LAMIVUDINA TEVA PHARMA B.V 300mg tablets medication leaflet

Lamivudine Teva Pharma B.V. 150 mg film-coated tablets

Lamivudine Teva Pharma B.V. 300 mg film-coated tablets

Lamivudine Teva Pharma B.V. 150 mg film-coated tablets

Each film-coated tablet contains 150 mg lamivudine.

Lamivudine Teva Pharma B.V. 300 mg film-coated tablets

Each film-coated tablet contains 300 mg lamivudine.

For the full list of excipients, see section 6.1.

Film-coated tablet

Lamivudine Teva Pharma B.V. 150 mg film-coated tablets

Light grey, diamond shaped, biconvex film-coated tablet with approx. 14.5 mm length and 7.0 mmwidth - engraved with “L 150” and breakline on one side and breakline on the other.

The tablet can be divided into equal doses.

Lamivudine Teva Pharma B.V. 300 mg film-coated tablets

Grey, diamond shaped, biconvex film-coated tablet with approx. 18.0 mm length and 8.0 mm width -engraved with “L 300” on one side and plain on the other

Lamivudine Teva Pharma B.V. is indicated as part of antiretroviral combination therapy for thetreatment of Human Immunodeficiency Virus (HIV) infected adults and children.

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

Lamivudine is also available as an oral solution for children over three months of age and who weighless than 14 kg or for patients who are unable to swallow tablets (see section 4.4).

Patients changing between lamivudine oral solution and lamivudine tablets should follow the dosingrecommendations that are specific for the formulation (see section 5.2)

Adults, adolescents and children (weighing at least 25 kg)

The recommended dose of lamivudine is 300 mg daily. This may be administered as either 150 mgtwice daily or 300 mg once daily (see section 4.4).

The 300 mg tablet is only suitable for the once a day regimen.

Children (weighing less than 25 kg)

Dosing according to weight bands is recommended for Lamivudine Teva Pharma B.V. tablets.

Children weighing ≥20 kg to <25 kg: The recommended dose is 225 mg daily. This may beadministered as either 75 mg (one-half of a 150 mg tablet) taken in the morning and 150 mg (onewhole 150 mg tablet) taken in the evening, or 225 mg (one and a half 150 mg tablets) taken once daily.

Children weighing 14 kg to <20 kg: The recommended dose is 150 mg daily. This may beadministered as 75 mg (one-half of a 150 mg tablet) taken twice daily, or 150 mg (one whole 150 mgtablet) taken once daily.

Children from three months of age: As an accurate dosage cannot be achieved with the 300 mg non-scored tablet formulation in this patient population, it is recommended that the Lamivudine Teva

Pharma B.V. 150 mg scored tablet formulation is used and the corresponding recommended dosageinstructions are followed.

Children less than three months of age: The limited data available are insufficient to propose specificdosage recommendations (see section 5.2).

Patients changing from the twice daily dosing regimen to the once daily dosing regimen should takethe recommended once daily dose (as described above) approximately 12 hours after the last twicedaily dose, and then continue to take the recommended once daily dose (as described above)approximately every 24 hours. When changing back to a twice daily regimen, patients should take therecommended twice daily dose approximately 24 hours after the last once daily dose.

Older people: No specific data are available; however, special care is advised in this age group due toage-associated changes such as the decrease in renal function and alteration of haematologicalparameters.

Renal impairment: Lamivudine concentrations are increased in patients with moderate - severe renalimpairment due to decreased clearance. The dose should therefore be adjusted, using an oral solutionpresentation of lamivudine for patients whose creatinine clearance falls below 30 ml/min (see tables).

Dosing recommendations - Adults, adolescents and children (weighing at least 25 kg):

Creatinine clearance (ml/min) First dose Maintenance dose≥50 300 mg 300 mg once dailyor or150 mg 150 mg twice daily30-<50 150 mg 150 mg once daily<30 As doses below 150 mg are needed the use ofan oral solution is recommended15 to <30 150 mg 100 mg once daily5 to <15 150 mg 50 mg once daily<5 50 mg 25 mg once daily

There are no data available on the use of lamivudine in children with renal impairment. Based on theassumption that creatinine clearance and lamivudine clearance are correlated similarly in children as inadults it is recommended that the dosage in children with renal impairment be reduced according totheir creatinine clearance by the same proportion as in adults. A 10 mg/mL oral solution may be themost appropriate formulation to achieve the recommended dose in children with renal impairmentaged at least 3 months and weighing less than 25kg.

Dosing recommendations - Children aged at least 3 months and weighing less than 25 kg:

Creatinine clearance (ml/min) First dose Maintenance dose≥50 10 mg/kg 10 mg/kg once dailyor or5 mg/kg 5 mg/kg twice daily30 to<50 5 mg/kg 5 mg/kg once daily15 to <30 5 mg/kg 3.3 mg/kg once daily5 to <15 5 mg/kg 1.6 mg/kg once daily<5 1.6 mg/kg 0.9 mg/kg once daily

Hepatic impairment: Data obtained in patients with moderate to severe hepatic impairment shows thatlamivudine pharmacokinetics are not significantly affected by hepatic dysfunction. Based on thesedata, no dose adjustment is necessary in patients with moderate or severe hepatic impairment unlessaccompanied by renal impairment.

Lamivudine Teva Pharma B.V. may be administered with or without food.

To ensure the administration of the entire dose, the tablet(s) should ideally be swallowed withoutcrushing.

Alternatively, for patients who are unable to swallow tablets, the tablet(s) may be crushed and addedto a small amount of semi-solid food or liquid, all of which should be consumed immediately (seesection 5.2).

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

Lamivudine Teva Pharma B.V. is not recommended for use as monotherapy.

Renal impairment: In patients with moderate to severe renal impairment, the terminal plasma half-lifeof lamivudine is increased due to decreased clearance; therefore the dose should be adjusted (seesection 4.2).

Triple nucleoside therapy: There have been reports of a high rate of virological failure and ofemergence of resistance at an early stage when lamivudine was combined with tenofovir disoproxilfumarate and abacavir as well as with tenofovir disoproxil fumarate and didanosine as a once dailyregimen.

Opportunistic infections: Patients receiving Lamivudine Teva Pharma B.V. or any other antiretroviraltherapy may continue to develop opportunistic infections and other complications of HIV infection,and therefore should remain under close clinical observation by physicians experienced in thetreatment of patients with associated HIV diseases.

Pancreatitis: Cases of pancreatitis have occurred rarely. However, it is not clear whether these caseswere due to the antiretroviral treatment or to the underlying HIV disease. Treatment with Lamivudine

Teva Pharma B.V. should be stopped immediately if clinical signs, symptoms or laboratoryabnormalities suggestive of pancreatitis occur.

Mitochondrial dysfunction following exposure in utero: Nucleoside and nucleotide analogues mayimpact mitochondrial function to a variable degree, which is most pronounced with stavudine,didanosine and zidovudine. There have been reports of mitochondrial dysfunction in HIV-negativeinfants exposed in utero and/or post-natally to nucleoside analogues; these have predominantlyconcerned treatment with regimens containing zidovudine. The main adverse reactions reported arehaematological disorders (anaemia, neutropenia) and metabolic disorders (hyperlactatemia,hyperlipasemia). These events have often been transitory. Late-onset neurological disorders have beenreported rarely (hypertonia, convulsion, abnormal behaviour). Whether such neurological disorders aretransient or permanent is currently unknown. These findings should be considered for any childexposed in utero to nucleoside and nucleotide analogues, who presents with severe clinical findings ofunknown etiology, particularly neurologic findings. These findings do not affect current nationalrecommendations to use antiretroviral therapy in pregnant women to prevent vertical transmission of

HIV.

Weight and metabolic parameters: An increase in weight and in levels of blood lipids and glucose mayoccur during antiretroviral therapy. Such changes may in part be linked to disease control and lifestyle. For lipids, there is in some cases evidence for a treatment effect, while for weight gain there isno strong evidence relating this to any particular treatment. For monitoring of blood lipids and glucosereference is made to established HIV treatment guidelines. Lipid disorders should be managed asclinically appropriate.

Immune Reactivation Syndrome: In HIV-infected patients with severe immune deficiency at the timeof institution of combination antiretroviral therapy (CART), an inflammatory reaction toasymptomatic or residual opportunistic pathogens may arise and cause serious clinical conditions, oraggravation of symptoms. Typically, such reactions have been observed within the first few weeks ormonths of initiation of CART. Relevant examples are cytomegalovirus retinitis, generalised and/orfocal mycobacterium infections, and Pneumocystis jirovecii pneumonia (often referred to as PCP).

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

Autoimmune disorders (such as Graves’ disease and autoimmune hepatitis) have also been reported tooccur in the setting of immune reactivation; however, the reported time to onset is more variable andthese events can occur many months after initiation of treatment.

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 isavailable in the lamivudine 100 mg SmPC.

Patients with chronic hepatitis B or C and treated with combination antiretroviral therapy are at anincreased risk of severe and potentially fatal hepatic adverse events. In case of concomitant antiviraltherapy for hepatitis B or C, please refer also to the relevant product information for these medicinalproducts.

If Lamivudine Teva Pharma B.V. is discontinued in patients co-infected with hepatitis B virus,periodic monitoring of liver function tests and markers of HBV replication is recommended, aswithdrawal of lamivudine may result in an acute exacerbation of hepatitis (see lamivudine 100 mg

SmPC).

Patients with pre-existing liver dysfunction, including chronic active hepatitis, have an increasedfrequency of liver function abnormalities during combination antiretroviral therapy, and should bemonitored according to standard practice. If there is evidence of worsening liver disease in suchpatients, interruption or discontinuation of treatment must be considered (see section 4.8).

Paediatric population: In a study performed in paediatric patients (see section 5.1 ARROW study),lower rates of virologic suppression and more frequent viral resistance were reported in childrenreceiving an oral solution of lamivudine as compared to those receiving the tablet formulation.

Whenever possible in children, lamivudine as tablet formulation should preferably be used.

Osteonecrosis: Although the etiology is considered to be multifactorial (including corticosteroid use,alcohol consumption, severe immunosuppression, higher body mass index), cases of osteonecrosishave been reported particularly in patients with advanced HIV-disease and/or long-term exposure tocombination antiretroviral therapy (CART). Patients should be advised to seek medical advice if theyexperience joint aches and pain, joint stiffness or difficulty in movement.

Drug Interactions: Lamivudine Teva Pharma B.V. should not be taken with any other medicinalproducts containing lamivudine or medicinal products containing emtricitabine (see section 4.5).

The combination of lamivudine with cladribine is not-recommended (see section 4.5).

Excipient(s)

This medicine contains less than 1 mmol sodium (23 mg) per film-coated tablet, that is to sayessentially “sodium-free”.

The likelihood of metabolic interactions is low due to limited metabolism and plasma protein bindingand almost complete renal clearance.

Administration of trimethoprim/sulfamethoxazole 160 mg/800 mg results in a 40% increase inlamivudine exposure, because of the trimethoprim component; the sulfamethoxazole component didnot interact. However, unless the patient has renal impairment, no dosage adjustment of lamivudine isnecessary (see section 4.2). Lamivudine has no effect on the pharmacokinetics of trimethoprim orsulfamethoxazole. When concomitant administration is warranted, patients should be monitoredclinically. 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 beconsidered, particularly when the main route of elimination is active renal secretion via the organiccationic transport system e.g. trimethoprim. Other medicinal products (e.g. ranitidine, cimetidine) areeliminated only in part by this mechanism and were shown not to interact with lamivudine. Thenucleoside analogues (e.g. didanosine) like zidovudine, are not eliminated by this mechanism and areunlikely to interact with lamivudine.

A modest increase in Cmax (28%) was observed for zidovudine when administered with lamivudine,however overall exposure (AUC) is not significantly altered. Zidovudine has no effect on thepharmacokinetics of lamivudine (see section 5.2).

Due to similarities, Lamivudine Teva Pharma B.V. should not be administered concomitantly withother cytidine analogues, such as emtricitabine. Moreover, Lamivudine Teva Pharma B.V. should notbe taken with any other medicinal products containing lamivudine (see section 4.4).

In vitro lamivudine inhibits the intracellular phosphorylation of cladribine leading to a potential risk ofcladribine loss of efficacy in case of combination in the clinical setting. Some clinical findings alsosupport a possible interaction between lamivudine and cladribine. Therefore, the concomitant use oflamivudine with cladribine is not recommended (see section 4.4).

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

Coadministration of sorbitol solution (3.2 g, 10.2 g, 13.4 g) with a single 300 mg dose of lamivudineoral solution resulted in dose-dependent decreases of 14%, 32%, and 36% in lamivudine exposure(AUC∞) and 28%, 52%, and 55% in the Cmax of lamivudine in adults. When possible, avoid chroniccoadministration of Lamivudine Teva Pharma B.V. with medicinal products containing sorbitol orother osmotic acting poly-alcohols or monosaccharide alcohols (e.g. xylitol, mannitol, lactitol,maltitol). Consider more frequent monitoring of HIV-1 viral load when chronic coadministrationcannot be avoided.

Interaction studies have only been performed in adults.

As a general rule, when deciding to use antiretroviral agents for the treatment of HIV infection inpregnant 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.

Animal studies with lamivudine showed an increase in early embryonic deaths in rabbits but not in rats(see section 5.3). Placental transfer of lamivudine has been shown to occur in humans.

More than 1000 outcomes from first trimester and more than 1000 outcomes from second and thirdtrimester exposure in pregnant women indicate no malformative and foeto/neonatal effect. Lamivudine

Teva Pharma B.V. can be used during pregnancy if clinically needed. The malformative risk isunlikely in humans based on those data.

For patients co-infected with hepatitis who are being treated with lamivudine and subsequentlybecome pregnant, consideration should be given to the possibility of a recurrence of hepatitis ondiscontinuation of lamivudine.

Mitochondrial dysfunction: Nucleoside and nucleotide analogues have been demonstrated in vitro andin vivo to cause a variable degree of mitochondrial damage. There have been reports of mitochondrialdysfunction in infants exposed in utero and/or post-natally to nucleoside analogues (see section 4.4).

Following oral administration lamivudine was excreted in breast milk at similar concentrations tothose found in serum. Based on more than 200 mother/child pairs treated for HIV, serumconcentrations of lamivudine in breastfed infants of mothers treated for HIV are very low (<4% ofmaternal serum concentrations) and progressively decrease to undetectable levels when breastfedinfants reach 24 weeks of age. There are no data available on the safety of lamivudine whenadministered to babies less than three months old. It is recommended that women living with HIV donot breast-feed their infants in order to avoid transmission of HIV.

Studies in animals showed that lamivudine had no effect on fertility (see section 5.3).

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

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 bodysystem, 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 decreasingseriousness.

Blood and lymphatic systems disorders

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

Very rare: Pure red cell aplasia.

Very rare: Lactic acidosis.

Common: Headache, insomnia.

Very rare: Peripheral neuropathy (or paraesthesia).

Common: Cough, nasal symptoms.

Common: Nausea, vomiting, abdominal pain or cramps, diarrhoea.

Rare: Pancreatitis, elevations in serum amylase.

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

Rare: Hepatitis.

Common: Rash, alopecia.

Rare: Angioedema.

Common: Arthralgia, muscle disorders.

Rare: Rhabdomyolysis.

Common: Fatigue, malaise, fever.

Weight and levels of blood lipids and glucose may increase during antiretroviral therapy (see section4.4)

In HIV-infected patients with severe immune deficiency at the time of initiation of combinationantiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunisticinfections may arise. Autoimmune disorders (such as Graves’ disease and autoimmune hepatitis) havealso been reported to occur in the setting of immune reactivation; however, the reported time to onsetis more variable and these events can occur many months after initiation of treatment (see section 4.4).

Cases of osteonecrosis have been reported, particularly in patients with generally acknowledged riskfactors, advanced HIV disease or long-term combined antiretroviral exposure (CART). The frequencyof which is unknown (see section 4.4).

Paediatric population1206 HIV-infected paediatric patients aged 3 months to 17 years were enrolled in the ARROW Trial(COL105677), 669 of whom received abacavir and lamivudine either once or twice daily (see section5.1). No additional safety issues have been identified in paediatric subjects receiving either once ortwice daily dosing compared to adults.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Administration of lamivudine at very high dose levels in acute animal studies did not result in anyorgan toxicity. No specific signs or symptoms have been identified following acute overdose withlamivudine, apart from those listed as undesirable effects.

If overdosage occurs the patient should be monitored, and standard supportive treatment applied asrequired. Since lamivudine is dialysable, continuous haemodialysis could be used in the treatment ofoverdosage, although this has not been studied.

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, lamivudine5’-triphosphate. Its main mode of action is as a chain terminator of viral reverse transcription. Thetriphosphate has selective inhibitory activity against HIV-1 and HIV-2 replication in vitro, it is alsoactive against zidovudine-resistant clinical isolates of HIV. No antagonistic effects in vitro were seenwith lamivudine and other anti retrovirals (tested agents: abacavir, didanosine, nevirapine andzidovudine).

HIV-1 resistance to lamivudine involves the development of a M184V amino acid change close to theactive site of the viral reverse transcriptase (RT). This variant arises both in vitro and in HIV-1infected patients treated with lamivudine-containing antiretroviral therapy. M184V mutants displaygreatly reduced susceptibility to lamivudine and show diminished viral replicative capacity in vitro. Invitro studies indicate that zidovudine-resistant virus isolates can become zidovudine sensitive whenthey 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 thedevelopment of M184V might provide residual anti-retroviral activity (likely through impaired viralfitness). The clinical relevance of these findings is not established. Indeed, the available clinical dataare 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, maintaininglamivudine therapy despite emergence of M184V mutation should only be considered in cases whereno other active NRTI’s are available.

Cross-resistance conferred by the M184V RT is limited within the nucleoside inhibitor class ofantiretroviral agents. Zidovudine and stavudine maintain their antiretroviral activities againstlamivudine-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-folddecrease in susceptibility to didanosine; the clinical significance of these findings is unknown. In vitrosusceptibility testing has not been standardised and results may vary according to methodologicalfactors.

Lamivudine demonstrates low cytotoxicity to peripheral blood lymphocytes, to establishedlymphocyte and monocyte-macrophage cell lines, and to a variety of bone marrow progenitor cells invitro.

In clinical trials, lamivudine in combination with zidovudine has been shown to reduce HIV-1 viralload and increase CD4 cell count. Clinical end-point data indicate that lamivudine in combination withzidovudine, 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 ofzidovudine resistant isolates in individuals with no prior antiretroviral therapy.

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

Clinical trial evidence from paediatric patients receiving lamivudine with other antiretroviral drugs(abacavir, nevirapine/efavirenz or zidovudine) has shown that the resistance profile observed inpaediatric patients is similar to that observed in adults, in terms of the genotypic substitutions detectedand their relative frequency.

Children receiving lamivudine oral solution concomitantly with other antiretroviral oral solutions inclinical trials developed viral resistance more frequently than children receiving tablets (see thedescription of the clinical experience in paediatric population (ARROW study) and section 5.2).

Multiple drug antiretroviral therapy containing lamivudine has been shown to be effective inantiretrovirally-naive patients as well as in patients presenting with viruses containing the M184Vmutations.

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

Lamivudine at a dose of 100 mg once daily has also been shown to be effective for the treatment ofadult patients with chronic HBV infection (for details of clinical studies, see the prescribinginformation for lamivudine 100 mg). However, for the treatment of HIV infection only a 300 mg dailydose 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 non-inferiority betweenlamivudine once a day and lamivudine twice a day containing regimens. These results were obtainedin an antiretroviral naïve-population, primarily consisting of asymptomatic HIV infected patients(CDC stage A).

Paediatric population: a randomised comparison of a regimen including once daily vs twice dailydosing of abacavir and lamivudine was undertaken within a randomised, multicentre, controlled studyof HIV-infected, paediatric patients. 1206 paediatric patients aged 3 months to 17 years enrolled in the

ARROW Trial (COL105677) and were dosed according to the weight-band dosing recommendationsin the World Health Organisation treatment guidelines (Antiretroviral therapy of HIV infection ininfants and children, 2006). After 36 weeks on a regimen including twice daily abacavir andlamivudine, 669 eligible subjects were randomised to either continue twice daily dosing or switch toonce daily abacavir and lamivudine for at least 96 weeks. Of note, from this study clinical data werenot available for children under one year old. The results are summarised in the table below:

Virological Response Based on Plasma HIV-1 RNA less than 80 copies/ml at Week 48 and Week96 in the Once Daily versus Twice Daily abacavir + lamivudine randomisation of ARROW(Observed Analysis)

Twice Daily Once Daily

N (%) N (%)

Week 0 (After ≥36 Weeks on Treatment)

Plasma HIV-1 RNA 250/331 (76) 237/335 (71)<80 c/mL

Risk difference (once -4.8% (95% CI -11.5% to +1.9%), p=0.16daily-twice daily)

Week 48

Plasma HIV-1 RNA 242/331 (73) 236/330 (72)<80 c/mL

Risk difference (once -1.6% (95% CI -8.4% to +5.2%), p=0.65daily-twice daily)

Week 96

Plasma HIV-1 RNA 234/326 (72) 230/331 (69)<80 c/mL

Risk difference (once -2.3% (95% CI -9.3% to +4.7%), p=0.52daily-twice daily)

In a pharmacokinetic study (PENTA 15), four virologically controlled subjects less than 12 months ofage switched from abacavir plus lamivudine oral solution twice daily to a once daily regimen. Threesubjects had undetectable viral load and one had plasmatic HIV-RNA of 900 copies/ml at Week 48.

No safety concerns were observed in these subjects.

The abacavir + lamivudine once daily dosing group was demonstrated to be non-inferior to the twicedaily group according to the pre-specified non-inferiority margin of -12%, for the primary endpoint of<80 c/mL at Week 48 as well as at Week 96 (secondary endpoint) and all other thresholds tested(<200 c/mL, <400 c/mL, <1000 c/mL), which all fell well within this non-inferiority margin.

Subgroup analyses testing for heterogeneity of once vs twice daily demonstrated no significant effectof sex, age, or viral load at randomisation. Conclusions supported non-inferiority regardless ofanalysis method.

At the time of randomization to once daily vs twice daily dosing (Week 0), those patients who hadreceived tablet formulations had a higher rate of viral load suppression than those who had receivedany solution formulations at any time. These differences were observed in each different age groupstudied. This difference in suppression rates between tablets and solutions remained through Week 96with once daily dosing.

Proportions of Subjects in the Once Daily versus Twice Daily Abacavir+Lamivudine

Randomisation of ARROW with Plasma HIV-1 RNA <80 copies/ml: Subgroup Analysis by

Formulation

Twice Daily Once Daily

Plasma HIV-1 RNA Plasma HIV-1 RNA<80 c/ml: <80 c/ml:n/N (%) n/N (%)

Week 0 (after 36 weeks on treatment)

Any solution regimen at any time 14/26 (54) 15/30 (50)

All tablet based regimen throughout 236/305 (77) 222/305 (73)

Week 96

Any solution regimen at any time 13/26 (50) 17/30 (57)

All tablet based regimen throughout 221/300 (74) 213/301 (71)

Genotypic resistance analyses were conducted on samples with plasma HIV-1 RNA >1000 copies/ml.

More cases of resistance were detected among patients who had received lamivudine solution, incombination with other antiretroviral solutions, compared with those who received similar doses oftablet formulation. This is consistent with the lower rates of antiviral suppression observed in thesepatients.

Lamivudine is well absorbed from the gastrointestinal tract, and the bioavailability of oral lamivudinein adults is normally between 80 and 85%. Following oral administration, the mean time (tmax) tomaximal serum concentrations (Cmax) is about an hour. Based on data derived from a study in healthyvolunteers, at a therapeutic dose of 150 mg twice daily, mean (CV) steady-state Cmax and Cmin oflamivudine in plasma are 1.2 µg/ml (24%) and 0.09 µg/ml (27%), respectively. The mean (CV) AUCover a dosing interval of 12 hours is 4.7 µg*h/ml (18%). At a therapeutic dose of 300 mg once daily,the mean (CV) steady-state Cmax, Cmin and 24h AUC are 2.0 µg/ml (26%), 0.04 µg/ml (34%) and8.9 µg*h/ml (21%), respectively.

The 150 mg tablet is bioequivalent and dose proportional to the 300 mg tablet with respect to AUC∞,

Cmax, and tmax. Administration of lamivudine tablets is bioequivalent to lamivudine oral solution withrespect to AUC∞ and Cmax in adults. Absorption differences have been observed between adult andpaediatric populations (see “Special populations”).

Co-administration of lamivudine with food results in a delay of tmax and a lower Cmax (decreased by47%). 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 beexpected to have an impact on the pharmaceutical quality, and would therefore not be expected to alterthe clinical effect. This conclusion is based on the physicochemical and pharmacokinetic dataassuming 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% increasein peak plasma levels. This is not considered to be of significance to patient safety and therefore nodosage adjustments are necessary.

From intravenous studies, the mean volume of distribution is 1.3 l/kg. The mean systemic clearance oflamivudine is approximately 0.32 l/h/kg, with predominantly renal clearance (>70%) via the organiccationic transport system.

Lamivudine exhibits linear pharmacokinetics over the therapeutic dose range and displays limitedbinding 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 cerebro-spinal fluid (CSF). The mean ratio CSF/serum lamivudine concentration 2-4 hours after oraladministration was approximately 0.12. The true extent of penetration or relationship with any clinicalefficacy is unknown.

The plasma lamivudine half-life after oral dosing is 18 to 19 hours and the active moiety, intracellularlamivudine triphosphate, has a prolonged terminal half-life in the cell (16 to 19 hours). In 60 healthyadult volunteers, lamivudine 300 mg once daily has been demonstrated to be pharmacokineticallyequivalent at steady-state to lamivudine 150 mg twice daily with respect to intracellular triphosphate

AUC24 and Cmax.

Lamivudine is predominately cleared unchanged by renal excretion. The likelihood of metabolicinteractions of lamivudine with other medicinal products is low due to the small extent of hepaticmetabolism (5-10%) and low plasma protein binding.

Studies in patients with renal impairment show lamivudine elimination is affected by renaldysfunction. A recommended dosage regimen for patients with creatinine clearance below 50 ml/minis shown in the dosage section (see section 4.2).

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

Children: The absolute bioavailability of lamivudine (approximately 58-66%) was reduced inpaediatric patients below 12 years of age. In children, administration of tablets given concomitantlywith other antiretroviral tablets delivered higher plasma lamivudine AUC∞ and Cmax than oral solutiongiven concomitantly with other antiretroviral oral solutions. Children receiving lamivudine oralsolution according to the recommended dosage regimen achieve plasma lamivudine exposure withinthe range of values observed in adults. Children receiving lamivudine oral tablets according to therecommended dosage regimen achieve higher plasma lamivudine exposure than children receivingoral solution because higher mg/kg doses are administered with the tablet formulation and the tabletformulation has higher bioavailability (see section 4.2). Paediatric pharmacokinetic studies with bothoral solution and tablet formulations have demonstrated that once daily dosing provides equivalent

AUC0-24 to twice daily dosing of the same total daily dose.

There are limited pharmacokinetic data for patients less than three months of age. In neonates oneweek of age, lamivudine oral clearance was reduced when compared to paediatric patients and is likelyto be due to immature renal function and variable absorption. Therefore, to achieve similar adult andpaediatric exposure, an appropriate dose for neonates is 4 mg/kg/day. Glomerular filtration estimatessuggests that to achieve similar adult and paediatric exposure, an appropriate dose for children agedsix weeks and older could be 8 mg/kg/day.

Pharmacokinetic data were derived from 3 pharmacokinetic studies (PENTA 13, PENTA 15 and

ARROW PK substudy) enrolling children under 12 years of age. The data are displayed in the tablebelow:

Summary of Stead-State Plasma Lamivudine AUC (0-24) (µg*h/mL) and Statistical

Comparisons for Once and Twice-Daily Oral Administration Across Studies

Lamivudine Lamivudine Once-Versus

Study Age Group 8 mg/kg Once- 4 mg/kg Twice- Twice-Daily

Daily Dosing Daily Dosing Comparison

Geometric Mean Geometric Mean GLS Mean Ratio(95% Cl) (95% Cl) (90% Cl)

ARROW PK 3 to 12 years 13.0 12.0 1.09

Substudy (N=35) (11.4,14.9) (10.7, 13.4) (0.979, 1.20)

Part 1

PENTA 13 2 to 12 years 9.80 8.88 1.12(N=19) (8.64, 11.1) (7.67, 10.3) (1.03, 1.21)

PENTA 15 3 to 36 months 8.66 9.48 0.91(N=17) (7.46, 10.1) (7.89, 11.40) (0.79, 1.06)

In PENTA 15 study, the geometric mean plasma lamivudine AUC(0-24) (95% CI) of the four subjectsunder 12 months of age who switch from a twice daily to a once daily regimen (see section 5.1) are10.31 (6.26, 17.0) µg*h/mL in the once-daily dosing and 9.24 (4.66, 18.3) µg*h/mL in the twice-dailydosing.

Pregnancy: Following oral administration, lamivudine pharmacokinetics in late-pregnancy weresimilar to non-pregnant women.

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

Lamivudine was not mutagenic in bacterial tests but, like many nucleoside analogues, showed activityin an in vitro cytogenetic assay and the mouse lymphoma assay. Lamivudine was not genotoxic in vivoat doses that gave plasma concentrations around 40-50 times higher than the anticipated clinicalplasma 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 undergoingtreatment.

A transplacental genotoxicity study conducted in monkeys compared zidovudine alone with thecombination of zidovudine and lamivudine at human-equivalent exposures. The study demonstratedthat 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 shorteningthan 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 carcinogenicpotential relevant for humans.

A fertility study in rats has shown that lamivudine had no effect on male or female fertility.

Microcrystalline cellulose

Sodium starch glycolate (Type A)

Magnesium Stearate

Hypromellose 3cP

Hypromellose 6cP

Titanium dioxide

Macrogol 400

Polysorbate 80

Iron oxide yellow

Iron oxide black

Not applicable.

2 years

This medicinal product does not require any special storage conditions.

White opaque PVC/PVdC - Aluminium blisters

Pack sizes of 20, 30, 60, 80, 90, 100 or 500 film-coated tablets

Tablet containers

Lamivudine Teva Pharma B.V. 150 mg film-coated tablets:

White opaque HDPE tablet containers with white opaque polyethylene child resistant screw cap withinduction seal

Pack size of 60 film-coated tablets

White opaque HDPE tablet containers with white opaque polypropylene child resistant, tamper-evident screw cap with induction seal

Pack size of 60 film-coated tablets

Lamivudine Teva Pharma B.V. 300 mg film-coated tablets:

White opaque HDPE tablet containers with white opaque polyethylene child resistant screw cap withinduction seal

Pack size of 30 film-coated tablets

White opaque HDPE tablet containers with white opaque polypropylene child resistant, tamper-evident screw cap with induction seal

Pack size of 30 film-coated tablets

Not all pack sizes may be marketed.

No special requirements for disposal.

Teva B.V.

Swensweg 52031GA Haarlem

Netherlands

Lamivudine Teva Pharma B.V. 150 mg film-coated tablets

EU/1/09/596/001 20 tablets (blister)

EU/1/09/596/002 30 tablets (blister)

EU/1/09/596/003 60 tablets (blister)

EU/1/09/596/004 90 tablets (blister)

EU/1/09/596/005 100 tablets (blister)

EU/1/09/596/006 500 tablets (blister)

EU/1/09/596/007 60 tablets (bottle)

EU/1/09/596/015 80 tablets (blister)

EU/1/09/596/017 60 tablets (bottle with tamper-evident cap)

Lamivudine Teva Pharma B.V. 300 mg film-coated tablets

EU/1/09/596/008 20 tablets (blister)

EU/1/09/596/009 30 tablets (blister)

EU/1/09/596/010 60 tablets (blister)

EU/1/09/596/011 90 tablets (blister)

EU/1/09/596/012 100 tablets (blister)

EU/1/09/596/013 500 tablets (blister)

EU/1/09/596/014 30 tablets (bottle)

EU/1/09/596/016 80 tablets(blister)

EU/1/09/596/018 30 tablets (bottle with tamper-evident cap)

Date of first authorisation: 10 December 2009

Date of latest renewal: 11 September 2014

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Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu/.