Delstrigo (doravirine/lamivudine/tenofovir disoproxil fumarate)

Each fixed-combination tablet of doravirine/lamivudine/tenofovir DF contains doravirine 100 mg, lamivudine 300 mg, and tenofovir DF 300 mg.

If doravirine/lamivudine/tenofovir DF is used for the treatment of HIV-1 infection in pediatric or adult patients receiving concomitant therapy with rifabutin, patients should receive 1 tablet of the fixed combination (100 mg of doravirine, 300 mg of lamivudine, and 300 mg of tenofovir DF) once daily and a 100-mg tablet of single-entity doravirine once daily given approximately 12 hours after the fixed-combination tablet.

The fixed combination of doravirine, lamivudine, and tenofovir disoproxil fumarate (doravirine/lamivudine/tenofovir DF) is administered orally once daily without regard to food.

Doravirine/lamivudine/tenofovir DF is used alone as a complete antiretroviral regimen for the treatment of HIV-1 infection.

If a dose is missed, the missed dose should be taken as soon as possible, unless it is almost time for the next dose; the patient should not take 2 doses at one time.

Store doravirine/lamivudine/tenofovir DF tablets at 20-25degreesC (excursions permitted between 15-30degreesC) in their original container and keep the container tightly closed; protect from moisture and do not remove the dessicant.

No dosing information is available for this tab.

The following drug interactions are based on studies using the individual components of the fixed combination of doravirine, lamivudine, and tenofovir disoproxil fumarate (doravirine/lamivudine/tenofovir DF).

When doravirine/lamivudine/tenofovir DF is used, interactions associated with each drug in the fixed combination should be considered.

Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

Anti-Retrovirals/Atidarsagene Autotemcel

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Atidarsagene autotemcel is prepared from apheresed cells that are transduced with a replication defective, self-inactivating lentiviral vector. Antiretrovirals may interfere with the manufacturing of apheresed cells.

CLINICAL EFFECTS: Use of antiretrovirals before mobilization and apheresis may interfere with the production of atidarsagene autotemcel.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Discontinue antiretrovirals for at least one month prior to mobilization (or the expected duration of time needed for elimination of the medication) until all cycles of apheresis are completed. If a patient requires antiretrovirals for HIV prophylaxis, then confirm a negative HIV test before beginning mobilization and apheresis of CD34+ cells.

DISCUSSION: Antiretroviral medications may interfere with the manufacturing of atidarsagene autotemcel therapy.(1)

Anti-Retrovirals/Elivaldogene Autotemcel

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Elivaldogene autotemcel is prepared from apheresed cells that are transduced with a replication defective, self-inactivating lentiviral vector. Antiretrovirals may interfere with the manufacturing of apheresed cells.

CLINICAL EFFECTS: Use of antiretrovirals before mobilization and apheresis may interfere with the production of elivaldogene autotemcel.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Discontinue antiretrovirals for at least one month prior to mobilization and until all cycles of apheresis are completed. If a patient requires antiretrovirals for HIV prophylaxis, then confirm a negative HIV test before beginning mobilization and apheresis of CD34+ cells.

DISCUSSION: Antiretroviral medications may interfere with the manufacturing of elivaldogene autotemcel therapy.(1)

Anti-Retrovirals/Etuvetidigene Autotemcel

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Etuvetidigene autotemcel is prepared from apheresed cells that are transduced with a replication defective, self-inactivating HIV-based lentiviral vector. Antiretrovirals may interfere with the manufacturing of the apheresed cells.

CLINICAL EFFECTS: Use of antiretrovirals before mobilization and apheresis may interfere with the production of etuvetidigene autotemcel.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Patients should not take antiretrovirals for at least one month prior to mobilization and until at least 7 days after etuvetidigene autotemcel infusion.(1) If a patient requires antiretroviral agents for HIV post-exposure prophylaxis, etuvetidigene autotemcel treatment should be delayed until HIV testing is negative at 6 months post-exposure.(1)

DISCUSSION: Antiretroviral medications may interfere with the manufacturing of etuvetidigene autotemcel therapy.(1)

Anti-Retrovirals/Lovotibeglogene Autotemcel

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Lovotibeglogene autotemcel is prepared from apheresed cells that are transduced with a replication defective, self-inactivating lentiviral vector. Antiretrovirals may interfere with the manufacturing of apheresed cells.

CLINICAL EFFECTS: Use of antiretrovirals before mobilization and apheresis may interfere with the production of lovotibeglogene autotemcel.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Discontinue antiretrovirals for at least one month prior to mobilization and until all cycles of apheresis are completed.(1) There are some long-acting antiretroviral medications that may require a longer duration of discontinuation for elimination of the medication. If a patient is taking anti-retrovirals for HIV prophylaxis, confirm a negative test for HIV before beginning mobilization and apheresis of CD34+ cells.(1)

DISCUSSION: Antiretroviral medications may interfere with the manufacturing of lovotibeglogene autotemcel therapy.(1)

Anti-Retrovirals; Hydroxyurea/Betibeglogene Autotemcel

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Betibeglogene autotemcel is prepared from apheresed cells that are transduced with a replication defective, self-inactivating lentiviral vector. Antiretrovirals may interfere with the manufacturing of apheresed cells. Hydroxyurea may interfere with hematopoietic stem cell (HSC) mobilization of CD34+ cells.(1)

CLINICAL EFFECTS: Use of hydroxyurea before mobilization may result in unsuccessful stem cell mobilization. Use of antiretrovirals before mobilization and apheresis may interfere with the production of betibeglogene autotemcel.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Discontinue antiretrovirals and hydroxyurea for at least one month prior to mobilization and until all cycles of apheresis are completed. If a patient requires antiretrovirals for HIV prophylaxis, then confirm a negative HIV test before beginning mobilization and apheresis of CD34+ cells.

DISCUSSION: Antiretroviral medications and hydroxyurea may interfere with the manufacturing of betibeglogene autotemcel therapy.(1)

Doravirine/Strong Cyp3a4 Inducers

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Strong inducers of CYP3A4 are expected to increase the metabolism of doravirine.(1)

CLINICAL EFFECTS: Concurrent or recent use of strong inducers of CYP3A4 may result in decreased levels and effectiveness of doravirine.(3)

PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.

PATIENT MANAGEMENT: Concurrent administration of strong inducers of CYP3A4 with doravirine is contraindicated. A washout period of 4 weeks for the CYP3A4 inducer is recommended prior to initiation of doravirine.(1)

DISCUSSION: Doravirine is metabolized by CYP3A4. Strong inducers of CYP3A4 are expected to reduce doravirine levels, which may lead to loss of response.(1) In a study in 10 subjects, rifampin (600 mg daily), a strong inducer of CYP3A4, decreased the area-under-curve (AUC), maximum concentration (Cmax), and 24 hour concentration (C24) of a single dose of doravirine (100 mg) by 88%, 57%, and 97% respectively.(1) Strong inducers of CYP3A4 include apalutamide, barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, oxcarbazepine, phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's wort.(1)

Emtricitabine; Lamivudine/Islatravir

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Emtricitabine and lamivudine may inhibit the intracellular phosphorylation of islatravir by deoxycytidine kinase (dCK).(1)

CLINICAL EFFECTS: Concurrent administration of emtricitabine or lamivudine with islatravir may result in decreased clinical efficacy of islatravir.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of the doravirine-islatravir fixed-dose combination states that co-administration with emtricitabine or lamivudine is contraindicated.(1)

DISCUSSION: Islatravir undergoes a series of phosphorylations to its active metabolites.(1) In a clinical study in healthy participants, co-administration of multiple daily doses of 300 mg lamivudine and a single dose of 2 mg islatravir (8 times the recommended dosage) decreased intracellular ISL-TP (islatravir active metabolite) area under the curve (AUC) level by 87% and maximum concentration (Cmax) by 76% relative to islatravir alone. A similar effect is anticipated when islatravir is co-administered with emtricitabine.(1,2) Compounds phosphorylated by dCK and linked to this monograph include: emtricitabine and lamivudine.

Lamivudine/Zalcitabine

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Lamivudine and zalcitabine may inhibit the intracellular phosphorylation of each other.(1-6)

CLINICAL EFFECTS: Concurrent administration of lamivudine and zalcitabine may result in decreased clinical efficacy of one or both agents.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of lamivudine states that the concurrent use of lamivudine and zalcitabine is not recommended.(1-3)

DISCUSSION: Both lamivudine(1-3) and zalcitabine(7) undergo a series of phosphorylations to their active metabolites. In an in vitro study, the presence of lamivudine significantly decreased the phosphorylation of zalcitabine, resulting in a 50% decrease in zalcitabine triphosphate levels.(4) In an in vitro study in peripheral blood mononuclear cells (PBMCs) and U937 cells, zalcitabine significantly inhibited the phosphorylation of lamivudine. No lamivudine triphosphate was found in the PBMCs and the amount of lamivudine triphosphate was decreased 33% when compared to control values in the U937 cell line.(5) In another in vitro study, lamivudine decreased total zalcitabine phosphates by 57%. There was no effect on lamivudine phosphorylation.(6)

Selected Nephrotoxic Agents/Bacitracin

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Bacitracin may cause renal failure due to glomerular and tubular necrosis. Concurrent administration of other nephrotoxic agents may result in additive renal toxicity.(1-3)

CLINICAL EFFECTS: Concurrent use of bacitracin with other potentially nephrotoxic agents may result in renal toxicity.(1-3)

PREDISPOSING FACTORS: Dehydration and high-dose bacitracin may predispose to adverse renal effects.(1)

PATIENT MANAGEMENT: Health Canada states that bacitracin is contraindicated in patients with renal impairment, including those taking other nephrotoxic drugs.(1) The Canadian and US manufacturers of bacitracin state that concomitant use of bacitracin with other potentially nephrotoxic agents should be avoided.(2,3)

DISCUSSION: Renal impairment is a major toxicity of bacitracin. Cases of nephrotoxicity have been reported when bacitracin was used off-label.(1-3)

Selected Nephrotoxic Agents/Cidofovir

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Cidofovir is nephrotoxic. Concurrent administration of other nephrotoxic agents may result in additive or synergistic effects on renal function.(1-3)

CLINICAL EFFECTS: Concurrent use of cidofovir with nephrotoxic agents such as adefovir, intravenous aminoglycosides, amphotericin B, foscarnet, intravenous pentamidine, tenofovir, vancomycin, voclosporin and non-steroidal anti-inflammatory agents may result in renal toxicity.(1-3) Other nephrotoxic agents include capreomycin, cisplatin, gallium nitrate, high-dose methotrexate, and streptozocin.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The Australian,(1) UK,(2) and US(3) manufacturers of cidofovir state that concurrent administration of potentially nephrotoxic agents such as adefovir, intravenous aminoglycosides, amphotericin B, foscarnet, intravenous pentamidine, tenofovir, vancomycin, voclosporin and non-steroidal anti-inflammatory agents may result in renal toxicity.(1-3) Other nephrotoxic agents include capreomycin, cisplatin, gallium nitrate, high-dose methotrexate, and streptozocin. These agents should be discontinued at least 7 days before the administration of cidofovir.

DISCUSSION: The safety of cidofovir has not been studied in patients receiving other known potentially nephrotoxic agents. Renal impairment is the major toxicity of cidofovir.(1-3)

Tenofovir/Adefovir

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: The mechanism involves competition for active tubular secretion sites in the kidney.(1-4)

CLINICAL EFFECTS: Concurrent use of adefovir and tenofovir in the treatment of hepatitis B may result in elevated levels of tenofovir or adefovir.

PREDISPOSING FACTORS: Renal impairment or use of concurrent renally excreted drugs.

PATIENT MANAGEMENT: The US manufacturer of adefovir(1) and the UK(2) and US(3) manufacturers of tenofovir state that adefovir and tenofovir should be not be administered together.

DISCUSSION: Tenofovir is eliminated principally by renal tubular secretion and any competitive inhibition of excretion of tenofovir by adefovir increases the likelihood of increased serum concentrations of tenofovir and resultant toxicity.(1-4)

Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

Anti-Retrovirals/Marnetegragene Autotemcel

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Marnetegragene autotemcel is prepared from apheresed cells that are transduced with a replication defective, self-inactivating lentiviral vector. Antiretrovirals may interfere with the manufacturing of transduced cells.

CLINICAL EFFECTS: Use of antiretrovirals before mobilization and apheresis may interfere with the production of marnetegragene autotemcel.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Discontinue antiretrovirals for at least one month prior to mobilization (or the expected duration of time needed for elimination of the antiretrovirals) until all cycles of apheresis are completed. If a patient requires antiretrovirals for HIV prophylaxis, then confirm a negative HIV test before beginning mobilization and apheresis of CD34+ cells.(1)

DISCUSSION: Antiretroviral medications may interfere with the manufacturing of marnetegragene autotemcel.(1)

Deoxycytidine Kinase Substrates/Cladribine Oral

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Clofarabine, cytarabine, emtricitabine, fludarabine, gemcitabine, lamivudine, molnupiravir, nelarabine and zalcitabine may inhibit the intracellular phosphorylation of cladribine by deoxycytidine kinase (dCK).

CLINICAL EFFECTS: Concurrent administration of clofarabine, cytarabine, emtricitabine, fludarabine, gemcitabine, lamivudine, molnupiravir, nelarabine, or zalcitabine with cladribine may result in decreased clinical efficacy of cladribine.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of lamivudine states that the concurrent use of lamivudine and cladribine is not recommended.(1) The manufacturer of cladribine states that concurrent use of compounds that require activation by intracellular phosphorylation should be avoided.(2)

DISCUSSION: Cladribine undergoes a series of phosphorylations to its active metabolites. In a case report, a patient on lamivudine who received cladribine concurrently did not experience a decrease in his lymphocyte count. After discontinuation of lamivudine and readministration of cladribine, his lymphocytes dropped as expected.(3) It is expected that other compounds phosphorylated by dCK would also decrease cladribine's efficacy.(4) Compounds phosphorylated by dCK include: clofarabine, cytarabine, emtricitabine, fludarabine, gemcitabine, lamivudine, molnupiravir, nelarabine and zalcitabine.

Doravirine/Efavirenz;Etravirine;Nevirapine

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Efavirenz, etravirine, and nevirapine may induce the metabolism of doravirine via CYP3A4.(1)

CLINICAL EFFECTS: Concurrent use of efavirenz, etravirine, or nevirapine may result in subtherapeutic levels of doravirine.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Coadministration of doravirine with efavirenz, etravirine, or nevirapine is not recommended.(1)

DISCUSSION: In a study in 17 healthy subjects, coadministration of efavirenz (600 mg daily) with a single dose of doravirine (100 mg) decreased doravirine's area-under-curve (AUC), maximum concentration (Cmax), and 24 hour concentration (C24) by 62%, 35%, and 85%, respectively.(1)

Doravirine/Moderate Cyp3a4 Inducers

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Moderate CYP3A4 inducers are expected to increase the metabolism of doravirine.(1-3)

CLINICAL EFFECTS: Concurrent or recent use of a moderate CYP3A4 inducer may result in decreased levels and effectiveness of doravirine.(1-3)

PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.

PATIENT MANAGEMENT: Recommendations for concurrent use of moderate CYP3A4 inducers with doravirine vary depending on the reference. The manufacturer of the fixed dose combination of doravirine-islatravir states concurrent use with moderate CYP3A4 inducers is not recommended.(3) The DHHS HIV guidelines state when coadministering doravirine with bosentan, dexamethasone, and eslicarbazepine (moderate CYP3A4 inducers): consider an alternative antiretroviral or alternative drug to the moderate CYP3A4 inducer. It would be prudent to consider alternative drugs to other moderate CYP3A4 inducers. If co-administration is necessary monitor virologic response.(4) The University of Liverpool HIV Drug Interactions Database states concurrent use with moderate CYP3A4 inducers should be avoided. If concurrent use cannot be avoided, dose adjustment of doravirine to 100 mg twice daily is recommended and should be maintained for at least 2 weeks following cessation of the moderate CYP3A4 inducer. If a patient is on eslicarbazepine, doravirine should not be coadministered.(5) The manufacturer of single ingredient doravirine and the fixed dose combination of doravirine-lamivudine-tenofovir does not have a recommendation for concurrent use with moderate CYP3A4 inducers.(1,3)

DISCUSSION: Doravirine is metabolized by CYP3A4. Moderate CYP3A4 inducers are expected to reduce doravirine levels, which may lead to loss of response.(1) In a study in 12 subjects, rifabutin (300 mg daily), a moderate CYP3A4 inducer, decreased the area-under-curve (AUC) and 24 hour concentration (C24) of a single dose of doravirine (100 mg) by 50% and 68%, respectively.(1) Moderate CYP3A4 inducers linked to this monograph include: belzutifan, bosentan, cenobamate, dabrafenib, dexamethasone, dipyrone, elagolix, eslicarbazepine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, sotorasib, telotristat, thioridazine and tovorafenib.(3-4)

Lamivudine/Sorbitol

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Sorbitol increases the osmotic pressure in the intestine, resulting in accelerated small intestinal transit time and decreased absorption and bioavailability of lamivudine.

CLINICAL EFFECTS: Concurrent administration of sorbitol and lamivudine may result in decreased clinical efficacy of lamivudine.(1) Reduction in lamivudine exposure is sorbitol dose-dependent.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of lamivudine states that the concurrent use of lamivudine and sorbitol should be avoided.(1) Consider more frequent monitoring of HBV viral load when chronic coadministration cannot be avoided.

DISCUSSION: In an open label, randomized sequence, 4-period, crossover trial in 16 healthy adults, coadministration of a single dose of lamivudine (300 mg) with sorbitol (3.2 grams) resulted in a dose-dependent decrease of lamivudine's area-under-the-curve (AUC(0-24), AUC infinity) and maximum concentration (Cmax) of 20%, 28%, and 28%. A single dose of lamivudine with sorbitol (10.2 grams) resulted in a decrease of lamivudine's AUC and Cmax of 39%, 52%, and 52%. A single dose of lamivudine with sorbitol (13.4 grams) resulted in a decrease of lamivudine's AUC and Cmax of 36%, 55%, and 55%.(1)

Selected Antiretrovirals/Orlistat

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: The exact mechanism is unknown. Orlistat may reduce the absorption of lipophilic antiretroviral HIV drugs by retention in the gastrointestinal tract or reduced gastrointestinal tract transit time.

CLINICAL EFFECTS: The concurrent administration of orlistat and atazanavir, efavirenz, emtricitabine, maraviroc, ritonavir, or tenofovir may result in a decrease in the levels and clinical effects of the antiretroviral, including loss of virological control.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: HIV RNA levels should be frequently monitored in patients taking orlistat while being treated for HIV infection. If there is a confirmed increase in HIV viral load, orlistat should be discontinued.(1)

DISCUSSION: Loss of virological control has been reported in HIV-infected patients taking orlistat concomitantly with lipophilic antiretroviral drugs.(1) There are three case reports of patients having an increased HIV viral load after taking orlistat concomitantly with their HIV therapy.(2-4) Antiretrovirals included in this monograph are atazanavir, efavirenz, emtricitabine, maraviroc, ritonavir, and tenofovir.

Selected Antiviral Agents/Cladribine Oral

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Antiviral agents may inhibit the intracellular phosphorylation of cladribine by competitive inhibition of intracellular kinases.(1-4)

CLINICAL EFFECTS: Concurrent administration of antiviral agents with cladribine may result in decreased clinical efficacy of cladribine.(1-4)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of cladribine states that concurrent use of compounds that require activation by intracellular phosphorylation is not recommended.(1)

DISCUSSION: Cladribine undergoes a series of phosphorylations to its active metabolites.(1) Compounds phosphorylated by kinases linked to this monograph include: acyclovir, entecavir, ganciclovir, tenofovir, valacyclovir, and valganciclovir.

Selected Nephrotoxic Agents/Colistimethate

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Colistimethate can cause nephrotoxicity.(1,2) Concurrent administration of other nephrotoxic agents may result in an increased risk of nephrotoxicity.(1) It is suspected that cephalothin interferes with the excretion of colistimethate resulting in enhanced nephrotoxicity.(2,3)

CLINICAL EFFECTS: Concurrent use of colistimethate with other nephrotoxic agents may result in additive nephrotoxic effects.

PREDISPOSING FACTORS: Factors predisposing to nephrotoxicity include higher cumulative doses of colistimethate, longer treatment duration, hypovolemia, and critical illness.

PATIENT MANAGEMENT: Concurrent use of potentially nephrotoxic agents with colistimethate should be avoided.(1,2) If concurrent use is necessary, it should be undertaken with great caution.(1)

DISCUSSION: In a case control study of 42 patients on intravenous colistimethate sodium, NSAIDs were identified as an independent risk factor for nephrotoxicity (OR 40.105, p=0.044).(4) In 4 case reports, patients developed elevated serum creatinine and blood urea nitrogen following concurrent colistimethate and cephalothin (3 patients) or when colistimethate followed cephalothin therapy (1 patient).(3) A literature review found that individual nephrotoxic agents, including aminoglycosides, vancomycin, amphotericin, IV contrast, diuretics, ACE inhibitors, ARBs, NSAIDs, and calcineurin inhibitors, were not consistently associated with additive nephrotoxicity when used with colistimethate. However, when multiple agents (at least 2 additional potential nephrotoxins) were used concurrently, there was a significant correlation to colistimethate nephrotoxicity.(5)

Selected Nephrotoxic Agents/Foscarnet

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Foscarnet is nephrotoxic. Concurrent administration of other nephrotoxic agents may result in additive or synergistic effects on renal function.(1) Concurrent intravenous pentamidine may also result in hypocalcemia.(1)

CLINICAL EFFECTS: Concurrent use of foscarnet with nephrotoxic agents such as acyclovir, adefovir, intravenous aminoglycosides, amphotericin B, cyclosporine, methotrexate, non-steroidal anti-inflammatory agents, intravenous pentamidine, tacrolimus, tenofovir, vancomycin and voclosporin may result in renal toxicity.(1) Other nephrotoxic agents include capreomycin, cisplatin, gallium nitrate, high-dose methotrexate, and streptozocin.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of foscarnet state that concurrent administration of potentially nephrotoxic agents such as acyclovir, intravenous aminoglycosides, amphotericin B, cyclosporine, methotrexate, tacrolimus, and intravenous pentamidine should be avoided.(1) Other nephrotoxic agents include adefovir, capreomycin, cisplatin, gallium nitrate, high-dose methotrexate, non-steroidal anti-inflammatory agents, streptozocin, tenofovir, vancomycin and voclosporin. If concurrent therapy is warranted, monitor renal function closely. In patients receiving concurrent foscarnet and pentamidine, also monitor serum calcium levels and instruct patients to report severe muscle spasms, mental/mood changes, and/or seizures.(1)

DISCUSSION: The safety of foscarnet has not been studied in patients receiving other known potentially nephrotoxic agents. Renal impairment is the major toxicity of foscarnet.(1)

Selected Nephrotoxic Agents/Inotersen

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Inotersen can cause glomerulonephritis and renal toxicity. Concurrent administration of other nephrotoxic agents may result in additive or synergistic effects on renal function.(1)

CLINICAL EFFECTS: Concurrent use of inotersen with nephrotoxic agents such as acyclovir, adefovir, intravenous aminoglycosides, amphotericin B, cyclosporine, methotrexate, non-steroidal anti-inflammatory agents, intravenous pentamidine, tacrolimus, tenofovir, vancomycin and voclosporin may result in renal toxicity.(1) Other nephrotoxic agents include capreomycin, cisplatin, gallium nitrate, high-dose methotrexate, and streptozocin.

PREDISPOSING FACTORS: Patients with pre-existing renal impairment.

PATIENT MANAGEMENT: The US manufacturer of inotersen state that caution should be used when administered concurrently with potentially nephrotoxic agents or agents that impair renal function.(1) If concurrent therapy is warranted, monitor renal function closely.(1)

DISCUSSION: The safety of inotersen has not been studied in patients receiving other known potentially nephrotoxic agents. Inotersen is only available through a Tegsedi REMS program because of the risk of glomerulonephritis and severe thrombocytopenia.(1)

Selected Protease Inhibitors And Nnrtis/Garlic

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: The exact mechanism is unknown. Garlic may induce the metabolism of protease inhibitors and non-nucleoside reverse transcriptase inhibitors (NNRTIs) by CYP3A4. P-glycoproteins may also be involved.(1,2)

CLINICAL EFFECTS: Concurrent use of garlic and a protease inhibitor or NNRTI may result in decreased levels and effectiveness of the protease inhibitor or NNRTI therapy.(2-3)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Patients taking a protease inhibitor or NNRTI should avoid taking garlic supplements. Garlic from food sources is not likely to cause a problem, although there may be some concern if patients are ingesting a large quantity of garlic on a regular basis.

DISCUSSION: A study in nine HIV-negative subjects examined the effects of the concurrent use of a garlic supplement (taken twice daily) on saquinavir (1200 mg twice daily). Concurrent use resulted in a decrease in saquinavir area-under-curve (AUC), maximum concentration (Cmax), and trough concentration (Cmin) by 51%, 49%, and 54%, respectively, when compared to the administration of saquinavir alone. Following a garlic washout period, saquinavir levels only returned to 60-70% of baseline.(2) In a study in 10 healthy subjects, the administration of garlic (10 mg twice daily) for four days had no significant effects on a single dose of ritonavir (400 mg). Ritonavir AUC and Cmax decreased by 17% and by 25%, respectively. However, the authors cautioned that their results should not be extrapolated to steady-state conditions.(4)

Tenofovir Disoproxil/Cobicistat

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: The exact mechanism is unknown.

CLINICAL EFFECTS: Coadministration of cobicistat with tenofovir disoproxil increases the risk of new onset or worsening renal impairment including acute renal failure and Fanconi syndrome.(1-10)

PREDISPOSING FACTORS: Patients with impaired baseline renal function or who are receiving concomitant nephrotoxic agents may have an increased risk of renal-related adverse events.(1-10)

PATIENT MANAGEMENT: The Canadian, UK, and US manufacturers of atazanavir/cobicistat, cobicistat and darunavir/cobicistat do not recommend coadministration with tenofovir disoproxil fumarate (DF) in patents with a creatinine clearance (CrCl) below 70 ml/min or with concomitant or recent use of an additional nephrotoxic agent.(2-10) In patients receiving concurrent therapy, check glucose and urine protein at baseline and routinely monitor CrCl, urine glucose, urine protein, and serum phosphorus. Discontinue concurrent therapy if CrCl decreases below 70 ml/min.(2-10)

DISCUSSION: Renal toxicity has been documented with coadministration of cobicistat with tenofovir disoproxil fumarate (DF) but not tenofovir alafenamide (AF). Monitoring of renal function is prudent and discontinuation is recommended when CrCl decreases below 70 ml/min to avoid renal impairment.(1-10)

Moderate Interaction: Assess the risk to the patient and take action as needed.

Doravirine/Rifabutin

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Rifabutin may induce the metabolism of doravirine by CYP3A4.(1-3)

CLINICAL EFFECTS: Concurrent or recent use of rifabutin may result in decreased levels and effectiveness of doravirine.(1-3)

PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.

PATIENT MANAGEMENT: If concurrent therapy is necessary, increase doravirine dosage to one tablet twice daily for the duration of coadministration with rifabutin.(1) Patients on the fixed-dose combination of doravirine-lamivudine-tenofovir should take 1 tablet (100 mg) of doravirine about 12 hours after their dose of doravirine-lamivudine-tenofovir for the duration of rifabutin co-administration.(2) Patients on the fixed-dose combination of doravirine-islatravir should take 1 tablet (100 mg) of doravirine about 12 hours after their dose of doravirine-islatravir for the duration of rifabutin co-administration.(3)

DISCUSSION: Doravirine is metabolized by CYP3A4. Moderate inducers of CYP3A4 such as rifabutin are expected to reduce doravirine levels, which may lead to loss of response.(1) In a study in 12 subjects, rifabutin (300 mg daily), a moderate inducer of CYP3A4, decreased the area-under-curve (AUC) and 24 hour concentration (C24) of a single dose of doravirine (100 mg) by 50% and 68%, respectively.(1) In a study of 15 patients, doravirine 100 mg twice daily given concurrently with rifabutin 300 mg once daily resulted in similar doravirine levels and exposure as doravirine 100 mg once daily alone.(3)

Doravirine/Tecovirimat

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Tecovirimat may induce the metabolism of doravirine via CYP3A4.(1-4)

CLINICAL EFFECTS: Concurrent or recent use of tecovirimat may result in decreased levels and effectiveness of doravirine, as well as the development of resistance.(1-4)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Coadministration of doravirine with tecovirimat should be approached with caution. Some experts state that dose adjustment of either drug is not necessary while others suggest the following dosage change: For adult and pediatric patients weighing at least 35 kg, consider increasing doravirine to 100 mg twice daily during treatment with tecovirimat and for approximately 2 weeks after the end of treatment.(1-4)

DISCUSSION: In a study in 17 healthy subjects, coadministration of efavirenz (600 mg daily) with a single dose of doravirine (100 mg) decreased doravirine's area-under-curve (AUC), maximum concentration (Cmax), and 24 hour concentration (C24) by 62%, 35%, and 85%, respectively.(1) In a pharmacokinetic study, tecovirimat decreased the Cmax and AUC of midazolam by 39% and 32%, respectively.(2-3)

Selected Nephrotoxic Agents/Immune Globulin Iv (IGIV)

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Immune Globulin Intravenous (IGIV) products, particularly those containing sucrose, can cause renal dysfunction, acute renal failure, osmotic nephrosis, and/or death. Concurrent administration of other nephrotoxic agents may result in additive or synergistic effects on renal function.(1-4)

CLINICAL EFFECTS: Concurrent use of Immune Globulin Intravenous (IGIV) products with nephrotoxic agents such as adefovir, intravenous aminoglycosides, amphotericin B, non-steroidal anti-inflammatory agents, tenofovir, and vancomycin may result in renal toxicity.(1-4) Other nephrotoxic agents include capreomycin, gallium nitrate, and streptozocin.

PREDISPOSING FACTORS: Patients at risk of acute renal failure include those with any degree of pre-existing renal insufficiency, diabetes mellitus, advanced age (above 65 years of age), volume depletion, sepsis, paraproteinemia, or receiving known nephrotoxic drugs.(1-4) Renal dysfunction and acute renal failure occur more commonly in patients receiving IGIV products containing sucrose.(3-4)

PATIENT MANAGEMENT: For patients at risk of renal dysfunction or renal failure, the US manufacturers of Immune Globulin Intravenous (IGIV) products recommends administration at the minimum dose and infusion rate practicable; ensure adequate hydration in patients before administration; and monitor renal function and urine output with assessment of blood urea nitrogen (BUN) and serum creatinine before initial infusion and at regular intervals during therapy.(1-3) Concurrent administration of potentially nephrotoxic agents should be avoided.(1) Review prescribing information for IGIV product to be administered for sucrose content. If concurrent therapy is warranted, monitor renal function closely. In high risk patients, consider selecting an IGIV product that does not contain sucrose.

DISCUSSION: The safety of Immune Globulin Intravenous (IGIV) has not been studied in patients receiving other known potentially nephrotoxic agents. Renal impairment is a major toxicity of IGIV products.(1-3) A review of the FDA renal adverse events (RAEs) (i.e. acute renal failure or insufficiency) from June 1985 to November 1998 identified 120 reports worldwide associated with IGIV administration. In the US, the FDA received 88 reports of cases with clinical and/or laboratory findings consistent with RAE (i.e. increased serum creatinine, oliguria, and acute renal failure). Patient cases involved a median age of 60.5 years and 55% were male. Of the 54 patients who developed acute renal failure, 65% were greater than 65 years, 56% had diabetes, and 26% had prior renal insufficiency; 59% had one, 35% had two, and 6% had three of these conditions. Upon review of the IGIV product received, 90% of cases received sucrose-containing IGIV products with the remaining patients receiving either maltose- or glucose-containing products. Approximately 40% of affected patients required dialysis and RAE may have contributed to death in 15% of patients.(4)

Tenofovir Disoproxil/Atazanavir

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Tenofovir disoproxil may induce the metabolism of atazanavir.(1) It is unknown how atazanavir increases tenofovir disoproxil levels.(2)

CLINICAL EFFECTS: Concurrent use of atazanavir and tenofovir disoproxil without concurrent ritonavir or cobicistat may result in decreased levels and effectiveness of atazanavir.(1-3) Concurrent use of atazanavir may result in increased levels and toxicity from tenofovir disoproxil.(2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of atazanavir states that patients on concurrent tenofovir disoproxil 300 mg daily should receive atazanavir 300 mg and ritonavir 100 mg once daily all as a single daily dose with food. Treatment-experienced patients on both tenofovir disoproxil and a H-2 antagonist should have their atazanavir dose increased to 400 mg with ritonavir 100 mg daily. Treatment-experienced pregnant patients in the second or third trimester on concurrent tenofovir disoproxil should also have their atazanavir dose increased to 400 mg with ritonavir 100 mg daily.(1) Atazanavir should not be administered with tenofovir disoproxil without concurrent ritonavir in adults or pediatric patients of at least 13 years of age and weighing at least 40 kg.(1-3) There are no data to recommend a dose of atazanavir with tenofovir disoproxil in pediatric patients weighing less than 40 kg.(1) Patients receiving concurrent therapy should be monitored for tenofovir associated adverse events and tenofovir should be discontinued in patients who experience adverse events.(1-2) The combination product containing efavirenz/emtricitabine/tenofovir disoproxil is not recommended for use in patients receiving atazanavir.(4) No dosage adjustment is required with the use of tenofovir alafenamide.(5)

DISCUSSION: In a study in healthy subjects, concurrent atazanavir (400 mg daily) with tenofovir disoproxil fumarate (300 mg daily) decreased atazanavir area-under-curve (AUC), maximum concentration (Cmax), and minimum concentration (Cmin) by 25%, 21%, and 40%, respectively. The AUC, Cmax, and Cmin of tenofovir increased by 24%, 14%, and 22%, respectively.(1,2) In another study, atazanavir AUC, Cmax, and Cmin decreased by 25%, 28%, and 23%, respectively, when atazanavir (300 mg daily), ritonavir (100 mg daily), and tenofovir disoproxil fumarate (300 mg daily) were coadministered, when compared to the administration of atazanavir and ritonavir alone. However, these decreased levels were approximately 2.3-fold and 4-fold higher that the respective values for atazanavir (400 mg daily) alone.(1,2) Interim data suggests that rate of moderate or severe adverse effects is similar between atazanavir-treated patients and unboosted atazanavir-treated patients.(1) In a study of 12 subjects, the AUC, Cmax and Cmin of tenofovir disoproxil fumarate (300 mg daily) increased 37%, 34% and 29% respectively, when given with atazanavir (300 mg daily) and ritonavir (100 mg daily).(1) Because both efavirenz and tenofovir disoproxil decrease atazanavir concentrations and the effect of taking both on atazanavir pharmacokinetics has not been studied, the use of atazanavir with the combination product efavirenz/emtricitabine/tenofovir disoproxil is not recommended.(4)

Tenofovir/Didanosine

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: The exact mechanism is unknown.

CLINICAL EFFECTS: Concurrent use of tenofovir and didanosine may result in elevated levels of didanosine(1-5) and toxicities(4-7) such as pancreatitis, symptomatic hyperlactatemia/lactic acidosis, peripheral neuropathy,(3-5) and renal failure.(8) Suppression of CD4 cell counts has been observed in patient receiving concurrent therapy.(1) Concurrent use of tenofovir, didanosine, and a non-nucleoside reverse transcriptase inhibitor (NNRTI) such as efavirenz or nevirapine may result in virological failure and the development of resistance.(3)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturers of tenofovir(1-3) and didanosine(4,5) state that these agents should be coadministered with caution and patients should be closely monitored for didanosine-related adverse events(1-5) and efficacy.(4) Caution should be used when coadministering reduced-dose didanosine, tenofovir, and an NNRTI in treatment-naive patients with high viral loads at baseline since such use has been associated with reports of a high rate of virologic failure and emergence of resistance at an early stage. All patients receiving tenofovir disoproxil fumarate and didanosine concomitantly should be closely monitored for didanosine-related adverse events and clinical response.(4) In patients weighing 60 kg or more(1-5) with creatinine clearance equal to or greater than 60 ml/min,(4,5) the daily dosage of didanosine should be decreased to 250 mg.(3,5) In patients weighing less than 60 kg with creatinine clearance equal to or greater than 60 ml/min who are receiving tenofovir or the combination product of tenofovir/emtricitabine, the daily dosage of didanosine should be decreased to 200 mg.(4,5) Data are not available to recommend a dosage adjustment in patients weighing less than 60 kg and receiving the combination product of tenofovir/emtricitabine/efavirenz.(3) When coadministered, tenofovir or tenofovir/emtricitabine with enteric coated didanosine may be taken under fasted conditions or with a light meal consisting of less than 400 kcal and 20% fat. When coadministered, tenofovir or tenofovir/emtricitabine and the buffered formulation of didanosine should be taken in the fasted state.(1,2) Didanosine should be discontinued in patients who develop didanosine related adverse effects.(1,4)

DISCUSSION: In a study in 26 subjects, the administration of tenofovir (300 mg daily) two hours after the administration of a single dose of didanosine (400 mg, enteric coated) on an empty stomach increased both the didanosine maximum concentration (Cmax) and area-under-curve (AUC) by 48%. In a study in 25 subjects, simultaneous administration of tenofovir (300 mg daily) with a single dose of didanosine (400 mg, enteric coated) with food increased the didanosine Cmax and AUC by 64% and 60%, respectively.(1,4) There were no effects on tenofovir pharmacokinetics.(1) In a study in 14 subjects, administration of didanosine (250 mg or 400 mg once daily for 7 days) with tenofovir (300 mg daily) had no effects on tenofovir pharmacokinetics. The Cmax and AUC of didanosine increased 28% and 44%, respectively.(1) In a study in 28 subjects, the administration of tenofovir (300 mg daily) with didanosine 250 mg enteric coated capsules, didanosine levels were similar to those seen with didanosine 400 mg enteric coated capsules alone under fasted conditions.(1) In a study in 33 subjects, simultaneous administration of tenofovir (300 mg daily) with a single dose of didanosine (200 mg, enteric coated) with food increased the AUC of didanosine by 16% and decreased didanosine Cmax by 12% when compared to a single 250 mg dose of didanosine.(5) In a study in 33 subjects, simultaneous administration of tenofovir (300 mg daily) with a single dose of didanosine (250 mg, enteric coated) with food had no effect on the AUC of didanosine and decreased didanosine Cmax by 20% when compared to a single 400 mg dose of didanosine.(5) In a study in 33 subjects, simultaneous administration of tenofovir (300 mg daily) with a single dose of didanosine (325 mg, enteric coated) with food increased the AUC of didanosine by 13% and decreased didanosine Cmax by 11% when compared to a single 400 mg dose of didanosine.(5) Pancreatitis,(7) fatal lactic acidosis,(6,8) and acute renal failure(8) have been reported in patients receiving concurrent therapy with tenofovir and didanosine. Virologic failure appears to be limited to the use of tenofovir and didanosine with either efavirenz or nevirapine. Data exist that support the efficacy of tenofovir with efavirenz and didanosine and efavirenz.(3)

Tenofovir/Selected Nephrotoxic Agents

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Tenofovir and other nephrotoxic agents may result in additive or synergistic effects on renal function and increase nephrotoxicity risk.(1)

CLINICAL EFFECTS: Concurrent use of tenofovir and other nephrotoxic agents may result in renal toxicity and acute renal failure.(1) Reports of acute renal failure and Fanconi syndrome have been reported with tenofovir use.(2,3) However, this has been reported in 3 case reports and the renal failure may have been complicated by other pre-existing conditions.(2)

PREDISPOSING FACTORS: Pre-existing renal dysfunction, long duration of use, low body weight, concomitant use of drugs that may increase tenofovir levels may increase the risk of nephrotoxicity.(1)

PATIENT MANAGEMENT: The US prescribing information for tenofovir recommends avoiding concurrent or recent use of a nephrotoxic agent.(3) Evaluate renal function prior to initiation of concurrent therapy and continue renal function monitoring during therapy. Dose adjustments may be required for impaired renal function. Tenofovir should be avoided with high-dose or multiple NSAIDs. Alternatives to NSAIDs should be considered in patients at risk for renal dysfunction.(3) Patients receiving concurrent NSAIDs with tenofovir should be monitored for possible renal toxicity.(1,2) The dosing interval should be adjusted in patients with a baseline creatinine clearance of less than 50 ml/min.(1-3)

DISCUSSION: From March 18, 2003 to December 1, 2005, Health Canada received 10 reports of nephrotoxic reactions with tenofovir. Three of these occurred following the addition of a NSAID to tenofovir therapy. In the first report, a patient maintained on tenofovir for 29 months developed acute renal failure and acute tubular necrosis requiring dialysis 5 days after beginning indomethacin (100 mg rectally twice daily). In the second report, a patient maintained on tenofovir for 7 months developed acute renal failure and acute tubular necrosis after taking 90 tablets of naproxen (375 mg) over 2 months. The patient died. In the third report, a patient maintained on tenofovir for over a year developed acute renal failure and nephrotic syndrome after 2 months of valdecoxib (20 mg daily) therapy. Symptoms subsided following discontinuation of valdecoxib.(1)

Tenofovir/Telaprevir

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: The exact mechanism is unknown.

CLINICAL EFFECTS: Concurrent use of telaprevir may result in elevated levels of and toxicity from tenofovir.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Monitor patients receiving concurrent therapy with telaprevir and tenofovir without efavirenz for increased tenofovir effects. Discontinue tenofovir in patients who develop tenofovir-associated toxicities.(1)

DISCUSSION: In a study in 16 healthy subjects, telaprevir (750 mg every 8 hours for 7 days) increased the maximum concentration (Cmax), area-under-curve (AUC), and minimum concentration (Cmin) of tenofovir (300 mg daily for 7 days) by 30%, 30%, and 41%, respectively. There were no significant effects on telaprevir pharmacokinetics.(1) In a study in 15 subjects, concurrent telaprevir (1125 mg every 8 hours for 7 days), tenofovir (300 mg daily for 7 days), and efavirenz (600 mg daily for 7 days) increased tenofovir Cmax, AUC, and Cmin by 22%, 10%, and 17%, respectively.(1) In a study in 16 subjects, concurrent telaprevir (1500 mg every 8 hours for 7 days), tenofovir (300 mg daily for 7 days), and efavirenz (600 mg daily for 7 days) increased tenofovir Cmax, AUC, and Cmin by 24%, 10%, and 6%, respectively.(1)

*Concomitant use with potent inducers of cytochrome P-450 (CYP) isoenzyme 3A (e.g., carbamazepine, oxcarbazepine, phenobarbital, phenytoin, enzalutamide, rifampin, rifapentine, mitotane, St. John's wort (Hypericum perforatum)).

*History of hypersensitivity reaction to lamivudine.

• Acute pancreatitis
• Chronic pancreatitis
• Lactation
• Lactic acidosis

• Acute renal failure
• Chronic kidney disease stage 3A (moderate) GFR 45-59 ml/min
• Chronic kidney disease stage 3B (moderate) GFR 30-44 ml/min
• Chronic kidney disease stage 4 (severe) GFR 15-29 ml/min
• Chronic kidney disease stage 5 (failure) GFr<15 ml/min
• Fanconi syndrome
• Hypophosphatemia
• Osteomalacia
• Pathological fracture

• Chronic kidney disease stage 3A (moderate) GFR 45-59 ml/min
• Kidney disease with likely reduction in glomerular filtration rate (GFr)
• Osteopenia
• Viral hepatitis B

Adverse effects reported in >=5% of patients receiving doravirine/lamivudine/tenofovir DF include dizziness, nausea, and abnormal dreams.

Rare or Very Rare

• Abnormal hepatic function tests
• Acute renal failure
• Anaphylaxis
• Anemia
• Angioedema
• Autoimmune hepatitis
• DRESS syndrome
• Fanconi syndrome
• Graves' disease
• Guillain-barre syndrome
• Hepatitis
• Hypokalemia
• Hypophosphatemia
• Increased creatine kinase level
• Interstitial nephritis
• Lactic acidosis
• Nephrogenic diabetes insipidus
• Osteopenia
• Pancreatitis
• Polymyositis
• Pure red cell aplasia
• Rhabdomyolysis
• Steatosis of liver
• Stevens-johnson syndrome
• Toxic epidermal necrolysis

More Frequent

• Dizziness
• Dream disorder
• Nausea

Less Frequent

• Altered consciousness
• Diarrhea
• Drowsy
• Insomnia
• Lethargy
• Skin rash
• Syncope

Rare or Very Rare

• Acute abdominal pain
• Alopecia
• Dyspnea
• General weakness
• Hyperglycemia
• Lipodystrophy associated with human immunodeficiency virus infection
• Muscle weakness
• Pruritus of skin
• Urticaria

No enhanced messaging available.

Safety and efficacy of doravirine/lamivudine/tenofovir DF have been established in pediatric patients weighing at least 35 kg.

Use of doravirine/lamivudine/tenofovir DF in this population is supported by data from randomized studies in adults, with additional pharmacokinetic, safety, and efficacy data from a 24-week, open-label study conducted in 54 antiretroviral naive or antiretroviral experienced pediatric patients 12 to <18 years of age. Doravirine/lamivudine/tenofovir DF demonstrated similar safety and efficacy in this population compared to adult patients, with no clinically important differences detected in exposures for the individual components of doravirine/lamivudine/tenofovir DF.

Safety and efficacy of doravirine/lamivudine/tenofovir DF have not been established in pediatric patients weighing <35 kg.

An Antiretroviral Pregnancy Registry is available at 800-258-4263 or https://www.apregistry.com/.

There are insufficient prospective data in pregnant women to assess the risk of birth defects and miscarriage in those receiving doravirine/lamivudine/tenofovir DF. In animal reproduction studies, no adverse developmental effects were observed when doravirine was administered to rabbits or rats at exposures that were 8 or 9 times higher, respectively, than human exposures at the recommended human dosage. Available data from the antiretroviral pregnancy registry show no differences in the overall risk of major birth defects for lamivudine and tenofovir DF.

It is not known whether doravirine is distributed into human milk. Doravirine was distributed into the milk of lactating rats following oral administration (milk concentrations were approximately 1.5 times higher than maternal plasma concentrations at 2 hours after a dose on lactation day 14). Lamivudine and tenofovir DF are distributed into milk in humans. It is not known whether doravirine/lamivudine/tenofovir DF or the individual drug components affect human milk production or the breast-fed infant.

The HHS perinatal HIV transmission guideline provides updated recommendations on infant feeding. The guideline states that patients with HIV should receive evidence-based, patient-centered counseling to support shared decision-making about infant feeding. During counseling, patients should be informed that feeding with appropriate formula or pasteurized donor human milk from a milk bank eliminates the risk of postnatal HIV transmission to the infant. Additionally, achieving and maintaining viral suppression with antiretroviral therapy during pregnancy and postpartum reduces the risk of breastfeeding HIV transmission to <1%, but does not eliminate the risk. Replacement feeding with formula or banked pasteurized donor milk is recommended when patients with HIV are not on antiretroviral therapy and/or do nothave a suppressed viral load during pregnancy (at a minimum throughout the third trimester), as well as at delivery.

The manufacturer makes no specific dosage recommendations for doravirine/lamivudine/tenofovir DF in geriatric patients, but recommends caution because of possible age-related decreases in hepatic, renal, and/or cardiac function and potential for concomitant disease and drug therapy.

Experience in patients 65 years of age and older is insufficient to determine whether they respond differently to doravirine, lamivudine, or tenofovir DF than younger patients.

Doravirine/lamivudine/tenofovir DF should be used with caution in geriatric patients because of age-related decreases in hepatic, renal, and/or cardiac function and potential for concomitant disease and drug therapy.