Vemlidy (tenofovir alafenamide)

Dosage of tenofovir alafenamide fumarate is expressed in terms of tenofovir alafenamide.

Tenofovir alafenamide fumarate is administered orally once daily with food.

Store at <30degreesC in the original container; keep container tightly closed.

No dosing information is available for this tab.

The following drug interactions are based on studies that used tenofovir alafenamide fumarate, or are predicted to occur with use of tenofovir alafenamide; refer to the prescribing information for specific details. Additional drug interactions may exist for fixed-dose combinations containing elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide (Genvoya(R)); emtricitabine, rilpivirine, and tenofovir alafenamide (Odefsey(R)); emtricitabine and tenofovir alafenamide (Descovy(R)); bictegravir, emtricitabine, and tenofovir alafenamide (Biktarvy(R)); and darunavir, cobicistat, emtricitabine, and tenofovir alafenamide (Symtuza(R)). See the full prescribing information for drug interactions of each of these combination products.

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)

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)

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)

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 Alafenamide (> 10 Mg)/Cobicistat; Ritonavir

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

MECHANISM OF ACTION: Tenofovir alafenamide (AF) is a substrate of P-glycoprotein (P-gp) and BCRP, which may be inhibited by cobicistat or ritonavir.(1-6) Ritonavir coadministered with tipranavir has a net inductive effect on P-gp.(7)

CLINICAL EFFECTS: Cobicistat or ritonavir in combination with tenofovir alafenamide (AF) may increase the concentration of tenofovir AF and the risk of renal or other toxicities in some patients.(1-6,8-9) Ritonavir-boosted tipranavir may decrease the levels of tenofovir AF.(4-6,8)

PREDISPOSING FACTORS: Patients with baseline impairment of renal function and/or receiving commitant nephrotoxic agents are at increased risk of renal-related adverse events.(1-6,8-9)

PATIENT MANAGEMENT: Regulatory agencies in different countries differ with regard to recommendations for the coadministration of cobicistat or ritonavir and tenofovir alafenamide (AF). The US manufacturer of emtricitabine-tenofovir AF states that coadministration with atazanavir-cobicistat in pediatric patients weighing 14 kg to 35 kg is not recommended.(4) The US manufacturer of emtricitabine-tenofovir AF states that there are no clinically significant interactions with cobicistat or ritonavir boosted atazanavir, darunavir, or lopinavir in patients weighing >=35 kg.(4) The US National Institute of Health HIV guidelines state that no dose adjustment is necessary when using tenofovir AF 25 mg concurrently with cobicistat or ritonavir boosted atazanavir, darunavir, or lopinavir in patients weighing >=35 kg.(8) Coadministration with tipranavir-ritonavir is not recommended.(8) Note that other countries have different recommendations. The Canadian and European manufacturers of emtricitabine-tenofovir alafenamide that that the dose of tenofovir alafenamide should be 10 mg when coadministered with cobicistat or ritonavir boosted atazanavir, darunavir, or lopinavir. Coadministration with tipranavir-ritonavir is not recommended. There are no data to make recommendations for use of tenofovir AF with other protease inhibitors.(5-6) 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 30 ml/min.(4-6)

DISCUSSION: In clinical trials, cobicistat 150 mg daily increased the area-under-curve (AUC) and maximal concentration (Cmax) of tenofovir alafenamide (AF) by 2.65-fold and 2.83-fold, respectively. Atazanavir 300 mg daily with ritonavir 100 mg daily increased the AUC and Cmax of tenofovir AF by 1.91-fold and 1.77-fold, respectively, whereas cobicistat-boosted atazanavir caused 1.75-fold and 1.8-fold increases in tenofovir AF AUC and Cmax. Darunavir 800 mg daily with cobicistat 150 mg daily did not affect the pharmacokinetics of tenofovir AF, but increased tenofovir AUC and Cmax by 3.24-fold and 3.16-fold, respectively. Similarly, darunavir 800 mg daily with ritonavir 100 mg daily did not affect the levels of tenofovir AF, but increased AUC and Cmax of tenofovir by 2.05-fold and 2.42-fold, respectively. Lopinavir 800 mg daily with ritonavir 200 mg daily increased AUC and Cmax of tenofovir AF by 1.47-fold and 2.19-fold, respectively.(4,6) Renal toxicity, including proximal renal tubulopathy and Fanconi syndrome, 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 30 ml/min to avoid renal impairment.(1-6,8-9) In a phase 3 trial of tenofovir AF versus tenofovir DF coformulated with elvitegravir, cobicistat, and emtricitabine, at 48 weeks patients in the tenofovir AF group had significantly smaller mean serum creatinine increases(0.08 vs 0.12 mg/dL; p<0.0001) and significantly less proteinuria (median % change -3 vs 20; p<0.0001).(9) Tenofovir AF strengths less than or equal to 10 mg are excluded from this interaction. In a pre-approval drug-drug interaction study, concurrent cobicistat (150 mg daily) increased tenofovir AF exposure (area-under-curve, AUC) 2.5-fold. Due to this interaction, the tenofovir AF strength in the cobicistat-elvitegravir-emtricitabine-tenofovir AF combination product was reduced from the originally proposed 25 mg to 10 mg.(10)

Tenofovir Alafenamide/Selected P-Gp Inducers; Phenobarbital

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

MECHANISM OF ACTION: Tenofovir alafenamide (TAF) is a substrate of the intestinal efflux transporter P-glycoprotein (P-gp). Inducers of P-gp may decrease systemic absorption of TAF.(1-4) Phenobarbital may also induce the metabolism of tenofovir alafenamide.(1-4) Primidone is metabolized to phenobarbital.

CLINICAL EFFECTS: Concurrent or recent use of P-gp inducers, phenobarbital, or primidone may result in decreased systemic levels and effectiveness of tenofovir alafenamide.(1-4)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Recommendations regarding concurrent use of tenofovir alafenamide and P-gp inducers vary depending on the region and drug formulation. The European manufacturer of tenofovir alafenamide (DESCOVY for HIV infection and VEMLIDY for hepatitis B) states that concurrent use is not recommended with carbamazepine, phenobarbital, phenytoin, primidone, rifabutin, rifampin, rifapentine, or St. John's wort.(1,2) The US manufacturer of DESCOVY states that rifabutin, rifampin, rifapentine, and St. John's wort are not recommended. Alternatives should be considered for carbamazepine, phenobarbital, phenytoin, and primidone.(3) The Australian and US manufacturers of tenofovir alafenamide (VEMLIDY for hepatitis B) states that concurrent use with phenobarbital, phenytoin, primidone, rifabutin, rifampin, rifapentine, or St. John's wort is not recommended. If concurrent therapy with carbamazepine is indicated during treatment for Hepatitis B, the manufacturer recommends increasing the dose of tenofovir alafenamide to two tablets (50 mg) once daily.(4-5)

DISCUSSION: When tenofovir alafenamide (TAF) was coadministered with carbamazepine, the maximum concentration (Cmax) and area-under-curve (AUC) were decreased 57% and 55%, respectively.(1-4) A subsequent study suggests that this interaction may not have clinically significant effects on intracellular levels of tenofovir diphosphate, the active metabolite of tenofovir alafenamide. In a study of 23 healthy volunteers, the intracellular Cmax and AUC of tenofovir diphosphate were 38% and 36% lower, respectively, when tenofovir alafenamide was coadministered with rifampin than without rifampin. However, these levels of tenofovir diphosphate were 4.4- and 4.21-fold higher, respectively, than levels obtained from tenofovir disoproxil 300 mg daily without rifampin.(6) Selected P-gp inducers linked to this monograph include: apalutamide, carbamazepine, fosphenytoin, lorlatinib, phenytoin, rifabutin, rifampin, rifapentine, or St. John's wort.(1-7) The manufacturer of tenofovir alafenamide also classifies phenobarbital as a P-gp inducer.(1-4)

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)

*None.

• Lactic acidosis

• Acute renal failure
• Chronic kidney disease stage 5 (failure) GFr<15 ml/min
• Fanconi syndrome
• Hypophosphatemia

There are no moderate contraindications for this drug.

The most common adverse effect (incidence >=10%, all grades) of tenofovir alafenamide is headache.

More Frequent

• Depression

Less Frequent

• Hypercholesterolemia
• Increased alanine transaminase
• Increased aspartate transaminase
• Osteopenia
• Pneumonia

Rare or Very Rare

• Abnormal hepatic function tests
• Acute renal failure
• Angioedema
• Dyspnea
• Fanconi syndrome
• Graves' disease
• Guillain-barre syndrome
• Hepatitis
• Hypokalemia
• Hypophosphatemia
• Interstitial nephritis
• Kidney disease with reduction in glomerular filtration rate (GFr)
• Lactic acidosis
• Nephrogenic diabetes insipidus
• Osteomalacia
• Pancreatitis
• Peripheral neuropathy
• Polymyositis
• Renal tubular necrosis
• Rhabdomyolysis
• Steatosis of liver

More Frequent

• Acute abdominal pain
• Back pain
• Cough
• Diarrhea
• Dizziness
• Dyspepsia
• Fatigue
• Fever
• General weakness
• Headache disorder
• Insomnia
• Nausea
• Pain
• Pruritus of skin

Less Frequent

• Anorexia
• Arthralgia
• Chest pain
• Elevated serum amylase
• Elevated serum lipase
• Flatulence
• Myalgia
• Pharyngitis
• Polyuria
• Proteinuria
• Sinusitis
• Skin rash
• Vomiting
• Weight loss

Rare or Very Rare

• Hyperhidrosis
• Hypertriglyceridemia
• Muscle weakness
• Myopathy
• Urticaria

No enhanced messaging available.

The steady-state pharmacokinetics, safety, and efficacy of tenofovir alafenamide for the treatment of chronic HBV infection have been established in pediatric patients 6 to <18 years of age and weighing >=25 kg. No clinically meaningful differences in pharmacokinetics or safety were observed in comparison to adults.

Safety and efficacy of tenofovir alafenamide have not been established in pediatric patients with chronic HBV infection <6 years of age or weighing <25 kg.

The Antiretroviral Pregnancy Registry (APR) monitors pregnancy outcomes in women exposed to tenofovir alafenamide during pregnancy. Clinicians are encouraged to register patients in the APR by calling 800-258-4263.

Data from the APR of more than 1330 exposures to tenofovir alafenamide-containing regimens showed that the prevalence of birth defects in live births was 3.9% and 4.8% following first and second/third trimester exposure, respectively. The rate of miscarriage is not reported in the APR. The overall risk of birth defects for tenofovir alafenamide was not markedly different compared to the background rate for major birth defects of 2.7% in the United States reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP). Use of the MACDP population as the comparator group has several limitations; the MACDP is not disease-specific, assesses populations from a limited geographic area, and does not include outcomes for births that occurred at <20 weeks' gestation.

In animal studies, there was no evidence of impaired fertility or harm to the fetus. Adverse developmental effects were not observed when tenofovir alafenamide was administered during organogenesis to rats or rabbits in dosages that resulted in exposures equal to or 51 times higher, respectively, than human exposures reported with the recommended daily dosage of tenofovir alafenamide.

Published data report the presence of tenofovir alafenamide and tenofovir in human milk; however, these data have not documented adverse effects of tenofovir alafenamide in the breastfed child. It is unknown if tenofovir alafenamide affects milk production.

Consider the benefits of breast-feeding and the importance of tenofovir alafenamide to the mother along with the potential adverse effects on the breast-fed infant from the drug or from the underlying maternal condition.

The manufacturer makes no specific dosage recommendations for geriatric patients.

In clinical trials of tenofovir alafenamide, no clinically significant differences in safety or efficacy were observed between patients >=65 years of age and patients 18 to <65 years of age.