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Drug Details

ZEFFIX Film-Coated Tablets

• Drug Class Description
  Nucleoside analogues (antiviral agents).
• Generic Name
  Lamivudine
• Presentation
  Zeffix film-coated tablets contain 100 mg lamivudine
• Description
  Film-coated tablet Butterscotch coloured, film-coated, capsule shaped, biconvex and engraved “GX CG5” on one face.
• Indications
  

  Zeffix is indicated for the treatment of chronic hepatitis B in adults with:

  • compensated liver disease with evidence of active viral replication, persistently elevated serum alanine aminotransferase (ALT) levels and histological evidence of active liver inflammation and / or fibrosis.

  • decompensated liver disease.

• Adult Dosage
  

  Therapy with Zeffix should be initiated by a physician experienced in the management of chronic hepatitis B.

  Adults: the recommended dosage of Zeffix is 100 mg once daily. Zeffix can be taken with or without food.

  Duration of treatment:

  • In patients with HBeAg positive chronic hepatitis B (CHB) treatment should be administered for at least 3-6 months after HBeAg seroconversion (HBeAg and HBV DNA loss with HBeAb detection) is confirmed, to limit the risk of virological relapse, or until HBsAg seroconversion. This recommendation is based on limited data.

  • In patients with HBeAg negative CHB (pre-core mutant), the optimal duration of treatment is unknown. Treatment discontinuation may be considered following HBsAg seroconversion.

  • In patients with either HBeAg positive or HBeAg negative CHB, the development of YMDD variant HBV may result in a diminished therapeutic response to lamivudine, indicated by a rise in HBV DNA and ALT from previous on-treatment levels. In patients with extended-duration YMDD variant HBV, a switch to or addition of an alternative agent should be considered.

  • In patients with decompensated liver disease and liver transplant recipients, treatment cessation is not recommended. If there is a loss of efficacy attributable to the emergence of YMDD variant HBV in these patients, additional or alternative therapies should be considered.

  If Zeffix is discontinued, patients should be periodically monitored for evidence of recurrent hepatitis.

  Children (less than 12 years of age) and adolescents (12 to 17 years of age): Zeffix is not recommended for use in children below age 12 and adolescents age 12 to 17 due to lack of data on safety and efficacy.

  Renal impairment: lamivudine serum concentrations (AUC) are increased in patients with moderate to severe renal impairment due to decreased renal clearance. The dosage should therefore be reduced for patients with a creatinine clearance of < 50 ml/minute. When doses below 100 mg are required Zeffix oral solution should be used (see Table 1 below).

  Table 1 : Dosage of Zeffix in patients with decreased renal clearance.

  Creatinine clearanceml/min	First Dose of Zeffixoral solution *	Maintenance DoseOnce daily
  30 to < 50	20 ml (100 mg)	10 ml (50 mg)
  15 to < 30	20 ml (100 mg)	5 ml (25 mg)
  5 to < 15	7 ml (35 mg)	3 ml (15 mg)
  < 5	7 ml (35 mg)	2 ml (10 mg)

  * Zeffix oral solution containing 5 mg/ml lamivudine.

  Data available in patients undergoing intermittent haemodialysis (for less than or equal to 4 hrs dialysis 2-3 times weekly), indicate that following the initial dosage reduction of lamivudine to correct for the patient's creatinine clearance, no further dosage adjustments are required while undergoing dialysis.

  Hepatic impairment: data obtained in patients with hepatic impairment, including those with end-stage liver disease awaiting transplant, show that lamivudine pharmacokinetics are not significantly affected by hepatic dysfunction. Based on these data, no dose adjustment is necessary in patients with hepatic impairment unless accompanied by renal impairment.

• Child Dosage
  Children (less than 12 years of age) and adolescents (12 to 17 years of age): Zeffix is not recommended for use in children below age 12 and adolescents age 12 to 17 due to lack of data on safety and efficacy.
• Contra Indications
  Hypersensitivity to the active substance or to any of the excipients.
• Special Precautions
  

  Lamivudine has been administered to children (2 years and above) and adolescents with compensated chronic hepatitis B. However, due to limitations of the data, the administration of lamivudine to this patient population is not currently recommended.

  The efficacy of lamivudine in patients co-infected with Delta hepatitis or hepatitis C has not been established.

  Data are limited on the use of lamivudine in HBeAg negative (pre-core mutant) patients and in those receiving concurrent immunosuppressive regimes, including cancer chemotherapy.

  During treatment with Zeffix patients should be monitored regularly. Serum ALT levels should be monitored at 3 month intervals and HBV DNA and HBeAg should be assessed every 6 months.

  Exacerbations of hepatitis

  HBV viral subpopulations with reduced susceptibility to lamivudine (YMDD variant HBV) have been identified with extended therapy. In some patients the development of YMDD variant HBV can lead to exacerbation of hepatitis, primarily detected by serum ALT elevations and re-emergence of HBV DNA. In patients who have YMDD variant HBV and worsening liver disease (increasing ALT with or without decompensated cirrhosis) or recurrent hepatitis B after liver transplantation, a switch to or addition of an alternative agent should be considered.

  If Zeffix is discontinued or there is a loss of efficacy due to the development of YMDD variant HBV, some patients may experience clinical or laboratory evidence of recurrent hepatitis. If Zeffix is discontinued, patients should be periodically monitored both clinically and by assessment of serum liver function tests (ALT and bilirubin levels), for at least four months, and then as clinically indicated. Exacerbation of hepatitis has primarily been detected by serum ALT elevations, in addition to the re-emergence of HBV DNA. Clinical experience for more information regarding frequency of post treatment ALT elevations. Most events have been self-limited, however some fatalities have been observed.

  For patients who develop evidence of recurrent hepatitis post-treatment, there are insufficient data on the benefits of re-initiation of lamivudine treatment.

  Transplantation recipients and patients with advanced liver disease are at greater risk from active viral replication. Due to the marginal liver function in these patients, hepatitis reactivation at discontinuation of lamivudine or loss of efficacy during treatment may induce severe and even fatal decompensation. These patients should be monitored for clinical, virological and serological parameters associated with hepatitis B, liver and renal function, and antiviral response during treatment (at least every month), and, if treatment is discontinued for any reason, for at least 6 months after treatment. Laboratory parameters to be monitored should include (as a minimum) serum ALT, bilirubin, albumin, blood urea nitrogen, creatinine, and virological status: HBV antigen/antibody, and serum HBV DNA concentrations when possible. Patients experiencing signs of hepatic insufficiency during or post-treatment should be monitored more frequently as appropriate.

  HIV co-infection

  For the treatment of patients who are co-infected with HIV and are currently receiving or plan to receive treatment with lamivudine or the combination lamivudine-zidovudine, the dose of lamivudine prescribed for HIV infection (usually 150 mg/twice daily in combination with other antiretrovirals) should be maintained. For HIV co-infected patients not requiring anti-retroviral therapy, there is a risk of HIV mutation when using lamivudine alone for treating chronic hepatitis B.

  Transmission of hepatitis B

  There is no information available on maternal-foetal transmission of hepatitis B virus in pregnant women receiving treatment with lamivudine. The standard recommended procedures for hepatitis B virus immunisation in infants should be followed.

  Patients should be advised that therapy with lamivudine has not been proven to reduce the risk of transmission of hepatitis B virus to others and therefore, appropriate precautions should still be taken

• Interactions
  

  Interaction studies have only been performed in adults.

  The likelihood of metabolic interactions is low due to limited metabolism and plasma protein binding and almost complete renal elimination of unchanged substance.

  Lamivudine is predominantly eliminated by active organic cationic secretion. The possibility of interactions with other medicinal products administered concurrently should be considered, particularly when their main route of elimination is active renal secretion via the organic cationic transport system e.g. trimethoprim. Other medicinal products (e.g. ranitidine, cimetidine) are eliminated only in part by this mechanism and were shown not to interact with lamivudine.

  Substances shown to be predominately excreted either via the active organic anionic pathway, or by glomerular filtration are unlikely to yield clinically significant interactions with lamivudine.

  Administration of trimethoprim/sulphamethoxazole 160 mg/800 mg increased lamivudine exposure by about 40 %. Lamivudine had no effect on the pharmacokinetics of trimethoprim or sulphamethoxazole. However, unless the patient has renal impairment, no dosage adjustment of lamivudine is necessary.

  A modest increase in C_max (28 %) was observed for zidovudine when administered with lamivudine, however overall exposure (AUC) was not significantly altered. Zidovudine had no effect on the pharmacokinetics of lamivudine.

  Lamivudine has no pharmacokinetic interaction with alpha-interferon when the two medicinal products are concurrently administered. There were no observed clinically significant adverse interactions in patients taking lamivudine concurrently with commonly used immunosuppressant medicinal products (e.g. cyclosporin A). However, formal interaction studies have not been performed.

  Lamivudine may inhibit the intracellular phosphorylation of zalcitabine when the two medicinal products are used concurrently. Zeffix is therefore not recommended to be used in combination with zalcitabine.

• Adverse Drug Reactions
  

  In clinical studies of patients with chronic hepatitis B, lamivudine was well tolerated. The incidence of adverse events and laboratory abnormalities (with the exception of elevations of ALT and CPK, see below) were similar between placebo and lamivudine treated patients). The most common adverse events reported were malaise and fatigue, respiratory tract infections, throat and tonsil discomfort, headache, abdominal discomfort and pain, nausea, vomiting and diarrhoea.

  Adverse reactions are listed below by system organ class and frequency. Frequency categories are only assigned to those adverse reactions considered to be at least possibly causally related to lamivudine. Frequencies are defined as: very common ( 1/10), common ( 1/100, < 1/10), uncommon ( 1/1000, < 1/100), rare ( 1/10,000, < 1/1000) and very rare (< 1/10,000).

  The frequency categories assigned to the adverse reactions below are estimates: for most events, suitable data for calculating incidence are not available. Very common and common adverse drug reaction frequency categories were determined from clinical trial data and the background incidence in placebo groups was not taken into account. Adverse drug reactions identified through post-marketing surveillance were categorised as rare or very rare.

  Blood and lymphatic system disorders:

  Very rare: Thrombocytopenia

  Hepatobiliary disorders:

  Very common: ALT elevations.

  Exacerbations of hepatitis, primarily detected by serum ALT elevations, have been reported 'on-treatment' and following lamivudine withdrawal. Most events have been self-limited, however fatalities have been observed very rarely.

  Musculoskeletal and connective tissue disorders:

  Common: Elevations of CPK

  Very rare: Muscle disorders, including myalgia, cramps and rhabdomyolysis

  In patients with HIV infection, cases of pancreatitis and peripheral neuropathy (or paresthesia) have been reported. In patients with chronic hepatitis B there was no observed difference in incidence of these events between placebo and lamivudine treated patients.

  Cases of lactic acidosis, sometimes fatal, usually associated with severe hepatomegaly and hepatic steatosis, have been reported with the use of combination nucleoside analogue therapy in patients with HIV. There have been rare reports of lactic acidosis in patients receiving lamivudine for hepatitis B.