Entecavir

J05A - Direct acting antivirals ATC J05AF10 Small molecule approved 2005 Oral Prodrug Black-box warning

Prodrug of Entecavir Anhydrous. Active form: Entecavir Triphosphate.

JFDA label: Pms- Entecavir 0.5mg Tablet

⚠ Black-Box Warning

Severe acute exacerbations of hepatitis B:
HIV and chronic hepatitis B virus coinfection:
Lactic acidosis and hepatomegaly:

Mechanism of Action

Inhibitor of DNA polymerase/reverse transcriptase — DNA polymerase/reverse transcriptase inhibitor

Target	Action	Gene / class
DNA polymerase/reverse transcriptase efficacy	INHIBITOR	P

Indications

Approved

Chronic hepatitis B

Off-label

HIV/HBV coinfection
Hepatitis B virus (HBV) reinfection prophylaxis, post liver transplant

Antimicrobial Spectrum

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

Viruses

Organism	Activity	MIC
Hepatitis B	Active	—

Class profile

targetVirus	HBV
viralClass	Hepadnaviridae (dsDNA/RT)
targetStep	HBV reverse transcriptase (NUC, tri-phosphate chain terminator)
resistanceBarrier	Very high in HBV-naive (3 mutations required: rtM204I/V + rtL180M + rtI169T)
crossResistance	Entecavir resistant strains cross-resistant to lamivudine; not to TDF
source	DHHS/AASLD/manufacturer-PIL

Contraindications

Source: Lexicomp

Hypersensitivity to entecavir or any component of the formulation Absolute
There are no contraindications listed in the manufacturer's US 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

Cardiac disorders (1)

Very Common Peripheral edema

Nervous system disorders (3)

Common dizziness · fatigue · Headache

Hepatobiliary disorders (4)

Very Common Ascites · increased serum ALT

Common Hepatic encephalopathy · increased serum bilirubin

Renal and urinary disorders (1)

Very Common Increased serum creatinine

Blood and lymphatic system disorders (1)

Common Hepatic carcinoma

Metabolism and nutrition disorders (3)

Common decreased serum bicarbonate · Glycosuria · hyperglycemia

Gastrointestinal disorders (6)

Common abdominal pain · diarrhea · increased serum amylase · Increased serum lipase · unpleasant taste · vomiting

Skin and subcutaneous tissue disorders (1)

Common Skin rash

General disorders and administration site conditions (1)

Very Common Fever

Respiratory, thoracic and mediastinal disorders (1)

Common Upper respiratory tract infection

Dosing

Source: Lexicomp

Hepatitis B virus (HBV) infection, treatment: Oral: Nucleoside treatment naive: 0.5 mg once daily Lamivudine-refractory or -resistant viremia (or known lamivudine- or telbivudine-resistant mutations): 1 mg once daily Decompensated liver disease: 1 mg once daily Treatment duration (AASLD practice guidelines): Treatment duration for nucleos(t)ide analog-based therapy (eg, entecavir) is variable and influenced by HBeAg status, duration of HBV suppression, and presence of cirrhosis/decompensation (AASLD [Terrault 2016]): Patients without cirrhosis: Hepatitis B e antigen (HBeAg) positive immune-active chronic hepatitis: Treat until HBeAg seroconversion; after seroconversion, prolonged duration of therapy is often required in patients treated with nucleos(t)ide anaglogues,. Optimal duration is unknown; however, consolidation therapy is generally a minimum of 12 months of persistently normal ALT and undetectable serum HBV DNA levels after HBeAg seroconversion HBeAg-negative immune-active chronic hepatitis: Indefinite antiviral therapy is suggested unless there is competing rationale for discontinuation (risk/benefit decision); treatment discontinuation may be considered in patients with loss of HBsAg; however, there is insufficient evidence to guide decisions in these patients. Patients with cirrhosis: HBeAg-positive immune-active chronic hepatitis: In patients who seroconvert on therapy, continue antiviral therapy indefinitely due to concerns with decompensation and death, unless there is a strong competing rationale for discontinuation. HBeAg-negative immune-active chronic hepatitis: Treatment discontinuation is not recommended due to potential for decompensation and death (limited data). Viral breakthrough (AASLD practice guidelines): Patients with confirmed viral breakthrough (HBV DNA ≥ 100 IU/mL with previously undetectable levels [1 log increase in HBV DNA) should either be switched to an alternative antiviral monotherapy agent with a high genetic barrier to resistance or receive a second antiviral agent with a complementary resistance profile; consult current clinical practice guidelines for recommended agents (AASLD [Terrault 2016]). HBV reinfection prophylaxis, post liver transplant (with or without HBIG) (off-label use): Oral: 0.5 mg once daily (Fung, 2011) or 1 mg once daily (Perrillo 2012) HIV/HBV coinfection (off-label use): Oral: Nucleoside treatment naive: 0.5 mg once daily Lamivudine refractory or resistant: 1 mg once daily Note: Only recommended in patients who cannot take tenofovir; must be used in addition to a fully suppressive antiretroviral therapy regimen (DHHS, 2013).

(For additional information see "Entecavir: Pediatric drug information") Hepatitis B virus (HBV) infection, treatment (nucleoside treatment naïve or lamivudine-refractory or -resistant viremia [or known lamivudine- or telbivudine-resistance mutations]): Children ≥2 years and Adolescents: Oral: Note: Oral solution should be used for patients weighing ≤30 kg. Treatment-naive: 10 to 11 kg: 0.15 mg once daily (oral solution) >11 to 14 kg: 0.2 mg once daily (oral solution) >14 to 17 kg: 0.25 mg once daily (oral solution) >17 to 20 kg: 0.3 mg once daily (oral solution) >20 to 23 kg: 0.35 mg once daily (oral solution) >23 to 26 kg: 0.4 mg once daily (oral solution) >26 to 30 kg: 0.45 mg once daily (oral solution) >30 kg: 0.5 mg once daily (oral solution or tablet) Lamivudine-experienced: 10 to 11 kg: 0.3 mg once daily (oral solution) >11 to 14 kg: 0.4 mg once daily (oral solution) >14 to 17 kg: 0.5 mg once daily (oral solution) >17 to 20 kg: 0.6 mg once daily (oral solution) >20 to 23 kg: 0.7 mg once daily (oral solution) >23 to 26 kg: 0.8 mg once daily (oral solution) >26 to 30 kg: 0.9 mg once daily (oral solution) >30 kg: 1 mg once daily (oral solution or tablet)

Refer to adult dosing.

Adults: Daily-dosage regimen preferred: CrCl ≥50 mL/minute: No dosage adjustment necessary. CrCl 30-49 mL/minute: Administer 50% of usual dose daily or administer the normal dose every 48 hours CrCl 10-29 mL/minute: Administer 30% of usual dose daily or administer the normal dose every 72 hours CrCl Children >2 years and Adolescents: Insufficient data to recommend a specific dose adjustment in pediatric patients with renal impairment; consider a reduction in the dose or an increase in the dosing interval similar to adjustments for adults.

Adults: No dosage adjustment necessary. Children >2 years and Adolescents: There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).

Warnings & Precautions

Source: Lexicomp

Lactic acidosis/hepatomegaly

Lactic acidosis and severe hepatomegaly with steatosis (including fatal cases) have been reported with nucleoside analogue inhibitors; use with caution in patients with risk factors for liver disease (risk may be increased with female gender, decompensated liver disease, obesity, or prolonged nucleoside inhibitor exposure) and suspend treatment in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or hepatotoxicity (transaminase elevation may/may not accompany hepatomegaly and steatosis). Disease-related concerns:

Chronic hepatitis B

Severe, acute exacerbation of hepatitis B may occur upon discontinuation of antihepatitis B therapy, including entecavir. Monitor liver function for at least several months after stopping treatment; reinitiation of antihepatitis B therapy may be required.

HIV

May cause the development of HIV resistance in chronic hepatitis B patients with unrecognized or untreated HIV infection. Determine HIV status prior to initiating treatment with entecavir. Not recommended for HIV/HBV coinfected patients unless also receiving antiretroviral therapy. The manufacturer's labeling states that entecavir does not exhibit any clinically-relevant activity against human immunodeficiency virus (HIV type 1). However, a small number of case reports have indicated declines in virus levels during entecavir therapy. HIV resistance to a common HIV drug has been reported in an HIV/HBV-infected patient receiving entecavir as monotherapy for HBV.

Hepatic impairment

Dose adjustment not required. Limited data supporting treatment of chronic hepatitis B in patients with decompensated liver disease; observe for increased adverse reactions, including hepatorenal dysfunction.

Renal impairment

Use with caution in patients with renal impairment or patients receiving concomitant therapy which may reduce renal function; dose adjustment recommended for CrCl Special populations:

Children

There are limited data available on the use of entecavir in lamivudine-experienced pediatric patients; use in these patients only if the potential benefit justifies the potential risk to the child. Dosage form specific issues:

Polysorbate 80

Some dosage forms may contain polysorbate 80 (also known as Tweens). Hypersensitivity reactions, usually a delayed reaction, have been reported following exposure to pharmaceutical products containing polysorbate 80 in certain individuals (Isaksson, 2002; Lucente 2000; Shelley, 1995). Thrombocytopenia, ascites, pulmonary deterioration, and renal and hepatic failure have been reported in premature neonates after receiving parenteral products containing polysorbate 80 (Alade, 1986; CDC, 1984). See manufacturer’s labeling. Other warnings/precautions:

Resistance

Cross-resistance may develop in patients failing previous therapy with lamivudine.

Pregnancy & Lactation

Pregnancy

FDA category C Teratogenic

Teratogenic effects have been observed in animal studies. Information related to use in pregnancy is limited; use only if other options are inappropriate (DHHS [OI], 2013). Pregnant women taking entecavir should enroll in the pregnancy registry by calling 1-800-258-4263.

Lactation

It is not known if entecavir is excreted in breast milk. Due to the potential for serious adverse reactions in the nursing infant, the manufacturer recommends a decision be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of treatment to the mother.

Monitoring

Efficacy	Viral load (undetectable = success); CD4 count (HIV); hepatic enzymes and HBV/HCV DNA (hepatitis); clinical resolution of acute viral illness
Toxicity	Renal function (most antivirals are renally cleared); LFTs; resistance testing if virological failure; CBC
Clinical pearl	For HIV, undetectable viral load at 6 months predicts long-term treatment success. Resistance testing is mandatory at virological failure.
Counseling	Do not miss doses — even brief interruptions can cause viral rebound and resistance selection. Report any side effects early rather than stopping independently.

Chemistry & Properties

Formula	C12H17N5O4
Molecular weight	295.3 g/mol
IUPAC name	2-amino-9-[(1S,3R,4S)-4-hydroxy-3-(hydroxymethyl)-2-methylidenecyclopentyl]-1H-purin-6-one
CAS	142217-69-4
PubChem CID	135398508
InChIKey	`YXPVEXCTPGULBZ-WQYNNSOESA-N`
logP	-0.83 (XLogP -1.3)
Polar surface area	130.05 Å²
H-bond acceptors / donors	7 / 4
Drug-likeness (QED)	0.53
Lipinski violations	0

SMILES

C=C1[C@H](CO)[C@@H](O)C[C@@H]1n1cnc2c(=O)[nH]c(N)nc21.O

Biology & Pharmacokinetics

Pharmacokinetics predicted

Bioavailability	10.0%
Half-life	2.066 h
Volume of distribution	1.215 L/kg
Protein binding	8.5%
BBB penetrant	No

Transporters

BCRP (Inhibitor)BSEP (Inhibitor)BSEP (Inhibitor)MRP1 (Inhibitor)MRP2 (Inhibitor)MRP4 (Inhibitor)OAT4 (Inhibitor)OATP1B1 (Inhibitor)OATP1B3 (Inhibitor)OCT3 (Inhibitor)P-gp (Inhibitor)BCRP (Substrate)CNT2 (Substrate)CNT3 (Substrate)ENT1 (Substrate)ENT2 (Substrate)MATE1 (Substrate)MATE2 (Substrate)MCT (Substrate)MDR1 (Substrate)MRP2 (Substrate)Nucleoside transporters (unspecified) (Substrate)OAT1 (Substrate)OAT3 (Substrate)OCT3 (Substrate)OCTN2 (Substrate)P-gp (Substrate)Transporter(unspecified) (Substrate)

Drug–drug interactions (44, DDInter)

Interacting drug	Severity	Management
Acyclovir	moderate
Amikacin	moderate
Amikacin (liposome)	moderate
Amoxicillin	moderate
Amphotericin B	moderate
Amphotericin B (cholesteryl sulfate)	moderate
Amphotericin B (lipid complex)	moderate
Amphotericin B (liposomal)	moderate
Bacitracin	moderate
Balsalazide	moderate
Celecoxib	moderate
Cimetidine	moderate
Cisplatin	moderate
Cladribine	moderate
Cyclosporine	moderate
Deferasirox	moderate
Diclofenac	moderate
Dyphylline	moderate
Famotidine	moderate
Flurbiprofen	moderate
Gentamicin	moderate
Ibuprofen	moderate
Iobenguane (I-131)	moderate
Kanamycin	moderate
Levofloxacin	moderate
Mesalazine	moderate
Metformin	moderate
Methotrexate	moderate
Mycophenolic acid	moderate
Neomycin	moderate
Olsalazine	moderate
Orlistat	moderate
Pemetrexed	moderate
Pentamidine	moderate
Polymyxin B	moderate
Pralatrexate	moderate
Ranitidine	moderate
Ranitidine (bismuth citrate)	moderate
Sirolimus	moderate
Streptomycin	moderate

Showing 40 of 44.

Registered Products (11)

Brand	Form / strength	Pack	Agent	Citizen (JOD)
Virente	Tablet 0.535 mg	30 tab	Ibn Rushd Drug Store	54.950
Virente	Tablet 1.069 mg	30 tab	Ibn Rushd Drug Store	59.590
entriliv	Tablet 0.5 mg	30 tab	Nabulsi Drug Store	93.870
entriliv	Tablet 1 mg	30 tab	Nabulsi Drug Store	95.160
Belivy	Tablet 0.5 mg	30 tab	Hikma Pharmaceuticals	115.910
Pms- Entecavir	Tablet 0.5 mg	30 tab	Reda Jardaneh Drug Store	115.910
Baraclude	Tablet 0.5 mg	30 tab	ORIENT DRUG STORE CO	—
Baraclude	Tablet 1 mg	30 tab	ORIENT DRUG STORE CO	—
Belivy	Tablet 1.0 mg	30 tab	Hikma Pharmaceuticals	—
Enterax	Tablet 1 mg	32 tab	Omicron Pharma	—
Pms- Entecavir	Tablet 1 mg	30 tab	Reda Jardaneh Drug Store	—