Tenofovir

J05A - Direct acting antivirals ATC J05AF13 Small molecule Prodrug Black-box warning

Prodrug of Tenofovir Anhydrous. Active form: Tenofovir Diphosphate.

JFDA label: Vemlidy

⚠ Black-Box Warning

Post-treatment severe acute exacerbation of hepatitis B:

Mechanism of Action

Tenofovir alafenamide, an analog of adenosine 5'-monophosphate, is converted intracellularly by hydrolysis to tenofovir and subsequently phosphorylated to the active tenofovir diphosphate. The active moiety inhibits replication of HBV by inhibiting HBV polymerase.

Indications

Approved

Chronic hepatitis B

Antimicrobial Spectrum

Expected / intrinsic spectrum (EUCAST breakpoints & labels) — not local resistance. Source: openfda-label.

Viruses

Organism	Activity	MIC
Hepatitis B	Active	—
Human Immunodeficiency	Active	—

Contraindications

Source: Lexicomp

Additional contraindications (not in US labeling): Hypersensitivity to tenofovir alafenamide or any component of the formulation Absolute
There are no contraindications listed in the US manufacturer's labeling Absolute

Adverse Reactions

Very Common >10%Common 1–10%Uncommon 0.1–1% Rare 0.01–0.1%Very Rare <0.01%Not Known

Nervous system disorders (3)

Common fatigue · Headache · Headache

Hepatobiliary disorders (2)

Common Increased serum ALT · increased serum AST

Renal and urinary disorders (1)

Uncommon Nephrotoxicity (Fanconi syndrome, renal tubulopathy)

Metabolism and nutrition disorders (4)

Common glycosuria · increased amylase · Increased LDL cholesterol

Rare Lactic acidosis (mitochondrial toxicity, severe)

Gastrointestinal disorders (4)

Common Abdominal pain · Diarrhoea · Nausea · nausea

Musculoskeletal and connective tissue disorders (4)

Common back pain · Decreased bone mineral density · Decreased bone mineral density (long-term) · increased serum creatine phosphokinase

Respiratory, thoracic and mediastinal disorders (1)

Common Cough

Dosing

Source: Lexicomp

Chronic hepatitis B: Oral: 25 mg once daily

Refer to adult dosing.

CrCl ≥15 mL/minute: No dosage adjustment necessary. CrCl

Mild impairment (Child-Pugh class A): No dosage adjustment necessary. Decompensated cirrhosis (Child-Pugh class B or C): Use is not recommended.

Warnings & Precautions

Source: Lexicomp

Lactic acidosis/hepatomegaly

Lactic acidosis and severe hepatomegaly with steatosis, sometimes fatal, have been reported with the use of nucleoside analogs, alone or in combination with other antiretrovirals. Suspend treatment in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (marked transaminase elevation may/may not accompany hepatomegaly and steatosis). Disease-related concerns:

Hepatic impairment

Use is not recommended in patients with Child-Pugh class B or C hepatic impairment.

Hepatitis B acute exacerbation

Discontinuation of anti-hepatitis B therapy may result in severe acute exacerbations of hepatitis B. Monitor clinical and laboratory data closely for several months after treatment discontinuation. If clinically indicated, anti-hepatitis B therapy may be resumed.

HIV-1 and HBV coinfection

Should not be used as a single agent for the treatment of HIV-1 due to resistance development risk.

Renal impairment

Use is not recommended in patients with CrCl • Renal toxicity: Cases of acute renal failure and/or Fanconi syndrome have been reported with use of tenofovir prodrugs; patients with preexisting renal impairment and those taking nephrotoxic agents (including NSAIDs) are at increased risk. Assess serum creatinine, estimated creatinine clearance, serum phosphorus, urine protein, and urine glucose prior to initiation of therapy and during therapy. Discontinue therapy in patients that develop clinically significant decreases in renal function or evidence of Fanconi syndrome. Concurrent drug therapy issues:

Drug-drug interactions

Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information. Other warnings/precautions:

HIV testing

HIV antibody testing should be offered to all HBV infected patients prior to treatment initiation. If HIV testing is positive, institute an appropriate antiretroviral (HIV-1) combination regimen.

Pregnancy & Lactation

Pregnancy

Limited data has been reported to the antiretroviral registry related to the use of this drug in pregnancy and no pharmacokinetic studies have been completed in pregnant females. Females coinfected with HIV and HBV who are taking tenofovir alafenamide prior to pregnancy should be offered a choice to switch to tenofovir disoproxil fumarate or continue with the current regimen (HHS [perinatal] 2017). Health care providers are encouraged to enroll pregnant females exposed to antiretroviral medications as early in pregnancy as possible in the Antiretroviral Pregnancy Registry (1-800-258-4263 or http://www.APRegistry.com).

Lactation

Contraindicated

It is not known if tenofovir alafenamide is present in breast milk. Breastfeeding is not contraindicated in women with hepatitis B; however, if nipples are cracked or bleeding, breastfeeding is not recommended (Tran 2016). Females coinfected with HIV infection should completely avoid breastfeeding (HHS [perinatal] 2017).

Monitoring

Clinical pearl	Serum creatinine, serum phosphorus, urine glucose, urine protein (prior to initiation and as clinically indicated during therapy); HIV testing (prior to initiation); hepatic function tests; monitor clinical and laboratory data closely for several months following therapy discontinuation.

Chemistry & Properties

Formula	C9H16N5O5P
Molecular weight	305.23 g/mol
IUPAC name	[(2R)-1-(6-aminopurin-9-yl)propan-2-yl]oxymethylphosphonic acid
CAS	147127-20-6
PubChem CID	464205
InChIKey	`PINIEAOMWQJGBW-FYZOBXCZSA-N`
logP	-0.05 (XLogP -1.6)
Polar surface area	136.38 Å²
H-bond acceptors / donors	7 / 3
Drug-likeness (QED)	0.65
Lipinski violations	0

SMILES

C[C@H](Cn1cnc2c(N)ncnc21)OCP(=O)(O)O.O

Biology & Pharmacokinetics

Pharmacokinetics predicted

Bioavailability	70.0%
Half-life	2.075 h
Volume of distribution	0.871 L/kg
Protein binding	13.0%
BBB penetrant	No

Transporters

BCRP (Inhibitor)BCRP (Inhibitor)BSEP (Inhibitor)MRP1 (Inhibitor)MRP1 (Inhibitor)MRP2 (Inhibitor)MRP3 (Inhibitor)OATP1B1 (Inhibitor)OATP1B1 (Inhibitor)OATP1B3 (Inhibitor)OATP1B3 (Inhibitor)OATP2B1 (Inhibitor)OCT1 (Inhibitor)P-gp (Inhibitor)BCRP (Substrate)MRP2 (Substrate)MRP4 (Substrate)OAT1 (Substrate)OAT3 (Substrate)P-gp (Substrate)

Registered Products (2)

Brand	Form / strength	Pack	Agent	Citizen (JOD)
Hivera	Tablet 300.000 mg	30 tab	Pharma International Company/ Jordan	—
Vemlidy	Tablet 25 mg	30 tab	Beta Drug Store	—