Combivir

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ANNEX I

SUMMARY OF PRODUCT CHARACTERISTICS



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1. NAME OF THE MEDICINAL PRODUCT

Combivir 150 mg/300 mg film-coated tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains 150 mg lamivudine and 300 mg zidovudine.

For the full list of excipients see section 6.1.

3. PHARMACEUTICAL FORM

Film-coated tablet

White to off-white, capsule-shaped film-coated scored tablets engraved with “GXFC3” on both sides. 

4. CLINICAL PARTICULARS

4.1 Therapeutic indications 

Combivir is indicated in antiretroviral combination therapy for the treatment of Human 
Immunodeficiency Virus (HIV) infection (see section 4.2).

4.2 Posology and method of administration

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 cannot 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.



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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 109/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.

4.3 Contraindications

Hypersensitivity to the active substances or to any of the excipients listed in section 6.1.

Zidovudine is contraindicated in patients with abnormally low neutrophil counts (<0.75 x 109/l), or 
abnormally low haemoglobin levels (<7.5 g/dl or 4.65 mmol/l).  Combivir is therefore contraindicated 
in these patients (see section 4.4).

4.4 Special warnings and precautions for use

While effective viral suppression with antiretroviral therapy has been proven to substantially reduce 
the risk of sexual transmission, a residual risk cannot be excluded.  Precautions to prevent 
transmission should be taken in accordance with national guidelines.

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.



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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 109/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 zidovudine.  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 zidovudine 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 zidovudine 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 following exposure in utero: Nucleoside and nucleotide analogues may 
impact mitochondrial function to a variable degree, which is most pronounced with stavudine, 
didanosine and zidovudine. There have been reports of mitochondrial dysfunction in HIV-negative 
infants exposed in utero and/or post-natally to nucleoside analogues; these have predominantly 
concerned treatment with regimens containing zidovudine.  The main adverse reactions reported are 
haematological disorders (anaemia, neutropenia) and metabolic disorders (hyperlactatemia, 
hyperlipasemia).  These events have often been transitory.  Late-onset neurological disorders have 
been reported rarely (hypertonia, convulsion, abnormal behaviour).  Whether such neurological 
disorders are transient or permanent is currently unknown. These findings should be considered for
any child exposed in utero to nucleoside and nucleotide analogues, who presents with severe clinical 
findings of unknown etiology particularly neurologic findings.  These findings do not affect current 
national recommendations to use antiretroviral therapy in pregnant women to prevent vertical 
transmission of HIV.



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Lipoatrophy: Treatment with zidovudine has been associated with loss of subcutaneous fat, which has 
been linked to mitochondrial toxicity. The incidence and severity of lipoatrophy are related to 
cumulative exposure. This fat loss, which is most evident in the face, limbs and buttocks, may not be 
reversible when switching to a zidovudine-free regimen. Patients should be regularly assessed for 
signs of lipoatrophy during therapy with zidovudine and zidovudine-containing products (Combivir 
and Trizivir). Therapy should be switched to an alternative regimen if there is suspicion of lipoatrophy 
development.

Weight and metabolic parameters: An increase in weight and in levels of blood lipids and glucose 
may occur during antiretroviral therapy. Such changes may in part be linked to disease control and life 
style. For lipids, there is in some cases evidence for a treatment effect, while for weight gain there is 
no strong evidence relating this to any particular treatment. For monitoring of blood lipids and glucose 
reference is made to established HIV treatment guidelines. Lipid disorders should be managed as 
clinically appropriate.

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 jirovecii pneumonia (often referred to as PCP).  
Any inflammatory symptoms should be evaluated and treatment instituted when necessary.
Autoimmune disorders (such as Graves’ disease and autoimmune hepatitis) have also been reported to 
occur in the setting of immune reactivation; however, the reported time to onset is more variable and
these events can occur many months after initiation of treatment.

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 SmPC.

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.



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Combivir should not be taken with any other medicinal products containing lamivudine or medicinal 
products containing emtricitabine.

The combination of lamivudine with cladribine is not recommended (see section 4.5).

4.5 Interaction with other medicinal products and other forms of interaction

Combivir contains lamivudine and zidovudine, therefore any interactions identified for these 
individually are relevant to Combivir. Clinical studies have shown that there are no clinically 
significant interactions between lamivudine and zidovudine.

Zidovudine is primarily metabolised by UGT enzymes; co-administration of inducers or inhibitors of 
UGT enzymes could alter zidovudine exposure. Lamivudine is cleared renally. Active renal secretion 
of lamivudine in the urine is mediated through organic cation transporters (OCTs); co-administration 
of lamivudine with OCT inhibitors or nephrotoxic drugs may increase lamivudine exposure.

Lamivudine and zidovudine are not significantly metabolised by cytochrome P450 enzymes (such as 
CYP 3A4, CYP 2C9 or CYP 2D6) nor do they inhibit or induce this enzyme system. Therefore, there 
is little potential for interactions with antiretroviral protease inhibitors, non-nucleosides and other 
medicinal products metabolised by major P450 enzymes.

Interaction studies have only been performed in adults.  The list below should not be considered 
exhaustive but is representative of the classes studied.

Drugs by Therapeutic Area Interaction
Geometric mean change (%)
(Possible mechanism)

Recommendation 
concerning co-
administration

ANTIRETROVIRAL MEDICINAL PRODUCTS
Didanosine/Lamivudine Interaction not studied. No dosage adjustment 

necessary.
Didanosine /Zidovudine Interaction not studied.
Stavudine/Lamivudine Interaction not studied. Combination not 

recommended.Stavudine/Zidovudine In vitro antagonism of anti-HIV 
activity between stavudine and 
zidovudine could result in 
decreased efficacy of both 
drugs.

ANTI-INFECTIVE PRODUCTS
Atovaquone/Lamivudine Interaction not studied. As only limited data available 

the clinical significance is 
unknown.

Atovaquone/Zidovudine
(750 mg twice daily with 

food/200 mg thrice daily)

Zidovudine AUC 33%
Atovaquone AUC 

Clarithromycin/Lamivudine Interaction not studied. Separate administration of  
Combivir and clarithromycin 
by at least 2 hours

Clarithromycin/Zidovudine
(500 mg twice daily/100 mg 
every 4 hours)

Zidovudine AUC 12%

Trimethoprim/sulfamethoxazole
(Co-trimoxazole)/Lamivudine
(160 mg/800 mg once daily for 
5 days/300 mg single dose)

Lamivudine: AUC 40%

Trimethoprim: AUC 
Sulfamethoxazole: AUC 

(organic cation transporter 
inhibition)

No Combivir dosage 
adjustment necessary, unless 
patient has renal impairment 
(See Section 4.2).

When concomitant 
administration with co-
trimoxazole is warranted, 
patients should be monitored 

Trimethoprim/sulfamethoxazole 
(Co-trimoxazole)/Zidovudine

Interaction not studied.



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clinically.  High doses of 
trimethoprim/ 
sulfamethoxazole for the 
treatment of Pneumocystis 
jirovecii pneumonia (PCP) 
and toxoplasmosis have not 
been studied and should be 
avoided.

ANTIFUNGALS
Fluconazole/Lamivudine Interaction not studied. As only limited data are 

available the clinical 
significance is not known.  
Monitor for signs of 
zidovudine toxicity (see 
section 4.8).

Fluconazole/Zidovudine
(400 mg once daily/200 mg 
thrice daily)

Zidovudine AUC 74%

(UGT inhibition)

ANTIMYCOBACTERIALS
Rifampicin/Lamivudine Interaction not studied. Insufficient data to 

recommend dosage 
adjustment.

Rifampicin/Zidovudine (600
mg once daily/200 mg thrice 
daily)

Zidovudine AUC 48%

(UGT induction)
ANTICONVULSANTS
Phenobarbital/Lamivudine Interaction not studied. Insufficient data to 

recommend dosage 
adjustment.

Phenobarbital/Zidovudine Interaction not studied.

Potential to slightly decrease 
zidovudine plasma 
concentrations through UGT 
induction.

Phenytoin/Lamivudine Interaction not studied. Monitor phenytoin 
concentrations.Phenytoin/Zidovudine Phenytoin AUC 

Valproic acid/Lamivudine Interaction not studied. As only limited data are 
available the clinical 
significance is not known.
Monitor for signs of 
zidovudine toxicity (see 
section 4.8).

Valproic acid/Zidovudine
(250 mg or 500 mg thrice 
daily/100 mg thrice daily)

Zidovudine AUC 80%

(UGT inhibition)

ANTIHISTAMINES (HISTAMINE H1 RECEPTOR ANTAGONISTS)
Ranitidine/Lamivudine Interaction not studied.

Clinically significant 
interaction unlikely.  Ranitidine 
eliminated only in part by renal 
organic cation transport system.

No dosage adjustment 
necessary.

Ranitidine/Zidovudine Interaction not studied
Cimetidine/Lamivudine Interaction not studied.

Clinically significant 
interaction unlikely.  
Cimetidine eliminated only in 
part by renal organic cation 
transport system.

No dosage adjustment 
necessary.

Cimetidine/Zidovudine Interaction not studied.
CYTOTOXICS
Cladribine/Lamivudine Interaction not studied Therefore the concomitant use 

of lamivudine with cladribine 
is not recommended



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Abbreviations:  = Increase; =decrease; = no significant change; AUC=area under the 
concentration versus time curve; Cmax=maximum observed concentration; CL/F=apparent oral 
clearance

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.

In vitro lamivudine inhibits the 
intracellular phosphorylation of 
cladribine leading to a potential 
risk of cladribine loss of 
efficacy in case of combination 
in the clinical setting. Some 
clinical findings also support a 
possible interaction between 
lamivudine and cladribine

(see section 4.4)

OPIOIDS
Methadone/Lamivudine Interaction not studied. As only limited data are 

available the clinical 
significance is not known.  
Monitor for signs of 
zidovudine toxicity (see 
section 4.8).

Methadone dosage adjustment 
unlikely in majority of 
patients; occasionally 
methadone re-titration may be 
required.

Methadone/Zidovudine
(30 to 90 mg once daily/200 mg 
every 4 hours)

Zidovudine AUC 43%
Methadone AUC 

URICOSURIC
Probenecid/Lamivudine Interaction not studied. As only limited data are 

available the clinical 
significance is not known.  
Monitor for signs of 
zidovudine toxicity (see 
section 4.8).

Probenecid/Zidovudine
(500 mg four times 
daily/2mg/kg thrice daily)

Zidovudine AUC 106%

(UGT inhibition)

MISCELLANEOUS
Sorbitol solution (3.2g , 10.2 g, 
13.4 g)/ Lamivudine

Single dose lamivudine oral 
solution 300 mg 

Lamivudine:

AUC  14%; 32%; 36% 

Cmax  28%; 52%, 55%.

When possible, avoid chronic 
coadministration of Combivir 
with medicinal products 
containing sorbitol or other 
osmotic acting poly-alcohols 
or monosaccharide alcohols 
(e.g. xylitol, mannitol, lactitol, 
maltitol). Consider more 
frequent monitoring of HIV-1 
viral load when chronic 
coadministration cannot be 
avoided.



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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.
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.

4.6 Fertility, pregnancy and lactation
Pregnancy

As a general rule, when deciding to use antiretroviral agents for the treatment of HIV infection in 
pregnant women and consequently for reducing the risk of HIV vertical transmission to the newborn, 
the animal data as well as the clinical experience in pregnant women should be taken into account. In 
the present case, the use in pregnant women of zidovudine, with subsequent treatment of the newborn 
infants, has been shown to reduce the rate of maternal-foetal transmission of HIV.  A large amount of 
data on pregnant women taking lamivudine or zidovudine indicate no malformative toxicity (more 
than 3000 outcomes from first trimester exposure each, of which over 2000 outcomes involved 
exposure to both lamivudine and zidovudine). The malformative risk is unlikely in humans based on 
the mentioned large amount of data.

The active ingredients of Combivir may inhibit cellular DNA replication and zidovudine has been 
shown to be transplacental carcinogen in one animal study (see section 5.3). The clinical relevance of 
these findings is unknown.

For patients co-infected with hepatitis who are being treated with lamivudine containing medicinal 
products such as Combivir and subsequently become pregnant, consideration should be given to the 
possibility of a recurrence of hepatitis on discontinuation of lamivudine.

Mitochondrial dysfunction: nucleoside and nucleotide analogues have been demonstrated in vitro and 
in vivo to cause a variable degree of mitochondrial damage. There have been reports of mitochondrial 
dysfunction in HIV-negative infants exposed in utero and/or post-natally to nucleoside analogues (see 
section 4.4).

Breast-feeding

Both lamivudine and zidovudine are excreted in breast milk at similar concentrations to those found in 
serum.  

Based on more than 200 mother/child pairs treated for HIV, serum concentrations of lamivudine in 
breastfed infants of mothers treated for HIV are very low (< 4% of maternal serum concentrations) and 
progressively decrease to undetectable levels when breastfed infants reach 24 weeks of age. There are 
no data available on the safety of lamivudine when administered to babies less than three months old.

After administration of a single dose of 200 mg zidovudine to HIV-infected women, the mean 
concentration of zidovudine was similar in human milk and serum.

It is recommended that mothers infected by HIV do not breast-feed their infants under any 
circumstances in order to avoid transmission of HIV.

Fertility

Neither zidovudine nor lamivudine have shown evidence of impairment of fertility in studies in male 
and female rats. There are no data on their affect on human female fertility. 



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In men zidovudine has not been shown to affect sperm count, morphology or motility.

4.7 Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been performed.

4.8 Undesirable effects

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 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 zidovudine (see section 4.4).

Treatment with zidovudine has been associated with loss of subcutaneous fat which is most evident in 
the face, limbs and buttocks.  Patients receiving Combivir should be frequently examined and 
questioned for signs of lipoatrophy. When such development is found, treatment with Combivir should 
not be continued (see section 4.4).

Weight and levels of blood lipids and glucose may increase during antiretroviral therapy (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. Autoimmune disorders (such as Graves’ disease and autoimmune hepatitis) 
have also been reported to occur in the setting of immune reactivation; however, the reported time to 
onset is more variable and these events can occur many months after initiation of treatment (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

Metabolism and nutrition disorders
Very Rare: Lactic acidosis



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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

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/mm3 (see section 4.4).

The incidence of neutropenia was also increased in those patients whose neutrophil counts, 
haemoglobin levels and serum vitamin B12 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



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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.

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system
listed in Appendix V.

4.9 Overdose

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.



13

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. PHARMACOLOGICAL PROPERTIES

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.  No 
antagonistic effects in vitro were seen with lamivudine and other antiretrovirals (tested agents: 
abacavir, didanosine and nevirapine). No antagonistic effects in vitro were seen with zidovudine and 
other antiretrovirals (tested agents: abacavir, didanosine and interferon-alpha).

HIV-1 resistance to lamivudine involves the development of a M184V amino acid change close to the 
active site of the viral reverse transcriptase (RT).  This variant arises both in vitro and in HIV-1 
infected patients treated with lamivudine-containing antiretroviral therapy.  M184V mutants display 
greatly reduced susceptibility to lamivudine and show diminished viral replicative capacity in vitro. In 
vitro studies indicate that zidovudine-resistant virus isolates can become zidovudine sensitive when 
they simultaneously acquire resistance to lamivudine.  The clinical relevance of such findings remains, 
however, not well defined.

In vitro data tend to suggest that the continuation of lamivudine in antiretroviral regimen despite the 
development of M184V might provide residual antiretroviral 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; 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 



14

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).

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 Cmax 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 tmax 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 



15

subjects, although the rates of absorption (Cmax, tmax) 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.

Biotransformation

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%. Cssmax
levels were 4.45 M (1.19 g/ml) following a dose of 120 mg zidovudine (in solution)/m2 body 
surface area and 7.7 M (2.06 g/ml) at 180 mg/m2 body surface area.  Dosages of 180 mg/m2 four 
times daily in children produced similar systemic exposure (24 hour AUC 40.0 h M or 10.7 h g/ml) 
as doses of 200 mg six times daily in adults (40.7 h M or 10.9 h g/ml).

In six HIV-infected children from 2 to 13 years of age, zidovudine plasma pharmacokinetics were 
evaluated while subjects were receiving 120 mg/m2 zidovudine three times daily and again after 
switching to 180 mg/m2 twice daily.  Systemic exposures (daily AUC and Cmax) in plasma from the 



16

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 AUC0-12 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.

Mutagenicity and carcinogenicity

Neither lamivudine nor zidovudine are mutagenic in bacterial tests, but consistent with other 
nucleoside analogues, inhibit cellular DNA replication 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 



17

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.

While the clinical relevance of these findings is unknown, these data suggest that a carcinogenic risk 
to humans is outweighed by the potential clinical 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. PHARMACEUTICAL PARTICULARS

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

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

Cartons containing opaque polyvinyl chloride/foil blister packs. Cartons containing 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



18

No special requirements for disposal

Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements.

7. MARKETING AUTHORISATION HOLDER

ViiV Healthcare BV
Van Asch van Wijckstraat 55H
3811 LP Amersfoort
Netherlands

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/98/058/001
EU/1/98/058/002

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation:18 March 1998
Date of renewal authorisation:13 February 2008

10. DATE OF REVISION OF THE TEXT

MM/YYYY

Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu.

http://www.ema.


19

ANNEX II

A. MANUFACTURER (S) RESPONSIBLE FOR BATCH 
RELEASE

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY 
AND USE

C. OTHER CONDITIONS AND REQUIREMENTS OF THE 
MARKETING AUTHORISATION

D. CONDITIONS OR RESTRICTIONS WITH REGARDS TO 
THE SAFE AND EFFECTIVE USE OF THE MEDICINAL 
PRODUCT



20

A. MANUFACTURER(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 OR RESTRICTIONS REGARDING SUPPLY AND USE

Medicinal product subject to restricted medical prescription (See Annex I: Summary of Product 
Characteristics, 4.2)

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 
AUTHORISATION

 Periodic Safety Update Reports

The marketing authorisation holder shall submit periodic safety update reports for this product in 
accordance with the requirements set out in the list of Union reference dates (EURD list) provided for 
under article 107c(7) of Directive 2001/83/EC and published on the European medicines web-portal.

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 
EFFECTIVE USE OF THE MEDICINAL PRODUCT 

 Risk Management Plan (RMP)

The MAH shall perform the required pharmacovigilance activities and interventions detailed in the 
agreed RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed subsequent 
updates of the RMP.

An updated RMP should be submitted:
 At the request of the European Medicines Agency
 Whenever the risk management system is modified, especially as the result of new information

being received that may lead to a significant change to the benefit/risk profile or as the result of 
an important (pharmacovigilance or risk minimisation) milestone being reached.

If the submission of a PSUR and the update of an RMP coincide, they can be submitted at the same 
time.



21

ANNEX III

LABELLING AND PACKAGE LEAFLET



22

A. LABELLING



23

PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE 
PACKAGING

OUTER CARTON 

1. NAME OF THE MEDICINAL PRODUCT

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. PHARMACEUTICAL FORM AND CONTENTS

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 SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP

9. SPECIAL STORAGE CONDITIONS

Do not store above 30°C



24

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

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

ViiV Healthcare BV
Van Asch van Wijckstraat 55H
3811 LP Amersfoort
Netherlands

12. MARKETING AUTHORISATION NUMBER(S)

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

17.     UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included

18.     UNIQUE IDENTIFIER – HUMAN READABLE DATA

PC:
SN:
NN:



25

PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE 
PACKAGING

BOTTLE LABEL

1. NAME OF THE MEDICINAL PRODUCT

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. PHARMACEUTICAL FORM AND CONTENTS

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 SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP

9. SPECIAL STORAGE CONDITIONS

Do not store above 30°C



26

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

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

ViiV Healthcare BV
Van Asch van Wijckstraat 55H
3811 LP Amersfoort
Netherlands

12. MARKETING AUTHORISATION NUMBER(S)

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

17.     UNIQUE IDENTIFIER – 2D BARCODE

18.     UNIQUE IDENTIFIER – HUMAN READABLE DATA



27

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

BLISTER PACK OUTER CARTON

1. NAME OF THE MEDICINAL PRODUCT

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. PHARMACEUTICAL FORM AND CONTENTS

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 SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP

9. SPECIAL STORAGE CONDITIONS

Do not store above 30°C



28

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

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

ViiV Healthcare BV
Van Asch van Wijckstraat 55H
3811 LP Amersfoort
Netherlands

12. MARKETING AUTHORISATION NUMBER(S)

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

17.     UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included

18.     UNIQUE IDENTIFIER – HUMAN READABLE DATA

PC:
SN:
NN:



29

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS

1. NAME OF THE MEDICINAL PRODUCT

Combivir 150 mg/300 mg tablets
Lamivudine/zidovudine

2. NAME OF THE MARKETING AUTHORISATION HOLDER

ViiV Healthcare BV

3. EXPIRY DATE

EXP 

4. BATCH NUMBER

Lot

5.       OTHER



30

B. PACKAGE LEAFLET



31

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 because it contains 
important information for you.

 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 only.  Do not pass it on to others. It may harm them 

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

effects not listed in this leaflet. See section 4. 

What is in this leaflet:

1. What Combivir is and what it is used for 
2. What you need to know before you take Combivir
3. How to take Combivir
4. Possible side effects
5. How to store Combivir
6. Contents of the pack and other 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 antiretroviral 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. What you need to know before you take Combivir

Do not take Combivir: 

 if you are allergic to lamivudine or zidovudine, or any of the other ingredients of this medicine
(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:



32

 if you have ever had liver disease, including hepatitis B or C (if you have hepatitis B 
infection, do not 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 are a woman)

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 
are 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 are 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). You can still pass on HIV when taking this 
medicine, although the risk is lowered by effective antiretroviral therapy.  

Discuss with your doctor the precautions needed to avoid infecting other people.

Other medicines and Combivir
Tell your doctor or pharmacist if you are taking any other medicines, or if you have 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 are taking 
Combivir.

These medicines should not be used with Combivir:
 other medicinal products containing lamivudine, to treat HIV infection or hepatitis B infection
 emtricitabine, to treat HIV infection
 stavudine, to treat HIV infection
 ribavirin or injections of ganciclovir to treat viral infections
 high doses of co-trimoxazole, an antibiotic
 cladribine, used to treat hairy cell leukaemia

Tell your doctor if you are 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 Pneumocystis jirovecii pneumonia
          (often referred to 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 are taking any of these.

Some medicines interact with Combivir



33

These include:
 clarithromycin, an antibiotic

if you are 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 are taking phenytoin.  Your doctor may need to monitor you while you 
are taking Combivir.

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

Tell your doctor or pharmacist if you are being treated with any of these.

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 have taken Combivir
during your pregnancy, your doctor may request regular blood tests and other diagnostic tests to 
monitor the development of your child. In children whose mothers took NRTIs during pregnancy, the 
benefit from the protection against HIV outweighed the risk of side effects.

Breast-feeding

Women who are HIV-positive must not breastfeed, because HIV infection can be passed on to the 
baby in breast milk.  

A small amount of the ingredients in Combivir can also pass into your 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.

Do not drive or operate machines unless you are feeling well.

3. How to take Combivir 

Always take this medicine exactly as your doctor or pharmacist has told you.  Check with your 
doctor or pharmacist if you are 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.



34

Keep in touch with your doctor, and do not 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

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 more Combivir than you should

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.  
Do not take a double dose to make up for a forgotten dose.

4. Possible side effects

During HIV therapy there may be an increase in weight and in levels of blood lipids and glucose. This 
is partly linked to restored health and life style, and in the case of blood lipids sometimes to the HIV 
medicines themselves. Your doctor will test for these changes. 

Treatment with Combivir often causes a loss of fat from legs, arms and face (lipoatrophy). This loss of 
body fat has been shown to be not fully reversible after discontinuation of zidovudine. Your doctor 
should monitor for signs of lipoatrophy. Tell your doctor if you notice any loss of fat from your legs, 
arms, and face. When these signs occur, Combivir should be stopped and your HIV treatment 
changed.

Like all medicines, this medicine can cause side effects, but not everyone gets them.

When you are being treated for HIV, it can be hard to tell whether a symptom is a side effect of 
Combivir or other medicines you are taking, or an effect of the HIV disease itself. So it is very 
important to talk to your doctor about any changes in your health.

As well as the side effects listed below for 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:



35

 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).

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 (excess lactic acid in the blood; 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



36

 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.

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.

In addition to the opportunistic infections, autoimmune disorders (a condition that occurs when the 
immune system attacks healthy body tissue) may also occur after you start taking medicines for the 
treatment of your HIV infection. Autoimmune disorders may occur many months after the start of 
treatment. If you notice any symptoms of infection or other symptoms such as muscle weakness, 
weakness beginning in the hands and feet and moving up towards the trunk of the body, palpitations, 
tremor or hyperactivity, please inform your doctor immediately to seek necessary treatment.

If you get any symptoms of infection while you are taking Combivir:

Tell your doctor immediately.  Do not take other medicines for the infection without your 
doctor’s advice.

Lactic acidosis is a rare but serious side effect

Some people taking Combivir 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.



37

During your treatment, your doctor will monitor you for signs of lactic acidosis.  If you have any of 
the symptoms listed above, or any other symptoms that worry you:

See your doctor as soon as possible.

You may have problems with your bones

Some people taking combination therapy for HIV develop a condition called osteonecrosis. With this 
condition, parts of the bone tissue die because of reduced blood supply to the bone. People may be 
more likely to get this condition:
 if they have been taking combination therapy for a long time
 if they are also taking anti-inflammatory medicines called corticosteroids
 if they drink alcohol
 if their immune systems are very weak
 if they are overweight.

Signs of osteonecrosis include:
 stiffness in the joints
 aches and pains (especially in the hip, knee or shoulder)
 difficulty moving.
If you notice any of these symptoms:

Tell your doctor.

Other effects may show up in blood tests

Combination therapy for HIV can also cause:
 increased levels of lactic acid in the blood, which on rare occasions can lead to lactic acidosis

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

5. How to store Combivir

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the carton.

Do not store above 30oC.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use.  These measures will help to protect the environment.

6. Contents of the pack and other information

What 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



38

Combivir film-coated tablets are provided in cartons, containing blister packs or bottles with a child 
resistant-closure. Each pack type contains 60 film-coated tablets. They are white to off-white, capsule-
shaped scored tablets marked with the code GXFC3 on both sides.

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

or

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

ViiV Healthcare BV
Van Asch van Wijckstraat 55H
3811 LP Amersfoort
Netherlands



39

For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder:

België/Belgique/Belgien
ViiV Healthcare srl/bv 
Tél/Tel: + 32 (0)10 85 65 00

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

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

Luxembourg/Luxemburg
ViiV Healthcare srl/bv 
Belgique/Belgien
Tél/Tel: + 32 (0)10 85 65 00

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

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

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

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

Deutschland
ViiV Healthcare GmbH 
Tel.: + 49 (0)89 203 0038-10 
viiv.med.info@viivhealthcare.com

Nederland
ViiV Healthcare BV
Tel: + 31 (0)33 2081199

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

Norge
GlaxoSmithKline AS
Tlf: + 47 22 70 20 00

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

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

España
Laboratorios ViiV Healthcare, S.L. 
Tel: +34 900 923 501
es-ci@viivhealthcare.com

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

France
ViiV Healthcare SAS 
Tél.: + 33 (0)1 39 17 6969
Infomed@viivhealthcare.com

Portugal
VIIVHIV HEALTHCARE, UNIPESSOAL, LDA
Tel: + 351 21 094 08 01 
viiv.fi.pt@viivhealthcare.com

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

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

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

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

mailto:dk-info@gsk.com
mailto:viiv.med.info@viivhealthcare.com
mailto:es-ci@viivhealthcare.com
mailto:Infomed@viivhealthcare.com
mailto:viiv.fi.pt@viivhealthcare.com


40

Ísland
Vistor hf. 
Sími: +354 535 7000

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

Italia
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
gskcyprus@gsk.com

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

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

United Kingdom
ViiV Healthcare UK Limited
Tel: + 44 (0)800 221441
customercontactuk@gsk.com 

This leaflet was last revised in {MM/YYYY}

Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu.

mailto:gskcyprus@gsk.com
http://www.ema.europa.eu

	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETINGAUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE ANDEFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET