Tenofovir Alafenamide (Monograph)

Brand name: Vemlidy
Drug class: Nucleosides and Nucleotides
Chemical name: l-alanine, N-[(S)-[[(1R)-2-(6-Amino-9H-purin-9-yl)-1methylethoxy]methyl]phenoxyphosphinyl]-, 1-methylethyl ester, (2E)-2-butenedioate
Molecular formula: C₄₆H₆₂N₁₂O₁₄P₂
CAS number: 1392275-56-7

Medically reviewed by Drugs.com on May 19, 2023. Written by ASHP.

Introduction

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

Uses for Tenofovir Alafenamide

Treatment of Chronic HBV Infection

Treatment of chronic HBV infection in adults 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.

Treatment of chronic HBV infection is complex and evolving; consult specialized references and experts. Information from the American Association for the Study of Liver Diseases (AASLD) regarding management of HBV infection, including recommendations for initial treatment, is available at [Web].

Tenofovir Alafenamide Dosage and Administration

General

• Prior to initiation for treatment of HBV infection, test patients for HIV-1 infection. Do not use alone in patients with HBV and HIV coinfection. (See Individuals with HBV and HIV Coinfection under Cautions.)

• Assess S_cr, serum phosphorus, estimated Cl_cr, urine glucose, and urine protein prior to initiating and monitor as clinically indicated during treatment with the drug. (See New Onset or Worsening Renal Impairment under Cautions.)

Administration

Oral Administration

Administer orally once daily with food.

Dosage

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

Adults

Treatment of 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): Not recommended. (See Hepatic Impairment under Cautions.)

Renal Impairment

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

End-stage renal disease (Cl_cr <15 mL/minute): Tenofovir alafenamide therapy not recommended. (See Renal Impairment under Cautions.)

Geriatric Patients

Limited data suggest no clinically important differences in pharmacokinetics in geriatric patients compared with younger adults. (See Geriatric Use under Cautions.)

Cautions for Tenofovir Alafenamide

Contraindications

• Manufacturer states 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.

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

Other Warnings/Precautions

Individuals with HBV and HIV Coinfection

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

Tenofovir alafenamide is not used alone for treatment of HIV-1 infection and should not be used alone for treatment of HBV infection in patients with HBV and HIV-1 coinfection because of risk of development of HIV-1 resistance.

Prior to initiation of tenofovir alafenamide for treatment of chronic HBV infection, offer HIV antibody testing to all patients 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

Renal impairment, including cases of acute renal failure and Fanconi syndrome (renal tubular injury with severe hypophosphatemia), reported in HIV-1 infected patients receiving tenofovir prodrugs (e.g., tenofovir DF); similar effects reported in animal toxicology studies.

No cases of Fanconi syndrome or proximal renal tubulopathy (PRT) reported in clinical trials evaluating tenofovir alafenamide for treatment of chronic HBV infection.

In pooled analysis of clinical studies in adults with chronic HBV infection, median baseline estimated GFR (eGFR) was 106 or 105 mL/minute prior to treatment with tenofovir alafenamide or tenofovir DF, respectively. Mean S_cr concentrations increased by <0.1 mg/dL and median serum phosphorus concentrations decreased by 0.1 mg/dL in both treatment groups. Median change in eGFR from baseline was −1.2 mL/minute in patients treated with tenofovir alafenamide compared with −5.4 mL/minute in those treated with tenofovir DF. Long-term clinical importance of these renal laboratory changes on incidence of adverse effects reported with these tenofovir prodrugs not known.

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. (See Nephrotoxic Drugs or Drugs Eliminated by Renal Excretion under Interactions.)

Assess S_cr, serum phosphorous, estimated Cl_cr, urine glucose, and urine protein prior to initiating tenofovir alafenamide and monitor as clinically appropriate during therapy with the drug. Discontinue 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 fatalities, reported in patients receiving nucleoside or nucleotide analogs (e.g., the tenofovir prodrug tenofovir disoproxil fumarate [tenofovir DF]) alone or in conjunction with other antiretroviral agents.

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

Bone Effects

In animal studies and clinical trials, tenofovir prodrugs (tenofovir alafenamide, tenofovir DF) were associated with decreases in bone mineral density (BMD) and increases in biochemical markers of bone metabolism, suggestive of increased bone turnover. Long-term clinical importance of these BMD changes not known.

Specific Populations

Pregnancy

Data not available regarding use in pregnant women.

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.

Antiretroviral Pregnancy Registry (APR) at 800-258-4263.

Lactation

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

Tenofovir 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

Safety and efficacy not established in pediatric patients <18 years of age.

Geriatric Use

Clinical trials did not include sufficient numbers of patients ≥65 years of age to determine if they respond differently than younger adults.

Hepatic Impairment

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

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

Renal Impairment

Cl_cr <15 mL/minute: Pharmacokinetics not studied; not recommended in such patients.

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

Common Adverse Effects

HBV-infected adults with compensated liver disease: Headache abdominal pain, fatigue, cough, nausea, back pain.

Interactions for Tenofovir Alafenamide

Weak inhibitor of CYP3A in vitro; does not induce or inhibit other CYP isoenzymes, including CYP1A2, 2B6, 2C8, 2C9, 2C19, or 2D6.

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.

Drugs Affecting P-glycoprotein Transport System

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.

Drugs Affecting Breast Cancer Resistance Protein

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 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

Mild hepatic impairment (Child-Pugh class A): Tenofovir alafenamide and tenofovir plasma exposures decreased by 7.5 and 11%, respectively, compared with exposures reported in those with normal hepatic function.

Severe renal impairment: Tenofovir alafenamide and tenofovir plasma exposures 1.9- and 5.7-fold higher, respectively, compared with exposures reported in those with normal renal function.

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 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.

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

Half-life

Median terminal plasma half-life: 0.5 hours.

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 and then phosphorylated to the active metabolite (tenofovir diphosphate).

• 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.

• 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

• Importance of reading patient information provided by the manufacturer.

• Importance of taking tenofovir alafenamide with food and on a regular dosing schedule and avoiding missed doses since this may result in development of resistance.

• Importance of informing patients that severe acute exacerbations of 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.

• Importance of informing patients that if they have or develop 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 renal impairment, including cases of acute renal failure or Fanconi syndrome, has been reported in patients receiving tenofovir prodrugs.

• Advise patients that lactic acidosis and severe hepatomegaly with steatosis, including fatalities, have occurred in patients receiving drugs similar to tenofovir alafenamide. Importance of immediately contacting a clinician and discontinuing tenofovir alafenamide if clinical symptoms suggestive of lactic acidosis or pronounced hepatotoxicity occur.

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal products, as well as any concomitant illnesses.

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed. Inform patients about the pregnancy registry to monitor fetal outcomes of pregnant women exposed to tenofovir alafenamide. (See Pregnancy under Cautions.)

• Importance of informing patients of other important precautionary information. (See Cautions.)

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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