New Zealand - English - Medsafe (Medicines Safety Authority)
NEW ZEALAND DATA SHEET
Lamivudine 150mg & Zidovudine 300mg tablets
COMBIVIR film-coated tablets contain 150mg lamivudine and 300mg
COMBIVIR film-coated tablets are white to off-white capsule-shaped
engraved with GXFC3 on one side.
Do not halvetablet.
Pharmacotherapeutic group- nucleoside analogue.
Lamivudine and zidovudine are potent, selective inhibitors of HIV-1 and HIV-
2. Lamivudine has been shown to be highly synergistic with zidovudine,
inhibiting the replication ofHIV in cell culture. Bothactive substances are
metabolised sequentially by intracellular kinases to the 5’-triphosphate (TP).
Lamivudine-TP and zidovudine-TP are substrates for and competitive
inhibitors of HIV reverse transcriptase. However, their main antiviralactivity is
through incorporation of the monophosphate form into the viral DNA chain,
resulting in chain termination. Lamivudine and zidovudine triphosphates show
significantly less affinity for host cell DNA polymerases.
In vitro, lamivudine demonstrates lowcytotoxicity to peripheral blood
lymphocytes, to established lymphocyte and monocyte-macrophage cell lines,
and to a variety of bone marrow progenitorcells in vitro. Lamivudine therefore
has, in vitro, a high therapeutic index.
HIV-1 resistance to lamivudine involvesthe development of a M184V amino
acid change close to the active site ofthe viral reverse transcriptase (RT).
This variant arises bothin vitroand in HIV-1 infectedpatients treated with
lamivudine-containing antiretroviral therapy. M184V mutants display greatly
reduced susceptibility to lamivudine andshow diminished viral replicative
capacityin vitro.Invitrostudies indicate thatzidovudine-resistant virus
isolates can become zidovudine sensitive when theysimultaneously acquire
resistance to lamivudine. The clinicalrelevance of such findings remains,
however, not well defined.
Cross-resistance conferred by the M184VRT is limited within the nucleoside
inhibitor class of antiretroviral agents.Zidovudine and stavudine maintain their
antiretroviral activitiesagainst lamivudine-resistant HIV-1. Abacavir maintains
its antiretroviral activities against lamivudine-resistant HIV-1 harbouring only
the M184V mutation. The M184V RTmutant shows a <4-fold decrease in
susceptibility to didanosine and zalcitabine; the clinical significance of these
findings is unknown.
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 phenotypicresistance to thymidine analogues
through the combination of mutationsat codons 41 and 215 or by the
accumulation of at least four of thesix mutations. These thymidine analogue
mutations alone do not cause high-level cross-resistance to any of the other
nucleosides, allowing for the subsequentuse 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 typically involving a T69S mutation plusa 6-base pair insert at
the same position, result in phenotypicresistance to AZT as well as to the
other approved nucleoside reverse transcriptase inhibitors. Either of these two
patterns of multinucleoside resistance mutations severely limits future
In clinical studies lamivudine incombination with zidovudine has been shown
to reduce HIV-1 viralload and to increase CD
cell counts. Clinicalend-point
data indicatethat lamivudine in combination with zidovudine alone or in
combination with zidovudine containingtreatment regimens results in a
significant reduction in the risk ofdisease progression and mortality.
Individually, lamivudine and zidovudine therapy has resulted in HIV clinical
isolates which show reduced sensitivityin vitroto the nucleoside analogue to
which they have been exposed. Evidencefrom clinicalstudies show that
lamivudine plus zidovudine delaysthe emergence of zidovudine-resistant
isolates in individuals with noprior anti-retroviral therapy.
In vitrosusceptibility testing has notbeen standardised and results may vary
according to methodological factors. The relationship betweenin vitro
susceptibility of HIV to lamivudine and/orzidovudine and the clinical response
to therapy remain under investigation.
Lamivudine and zidovudine have beenwidely used as componentsof
antiretroviral combination therapywith other antiretroviral agents of the same
class (nucleoside reverse transcriptaseinhibitors) or different classes
(protease inhibitors, non-nucleosidereverse transcriptase inhibitors).
Multiple medicine 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.
Absorption:Lamivudine and zidovudine are well absorbed from the gut. The
bioavailability of oral lamivudine inadults is normally between 80-85% and for
zidovudine 60-70%. Abioequivalence study compared COMBIVIR with 3TC
150mg and Retrovir 300mg tablets takentogether. The effect of food on the
rate and extent of absorption wasalsostudied. COMBIVIR was shown to be
bioequivalent to 3TC 150mg and Retrovir 300mg given as separate tablets,
when administered to fasting subjects.
Following COMBIVIR administration, lamivudine and zidovudine C
confidence interval) values were 1.5(1.3-1.8)mg/mL and1.8 (1.5-2.2)mg/mL
respectively. The median (range) lamivudine and zidovudine t
0.75 (0.50-2.00) hours and 0.50 (0.25-2.00) hours respectively. The extent
(AUC) of lamivudine and zidovudine absorption and estimates of half-life
following administration of COMBIVIRwith food were similar when compared
to fasting subjects, although the rate of absorption (C
) was slowed.
Based on these data COMBIVIR may beadministered with or without food.
Distribution: Intravenous studies with lamivudine and zidovudine showed that
the mean apparent volume of distribution is 1.3 and 1.6L/kg respectively.
Lamivudine exhibits linear pharmacokinetics over the therapeutic dose range
and displayslimited binding to the major plasma protein albumin (less than
36% serum albuminin vitro). Zidovudine plasma protein binding is 34% to
38%. Interactions with medicinal productsinvolving binding site displacement
are not anticipated with COMBIVIR.
Data show that lamivudine and zidovudine penetrate the central nervous
system and reach the cerebrospinal fluid (CSF). The mean ratios of
CSF/serum lamivudine and zidovudine concentrations 2-4 hours after oral
administration were approximately0.12 and 0.5 respectively. The true extent
of penetration of lamivudine or relationship with any clinical efficacy is
Metabolism: Metabolism of lamivudine is aminor route of elimination.
Lamivudine is predominately clearedby renal excretion of the unchanged
active substance. The likelihood of metabolic interactionswith lamivudine is
low due to the small extent of hepaticmetabolism (5-10%) and low plasma
The 5'-glucuronide of zidovudine is the major metabolite in both plasma and
urine, accounting for approximately50-80% 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 ofelimination is 5 to 7 hours.
The mean systemic clearance of lamivudine is approximately 0.32L/h/kg, with
predominantly renal clearance (greaterthan 70%) via the organic cationic
From studies with intravenous zidovudine,the mean terminal plasma half-life
was 1.1 hours and the mean systemicclearance was 1.6L/h/kg. Renal
clearance of zidovudine is estimated tobe 0.34L/h/kg, indicating glomerular
filtration and active tubularsecretion by the kidneys.
Renally impaired: Studies in patients with renalimpairment show lamivudine
elimination is affectedbyrenal dysfunction, due to decreased renal clearance.
Dose reduction is required for patientswith creatinine clearance of less than
50mL/min. Zidovudine concentrationshave also been shown to be increased
in patients with advanced renal failure.
Hepaticallyimpaired: Limited data in patients with cirrhosis suggest that
accumulation of zidovudine may occurin patients with hepatic impairment
because of decreased glucuronidation.Dosage adjustment of zidovudine may
be necessary in patients with severe hepaticimpairment.
Elderly: The pharmacokinetics of lamivudine and zidovudine have not been
studied in patients over 65 years of age.
Pregnancy:The pharmacokinetics of lamivudine and zidovudine were similar
to that of non-pregnant adults. Inhumans, consistent with passive
transmission of lamivudine acrossthe placenta, lamivudine concentrations in
infant serum at birth were similar tothose in maternal and cord serum at
delivery. Zidovudine was measured in plasmaand gave similar results to
those observed for lamivudine.
COMBIVIR is indicated for the treatment of HIV infected adults and
adolescents over the age of 12 years,with progressive immunodeficiency
4 = Count = < 500 cells/mm 3
Dosage and Administration
COMBIVIR therapy should be initiated and monitored bya physician
experienced in the management of HIV infection.
The recommended dose of COMBIVIR isone tablet twice daily. COMBIVIR
may be administered with or without food. Do not halvethe tablet.
If a reduction in dose of COMBIVIR appears clinically indicated,or if one of
the components of COMBIVIR (lamivudineor zidovudine) requires reduction
or discontinuation, separate preparations of lamivudine (3TC ®
zidovudine (Retrovir ® ) are available in tablets/capsules and oral solution.
Renal impairment:-Dosage adjustment of lamivudine isrequired in patients
with a creatinine clearance of less than 50mL/min (see Pharmacokinetics). It
is therefore recommended that separate preparations of lamivudine and
zidovudine should be administered to these patients.
Hepatic impairment:-Dosage adjustments for zidovudine may be necessary in
patients with hepatic impairment (see Pharmacokinetics). It is therefore
recommended that separate preparations of lamivudine and zidovudine
should be administered to patients with severe hepatic impairment.
Dosage adjustments in patients with haematological adverse reactions:-
Dosage adjustment of zidovudine may benecessary if the haemoglobin level
falls below 9g/dL or 5.59mmol/L or the neutrophil count falls below 1.0 x 10 9
(see Contraindications and Warnings and Precautions). As dosage
adjustment of COMBIVIR is not possible separate preparations of zidovudine
and lamivudine should be used.
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.
The use of COMBIVIR is contraindicated in patients with known
hypersensitivity to lamivudine, zidovudine or to any ingredient of the
Zidovudine is contra-indicated inpatients with abnormally low neutrophil
counts (less than 0.75 x 10 9 /L), or abnormally low haemoglobin levels (less
than 7.5g/dL or 4.65mmol/L). COMBIVIR istherefore contra-indicated in these
patients (see Warnings and Precautions).
Warnings and Precautions
The special warnings and precautionsrelevant to both lamivudine and
zidovudine are included in this section. There are no additional precautions
and warnings relevant tothe combination COMBIVIR.
It is recommended that separate preparations of lamivudine and zidovudine
should be administered in caseswhere dosage adjustment is necessary. In
these cases the physician should refer to the individual prescribing
information for these medicinal products.
Patients should be cautioned about the concomitant use of self-administered
medications (see Interactions).
Patients should be advised that currentantiretroviral therapy, including
COMBIVIR, has not been proven to preventthe risk of transmission of HIV to
others through sexual contact orblood contamination. Appropriate
precautions should continue to be taken.
Patients treated with COMBIVIR or anyother antiretroviral therapy may
continue to develop opportunisticinfections and other complications of HIV
infection. Therefore patients should remain under close clinical observation by
physicians experienced in thetreatment of HIV infection.
Haematological adverse reactions:Anaemia, neutropenia and leucopenia
(usually secondary to neutropenia) can be expected to occur in patients
receiving zidovudine. These occurredmore frequently at higher zidovudine
dosages (1200-1500mg/day), in patientswith advanced HIV disease and in
those who had poor marrow reserve priorto treatment (see Adverse Effects).
Haematological parameters should therefore be carefully monitored (see
Contraindications) in patients receiving COMBIVIR.
These haematological effects are not usuallyobserved before four to six
weeks therapy. For patients with advancedsymptomatic HIV disease, it is
generally recommended that blood testsare 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 thepatient, blood tests may
be performed less often, for example every one to three months.
Additionallydosage adjustment of zidovudine may be required if severe
anaemia ormyelosuppression occurs during treatment with COMBIVIR, or in
patients with pre-existing bone marrow compromise for example haemoglobin
less than 9g/dL (5.59mmol/L) orneutrophil count less than 1.0 x 10 9
dosage adjustment of COMBIVIR is notpossible separate preparations of
zidovudine and lamivudine should be used (see Contraindications).
Children:COMBIVIR isnot indicated for children under 12 years of age as
appropriate dose reduction for the weight of the child cannot be made.
Pancreatitis:Cases of pancreatitis have occurred rarely in patients treated
with lamivudine and zidovudine. However itis not clear whether these cases
were due to treatment with the medicinalproducts or tothe underlying HIV
disease. Pancreatitis must be considered whenever a patient develops
abdominal pain, nausea, vomiting orelevated biochemical markers.
Discontinue use of COMBIVIR until diagnosis of pancreatitis is excluded.
Lactic acidosis/severehepatomegaly with steatosis:Lactic acidosis and
severe hepatomegaly with steatosis,including fatal cases, have been
reported with the useof antiretroviral nucleoside analogues either alone or in
combination, including lamivudine and zidovudine. A majority of these cases
have been in women. Clinical features which may be indicative of the
development of lactic acidosis include generalised weakness, anorexia and
sudden unexplained weight loss, gastrointestinal symptoms and respiratory
symptoms (dyspnoea and tachypnoea). Caution should be exercised when
administering COMBIVIR to any patient, and particularly to those with known
risk factors for liver disease. Treatment with COMBIVIR should be suspended
in any patient who develops clinical orlaboratory findings suggestive of lactic
acidosis or hepatotoxicity (whichmay include hepatomegaly and steatosis
even in the absence of marked transaminase elevations).
Fat redistribution: Redistribution/accumulationof body fat, including central
obesity, dorsocervical fat enlargement(buffalo hump), peripheral wasting,
facial wasting, breast enlargement, elevated serum lipid and blood glucose
levels have been observed either separately or together in some patients
receiving combination antiretroviral therapy (see Adverse Effects).
Whilst all members of the PI and NRTIclasses of medicinal products have
been associated with one or more of these specific adverse events, linked to
a general syndrome commonly referred toas lipodystrophy, data indicate that
there are differences in the risk betweenindividual members of the respective
In addition, the lipodystrophy syndromehas a multi-factorial aetiology with
HIV disease status, older age and duration of antiretroviral treatment all
playing important possibly synergistic roles.
The long-term consequences of these events are currently unknown.
Clinical examination should include evaluation for physical signs of fat
redistribution. Consideration should be given to the measurement of serum
lipids and blood glucose. Lipid disorders should be managed as clinically
Immune Reconstitution Syndrome:In HIV-infected patients with severe
immune deficiency at the time of initiation of anti-retroviral therapy (ART), an
inflammatory reaction to asymptomaticor residual opportunistic infections
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 ART. Relevantexamples are cytomegalovirus retinitis,
generalised and/or focal mycobacterial infections and Pneumocystis jiroveci
(P. carinii) pneumonia. Any inflammatory symptoms must be evaluated
without delay and treatmentinitiated when necessary. Autoimmune disorders
(such as Graves’ disease, polymyositis and Guillain-Barre syndrome) have
also been reported to occur in the setting of immune reconstitution, however
the time to onset is morevariable, and can occur manymonths after initiation
of treatment and sometimes can be an atypical presentation.
Patients co-infected with Hepatitis B virus: Clinical trial and marketed use of
lamivudine,have shown that some patients with chronic hepatitis B virus
(HBV) disease may experience clinical or laboratory evidence of recurrent
hepatitis upon discontinuation of lamivudine, which may have more severe
consequences in patients with decompensated liver disease. If COMBIVIR is
discontinued in patients co-infected with Hepatitis B virus, periodic monitoring
of both liver function tests and markers of HBV replication should be
Patients co-infected with hepatitis C virus: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. Therefore,
the co-administration of ribavirinand zidovudine is not advised and
consideration should be given to replacing zidovudine in a combination ART
regimen if this is already established. This isparticularlyimportant inpatients
with a known history of zidovudine induced anaemia.
As COMBIVIR contains lamivudine and zidovudine, any interactions that have
been identified with these agents individually may occur with COMBIVIR. The
interactionslisted below should not be considered exhaustive but are
representative of the classes of medicinal products where caution should be
Interactions relevant to lamivudine:
The likelihood of metabolic interactions with lamivudine is low due to limited
metabolismand plasma protein binding, and almost complete renal
elimination of unchanged lamivudine.
Lamivudine is predominantlyeliminated by active organic cationic secretion.
The possibility of interactions withother medicinal products administered
concurrently should be considered, particularly when their main route of
elimination is active renal secretion via the organic cationic transport system
e.g. trimethoprim. Other active substances (e.g. ranitidine, cimetidine) are
eliminated only in part by this mechanismand were shown not to interact with
Active substances shown to be predominantely excreted either via the active
organic anionic pathway, or by glomerular filtration are unlikely to yield
clinically significant interactions with lamivudine.
Trimethoprim:-Administration of trimethoprim/sulphamethoxazole
160mg/800mg (co-trimoxazole) causesa 40% increase in lamivudine
exposure because of the trimethoprim component. However, unless the
patient has renal impairment, no dosage adjustment of lamivudine is
necessary. Lamivudine has no effect onthe pharmacokinetics of trimethoprim
or sulphamethoxazole.The effect ofco-administration of lamivudine with
higher doses of co-trimoxazoleused for the treatment ofPneumocystis
jiroveci (P. carinii)pneumonia and toxoplasmosis has not been studied.
Zalcitabine:-Lamivudine may inhibit the intracellular phosphorylation of
Zalicitabine when the two medicinalproducts are used concurrently.
COMBIVIR is therefore not recommended to be used in combination with
Interactions relevant to zidovudine:
Zidovudine is primarilyeliminated by hepatic conjugationto an inactive
glucuronidated metabolite.Active substances whichare primarily eliminated
by hepatic metabolismespecially via glucuronidation may have the potential
to inhibit metabolism of zidovudine.
Atovaquone:Zidovudine does not appear to affect the pharmacokinetics of
atovaquone. However, pharmacokineticdata have shown that atovaquone
appears to decrease the rate of metabolism of zidovudine to itsglucuronide
metabolite (steady stateAUC of zidovudine was increased by33% and peak
plasma concentration ofthe glucuronide was decreased by19%). At
zidovudine dosages of 500 or600 mg/day itwould seem unlikely that a three
week, concomitant course of atovaquonefor the treatment of acute PCP
would result in anincreased incidence of adverse reactions attributable to
higher plasma concentrationsof zidovudine. Extra careshould be taken in
monitoring patients receiving prolonged atovaquone therapy.
Clarithromycin:Clarithromycin tablets reduce the absorption of zidovudine.
This can be avoided by separating the administration ofzidovudine and
clarithromycin by at least two hours.
Lamivudine:- Co-administration of zidovudinewith lamivudine results in a 13%
increase in zidovudine exposure and a28% increase in peak plasmalevels.
However overall exposure (AUC) is notsignificantly altered. Zidovudine has
no effect on the pharmacokinetics of lamivudine.
Phenytoin:- Phenytoin blood levels havebeen reported to be low in some
patients receiving zidovudine, while inone patient a high level was noted.
These observations suggest that phenytoin concentrations should be carefully
monitored in patients receiving COMBIVIR and phenytoin.
Probenecid:- Limited data suggest that probenecid increases the mean half-
life and AUC of zidovudine by decreasingglucuronidation. Renal excretion of
the glucuronide (and possibly zidovudineitself) is reduced in the presence of
Ribavirin:- The nucleoside analogue ribavirin antagonises thein vitroantiviral
activity of zidovudine and so concomitant use of COMBIVIR with this
medicinal product should be avoided.
Rifampicin:- Limited data suggests that co-administration of zidovudine and
rifampicin decreases AUC of zidovudine by 48%±34%. However the clinical
significance of this is unknown.
Stavudine:- Zidovudine may inhibit the intracellular phosphorylationof
stavudine when the two medicinal productsare used concurrently. Stavudine,
is therefore not recommended to be used in combination with COMBIVIR.
Miscellaneous:-Other medicinal products, including but not limited to, aspirin,
codeine, morphine, methadone, indomethacin, ketoprofen, naproxen,
oxazepam, lorazepam, cimetidine, clofibrate, dapsone and isoprinosine, may
alter the metabolism of zidovudine by competitively inhibiting glucuronidation
or directly inhibiting hepatic microsomal metabolism. Careful thought should
be given to the possibilities of interactions before using such medicinal
products particularly for chronic therapy, in combination with COMBIVIR.
Concomitant treatment, especially acute therapy, with potentially nephrotoxic
or myelosuppressive medicinal products(for example systemic pentamidine,
dapsone, pyrimethamine, co-trimoxazole, amphotericin, flucytosine,
ganciclovir, interferon, vincristine,vinblastine and doxorubicin) may also
increase the risk of adverse reactionsto 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 ormore agents should be
Since somepatients receiving COMBIVIR may continue to experience
opportunistic infections, concomitant useof prophylactic antimicrobial therapy
may have to be considered. Such prophylaxishas included co-trimoxazole,
aerosolised pentamidine, pyrimethamine and aciclovir. Limited data from
clinical trials do not indicate a significantly increased risk of adverse reactions
to zidovudine with these medicinal products.
Pregnancy and Lactation
The safety of lamivudine in humanpregnancy has not been established. The
use of zidovudine in pregnant women,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. Both
lamivudine and zidovudine have been shownto cross the placenta. Although
animal reproductive studies (see Preclinical Safety Data) are not always
predictive of the human response, administration of COMBIVIRduring the first
three months of pregnancy is notrecommended unless the benefit to the
mother outweighs the risk to the foetus.
Based on the animal carcinogenicity and mutagenicity findings for zidovudine
(see Preclinical SafetyData) a carcinogenicrisk to humans cannot be
excluded. The relevance of these findings to both infected and uninfected
infants exposed to zidovudine isunknown. However, pregnant women
considering using COMBIVIR duringpregnancy should be made aware of
There have been reports of mild, transientelevations in serum lactate levels,
which may be due to mitochondrial dysfunction, in neonates and infants
exposed in utero or peri-partum to nucleoside reversetranscriptase inhibitors
(NRTIs). The clinical relevance of transient elevations in serum lactate is
unknown. There have also been very rarereports of developmental delay,
seizures and other neurological disease. However, a causal relationship
between these events and NRTI exposure inutero or peri-partum has not
been established. These findings do notaffect current recommendations to
use antiretroviral therapyin pregnant women to prevent vertical transmission
Health experts recommend that wherepossible HIV infected women do not
breast feed their infants under any circumstances in order to avoid
transmission of HIV.Both lamivudine and zidovudine are excreted in human
milk at similar concentrations to those found in serum. Since lamivudine,
zidovudine and HIV virus pass into breast milk it is recommended that
mothers taking COMBIVIR do notbreast feed their infants.
There are no data on the affect of lamivudine or zidovudine on human female
fertility. In men, zidovudine has been shown to have no effect on sperm count,
morphology or motility.
Effects on Ability to Drive and Use Machines
There have been no studies to investigate the effect of lamivudineor
zidovudine on driving performance orthe ability to operate machinery.
Further, a detrimental effect on such activities cannot be predicted from the
pharmacology of the active substances.Nevertheless, the clinical status of
the patient and the adverseevent profile of lamivudine and zidovudine should
be borne inmind whenconsidering the patient's ability to drive or operate
Adverse events have been reported during therapy for HIV disease with
lamivudine and zidovudine separately or incombination. With many it is
unclear whether they arerelated to lamivudine, zidovudine, or to the wide
range of medicinal products used in the management of HIV disease or are as
a result of the underlyingdisease process. As COMBIVIR contains lamivudine
and zidovudine the type and severity of adverse reactions associated with
each of the compounds, which are listed below may be expected. There is no
evidence of added toxicity following concurrent administration of the two
The following convention has been utilisedfor the classification of undesirable
Very common (>1/10), common (>1/100,<1/10), uncommon (>1/1,000,
<1/100), rare (>1/10,000, <1/1,000) very rare (<1/10,000).
Blood and lymphatic systems disorders
Uncommon: Neutropenia,anaemia, thrombocytopenia
Very rare: Pure red cell aplasia
Metabolism and nutrition disorders
Rare: Lactic acidosis (see Special Warnings and Special Precautions for use).
Redistribution/accumulation of body fat(see Warnings and Precautions). The
incidence of this event is dependent on multiple factors including the particular
antiretroviral medicine combination.
Very rare: Paraesthesia. Peripheral neuropathy has been reported although a
causal relationship to treatment is uncertain
Common: Nausea, vomiting,upper abdominal pain, diarrhoea
Rare: Pancreatitis, although a causal relationship to treatment is uncertain.
Rises in serum amylase.
Uncommon: Transient rises inliverenzymes (AST, ALT)
Skin and subcutaneous tissue disorders
Common: Rash, alopecia
Musculoskeletal and connective tissue disorders
Common: Arthralgia, muscle disorders
General disorders and administration site conditions
Common:Fatigue, malaise, fever
Blood and lymphatic systemdisorders
Common: Anaemia (which may require transfusions), neutropenia and
These occur more frequently at higher dosages (1200-1500mg/day) and in
patients with advanced HIV disease(especially when there is poor bone
marrow reserve prior to treatment), and particularly in patients with CD
counts less than 100/mm 3
. Dosage reduction or cessation of therapy may
become necessary (see Warnings andPrecautions ). The incidence of
neutropenia was also increased in those patients whose neutrophil counts,
haemoglobin levels and serum vitamin B
levels were low at the start of
Uncommon: Thrombocytopenia and pancytopenia (with marrow hypoplasia)
Rare: Pure red cell aplasia
Very rare: Aplastic anaemia
Metabolism and nutrition disorders
Rare:Lactic acidosis (see Special Warningsand Special Precautions for use),
Redistribution/accumulation of body fat (see Warnings and Precautions). The
incidence of this event is dependent on multiple factors including the particular
antiretroviral medicine combination.
Rare: anxiety and depression
Very common: Headache
Rare: Insomnia, paraesthesia, somnolence, loss of mental acuity,
Respiratory,thoracic and mediastinal disorders
Very common: Nausea
Common: Vomiting, abdominal pain, and diarrhoea
Rare: Oral mucosa pigmentation,taste disturbance and dyspepsia.
Common: Raised blood levelsofliver enzymes and bilirubin
Rare:Liver disorders such as severehepatomegaly with steatosis,
Skin and subcutaneous tissue disorders
Uncommon: Rash and pruritus
Rare: Nail and skin pigmentation, urticaria and sweating
Musculoskeletal and connective tissue disorders
Renal and urinary disorders
Rare: Urinary frequency
Reproductive systemand breast disorders
General disorders and administration site conditions
Uncommon: Fever, generalised pain and asthenia
Rare: Chills, chest pain and influenza-like syndrome
There is limited experience of overdosage with COMBIVIR. No specific
symptoms or signs havebeen identified following acute overdose with
zidovudine or lamivudine apart from those listed as undesirable effects. No
fatalities occurred, and all patientsrecovered.
If overdosage occurs the patient shouldbe monitored for evidence of toxicity
(see Adverse Effects), and standardsupportive treatment applied as
necessary. Since lamivudine is dialysable, continuous haemodialysis could be
used in the treatment ofoverdosage, although this has not been studied.
Haemodialysis and peritoneal dialysis appearto have a limited effect on
elimination of zidovudine,but enhance the elimination of the glucuronide
metabolite. For more details physiciansshould refer to the individual
prescribing information for lamivudine and zidovudine.
Special precautions for storage
Store below 30 C.
Instructions for use/handling
Prescription Only Medicine
Tamper-evident cartons containing opaque polyvinyl chloride/foil blister packs.
Each pack contains 60 coated tablets.
Preclinical Safety Data
No synergy of toxicity has been observed in studies with lamivudine in
combination with zidovudine.The clinically relevant effects of the two
medicinal products in combinationare anaemia, neutropenia and leucopenia.
Mutagenicity:-Neither lamivudine nor zidovudine are mutagenic in bacterial
tests, but like many nucleoside analogues they show activity inin vitro
mammalian tests such as the mouse lymphoma assay. Lamivudine has not
shown any genotoxic activity inin vivostudies at doses that gave plasma
concentrations up to 40-50 times higher than clinical plasma levels. As thein
vitromutagenic activityof lamivudine could not be confirmed inin vivotests, it
is concluded that lamivudine should not represent a genotoxic hazard to
patients undergoing treatment.
Zidovudine showed clastogenic effects inan oral repeated dose micronucleus
test in mice. Peripheral blood lymphocytes from AIDS patients receiving
zidovudine treatment havealso been observed to contain higher numbers of
chromosome breakages. A pilot study has demonstrated that zidovudine is
incorporated into leukocyte nuclear DNAof 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. The
clinical implications ofthese findings is unknown.
Carcinogenicity:-In long-term oral carcinogenicity studies in rats and mice,
lamivudine did not show anycarcinogenic potential.
In oral carcinogenicity studies withzidovudine in mice and rats, late
appearing-vaginal epithelial tumours were observed. There were no other
zidovudine-related tumours observed ineither sex of either species.A
subsequent intravaginal carcinogenicitystudy confirmed the hypothesis that
the vaginal tumours were the result oflong-term local exposure of the rodent
vaginal epithelium to high concentrations of unmetabolised zidovudine in
urine. The predictive value of rodentcarcinogenicity studies for humans is
uncertain and thus the clinical significance ofthese findings is unclear.
In addition, two transplacental carcinogenicitystudies have been conducted in
mice. In one study, by the US NationalCancer Institute, zidovudinewas
administered at maximum tolerated dosesto pregnant mice from day 12 to 18
of gestation. One year post-natally, there was an increase in the incidenceof
tumours in the lung, liverand female reproductive tractof offspring exposed to
the highest dose level (420mg/kg/term body weight).
In a second study, mice were administered zidovudine at doses up to
40mg/kg for 24 months, with exposurebeginning prenatallyon gestation day
10. Treatment related findings were limited to late-occurring vaginal epithelial
tumours, which were seen with a similarincidence and time of onset as in the
standard oral carcinogenicity study.The second study thus provided no
evidence that zidovudine acts asa transplacental carcinogen.
It is concluded that the transplacental carcinogenicity data from the first study
represents a hypotheticalrisk, whereas the reduction in risk of maternal
transfection of HIV to the uninfected child bythe use of zidovudine in
pregnancy has been well proven.
Reproductive toxicology:- In reproductive studies inanimals both lamivudine
and zidovudine were shown to crossthe placenta, this has also been
confirmed in humans. Lamivudine hasdemonstrated evidence of causing an
increase in early embryonic deaths in the rabbit at relatively low systemic
exposures, comparable to those achievedin 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 animalstudies. At maternally toxic doses,
zidovudine given to rats during organogenesis resulted in an increased
incidence of malformations, but noevidence of foetal abnormalities was
observed at lower doses.
Fertility:-Neither zidovudine nor lamivudine have shown evidence of
impairment of fertility in studies inmale and female rats.
List of Excipients
Tablet core: Microcrystalline cellulose, Sodiumstarch glycollate, Colloidal
silicon dioxide, Magnesium stearate.
Tablet filmcoat: Hydroxypropylmethyl cellulose, Titanium dioxide,Macrogol
400, Polysorbate 80.
Post-exposure prophylaxis (PEP)
Internationally recognised guidelines(Centre for Disease Control and
Prevention - June 1998), recommend that inthe event of accidental exposure
to HIV infected blood e.g.from a needlestickinjury, a combination of
zidovudine and lamivudine should be administered promptly (within one to two
hours). In cases of higher risk of infection a protease inhibitor should be
included in the regimen. It is recommended that antiretroviral prophylaxis be
continued for four weeks. No controlled clinical studies have been carried out
in post-exposure prophylaxis and supporting data is limited. Seroconversion
may still occur despite prompt treatment with antiretroviral agents.
GlaxoSmithKline NZ Ltd
Private Bag 106600
Phone: (09) 367 2900
Facsimile: (09) 367 2910
Date of Preparation
Date of preparation: 15 October 2012
, 3TC ®
and Retrovir ®
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© This data sheet is copyrighted toGlaxoSmithKline and may be reproduced
but not altered in any way.