Valfix

Valfix

lamivudine

Manufacturer:

Y.S.P. Industries

Distributor:

Y.S.P. Industries
Full Prescribing Info
Contents
Lamivudine.
Description
100 mg: Each tablet contains: Lamivudine 100 mg.
150 mg: Each tablet contains: Lamivudine 150 mg.
Action
Pharmacology: Pharmacodynamics: 100 mg: Lamivudine is an antiviral agent which is highly active against hepatitis B virus (HBV) in all cell lines tested and in experimentally infected animals.
Lamivudine is metabolised by both infected and uninfected cells to the triphosphate (TP) derivative which is the active form of the parent compound. The intracellular half-life of the triphosphate in hepatocytes is 17-19 hrs in vitro. Lamivudine-TP acts as a substrate for the HBV viral polymerase. The formation of further viral DNA is blocked by incorporation of lamivudine-TP into the chain and subsequent chain termination.
Lamivudine-TP does not interfere with normal cellular deoxynucleotide metabolism. It is also only a weak inhibitor of mammalian DNA polymerases α and β. Furthermore, lamivudine-TP has little effect on mammalian cell DNA content.
In assays relating to potential drug effects on mitochondrial structure and DNA content and function, lamivudine lacked appreciable toxic effects. It has a very low potential to decrease mitochondrial DNA content, is not permanently incorporated into mitochondrial DNA and does not act as an inhibitor of mitochondrial DNA polymerase γ.
150 mg: Lamivudine is a nucleoside analogue which has activity against human immunodeficiency virus (HIV) and hepatitis B virus (HBV). It is metabolised intracellularly to the active moiety, lamivudine 5'-triphosphate. Its main mode of action is as a chain terminator of viral reverse transcription. The triphosphate has selective inhibitory activity against HIV-1 and HIV-2 replication in vitro, it is also active against zidovudine-resistant clinical isolates of HIV. No antagonistic effects in vitro were seen with lamivudine and other anti retrovirals (tested agents: abacavir, didanosine, nevirapine and zidovudine).
Pharmacokinetics: Absorption: Lamivudine is well absorbed from the gastrointestinal tract, and the bioavailability of oral lamivudine in adults is normally between 80-85%. Following oral administration, the mean time (tmax) to maximal serum concentrations (Cmax) is about an hour.
100 mg: At therapeutic dose levels ie. 100mg once daily, Cmax is in the order of 1.1-1.5 mcg/ml and trough levels were 0.015-0.02mcg/ml.
Co-administration of lamivudine with food resulted in a delay of tmax and a lower Cmax (decreased by up to 47%). However, the extent (based on the AUC) of lamivudine absorbed was not influenced, therefore lamivudine can be administered with or without food.
150 mg: Co-administration of lamivudine with food results in a delay of tmax and a lower Cmax. However, the extend (based on the AUC) of lamivudine absorbed is not influenced.
Administration of crushed tablets with a small amount of semi-solid food or liquid would not be expected to have an impact on the pharmaceutical quality, and would therefore not be expected to alter the clinical effect. This conclusion is based on the physiochemical and pharmacokinetic data assuming that the patient crushes and transfers 100% of the tablet and ingests immediately.
Distribution: 100 mg: From IV studies, the mean volume of distribution is 1.3L/kg.
Lamivudine exhibits linear pharmacokinetics over the therapeutic dose range and displays low plasma protein-binding to albumin.
Limited data shows lamivudine penetrates the central nervous system and reaches the cerebrospinal fluid (CSF).
The mean lamivudine CSF/serum concentration ratio 2-4 hrs after oral administration was approximately 0.12.
150 mg: The mean volume of distribution is 1.3 l/kg. The observed half-life of elimination is 5 to 7 hours. The mean systemic clearance of lamivudine is approximately 0.32 l/h/kg, with predominantly renal clearance (> 70%) via the organic cationic transport system.
Lamivudine exhibits linear pharmacokinetics over the therapeutic dose range and displays limited binding to the major plasma protein albumin.
Metabolism: 100 mg: Lamivudine is predominantly cleared by renal excretion of unchanged drug. The likelihood of metabolic drug interactions with lamivudine is low due to the small (5-10%) extent of hepatic metabolism and the low plasma protein-binding.
Elimination: 100 mg: The mean systemic clearance of lamivudine is approximately 0.3L/hr/kg. The observed elimination half-life is 5-7 hrs. The majority of lamivudine is excreted unchanged in the urine via glomerular filtration and active secretion (organic cationic transport system).
Renal clearance accounts for about 70% of lamivudine elimination.
150 mg: Lamivudine elimination is affected by renal dysfunction. A recommended dosage regimen for patients with creatinine clearance below 50 ml/min is shown in the Dosage & Administration.
Biotransformation: 150 mg: The active moiety, intracellular lamivudine triphosphate, has a prolonged terminal half-life in the cell (16 to 19 hours) compared to the plasma lamivudine half-life (5 to 7 hours).
Lamivudine is predominantly cleared unchanged by renal excretion. The likelihood of metabolic interactions of lamivudine with other medicinal products is low due to the small extent of hepatic metabolism (5-10%) and low plasma protein binding.
Special populations: 100 mg: Studies in patients with renal impairment show lamivudine elimination is affected by renal dysfunction. Dose reduction in patients with a creatinine clearance of <50mL/min is necessary.
A study in hepatically impaired patients (non-HIV and non-HBV infected) showed lamivudine is well tolerated in this patient group with no changes in laboratory parameter or the adverse event profile of lamivudine. The pharmacokinetics of lamivudine are unaffected by hepatic impairment.
Limited data in patients undergoing liver transplantation show that impairment of hepatic function does not impact significantly on the pharmacokinetics of lamivudine unless accompanied by renal dysfunction.
In elderly patients, the pharmacokinetics profile of lamivudine suggests that normal ageing with accompanying renal decline has no clinically significant effect on lamivudine exposure, except in patients with creatinine clearance of <50mL/min.
Following oral administration, lamivudine pharmacokinetics in late pregnancy were similar to non-pregnant adults.
Indications/Uses
100 mg: For treatment of patients ≥16 years of age with chronic hepatitis B and evidence of hepatitis B virus (HBV) replication.
150 mg: In combination with other antiretroviral agents for treating HIV infected adults & children.
Dosage/Direction for Use
100 mg: 100 mg once daily to be taken with or without food.
Patient compliance should be monitored while taking lamivudine. Discontinuation may be considered in immunocompetent patients when HBeAg and/or HBsAg seroconversion occur. Discontinuation may also be considered when loss of efficacy occurs, as indicated by recurrent signs of hepatitis.
After treatment discontinuation, patients should be periodically monitored for evidence of recurrent hepatitis.
Discontinuation of treatment is not recommended in patients with decompensated liver disease. There are limited data regarding the maintenance of long-term seroconversion after stopping treatment with lamivudine.
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 in patients with creatinine clearance <50ml/min.
Data available in patients undergoing intermittent haemodialysis (≤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.
150 mg: Adults and adolescents (weighing at least 30 kg): 150mg twice daily or 300 mg once daily, to be taken with or without food.
Children aged more than 3 months: Children weighing between 21kg to 30kg: 75mg taken in the morning and 150mg taken in the evening.
Children weigihing between 14kg to 21kg: 75mg twice daily.
Children less than three months of age: The limited data available are insufficient to propose specific dosage recommendations.
Special populations: Elderly: No specific data are available; however, special care is advised in this age group due to age-associated changes such as the decrease in renal function and alteration of haematological parameters.
Renal impairment: Lamivudine plasma concentrations (AUC) are increased in patients with moderate - severe renal impairment due to decreased clearance. The dosage should therefore be reduced for patients with a creatinine clearance of less than 50ml/min as shown in Table 1 and Table 2. The same percentage reduction in dose applied for paediatric patients with renal impairment. (See Table 1 and Table 2).

Click on icon to see table/diagram/image


Click on icon to see table/diagram/image

Hepatic impairment: No dose adjustment is necessary in patients with moderate or severe hepatic impairment unless accompanied by renal impairment.
Mode of Administration: To be taken orally with or without food.
150 mg: To ensure administration of the entire dose, the tablet(s) should ideally be swallowed without crushing.
Alternatively, for patients who are unable to swallow tablets, the tablet(s) may be crushed and added to a small amount of semi-solid food or liquid, all of which should be consumed immediately.
Overdosage
Symptoms and Treatment for Overdosage, and Antidote(s): Limited data are available on the consequences of ingestion of acute overdoses in humans. No fatalities occurred, and the patients recovered. No specific signs or symptoms have been identified following such overdose. If overdose occurs, the patient should be monitored, and standard supportive treatment applied as required. Since lamivudine is dialysable, continuous haemodialysis could be used in the treatment of overdose, although this has not been studied.
100 mg: Administration of lamivudine at very high dose levels in acute animal studies did not result in any organ toxicity.
Contraindications
The use of Lamivudine Tablet is contraindicated in patients with known hypersensitivity to lamivudine or to any ingredient of the preparation.
Special Precautions
Effect on the ability to drive or operate machinery: There have been no studies to investigate the effect of lamivudine on driving performance or the ability to operate machinery. Furthermore, a detrimental effect on such activities would not be predicted from the pharmacology of lamivudine.
100 mg: During treatment, patients should be monitored regularly by a physician experienced in the management of chronic hepatitis B.
If this product is discontinued or there is a loss of efficacy, some patients may experience clinical or laboratory evidence of recurrent hepatitis. Exacerbation of hepatitis has primarily been detected by serum ALT elevations, in addition to the re-emergence of HBV DNA.
If this product is discontinued, patients should be periodically monitored both clinically and by assessment of serum liver function tests (ALT and bilirubin levels), for at least 4 months for evidence for recurrent hepatitis; patients should then be followed as clinically indicated. For patients who develop evidence of recurrent post-treatment hepatitis, there are insufficient data on the benefits of re-initiation of lamivudine treatment.
In patients with moderate to severe renal impairment, serum lamivudine concentrations (AUC) are increased due to decreased renal clearance, therefore, the dose should be reduced in patient with creatinine clearance <50 ml/min.
Transplantation recipients and patients with advanced liver disease are at greater risk from active viral replication. Due to 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. It is recommended that these patients are monitored for parameters associated with hepatitis B, for liver and renal function, and for antiviral response during treatment. If treatment is discontinued for any reason, it is recommended that these patients are monitored for at least 6 months after cessation of treatment. Patients experiencing signs of hepatic insufficiency during or post-treatment should be monitored frequently, as appropriate.
There are limited data on the use of lamivudine in patients receiving concurrent immunosuppressive regimens, including cancer chemotherapy.
HBV viral subpopulations (YMDD variant HBV) with reduced susceptibility to lamivudine have been identified during extended therapy. In a minority of cases, this variant can lead to recurrent hepatitis.
For the treatment of patients who are co-infected with HIV and are currently receiving or are planning to receive an antiretroviral treatment regimen including lamivudine, the dose of lamivudine usually prescribed for HIV infection should be maintained.
There is no information available on maternal-foetal transmission of hepatitis B virus in pregnant women receiving treatment with this product. The standard recommended procedures for hepatitis B virus immunization in infants should be followed.
Patients should be advised that therapy with this product have not been proven to reduce the risk of transmission of hepatitis B virus to others and therefore, appropriate precaution should still be taken.
150 mg: While effective viral suppression with antiretroviral therapy has been proven to substantially reduce the risk of sexual transmission, a residual risk cannot be excluded. Precautions to prevent transmission should be taken.
Lamivudine is not recommended for use as monotherapy.
Triple nucleoside therapy: There have been reports of a high rate of virological failure and of emergence of resistance at an early stage when lamivudine was combined with tenofovir disoproxil fumarate and abacavir as well as with tenofovir disoproxil fumarate and didanosine as a once daily regimen.
Opportunistic infections: Patients receiving lamivudine or any other antiretroviral therapy may continue to develop opportunistic infections and other complications of HIV infection, and therefore should remain under close clinical observation by physicians experienced in the treatment of patients with associated HIV diseases.
Pancreatitis: Cases of pancreatitis have occurred rarely. However, it is not clear whether these cases were due to the antiretroviral treatment or to the underlying HIV disease. Treatment with lamivudine should be stopped immediately if clinical signs, symptoms or laboratory abnormalities suggestive of pancreatitis occur.
Mitochondrial dysfunction following exposure in utero: Nucleoside and nucleotide analogues may impact mitochondrial function to a variable degree, which is most pronounced with stavudine, didanosine and zidovudine. There have been reports of mitochondrial dysfunction in HIV-negative infants exposed in utero and/or post-natally to nucleoside analogues; these have predominantly concerned treatment with regimens containing zidovudine. The main adverse reactions reported are haematological disorders (anaemia, neutropenia) and metabolic disorders (hyperlactatemia, hyperlipasemia). These events have often been transitory. Late-onset neurological disorders have been reported rarely (hypertonia, convulsion, abnormal behaviour). Whether such neurological disorders are transient or permanent is currently unknown. These findings should be considered for any child exposed in utero to nucleoside and nucleotide analogues, who presents with severe clinical findings of unknown aetiology, particularly neurologic findings.
Weight and metabolic parameters: An increase in weight and in levels of blood lipids and glucose may occur during antiretroviral therapy. Such changes may in part be linked to disease control and life style. For lipids, there is in some cases evidence for a treatment effect, while for weight gain there is no strong evidence relating this to any particular treatment. For monitoring of blood lipids and glucose reference is made to established HIV treatment guidelines. Lipid disorders should be managed as clinically appropriate.
Immune Reactivation Syndrome: In HIV-infected patients with severe immune deficiency at the time of institution of combination antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic pathogens may arise and cause serious clinical conditions, or aggravation of symptoms. Typically, such reactions have been observed within the first few weeks or months of initiation of CART. Relevant examples are cytomegalovirus retinitis, generalised and/or focal mycobacterium infections, and Pneumocystis carinii pneumonia. Any inflammatory symptoms should be evaluated and treatment instituted when necessary. Autoimmune disorders (such as Graves' disease) have also been reported to occur in the setting of immune reactivation; however, the reported time to onset is more variable and these events can occur many months after initiation of treatment.
Patients with chronic hepatitis B or C and treated with combination antiretroviral therapy are at an increased risk of severe and potentially fatal hepatic adverse events. In case of concomitant antiviral therapy for hepatitis B or C, please refer also to the relevant product information for these medicinal products.
If lamivudine is discontinued in patients co-infected with hepatitis B virus, periodic monitoring of liver function tests and markers of HBV replication is recommended, as withdrawal of lamivudine may result in an acute exacerbation of hepatitis.
Patients with pre-existing liver dysfunction, including chronic active hepatitis, have an increased frequency of liver function abnormalities during combination antiretroviral therapy, and should be monitored according to standard practice. If there is evidence of worsening liver disease in such patients, interruption or discontinuation of treatment must be considered.
Osteonecrosis: Although the aetiology is considered to be multifactorial (including corticosteroid use, alcohol consumption, severe immunosuppression, higher body mass index), cases of osteonecrosis have been reported particularly in patients with advanced HIV-disease and/or long-term exposure to combination antiretroviral therapy (CART). Patients should be advised to seek medical advice if they experience joint aches and pain, joint stiffness or difficulty in movement.
Renal impairment: In patients with moderate to severe renal impairment, the terminal plasma half-life of lamivudine is increased due to decreased clearance, therefore the dose should be adjusted.
Use In Pregnancy & Lactation
Pregnancy: 100 mg: Studies in humans have confirmed that Lamivudine crosses the placenta. Lamivudine concentrations in infant serum at birth were similar to those in maternal and cord serum at delivery.
Use in pregnancy should be considered only if the benefit outweighs the risk. Although the results of animal studies are not always predictive of human response, the findings in the rabbit suggest a potential risk of early embryonic loss.
Consequently, Lamivudine administration is not recommended during the first three months of pregnancy.
For patients who are being treated with Lamivudine and subsequently become pregnant consideration should be given to the possibility of a recurrence of hepatitis on discontinuation of Lamivudine.
150 mg: As a general rule, when deciding to use antiretroviral agents for the treatment of HIV infection in pregnant women and consequently for reducing the risk of HIV vertical transmission to the newborn, the animal data as well as the clinical experience in pregnant women should be taken into account.
Lamivudine can be used during pregnancy if clinically needed. The malformative risk is unlikely in humans.
For patients co-infected with hepatitis who are being treated with lamivudine and subsequently become pregnant, consideration should be given to the possibility of a recurrence of hepatitis on discontinuation of lamivudine.
Mitochondrial dysfunction: Nucleoside and nucleotide analogues have been demonstrated in vitro and in vivo to cause a variable degree of mitochondrial damage.
100 mg: Lactation: Lamivudine should only be used in a nursing mother if the expected benefit justifies the potential risk to the infant. A decision must be made whether to discontinue breast feeding or to discontinue/abstain from Lamivudine therapy, taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.
150 mg: Breastfeeding: Following oral administration lamivudine was excreted in breast milk at similar concentrations to those found in serum. Serum concentrations of lamivudine in breastfed infants of mothers treated for HIV are very low and progressively decrease to undetectable levels when breastfed infants reach 24 weeks of age. There are no data available on the safety of lamivudine when administered to babies less than three months old. It is recommended that HIV infected women do not breast-feed their infants under any circumstances in order to avoid transmission of HIV. Fertility: Lamivudine had no effect on fertility.
Adverse Reactions
100 mg: The most common adverse events reported are malaise and fatigue, respiratory tract infections, headache, abdominal discomfort and pain, nausea, vomiting and diarrhoea.
Hepatobiliary disorders: Elevation of ALT.
Musculoskeletal, connective tissue and bone disorders: Elevation of CPK, muscle disorders, including myalgia and cramps.
Blood and lymphatic system disorders: Thrombocytopenia.
In patients with HIV infection, cases of pancreatitis and peripheral neuropathy (or paresthesia) have been reported, although no relationship to treatment with lamivudine has been clearly established.
Cases of lactic acidosis, usually associated with severe hepatomegaly and hepatic steatosis, have been reported with the use of nucleoside analogue combination therapy in patients with HIV. There have been occasional reports of these adverse events in hepatitis B patients with decompensated liver disease.
150 mg: The most common adverse events reported are hyperlactataemia, headache, nausea, vomiting, upper abdominal pain, diarrhoea, rash, alopecia, arthralgia, muscle disorders, fatigue, malaise and fever.
Weight and levels of blood lipids and glucose may increase during antiretroviral therapy.
In HIV-infected patients with severe immune deficiency at the time of initiation of combination antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic infections may arise. Autoimmune disorders (such as Graves' disease) have also been reported to occur in the setting of immune reactivation; however, the reported time to onset is more variable and these events can occur many months after initiation of treatment.
Cases of osteonecrosis have been reported, particularly in patients with generally acknowledged risk factors, advanced HIV disease or long-term combined antiretroviral exposure (CART). The frequency of which is unknown.
Drug Interactions
100 mg: The likelihood of metabolic interactions is low due to limited metabolism and plasma protein-binding and almost complete renal elimination of unchanged drug.
Lamivudine is predominantly eliminated by active organic cationic secretion. The possibility of interactions with other drugs administered concurrently should be considered, particularly when their main route of elimination is active renal sceretion via the organic cationic transport system eg. trimethoprim. Other drugs (eg. ranitidine, cimetidine) are eliminated only in part by this mechanism and were shown not to interact with lamivudine.
Drugs shown to be predominantly excreted either via the active organic anionic pathway or by glomerular filtration are unlikely to yield clinically significant interactions with lamivudine.
Lamivudine has no pharmacokinetic interaction with α-interferon when the 2 drugs are concurrently administered. There were no observed clinically significant adverse interactions in patients taking this product with commonly used immunosuppressant drugs (eg. cyclosporine A). However, formal interaction studies have not been performed.
Lamivudine may inhibit the intracellular phosphorylation of zalcitabine when the 2 medicinal products are used concurrently. This product is therefore not recommended to be used in combination with zalcitabine.
Emtricitabine: Due to similarities, lamivudine should not be administered concomitantly with other cytidine analogues, such as emtricitabine. Moreover, lamivudine should not be taken with any other medicinal products containing lamivudine.
150 mg: The likelihood of metabolic interactions is low due to limited metabolism and plasma protein-binding and almost complete renal clearance.
Administration of trimethoprim/sulfamethoxazole 160 mg/800 mg results in an increase in lamivudine exposure, because of the trimethoprim component; the sulfamethoxazole component did not interact. However, unless the patient has renal impairment, no dosage adjustment of lamivudine is necessary. Lamivudine has no effect on the pharmacokinetics of trimethoprim or sulfamethoxazole. When concomitant administration is warranted, patients should be monitored clinically. Co-administration of lamivudine with high doses of co-trimoxazole for the treatment of Pneumocystis carinii pneumonia (PCP) and toxoplasmosis should be avoided.
The possibility of interactions with other medicinal products administered concurrently should be considered, particularly when the 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. The nucleoside analogues (e.g. didanosine and zidovudine) are not eliminated by this mechanism and are unlikely to interact with lamivudine.
A modest increase in Cmax was observed for zidovudine when administered with lamivudine, however overall exposure (AUC) is not significantly altered. Zidovudine has no effect on the pharmacokinetics of lamivudine.
Due to similarities, lamivudine should not be administered concomitantly with other cytidine analogues, such as emtricitabine. Moreover, lamivudine should not be taken with any other medicinal products containing lamivudine.
In vitro lamivudine inhibits the intracellular phosphorylation of cladribine leading to a potential risk of cladribine loss of efficacy in case of combination in the clinical setting. Some clinical findings also support a possible interaction between lamivudine and cladribine. Therefore, the concomitant use of lamivudine with cladribine is not recommended.
Lamivudine metabolism does not involve CYP3A, making interactions with medicinal products metabolised by this system (e.g. PIs) unlikely.
Storage
Store at temperature below 30°C.
Shelf-Life: 3 years from the date of manufacture.
MIMS Class
ATC Classification
J05AF05 - lamivudine ; Belongs to the class of nucleoside and nucleotide reverse transcriptase inhibitors. Used in the systemic treatment of viral infections.
Presentation/Packing
FC tab 100 mg (an orange-brown elliptical tablet, one side impressed with 'BM' "
Click on icon to see table/diagram/image
") x 3 x 10's, 6 x 10's, 10 x 10's, 50 x 10's, 100 x 10's. 150 mg (a white colour diamond shaped tablet, one side impressed with "
Click on icon to see table/diagram/image
") x 3 x 10's, 6 x 10's, 12 x 10's.
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