LAMIVUDINA/ZIDOVUDINA TEVA 150mg / 300mg tablets medication leaflet

Lamivudine/Zidovudine Teva 150 mg/300 mg film-coated tablets

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

For the full list of excipients see section 6.1.

Film-coated tablet

White, capsule shaped, biconvex, film-coated scored tablet - engraved with “L/Z” on one side and“150/300” on the other side.

The tablet can be divided into equal doses.

Lamivudine/Zidovudine Teva is indicated in antiretroviral combination therapy for the treatment of

Human Immunodeficiency Virus (HIV) infection (see section 4.2).

Therapy should be initiated by a physician experienced in the management of HIV infection.

Lamivudine/Zidovudine Teva may be administered with or without food.

To ensure administration of the entire dose, the tablet(s) should ideally be swallowed withoutcrushing. For patients who are unable to swallow tablets, tablets may be crushed and added to a smallamount of semi-solid food or liquid, all of which should be consumed immediately (see section 5.2).

Adults and adolescents weighing at least 30 kg

The recommended oral dose of Lamivudine/Zidovudine Teva is one tablet twice daily.

Children weighing between 21 kg and 30 kg

The recommended oral dose of Lamivudine/Zidovudine Teva is one-half tablet taken in the morningand one whole tablet taken in the evening.

Children weighing from 14 kg to 21 kg

The recommended oral dose of Lamivudine/Zidovudine Teva is one-half tablet taken twice daily.

The dosing regimen for paediatric patients weighing 14-30 kg is based primarily on pharmacokineticmodelling and supported by data from clinical studies using the individual components lamivudineand zidovudine. A pharmacokinetic overexposure of zidovudine can occur, therefore close safetymonitoring is warranted in these patients. If gastrointestinal intolerance occurs in patients weighing21-30 kg, an alternative dosing schedule with one-half tablet taken thrice daily can be applied inattempt to improve tolerability.

Lamivudine/Zidovudine Teva tablets should not be used for children weighing less than 14 kg, sincedoses cannot be appropriately adjusted for the weight of the child. In these patients, lamivudine andzidovudine should be taken as separate formulations according to the prescribed dosingrecommendations for these products. For these patients and for patients, who are unable to swallowtablets, oral solutions of lamivudine and zidovudine are available.

For situations where discontinuation of therapy with one of the active substances of

Lamivudine/Zidovudine Teva, or dose reduction is necessary, separate preparations of lamivudine andzidovudine are available in tablets/capsules and oral solution.

Lamivudine and zidovudine concentrations are increased in patients with renal impairment due todecreased clearance (see section 4.4). Therefore as dosage adjustment of these may be necessary it isrecommended that separate preparations of lamivudine and zidovudine be administered to patientswith severe renal impairment (creatinine clearance ≤30 mL/min). Physicians should refer to theindividual prescribing information for these medicinal products.

Limited data in patients with cirrhosis suggest that accumulation of zidovudine may occur in patientswith hepatic impairment because of decreased glucuronidation. Data obtained in patients withmoderate to severe hepatic impairment show that lamivudine pharmacokinetics are not significantlyaffected by hepatic dysfunction. However, as dosage adjustments for zidovudine may be necessary, itis recommended that separate preparations of lamivudine and zidovudine be administered to patientswith severe hepatic impairment. Physicians should refer to the individual prescribing information forthese 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 or5.59 mmol/L or the neutrophil count falls below 1.0 x 109/L (see sections 4.3 and 4.4). As dosageadjustment of Lamivudine/Zidovudine Teva is not possible, separate preparations of zidovudine andlamivudine should be used. Physicians should refer to the individual prescribing information for thesemedicinal products.

Dosage in the elderly

No specific data are available, however special care is advised in this age group due to age associatedchanges such as the decrease in renal function and alteration of haematological parameters.

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), orabnormally low haemoglobin levels (<7.5 g/dL or 4.65 mmol/L). Lamivudine/Zidovudine Teva istherefore contraindicated in these patients (see section 4.4).

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

The special warnings and precautions relevant to both lamivudine and zidovudine are included in thissection. There are no additional precautions and warnings relevant to the combination

Lamivudine/Zidovudine Teva.

It is recommended that separate preparations of lamivudine and zidovudine should be administered incases where dosage adjustment is necessary (see section 4.2). In these cases the physician should referto the individual prescribing information for these medicinal products.

The concomitant use of stavudine with zidovudine should be avoided (see section 4.5).

Patients receiving Lamivudine/Zidovudine Teva or any other antiretroviral therapy may continue todevelop opportunistic infections and other complications of HIV infection. Therefore patients shouldremain under close clinical observation by physicians experienced in the treatment of HIV infection.

Haematological adverse reactions

Anaemia, neutropenia and leukopenia (usually secondary to neutropenia) can be expected to occur inpatients 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, particularlywith advanced HIV disease. Haematological parameters should therefore be carefully monitored (seesection 4.3) in patients receiving Lamivudine/Zidovudine Teva. These haematological effects are notusually observed before four to six weeks therapy. For patients with advanced symptomatic HIVdisease, it is generally recommended that blood tests are performed at least every two weeks for thefirst three months of therapy and at least monthly thereafter.

In patients with early HIV disease haematological adverse reactions are infrequent. Depending on theoverall condition of the patient, blood tests may be performed less often, for example every one tothree months. Additionally dosage adjustment of zidovudine may be required if severe anaemia ormyelosuppression occurs during treatment with Lamivudine/Zidovudine Teva, or in patients with pre-existing bone marrow compromise e.g. haemoglobin <9 g/dL (5.59 mmol/L) or neutrophil count<1.0 x 109/L (see section 4.2). As dosage adjustment of Lamivudine/Zidovudine Teva is not possibleseparate preparations of zidovudine and lamivudine should be used. Physicians should refer to theindividual prescribing information for these medicinal products.

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 theunderlying HIV disease. Treatment with Lamivudine/Zidovudine Teva should be stopped immediatelyif 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 theuse of zidovudine. Early symptoms (symptomatic hyperlactatemia) include benign digestivesymptoms (nausea, vomiting and abdominal pain) non-specific malaise, loss of appetite, weight loss,respiratory symptoms (rapid and/or deep breathing) or neurological symptoms (including motorweakness).

Lactic acidosis has a high mortality and may be associated with pancreatitis, liver failure, or renalfailure.

Lactic acidosis generally occurred after a few or several months of treatment.

Treatment with zidovudine should be discontinued if there is symptomatic hyperlactatemia andmetabolic/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 treatedwith alpha interferon and ribavirin may constitute a special risk.

Patients at increased risk should be followed closely.

Nucleoside and nucleotide analogues may impact mitochondrial function to a variable degree, which ismost pronounced with stavudine, didanosine and zidovudine. There have been reports ofmitochondrial dysfunction in HIV-negative infants exposed in utero and/or post-natally to nucleosideanalogues; these have predominantly concerned treatment with regimens containing zidovudine. Themain adverse reactions reported are haematological disorders (anaemia, neutropenia) and metabolicdisorders (hyperlactatemia, hyperlipasemia). These events have often been transitory. Late-onsetneurological disorders have been reported rarely (hypertonia, convulsion, abnormal behaviour).

Whether such neurological disorders are transient or permanent is currently unknown. These findingsshould be considered for any child exposed in utero to nucleoside and nucleotide analogues, whopresents with severe clinical findings of unknown etiology particularly neurologic findings. Thesefindings do not affect current national recommendations to use antiretroviral therapy in pregnantwomen to prevent vertical transmission of HIV.

Lipoatrophy

Treatment with zidovudine has been associated with loss of subcutaneous fat, which has been linked tomitochondrial 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 whenswitching to a zidovudine-free regimen. Patients should be regularly assessed for signs of lipoatrophyduring therapy with zidovudine and zidovudine-containing products. Therapy should be switched to analternative regimen if there is suspicion of lipoatrophy development.

An increase in weight and in levels of blood lipids and glucose may occur during antiretroviraltherapy. Such changes may in part be linked to disease control and life style. For lipids, there is insome cases evidence for a treatment effect, while for weight gain there is no strong evidence relatingthis to any particular treatment. For monitoring of blood lipids and glucose reference is made toestablished HIV treatment guidelines. Lipid disorders should be managed as clinically appropriate.

In HIV-infected patients with severe immune deficiency at the time of institution of combinationantiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunisticpathogens 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 symptomsshould 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 immunereactivation; however, the reported time to onset is more variable and these events can occur manymonths after initiation of treatment.

If lamivudine is being used concomitantly for the treatment of HIV and hepatitis B virus (HBV),additional information relating to the use of lamivudine in the treatment of hepatitis B infection isavailable in the lamivudine 100 mg SmPC.

The safety and efficacy of zidovudine has not been established in patients with significant underlyingliver disorders.

Patients with chronic hepatitis B or C and treated with combination antiretroviral therapy are at anincreased risk of severe and potentially fatal hepatic adverse events. In case of concomitant antiviraltherapy for hepatitis B or C, please refer also to the relevant product information for these medicinalproducts.

If Lamivudine/Zidovudine Teva is discontinued in patients co-infected with HBV, periodic monitoringof both liver function tests and markers of HBV replication for 4 months is recommended, aswithdrawal of lamivudine may result in an acute exacerbation of hepatitis.

Patients with pre-existing liver dysfunction, including chronic active hepatitis, have an increasedfrequency of liver function abnormalities during combination antiretroviral therapy, and should bemonitored according to standard practice. If there is evidence of worsening liver disease in suchpatients, 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 ofanaemia (see section 4.5).

Although the etiology is considered to be multifactorial (including corticosteroid use, alcoholconsumption, severe immunosuppression, higher body mass index), cases of osteonecrosis have beenreported particularly in patients with advanced HIV-disease and/or long-term exposure to combinationantiretroviral therapy (CART). Patients should be advised to seek medical advice if they experiencejoint aches and pain, joint stiffness or difficulty in movement.

Lamivudine/Zidovudine Teva should not be taken with any other medicinal products containinglamivudine or medicinal products containing emtricitabine.

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

Patients with a creatinine clearance between 30 and 49 mL/min receiving Lamivudine/Zidovudine

Teva may experience a 1.6-to 3.3-fold higher lamivudine exposure (AUC) than patients with acreatinine clearance ≥50 mL/min. There are no safety data from randomized, controlled trialscomparing Lamivudine/Zidovudine to the individual components in patients with a creatinineclearance between 30 and 49 mL/min who received dose-adjusted lamivudine. In the originallamivudine registrational trials in combination with zidovudine, higher lamivudine exposures wereassociated with higher rates of haematologic toxicities (neutropenia and anaemia), althoughdiscontinuations due to neutropenia or anaemia each occurred in <1% of subjects. Other lamivudine-related adverse events (such as gastro-intestinal and hepatic disorders) may occur.

Patients with a sustained creatinine clearance between 30 and 49 mL/min who receive

Lamivudine/Zidovudine Teva should be monitored for lamivudine-related adverse events, notablyhaematologic toxicities. If new or worsening neutropenia or anaemia develop, a dose adjustment oflamivudine, per lamivudine prescribing information, is indicated, which cannot be achieved with

Lamivudine/Zidovudine Teva. Lamivudine/Zidovudine Teva should be discontinued and theindividual components should be used to construct the treatment regimen.

Excipient(s)

This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium-free’.

Lamivudine/Zidovudine Teva contains lamivudine and zidovudine, therefore any interactionsidentified for these individually are relevant to Lamivudine/Zidovudine Teva. Clinical studies haveshown 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 secretionof lamivudine in the urine is mediated through organic cation transporters (OCTs); co-administrationof 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, thereis little potential for interactions with antiretroviral protease inhibitors, non-nucleosides and othermedicinal products metabolised by major P450 enzymes.

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

Drugs by Therapeutic Area Interaction Recommendation

Geometric mean change (%) concerning co-(Possible mechanism) administration

ANTIRETROVIRAL MEDICINAL PRODUCTS

Didanosine/Lamivudine Interaction not studied. No dosage adjustmentnecessary.

Didanosine /Zidovudine Interaction not studied.

Stavudine/Lamivudine Interaction not studied. Combination not

Stavudine/Zidovudine In vitro antagonism of anti-HIV recommended.

activity between stavudine andzidovudine could result indecreased efficacy of bothdrugs.

ANTI-INFECTIVE PRODUCTS

Atovaquone/Lamivudine Interaction not studied. As only limited data available

Atovaquone/Zidovudine Zidovudine AUC ↑33% the clinical significance is(750 mg twice daily with Atovaquone AUC ↔ unknown.food/200 mg thrice daily)

Clarithromycin/Lamivudine Interaction not studied. Separate administration of

Clarithromycin/Zidovudine Zidovudine AUC ↓12% Lamivudine/Zidovudine Teva(500 mg twice daily/100 mg and clarithromycin by at leastevery 4 hours) 2 hours

Trimethoprim/sulfamethoxazole Lamivudine: AUC ↑40% No Lamivudine/Zidovudine(Co-trimoxazole)/Lamivudine Teva dosage adjustment(160 mg/800 mg once daily for Trimethoprim: AUC ↔ necessary, unless patient has5 days/300 mg single dose) Sulfamethoxazole: AUC ↔ renal impairment (See Section4.2).(organic cation transporterinhibition) When concomitant

Trimethoprim/sulfamethoxazole Interaction not studied. administration with co-(Co-trimoxazole)/Zidovudine trimoxazole is warranted,patients should be monitoredclinically. High doses oftrimethoprim/sulfamethoxazole for thetreatment of Pneumocystisjirovecii pneumonia (PCP) andtoxoplasmosis have not beenstudied and should be avoided.

ANTIFUNGALS

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

Fluconazole/Zidovudine Zidovudine AUC ↑74% available the clinical(400 mg once daily/200 mg significance is not known.thrice daily) (UGT inhibition) Monitor for signs ofzidovudine toxicity (seesection 4.8).

ANTIMYCOBACTERIALS

Rifampicin/Lamivudine Interaction not studied. Insufficient data to

Rifampicin/Zidovudine Zidovudine AUC ↓48% recommend dosage(600 mg once daily/200 mg adjustment.thrice daily) (UGT induction)

ANTICONVULSANTS

Phenobarbital/Lamivudine Interaction not studied. Insufficient data to

Phenobarbital/Zidovudine Interaction not studied. recommend dosageadjustment.

Potential to slightly decreasezidovudine plasmaconcentrations through UGTinduction.

Phenytoin/Lamivudine Interaction not studied. Monitor phenytoin

Phenytoin/Zidovudine Phenytoin AUC ↑↓ concentrations.

Valproic acid/Lamivudine Interaction not studied. As only limited data are

Valproic acid/Zidovudine Zidovudine AUC ↑80% available the clinical(250 mg or 500 mg thrice significance is not known.daily/100 mg thrice daily) (UGT inhibition) Monitor for signs ofzidovudine toxicity (seesection 4.8).

ANTIHISTAMINES (HISTAMINE H1 RECEPTOR ANTAGONISTS)

Ranitidine/Lamivudine Interaction not studied. No dosage adjustmentnecessary.

Clinically significantinteraction unlikely. Ranitidineeliminated only in part by renalorganic cation transport system.

Ranitidine/Zidovudine Interaction not studied

Cimetidine/Lamivudine Interaction not studied. No dosage adjustmentnecessary.

Clinically significantinteraction unlikely. Cimetidineeliminated only in part by renalorganic cation transport system.

Cimetidine/Zidovudine Interaction not studied.

CYTOTOXICS

Cladribine/Lamivudine Interaction not studied Therefore the concomitant useof lamivudine with cladribine

In vitro lamivudine inhibits the is not recommendedintracellular phosphorylation of (see section 4.4)cladribine leading to a potentialrisk of cladribine loss ofefficacy in case of combinationin the clinical setting. Someclinical findings also support apossible interaction betweenlamivudine and cladribine

OPIOIDS

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

Methadone/Zidovudine Zidovudine AUC ↑43% available the clinical(30 to 90 mg once daily/200 mg Methadone AUC ↔ significance is not known.every 4 hours) Monitor for signs ofzidovudine toxicity (seesection 4.8).

Methadone dosage adjustmentunlikely in majority ofpatients; occasionallymethadone re-titration may berequired.

URICOSURIC

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

Probenecid/Zidovudine Zidovudine AUC ↑106% available the clinical(500 mg four times significance is not known.daily/2 mg/kg thrice daily) (UGT inhibition) Monitor for signs ofzidovudine toxicity (seesection 4.8).

MISCELLANEOUS

Sorbitol solution (3.2g , 10.2 g, Single dose lamivudine oral When possible, avoid chronic13.4 g)/ Lamivudine solution 300 mg coadministration of

Lamivudine: Lamivudine/Zidovudine Tevawith medicinal products

AUC ↓ 14%; 32%; 36% containing sorbitol or otherosmotic acting poly-alcohols

Cmax ↓ 28%; 52%, 55%. or monosaccharide alcohols(e.g. xylitol, mannitol, lactitol,maltitol). Consider morefrequent monitoring of HIV-1viral load when chroniccoadministration cannot beavoided.

Abbreviations: ↑ = Increase; ↓=decrease; ↔= no significant change; AUC=area under theconcentration versus time curve; Cmax=maximum observed concentration; CL/F=apparent oralclearance

Exacerbation of anaemia due to ribavirin has been reported when zidovudine is part of the regimenused to treat HIV although the exact mechanism remains to be elucidated. The concomitant use ofribavirin 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 isalready established. This would be particularly important in patients with a known history ofzidovudine induced anaemia.

Concomitant treatment, especially acute therapy, with potentially nephrotoxic or myelosuppressivemedicinal products (e.g. systemic pentamidine, dapsone, pyrimethamine, co-trimoxazole,amphotericin, flucytosine, ganciclovir, interferon, vincristine, vinblastine and doxorubicin) may alsoincrease the risk of adverse reactions to zidovudine. If concomitant therapy with

Lamivudine/Zidovudine Teva and any of these medicinal products is necessary then extra care shouldbe taken in monitoring renal function and haematological parameters and, if required, the dosage ofone or more agents should be reduced.

Limited data from clinical trials do not indicate a significantly increased risk of adverse reactions tozidovudine with cotrimoxazole (see interaction information above relating to lamivudine and co-trimoxazole), aerosolised pentamidine, pyrimethamine and acyclovir at doses used in prophylaxis.

As a general rule, when deciding to use antiretroviral agents for the treatment of HIV infection inpregnant 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. Inthe present case, the use in pregnant women of zidovudine, with subsequent treatment of the newborninfants, has been shown to reduce the rate of maternal-foetal transmission of HIV. A large amount ofdata on pregnant women taking lamivudine or zidovudine indicate no malformative toxicity (morethan 3000 outcomes from first trimester exposure each of which over 2000 outcomes involvedexposure to both lamivudine and zidovudine). The malformative risk is unlikely in humans based onthe mentioned large amount of data.

The active ingredients of Lamivudine/Zidovudine Teva may inhibit cellular DNA replication andzidovudine has been shown to be transplacental carcinogen in one animal study (see section 5.3). Theclinical relevance of these findings is unknown.

For patients co-infected with hepatitis who are being treated with lamivudine containing medicinalproducts such as Lamivudine/Zidovudine Teva and subsequently become pregnant, considerationshould 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 andin vivo to cause a variable degree of mitochondrial damage. There have been reports of mitochondrialdysfunction in HIV-negative infants exposed in utero and/or post-natally to nucleoside analogues (seesection 4.4).

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

Based on more than 200 mother/child pairs treated for HIV, serum concentrations of lamivudine inbreastfed infants of mothers treated for HIV are very low (< 4% of maternal serum concentrations) andprogressively decrease to undetectable levels when breastfed infants reach 24 weeks of age. There areno 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 meanconcentration of zidovudine was similar in human milk and serum.

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

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

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

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

Adverse reactions have been reported during therapy for HIV disease with lamivudine and zidovudineseparately or in combination. For many of these events, it is unclear whether they are related tolamivudine, zidovudine, the wide range of medicinal products used in the management of HIVdisease, or as a result of the underlying disease process.

As Lamivudine/Zidovudine Teva contains lamivudine and zidovudine, the type and severity ofadverse reactions associated with each of the compounds may be expected. There is no evidence ofadded toxicity following concurrent administration of the two compounds.

Cases of lactic acidosis, sometimes fatal, usually associated with severe hepatomegaly and hepaticsteatosis, 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 inthe face, limbs and buttocks. Patients receiving Lamivudine/Zidovudine Teva should be frequentlyexamined and questioned for signs of lipoatrophy. When such development is found, treatment with

Lamivudine/Zidovudine Teva should not be continued (see section 4.4).

Weight and levels of blood lipids and glucose may increase during antiretroviral therapy (seesection 4.4).

In HIV-infected patients with severe immune deficiency at the time of initiation of combinationantiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunisticinfections may arise. Autoimmune disorders (such as Graves’ disease and autoimmune hepatitis) havealso been reported to occur in the setting of immune reactivation; however, the reported time to onsetis 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 riskfactors, advanced HIV disease or long-term exposure to CART. The frequency of this is unknown (seesection 4.4).

Lamivudine

The adverse reactions considered at least possibly related to the treatment are listed below by bodysystem, 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 decreasingseriousness.

Blood and lymphatic systems disorders

Uncommon: Neutropenia and anaemia (both occasionally severe), thrombocytopenia

Very rare: Pure red cell aplasia

Very Rare: Lactic acidosis

Common: Headache, insomnia

Very rare: Peripheral neuropathy (or paraesthesiae)

Common: Cough, nasal symptoms

Common: Nausea, vomiting, abdominal pain or cramps, diarrhoea

Rare: Pancreatitis, rises in serum amylase

Uncommon: Transient rises in liver enzymes (AST, ALT)

Rare: Hepatitis

Common: Rash, alopecia

Rare: Angioedema

Common: Arthralgia, muscle disorders

Rare: Rhabdomyolysis

Common: Fatigue, malaise, fever

Zidovudine

The adverse reactions profile appears similar for adults and adolescents. The most serious adversereactions include anaemia (which may require transfusions), neutropenia and leukopenia. Theseoccurred more frequently at higher dosages (1200-1500 mg/day) and in patients with advanced HIVdisease (especially when there is poor bone marr3ow reserve prior to treatment), and particularly inpatients with CD4 cell counts less than 100/mm (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 bodysystem, 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 decreasingseriousness.

Common: Anaemia, neutropenia and leukopenia

Uncommon: Thrombocytopenia and pancytopenia (with marrow hypoplasia)

Rare: Pure red cell aplasia

Very rare: Aplastic anaemia

Rare: Lactic acidosis in the absence of hypoxaemia, anorexia

Rare: Anxiety and depression

Very common: Headache

Common: Dizziness

Rare: Insomnia, paraesthesiae, somnolence, loss of mental acuity, convulsions

Rare:Cardiomyopathy

Uncommon: Dyspnoea

Rare: Cough

Very common: Nausea

Common: Vomiting, abdominal pain and diarrhoea

Uncommon: Flatulence

Rare: Oral mucosa pigmentation, taste perversion and dyspepsia. Pancreatitis

Common: Raised blood levels of liver enzymes and bilirubin

Rare: Liver disorders such as severe hepatomegaly with steatosis

Uncommon: Rash and pruritus

Rare: Nail and skin pigmentation, urticaria and sweating

Common: Myalgia

Uncommon: Myopathy

Rare: Urinary frequency

Rare: Gynaecomastia

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 ofnausea and other frequently reported clinical adverse events consistently decreases over time duringthe first few weeks of therapy with zidovudine.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

There is limited experience of overdosage with lamivudine/zidovudine. No specific symptoms or signshave been identified following acute overdose with zidovudine or lamivudine apart from those listedas undesirable effects.

If overdosage occurs the patient should be monitored for evidence of toxicity (see section 4.8), andstandard supportive treatment applied as necessary. Since lamivudine is dialysable, continuoushaemodialysis 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, butenhance the elimination of the glucuronide metabolite. For more details physicians should refer to theindividual prescribing information for lamivudine and zidovudine.

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 metabolisedintracellularly to their active moieties, lamivudine 5’-triphosphate (TP) and zidovudine 5’-TPrespectively. 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-2replication in vitro; lamivudine is also active against zidovudine-resistant clinical isolates of HIV. Noantagonistic 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 andother antiretrovirals (tested agents: abacavir, didanosine and interferon-alpha).

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

In vitro data tend to suggest that the continuation of lamivudine in anti-retroviral regimen despite thedevelopment of M184V might provide residual anti-retroviral activity (likely through impaired viralfitness). The clinical relevance of these findings is not established. Indeed, the available clinical dataare very limited and preclude any reliable conclusion in the field. In any case, initiation of susceptiblenucleoside analogue reverse-transcriptase inhibitors (NRTIs) should always be preferred tomaintenance 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 ofantiretroviral agents. Zidovudine and stavudine maintain their antiretroviral activities againstlamivudine-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-folddecrease in susceptibility to didanosine; the clinical significance of these findings is unknown. In vitrosusceptibility testing has not been standardised and results may vary according to methodologicalfactors.

Lamivudine demonstrates low cytotoxicity to peripheral blood lymphocytes, to establishedlymphocyte and monocyte-macrophage cell lines, and to a variety of bone marrow progenitor cells invitro. Resistance to thymidine analogues (of which zidovudine is one) is well characterised and isconferred by the stepwise accumulation of up to six specific mutations in the HIV reverse transcriptaseat codons 41, 67, 70, 210, 215 and 219. Viruses acquire phenotypic resistance to thymidine analoguesthrough the combination of mutations at codons 41 and 215 or by the accumulation of at least four ofthe six mutations. These thymidine analogue mutations alone do not cause high-level cross-resistanceto any of the other nucleosides, allowing for the subsequent use of any of the other approved reversetranscriptase inhibitors.

Two patterns of multi-drug resistance mutations, the first characterised by mutations in the HIVreverse transcriptase at codons 62, 75, 77, 116 and 151 and the second involving a T69S mutation plusa 6-base pair insert at the same position, result in phenotypic resistance to AZT as well as to the otherapproved NRTIs. Either of these two patterns of multinucleoside resistance mutations severely limitsfuture therapeutic options.

Clinical Experience

In clinical trials, lamivudine in combination with zidovudine has been shown to reduce HIV-1 viralload and increase CD4 cell count. Clinical end-point data indicate that lamivudine in combination withzidovudine, results in a significant reduction in the risk of disease progression and mortality.

Lamivudine and zidovudine have been widely used as components of antiretroviral combinationtherapy 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 inantiretroviral-naive patients as well as in patients presenting with viruses containing the M184Vmutations.

Evidence from clinical studies shows that lamivudine plus zidovudine delays the emergence ofzidovudine resistant isolates in individuals with no prior antiretroviral therapy. Subjects receivinglamivudine and zidovudine with or without additional concomitant antiretroviral therapies and whoalready present with the M184V mutant virus also experience a delay in the onset of mutations thatconfer resistance to zidovudine and stavudine (Thymidine Analogue Mutations; TAMs).

The relationship between in vitro susceptibility of HIV to lamivudine and zidovudine and clinicalresponse 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 ofadult patients with chronic HBV infection (for details of clinical studies, see the prescribinginformation for lamivudine 100 mg). However, for the treatment of HIV infection only a 300 mg dailydose 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.

Lamivudine and zidovudine are well absorbed from the gastrointestinal tract. The bioavailability oforal lamivudine in adults is normally between 80-85 % and for zidovudine 60-70 %.

A bioequivalence study compared lamivudine/zidovudine with lamivudine 150 mg and zidovudine300 mg tablets taken together. The effect of food on the rate and extent of absorption was also studied.

Lamivudine/zidovudine was shown to be bioequivalent to lamivudine 150 mg and zidovudine 300 mggiven as separate tablets, when administered to fasting subjects.

Following single dose lamivudine/zidovudine administration in healthy volunteers, mean (CV)lamivudine and zidovudine Cmax values were 1.6 µg/mL (32 %) and 2.0 µg/mL (40 %), respectivelyand 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∞) andestimates of half-life following administration of lamivudine/zidovudine with food were similar whencompared to fasting subjects, although the rates of absorption (Cmax, tmax) were slowed. Based on thesedata lamivudine/zidovudine may be administered with or without food.

Administration of crushed tablets with a small amount of semi-solid food or liquid would not beexpected to have an impact on the pharmaceutical quality, and would therefore not be expected to alterthe clinical effect. This conclusion is based on the physicochemical and pharmacokinetic dataassuming that the patient crushes and transfers 100 % of the tablet and ingests immediately.

Intravenous studies with lamivudine and zidovudine showed that the mean apparent volume ofdistribution is 1.3 and 1.6 l/kg respectively. Lamivudine exhibits linear pharmacokinetics over thetherapeutic 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 involvingbinding site displacement are not anticipated with Lamivudine/Zidovudine Teva.

Data show that lamivudine and zidovudine penetrate the central nervous system (CNS) and reach thecerebrospinal fluid (CSF). The mean ratios of CSF/serum lamivudine and zidovudine concentrations2-4 hours after oral administration were approximately 0.12 and 0.5 respectively. The true extent of

CNS penetration of lamivudine and its relationship with any clinical efficacy is unknown.

Metabolism of lamivudine is a minor route of elimination. Lamivudine is predominately clearedunchanged by renal excretion. The likelihood of metabolic drug interactions with lamivudine is lowdue 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 forapproximately 50-80 % of the administered dose eliminated by renal excretion. 3’-amino-3’-deoxythymidine (AMT) has been identified as a metabolite of zidovudine following intravenousdosing.

The observed lamivudine half-life of elimination is 18 to 19 hours. The mean systemic clearance oflamivudine is approximately 0.32 l/h/kg, with predominantly renal clearance (>70 %) via the organiccationic transport system. Studies in patients with renal impairment show lamivudine elimination isaffected by renal dysfunction. Dose reduction is required for patients with creatinine clearance≤30 mL/min (see section 4.2).

From studies with intravenous zidovudine, the mean terminal plasma half-life was 1.1 hours and themean 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 concentrationsare 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 inadults. 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 μM(1.19 μg/mL) following a dose of 120 mg zidovudine (in solution)/m2 body surface area and 7.7 μM(2.06 μg/mL) at 180 mg/m2 body surface area. Dosages of 180 mg/m2 four times daily in childrenproduced similar systemic exposure (24 hour AUC 40.0 h μM or 10.7 h μg/mL) as doses of 200 mgsix times daily in adults (40.7 h μM or 10.9 h μg/mL).

In six HIV-infected children from 2 to 13 years of age, zidovudine plasma pharmacokinetics wereevaluated while subjects were receiving 120 mg/m2 zidovudine three times daily and again afterswitching to 180 mg/m2 twice daily. Systemic exposures (daily AUC and Cmax) in plasma from thetwice daily regimen appeared equivalent to those from the same total daily dose given in three divideddoses [Bergshoeff, 2004].

In general, lamivudine pharmacokinetics in paediatric patients are similar to adults. However, absolutebioavailability (approximately 55-65 %) was reduced in paediatric patients below 12 years of age. Inaddition, 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 forlamivudine in children (aged more than three months and weighing less than 30 kg) is 4 mg/kg twice aday. 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.

The clinically relevant effects of lamivudine and zidovudine in combination are anaemia, neutropeniaand leukopenia.

Neither lamivudine nor zidovudine are mutagenic in bacterial tests, but consistent with othernucleoside analogues, inhibit cellular DNA replication in in vitro mammalian tests such as the mouselymphoma assay.

Lamivudine has not shown any genotoxic activity in in vivo studies at doses that gave plasmaconcentrations up to 40-50 times higher than clinical plasma levels. Zidovudine showed clastogeniceffects in an oral repeated dose micronucleus test in mice. Peripheral blood lymphocytes fromacquired immune deficiency syndrome (AIDS) patients receiving zidovudine treatment have also beenobserved 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 preventionof mother to child viral transmission. Zidovudine was also incorporated into DNA from cord bloodleukocytes of infants from zidovudine-treated mothers. A transplacental genotoxicity study conductedin 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 combinationsustained a higher level of nucleoside analogue-DNA incorporation into multiple foetal organs, andshowed evidence of more telomere shortening than in those exposed to zidovudine alone. The clinicalsignificance 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 carcinogenicpotential.

In oral carcinogenicity studies with zidovudine in mice and rats, late appearing vaginal epithelialtumours were observed. A subsequent intravaginal carcinogenicity study confirmed the hypothesis thatthe vaginal tumours were the result of long term local exposure of the rodent vaginal epithelium tohigh concentrations of unmetabolised zidovudine in urine. There were no other zidovudine-relatedtumours observed in either sex of either species.

In addition, two transplacental carcinogenicity studies have been conducted in mice. In one study, bythe US National Cancer Institute, zidovudine was administered at maximum tolerated doses topregnant mice from day 12 to 18 of gestation. One year post-natally, there was an increase in theincidence of tumours in the lung, liver and female reproductive tract of offspring exposed to thehighest 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, withexposure 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 inthe standard oral carcinogenicity study. The second study thus provided no evidence that zidovudineacts as a transplacental carcinogen.

While the clinical relevance of these findings is unknown, these data suggest that a carcinogenic riskto humans is outweighed by the potential clinical benefit.

In reproductive toxicity studies lamivudine has demonstrated evidence of causing an increase in earlyembryonic deaths in the rabbit at relatively low systemic exposures, comparable to those achieved inman, but not in the rat even at very high systemic exposure. Zidovudine had a similar effect in bothspecies, 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 increasedincidence of malformations, but no evidence of foetal abnormalities was observed at lower doses.

Cellulose, microcrystalline

Sodium starch glycolate (Type A)

Sodium stearyl fumarate

Tablet film-coat

Hypromellose 3cP

Hypromellose 6cP

Polysorbate 80

Macrogol 400

Titanium dioxide E171

Not applicable.

30 months

This medicinal product does not require any special storage conditions.

OPA/Alu/PVC Aluminium blisters

Containers:

White opaque HDPE containers with white opaque polyethylene child resistant screw cap with

Aluminium seal.

Each pack type contains 60 film-coated tablets.

Not all pack sizes may be marketed.

No special requirements for disposal.

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

Teva B.V.

Swensweg 52031GA Haarlem

The Netherlands

EU/1/10/663/001

EU/1/10/663/002

Date of first authorisation: 02 March 2011

Date of latest renewal: 19 November 2015

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.