Tenofovir Alafenamide Fumarate (Monograph)

Brand name: Vemlidy (https://www.vemlidy.com)
Drug class: Nucleosides and Nucleotides

Medically reviewed by Drugs.com on Apr 10, 2024. Written by ASHP.

Introduction

Antiviral; nucleotide reverse transcriptase inhibitor active against HBV; also has antiretroviral activity against HIV.

Uses for Tenofovir Alafenamide Fumarate

Treatment of Chronic HBV Infection

Treatment of chronic HBV infection in adults and pediatric patients ≥12 years of age with compensated liver disease.

Safety and efficacy not established in patients with decompensated cirrhosis (Child-Pugh class B or C); not recommended for treatment of HBV infection in such patients.

Tenofovir alafenamide fumarate is also available in various fixed-combination preparations that contain additional antiretroviral agents; these products are used for the treatment of HIV infection and/or for HIV pre-exposure prophylaxis (PrEP). Refer to separate combination product monographs for information related to the specific uses of these products and the role of tenofovir alafenamide fumarate-containing regimens in the treatment and prevention of HIV infection.

Tenofovir alafenamide is a preferred initial treatment option in adults when chronic HBV treatment is indicated; choice of antiviral medication should be individualized based on patient characteristics and comorbidities, treatment tolerability, and cost.

Tenofovir Alafenamide Fumarate Dosage and Administration

General

Pretreatment Screening

• Perform testing for HIV-1 infection prior to initiating tenofovir alafenamide. Do not use tenofovir alafenamide alone to treat HIV-1 infection.

• Assess S_cr, estimated Cl_cr, urine glucose, and urine protein prior to initiating tenofovir alafenamide in all patients. In patients with chronic kidney disease, also assess serum phosphorus.

Patient Monitoring

• Assess S_cr, estimated Cl_cr, urine glucose, and urine protein on a clinically appropriate schedule during treatment with tenofovir alafenamide in all patients. In patients with chronic kidney disease, also monitor serum phosphorus.

• After discontinuing treatment with tenofovir alafenamide, closely monitor hepatic function with both clinical and laboratory follow-up for at least several months.

Dispensing and Administration Precautions

• Tenofovir alafenamide is commercially available as a single entity and in various fixed-combination preparations containing additional antiretroviral agents. Refer to the full prescribing information for specific, distinct uses of the combination products. Since the antiretroviral agents contained in the fixed-combination preparations also may be available in single-entity or other fixed-combination preparations, exercise care to ensure that therapy is not duplicated if a fixed combination is used in conjunction with other antiretrovirals.

Administration

Oral Administration

Administer orally once daily with food.

Fixed Combinations Containing Tenofovir Alafenamide

Tenofovir alafenamide is also commercially available in the following fixed-combination tablets for oral use: elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide (Genvoya); emtricitabine, rilpivirine, and tenofovir alafenamide (Odefsey); emtricitabine and tenofovir alafenamide (Descovy); bictegravir, emtricitabine, and tenofovir alafenamide (Biktarvy); and darunavir, cobicistat, emtricitabine, and tenofovir alafenamide (Symtuza). See the full prescribing information for administration of each of these combination products.

Dosage

Available as tenofovir alafenamide fumarate; dosage expressed in terms of tenofovir alafenamide.

Pediatric Patients

Chronic HBV Infection

Oral

≥12 years of age: 25 mg once daily.

Adults

Chronic HBV Infection

Oral

25 mg once daily.

Special Populations

Hepatic Impairment

Mild hepatic impairment (Child-Pugh class A): Dosage adjustments not needed.

Decompensated hepatic impairment (Child-Pugh class B or C): Tenofovir alafenamide therapy not recommended.

Renal Impairment

Mild, moderate, or severe renal impairment: Dosage adjustments not needed.

End-stage renal disease (Cl_cr <15 mL/minute) and on chronic hemodialysis: Dosage adjustments not needed. On days of hemodialysis, administer tenofovir alafenamide after completion of hemodialysis treatment.

End-stage renal disease (Cl_cr <15 mL/minute) and not on chronic hemodialysis: Tenofovir alafenamide therapy not recommended.

Pedatric patients: No data available to make specific dosage recommendations.

Geriatric Patients

No specific dosage recommendations.

Cautions for Tenofovir Alafenamide Fumarate

Contraindications

• None.

Warnings/Precautions

Warnings

Severe Acute Exacerbation of HBV Infection after Discontinuance of Treatment

Severe acute exacerbations of HBV infection may occur following discontinuance of HBV treatment, including tenofovir alafenamide. (See Boxed Warning.)

Closely monitor hepatic function with clinical and laboratory follow-up for at least several months after tenofovir alafenamide is discontinued. If appropriate, resumption of HBV treatment may be warranted.

Other Warnings/Precautions

Individuals with HBV and HIV-1 Coinfection

Safety and efficacy not established in patients with HBV and HIV-1 coinfection.

Do not use tenofovir alafenamide alone for treatment of HIV-1 infection due to risk of development of HIV-1 resistance.

Prior to initiation of tenofovir alafenamide, offer HIV antibody testing to all patients with HBV infection and, if positive, use an appropriate antiretroviral regimen that is recommended for patients with HBV and HIV-1 coinfection.

New Onset or Worsening Renal Impairment

Postmarketing cases of renal impairment, including cases of acute renal failure, proximal renal tubulopathy, and Fanconi syndrome, reported in patients receiving tenofovir alafenamide-containing products. While potential confounders may have contributed to the reported renal events, these factors may have also predisposed patients to tenofovir-related adverse events.

Patients receiving a tenofovir prodrug who have impaired renal function or are receiving nephrotoxic agents (e.g., nonsteroidal anti-inflammatory agents [NSAIAs]) are at increased risk of developing adverse renal effects.

Assess S_cr, estimated Cl_cr, urine glucose, and urine protein on a clinically appropriate schedule prior to or when initiating tenofovir alafenamide, and during treatment with the drug. In patients with chronic kidney disease, also assess serum phosphorous.

Discontinue tenofovir alafenamide in patients who develop clinically important decreases in renal function or evidence of Fanconi syndrome.

Lactic Acidosis and Severe Hepatomegaly with Steatosis

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, reported in patients receiving nucleoside analogs (e.g., tenofovir disoproxil fumarate [tenofovir DF], another tenofovir prodrug) alone or in conjunction with other antiretroviral agents.

Discontinue tenofovir alafenamide treatment in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked increases in serum aminotransferase concentrations).

Bone Mineral Density Effects

In clinical trials, tenofovir prodrugs (tenofovir alafenamide, tenofovir DF) were associated with changes in bone mineral density (BMD). Long-term clinical importance of these BMD changes not known.

Specific Populations

Pregnancy

Clinicians encouraged to register patients in the Antiretroviral Pregnancy Registry (APR) at 800-258-4263.

Available data from the APR showed that the overall risk of birth defects for tenofovir alafenamide was not markedly different compared to background rate for major birth defects of 2.7% in the United States reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP). The rate of miscarriage is not reported in the APR.

In animal studies, no evidence of impaired fertility or harm to fetus. No adverse developmental effects observed in rats or rabbits receiving tenofovir alafenamide during organogenesis.

Lactation

Not known whether tenofovir alafenamide and its metabolites distribute into human milk, affect human milk production, or have effects on breast-fed infant.

Distributed into milk of lactating rats and rhesus monkeys receiving tenofovir DF.

Consider benefits of breast-feeding and importance of the drug to the woman; also consider potential adverse effects on the breast-fed infant from the drug or underlying maternal condition.

Pediatric Use

Pharmacokinetics, safety, and efficacy for treatment of chronic HBV infection established in pediatric patients 12 to <18 years of age; no clinically meaningful differences in pharmacokinetics or safety observed in comparison to adults.

Safety and efficacy not established in pediatric patients <12 years of age with chronic HBV infection.

Geriatric Use

No clinically significant differences in safety or efficacy observed in clinical trials between patients ≥65 years of age and patients 18 to <65 years of age.

Hepatic Impairment

Decompensated cirrhosis (Child-Pugh class B or C): Safety and efficacy not established; tenofovir alafenamide therapy not recommended in such patients.

Mild hepatic impairment (Child-Pugh class A): Dosages adjustments not needed.

Renal Impairment

Mild, moderate, or severe renal impairment: Dosage adjustments not needed.

End-stage renal disease (Cl_cr <15 mL/minute) and on chronic hemodialysis: Dosage adjustments not needed.

End-stage renal disease (Clcr <15 mL/minute) and not on chronic hemodialysis: Safety not established; tenofovir alafenamide therapy not recommended in such patients.

Common Adverse Effects

The most common adverse effect (incidence ≥10%, all grades) is headache.

Drug Interactions

Weak inhibitor of CYP3A in vitro; does not induce or inhibit other CYP isoenzymes.

Substrate of P-glycoprotein (P-gp) transport system.

Substrate of breast cancer resistance protein (BCRP).

The following drug interactions are based on studies using tenofovir alafenamide fumarate or are predicted to occur with use of tenofovir alafenamide; refer to the prescribing information for specific details.

Drugs Affecting P-glycoprotein Transport System and Breast Cancer Resistance Protein

P-gp inducers: Decreased absorption of tenofovir alafenamide expected; may result in decreased tenofovir alafenamide concentrations and loss of therapeutic effect.

P-gp inhibitors: Possible increased absorption of tenofovir alafenamide resulting in increased plasma concentrations of the drug.

BCRP inhibitors: Possible increased absorption of tenofovir alafenamide resulting in increased plasma concentrations of the drug.

Nephrotoxic Drugs or Drugs Eliminated by Renal Excretion

Drugs that reduce renal function or compete for active tubular secretion: Possible increased concentrations of tenofovir and/or concomitant drug; possible increased risk of adverse effects.

Specific Drugs

Tenofovir Alafenamide Fumarate Pharmacokinetics

Absorption

Bioavailability

Tenofovir alafenamide is a phosphonamidate prodrug of tenofovir.

Following oral administration, peak plasma concentrations occur approximately 0.5 hours after the dose.

Food

Administration with a high-fat meal increases AUC by 1.65-fold compared with administration in the fasted state.

Special Populations

Severe renal impairment: Pharmacokinetics of tenofovir alafenamide are similar among individuals with normal renal function, individuals with severe renal impairment, and individuals with end-stage renal disease receiving chronic hemodialysis: Increased tenofovir exposures observed in individuals with severe renal impairment and those with end-stage renal disease receiving hemodialysis compared with exposures reported in those with normal renal function. In patients receiving chronic hemodialysis, those with HBV had increased tenofovir exposures relative to those with HIV; clinical importance of these higher exposures not established.

Distribution

Plasma Protein Binding

80%.

Elimination

Metabolism

Tenofovir alafenamide requires initial hydrolysis for intracellular conversion to tenofovir and subsequent phosphorylation by cellular enzymes to form the active metabolite tenofovir diphosphate.

Principally hydrolyzed intracellularly by carboxylesterase 1 (CES1) in hepatocytes and cathepsin A in peripheral blood mononuclear cells (PBMCs) and macrophages.

Only minimally metabolized by CYP3A.

Elimination Route

Eliminated by kidneys using combination of glomerular filtration and active tubular secretion. Major route of elimination is metabolism (>80% of oral dose).

Approximately 32% of dose excreted in feces; <1% excreted in urine.

Half-life

Median terminal plasma half-life: Approximately 0.5 hours.

Special Populations

Mild hepatic impairment: Pharmacokinetics of tenofovir alafenamide and its metabolite tenofovir similar in patients with mild hepatic impairment (Child-Pugh class A) and in individuals with normal hepatic function.

No clinically important differences identified in pharmacokinetics due to race or gender.

Stability

Storage

Oral

Film-coated Tablets

<30°C.

Store in original container; keep tightly closed.

Actions and Spectrum

• Nucleotide reverse transcriptase inhibitor antiviral agent. Phosphonamidate prodrug of tenofovir; inactive until hydrolyzed in vivo to tenofovir (major metabolite) and then phosphorylated to tenofovir diphosphate (pharmacologically active metabolite).

• Tenofovir alafenamide enters primary hepatocytes by passive diffusion and by organic anion transport protein (OATP) 1B1 and 1B3. Converted to tenofovir within hepatocytes through hydrolysis (principally by CES1) and subsequently phosphorylated by cellular kinases to tenofovir diphosphate. Also converted to tenofovir within PBMCs and macrophages through hydrolysis by cathepsin A and subsequently phosphorylated by cellular kinases to tenofovir diphosphate.

• Active against HBV; also active against HIV-1 and has some in vitro activity against HIV-2.

• Tenofovir diphosphate inhibits HBV replication through incorporation into viral DNA by HBV reverse transcriptase, resulting in DNA chain termination. Weak inhibitor of mammalian DNA polymerases, including mitochondrial DNA polymerase γ; no evidence of toxicity to mitochondria in cell culture.

• Antiviral activity of tenofovir alafenamide was assessed in a transient transfection assay (HepG2 cells) against a panel of HBV clinical isolates representing genotypes A–H. EC₅₀ (50% effective concentration) for tenofovir alafenamide ranged from 34.7–134.4 nM, with an overall mean EC₅₀ of 86.6 nM.

• Treatment-emergent amino acid substitutions observed in some HBV isolates; however, no specific substitutions occurred at a sufficient frequency to be associated with tenofovir alafenamide resistance. No HBV amino acid substitutions known to be associated with resistance to tenofovir alafenamide detected through 24 weeks of treatment in pediatric patients.

• HBV isolates resistant to some other nucleoside or nucleotide reverse transcriptase inhibitor antivirals used for treatment of HBV infection (e.g., adefovir, entecavir, lamivudine) may also have reduced susceptibility to tenofovir.

Advice to Patients

• Advise patients to read the patient information provided by the manufacturer.

• Inform patients to take tenofovir alafenamide fumarate on a regular dosing schedule with food and to avoid missed doses in order to prevent the development of resistance.

• Inform patients that severe acute exacerbations of hepatitis B virus (HBV) infection have been reported following discontinuance of HBV treatment, including tenofovir alafenamide. Advise patients not to discontinue tenofovir alafenamide without first informing a clinician.

• Inform patients that if they have or develop human immunodeficiency virus (HIV) infection and are not receiving effective HIV treatment, use of tenofovir alafenamide alone may increase the risk of development of resistance to HIV treatment.

• Advise patients that postmarketing cases of renal impairment, including cases of acute renal failure, have been reported in patients receiving tenofovir alafenamide fumarate-containing formulations.

• Advise patients that lactic acidosis and severe hepatomegaly with steatosis, including fatalities, have occurred in patients receiving drugs similar to tenofovir alafenamide. Inform patients to contact their clinician immediately and discontinue tenofovir alafenamide if they develop clinical symptoms suggestive of lactic acidosis or pronounced hepatotoxicity.

• Advise women to inform their clinician if they are or plan to become pregnant or plan to breast-feed. Inform patients that there is a pregnancy registry to monitor fetal outcomes of pregnant women exposed to tenofovir alafenamide.

• Advise patients to inform their clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal products (e.g., St. John's wort), as well as any concomitant illnesses.

• Advise patients of other important precautionary information.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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