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||See TERMINOLOGY & ABBREVIATIONS ||
SEVERE ACUTE EXACERBATIONS OF HEPATITIS B, PATIENTS CO-INFECTED WITH HIV AND HBV, and LACTIC ACIDOSIS AND HEPATOMEGALY
Severe acute exacerbations of hepatitis B have been reported in patients who have discontinued anti-hepatitis B therapy, including entecavir. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who discontinue anti-hepatitis B therapy. If appropriate, initiation of anti-hepatitis B therapy may be warranted.
Limited clinical experience suggests there is a potential for the development of resistance to HIV (human immunodeficiency virus) nucleoside reverse transcriptase inhibitors if Entecavir is used to treat chronic hepatitis B virus (HBV) infection in patients with HIV infection that is not being treated. Therapy with Entecavir is not recommended for HIV/HBV co-infected patients who are not also receiving highly active antiretroviral therapy (HAART).
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination with antiretrovirals.
|Content & Description||
Entecavir (Monohydrate) 0.5 & 1mg.
Tablets may also contain: Lactose monohydrate, microcrystalline cellulose, crospovidone, povidone and magnesium stearate. The tablet coating contains titanium dioxide, hypromellose, polyethylene glycol 400, polysorbate 80 (0.5-mg tablet only) and iron oxide red (1-mg tablet only).
|Indication(s)||Treatment of chronic hepatitis B virus infection in adults with evidence of active viral replication and either evidence of persistent elevations in serum aminotransferases (ALT or AST) or histologically active disease.
This indication is based on histologic, virologic, biochemical, and serologic responses after 1 year of treatment in nucleoside-treatment-naive and lamivudine-resistant adult patients with HBeAg-positive or HBeAg-negative chronic HBV infection with compensated liver disease and on more limited data in adult patients with HIV/HBV co-infection who have received prior lamivudine therapy.
|Dosage & Administration||
Recommended Dosage: Adults and Adolescents ≥16 years: Chronic Hepatitis B Virus Infection in Nucleoside - Treatment-Naive: 0.5 mg once daily.
Lamivudine-refractory, known lamivudine or telbivudine resistance mutations, or decompensated liver disease
Duration of Therapy: The optimal duration of treatment with Entecavir for patients with chronic hepatitis B infection and the relationship between treatment and long-term outcomes eg, cirrhosis and hepatocellular carcinoma are unknown.
0.5-mg tab: Should be taken with food. 1-mg tab: Should be taken on an empty stomach.: Take on an empty stomach at least 2 hr after a meal & 2 hr before the next meal.
|Overdose||There is no experience of entecavir overdosage reported in patients. Healthy subjects who received single entecavir doses up to 40 mg or multiple doses up to 20 mg/day for up to 14 days had no increase in or unexpected adverse events. If overdose occurs, the patient must be monitored for evidence of toxicity, and standard supportive treatment applied as necessary.
Following a single 1-mg dose of entecavir, a 4-hr hemodialysis session removed approximately 13% of the entecavir dose.
|Contraindications||Patients with known hypersensitivity to entecavir or any component of the medication.|
|Warning||Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination with antiretrovirals.
Exacerbations of Hepatitis B After Discontinuation of Treatment: Severe acute exacerbations of hepatitis B have been reported in patients who have discontinued anti-hepatitis B therapy, including entecavir. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who discontinue anti-hepatitis B therapy. If appropriate, initiation of anti-hepatitis B therapy may be warranted. (See Exacerbations of Hepatitis After Discontinuation of Treatment under Adverse Reactions).
General: Renal Impairment: Dosage adjustment of Entecavir is recommended for patients with a creatinine clearance <50 mL/min, including patients on hemodialysis or CAPD (see Renal Impairment under Dosage & Administration).
|Drug Interactions||- Since entecavir is primarily eliminated by the kidneys, so the generic drug entecavir with impairment of renal function or excretion of drugs active competition with entecavir in renal tubules may increase serum concentrations of entecavir or of the generic drug.
- The concomitant use of entecavir with lamivudine, adefovir or tenofovir disoproxil fumarate dipovoxil not cause significant drug interactions. The resulting shared with the drug entecavir is excreted through the kidneys or are known to affect renal function is not evaluated, so patients should be monitored closely for adverse effects of drugs when entecavir is used in conjunction with this kind of medicine.
|Adverse Drug Reaction(s)||
The most common side effects reported in patients with chronic hepatitis B virus (HBV) infection and compensated liver disease during clinical trials have included headache, fatigue, dizziness, and nausea. One percent of patients discontinued treatment due to side effects or laboratory abnormalities (compared to 4% of lamivudine-treated patients).
Hepatic side effects have included elevated ALT (greater than 10 times ULN and greater than 2 times baseline: 2%; greater than 5 times ULN: up to 12%) and total bilirubin (greater than 2.5 times ULN; up to 3%). Elevated AST and ALT flares have also been reported. Hepatic encephalopathy (10%) and deaths due to liver-related causes (such as hepatic failure, hepatic encephalopathy, and hepatorenal syndrome) have been reported in entecavir-treated patients with hepatic decompensation. Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside/nucleotide analogs alone or in combination with other antiretroviral agents. Severe acute exacerbations of hepatitis have been reported in patients with hepatitis B after discontinuation of entecavir. Increased transaminases have been reported during postmarketing experience.
Posttreatment exacerbations of hepatitis or ALT flare, as defined by ALT greater than 10 times ULN and greater than 2 times baseline, have been reported in patients who discontinued treatment at or after 52 weeks after achieving a defined treatment response (nucleoside-naive HBeAg-positive, 2%; nucleoside-naive HBeAg-negative, 8%; lamivudine-refractory, 12%). The median time to exacerbation was 23 to 24 weeks. The rate may be higher in patients who discontinue entecavir without regard to treatment response.
Other side effects of moderate to severe intensity (Grade 2 to 4) have included fatigue (up to 3%). Fever, accidental injury, influenza, and back pain have also been reported. Peripheral edema (16%), ascites (15%), and pyrexia (14%) have been reported in entecavir-treated patients with hepatic decompensation.
Metabolic side effects have included elevated lipase (greater than or equal to 2.1 times ULN; 7%), fasting hyperglycemia (greater than 250 mg/dL; up to 3%), elevated alkaline phosphatase, and elevated amylase. Decreased blood bicarbonate has been reported in 2% of entecavir-treated patients with hepatic decompensation. Lactic acidosis has been reported during postmarketing experience.
Genitourinary side effects have included hematuria (Grade 3 to 4; 9%), glycosuria (Grade 3 to 4; 4%), and dysuria.
Renal side effects have included confirmed creatinine increases of 0.5 mg/dL or more (up to 2%). A confirmed increase in serum creatinine of 0.5 mg/dL (11%) and renal failure (less than 1%) have been reported in entecavir-treated patients with hepatic decompensation.
Respiratory side effects have included upper respiratory tract infection, cough, nasopharyngitis, and rhinitis. Upper respiratory infection has been reported in 10% of entecavir-treated patients with hepatic decompensation.
Gastrointestinal side effects of moderate to severe intensity (Grade 2 to 4) have included diarrhea (up to 1%), dyspepsia (up to 1%), nausea (less than 1%), and vomiting (less than 1%). Abdominal pain (unspecified) and upper abdominal pain have also been reported. Deaths due to gastrointestinal hemorrhage were reported in entecavir-treated patients with hepatic decompensation.
Oncologic side effects have included malignant neoplasms occurring at a rate of 8.4 per 1000 patient-years. Hepatocellular carcinoma has been reported in 6% of entecavir-treated patients with hepatic decompensation.
Nervous system side effects of moderate to severe intensity (Grade 2 to 4) have included headache (up to 4%), dizziness (less than 1%), and somnolence (less than 1%).
Hematologic side effects have included decreased albumin (less than 2.5 g/dL) and platelets (less than 50,000/mm3) in less than 1% of patients.
Immunologic side effects have included anaphylactoid reaction during postmarketing experience.
Psychiatric side effects of moderate to severe intensity (Grade 2 to 4) have included insomnia (less than 1%).
Musculoskeletal side effects have included arthralgia and myalgia.
Dermatologic side effects have included erythema. Rash and alopecia have been reported during postmarketing experience.
Hypersensitivity side effects have included photosensitivity with lethargy in at least one patient, which resolved after stopping entecavir.
Microbiology: Mechanism of Action: Entecavir, a guanosine nucleoside analogue with activity against HBV polymerase, is efficiently phosphorylated to the active triphosphate form, which has an intracellular half-life of 15 hrs. By competing with the natural substrate deoxyguanosine triphosphate, entecavir triphosphate functionally inhibits all 3 activities of the HBV polymerase (reverse transcriptase): Base priming; reverse transcription of the negative strand from the pregenomic messenger RNA; and synthesis of the positive strand of HBV DNA. Entecavir triphosphate has an inhibition constant (Ki) for HBV DNA polymerase of 0.0012 micromolar. Entecavir triphosphate is a weak inhibitor of cellular DNA polymerases Î±, Î², and Î´ and mitochondrial DNA polymerase gamma with Ki values ranging from 18 to >160 micromolar.
Post-Treatment Follow-Up: The optimal duration of therapy with Entecavir is unknown. According to protocol-mandated criteria in the phase 3 clinical trials, patients discontinued Entecavir or lamivudine treatment after 52 weeks according to a definition of response based on HBV virologic suppression (<0.7 mEq/mL by bDNA assay) and loss of HBeAg (in HBeAg-positive patients) or ALT normalization (<1.25 X ULN, in HBeAg-negative patients) at week 48. For the 21% of nucleoside-naive, HBeAg-positive Entecavir-treated patients who met response criteria, response was sustained throughout the 24-week post-treatment follow-up period in 82%. For the 85% of nucleoside-naive, HBeAg-negative Entecavir-treated patients who met response criteria, response was sustained throughout the 24-week post-treatment follow-up period in 48%. Few lamivudine-refractory patients met the response criteria and were eligible to discontinue treatment. These protocol-specified patient management guidelines are not intended as guidance for clinical practice.
- concentrations of entecavir peak plasma in healthy subjects obtained in about 0.5-1.5 hours after ingestion.
â€¢ Distribution : - Based on the analysis of entecavir pharmacokinetics following oral dosing, the apparent volume of distribution was estimated to be more than the sum of body water, suggesting that entecavir is more distributed in tissues. - In vitro , approximately 13% of entecavir linked to human serum proteins.
â€¢ Metabolism and excretion : Not seen as oxidative metabolites or acetylation in humans after ingestion of 14 C-entecavir. Observed negligible amounts of phase II metabolites (glucuronide conjugate materials and sulfates). Entecavir is not a substrate, inhibitor or an inducible enzyme system cytochrome P450 (CYP450). After reaching peak concentration, entecavir plasma concentrations decreased exponentially with a half level 2 finally discharged approximately 128-149 hours. Drug accumulation index is observed to be nearly double dose 1 time / day, indicating accumulation half-life is approximately 24 hours really. Entecavir is excreted primarily through the kidneys with no transfer of drugs goods recovered in the urine in the steady state from 62% -73% of the administered dose. Renal clearance is not dependent on the administered dose and ranged from 360-471 ml / min, suggesting that entecavir undergoes both glomerular filtration and tubule secretion.
|Pregnancy Category (FDA) and use in Specific Population||
Use in pregnancy:
Category C: Either studies in animals have revealed adverse effects on the foetus (teratogenic or embryocidal or other) and there are no controlled studies in women or studies in women and animals are not available. Drugs should be given only if the potential benefit justifies the potential risk to the foetus.
Reproduction studies have been performed in rats and rabbits at orally administered doses up to 200 and 16 mg/kg/day and showed no embryotoxicity or maternal toxicity at systemic exposures approximately 28 and 212 times those achieved at the highest recommended dose of 1 mg/day in humans. In rats, maternal toxicity, embryo-fetal toxicity (resorptions), lower fetal body weights, tail and vertebral malformations, reduced ossification (vertebrae, sternebrae, and phalanges), and extra lumbar vertebrae and ribs were observed at exposures 3100 times those in humans. In rabbits, embryo-fetal toxicity (resorptions), reduced ossification (hyoid), and an increased incidence of 13th rib were observed at exposures 883 times those in humans. In a peri-postnatal study, no adverse effects on offspring were seen with entecavir administered orally to rats at exposures >94 times those in humans. There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, Entecavir should be used during pregnancy only if clearly needed and after careful consideration of the risks and benefits.
|ATC Classification||J05AF10 - entecavir; Belongs to the class of nucleoside and nucleotide reverse transcriptase inhibitors. Used in the systemic treatment of viral infections.|
|Brand Name||Manufacturer/Marketer||Composition||Dosage Form||Pack Size & Price|
|Barcavir 0.5||Incepta Pharmaceuticals Limited||Entecavir 0.5 mg Tablet||Tablet||10x1's:MRP 480 Tk|
|Barcavir 1||Incepta Pharmaceuticals Limited||Entecavir 1 mg Tablet||Tablet||10x1's:MRP 900 Tk|
|CAVIR 0.5||Square Pharmaceuticals Ltd.||Entecavir 0.5mg||Tablet||2x5's: 481.40 MRP|
|CAVIR 1||Square Pharmaceuticals Ltd.||Entecavir 1mg||Tablet||1x5's: 451.35 MRP|
|CAVIRAL||Beacon Pharmaceuticals Limited||Entecavir INN 0.5mg||Tablet||10's: 600.00 MRP|
|ENTAVIR||Drug International Ltd||Entecavir INN 0.5mg||Tablet||10's: 600.00 MRP|
|ENVIRAL||Opsonin Pharma Limited||Entecavir INN 0.5mg & 1mg||Tablet||10's each: 481.80 & 903.40 MRP|
|ENVIRAL Solution||Opsonin Pharma Limited||Entecavir INN 0.25mg/5ml||Oral Solution||100ml: 301.14 MRP|
|TECAVIR||Aristopharma Ltd.||Entecavir INN 0.5mg & 1mg||Tablet||10's each: 600.00 & 1000.00 MRP|
|TEVIRAL||ACI Ltd.||Entecavir INN 0.5mg & 1mg||Tablet||10's each: 481.80 & 900.00 MRP|
Entecavir can cause serious or life-threatening damage to the liver and a condition called lactic acidosis (a buildup of acid in the blood). inform your doctor if you drink or have ever drunk large amounts of alcohol, if you use or have ever used injectable street drugs, and if you have or have ever had cirrhosis (scarring) of the liver or any liver disease other than hepatitis B. If you experience any of the following symptoms, call your doctor immediately: yellowing of the skin or eyes; dark-colored urine; light-colored bowel movements; difficulty breathing; stomach pain or swelling; nausea; vomiting; unusual muscle pain; loss of appetite for at least several days; lack of energy; extreme weakness or tiredness; feeling cold, especially in the arms or legs; dizziness or lightheadedness; or fast or irregular heartbeat.
Do not stop taking entecavir without talking to your doctor. When you stop taking entecavir, your hepatitis may get worse. This is most likely to happen during the first several months after you stop taking entecavir. Take entecavir exactly as directed. Be careful not to miss doses or run out of entecavir. Refill your prescription at least 5 days before you expect that you will need the new supply of medication. If you experience any of the following symptoms after you stop taking entecavir, call your doctor immediately: extreme tiredness, weakness, nausea, vomiting, loss of appetite, yellowing of the skin or eyes, dark-colored urine, light-colored bowel movements, or muscle or joint pain.
If you have human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS) that is not being treated with medications and you take entecavir, your HIV infection may become more difficult to treat. inform your doctor if you have HIV or AIDS or if there is a chance that you have been exposed to HIV. Your doctor may test you for HIV infection before you begin treatment with entecavir and at any time during your treatment if there is a chance that you have been exposed to HIV. Entecavir will not treat HIV infection.
Keep all appointments with your doctor and the laboratory before, during, and for a few months after your treatment with entecavir. Your doctor will order certain tests to check your body's response to entecavir during this time.
Talk to your doctor about the risks of taking entecavir.
Why is Entecavir prescribed?
Entecavir is used to treat chronic (long-term) hepatitis B infection (swelling of the liver caused by a virus) in people who have liver damage. Entecavir is in a class of medications called nucleoside analogs. It works by decreasing the amount of hepatitis B virus (HBV) in the body. Entecavir does not cure HBV and may not prevent complications of chronic hepatitis B such as cirrhosis of the liver or liver cancer. Entecavir does not prevent the spread of HBV to other people.
How should Entecavir be used?
Entecavir comes as a tablet and solution (liquid) to take by mouth. It is usually taken once a day on an empty stomach, at least 2 hours after a meal and at least 2 hours before the next meal. Take entecavir at around the same time every day. Follow the directions on your prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand. Take entecavir exactly as directed. Do not take more or less of it or take it more often than prescribed by your doctor.
To use the entecavir solution, follow these steps:
Hold the spoon that came with your medication upright and slowly fill it with entecavir solution up to the mark that matches your dose.
Hold the spoon with the volume marks facing you and check to see that the top of the liquid is level with the mark that matches your dose.
Swallow the medication right from the measuring spoon. Do not mix the medication with water or any other liquid.
Rinse the spoon with water after each use, and allow it to air dry.
- Put the spoon in a safe place where it will not get lost because you will need to use it every time you take your medication. If you do lose the dosing spoon, call your doctor or pharmacist.
Other uses for Entecavir
Entecavir may be prescribed for other uses; ask your doctor or pharmacist for more information.
What special precautions to follow?
Before taking entecavir,
- inform your doctor if you are allergic to entecavir, or any other medications, or any of the ingredients in entecavir tablets or solution. Ask your pharmacist for a list of the ingredients.
- inform your doctor what other prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking or plan to take. Be sure to mention the medications listed in the IMPORTANT WARNING section and any of the following: aminoglycoside antibiotics such as amikacin, gentamicin, kanamycin, neomycin, paromomycin, streptomycin, and tobramycin; amphotericin B; medications to prevent rejection of a transplanted organ such as cyclosporine (Neoral, Sandimmune) or tacrolimus (Prograf); probenecid; or vancomycin. Your doctor may need to change the doses of your medications or monitor you carefully for side effects.
- inform your doctor if you have had a liver transplant (surgery to replace a diseased liver) or if you have or have ever had kidney disease.
- inform your doctor if you are pregnant, plan to become pregnant, or are breast-feeding. If you become pregnant while taking entecavir, call your doctor. Do not breast-feed while you are taking entecavir.
- if you are having surgery, including dental surgery, inform the doctor or dentist that you are taking entecavir.
What special dietary instructions to follow?
Unless your doctor informs you otherwise, continue your normal diet.
What to do if I forget a dose?
Take the missed dose as soon as you remember it. However, if it is almost time for the next dose, skip the missed dose and continue your regular dosing schedule. Do not take a double dose to make up for a missed one.
What side effects can Entecavir cause?
Entecavir may cause side effects. inform your doctor if this symptom is severe or does not go away:
Some side effects can be serious. If you experience any of the symptoms listed in the IMPORTANT WARNING section, call your doctor immediately.
Entecavir may cause other side effects. Call your doctor if you have any unusual problems while using Entecavir.
In case of emergency/overdose
In case of overdose, consult your doctor. If the victim has collapsed or is not breathing, consult local medical emergency services.
What other information to know?
Keep all appointments with your doctor and the laboratory. Your doctor will order certain lab tests to check your response to Entecavir.
Do not let anyone else use your medication. If you still have symptoms and need further treatment, consult your doctor.
It is important for you to keep a written list of all of the prescription and nonprescription (over-the-counter) medicines you are taking, as well as any products such as vitamins, minerals, or other dietary supplements. You should bring this list with you each time you visit a doctor or if you are admitted to a hospital. It is also important information to carry with you in case of emergencies.
Ref: U.S. National Library of Medicine.
This information is provided for reference only and not a replacement for and should only be used in conjunction with full consultation with a registered medical practitioner. It may not contain all the available information you require and cannot substitute professional medical care, nor does it take into account all individual circumstances. Although great effort has been made to ensure content accuracy, mph-bd shall not be held responsible or liable for any claims or damages arising from the use or misuse of the information contained herein, its contents or omissions, or otherwise.
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*Trademark name & prescribing information are the property of their respective Manufacturers.