Combivir

New Zealand - English - Medsafe (Medicines Safety Authority)

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Active ingredient:
Lamivudine 150 mg;  ; Zidovudine 300 mg
Available from:
GlaxoSmithKline (NZ) Ltd
INN (International Name):
Lamivudine 150 mg
Dosage:
150 mg/300 mg
Pharmaceutical form:
Film coated tablet
Composition:
Active: Lamivudine 150 mg   Zidovudine 300 mg Excipient: Colloidal silicon dioxide Magnesium stearate Microcrystalline cellulose Opadry white YS-1-7706-G Purified water Sodium starch glycolate
Units in package:
Blister pack, PVC & aluminium, 60 tablets
Class:
Prescription
Prescription type:
Prescription
Manufactured by:
Mylan Laboratories Limited
Therapeutic indications:
Indicated for the treatment of HIV infected adults and adolescents over the age of 12 years, with progressive immunodeficiency (CD4 = Count = < 500 cells/mm3).
Product summary:
Package - Contents - Shelf Life: Blister pack, PVC/Al - 60 tablets - 24 months from date of manufacture stored at or below 30°C
Authorization number:
TT50-6080
Authorization date:
1997-11-18

NEW ZEALAND DATA SHEET

Combivir ®

Tablets

Lamivudine 150mg & Zidovudine 300mg tablets

Presentation

COMBIVIR film-coated tablets contain 150mg lamivudine and 300mg

zidovudine.

COMBIVIR film-coated tablets are white to off-white capsule-shaped

engraved with GXFC3 on one side.

Do not halvetablet.

Uses

Actions

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

therapeuticoptions.

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.

Pharmacokinetics

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

(95%

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

values were

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

unknown.

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

binding.

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

transport system.

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.

Indications

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 ®

) and

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

/L

(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.

Contraindications

The use of COMBIVIR is contraindicated in patients with known

hypersensitivity to lamivudine, zidovudine or to any ingredient of the

preparation.

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

/L. As

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

therapeuticclasses.

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

appropriate.

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

considered.

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.

Interactions

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

exercised.

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

lamivudine.

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

zalcitabine.

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

probenecid.

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

reduced.

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

Pregnancy:

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

these findings.

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

of HIV.

Lactation:

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.

Fertility:

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

machinery.

Adverse Effects

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

compounds.

The following convention has been utilisedfor the classification of undesirable

effects:-

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).

Lamivudine:

Blood and lymphatic systems disorders

Uncommon: Neutropenia,anaemia, thrombocytopenia

Very rare: Pure red cell aplasia

Metabolism and nutrition disorders

Common: Hyperlactataemia

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.

Nervous systemdisorders

Common: Headache

Very rare: Paraesthesia. Peripheral neuropathy has been reported although a

causal relationship to treatment is uncertain

Gastrointestinal disorders

Common: Nausea, vomiting,upper abdominal pain, diarrhoea

Rare: Pancreatitis, although a causal relationship to treatment is uncertain.

Rises in serum amylase.

Hepatobiliary disorders

Uncommon: Transient rises inliverenzymes (AST, ALT)

Skin and subcutaneous tissue disorders

Common: Rash, alopecia

Musculoskeletal and connective tissue disorders

Common: Arthralgia, muscle disorders

Rare: Rhabdomyolysis

General disorders and administration site conditions

Common:Fatigue, malaise, fever

Zidovudine:

Blood and lymphatic systemdisorders

Common: Anaemia (which may require transfusions), neutropenia and

leucopenia

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

+ cell

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

zidovudine therapy.

Uncommon: Thrombocytopenia and pancytopenia (with marrow hypoplasia)

Rare: Pure red cell aplasia

Very rare: Aplastic anaemia

Metabolism and nutrition disorders

Common: Hyperlactataemia

Rare:Lactic acidosis (see Special Warningsand Special Precautions for use),

anorexia.

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.

Psychiatric disorders

Rare: anxiety and depression

Nervous systemdisorders

Very common: Headache

Common: Dizziness

Rare: Insomnia, paraesthesia, 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 disturbance and dyspepsia.

Pancreatitis.

Hepatobiliary disorders

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

Common: Myalgia

Uncommon: Myopathy

Renal and urinary disorders

Rare: Urinary frequency

Reproductive systemand 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

Overdosage

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.

Pharmaceutical Precautions

Incompatibilities

None reported.

Shelf-life

2 years.

Special precautions for storage

Store below 30 C.

Instructions for use/handling

None required.

Medicines Classification

Prescription Only Medicine

Package Quantities

Tamper-evident cartons containing opaque polyvinyl chloride/foil blister packs.

Each pack contains 60 coated tablets.

Further Information

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.

Sponsor Details

GlaxoSmithKline NZ Ltd

Private Bag 106600

Downtown Auckland

NEW ZEALAND

Phone: (09) 367 2900

Facsimile: (09) 367 2910

Date of Preparation

Date of preparation: 15 October 2012

Version: 4.0

Combivir ®

, 3TC ®

and Retrovir ®

are registered trade marks of the ViiV

Healthcare group of companies.

© This data sheet is copyrighted toGlaxoSmithKline and may be reproduced

but not altered in any way.

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