ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
Zeffix 100 mg film-coated tablets
2.
Zeffix film-coated tablets contain 100 mg lamivudine
For a full list of excipients see section 6.1.
3.
Film-coated tablet
Butterscotch coloured, film-coated, capsule shaped, biconvex and engraved “GX CG5” on one face.
4.
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 in
section 5.1).
decompensated liver disease in combination with a second agent without cross-resistance to
lamivudine (see section 4.2).
Posology
Therapy with Zeffix should be initiated by a physician experienced in the management of chronic
hepatitis B.
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.
•
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.
2
•
In patients with decompensated liver disease or cirrhosis and in liver transplant recipients,
treatment cessation is not recommended (see section 5.1).
If Zeffix 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 modification of treatment should be considered if serum HBV DNA remains
detectable at or beyond 24 weeks of treatment. In patients with YMDD mutant HBV, addition of an
alternative agent without cross-resistance to lamivudine should be considered (see section 5.1).
Special populations
Paediatric population
The safety and efficacy of Zeffix in 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.
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.
Method of administration
Zeffix can be taken with or without food.
3
Hypersensitivity to the active substance or to any of the excipients.
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).
The efficacy of lamivudine in patients co-infected with Delta hepatitis or hepatitis C has not been
established and caution is advised.
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.
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.
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, addition of a second agent without
cross resistance to lamivudine, 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 more information regarding
frequency of post treatment ALT elevations. 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 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.
4
For patients who develop evidence of recurrent hepatitis post-treatment, there are insufficient data on
the benefits of re-initiation of lamivudine treatment.
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.
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.
Lactic acidosis and severe hepatomegaly with steatosis
Occurrences of lactic acidosis (in the absence of hypoxaemia), sometimes fatal, usually associated
with severe hepatomegaly and hepatic steatosis, have been reported with the use of nucleoside
analogues. As Zeffix is a nucleoside analogue, this risk cannot be excluded. Treatment with nucleoside
analogues should be discontinued when rapidly elevating aminotransferase levels, progressive
hepatomegaly or metabolic/lactic acidosis of unknown aetiology occur. Benign digestive symptoms,
such as nausea, vomiting and abdominal pain, might be indicative of lactic acidosis development.
Severe cases, sometimes with fatal outcome, were associated with pancreatitis, liver failure/hepatic
steatosis, renal failure and higher levels of serum lactate. Caution should be exercised when
prescribing nucleoside analogues to any patient (particularly obese women) with hepatomegaly,
hepatitis or other known risk factors for liver disease and hepatic steatosis (including certain medicinal
products and alcohol). Patients co-infected with hepatitis C and treated with alpha interferon and
ribivirin may constitute a special risk. These patients should be followed closely.
Mitochondrial dysfunction
Nucleoside and nucleotide analogues have been demonstrated
in vitro
and
in vivo
to cause a variable
degree of mitochondrial damage. There have been reports of mitochondrial dysfunction in infants
exposed in utero and/or post-natally to nucleoside analogues. The main adverse events reported are
haematological disorders (anaemia, neutropenia), metabolic disorders (hyperlactatemia,
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.
Zeffix should not be taken with any other medicinal products containing lamivudine or medicinal
products containing emtricitabine.
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.
5
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 C
max
(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.
Pregnancy
A large amount of data on pregnant women (more than 1000 exposed outcomes) indicate no
malformative toxicity. 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 130 mother/child pairs treated for HIV, serum concentrations of lamivudine in
breastfed infants of mothers treated for HIV are very low (about 0.06 to 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 events in breastfed infants. Therefore breastfeeding may be considered in lactating
mothers being treated with lamivudine for HBV taking into account the benefit of breast feeding for
the child and the benefit of therapy for the woman. Where there is maternal transmission of HBV,
despite adequate prophylaxis, consideration should be given to discontinuing breastfeeding to reduce
the risk of the emergence of lamivudine resistant mutants in the infant.
Fertility
No data available.
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).
6
No studies on the effects on the ability to drive and use machines have been performed.
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.
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 1171 patients with chronic hepatitis B receiving lamivudine at
100mg.
Blood and lymphatic system disorders
Not known Thrombocytopenia
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
In patients with HIV infection, cases of pancreatitis and peripheral neuropathy (or paresthesia) have
been reported. In patients with chronic hepatitis B there was no observed difference in incidence of
these events between placebo and lamivudine treated patients.
Cases of lactic acidosis, sometimes fatal, usually associated with severe hepatomegaly and hepatic
steatosis, have been reported with the use of combination nucleoside analogue therapy in patients with
HIV. There have been rare reports of lactic acidosis in patients receiving lamivudine for hepatitis B.
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.
7
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group - Antivirals for systemic use, nucleoside and nucleotide reverse
transcriptase inhibitors, ATC Code: J05AF05.
Lamivudine is an antiviral agent which is active against hepatitis B virus in all cell lines tested and in
experimentally infected animals.
Lamivudine is metabolised by both infected and uninfected cells to the triphosphate (TP) derivative
which is the active form of the parent compound. The intracellular half life of the triphosphate in
hepatocytes is 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 experience
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.
8
Table 2: Efficacy results 5 years by YMDD status (Asian Study) NUCB3018
Subjects, % (no.)
YMDD mutant
HBV status
YMDD
1
Non-YMDD
1
HBeAg seroconversion
38
9
60
(15/40)
(1/11)
(9/15)
72
33
100
(13/18)
(2/6)
(11/11)
- All patients
- Baseline ALT ≤ 1 x ULN
2
- Baseline ALT > 2 x ULN
Undetectable HBV DNA
5
(2/40)
6
(1/18)
- Baseline
3
- Week 260
4
negative
positive < baseline
positive > baseline
8
92
0
(2/25)
(23/25)
0
100
0
(4/4)
ALT normalisation
-
Baseline
normal
above normal
28
73
(11/40)
(29/40)
33
67
(6/18)
(12/18)
-
Week 260
normal
above normal < baseline
above normal > baseline
46
21
32
(13/28)
(6/28)
(9/28)
50
0
50
(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
9
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 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. The
optimal therapeutic management of patients with YMDD mutant HBV has not yet been established
(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 log
10
copies/ml compared to a median increase of 0.3
log
10
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
10
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 log
10
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 (t
max
) to maximal serum concentrations (C
max
) is about an hour. At therapeutic dose levels i.e.
100 mg once daily, C
max
is in the order of 1.1-1.5 µg/ml and trough levels were 0.015-0.020 µg/ml.
11
Co-administration of lamivudine with food resulted in a delay of t
max
and a lower C
max
(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
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.
12
6.
6.1 List of excipients
Tablet core
:
Microcrystalline cellulose
Sodium starch glycolate
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.
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 product should be disposed of in accordance with local requirements.
7.
Glaxo Group Ltd
Greenford Road
Greenford
Middlesex UB6 0NN
United Kingdom
8.
EU/1/99/114/001
EU/1/99/114/002
9.
13
Magnesium stearate
Date of first authorisation: 29 July 1999
Date of latest renewal: 27 August 2009
Detailed information on this medicinal product is available on the website of the European Medicines
Agency http://www.ema.europa.eu
14
1.
Zeffix 5 mg/ml oral solution
2.
Each ml of the oral solution contains 5 mg lamivudine
Excipients:
Sucrose 20 % (4 g/20 ml)
Methyl parahydroxybenzoate (E218) 1.5 mg/ml
Propyl parahydroxybenzoate (E216) 0.18 mg/ml
For a full list of excipients see section 6.1.
3.
Oral solution
Clear, colourless to pale yellow in colour.
4.
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 in
section 5.1).
decompensated liver disease in combination with a second agent, without cross-resistance to
lamivudine (see section 4.2).
Posology
Therapy with Zeffix should be initiated by a physician experienced in the management of chronic
hepatitis B.
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
15
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 Zeffix 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 modification of treatment should be considered if serum HBV DNA remains
detectable at or beyond 24 weeks of treatment. In patients with YMDD mutant HBV, addition of an
alternative agent without cross-resistance to lamivudine should be considered (see section 5.1).
Special populations
Paediatric population
The safety and efficacy of Zeffix in 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.
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
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
16
dysfunction. Based on these data, no dose adjustment is necessary in patients with hepatic impairment
unless accompanied by renal impairment.
Method of administration
Zeffix can be taken with or without food.
Hypersensitivity to the active substance or to any of the excipients.
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).
The efficacy of lamivudine in patients co-infected with Delta hepatitis or hepatitis C has not been
established and caution is advised.
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.
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.
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, addition of a second agent without
cross-resistance to lamivudine, 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 more information regarding
frequency of post treatment ALT elevations. 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
17
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.
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.
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.
Excipient intolerance
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.
The oral solution contains propyl and methyl parahydroxybenzoate. These products may cause an
allergic reaction in some individuals. This reaction may be delayed.
Lactic acidosis and severe hepatomegaly with steatosis
Occurrences of lactic acidosis (in the absence of hypoxaemia), sometimes fatal, usually associated
with severe hepatomegaly and hepatic steatosis, have been reported with the use of nucleoside
analogues. As Zeffix is a nucleoside analogue, this risk cannot be excluded. Treatment with nucleoside
analogues should be discontinued when rapidly elevating aminotransferase levels, progressive
hepatomegaly or metabolic/lactic acidosis of unknown aetiology occur. Benign digestive symptoms,
such as nausea, vomiting and abdominal pain, might be indicative of lactic acidosis development.
Severe cases, sometimes with fatal outcome, were associated with pancreatitis, liver failure/hepatic
steatosis, renal failure and higher levels of serum lactate. Caution should be exercised when
prescribing nucleoside analogues to any patient (particularly obese women) with hepatomegaly,
hepatitis or other known risk factors for liver disease and hepatic steatosis (including certain medicinal
products and alcohol). Patients co-infected with hepatitis C and treated with alpha interferon and
ribivirin may constitute a special risk. These patients should be followed closely.
Mitochondrial dysfunction
18
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 (hyperlactatemia,
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.
Zeffix should not be taken with any other medicinal products containing lamivudine or medicinal
products containing emtricitabine.
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 C
max
(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.
Pregnancy
A large amount of data on pregnant women (more than 1000 exposed outcomes) indicate no
malformative toxicity. Zeffix can be used in 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 130 mother/child pairs treated for HIV, serum concentrations of lamivudine in
breastfed infants of mothers treated for HIV are very low (about 0.06 to 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
19
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 events in breastfed infants. Therefore breastfeeding may be considered in lactating
mothers being treated with lamivudine for HBV taking into account the benefit of breast feeding for
the child and the benefit of therapy for the woman. Where there is maternal transmission of HBV,
despite adequate prophylaxis, consideration should be given to discontinuing breastfeeding to reduce
the risk of the emergence of lamivudine resistant mutants in the infant.
Fertility
No data available.
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).
No studies on the effects on the ability to drive and use machines have been performed.
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.
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 1171 patients with chronic hepatitis B receiving lamivudine at
100mg.
Blood and lymphatic system disorders
Not known Thrombocytopenia
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
20
In patients with HIV infection, cases of pancreatitis and peripheral neuropathy (or paresthesia) have
been reported. In patients with chronic hepatitis B there was no observed difference in incidence of
these events between placebo and lamivudine treated patients.
Cases of lactic acidosis, sometimes fatal, usually associated with severe hepatomegaly and hepatic
steatosis, have been reported with the use of combination nucleoside analogue therapy in patients with
HIV. There have been rare reports of lactic acidosis in patients receiving lamivudine for hepatitis B.
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.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group - Antivirals for systemic use, nucleoside and nucleotide reverse
transcriptase inhibitors, ATC Code: J05AF05.
Lamivudine is an antiviral agent which is active against hepatitis B virus in all cell lines tested and in
experimentally infected animals.
Lamivudine is metabolised by both infected and uninfected cells to the triphosphate (TP) derivative
which is the active form of the parent compound. The intracellular half life of the triphosphate in
hepatocytes is 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 experience
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.
21
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
YMDD
1
Non-YMDD
1
HBeAg seroconversion
38
9
60
(15/40)
(1/11)
(9/15)
72
33
100
(13/18)
(2/6)
(11/11)
- All patients
- Baseline ALT ≤ 1 x ULN
2
- Baseline ALT > 2 x ULN
Undetectable HBV DNA
5
(2/40)
6
(1/18)
- Baseline
3
- Week 260
4
negative
positive < baseline
positive > baseline
8
92
0
(2/25)
(23/25)
0
100
0
(4/4)
ALT normalisation
-
Baseline
normal
above normal
28
73
(11/40)
(29/40)
33
67
(6/18)
(12/18)
-
Week 260
normal
above normal < baseline
above normal > baseline
46
21
32
(13/28)
(6/28)
(9/28)
50
0
50
(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
22
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 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. The
23
optimal therapeutic management of patients with YMDD mutant HBV has not yet been established
(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 log
10
copies/ml compared to a median increase of 0.3
log
10
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 log
10
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.
24
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 (t
max
) to maximal serum concentrations (C
max
) is about an hour. At therapeutic dose levels i.e.
100 mg once daily, C
max
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 t
max
and a lower C
max
(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
25
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.
6.1 List of excipients
Sucrose (20 % w/v)
Methyl Parahydroxybenzoate (E218)
Propyl Parahydroxybenzoate (E216)
Citric Acid (anhydrous)
Propylene Glycol
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 includes a clear polypropylene
oral dosing syringe and a polyethylene syringe-adapter.
The oral dosing syringe is provided for accurate measurement of the prescribed dose of oral solution.
Instructions for use are included in the pack.
6.6 Special precautions for disposal
26
Any unused product should be disposed of in accordance with local requirements.
7.
Glaxo Group Ltd
Greenford Road
Greenford
Middlesex UB6 0NN
United Kingdom
8.
MARKETING AUTHORISATION NUMBER
EU/1/99/114/003
9.
Date of first authorisation: 29 July 1999
Date of latest renewal: 27 August 2009
Detailed information on this medicinal product is available on the website of the European Medicines
Agency http://www.ema.europa.eu
27
ANNEX II
A. MANUFACTURING AUTHORISATION HOLDERS
RESPONSIBLE FOR BATCH RELEASE
B. CONDITIONS OF THE MARKETING AUTHORISATION
28
A. MANUFACTURING AUTHORISATION HOLDERS RESPONSIBLE FOR BATCH
RELEASE
Name and address of the manufacturers responsible for batch release
Film-coated tablet:
Glaxo Wellcome Operations
Priory Street, Ware
Hertfordshire
SG12 0DJ
United Kingdom
or
GlaxoSmithKline Pharmaceuticals S.A.
ul. Grunwaldzka 189
60-322 Poznan
Poland
Oral solution:
Glaxo Wellcome GmbH & Co. KG
Industriestrasse 32-36
23843 Bad Oldesloe
Germany
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 OF THE MARKETING AUTHORISATION
•
CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE IMPOSED ON
Medicinal product subject to restricted medical prescription (See Annex I: Summary of Product
Characteristics, section 4.2).
•
CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND
EFFECTIVE USE OF THE MEDICINAL PRODUCT
Not applicable.
•
OTHER CONDITIONS
The MAH will continue to submit yearly PSURs, unless otherwise specified by the CHMP.
29
ANNEX III
LABELLING AND PACKAGE LEAFLET
30
A. LABELLING
31
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
OUTER CARTON FOR TABLETS: 28 tablet box, 84 tablet box
1.
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.
28 film-coated tablets
84 film-coated tablets
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Oral use
Read the package leaflet before use
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
9.
SPECIAL STORAGE CONDITIONS
Do not store above 30°C
32
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Glaxo Group Ltd
Greenford
Middlesex UB6 0NN
United Kingdom
EU/1/99/114/001 28 tablets
EU/1/99/114/002 84 tablets
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
zeffix 100 mg
33
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
28 tablet box, 84 tablet box
1.
Zeffix 100 mg tablets
Lamivudine
2.
Glaxo Group Ltd
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
Lot
5.
OTHER
34
35
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
OUTER CARTON FOR ORAL SOLUTION
1.
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), preservatives: methyl parahydroxybenzoate (E218) and propyl parahydroxybenzoate
(E216)
4.
Each bottle contains 240 ml oral solution
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Oral use
Read the package leaflet before use
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
36
9.
SPECIAL STORAGE CONDITIONS
Do not store above 25°C
Discard one month after first opening
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Glaxo Group Ltd
Greenford
Middlesex UB6 0NN
United Kingdom
EU/1/99/114/003
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
zeffix 5 mg/ml
37
PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING
BOTTLE LABEL FOR ORAL SOLUTION
1.
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), and preservatives: methyl parahydroxybenzoate (E218) and propyl
parahydroxybenzoate (E216)
4.
Each bottle contains 240 ml oral solution
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Oral use
Read the package leaflet before use
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED
OUT OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
9.
SPECIAL STORAGE CONDITIONS
Do not store above 25°C
Discard one month after first opening
38
10.
SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Glaxo Group Ltd
Greenford
Middlesex UB6 0NN
United Kingdom
EU/1/99/114/003
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
39
B. PACKAGE LEAFLET
40
PACKAGE LEAFLET: INFORMATION FOR THE USER
Zeffix 100 mg film-coated tablets
Lamivudine
Read all of this leaflet carefully before you start taking this medicine.
-
If you have further questions, ask your doctor or pharmacist.
This medicine has been prescribed for you. Do not pass it on to others. It may harm them even if
their symptoms are the same as yours.
-
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet,
please tell your doctor or pharmacist.
-
In this leaflet:
1.
What Zeffix is and what it is used for
2.
Before you take Zeffix
4.
Possible side effects
5.
How to store Zeffix
6.
Further information
1.
WHAT ZEFFIX IS AND WHAT IT IS USED FOR
Zeffix belongs to a group of medicines called antivirals. It is used for the treatment of hepatitis B virus
infection. Hepatitis B is a virus which infects the liver, and leads to liver damage. Zeffix can be used in
people whose liver is damaged but still functions (
compensated liver disease
) and in people whose
liver is damaged and does not function normally (
decompensated liver disease).
Zeffix is used to treat patients 18 years of age or over with long term (chronic) hepatitis B.
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.
2.
BEFORE YOU TAKE ZEFFIX
Do not take Zeffix:
•
if you are allergic (hypersensitive) to
lamivudine or to any of the other ingredients of Zeffix.
If you are not sure please consult your doctor.
Take special care with Zeffix
Zeffix reduces the amount of hepatitis B virus in your body, and keeps the liver disease under control,
therefore reducing health problems relating to your liver in the future. For effective treatment you will
need to take Zeffix every day. Patients respond to the treatment differently, therefore it is not known
for how long you will have to take this medicine.
Your doctor will be checking your response to treatment by taking regular blood samples. The results
of these tests will help your doctor to decide when your treatment with Zeffix can be stopped.
Before treatment with Zeffix you should have discussed any additional medical problems that you have
with your doctor. If you have kidney disease the dose of this medicine may have to be reduced, as it is
your kidneys that are mainly responsible for getting rid of the medicine from your body. Zeffix is also
41
-
Keep this leaflet. You may need to read it again.
3.
How to take Zeffix
available as an oral solution. This means that your doctor can prescribe a lower dose for you if
necessary.
Do not stop taking Zeffix without instruction from your doctor, as there is a small risk of your hepatitis
getting worse. When you stop taking Zeffix your doctor will monitor you for at least the following four
months to check for any problems. This will mean taking blood samples to check for any abnormal
liver enzymes, indicating liver damage.
The active substance in Zeffix is lamivudine. If you are already taking this medicinal product for HIV
infection, your doctor will continue to treat you with the higher dose, usually 150 mg twice a day, as
the lower dose of 100 mg lamivudine is insufficient to treat HIV infection.
Because your medicine helps to control your hepatitis B and it is not yet known whether it will cure it,
you are still at risk of transmitting this virus to others through sexual contact or by blood transfer, and
you should use appropriate precautions to prevent this. There is an effective vaccine available to
protect those at risk from becoming infected with hepatitis B virus.
The class of medicines to which Zeffix belongs (NRTIs) can cause a condition called lactic acidosis
(build up of lactic acid in the body), together with an enlarged liver. Lactic acidosis, if it occurs,
usually develops after a few months of treatment. Deep, rapid breathing, drowsiness, and non specific
symptoms such as nausea, vomiting and stomach pain, might indicate the development of lactic
acidosis. This rare, but serious side effect occurs more often in women, particularly if very
overweight. As you have liver disease you may also be more at risk of getting this condition. While
you are being treated with Zeffix your doctor will monitor you closely for any signs that you may be
developing lactic acidosis.
Taking other medicines
Some medicines may affect the action of Zeffix. Please tell your doctor or pharmacist if you are taking
or have recently taken any other medicines, including medicines obtained without a prescription.
Zeffix should not be taken with:
•
zalcitabine or lamivudine (used to treat HIV infection)
•
emtricitabine (used to treat HIV or hepatitis B infection).
Taking Zeffix with food and drink
Zeffix can be taken with food or on an empty stomach.
Pregnancy
Ask your doctor or pharmacist for advice before taking any medicine.
Tell your doctor if you are pregnant, or are planning to become pregnant, or if you are breast-feeding.
Your doctor will advise whether you should continue to take Zeffix while you are pregnant. Do not
stop treatment with Zeffix without your doctor’s advice.
Breast-feeding
The ingredients in Zeffix can pass into breast-milk.
If you are breast-feeding, you must check with
your doctor
before you take Zeffix.
Driving and using machines
No studies on the effect of Zeffix on the ability to drive and use machines have been performed.
3.
HOW TO TAKE ZEFFIX
Always take Zeffix exactly as your doctor has told you. You should check with your doctor or
pharmacist if you are not sure.
42
The recommended dose of Zeffix is one tablet (100 mg lamivudine) once a day. The tablet should be
swallowed whole with water. It can be taken with food or on an empty stomach.
Your doctor will advise you on how long you will need to take the medicine for.
Your doctor may need to reduce your dose of Zeffix if you have kidney problems. It may be necessary
for you to take an oral solution instead of tablets so that the dose of your medicine can be accurately
reduced.
If you take more Zeffix than you should
Accidentally taking too much of your medicine is unlikely to cause any serious problems. However,
you should 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 your medicine, take it as soon as you remember and then continue to take it as
instructed. Do not take a double dose to make up for forgotten individual doses.
If you stop taking Zeffix
You must not stop taking Zeffix without consulting your doctor (see section 2).
If you have any further questions on the use of this product, ask you doctor or pharmacist.
4.
POSSIBLE SIDE EFFECTS
Like all medicines, Zeffix can cause side effects, although not everybody gets them. Side effects
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).
Some people may be allergic to medicines. If you have any of the following symptoms soon after
taking Zeffix
STOP
taking the medicine and tell your doctor immediately:
* Sudden wheeziness and chest pain or tightening.
* Swelling of eyelids, face or lips.
* Skin rash or ‘hives’ anywhere on the body.
Side effects thought to be caused by Zeffix are listed below:
Very common side effects
These may affect more than
1 in 10
people
•
Increases in enzymes produced by the liver called transaminases
Common side effects
These may affect up to
1 in 10
people
•
Increases in an enzyme called creatine phosphokinase produced in the muscles
•
Cramps and muscle pains
Other side effects
Other side effects
have occurred in a very small number of people but their exact frequency is
unknown
•
Reductions in platelets, blood cells important for blood clotting. If you have a low platelet
count you may notice you bruise more easily
•
Breakdown of muscle
•
Marked worsening of liver disease after Zeffix is stopped or during treatment if resistance
develops. This can be fatal in some patients.
43
If any of the side effects gets serious, or you notice any side effects not listed in this leaflet, please tell
your doctor or pharmacist.
5.
HOW TO STORE ZEFFIX
Keep out of the reach and sight of children.
Do not use Zeffix after the expiry date which is stated on the tablet carton and blister pack.
Do not store above 30 °C.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to
dispose of medicines no longer required. These measures will help to protect the environment.
6.
FURTHER 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 blister packs containing 28 or 84 tablets.
The tablets are butterscotch coloured, capsule shaped, biconvex and engraved “GX CG5” on one face.
Not all pack-sizes may be marketed.
Marketing Authorisation Holder and Manufacturer
Manufacturer
Marketing Authorisation Holder
Glaxo Wellcome Operations
Priory Street
Ware
Herts SG12 0DJ
United Kingdom
Glaxo Group Ltd
Greenford Road
Greenford
Middlesex UB6 0NN
United Kingdom
or
GlaxoSmithKline
Pharmaceuticals S.A.
ul. Grunwaldzka 189
60-322 Poznan
Poland
For any information about this medicinal product, please contact the local representative of the
Marketing Authorisation Holder:
44
België/Belgique/Belgien
GlaxoSmithKline s.a./n.v.
Tél/Tel: + 32 (0)2 656 21 11
Luxembourg/Luxemburg
GlaxoSmithKline s.a./n.v.
Belgique/Belgien
Tél/Tel: + 32 (0)2 656 21 11
България
ГлаксоСмитКлайн ЕООД
Teл.: + 359 2 953 10 34
Magyarország
GlaxoSmithKline Kft.
Tel.: + 36 1 225 5300
Česká republika
GlaxoSmithKline s.r.o.
Tel: + 420 222 001 111
gsk.czmail@gsk.com
Malta
GlaxoSmithKline Malta
Tel: + 356 21 238131
Danmark
GlaxoSmithKline Pharma A/S
Tlf: + 45 36 35 91 00
dk-info@gsk.com
Nederland
GlaxoSmithKline BV
Tel: + 31 (0)30 6938100
nlinfo@gsk.com
Deutschland
GlaxoSmithKline GmbH & Co. KG
Tel.: + 49 (0)89 36044 8701
produkt.info@gsk.com
Norge
GlaxoSmithKline AS
Tlf: + 47 22 70 20 00
firmapost@gsk.no
Eesti
GlaxoSmithKline Eesti OÜ
Tel: + 372 6676 900
estonia@gsk.com
Österreich
GlaxoSmithKline Pharma GmbH
Tel: + 43 (0)1 97075 0
at.info@gsk.com
Ελλάδα
GlaxoSmithKline A.E.B.E.
Τηλ: + 30 210 68 82 100
Polska
GSK Commercial Sp. z o.o.
Tel.: + 48 (0)22 576 9000
España
GlaxoSmithKline, S.A.
Tel: + 34 902 202 700
es-ci@gsk.com
Portugal
Glaxo Wellcome Farmacêutica, Lda.
Tel: + 351 21 412 95 00
FI.PT@gsk.com
France
Laboratoire GlaxoSmithKline
Tél.: + 33 (0)1 39 17 84 44
diam@gsk.com
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
GlaxoSmithKline ehf.
Sími: + 354 530 3700
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 9218 111
Suomi/Finland
GlaxoSmithKline Oy
Puh/Tel: + 358 (0)10 30 30 30
Finland.tuoteinfo@gsk.com
45
Κύπρος
GlaxoSmithKline (Cyprus) Ltd
Τηλ: + 357 22 39 70 00
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
Tel: + 44 (0)800 221441
customercontactuk@gsk.com
Lietuva
GlaxoSmithKline Lietuva UAB
Tel: + 370 5 264 90 00
info.lt@gsk.com
This leaflet was approved on
Detailed information on this medicine is available on the European Medicines Agency web site:
http://www.ema.europa.eu
46
PACKAGE LEAFLET: INFORMATION FOR THE USER
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. Do not pass it on to others. It may harm them even if
their symptoms are the same as yours.
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet,
please tell your doctor or pharmacist.
-
In this leaflet:
1.
What Zeffix is and what it is used for
3.
How to take Zeffix
4.
Possible side effects
5.
How to store Zeffix
6.
Further information
1.
WHAT ZEFFIX IS AND WHAT IT IS USED FOR
Zeffix belongs to a group of medicines called antivirals. It is used for the treatment of hepatitis B virus
infection. Hepatitis B is a virus which infects the liver, and leads to liver damage. Zeffix can be used in
people whose liver is damaged but still functions (
compensated liver disease
) and in people whose
liver is damaged and does not function normally (
decompensated liver disease).
Zeffix is used to treat patients 18 years of age or over with long term (chronic) hepatitis B.
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.
2.
BEFORE YOU TAKE ZEFFIX
Do not take Zeffix:
•
if you are allergic (hypersensitive) to
lamivudine or to any of the other ingredients of Zeffix.
If you are not sure please consult your doctor
Take special care with Zeffix
Zeffix reduces the amount of hepatitis B virus in your body, and keeps the liver disease under control,
therefore reducing health problems relating to your liver in the future. For effective treatment you will
need to take Zeffix every day. Patients respond to the treatment differently, therefore it is not known
for how long you will have to take this medicine.
Your doctor will be checking your response to treatment by taking regular blood samples. The results
of these tests will help your doctor to decide when your treatment with Zeffix can be stopped.
Before treatment with Zeffix you should have discussed any additional medical problems that you have
with your doctor. If you have kidney disease the dose of this medicine may have to be reduced, as it is
your kidneys that are mainly responsible for getting rid of the medicine from your body. Your doctor
will advise you on the correct dose of Zeffix to take if required.
47
2.
Before you take Zeffix
Do not stop taking Zeffix without instruction from your doctor, as there is a small risk of your hepatitis
getting worse. When you stop taking Zeffix your doctor will monitor you for at least the following four
months to check for any problems. This will mean taking blood samples to check for any abnormal
liver enzymes, indicating liver damage.
The active substance in Zeffix is lamivudine. If you are already taking this medicinal product for HIV
infection, your doctor will continue to treat you with the higher dose, usually 150 mg twice a day, as
the lower dose of 100 mg of lamivudine is insufficient to treat HIV infection.
Because your medicine helps to control your hepatitis B and it is not yet known whether it will cure it,
you are still at risk of transmitting this virus to others through sexual contact or by blood transfer, and
you should use appropriate precautions to prevent this. There is an effective vaccine available to
protect those at risk from becoming infected with hepatitis B virus.
If you are a diabetic, please note that each dose of Zeffix (100 mg = 20 ml) contains 4 g sugar.
The class of medicines to which Zeffix belongs (NRTIs) can cause a condition called lactic acidosis
(build up of lactic acid in the body), together with an enlarged liver. Lactic acidosis, if it occurs,
usually develops after a few months of treatment. Deep, rapid breathing, drowsiness, and non specific
symptoms such as nausea, vomiting and stomach pain, might indicate the development of lactic
acidosis. This rare, but serious side effect occurs more often in women, particularly if very
overweight. As you have liver disease you may also be more at risk of getting this condition. While
you are being treated with Zeffix your doctor will monitor you closely for any signs that you may be
developing lactic acidosis.
Taking other medicines
Some medicines may affect the action of Zeffix. Please tell your doctor or pharmacist if you are taking
or have recently taken any other medicines, including medicines obtained without a prescription.
Zeffix should not be taken with:
•
zalcitabine or lamivudine (used to treat HIV infection)
•
emtricitabine (used to treat HIV or hepatitis B infection)
Taking Zeffix with food and drink:
Zeffix can be taken with food or on an empty stomach.
Pregnancy
Ask your doctor or pharmacist for advice before taking any medicine.
Tell your doctor if you are pregnant, or are planning to become pregnant, or if you are breast-feeding.
Your doctor will advise whether you should continue to take Zeffix while you are pregnant. Do not
stop treatment with Zeffix without your doctor’s advice.
Breast-feeding
The ingredients in Zeffix can pass into breast-milk.
If you are breast-feeding, you must check with
your doctor
before you take Zeffix.
Driving and using machines
No studies on the effect of Zeffix on the ability to drive and use machines have been performed.
Important information about ingredients of Zeffix oral solution
This medicine contains preservatives (propyl parahydroxybenzoate: E216 and methyl
parahydroxybenzoate: E218) which may cause allergic reactions (possibly delayed).
This medicinal product contains sucrose. If you have been told by your doctor that you have an
intolerance to some sugars, contact your doctor before taking this medicinal product. Sucrose may be
harmful to the teeth.
48
3.
HOW TO TAKE ZEFFIX
Always take Zeffix exactly as your doctor has told you. You should check with your doctor or
pharmacist if you are not sure.
The recommended dose of Zeffix is 20 ml (100 mg lamivudine) once a day. It can be taken with food
or on an empty stomach.
Your doctor will advise you on how long you will need to take the medicine for.
Your doctor may need to reduce your dose of Zeffix if you have kidney problems.
To measure your dose of medicine accurately use the oral dosing syringe supplied with the pack as
follows:
1. Remove the bottle cap
2. Push the plastic adapter into the neck of the bottle, while holding the bottle firmly
3. Insert the syringe firmly into the adapter
4. Turn the bottle upside down
5.
Pull out syringe plunger until the first portion of your full dose is withdrawn
6.
Turn the bottle the correct way up and remove the syringe from the adapter
7.
Administer the dose into the mouth by placing the tip of the syringe against the inside of the
cheek. Slowly depress the plunger, allowing time to swallow. Forceful squirting to the back of
the throat may cause choking.
8.
Repeat steps 3 to 7 in the same way until you have taken the whole dose
9.
After use the syringe must not be left in the bottle. Take off the syringe and adapter and wash
them thoroughly in clean water. Let them dry completely before you use them again.
10. Replace and tighten the bottle cap
If you take more Zeffix than you should
Accidentally taking too much of your medicine is unlikely to cause any serious problems. However,
you should 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 your medicine, take it as soon as you remember and then continue to take it as
instructed. Do not take a double dose to make up for forgotten individual doses.
If you stop taking Zeffix
You must not stop taking Zeffix without consulting your doctor (see section 2).
If you have any further questions on the use of this product, ask you doctor or pharmacist.
4.
POSSIBLE SIDE EFFECTS
Like all medicines, Zeffix can cause side effects, although not everybody gets them. Side effects
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).
Some people may be allergic to medicines. If you have any of the following symptoms soon after
taking Zeffix
STOP
taking the medicine and tell your doctor immediately:
* Sudden wheeziness and chest pain or tightening.
* Swelling of eyelids, face or lips.
* Skin rash or ‘hives’ anywhere on the body.
49
Side effects thought to be caused by Zeffix are listed below:
Very common side effects
These may affect more than
1 in 10
people
•
Increases in enzymes produced by the liver called transaminases
Common side effects
These may affect up to
1 in 10
people
•
Increases in an enzyme called creatine phosphokinase produced in the muscles
•
Cramps and muscle pains
Other side effects
Other side effects
have occurred in a very small number of people but their exact frequency is
unknown
•
Reductions in platelets, blood cells important for blood clotting. If you have a low platelet
count you may notice you bruise more easily
•
Breakdown of muscle
•
Marked worsening of liver disease after Zeffix is stopped or during treatment if resistance
develops. This can be fatal in some patients.
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please
tell your doctor or pharmacist
5.
HOW TO STORE ZEFFIX
Keep out of the reach and sight of children.
Do not use Zeffix after the expiry date which is stated on the bottle and the carton.
Do not store above 25 °C.
Discard one month after first opening.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to
dispose of medicines no longer required. These measures will help to protect the environment.
6.
FURTHER INFORMATION
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, 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 dosing syringe and
a syringe-adapter for the bottle.
50
Marketing Authorisation Holder and Manufacturer
Manufacturer
Marketing Authorisation
Holder
Glaxo Wellcome GmbH & Co. KG
Industriestrasse 32-36
23843 Bad Oldesloe
Germany
Glaxo Group Ltd
Greenford Road
Greenford
Middlesex UB6 0NN
United Kingdom
For any information about this medicinal product, please contact the local representative of the
Marketing Authorisation Holder:
België/Belgique/Belgien
GlaxoSmithKline s.a./n.v.
Tél/Tel: + 32 (0)2 656 21 11
Luxembourg/Luxemburg
GlaxoSmithKline s.a./n.v.
Belgique/Belgien
Tél/Tel: + 32 (0)2 656 21 11
България
ГлаксоСмитКлайн ЕООД
Teл.: + 359 2 953 10 34
Magyarország
GlaxoSmithKline Kft.
Tel.: + 36 1 225 5300
Česká republika
GlaxoSmithKline s.r.o.
Tel: + 420 222 001 111
gsk.czmail@gsk.com
Malta
GlaxoSmithKline Malta
Tel: + 356 21 238131
Danmark
GlaxoSmithKline Pharma A/S
Tlf: + 45 36 35 91 00
dk-info@gsk.com
Nederland
GlaxoSmithKline BV
Tel: + 31 (0)30 6938100
nlinfo@gsk.com
Deutschland
GlaxoSmithKline GmbH & Co. KG
Tel.: + 49 (0)89 36044 8701
produkt.info@gsk.com
Norge
GlaxoSmithKline AS
Tlf: + 47 22 70 20 00
firmapost@gsk.no
Eesti
GlaxoSmithKline Eesti OÜ
Tel: + 372 6676 900
estonia@gsk.com
Österreich
GlaxoSmithKline Pharma GmbH
Tel: + 43 (0)1 97075 0
at.info@gsk.com
España
GlaxoSmithKline, S.A.
Tel: + 34 902 202 700
es-ci@gsk.com
Portugal
Glaxo Wellcome Farmacêutica, Lda.
Tel: + 351 21 412 95 00
FI.PT@gsk.com
France
Laboratoire GlaxoSmithKline
Tél.: + 33 (0)1 39 17 84 44
diam@gsk.com
România
GlaxoSmithKline (GSK) S.R.L.
Tel: + 4021 3028 208
Ireland
Slovenija
51
Ελλάδα
GlaxoSmithKline A.E.B.E.
Τηλ: + 30 210 68 82 100
Polska
GSK Commercial Sp. z o.o.
Tel.: + 48 (0)22 576 9000
GlaxoSmithKline (Ireland) Limited
Tel: + 353 (0)1 4955000
GlaxoSmithKline d.o.o.
Tel: + 386 (0)1 280 25 00
medical.x.si@gsk.com
Ísland
GlaxoSmithKline ehf.
Sími: + 354 530 3700
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 9218 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
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
Tel: + 44 (0)800 221441
customercontactuk@gsk.com
Lietuva
GlaxoSmithKline Lietuva UAB
Tel: + 370 5 264 90 00
info.lt@gsk.com
This leaflet was approved on
Detailed information on this medicine is available on the European Medicines Agency web site:
http://www.ema.europa.eu
52
Source: European Medicines Agency
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