events. |
Rifabutin, rifampin |
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Abbreviations: CYP, cytochrome P450; DTG, dolutegravir; INSTI, integrase strand transfer inhibitor; MATE, multidrug and toxin extrusion; OCT, organic cation transporter; P-gP, P-glycoprotein; TDM, therapeutic drug monitoring. No significant interactions/no dose adjustments necessary: Common oral antibiotics; anticoagulants; antiplatelet drugs; statins; acid-reducing agents; asthma and allergy medications; long-acting beta agonists; inhaled and injected corticosteroids; antidepressants; benzodiazepines; sleep medications; antipsychotics; non-opioid pain medications; opioid analgesics and tramadol; hormonal contraceptives; erectile and sexual dysfunction agents; tobacco and smoking cessation products; alcohol, disulfiram, and acamprosate; methadone, buprenorphine, naloxone, and naltrexone; gender-affirming hormones. |
Table 5: Dolutegravir (DTG) Interactions (also see drug package inserts) | ||
Print this table | ||
Class or Drug | Mechanism of Action | Clinical Comments |
Dofetilide [Max and Vibhakar 2014; Feng and Varma 2016] |
DTG inhibits renal OCT2 and MATE1, and these transporters eliminate dofetilide. | Avoid concomitant use (may cause QT prolongation or torsade de pointes). |
Metformin [Song, et al. 2016; Gervasoni, et al. 2017] |
DTG inhibits renal OCT2, MATE1, and MATE2, which are involved in elimination of metformin. |
|
Divalent and trivalent cations (aluminum, magnesium, calcium, zinc, etc.) [Cottrell, et al. 2013; Song, et al. 2015] |
DTG chelates with cations forming insoluble compounds that inactivate both drugs |
|
Iron salts [Song, et al. 2015] |
DTG chelates with cations, forming insoluble compounds that inactivate both drugs. |
|
Atenolol |
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Rifabutin, rifampin |
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Rifampin: When used concomitantly, dose DTG at 50 mg twice per day instead of 50 mg once per day. |
Abbreviations: ARV, antiretroviral; CYP, cytochrome P450; INSTI, integrase strand transfer inhibitor; MATE, multidrug and toxin extrusion; OCT, organic cation transporter. No significant interactions/no dose adjustments necessary: Common oral antibiotics; anticoagulants; antiplatelet drugs; statins; acid-reducing agents; asthma and allergy medications; long-acting beta agonists; inhaled and injected corticosteroids; antidepressants; benzodiazepines; sleep medications; antipsychotics; non-opioid pain medications; opioid analgesics and tramadol; hormonal contraceptives; erectile and sexual dysfunction agents; tobacco and smoking cessation products; alcohol, disulfiram, and acamprosate; methadone, buprenorphine, naloxone, and naltrexone; immunosuppressants; gender-affirming hormones. |
Table 6: Boosted Elvitegravir (EVG) Interactions (also see drug package inserts) | ||
Print this table | ||
Class or Drug | Mechanism of Action | Clinical Comments |
Antacids | EVG chelates with polyvalent cations, which may reduce the efficacy of both agents. | Administer at least 2 hours before or 6 hours after EVG. |
Factor Xa inhibitors [Egan, et al. 2014] |
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Warfarin | Could potentially decrease (or more rarely) increase metabolism of warfarin. |
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Cilostazol, ticagrelor, clopidogrel [Egan, et al. 2014; Tseng, et al. 2017] |
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Aliskiren | COBI inhibits P-gP, which may decrease aliskiren elimination, increasing risk of adverse events. | Do not coadminister. |
Other polyvalent cations (calcium, zinc, iron, etc.) | EVG chelates with polyvalent cations. | Administer at least 2 hours before or 6 hours after EVG. |
Atenolol | COBI-boosted EVG may increase atenolol concentrations via inhibition of MATE-1 elimination. |
|
Calcium channel blockers (CCBs) | COBI-boosted EVG may increase CCB concentrations by as much as 50%. | Decrease the original dose of CCB by as much as 50% when using with boosted EVG and slowly titrate to effect. |
Eplerenone [Keating and Plosker 2004; Tseng, et al. 2017] |
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Simvastatin, lovastatin [Perry 2014] |
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Avoid concomitant use (may increase muscle aches and risk of rhabdomyolysis). |
Pitavastatin [Tseng, et al. 2017] |
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Pravastatin [Tseng, et al. 2017] |
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Atorvastatin [Tseng, et al. 2017] |
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Rosuvastatin |
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Fluvastatin |
Interaction has not been studied, but potential for moderate increase is possible. |
Do not use, but if clinical use is desired, use the lowest effective dose; monitor closely for safety and efficacy before increasing statin dose. |
Antidiabetic drugs |
|
|
Long-acting beta-agonists (formoterol, salmeterol, etc.) |
|
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Inhaled and injected corticosteroids |
Risk of Cushing’s syndrome when coadministered with the following:
|
|
Trazodone |
May increase trazodone concentrations. |
Monitor antidepressant and/or sedative effects. |
Alprazolam, clonazepam, diazepam |
These benzodiazepines are substrates of CYP3A and may be increased in the presence of strong inhibitors of this enzyme. |
|
Antipsychotics |
Several of these agents are substrates of CYP3A, and inhibitors of this enzyme may increase their concentrations. |
|
PDE5 inhibitors [Perry 2014] |
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Suvorexant [Kishi, et al. 2015] |
|
Avoid concomitant use or use the lowest effective dose (may increase somnolence, dizziness, and risk of sleep hangover). |
Zolpidem, eszopiclone |
These drugs are CYP3A substrates and may be increased by strong inhibitors of this enzyme. |
|
Carbamazepine, oxcarbazepine, phenobarbital, phenytoin |
Coadministration may significantly reduce concentrations of ARV agents through induction of CYP450 system |
|
Eletriptan |
Eletriptan is a CYP3A substrate and concentrations may be increased if given with strong inhibitors of this enzyme. |
Do not coadminister. Select an alternative triptan medication. |
Opioid analgesics |
Complex mechanisms of metabolism and formation of both active and inactive metabolites create interactions of unclear significance between these drugs and boosted EVG. |
Monitor for signs of opiate toxicity and analgesic effect and dose these analgesics accordingly. |
Tramadol |
Tramadol exposure is increased with inhibition of CYP3A, but this reduces conversion to the more potent active metabolite seen when tramadol is metabolized by CYP2D6. |
When tramadol is given with COBI or RTV, monitoring for tramadol-related side effects and for the analgesic effect may be required as clinically indicated; adjust tramadol dosage if needed. |
Hormonal contraceptives |
Drospirenone: Potential for hyperkalemia. |
|
Immunosuppressants |
|
|
Rifabutin, rifampin |
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|
Abbreviations: ARV, antiretroviral; COBI, cobicistat; CYP, cytochrome P450; GFR, glomerular filtration rate; INR, international normalized ratio; MATE, multidrug and toxin extrusion; OATP, organic anion transporting polypeptide; P-gP, P-glycoprotein; PI, protease inhibitor; RTV, ritonavir; TDM, therapeutic drug monitoring; UGT, uridine glucuronosyltransferase. No significant interactions/no dose adjustments necessary: Common oral antibiotics; acid-reducing agents; asthma and allergy medications; tobacco and smoking cessation products; alcohol, disulfiram, and acamprosate; methadone, buprenorphine, naloxone, and naltrexone; gender-affirming hormones. |
Table 7: Raltegravir (RAL) Interactions (also see drug package inserts) | ||
Print this table | ||
Class or Drug | Mechanism of Action | Clinical Comments |
Antacids and other polyvalent cations [Kiser, et al. 2010; Calcagno, et al. 2015; Krishna, et al. 2016] |
RAL chelates with cations, forming insoluble compounds that inactivate both drugs. |
|
Anticonvulsants | Coadministration with strong inducers of UGT1A1 (phenytoin, phenobarbital, etc.) may decrease RAL concentrations. | Coadministration with strong inducers of UGT1A1 are not recommended |
Rifabutin, rifampin |
|
|
Abbreviation: UGT1A1, uridine diphosphate glucuronosyltransferase 1A1. No significant interactions/no dose adjustments necessary: Common oral antibiotics; drugs used as antihypertensive agents; anticoagulants; antiplatelet drugs; statins; antidiabetic drugs; acid-reducing agents; asthma and allergy medications; long-acting beta-agonists; inhaled and injected corticosteroids; antidepressants; benzodiazepines; sleep medications; antipsychotics; non-opioid pain medications; opioid analgesics and tramadol; hormonal contraceptives; erectile and sexual dysfunction agents; tobacco and smoking cessation products; alcohol, disulfiram, and acamprosate; methadone, buprenorphine, naloxone, and naltrexone; immunosuppressants; gender-affirming hormones. |
References
Calcagno A, D’Avolio A, Bonora S. Pharmacokinetic and pharmacodynamic evaluation of raltegravir and experience from clinical trials in HIV-positive patients. Expert Opin Drug Metab Toxicol 2015;11(7):1167-1176. [PMID: 26073580]
Cottrell ML, Hadzic T, Kashuba AD. Clinical pharmacokinetic, pharmacodynamic and drug-interaction profile of the integrase inhibitor dolutegravir. Clin Pharmacokinet 2013;52(11):981-994. [PMID: 23824675]
Custodio J, Wang H, Hao J, et al. Pharmacokinetics of cobicistat boosted-elvitegravir administered in combination with rosuvastatin. J Clin Pharmacol 2014;54(6):649-656. [PMID: 24375014]
Custodio J, West S, Yu A, et al. Lack of clinically relevant effect of bictegravir (BIC, B) on metformin (MET) pharmacokinetics (PK) and pharmacodynamics (PD). Open Forum Infect Dis 2017;4(suppl_1):S429-S429. [Link]
Egan G, Hughes CA, Ackman ML. Drug interactions between antiplatelet or novel oral anticoagulant medications and antiretroviral medications. Ann Pharmacother 2014;48(6):734-740. [PMID: 24615627]
Feng B, Varma MV. Evaluation and quantitative prediction of renal transporter-mediated drug-drug interactions. J Clin Pharmacol 2016;56 Suppl 7:S110-121. [PMID: 27385169]
Gervasoni C, Minisci D, Clementi E, et al. How relevant is the interaction between dolutegravir and metformin in real life? J Acquir Immune Defic Syndr 2017;75(1):e24-e26. [PMID: 28114188]
Keating GM, Plosker GL. Eplerenone: A review of its use in left ventricular systolic dysfunction and heart failure after acute myocardial infarction. Drugs 2004;64(23):2689-2707. [PMID: 15537370]
Kiser JJ, Bumpass JB, Meditz AL, et al. Effect of antacids on the pharmacokinetics of raltegravir in human immunodeficiency virus-seronegative volunteers. Antimicrob Agents Chemother 2010;54(12):4999-5003. [PMID: 20921313]
Kishi T, Matsunaga S, Iwata N. Suvorexant for primary insomnia: A systematic review and meta-analysis of randomized placebo-controlled trials. PLoS One 2015;10(8):e0136910. [PMID: 26317363]
Krishna R, East L, Larson P, et al. Effect of metal-cation antacids on the pharmacokinetics of 1200 mg raltegravir. J Pharm Pharmacol 2016;68(11):1359-1365. [PMID: 27671833]
Max B, Vibhakar S. Dolutegravir: a new HIV integrase inhibitor for the treatment of HIV infection. Future Virol 2014;9(11):967-978.
Perry CM. Elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate single-tablet regimen (Stribild(R)): a review of its use in the management of HIV-1 infection in adults. Drugs 2014;74(1):75-97. [PMID: 24338165]
Song I, Borland J, Arya N, et al. Pharmacokinetics of dolutegravir when administered with mineral supplements in healthy adult subjects. J Clin Pharmacol 2015;55(5):490-496. [PMID: 25449994]
Song I, Zong J, Borland J, et al. The effect of dolutegravir on the pharmacokinetics of metformin in healthy subjects. J Acquir Immune Defic Syndr 2016;72(4):400-407. [PMID: 26974526]
Tseng A, Hughes CA, Wu J, et al. Cobicistat versus ritonavir: Similar pharmacokinetic enhancers but some important differences. Ann Pharmacother 2017;51(11):1008-1022. [PMID: 28627229]
Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs): DOR, RPV, EFV, ETR
Lead author: Joshua R. Sawyer, PharmD, AAHIVP, with the Medical Care Criteria Committee, updated February 2021
Table 8: Doravirine (DOR) Interactions (also see drug package inserts) | ||
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Class or Drug | Mechanism of Action | Clinical Comments |
Strong inducers or inhibitors of CYP3A |
DOR is a substrate of CYP3A, and as such, drugs that affect its metabolism affect its concentrations. |
|
Carbamazepine, oxcarbazepine, phenobarbital, phenytoin | Coadministration may significantly reduce concentrations of ARV agents through induction of CYP450 system. |
|
Abbreviations: ARV, antiretroviral; CYP, cytochrome P450. No significant interactions/no dose adjustments necessary: Common oral antibiotics; drugs used as antihypertensive agents; anticoagulants; antiplatelet drugs; statins; antidiabetic drugs; polyvalent cations; asthma and allergy medications; long-acting beta-agonists; inhaled and injected corticosteroids; antidepressants; benzodiazepines; sleep medications; antipsychotics; non-opioid pain medications; opioid analgesics and tramadol; hormonal contraceptives; erectile and sexual dysfunction agents; tobacco and smoking cessation products; alcohol, disulfiram, and acamprosate; methadone, buprenorphine, naloxone, and naltrexone; immunosuppressants; gender-affirming hormones. |
Table 9: Rilpivirine (RPV) Interactions (also see drug package inserts) | ||
Print this table | ||
Class or Drug | Mechanism of Action | Clinical Comments |
Proton pump inhibitors (PPIs) [Schafer and Short 2012] |
|
Avoid concomitant use; may decrease RPV absorption. |
Histamine 2 antagonists (H2As) [Schafer and Short 2012] |
|
|
Antacids [Schafer and Short 2012] |
|
Give antacids 2 hours before or 4 hours after RPV. |
GLP-1 agonists | Caution should be exercised when coadministering with RPV and GLP-1 agonists, such as exenatide, due to their potential to inhibit gastric secretion, thereby reducing absorption of RPV. Furthermore, exenatide has the potential to slow gastric emptying. | Consider taking RPV 4 hours before exenatide. |
Dexamethasone [Welz, et al. 2017] |
Dexamethasone is an inducer of CYP3A, which is primarily responsible for the metabolism of RPV. |
Systemic dexamethasone: 1) Contraindicated; consider use of alternative agents. 2) If using more than single dose, do not coadminister. |
Anti-arrhythmic drugs [Sanford 2012] |
Supratherapeutic doses of RPV have caused QT prolongation, and additive effects may be seen. | Avoid concomitant use (may cause QT prolongation and torsades de pointes). |
Long-acting beta-agonists (LABAs) | RPV and drugs from the LABA class may both theoretically increase QT interval, especially at high doses. |
|
Antipsychotics | No significant interactions noted. | No dose adjustments necessary, but avoid excess doses of either antipsychotic or RPV because excess doses of both drugs may increase risk of QT prolongation. |
Carbamazepine, oxcarbazepine, phenobarbital, phenytoin | Coadministration may significantly reduce concentrations of ARV agents through induction of CYP450 system. |
|
Methadone, buprenorphine (BUP) |
|
|
Strong inducers or inhibitors of CYP3A | RPV is a substrate of CYP3A, and as such, drugs that affect its metabolism affect its concentrations. |
|
Abbreviations: ARV, antiretroviral; BUP, buprenorphine; CYP, cytochrome P450 No significant interactions/no dose adjustments necessary: Common oral antibiotics; drugs used as antihypertensive agents; anticoagulants; antiplatelet drugs; statins; asthma and allergy medications; antidepressants; benzodiazepines; sleep medications; anticonvulsants not specifically stated above; non-opioid pain medications; opioid analgesics and tramadol; erectile and sexual dysfunction agents; tobacco and smoking cessation products; alcohol, disulfiram, and acamprosate; naloxone and naltrexone; immunosuppressants; gender-affirming hormones. |
Table 10: Efavirenz (EFV) Interactions (also see drug package inserts) | ||
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Class or Drug | Mechanism of Action | Clinical Comments |
Warfarin | Could potentially increase (or, more rarely, decrease) metabolism of warfarin. |
|
Bupropion |
EFV may induce CYP2B6, the enzyme that is primarily responsible for metabolism of bupropion. | Monitor clinical effect and increase as needed, but do not exceed recommended maximum dose. |
Levonorgestrel/norgestimate, levonorgestrel [Carten, et al. 2012; Scarsi, et al. 2016] |
EFV may induce CYP3A, the enzyme that is primarily responsible for metabolism of levonorgestrel. | Effectiveness of levonorgestrel or norgestimate may be decreased. |
Cilostazol |
May reduce concentrations of cilostazol. |
Monitor for antiplatelet effect; may be necessary to use an alternative antiplatelet drug or alternative ARV agent. |
Dipyridamole | EFV may induce UGT enzymes, which are responsible for metabolism. | Monitor for antiplatelet effect; use another ARV agent if necessary. |
Ticagrelor, clopidogrel | EFV reduce ticagrelor concentrations and the conversion of clopidogrel to its active metabolite. | Use with EFV may reduce the antiplatelet effect; monitor closely and use an alternative ARV agent if necessary. |
Statins |
|
|
Pioglitazone | EFV may increase concentrations by inhibition of CYP2C8. No significant interactions expected. | Monitor for signs of adverse events with EFV; decrease dose if necessary. |
Saxagliptin, sitagliptin | EFV may decrease concentration. | Monitor for efficacy; if necessary, increase dose of the DPP-4 inhibitor. |
Inhaled and injected corticosteroids | Coadministration may reduce concentrations of corticosteroids. | Systemic dexamethasone: Consider alternative corticosteroid for long-term use; if benefits of use outweigh risks, monitor virologic response. |
Trazodone | May decrease trazodone concentrations. | Monitor antidepressant and/or sedative effects. |
Bupropion | EFV induces bupropion metabolism. | Monitor clinical effect and increase as needed, but do not exceed recommended maximum dose. |
Benzodiazepines | Alprazolam, diazepam: Potential for reduced alprazolam and diazepam concentrations. |
|
Sleep medications | Zolpidem: Potential for reduced concentrations of zolpidem. |
|
Antipsychotics |
|
|
Carbamazepine, oxcarbazepine, phenobarbital, phenytoin | Coadministration may significantly reduce concentrations of antiretroviral agents through induction of CYP450 system. |
|
Lamotrigine, zonisamide | EFV may reduce efficacy of lamotrigine or zonisamide. | Monitor efficacy; titrate dose slowly as needed. |
Opioid analgesics and tramadol |
|
|
Hormonal contraceptives | Decreased concentrations of combined progestins. |
|
Erectile and sexual dysfunction agents |
|
|
Methadone [Clarke, et al. 2001; Gruber and McCance-Katz 2010; Kharasch, et al. 2012] |
EFV induces methadone metabolism via CYP3A4. Reduces methadone concentrations. | Monitor for signs and symptoms of opioid withdrawal and titrate methadone dose to effect. |
Buprenorphine (BUP) [McCance-Katz, et al. 2006; Gruber and McCance-Katz 2010] |
|
|
NS3/4A inhibitors (glecaprevir, simeprevir, grazoprevir, etc.) [Soriano, et al. 2017; Garrison, et al. 2018] |
EFV induces NS3/4A PI metabolism via CYP3A4. | Concomitant use is not recommended (may result in failure of HCV treatment regimens containing PIs, reducing SVR rates and increasing resistance). |
Daclatasvir [Soriano, et al. 2017; Garrison, et al. 2018] |
EFV induces daclatasvir metabolism via CYP3A4. | Increase daclatasvir dose to 60 mg per day. |
Sofosbuvir/ velpatasvir (available as coformulated product) [Greig 2016] |
EFV may decrease levels of velpatasvir through induction of CYP3A. | Coadministration of sofosbuvir/ velpatasvir is contraindicated. |
Cyclosporine, tacrolimus | Concentrations may be lower when used with EFV. |
|
Rifabutin, rifampin |
|
Rifabutin: If EFV and rifabutin are used concomitantly, increase dose of rifabutin by 50%, especially if rifabutin is dosed 3 times weekly. |
Gender-affirming hormones |
|
|
Abbreviations: ARV, antiretroviral; BUP, buprenorphine; CYP, cytochrome P450; HCV, hepatitis C virus; INR, international normalized ratio; NNRTI, non-nucleoside reverse transcriptase inhibitor; NS3/4A, nonstructural protein 3/4A; PDE5, phosphodiesterase type 5; PI, protease inhibitor; SVR, sustained viral response; UGT, uridine diphosphate glucoronosyltransferase. No significant interactions/no dose adjustments necessary: Common oral antibiotics; drugs used as antihypertensive medicines; acid-reducing agents; polyvalent cations; asthma and allergy medications; long-acting beta-agonists; non-opioid pain medications; alcohol, disulfiram, and acamprosate. |
Table 11: Etravirine (ETR) Interactions (also see drug package inserts) | ||
Print this table | ||
Class or Drug | Mechanism of Action | Clinical Comments |
Aliskiren | ETR is a minor inhibitor of P-gP and may minimally increase concentrations of aliskiren, but this has not been studied. |
|
Warfarin | Could potentially increase (or more rarely decrease) metabolism of warfarin. |
|
Antiplatelet drugs [Rathbun and Liedtke 2010; Kakuda, et al. 2011] |
|
|
Statins |
|
|
Saxagliptin, sitagliptin |
ETR may decrease concentration. |
Monitor for efficacy; if necessary, increase dose of the DPP-4 inhibitor. |
Inhaled and injected corticosteroids |
Coadministration may reduce concentrations of corticosteroids. |
Systemic dexamethasone: Consider alternative corticosteroid for long-term use; if benefits of use outweigh risks, monitor virologic response |
Trazodone |
May decrease trazodone concentrations. |
Monitor antidepressant and/or sedative effects. |
Bupropion |
No significant interactions. |
Monitor clinical effect and increase as needed, but do not exceed recommended maximum dose. |
Alprazolam |
Potential for reduced alprazolam concentrations. |
Monitor for benzodiazepine withdrawal. |
Diazepam |
Potential for reduced diazepam concentrations. |
No dose adjustments necessary. |
Sleep medications |
Zolpidem: Potential for reduced concentrations of zolpidem. |
|
Antipsychotics |
|
|
Carbamazepine, oxcarbazepine, phenobarbital, phenytoin |
Coadministration may significantly reduce concentrations of ARV agents through induction of CYP450 system. |
|
Lamotrigine, zonisamide |
May reduce efficacy of lamotrigine or zonisamide. |
Monitor efficacy; titrate dose slowly as needed. |
Hormonal contraceptives |
Information is based on what is known with EFV drug interactions |
|
Erectile and sexual dysfunction agents |
|
|
Bupropion |
No significant interactions noted. |
Monitor clinical effect and increase as needed, but do not exceed recommended maximum dose. |
Buprenorphine |
No significant interactions expected. |
Monitor for signs of withdrawal or opioid toxicity and titrate dose of opioid or antagonist as required. |
Methadone |
May slightly increase concentrations of methadone. |
|
Cyclosporine, tacrolimus |
Concentrations may be lower when used with ETR. |
|
HCV PIs (“-previr” drugs) [Kaur, et al. 2015; Yeh 2015; Mak, et al. 2018] |
ETR may decrease levels of HCV PIs through induction of CYP3A. |
Do not coadminister HCV PIs with ETR. |
Sofosbuvir/ velpatasvir (available as coformulated product) [Greig 2016] |
ETR may decrease levels of velpatasvir through induction of CYP3A and (weak) inhibition of P-gP. |
Do not coadminister sofosbuvir/ velpatasvir with ETR. |
Daclatasvir [Garrison, et al. 2018] |
ETR induces CYP3A, lowering daclatasvir levels. |
Increase dose of daclatasvir to 90 mg per day. |
Atazanavir (ATV) [Orrell, et al. 2015; Marzolini, et al. 2016] |
|
|
Dolutegravir (DTG) [Green, et al. 2017] |
|
|
Rifabutin, rifampin |
|
|
Gender-affirming hormones |
|
|
Abbreviations: ARV, antiretroviral; COBI, cobicistat; CYP, cytochrome P450; EFV, efavirenz; HCV, hepatitis C virus; INR, international normalized ratio; NNRTI, non-nucleoside reverse transcriptase inhibitor; P-gP, P-glycoprotein; PI, protease inhibitor; RTV, ritonavir; UGT, uridine diphosphate glucuronosyltransferase. No significant interactions/no dose adjustments necessary: Common oral antibiotics; acid-reducing agents; polyvalent cations; asthma and allergy medications; long-acting beta-agonists; non-opioid pain medications; opioid analgesics and tramadol; alcohol, disulfiram, and acamprosate. |
References
Carten ML, Kiser JJ, Kwara A, et al. Pharmacokinetic interactions between the hormonal emergency contraception, levonorgestrel (Plan B), and Efavirenz. Infect Dis Obstet Gynecol 2012;2012:137192. [PMID: 22536010]
Clarke SM, Mulcahy FM, Tjia J, et al. The pharmacokinetics of methadone in HIV-positive patients receiving the non-nucleoside reverse transcriptase inhibitor efavirenz. Br J Clin Pharmacol 2001;51(3):213-217. [PMID: 11298066]
Deeks ED. Doravirine: First global approval. Drugs 2018;78(15):1643-1650. [PMID: 30341683]
Garrison KL, German P, Mogalian E, et al. The drug-drug interaction potential of antiviral agents for the treatment of chronic hepatitis C infection. Drug Metab Dispos 2018;46(8):1212-1225. [PMID: 29695614]
Green B, Crauwels H, Kakuda TN, et al. Evaluation of concomitant antiretrovirals and CYP2C9/CYP2C19 polymorphisms on the pharmacokinetics of etravirine. Clin Pharmacokinet 2017;56(5):525-536. [PMID: 27665573]
Greig SL. Sofosbuvir/velpatasvir: A review in chronic hepatitis C. Drugs 2016;76(16):1567-1578. [PMID: 27730529]
Gruber VA, McCance-Katz EF. Methadone, buprenorphine, and street drug interactions with antiretroviral medications. Curr HIV/AIDS Rep 2010;7(3):152-160. [PMID: 20532839]
Kakuda TN, Scholler-Gyure M, Hoetelmans RM. Pharmacokinetic interactions between etravirine and non-antiretroviral drugs. Clin Pharmacokinet 2011;50(1):25-39. [PMID: 21142266]
Kaur K, Gandhi MA, Slish J. Drug-drug interactions among hepatitis C virus (HCV) and human immunodeficiency virus (HIV) medications. Infect Dis Ther 2015;4(2):159-172. [PMID: 25896480]
Kharasch ED, Whittington D, Ensign D, et al. Mechanism of efavirenz influence on methadone pharmacokinetics and pharmacodynamics. Clin Pharmacol Ther 2012;91(4):673-684. [PMID: 22398970]
Mak LY, Seto WK, Lai CL, et al. An update on the toxicological considerations for protease inhibitors used for hepatitis C infection. Expert Opin Drug Metab Toxicol 2018;14(5):483-491. [PMID: 29718748]
Marzolini C, Gibbons S, Khoo S, et al. Cobicistat versus ritonavir boosting and differences in the drug-drug interaction profiles with co-medications. J Antimicrob Chemother 2016;71(7):1755-1758. [PMID: 26945713]
McCance-Katz EF, Moody DE, Morse GD, et al. Interactions between buprenorphine and antiretrovirals. I. The nonnucleoside reverse-transcriptase inhibitors efavirenz and delavirdine. Clin Infect Dis 2006;43 Suppl 4:S224-234. [PMID: 17109309]
Orrell C, Felizarta F, Nell A, et al. Pharmacokinetics of etravirine combined with atazanavir/ritonavir and a nucleoside reverse transcriptase inhibitor in antiretroviral treatment-experienced, HIV-1-infected patients. AIDS Res Treat 2015;2015:938628. [PMID: 25664185]
Rathbun C, Liedtke MD. The next generation: etravirine in the treatment of HIV-1 infection in adults refractory to other antiretrovirals. Virus Adapt Treat 2010;2:91-102. [Link]
Robertson SM, Maldarelli F, Natarajan V, et al. Efavirenz induces CYP2B6-mediated hydroxylation of bupropion in healthy subjects. J Acquir Immune Defic Syndr 2008;49(5):513-519. [PMID: 18989234]
Sanford M. Rilpivirine. Drugs 2012;72(4):525-541. [PMID: 22356290]
Scarsi KK, Darin KM, Nakalema S, et al. Unintended pregnancies observed with combined use of the levonorgestrel contraceptive implant and efavirenz-based antiretroviral therapy: A three-arm pharmacokinetic evaluation over 48 weeks. Clin Infect Dis 2016;62(6):675-682. [PMID: 26646680]
Schafer JJ, Short WR. Rilpivirine, a novel non-nucleoside reverse transcriptase inhibitor for the management of HIV-1 infection: a systematic review. Antivir Ther 2012;17(8):1495-1502. [PMID: 22878339]
Soriano V, Labarga P, Fernandez-Montero JV, et al. Drug interactions in HIV-infected patients treated for hepatitis C. Expert Opin Drug Metab Toxicol 2017;13(8):807-816. [PMID: 28689442]
Welz T, Wyen C, Hensel M. Drug interactions in the treatment of malignancy in HIV-infected patients. Oncol Res Treat 2017;40(3):120-127. [PMID: 28253501]
Yeh WW. Drug-drug interactions with grazoprevir/elbasvir: Practical considerations for the care of HIV/HCV co-infected patients. 16th International Workshop on Clinical Pharmacology of HIV & Hepatitis Therapy; 2015 May 26-28; Washington, DC. http://www.natap.org/2015/Pharm/Pharm_31.htm
Nucleoside Reverse Transcriptase Inhibitors (NRTIs): ABC, TDF/TAF, 3TC
Lead author: Joshua R. Sawyer, PharmD, AAHIVP, with the Medical Care Criteria Committee, updated February 2021
Table 12: Abacavir (ABC) Interactions (also see drug package inserts) | ||
Print this table | ||
Class or Drug | Mechanism of Action | Clinical Comments |
Ethanol |
ABC is metabolized via alcohol dehydrogenase, and competitive metabolism may increase exposure to ABC. | Use cautiously and monitor for adverse events of ABC. |
Rifabutin, rifampin
|
|
Rifampin: No dose adjustments recommended for concomitant use with ABC. |
No significant interactions/no dose adjustments necessary: Common oral antibiotics; drugs used as antihypertensive medicines; anticoagulants; antiplatelet drugs; statins; antidiabetic drugs; acid-reducing agents; polyvalent cations; asthma and allergy medications; long-acting beta-agonists; inhaled and injected corticosteroids; antidepressants; benzodiazepines; sleep medications; antipsychotics; anticonvulsants; non-opioid pain medications; opioid analgesics and tramadol; hormonal contraceptives; erectile and sexual dysfunction agents; tobacco and smoking cessation products; methadone, buprenorphine, naloxone, and naltrexone; immunosuppressants; gender-affirming hormones. |
Table 13: Tenofovir Disoproxil Fumarate (TDF) and Tenofovir Alafenamide (TAF) Interactions (also see drug package inserts) | ||
Print this table | ||
Class or Drug | Mechanism of Action | Clinical Comments |
Adefovir [Jafari, et al. 2014] |
Similar mechanisms of action and elimination, and thus, similar adverse event profiles. Competitive inhibition of elimination results in additive adverse events. | Avoid concomitant use to avoid increased risk of hepatic steatosis and lactic acidosis. |
Other nephrotoxic agents [Jafari, et al. 2014] |
Competitive inhibition of elimination results in additive adverse events. |
|
Sofosbuvir/velpatasvir/ |
|
|
Potent CYP3A4 or P-gP inducers (phenytoin, rifampin, carbamazepine, St. John’s wort, etc.) [Gibson, et al. 2016] |
|
Avoid coadministration of TAF with potent inducers of CYP3A4 or P-gP. |
Zonisamide | TDF may increase concentration of zonisamide. | Monitor for adverse events of zonisamide with TDF. |
Topiramate | No significant interactions noted. | Monitor renal function when coadministered (topiramate may cause kidney stones; TDF is associated with renal toxicity). |
Abbreviations: BCRP, breast cancer resistance protein; CYP, cytochrome P450; P-gP, P-glycoprotein. No significant interactions/no dose adjustments necessary: Common oral antibiotics; drugs used as antihypertensive medicines; anticoagulants; antiplatelet drugs; statins; antidiabetic drugs; acid-reducing agents; polyvalent cations; asthma and allergy medications; long-acting beta-agonists; inhaled and injected corticosteroids; antidepressants; benzodiazepines; sleep medications; antipsychotics; non-opioid pain medications; opioid analgesics and tramadol; hormonal contraceptives; erectile and sexual dysfunction drugs; tobacco and smoking cessation products; alcohol, disulfiram, and acamprosate; methadone, buprenorphine, naloxone, and naltrexone; immunosuppressants; gender-affirming hormones. |
Table 14: Lamivudine (3TC) and Emtricitabine (FTC) Interactions (also see drug package inserts) | ||
Class or Drug | Mechanism of Action | Clinical Comments |
– | – | – |
Note: There are no known clinically significant drug-drug interactions between 3TC or FTC and concomitant agents. |
References
Garrison KL, Mogalian E, Zhang H, et al. Evaluation of drug-drug interactions between sofosbuvir/velpatasvir/voxilapevir and boosted or unboosted HIV antiretroviral regimens. 18th International Workshop on Clinical Pharmacology of Antiviral Therapy; 2017 Jun 14-17; Chicago, IL. http://www.natap.org/2017/Pharm/Pharm_19.htm
Gibson AK, Shah BM, Nambiar PH, et al. Tenofovir alafenamide: A review of its use in the treatment of HIV-1 infection. Ann Pharmacother 2016;50(11):942-952. [PMID: 27465879]
Jafari A, Khalili H, Dashti-Khavidaki S. Tenofovir-induced nephrotoxicity: incidence, mechanism, risk factors, prognosis and proposed agents for prevention. Eur J Clin Pharmacol 2014;70(9):1029-1040. [PMID: 24958564]
McDowell JA, Chittick GE, Stevens CP, et al. Pharmacokinetic interaction of abacavir (1592U89) and ethanol in human immunodeficiency virus-infected adults. Antimicrob Agents Chemother 2000;44(6):1686-1690. [PMID: 10817729]
Yuen GJ, Weller S, Pakes GE. A review of the pharmacokinetics of abacavir. Clin Pharmacokinet 2008;47(6):351-371. [PMID: 18479171]
Entry Inhibitors (EIs): FTR, MVC
Lead author: Joshua R. Sawyer, PharmD, AAHIVP, with the Medical Care Criteria Committee, updated February 2021
Table 14A: Fostemsavir (FTR) Interactions (also see drug package inserts) | ||
Print this table | ||
Class or Drug | Mechanism of Action | Clinical Comments |
Potent CYP3A4 or P-gP inducers (phenytoin, rifampin, carbamazepine, St. John’s wort, etc.) | Reduces fostemsavir levels due to CYP3A4 induction. | Do not coadminister. |
Antineoplastic agent (mitotane) | Reduces fostemsavir levels due to CYP3A4 induction. | Do not coadminister. |
Androgen receptor inhibitor (enzalutamide) | Reduces fostemsavir levels due to CYP3A4 induction. | Do not coadminister. |
HCV antiviral agents | Increases grazoprevir and voxilaprevir levels. |
|
Hormonal contraceptives | Increases ethinyl estradiol levels. |
|
Statins | Increases rosuvastatin, atorvastatin, fluvastatin, pitavastatin, and simvastatin levels. | Use lowest possible starting dose for statins; monitor for statin-associated adverse events. |
Abbreviations: CYP, cytochrome P450; HCV, hepatitis C virus; P-gP, P-glycoprotein. No significant interactions/no dose adjustments necessary: common oral antibiotics; drugs used as antihypertensive medicines; antidiabetic drugs; acid-reducing agents; polyvalent cations; inhaled and injected corticosteroids; benzodiazepines; sleep medications; non-opioid pain medications; opioid analgesics and tramadol; tobacco and smoking cessation products; alcohol, disulfiram, and acamprosate; methadone, buprenorphine, naloxone, and naltrexone; gender-affirming hormones. |
Table 14B: Maraviroc (MVC) Interactions (also see drug package inserts) | ||
Print this table | ||
Class or Drug | Mechanism of Action | Clinical Comments |
Potent CYP3A4 or P-gP inducers (St. John’s wort) | Reduced maraviroc levels due to CYP3A4 induction. | Do not coadminister. |
Abbreviations: CYP, cytochrome P450; P-gP, P-glycoprotein. No significant interactions/no dose adjustments necessary: common oral antibiotics; drugs used as antihypertensive medicines; antidiabetic drugs; acid-reducing agents; polyvalent cations; inhaled and injected corticosteroids; benzodiazepines; sleep medications; non-opioid pain medications; opioid analgesics and tramadol; tobacco and smoking cessation products; alcohol, disulfiram, and acamprosate; methadone, buprenorphine, naloxone, and naltrexone; gender-affirming hormones. |