ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
Combivir 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 to off-white, capsule-shaped film-coated scored tablets engraved with “GXFC3” on both sides.
4.
Combivir 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.
Combivir 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 dose of Combivir is one tablet twice
daily.
Children weighing between 21 kg and 30 kg:
the recommended oral dose of COMBIVIR 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 COMBIVIR 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
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.
Combivir 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.
2
For situations where discontinuation of therapy with one of the active substances of Combivir, 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 Combivir
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). Combivir is therefore contra-
indicated in these patients (see section 4.4).
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 Combivir.
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 Combivir 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
Combivir, 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.
3
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 Combivir. 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 Combivir, 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
9
/l (see
section 4.2). As dosage adjustment of Combivir is not possible separate preparations of zidovudine
and lamivudine should be used. Physicians should refer to the individual prescribing information for
these medicinal products.
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 Combivir
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 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.
4
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
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 Zeffix 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 Combivir 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 Combivir contains lamivudine and zidovudine, any interactions that have been identified with these
agents individually may occur with Combivir. 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.
5
Lamivudine and zidovudine metabolism do not involve CYP3A, making interactions with medicinal
products metabolised by this system (e.g. PIs) unlikely.
Interactions relevant to lamivudine
The possibility of interactions with other medicinal products administered concurrently with Combivir
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 Combivir 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 Combivir 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 Combivir should be avoided (see section 4.4).
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).
6
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 Combivir 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 Combivir 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 co-
trimoxazole (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 Combivir 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 Combivir 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 Combivir during pregnancy should only be considered if expected benefits outweigh
any possible risks.
Pregnant women considering using Combivir 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 Combivir 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.
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
7
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 Combivir 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
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
Rare:
Angioedema
8
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:
Thrombocyopenia 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
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
9
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.
There is limited experience of overdosage with Combivir. 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. Additionally,
lamivudine has activity against hepatitis B virus (HBV). 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
;
lamivudine 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
10
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 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. 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 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
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. These thymidine analogue mutations alone do not cause high-level cross-resistance
to any of the other nucleosides, allowing for the subsequent use of any of the other approved reverse
transcriptase inhibitors.
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.
Lamivudine and zidovudine have been widely used as components 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.
Evidence from clinical studies shows that lamivudine plus zidovudine delays the emergence of
zidovudine resistant isolates in individuals with no prior antiretroviral therapy. 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).
11
The relationship between
in vitro
susceptibility of HIV to lamivudine and zidovudine and clinical
response to lamivudine/zidovudine 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.
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 Combivir 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. Combivir
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 Combivir 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 Combivir with food were similar when compared to fasting
subjects, although the rates of absorption (C
max,
t
max
) were slowed. Based on these data Combivir 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 physiochemical and pharmacokinetic data
assuming that the patient crushes and transfers 100% of the tablet and ingests immediately.
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 Combivir.
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
12
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
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 or
al 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-
13
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).
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
:
Microcrystalline cellulose (E460),
sodium starch glycollate,
colloidal silicon dioxide,
magnesium stearate
Tablet film coat:
Hypromellose (E464),
titanium dioxide (E171),
macrogol 400,
polysorbate 80
14
6.2 Incompatibilities
Not applicable
6.3 Shelf-life
2 years
6.4 Special precautions for storage
Do not store above 30°C
6.5 Nature and content of container
Tamper-evident cartons containing opaque polyvinyl chloride/foil blister packs or white high density
polyethylene (HDPE) bottle with a child-resistant closure. Each pack type contains 60 film-coated
tablets.
6.6
Special precautions for disposal
No special requirements
Any unused product or waste material should be disposed of in accordance with local requirements.
7.
ViiV Healthcare UK Limited
980 Great West Road
Brentford
Middlesex
TW8 9GS
United Kingdom
8.
EU/1/98/058/001
EU/1/98/058/002
9.
18 March 2003
MM/YYYY
Detailed information on this medicinal product is available on the website of the European Medicines
Agency
http://www.ema.europa.eu
15
ANNEX II
A.
MANUFACTURING AUTHORISATION HOLDER(S)
RESPONSIBLE FOR BATCH RELEASE
B.
CONDITIONS OF THE MARKETING AUTHORISATION
16
A. MANUFACTURING AUTHORISATION HOLDER(S) RESPONSIBLE FOR BATCH
RELEASE
Name and address of the manufacturer(s) responsible for batch release
Glaxo Operations U.K 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
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, 4.2)
•
CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE
USE OF THE MEDICINAL PRODUCT
Not applicable.
•
OTHER CONDITIONS
Pharmacovigilance System
The MAH must ensure that the system of pharmacovigilance, as described in version 7.2 presented in
Module 1.8.1. of the Marketing Authorisation Application, is in place and functioning before and
whilst the product is on the market.
Risk Management Plan
The MAH commits to performing the studies and additional pharmacovigilance activities detailed in
the Pharmacovigilance Plan, as agreed in version 01 of the Risk Management Plan (RMP) presented in
Module 1.8.2. of the Marketing Authorisation Application and any subsequent updates of the RMP
agreed by the CHMP.
As per the CHMP Guideline on Risk Management Systems for medicinal products for human use, the
updated RMP should be submitted at the same time as the next Periodic Safety Update Report
(PSUR).
In addition, an updated RMP should be submitted:
When new information is received that may impact on the current Safety Specification,
Pharmacovigilance Plan or risk minimisation activities.
17
Within 60 days of an important (pharmacovigilance or risk minimisation) milestone being reached.
At the request of the EMA.
18
ANNEX III
LABELLING AND PACKAGE LEAFLET
19
A. LABELLING
20
PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE
PACKAGING
OUTER CARTON
1.
Combivir 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
Scored 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
Do not store above 30°C
21
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/1/98/058/002
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
combivir
22
PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE
PACKAGING
BOTTLE LABEL
1.
Combivir 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
Scored tablet
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
Do not store above 30°C
23
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/1/98/058/002
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
24
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
BLISTER PACK OUTER CARTON
1.
Combivir 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
Scored 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
Do not store above 30°C
25
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/1/98/058/001
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
combivir
26
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
1.
Combivir 150 mg/300 mg film-coated tablets
Lamivudine/zidovudine
2.
ViiV Healthcare UK Limited
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
Lot
5. OTHER
27
B. PACKAGE LEAFLET
28
PACKAGE LEAFLET: INFORMATION FOR THE USER
Combivir 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 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 Combivir is and what it is used for
2.
Before you take Combivir
3.
How to take Combivir
5.
How to store Combivir
6.
Further information
1.
What Combivir is and what it is used for
Combivir is used to treat HIV (human immunodeficiency virus) infection in adults and children.
Combivir contains two active ingredients that are used to treat HIV infection: lamivudine and
zidovudine. Both of these belong to a group of anti-retroviral medicines called
nucleoside analogue
reverse transcriptase inhibitors
(
NRTIs
)
.
Combivir 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 Combivir in the same way. Your doctor will monitor the
effectiveness of your treatment.
2.
Before you take Combivir
Don’t take Combivir:
•
if you’re
allergic
(
hypersensitive
) to lamivudine or zidovudine, or any of the other ingredients of
Combivir tablets
(
listed in section 6
)
•
if you have
a very low red blood cell count
(
anaemia
)
or
a
very low white blood cell count
(
neutropenia
).
Check with your doctor
if you think any of these apply to you.
Take special care with Combivir
Some people taking Combivir or other combination treatments for HIV are more at risk of serious side
effects. You need to be aware of the extra risks:
29
4.
Possible side effects
•
if you have ever had
liver disease,
including hepatitis B or C (if you have hepatitis B
infection, don’t stop Combivir without your doctor’s advice, as your hepatitis may come back)
•
if you have
kidney disease
•
if you are seriously
overweight
(especially if you’re a woman)
•
if you’re
diabetic
and using insulin.
Talk to your doctor if any of these apply to you.
Your doctor will decide if the active
substances are suitable for 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 Combivir.
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). Combivir 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 Combivir
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
Combivir.
These medicines should not be used with Combivir:
•
stavudine or zalcitabine,
to treat
HIV infection
•
ribavirin, or injections of ganciclovir or foscarnet
to treat
viral infections
•
high doses of
co-trimoxazole
,
an antibiotic.
Tell your doctor
if you’re being treated with any of these.
Some medicines can make it more likely that you’ll have side effects, or make side effects worse.
These include:
•
sodium valproate,
to treat
epilepsy
•
interferon,
to treat
viral infections
•
pyrimethamine, to treat
malaria
and other parasitic infections
•
dapsone,
to prevent
pneumonia
and treat skin infections
•
fluconazole or flucytosine
,
to treat
fungal infections
such as
candida
•
pentamidine or atovaquone
to treat parasitic infections such as
PCP
•
amphotericin or co-trimoxazole,
to treat
fungal and bacterial infections
•
probenecid,
to treat
gout
and similar conditions, and given with some antibiotics to make them
more effective
•
methadone,
used as a
heroin substitute
•
vincristine, vinblastine or doxorubicin
,
to treat
cancer.
Tell your doctor
if you’re taking any of these.
Some medicines interact with Combivir
These include:
•
clarithromycin,
an antibiotic
30
if you’re taking clarithromycin, take your dose at least 2 hours before or after you take your
Combivir.
•
phenytoin
, for treating
epilepsy.
Tell your doctor
if you’re taking phenytoin. Your doctor may need to monitor you while you’re
taking Combivir.
Pregnancy
If you are pregnant, if you become pregnant or if you are planning to become pregnant talk to your
doctor about the risks and benefits to you and your baby of taking Combivir.
Combivir and similar medicines may cause side effects in unborn babies. If you become pregnant
while you’re taking Combivir, 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 Combivir) 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
Combivir can make you dizzy
and have other side effects that make you less alert.
Don’t drive or operate machines
unless you’re feeling well.
3.
How to take Combivir
Always take Combivir exactly as your doctor has told you to.
Check with your doctor or
pharmacist if you’re not sure.
Swallow Combivir tablets, with some water. Combivir 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
Combivir 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 Combivir
without your doctor’s advice.
How much to take
Adults and adolescents 30 kg or more
The usual dose of Combivir is one tablet twice a day.
Take the tablets at regular times, leaving approximately 12 hours between each tablet.
Children who weigh between 21 and 30 kg
31
The usual starting dose of Combivir is one half tablet (½) taken in the morning and one whole tablet
taken in the evening.
Children who weigh between 14 and 21 kg
The usual starting dose of Combivir is one half tablet (½) taken in the morning and one half tablet (½)
taken in the evening.
For children who weigh less than 14 kg lamivudine and zidovudine (the ingredients of Combivir)
should be taken separately.
If you take too much Combivir
If you accidentally take too much Combivir, tell your doctor or your pharmacist, or contact your
nearest hospital emergency department for further advice.
If you forget to take Combivir
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, Combivir 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
Combivir or other medicines you’re 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 Combivir,
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’.
Very common side effects
These may affect
more than than 1 in 10
people:
•
headache
•
feeling sick (
nausea
).
Common side effects
These may affect
up to 1 in 10
people:
•
being sick (
vomiting
)
•
diarrhoea
•
stomach pains
•
loss of appetite
•
feeling dizzy
•
tiredness, lack of energy
•
fever (high temperature)
•
general feeling of being unwell
•
difficulty in sleeping (
insomnia
)
•
muscle pain and discomfort
•
joint pain
•
cough
•
irritated or runny nose
•
skin rash
•
hair loss (
alopecia
).
32
Common side effects that might show up in blood tests are:
•
a low red blood cell count (
anaemia
) or low white blood cell count (
neutropenia
or
leucopenia
)
•
an increase in the level of liver enzymes
•
an increased amount in the blood of
bilirubin
(a substance produced in the liver) which may make
your skin appear yellow.
Uncommon side effects
These may affect
up to 1 in 100
people:
•
feeling breathless
•
wind (
flatulence
)
•
itching
•
muscle weakness.
An uncommon side effect that may show up in blood test is:
•
a decrease in the number of cells involved in blood clotting (
thrombocytopenia
)
or in all kinds of
blood cells (
pancytopenia
).
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
•
liver disorders, such as jaundice, enlarged liver or fatty liver, inflammation (
hepatitis
)
•
lactic acidosis (
see the next section, ‘Other possible side effects of combination therapy for
HIV’
)
•
inflammation of the pancreas (
pancreatitis
)
•
chest pain; disease of the heart muscle (
cardiomyopathy
)
•
fits (
convulsions
)
•
feeling depressed or anxious, not being able to concentrate, feeling drowsy
•
indigestion, taste disturbance
•
changes in the colour of your nails, your skin or the skin inside your mouth
•
a flu-like feeling – chills and sweating
•
tingly feelings in the skin (pins and needles)
•
sensation of weakness in the limbs
•
breakdown of muscle tissue
•
numbness
•
passing urine more often
•
enlarged breasts in men.
Rare side effects that may show up in blood tests are:
•
an increase in an enzyme called amylase
•
a failure of the bone marrow to produce new red blood cells (
pure red cell aplasia
).
Very rare side effects
These may affect
up to 1 in 10,000 people:
A very rare side effect that may show up in blood tests is:
•
a failure of the bone marrow to produce new red or white blood cells (
aplastic anaemia
).
If you get side effects
Tell your doctor or pharmacist
if any of the side effects get 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 Combivir may cause other conditions to develop during HIV treatment.
33
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 Combivir:
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 Combivir, 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
34
•
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 Combivir
Keep Combivir out of the reach and sight of children.
Do not take Combivir after the expiry date shown on the carton.
Do not store above 30
o
C.
If you have any unwanted Combivir 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 Combivir contains
The active substances are lamivudine and zidovudine.The other ingredients are
•
tablet core;
microcrystalline cellulose, sodium starch glycollate (gluten free), magnesium
stearate, colloidal silicon dioxide
•
tablet film-coat;
hypromellose, titanium dioxide, macrogol 400 and polysorbate 80.
What Combivir looks like and contents of the pack
Combivir
film-coated tablets are provided in tamper evident blister packs containing 60 tablets. They
are white to off-white, capsule-shaped scored tablets marked with the code GXFC3 on both sides.
35
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
36
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
www.gsk.ro
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
37
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 last approved in
Detailed information on this medicine is available on the European Medicines Agency web site:
http://www.ema.europa.eu
38
Source: European Medicines Agency
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