Truvada (emtricitabine/tenofovir disoproxil fumarate)

Fixed-combination tablets of FTC/TDF contain emtricitabine and tenofovir DF; dosage of tenofovir DF is expressed in terms of tenofovir DF.

Emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) tablets are administered orally once daily without regard to food. A fixed-combination tablet containing 200 mg of emtricitabine and 300 mg of tenofovir DF is bioequivalent to a 200-mg capsule of FTC and a 300-mg tablet of tenofovir DF given simultaneously.

For the treatment of HIV-1 infection, FTC/TDF is used in conjunction with other antiretrovirals. For preexposure prophylaxis (PrEP) for prevention of HIV-1 infection, FTC/TDF is used alone without any other antiretrovirals.

Tablets should be stored at 25oC; excursions permitted to 15-30oC.

The following drug interactions are based on studies that used emtricitabine or tenofovir disoproxil fumarate alone or the fixed combination of emtricitabine and tenofovir disoproxil fumarate (FTC/TDF) or are predicted to occur.

Potential drug 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)

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.

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.

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)

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.

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)

*Do not use for preexposure prophylaxis (PrEP) of HIV-1 infection in individuals with unknown or positive HIV-1 status.

• 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 hepatitis B
• Chronic kidney disease stage 3A (moderate) GFR 45-59 ml/min
• Osteopenia

Adverse effects reported in >=10% of HIV-infected patients receiving FTC/TDF in conjunction with other antiretrovirals are diarrhea, nausea, fatigue, headache, dizziness, depression, insomnia, abnormal dreams, and rash.

Adverse effects reported in >=2% of patients receiving FTC/TDF for preexposure prophylaxis of HIV-1 infection (PrEP) and more frequently than in patients receiving placebo include headache, abdominal pain, and decrease in weight.

Less Frequent

• Dyspnea
• Fanconi syndrome
• Hypervolemia
• Hypophosphatemia
• Kidney disease with reduction in glomerular filtration rate (GFr)

Rare or Very Rare

• Abnormal hepatic function tests
• Acute renal failure
• Angioedema
• Autoimmune hepatitis
• Drug-induced hepatitis
• Graves' disease
• Guillain-barre syndrome
• Hypokalemia
• Increased alanine transaminase
• Increased aspartate transaminase
• Interstitial nephritis
• Lactic acidosis
• Osteomalacia
• Osteopenia
• Pancreatitis
• Paresthesia
• Peripheral neuropathy
• Pneumonia
• Polymyositis
• Renal failure
• Renal tubular necrosis
• Rhabdomyolysis
• Steatosis of liver

More Frequent

• Depression
• Diarrhea
• Dizziness
• Dream disorder
• Fatigue
• Headache disorder
• Insomnia
• Lipodystrophy associated with human immunodeficiency virus infection
• Nausea
• Skin rash

Less Frequent

• Acute abdominal pain
• Bullous dermatitis
• General weakness
• Maculopapular rash
• Pharyngitis
• Pruritus of skin
• Sinusitis
• Symptoms of anxiety
• Urticaria
• Vomiting
• Weight loss

Rare or Very Rare

• Arthralgia
• Back pain
• Cough
• Dyschromia
• Dyspepsia
• Fever
• Hyperhidrosis
• Muscle weakness
• Myalgia
• Myopathy
• Pain
• Rhinitis

No enhanced messaging available.

Safety and efficacy of FTC/TDF for treatment of HIV-1 infection have not been established in pediatric patients weighing <17 kg; safety and efficacy of this fixed combination for HIV-1 PrEP have not been established in pediatric patients weighing <35 kg.

Adverse effects reported in pediatric patients 3 months to <18 years of age receiving emtricitabine in clinical studies have been similar to those in adults, with the exception of a higher frequency of anemia and hyperpigmentation. Adverse effects reported in pediatric patients 2 to <18 years of age receiving tenofovir DF in clinical studies have been similar to those in adults.

Adverse effects reported in adolescents 15-18 years of age receiving FTC/TDF in clinical trials for HIV-1 PrEP were similar to those in adults.

In clinical trials in HIV-1 infected subjects 2 to <18 years of age, bone effects in pediatric and adolescent subjects receiving tenofovir DF were similar to those observed in adult subjects, suggesting increased bone turnover. Total body bone mineral density (BMD) gain was less in the tenofovir DF-treated HIV-1 infected pediatric subjects compared with control groups. Similar trends were observed in adolescent subjects 12 to <18 years of age treated for chronic hepatitis B infection. Skeletal growth (height) appeared to be unaffected in all pediatric trials.

BMD monitoring should be considered in pediatric patients who have a history of pathologic bone fracture or other risk factors for osteoporosis or bone loss. Although the effect of calcium and vitamin D supplementation was not studied, such supplementation may be beneficial. If bone abnormalities are suspected, appropriate consultation should be obtained.

Antiretroviral Pregnancy Registry (APR) at 800-258-4263 or https://www.APRegistry.com.

Available data from the APR show an incidence of major birth defects with first-trimester exposure of 2.3 or 2.1% for emtricitabine or tenofovir DF, respectively, compared with a background rate for major birth defects of 2.7% in a US reference population of the Metropolitan Atlanta Congenital Defects Program. In animal reproduction studies, no adverse developmental effects were observed when the components of emtricitabine/tenofovir DF (FTC/TDF) were administered separately at doses/exposures >=60 (emtricitabine), >=14 (tenofovir DF), and 2.7 (tenofovir) times those of the recommended daily dose of FTC/TDF.

In HIV-1-negative women at risk of acquiring HIV-1, consideration should be given to methods to prevent HIV-1, including initiating or continuing FTC/TDF PrEP, taking into account the potential increased risk of HIV-1 infection during pregnancy and the increased risk of mother-to-child transmission during acute HIV-1 infection.

Emtricitabine and tenofovir DF are distributed into human milk in low concentrations. It is not known whether emtricitabine/tenofovir DF (FTC/TDF) affects human milk production or affects 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 completely 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 not have 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 geriatric patients.

Experience in patients >=65 years of age is insufficient to determine whether they respond differently to FTC/TDF than younger adults.