= Additional active ingredients
PRESENTATION AND DOSSAGE
TABS: 28 X 100 mg
Bottle: 240 ml
Chronic hepatitis B, evidence of hepatitis virus (HBV) replication and active liver inflammation.
Hypersensitivity to any of the components.
LACTIC ACIDOSIS AND SEVERE HEPATOMEGALY WITH STEATOSIS, INCLUDING FATAL CASES, HAVE BEEN REPORTED WITH THE USE OF NUCLEOSIDE ANALOGUES ALONE OR IN COMBINATION, INCLUDING LAMIVUDINE AND OTHER ANTIRETROVIRALS. HUMAN IMMUNODEFICIENCY VIRUS (HIV) COUNSELING AND TESTING SHOULD BE OFFERED TO ALL PATIENTS BEFORE BEGINNING ZEFFIX AND PERIODICALLY DURING TREATMENT, BECAUSE ZEFFIX TABLETS AND ORAL SOLUTION CONTAIN A LOWER DOSE OF THE SAME ACTIVE INGREDIENT (LAMIVUDINE) AS EPIVIR TABLETS AND ORAL SOLUTION USED TO TREAT HIV INFECTION. IF TREATMENT WITH ZEFFIX IS PRESCRIBED FOR CHRONIC HEPATITIS B FOR A PATIENT WITH UNRECOGNIZED OR UNTREATED HIV INFECTION, RAPID EMERGENCE OF HIV RESISTANCE IS LIKELY BECAUSE OF SUBTHERAPEUTIC DOSE AND INAPPROPRIATE MONOTHERAPY. SEVERE ACUTE EXACERBATIONS OF HEPATITIS B HAVE BEEN REPORTED IN PATIENTS WHO HAVE DISCONTINUED ANTI-HEPATITIS B THERAPY (INCLUDING ZEFFIX). 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.
General: Patients should be assessed before beginning treatment with this product by a physician experienced in the management of chronic hepatitis B.
Emergence of Resistance-Associated HBV Mutations: In controlled clinical trials, YMDD-mutant HBV were detected in patients with on-lamivudine re-appearance of HBV DNA after an initial decline below the solution hybridization assay limit. These mutations can be detected by a research assay and have been associated with reduced susceptibility to lamivudine in vitro. Lamivudine-treated patients (adults and pediatric) with YMDD-mutant HBV at 52 weeks showed diminished treatment responses in comparison to lamivudine-treated patients (adult & pediatric) without evidence of YMDD mutations, including lower rates of HBeAg seroconversion and HBeAg loss (no greater than placebo recipients), more frequent return of positive HBV DNA by solution hybridization or branded chain DNA assay, and more frequent ALT elevations. In the controlled trials, when patients developed YMDD-mutant HBV, they had a rise in HBV DNA and ALT from their own previous on-treatment levels. Progression of hepatitis B, including death, has been reported in some patients with YMDD-mutant HBV, including patients from the liver transplant setting and from other clinical trials. The long-term clinical significance of YMDD-mutant HBV is not known. Increased clinical and laboratory monitoring may aid in treatment decisions if emergence of viral mutants is suspected.
Limitations of Populations Studied: Safety and efficacy have not been established in patients with decompensated liver disease or organ transplants; pediatric patients <2 years of age; patients dually infected with HBV and HCV, hepatitis delta, or HIV; or other populations not included in the principal phase III controlled studies. There are no studies in pregnant women and no data regarding effect on vertical transmission, and appropriate infant immunizations should be used to prevent neonatal acquisition of HBV.
Assessing Patients During Treatment: Patients should be monitored regularly during treatment by a physician experienced in the management of chronic hepatitis B. The safety and effectiveness of treatment with this product beyond 1 year have not been established. During treatment, combinations of such events such as return of persistently elevated ALT, increasing levels of HBV DNA over time after an initial decline below assay limit, progression of clinical signs or symptoms of hepatic disease, and/or worsening of hepatic necroinflammatory findings may be considered as potentially reflecting loss of therapeutic response. Such observations should be taken into consideration when determining the advisability of continuing therapy with this product. The optimal duration of treatment, the durability of HBeAg seroconversions occurring during treatment, and the relationship between treatment response and long-term outcomes such as hepatocellular carcinoma or decompensated cirrhosis are not known.
Patients with Impaired Renal Function: Reduction of the dosage is recommended for patients with impaired renal function.
Pancreatitis has been reported in patients receiving lamivudine. Malaise and fatigue, fever or chills. Ear, nose and throat infections, nausea and vomiting, abdominal discomfort, diarrhea. Myalgia, arthralgia, headache, skin rashes.
Multiple doses of lamivudine and a single dose of interferon were coadministered to 19 healthy male subjects in a pharmacokinetics study. Results indicated a small (10%) reduction in lamivudine AUC, but no change in interferon pharmacokinetic parameters when the two drugs were given in combination. All other pharmacokinetic parameters (Cmax, Tmax, and t½) were unchanged. There was no significant pharmacokinetic interaction between lamivudine and interferon alfa in this study. Lamivudine and zidovudine were coadministered to 12 asymptomatic HIV-positive adult patients in a single-center, open-label, randomized, crossover study. No significant differences were observed in AUC or total clearance for lamivudine or zidovudine when the two drugs were administered together. Coadministration of lamivudine with zidovudine resulted in an increase of 39% 62% (mean SD) in Cmax of zidovudine. Lamivudine and trimethoprim/sulfamethoxazole (TMP/SMX) were coadministered to 14 HIV-positive patients in a single-center, open-label, randomized, crossover study. Each patient received treatment with a single 300-mg dose of lamivudine and TMP 160 mg/SMX 800 mg once a day for 5 days with concomitant administration of lamivudine 300 mg with the fifth dose in a crossover design. Coadministration of TMP/SMX with lamivudine resulted in an increase of 44% 23% (mean SD) in lamivudine AUC, a decrease of 29% 13% in lamivudine oral clearance, and a decrease of 30% 36% in lamivudine renal clearance. The pharmacokinetic properties of TMP and SMX were not altered by coadministration with lamivudine. Lamivudine and zalcitabine may inhibit the intracellular phosphorilation of one another. Therefore, use of lamivudine in combination with zalcitabine is not recommended.
Adults: The recommended oral dose of this product for treatment of chronic hepatitis B in adults is 100 mg once daily. Safety and effectiveness of treatment beyond 1 year have not been established and the optimum duration of treatment is not known.
The formulation and dosage of lamivudine in this product are not appropriate for patients dually infected with HBV and HIV. If lamivudine is administered to such patients, the higher dosage indicated for HIV therapy should be used as part of an appropriate combination regimen, and the prescribing information for EPIVIR as well as this product should be consulted.
Pediatric Patients: The recommended oral dose of EPIVIR-HBV for pediatric patients 2 to 17 years of age with chronic hepatitis B is 3 mg/kg once daily up to a maximum daily dose of 100 mg. Safety and effectiveness of treatment beyond 1 year have not been established and the optimum duration of treatment is not known.
Zeffix is available in a 5-mg/mL oral solution when a liquid formulation is needed. (Please see information above regarding distinctions between different lamivudine-containing products.)
Dose Adjustment: It is recommended that doses of this product be adjusted in accordance with renal function.
There is no known antidote for this product. One case of an adult ingesting 6 g of EPIVIR was reported; there were no clinical signs or symptoms noted and hematologic tests remained normal. Because a negligible amount of lamivudine was removed via (4-hour) hemodialysis, continuous ambulatory peritoneal dialysis, and automated peritoneal dialysis, it is not known if continuous hemodialysis would provide clinical benefit in a lamivudine overdose event. If overdose occurs, the patient should be monitored, and standard supportive treatment applied as required.
PREGNANCY & LACTATION
Carcinogenesis, Mutagenesis, and Impairment of Fertility: Lamivudine long-term carcinogenicity studies in mice and rats showed no evidence of carcinogenic potential at exposures up to 34 times (mice) and 200 times (rats) those observed in humans at the recommended therapeutic dose for chronic hepatitis B. Lamivudine was not active in a microbial mutagenicity screen or an in vitro cell transformation assay, but showed weak in vitro mutagenic activity in a cytogenetic assay using cultured human lymphocytes and in the mouse lymphoma assay. However, lamivudine showed no evidence of in vivo genotoxic activity in the rat at oral doses of up to 2000 mg/kg producing plasma levels of 60 to 70 times those in humans at the recommended dose for chronic hepatitis B. In a study of reproductive performance, lamivudine administered to rats at doses up to 4000 mg/kg per day, producing plasma levels 80 to 120 times those in humans, revealed no evidence of impaired fertility and no effect on the survival, growth, and development to weaning of the offspring.
Pregnancy: Pregnancy Category C. Reproduction studies have been performed in rats and rabbits at orally administered doses up to 4000 mg/kg per day and 1000 mg/kg per day, respectively, producing plasma levels up to approximately 60 times that for the adult HBV dose. No evidence of teratogenicity due to lamivudine was observed. Evidence of early embryolethality was seen in the rabbit at exposure levels similar to those observed in humans, but there was no indication of this effect in the rat at exposures up to 60 times that in humans. Studies in pregnant rats and rabbits showed that lamivudine is transferred to the fetus through the placenta. There are no adequate and well-controlled studies in pregnant women. Because animal reproductive toxicity studies are not always predictive of human response, lamivudine should be used during pregnancy only if the potential benefits outweigh the risks.
Lamivudine has not been shown to affect the transmission of HBV from mother to infant, and appropriate infant immunizations should be used to prevent neonatal acquisition of HBV.
Pergnanct Registry: To monitor maternal-fetal outcomes of pregnant women exposed to lamivudine, a pregnancy registry has been established. Physicians are encouraged to register patients by calling 039297100.
Nursing Mothers: A study in lactating rats administered 45 mg/kg of lamivudine showed that lamivudine concentrations in milk were were slightly greater than those in plasma.Lamivudine is also
Zeffix Tabs&Oral MOH Apr. 10.2008 excreted in human milk.Samples of breast milk obtained from 20 mothers receiving lamivudine monotherapy (300 mg twice daily) or combination therapy (150 mg lamivudine twice daily and 300 mg zidovudine twice daily) had measurable concentrations of lamivudine.
Because of the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breastfeed if they are receiving lamivudine.
MANUFACTURER & DISTRIBUTER:
License Holder: GlaxoSmithKline Israel Ltd.