Zeffix

1 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 



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1. NAME OF THE MEDICINAL PRODUCT 
 
Zeffix 100 mg film-coated tablets 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each film-coated tablet contains 100 mg lamivudine 
 
For the full list of excipients, see section 6.1.  
 
 
3. PHARMACEUTICAL FORM 
 
Film-coated tablet (tablet) 
 
Butterscotch coloured, film-coated, capsule shaped, biconvex, approximate dimensions 11mm x 5mm 
and engraved “GX CG5” on one face. 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications  
 
Zeffix 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 section 
5.1). 

 
 decompensated liver disease in combination with a second agent without cross-resistance to 

lamivudine (see section 4.2). 
 
4.2 Posology and method of administration  
 
Therapy with Zeffix should be initiated by a physician experienced in the management of chronic 
hepatitis B. 
 
Posology 
 
Adults 
The recommended dosage of Zeffix is 100 mg once daily.   
 
In patients with decompensated liver disease, lamivudine should always be used in combination with a 
second agent, without cross-resistance to lamivudine, to reduce the risk of resistance and to achieve 
rapid viral suppression.   
 
Duration of treatment 
The optimal duration of treatment is unknown. 
 
• In patients with HBeAg positive chronic hepatitis B (CHB) without cirrhosis, treatment should 

be administered for at least 6-12 months after HBeAg seroconversion (HBeAg and HBV DNA 
loss with HBeAb detection) is confirmed, to limit the risk of virological relapse, or until HBsAg 
seroconversion or there is loss of efficacy (see section 4.4). Serum ALT and HBV DNA levels 
should be followed regularly after treatment discontinuation to detect any late virological 
relapse. 



 3 

• In patients with HBeAg negative CHB (pre-core mutant) without cirrhosis, treatment should be 
administered at least until HBs seroconversion or there is evidence of loss of efficacy. With 
prolonged treatment, regular reassessment is recommended to confirm that continuation of the 
selected therapy remains appropriate for the patient. 

• In patients with decompensated liver disease or cirrhosis and in liver transplant recipients, 
treatment cessation is not recommended (see section 5.1). 

 
If lamivudine is discontinued, patients should be periodically monitored for evidence of recurrent 
hepatitis (see section 4.4). 
 
Clinical resistance 
In patients with either HBeAg positive or HBeAg negative CHB, the development of YMDD 
(tyrosine-methionine-aspartate-aspartate) mutant HBV may result in a diminished therapeutic response 
to lamivudine, indicated by a rise in HBV DNA and ALT from previous on-treatment levels. In order 
to reduce the risk of resistance in patients receiving lamivudine monotherapy, a switch to or addition 
of an alternative agent without cross-resistance to lamivudine based on therapeutic guidelines should 
be considered if serum HBV DNA remains detectable at or beyond 24 weeks of treatment (see section 
5.1). 
 
For the treatment of patients who are co-infected with HIV and are currently receiving or plan to 
receive treatment with lamivudine or the combination lamivudine-zidovudine, the dose of lamivudine 
prescribed for HIV infection (usually 150 mg/twice daily in combination with other antiretrovirals) 
should be maintained. 
 
Special populations 
 
Renal impairment 
Lamivudine serum concentrations (AUC) are increased in patients with moderate to severe renal 
impairment due to decreased renal clearance. The dosage should, therefore, be reduced for patients 
with a creatinine clearance of < 50 ml/minute. When doses below 100 mg are required Zeffix oral 
solution should be used (see Table 1 below). 
 
Table 1: Dosage of Zeffix in patients with decreased renal clearance. 
 

 
Creatinine clearance 

ml/min 

 
First dose of Zeffix 

oral solution * 

 
Maintenance dose 

once daily 
 

30 to < 50 
 

20 ml (100 mg) 
 

10 ml (50 mg) 
 

15 to < 30 
 

20 ml (100 mg) 
 

5 ml (25 mg) 
 

5 to < 15 
 

7 ml (35 mg) 
 

3 ml (15 mg) 
 

< 5 
 

7 ml (35 mg) 
 

2 ml (10 mg) 
* Zeffix oral solution containing 5 mg/ml lamivudine. 
 
Data available in patients undergoing intermittent haemodialysis (for less than or equal to 4 hrs 
dialysis 2-3 times weekly), indicate that following the initial dosage reduction of lamivudine to correct 
for the patient’s creatinine clearance, no further dosage adjustments are required while undergoing 
dialysis. 
 
Hepatic impairment 
Data obtained in patients with hepatic impairment, including those with end-stage liver disease 
awaiting transplant, show that lamivudine pharmacokinetics are not significantly affected by hepatic 
dysfunction. Based on these data, no dose adjustment is necessary in patients with hepatic impairment 
unless accompanied by renal impairment. 



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Elderly 
In elderly patients, normal ageing with accompanying renal decline has no clinically significant effect 
on lamivudine exposure, except in patients with creatinine clearance of < 50 ml/min. 
 
Paediatric population 
The safety and efficacy of Zeffix 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. 
Zeffix can be taken with or without food. 
 
4.3 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 
 
Exacerbations of hepatitis 
 
Exacerbations on treatment 
Spontaneous exacerbations in chronic hepatitis B are relatively common and are characterised by 
transient increases in serum ALT. After initiating antiviral therapy, serum ALT may increase in some 
patients as serum HBV DNA levels decline. In patients with compensated liver disease, these 
increases in serum ALT were generally not accompanied by an increase in serum bilirubin 
concentrations or signs of hepatic decompensation. 
 
HBV viral subpopulations with reduced susceptibility to lamivudine (YMDD mutant HBV) have been 
identified with extended therapy. In some patients the development of YMDD mutant HBV can lead 
to exacerbation of hepatitis, primarily detected by serum ALT elevations and re-emergence of HBV 
DNA (see section 4.2). In patients who have YMDD mutant HBV, a switch to or addition of an 
alternative agent without cross resistance to lamivudine based on therapeutic guidelines should be 
considered (see section 5.1). 
 
Exacerbations after treatment discontinuation 
Acute exacerbation of hepatitis has been observed in patients who have discontinued hepatitis B 
therapy and is usually detected by serum ALT elevations and re-emergence of HBV DNA. In the 
controlled Phase III trials with no-active-treatment follow-up, the incidence of post-treatment ALT 
elevations (more than 3 times baseline) was higher in lamivudine-treated patients (21%) compared 
with those receiving placebo (8%). However, the proportion of patients who had post-treatment 
elevations associated with bilirubin elevations was low and similar in both treatment arms (see Table 3 
in section 5.1). For lamivudine-treated patients, the majority of post-treatment ALT elevations 
occurred between 8 and 12 weeks post-treatment. Most events have been self-limiting, however some 
fatalities have been observed. If Zeffix is discontinued, patients should be periodically monitored both 
clinically and by assessment of serum liver function tests (ALT and bilirubin levels), for at least four 
months, and then as clinically indicated.  
 
Exacerbations in patients with decompensated cirrhosis 
Transplantation recipients and patients with decompensated cirrhosis are at greater risk from active 
viral replication. Due to the marginal liver function in these patients, hepatitis reactivation at 
discontinuation of lamivudine or loss of efficacy during treatment may induce severe and even fatal 
decompensation. These patients should be monitored for clinical, virological and serological 
parameters associated with hepatitis B, liver and renal function, and antiviral response during 
treatment (at least every month), and, if treatment is discontinued for any reason, for at least 6 months 



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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 post-treatment should be monitored more frequently as appropriate. 
 
For patients who develop evidence of recurrent hepatitis post-treatment, there are insufficient data on 
the benefits of re-initiation of lamivudine treatment. 
 
Mitochondrial dysfunction 
 
Nucleoside and nucleotide analogues have been demonstrated in vitro and in vivo to cause a variable 
degree of mitochondrial damage. There have been reports of mitochondrial dysfunction in infants 
exposed in utero and/or post-natally to nucleoside analogues. The main adverse events reported are 
haematological disorders (anaemia, neutropenia), metabolic disorders (hyperlipasemia). Some late-
onset neurological disorders have been reported (hypertonia, convulsion, abnormal behaviour). The 
neurological disorders might be transient or permanent. Any child exposed in utero to nucleoside and 
nucleotide analogues, should have clinical and laboratory follow-up and should be fully investigated 
for possible mitochondrial dysfunction in cases which have relevant signs or symptoms. 
 
Paediatric patients 
 
Lamivudine has been administered to children (2 years and above) and adolescents with compensated 
chronic hepatitis B. However, due to limitations of the data, the administration of lamivudine to this 
patient population is not currently recommended (see section 5.1). 
 
Delta hepatitis or hepatitis C 
 
The efficacy of lamivudine in patients co-infected with Delta hepatitis or hepatitis C has not been 
established and caution is advised. 
 
Immunosuppressive treatments 
 
Data are limited on the use of lamivudine in HBeAg negative (pre-core mutant) patients and in those 
receiving concurrent immunosuppressive regimes, including cancer chemotherapy. Lamivudine should 
be used with caution in these patients. 
 
Monitoring 
 
During treatment with Zeffix patients should be monitored regularly. Serum ALT and HBV DNA 
levels should be monitored at 3 month intervals and in HBeAg positive patients HBeAg should be 
assessed every 6 months. 
 
HIV co-infection 
 
For the treatment of patients who are co-infected with HIV and are currently receiving or plan to 
receive treatment with lamivudine or the combination lamivudine-zidovudine, the dose of lamivudine 
prescribed for HIV infection (usually 150 mg/twice daily in combination with other antiretrovirals) 
should be maintained. For HIV co-infected patients not requiring anti-retroviral therapy, there is a risk 
of HIV mutation when using lamivudine alone for treating chronic hepatitis B.  
 
Transmission of hepatitis B 
 
There is no information available on maternal-foetal transmission of hepatitis B virus in pregnant 
women receiving treatment with lamivudine. The standard recommended procedures for hepatitis B 
virus immunisation in infants should be followed. 
 



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Patients should be advised that therapy with lamivudine has not been proven to reduce the risk of 
transmission of hepatitis B virus to others and therefore, appropriate precautions should still be taken. 
 
Interactions with other medicinal products 
 
Zeffix 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). 
 
Excipients 
 
This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium-
free’. 
 
 
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 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 alpha-interferon when the two medicinal 
products are concurrently administered. There were no observed clinically significant adverse 
interactions in patients taking lamivudine concurrently with commonly used immunosuppressant 
medicinal products (e.g. cyclosporin A). However, formal interaction studies have not been 
performed.  
 
Emtricitabine 
 
Due to similarities, Zeffix should not be administered concomitantly with other cytidine analogues, 
such as emtricitabine. Moreover, Zeffix should not be taken with any other medicinal products 
containing lamivudine (see section 4.4). 
 
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 



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support a possible interaction between lamivudine and cladribine. Therefore, the concomitant use of 
lamivudine with cladribine is not recommended (see section 4.4). 
 
Sorbitol 
 
Co-administration of sorbitol solution (3.2 g, 10.2 g, 13.4 g) with a single 300 mg dose (Adult HIV 
daily dose) of lamivudine oral 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 chronic co-administration of Zeffix with medicinal products containing sorbitol or 
other osmotic acting poly-alcohols or monosaccharide alcohols (e.g. xylitol, mannitol, lactitol, 
maltitol). Consider more frequent monitoring of HBV viral load when chronic co-administration 
cannot be avoided.  
 
4.6 Fertility, pregnancy and lactation 
 
Pregnancy 
 
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.  
 
Available human data from the Antiretroviral Pregnancy Registry reporting more than 1000 outcomes 
from first trimester and more than 1000 outcomes from second and third trimester exposure in 
pregnant women indicate no malformative and foeto/neonatal effect. Less than 1% of these women 
have been treated for HBV, whereas the majority was treated for HIV at higher doses and with other 
concomitant medications. Zeffix 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. 
 
Breast-feeding 
 
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 sub-optimal antiviral effect. Maternal hepatitis B is 
not a contraindication to breast-feeding if the newborn is adequately managed for hepatitis B 
prevention at birth, and there is no evidence that the low concentration of lamivudine in human milk 
leads to adverse reactions in breastfed infants. Therefore, breastfeeding may be considered in breast-
feeding mothers being treated with lamivudine for HBV taking into account the benefit of breast 
feeding for the child and the benefit of therapy for the woman. Where there is maternal transmission of 
HBV, despite adequate prophylaxis, consideration should be given to discontinuing breastfeeding to 
reduce the risk of the emergence of lamivudine resistant mutants in the infant.  
 
Fertility 
 
Reproductive studies in animals have shown no effect on male or female fertility (see section 5.3). 
 
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). 
 
4.7 Effects on ability to drive and use machines 
 



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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. 
 
4.8 Undesirable effects 
 
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 
Not known Thrombocytopenia 
Metabolism and nutrition disorders 
Very rare Lactic acidosis 
Immune system disorders: 
Rare Angioedema 
Hepatobiliary disorders 
Very common 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 self-limited, however 
fatalities have been observed very rarely (see section 4.4). 
Skin and subcutaneous tissue disorders 
Common Rash, pruritus 
Musculoskeletal and connective tissue disorders 
Common Elevations of CPK 
Common Muscle disorders, including myalgia and cramps*  

 
Not known Rhabdomyolysis 
* In Phase III studies frequency observed in the lamivudine treatment group was not greater than 
observed in the placebo group 
 
Paediatric population  
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. 
 



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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. 
 
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 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. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group - Antivirals for systemic use, nucleoside and nucleotide reverse 
transcriptase inhibitors, ATC Code: J05AF05. 
 
Mechanism of action 
 
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 17-19 hours in vitro. Lamivudine-TP acts as a substrate for the HBV viral polymerase. 
 
The formation of further viral DNA is blocked by incorporation of lamivudine-TP into the chain and 
subsequent chain termination. 
 
Lamivudine-TP does not interfere with normal cellular deoxynucleotide metabolism. It is also only a 
weak inhibitor of mammalian DNA polymerases alpha and beta. Furthermore, lamivudine-TP has little 
effect on mammalian cell DNA content. 
 
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. 
 
Clinical efficacy and safety 
 
Experience in patients with HBeAg positive CHB and compensated liver disease 
In controlled studies, 1 year of lamivudine therapy significantly suppressed HBV DNA replication 
[34-57 % of patients were below the assay detection limits (Abbott Genostics solution hybridization 
assay, LLOD < 1.6pg/ml)}, normalised ALT level (40-72 % of patients), induced HBeAg 
seroconversion (HBeAg loss and HBeAb detection with HBV DNA loss [by conventional assay], 16-
18 % of patients), improved histology (38-52 % of patients had a ≥ 2 point decrease in the Knodell 
Histologic Activity Index [HAI]) and reduced progression of fibrosis (in 3-17 % of patients) and 
progression to cirrhosis.  

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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 pre-treatment ALT > 2 x ULN seroconverted. At the end of 5 years, all patients had 
HBV DNA levels that were undetectable or lower than pre-treatment levels. 
 
Further results from the trial by YMDD mutant status are summarised in Table 2. 
 
Table 2: Efficacy results 5 years by YMDD status (Asian Study) NUCB3018 
 

 Subjects, % (no.) 
YMDD mutant HBV status YMDD1 Non-YMDD1 

    HBeAg seroconversion  
 
 - All patients 
 - Baseline ALT ≤ 1 x ULN2 

 - Baseline ALT > 2 x ULN 
 
    Undetectable HBV DNA 
 
 - Baseline 3 

   
 - Week 260 4 

    negative 
    positive < baseline 
    positive > baseline 
 
 
    ALT normalisation 
 
 - Baseline 
   normal 
   above normal 
 
 - Week 260 
   normal 
   above normal < baseline 
   above normal > baseline 

 

 
 

38 
9 

60 
 
 
 

5 
 
 

8 
92 
0 
 
 
 
 
 

28 
73 
 
 

46 
21 
32 

 
 

(15/40) 
(1/11) 
(9/15) 

 
 
 

(2/40) 
 
 

(2/25) 
(23/25) 

 
 
 
 
 
 

(11/40) 
(29/40) 

 
 

(13/28) 
(6/28) 
(9/28) 

 

 
 

72 
33 

100 
 
 
 

6 
 
 

0 
100 
0 
 
 
 
 
 

33 
67 
 
 

50 
0 

50 

 
 

(13/18) 
(2/6) 

(11/11) 
 
 
 

(1/18) 
 

 
 

(4/4) 
 
 
 
 
 
 

(6/18) 
(12/18) 

 
 

(2/4) 
 

(2/4) 

 
1 Patients designated as YMDD mutant were those with ≥5% YMDD mutant HBV at any annual time-point during 

the 5-year period. Patients categorised as non-YMDD mutant were those with > 95% wild-type HBV at all annual 
time-points during the 5-year study period 

2 Upper limit of normal 
3 Abbott Genostics solution hybridisation assay (LLOD < 1.6 pg/ml 
4 Chiron Quantiplex assay (LLOD 0.7 Meq/ml) 

 



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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 long-term 
follow-up study of patients who had previously seroconverted and discontinued lamivudine, late 
virological relapse occurred in 39 % of the subjects. Therefore, following HBeAg seroconversion, 
patients should be periodically monitored to determine that serologic and clinical responses are being 
maintained. In patients who do not maintain a sustained serological response, consideration should be 
given to retreatment with either lamivudine or an alternative antiviral agent for resumption of clinical 
control of HBV. 
 
In patients followed for up to 16 weeks after discontinuation of treatment at one year, post-treatment 
ALT elevations were observed more frequently in patients who had received lamivudine than in 
patients who had received placebo. A comparison of post-treatment ALT elevations between weeks 52 
and 68 in patients who discontinued lamivudine at week 52 and patients in the same studies who 
received placebo throughout the treatment course is shown in Table 3. The proportion of patients who 
had post-treatment ALT elevations in association with an increase in bilirubin levels was low and 
similar in patients receiving either lamivudine or placebo. 
 
Table 3: Post-treatment ALT Elevations in 2 Placebo-Controlled Studies in Adults 
 
 Patients with ALT Elevation/ 

Patients with Observations* 
Abnormal Value Lamivudine Placebo 

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 IU/l 

 
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 pre-treatment. In patients with the mutant, 4/26 (15 %) patients showed 
improvement in necroinflammatory score and 8/26 (31 %) patients worsened compared to pre-
treatment. No patients in either group progressed to cirrhosis. 
 
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 



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by increased HBV DNA levels and ALT elevations from previous on-therapy levels, progression of 
signs and symptoms of hepatitis disease and/or worsening of hepatic necroinflammatory findings. 
Given the risk of YMDD mutant HBV, maintenance of lamivudine monotherapy is not appropriate in 
patients with detectable serum HBV DNA at or beyond 24 weeks of treatment (see section 4.4). 
 
In a double-blind study in CHB patients with YMDD mutant HBV and compensated liver disease 
(NUC20904), with a reduced virological and biochemical response to lamivudine (n=95), the addition 
of adefovir dipivoxil 10 mg once daily to ongoing lamivudine 100mg for 52 weeks resulted in a 
median decrease in HBV DNA of 4.6 log10 copies/ml compared to a median increase of 0.3 
log10 copies/ml in those patients receiving lamivudine monotherapy. Normalisation of ALT levels 
occurred in 31 % (14/45) of patients receiving combined therapy versus 6 % (3/47) receiving 
lamivudine alone. Viral suppression was maintained (follow-on study NUC20917) with combined 
therapy during the second year of treatment to week 104 with patients having continued improvement 
in virologic and biochemical responses. 
 
In a retrospective study to determine the factors associated with HBV DNA breakthrough, 159 Asian 
HBeAg-positive patients were treated with lamivudine and followed up for a median period of almost 
30 months. Those with HBV DNA levels greater than 200 copies/mL at 6 months (24 weeks) of 
lamivudine therapy had a 60 % chance of developing the YMDD mutant compared with 8 % of those 
with HBV DNA levels less than 200 copies/mL at 24 weeks of lamivudine therapy. The risk for 
developing YMDD mutant was 63% versus 13% with a cut off of 1000 copies/ml (NUCB3009 and 
NUCB3018). 
 
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 non-controlled studies, where lamivudine was administered 
prior to and during transplantation, effective HBV DNA suppression and ALT normalisation was 
demonstrated. When lamivudine therapy was continued post transplantation there was reduced graft 
re-infection by HBV, increased HBsAg loss and on one-year survival rate of 76 – 100 %. 
 
As anticipated due to the concomitant immunosuppression, the rate of emergence of YMDD mutant 
HBV after 52 weeks treatment was higher (36 % - 64 %) in the liver transplant population than in the 
immunocompetent CHB patients (14 % - 32 %).  
 
Forty patients (HBeAg negative or HBeAg positive) with either decompensated liver disease or 
recurrent HBV following liver transplantation and YMDD mutant were enrolled into an open label 
arm of study NUC20904. Addition of 10 mg adefovir dipivoxil once daily to ongoing lamivudine 
100mg for 52 weeks resulted in a median decrease in HBV DNA of 4.6 log10 copies/ml. Improvement 
in liver function was also seen after one year of therapy. This degree of viral suppression was 
maintained (follow-on study NUC20917) with combined therapy during the second year of treatment 
to week 104 and most patients had improved markers of liver function and continued to derive clinical 
benefit. 
 
Experience in CHB patients with advanced fibrosis or cirrhosis 
In a placebo-controlled study in 651 patients with clinically compensated chronic hepatitis B and 
histologically confirmed fibrosis or cirrhosis, lamivudine treatment (median duration 32 months) 
significantly reduced the rate of overall disease progression (34/436, 7.8 % for lamivudine versus 
38/215, 17.7 % for placebo, p=0.001), demonstrated by a significant reduction in the proportion of 
patients having increased Child-Pugh scores (15/436, 3.4 % versus 19/215, 8.8 %, p=0.023) or 
developing hepatocellular carcinoma (17/436, 3.9 % versus 16/215, 7.4 %, p=0.047). The rate of 
overall disease progression in the lamivudine group was higher for subjects with detectable YMDD 
mutant HBV DNA (23/209, 11 %) compared to those without detectable YMDD mutant HBV 
(11/221, 5 %). However, disease progression in YMDD subjects in the lamivudine group was lower 
than the disease progression in the placebo group (23/209, 11 % versus 38/214, 18 % respectively). 
Confirmed HBeAg seroconversion occurred in 47 % (118/252) of subjects treated with lamivudine 
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. 



 13 

 
 
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. 
 
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 (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 1.1-1.5 µg/ml and trough levels were 0.015-0.020 µg/ml. 
 
Co-administration of lamivudine with food resulted in a delay of tmax and a lower Cmax (decreased by 
up to 47 %). However, the extent (based on the AUC) of lamivudine absorbed was not influenced, 
therefore lamivudine can be administered with or without food. 
 
Distribution 
 
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 cerebro-spinal 
fluid (CSF). The mean lamivudine CSF/serum concentration ratio 2-4 hours after oral administration 
was approximately 0.12. 
 
Biotransformation 
 
Lamivudine is predominately cleared by renal excretion of unchanged substance. The likelihood of 
metabolic substance interactions with lamivudine is low due to the small (5-10 %) extent of hepatic 
metabolism and the low plasma protein binding. 
 
Elimination 
 
The mean systemic clearance of lamivudine is approximately 0.3 l/h/kg. The observed half-life of 
elimination is 5 to 7 hours. The majority of lamivudine is excreted unchanged in the urine via 
glomerular filtration and active secretion (organic cationic transport system). Renal clearance accounts 
for about 70 % of lamivudine elimination. 
 
Special populations 
 
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. 



 14 

 
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). 
 
5.3 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 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 60-70 times higher than the anticipated clinical 
plasma levels. As the in vitro mutagenic activity of lamivudine could not be confirmed by in vivo tests, 
it is concluded that lamivudine should not represent a genotoxic hazard to patients undergoing 
treatment. 
 
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. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Tablet core 
Microcrystalline cellulose 
Sodium starch glycolate 
Magnesium stearate 
 
Tablet film coat 
Hypromellose 
Titanium dioxide 
Macrogol 400 
Polysorbate 80 
Synthetic yellow and red iron oxides 
 
6.2 Incompatibilities 
 
Not applicable 
 
6.3 Shelf life 
 
3 years  
 
6.4 Special precautions for storage 
 
Do not store above 30ºC. 
 



 15 

 
6.5 Nature and contents of container 
 
Boxes containing 28 or 84 film-coated tablets in double foil blisters, laminated with polyvinyl 
chloride. 
 
Not all pack-sizes may be marketed. 
 
6.6 Special precautions for disposal 
 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
GlaxoSmithKline (Ireland) Limited  
12 Riverwalk  
Citywest Business Campus 
Dublin 24 
Ireland 
 
 
8. MARKETING AUTHORISATION NUMBERS 
 
EU/1/99/114/001 
EU/1/99/114/002 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 29 July 1999 
Date of latest renewal: 23 June 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 
 

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


 16 

1. NAME OF THE MEDICINAL PRODUCT 
 
Zeffix 5 mg/ml oral solution 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each ml of the oral solution contains 5 mg lamivudine 
 
Excipients with known effect 
 
Each 20 ml dose contains: 

- 4 g of sucrose 
- 30 mg of methyl parahydroxybenzoate (E218) 
- 3.6 mg of propyl parahydroxybenzoate (E216) 
- 400 mg of propylene glycol (E1520) 
- 58.8 mg of sodium 

 
For the full list of excipients, see section 6.1.  
 
 
3. PHARMACEUTICAL FORM 
 
Oral solution 
 
Clear, colourless to pale yellow in colour. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications  
 
Zeffix 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 section 
5.1). 

 
 decompensated liver disease in combination with a second agent, without cross-resistance to 

lamivudine (see section 4.2). 
 
4.2  Posology and method of administration  
 
Therapy with Zeffix should be initiated by a physician experienced in the management of chronic 
hepatitis B. 
 
Posology 
 
Adults 
The recommended dosage of Zeffix is 100 mg once daily.   
 
In patients with decompensated liver disease, lamivudine should always be used in combination with a 
second agent, without cross-resistance to lamivudine, to reduce the risk of resistance and to achieve 
rapid viral suppression.   
 



 17 

Duration of treatment 
he optimal duration of treatment is unknown. 
 
• In patients with HBeAg positive chronic hepatitis B (CHB) without cirrhosis, treatment should 

be administered for at least 6-12 months after HBeAg seroconversion (HBeAg and HBV DNA 
loss with HBeAb detection) is confirmed, to limit the risk of virological relapse, or until HBsAg 
seroconversion or there is loss of efficacy (see section 4.4). Serum ALT and HBV DNA levels 
should be followed regularly after treatment discontinuation to detect any late virological 
relapse. 

• In patients with HBeAg negative CHB (pre-core mutant), without cirrhosis, treatment should be 
administered at least until HBs seroconversion or there is evidence of loss of efficacy. With 
prolonged treatment, regular reassessment is recommended to confirm that continuation of the 
selected therapy remains appropriate for the patient.  

• In patients with decompensated liver disease or cirrhosis and in liver transplant recipients, 
treatment cessation is not recommended (see section 5.1). 

 
If lamivudine is discontinued, patients should be periodically monitored for evidence of recurrent 
hepatitis (see section 4.4). 
 
Clinical resistance 
In patients with either HBeAg positive or HBeAg negative CHB, the development of YMDD 
(tyrosine-methionine-aspartate-aspartate) mutant HBV may result in a diminished therapeutic response 
to lamivudine, indicated by a rise in HBV DNA and ALT from previous on-treatment levels. In order 
to reduce the risk of resistance in patients receiving lamivudine monotherapy, a switch to or addition 
of an alternative agent without cross-resistance to lamivudine based on therapeutic guidelines should 
be considered if serum HBV DNA remains detectable at or beyond 24 weeks of treatment (see section 
5.1). 
 
For the treatment of patients who are co-infected with HIV and are currently receiving or plan to 
receive treatment with lamivudine or the combination lamivudine-zidovudine, the dose of lamivudine 
prescribed for HIV infection (usually 150 mg/twice daily in combination with other antiretrovirals) 
should be maintained. 
 
Special populations 
 
Renal impairment 
Lamivudine serum concentrations (AUC) are increased in patients with moderate to severe renal 
impairment due to decreased renal clearance. The dosage should, therefore, be reduced for patients 
with a creatinine clearance of < 50 ml/minute. When doses below 100 mg are required Zeffix oral 
solution should be used (see Table 1 below).  
 
Table 1: Dosage of Zeffix in patients with decreased renal clearance. 
 

 
Creatinine clearance 

ml/min 

 
First dose of Zeffix 

oral solution 

 
Maintenance dose 

once daily 
 

30 to < 50 
 

20 ml (100 mg) 
 

10 ml (50 mg) 
 

15 to < 30 
 

20 ml (100 mg) 
 

5 ml (25 mg) 
 

5 to < 15 
 

7 ml (35 mg) 
 

3 ml (15 mg) 
 

< 5 
 

7 ml (35 mg) 
 

2 ml (10 mg) 
 
Data available in patients undergoing intermittent haemodialysis (for less than or equal to 4 hrs 
dialysis 2-3 times weekly), indicate that following the initial dosage reduction of lamivudine to correct 



 18 

for the patient’s creatinine clearance, no further dosage adjustments are required while undergoing 
dialysis. 
 
Hepatic impairment 
Data obtained in patients with hepatic impairment, including those with end-stage liver disease 
awaiting transplant, show that lamivudine pharmacokinetics are not significantly affected by hepatic 
dysfunction. Based on these data, no dose adjustment is necessary in patients with hepatic impairment 
unless accompanied by renal impairment. 
 
Elderly 
In elderly patients, normal ageing with accompanying renal decline has no clinically significant effect 
on lamivudine exposure, except in patients with creatinine clearance of < 50 ml/min. 
 
Paediatric population 
The safety and efficacy of Zeffix 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.  
Zeffix can be taken with or without food. 
 
4.3 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 
 
Exacerbations of hepatitis 
 
Exacerbations on treatment 
Spontaneous exacerbations in chronic hepatitis B are relatively common and are characterised by 
transient increases in serum ALT. After initiating antiviral therapy, serum ALT may increase in some 
patients as serum HBV DNA levels decline. In patients with compensated liver disease, these 
increases in serum ALT were generally not accompanied by an increase in serum bilirubin 
concentrations or signs of hepatic decompensation. 
 
HBV viral subpopulations with reduced susceptibility to lamivudine (YMDD mutant HBV) have been 
identified with extended therapy. In some patients the development of YMDD mutant HBV can lead 
to exacerbation of hepatitis, primarily detected by serum ALT elevations and re-emergence of HBV 
DNA (see section 4.2). In patients who have YMDD mutant HBV, a switch to or addition of an 
alternative agent without cross-resistance to lamivudine based on therapeutic guideline should be 
considered (see section 5.1). 
 
Exacerbations after treatment discontinuation 
Acute exacerbation of hepatitis has been observed in patients who have discontinued hepatitis B 
therapy and is usually detected by serum ALT elevations and re-emergence of HBV DNA. In the 
controlled Phase III trials with no-active-treatment follow-up, the incidence of post-treatment ALT 
elevations (more than 3 times baseline) was higher in lamivudine-treated patients (21%) compared 
with those receiving placebo (8%). However, the proportion of patients who had post-treatment 
elevations associated with bilirubin elevations was low and similar in both treatment arms (see Table 3 
in section 5.1). For lamivudine-treated patients, the majority of post-treatment ALT elevations 
occurred between 8 and 12 weeks post-treatment. Most events have been self-limiting, however some 
fatalities have been observed. If Zeffix is discontinued , patients should be periodically monitored both 
clinically and by assessment of serum liver function tests (ALT and bilirubin levels), for at least four 
months, and then as clinically indicated. 



 19 

 
Exacerbations in patients with decompensated cirrhosis 
Transplantation recipients and patients with decompensated cirrhosis are at greater risk from active 
viral replication. Due to the marginal liver function in these patients, hepatitis reactivation at 
discontinuation of lamivudine or loss of efficacy during treatment may induce severe and even fatal 
decompensation. These patients should be monitored for clinical, virological and serological 
parameters associated with hepatitis B, liver and renal function, and antiviral response during 
treatment (at least every month), and, if treatment is discontinued for any reason, for at least 6 months 
after treatment. Laboratory parameters to be monitored should include (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 post-treatment should be monitored more frequently as appropriate. 
 
For patients who develop evidence of recurrent hepatitis post-treatment, there are insufficient data on 
the benefits of re-initiation of lamivudine treatment. 
 
Mitochondrial dysfunction 
 
Nucleoside and nucleotide analogues have been demonstrated in vitro and in vivo to cause a variable 
degree of mitochondrial damage. There have been reports of mitochondrial dysfunction in infants 
exposed in utero and/or post-natally to nucleoside analogues. The main adverse events reported are 
haematological disorders (anaemia, neutropenia), metabolic disorders (hyperlipasemia). Some late-
onset neurological disorders have been reported (hypertonia, convulsion, abnormal behaviour). The 
neurological disorders might be transient or permanent. Any child exposed in utero to nucleoside and 
nucleotide analogues, should have clinical and laboratory follow-up and should be fully investigated 
for possible mitochondrial dysfunction in cases which have relevant signs or symptoms. 
 
Paediatric patients 
 
Lamivudine has been administered to children (2 years and above) and adolescents with compensated 
chronic hepatitis B. However, due to limitations of the data, the administration of lamivudine to this 
patient population is not currently recommended (see section 5.1). 
 
Delta hepatitis or hepatitis C 
 
The efficacy of lamivudine in patients co-infected with Delta hepatitis or hepatitis C has not been 
established and caution is advised. 
 
Immunosuppressive treatments 
 
Data are limited on the use of lamivudine in HBeAg negative (pre-core mutant) patients and in those 
receiving concurrent immunosuppressive regimes, including cancer chemotherapy. Lamivudine should 
be used with caution in these patients. 
 
Monitoring 
 
During treatment with Zeffix patients should be monitored regularly. Serum ALT and HBV DNA 
levels should be monitored at 3 month intervals and in HBeAg positive patients HBeAg should be 
assessed every 6 months. 
 
HIV co-infection 
 
For the treatment of patients who are co-infected with HIV and are currently receiving or plan to 
receive treatment with lamivudine or the combination lamivudine-zidovudine, the dose of lamivudine 
prescribed for HIV infection (usually 150 mg/twice daily in combination with other antiretrovirals) 
should be maintained. For HIV co-infected patients not requiring anti-retroviral therapy, there is a risk 
of HIV mutation when using lamivudine alone for treating chronic hepatitis B.  



 20 

 
Transmission of hepatitis B 
 
There is no information available on maternal-foetal transmission of hepatitis B virus in pregnant 
women receiving treatment with lamivudine. The standard recommended procedures for hepatitis B 
virus immunisation in infants should be followed. 
 
Patients should be advised that therapy with lamivudine has not been proven to reduce the risk of 
transmission of hepatitis B virus to others and therefore, appropriate precautions should still be taken. 
 
Interactions with other medicinal products 
 
Zeffix 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). 
 
Excipients 
 
Sucrose 
Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or 
sucrase-isomaltase insufficiency should not take this medicine. 
Diabetic patients should be advised that each dose of oral solution (100 mg = 20 ml) contains 4 g of 
sucrose. 
 
Propyl parahydroxybenzoate and methyl parahydroxybenzoate 
The oral solution contains propyl and methyl parahydroxybenzoate. These products may cause allergic 
reactions (possibly delayed). 
 
Sodium 
This medicinal product contains 58.8 mg sodium per 20 ml, equivalent to 2.9% of the WHO 
recommended maximum daily intake of 2 g sodium for an adult. 
 
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 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). 
 



 21 

Lamivudine has no pharmacokinetic interaction with alpha-interferon when the two medicinal 
products are concurrently administered. There were no observed clinically significant adverse 
interactions in patients taking lamivudine concurrently with commonly used immunosuppressant 
medicinal products (e.g. cyclosporin A). However, formal interaction studies have not been 
performed. 
 
Emtricitabine 
 
Due to similarities, Zeffix should not be administered concomitantly with other cytidine analogues, 
such as emtricitabine. Moreover, Zeffix should not be taken with any other medicinal products 
containing lamivudine (see section 4.4). 
 
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). 
 
Sorbitol 
 
Co-administration of sorbitol solution (3.2 g, 10.2 g, 13.4 g) with a single 300 mg dose (Adult HIV 
daily dose) of lamivudine oral 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 chronic co-administration of Zeffix with medicinal products containing sorbitol or 
other osmotic acting poly-alcohols or monosaccharide alcohols (e.g. xylitol, mannitol, lactitol, 
maltitol). Consider more frequent monitoring of HBV viral load when chronic co-administration 
cannot be avoided.  
 
4.6 Fertility, pregnancy and lactation 
 
Pregnancy 
 
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.  
 
Available human data from the Antiretroviral Pregnancy Registry reporting more than 1000 outcomes 
from first trimester and more than 1000 outcomes from second and third trimester exposure in 
pregnant women indicate no malformative and foeto/neonatal effect. Less than 1% of these women 
have been treated for HBV, whereas the majority was treated for HIV at higher doses and with other 
concomitant medications. Zeffix 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. 
 
Breast-feeding 
 
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 sub-optimal antiviral effect. Maternal hepatitis B is 
not a contraindication to breast-feeding if the newborn is adequately managed for hepatitis B 
prevention at birth, and there is no evidence that the low concentration of lamivudine in human milk 
leads to adverse reactions in breastfed infants. Therefore breastfeeding may be considered in breast-
feeding mothers being treated with lamivudine for HBV taking into account the benefit of breast 
feeding for the child and the benefit of therapy for the woman. Where there is maternal transmission of 



 22 

HBV, despite adequate prophylaxis, consideration should be given to discontinuing breastfeeding to 
reduce the risk of the emergence of lamivudine resistant mutants in the infant.  
 
Fertility 
 
Reproductive studies in animals have shown no effect on male or female fertility (see section 5.3). 
 
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). 
 
4.7 Effects 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. 
 
4.8 Undesirable effects 
 
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 
Not known Thrombocytopenia 
Metabolism and nutrition disorders  
Very rare Lactic acidosis 
Immune system disorders: 
Rare Angioedema 
Hepatobiliary disorders 
Very common 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 self-limited, however 
fatalities have been observed very rarely (see section 4.4). 
Skin and subcutaneous tissue disorders 
Common Rash, pruritus 
Musculoskeletal and connective tissue disorders 
Common Elevations of CPK 
Common Muscle disorders, including myalgia and cramps* 



 23 

Not known Rhabdomyolysis 
* In Phase III studies frequency observed in the lamivudine treatment group was not greater than 
observed in the placebo group 
 
Paediatric population  
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. 
 
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. 
 
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 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. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group - Antivirals for systemic use, nucleoside and nucleotide reverse 
transcriptase inhibitors, ATC Code: J05AF05. 
 
Mechanism of action 
 
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 17-19 hours in vitro. Lamivudine-TP acts as a substrate for the HBV viral polymerase. 
 
The formation of further viral DNA is blocked by incorporation of lamivudine-TP into the chain and 
subsequent chain termination. 
 
Lamivudine-TP does not interfere with normal cellular deoxynucleotide metabolism. It is also only a 
weak inhibitor of mammalian DNA polymerases alpha and beta. Furthermore, lamivudine-TP has little 
effect on mammalian cell DNA content. 
 

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 24 

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. 
 
Clinical efficacy and safety 
 
Experience in patients with HBeAg positive CHB and compensated liver disease 
In controlled studies, 1 year of lamivudine therapy significantly suppressed HBV DNA replication 
(34-57 % of patients were below the assay detection limits (Abbott Genostics solution hybridization 
assay, LLOD < 1.6pg/ml)], normalised ALT level (40-72 % of patients), induced HBeAg 
seroconversion (HBeAg loss and HBeAb detection with HBV DNA loss [by conventional assay], 16-
18 % of patients), improved histology (38-52 % of patients had a ≥ 2 point decrease in the Knodell 
Histologic Activity Index [HAI]) and reduced progression of fibrosis (in 3-17 % of patients) and 
progression to cirrhosis. 
 
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 pre-treatment ALT > 2 x ULN seroconverted. At the end of 5 years, all patients had 
HBV DNA levels that were undetectable or lower than pre-treatment levels. 
 
Further results from the trial by YMDD mutant status are summarised in Table 2.  
 
Table 2: Efficacy results 5 years by YMDD status (Asian Study) NUCB3018 
 



 25 

 Subjects, % (no.) 
YMDD mutant HBV status YMDD1 Non-YMDD1 

    HBeAg seroconversion  
 
 - All patients 
 - Baseline ALT     ≤ 1 x ULN2 

 - Baseline ALT > 2 x ULN 
 
    Undetectable HBV DNA 
 
 - Baseline 3 

   
 - Week 260 4 

    negative 
    positive < baseline 
    positive > baseline 
 
 
    ALT normalisation 
 
 - Baseline 
   normal 
   above normal 
 
 - Week 260 
   normal 
   above normal < baseline 
   above normal > baseline 

 

 
 

38 
9 

60 
 
 
 

5 
 
 

8 
92 
0 
 
 
 
 
 

28 
73 
 
 

46 
21 
32 

 
 

(15/40) 
(1/11) 
(9/15) 

 
 
 

(2/40) 
 
 

(2/25) 
(23/25) 

 
 
 
 
 
 

(11/40) 
(29/40) 

 
 

(13/28) 
(6/28) 
(9/28) 

 

 
 

72 
33 

100 
 
 
 

6 
 
 

0 
100 
0 
 
 
 
 
 

33 
67 
 
 

50 
0 

50 

 
 

(13/18) 
(2/6) 

(11/11) 
 
 
 

(1/18) 
 

 
 

(4/4) 
 
 
 
 
 
 

(6/18) 
(12/18) 

 
 

(2/4) 
 

(2/4) 

 
1  Patients designated as YMDD mutant were those with ≥5% YMDD mutant HBV at any annual time-point during the 
5-year period. Patients categorised as non-YMDD mutant were those with > 95% wild-type HBV at all annual time-points 
during the 5-year study period 
2 Upper limit of normal 
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 long-term 
follow-up study of patients who had previously seroconverted and discontinued lamivudine, late 
virological relapse occurred in 39 % of the subjects. Therefore, following HBeAg seroconversion, 
patients should be periodically monitored to determine that serologic and clinical responses are being 
maintained. In patients who do not maintain a sustained serological response, consideration should be 
given to retreatment with either lamivudine or an alternative antiviral agent for resumption of clinical 
control of HBV. 
 
In patients followed for up to 16 weeks after discontinuation of treatment at one year, post-treatment 
ALT elevations were observed more frequently in patients who had received lamivudine than in 
patients who had received placebo. A comparison of post-treatment ALT elevations between weeks 52 
and 68 in patients who discontinued lamivudine at week 52 and patients in the same studies who 
received placebo throughout the treatment course is shown in Table 3. The proportion of patients who 
had post-treatment ALT elevations in association with an increase in bilirubin levels was low and 
similar in patients receiving either lamivudine or placebo. 
 



 26 

Table 3: Post-treatment ALT Elevations in 2 Placebo-Controlled Studies in Adults 
 

 Patients with ALT Elevation/ 
Patients with Observations* 

Abnormal Value Lamivudine Placebo 
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 IU/l 

 
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 pre-treatment. In patients with the mutant, 4/26 (15%) patients showed 
improvement in necroinflammatory score and 8/26 (31 %) patients worsened compared to pre-
treatment. No patients in either group progressed to cirrhosis. 
 
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 on-therapy levels, progression of 
signs and symptoms of hepatitis disease and/or worsening of hepatic necroinflammatory findings. 
Given the risk of YMDD mutant HBV, maintenance of lamivudine monotherapy is not appropriate in 
patients with detectable serum HBV DNA at or beyond 24 weeks of treatment (see section 4.4). 
 
In a double-blind study in CHB patients with YMDD mutant HBV and compensated liver disease 
(NUC20904), with a reduced virological and biochemical response to lamivudine (n=95), the addition 
of adefovir dipivoxil 10 mg once daily to ongoing lamivudine 100mg for 52 weeks resulted in a 
median decrease in HBV DNA of 4.6 log10 copies/ml compared to a median increase of 0.3 
log10 copies/ml in those patients receiving lamivudine monotherapy. Normalisation of ALT levels 
occurred in 31 % (14/45) of patients receiving combined therapy versus 6 % (3/47) receiving 
lamivudine alone. Viral suppression was maintained (follow-on study NUC20917) with combined 
therapy during the second year of treatment to week 104 with patients having continued improvement 
in virologic and biochemical responses. 
 
In a retrospective study to determine the factors associated with HBV DNA breakthrough, 159 Asian 
HBeAg-positive patients were treated with lamivudine and followed up for a median period of almost 
30 months. Those with HBV DNA levels greater than 200 copies/mL at 6 months (24 weeks) of 
lamivudine therapy had a 60 % chance of developing the YMDD mutant compared with 8 % of those 
with HBV DNA levels less than 200 copies/mL at 24 weeks of lamivudine therapy. The risk for 
developing YMDD mutant was 63% versus 13% with a cut off of 1000 copies/ml (NUCB3009 and 
NUCB3018). 



 27 

 
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 non-controlled studies, where lamivudine was administered 
prior to and during transplantation, effective HBV DNA suppression and ALT normalisation was 
demonstrated. When lamivudine therapy was continued post transplantation there was reduced graft 
re-infection by HBV, increased HBsAg loss and on one-year survival rate of 76 – 100 %. 
 
As anticipated due to the concomitant immunosuppression, the rate of emergence of YMDD mutant 
HBV after 52 weeks treatment was higher (36 % - 64 %) in the liver transplant population than in the 
immunocompetent CHB patients (14 % - 32 %).  
 
Forty patients (HBeAg negative or HBeAg positive) with either decompensated liver disease or 
recurrent HBV following liver transplantation and YMDD mutant were enrolled into an open label 
arm of study NUC20904. Addition of 10 mg adefovir dipivoxil once daily to ongoing lamivudine 
100mg for 52 weeks resulted in a median decrease in HBV DNA of 4.6 log10 copies/ml. Improvement 
in liver function was also seen after one year of therapy. This degree of viral suppression was 
maintained (follow-on study NUC20917) with combined therapy during the second year of treatment 
to week 104 and most patients had improved markers of liver function and continued to derive clinical 
benefit. 
 
Experience in CHB patients with advanced fibrosis or cirrhosis 
In a placebo-controlled study in 651 patients with clinically compensated chronic hepatitis B and 
histologically confirmed fibrosis or cirrhosis, lamivudine treatment (median duration 32 months) 
significantly reduced the rate of overall disease progression (34/436, 7.8 % for lamivudine versus 
38/215, 17.7 % for placebo, p=0.001), demonstrated by a significant reduction in the proportion of 
patients having increased Child-Pugh scores (15/436, 3.4 % versus 19/215, 8.8 %, p=0.023) or 
developing hepatocellular carcinoma (17/436, 3.9 % versus 16/215, 7.4 %, p=0.047). The rate of 
overall disease progression in the lamivudine group was higher for subjects with detectable YMDD 
mutant HBV DNA (23/209, 11 %) compared to those without detectable YMDD mutant HBV 
(11/221, 5 %). However, disease progression in YMDD subjects in the lamivudine group was lower 
than the disease progression in the placebo group (23/209, 11 % versus 38/214, 18 % respectively). 
Confirmed HBeAg seroconversion occurred in 47 % (118/252) of subjects treated with lamivudine 
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. 
 
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 (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 1.1-1.5 µg/ml and trough levels were 0.015-0.020 µg/ml. 
 



 28 

Co-administration of lamivudine with food resulted in a delay of tmax and a lower Cmax (decreased by 
up to 47 %). However, the extent (based on the AUC) of lamivudine absorbed was not influenced, 
therefore lamivudine can be administered with or without food. 
 
Distribution 
 
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 cerebro-spinal 
fluid (CSF). The mean lamivudine CSF/serum concentration ratio 2-4 hours after oral administration 
was approximately 0.12. 
 
Biotransformation 
 
Lamivudine is predominately cleared by renal excretion of unchanged substance. The likelihood of 
metabolic substance interactions with lamivudine is low due to the small (5-10 %) extent of hepatic 
metabolism and the low plasma protein binding. 
 
Elimination 
 
The mean systemic clearance of lamivudine is approximately 0.3 l/h/kg. The observed half-life of 
elimination is 5 to 7 hours. The majority of lamivudine is excreted unchanged in the urine via 
glomerular filtration and active secretion (organic cationic transport system). Renal clearance accounts 
for about 70 % of lamivudine elimination. 
 
Special populations 
 
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). 
 
5.3 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 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 60-70 times higher than the anticipated clinical 
plasma levels. As the in vitro mutagenic activity of lamivudine could not be confirmed by in vivo tests, 
it is concluded that lamivudine should not represent a genotoxic hazard to patients undergoing 
treatment. 
 
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 



 29 

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. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Sucrose (20 % w/v) 
Methyl parahydroxybenzoate (E218) 
Propyl parahydroxybenzoate (E216) 
Citric acid (anhydrous) 
Propylene glycol (E1520) 
Sodium citrate 
Artificial strawberry flavour 
Artificial banana flavour 
Purified water 
 
6.2 Incompatibilities 
 
Not applicable 
 
6.3 Shelf life 
 
2 years  
 
After first opening: 1 month 
 
6.4 Special precautions for storage 
 
Do not store above 25 ºC. 
 
6.5 Nature and contents of container 
 
Cartons containing 240 ml lamivudine oral solution in an opaque, white, high-density polyethylene 
(HDPE) bottle with a polypropylene child resistant closure. The pack also includes a polyethylene 
applicator-adapter, and a 10 ml oral applicator comprised of a polypropylene barrel (with ml 
graduations) and a polyethylene plunger. 
 
The oral applicator is provided for accurate measurement of the prescribed dose of oral solution. 
 
6.6 Special precautions for disposal 
 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
GlaxoSmithKline (Ireland) Limited  
12 Riverwalk  
Citywest Business Campus 
Dublin 24 
Ireland 



 30 

 
 
8.  MARKETING AUTHORISATION NUMBER 
 
EU/1/99/114/003 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 29 July 1999 
Date of latest renewal: 23 June 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 
 
 



 31 

 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX II 
 
A.  MANUFACTUR ER(S) RESPONSIBLE FOR BATCH 

RELEASE 
 
B.  CONDITIONS OR RESTRICTIONS REGARDING SUPPLY 

AND USE 
 
C.  OTHER CONDITIONS AND REQUIREMENTS OF THE 

MARKETING AUTHORISATION 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO 

THE SAFE AND EFFECTIVE USE OF THE MEDICINAL 
PRODUCT 

 



 32 

A.  MANUFACTUR ER(S) RESPONSIBLE FOR BATCH RELEASE 
 

Name and address of the manufacturers responsible for batch release 
 
Film-coated tablet: 
 
GlaxoSmithKline Pharmaceuticals S.A. 
ul. Grunwaldzka 189 
60-322 Poznan 
Poland 
 
Oral solution: 
 
GlaxoSmithKline Trading Services Limited  
12 Riverwalk,  
Citywest Business Campus  
Dublin 24, 
Ireland 
 
The printed package leaflet of the medicinal product must state the name and address of the 
manufacturer responsible for the release of the concerned batch 
 
 
B.  CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
 
Medicinal product subject to restricted medical prescription (See Annex I: Summary of Product 
Characteristics, section 4.2). 
 
 
C.  OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 
 
• Periodic safety update reports (PSURs) 

 
The requirements for submission of PSURs for this medicinal products are set out in the list of Union 
reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and any 
subsequent updates published on the European medicines web-portal. 
 
 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT   
 
• Risk management plan (RMP) 

 
Not applicable. 
 



 33 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 
 
 



 34 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 



 35 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON FOR TABLETS: 28 tablet box, 84 tablet box 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Zeffix 100 mg film-coated tablets 
lamivudine 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each film-coated tablet contains 100 mg lamivudine  
 
 
3. LIST OF EXCIPIENTS 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
28 film-coated tablets 
84 film-coated tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use 
 
Oral use 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Do not store above 30°C 
 
 



 36 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
GlaxoSmithKline (Ireland) Limited  
12 Riverwalk  
Citywest Business Campus 
Dublin 24 
Ireland 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/99/114/001 28 tablets 
EU/1/99/114/002 84 tablets 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
zeffix 100 mg 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included.  
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
PC: 
SN: 
NN: 
 



 37 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
28 tablet box, 84 tablet box 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Zeffix 100 mg tablets 
lamivudine 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
GlaxoSmithKline (Ireland) Limited  
 
 
3. EXPIRY DATE 
 
EXP  
 
 
4. BATCH NUMBER 
 
Lot 
 
5. OTHER 
 
 



 38 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON FOR ORAL SOLUTION 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Zeffix 5 mg/ml oral solution 
lamivudine 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each ml of the oral solution contains 5 mg lamivudine.  
 
 
3. LIST OF EXCIPIENTS 
 
Contains amongst others: 
sugar (sucrose), sodium, propylene glycol (E1520), preservatives: methyl parahydroxybenzoate 
(E218) and propyl parahydroxybenzoate (E216) 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Each bottle contains 240 ml oral solution 
The pack contains an oral applicator. 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use 
 
Oral use 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP  
 
Discard one month after first opening 
 



 39 

 
9. SPECIAL STORAGE CONDITIONS 
 
Do not store above 25°C 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
GlaxoSmithKline (Ireland) Limited  
12 Riverwalk  
Citywest Business Campus 
Dublin 24 
Ireland 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/99/114/003 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
 
16. INFORMATION IN BRAILLE 
 
zeffix 5 mg/ml 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included.  
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC: 
SN: 
NN: 
 



 40 

 
PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING 
 
BOTTLE LABEL FOR ORAL SOLUTION 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Zeffix 5 mg/ml oral solution 
lamivudine 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each ml of the oral solution contains 5 mg lamivudine. 
 
3. LIST OF EXCIPIENTS 
 
Contains amongst others: 
sugar (sucrose), sodium, propylene glycol (E1520), preservatives: methyl parahydroxybenzoate 
(E218) and propyl parahydroxybenzoate (E216)  
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Each bottle contains 240 ml oral solution 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use 
 
Oral use 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED 

OUT OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP  
 
Discard one month after first opening 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Do not store above 25°C 
 



 41 

 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
GlaxoSmithKline (Ireland) Limited  
12 Riverwalk  
Citywest Business Campus 
Dublin 24 
Ireland 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/99/114/003 
 
 
13. BATCH NUMBER 
 
Lot 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
 
15. INSTRUCTIONS ON USE 
 
 
 
16. INFORMATION IN BRAILLE 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
 
 



 42 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 
 
 
 
 
 
 
 
 
 



 43 

Package leaflet: Information for the patient 
 

Zeffix 100 mg film-coated tablets 
lamivudine 

 
Read all of this leaflet carefully before you start taking this medicine. 
- Keep this leaflet. You may need to read it again. 
- If you have further questions, ask your doctor or pharmacist. 
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them 

even if their signs of illness are the same as yours. 
- If you get any side effects, talk to your doctor or pharmacist. This includes any possible side 

effects not listed in this leaflet. See section 4. 
 
What is in this leaflet: 
1. What Zeffix is and what it is used for 
2. What you need to know before you take Zeffix 
3. How to take Zeffix 
4. Possible side effects 
5. How to store Zeffix 
6. Contents of the pack and other information 
 
 
1. What Zeffix is and what it is used for 
 
The active ingredient in Zeffix is lamivudine.   
 
Zeffix is used to treat long term (chronic) hepatitis B infection in adults. 
 
Zeffix is an antiviral medicine that suppresses the hepatitis B virus and belongs to a group of 
medicines called nucleoside analogue reverse transcriptase inhibitors (NRTIs). 
 
Hepatitis B is a virus which infects the liver, causes long term (chronic) infection, and can lead to liver 
damage. Zeffix can be used in people whose liver is damaged, but still functions normally 
(compensated liver disease) and in combination with other medicines in people whose liver is damaged 
and does not function normally (decompensated liver disease). 
 
Treatment with Zeffix can reduce the amount of hepatitis B virus in your body. This should lead to a 
reduction in liver damage and an improvement in your liver function. Not everyone responds to 
treatment with Zeffix in the same way. Your doctor will monitor the effectiveness of your treatment 
with regular blood tests. 
 
 
2. What you need to know before you take Zeffix 
 
Do not take Zeffix 
• if you’re allergic to lamivudine or to any of the other ingredients of this medicine (listed in 

Section 6). 
 Check with your doctor if you think this applies to you. 
 
Warnings and precautions 
 
Some people taking Zeffix or other similar medicines are more at risk of serious side effects. You need 
to be aware of the extra risks: 
• if you have ever had other types of liver disease, such as hepatitis C 
• if you’re seriously overweight (especially if you’re a woman). 
 Talk to your doctor if any of these apply to you. You may need extra check-ups, including blood 
tests, while you’re taking your medication. See Section 4 for more information about the risks.  



 44 

 
Don’t stop taking Zeffix without your doctor’s advice, as there is a risk of your hepatitis getting 
worse. When you stop taking Zeffix your doctor will monitor you for at least four months to check for 
any problems. This will mean taking blood samples to check for any raised liver enzyme levels, which 
may indicate liver damage. See section 3 for more information about how to take Zeffix. 
 
Protect other people 
Hepatitis B infection is spread by sexual contact with someone who has the infection, or by transfer of 
infected blood (for example, by sharing injection needles). Zeffix will not stop you passing hepatitis B 
infection on to other people. To protect other people from becoming infected with hepatitis B: 
 Use a condom when you have oral or penetrative sex. 
 Don’t risk blood transfer — for example, don’t share needles. 
 
Other medicines and Zeffix 
Tell your doctor or pharmacist if you’re taking, have recently taken or might take any other medicines, 
including herbal medicines or other medicines you bought without a prescription.  
 
Remember to tell your doctor or pharmacist if you begin taking a new medicine while you’re taking 
Zeffix. 
 
These medicines should not be used with Zeffix: 

• medicines (usually liquids) containing sorbitol and other sugar alcohols (such as xylitol, 
mannitol, lactitol or maltitol), if taken regularly 

• other medicines containing lamivudine, used to treat HIV infection (sometimes called the AIDS 
virus) 

• emtricitabine used to treat HIV or hepatitis B infection 
• cladribine, used to treat hairy cell leukaemia 

 Tell your doctor if you’re being treated with any of these.  
 
Pregnancy 
If you are pregnant, think you may be pregnant or are planning to have a baby: 
 Talk to your doctor about the risks and benefits of taking Zeffix during your pregnancy. 
Do not stop treatment with Zeffix without your doctor’s advice. 
 
Breast-feeding  
Zeffix can pass into breast-milk. If you are breast-feeding, or thinking about breast-feeding: 
 Talk to your doctor before you take Zeffix. 

 
Driving and using machines 
Zeffix may make you feel tired, which could affect your ability to drive or use machines.  
 Don’t drive or use machines unless you are sure you’re not affected. 

 
Zeffix contains sodium 
This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium-
free’. 
 
 
3. How to take Zeffix 
 
Always take this medicine exactly as your doctor has told you to. Check with your doctor or 
pharmacist if you’re not sure. 
 
Stay in regular contact with your doctor 
Zeffix helps to control your hepatitis B infection. You need to keep taking it every day to control your 
infection and stop your illness getting worse. 
 Keep in touch with your doctor, and don’t stop taking Zeffix without your doctor’s advice. 
 



 45 

How much to take 
The usual dose of Zeffix is one tablet (100 mg lamivudine) once a day.  
 
Your doctor may prescribe a lower dose if you have problems with your kidneys. An oral solution of 
Zeffix is available for people who need a lower than usual dose, or who can’t take tablets. 
 
 Talk to your doctor if this applies to you. 
 
If you are already taking another medicine that contains lamivudine for HIV infection, your doctor 
will continue to treat you with the higher dose, (usually 150 mg twice a day), because the dose of 
lamivudine in Zeffix (100 mg) is not enough to treat HIV infection. If you are planning to change your 
HIV treatment, discuss this change with your doctor first. 
 
Swallow the tablet whole, with some water. Zeffix can be taken with or without food. 
 
If you take more Zeffix than you should  
Accidentally taking too much Zeffix is unlikely to cause any serious problems. If you accidentally take 
too much, tell your doctor or your pharmacist, or contact your nearest hospital emergency department 
for further advice. 
 
If you forget to take Zeffix 
If you forget to take a dose, take it as soon as you remember. Then continue your treatment as before. 
Don’t take a double dose to make up for a missed dose.  
 
Don’t stop taking Zeffix 
You must not stop taking Zeffix without consulting your doctor. There is a risk of your hepatitis 
getting worse (see section 2). When you stop taking Zeffix your doctor will monitor you for at least 
four months to check for any problems. This will mean taking blood samples to check for any raised 
liver enzyme levels, which may indicate liver damage. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them.  
 
Side effects that were commonly reported in Zeffix clinical trials were tiredness, respiratory tract 
infections, throat discomfort, headache, stomach discomfort and pain, nausea, vomiting and diarrhoea, 
increases in liver enzymes and enzymes produced in the muscles (see below).  
 
Allergic reaction  
These are rare (may affect up to 1 in 1,000 people). Signs include: 

• swelling of eyelids, face or lips 
• difficulty swallowing or breathing 

 Contact a doctor immediately if you get these symptoms. Stop taking Zeffix. 
 
Side effects thought to be caused by Zeffix  
 
A very common side effect (these may affect more than 1 in 10 people) which may show up in 
blood tests is: 

• an increase in the level of some liver enzymes (transaminases), which may be a sign of 
inflammation or damage in the liver. 
 

A common side effect (these may affect up to 1 in 10 people) is: 
• cramps and muscle pains  
• skin rash or ‘hives’ anywhere on the body 
 

A common side effect which may show up in blood tests is: 



 46 

• an increase in the level of an enzyme produced in the muscles (creatine phosphokinase) which 
may be a sign that body tissue is damaged. 

 
A very rare side effect (these may affect up to 1 in 10,000 people) is: 

• lactic acidosis (excess lactic acid in the blood). 
 
Other side effects  
Other side effects have occurred in a very small number of people but their exact frequency is 
unknown 

• breakdown of muscle tissue 
• a worsening of liver disease after Zeffix is stopped or during treatment if the hepatitis B virus 

becomes resistant to Zeffix. This can be fatal in some people. 
 
A side effect which may show up in blood tests is: 

• a decrease in the number of cells involved in blood clotting (thrombocytopenia).  
 
If you get any side effects 
 Talk to your doctor or pharmacist. This includes any possible side effects not listed in this 

leaflet.  
 
Reporting of side effects 
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects 
not listed in this leaflet. You can also report side effects directly via the national reporting system 
listed in Appendix V. By reporting side effects you can help provide more information on the safety of 
this medicine. 

 
5. How to store Zeffix 
 
Keep this medicine out of the sight and reach of children. 
 
Don’t take this medicine after the expiry date shown on the carton and blister. 
 
Don’t store above 30 °C. 
 
Do not throw away any medicines in your wastewater or household rubbish. Ask your pharmacist how 
to throw away medicines you no longer use. These measures will help to protect the environment. 
 
 
6. Contents of the pack and other information 
 
What Zeffix contains 
 
The active substance is lamivudine. Each film-coated tablet contains 100 mg of lamivudine. 
 
The other ingredients are: microcrystalline cellulose, sodium starch glycolate, magnesium stearate, 
hypromellose, titanium dioxide, macrogol 400, polysorbate 80, synthetic yellow and red iron oxide. 
 
What Zeffix looks like and contents of the pack 
 
Zeffix film-coated tablets are supplied in tamper evident foil blisters containing 28 or 84 tablets. 
The tablets are butterscotch coloured, capsule shaped, biconvex and engraved “GX CG5” on one side. 
 
Not all pack-sizes may be available in your country. 
 
 
 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


 47 

Manufacturer 
 

Marketing Authorisation Holder 

GlaxoSmithKline 
Pharmaceuticals S.A. 
ul. Grunwaldzka 189 
60-322 Poznan 
Poland 
 

GlaxoSmithKline (Ireland) Limited  
12 Riverwalk  
Citywest Business Campus 
Dublin 24 
Ireland 
 

 
 
For any information about this medicinal product, please contact the local representative of the 
Marketing Authorisation Holder: 
 
  
België/Belgique/Belgien 
GlaxoSmithKline Pharmaceuticals s.a./n.v. 
Tél/Tel: + 32 (0)10 85 52 00 

Lietuva 
GlaxoSmithKline Lietuva UAB 
Tel: + 370 5 264 90 00 
info.lt@gsk.com 
 

България 
ГлаксоСмитКлайн ЕООД 
Teл.: + 359 2 953 10 34 
 

Luxembourg/Luxemburg 
GlaxoSmithKline Pharmaceuticals s.a./n.v. 
Belgique/Belgien 
Tél/Tel: + 32 (0)10 85 52 00 
 

Česká republika 
GlaxoSmithKline s.r.o. 
Tel: + 420 222 001 111 
cz.info@gsk.com 
 

Magyarország 
GlaxoSmithKline Kft. 
Tel.: + 36 1 225 5300 

Danmark 
GlaxoSmithKline Pharma A/S 
Tlf: + 45 36 35 91 00 
dk-info@gsk.com 
 

Malta 
GlaxoSmithKline (Malta) Limited 
Tel: + 356 21 238131 

Deutschland 
GlaxoSmithKline GmbH & Co. KG 
Tel.: + 49 (0)89 36044 8701 
produkt.info@gsk.com 
 

Nederland 
GlaxoSmithKline BV 
Tel: + 31 (0)33 2081100 
 

Eesti 
GlaxoSmithKline Eesti OÜ 
Tel: + 372 6676 900 
estonia@gsk.com 
 

Norge 
GlaxoSmithKline AS 
Tlf: + 47 22 70 20 00 
 

Ελλάδα 
GlaxoSmithKline Μονοπρόσωπη A.E.B.E. 
Τηλ: + 30 210 68 82 100 

Österreich 
GlaxoSmithKline Pharma GmbH 
Tel: + 43 (0)1 97075 0 
at.info@gsk.com 
 

España 
GlaxoSmithKline, S.A. 
Tel: + 34 900 202 700 
es-ci@gsk.com 
 

Polska 
GSK Services Sp. z o.o. 
Tel.: + 48 (0)22 576 9000 

France 
Laboratoire GlaxoSmithKline 
Tél.: + 33 (0)1 39 17 84 44 

Portugal 
Glaxo Wellcome Farmacêutica, Lda.  
Tel: + 351 21 412 95 00 



 48 

diam@gsk.com 
 

FI.PT@gsk.com 
 

Hrvatska 
GlaxoSmithKline d.o.o. 
Tel: + 385 1 6051 999 
 

România 
GlaxoSmithKline (GSK) S.R.L.  
Tel: + 4021 3028 208 

Ireland 
GlaxoSmithKline (Ireland) Limited 
Tel: + 353 (0)1 4955000 

Slovenija 
GlaxoSmithKline d.o.o. 
Tel: + 386 (0)1 280 25 00 
medical.x.si@gsk.com 
 

Ísland 
Vistor hf. 
Sími: + 354 535 7000 

Slovenská republika 
GlaxoSmithKline Slovakia s. r. o. 
Tel: + 421 (0)2 48 26 11 11 
recepcia.sk@gsk.com 
 

Italia 
GlaxoSmithKline S.p.A. 
Tel: + 39 (0)45 7741 111 

Suomi/Finland 
GlaxoSmithKline Oy 
Puh/Tel: + 358 (0)10 30 30 30 
Finland.tuoteinfo@gsk.com 
 

Κύπρος 
GlaxoSmithKline (Cyprus) Ltd 
Τηλ: + 357 22 39 70 00  
gskcyprus@gsk.com 
 

Sverige 
GlaxoSmithKline AB 
Tel: + 46 (0)8 638 93 00 
info.produkt@gsk.com 

Latvija 
GlaxoSmithKline Latvia SIA 
Tel: + 371 67312687 
lv-epasts@gsk.com 

United Kingdom 
GlaxoSmithKline UK Ltd 
Tel: + 44 (0)800 221441 
customercontactuk@gsk.com  
 

  
 
This leaflet was last revised in  
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu  
 

 



 49 

 
Package leaflet: Information for the patient 

 
Zeffix 5 mg/ml oral solution 

lamivudine 
 
Read all of this leaflet carefully before you start taking this medicine. 
- Keep this leaflet. You may need to read it again. 
- If you have further questions, ask your doctor or pharmacist. 
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them 

even if their signs of illness are the same as yours. 
- If you get any side effects, talk to your doctor or pharmacist. This includes any possible side 

effects not listed in this leaflet. See section 4. 
 
What is in this leaflet: 
1. What Zeffix is and what it is used for 
2. What you need to know before you take Zeffix 
3. How to take Zeffix 
4. Possible side effects 
5. How to store Zeffix 
6. Contents of the pack and other information 
 
 
1. What Zeffix is and what it is used for 
 
The active ingredient in Zeffix is lamivudine.   
 
Zeffix is used to treat long term (chronic) hepatitis B infection in adults. 
 
Zeffix is an antiviral medicine that suppresses the hepatitis B virus and belongs to a group of 
medicines called nucleoside analogue reverse transcriptase inhibitors (NRTIs).  
 
Hepatitis B is a virus which infects the liver, causes long term (chronic) infection, and can lead to liver 
damage. Zeffix can be used in people whose liver is damaged, but still functions normally 
(compensated liver disease) and in combination with other medicines in people whose liver is 
damaged and does not function normally (decompensated liver disease). 
 
Treatment with Zeffix can reduce the amount of hepatitis B virus in your body. This should lead to a 
reduction in liver damage and an improvement in your liver function. Not everyone responds to 
treatment with Zeffix in the same way. Your doctor will monitor the effectiveness of your treatment 
with regular blood tests. 
 
 
2. What you need to know before you take Zeffix 
 
Do not take Zeffix 
• if you’re allergic to lamivudine or to any of the other ingredients of this medicine (listed in 

Section 6). 
 Check with your doctor if you think this applies to you. 
  
Warnings and precautions 
Some people taking Zeffix or other similar medicines are more at risk of serious side effects. You need 
to be aware of the extra risks: 
• if you have ever had other types of liver disease, such as hepatitis C 
• if you’re seriously overweight (especially if you’re a woman). 
 Talk to your doctor if any of these apply to you. You may need extra check-ups, including blood 
tests, while you’re taking your medication. See Section 4 for more information about the risks.  



 50 

 
Don’t stop taking Zeffix without your doctor’s advice, as there is a risk of your hepatitis getting 
worse. When you stop taking Zeffix your doctor will monitor you for at least four months to check for 
any problems. This will mean taking blood samples to check for any raised liver enzyme levels, which 
may indicate liver damage. See section 3 for more information about how to take Zeffix. 
 
Protect other people 
Hepatitis B infection is spread by sexual contact with someone who has the infection, or by transfer of 
infected blood (for example, by sharing injection needles). Zeffix will not stop you passing hepatitis B 
infection on to other people. To protect other people from becoming infected with hepatitis B: 
 Use a condom when you have oral or penetrative sex. 
 Don’t risk blood transfer — for example, don’t share needles. 
 
Other medicines and Zeffix 
Tell your doctor or pharmacist if you’re taking, have recently taken or might take any other medicines, 
including herbal medicines or other medicines you bought without a prescription.  
 
Remember to tell your doctor or pharmacist if you begin taking a new medicine while you’re taking 
Zeffix. 
 
These medicines should not be used with Zeffix: 

• medicines (usually liquids) containing sorbitol and other sugar alcohols (such as xylitol, 
mannitol, lactitol or maltitol), if taken regularly 

• other medicines containing lamivudine, used to treat HIV infection (sometimes called the AIDS 
virus) 

• emtricitabine, used to treat HIV or hepatitis B infection 
• cladribine, used to treat hairy cell leukaemia 

 Tell your doctor if you’re being treated with any of these.  
 
Pregnancy 
If you are pregnant, think you may be pregnant or are planning to have a baby: 
 Talk to your doctor about the risks and benefits of taking Zeffix during your pregnancy. 
Do not stop treatment with Zeffix without your doctor’s advice. 
 
Breast-feeding 
Zeffix can pass into breast-milk. If you are breast-feeding, or thinking about breast-feeding:  
 Talk to your doctor before you take Zeffix. 

 
Driving and using machines 
Zeffix may make you feel tired, which could affect your ability to drive or use machines.  
 Don’t drive or use machines unless you are sure you’re not affected. 

 
Zeffix contains sugar, preservatives, propylene glycol and sodium 
 
If you are diabetic, please note that each dose of Zeffix (100 mg = 20 ml) contains 4 g of sucrose.  
 
Zeffix contains sucrose. If you have been told by your doctor that you have an intolerance to some 
sugars, contact your doctor before taking Zeffix. Sucrose may be harmful to the teeth. 
 
Zeffix contains preservatives (parahydroxybenzoates) which may cause allergic reactions (possibly 
delayed). 
 
This medicine contains 400 mg propylene glycol in each 20 ml. 
 
This medicine contains 58.8 mg sodium (main component of cooking/table salt) in each 20 ml. This is 
equivalent to 2.9% of the recommended maximum daily dietary intake of sodium for an adult. 
 



 51 

 
3. How to take Zeffix 
 
Always take this medicine exactly as your doctor has told you to. Check with your doctor or 
pharmacist if you’re not sure. 
 
Stay in regular contact with your doctor 
Zeffix helps to control your hepatitis B infection. You need to keep taking it every day to control your 
infection and stop your illness getting worse. 
 Keep in touch with your doctor, and don’t stop taking Zeffix without your doctor’s advice. 
 
How much to take 
The usual dose of Zeffix is 20 ml (100 mg lamivudine) once a day.  
 
Your doctor may prescribe a lower dose if you have problems with your kidneys.   
 
 Talk to your doctor if this applies to you. 
 
If you are already taking another medicine that contains lamivudine for HIV infection, your doctor 
will continue to treat you with the higher dose, (usually 150 mg twice a day), because the dose of 
lamivudine in Zeffix (100 mg) is not enough to treat HIV infection. If you are planning to change your 
HIV treatment, discuss this change with your doctor first. 
 
Zeffix can be taken with or without food. 
 
See the diagram and instructions after section 6 of this leaflet for how to measure and take a 
dose of medicine. 
 
If you take more Zeffix than you should 
Accidentally taking too much Zeffix is unlikely to cause any serious problems. If you accidentally take 
too much, tell your doctor or your pharmacist, or contact your nearest hospital emergency department 
for further advice. 
 
If you forget to take Zeffix 
If you forget to take a dose, take it as soon as you remember. Then continue your treatment as before. 
Don’t take a double dose to make up for a missed dose. 
 
Don’t stop taking Zeffix 
You must not stop taking Zeffix without consulting your doctor. There is a risk of your hepatitis 
getting worse (see section 2). When you stop taking Zeffix your doctor will monitor you for at least 
four months to check for any problems. This will mean taking blood samples to check for any raised 
liver enzyme levels, which may indicate liver damage. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them.  
 
Side effects that were commonly reported in Zeffix clinical trials were tiredness, respiratory tract 
infections, throat discomfort, headache, stomach discomfort and pain, nausea, vomiting and diarrhoea, 
increases in liver enzymes and enzymes produced in the muscles (see below).  
 
Allergic reaction  
These arerare (may affect up to 1 in 1,000 people). Signs include: 

• swelling of eyelids, face or lips 
•  difficulty swallowing or breathing 



 52 

 Contact a doctor immediately if you get these symptoms. Stop taking Zeffix. 
 
Side effects thought to be caused by Zeffix 
 
A very common side effect (these may affect more than 1 in 10 people) which may show up in 
blood tests is: 

• an increase in the level of some liver enzymes (transaminases), which may be a sign of 
inflammation or damage in the liver. 

 
A common side effect (these may affect up to 1 in 10 people) is: 

• cramps and muscle pains 
• skin rash or ‘hives’ anywhere on the body 

 
A common side effect which may show up in blood tests is: 

• an increase in the level of an enzyme produced in the muscles (creatine phosphokinase) which 
may be a sign that body tissue is damaged. 

 
A very rare side effect (these may affect up to 1 in 10,000 people) is: 

• lactic acidosis (excess lactic acid in the blood). 
 
Other side effects  
Other side effects have occurred in a very small number of people but their exact frequency is 
unknown  

• breakdown of muscle tissue 
• a worsening of liver disease after Zeffix is stopped or during treatment if the hepatitis B virus 

becomes resistant to Zeffix. This can be fatal in some people. 
 
A side effect which may show up in blood tests is: 

• a decrease in the number of cells involved in blood clotting (thrombocytopenia).  
 
If you get any side effects 
 Talk to your doctor or pharmacist. This includes any possible side effects not listed in this 

leaflet.  
 
Reporting of side effects 
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects 
not listed in this leaflet. You can also report side effects directly via the national reporting system 
listed in Appendix V. By reporting side effects you can help provide more information on the safety of 
this medicine. 

 
5. How to store Zeffix 
 
Keep this medicine out of the sight and reach of children. 
 
Don’t take this medicine after the expiry date shown on the bottle and the carton.  
 
Don’t store above 25 °C. 
 
Discard one month after first opening. 
 
Do not throw away any medicines in your wastewater or household rubbish. Ask your pharmacist how 
to throw away medicines you no longer use. These measures will help to protect the environment. 
 
 
6. Contents of the pack and other information 
 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


 53 

What Zeffix contains 
 
The active substance is lamivudine. Each ml of oral solution contains 5 mg of lamivudine. 
 
The other ingredients are: sucrose, methyl parahydroxybenzoate (E218), propyl parahydroxybenzoate 
(E216), citric acid, propylene glycol (E1520), sodium citrate, artificial strawberry flavour, artificial 
banana flavour, purified water. 
 
What Zeffix looks like and contents of the pack 
 
Zeffix oral solution is supplied in cartons containing a white polyethylene bottle, with a child resistant 
cap. The solution is clear, colourless to pale yellow in colour with strawberry/banana flavouring. The 
bottle contains 240 ml of lamivudine solution (5 mg/ml). The pack includes an oral applicator with ml 
graduations and an applicator-adapter, which should be fitted to the bottle before use. 
 
 
Manufacturer 
 

Marketing Authorisation 
Holder 

GlaxoSmithKline Trading Services 
Limited  
12 Riverwalk,  
Citywest Business Campus  
Dublin 24, 
Ireland 
 

GlaxoSmithKline (Ireland) 
Limited  
12 Riverwalk  
Citywest Business Campus 
Dublin 24 
Ireland 
 

 
 
For any information about this medicinal product, please contact the local representative of the 
Marketing Authorisation Holder: 
 
België/Belgique/Belgien 
GlaxoSmithKline Pharmaceuticals s.a./n.v. 
Tél/Tel: + 32 (0)10 85 52 00 

Lietuva 
GlaxoSmithKline Lietuva UAB 
Tel: + 370 5 264 90 00 
info.lt@gsk.com 
 

България 
ГлаксоСмитКлайн ЕООД 
Teл.: + 359 2 953 10 34 
 

Luxembourg/Luxemburg 
GlaxoSmithKline Pharmaceuticals s.a./n.v. 
Belgique/Belgien 
Tél/Tel: + 32 (0)10 85 52 00 
 

Česká republika 
GlaxoSmithKline s.r.o. 
Tel: + 420 222 001 111 
cz.info@gsk.com 
 

Magyarország 
GlaxoSmithKline Kft. 
Tel.: + 36 1 225 5300 

Danmark 
GlaxoSmithKline Pharma A/S 
Tlf: + 45 36 35 91 00 
dk-info@gsk.com 
 

Malta 
GlaxoSmithKline (Malta) Limited 
Tel: + 356 21 238131 

Deutschland 
GlaxoSmithKline GmbH & Co. KG 
Tel.: + 49 (0)89 36044 8701 
produkt.info@gsk.com 
 

Nederland 
GlaxoSmithKline BV 
Tel: + 31 (0)33 2081100 
 

Eesti 
GlaxoSmithKline Eesti OÜ 

Norge 
GlaxoSmithKline AS 



 54 

Tel: + 372 6676 900 
estonia@gsk.com 
 

Tlf: + 47 22 70 20 00 
 

Ελλάδα 
GlaxoSmithKline Μονοπρόσωπη A.E.B.E. 
Τηλ: + 30 210 68 82 100 

Österreich 
GlaxoSmithKline Pharma GmbH 
Tel: + 43 (0)1 97075 0 
at.info@gsk.com 
 

España 
GlaxoSmithKline, S.A. 
Tel: + 34 900 202 700 
es-ci@gsk.com 
 

Polska 
GSK Services Sp. z o.o. 
Tel.: + 48 (0)22 576 9000 

France 
Laboratoire GlaxoSmithKline 
Tél.: + 33 (0)1 39 17 84 44 
diam@gsk.com 

Portugal 
Glaxo Wellcome Farmacêutica, Lda.  
Tel: + 351 21 412 95 00 
FI.PT@gsk.com 
 

Hrvatska 
GlaxoSmithKline d.o.o. 
Tel: + 385 1 6051 999 
 

România 
GlaxoSmithKline (GSK) S.R.L.  
Tel: + 4021 3028 208 

Ireland 
GlaxoSmithKline (Ireland) Limited 
Tel: + 353 (0)1 4955000 

Slovenija 
GlaxoSmithKline d.o.o. 
Tel: + 386 (0)1 280 25 00 
medical.x.si@gsk.com 
 

Ísland 
Vistor hf. 
Sími: + 354 535 7000 

Slovenská republika 
GlaxoSmithKline Slovakia s. r. o. 
Tel: + 421 (0)2 48 26 11 11 
recepcia.sk@gsk.com 
 

Italia 
GlaxoSmithKline S.p.A. 
Tel: + 39 (0)45 7741 111 

Suomi/Finland 
GlaxoSmithKline Oy 
Puh/Tel: + 358 (0)10 30 30 30 
Finland.tuoteinfo@gsk.com 
 

Κύπρος 
GlaxoSmithKline (Cyprus) Ltd 
Τηλ: + 357 22  39 70 00  
gskcyprus@gsk.com 
 

Sverige 
GlaxoSmithKline AB 
Tel: + 46 (0)8 638 93 00 
info.produkt@gsk.com 
 

Latvija 
GlaxoSmithKline Latvia SIA 
Tel: + 371 67312687 
lv-epasts@gsk.com 

United Kingdom 
GlaxoSmithKline UK Ltd 
Tel: + 44 (0)800 221441 
customercontactuk@gsk.com  
 

  
 
This leaflet was last revised in 
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu  



 55 

 
How to measure the dose and take the medicine 
 

 
 

Use the oral applicator supplied with the pack to measure your dose accurately (see also 
Section 3).  
When full, the applicator contains 10 ml of solution. 

 1 Remove the child-proof bottle cap (A). Keep it safely. 

 2 Hold the bottle. Push the adapter (B) firmly into the neck of the bottle, as far as it 
will go. 

 3 Insert the applicator (C) firmly into the adapter. 

 4 Turn the bottle upside down. 

 5 Pull out the applicator plunger (D) until the applicator contains the first part of your 
full dose. 

 6 Turn the bottle the right way up. Remove the applicator from the adapter. 

 7 Put the applicator into your mouth, placing the tip of the applicator against the inside 
of your cheek. Slowly push the plunger in, allowing time to swallow. Don’t push too 
hard and squirt the liquid into the back of your throat, or you may choke. 

 8 Repeat steps 3 to 7 in the same way until you have taken your whole dose. For example, 
if your dose is 20 ml, you need to take 2 applicator-fulls of medicine. 

 9 Take the applicator out of the bottle and wash it thoroughly in clean water. Let it dry 
completely before you use it again. Leave the adapter in the bottle. 

 10 Close the bottle tightly with the cap. 


	SUMMARY OF PRODUCT CHARACTERISTICS
	A.  MANUFACTUR ER(S) RESPONSIBLE FOR BATCH RELEASE
	B.  CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C.  OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	A. LABELLING
	B. PACKAGE LEAFLET