- 1. NAME OF THE MEDICINAL PRODUCT
- 2. QUALITATIVE AND QUANTITATIVE COMPOSITION
- 3. PHARMACEUTICAL FORM
- 4. CLINICAL PARTICULARS
- 4.1 Therapeutic indications
- 4.2 Posology and method of administration
- 4.3 Contraindications
- 4.4 Special warnings and precautions for use
- 4.5 Interaction with other medicinal products and other forms of interaction
- 4.6 Fertility, pregnancy and lactation
- 4.7 Effects on ability to drive and use machines
- 4.8 Undesirable effects
- 4.9 Overdose
- 5. PHARMACOLOGICAL PROPERTIES
- 6. PHARMACEUTICAL PARTICULARS
- 7. MARKETING AUTHORISATION HOLDER
- 8. MARKETING AUTHORISATION NUMBER(S)
- 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
- 10. DATE OF REVISION OF THE TEXT
1.NAME OF THE MEDICINAL PRODUCT
Lamivudine Teva 100 mg
2.QUALITATIVE AND QUANTITATIVE COMPOSITION
For the full list of excipients see section 6.1.
Orange, capsule shaped, biconvex
Lamivudine Teva is indicated for the treatment of chronic hepatitis B in adults with:
•compensated liver disease with evidence of active viral replication, persistently elevated serum alanine aminotransferase (ALT) levels and histological evidence of active liver inflammation and / or fibrosis. Initiation of lamivudine treatment should only be considered when the use of an alternative antiviral agent with a higher genetic barrier is not available or appropriate (see in section 5.1).
4.2Posology and method of administration
Therapy with Lamivudine Teva should be initiated by a physician experienced in the management of chronic hepatitis B.
The recommended dosage of Lamivudine Teva is 100 mg once daily.
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
•In patients with HBeAg negative CHB
•In patients with cirrhosis and in liver transplant recipients, treatment cessation is not recommended. (see section 5.1).
If lamivudine is discontinued, patients should be periodically monitored for evidence of recurrent hepatitis (see section 4.4).
In patients with either HBeAg positive or HBeAg negative CHB, the development of YMDD
In order to reduce the risk of resistance in patients receiving lamivudine monotherapy, a modification of treatment should be considered if serum HBV DNA remainsdetectable at or beyond 24 weeks of
treatment. In patients with YMDD mutant HBV, addition of an alternative agent without- cross resistance to lamivudine should be considered.
For the treatment of patients who are
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. Lamivudine Teva is not suitable for patients who require doses below 100 mg.
Data available in patients undergoing intermittent haemodialysis (for less than or equal to 4 hrs dialysis
Data obtained in patients with hepatic impairment, including those with
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.
The safety and efficacy of Lamivudine Teva in infants, children and adolescents aged below 18 years have not been established. Currently available data are described in sections 4.4 and 5.1 but no recommendation on a posology can be made.
Method of administration
Oral use.Lamivudine Teva can be taken with or without food.
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
4.4 Special 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
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
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
Transplantation recipients are at greater risk from active viral replication. Due to the marginal liver function in these patients, hepatitis reactivation at discontinuation of lamivudine or loss of efficacy during treatment may induce severe and even fatal decompensation. These patients should be monitored for clinical, virological and serological parameters associated with hepatitis B, liver and renal function, and antiviral response during treatment (at least every month), and, if treatment is discontinued for any reason, for at least 6 months after treatment. Laboratory parameters to be monitored should include (as a minimum) serum ALT, bilirubin, albumin, blood urea nitrogen, creatinine, and virological status: HBV antigen/antibody, and serum HBV DNA concentrations when possible. Patients experiencing signs of hepatic insufficiency during or
For patients who develop evidence of recurrent hepatitis
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
Paediatric patientsLamivudine has been administered to children (2 years and above) and adolescents with compensated chronic hepatitis B. However, due to limitations of the data, the administration of lamivudine to this patient population is not currently recommended (see section 5.1).
Delta hepatitis or hepatitis C
The efficacy of lamivudine in patients
Data are limited on the use of lamivudine in HBeAg negative
During treatment with Lamivudine Teva 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.
For the treatment of patients who are
Transmission of hepatitis B
There is no information available on
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 productsLamivudine Teva should not be taken with any other medicinal products containing lamivudine or medicinal products containing emtricitabine. (see section 4.5).
The combination of lamivudine with cladribine is not recommended (see section 4.5).
4.5Interaction 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 elimination of unchanged substance.
Lamivudine is predominantly eliminated by active organic cationic secretion. The possibility of interactions with other medicinal products administered concurrently should be considered, particularly when their main route of elimination is active renal secretion via the organic cationic transport system e.g. trimethoprim. Other medicinal products (e.g. ranitidine, cimetidine) are eliminated only in part by this mechanism and were shown not to interact with lamivudine.
Substances shown to be predominately excreted either via the active organic anionic pathway, or by glomerular filtration are unlikely to yield clinically significant interactions with lamivudine. Administration of trimethoprim/sulphamethoxazole 160 mg/800 mg increased lamivudine exposure by about 40 %. Lamivudine had no effect on the pharmacokinetics of trimethoprim or sulphamethoxazole. However, unless the patient has renal impairment, no dosage adjustment of lamivudine is necessary.
A modest increase in Cmax (28 %) was observed for zidovudine when administered with lamivudine, however overall exposure (AUC) was not significantly altered. Zidovudine had no effect on the pharmacokinetics of lamivudine (see section 5.2).
Lamivudine has no pharmacokinetic interaction with
Due to similarities, Lamivudine Teva should not be administered concomitantly with other cytidine analogues, such as emtricitabine. Moreover, Lamivudine Teva should not be 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 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).
4.6Fertility, pregnancy and lactation
A large amount of data on pregnant women (more than 1000 exposed outcomes) indicate no malformative toxicity. Lamivudine Teva 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.
Based on more than 200 mother/child pairs treated for HIV, serum concentrations of lamivudine in breastfed infants of mothers treated for HIV are very low ( less than 4% of maternal serum concentrations) and progressively decrease to undetectable levels when breastfed infants reach 24 weeks of age. The total amount of lamivudine ingested by a breastfed infant is very low and is therefore likely to result in exposures exerting a
not a contraindication to
Reproductive studies in animals have shown no effect on male or female fertility (see section
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
4.7Effects on ability to drive and use machines
Patients should be informed that malaise and fatigue have been reported during treatment with lamivudine. The clinical status of the patient and the adverse reaction profile of lamivudine should be borne in mind when considering the patient's ability to drive or operate machinery.
Summary of the safety profile
The incidence of adverse reactions and laboratory abnormalities (with the exception of elevations of ALT and CPK, see below) were similar between placebo and lamivudine treated patients). The most common adverse reactions reported were malaise and fatigue, respiratory tract infections, throat and tonsil discomfort, headache, abdominal discomfort and pain, nausea, vomiting and diarrhoea.
Tabulated list of adverse reactions
Adverse reactions are listed below by system organ class and frequency. Frequency categories are only assigned to those adverse reactions considered to be at least possibly causally related to lamivudine. Frequencies are defined as: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10,000 to < 1/1000),very rare (< 1/10,000) and not known (cannot be estimated from the available data).
The frequency categories assigned to the adverse reactions are mainly based on experience from clinical trials including a total of 1,171 patients with chronic hepatitis B receiving lamivudine at 100mg.
Blood and lymphatic system disorders
Immune system disorders:
ALT elevations (see section 4.4)
Exacerbations of hepatitis, primarily detected by serum ALT elevations, have been reported ‘on- treatment’ and following lamivudine withdrawal. Most events have been
Skin and subcutaneous tissue disorders
Musculoskeletal and connective tissue disorders
Elevations of CPK
Muscle disorders, including myalgia and cramps*
* In Phase III studies frequency observed in the lamivudine treatment group was not greater than observed in the placebo group
Based on limited data in children aged 2 to 17 years, there were no new safety issues identified compared to adults.
Other special populations
In patients with HIV infection, cases of pancreatitis and peripheral neuropathy (or paresthesia) have been reported. In patients with chronic hepatitis B there was no observed difference in incidence of these events between placebo and lamivudine treated patients.
Cases of lactic acidosis, sometimes fatal, usually associated with severe hepatomegaly and hepatic steatosis, have been reported with the use of combination nucleoside analogue therapy in patients with HIV. There have been rare reports of lactic acidosis in patients receiving lamivudine for hepatitis B.
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 the national reporting system listed in Appendix V
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 overdose occurs the patient should be monitored and standard supportive treatment applied as required. Since lamivudine is dialysable, continuous haemodialysis could be used in the treatment of overdose, although this has not been studied.
Pharmacotherapeutic group - Antivirals for systemic use, nucleoside and nucleotide reverse transcriptase inhibitors,ATC Code: J05AF05.
Lamivudine is an antiviral agent which is active against hepatitis B virus in all cell lines tested and in experimentally infected animals.
Lamivudine is metabolised by both infected and uninfected cells to the triphosphate (TP) derivative which is the active form of the parent compound. The intracellular half life of the triphosphate in hepatocytes is
The formation of further viral DNA is blocked by incorporation of
In assays relating to potential substance effects on mitochondrial structure and DNA content and function, lamivudine lacked appreciable toxic effects. It has a very low potential to decrease mitochondrial DNA content, is not permanently incorporated into mitochondrial DNA, and does not act as an inhibitor of mitochondrial DNA polymerase gamma.
Experience in patients with HBeAg positive CHB and compensated liver disease
In controlled studies, 1 year of lamivudine therapy significantly suppressed HBV DNA replication
Continued lamivudine treatment for an additional 2 years in patients who had failed to achieve HBeAg seroconversion in the initial 1 year controlled studies resulted in further improvement in bridging fibrosis. In patients with YMDD mutant HBV, 41/82 (50 %) patients had improvement in liver inflammation and 40/56 (71 %) patients without YMDD mutant HBV had improvement. Improvement in bridging fibrosis occurred in 19/30 (63 %) patients without YMDD mutant and 22/44 (50 %) patients with the mutant. Five percent (3/56) of patients without the YMDD mutant and 13 % (11/82) of patients with YMDD mutant showed worsening in liver inflammation compared to pre- treatment. Progression to cirrhosis occurred in 4/68 (6 %) patients with the YMDD mutant, whereas no patients without the mutant progressed to cirrhosis.
In an extended treatment study in Asian patients (NUCB3018) the HBeAg seroconversion rate and ALT normalisation rate at the end of the 5 year treatment period was 48 % (28/58) and 47 % (15/32), respectively. HBeAg seroconversion was increased in patients with elevated ALT levels; 77 % (20/26) of patients with
Further results from the trial by YMDD mutant status are summarised in Table 1.
Table 1: Efficacy results 5 years by YMDD status (Asian Study) NUCB3018
Subjects, % (no.)
YMDD mutant HBV status
- All patients
- Baseline ALT ≤ 1 x ULN2
- Baseline ALT > 2 x ULN
Undetectable HBV DNA
- Week 2604
positive < baseline
positive > baseline
- Week 260
above normal < baseline
above normal > baseline
1 Patients designated as YMDD mutant were those with ≥5 % YMDD mutant HBV at any annual
3 Abbott Genostics solution hybridisation assay (LLOD < 1.6 pg/ml 4 Chiron Quantiplex assay (LLOD 0.7 Meq/ml)
Comparative data according to YMDD status were also available for histological assessment but only up to three years. In patients with YMDD mutant HBV, 18/39 (46 %) had improvements in necroinflammatory activity and 9/39 (23 %) had worsening. In patients without the mutant, 20/27 (74 %) had improvements in necroinflammatory activity and 2/27 (7 %) had worsening.
Following HBeAg seroconversion, serologic response and clinical remission are generally durable after stopping lamivudine. However, relapse following seroconversion can occur. In a
In patients followed for up to 16 weeks after discontinuation of treatment at one year,
Patients with ALT Elevation/
Patients with Observations*
ALT ≥ 2 x baseline value
37/137 (27 %)
22/116 (19 %)
ALT ≥ 3 x baseline value†
29/137 (21 %)
9/116 (8 %)
ALT ≥ 2 x baseline value and absolute ALT > 500
21/137 (15 %)
8/116 (7 %)
ALT ≥2 x baseline value; and bilirubin >2 x ULN
and ≥2 x baseline value
1/137 (0.7 %)
1/116 (0.9 %)
*Each patient may be represented in one or more category.
†Comparable to a Grade 3 toxicity in accordance with modified WHO criteria.
ULN = Upper limit of normal.
Experience in patients with HBeAg negative CHB:
Initial data indicate the efficacy of lamivudine in patients with HBeAg negative CHB is similar to patients with HBeAg positive CHB, with 71 % of patients having HBV DNA suppressed below the detection limit of the assay, 67 % ALT normalisation and 38 % with improvement in HAI after one year of treatment. When lamivudine was discontinued, the majority of patients (70 %) had a return of viral replication. Data is available from an extended treatment study in HBeAg negative patients (NUCAB3017) treated with lamivudine. After two years of treatment in this study, ALT normalisation and undetectable HBV DNA occurred in 30/69 (43 %) and 32/68 (47 %) patients respectively and improvement in necroinflammatory score in 18/49 (37 %) patients. In patients without YMDD mutant HBV, 14/22 (64 %) showed improvement in necroinflammatory score and 1/22 (5 %) patients worsened compared to
Frequency of emergence of YMDD mutant HBV and impact on the treatment response:
Lamivudine monotherapy results in the selection of YMDD mutant HBV in approximately 24 % of patients following one year of therapy, increasing to 69 % following 5 years of therapy. Development of YMDD mutant HBV is associated with reduced treatment response in some patients, as evidenced by increased HBV DNA levels and ALT elevations from previous
In a retrospective study to determine the factors associated with HBV DNA breakthrough, 159 Asian
Experience in patients with decompensated liver disease:
Placebo controlled studies have been regarded as inappropriate in patients with decompensated liver disease, and have not been undertaken.In
As anticipated due to the concomitant immunosuppression, the rate of emergence of YMDDmutant HBV after 52 weeks treatment was higher
Experience in CHB patients with advanced fibrosis or cirrhosis:
and 93 % (320/345) of subjects receiving lamivudine became HBV DNA negative (VERSANT [version 1], bDNA assay, LLOD < 0.7 MEq/ml) during the study.
Experience in children and adolescents:
Lamivudine has been administered to children and adolescents with compensated CHB in a placebo controlled study of 286 patients aged 2 to 17 years. This population primarily consisted of children with minimal hepatitis B. A dose of 3 mg/kg once daily (up to a maximum of 100 mg daily) was used in children aged 2 to 11 years and a dose of 100 mg once daily in adolescents aged 12 years and above. This dose needs to be further substantiated. The difference in the HBeAg seroconversion rates (HBeAg and HBV DNA loss with HBeAb detection) between placebo and lamivudine was not statistically significant in this population (rates after one year were 13 % (12/95) for placebo versus 22 % (42/191) for lamivudine; p=0.057). The incidence of YMDD mutant HBV was similar to that observed in adults, ranging from 19 % at week 52 up to 45 % in patients treated continuously for 24 months.
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 (tmax) to maximal serum concentrations (Cmax) is about an hour. At therapeutic dose levels i.e. 100 mg once daily, Cmax is in the order of
From intravenous studies the mean volume of distribution is 1.3 l/kg. Lamivudine exhibits linear pharmacokinetics over the therapeutic dose range and displays low plasma protein binding to albumin. Limited data shows lamivudine penetrates the central nervous system and reaches the
Lamivudine is predominately cleared by renal excretion of unchanged substance. The likelihood of metabolic substance interactions with lamivudine is low due to the small
The mean systemic clearance of lamivudine is approximately 0.3 l/h/kg. The observed
Studies in patients with renal impairment show lamivudine elimination is affected by renal dysfunction. Dose reduction in patients with a creatinine clearance of < 50 ml/min is necessary (see section 4.2).
The pharmacokinetics of lamivudine are unaffected by hepatic impairment. Limited data in patients undergoing liver transplantation show that impairment of hepatic function does not impact significantly on the pharmacokinetics of lamivudine unless accompanied by renal dysfunction.
In elderly patients the 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 (see section 4.2).
5.3Preclinical 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 reduction in liver weights. Reduction of erythrocytes and neutrophil counts were identified as the effects most likely to be of clinical relevance. These events were seen infrequently in clinical studies.
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
Reproductive studies in animals have not shown evidence of teratogenicity and showed no effect on male or female fertility. Lamivudine induces early embryolethality when administered to pregnant rabbits at exposure levels comparable to those achieved in man, but not in the rat even at very high systemic exposures.
The results of long term carcinogenicity studies with lamivudine in rats and mice did not shown any carcinogenic potential.
6.1List of excipients
Sodium starch glycolate (Type A)
Tablet film coat
Iron oxide yellow
Iron oxide red
6.4Special precautions for storage
This medicinal product does not require any special storage conditions.
6.5Nature and contents of container
White opaque PVC/PVdC – Aluminium blisters
Pack sizes of 28, 30, 84 or 100
White opaque HDPE containers with white opaque polyethylene child resistent screw cap with induction seal.
Pack size of 60
Not all pack sizes may be marketed.
6.6Special precautions for disposal
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
7.MARKETING AUTHORISATION HOLDER
8.MARKETING AUTHORISATION NUMBER(S)
EU/1/09/566/001– 28 Tablets
EU/1/09/566/002 – 30 Tablets
EU/1/09/566/003 – 84 Tablets
EU/1/09/566/004 – 100 Tablets
EU/1/09/566/005 – 60 Tablets
9.DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
Date of first authorisation: 23 October 2009
Date of latest renewal: 09 September 2014
10.DATE OF REVISION OF THE TEXT
Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu