ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
Lamivudine/Zidovudine Teva
150 mg/300 mg film-coated tablets
2.
Each film-coated tablet contains 150 mg lamivudine and 300 mg zidovudine.
For a full list of excipients see section 6.1.
3.
Film-coated tablet
White, capsule shaped, biconvex, film-coated scored tablet – engraved with “L/Z” on one side and
“150/300” on the other side.
The tablet can be divided into equal halves.
4.
Lamivudine/Zidovudine Teva is indicated in antiretroviral combination therapy for the treatment of
Human Immunodeficiency Virus (HIV) infection (see section 4.2).
Therapy should be initiated by a physician experienced in the management of HIV infection.
Lamivudine/Zidovudine Teva 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, 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 weighing at least 30 kg:
the recommended oral dose of
Lamivudine/Zidovudine Teva is one tablet twice daily.
Children weighing between 21 kg and 30 kg: the recommended oral dose of Lamivudine/Zidovudine
Teva is one-half tablet taken in the morning and one whole tablet taken in the evening.
Children weighing from 14 kg to 21 kg:
the recommended oral dose of Lamivudine/Zidovudine Teva
is one-half tablet taken twice daily.
The dosing regimen for paediatric patients weighing 14-30 kg is based primarily on pharmacokinetic
modelling and supported by data from clinical studies using the individual components lamivudine
and zidovudine. A pharmacokinetic overexposure of zidovudine can occur, therefore close safety
2
monitoring is warranted in these patients. If gastrointestinal intolerance occurs in patients weighing
21-30 kg, an alternative dosing schedule with one-half tablet taken thrice daily can be applied in
attempt to improve tolerability.
Lamivudine/Zidovudine Teva tablets should not be used for children weighing less than 14 kg, since
doses can not be appropriately adjusted for the weight of the child. In these patients, lamivudine and
zidovudine should be taken as separate formulations according to the prescribed dosing
recommendations for these products. For these patients and for patients who are unable to swallow
tablets, oral solutions of lamivudine and zidovudine are available.
For situations where discontinuation of therapy with one of the active substances of
Lamivudine/Zidovudine Teva, or dose reduction is necessary, separate preparations of lamivudine and
zidovudine are available in tablets/capsules and oral solution.
Renal impairment
:
Lamivudine and zidovudine concentrations are increased in patients with renal
impairment due to decreased clearance. Therefore as dosage adjustment of these may be necessary it
is recommended that separate preparations of lamivudine and zidovudine be administered to patients
with reduced renal function (creatinine clearance ≤50 ml/min). Physicians should refer to the
individual prescribing information for these medicinal products.
Hepatic impairment:
Limited data in patients with cirrhosis suggest that accumulation of zidovudine
may occur in patients with hepatic impairment because of decreased glucuronidation. Data obtained in
patients with moderate to severe hepatic impairment show that lamivudine pharmacokinetics are not
significantly affected by hepatic dysfunction. However, as dosage adjustments for zidovudine may be
necessary, it is recommended that separate preparations of lamivudine and zidovudine be administered
to patients with severe hepatic impairment. Physicians should refer to the individual prescribing
information for these medicinal products.
Dosage adjustments in patients with haematological adverse reactions:
Dosage adjustment of
zidovudine may be necessary if the haemoglobin level falls below 9 g/dl or 5.59 mmol/l or the
neutrophil count falls below 1.0 x 10
9
/l (see sections 4.3 and 4.4). As dosage adjustment of
Lamivudine/Zidovudine Teva is not possible, separate preparations of zidovudine and lamivudine
should be used. Physicians should refer to the individual prescribing information for these medicinal
products.
Dosage in the elderly:
No specific data are available, however special care is advised in this age group
due to age associated changes such as the decrease in renal function and alteration of haematological
parameters.
Hypersensitivity to the active substances or to any of the excipients.
Zidovudine is contraindicated in patients with abnormally low neutrophil counts (<0.75 x 10
9
/l), or
abnormally low haemoglobin levels (<7.5 g/dl or 4.65 mmol/l). Lamivudine/Zidovudine Teva is
therefore contraindicated in these patients (see section 4.4).
3
The special warnings and precautions relevant to both lamivudine and zidovudine are included in this
section. There are no additional precautions and warnings relevant to the combination
Lamivudine/Zidovudine Teva.
It is recommended that separate preparations of lamivudine and zidovudine should be administered in
cases where dosage adjustment is necessary (see section 4.2). In these cases the physician should refer
to the individual prescribing information for these medicinal products.
The concomitant use of stavudine with zidovudine should be avoided (see section 4.5).
Opportunistic infections:
Patients receiving Lamivudine/Zidovudine Teva or any other antiretroviral
therapy may continue to develop opportunistic infections and other complications of HIV infection.
Therefore patients should remain under close clinical observation by physicians experienced in the
treatment of HIV infection.
Transmission of HIV:
Patients should be advised that current antiretroviral therapy, including
Lamivudine/Zidovudine Teva, 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.
Haematological adverse reactions:
Anaemia, neutropenia and leucopenia (usually secondary to
neutropenia) can be expected to occur in patients receiving zidovudine. These occurred more
frequently at higher zidovudine dosages (1200-1500 mg/day) and in patients with poor bone marrow
reserve prior to treatment, particularly with advanced HIV disease. Haematological parameters should
therefore be carefully monitored (see section 4.3) in patients receiving Lamivudine/Zidovudine Teva.
These haematological effects are not usually observed before four to six weeks therapy. For patients
with advanced symptomatic HIV disease, it is generally recommended that blood tests are performed
at least every two weeks for the first three months of therapy and at least monthly thereafter.
In patients with early HIV disease haematological adverse reactions are infrequent. Depending on the
overall condition of the patient, blood tests may be performed less often, for example every one to
three months. Additionally dosage adjustment of zidovudine may be required if severe anaemia or
myelosuppression occurs during treatment with Lamivudine/Zidovudine Teva. or in patients with pre-
existing bone marrow compromise e.g. haemoglobin <9 g/dl (5.59 mmol/l) or neutrophil count
<1.0 x 10
Pancreatitis:
Cases of pancreatitis have occurred rarely in patients treated with lamivudine and
zidovudine. However it is not clear whether these cases were due to the antiretroviral treatment or to
the underlying HIV disease. Treatment with Lamivudine/Zidovudine Teva should be stopped
immediately if clinical signs, symptoms or laboratory abnormalities suggestive of pancreatitis occur.
4
9
/l (see section 4.2). As dosage adjustment of Lamivudine/Zidovudine Teva is not possible
separate preparations of zidovudine and lamivudine should be used. Physicians should refer to the
individual prescribing information for these medicinal products.
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 if there is 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).
5
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 jiroveci pneumonia (
formerly known as
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 Lamivudine Teva SPC.
The safety and efficacy of zidovudine has not been established in patients with significant underlying
liver disorders.
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 Lamivudine/Zidovudine Teva is discontinued in patients co-infected with hepatitis B virus, periodic
monitoring of both liver function tests and markers of HBV replication for 4 months is recommended,
as withdrawal of lamivudine may result in an acute exacerbation of hepatitis.
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.
Patients co-infected with hepatitis C virus:
The concomitant use of ribavirin with zidovudine is not
recommended due to an increased risk of anaemia (see section 4.5).
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.
As Lamivudine/Zidovudine Teva contains lamivudine and zidovudine, any interactions that have been
identified with these agents individually may occur with Lamivudine/Zidovudine Teva. The
likelihood of metabolic interactions with lamivudine is low due to limited metabolism and plasma
protein binding, and almost complete renal clearance. Zidovudine is primarily eliminated by hepatic
conjugation to an inactive glucuronidated metabolite. Medicinal products which are primarily
eliminated by hepatic metabolism especially via glucuronidation may have the potential to inhibit
metabolism of zidovudine. The interactions listed below should not be considered exhaustive but are
representative of the classes of medicinal products where caution should be exercised.
Lamivudine and zidovudine metabolism do not involve CYP3A, making interactions with medicinal
products metabolised by this system (e.g. PIs) unlikely.
6
Interactions relevant to lamivudine
The possibility of interactions with other medicinal products administered concurrently with
Lamivudine/Zidovudine Teva should be considered, particularly when the main route of elimination is
active renal secretion, especially via the cationic transport system e.g. trimethoprim. Nucleoside
analogues (e.g. zidovudine, didanosine and zalcitabine) and other medicinal products (e.g. ranitidine,
cimetidine) are eliminated only in part by this mechanism and were shown not to interact with
lamivudine.
Administration of trimethoprim/sulfamethoxazole 160 mg/800 mg results in a 40 % increase in
lamivudine exposure, because of the trimethoprim component; the sulfamethoxazole component does
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 with co-trimoxazole is warranted, patients
should be monitored clinically. Co-administration of Lamivudine/Zidovudine Teva with high doses of
co-trimoxazole for the treatment of
Pneumocystis jiroveci pneumonia (
formerly known as
Pneumocystis carinii pneumonia
[PCP]) and toxoplasmosis should be avoided.
Co-administration of lamivudine with intravenous ganciclovir or foscarnet is not recommended.
Interactions relevant to zidovudine
Limited data suggest that co-administration of zidovudine and rifampicin decreases the AUC of
zidovudine by 48 %
±
34 %. However the clinical significance of this is unknown. Dose
modifications of zidovudine in this situation have not been formally evaluated.
Limited data suggest that probenecid increases the mean half-life and area under the plasma
concentration curve of zidovudine by decreasing glucuronidation. Renal excretion of the glucuronide
(and possibly zidovudine itself) is reduced in the presence of probenecid. Patients receiving both
medicinal products should be closely monitored for haematological toxicity.
Phenytoin blood levels have been reported to be low in some patients receiving zidovudine, while in
one patient a high level was noted. These observations suggest that phenytoin concentrations should
be carefully monitored in patients receiving Lamivudine/Zidovudine Teva and phenytoin.
In a pharmacokinetic study co-administration of zidovudine and atovaquone tablets showed a decrease
in zidovudine clearance after oral dosing leading to a 35 %
±
23 % increase in plasma zidovudine
AUC. The mode of interaction is unknown and as higher concentrations of atovaquone can be
achieved with atovaquone suspension it is possible that greater changes in AUC values for zidovudine
might be induced when atovaquone is administered as a suspension. Given the limited data available
the clinical significance of this is unknown.
Valproic acid, fluconazole or methadone when co-administered with zidovudine have been shown to
increase the AUC of zidovudine, with a corresponding decrease in its clearance. As only limited data
are available the clinical significance is not known. If zidovudine is used concurrently with either
valproic acid, fluconazole or methadone, patients should be monitored closely for potential toxicity of
zidovudine.
Zidovudine and stavudine in combination are antagonistic
in vitro
, therefore the concomitant use of
stavudine with Lamivudine/Zidovudine Teva should be avoided (see section 4.4).
7
Exacerbation of anaemia due to ribavirin has been reported when zidovudine is part of the regimen
used to treat HIV although the exact mechanism remains to be elucidated. The concomitant use of
ribavirin with zidovudine is not recommended due to an increased risk of anaemia (see section 4.4).
Consideration should be given to replacing zidovudine in a combination ART regimen if this is
already established. This would be particularly important in patients with a known history of
zidovudine induced anaemia.
Concomitant treatment, especially acute therapy, with potentially nephrotoxic or myelosuppressive
medicinal products (e.g. systemic pentamidine, dapsone, pyrimethamine, co-trimoxazole,
amphotericin, flucytosine, ganciclovir, interferon, vincristine, vinblastine and doxorubicin) may also
increase the risk of adverse reactions to zidovudine. If concomitant therapy with
Lamivudine/Zidovudine Teva and any of these medicinal products is necessary then extra care should
be taken in monitoring renal function and haematological parameters and, if required, the dosage of
one or more agents should be reduced.
Since some patients receiving Lamivudine/Zidovudine Teva may continue to experience opportunistic
infections, concomitant use of prophylactic antimicrobial therapy may have to be considered. Limited
data from clinical trials do not indicate a significantly increased risk of adverse reactions to zidovudine
with cotrimoxazole (see interaction information above relating to lamivudine and co-trimoxazole),
aerosolised pentamidine, pyrimethamine and acyclovir at doses used in prophylaxis.
Clarithromycin tablets reduce the absorption of zidovudine. This can be avoided by separating the
administration of Lamivudine/Zidovudine Teva and clarithromycin by at least two hours.
Pregnancy:
The safety of lamivudine in human pregnancy has not been established. No data are
available for the treatment with a combination of lamivudine and zidovudine in humans or animals
(see also section 5.3). The use in pregnant women of zidovudine alone, with subsequent treatment of
the newborn infants, has been shown to reduce the rate of maternal-foetal transmission of HIV.
However, no such data are available for lamivudine.
In humans, consistent with passive transmission of lamivudine across the placenta, lamivudine
concentrations in infant serum at birth were similar to those in maternal and cord serum at delivery.
Zidovudine was measured in plasma and gave similar results to those observed for lamivudine (see
section 5.2).
As the active ingredients of Lamivudine/Zidovudine Teva may inhibit cellular DNA replication, any
use, especially during the first trimester of pregnancy, presents a potential risk to the foetus.
Consequently the administration of Lamivudine/Zidovudine Teva during pregnancy should only be
considered if expected benefits outweigh any possible risks.
Pregnant women considering using Lamivudine/Zidovudine Teva during pregnancy should be made
aware of the findings from animal carcinogenicity and mutagenicity studies (see section 5.3).
In men zidovudine has not been shown to affect sperm count, morphology or motility.
Lactation:
Both lamivudine and zidovudine are excreted in breast milk at similar concentrations to
those found in serum. It is recommended that mothers taking Lamivudine/Zidovudine Teva do not
8
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.
Adverse reactions have been reported during therapy for HIV disease with lamivudine and zidovudine
separately or in combination. For many of these events, it is unclear whether they are related to
lamivudine, zidovudine, the wide range of medicinal products used in the management of HIV disease,
or as a result of the underlying disease process.
As Lamivudine/Zidovudine Teva contains lamivudine and zidovudine, the type and severity of
adverse reactions associated with each of the compounds may be expected. There is no evidence of
added toxicity following concurrent administration of the two compounds.
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 exposure to combination antiretroviral therapy (CART).
The frequency of this is unknown (see section 4.4).
Lamivudine:
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 (≥1/1000 to <1/100), rare (≥1/10,000 to <1/1000), 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
9
Common:
Headache, insomnia
Very rare:
Peripheral neuropathy (or paraesthesiae)
Respiratory, thoracic and mediastinal disorders
Common:
Cough, nasal symptoms
Gastrointestinal disorders
Common:
Nausea, vomiting, abdominal pain or cramps, diarrhoea
Rare:
Pancreatitis, rises in serum amylase
Hepatobiliary disorders
Uncommon:
Transient rises in liver enzymes (AST, ALT)
Rare:
Hepatitis
Skin and subcutaneous tissue disorders
Common:
Rash, alopecia
Musculoskeletal and connective tissue disorders
Common:
Arthralgia, muscle disorders
Rare:
Rhabdomyolysis
General disorders and administration site conditions
Common:
Fatigue, malaise, fever
Zidovudine:
The adverse reactions profile appears similar for adults and adolescents. The most serious adverse
reactions include anaemia (which may require transfusions), neutropenia and leucopenia. These
occurred more frequently at higher dosages (1200-1500 mg/day) and in patients with advanced HIV
disease (especially when there is poor bone marrow reserve prior to treatment), and particularly in
patients with CD4 cell counts less than 100/mm
3
(see section 4.4).
The incidence of neutropenia was also increased in those patients whose neutrophil counts,
haemoglobin levels and serum vitamin B
12
levels were low at the start of zidovudine therapy.
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 (≥1/1000 to <1/100), rare (≥1/10,000 to <1/1000), very rare
(<1/10,000). Within each frequency grouping, undesirable effects are presented in order of decreasing
seriousness.
Blood and lymphatic system disorders
Common:
Anaemia, neutropenia and leucopenia
Uncommon:
Thrombocytopenia and pancytopenia (with marrow hypoplasia)
Rare:
Pure red cell aplasia
Very rare:
Aplastic anaemia
Metabolism and nutrition disorders
Rare:
Lactic acidosis in the absence of hypoxaemia, anorexia
10
Psychiatric disorders
Rare:
Anxiety and depression
Nervous system disorders
Very common
: Headache
Common
Dizziness
Rare:
Insomnia, paraesthesiae, somnolence, loss of mental acuity, convulsions
Cardiac disorders
Rare:
Cardiomyopathy
Respiratory, thoracic and mediastinal disorders
Uncommon
: Dyspnoea
Rare:
Cough
Gastrointestinal disorders
Very common
: Nausea
Common
: Vomiting, abdominal pain and diarrhoea
Uncommon:
Flatulence
Rare:
Oral mucosa pigmentation, taste perversion and dyspepsia. Pancreatitis
Hepatobiliary disorders
Common
: Raised blood levels of liver enzymes and bilirubin
Rare :
Liver disorders such as severe hepatomegaly with steatosis
Skin and subcutaneous tissue disorders
Uncommon:
Rash and pruritus
Rare:
Nail and skin pigmentation, urticaria and sweating
Musculoskeletal and connective tissue disorders
Common
: Myalgia
Uncommon
: Myopathy
Renal and urinary disorders
Rare:
Urinary frequency
Reproductive system and breast disorders
Rare:
Gynaecomastia
General disorders and administration site conditions
Common
: Malaise
Uncommon
: Fever, generalised pain and asthenia
Rare:
Chills, chest pain and influenza-like syndrome
The available data from both placebo-controlled and open-label studies indicate that the incidence of
nausea and other frequently reported clinical adverse events consistently decreases over time during
the first few weeks of therapy with zidovudine.
11
There is limited experience of overdosage with lamivudine/zidovudine. No specific symptoms or
signs have been identified following acute overdose with zidovudine or lamivudine apart from those
listed as undesirable effects. No fatalities occurred, and all patients recovered.
If overdosage occurs the patient should be monitored for evidence of toxicity (see section 4.8), and
standard supportive treatment applied as necessary. Since lamivudine is dialysable, continuous
haemodialysis could be used in the treatment of overdosage, although this has not been studied.
Haemodialysis and peritoneal dialysis appear to have a limited effect on elimination of zidovudine, but
enhance the elimination of the glucuronide metabolite. For more details physicians should refer to the
individual prescribing information for lamivudine and zidovudine.
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Antivirals for treatment of HIV infections, combinations, ATC Code:
J05AR01
Lamivudine and zidovudine are nucleoside analogues which have activity against HIV. Both
medicinal products are metabolised intracellularly to their active moieties, lamivudine 5’-triphosphate
(TP) and zidovudine 5’-TP respectively. Their main modes of action are as chain terminators of viral
reverse transcription. Lamivudine-TP and zidovudine-TP have selective inhibitory activity against
HIV-1 and HIV-2 replication
in vitro
.
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
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 NRTIs 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. The M184V RT mutant shows a <4-fold decrease in susceptibility to
didanosine and zalcitabine; 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
. Resistance to thymidine analogues (of which zidovudine is one) is well characterised and is
conferred by the stepwise accumulation of up to six specific mutations in the HIV reverse transcriptase
12
at codons 41, 67, 70, 210, 215 and 219. Viruses acquire phenotypic resistance to thymidine analogues
through the combination of mutations at codons 41 and 215 or by the accumulation of at least four of
the six mutations.
Two patterns of multi-drug resistance mutations, the first characterised by mutations in the HIV
reverse transcriptase at codons 62, 75, 77, 116 and 151 and the second involving a T69S mutation plus
a 6-base pair insert at the same position, result in phenotypic resistance to AZT as well as to the other
approved NRTIs. Either of these two patterns of multinucleoside resistance mutations severely limits
future therapeutic options.
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 subjects receiving lamivudine and zidovudine with or
without additional concomitant antiretroviral therapies and who already present with the M184V
mutant virus also experience a delay in the onset of mutations that confer resistance to zidovudine and
stavudine (Thymidine Analogue Mutations; TAMs).
The relationship between
in vitro
susceptibility of HIV to lamivudine and zidovudine and clinical
response to lamivudine/zidovudine containing therapy remains under investigation.
Lamivudine has not been specifically investigated in HIV patients co-infected with HBV.
5.2 Pharmacokinetic properties
Absorption:
Lamivudine and zidovudine are well absorbed from the gastrointestinal tract. The
bioavailability of oral lamivudine in adults is normally between 80-85 % and for zidovudine 60-70 %.
A bioequivalence study compared lamivudine/zidovudine with lamivudine 150 mg and zidovudine
300 mg tablets taken together. The effect of food on the rate and extent of absorption was also studied.
lamivudine/zidovudine was shown to be bioequivalent to lamivudine 150 mg and zidovudine 300 mg
given as separate tablets, when administered to fasting subjects.
Following single dose lamivudine/zidovudine administration in healthy volunteers, mean (CV)
lamivudine and zidovudine C
max
values were 1.6 µg/ml (32 %) and 2.0 µg/ml (40 %), respectively and
the corresponding values for AUC were 6.1 µg h/ml (20 %) and 2.4 µg h/ml (29 %) respectively. The
median (range) lamivudine and zidovudine t
max
values were 0.75 (0.50-2.00) hours and 0.50
(0.25-2.00) hours respectively. The extent of lamivudine and zidovudine absorption (AUC
∞
) and
estimates of half-life following administration of lamivudine/zidovudine with food were similar when
compared to fasting subjects, although the rates of absorption (C
max,
t
max
) were slowed. Based on these
data lamivudine/zidovudine may be administered with or without food.
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 physicochemical and pharmacokinetic data
assuming that the patient crushes and transfers 100 % of the tablet and ingests immediately.
13
Distribution:
Intravenous studies with lamivudine and zidovudine showed that the mean apparent
volume of distribution is 1.3 and 1.6 l/kg respectively. Lamivudine exhibits linear pharmacokinetics
over the therapeutic dose range and displays limited binding to the major plasma protein albumin
(<36 % serum albumin
in vitro
). Zidovudine plasma protein binding is 34 % to 38 %. Interactions
involving binding site displacement are not anticipated with Lamivudine/Zidovudine Teva.
Data show that lamivudine and zidovudine penetrate the central nervous system (CNS) and reach the
cerebrospinal fluid (CSF). The mean ratios of CSF/serum lamivudine and zidovudine concentrations
2-4 hours after oral administration were approximately 0.12 and 0.5 respectively. The true extent of
CNS penetration of lamivudine and its relationship with any clinical efficacy is unknown.
Metabolism:
Metabolism of lamivudine is a minor route of elimination. Lamivudine is predominately
cleared unchanged by renal excretion. The likelihood of metabolic drug interactions with lamivudine
is low due to the small extent of hepatic metabolism (5-10 %) and low plasma binding.
The 5’-glucuronide of zidovudine is the major metabolite in both plasma and urine, accounting for
approximately 50-80 % of the administered dose eliminated by renal excretion. 3’-amino-3’-
deoxythymidine (AMT) has been identified as a metabolite of zidovudine following intravenous
dosing.
Elimination:
The observed lamivudine 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. Studies in patients with renal impairment show lamivudine
elimination is affected by renal dysfunction. Dose reduction is required for patients with creatinine
clearance ≤50 ml/min (see section 4.2).
From studies with intravenous zidovudine, the mean terminal plasma half-life was 1.1 hours and the
mean systemic clearance was 1.6 l/h/kg. Renal clearance of zidovudine is estimated to be
0.34 l/h/kg, indicating glomerular filtration and active tubular secretion by the kidneys. Zidovudine
concentrations are increased in patients with advanced renal failure.
Pharmacokinetics in children:
In children over the age of 5-6 months, the pharmacokinetic profile of
zidovudine is similar to that in adults. Zidovudine is well absorbed from the gut and at all dose levels
studied in adults and children, the bioavailability was between 60-74 % with a mean of 65 %. Css
max
levels were 4.45 μM (1.19 μg/ml) following a dose of 120 mg zidovudine (in solution)/m
2
body
surface area and 7.7 μM (2.06 μg/ml) at 180 mg/m
2
body surface area. Dosages of 180 mg/m
2
four
times daily in children produced similar systemic exposure (24 hour AUC 40.0 h μM or 10.7 h μg/ml)
as doses of 200 mg six times daily in adults (40.7 h μM or 10.9 h μg/ml).
In six HIV-infected children from 2 to 13 years of age, zidovudine plasma pharmacokinetics were
evaluated while subjects were receiving 120 mg/m
2
zidovudine three times daily and again after
switching to 180 mg/m
2
twice daily. Systemic exposures (daily AUC and C
max
) in plasma from the
twice daily regimen appeared equivalent to those from the same total daily dose given in three divided
doses [Bergshoeff, 2004].
In general, lamivudine pharmacokinetics in paediatric patients are 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
14
30 kg) is 4 mg/kg twice a day. 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.
Pharmacokinetics in pregnancy:
The pharmacokinetics of lamivudine and zidovudine were similar to
that of non-pregnant women.
5.3 Preclinical safety data
The clinically relevant effects of lamivudine and zidovudine in combination are anaemia, neutropenia
and leucopenia.
Neither lamivudine nor zidovudine are mutagenic in bacterial tests, but like many nucleoside
analogues they show activity in
in vitro
mammalian tests such as the mouse lymphoma assay.
Lamivudine has not shown any genotoxic activity in
in vivo
studies at doses that gave plasma
concentrations up to 40-50 times higher than clinical plasma levels. Zidovudine showed clastogenic
effects in an oral repeated dose micronucleus test in mice. Peripheral blood lymphocytes from AIDS
patients receiving zidovudine treatment have also been observed to contain higher numbers of
chromosome breakages.
A pilot study has demonstrated that zidovudine is incorporated into leukocyte nuclear DNA of adults,
including pregnant women, taking zidovudine as treatment for HIV-1 infection, or for the prevention
of mother to child viral transmission. Zidovudine was also incorporated into DNA from cord blood
leukocytes of infants from zidovudine-treated mothers. 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 carcinogenic potential of a combination of lamivudine and zidovudine has not been tested.
In long-term oral carcinogenicity studies in rats and mice, lamivudine did not show any carcinogenic
potential.
In oral carcinogenicity studies with zidovudine in mice and rats, late appearing vaginal epithelial
tumours were observed. A subsequent intravaginal carcinogenicity study confirmed the hypothesis
that the vaginal tumours were the result of long term local exposure of the rodent vaginal epithelium to
high concentrations of unmetabolised zidovudine in urine. There were no other zidovudine-related
tumours observed in either sex of either species.
In addition, two transplacental carcinogenicity studies have been conducted in mice. In one study, by
the US National Cancer Institute, zidovudine was administered at maximum tolerated doses to
pregnant mice from day 12 to 18 of gestation. One year post-natally, there was an increase in the
incidence of tumours in the lung, liver and female reproductive tract of offspring exposed to the
highest dose level (420 mg/kg term body weight).
15
In a second study, mice were administered zidovudine at doses up to 40 mg/kg for 24 months, with
exposure beginning prenatally on gestation day 10. Treatment related findings were limited to late-
occurring vaginal epithelial tumours, which were seen with a similar incidence and time of onset as in
the standard oral carcinogenicity study. The second study thus provided no evidence that zidovudine
acts as a transplacental carcinogen.
It is concluded that as the increase in incidence of tumours in the first transplacental carcinogenicity
study represents a hypothetical risk, this should be balanced against the proven therapeutic benefit.
In reproductive toxicity studies lamivudine has demonstrated evidence of causing an increase in early
embryonic deaths in the rabbit at relatively low systemic exposures, comparable to those achieved in
man, but not in the rat even at very high systemic exposure. Zidovudine had a similar effect in both
species, but only at very high systemic exposures. Lamivudine was not teratogenic in animal studies.
At maternally toxic doses, zidovudine given to rats during organogenesis resulted in an increased
incidence of malformations, but no evidence of foetal abnormalities was observed at lower doses.
6.
6.1 List of excipients
Tablet core
Cellulose, microcrystalline
Sodium starch glycolate (Type A)
Sodium stearyl fumarate
Tablet film-coat
Hypromellose 3cP
Hypromellose 6cP
Polysorbate 80
Macrogol 400
Titanium dioxide E171
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
30 months
6.4 Special precautions for storage
This medicinal product does not require any special storage conditions.
6.5
Nature and contents of container
Blisters:
OPA/Alu/PVC Aluminium blisters
16
Containers:
White opaque HDPE containers with white opaque polyethylene child resistant screw cap with
Aluminium seal.
Each pack type contains 60 film-coated tablets.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
Any unused product or waste material should be disposed of in accordance with local requirements.
7.
TEVA Pharma B.V
Computerweg 10, 3542DR Utrecht,
The Netherlands
8.
9.
Detailed information on this product is available on the website of the European Medicines Agency
17
ANNEX II
A.
MANUFACTURING AUTHORISATION HOLDER(S)
RESPONSIBLE FOR BATCH RELEASE
B.
CONDITIONS OF THE MARKETING AUTHORISATION
18
A. MANUFACTURING AUTHORISATION HOLDERS RESPONSIBLE FOR BATCH
RELEASE
Name and address of the manufacturers responsible for batch release
Teva Pharmaceutical Works Private Limited Company
Pallagi út 13
Debrecen H-4042
Hungary
TEVA Pharmaceutical Works Private Limited Company
H-2100 Gödöllö
Táncsics Mihály út 82
Hungary
TEVA UK Ltd
Brampton Road
Hampden Park
Eastbourne, East Sussex
BN22 9AG UK
Pharmachemie B.V.
Swensweg 5
2031 GA Haarlem
The Netherlands
TEVA Santé SA
Rue Bellocier
89107 Sens
France
Pliva Krakow
Zaklady Farmaceutyczne S.A.
80 Mogilska St.
31-546 Krakow
Poland
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
Medicinal product subject to restricted medical prescription (See Annex I: Summary of Product
Characteristics, Section 4.2)
•
CONDITSIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE
USE OF THE MEDICINAL PRODUCT
19
Not applicable
•
OTHER CONDITIONS
Pharmacovigilance system
The MAH must ensure that the system of pharmacovigilance, presented in Module 1.8.1 of the
Marketing Authorisation, is in place and functioning before and whilst the product is on the market.
PSURs
The PSUR submission schedule should follow the PSUR submission schedule for the reference
medicinal product.
20
ANNEX III
LABELLING AND PACKAGE LEAFLET
21
A. LABELLING
22
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
OUTER CARTON – BLISTER PACK
1.
Lamivudine/Zidovudine Teva 150 mg/300 mg film-coated tablets
lamivudine/zidovudine
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each film-coated tablet contains
lamivudine 150 mg
zidovudine 300 mg
3.
LIST OF EXCIPIENTS
4.
60 film-coated tablets
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Read the package leaflet before use.
Oral use
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE 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
23
9.
SPECIAL STORAGE CONDITIONS
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
TEVA Pharma B.V
Computerweg 10, 3542DR Utrecht,
The Netherlands
EU/0/00/000/000
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Lamivudine/Zidovudine Teva
24
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
BLISTER FOIL
1.
Lamivudine/Zidovudine Teva 150 mg/300 mg film-coated tablets
lamivudine/zidovudine
2.
Teva Pharma B.V.
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
Lot
5.
OTHER
25
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
OUTER CARTON FOR THE CONTAINER
1.
Lamivudine/Zidovudine Teva 150 mg/300 mg film-coated tablets
lamivudine/zidovudine
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each film-coated tablet contains
lamivudine 150 mg
zidovudine 300 mg
3.
LIST OF EXCIPIENTS
4.
60 film-coated tablets
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Read the package leaflet before use.
Oral use
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
9.
SPECIAL STORAGE CONDITIONS
26
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
TEVA Pharma B.V
Computerweg 10, 3542DR Utrecht,
The Netherlands
EU/0/00/000/000
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Lamivudine/Zidovudine Teva
27
PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING
CONTAINERS
1.
Lamivudine/Zidovudine Teva 150 mg/300 mg film-coated tablets
lamivudine/zidovudine
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each film-coated tablet contains
lamivudine 150 mg
zidovudine 300 mg
3.
LIST OF EXCIPIENTS
4.
60 film-coated tablets
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Read the package leaflet before use.
Oral use
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
9.
SPECIAL STORAGE CONDITIONS
28
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
TEVA Pharma B.V
Computerweg 10, 3542DR Utrecht,
The Netherlands
EU/0/00/000/000
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
29
B. PACKAGE LEAFLET
30
PACKAGE LEAFLET: INFORMATION FOR THE USER
Lamivudine/Zidovudine Teva 150 mg/300 mg film-coated tablets
lamivudine/zidovudine
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. 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 Lamivudine/Zidovudine Teva is and what it is used for
2. Before you take Lamivudine/Zidovudine Teva
3. How to take Lamivudine/Zidovudine Teva
4. Possible side effects
5.
How to store Lamivudine/Zidovudine Teva
6.
Further information
1.
WHAT LAMIVUDINE/ZIDOVUDINE TEVA IS AND WHAT IT IS USED FOR
Lamivudine/Zidovudine Teva belongs to a group of antiviral medicines, also known as antiretrovirals,
called nucleoside analogue reverse transcriptase inhibitors (NRTIs). These are used to treat Human
Immunodeficiency Virus (HIV) infection.
Lamivudine/Zidovudine Teva is used in antiretroviral combination therapy for the treatment of HIV
infection in patients weighing more than 14 kg. Lamivudine/Zidovudine Teva reduces the amount of
HIV virus in your body, and keeps it at a low level. It also increases CD4 cell counts. CD4 cells are a
type of white blood cell, that play an important role in maintaining a healthy immune system to help
fight infection. Lamivudine/Zidovudine Teva has been shown to significantly reduce the risk of
disease progression. Response to treatment with Lamivudine/Zidovudine Teva varies between
patients. Your doctor will be monitoring the effectiveness of your treatment.
2.
BEFORE YOU TAKE LAMIVUDINE/ZIDOVUDINE TEVA
Do not take Lamivudine/Zidovudine Teva
-
if you are allergic (hypersensitive) to lamivudine or zidovudine or any of the other ingredients
of Lamivudine/Zidovudine Teva.
-
if you have very low red blood cell count (severe anaemia) or very low white blood cell count
(neutropenia).
If you are not sure please ask your doctor.
Take special care with Lamivudine/Zidovudine Teva
Discuss the use of Lamivudine/Zidovudine Teva with your doctor if you have kidney or liver disease
to ensure the doses of the active substances in Lamivudine/Zidovudine Teva are suitable for you.
31
It is important that your doctor knows about all your symptoms even if you think they are not related
to HIV infection. Your doctor may decide to prescribe lamivudine or zidovudine as separate medicines
instead of Lamivudine/Zidovudine Teva.
Anaemia (low red blood cell count) and neutropenia/leucopenia (low white blood cell count) may
occur within 4-6 weeks due to treatment with zidovudine, one of the active substances in
Lamivudine/Zidovudine Teva. If severe, your physician may stop treatment with
Lamivudine/Zidovudine Teva. This has occurred more commonly in patients with advanced HIV
disease and with higher doses of zidovudine than the dose in Lamivudine/Zidovudine Teva. Regular
blood tests will be arranged to check whether there is a problem with your white and red blood cell
count. This adverse reaction is infrequent in patients with early HIV disease and blood tests may be
performed less frequently.
If you take ribavirin and zidovudine together it may cause or worsen anaemia. Please contact your
doctor if you notice symptoms of anaemia (such as tiredness and shortness of breath). Your doctor
will advise you whether you should stop taking Lamivudine/Zidovudine Teva.
The class of medicines to which Combivir belongs (NRTIs) can cause a condition called lactic
acidosis, together with an enlarged liver. Lactic acidosis, if it occurs, usually develops after a few
months of treatment. Deep, rapid breathing, drowsiness, and non specific symptoms such as nausea,
vomiting and stomach pain, might indicate the development of lactic acidosis. This rare, but serious
side effect occurs more often in women, particularly if very overweight. If you have liver disease you
may also be more at risk of getting this condition. While you are being treated with
Lamivudine/Zidovudine Teva, your doctor will monitor you closely for any signs that you may be
developing lactic acidosis.
Redistribution, accumulation or loss of body fat may occur in patients receiving combination
antiretroviral therapy. Contact your doctor if you notice changes in body fat.
In some patients with advanced HIV infection (AIDS) and a history of opportunistic infection, signs
and symptoms of inflammation from previous infections may occur soon after anti-HIV treatment is
started. It is believed that these symptoms are due to an improvement in the body’s immune response,
enabling the body to fight infections that may have been present with no obvious symptoms. If you
notice any symptoms of infection, please inform your doctor immediately.
Please speak with your doctor if you have a history of liver disease. Patients with chronic hepatitis B
or C and treated with antiretroviral agents are at increased risk of severe and potentially fatal liver
adverse events and may require blood tests for monitoring of liver function.
If you have a chronic hepatitis B infection, you should not stop your treatment without instructions
from your doctor, as you may have a recurrence of your hepatitis. This recurrence may be more
severe if you have serious liver disease.
You will need to take Lamivudine/Zidovudine Teva every day. This medicine helps to control your
condition and delay disease progression, but it is not a cure for HIV infection. You may continue to
develop other infections and other illnesses associated with HIV disease. You should keep in regular
contact with your doctor. Do not stop taking your medicine without first talking to your doctor.
32
Treatment with Lamivudine/Zidovudine Teva has not been shown to reduce the risk of passing HIV
infection on to others by unprotected sexual contact or by blood transfer (for example, blood
transfusions or sharing needles). You should continue to use appropriate precautions to prevent this.
Bone problems
Some patients taking combination antiretroviral therapy may develop a bone disease called
osteonecrosis (death of bone tissue caused by loss of blood supply to the bone). The length of
combination antiretroviral therapy, corticosteroid use, alcohol consumption, severe
immunosuppression, higher body mass index, among others, may be some of the many risk factors for
developing this disease. Signs of osteonecrosis are joint stiffness, aches and pains (especially of the
hip, knee and shoulder) and difficulty in movement. If you notice any of these symptoms please
inform your doctor.
Taking other medicines
It is important that you tell your doctor about all the medicines you are taking including those you
have bought yourself. These may affect the action of Lamivudine/Zidovudine Teva, or
Lamivudine/Zidovudine Teva may affect their action. Lamivudine/Zidovudine Teva should not be
taken with high doses of co-trimoxazole, or injections of ganciclovir or foscarnet, as lamivudine, one
of the active substances in Lamivudine/Zidovudine Teva may interact with these.
Lamivudine/Zidovudine Teva should also not be taken with stavudine, as zidovudine the other active
substance in Lamivudine/Zidovudine Teva may reduce the action of this medicinal product.
Zidovudine, may also interact with the following medicines and may make any side effects worse:
Phenytoin, probenecid, rifampicin, atovaquone, valproic acid, methadone, dapsone, pentamidine,
pyrimethamine, co-trimoxazole, fluconazole, amphotericin, flucytosine, ganciclovir, interferon,
clarithromycin, vincristine, vinblastine and doxorubicin.
Pregnancy and breast-feeding
If you become pregnant, or are planning to become pregnant, you must contact your doctor to discuss
the potential adverse effects and the benefits and risks of your antiretroviral therapy to you and your
child.
If you have taken Lamivudine/Zidovudine Teva during your pregnancy, your doctor may request
regular visits to monitor the development of your child. Such visits may include blood tests and other
diagnostic tests.
In children whose mothers took nucleoside and nucleotide analogues during pregnancy, the benefit
from the reduced chance of being infected with HIV is greater than the risk of suffering from side
effects.
If you are breast-feeding please inform your doctor before taking any medicines.
Lamivudine/Zidovudine Teva is not recommended if you are breast-feeding. It is recommended that
HIV infected women do not breast-feed their infants under any circumstances in order to avoid
transmission of HIV.
Ask your doctor or pharmacist for advice before taking any medicine.
33
3.
HOW TO TAKE LAMIVUDINE/ZIDOVUDINE TEVA
Always take Lamivudine/Zidovudine Teva exactly as your doctor has told you. You should check
with your doctor or pharmacist if you are not sure. Swallow Lamivudine/Zidovudine Teva tablets
with water. The tablets can be taken with or without food.
If you cannot swallow the tablet(s), you may crush and combine them with a small amount of food or
drink and take all the dose immediately.
The usual dose of Lamivudine/Zidovudine Teva for adults and adolescents weighing at least 30 kg is
one tablet twice a day.
For children weighing between 21 kg and 30 kg the recommended oral dose of
Lamivudine/Zidovudine Teva is one-half tablet taken in the morning and one whole tablet taken in the
evening.
For children weighing 14 kg to 21 kg the recommended oral dose of Lamivudine/Zidovudine Teva is
one-half tablet taken twice daily.
Each dose of Lamivudine/Zidovudine Teva should be taken approximately 12 hours apart.
For children weighing less than 14 kg, lamivudine and zidovudine should be taken as separate
formulations according to the prescribed dosing for these products.
A liquid formulation is available for both lamivudine and zidovudine for the treatment of patients
unable to take tablets.
If your doctor wishes to reduce your dose of Lamivudine/Zidovudine Teva, for example if you have
kidney problems, then your medicine may be changed to lamivudine and zidovudine taken as separate
medicines, which are available as tablets or liquid.
If you take more Lamivudine/Zidovudine Teva than you should
Accidentally taking too much Lamivudine/Zidovudine Teva is unlikely to cause any serious problems.
However, you should tell your doctor or your pharmacist, or contact your nearest hospital emergency
department for further advice.
If you forget to take Lamivudine/Zidovudine Teva
If you forget to take a dose of Lamivudine/Zidovudine Teva, take is as soon as you remember and then
continue as before.
Do not take a double dose to make up for a forgotten dose.
If you have any further questions on the use of this product, ask your doctor or pharmacist.
4.
POSSIBLE SIDE EFFECTS
Like all medicines, Lamivudine/Zidovudine Teva can cause side effects, although not everybody gets
them.
34
When treating HIV infection, it is not always possible to tell whether some of the undesirable effects
that occur are caused by Lamivudine/Zidovudine Teva, by other medicines you are taking at the same
time or by the HIV disease. For this reason it is very important that you inform your doctor about any
changes in your health. Combination antiretroviral therapy may cause changes in body shape due to
changes in fat distribution. These may include loss of fat from legs, arms and face, increased fat in the
abdomen (belly), and other internal organs, breast enlargement and fatty lumps on the back of the neck
(‘buffalo hump’). The cause and long-term health effects of these conditions are not known at this
time.
Combination antiretroviral therapy may also cause raised lactic acid and sugar in the blood,
hyperlipaemia (increased fats in the blood) and resistance to insulin.
Very common side effects (affect more than 1 user in 10)
Headache and nausea.
Common side effects (affects 1 to 10 users in 100)
Vomiting, stomach pain, diarrhoea, increase in certain liver enzymes, joint pain, muscle pain and other
muscle disorders, dizziness, tiredness, difficulty sleeping, hair loss, anaemia (low red blood cell count)
and neutropenia (low white blood cell count). If the number of red blood cells is reduced you may
have symptoms of tiredness or breathlessness and a reduction in your white blood cell count can make
you more prone to infection.
Uncommon side effects (affects 1 to 10 users in 1,000)
Flatulence, breathlessness, rash (red, raised or itchy), fever, general aches and pains and reduction in
platelets (blood cells important for blood clotting). If you have a low platelet count you may notice
that you bruise more easily.
Rare side effects (affects 1 to 10 users in 10,000)
Cough, nasal symptoms, patchy colour changes inside the mouth, heartburn, chest pain (possibly
indicating a heart muscle disease called cardiomyopathy), breakdown of muscle tissue, liver disorders
such as enlarged liver, fatty liver, inflammation of the liver (hepatitis), inflammation of the pancreas,
nail and skin colour changes, sweating, flu-like feeling, drowsiness, passing urine more frequently,
breast enlargement in male patients, chills, loss of appetite, taste changes, tingling in the limbs,
seizures, inability to concentrate, depression and feeling anxious, increase of lactic acid in the body
known as lactic acidosis (see Take special care with Lamivudine/Zidovudine Teva).
While many of the side effects that have been reported occur with both lamivudine and zidovudine
when given as separate medicines, some are more likely to occur with one of the medicines only.
Your doctor may decide that you need to stop taking Lamivudine/Zidovudine Teva and take
lamivudine and zidovudine separately. This will allow your doctor to vary the dose or stop one of the
active substances if it is considered that this will help manage any side effects.
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.
35
5.
HOW TO STORE LAMIVUDINE/ZIDOVUDINE TEVA
Keep out of the reach and sight of children.
Do not use Lamivudine/Zidovudine Teva after the expiry date which is stated on the blister or
container. The expiry date refers to the last day of that month.
This medicinal product does not require any special storage conditions.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to
dispose of medicines no longer required. These measures will help to protect the environment.
6.
FURTHER INFORMATION
What Lamivudine/Zidovudine Teva contains
-
The active substances are lamivudine 150 mg and zidovudine 300 mg.
-
The other ingredients are: Tablet core: Cellulose microcrystalline, sodium starch glycolate
(Type A), sodium stearyl fumarate. Tablet film-coat: Hypromellose 3cP, hypromellose 6cP,
polysorbate 80, macrogol 400, titanium dioxide E171.
What Lamivudine/Zidovudine Teva looks like and contents of the pack
White, capsule shaped, biconvex, film-coated scored tablet – engraved with “L/Z” on one side and
“150/300” on the other side.
The tablet is a breakable tablet.
Lamivudine/Zidovudine Teva is available in aluminium blisters or HDPE containers containing 60
tablets.
Marketing Authorisation Holder and Manufacturer
Marketing Autnorisation Holder
TEVA Pharma B.V.
Computerweg 10, 3542DR Utrecht,
The Netherlands
Manufacturer
Teva Pharmaceutical Works Private Limited Company
Pallagi út 13
Debrecen H-4042
Hungary
TEVA Pharmaceutical Works Private Limited Company
H-2100 Gödöllö
Táncsics Mihály út 82
36
Hungary
TEVA UK Ltd
Brampton Road
Hampden Park
Eastbourne, East Sussex
BN22 9AG UK
Pharmachemie B.V.
Swensweg 5
2031 GA Haarlem
The Netherlands
TEVA Santé SA
Rue Bellocier
89107 Sens
France
Pliva Krakow
Zaklady Farmaceutyczne S.A.
80 Mogilska St.
31-546 Krakow
Poland
For any information about this medicine, please contact the local representative of the Marketing
Authorisation Holder:
België/Belgique/Belgien
Teva Pharma Belgium N.V./S.A.
Tel/Tél: +32 3 820 73 73
Luxembourg/Luxemburg
Teva Pharma Belgium S.A.
Tél: +32 3 820 73 73
България
Тева Фармасютикълс България ЕООД
Teл: +359 2 489 95 82
Magyarország
Teva Magyarország Zrt
Tel.: +36 1 288 64 00
Česká republika
Teva Pharmaceuticals CR, s.r.o.
Tel: +420 251 007 111
Malta
Teva Ελλάς Α.Ε.
Τel: +30 210 72 79 099
Danmark
Teva Denmark A/S
Tlf: +45 44 98 55 11
Nederland
Teva Nederland B.V.
Tel: +31 (0) 800 0228400
Deutschland
Teva GmbH
Tel: (49) 351 834 0
Norge
Teva Sweden AB
Tlf: (46) 42 12 11 00
Eesti
Teva Eesti esindus UAB Sicor Biotech
Österreich
ratiopharm Arzneimittel Vertriebs-GmbH
37
Eesti filiaal
Tel: +372 611 2409
Tel: +43 1 97007
Ελλάδα
Teva Ελλάς Α.Ε.
Τηλ: +30 210 72 79 099
Polska
Teva Pharmaceuticals Polska Sp. z o.o.
Tel.: +(48) 22 345 93 00
España
Teva Pharma, S.L.U
Tél: +(34) 91 387 32 80
Portugal
Teva Pharma - Produtos Farmacêuticos Lda
Tel: (351) 214 235 910
France
Teva Santé
Tél: +(33) 1 55 91 7800
România
Teva Pharmaceuticals S.R.L
Tel: +4021 212 08 90
Ireland
Teva Pharmaceuticals Ireland
Tel: +353 (0)42 9395 892
Slovenija
Pliva Ljubljana d.o.o.
Tel: +386 1 58 90 390
Ísland
Teva UK Limited
Sími: +(44) 1323 501 111.
Slovenská republika
Teva Pharmaceuticals Slovakia s.r.o.
Tel: +(421) 2 5726 7911
Italia
Teva Italia S.r.l.
Tel: +(39) 0289179805
Suomi/Finland
Teva Sweden AB
Puh/Tel: +(46) 42 12 11 00
Κύπρος
Teva Ελλάς Α.Ε.
Τηλ: +30 210 72 79 099
Sverige
Teva Sweden AB
Tel: +(46) 42 12 11 00
Latvija
UAB Sicor Biotech filiāle Latvijā
Tel: +371 67 784 980
United Kingdom
Teva UK Limited
Tel: +(44) 1323 501 111
Lietuva
UAB “Sicor Biotech”
Tel: +370 5 266 02 03
This leaflet was last approved in
{MM/YYYY}.
Detailed information on this medicine is available on the European Medicines Agency web site:
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39
Source: European Medicines Agency
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