ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
Epivir 150 mg film-coated tablets
2.
Each film-coated tablet contains 150 mg lamivudine.
For a full list of excipients, see section 6.1.
3.
Film-coated tablet
White, diamond shaped scored tablets engraved with “GX CJ7” on both faces.
4.
4.1
Epivir is indicated as part of antiretroviral combination therapy for the treatment of Human
Immunodeficiency Virus (HIV) infected adults and children.
4.2
The therapy should be initiated by a physician experienced in the management of HIV infection.
Epivir may be administered with or without food.
To ensure administration of the entire dose, the tablet(s) should ideally be swallowed without
crushing. For patients who are unable to swallow tablets, lamivudine is available as an oral solution.
Alternatively, the tablets may be crushed and added to a small amount of semi-solid food or liquid, all
of which should be consumed immediately (see section 5.2).
Adults and adolescents (over 12 years of age):
the recommended dose of Epivir is 300 mg daily. This
may be administered as either 150 mg twice daily or 300 mg once daily (see section 4.4). The 300 mg
tablet is only suitable for the once a day regimen.
Patients changing to the once daily regimen should take 150 mg twice a day and switch to 300 mg
once a day the following morning. Where an evening once daily regimen is preferred, 150 mg of
Epivir should be taken on the first morning only, followed by 300 mg in the evening. When changing
back to a twice daily regimen patients should complete the days treatment and start 150 mg twice a
day the following morning.
Children (under 12 years of age):
Since an accurate dosing can not be achieved with this formulation, dosing according to weight bands
is recommended for Epivir tablets. This dosing regimen for paediatric patients weighing 14-30 kg is
based primarily on pharmacokinetic modelling, with supporting data from clinical studies
.
For children weighing at least 30 kg
: the adult dosage of 150 mg twice daily should be taken.
For children weighing between 21 kg to 30 kg
:
the recommended oral dose of Epivir (150 mg) is one-
half tablet taken in the morning and one whole tablet taken in the evening
.
2
For children weighing 14 to 21 kg
: the recommended oral dose of Epivir (150 mg) is one half of a
scored tablet taken twice daily.
Epivir is also available as an oral solution for children over three months of age and who weigh less
than 14 kg or for patients who are unable to swallow tablets.
Less than three months of age:
the limited data available are insufficient to propose specific dosage
recommendations (see section 5.2).
Renal impairment:
Lamivudine concentrations are increased in patients with moderate - severe renal
impairment due to decreased clearance. The dose should therefore be adjusted, using oral solution
presentation of Epivir for patients whose creatinine clearance falls below 30 ml/min (see tables).
Dosing recommendations – Adults and adolescents weighing at least 30 kg:
First dose
Maintenance dose
Creatinine clearance
(ml/min)
≥50
150 mg
150 mg twice daily
30-<50
150 mg
150 mg once daily
<30
As doses below 150 mg are needed the use of the oral solution is
recommended
There are no data available on the use of lamivudine in children with renal impairment. Based on the
assumption that creatinine clearance and lamivudine clearance are correlated similarly in children as in
adults it is recommended that the dosage in children with renal impairment be reduced according to
their creatinine clearance by the same proportion as in adults.
Dosing recommendations – Children aged at least 3 months and weighing less than 30 kg:
Creatinine clearance
(ml/min)
First dose
Maintenance dose
≥50
4 mg/kg
4 mg/kg twice daily
30 to<50
4 mg/kg
4 mg/kg once daily
15 to <30
4 mg/kg
2.6 mg/kg once daily
5 to <15
4 mg/kg
1.3 mg/kg once daily
<5
1.3 mg/kg
0.7 mg/kg once daily
Hepatic impairment:
Data obtained in patients with moderate to severe hepatic impairment shows that
lamivudine pharmacokinetics are not significantly affected by hepatic dysfunction. Based on these
data, no dose adjustment is necessary in patients with moderate or severe hepatic impairment unless
accompanied by renal impairment.
4.3
Hypersensitivity to the active substance or to any of the excipients.
4.4
Epivir is not recommended for use as monotherapy.
Renal impairment:
In patients with moderate to severe renal impairment, the terminal plasma half-life
of lamivudine is increased due to decreased clearance, therefore the dose should be adjusted (see
section 4.2).
3
Triple nucleoside therapy:
There have been reports of a high rate of virological failure and of
emergence of resistance at an early stage when lamivudine was combined with tenofovir disoproxil
fumarate and abacavir as well as with tenofovir disoproxil fumarate and didanosine as a once daily
regimen.
Opportunistic infections:
Patients receiving Epivir or any other antiretroviral therapy may continue to
develop opportunistic infections and other complications of HIV infection, and therefore should
remain under close clinical observation by physicians experienced in the treatment of patients with
associated HIV diseases.
Transmission of HIV:
Patients should be advised that current antiretroviral therapy, including Epivir,
has not been proven to prevent the risk of transmission of HIV to others through sexual contact or
contamination with blood. Appropriate precautions should continue to be taken.
Pancreatitis
: Cases of pancreatitis have occurred rarely. However it is not clear whether these cases
were due to the antiretroviral treatment or to the underlying HIV disease. Treatment with Epivir
should be stopped immediately if clinical signs, symptoms or laboratory abnormalities suggestive of
pancreatitis occur.
Lactic acidosis:
lactic acidosis, usually associated with hepatomegaly and hepatic steatosis, has been
reported with the use of nucleoside analogues. Early symptoms (symptomatic hyperlactatemia)
include benign digestive symptoms (nausea, vomiting and abdominal pain), non-specific malaise, loss
of appetite, weight loss, respiratory symptoms (rapid and/or deep breathing) or neurological symptoms
(including motor weakness).
Lactic acidosis has a high mortality and may be associated with pancreatitis, liver failure, or renal
failure.
Lactic acidosis generally occurred after a few or several months of treatment.
Treatment with nucleoside analogues should be discontinued in the setting of symptomatic
hyperlactatemia and metabolic/lactic acidosis, progressive hepatomegaly, or rapidly elevating
aminotransferase levels.
Caution should be exercised when administering nucleoside analogues to any patient (particularly
obese women) with hepatomegaly, hepatitis or other known risk factors for liver disease and hepatic
steatosis (including certain medicinal products and alcohol). Patients co-infected with hepatitis C and
treated with alpha interferon and ribavirin may constitute a special risk.
Patients at increased risk should be followed closely.
Mitochondrial dysfunction:
Nucleoside and nucleotide analogues have been demonstrated
in vitro
and
in vivo
to cause a variable degree of mitochondrial damage. There have been reports of mitochondrial
dysfunction in HIV-negative infants exposed
in utero
and/or post-natally to nucleoside analogues. The
main adverse events reported are haematological disorders (anaemia, neutropenia), metabolic
disorders (hyperlactatemia, hyperlipasemia). These events are often transitory. Some late-onset
neurological disorders have been reported (hypertonia, convulsion, abnormal behaviour). Whether the
neurological disorders are transient or permanent is currently unknown. Any child exposed
in utero
to
nucleoside and nucleotide analogues, even HIV-negative children, should have clinical and laboratory
follow-up and should be fully investigated for possible mitochondrial dysfunction in case of relevant
signs or symptoms. These findings do not affect current national recommendations to use antiretroviral
therapy in pregnant women to prevent vertical transmission of HIV.
Lipodystrophy:
Combination antiretroviral therapy has been associated with the redistribution of body
fat (lipodystrophy) in HIV patients. The long-term consequences of these events are currently
unknown. Knowledge about the mechanism is incomplete. A connection between visceral lipomatosis
and protease inhibitors (PIs) and lipoatrophy and nucleoside reverse transcriptase inhibitors (NRTIs)
4
has been hypothesised. A higher risk of lipodystrophy has been associated with individual factors such
as older age, and with drug related factors such as longer duration of antiretroviral treatment and
associated metabolic disturbances. Clinical examination should include evaluation for physical signs
of fat redistribution. Consideration should be given to the measurement of fasting serum lipids and
blood glucose. Lipid disorders should be managed as clinically appropriate (see section 4.8).
Immune Reactivation Syndrome:
In HIV-infected patients with severe immune deficiency at the time
of institution of combination antiretroviral therapy (CART), an inflammatory reaction to
asymptomatic or residual opportunistic pathogens may arise and cause serious clinical conditions, or
aggravation of symptoms. Typically, such reactions have been observed within the first few weeks or
months of initiation of CART. Relevant examples are cytomegalovirus retinitis, generalised and/or
focal mycobacterium infections, and
Pneumocystis carinii
pneumonia. Any inflammatory symptoms
should be evaluated and treatment instituted when necessary.
Liver disease:
If lamivudine is being used concomitantly for the treatment of HIV and HBV,
additional information relating to the use of lamivudine in the treatment of hepatitis B infection is
available in the Zeffix SPC.
Patients with chronic hepatitis B or C and treated with combination antiretroviral therapy are at an
increased risk of severe and potentially fatal hepatic adverse events. In case of concomitant antiviral
therapy for hepatitis B or C, please refer also to the relevant product information for these medicinal
products.
If Epivir is discontinued in patients co-infected with hepatitis B virus, periodic monitoring of liver
function tests and markers of HBV replication is recommended, as withdrawal of lamivudine may
result in an acute exacerbation of hepatitis (see Zeffix SPC).
Patients with pre-existing liver dysfunction, including chronic active hepatitis, have an increased
frequency of liver function abnormalities during combination antiretroviral therapy, and should be
monitored according to standard practice. If there is evidence of worsening liver disease in such
patients, interruption or discontinuation of treatment must be considered (see section 4.8).
Osteonecrosis: Although the etiology is considered to be multifactorial (including corticosteroid use,
alcohol consumption, severe immunosuppression, higher body mass index), cases of osteonecrosis
have been reported particularly in patients with advanced HIV-disease and/or long-term exposure to
combination antiretroviral therapy (CART). Patients should be advised to seek medical advice if they
experience joint aches and pain, joint stiffness or difficulty in movement.
Epivir should not be taken with any other medicinal products containing lamivudine or medicinal
products containing emtricitabine.
4.5
Interaction studies have only been performed in adults
The likelihood of metabolic interactions is low due to limited metabolism and plasma protein binding
and almost complete renal clearance.
Administration of trimethoprim/sulfamethoxazole 160 mg/800 mg results in a 40 % increase in
lamivudine exposure, because of the trimethoprim component; the sulfamethoxazole component did
not interact. However, unless the patient has renal impairment, no dosage adjustment of lamivudine is
necessary (see section 4.2). Lamivudine has no effect on the pharmacokinetics of trimethoprim or
sulfamethoxazole. When concomitant administration is warranted, patients should be monitored
5
clinically. Co-administration of lamivudine with high doses of co-trimoxazole for the treatment of
Pneumocystis carinii
pneumonia (PCP) and toxoplasmosis should be avoided.
The possibility of interactions with other medicinal products administered concurrently should be
considered, particularly when the main route of elimination is active renal secretion via the organic
cationic transport system e.g. trimethoprim. Other medicinal products (e.g. ranitidine, cimetidine) are
eliminated only in part by this mechanism and were shown not to interact with lamivudine. The
nucleoside analogues (e.g. didanosine) like zidovudine, are not eliminated by this mechanism and are
unlikely to interact with lamivudine.
A modest increase in C
max
(28 %) was observed for zidovudine when administered with lamivudine,
however overall exposure (AUC) is not significantly altered. Zidovudine has no effect on the
pharmacokinetics of lamivudine (see section 5.2).
Lamivudine metabolism does not involve CYP3A, making interactions with medicinal products
metabolised by this system (e.g. PIs) unlikely.
4.6
A large amount of data on pregnant women (more than 1000 exposed outcomes) indicate no
malformative toxicity. Epivir can be used during pregnancy if clinically needed.
For patients co-infected with hepatitis who are being treated with lamivudine and subsequently
become pregnant, consideration should be given to the possibility of a recurrence of hepatitis on
discontinuation of lamivudine.
Mitochondrial dysfunction:
Nucleoside and nucleotide analogues have been demonstrated in vitro and in vivo to cause a variable
degree of mitochondrial damage. There have been reports of mitochondrial dysfunction in infants
exposed in utero and/or post-natally to nucleoside analogues (see section 4.4).
Following oral administration lamivudine was excreted in breast milk at similar concentrations to
those found in serum. Since lamivudine and the virus pass into breast milk, it is recommended that
mothers taking Epivir do not breast-feed their infants. It is recommended that HIV infected women do
not breast-feed their infants under any circumstances in order to avoid transmission of HIV.
4.7
No studies on the effects on the ability to drive and use machines have been performed.
4.8
The following adverse reactions have been reported during therapy for HIV disease with Epivir.
The adverse reactions considered at least possibly related to the treatment are listed below by body
system, organ class and absolute frequency. Frequencies are defined as very common (≥1/10),
common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare
(<1/10,000). Within each frequency grouping, undesirable effects are presented in order of decreasing
seriousness.
Blood and lymphatic systems disorders
Uncommon
: Neutropenia and anaemia (both occasionally severe), thrombocytopenia
Very rare
: Pure red cell aplasia
Nervous system disorders
Common:
Headache, insomnia
Very rare:
peripheral neuropathy (or paraesthesia)
6
Respiratory, thoracic and mediastinal disorders
Common:
Cough, nasal symptoms
Gastrointestinal disorders
Common:
Nausea, vomiting, abdominal pain or cramps, diarrhoea
Rare:
Pancreatitis. elevations in serum amylase.
Hepatobiliary disorders
Uncommon:
Transient elevations in liver enzymes (AST, ALT).
Rare:
Hepatitis
Skin and subcutaneous tissue disorders
Common:
Rash, alopecia
Rare:
Angioedema
Musculoskeletal and connective tissue disorders
Common:
Arthralgia,
muscle disorders
Rare:
Rhabdomyolysis
General disorders and administration site conditions
Common:
Fatigue, malaise, fever.
Cases of lactic acidosis, sometimes fatal, usually associated with severe hepatomegaly and hepatic
steatosis, have been reported with the use of nucleoside analogues (see section 4.4).
Combination antiretroviral therapy has been associated with redistribution of body fat (lipodystrophy)
in HIV patients including the loss of peripheral and facial subcutaneous fat, increased intra-abdominal
and visceral fat, breast hypertrophy and dorsocervical fat accumulation (buffalo hump).
Combination antiretroviral therapy has been associated with metabolic abnormalities such as
hypertriglyceridaemia, hypercholesterolaemia, insulin resistance, hyperglycaemia and
hyperlactataemia (see section 4.4).
In HIV-infected patients with severe immune deficiency at the time of initiation of combination
antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic
infections may arise (see section 4.4).
Cases of osteonecrosis have been reported, particularly in patients with generally acknowledged risk
factors, advanced HIV disease or long-term combined antiretroviral exposure (cART). The frequency
of which is unknown (see section 4.4).
4.9
Administration of lamivudine at very high dose levels in acute animal studies did not result in any
organ toxicity. Limited data are available on the consequences of ingestion of acute overdoses in
humans. No fatalities occurred, and the patients recovered. No specific signs or symptoms have been
identified following such overdose.
If overdosage occurs the patient should be monitored, and standard supportive treatment applied as
required. Since lamivudine is dialysable, continuous haemodialysis could be used in the treatment of
overdosage, although this has not been studied.
5.
5.1
Pharmacodynamic properties
7
Pharmacotherapeutic group: nucleoside analogue, ATC Code: J05AF05.
Lamivudine is a nucleoside analogue which has activity against human immunodeficiency virus (HIV)
and hepatitis B virus (HBV). It is metabolised intracellularly to the active moiety, lamivudine 5’-
triphosphate. Its main mode of action is as a chain terminator of viral reverse transcription. The
triphosphate has selective inhibitory activity against HIV-1 and HIV-2 replication
in vitro
,
it is also
active against zidovudine-resistant clinical isolates of HIV. Lamivudine in combination with
zidovudine exhibits synergistic anti-HIV activity against clinical isolates in cell culture.
HIV-1 resistance to lamivudine involves the development of a M184V amino acid change close to the
active site of the viral reverse transcriptase (RT). This variant arises both
in vitro
and in HIV-1
infected patients treated with lamivudine-containing antiretroviral therapy. M184V mutants display
greatly reduced susceptibility to lamivudine and show diminished viral replicative capacity
in vitro
.
In
vitro
studies indicate that zidovudine-resistant virus isolates can become zidovudine sensitive when
they simultaneously acquire resistance to lamivudine. The clinical relevance of such findings remains,
however, not well defined.
In vitro
data tend to suggest that the continuation of lamivudine in anti-retroviral regimen despite the
development of M184V might provide residual anti-retroviral activity (likely through impaired viral
fitness). The clinical relevance of these findings is not established. Indeed, the available clinical data
are very limited and preclude any reliable conclusion in the field. In any case, initiation of susceptible
NRTI’s should always be preferred to maintenance of lamivudine therapy. Therefore, maintaining
lamivudine therapy despite emergence of M184V mutation should only be considered in cases where
no other active NRTI’s are available.
Cross-resistance conferred by the M184V RT is limited within the nucleoside inhibitor class of
antiretroviral agents. Zidovudine and stavudine maintain their antiretroviral activities against
lamivudine-resistant HIV-1. Abacavir maintains its antiretroviral activities against lamivudine-
resistant HIV-1 harbouring only the M184V mutation. The M184V RT mutant shows a <4-fold
decrease in susceptibility to didanosine; the clinical significance of these findings is unknown.
In vitro
susceptibility testing has not been standardised and results may vary according to methodological
factors.
Lamivudine demonstrates low cytotoxicity to peripheral blood lymphocytes, to established
lymphocyte and monocyte-macrophage cell lines, and to a variety of bone marrow progenitor cells
in
vitro
.
Clinical experience:
In clinical trials, lamivudine in combination with zidovudine
has been shown to reduce HIV-1 viral
load and increase CD4 cell count. Clinical end-point data indicate that lamivudine in combination
with zidovudine, results in a significant reduction in the risk of disease progression and mortality.
Evidence from clinical studies shows that lamivudine plus zidovudine
delays the emergence of
zidovudine resistant isolates in individuals with no prior antiretroviral therapy.
Lamivudine has been widely used as a component of antiretroviral combination therapy with other
antiretroviral agents of the same class (NRTIs) or different classes (PIs, non-nucleoside reverse
transcriptase inhibitors).
Multiple drug antiretroviral therapy containing lamivudine has been shown to be effective in
antiretrovirally-naive patients as well as in patients presenting with viruses containing the M184V
mutations.
The relationship between
in vitro
susceptibility of HIV to lamivudine and clinical response to
lamivudine-containing therapy remains under investigation.
8
Lamivudine at a dose of 100 mg once daily has also been shown to be effective for the treatment of
adult patients with chronic HBV infection (for details of clinical studies, see the prescribing
information for Zeffix). However, for the treatment of HIV infection only a 300 mg daily dose of
lamivudine (in combination with other antiretroviral agents) has been shown to be efficacious.
Lamivudine has not been specifically investigated in HIV patients co-infected with HBV.
Once daily dosing (300 mg once a day):
a clinical study has demonstrated the non inferiority between
Epivir once a day and Epivir twice a day containing regimens. These results were obtained in an
antiretroviral naïve-population, primarily consisting of asymptomatic HIV infected patients (CDC
stage A).
5.2
Pharmacokinetic properties
Absorption:
Lamivudine is well absorbed from the gastrointestinal tract, and the bioavailability of oral
lamivudine in adults is normally between 80 and 85%. Following oral administration, the mean time
(t
max
) to maximal serum concentrations (C
max
) is about an hour. Based on data derived from a study in
healthy volunteers, at a therapeutic dose of 150mg twice daily, mean (CV) steady-state C
max
and C
min
of lamivudine in plasma are 1.2 µg/ml (24%) and 0.09 µg/ml (27%), respectively. The mean (CV)
AUC over a dosing interval of 12 hours is 4.7 µg.h/ml (18%). At a therapeutic dose of 300mg once
daily, the mean (CV) steady-state C
max
, C
min
and 24h AUC are 2.0 µg/ml (26%), 0.04 µg/ml (34%) and
8.9 µg.h/ml (21%), respectively.
The 150 mg tablet is bioequivalent and dose proportional to the 300 mg tablet with respect to AUC
∞
,
C
max
, and t
max
.
Co-administration of lamivudine with food results in a delay of t
max
and a lower C
max
(decreased by
47%). However, the extent (based on the AUC) of lamivudine absorbed is not influenced.
Administration of crushed tablets with a small amount of semi-solid food or liquid would not be
expected to have an impact on the pharmaceutical quality, and would therefore not be expected to alter
the clinical effect. This conclusion is based on the physiochemical and pharmacokinetic data
assuming that the patient crushes and transfers 100% of the tablet and ingests immediately.
Co-administration of zidovudine results in a 13% increase in zidovudine exposure and a 28 % increase
in peak plasma levels. This is not considered to be of significance to patient safety and therefore no
dosage adjustments are necessary.
Distribution:
From intravenous studies, the mean volume of distribution is 1.3 l/kg. The observed
half-life of elimination is 5 to 7 hours. The mean systemic clearance of lamivudine is approximately
0.32 l/h/kg, with predominantly renal clearance (> 70%) via the organic cationic transport system.
Lamivudine exhibits linear pharmacokinetics over the therapeutic dose range and displays limited
binding to the major plasma protein albumin (< 16% - 36% to serum albumin in
in vitro
studies).
Limited data show that lamivudine penetrates the central nervous system and reaches the cerebro-
spinal fluid (CSF). The mean ratio CSF/serum lamivudine concentration 2-4 hours after oral
administration was approximately 0.12. The true extent of penetration or relationship with any clinical
efficacy is unknown.
Metabolism:
The active moiety, intracellular lamivudine triphosphate, has a prolonged terminal half-
life in the cell (16 to 19 hours) compared to the plasma lamivudine half-life (5 to 7 hours). In 60
healthy adult volunteers, Epivir 300 mg once daily has been demonstrated to be pharmacokinetically
equivalent at steady-state to Epivir 150 mg twice daily with respect to intracellular triphosphate
AUC
24
and C
max
.
9
Lamivudine is predominately cleared unchanged by renal excretion. The likelihood of metabolic
interactions of lamivudine with other medicinal products is low due to the small extent of hepatic
metabolism (5-10%) and low plasma protein binding.
Elimination:
Studies in patients with renal impairment show lamivudine elimination is affected by
renal dysfunction. A recommended dosage regimen for patients with creatinine clearance below
50 ml/min is shown in the dosage section (see section 4.2).
An interaction with trimethoprim, a constituent of co-trimoxazole, causes a 40% increase in
lamivudine exposure at therapeutic doses. This does not require dose adjustment unless the patient
also has renal impairment (see sections 4.5 and 4.2). Administration of co-trimoxazole with
lamivudine in patients with renal impairment should be carefully assessed.
Pharmacokinetics in children:
In general, lamivudine pharmacokinetics in paediatric patients is
similar to adults. However, absolute bioavailability (approximately 55-65%) was reduced in
paediatric patients below 12 years of age. In addition, systemic clearance values were greater in
younger paediatric patients and decreased with age, approaching adult values around 12 years of age.
Due to these differences, the recommended dose for lamivudine in children (aged more than three
months and weighing less than 30 kg) is 4 mg/kg twice daily. This dose will achieve an average
AUC
0-12
ranging from approximately 3,800 to 5,300 ng.h/ml. Recent findings indicate that exposure
in children < 6 years of age may be reduced by about 30% compared with other age groups. Further
data addressing this issue are currently awaited. At present, the available data do not suggest that
lamivudine is less efficacious in this age group.
There are limited pharmacokinetic data for patients less than three months of age. In neonates one
week of age, lamivudine oral clearance was reduced when compared to paediatric patients and is likely
to be due to immature renal function and variable absorption. Therefore to achieve similar adult and
paediatric exposure, the recommended dose for neonates is 4 mg/kg/day. Glomerular filtration
estimates suggests that to achieve similar adult and paediatric exposure, the recommended dose for
children aged six weeks and older could be 8 mg/kg/day.
Pharmacokinetics in pregnancy:
Following oral administration, lamivudine pharmacokinetics in late-
pregnancy were similar to non-pregnant women.
5.3
Preclinical safety data
Administration of lamivudine in animal toxicity studies at high doses was not associated with any
major organ toxicity. At the highest dosage levels, minor effects on indicators of liver and kidney
function were seen together with occasional reductions in liver weight. The clinically relevant effects
noted were a reduction in red blood cell count and neutropenia.
Lamivudine was not mutagenic in bacterial tests but, like many nucleoside analogues, showed activity
in an
in vitro
cytogenetic assay and the mouse lymphoma assay. Lamivudine was not genotoxic
in
vivo
at doses that gave plasma concentrations around 40-50 times higher than the anticipated clinical
plasma levels. As the
in vitro
mutagenic activity of lamivudine could not be confirmed in
in vivo
tests,
it is concluded that lamivudine should not represent a genotoxic hazard to patients undergoing
treatment.
A transplacental genotoxicity study conducted in monkeys compared zidovudine alone with the
combination of zidovudine and lamivudine at human-equivalent exposures. The study demonstrated
that foetuses exposed
in utero
to the combination sustained a higher level of nucleoside analogue-
DNA incorporation into multiple foetal organs, and showed evidence of more telomere shortening
than in those exposed to zidovudine alone. The clinical significance of these findings is unknown.
The results of long-term carcinogenicity studies in rats and mice did not show any carcinogenic
potential relevant for humans.
10
6.
6.1
List of excipients
Tablet core:
Microcrystalline cellulose (E460),
Sodium starch glycollate
Magnesium stearate
Tablet film-coat:
Hypromellose (E464)
Titanium dioxide (E171),
Macrogol,
Polysorbate 80
6.2
Incompatibilities
Not applicable.
6.3
Shelf life
HDPE bottles:
5 years
PVC/aluminium foil blister packs:
2 years
6.4
Special precautions for storage
Do not store above 30°C
6.5
Nature and contents of container
Child resistant HDPE bottles or PVC/aluminium foil blister packs each containing 60 tablets.
6.6
Special precautions for disposal
No special requirements
7.
ViiV Healthcare UK Limited
980 Great West Road
Brentford
Middlesex
TW8 9GS
United Kingdom
8.
EU/1/96/015/001 (Bottle)
EU/1/96/015/004 (Blister pack)
9.
11
Date of first authorisation: 8 August 1996
Date of last renewal: 28 July 2006
10.
Detailed information on this medicinal product is available on the website of the European Medicines
Agency
http://www.ema.europa.eu
12
1.
Epivir 10 mg/ml oral solution
2.
Each ml of oral solution contains 10 mg of lamivudine.
Excipients:
Sucrose 20% (3 g/15 ml)
Methyl parahydroxybenzoate
Propyl parahydroxybenzoate
For a full list of excipients, see section 6.1.
3.
Oral solution
Clear, colourless to pale yellow solution.
4.
Epivir is indicated as part of antiretroviral combination therapy for the treatment of Human
Immunodeficiency Virus (HIV) infected adults and children.
The therapy should be initiated by a physician experienced in the management of HIV infection.
Adults and adolescents over 12 years of age:
the recommended dose of Epivir is 300 mg daily. This
may be administered as either 150 mg (15 ml) twice daily or 300 mg (30 ml) once daily (see section
4.4).
Patients changing to the once daily regimen should take 150 mg (15 ml) twice a day and switch to
300 mg (30 ml) once a day the following morning. Where an evening once daily regimen is preferred,
150 mg (15 ml) of Epivir should be taken on the first morning only, followed by 300 mg (30 ml) in the
evening. When changing back to a twice daily regimen, patients should complete the days treatment
and start 150 mg (15 ml) twice a day the following morning.
Children
Three months to 12 years of age:
the recommended dose is 4 mg/kg twice daily up to a maximum of
300 mg daily.
Less than three months of age:
the limited data available are insufficient to propose specific dosage
recommendations (see section 5.2).
Epivir is also available as a tablet formulation.
Epivir may be administered with or without food.
13
Renal impairment:
Lamivudine concentrations are increased in patients with moderate - severe renal
impairment due to decreased clearance. The dose should therefore be adjusted (see tables).
Dosing recommendations – Adults and adolescents over 12 years:
Creatinine clearance
(ml/min)
First dose
Maintenance dose
≥50
150 mg (15 ml)
150 mg (15 ml) twice daily
30 to<50
150 mg (15 ml)
150 mg (15 ml) once daily
15 to <30
150 mg (15 ml)
100 mg (10 ml) once daily
5 to <15
150 mg (15 ml)
50 mg (5 ml) once daily
<5
50 mg (5 ml)
25 mg (2.5 ml) once daily
There are no data available on the use of lamivudine in children with renal impairment. Based on the
assumption that creatinine clearance and lamivudine clearance are correlated similarly in children as in
adults it is recommended that the dosage in children with renal impairment be reduced according to
their creatinine clearance by the same proportion as in adults.
Dosing recommendations – Children from 3 months to 12 years:
Creatinine clearance
(ml/min)
First dose
Maintenance dose
≥50
4 mg/kg
4 mg/kg twice daily
30 to<50
4 mg/kg
4 mg/kg once daily
15 to <30
4 mg/kg
2.6 mg/kg once daily
5 to <15
4 mg/kg
1.3 mg/kg once daily
<5
1.3 mg/kg
0.7 mg/kg once daily
Hepatic impairment:
Data obtained in patients with moderate to severe hepatic impairment shows that
lamivudine pharmacokinetics are not significantly affected by hepatic dysfunction. Based on these
data, no dose adjustment is necessary in patients with moderate or severe hepatic impairment unless
accompanied by renal impairment.
4.3
Hypersensitivity to the active substance or to any of the excipients.
4.4
Epivir is not recommended for use as monotherapy.
Renal impairment:
In patients with moderate –to- severe renal impairment, the terminal plasma half-
life of lamivudine is increased due to decreased clearance, therefore the dose should be adjusted (see
section 4.2).
Triple nucleoside therapy:
There have been reports of a high rate of virological failure and of
emergence of resistance at an early stage when lamivudine was combined with tenofovir disoproxil
fumarate and abacavir as well as with tenofovir disoproxil fumarate and didanosine as a once daily
regimen.
Opportunistic infections:
Patients receiving Epivir or any other antiretroviral therapy may continue to
develop opportunistic infections and other complications of HIV infection, and therefore should
remain under close clinical observation by physicians experienced in the treatment of patients with
associated HIV diseases.
14
Transmission of HIV:
Patients should be advised that current antiretroviral therapy, including Epivir,
has not been proven to prevent the risk of transmission of HIV to others through sexual contact or
contamination with blood. Appropriate precautions should continue to be taken.
Pancreatitis
: Cases of pancreatitis have occurred rarely. However it is not clear whether these cases
were due to the antiretroviral treatment or to the underlying HIV disease. Treatment with Epivir
should be stopped immediately if clinical signs, symptoms or laboratory abnormalities suggestive of
pancreatitis occur.
Lactic acidosis
: lactic acidosis, usually associated with hepatomegaly and hepatic steatosis, has been
reported with the use of nucleoside analogues. Early symptoms (symptomatic hyperlactatemia)
include benign digestive symptoms (nausea, vomiting and abdominal pain), non-specific malaise, loss
of appetite, weight loss, respiratory symptoms (rapid and/or deep breathing) or neurological symptoms
(including motor weakness).
Lactic acidosis has a high mortality and may be associated with pancreatitis, liver failure, or renal
failure.
Lactic acidosis generally occurred after a few or several months of treatment.
Treatment with nucleoside analogues should be discontinued in the setting of symptomatic
hyperlactatemia and metabolic/lactic acidosis, progressive hepatomegaly, or rapidly elevating
aminotransferase levels.
Caution should be exercised when administering nucleoside analogues to any patient (particularly
obese women) with hepatomegaly, hepatitis or other known risk factors for liver disease and hepatic
steatosis (including certain medicinal products and alcohol). Patients co-infected with hepatitis C and
treated with alpha interferon and ribavirin may constitute a special risk.
Patients at increased risk should be followed closely .
Mitochondrial dysfunction:
Nucleoside and nucleotide analogues have been demonstrated
in vitro
and
in vivo
to cause a variable degree of mitochondrial damage. There have been reports of mitochondrial
dysfunction in HIV-negative infants exposed
in utero
and/or post-natally to nucleoside analogues. The
main adverse events reported are haematological disorders (anaemia, neutropenia), metabolic
disorders (hyperlactatemia, hyperlipasemia). These events are often transitory. Some late-onset
neurological disorders have been reported (hypertonia, convulsion, abnormal behaviour). Whether the
neurological disorders are transient or permanent is currently unknown. Any child exposed
in utero
to
nucleoside and nucleotide analogues, even HIV-negative children, should have clinical and laboratory
follow-up and should be fully investigated for possible mitochondrial dysfunction in case of relevant
signs or symptoms. These findings do not affect current national recommendations to use antiretroviral
therapy in pregnant women to prevent vertical transmission of HIV.
Lipodystrophy:
Combination antiretroviral therapy has been associated with the redistribution of body
fat (lipodystrophy) in HIV patients. The long-term consequences of these events are currently
unknown. Knowledge about the mechanism is incomplete. A connection between visceral lipomatosis
and protease inhibitors (PIs) and lipoatrophy and nucleoside analogue reverse transcriptase inhibitors
(NRTIs) has been hypothesised. A higher risk of lipodystrophy has been associated with individual
factors such as older age, and with drug related factors such as longer duration of antiretroviral
treatment and associated metabolic disturbances. Clinical examination should include evaluation for
physical signs of fat redistribution. Consideration should be given to the measurement of fasting serum
lipids and blood glucose. Lipid disorders should be managed as clinically appropriate (see section 4.8).
Immune Reactivation Syndrome:
In HIV-infected patients with severe immune deficiency at the time
of institution of combination antiretroviral therapy (CART), an inflammatory reaction to
asymptomatic or residual opportunistic pathogens may arise and cause serious clinical conditions, or
15
aggravation of symptoms. Typically, such reactions have been observed within the first few weeks or
months of initiation of CART. Relevant examples are cytomegalovirus retinitis, generalised and/or
focal mycobacterium infections, and
Pneumocystis carinii
pneumonia. Any inflammatory symptoms
should be evaluated and treatment instituted when necessary.
Liver disease:
If lamivudine is being used concomitantly for the treatment of HIV and HBV,
additional information relating to the use of lamivudine in the treatment of hepatitis B infection is
available in the Zeffix SPC.
Patients with chronic hepatitis B or C and treated with combination antiretroviral therapy are at an
increased risk of severe and potentially fatal hepatic adverse events. In case of concomitant antiviral
therapy for hepatitis B or C, please refer also to the relevant product information for these medicinal
products.
If Epivir is discontinued in patients co-infected with hepatitis B virus, periodic monitoring of liver
function tests and markers of HBV replication is recommended, as withdrawal of lamivudine may
result in an acute exacerbation of hepatitis (see Zeffix SPC).
Patients with pre-existing liver dysfunction, including chronic active hepatitis, have an increased
frequency of liver function abnormalities during combination antiretroviral therapy, and should be
monitored according to standard practice. If there is evidence of worsening liver disease in such
patients, interruption or discontinuation of treatment must be considered (see section 4.8).
Diabetic patients should be advised that each dose (150 mg = 15 ml) contains 3 g of sucrose.
Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or
sucrase-isomaltase insufficiency should not take this medicine.
Epivir contains methyl parahydroxybenzoate and propyl parahydroxybenzoate. These may cause
allergic reactions (possibly delayed).
Osteonecrosis: Although the etiology is considered to be multifactorial (including corticosteroid use,
alcohol consumption, severe immunosuppression, higher body mass index), cases of osteonecrosis
have been reported particularly in patients with advanced HIV-disease and/or long-term exposure to
combination antiretroviral therapy (CART). Patients should be advised to seek medical advice if they
experience joint aches and pain, joint stiffness or difficulty in movement.
Epivir should not be taken with any other medicinal products containing lamivudine or medicinal
products containing emtricitabine.
4.5
Interaction studies have only been performed in adults
The likelihood of metabolic interactions is low due to limited metabolism and plasma protein binding
and almost complete renal clearance.
Administration of trimethoprim/sulfamethoxazole 160 mg/800 mg results in a 40 % increase in
lamivudine exposure, because of the trimethoprim component; the sulfamethoxazole component did
not interact. However, unless the patient has renal impairment, no dosage adjustment of lamivudine is
necessary (see section 4.2). Lamivudine has no effect on the pharmacokinetics of trimethoprim or
sulfamethoxazole. When concomitant administration is warranted, patients should be monitored
clinically. Co-administration of lamivudine with high doses of co-trimoxazole for the treatment of
Pneumocystis carinii
pneumonia (PCP) and toxoplasmosis should be avoided.
16
The possibility of interactions with other medicinal products administered concurrently should be
considered, particularly when the main route of elimination is active renal secretion via the organic
cationic transport system e.g. trimethoprim. Other medicinal products (e.g. ranitidine, cimetidine) are
eliminated only in part by this mechanism and were shown not to interact with lamivudine. The
nucleoside analogues (e.g. didanosine) like zidovudine, are not eliminated by this mechanism and are
unlikely to interact with lamivudine.
A modest increase in C
max
(28 %) was observed for zidovudine when administered with lamivudine,
however overall exposure (AUC) is not significantly altered. Zidovudine has no effect on the
pharmacokinetics of lamivudine (see section 5.2).
Lamivudine metabolism does not involve CYP3A, making interactions with medicinal products
metabolised by this system (e.g. PIs) unlikely.
4.6
A large amount of data on pregnant women (more than 1000 exposed outcomes) indicate no
malformative toxicity. Epivir can be used during pregnancy if clinically needed.
For patients co-infected with hepatitis who are being treated with lamivudine and subsequently
become pregnant, consideration should be given to the possibility of a recurrence of hepatitis on
discontinuation of lamivudine.
Mitochondrial dysfunction:
Nucleoside and nucleotide analogues have been demonstrated in vitro and in vivo to cause a variable
degree of mitochondrial damage. There have been reports of mitochondrial dysfunction in infants
exposed in utero and/or post-natally to nucleoside analogues (see section 4.4).
Following oral administration lamivudine was excreted in breast milk at similar concentrations to
those found in serum. Since lamivudine and the virus pass into breast milk, it is recommended that
mothers taking Epivir do not breast-feed their infants. It is recommended that HIV infected women do
not breast-feed their infants under any circumstances in order to avoid transmission of HIV.
No studies on the effects on the ability to drive and use machines have been performed.
The following adverse reactions have been reported during therapy for HIV disease with Epivir.
The adverse reactions considered at least possibly related to the treatment are listed below by body
system, organ class and absolute frequency. Frequencies are defined as very common (≥1/10),
common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare
(<1/10,000). Within each frequency grouping, undesirable effects are presented in order of decreasing
seriousness.
Blood and lymphatic systems disorders
Uncommon
: Neutropenia and anaemia (both occasionally severe), thrombocytopenia
Very rare
: Pure red cell aplasia
Nervous system disorders
Common:
Headache, insomnia
Very rare:
Peripheral neuropathy (or paraesthesia)
Respiratory, thoracic and mediastinal disorders
Common:
Cough, nasal symptoms
17
Gastrointestinal disorders
Common:
Nausea, vomiting, abdominal pain or cramps, diarrhoea
Rare:
Pancreatitis elevations in serum amylase.
Hepatobiliary disorders
Uncommon:
Transient elevations in liver enzymes (AST, ALT).
Rare:
Hepatitis
Skin and subcutaneous tissue disorders
Common:
Rash, alopecia
Rare:
Angioedema
Musculoskeletal and connective tissue disorders
Common:
Arthralgia,
muscle disorders
Rare:
Rhabdomyolysis
General disorders and administration site conditions
Common:
Fatigue, malaise, fever.
Cases of lactic acidosis, sometimes fatal, usually associated with severe hepatomegaly and hepatic
steatosis, have been reported with the use of nucleoside analogues (see section 4.4).
Combination antiretroviral therapy has been associated with redistribution of body fat (lipodystrophy)
in HIV patients including the loss of peripheral and facial subcutaneous fat, increased intra-abdominal
and visceral fat, breast hypertrophy and dorsocervical fat accumulation (buffalo hump).
Combination antiretroviral therapy has been associated with metabolic abnormalities such as
hypertriglyceridaemia, hypercholesterolaemia, insulin resistance, hyperglycaemia and
hyperlactataemia (see section 4.4).
In HIV-infected patients with severe immune deficiency at the time of initiation of combination
antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic
infections may arise (see section 4.4).
Cases of osteonecrosis have been reported, particularly in patients with generally acknowledged risk
factors, advanced HIV disease or long-term combined antiretroviral exposure (CART). The frequency
of which is unknown (see section 4.4).
Administration of lamivudine at very high dose levels in acute animal studies did not result in any
organ toxicity. Limited data are available on the consequences of ingestion of acute overdoses in
humans. No fatalities occurred, and the patients recovered. No specific signs or symptoms have been
identified following such overdose.
If overdosage occurs the patient should be monitored, and standard supportive treatment applied as
required. Since lamivudine is dialysable, continuous haemodialysis could be used in the treatment of
overdosage, although this has not been studied.
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: nucleoside analogue, ATC Code: J05AF05.
18
Lamivudine is a nucleoside analogue which has activity against human immunodeficiency virus (HIV)
and hepatitis B virus (HBV). It is metabolised intracellularly to the active moiety, lamivudine 5’-
triphosphate. Its main mode of action is as a chain terminator of viral reverse transcription. The
triphosphate has selective inhibitory activity against HIV-1 and HIV-2 replication
in vitro
;
it is also
active against zidovudine-resistant clinical isolates of HIV. Lamivudine in combination with
zidovudine exhibits synergistic anti-HIV activity against clinical isolates in cell culture.
HIV-1 resistance to lamivudine involves the development of a M184V amino acid change close to the
active site of the viral reverse transcriptase (RT). This variant arises both
in vitro
and in HIV-1
infected patients treated with lamivudine-containing antiretroviral therapy. M184V mutants display
greatly reduced susceptibility to lamivudine and show diminished viral replicative capacity
in vitro
.
In
vitro
studies indicate that zidovudine-resistant virus isolates can become zidovudine sensitive when
they simultaneously acquire resistance to lamivudine. The clinical relevance of such findings remains,
however, not well defined.
In vitro
data tend to suggest that the continuation of lamivudine in anti-retroviral regimen despite the
development of M184V might provide residual anti-retroviral activity (likely through impaired viral
fitness). The clinical relevance of these findings is not established. Indeed, the available clinical data
are very limited and preclude any reliable conclusion in the field. In any case, initiation of susceptible
NRTI’s should always be preferred to maintenance of lamivudine therapy. Therefore, maintaining
lamivudine therapy despite emergence of M184V mutation should only be considered in cases where
no other active NRTI’s are available.
Cross-resistance conferred by the M184V RT is limited within the nucleoside inhibitor class of
antiretroviral agents. Zidovudine and stavudine maintain their antiretroviral activities against
lamivudine-resistant HIV-1. Abacavir maintains its antiretroviral activities against lamivudine-
resistant HIV-1 harbouring only the M184V mutation. The M184V RT mutant shows a <4-fold
decrease in susceptibility to didanosine; the clinical significance of these findings is unknown.
In vitro
susceptibility testing has not been standardised and results may vary according to methodological
factors.
Lamivudine demonstrates low cytotoxicity to peripheral blood lymphocytes, to established
lymphocyte and monocyte-macrophage cell lines, and to a variety of bone marrow progenitor cells
in
vitro
.
Clinical experience:
In clinical trials, lamivudine in combination with zidovudine
has been shown to reduce HIV-1 viral
load and increase CD4 cell count. Clinical end-point data indicate that lamivudine in combination
with zidovudine, results in a significant reduction in the risk of disease progression and mortality.
Evidence from clinical studies shows that lamivudine plus zidovudine
delays the emergence of
zidovudine resistant isolates in individuals with no prior antiretroviral therapy.
Lamivudine has been widely used as a component of antiretroviral combination therapy with other
antiretroviral agents of the same class (NRTIs) or different classes (PIs, non-nucleoside reverse
transcriptase inhibitors).
Multiple drug antiretroviral therapy containing lamivudine has been shown to be effective in
antiretrovirally-naive patients as well as in patients presenting with viruses containing the M184V
mutations.
The relationship between
in vitro
susceptibility of HIV to lamivudine and clinical response to
lamivudine-containing therapy remains under investigation.
Lamivudine at a dose of 100 mg once daily has also been shown to be effective for the treatment of
adult patients with chronic HBV infection (for details of clinical studies, see the prescribing
19
information for Zeffix). However, for the treatment of HIV infection, only a 300 mg daily dose of
lamivudine (in combination with other antiretroviral agents) has been shown to be efficacious.
Lamivudine has not been specifically investigated in HIV patients co-infected with HBV.
Once daily dosing (300 mg once a day):
a clinical study has demonstrated the non inferiority between
Epivir once a day and Epivir twice a day containing regimens. These results were obtained in an
antiretroviral naïve-population, primarily consisting of asymptomatic HIV infected patients (CDC
stage A).
5.2
Pharmacokinetic properties
Absorption:
Lamivudine is well absorbed from the gastrointestinal tract, and the bioavailability of oral
lamivudine in adults is normally between 80 and 85%. Following oral administration, the mean time
(t
max
) to maximal serum concentrations (C
max
) is about an hour. Based on data derived from a study in
healthy volunteers, at a therapeutic dose of 150mg twice daily, mean (CV) steady-state C
max
and C
min
of lamivudine in plasma are 1.2 µg/ml (24%) and 0.09 µg/ml (27%), respectively. The mean (CV)
AUC over a dosing interval of 12 hours is 4.7 µg.h/ml (18%). At a therapeutic dose of 300mg once
daily, the mean (CV) steady-state C
max
, C
min
and 24h AUC are 2.0 µg/ml (26%), 0.04 µg/ml (34%) and
8.9 µg.h/ml (21%), respectively.
Co-administration of lamivudine with food results in a delay of t
max
and a lower C
max
(decreased by
47 %). However, the extent (based on the AUC) of lamivudine absorbed is not influenced.
Co-administration of zidovudine results in a 13% increase in zidovudine exposure and a 28% increase
in peak plasma levels. This is not considered to be of significance to patient safety and therefore no
dosage adjustments are necessary.
Distribution:
From intravenous studies, the mean volume of distribution is 1.3 l/kg. The observed
half-life of elimination is 5 to 7 hours. The mean systemic clearance of lamivudine is approximately
0.32 l/h/kg, with predominantly renal clearance (>70 %) via the organic cationic transport system.
Lamivudine exhibits linear pharmacokinetics over the therapeutic dose range and displays limited
binding to the major plasma protein albumin (< 16% - 36% to serum albumin in
in vitro
studies).
Limited data show that lamivudine penetrates the central nervous system and reaches the cerebro-
spinal fluid (CSF). The mean ratio CSF/serum lamivudine concentration 2-4 hours after oral
administration was approximately 0.12. The true extent of penetration or relationship with any clinical
efficacy is unknown.
Metabolism:
The active moiety, intracellular lamivudine triphosphate, has a prolonged terminal half-
life in the cell (16 to 19 hours) compared to the plasma lamivudine half-life (5 to 7 hours). In 60
healthy adult volunteers, Epivir 300 mg once daily has been demonstrated to be pharmacokinetically
equivalent at steady-state to Epivir 150 mg twice daily with respect to intracellular triphosphate
AUC
24
and C
max
.
Lamivudine is predominately cleared unchanged by renal excretion. The likelihood of metabolic
interactions of lamivudine with other medicinal products is low due to the small extent of hepatic
metabolism (5-10%) and low plasma protein binding.
Elimination:
Studies in patients with renal impairment show lamivudine elimination is affected by
renal dysfunction. A recommended dosage regimen for patients with creatinine clearance below
50 ml/min is shown in the dosage section (see section 4.2).
An interaction with trimethoprim, a constituent of co-trimoxazole, causes a40 % increase in
lamivudine exposure at therapeutic doses. This does not require dose adjustment unless the patient
20
also has renal impairment (see sections 4.5 and 4.2). Administration of co-trimoxazole with
lamivudine in patients with renal impairment should be carefully assessed.
Pharmacokinetics in children:
In general, lamivudine pharmacokinetics in paediatric patients is
similar to adults. However, absolute bioavailability (approximately 55-65%) was reduced in
paediatric patients below 12 years of age. In addition, systemic clearance values were greater in
younger paediatric patients and decreased with age, approaching adult values around 12 years of age.
Due to these differences, the recommended dose for lamivudine in children (aged more than three
months and weighing less than 30 kg) is 4 mg/kg twice daily. This dose will achieve an average
AUC
0-12
ranging from approximately 3,800 to 5,300 ng.h/ml. Recent findings indicate that exposure
in children < 6 years of age may be reduced by about 30% compared with other age groups. Further
data addressing this issue are currently awaited. At present, the available data do not suggest that
lamivudine is less efficacious in this age group.
There are limited pharmacokinetic data for patients less than three months of age. In neonates one
week of age, lamivudine oral clearance was reduced when compared to paediatric patients and is likely
to be due to immature renal function and variable absorption. Therefore to achieve similar adult and
paediatric exposure, the recommended dose for neonates is 4 mg/kg/day. Glomerular filtration
estimates suggests that to achieve similar adult and paediatric exposure, the recommended dose for
children aged six weeks and older could be 8 mg/kg/day.
Pharmacokinetics in pregnancy:
Following oral administration, lamivudine pharmacokinetics in late-
pregnancy were similar to non-pregnant women.
5.3
Preclinical safety data
Administration of lamivudine in animal toxicity studies at high doses was not associated with any
major organ toxicity. At the highest dosage levels, minor effects on indicators of liver and kidney
function were seen together with occasional reductions in liver weight. The clinically relevant effects
noted were a reduction in red blood cell count and neutropenia.
Lamivudine was not mutagenic in bacterial tests but, like many nucleoside analogues, showed activity
in an
in vitro
cytogenetic assay and the mouse lymphoma assay. Lamivudine was not genotoxic
in
vivo
at doses that gave plasma concentrations around 40-50 times higher than the anticipated clinical
plasma levels. As the
in vitro
mutagenic activity of lamivudine could not be confirmed in
in vivo
tests,
it is concluded that
lamivudine should not represent a genotoxic hazard to patients undergoing
treatment.
A transplacental genotoxicity study conducted in monkeys compared zidovudine alone with the
combination of zidovudine and lamivudine at human-equivalent exposures. The study demonstrated
that foetuses exposed
in utero
to the combination sustained a higher level of nucleoside analogue-
DNA incorporation into multiple foetal organs, and showed evidence of more telomere shortening
than in those exposed to zidovudine alone. The clinical significance of these findings is unknown.
The results of long-term carcinogenicity studies in rats and mice did not show any carcinogenic
potential relevant for humans.
6.
6.1 List of excipients
Sucrose 20 % (3 g/15 ml)
Methyl parahydroxybenzoate
Propyl parahydroxybenzoate
Citric acid Anhydrous
Propylene glycol
21
Sodium citrate
Artificial strawberry flavour
Artificial banana flavour
Purified water
6.2 Incompatibilities
Not applicable
6.3 Shelf life
2 years
Discard the oral solution one month after first opening.
6.4 Special precautions for storage
Do not store above 25°C.
6.5 Nature and contents of container
Cartons containing 240 ml oral solution in a white high density polyethylene (HDPE) bottle, with a
child resistant closure. A 10 ml polypropylene oral dosing syringe and a polyethylene adapter are also
included in the pack.
The oral dosing syringe is provided for accurate measurement of the prescribed dose of the oral
solution. Instructions for use are included in the pack.
6.6 Special precautions for disposal
No special requirements.
7.
ViiV Healthcare UK Limited
980 Great West Road
Brentford
Middlesex
TW8 9GS
United Kingdom
8.
EU/1/96/015/002
9.
Date of first authorisation: 8 August 1996
Date of last renewal: 28 July 2006
22
Detailed information on this medicinal product is available on the website of the European Medicines
Agency
http://www.ema.europa.eu
23
1.
Epivir 300 mg film-coated tablets
2.
Each film-coated tablet contains 300 mg lamivudine.
For a full list of excipients, see section 6.1.
3.
Film-coated tablet
Grey, diamond shaped and engraved with “GX EJ7” on one face.
4.
Epivir is indicated as part of antiretroviral combination therapy for the treatment of Human
Immunodeficiency Virus (HIV) infected adults and children.
4.2
The therapy should be initiated by a physician experienced in the management of HIV infection.
Epivir may be administered with or without food.
To ensure administration of the entire dose, the tablet(s) should ideally be swallowed without
crushing. For patients who are unable to swallow tablets, lamivudine is available as an oral solution.
Alternatively, the tablets may be crushed and added to a small amount of semi-solid food or liquid, all
of which should be consumed immediately (see section 5.2).
Adults and adolescents over 12 years of age:
the recommended dose of Epivir is 300 mg daily. This
may be administered as either 150 mg twice daily or 300 mg once daily (see section 4.4). The 300 mg
tablet is only suitable for the once a day regimen.
Patients changing to the once daily regimen should take 150 mg twice a day and switch to 300 mg
once a day the following morning. Where an evening once daily regimen is preferred, 150 mg of
Epivir should be taken on the first morning only, followed by 300 mg in the evening. When changing
back to a twice daily regimen patients should complete the days treatment and start 150 mg twice a
day the following morning.
Children:
Three months to 12 years of age:
the recommended dose is 4 mg/kg twice daily up to a maximum of
300 mg daily.
Less than three months of age:
the limited data available are insufficient to propose specific dosage
recommendations (see section 5.2)
24
Renal impairment:
Lamivudine concentrations are increased in patients with moderate - severe renal
impairment due to decreased clearance. The dose should therefore be adjusted, using oral solution
presentation of Epivir for patients whose creatinine clearance falls below 30 ml/min (see tables).
Dosing recommendations – Adults and adolescents over 12 years:
Creatinine clearance
(ml/min)
First dose
Maintenance dose
≥50
150 mg
150 mg twice daily
30-<50
150 mg
150 mg once daily
<30
As doses below 150 mg are needed the use of the oral solution is
recommended
There are no data available on the use of lamivudine in children with renal impairment. Based on the
assumption that creatinine clearance and lamivudine clearance are correlated similarly in children as in
adults it is recommended that the dosage in children with renal impairment be reduced according to
their creatinine clearance by the same proportion as in adults.
Dosing recommendations – Children from 3 months to 12 years:
Creatinine clearance
(ml/min)
First dose
Maintenance dose
≥50
4 mg/kg
4 mg/kg twice daily
30 to<50
4 mg/kg
4 mg/kg once daily
15 to <30
4 mg/kg
2.6 mg/kg once daily
5 to <15
4 mg/kg
1.3 mg/kg once daily
<5
1.3 mg/kg
0.7 mg/kg once daily
Hepatic Impairment:
Data obtained in patients with moderate to severe hepatic impairment shows that
lamivudine pharmacokinetics are not significantly affected by hepatic dysfunction. Based on these
data, no dose adjustment is necessary in patients with moderate or severe hepatic impairment unless
accompanied by renal impairment.
Hypersensitivity to the active substance or to any of the excipients.
Epivir is not recommended for use as monotherapy.
Renal impairment:
In patients with moderate to severe renal impairment, the terminal plasma half-life
of lamivudine is increased due to decreased clearance, therefore the dose should be adjusted (see
section 4.2).
Triple nucleoside therapy:
There have been reports of a high rate of virological failure and of
emergence of resistance at an early stage when lamivudine was combined with tenofovir disoproxil
fumarate and abacavir as well as with tenofovir disoproxil fumarate and didanosine as a once daily
regimen.
Opportunistic infections:
Patients receiving Epivir or any other antiretroviral therapy may continue to
develop opportunistic infections and other complications of HIV infection, and therefore should
remain under close clinical observation by physicians experienced in the treatment of patients with
associated HIV diseases.
25
Transmission of HIV:
Patients should be advised that current antiretroviral therapy, including Epivir,
has not been proven to prevent the risk of transmission of HIV to others through sexual contact or
contamination with blood. Appropriate precautions should continue to be taken.
Pancreatitis:
Cases of pancreatitis have occurred rarely. However it is not clear whether these cases
were due to the antiretroviral treatment or to the underlying HIV disease. Treatment with Epivir
should be stopped immediately if clinical signs, symptoms or laboratory abnormalities suggestive of
pancreatitis occur.
Lactic acidosis
: lactic acidosis, usually associated with hepatomegaly and hepatic steatosis, has been
reported with the use of nucleoside analogues. Early symptoms (symptomatic hyperlactatemia)
include benign digestive symptoms (nausea, vomiting and abdominal pain), non-specific malaise, loss
of appetite, weight loss, respiratory symptoms (rapid and/or deep breathing) or neurological symptoms
(including motor weakness).
Lactic acidosis has a high mortality and may be associated with pancreatitis, liver failure, or renal
failure.
Lactic acidosis generally occurred after a few or several months of treatment.
Treatment with nucleoside analogues should be discontinued in the setting of symptomatic
hyperlactatemia and metabolic/lactic acidosis, progressive hepatomegaly, or rapidly elevating
aminotransferase levels.
Caution should be exercised when administering nucleoside analogues to any patient (particularly
obese women) with hepatomegaly, hepatitis or other known risk factors for liver disease and hepatic
steatosis (including certain medicinal products and alcohol). Patients co-infected with hepatitis C and
treated with alpha interferon and ribavirin may constitute a special risk.
Patients at increased risk should be followed closely.
Mitochondrial dysfunction:
Nucleoside and nucleotide analogues have been demonstrated
in vitro
and
in vivo
to cause a variable degree of mitochondrial damage. There have been reports of mitochondrial
dysfunction in HIV-negative infants exposed
in utero
and/or post-natally to nucleoside analogues. The
main adverse events reported are haematological disorders (anaemia, neutropenia), metabolic
disorders (hyperlactatemia, hyperlipasemia). These events are often transitory. Some late-onset
neurological disorders have been reported (hypertonia, convulsion, abnormal behaviour). Whether the
neurological disorders are transient or permanent is currently unknown. Any child exposed
in utero
to
nucleoside and nucleotide analogues, even HIV-negative children, should have clinical and laboratory
follow-up and should be fully investigated for possible mitochondrial dysfunction in case of relevant
signs or symptoms. These findings do not affect current national recommendations to use antiretroviral
therapy in pregnant women to prevent vertical transmission of HIV.
Lipodystrophy:
Combination antiretroviral therapy has been associated with the redistribution of body
fat (lipodystrophy) in HIV patients. The long-term consequences of these events are currently
unknown. Knowledge about the mechanism is incomplete. A connection between visceral lipomatosis
and protease inhibitors (PIs) and lipoatrophy and nucleoside reverse transcriptase inhibitors (NRTIs)
has been hypothesised. A higher risk of lipodystrophy has been associated with individual factors such
as older age, and with drug related factors such as longer duration of antiretroviral treatment and
associated metabolic disturbances. Clinical examination should include evaluation for physical signs
of fat redistribution. Consideration should be given to the measurement of fasting serum lipids and
blood glucose. Lipid disorders should be managed as clinically appropriate (see section 4.8).
Immune Reactivation Syndrome:
In HIV-infected patients with severe immune deficiency at the time
of institution of combination antiretroviral therapy (CART), an inflammatory reaction to
asymptomatic or residual opportunistic pathogens may arise and cause serious clinical conditions, or
aggravation of symptoms. Typically, such reactions have been observed within the first few weeks or
months of initiation of CART. Relevant examples are cytomegalovirus retinitis, generalised and/or
26
focal mycobacterium infections, and
Pneumocystis carinii
pneumonia. Any inflammatory symptoms
should be evaluated and treatment instituted when necessary.
Liver disease
: If lamivudine is being used concomitantly for the treatment of HIV and HBV,
additional information relating to the use of lamivudine in the treatment of hepatitis B infection is
available in the Zeffix SPC.
Patients with chronic hepatitis B or C and treated with combination antiretroviral therapy are at an
increased risk of severe and potentially fatal hepatic adverse events. In case of concomitant antiviral
therapy for hepatitis B or C, please refer also to the relevant product information for these medicinal
products.
If Epivir is discontinued in patients co-infected with hepatitis B virus, periodic monitoring of liver
function tests and markers of HBV replication is recommended, as withdrawal of lamivudine may
result in an acute exacerbation of hepatitis (see Zeffix SPC).
Patients with pre-existing liver dysfunction, including chronic active hepatitis, have an increased
frequency of liver function abnormalities during combination antiretroviral therapy, and should be
monitored according to standard practice. If there is evidence of worsening liver disease in such
patients, interruption or discontinuation of treatment must be considered (see section 4.8).
Osteonecrosis: Although the etiology is considered to be multifactorial (including corticosteroid use,
alcohol consumption, severe immunosuppression, higher body mass index), cases of osteonecrosis
have been reported particularly in patients with advanced HIV-disease and/or long-term exposure to
combination antiretroviral therapy (CART). Patients should be advised to seek medical advice if they
experience joint aches and pain, joint stiffness or difficulty in movement.
Epivir should not be taken with any other medicinal products containing lamivudine or medicinal
products containing emtricitabine.
4.5
Interaction studies have only been performed in adults
The likelihood of metabolic interactions is low due to limited metabolism and plasma protein binding
and almost complete renal clearance.
Administration of trimethoprim/sulfamethoxazole 160 mg/800 mg results in a 40 % increase in
lamivudine exposure, because of the trimethoprim component; the sulfamethoxazole component did
not interact. However, unless the patient has renal impairment, no dosage adjustment of lamivudine is
necessary (see section 4.2). Lamivudine has no effect on the pharmacokinetics of trimethoprim or
sulfamethoxazole. When concomitant administration is warranted, patients should be monitored
clinically. Co-administration of lamivudine with high doses of co-trimoxazole for the treatment of
Pneumocystis carinii
pneumonia (PCP) and toxoplasmosis should be avoided.
The possibility of interactions with other medicinal products administered concurrently should be
considered, particularly when the main route of elimination is active renal secretion via the organic
cationic transport system e.g. trimethoprim. Other medicinal products (e.g. ranitidine, cimetidine) are
eliminated only in part by this mechanism and were shown not to interact with lamivudine. The
nucleoside analogues (e.g. didanosine) like zidovudine, are not eliminated by this mechanism and are
unlikely to interact with lamivudine.
27
A modest increase in C
max
(28 %) was observed for zidovudine when administered with lamivudine,
however overall exposure (AUC) is not significantly altered. Zidovudine has no effect on the
pharmacokinetics of lamivudine (see section 5.2).
Lamivudine metabolism does not involve CYP3A, making interactions with medicinal products
metabolised by this system (e.g. PIs) unlikely.
4.6
A large amount of data on pregnant women (more than 1000 exposed outcomes) indicate no
malformative toxicity. Epivir can be used during pregnancy if clinically needed.
For patients co-infected with hepatitis who are being treated with lamivudine and subsequently
become pregnant, consideration should be given to the possibility of a recurrence of hepatitis on
discontinuation of lamivudine.
Mitochondrial dysfunction:
Nucleoside and nucleotide analogues have been demonstrated in vitro and in vivo to cause a variable
degree of mitochondrial damage. There have been reports of mitochondrial dysfunction in infants
exposed in utero and/or post-natally to nucleoside analogues (see section 4.4).
Following oral administration lamivudine was excreted in breast milk at similar concentrations to
those found in serum. Since lamivudine and the virus pass into breast milk, it is recommended that
mothers taking Epivir do not breast-feed their infants. It is recommended that HIV infected women do
not breast-feed their infants under any circumstances in order to avoid transmission of HIV.
4.7
No studies on the effects on the ability to drive and use machines have been performed.
4.8
The following adverse reactions have been reported during therapy for HIV disease with Epivir.
The adverse reactions considered at least possibly related to the treatment are listed below by body
system, organ class and absolute frequency. Frequencies are defined as very common (≥1/10),
common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare
(<1/10,000). Within each frequency grouping, undesirable effects are presented in order of decreasing
seriousness.
Blood and lymphatic systems disorders
Uncommon
: Neutropenia and anaemia (both occasionally severe), thrombocytopenia
Very rare
: Pure red cell aplasia
Nervous system disorders
Common:
Headache, insomnia
Very rare:
Peripheral neuropathy (or paraesthesia)
Respiratory, thoracic and mediastinal disorders
Common:
Cough, nasal symptoms
Gastrointestinal disorders
Common:
Nausea, vomiting, abdominal pain or cramps, diarrhoea
Rare:
Pancreatitis. Elevations in serum amylase.
Hepatobiliary disorders
28
Uncommon:
Transient elevations in liver enzymes (AST, ALT).
Rare:
Hepatitis
Skin and subcutaneous tissue disorders
Common:
Rash, alopecia
Rare:
Angioedema
Musculoskeletal and connective tissue disorders
Common:
Arthralgia,
muscle disorders
Rare:
Rhabdomyolysis
General disorders and administration site conditions
Common:
Fatigue, malaise, fever.
Cases of lactic acidosis, sometimes fatal, usually associated with severe hepatomegaly and hepatic
steatosis, have been reported with the use of nucleoside analogues (see section 4.4).
Combination antiretroviral therapy has been associated with redistribution of body fat (lipodystrophy)
in HIV patients including the loss of peripheral and facial subcutaneous fat, increased intra-abdominal
and visceral fat, breast hypertrophy and dorsocervical fat accumulation (buffalo hump).
Combination antiretroviral therapy has been associated with metabolic abnormalities such as
hypertriglyceridaemia, hypercholesterolaemia, insulin resistance, hyperglycaemia and
hyperlactataemia (see section 4.4).
In HIV-infected patients with severe immune deficiency at the time of initiation of combination
antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic
infections may arise (see section 4.4).
Cases of osteonecrosis have been reported, particularly in patients with generally acknowledged risk
factors, advanced HIV disease or long-term combined antiretroviral exposure (CART). The frequency
of which is unknown (see section 4.4).
Administration of lamivudine at very high dose levels in acute animal studies did not result in any
organ toxicity. Limited data are available on the consequences of ingestion of acute overdoses in
humans. No fatalities occurred, and the patients recovered. No specific signs or symptoms have been
identified following such overdose.
If overdosage occurs the patient should be monitored, and standard supportive treatment applied as
required. Since lamivudine is dialysable, continuous haemodialysis could be used in the treatment of
overdosage, although this has not been studied.
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: nucleoside analogue, ATC Code: J05AF05.
Lamivudine is a nucleoside analogue which has activity against human immunodeficiency virus (HIV)
and hepatitis B virus (HBV). It is metabolised intracellularly to the active moiety, lamivudine 5’-
triphosphate. Its main mode of action is as a chain terminator of viral reverse transcription. The
triphosphate has selective inhibitory activity against HIV-1 and HIV-2 replication
in vitro
;
it is also
active against zidovudine-resistant clinical isolates of HIV. Lamivudine in combination with
zidovudine exhibits synergistic anti-HIV activity against clinical isolates in cell culture.
29
HIV-1 resistance to lamivudine involves the development of a M184V amino acid change close to the
active site of the viral reverse transcriptase (RT). This variant arises both
in vitro
and in HIV-1
infected patients treated with lamivudine-containing antiretroviral therapy. M184V mutants display
greatly reduced susceptibility to lamivudine and show diminished viral replicative capacity
in vitro
.
In
vitro
studies indicate that zidovudine-resistant virus isolates can become zidovudine sensitive when
they simultaneously acquire resistance to lamivudine. The clinical relevance of such findings remains,
however, not well defined.
In vitro
data tend to suggest that the continuation of lamivudine in anti-retroviral regimen despite the
development of M184V might provide residual anti-retroviral activity (likely through impaired viral
fitness). The clinical relevance of these findings is not established. Indeed, the available clinical data
are very limited and preclude any reliable conclusion in the field. In any case, initiation of susceptible
NRTI’s should always be preferred to maintenance of lamivudine therapy. Therefore, maintaining
lamivudine therapy despite emergence of M184V mutation should only be considered in cases where
no other active NRTI’s are available.
Cross-resistance conferred by the M184V RT is limited within the nucleoside inhibitor class of
antiretroviral agents. Zidovudine and stavudine maintain their antiretroviral activities against
lamivudine-resistant HIV-1. Abacavir maintains its antiretroviral activities against lamivudine-
resistant HIV-1 harbouring only the M184V mutation. The M184V RT mutant shows a <4-fold
decrease in susceptibility to didanosine; the clinical significance of these findings is unknown.
In vitro
susceptibility testing has not been standardised and results may vary according to methodological
factors.
Lamivudine demonstrates low cytotoxicity to peripheral blood lymphocytes, to established
lymphocyte and monocyte-macrophage cell lines, and to a variety of bone marrow progenitor cells
in
vitro
.
Clinical experience:
In clinical trials, lamivudine in combination with zidovudine
has been shown to reduce HIV-1 viral
load and increase CD4 cell count. Clinical end-point data indicate that lamivudine in combination
with zidovudine, results in a significant reduction in the risk of disease progression and mortality.
Evidence from clinical studies shows that lamivudine plus zidovudine
delays the emergence of
zidovudine resistant isolates in individuals with no prior antiretroviral therapy.
Lamivudine has been widely used as a component of antiretroviral combination therapy with other
antiretroviral agents of the same class (NRTIs) or different classes (PIs, non-nucleoside reverse
transcriptase inhibitors).
Multiple drug antiretroviral therapy containing lamivudine has been shown to be effective in
antiretrovirally-naive patients as well as in patients presenting with viruses containing the M184V
mutations.
The relationship between
in vitro
susceptibility of HIV to lamivudine and clinical response to
lamivudine-containing therapy remains under investigation.
Lamivudine at a dose of 100 mg once daily has also been shown to be effective for the treatment of
adult patients with chronic HBV infection (for details of clinical studies, see the prescribing
information for Zeffix). However, for the treatment of HIV infection, only a 300 mg daily dose of
lamivudine (in combination with other antiretroviral agents) has been shown to be efficacious.
Lamivudine has not been specifically investigated in HIV patients co-infected with HBV.
Once daily dosing (300 mg once a day):
a clinical study has demonstrated the non inferiority between
30
Epivir once a day and Epivir twice a day containing regimens. These results were obtained in an
antiretroviral naïve-population, primarily consisting of asymptomatic HIV infected patients (CDC
stage A).
5.2
Pharmacokinetic properties
Absorption:
Lamivudine is well absorbed from the gastrointestinal tract, and the bioavailability of oral
lamivudine in adults is normally between 80 and 85%. Following oral administration, the mean time
(t
max
) to maximal serum concentrations (C
max
) is about an hour. Based on data derived from a study in
healthy volunteers, at a therapeutic dose of 150mg twice daily, mean (CV) steady-state C
max
and C
min
of lamivudine in plasma are 1.2 µg/ml (24%) and 0.09 µg/ml (27%), respectively. The mean (CV)
AUC over a dosing interval of 12 hours is 4.7 µg.h/ml (18%). At a therapeutic dose of 300mg once
daily, the mean (CV) steady-state C
max
, C
min
and 24h AUC are 2.0 µg/ml (26%), 0.04 µg/ml (34%) and
8.9 µg.h/ml (21%), respectively.
The 150 mg tablet is bioequivalent and dose proportional to the 300 mg tablet with respect to AUC
∞
,
C
max
, and t
max
.
Co-administration of lamivudine with food results in a delay of t
max
and a lower C
max
(decreased by
47%). However, the extent (based on the AUC) of lamivudine absorbed is not influenced.
Administration of crushed tablets with a small amount of semi-solid food or liquid would not be
expected to have an impact on the pharmaceutical quality, and would therefore not be expected to alter
the clinical effect. This conclusion is based on the physiochemical and pharmacokinetic data
assuming that the patient crushes and transfers 100% of the tablet and ingests immediately.
Co-administration of zidovudine results in a 13 % increase in zidovudine exposure and a 28 %
increase in peak plasma levels. This is not considered to be of significance to patient safety and
therefore no dosage adjustments are necessary.
Distribution:
From intravenous studies, the mean volume of distribution is 1.3 l/kg. The observed
half-life of elimination is 5 to 7 hours. The mean systemic clearance of lamivudine is approximately
0.32 l/h/kg, with predominantly renal clearance (> 70%) via the organic cationic transport system.
Lamivudine exhibits linear pharmacokinetics over the therapeutic dose range and displays limited
binding to the major plasma protein albumin (< 16% - 36% to serum albumin in
in vitro
studies).
Limited data show that lamivudine penetrates the central nervous system and reaches the cerebro-
spinal fluid (CSF). The mean ratio CSF/serum lamivudine concentration 2-4 hours after oral
administration was approximately 0.12. The true extent of penetration or relationship with any clinical
efficacy is unknown.
Metabolism:
The active moiety, intracellular lamivudine triphosphate, has a prolonged terminal half-
life in the cell (16 to 19 hours) compared to the plasma lamivudine half-life (5 to 7 hours). In 60
healthy adult volunteers, Epivir 300 mg once daily has been demonstrated to be pharmacokinetically
equivalent at steady-state to Epivir 150 mg twice daily with respect to intracellular triphosphate
AUC
24
and C
max
.
Lamivudine is predominately cleared unchanged by renal excretion. The likelihood of metabolic
interactions of lamivudine with other medicinal products is low due to the small extent of hepatic
metabolism (5-10%) and low plasma protein binding.
Elimination:
Studies in patients with renal impairment show lamivudine elimination is affected by
renal dysfunction. A recommended dosage regimen for patients with creatinine clearance below
50 ml/min is shown in the dosage section (see section 4.2).
31
An interaction with trimethoprim, a constituent of co-trimoxazole, causes a 40% increase in
lamivudine exposure at therapeutic doses. This does not require dose adjustment unless the patient
also has renal impairment (see sections 4.5 and 4.2). Administration of co-trimoxazole with
lamivudine in patients with renal impairment should be carefully assessed.
Pharmacokinetics in children:
In general, lamivudine pharmacokinetics in paediatric patients is
similar to adults. However, absolute bioavailability (approximately 55-65%) was reduced in
paediatric patients below 12 years of age. In addition, systemic clearance values were greater in
younger paediatric patients and decreased with age, approaching adult values around 12 years of age.
Due to these differences, the recommended dose for lamivudine in children (aged more than three
months and weighing less than 30 kg) is 4 mg/kg twice daily. This dose will achieve an average
AUC
0-12
ranging from approximately 3,800 to 5,300 ng.h/ml. Recent findings indicate that exposure
in children < 6 years of age may be reduced by about 30% compared with other age groups. Further
data addressing this issue are currently awaited. At present, the available data do not suggest that
lamivudine is less efficacious in this age group.
There are limited pharmacokinetic data for patients less than three months of age. In neonates one
week of age, lamivudine oral clearance was reduced when compared to paediatric patients and is likely
to be due to immature renal function and variable absorption. Therefore to achieve similar adult and
paediatric exposure, the recommended dose for neonates is 4 mg/kg/day. Glomerular filtration
estimates suggests that to achieve similar adult and paediatric exposure, the recommended dose for
children aged six weeks and older could be 8 mg/kg/day.
Pharmacokinetics in pregnancy:
Following oral administration, lamivudine pharmacokinetics in late-
pregnancy were similar to non-pregnant women.
5.3 Preclinical safety data
Administration of lamivudine in animal toxicity studies at high doses was not associated with any
major organ toxicity. At the highest dosage levels, minor effects on indicators of liver and kidney
function were seen together with occasional reductions in liver weight. The clinically relevant effects
noted were a reduction in red blood cell count and neutropenia.
Lamivudine was not mutagenic in bacterial tests but, like many nucleoside analogues, showed activity
in an
in vitro
cytogenetic assay and the mouse lymphoma assay. Lamivudine was not genotoxic
in
vivo
at doses that gave plasma concentrations around 40-50 times higher than the anticipated clinical
plasma levels. As the
in vitro
mutagenic activity of lamivudine could not be confirmed in
in vivo
tests,
it is concluded that lamivudine should not represent a genotoxic hazard to patients undergoing
treatment.
A transplacental genotoxicity study conducted in monkeys compared zidovudine alone with the
combination of zidovudine and lamivudine at human-equivalent exposures. The study demonstrated
that foetuses exposed
in utero
to the combination sustained a higher level of nucleoside analogue-
DNA incorporation into multiple foetal organs, and showed evidence of more telomere shortening
than in those exposed to zidovudine alone. The clinical significance of these findings is unknown.
The results of long-term carcinogenicity studies in rats and mice did not show any carcinogenic
potential relevant for humans.
6.
6.1 List of excipients
Tablet core:
Microcrystalline cellulose (E460),
Sodium starch glycollate
32
Magnesium stearate
Tablet film-coat:
Hypromellose (E464),
Titanium dioxide (E171),
Black iron oxide (E172),
Macrogol, Polysorbate 80
6.2
Incompatibilities
Not applicable
6.3 Shelf life
HDPE bottles :
3 years
PVC/aluminium foil blister packs:
2 years
6.4 Special precautions for storage
Do not store above 30°C
6.5 Nature and contents of container
Child resistant HDPE bottles or PVC/aluminium foil blister packs each containing 30 tablets.
6.6 Special precautions for disposal
No special requirements
7.
ViiV Healthcare UK Limited
980 Great West Road
Brentford
Middlesex
TW8 9GS
United Kingdom
EU/1/96/015/003 (Bottle)
EU/1/96/015/005 (Blister pack)
Date of first authorisation: 15 November 2001
Date of last renewal: 28 July 2006
10.
33
Detailed information on this medicinal product is available on the website of the European Medicines
Agency
http://www.ema.europa.eu
34
ANNEX II
A. MANUFACTURING AUTHORISATION HOLDER
RESPONSIBLE FOR BATCH RELEASE
B. CONDITIONS OF THE MARKETING AUTHORISATION
35
A. MANUFACTURING AUTHORISATION HOLDER(S) RESPONSIBLE FOR BATCH
RELEASE
Name and address of the manufacturer(s) responsible for batch release
Film-coated tablets:
Glaxo Operations UK Limited
(trading as 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
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.
36
ANNEX III
LABELLING AND PACKAGE LEAFLET
37
A. LABELLING
38
PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE
PACKAGING
BOTTLE CARTON X 60 FILM-COATED TABLETS (150 mg)
1.
Epivir 150 mg film-coated tablets
Lamivudine
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each film-coated tablet contains lamivudine 150 mg
3.
LIST OF EXCIPIENTS
4.
60 film-coated tablets
Scored 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 {MM/YYYY}
9.
SPECIAL STORAGE CONDITIONS
Do not store above 30°C
39
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
ViiV Healthcare UK Limited
980 Great West Road
Brentford
Middlesex
TW8 9GS
United Kingdom
EU/1/96/015/001
13. BATCH NUMBER
LOT
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
epivir 150 mg
40
PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE
PACKAGING
BOTTLE LABEL X 60 FILM-COATED TABLETS (150 mg)
1.
Epivir 150 mg film-coated tablets
Lamivudine
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each film-coated tablet contains lamivudine 150 mg
3.
LIST OF EXCIPIENTS
4.
60 film-coated tablets
Scored 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 {MM/YYYY}
9.
SPECIAL STORAGE CONDITIONS
Do not store above 30°C
41
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
ViiV Healthcare UK Limited
980 Great West Road
Brentford
Middlesex
TW8 9GS
United Kingdom
EU/1/96/015/001
13. BATCH NUMBER
LOT
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
42
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
BLISTER CARTON X 60 FILM-COATED TABLETS (150 mg)
1.
Epivir 150 mg film-coated tablets
Lamivudine
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each film-coated tablet contains
lamivudine 150 mg
3.
LIST OF EXCIPIENTS
4.
60 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 {MM/YYYY}
9.
SPECIAL STORAGE CONDITIONS
Do not store above 30°C
43
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
ViiV Healthcare UK Limited
980 Great West Road
Brentford
Middlesex
TW8 9GS
United Kingdom
EU/1/96/015/004
13. BATCH NUMBER
LOT
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
epivir 150 mg
44
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
1.
Epivir 150 mg tablets
lamivudine
2.
ViiV Healthcare UK Limited
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
LOT
5.
OTHER
45
PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE
PACKAGING
BOTTLE CARTON FOR ORAL SOLUTION
1.
Epivir 10 mg/ml oral solution
Lamivudine
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each ml of oral solution contains 10 mg lamivudine
3.
LIST OF EXCIPIENTS
This product also contains sugar, preservatives: methyl parahydroxybenzoate and propyl
parahydroxybenzoate
4.
Bottle contents:
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 {MM/YYYY}
9.
SPECIAL STORAGE CONDITIONS
Do not store above 25°C
Discard one month after first opening
46
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
ViiV Healthcare UK Limited
980 Great West Road
Brentford
Middlesex
TW8 9GS
United Kingdom
EU/1/96/015/002
13. BATCH NUMBER
LOT
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
epivir 10 mg/ml
47
PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE
PACKAGING
BOTTLE LABEL FOR ORAL SOLUTION
1.
Epivir 10 mg/ml oral solution
Lamivudine
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each ml of oral solution contains 10 mg lamivudine
3.
LIST OF EXCIPIENTS
This product also contains sugar, preservatives: methyl parahydroxybenzoate and propyl
parahydroxybenzoate
4.
Bottle contents:
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 {MM/YYYY}
9.
SPECIAL STORAGE CONDITIONS
Do not store above 25°C
Discard one month after first opening
48
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
ViiV Healthcare UK Limited
980 Great West Road
Brentford
Middlesex
TW8 9GS
United Kingdom
EU/1/96/015/002
13. BATCH NUMBER
LOT
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
49
PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE
PACKAGING
BOTTLE CARTON X 30 FILM-COATED TABLETS (300 mg )
1.
Epivir 300 mg film-coated tablets
Lamivudine
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each film-coated tablet contains
Lamivudine 300 mg
3.
LIST OF EXCIPIENTS
4.
30 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 {MM/YYYY}
9.
SPECIAL STORAGE CONDITIONS
Do not store above 30°C
50
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
ViiV Healthcare UK Limited
980 Great West Road
Brentford
Middlesex
TW8 9GS
United Kingdom
EU/1/96/015/003
13. BATCH NUMBER
LOT
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
epivir 300 mg
51
PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE
PACKAGING
BOTTLE LABEL X 30 FILM-COATED TABLETS (300 mg )
1.
Epivir 300 mg film-coated tablets
Lamivudine
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each film-coated tablet contains
Lamivudine 300 mg
3.
LIST OF EXCIPIENTS
4.
30 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 {MM/YYYY}
9.
SPECIAL STORAGE CONDITIONS
Do not store above 30°C
52
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
ViiV Healthcare UK Limited
980 Great West Road
Brentford
Middlesex
TW8 9GS
United Kingdom
EU/1/96/015/003
13. BATCH NUMBER
LOT
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
53
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
BLISTER CARTON X 30 FILM-COATED TABLETS (300 mg )
1.
Epivir 300 mg film-coated tablets
Lamivudine
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each film-coated tablet contains
lamivudine 300 mg
3.
LIST OF EXCIPIENTS
4.
30 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 {MM/YYYY}
9.
SPECIAL STORAGE CONDITIONS
Do not store above 30°C
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
54
ViiV Healthcare UK Limited
980 Great West Road
Brentford
Middlesex
TW8 9GS
United Kingdom
EU/1/96/015/005
13. BATCH NUMBER
LOT
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
epivir 300 mg
55
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
1.
Epivir 300 mg tablet
lamivudine
2.
ViiV Healthcare UK Limited
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
LOT
5.
OTHER
56
B. PACKAGE LEAFLET
57
PACKAGE LEAFLET: INFORMATION FOR THE USER
Epivir 150 mg film-coated tablets
lamivudine
Read all of this leaflet carefully before you start taking this medicine.
−
Keep this leaflet, you may need to read it again.
−
If you have any further questions, ask your doctor or pharmacist.
−
This medicine has been prescribed for you personally. 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 Epivir is and what it is used for
2.
Before you take Epivir
3.
Possible side effects
5.
How to store Epivir
6.
Further information
1.
What Epivir is and what it is used for
Epivir is used to treat HIV (human immunodeficiency virus) infection in adults and children.
The active ingredient in Epivir is lamivudine. Epivir is a type of medicine known as an anti-retroviral.
It belongs to a group of medicines called
nucleoside analogue reverse transcriptase inhibitors
(
NRTIs
).
Epivir does not completely cure HIV infection; it reduces the amount of virus in your body, and keeps
it at a low level. It also increases the CD4 cell count in your blood. CD4 cells are a type of white blood
cells that are important in helping your body to fight infection.
Not everyone responds to treatment with Epivir in the same way. Your doctor will monitor the
effectiveness of your treatment.
2.
Before you take Epivir
Don’t take Epivir:
•
if you’re
allergic
(
hypersensitive
)
to
lamivudine or any of the other ingredients of Epivir (
listed
in Section 6
)
.
Check with your doctor
if you think this applies to you.
Take special care with Epivir
Some people taking Epivir or other combination treatments for HIV are more at risk of serious side
effects. You need to be aware of the extra risks:
•
if you have ever had
liver disease,
including hepatitis B or C (if you have hepatitis B infection,
don’t stop Epivir without your doctor’s advice, as your hepatitis may come back)
58
4.
How to take Epivir
•
if you’re seriously
overweight
(especially if you’re a woman)
•
if you’re
diabetic
and using insulin
•
if you or your child has a kidney problem
, your dose may be altered.
Talk to your doctor if any of these apply to you
. You may need extra check-ups, including
blood tests, while you’re taking your medicine.
See Section 4 for more information
.
Look out for important symptoms
Some people taking medicines for HIV infection develop other conditions, which can be serious. You
need to know about important signs and symptoms to look out for while you’re taking Epivir.
Read the information ‘Other possible side effects of combination therapy for HIV’ in
Section 4 of this leaflet
.
Protect other people
HIV infection is spread by sexual contact with someone who has the infection, or by transfer of
infected blood (for example, by sharing injection needles). Epivir will not stop you passing HIV
infection on to other people. To protect other people from becoming infected with HIV:
•
Use a condom
when you have oral or penetrative sex.
•
Don’t risk blood transfer
— for example, don’t share needles.
Other medicines and Epivir
Tell your doctor or pharmacist if you’re taking any other medicines
, or if you’ve taken any
recently, including herbal medicines or other medicines you bought without a prescription.
Remember to tell your doctor or pharmacist if you begin taking a new medicine while you’re taking
Epivir.
These medicines should not be used with Epivir:
•
other medicines containing lamivudine, (used to treat
HIV infection
or
hepatitis B infection
)
•
emtricitabine (used to treat
HIV infection
)
•
high doses of
co-trimoxazole
, an antibiotic.
Tell your doctor
if you’re being treated with any of these.
Pregnancy
If you are pregnant, if you become pregnant, or are planning to become pregnant, talk to your doctor
about the risks and benefits to you and your baby of taking Epivir.
Epivir and similar medicines may cause side effects in unborn babies. If you become pregnant while
you’re taking Epivir, your baby may be given extra check-ups (including blood tests) to make sure it is
developing normally.
Children whose mothers took NRTIs (medicines like Epivir) during pregnancy had a reduced risk of
being infected with HIV. This benefit is greater than the risk of having side effects.
Breast-feeding
Women who are HIV-positive must not breast-feed
, because HIV infection can be passed on to the
baby in breast milk.
If you’re breast-feeding, or thinking about breast-feeding:
Talk to your doctor immediately
.
59
Driving and using machines
Epivir is unlikely to affect your ability to drive or use machines.
3.
How to take Epivir
Always take Epivir exactly as your doctor has told you to
. Check with your doctor or pharmacist if
you’re not sure.
Swallow the tablets, with some water. Epivir can be taken with or without food.
If you cannot swallow the tablets whole, you may crush and combine them with a small amount of
food or drink, and take all the dose immediately.
Stay in regular contact with your doctor
Epivir helps to control your condition. You need to keep taking it every day to stop your illness getting
worse. You may still develop other infections and illnesses linked to HIV infection.
Keep in touch with your doctor, and don’t stop taking Epivir
without your doctor’s advice.
How much to take
Adults and children who weigh at least 30 kg:
The usual dose of Epivir is 300 mg
a day to be taken as:
•
one 150 mg tablet
twice a day
, approximately 12 hours apart
Children weighing 21 – 30 kg
•
one half (½) of an Epivir tablet
(75 mg) in the morning, and
•
one whole Epivir tablet
(150 mg) in the evening.
Children weighing 14 – 21 kg
•
one half (½) of an Epivir tablet
(75 mg) in the morning, and
•
one half (½) of an Epivir tablet
(75 mg) in the evening.
An
oral solution
is also available for the treatment of children over 3 months of age, or for people
who need a lower dose than usual, or who can’t take tablets.
If you or your child has a kidney problem
, your dose may be altered.
Talk to your doctor
if this applies to you or your child.
If you take too much Epivir
Accidentally taking too much Epivir is unlikely to cause any serious problems. If you take too much,
tell your doctor or your pharmacist, or contact your nearest hospital emergency department for further
advice.
If you forget to take Epivir
If you forget to take a dose, take it as soon as you remember. Then continue your treatment as before.
Don’t take a double dose to make up for a missed dose.
4.
Possible side effects
Like all medicines, Epivir can cause side effects, but not everyone gets them.
60
When you’re being treated for HIV, it can be hard to tell whether a symptom is a side effect of Epivir
or other medicines you are taking, or an effect of the HIV disease itself.
So it is very important to
talk to your doctor about any changes in your health
.
As well as the side effects listed below for Epivir
, other conditions can develop during combination
therapy for HIV.
It is important to read the information later in this section under ‘Other possible side effects of
combination therapy for HIV’.
Common side effects
These may affect
up to 1 in 10
people:
•
headache
•
feeling sick (
nausea
)
•
being sick (
vomiting
)
•
diarrhoea
•
stomach pains
•
tiredness, lack of energy
•
fever (high temperature)
•
general feeling of being unwell
•
muscle pain and discomfort
•
joint pain
•
difficulty in sleeping (
insomnia
)
•
cough
•
irritated or runny nose
•
rash
•
hair loss (
alopecia
).
Uncommon side effects
These may affect
up to 1 in 100
people:
Uncommon side effects that may show up in blood tests are:
•
a decrease in the number of cells involved in blood clotting (
thrombocytopenia
)
•
a low red blood cell count (
anaemia
) or low white blood cell count (
neutropenia
)
•
an increase in the level of liver enzymes.
Rare side effects
These may affect
up to 1 in 1000
people:
•
serious allergic reaction causing swelling of the face, tongue or throat which may cause
difficulty in swallowing or breathing
•
lactic acidosis (
see the next section, ‘Other possible side effects of combination therapy for
HIV
’)
•
inflammation of the pancreas (
pancreatitis
)
•
breakdown of muscle tissue
•
liver disorders, such as jaundice, enlarged liver or fatty liver, inflammation (
hepatitis
).
A rare side effect that may show up in blood tests is:
•
an increase in an enzyme called amylase.
Very rare side effects
These may affect
up to 1 in 10,000
people:
•
tingling or numbness of the arms, legs, hands or feet.
A very rare side effect that may show up in blood tests is:
•
a failure of the bone marrow to produce new red blood cells
(pure red cell aplasia)
.
61
If you get side effects
Tell your doctor or pharmacist
if any of the side effects gets severe or troublesome, or if you
notice any side effects not listed in this leaflet.
Other possible side effects of combination therapy for HIV
Combination therapy including Epivir may cause other conditions to develop during HIV treatment.
Old infections may flare up
People with advanced HIV infection (AIDS) have weak immune systems, and are more likely to
develop serious infections (opportunistic infections). When these people start treatment, they may find
that old, hidden infections flare up, causing signs and symptoms of inflammation. These symptoms are
probably caused by the body’s immune system becoming stronger, so that the body starts to fight these
infections.
If you get any symptoms of infection while you’re taking Epivir:
Tell your doctor immediately
. Don’t take other medicines for the infection without your
doctor’s advice.
Your body shape may change
People taking combination therapy for HIV may find that their body shape changes, because of
changes in fat distribution:
•
Fat may be lost from the legs, arms or face.
•
Extra fat may build up around the tummy (abdomen), or on the breasts or internal organs.
•
Fatty lumps (sometimes called buffalo hump) may appear on the back of the neck.
It is not yet known what causes these changes, or whether they have any long-term effects on your
health. If you notice changes in your body shape:
Tell your doctor
.
Lactic acidosis is a rare but serious side effect
Some people taking Epivir, or other medicines like it (NRTIs), develop a condition called lactic
acidosis, together with an enlarged liver.
Lactic acidosis is caused by a build-up of lactic acid in the body. It is rare; if it happens, it usually
develops after a few months of treatment. It can be life-threatening, causing failure of internal organs.
Lactic acidosis is more likely to develop in people who have liver disease, or in obese (very
overweight) people, especially women.
Signs of lactic acidosis include:
•
deep, rapid, difficult breathing
•
drowsiness
•
numbness or weakness in the limbs
•
feeling sick (
nausea
), being sick (
vomiting
)
•
stomach pain.
During your treatment, your doctor will monitor you for signs of lactic acidosis. If you have any of the
symptoms listed above, or any other symptoms that worry you:
See your doctor as soon as possible
.
You may have problems with your bones
Some people taking combination therapy for HIV develop a condition called
osteonecrosis
. With this
condition, parts of the bone tissue die because of reduced blood supply to the bone. People may be
more likely to get this condition:
62
•
if they have been taking combination therapy for a long time
•
if they are also taking anti-inflammatory medicines called corticosteroids
•
if they drink alcohol
•
if their immune systems are very weak
•
if they are overweight.
Signs of osteonecrosis include:
•
stiffness in the joints
•
aches and pains (especially in the hip, knee or shoulder)
•
difficulty moving.
If you notice any of these symptoms:
Tell your doctor
.
Other effects may show up in blood tests
Combination therapy for HIV can also cause:
•
increased levels of lactic acid in the blood, which on rare occasions can lead to lactic acidosis
•
increased levels of sugar and fats (triglycerides and cholesterol) in the blood
•
resistance to insulin (so if you’re diabetic, you may have to change your insulin dose to control
your blood sugar).
5.
How to store Epivir
Keep out of the reach and sight of children.
Do not take Epivir after the expiry date shown on the carton.
Do not store Epivir above 30
o
C.
If you have any unwanted Epivir tablets, don’t dispose of them in your waste water or your household
rubbish. Ask your pharmacist how to dispose of medicines no longer required. These measures will
help to protect the environment.
6
Further information
What Epivir contains
The active substance is lamivudine.
The tablets also contain the following other ingredients:
Tablet core
: microcrystalline cellulose, sodium starch glycollate (gluten free), magnesium stearate
Film-coat
: hypromellose, titanium dioxide, macrogol, polysorbate 80
What Epivir looks like and the contents of the pack
Epivir 150 mg film-coated tablets are supplied in white polyethylene bottles or blister packs
containing 60 tablets. They are white, diamond shaped, scored, film-coated tablets, marked with the
code ‘GXCJ7’ on both sides.
63
Marketing Authorisation Holder and Manufacturer
Manufacturer
Marketing Authorisation Holder
Glaxo Operations UK Limited
(trading as Glaxo Wellcome
Operations)
Priory Street
Ware
Herts SG12 0DJ
United Kingdom
ViiV Healthcare UK Limited
980 Great West Road
Brentford
Middlesex
TW8 9GS
United Kingdom
or
GlaxoSmithKline
Pharmaceuticals S.A.
ul. Grunwaldzka 189
60-322 Poznan
Poland
64
For any information about this medicinal product please contact the local representative of the
Marketing Authorisation Holder.
België/Belgique/Belgien
ViiV Healthcare sprl/bvba
Tél/Tel: + 32 (0)2 656 25 11
Luxembourg/Luxemburg
ViiV Healthcare sprl/bvba
Belgique/Belgien
Tél/Tel: + 32 (0)2 656 25 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
ViiV Healthcare BV
Tel: + 31 (0)30 6986060
c
ontact-nl@viivhealthcare.com
Deutschland
ViiV Healthcare GmbH
Tel.: + 49 (0)89 203 0038-10
viiv.med.info@viivhealthcare.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
Laboratorios ViiV Healthcare, S.L.
Tel: + 34 902 051 260
es-ci@viivhealthcare.com
Portugal
VIIVHIV HEALTHCARE, UNIPESSOAL,
LDA.
Tel: + 351 21 094 08 01
viiv.fi.pt@viivhealthcare.com
France
ViiV Healthcare SAS
Tél.: + 33 (0)1 39 17 6969
Infomed@viivhealthcare.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.
Simi: + 354 530 3700
Slovenská republika
GlaxoSmithKline Slovakia s. r. o.
Tel: + 421 (0)2 48 26 11 11
recepcia.sk@gsk.com
65
Italia
ViiV Healthcare S.r.l.
Tel: + 39 (0)45 9212611
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
ViiV Healthcare UK Limited
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 in
Detailed information on this medicine is available on the European Medicines Agency web site:
http://www.ema.europa.eu.
66
PACKAGE LEAFLET: INFORMATION FOR THE USER
Epivir 10 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 any further questions, ask your doctor or pharmacist.
−
This medicine has been prescribed for you or for your child. 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 Epivir is and what it is used for
2.
Before you take Epivir
3.
Possible side effects
5.
How to store Epivir
6.
Further information
1.
What Epivir is and what it is used for
Epivir is used to treat HIV (human immunodeficiency virus) infection in adults and children.
The active ingredient in Epivir is lamivudine. Epivir is a type of medicine known as an anti-retroviral.
It belongs to a group of medicines called
nucleoside analogue reverse transcriptase inhibitors
(
NRTIs
).
Epivir does not completely cure HIV infection; it reduces the amount of virus in your body, and keeps
it at a low level. It also increases the CD4 cell count in your blood. CD4 cells are a type of white blood
cells that are important in helping your body to fight infection.
Not everyone responds to treatment with Epivir in the same way. Your doctor will monitor the
effectiveness of your treatment.
2.
Before you take Epivir
Don’t take Epivir:
•
if you’re
allergic
(
hypersensitive
) to
lamivudine or any of the other ingredients in Epivir oral
solution (
listed in Section 6
).
Check with your doctor
if you think this applies to you.
Take special care with Epivir
Some people taking Epivir or other combination treatments for HIV are more at risk of serious side
effects. You need to be aware of the extra risks:
67
4.
How to take Epivir
•
if you have ever had
liver disease,
including hepatitis B or C (if you have hepatitis B infection,
don’t stop Epivir without your doctor’s advice, as your hepatitis may come back)
•
if you’re seriously
overweight
(especially if you’re a woman)
•
if you’re
diabetic
and using insulin.
•
if you or your child has a kidney problem
, your dose may be altered.
Talk to your doctor if any of these apply to you
. You may need extra check-ups, including
blood tests, while you’re taking your medicine.
See Section 4 for more information
.
Look out for important symptoms
Some people taking medicines for HIV infection develop other conditions, which can be serious. You
need to know about important signs and symptoms to look out for while you’re taking Epivir.
Read the information ‘Other possible side effects of combination therapy for HIV’ in
Section 4 of this leaflet
.
Protect other people
HIV infection is spread by sexual contact with someone who has the infection, or by transfer of
infected blood (for example, by sharing injection needles). Epivir will not stop you passing HIV
infection on to other people. To protect other people from becoming infected with HIV:
•
Use a condom
when you have oral or penetrative sex.
•
Don’t risk blood transfer
— for example, don’t share needles.
Other medicines and Epivir
Tell your doctor or pharmacist if you’re taking any other medicines
, or if you’ve taken any
recently, including herbal medicines or other medicines you bought without a prescription.
Remember to tell your doctor or pharmacist if you begin taking a new medicine while you’re taking
Epivir.
These medicines should not be used with Epivir:
•
other medicines containing lamivudine, (used to treat
HIV infection
or
hepatitis B infection
)
•
emtricitabine (used to treat
HIV infection
)
•
high doses of
co-trimoxazole
, an antibiotic.
Tell your doctor
if you’re being treated with any of these.
Pregnancy
If you are pregnant, if you become pregnant, or are planning to become pregnant, talk to your doctor
about the risks and benefits and risks to you and your baby of taking Epivir.
Epivir and similar medicines may cause side effects in unborn babies. If you become pregnant while
you’re taking Epivir, your baby may be given extra check-ups (including blood tests) to make sure it is
developing normally.
Children whose mothers took NRTIs (medicines like Epivir) during pregnancy had a reduced risk of
being infected with HIV. This benefit is greater than the risk of having side effects.
Breast-feeding
Women who are HIV-positive must not breast-feed
, because HIV infection can be passed on to the
baby in breast milk.
If you’re breast-feeding, or thinking about breast-feeding:
Talk to your doctor immediately
.
68
Driving and using machines
Epivir is unlikely to affect your ability to drive or use machines.
Important information about some of the ingredients of Epivir
If you are a diabetic, please note that each dose (150 mg = 15 ml) contains 3 g sugar.
Epivir contains sucrose. If you have been told by your doctor that you have an intolerance to some
sugars, contact your doctor before taking Epivir. Sucrose may be harmful to the teeth.
Epivir also contains preservatives (
parahydroxybenzoates
) which may cause allergic reactions
(possibly delayed).
3.
How to take Epivir
Always take Epivir exactly as your doctor has told you to
. Check with your doctor or pharmacist if
you’re not sure.
Epivir can be taken with or without food.
Stay in regular contact with your doctor
Epivir helps to control your condition. You need to keep taking it every day to stop your illness getting
worse. You may still develop other infections and illnesses linked to HIV infection.
Keep in touch with your doctor, and don’t stop taking Epivir
without your doctor’s advice.
How much to take
Adults and adolescents over 12 years of age
The usual dose of Epivir is 30 ml a day (300 mg)
to be taken as 15 ml (150 mg) twice a day
at
regular times, leaving approximately 12 hours between each dose.
Children 3 months to 12 years of age
The usual dose of Epivir is 4 mg/kg twice daily up to a maximum of 300 mg daily.
Give each dose
to your child at regular times, leaving approximately 12 hours between each dose.
Use the oral dosing syringe supplied with the pack to measure your dose accurately.
1.
Remove the bottle cap
. Keep it safely
2. Hold the bottle firmly.
Push the plastic adapter into the neck of the bottle
.
3.
Insert the syringe
firmly into the adapter.
4. Turn the bottle upside down.
5.
Pull out syringe plunger
until the syringe contains the first part of your full dose.
6. Turn the bottle the correct way up.
Remove the syringe
from the adapter.
7.
Put the syringe into your mouth,
placing the tip of the syringe against the inside of your
cheek.
Slowly push the plunger in,
allowing time to swallow.
Don’t
push too hard and squirt
the liquid into the back of your throat or you may choke.
8.
Repeat steps 3 to 7
in the same way until you have taken your whole dose.
For example, if your
dose is 15 ml, you need to take one and a half syringe-fulls of medicine.
9.
Take the syringe out of the bottle
and
wash
it thoroughly in clean water. Let it dry completely
before you use it again.
10.
Close the bottle tightly
with the cap, leaving the adaptor in place.
If you or your child has a kidney problem
, the dose may be altered.
Talk to your doctor
if this applies to you or your child.
If you take too much Epivir
69
Accidentally taking too much Epivir is unlikely to cause any serious problems. If you take too much,
tell your doctor or your pharmacist, or contact your nearest hospital emergency department for further
advice.
If you forget to take Epivir
If you forget to take a dose, take it as soon as you remember. Then continue your treatment as before.
Don’t take a double dose to make up for a missed dose.
4.
Possible side effects
Like all medicines, Epivir can cause side effects, but not everyone gets them.
When you’re being treated for HIV, it can be hard to tell whether a symptom is a side effect of Epivir
or other medicines you are taking, or an effect of the HIV disease itself.
So it is very important to
talk to your doctor about any changes in your health
.
As well as the side effects listed below for Epivir
, other conditions can develop during combination
therapy for HIV.
It is important to read the information later in this section under ‘Other possible side effects of
combination therapy for HIV’.
Common side effects
These may affect
up to 1 in 10
people:
•
headache
•
feeling sick (
nausea
)
•
being sick (
vomiting)
•
diarrhoea
•
stomach pains
•
tiredness, lack of energy
•
fever (high temperature)
•
general feeling of being unwell
•
muscle pain and discomfort
•
joint pain
•
difficulty in sleeping (
insomnia
)
•
cough
•
irritated or runny nose
•
rash
•
hair loss (
alopecia
).
Uncommon side effects
These may affect
up to 1 in 100
people:
Uncommon side effects that may show up in blood tests are:
•
a decrease in the number of cells involved in blood clotting (
thrombocytopenia
)
•
a low red blood cell count (
anaemia
) or low white blood cell count (
neutropenia
)
•
an increase in the level of liver enzymes.
Rare side effects
These may affect
up to 1 in 1000
people:
•
serious allergic reaction causing swelling of the face, tongue or throat which may cause
difficulty in swallowing or breathing
•
lactic acidosis (
see the next section, ‘Other possible side effects of combination therapy for
HIV’
)
•
inflammation of the pancreas (
pancreatitis
)
70
•
breakdown of muscle tissue
•
liver disorders, such as jaundice, enlarged liver or fatty liver, inflammation (
hepatitis
).
A rare side effect that may show up in blood tests is:
•
increase in an enzyme called amylase.
Very rare side effects
These may affect
up to 1 in 10,000
people:
•
tingling or numbness of the arms, legs, hands or feet.
A very rare side effect that may show up in blood tests is:
•
a failure of the bone marrow to produce new red blood cells
(pure red cell aplasia)
.
If you get side effects
Tell your doctor or pharmacist
if any of the side effects gets severe or troublesome, or if you
notice any side effects not listed in this leaflet.
Other possible side effects of combination therapy for HIV
Combination therapy such as Epivir may cause other conditions to develop during HIV treatment.
Old infections may flare up
People with advanced HIV infection (AIDS) have weak immune systems, and are more likely to
develop serious infections (opportunistic infections). When these people start treatment, they may find
that old, hidden infections flare up, causing signs and symptoms of inflammation. These symptoms are
probably caused by the body’s immune system becoming stronger, so that the body starts to fight these
infections.
If you get any symptoms of infection while you’re taking Epivir:
Tell your doctor immediately
. Don’t take other medicines for the infection without your
doctor’s advice.
Your body shape may change
People taking combination therapy for HIV may find that their body shape changes, because of
changes in fat distribution:
•
Fat may be lost from the legs, arms or face.
•
Extra fat may build up around the tummy (abdomen), or on the breasts or internal organs.
•
Fatty lumps (sometimes called buffalo hump) may appear on the back of the neck.
It is not yet known what causes these changes, or whether they have any long-term effects on your
health. If you notice changes in your body shape:
Tell your doctor
.
Lactic acidosis is a rare but serious side effect
Some people taking Epivir, or other medicines like it (NRTIs), develop a condition called lactic
acidosis, together with an enlarged liver.
Lactic acidosis is caused by a build-up of lactic acid in the body. It is rare; if it happens, it usually
develops after a few months of treatment. It can be life-threatening, causing failure of internal organs.
Lactic acidosis is more likely to develop in people who have liver disease, or in obese (very
overweight) people, especially women.
Signs of lactic acidosis include:
•
deep, rapid, difficult breathing
•
drowsiness
•
numbness or weakness in the limbs
•
feeling sick (
nausea
), being sick (
vomiting
)
71
•
stomach pain.
During your treatment, your doctor will monitor you for signs of lactic acidosis. If you have any of the
symptoms listed above, or any other symptoms that worry you:
See your doctor as soon as possible
.
You may have problems with your bones
Some people taking combination therapy for HIV develop a condition called osteonecrosis. With this
condition, parts of the bone tissue die because of reduced blood supply to the bone. People may be
more likely to get this condition:
•
if they have been taking combination therapy for a long time
•
if they are also taking anti-inflammatory medicines called corticosteroids
•
if they drink alcohol
•
if their immune systems are very weak
•
if they are overweight.
Signs of osteonecrosis include:
•
stiffness in the joints
•
aches and pains (especially in the hip, knee or shoulder)
•
difficulty moving.
If you notice any of these symptoms:
Tell your doctor
.
Other effects may show up in blood tests
Combination therapy for HIV can also cause:
•
increased levels of lactic acid in the blood, which on rare occasions can lead to lactic acidosis
•
increased levels of sugar and fats (triglycerides and cholesterol) in the blood
•
resistance to insulin (so if you’re diabetic, you may have to change your insulin dose to control
your blood sugar).
5.
How to store Epivir
Keep out of the reach and sight of children
Do not take Epivir after the expiry date shown on the container.
Discard one month after first opening.
Do not store above 25
o
C.
If you have any unwanted Epivir, don’t dispose of it in your waste water or your household rubbish.
Ask your pharmacist how to dispose of medicines no longer required. These measures will help to
protect the environment.
6.
Further information
What Epivir contains
The active substance is lamivudine.
The oral solution also contains the following other ingredients: sugar (sucrose 3 g/15 ml), methyl
parahydroxybenzoate, propyl parahydroxybenzoate, anhydrous citric acid, sodium citrate, propylene
glycol, water, artificial strawberry and banana flavourings.
What Epivir looks like and the contents of the pack
72
Epivir oral solution is supplied in a white polyethylene bottle containing 240 ml of solution. An oral
dosing syringe and a plastic adapter for the bottle is included in the pack.
Marketing Authorisation Holder and Manufacturer
Manufacturer
Marketing Authorisation Holder
Glaxo Wellcome GmbH & Co. KG
Industriestrasse 32-36
23843 Bad Oldesloe
Germany
ViiV Healthcare UK Limited
980 Great West Road
Brentford
Middlesex
TW8 9GS
United Kingdom
For any information about this medicinal product please contact the local representative of the
Marketing Authorisation Holder.
België/Belgique/Belgien
ViiV Healthcare sprl/bvba
Tél/Tel: + 32 (0)2 656 25 11
Luxembourg/Luxemburg
ViiV Healthcare sprl/bvba
Belgique/Belgien
Tél/Tel: + 32 (0)2 656 25 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
ViiV Healthcare BV
Tel: + 31 (0)30 6986060
c
ontact-nl@viivhealthcare.com
Deutschland
ViiV Healthcare GmbH
Tel.: + 49 (0)89 203 0038-10
viiv.med.info@viivhealthcare.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
Laboratorios ViiV Healthcare, S.L.
Tel: + 34 902 051 260
es-ci@viivhealthcare.com
Portugal
VIIVHIV HEALTHCARE, UNIPESSOAL,
LDA.
Tel: + 351 21 094 08 01
viiv.fi.pt@viivhealthcare.com
73
France
ViiV Healthcare SAS
Tél.: + 33 (0)1 39 17 6969
Infomed@viivhealthcare.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.
Simi: + 354 530 3700
Slovenská republika
GlaxoSmithKline Slovakia s. r. o.
Tel: + 421 (0)2 48 26 11 11
recepcia.sk@gsk.com
Italia
ViiV Healthcare S.r.l.
Tel: + 39 (0)45 9212611
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
ViiV Healthcare UK Limited
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 in
Detailed information on this medicine is available on the European Medicines Agency web site:
http://www.ema.europa.eu
74
PACKAGE LEAFLET: INFORMATION FOR THE USER
Epivir 300 mg film-coated tablets
lamivudine
Read all of this leaflet carefully before you start taking this medicine.
−
Keep this leaflet, you may need to read it again.
−
If you have any further questions, ask your doctor or pharmacist.
−
This medicine has been prescribed for you personally. 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 Epivir is and what it is used for
3.
How to take Epivir
4.
Possible side effects
5.
How to store Epivir
6.
Further information
1.
What Epivir is and what it is used for
Epivir is used to treat HIV (human immunodeficiency virus) infection in adults and children
.
The active ingredient in Epivir is lamivudine. Epivir is a type of medicine known as an anti-retroviral.
It belongs to a group of medicines called
nucleoside analogue reverse transcriptase inhibitors
(
NRTIs
).
Epivir does not completely cure HIV infection; it reduces the amount of virus in your body, and keeps
it at a low level. It also increases the CD4 cell count in your blood. CD4 cells are a type of white blood
cells that are important in helping your body to fight infection.
Not everyone responds to treatment with Epivir in the same way. Your doctor will monitor the
effectiveness of your treatment.
2.
Before you take Epivir
Don’t take Epivir:
•
if you’re
allergic
(hypersensitive)
to
lamivudine or any of the other ingredients in Epivir (
listed in
Section 6
).
Check with your doctor
if you think this applies to you.
Take special care with Epivir
Some people taking Epivir or other combination treatments for HIV are more at risk of serious side
effects. You need to be aware of the extra risks:
•
if you have ever had
liver disease,
including hepatitis B or C (if you have hepatitis B infection,
don’t stop Epivir without your doctor’s advice, as your hepatitis may come back)
•
if you’re seriously
overweight
(especially if you’re a woman)
75
2.
Before you take Epivir
•
if you’re
diabetic
and using insulin
•
if you have a kidney problem
, your dose may be altered.
Talk to your doctor if any of these apply to you
. You may need extra check-ups, including
blood tests, while you’re taking your medicine.
See Section 4 for more information
.
Look out for important symptoms
Some people taking medicines for HIV infection develop other conditions, which can be serious. You
need to know about important signs and symptoms to look out for while you’re taking Epivir.
Read the information ‘Other possible side effects of combination therapy for HIV’ in
Section 4 of this leaflet
.
Protect other people
HIV infection is spread by sexual contact with someone who has the infection, or by transfer of
infected blood (for example, by sharing injection needles). Epivir will not stop you passing HIV
infection on to other people. To protect other people from becoming infected with HIV:
•
Use a condom
when you have oral or penetrative sex.
•
Don’t risk blood transfer
— for example, don’t share needles.
Other medicines and Epivir
Tell your doctor or pharmacist if you’re taking any other medicines
, or if you’ve taken any
recently, including herbal medicines or other medicines you bought without a prescription.
Remember to tell your doctor or pharmacist if you begin taking a new medicine while you’re taking
Epivir.
These medicines should not be used with Epivir:
•
other medicines containing lamivudine, (used to treat
HIV infection
or
hepatitis B infection)
•
emtricitabine (used to treat
HIV infection
)
•
high doses of
co-trimoxazole
, an antibiotic.
Tell your doctor
if you’re being treated with any of these.
Pregnancy
If you are pregnant, if you become pregnant, or are planning to become pregnant, talk to your doctor
about the risks and benefits to you and your baby of taking Epivir.
Epivir and similar medicines may cause side effects in unborn babies. If you become pregnant while
you’re taking Epivir, your baby may be given extra check-ups (including blood tests) to make sure it is
developing normally.
Children whose mothers took NRTIs (medicines like Epivir) during pregnancy had a reduced risk of
being infected with HIV. This benefit is greater than the risk of having side effects.
Breast-feeding
Women who are HIV-positive must not breast-feed
, because HIV infection can be passed on to the
baby in breast milk.
If you’re breast-feeding, or thinking about breast-feeding:
Talk to your doctor immediately
.
Driving and using machines
Epivir is unlikely to affect your ability to drive or use machines.
76
3.
How to take Epivir
Always take Epivir exactly as your doctor has told you to.
Check with your doctor or pharmacist if
you’re not sure.
Swallow the tablet with some water. Epivir can be taken with or without food.
If you cannot swallow the tablet whole, you may crush and combine it with a small amount of food or
drink, and take all the dose immediately.
Stay in regular contact with your doctor
Epivir helps to control your condition. You need to keep taking it every day to stop your illness getting
worse. You may still develop other infections and illnesses linked to HIV infection.
Keep in touch with your doctor, and don’t stop taking Epivir
without your doctor’s advice.
How much to take
The usual dose of Epivir for adults and children who weigh at least 30 kg is:
•
one tablet once a day.
An oral solution is also available for the treatment of children over 3 months of age, or for people who
need a lower dose than usual, or who can’t take tablets.
If you have a kidney problem
, your dose may be altered.
Talk to your doctor
if this applies to you.
If you take too much Epivir
Accidentally taking too much Epivir is unlikely to cause any serious problems. If you take too much,
tell your doctor or your pharmacist, or contact your nearest hospital emergency department for further
advice.
If you forget to take Epivir
If you forget to take a dose, take it as soon as you remember. Then continue your treatment as before.
Don’t take a double dose to make up for a missed dose.
4.
Possible side effects
Like all medicines, Epivir can cause side effects, but not everyone gets them.
When you’re being treated for HIV, it can be hard to tell whether a symptom is a side effect of Epivir
or other medicines you are taking, or an effect of the HIV disease itself.
So it is very important to
talk to your doctor about any changes in your health
.
As well as the side effects listed below for Epivir
, other conditions can develop during combination
therapy for HIV.
It is important to read the information later in this section under ‘Other possible side effects of
combination therapy for HIV’.
Common side effects
These may affect
up to 1 in 10
people:
•
headache
•
feeling sick (
nausea
)
•
being sick (
vomiting
)
77
•
diarrhoea
•
stomach pains
•
tiredness, lack of energy
•
fever (high temperature)
•
general feeling of being unwell
•
muscle pain and discomfort
•
joint pain
•
difficulty in sleeping (
insomnia
)
•
cough
•
irritated or runny nose
•
rash
•
hair loss (
alopecia
).
Uncommon side effects
These may affect
up to 1 in 100
people:
Uncommon side effects that may show up in blood tests are:
•
a decrease in the number of cells involved in blood clotting (
thrombocytopenia
)
•
a low red blood cell count (
anaemia
) or low white blood cell count (
neutropenia
)
•
an increase in the level of liver enzymes.
Rare side effects
These may affect
up to 1 in 1000
people:
•
serious allergic reaction causing swelling of the face, tongue or throat which may cause
difficulty in swallowing or breathing
•
lactic acidosis (
see the next section, ‘Other possible side effects of combination therapy for
HIV’
)
•
inflammation of the pancreas
(pancreatitis)
•
breakdown of muscle tissue
•
liver disorders, such as jaundice, enlarged liver or fatty liver, inflammation (
hepatitis
).
A rare side effect that may show up in blood tests is:
•
increase in an enzyme called amylase.
Very rare side effects
These may affect
up to 1 in 10,000
people:
•
tingling or numbness of the arms, legs, hands or feet.
A very rare side effect that may show up in blood tests is:
•
a failure of the bone marrow to produce new red blood cells
(pure red cell aplasia)
.
If you get side effects
Tell your doctor or pharmacist
if any of the side effects gets severe or troublesome, or if you
notice any side effects not listed in this leaflet.
Other possible side effects of combination therapy for HIV
Combination therapy including Epivir may cause other conditions to develop during HIV treatment.
Old infections may flare up
People with advanced HIV infection (AIDS) have weak immune systems, and are more likely to
develop serious infections (opportunistic infections). When these people start treatment, they may find
that old, hidden infections flare up, causing signs and symptoms of inflammation. These symptoms are
probably caused by the body’s immune system becoming stronger, so that the body starts to fight these
infections.
78
If you get any symptoms of infection while you’re taking Epivir:
Tell your doctor immediately
. Don’t take other medicines for the infection without your
doctor’s advice.
Your body shape may change
People taking combination therapy for HIV may find that their body shape changes, because of
changes in fat distribution:
•
Fat may be lost from the legs, arms or face.
•
Extra fat may build up around the tummy (abdomen), or on the breasts or internal organs.
•
Fatty lumps (sometimes called buffalo hump) may appear on the back of the neck.
It is not yet known what causes these changes, or whether they have any long-term effects on your
health. If you notice changes in your body shape:
Tell your doctor.
Lactic acidosis is a rare but serious side effect
Some people taking Epivir, or other medicines like it (NRTIs), develop a condition called lactic
acidosis, together with an enlarged liver.
Lactic acidosis is caused by a build-up of lactic acid in the body. It is rare; if it happens, it usually
develops after a few months of treatment. It can be life-threatening, causing failure of internal organs.
Lactic acidosis is more likely to develop in people who have liver disease, or in obese (very
overweight) people, especially women.
Signs of lactic acidosis include:
•
deep, rapid, difficult breathing
•
drowsiness
•
numbness or weakness in the limbs
•
feeling sick (
nausea
), being sick (
vomiting
)
•
stomach pain.
During your treatment, your doctor will monitor you for signs of lactic acidosis. If you have any of the
symptoms listed above, or any other symptoms that worry you:
See your doctor as soon as possible
.
You may have problems with your bones
Some people taking combination therapy for HIV develop a condition called
osteonecrosis
. With this
condition, parts of the bone tissue die because of reduced blood supply to the bone. People may be
more likely to get this condition:
•
if they have been taking combination therapy for a long time
•
if they are also taking anti-inflammatory medicines called corticosteroids
•
if they drink alcohol
•
if their immune systems are very weak
•
if they are overweight.
Signs of osteonecrosis include:
•
stiffness in the joints
•
aches and pains (especially in the hip, knee or shoulder)
•
difficulty moving.
If you notice any of these symptoms:
Tell your doctor
.
Other effects may show up in blood tests
Combination therapy for HIV can also cause:
79
•
increased levels of lactic acid in the blood, which on rare occasions can lead to lactic acidosis
•
increased levels of sugar and fats (triglycerides and cholesterol) in the blood
•
resistance to insulin (so if you’re diabetic, you may have to change your insulin dose to control
your blood sugar).
5.
How to store Epivir
Keep out of the reach and sight of children.
Do not take Epivir after the expiry date shown on the carton.
Do not store Epivir above 30
o
C.
If you have any unwanted Epivir tablets, don’t dispose of them in your waste water or your household
rubbish. Ask your pharmacist how to dispose of medicines no longer required. These measures will
help to protect the environment.
6
Further information
What Epivir contains
The active substance is lamivudine.
The tablets also contain the following other ingredients:
Tablet core
: microcrystalline cellulose, sodium starch glycollate (gluten free), magnesium stearate
Film-coat
: hypromellose, titanium dioxide, black iron oxide (E172), macrogol, polysorbate 80
What Epivir looks like and the contents of the pack
Epivir 300 mg film-coated tablets are supplied in white polyethylene bottles or blister packs
containing 30 tablets. They are grey, diamond shaped film-coated tablets, marked with the code
‘GXEJ7’ on one side.
Marketing Authorisation Holder and Manufacturer
Manufacturer
Marketing Authorisation Holder
Glaxo Operations UK Limited
(trading as Glaxo Wellcome
Operations)
Priory Street
Ware
Herts SG12 0DJ
United Kingdom
ViiV Healthcare UK Limited
980 Great West Road
Brentford
Middlesex
TW8 9GS
United Kingdom
or
GlaxoSmithKline
Pharmaceuticals S.A.
ul. Grunwaldzka 189
60-322 Poznan
Poland
80
For any information about this medicinal product please contact the local representative of the
Marketing Authorisation Holder.
België/Belgique/Belgien
ViiV Healthcare sprl/bvba
Tél/Tel: + 32 (0)2 656 25 11
Luxembourg/Luxemburg
ViiV Healthcare sprl/bvba
Belgique/Belgien
Tél/Tel: + 32 (0)2 656 25 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
ViiV Healthcare BV
Tel: + 31 (0)30 6986060
c
ontact-nl@viivhealthcare.com
Deutschland
ViiV Healthcare GmbH
Tel.: + 49 (0)89 203 0038-10
viiv.med.info@viivhealthcare.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
Laboratorios ViiV Healthcare, S.L.
Tel: + 34 902 051 260
es-ci@viivhealthcare.com
Portugal
VIIVHIV HEALTHCARE, UNIPESSOAL, LDA
Tel: + 351 21 094 08 01
viiv.fi.pt@viivhealthcare.com
France
ViiV Healthcare SAS
Tél.: + 33 (0)1 39 17 6969
Infomed@viivhealthcare.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.
Simi: + 354 530 3700
Slovenská republika
GlaxoSmithKline Slovakia s. r. o.
Tel: + 421 (0)2 48 26 11 11
recepcia.sk@gsk.com
81
Italia
ViiV Healthcare S.r.l
Tel: + 39 (0)45 9212611
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
ViiV Healthcare UK Limited
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 in
Detailed information on this medicine is available on the European Medicines Agency web site:
http://www.ema.europa.eu
.
82
Source: European Medicines Agency
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