AGIMIDIN®

Composition: Each film-coated tablet contains:
Lamivudine. . . . . . . . . . . . . . . . . . . . . . .100 mg
Presentation:
Cardboard box containing 3 blisters of 10 film-coated tablets.
Indications:
Agimidin tablets containing lamivudine is indicated for the treatment of chronic hepatitis B in adults with:
– Compensated liver disease (liver is damaged, but its function remains normal) 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: (liver is damaged and does not function normally) lamivudine should always be used in combination with a second agent, without cross-resistance to lamivudine, to reduce the risk of resistance and to achieve rapid viral suppression.

Additional information

Dosage and administration

Lamivudine therapy should be initiated by a physician experienced in the treatment of chronic hepatitis B.
Dosage:
Adults
The recommended dosage of lamivudine is 100 mg once daily.
In patients with decompensated liver disease, lamivudine should always be used in combination with a second agent, without cross-resistance to lamivudine, to reduce the risk of resistance and to achieve rapid viral suppression.
Duration of treatment
The optimal duration of treatment is unknown.
– In patients with HBeAg positive chronic hepatitis B (CHB) without cirrhosis, treatment should be administered for at least 6 – 12 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 or there is loss of efficacy. Serum ALT and HBV DNA levels should be followed regularly after treatment discontinuation to detect any late virological relapse.
– In patients with HBeAg negative CHB (precore mutant) without cirrhosis, treatment should be administered at least until HBs seroconversion or there is evidence of loss of efficacy. With prolonged treatment, regular reassessment is recommended to confirm that continuation of the selected therapy remains appropriate for the patient.
– In patients with decompensated liver disease or cirrhosis and in liver transplant recipients, treatment cessation is not recommended.
If lamivudine is discontinued, patients should be periodically monitored for evidence of recurrent hepatitis.
Clinical resistance
In patients with either HBeAg positive or HBeAg negative CHB, the development of YMDD (tyrosine-methionine-aspartate-aspartate) mutant 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 order to reduce the risk of resistance in patients receiving lamivudine monotherapy, a switch to or addition of an alternative agent without cross-resistance to lamivudine based on therapeutic guidelines should be considered if serum HBV DNA remains detectable at or beyond 24 weeks of treatment.
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 of lamivudine and zidovudine, the dose of lamivudine prescribed for HIV infection (usually 150 mg/twice daily in combination with other antiretrovirals) should be maintained.
Special populations
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.
Recommended dosing in renal impairment (creatinine clearance < 50 ml/minute) (for treatment of hepatitis B):
Creatinine clearance ~ First Dose of lamivudine ~ Maintenance Dose
– 30 to < 50 ml/min ~ 100 mg ~ 50 mg once daily
– 15 to < 30 ml/min ~ 100 mg ~ 25 mg once daily
– 5 to < 15 ml/min ~ 35 mg ~ 15 mg once daily
– < 5 ~ 35 mg ~ 10 mg once daily
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.
Elderly
In elderly patients, normal ageing with accompanying renal decline has no clinically significant effect on lamivudine exposure, except in patients with creatinine clearance of < 50 ml/min.
Children
The safety and efficacy of lamivudine in infants, children and adolescents aged below 18 years have not been established.
Administration: Lamivudine tablets are orally taken with or without food.

Contraindications

Hypersensitivity to lamivudine or any of excipients of the drug.

Warnings and precautions for use

Lactic acidosis and severe hepatomegaly with steatosis
Occurrences of lactic acidosis (in the absence of hypoxaemia), sometimes fatal, usually associated with severe hepatomegaly and hepatic steatosis, have been reported with the use of nucleoside analogues. As lamivudine is a nucleoside analogue, this risk cannot be excluded. Treatment with nucleoside analogues should be discontinued when rapidly elevating aminotransferase levels, progressive hepatomegaly or metabolic/lactic acidosis of unknown aetiology occur. Benign digestive symptoms, such as nausea, vomiting and abdominal pain, might be indicative of lactic acidosis development. Severe cases, sometimes with fatal outcome, were associated with pancreatitis, liver failure/hepatic steatosis, renal failure and higher levels of serum lactate. Caution should be exercised when prescribing nucleoside analogues to any patient (particularly obese women) with hepatomegaly, hepatitis or other known risk factors for liver disease and hepatic steatosis (including certain medicinal products and alcohol). Patients co-infected with hepatitis C and treated with alpha interferon and ribavirin may constitute a special risk. These patients should be followed closely.
Exacerbations of hepatitis
– Exacerbations on treatment
Spontaneous exacerbations in chronic hepatitis B are relatively common and are characterised by transient increases in serum ALT. After initiating antiviral therapy, serum ALT may increase in some patients as serum HBV DNA levels decline. In patients with compensated liver disease, these increases in serum ALT were generally not accompanied by an increase in serum bilirubin concentrations or signs of hepatic decompensation.
HBV viral subpopulations with reduced susceptibility to lamivudine (YMDD mutant HBV) have been identified with extended therapy. In some patients the development of YMDD mutant HBV can lead to exacerbation of hepatitis, primarily detected by serum ALT elevations and re-emergence of HBV DNA. In patients who have YMDD mutant HBV, a switch to or addition of an alternative agent without cross resistance to lamivudine based on therapeutic guidelines should be considered.
– Exacerbations after treatment discontinuation
Acute exacerbation of hepatitis has been observed in patients who have discontinued hepatitis B therapy and is usually detected by serum ALT elevations and re-emergence of HBV DNA. In the controlled Phase III trials with no-active-treatment follow-up, the incidence of post-treatment ALT elevations (more than 3 times baseline) was higher in lamivudine-treated patients (21%) compared with those receiving placebo (8%). However, the proportion of patients who had post-treatment elevations associated with bilirubin elevations was low and similar in both treatment arms. For lamivudine-treated patients, the majority of posttreatment ALT elevations occurred between 8 and 12 weeks post-treatment. Most events have been self-limiting, however some fatalities have been observed.
– Exacerbations in patients with decompensated cirrhosis
Liver transplant recipients and patients with decompensated cirrhosis 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 serum ALT, bilirubin, albumin, blood urea nitrogen, creatinine, and virological status: HBV antigen/antibody, and serum HBV DNA concentrations when possible.
For patients who develop evidence of recurrent hepatitis post-treatment, there are insufficient data on the benefits of re-initiation of lamivudine treatment.
Mitochondrial dysfunction
Nucleoside and nucleotide analogues have been demonstrated in vitro and in vivo to cause a variable degree of mitochondrial damage. There have been reports of mitochondrial dysfunction in infants exposed in utero and/or post-natally to nucleoside analogues. The main adverse events reported are haematological disorders (anaemia, neutropenia), metabolic disorders (hyperlipasemia). Some late-onset neurological disorders have been reported (hypertonia, convulsion, abnormal behaviour). The neurological disorders might be transient or permanent. Any child exposed in utero to nucleoside and nucleotide analogues, should have clinical and laboratory follow-up and should be fully investigated for possible mitochondrial dysfunction in cases which have relevant signs or symptoms.
Paediatric patients
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 these subjects are not currently recommended.
Delta hepatitis or hepatitis C
The efficacy of lamivudine in patients co-infected with Delta hepatitis or hepatitis C has not been established and caution is advised.
Immunosuppressive treatments
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. Lamivudine should be used with caution in these patients.
Monitoring
During treatment with lamivudine patients should be monitored regularly. Serum ALT and HBV DNA levels should be monitored at 3-month intervals and in HBeAg positive patients HBeAg should be assessed every 6 months.
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 of lamivudine and 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 limited 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 with other medicinal products
Agimidin should not be taken with any other medicinal products containing lamivudine or medicinal products containing emtricitabine.
The combination of lamivudine with cladribine is not recommended.
Agimidin contains lactose
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Recommendation for pregnancy and breastfeeding

Pregnancy
Some data on pregnant women showed that there were more than 1000 results from the first trimester and more than 1000 results from the second and third trimesters in lamivudine-designated pregnant women indicating no deformities in the fetus/newborn. Less than 1% of these women were treated for HBV, while the majority were treated at higher doses and in combination with other drugs. Lamivudine can be used during pregnancy if clinically needed. 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.
Breastfeeding
Maternal hepatitis B is not a contraindication to breast-feeding if the newborn is adequately managed for hepatitis B prevention at birth, and there is no evidence that the low concentration of lamivudine in human milk leads to adverse events in breastfed infants. Therefore breastfeeding may be considered in lactating mothers being treated with lamivudine for HBV taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman. Where there is maternal transmission of HBV, despite adequate prophylaxis, consideration should be given to discontinuing breastfeeding to reduce the risk of the emergence of lamivudine resistant mutants in the infant.

Effects on ability to drive and use machines

The influence of Agimidin on the ability to drive and use machines has not been studied. However dizziness, headache, fatigue may occur and may affect the patient's activity requiring alertness.

Interactions, incompatibilities of medicine

– HIV entry inhibitor and HIV fusion inhibitor (enfuvirtide, maraviroc): These drugs have synergistic anti-HIV effect when combined with lamivudine.
– HIV integrase inhibitors (raltegravir): No clinically meaningful effect on the pharmacokinetics of lamivudine.
– HIV protease inhibitors (amprenavir/fosamprenavir, nelfinavir, ritonavir, saquinavir): Have in vitro synergistic antiretroviral effects with lamivudine. There is no evidence of antagonism between lamivudine and atazanavir or darunavir. It is not known whether there is the pharmacokinetic interaction between darunavir boosted ritonavir and lamivudine. It is not known whether there is pharmacokinetic interaction between lopinavir/ritonavir product and lamivudine when concomitantly administered. Peak plasma concentrations and AUC of lamivudine increase with concomitant use of nelfinavir; however, this has no clinical significance and no dose adjustment is necessary. Tipranavir boosted ritonavir has no effect on the pharmacokinetics of lamivudine when used concomitantly.
– Non-nucleoside reverse transcriptase inhibitors (delavirdine, efavirenz, nevirapine): Synergistic effects with lamivudine on HIV-1. No dose adjustment is required when efavirenz and lamivudine are co-administered. There is no pharmacokinetic interaction when lamivudine and rilpivirine are co-administered.
– Reverse nucleoside and nucleotide reverse transcriptase enzyme (abacavir, emtricitabine, stavudine, tenofovir, zidovudine): Plasma zidovudine concentrations increase by approximately 13% when used in combination with lamivudine but no dose adjustment is required when concomitantly administered. Abacavir, stavudine reduce the AUC of lamivudine but this interaction is not considered clinically significant. Tenofovir reduces plasma concentrations of lamivudine by 24%. Lamivudine and emtricitabine should not be used concurrently (due to similarities between emtricitabine and lamivudine, and since these two drugs have no significant additive potency and have equivalent resistance profiles). Lamivudine and zalcitabine should not be used concurrently because lamivudine may strongly inhibits intracellular phosphorylation of zalcitabine.
– Interferon and peginterferon: Concomitant use of antiretroviral (with or without ribavirin) and interferon alpha (or peginterferon alpha) in HIV and HCV co-infected patients can increase risk of liver failure which may be fatal. Patients receiving lamivudine in combination with interferon alpha (or peginterferon alpha) with or without ribavirin should be closely monitored for treatment-associated toxicities, especially hepatic decompensation and discontinuation of the drug should be considered, if necessary. If if toxicities develop (e.g. hepatic failure Childs-Pugh >= 6), dose reduction or discontinuation of interferon alpha (or peginterferon) and/or ribavirin should be considered. Ribavirin reduces phosphorylation of lamivudine. HIV and HCV co-infected patients are at risk of impaired liver function when antiretroviral and interferon alpha (or peginterferon alpha) with or without ribavirin are co-administered.
– Methadone: The addition of methadone has no clinically significant effect on the pharmacokinetic properties of lamivudine. Dose adjustment is not required when these drugs are used concomitantly.
– Administration of trimethoprim/sulphamethoxazole increases lamivudine AUC by 43 % but dose adjustment is not required.
– Buprenorphine: There is no clinically significant pharmacokinetic interaction; No dose adjustment is needed if they are used concurrently.
– Cladribin: In vitro lamivudine inhibits intracellular phosphorylation of cladribine, leading to the potential risk of cladribine loss of efficacy in case of combination in the clinical setting. Some clinical results also showed that there is an interaction between lamivudine and cladribin. Therefore, the concomitant use of lamivudine with cladribine is not recommended.

Undesirable effects (ADRs)

The incidence of side effects listed below is in adults, that HIV or HBV infection is treated with lamivudine in combination with other antiretroviral drugs.
Very common, ADR > 10/100:
Central nervous system: Headache, insomnia, malaise, fatigue.
Gastrointestinal: Nausea, vomiting, diarrhea, pancreatitis, abdominal pain.
Blood and lymphatic systems disorders: Neutropenia.
Hepatobiliary: Increases in aminotransferase AST, ALT.
Nervous and musculoskeletal: Muscle pain, peripheral neuropathy, musculoskeletal pain.
Respiratory: Signs and symptoms of the nose, cough, sore throat.
Other: Infections (including ear, nose and throat infections).
Common, ADR > 1/100
Central nervous system: Dizziness, depression, fever, tremor.
Skin: Rash.
Gastrointestinal: Anorexia, increased lipase, abdominal cramps, indigestion, increased amylase, stomach burning sensation.
Blood and lymphatic systems disorders: Thrombocytopenia, hemoglobin in plasma.
Nervous and musculoskeletal: Elevated creatine phosphokinase, joint pain.
Uncommon, 1/1000 < ADR < 1/100
Neurological – Musculoskeletal: Paresthesia, muscle weakness, rhabdomyolysis, peripheral neuropathy, seizures, abnormal behavior.
Blood and lymphatic systems disorders: Anemia, pure red cell aplasia, swollen lymph nodes.
Body as a whole: Anaphylaxis, immune reconstitution syndrome, disorders in fat distribution accumulation of body fat.
Liver – spleen: Hepatomegaly, hyperbilirubinemia, aggravated hepatitis B, splenomegaly.
Metabolic: Hypertriglyceridemia, hypercholesterolemia, insulin resistance, hyperglycaemia, hyperlactatemia.
Skin: Pruritus, hair loss, hives.
Other: Stomatitis, wheeze, osteonecrosis.
Management of ADRs
Lamivudine should be discontinued immediately if clinical signs, symptoms or investigations suggest that pancreatitis may occur. Lamivudine should be discontinued immediately if clinical signs, symptoms or investigations show lactic acidosis, or hepatic toxicity (hepatomegaly, fatty liver, even if the transaminase level is not high).

Overdose and management

Overdose:
There is limited information regarding lamivudine overdose.
Symptoms of severe poisoning occurring after the treatment or long-term use include: Pancreatitis, peripheral neuropathy, fatty liver, acute kidney failure, lactic acidosis.
Treatment:
There is no specific antidote. Hemodialysis or peritoneal dialysis after 4 hours only removes a negligible amount.
Treatment of severe poisoning includes drug withdrawal, symptomatic and supportive treatment.

Pharmacodynamic properties

– Lamivudine (referred to as (-)2', 3'-dideoxy, 3'thiacytidine) is a nucleoside reverse transcriptase inhibitor. Lamivudine is structurally similar to zalcitabine. Lamivudine is converted by intracellular enzymes to the active metabolite, lamivudine-5'-triphosphate (3TC-TP). Because its structure is similar to that of deoxycytidine triphosphate, the natural substrate for reverse transcriptase, 3TC-TP competes with natural deoxycytidine triphosphate and for binding to reverse transcriptase, and incorporation into DNA results in chain termination. Lamivudine demonstrates low cytotoxicity to peripheral blood lymphocytes, to established lymphocyte and monocyte-macrophage cell lines, and to a variety of bone marrow progenitor cells in vitro.
– Lamivudine inhibits hepatitis B virus in patients with chronic hepatitis B. Although lamivudine is well tolerated, lamivudine must not be used alone, as drug resistance may easily occur. This resistance is due to mutations in reverse transcriptase, which causes 100 fold decrease in the susceptibility to lamivudine and remove antiviral effect in patients.
– Treatment of chronic hepatitis B with lamivudine for some time will result in resistant mutants on the polymerase enzyme. After prolonged therapy lamivudine resistant mutants occur which is associated with mutations in the HBV polymerase gene. HBV DNA polymerase mutants showed resistance to lamivudine are M552V and M552I with the methionine (M) at HBV codon 552 replaced by isoleucine (I) or valine (V). Despite the presence of anti-HBe antibody, HBV DNA is highly elevated and ALT increases after cessation of lamivudine, hepatitis will recur. The frequency of resistance to lamivudine increases with time: 24% at one year, 38% at two years, 50% at three years.
– Lamivudine-zidovudine combination therapy in patients who have not been treated before, results in a 10-fold decrease in plasma viral load, the effect lasts more than a year.

Pharmacokinetic properties

Absorption: After oral administration, lamivudine is rapidly absorbed and peak serum concentrations occur about 1 hour (in the fasted state), 3.2 hours (in the fed state). Food slows down but does not reduce the absorption of the drug. Food delays the absorption, but it does not affect the amount absorbed. The oral bioavailability of lamivudine in adults is usually between 80 and 85%.
Distribution: Lamivudine is moderately bound to plasma proteins (36%). Volume of distribution is independent of dose and does not correlate with body weight. Only about 10% of lamivudine crosses the blood-brain barrier; the mean ratio of cerebrospinal fluid/serum lamivudine is approximately 0.12.
Metabolism: Intracellularly, lamivudine is phosphorylated to its active 5′ triphosphate metabolite, lamivudine triphosphate. Lamivudine undergoes minimal hepatic metabolism.
Elimination: Lamivudine is predominately cleared by renal excretion of unchanged substance. Half-life in peripheral blood lymphocytes is 10 – 19 hours. Half-life after a single oral dose is 5-7 hours in adults; 2 hours in children from 4 months to 14 years.
Patients with renal impairment:
Studies in patients with renal impairment show that lamivudine elimination is affected by renal dysfunction. Dose reduction is recommended in patients with a creatinine clearance of < 50 ml/min is necessary.
Patients with liver impairment: 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.
Elderly: In elderly patients the pharmacokinetic 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 < 50 ml/min.

Storage conditions, shelf-life, quality specification of the medicine

Storage conditions: Protect from humidity and light, below 30 degrees C.
Shelf – life: 36 months from the manufacture date.
Quality specification: In house specification.