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1. Lamivudine Hetero 300 Mg Film-Coated Tablets
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SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Lamivudine Hetero 300 mg Film-coated tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 300 mg lamivudine.

Excipient with known effect: Isomalt (Ph. Eur.)

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Film-coated tablet.

White capsule shaped, biconvex film coated tablets with a dimension of 19.10 x 8.90 mm, debossed with 17 on one side and J on the other side.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Lamivudine Hetero is indicated as part of antiretroviral combination therapy for the treatment of Human Immunodeficiency Virus (HIV) infected adults and children.

4.2 Posology and method of administration

The therapy should be initiated by a physician experienced in the management of HIV infection.

Method of administration

Lamivudine Hetero may be administered with or without food.

To ensure administration of the entire dose, the tablet(s) should ideally be swallowed without crushing. For patients who are unable to swallow tablets, lamivudine is available as an oral solution. Alternatively, the tablets may be crushed and added to a small amount of semi-solid food or liquid, all of which should be consumed immediately (see section 5.2).

Posology

Adults and adolescents (over 12 years of age): the recommended dose of Lamivudine Hetero is 300 mg daily. This may be administered as either 150 mg twice daily or 300 mg once daily (see section 4.4). The 300 mg tablet is only suitable for the once a day regimen.

Patients changing to the once daily regimen should take 150 mg twice a day and switch to 300 mg once a day the following morning. Where an evening once daily regimen is preferred, 150 mg of Lamivudine Hetero should be taken on the first morning only, followed by 300 mg in the evening. When changing back to a twice daily regimen patients should complete the days treatment and start 150 mg twice a day the following morning.

Children:

Three months to 12 years of age: the recommended dose is 4 mg/kg twice daily up to a maximum of 300 mg daily.

Lamivudine is available as an oral solution for children over three months of age and who weigh less than 14 kg or for patients who are unable to swallow tablets. Other formulations containing less lamivudine are available for the treatment of children less than 12 years of age.

Less than three months of age: the limited data available are insufficient to propose specific dosage recommendations (see section 5.2)

Renal impairment: Lamivudine concentrations are increased in patients with moderate - severe renal impairment due to decreased clearance. The dose should therefore be adjusted, using oral solution presentation of lamivudine for patients whose creatinine clearance falls below 30 ml/min and the 150 mg tablet formulation for patients whose creatinine clearance falls below 50 ml/min (see tables).

Dosing recommendations - Adults and adolescents over 12 years:

Creatinine clearance (ml/min)	First dose	Maintenance dose
> 50	150 mg	150 mg twice daily
30 - 50	150 mg	150 mg once daily
< 30	As doses below 150 mg are needed the use of the oral solution is
	recommended

There are no data available on the use of lamivudine in children with renal impairment. Based on the assumption that creatinine clearance and lamivudine clearance are correlated similarly in children as in adults it is recommended that the dosage in children with renal impairment be reduced according to their creatinine clearance by the same proportion as in adults.

Dosing recommendations - Children from 3 months to 12 years:

Creatinine clearance (ml/min)	First dose	Maintenance dose
> 50	4 mg/kg	4 mg/kg twice daily
30 to <50	4 mg/kg	4 mg/kg once daily
15 to <30	4 mg/kg	2.6 mg/kg once daily

Hepatic impairment: Data obtained in patients with moderate to severe hepatic impairment shows that lamivudine pharmacokinetics are not significantly affected by hepatic dysfunction. Based on these data, no dose adjustment is necessary in patients with moderate or severe hepatic impairment unless accompanied by renal impairment.

Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

4.4 Special warnings and precautions for use

Lamivudine Hetero is not recommended for use as monotherapy.

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 (see section 4.2).

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 Hetero 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.

Transmission of HIV: Patients should be advised that current antiretroviral therapy, including Lamivudine Hetero, has not been proven to prevent the risk of transmission of HIV to others through sexual contact or contamination with blood. Appropriate precautions should continue to be taken.

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 Hetero should be stopped immediately if clinical signs, symptoms or laboratory abnormalities suggestive of pancreatitis occur.

Lactic acidosis: lactic acidosis, usually associated with hepatomegaly and hepatic steatosis, has been reported with the use of nucleoside analogues. Early symptoms (symptomatic hyperlactataemia) include benign digestive symptoms (nausea, vomiting and abdominal pain), non-specific malaise, loss of appetite, weight loss, respiratory symptoms (rapid and/or deep breathing) or neurological symptoms (including motor weakness).

Lactic acidosis has a high mortality and may be associated with pancreatitis, liver failure, or renal failure.

Lactic acidosis generally occurred after a few or several months of treatment.

Treatment with nucleoside analogues should be discontinued in the setting of symptomatic

hyperlactataemia and metabolic/lactic acidosis, progressive hepatomegaly, or rapidly elevating aminotransferase levels.

Caution should be exercised when administering 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.

Patients at increased risk should be followed closely.

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 HIV-negative infants exposed in utero and/or post-natally to nucleoside analogues. The main adverse events reported are haematological disorders (anaemia, neutropenia), metabolic disorders (hyperlactataemia, hyperlipasaemia). These events are often transitory. Some late-onset neurological disorders have been reported (hypertonia, convulsion, abnormal behaviour). Whether the neurological disorders are transient or permanent is currently unknown. Any child exposed in utero to nucleoside and nucleotide analogues, even HIV-negative children, should have clinical and laboratory follow-up and should be fully investigated for possible mitochondrial dysfunction in case of relevant signs or symptoms. These findings do not affect current national recommendations to use antiretroviral therapy in pregnant women to prevent vertical transmission of HIV.

Lipodystrophy: Combination antiretroviral therapy has been associated with the redistribution of body fat (lipodystrophy) in HIV patients. The long-term consequences of these events are currently unknown. Knowledge about the mechanism is incomplete. A connection between visceral lipomatosis and protease inhibitors (PIs) and lipoatrophy and nucleoside reverse transcriptase inhibitors (NRTIs) has been hypothesised. A higher risk of lipodystrophy has been associated with individual factors such as older age, and with drug related factors such as longer duration of antiretroviral treatment and associated metabolic disturbances. Clinical examination should include evaluation for physical signs of fat redistribution. Consideration should be given to the measurement of fasting serum lipids and blood glucose. Lipid disorders should be managed as clinically appropriate (see section 4.8).

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 jirovecii pneumonia. Any inflammatory symptoms should be evaluated and treatment instituted when necessary.

Liver disease: If lamivudine is being used concomitantly for the treatment of HIV and HBV, additional information relating to the use of lamivudine in the treatment of hepatitis B infection is available in the Lamivudine Hetero 100 mg SPC.

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 Hetero 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 (see Lamivudine Hetero 100 mg SPC).

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 (see section 4.8).

Osteonecrosis: Although the etiology 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.

Lamivudine Hetero 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 (see section 4.5). Fructose intolerance:

Patients with rare hereditary problems of fructose intolerance should not take this medicine.

4.5 Interaction with other medicinal products and other forms of interaction

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 clearance.

Administration of trimethoprim/sulfamethoxazole 160 mg/800 mg results in a 40 % 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 (see section 4.2). 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 jirovecii 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 or zidovudine) are not eliminated by this mechanism and are unlikely to interact with lamivudine.

A modest increase in C_max (28 %) 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 (see section 5.2).

Lamivudine metabolism does not involve CYP3A, making interactions with medicinal products metabolised by this system (e.g. PIs) unlikely.

Cladribine: 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 (see section 4.4).

4.6 Fertility, pregnancy and lactation

Pregnancy

A large amount of data on pregnant women (more than 1000 pregnancy outcomes) indicate no malformative toxicity of lamivudine. Lamivudine Hetero can be used during pregnancy if clinically needed.

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. There have been reports of mitochondrial dysfunction in infants exposed in utero and/or post-natally to nucleoside analogues (see section 4.4).

Breastfeeding

Following oral administration lamivudine was excreted in breast milk at similar concentrations to those found in serum. Since lamivudine and the virus pass into breast milk, it is recommended that mothers taking Lamivudine Hetero do not breastfeed their infants. It is recommended that HIV infected women do not breast-feed their infants under any circumstances in order to avoid transmission of HIV.

4.7 Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been performed.

4.8 Undesirable effects

The following adverse reactions have been reported during therapy for HIV disease with lamivudine.

The adverse reactions considered at least possibly related to the treatment are listed below by body system, organ class and absolute frequency. Frequencies are defined as very common (>1/10), common (>1/100 to <1/10), uncommon (>1/1,000 to <1/100), rare (>1/10,000 to <1/1,000), very rare (<1/10,000). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Blood and lymphatic systems disorders

Uncommon: Neutropenia and anaemia (both occasionally severe), thrombocytopenia

Very rare: Pure red cell aplasia

Nervous system disorders

Common: Headache, insomnia

Very rare: peripheral neuropathy (or paraesthesia)

Respiratory, thoracic and mediastinal disorders Common: Cough nasal symptoms Gastrointestinal disorders

Common: Nausea, vomiting, abdominal pain or cramps, diarrhoea Rare: Pancreatitis, elevations in serum amylase Hepatobiliary disorders

Uncommon: Transient elevations in liver enzymes (AST, ALT).

Rare: Hepatitis

Skin and subcutaneous tissue disorders Common: Rash, alopecia Rare: Angioedema

Musculoskeletal and connective tissue disorders Common: Arthralgia, muscle disorders Rare: Rhabdomyolysis

General disorders and administration site conditions Common: Fatigue, malaise, fever

Cases of lactic acidosis, sometimes fatal, usually associated with severe hepatomegaly and hepatic steatosis, have been reported with the use of nucleoside analogues (see section 4.4).

Combination antiretroviral therapy has been associated with redistribution of body fat (lipodystrophy) in HIV patients including the loss of peripheral and facial subcutaneous fat, increased intra-abdominal and visceral fat, breast hypertrophy and dorsocervical fat accumulation (buffalo hump).

Combination antiretroviral therapy has been associated with metabolic abnormalities such as hypertriglyceridaemia, hypercholesterolaemia, insulin resistance, hyperglycaemia and hyperlactataemia (see section 4.4).

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 (see section 4.4).

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 (see section 4.4).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via Yellow Card Scheme (www.mhra.gov.uk/yellowcard).

4.9 Overdose

Administration of lamivudine at very high dose levels in acute animal studies did not result in any organ toxicity. 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 overdosage 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 overdosage, although this has not been studied.

5    PHARMACOLOGICAL PROPERTIES

5.1    Pharmacodynamic properties

Pharmacotherapeutic group: nucleoside analogue, ATC Code: J05AF05.

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. Lamivudine in combination with zidovudine exhibits synergistic anti-HIV activity against clinical isolates in cell culture.

HIV-1 resistance to lamivudine involves the development of a M184V amino acid change close to the active site of the viral reverse transcriptase (RT). This variant arises both in vitro and in HIV-1 infected patients treated with lamivudine-containing antiretroviral therapy. M184V mutants display greatly reduced susceptibility to lamivudine and show diminished viral replicative capacity in vitro. In vitro studies indicate that zidovudine-resistant virus isolates can become zidovudine sensitive when they simultaneously acquire resistance to lamivudine. The clinical relevance of such findings remains, however, not well defined.

In vitro data tend to suggest that the continuation of lamivudine in anti-retroviral regimen despite the development of M184V might provide residual anti-retroviral activity (likely through impaired viral fitness). The clinical relevance of these findings is not established. Indeed, the available clinical data are very limited and preclude any reliable conclusion in the field. In any case, initiation of susceptible NRTI’s should always be preferred to maintenance of lamivudine therapy. Therefore, maintaining lamivudine therapy despite emergence of M184V mutation should only be considered in cases where no other active NRTI’s are available.

Cross-resistance conferred by the M184V RT is limited within the nucleoside inhibitor class of antiretroviral agents. Zidovudine and stavudine maintain their antiretroviral activities against lamivudine-resistant HIV-1. Abacavir maintains its antiretroviral activities against lamivudine-resistant HIV-1 harbouring only the M184V mutation. The M184V RT mutant shows a <4-fold decrease in susceptibility to didanosine; the clinical significance of these findings is unknown. In vitro susceptibility testing has not been standardised and results may vary according to methodological factors.

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.

Clinical experience:

In clinical trials, lamivudine in combination with zidovudine has been shown to reduce HIV-1 viral load and increase CD4 cell count. Clinical end-point data indicate that lamivudine in combination with zidovudine, results in a significant reduction in the risk of disease progression and mortality.

Evidence from clinical studies shows that lamivudine plus zidovudine delays the emergence of zidovudine resistant isolates in individuals with no prior antiretroviral therapy.

Lamivudine has been widely used as a component of antiretroviral combination therapy with other antiretroviral agents of the same class (NRTIs) or different classes (PIs, non-nucleoside reverse transcriptase inhibitors).

Multiple drug antiretroviral therapy containing lamivudine has been shown to be effective in antiretrovirally-naive patients as well as in patients presenting with viruses containing the M184V mutations.

The relationship between in vitro susceptibility of HIV to lamivudine and clinical response to lamivudine-containing therapy remains under investigation.

Lamivudine at a dose of 100 mg once daily has also been shown to be effective for the treatment of adult patients with chronic HBV infection (for details of clinical studies, see the prescribing information for Lamivudine Hetero 100 mg). However, for the treatment of HIV infection only a 300 mg daily dose of lamivudine (in combination with other antiretroviral agents) has been shown to be efficacious.

Lamivudine has not been specifically investigated in HIV patients co-infected with HBV.

Once daily dosing (300 mg once a day): a clinical study has demonstrated the noninferiority between lamivudine 300 mg once a day and lamivudine 150 mg twice a day containing regimens. These results were obtained in an antiretroviral naive-population, primarily consisting of asymptomatic HIV infected patients (CDC stage A).

5.2 Pharmacokinetic properties

Absorption

Lamivudine is well absorbed from the gastrointestinal tract, and the bioavailability of oral lamivudine in adults is normally between 80 and 85 %. Following oral administration, the mean time (t_max) to maximal serum concentrations (C_max) is about an hour. Based on data derived from a study in healthy volunteers, at a therapeutic dose of 150mg twice daily, mean (CV) steady-state C_max and C_min of lamivudine in plasma are 1.2 frg/ml (24 %) and 0.09 frg/ml (27 %), respectively. The mean (CV) AUC over a dosing interval of 12 hours is 4.7 frg.h/ml (18 %). At a therapeutic dose of 300mg once daily, the mean (CV) steady-state C_max, C_min and 24 h AUC are 2.0 gg/ml (26 %), 0.04 frg/ml (34 %) and 8.9 frg.h/ml (21 %), respectively.

The 150 mg tablet is bioequivalent and dose proportional to the 300 mg tablet with respect to AUC*, C_max, and W.

Co-administration of lamivudine with food results in a delay of C_ax and a lower C_max (decreased by 47 %). However, the extent (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.

Co-administration of zidovudine results in a 13 % increase in zidovudine exposure and a 28 % increase in peak plasma levels. This is not considered to be of significance to patient safety and therefore no dosage adjustments are necessary.

Distribution

From intravenous studies, 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 (< 16 % - 36 % to serum albumin in in vitro studies).

Limited data show that lamivudine penetrates the central nervous system and reaches the cerebrospinal fluid (CSF). The mean ratio CSF/serum lamivudine concentration 2-4 hours after oral administration was approximately 0.12. The true extent of penetration or relationship with any clinical efficacy is unknown.

Metabolism

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). In 60 healthy adult volunteers, lamivudine 300 mg once daily has been demonstrated to be pharmacokinetically equivalent at steady-state to lamivudine 150 mg twice daily with respect to intracellular triphosphate AUC₂₄ and C_max.

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.

Elimination

Studies in patients with renal impairment show 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 section (see section 4.2).

An interaction with trimethoprim, a constituent of co-trimoxazole, causes a 40 % increase in lamivudine exposure at therapeutic doses. This does not require dose adjustment unless the patient also has renal impairment (see sections 4.5 and 4.2). Administration of co-trimoxazole with lamivudine in patients with renal impairment should be carefully assessed.

Pharmacokinetics in children: In general, lamivudine pharmacokinetics in paediatric patients is similar to adults. However, absolute bioavailability (approximately 55-65 %) was reduced in paediatric patients below 12 years of age. In addition, systemic clearance values were greater in younger paediatric patients and decreased with age, approaching adult values around 12 years of age. Due to these differences, the recommended dose for lamivudine in children (aged more than three months and weighing less than 30 kg) is 4 mg/kg twice daily. This dose will achieve an average AUC_0-12 ranging from approximately 3,800 to 5,300 ng.h/ml. Recent findings indicate that exposure in children < 6 years of age may be reduced by about 30 % compared with other age groups. Further data addressing this issue are currently awaited. At present, the available data do not suggest that lamivudine is less efficacious in this age group.

There are limited pharmacokinetic data for patients less than three months of age. In neonates one week of age, lamivudine oral clearance was reduced when compared to paediatric patients and is likely to be due to immature renal function and variable absorption. Therefore to achieve similar adult and paediatric exposure, the recommended dose for neonates is 4 mg/kg/day. Glomerular filtration estimates suggests that to achieve similar adult and paediatric exposure, the recommended dose for children aged six weeks and older could be 8 mg/kg/day.

Pharmacokinetics in pregnancy: Following oral administration, lamivudine pharmacokinetics in late-pregnancy were similar to non-pregnant women.

5.3 Preclinical safety data

Administration of lamivudine in animal toxicity studies at high doses was not associated with any major organ toxicity. At the highest dosage levels, minor effects on indicators of liver and kidney function were seen together with occasional reductions in liver weight. The clinically relevant effects noted were a reduction in red blood cell count and neutropenia.

Lamivudine was not mutagenic in bacterial tests but, like many nucleoside analogues, showed activity in an in vitro cytogenetic assay and the mouse lymphoma assay. Lamivudine was not genotoxic in vivo at doses that gave plasma concentrations around 40-50 times higher than the anticipated clinical plasma levels. As the in vitro mutagenic activity of lamivudine could not be confirmed in in vivo tests, it is concluded that lamivudine should not represent a genotoxic hazard to patients undergoing treatment.

A transplacental genotoxicity study conducted in monkeys compared zidovudine alone with the combination of zidovudine and lamivudine at human-equivalent exposures. The study demonstrated that foetuses exposed in utero to the combination sustained a higher level of nucleoside analogue- DNA incorporation into multiple foetal organs, and showed evidence of more telomere shortening than in those exposed to zidovudine alone. The clinical significance of these findings is unknown.

The results of long-term carcinogenicity studies in rats and mice did not show any carcinogenic potential relevant for humans.

PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Tablet core:

Isomalt (E953) Crospovidone A Magnesium stearate (E572) Tablet film coat: Hypromellose (E464) Titanium dioxide (E171) Macrogol 400 Polysorbate 80 (E433)

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

30 months.

Shelf life after first opening the HDPE container is 3 months.

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

Alu/PVC-Alu-OPA blister pack - 30 tablets

HDPE container with child resistant polypropylene cap - 30 tablets

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

Any unused product or waste material should be disposed of in accordance with local requirements.

7 MARKETING AUTHORISATION HOLDER

Hetero Europe S.L.

Viladecans Business Park - Edificio Brasil

Catalunya 83-85

08840 Viladecans (Barcelona)

Spain

8    MARKETING AUTHORISATION NUMBER(S)

PL No. 37222/0016

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE

AUTHORISATION

10 DATE OF REVISION OF THE TEXT