Odefsey (emtricitabine/rilpivirine HCl/tenofovir alafenamide fumarate)

Emtricitabine capsules and oral solution are not bioequivalent. Bioavailability of the oral solution is 80% relative to that of the capsule.

Rilpivirine is commercially available as rilpivirine hydrochloride; dosage is expressed in terms of rilpivirine.

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

Reduce dosage in patients with renal impairment; emtricitabine is principally eliminated by the kidney.

If rilpivirine (Edurant(R)) is coadministered with rifabutin, the rilpivirine dosage should be increased to 50 mg once daily. If rifabutin coadministration is halted, the rilpivirine dosage should be decreased to 25 mg once daily.

Emtricitabine is administered orally once daily without regard to meals.

Single-entity emtricitabine is commercially available as 200-mg capsules or an oral solution containing 10 mg/mL.

Emtricitabine is also commercially available in the following fixed-combination tablets for oral use: emtricitabine/tenofovir DF (Truvada(R)), efavirenz/emtricitabine/tenofovir DF (Atripla(R)), emtricitabine/rilpivirine/tenofovir DF (Complera(R)), elvitegravir/cobicistat/emtricitabine/tenofovir DF (Stribild(R)), elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (Genvoya(R)), emtricitabine/rilpivirine/tenofovir alafenamide (Odefsey(R)), emtricitabine/tenofovir alafenamide (Descovy(R)), and bictegravir/emtricitabine/tenofovir alafenamide (Biktarvy(R)). See the full prescribing information for administration of each of these combination products.

Emtricitabine is used in conjunction with other antiretrovirals. Single-entity emtricitabine should not be used concomitantly with any other emtricitabine-containing preparations.

Store capsules at 25degreesC (excursions permitted to 15-30degreesC).

Store oral solution at 2-8degreesC. For patient use, store at 25degreesC (excursions permitted to 15-30degreesC); use within 3 months.

Rilpivirine hydrochloride is available as oral tablets (Edurant(R)) and tablets for oral suspension (Edurant PED(R)); both formulations are administered once daily with a meal. Rilpivirine tablets should be administered to adults and pediatric patients weighing >=25 kg. Rilpivirine tablets for oral suspension should be administered only to pediatric patients weighing >=14 kg to <25 kg.

Rilpivirine oral tablets and tablets for oral suspension have differing pharmacokinetic profiles; therefore, the tablets and tablets for oral suspension should not be substituted on a milligram-per-milligram basis.

Rilpivirine tablets for oral suspension must be dispersed in drinking water and immediately consumed with a meal. If not consumed immediately, the suspension should be discarded and a new dose prepared. Rilpivirine tablets for oral suspension should not be crushed, chewed, or swallowed whole.

In order to properly prepare the tablets for oral suspension for administration, an appropriate number of tablets should be placed in a cup and 5 mL of room temperature drinking water should be added. The cup should be swirled carefully for 1--2 minutes; the oral suspension should begin to have a cloudy appearance. After swirling the cup for 1--2 minutes, the oral suspension may be consumed immediately or the suspension can be further diluted with 5 mL of drinking water, orange juice, or applesauce to assist in administration. All the medicine within the cup should be consumed immediately; a spoon may be used if needed. If medicine is still present in the cup, another 5 mL of drinking water (or alternative beverage or soft food) may be added to the cup, swirled, and consumed immediately.

Food enhances rilpivirine bioavailability. Systemic exposure is approximately 40 or 50% lower if rilpivirine tablets are administered under fasting conditions or with only a protein-rich nutritional drink, respectively, compared with following a standard meal (533 kcal) or high-caloric meal (928 kcal). Systemic exposure is 31 or 28% lower if rilpivirine tablets for oral suspension are dispersed in drinking water in fasted conditions or after yogurt consumption, respectively, compared with following a meal in adults containing 533 kcal.

If a dose of rilpivirine is missed within 12 hours of the time it is usually taken, take the missed dose as soon as possible with a meal. If a dose of rilpivirine is missed by more than 12 hours, then skip the missed dose and resume the normal dosing schedule.

Rilpivirine must be used in conjunction with other antiretrovirals. Single-entity rilpivirine should not be used concomitantly with emtricitabine/rilpivirine/tenofovir alafenamide or cabotegravir/rilpivirine injeciton. Single-entity rilpivirine should not be used concomitantly with emtricitabine/rilpivirine/tenofovir DF, unless needed for adjustment of rilpivirine dosage (e.g., when the fixed combination is used concomitantly with rifabutin).

Store rilpivirine tablets and tablets for oral suspension at 20--25oC; (excursions permitted between 15-30oC). Store tablets in original bottle to protect from light and tablets for oral suspension in original package to protect from moisture.

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.

In vitro studies indicate that emtricitabine does not inhibit cytochrome P-450 (CYP) isoenzymes 1A2, 2A6, 2B6, 2C9, 2C19, 2D6, or 3A4. Emtricitabine does not inhibit uridine-5'-disphosphoglucuronyl transferase. The following drug interactions are based on studies using emtricitabine. When a fixed combination containing emtricitabine is used, interactions associated with each drug in the fixed combination should be considered.

Most rilpivirine drug interaction studies reported to date used rilpivirine dosages of 75 or 150 mg once daily; these dosages are considerably higher than the usually recommended rilpivirine dosage (25 mg once daily). Rilpivirine is primarily metabolized by cytochrome P-450 isoenzyme 3A (CYP3A).

The following drug interactions are based on studies using single-entity rilpivirine. When rilpivirine fixed combinations are used, interactions associated with each drug in the fixed combination should be considered.

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)

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.

Nnrtis/Cobicistat-Elvitegravir

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: Cobicistat inhibits CYP2D6, CYP3A4, BCRP, OATP1B1 and OATP1B3. Elvitegravir induces CYP2C9. Efavirenz may induce the metabolism of cobicistat via CYP3A4.(1)

CLINICAL EFFECTS: Concurrent use of cobicistat-elvitegravir with non-nucleoside reverse transcriptase inhibitors (NNRTIs) may result in altered and/or suboptimal pharmacokinetics of cobicistat, elvitegravir, and/or the NNRTI.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The combination product containing cobicistat-elvitegravir-emtricitabine-tenofovir should not be used with non-nucleoside reverse transcriptase inhibitors.(1)

DISCUSSION: Concurrent use of cobicistat-elvitegravir with non-nucleoside reverse transcriptase inhibitors may result in altered and/or suboptimal pharmacokinetics of cobicistat, elvitegravir, and/or the NNRTI.(1)

Rilpivirine/Proton Pump Inhibitors

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: Rilpivirine requires an acidic medium for absorption. The proton pump inhibitor induced decrease in gastric pH may result in a decrease in rilpivirine absorption.(1)

CLINICAL EFFECTS: Concurrent use of a proton pump inhibitor may result in decreased levels and effectiveness of rilpivirine, as well as the development of resistance.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of rilpivirine states that concurrent use of proton pump inhibitors is contraindicated.(1) When substituting antacids for proton pump inhibitors in patients maintained on rilpivirine, administer the antacid at least 2 hours before or 4 hours after rilpivirine.(1) When substituting H2 antagonists for proton pump inhibitors in patients maintained on rilpivirine, administer the H2 antagonist at least 12 hours before or 4 hours after rilpivirine.(1)

DISCUSSION: In a study in 16 subjects, omeprazole (20 mg daily) decreased the maximum concentration (Cmax), area-under-curve (AUC), and minimum concentration (Cmin) of rilpivirine (150 mg daily) by 40%, 40%, and 33%, respectively. The Cmax and AUC of omeprazole decreased by 14% and 14%, respectively.(1) In a study in 24 subjects, famotidine (40 mg single dose) administered 12 hours before a single dose of rilpivirine (150 mg) had no significant effect on rilpivirine Cmax or AUC.(1) In a study in 23 subjects, famotidine (40 mg single dose) administered 2 hours before a single dose of rilpivirine (150 mg) decreased the rilpivirine Cmax and AUC by 85% and 76%, respectively.(1) In a study in 24 subjects, famotidine (40 mg single dose) administered 4 hours after a single dose of rilpivirine (150 mg) increased the rilpivirine Cmax and AUC by 21% and 13%, respectively.(1)

Rilpivirine/Selected 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: Apalutamide, barbiturates, carbamazepine, dexamethasone, enzalutamide, eslicarbazepine, fosphenytoin, ivosidenib, lumacaftor, mitotane, natisedine, phenobarbital, phenytoin, primidone, oxcarbazepine, rifampin, rifapentine, and St. John's wort may induce the metabolism of rilpivirine by CYP3A4.(1)

CLINICAL EFFECTS: Concurrent or recent use of apalutamide, barbiturates, carbamazepine, dexamethasone, enzalutamide, eslicarbazepine, fosphenytoin, ivosidenib, lumacaftor, mitotane, natisedine, phenobarbital, phenytoin, primidone, oxcarbazepine, rifampin, rifapentine, or St. John's wort may result in decreased levels and effectiveness of rilpivirine, as well as the development of resistance.(1)

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

PATIENT MANAGEMENT: The US manufacturer of rilpivirine states that concurrent use of CYP3A4 inducers such as apalutamide, barbiturates, carbamazepine, dexamethasone, enzalutamide, eslicarbazepine, fosphenytoin, ivosidenib, lumacaftor, mitotane, natisedine, phenobarbital, phenytoin, primidone, oxcarbazepine, rifampin, rifapentine, or St. John's wort is contraindicated.(1) It may take several weeks after the discontinuation of an enzyme inducer for enzyme activity to return to normal.(1)

DISCUSSION: In a study in 16 subjects, rifampin (600 mg daily) decreased the Cmax, AUC, and Cmin of rilpivirine (150 mg daily) by 69%, 80%, and 89%, respectively. There were no significant effects on the Cmax or AUC of rifampin or 25-desacetylrifampin.(1) Strong CYP3A4 inducers linked include: apalutamide, barbiturates, carbamazepine, dexamethasone, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, natisedine, phenobarbital, phenytoin, primidone, oxcarbazepine, rifampin, rifapentine, or St. John's wort.

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.

Emtricitabine-Rilpivirine-Taf/P-Gp & Moderate Cyp3a4 Inducer

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

MECHANISM OF ACTION: Moderate CYP3A4 inducers may induce the metabolism of rilpivirine. P-glycoprotein (P-gp) inducers may decrease the absorption of tenofovir alafenamide (TAF).(1)

CLINICAL EFFECTS: Concurrent or recent use of dual P-gp and moderate CYP3A4 inducers may result in decreased levels and effectiveness of rilpivirine and TAF, as well as the development of resistance.(1)

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

PATIENT MANAGEMENT: The US manufacturer of emtricitabine-rilpivirine-TAF states that concurrent use of P-gp and moderate CYP3A4 inducers is not recommended.(1)

DISCUSSION: In a study in 18 subjects, rifabutin (300 mg daily) decreased the maximum concentration (Cmax), area-under-curve (AUC), and minimum concentration (Cmin) of rilpivirine (25 mg orally daily) by 31%, 42%, and 48%, respectively.(1) P-gp and moderate CYP3A4 inducers linked to this monograph include: efavirenz, lorlatinib, and rifabutin.(2)

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)

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

Delavirdine; Rilpivirine/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: The simultaneous administration of delavirdine or rilpivirine and didanosine may result in decreased levels and effectiveness of the NNRTI and didanosine.(1-3)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturers of delavirdine(1) and didanosine(2) recommend that the administration of delavirdine and didanosine be separated by at least one hour. The manufacturer of rilpivirine recommends that didanosine be administered at least 2 hours before or 4 hours after rilpivirine.(3)

DISCUSSION: In a study in nine HIV-1 infected patients, the simultaneous administration of delavirdine (400 mg three times daily) with didanosine (either 125 mg or 250 mg twice daily) for 4 weeks decreased the maximum concentration (Cmax) and area-under-curve (AUC) of didanosine by 20% and 21%, respectively. The Cmax and AUC of delavirdine decreased by 32% and 19%, respectively.(1) In a study in 12 HIV-infected patients, the simultaneous administration of delavirdine (400 mg single dose) with didanosine (125 mg or 200 mg every 12 hours) decreased delavirdine Cmax and AUC by 53% and 32%, respectively. Administration of delavirdine (400 mg single dose) 1 hour before didanosine (125 mg or 200 mg every 12 hours) increased delavirdine Cmax and AUC by 18% and 20%, respectively.(2) In a study in 21 subjects, administration of didanosine (400 mg delayed-release capsule daily) 2 hours before rilpivirine (150 mg daily) had no effect on the Cmax, AUC, or minimum concentration (Cmin) of rilpivirine. There were no significant effects on the Cmax or AUC of didanosine.(3)

Emtricitabine-Rilpivirine-Taf/Select Moderate Cyp3a4 Inducer

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

MECHANISM OF ACTION: Moderate CYP3A4 inducers may induce the metabolism of rilpivirine.(1-2)

CLINICAL EFFECTS: Concurrent or recent use of moderate CYP3A4 inducers may result in decreased levels and effectiveness of rilpivirine, as well as the development of resistance.(1-2)

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

PATIENT MANAGEMENT: The US DHHS HIV guidelines state that concurrent use of bosentan or mavacamten (moderate CYP3A4 inducers) with oral rilpivirine should be monitored closely. Consider alternative therapies that do not affect CYP3A4 or alternative antiretroviral agents. If concurrent use is necessary, virologic response should be monitored.(3) The US manufacturer of oral rilpivirine states that concurrent use of rifabutin (moderate CYP3A4 inducer) warrants dose adjustment. When administering moderate CYP3A4 inducers with oral rilpivirine, increase the dose of rilpivirine to 50 mg once daily. When rifabutin co-administration is stopped, the rilpivirine dose should be decreased to 25 mg once daily. It may take several weeks after the discontinuation of an enzyme inducer for enzyme activity to return to normal.(2)

DISCUSSION: In a study in 18 subjects, rifabutin (300 mg daily) decreased the maximum concentration (Cmax), area-under-curve (AUC), and minimum concentration (Cmin) of rilpivirine (25 mg orally daily) by 31%, 42%, and 48%, respectively.(1) A study in 18 subjects compared rilpivirine administered alone (25 mg orally daily) to coadministration with rifabutin (300 mg daily) and rilpivirine (50 mg orally daily). A significant difference was not found with the Cmax (1.43), AUC (1.16), or Cmin (0.93) of rilpivirine. (2) Selected moderate CYP3A4 inducers linked to this monograph include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, elagolix, eslicarbazepine, fexinidazole, lesinurad, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, sotorasib, telotristat, thioridazine and tovorafenib.(3)

Rilpivirine/Antacids; H2 Antagonists

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

MECHANISM OF ACTION: Rilpivirine requires an acidic medium for absorption. Antacid or H2 antagonist induced decrease in gastric pH may result in a decrease in rilpivirine absorption.(1)

CLINICAL EFFECTS: Simultaneous administration of an antacid or a H2 antagonist may result in decreased levels and effectiveness of rilpivirine, as well as the development of resistance.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: In patients maintained on rilpivirine, administer antacids at least 2 hours before or 4 hours after rilpivirine.(1) In patients maintained on rilpivirine, administer H2 antagonists at least 12 hours before or 4 hours after rilpivirine.(1) Concurrent use of proton pump inhibitors with rilpivirine is contraindicated.(1) Some vitamin preparations may contain sufficient quantities of calcium and/or magnesium salts with antacid properties to interact as well.

DISCUSSION: In a study in 16 subjects, omeprazole (20 mg daily) decreased the maximum concentration (Cmax), area-under-curve (AUC), and minimum concentration (Cmin) of rilpivirine (150 mg daily) by 40%, 40%, and 33%, respectively. The Cmax and AUC of omeprazole decreased by 14% and 14%, respectively.(1) In a study in 24 subjects, famotidine (40 mg single dose) administered 12 hours before a single dose of rilpivirine (150 mg) had no significant effect on rilpivirine Cmax or AUC.(1) In a study in 23 subjects, famotidine (40 mg single dose) administered 2 hours before a single dose of rilpivirine (150 mg) decreased the rilpivirine Cmax and AUC by 85% and 76%, respectively.(1) In a study in 24 subjects, famotidine (40 mg single dose) administered 4 hours after a single dose of rilpivirine (150 mg) increased the rilpivirine Cmax and AUC by 21% and 13%, respectively.(1)

Rilpivirine/Ombitasvir-Paritaprevir-Ritonavir

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

MECHANISM OF ACTION: Ombitasvir-paritaprevir-ritonavir may inhibit the CYP3A4 mediated metabolism of rilpivirine leading to increased systemic exposure (area-under-curve, AUC).(1)

CLINICAL EFFECTS: Increased exposure to rilpivirine may result in toxicity, including potentially life-threatening cardiac arrhythmias, such as torsades de pointes.(1)

PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, advanced age or when receiving concomitant treatment with additional inhibitors of CYP3A4.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose, or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)

PATIENT MANAGEMENT: The concurrent use of rilpivirine with ombitasvir-paritaprevir-ritonavir is not recommended due to the potential risk for QT prolongation.(1) Rilpivirine does not prolong the QT interval at the recommended dose of 25 mg daily. In interaction studies the combination of ombitasvir-paritaprevir-ritonavir and dasabuvir with rilpivirine (25 mg daily) increased rilpivirine exposure (AUC) approximately 3-fold (range: 2.80-3.77), similar to the exposure associated with a rilpivirine dose of 75 mg daily.(3) In rilpivirine QT studies, a 75 mg daily dose increased the QTc interval by 10.7 msec, just above the 10 msec threshold for regulatory concern.(3,4) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: In a clinical trial in healthy adults, rilpivirine at recommended dosages (25 mg daily) had no significant effects on the QTc interval. However, supratherapeutic dosages (75 mg daily and 300 mg daily) increased the QTc interval by 10.7 msec and 23.3 msec, respectively. Rilpivirine dosages of 75 mg daily and 300 mg daily resulted in rilpivirine maximum concentration (Cmax) levels of 2.6-fold and 6.7-respectively.(4)

Rilpivirine/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 rilpivirine by CYP3A4.(1-4)

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

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Coadministration of rilpivirine with tecovirimat should be approached with caution. Consider increasing rilpivirine to 50 mg daily during treatment with tecovirimat and for approximately 2 weeks after the end of treatment.(1-4)

DISCUSSION: In a study in 18 subjects, rifabutin (300 mg daily), a moderate CYP3A4 inducer, decreased the maximum concentration (Cmax), area-under-curve (AUC), and minimum concentration (Cmin) of rilpivirine (25 mg orally daily) by 31%, 42%, and 48%, respectively.(1) A study in 18 subjects compared rilpivirine administered alone (25 mg orally daily) to coadministration with rifabutin (300 mg daily) and rilpivirine (50 mg orally daily). A significant difference was not found with the Cmax (1.43), AUC (1.16), or Cmin (0.93) of rilpivirine.(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 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/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)

*Known hypersensitivity to the drug or any ingredient in the formulation.

*Concomitant use of rilpivirine with drugs that induce cytochrome P-450 isoenzyme 3A (CYP3A) or drugs that elevate gastric pH is contraindicated since substantially decreased plasma rilpivirine concentrations may occur and may result in loss of virologic response and development of resistance to rilpivirine and/or class resistance to HIV NNRTIs.

*None.

• 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
• Depression
• Disease of liver
• Fanconi syndrome
• Hypophosphatemia
• Suicidal ideation

• Chronic hepatitis B
• Chronic kidney disease stage 4 (severe) GFR 15-29 ml/min
• Chronic kidney disease stage 5 (failure) GFr<15 ml/min
• Viral hepatitis

The most common adverse reactions experienced in at least 10% of adult patients with HIV-1 treated with emtricitabine include headache, GI effects (diarrhea, nausea), fatigue, dizziness, depression, insomnia, abnormal dreams, rash, abdominal pain, asthenia, increased cough, and rhinitis. Adverse effects reported in pediatric patients 3 months of age or older receiving emtricitabine in clinical studies have been similar to those in adults, with the exception of a higher frequency of hyperpigmentation.

Adverse effects of at least moderate to severe intensity reported in 2% or more of patients in clinical trials include depressive disorders, insomnia, headache, and rash.

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

More Frequent

• Depression
• Depression
• Gastroenteritis
• Vomiting

Less Frequent

• Anemia
• Bullous dermatitis
• Hypercholesterolemia
• Increased alanine transaminase
• Increased aspartate transaminase
• Maculopapular rash
• Osteopenia
• Peripheral neuropathy
• Pneumonia
• Urticaria

Rare or Very Rare

• Abnormal hepatic function tests
• Abnormal hepatic function tests
• Acute renal failure
• Angioedema
• Angioedema
• Autoimmune hepatitis
• Autoimmune hepatitis
• Biliary calculus
• Blistering skin
• Bronchospastic pulmonary disease
• Cholecystitis
• Conjunctivitis
• DRESS syndrome
• Dyspnea
• Dyspnea
• Eosinophilia
• Facial edema
• Fanconi syndrome
• Glomerulonephritis
• Graves' disease
• Graves' disease
• Graves' disease
• Guillain-barre syndrome
• Guillain-barre syndrome
• Guillain-barre syndrome
• Hepatitis
• Hypersensitivity drug reaction
• Hypokalemia
• Hypophosphatemia
• Interstitial nephritis
• Kidney disease with reduction in glomerular filtration rate (GFr)
• Kidney stone
• Lactic acidosis
• Lactic acidosis
• Nephrogenic diabetes insipidus
• Nephrotic syndrome
• Osteomalacia
• Pancreatitis
• Peripheral neuropathy
• Pneumonia
• Polymyositis
• Polymyositis
• Polymyositis
• Renal tubular necrosis
• Rhabdomyolysis
• Steatosis of liver
• Steatosis of liver
• Suicidal
• Suicidal ideation

More Frequent

• Acute abdominal pain
• Acute abdominal pain
• Back pain
• Cough
• Cough
• Diarrhea
• Diarrhea
• Dizziness
• Dizziness
• Dream disorder
• Dyspepsia
• Fatigue
• Fatigue
• Fever
• General weakness
• General weakness
• Headache disorder
• Headache disorder
• Headache disorder
• Injection site sequelae
• Insomnia
• Insomnia
• Musculoskeletal pain
• Nausea
• Nausea
• Pain
• Pruritus of skin
• Pruritus of skin
• Rhinitis
• Skin rash
• Skin rash

Less Frequent

• Acute bacterial otitis media
• Anorexia
• Arthralgia
• Arthralgia
• Chest pain
• Diarrhea
• Dizziness
• Dream disorder
• Dyspepsia
• Elevated serum amylase
• Elevated serum lipase
• Fatigue
• Fever
• Flatulence
• Insomnia
• Myalgia
• Myalgia
• Nausea
• Paresthesia
• Pharyngitis
• Polyuria
• Proteinuria
• Sinusitis
• Skin rash
• Vomiting
• Vomiting
• Weight loss

Rare or Very Rare

• Acute abdominal pain
• Agitation
• Anorexia
• Depression
• Drowsy
• Drug fever
• Dyschromia
• Hyperhidrosis
• Hypertriglyceridemia
• Muscle weakness
• Myopathy
• Oral hypoesthesia
• Sleep disorder
• Stomatitis
• Symptoms of anxiety
• Urticaria
• Urticaria
• Weight gain

No enhanced messaging available.

Safety and efficacy of emtricitabine have been established for treatment of HIV-1 infection in children 3 months of age and older.

The pharmacokinetics and safety of emtricitabine were evaluated in a dose-finding study in 20 neonates born to HIV-infected mothers. These neonates received zidovudine prophylaxis for 6 weeks. In addition, these neonates received 2 short courses of emtricitabine (3 mg/kg daily for 4 days per course) during the first 12 weeks of life. This dosage was not associated with any safety issues. Systemic exposure (AUC) in infants 0-3 months of age receiving emtricitabine 3 mg/kg daily was similar to that reported in children 3 months to 17 years of age receiving emtricitabine 6 mg/kg daily. All neonates were HIV-1 negative at the end of the study (6 months postpartum); the efficacy of emtricitabine for the prevention or treatment of HIV was not determined.

Safety and efficacy of rilpivirine tablets (Edurant(R)) and tablets for oral suspension (Edurant PED(R)) have been established for the treatment of HIV-1 infection in treatment-naive pediatric patients >=2 years of age and weighing >=14 kg.

The use of rilpivirine in this patient population is supported by the results of 3 trials (i.e., Trial TMC278-C213, Trial TMC278HTX2002, MOCHA trial). The single arm, open-label, phase 2, TMC278-C213 trial involved 2 cohorts of treatment-naive HIV-1 infected pediatric patients. Cohort 1 assessed the efficacy, safety, and pharmacokinetics of rilpivirine tablets in 36 pediatric patients (12 to <18 years of age and weighing >=32 kg). Cohort 2 assessed the safety, tolerability, antiviral activity, and pharmacokinetics of rilpivirine tablets and tablets for oral suspension weight-adjusted doses in 18 pediatric patients (6 to <12 years of age and weighing >=17 kg). The single-arm, open-label, phase 2, TMC278HTX2002 trial assessed the safety, tolerability, antiviral activity, and pharmacokinetics of rilpivirine tablets and tablets for oral suspension weight-adjusted doses in 26 pediatric patients (2 to <12 years of age and weighing >=16 kg). In the ongoing MOCHA trial, the safety, tolerability, and pharmacokinetics of oral/injectable cabotegravir and oral/injectable rilpivirine are being evaluated.

Rilpivirine tablets for oral suspension (Edurant PED(R)) are not recommended for use in pediatric patients <2 years of age or weighing <14 kg.

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 emtricitabine during pregnancy. Clinicians are encouraged to register patients in the APR by calling 800-258-4263 or visiting https://www.APRegistry.com.

Based on prospective reports to the APR, the overall risk of birth defects among live births with first-trimester exposure to emtricitabine was 2.4%, and 2.3% with second/third trimester exposure, 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). Limitations of using an external comparator (i.e., MACDP) include differences in populations and methodology, and confounding due to the underlying disease. The rate of miscarriage for individual drugs is not reported in the APR.

Additional observational data have not shown an increase in major malformations with emtricitabine exposure in pregnancy.

The Antiretroviral Pregnancy Registry (APR) monitors pregnancy outcomes in women exposed to rilpivirine during pregnancy. Clinicians are encouraged to register patients in the APR by calling 800-258-4263 or visiting https://www.apregistry.com/.

The overall risk of birth defects with first-trimester exposure for rilpivirine 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). Limitations of using an external comparator (the MACDP) includes differences in populations and methodology, and confounding due to the underlying disease. The rate of miscarriage is not reported in the APR.

In a small study of 19 HIV-1 infected women on a rilpivirine-based regimen, protein binding was similar during the second and third trimesters and the postpartum period; however, total exposure of rilpivirine was approximately 30-40% lower during pregnancy when compared to the postpartum period. Of the 12 virologically suppressed patients at baseline (<50 copies/mL), virologic suppression with a rilpivirine-based regimen was maintained through the third trimester in 10 patients, and was well-tolerated. Among 10 infants born to HIV-1 infected women, all were HIV-1 negative at delivery and for 16 weeks post-partum. All infants received prophylactic zidovudine treatment at delivery.

Animal data have shown no increases in embryo-fetal toxicity at rilpivirine exposures 15-70 times the equivalent human exposure.

Monitor viral load closely in pregnant women; lower rilpivirine exposures have been observed in pregnant individuals.

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.

Based on published data, emtricitabine is distributed into human milk. It is not known whether emtricitabine affects milk production or has effects on 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.

Based on limited data, rilpivirine is present in human milk; however, there are no data on the effects of rilpivirine on the breast-fed infant or on milk production.

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.

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, but recommends cautious dosage selection due to the greater frequency of decreased hepatic, renal, and/or cardiac function, and of concomitant disease and drug therapy.

The manufacturer makes no specific dosage recommendations for geriatric patients.

Experience in those 65 years of age or older is insufficient to determine whether they respond differently to emtricitabine than younger adults. Dosage should be selected with caution because of age-related decreases in hepatic, renal, and/or cardiac function and potential for concomitant disease and drug therapy.

The manufacturer makes no specific dosage recommendations for geriatric patients.

Consult the product labeling of commercially available fixed-combination products containing rilpivirine for specific dosage adjustments of each component in geriatric patients.

Experience in those 65 years of age and older is insufficient to determine whether they respond differently to rilpivirine than younger adults. Dosage should be selected with caution because of age-related decreases in hepatic, renal, and/or cardiac function and potential for concomitant disease and drug therapy.

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.