KIVEXA 600mg / 300mg tablets medication leaflet

Kivexa 600 mg/300 mg film-coated tablets

Each film-coated tablet contains 600 mg of abacavir (as sulfate) and 300 mg lamivudine.

Each 600 mg/300 mg tablet contains 1.7 mg sunset yellow FCF (E110) and 2.31 mg sodium.

For the full list of excipients see section 6.1.

Film-coated tablet (tablet).

Orange, film-coated, modified capsule shaped tablets, debossed with GS FC2 on one side.

Kivexa is indicated in antiretroviral combination therapy for the treatment of Human

Immunodeficiency Virus (HIV) infection in adults, adolescents and children weighing at least 25 kg(see sections 4.4 and 5.1).

Before initiating treatment with abacavir, screening for carriage of the HLA-B*5701 allele should beperformed in any HIV-infected patient, irrespective of racial origin (see section 4.4). Abacavir shouldnot be used in patients known to carry the HLA-B*5701 allele.

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

Adults, adolescents and children weighing at least 25 kg

The recommended dose of Kivexa is one tablet once daily.

Children Under 25 kg

Kivexa should not be administered to children who weigh less than 25 kg because it is a fixed-dosetablet that cannot be dose reduced.

Kivexa is a fixed-dose tablet and should not be prescribed for patients requiring dose adjustments.

Separate preparations of abacavir or lamivudine are available in cases where discontinuation or doseadjustment of one of the active substances is indicated. In these cases the physician should refer to theindividual product information for these medicinal products.

No pharmacokinetic data are currently available in patients over 65 years of age. Special care isadvised in this age group due to age associated changes such as the decrease in renal function andalteration of haematological parameters.

Kivexa is not recommended for use in patients with a creatinine clearance < 30 mL/min (see section5.2). No dose adjustment is required in patients with mild or moderate renal impairment. However, thelamivudine exposure is significantly increased in patients with a creatinine clearance < 50 mL/min (seesection 4.4).

Abacavir is primarily metabolised by the liver. No clinical data are available in patients with moderateor severe hepatic impairment, therefore the use of Kivexa is not recommended unless judged necessary.

In patients with mild hepatic impairment (Child-Pugh score 5-6) close monitoring is required, includingmonitoring of abacavir plasma levels if feasible (see sections 4.4 and 5.2).

The safety and efficacy of Kivexa in children weighing less than 25 kg has not been established.

Currently available data are described in section 4.8, 5.1 and 5.2 but no recommendation on posologycan be made.

Oral use

Kivexa can be taken with or without food.

Hypersensitivity to the active substances or to any of the excipients listed in section 6.1. See sections4.4 and 4.8.

The special warnings and precautions relevant to abacavir and lamivudine are included in this section.

There are no additional precautions and warnings relevant to Kivexa.

Hypersensitivity reactions (see also section 4.8 )

Abacavir is associated with a risk for hypersensitivity reactions (HSR) (see section4.8) ) characterisedby fever and/or rash with other symptoms indicating multi-organ involvement. HSRs have beenobserved with abacavir, some of which have been life-threatening, and in rare cases fatal, when notmanaged appropriately.

The risk for abacavir HSR to occur is high for patients who test positive for the HLA-B*5701 allele.

However, abacavir HSRs have been reported at a lower frequency in patients who do not carry thisallele.

Therefore the following should be adhered to:

* HLA-B*5701 status must always be documented prior to initiating therapy.

* Kivexa should never be initiated in patients with a positive HLA-B*5701 status, nor in patientswith a negative HLA-B*5701 status who had a suspected abacavir HSR on a previous abacavir-containing regimen. (e.g. Ziagen, Trizivir, Triumeq)

* Kivexa must be stopped without delay, even in the absence of the HLA-B*5701 allele, if an

HSR is suspected. Delay in stopping treatment with Kivexa after the onset of hypersensitivitymay result in a life-threatening reaction.

* After stopping treatment with Kivexa for reasons of a suspected HSR, Kivexa or any othermedicinal product containing abacavir (e.g. Ziagen, Trizivir, Triumeq) must never be re-initiated.

* Restarting abacavir containing products following a suspected abacavir HSR can result in aprompt return of symptoms within hours. This recurrence is usually more severe than on initialpresentation, and may include life-threatening hypotension and death.

* In order to avoid restarting abacavir, patients who have experienced a suspected HSR should beinstructed to dispose of their remaining Kivexa tablets

* Clinical Description of abacavir HSR

Abacavir HSR has been well characterised through clinical studies and during post marketing follow-up.

Symptoms usually appeared within the first six weeks (median time to onset 11 days) of initiation oftreatment with abacavir, although these reactions may occur at any time during therapy.

Almost all HSR to abacavir include fever and/or rash. Other signs and symptoms that have beenobserved as part of abacavir HSR are described in detail in section 4.8 (Description of selected adversereactions), including respiratory and gastrointestinal symptoms. Importantly, such symptoms may leadto misdiagnosis of HSR as respiratory disease (pneumonia, bronchitis, pharyngitis), orgastroenteritis.

The symptoms related to HSR worsen with continued therapy and can be life-threatening. Thesesymptoms usually resolve upon discontinuation of abacavir.

Rarely, patients who have stopped abacavir for reasons other than symptoms of HSR have alsoexperienced life-threatening reactions within hours of re- initiating abacavir therapy (see Section 4.8

Description of selected adverse reactions). Restarting abacavir in such patients must be done in a settingwhere medical assistance is readily available.

An increase in weight and in levels of blood lipids and glucose may occur during antiretroviral therapy.

Such changes may in part be linked to disease control and life style. For lipids, there is in some casesevidence for a treatment effect, while for weight gain there is no strong evidence relating this to anyparticular treatment. For monitoring of blood lipids and glucose reference is made to established HIVtreatment guidelines. Lipid disorders should be managed as clinically appropriate.

Pancreatitis has been reported, but a causal relationship to lamivudine and abacavir is uncertain.

Risk of virological failure

- Triple nucleoside therapy: There have been reports of a high rate of virological failure, and ofemergence of resistance at an early stage when abacavir and lamivudine were combined with tenofovirdisoproxil fumarate as a once daily regimen.

- The risk of virological failure with Kivexa might be higher than with other therapeutic options (seesection 5.1).

The safety and efficacy of Kivexa has not been established in patients with significant underlying liverdisorders. Kivexa is not recommended in patients with moderate or severe hepatic impairment (seesections 4.2 and 5.2).

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 chronic hepatitis B or C virus

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

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 can befound in the Summary of Product Characteristics for products containing lamivudine that are indicatedfor the treatment of HBV.

If Kivexa is discontinued in patients co-infected with HBV, periodic monitoring of both liver functiontests and markers of HBV replication is recommended, as withdrawal of lamivudine may result in anacute exacerbation of hepatitis (see the Summary of Product Characteristics for products containinglamivudine that are indicated for the treatment of HBV).

Nucleoside and nucleotide analogues may impact mitochondrial function to a variable degree, which ismost pronounced with stavudine, didanosine and zidovudine. There have been reports of mitochondrialdysfunction in HIV-negative infants exposed in utero and/or post-natally to nucleoside analogues: thesehave predominantly concerned treatment with regimens containing zidovudine. The main adversereactions reported are haematological disorders (anaemia, neutropenia) and metabolic disorders(hyperlactatemia, hyperlipasemia). These reactions have often been transitory. Late onset neurologicaldisorders have been reported rarely (hypertonia, convulsion, abnormal behaviour). Whether suchneurological disorders are transient or permanent is currently unknown. These findings should beconsidered for any child exposed in utero to nucleotide and nucleotide analogues, who presents withsevere clinical findings of unknown etiology, particularly neurologic findings. These findings do notaffect current national recommendations to use antiretroviral therapy in pregnant women to preventvertical transmission of HIV.

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, suchreactions have been observed within the first few weeks or months of initiation of CART. Relevantexamples are cytomegalovirus retinitis, generalised and/or focal mycobacterial infections, and

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

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 CART.

Patients should be advised to seek medical advice if they experience joint aches and pain, joint stiffnessor difficulty in movement.

Patients should be advised that Kivexa or any other antiretroviral therapy does not cure HIV infectionand that they may still develop opportunistic infections and other complications of HIV infection.

Therefore patients should remain under close clinical observation by physicians experienced in thetreatment of these associated HIV diseases.

Although the available data from clinical and observational studies with abacavir show inconsistentresults, several studies suggest an increased risk of cardiovascular events (notably myocardialinfarction) in patients treated with abacavir. Therefore, when prescribing Kivexa, action should betaken to minimize all modifiable risk factors (e.g. smoking, hypertension, and hyperlipidaemia).

In addition, alternative treatment options to the abacavir containing regimen should be considered whentreating patients with a high cardiovascular risk.

Patients with a creatinine clearance between 30 and 49 mL/min receiving Kivexa may experience a1.6 - to 3.3 - fold higher lamivudine exposure (AUC) than patients with a creatinine clearance≥50 mL/min. There are no safety data from randomized, controlled trials comparing Kivexa to theindividual components in patients with a creatinine clearance between 30 and 49 mL/min who receiveddose-adjusted lamivudine. In the original lamivudine registrational trials in combination withzidovudine, higher lamivudine exposures were associated with higher rates of haematologic toxicities(neutropenia and anaemia), although discontinuations due to neutropenia or anaemia each occurred in<1% of subjects. Other lamivudine-related adverse events (such as gastro-intestinal and hepaticdisorders) may occur.

Patients with a sustained creatinine clearance between 30 and 49 mL/min who receive Kivexa shouldbe monitored for lamivudine-related adverse events, notably haematologic toxicities. If new orworsening neutropenia or anaemia develop, a dose adjustment of lamivudine, per lamivudineprescribing information, is indicated, which cannot be achieved with Kivexa. Kivexa should bediscontinued and the individual components should be used to construct the treatment regimen.

Drug Interactions

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

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

Kivexa contains the azo colouring agent sunset yellow, which may cause allergic reactions.

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

Kivexa contains abacavir and lamivudine, therefore any interactions identified for these individuallyare relevant to Kivexa. Clinical studies have shown that there are no clinically significant interactionsbetween abacavir and lamivudine.

Abacavir is metabolised by UDP-glucuronyltransferase (UGT) enzymes and alcohol dehydrogenase;co-administration of inducers or inhibitors of UGT enzymes or with compounds eliminated throughalcohol dehydrogenase could alter abacavir exposure. Lamivudine is cleared renally. Active renalsecretion of lamivudine in the urine is mediated through organic cation transporters (OCTs);co-administration of lamivudine with OCT inhibitors may increase lamivudine exposure.

Abacavir and lamivudine are not significantly metabolised by cytochrome P450 enzymes (such as CYP3A4, CYP 2C9 or CYP 2D6) nor do they induce this enzyme system. Lamivudine does not inhibitcytochrome P450 enzymes. Abacavir shows limited potential to inhibit metabolism mediated by

CYP3A4 and has been shown in vitro not to inhibit CYP2C9 or CYP 2D6 enzymes. In vitro studieshave shown that abacavir has potential to inhibit cytochrome P450 1A1 (CYP1A1). Therefore, there islittle potential for interactions with antiretroviral protease inhibitors, non-nucleosides and othermedicinal products metabolised by major P450 enzymes.

Kivexa should not be taken with any other medicinal products containing lamivudine (see section 4.4).

The list below should not be considered exhaustive but is representative of the classes studied.

Drugs by Therapeutic Area Interaction Recommendation concerning

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

ANTIRETROVIRAL MEDICINAL PRODUCTS

Didanosine /Abacavir Interaction not studied. No dosage adjustment

Didanosine/Lamivudine Interaction not studied. necessary.

Zidovudine/Abacavir Interaction not studied

Zidovudine/Lamivudine Lamivudine: AUC ↔

Zidovudine 300 mg single dose Zidovudine : AUC ↔

Lamivudine 150 mg single dose

Emtricitabine/Lamivudine Due to similarities, Kivexashould not be administeredconcomitantly with othercytidine analogues, such asemtricitabine.

ANTI-INFECTIVE PRODUCTS

Trimethoprim/sulfamethoxazole Interaction not studied. No Kivexa dosage adjustment(Co-trimoxazole)/Abacavir necessary.

Trimethoprim/sulfamethoxazole Lamivudine: AUC ↑40%(Co-trimoxazole)/Lamivudine When concomitant(160 mg/800 mg once daily for Trimethoprim: AUC ↔ administration with5 days/300 mg single dose) Sulfamethoxazole: AUC ↔ co-trimoxazole is warranted,patients should be monitored(organic cation transporter clinically. High doses ofinhibition) trimethoprim/sulfamethoxazole for thetreatment of Pneumocystisjirovecii pneumonia (PCP) andtoxoplasmosis have not beenstudied and should be avoided

ANTIMYCOBACTERIALS

Rifampicin/Abacavir Interaction not studied. Insufficient data to recommenddosage adjustment.

Potential to slightly decreaseabacavir plasma concentrationsthrough UGT induction.

Rifampicin/Lamivudine Interaction not studied.

ANTICONVULSANTS

Phenobarbital/Abacavir Interaction not studied. Insufficient data to recommenddosage adjustment.

Potential to slightly decreaseabacavir plasma concentrationsthrough UGT induction.

Phenobarbital/Lamivudine Interaction not studied.

Phenytoin/Abacavir Interaction not studied. Insufficient data to recommenddosage adjustment.

Potential to slightly decreaseabacavir plasma concentrations Monitor phenytointhrough UGT induction. concentrations.

Phenytoin/Lamivudine Interaction not studied.

Drugs by Therapeutic Area Interaction Recommendation concerning

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

ANTIHISTAMINES (HISTAMINE H2 RECEPTOR ANTAGONISTS)

Ranitidine/Abacavir Interaction not studied. No dosage adjustment

Ranitidine/Lamivudine Interaction not studied. necessary.

Clinically significant interactionunlikely. Ranitidine eliminatedonly in part by renal organiccation transport system.

Cimetidine/Abacavir Interaction not studied. No dosage adjustment

Cimetidine/Lamivudine Interaction not studied. necessary.

Clinically significant interactionunlikely. Cimetidine eliminatedonly in part by renal organiccation transport system.

CYTOTOXICS

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

In vitro lamivudine inhibits the is not recommended (seeintracellular phosphorylation of 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/Abacavir Abacavir: AUC ↔ No Kivexa dosage adjustment(40 to 90mg once daily for 14 Cmax ↓35% necessary.days/600mg single dose, then600mg twice daily for 14 days) Methadone: CL/F ↑22% Methadone dosage adjustmentunlikely in majority of

Methadone/Lamivudine Interaction not studied. patients; occasionallymethadone re-titration may berequired.

RETINOIDS

Retinoid compounds Interaction not studied. Insufficient data to(e.g. isotretinoin)/Abacavir recommend dosage

Possible interaction given adjustment.common pathway of eliminationvia alcohol dehydrogenase.

Retinoid compounds Interaction not studied.(e.g. isotretinoin)/Lamivudine

No drug interaction studies

Drugs by Therapeutic Area Interaction Recommendation concerning

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

MISCELLANEOUS

Ethanol/Abacavir Abacavir: AUC ↑41% No dosage adjustment(0.7 g/kg single dose/600 mg Ethanol: AUC ↔ necessary.single dose)(Inhibition of alcoholdehydrogenase)

Ethanol/Lamivudine Interaction not studied.

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

Lamivudine: with medicinal productscontaining sorbitol or other

AUC ↓ 14%; 32%; 36% osmotic 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.

Riociguat/Abacavir Riociguat Riociguat dose may need to be

In vitro, abacavir inhibits reduced. Consult the riociguat

CYP1A1. Concomitant prescribing information foradministration of a single dose dosing recommendations.

of riociguat (0.5 mg) to HIVpatients receiving thecombination ofabacavir/dolutegravir/lamivudine(600mg/50mg/300mg oncedaily) led to an approximatelythree-fold higher riociguat

AUC(0-∞) when compared tohistorical riociguat AUC(0-∞)reported in healthy subjects.

Abbreviations: ↑ = Increase; ↓ = decrease; ↔ = no significant change; AUC = area under the concentration versus time curve;

Cmax = maximum observed concentration; CL/F = apparent oral clearance

Interaction studies have only been performed in adults.

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.

Animal studies with abacavir have shown toxicity to the developing embryo and foetus in rats, but notin rabbits. Animal studies with lamivudine showed an increase in early embryonic deaths in rabbits butnot in rats. (see section 5.3). The active ingredients of Kivexa may inhibit cellular DNA replication andabacavir has been shown to be carcinogenic in animal models (see section 5.3). The clinical relevanceof these findings is unknown. Placental transfer of abacavir and lamivudine has been shown to occur inhumans.

In pregnant women treated with abacavir, more than 800 outcomes after first trimester exposure andmore than 1000 outcomes after second and third trimester exposure indicate no malformative andfoetal/neonatal effect. In pregnant women treated with lamivudine, more than 1000 outcomes from firsttrimester and more than 1000 outcomes from second and third trimester exposure indicate nomalformative and foeto/neonatal effect. There are no data on the use of Kivexa in pregnancy, howeverthe malformative risk is unlikely in humans based on those data.

For patients co-infected with hepatitis who are being treated with a lamivudine containing medicinalproduct such as Kivexa and subsequently become pregnant, consideration should be given to thepossibility of a recurrence of hepatitis on discontinuation of lamivudine.

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

Abacavir and its metabolites are excreted into the milk of lactating rats. Abacavir is also excreted intohuman milk.

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 abacavir and lamivudine when administered to babies less than threemonths old.

It is recommended that women living with HIV do not breast-feed their infants in order to avoidtransmission of HIV.

Studies in animals showed that neither abacavir nor lamivudine had any effect on fertility (see section5.3).

No studies on the effects on ability to drive and use machines have been performed. The clinical statusof the patient and the adverse reaction profile of Kivexa should be borne in mind when considering thepatient’s ability to drive or operate machinery.

The adverse reactions reported for Kivexa were consistent with the known safety profiles of abacavirand lamivudine when given as separate medicinal products. For many of these adverse reactions it isunclear whether they are related to the active substance, the wide range of other medicinal productsused in the management of HIV infection, or whether they are a result of the underlying diseaseprocess.

Many of the adverse reactions listed in the table below occur commonly (nausea, vomiting, diarrhoea,fever, lethargy, rash) in patients with abacavir hypersensitivity. Therefore, patients with any of thesesymptoms should be carefully evaluated for the presence of this hypersensitivity (see section 4.4). Veryrarely cases of erythema multiforme, Stevens-Johnson syndrome or toxic epidermal necrolysis havebeen reported where abacavir hypersensitivity could not be ruled out. In such cases medicinal productscontaining abacavir should be permanently discontinued.

The adverse reactions considered at least possibly related to abacavir or lamivudine are listed 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).

Body system Abacavir Lamivudine

Blood and lymphatic systems Uncommon: Neutropenia anddisorders anaemia (both occasionallysevere), thrombocytopenia

Very rare: Pure red cell aplasia

Immune system disorders Common: hypersensitivity

Metabolism and nutrition Common: anorexia Very rare: lactic acidosisdisorders Very rare: lactic acidosis

Nervous system disorders Common: headache Common: Headache, insomnia.

Very rare: Cases of peripheralneuropathy (or paraesthesia)have been reported

Respiratory, thoracic and Common: Cough, nasalmediastinal disorders symptoms

Gastrointestinal disorders Common: nausea, vomiting, Common: Nausea, vomiting,diarrhoea abdominal pain or cramps,

Rare: pancreatitis has been diarrhoeareported, but a causal Rare: Rises in serum amylase.relationship to abacavir Cases of pancreatitis have beentreatment is uncertain reported

Hepatobiliary disorders Uncommon: Transient rises inliver enzymes (AST, ALT),

Rare: Hepatitis

Skin and subcutaneous tissue Common: rash (without Common: Rash, alopeciadisorders systemic symptoms) Rare: Angioedema

Very rare: erythemamultiforme, Stevens-Johnsonsyndrome and toxic epidermalnecrolysis

Musculoskeletal and connective Common: Arthralgia, muscletissue disorders disorders

Rare: Rhabdomyolysis

General disorders and Common: fever, lethargy, Common: fatigue, malaise,administration site conditions fatigue. fever.

The signs and symptoms of this HSR are listed below. These have been identified either from clinicalstudies or post marketing surveillance. Those reported in at least 10% of patients with ahypersensitivity reaction are in bold text.

Almost all patients developing hypersensitivity reactions will have fever and/or rash (usuallymaculopapular or urticarial) as part of the syndrome, however reactions have occurred without rash orfever. Other key symptoms include gastrointestinal, respiratory or constitutional symptoms such aslethargy and malaise.

Skin Rash (usually maculopapular or urticarial)

Gastrointestinal tract Nausea, vomiting, diarrhoea, abdominal pain, mouth ulceration

Respiratory tract Dyspnoea, cough, sore throat, adult respiratory distress syndrome,respiratory failure

Miscellaneous Fever, lethargy, malaise, oedema, lymphadenopathy, hypotension,conjunctivitis, anaphylaxis

Neurological/Psychiatry Headache, paraesthesia

Haematological Lymphopenia

Liver/pancreas Elevated liver function tests, hepatitis, hepatic failure

Musculoskeletal Myalgia, rarely myolysis, arthralgia, elevated creatine phosphokinase

Urology Elevated creatinine, renal failure

Symptoms related to this HSR worsen with continued therapy and can be life- threatening and in rareinstance, have been fatal.

Restarting abacavir following an abacavir HSR results in a prompt return of symptoms within hours.

This recurrence of the HSR is usually more severe than on initial presentation, and may include life-threatening hypotension and death. Similar reactions have also occurred infrequently after restartingabacavir in patients who had only one of the key symptoms of hypersensitivity (see above) prior tostopping abacavir; and on very rare occasions have also been seen in patients who have restartedtherapy with no preceding symptoms of a HSR (i.e., patients previously considered to be abacavirtolerant).

Weight and levels of blood lipids and glucose may increase during antiretroviral therapy (see section4.4)

In HIV-infected patients with severe immune deficiency at the time of initiation of combinationantiretroviral therapy, an inflammatory reaction to asymptomatic or residual opportunistic infectionsmay arise. Autoimmune disorders (such as Graves’ disease and autoimmune hepatitis) have also beenreported to occur in the setting of immune reconstitution; however, the reported time to onset is morevariable 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).

The safety database to support once daily dosing in paediatric patients comes from the ARROW Trial(COL105677) in which 669 HIV-1 infected paediatric subjects (from 12 months to ≤17 years old).received abacavir and lamivudine either once or twice daily (see section 5.1). Within this population,104 HIV-1 infected paediatric subjects weighing at least 25 kg received abacavir and lamivudine as

Kivexa once daily. No additional safety issues have been identified in paediatric subjects receivingeither once or twice daily dosing compared to adults.

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.

No specific symptoms or signs have been identified following acute overdose with abacavir orlamivudine, apart from those listed as undesirable effects.

If overdose 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 overdose, although this has not been studied. It is notknown whether abacavir can be removed by peritoneal dialysis or haemodialysis.

Pharmacotherapeutic group

Antivirals for systemic use, antivirals for treatment of HIV infections, combinations. ATC code:

J05AR02.

Abacavir and lamivudine are nucleoside analogue reverse transcriptase inhibitors (NRTIs), and arepotent selective inhibitors of HIV-1 and HIV-2 (LAV2 and EHO) replication. Both abacavir andlamivudine are metabolised sequentially by intracellular kinases to the respective 5'-triphosphate (TP)which are the active moieties. Lamivudine-TP and carbovir-TP (the active triphosphate form ofabacavir) are substrates for and competitive inhibitors of HIV reverse transcriptase (RT). However,their main antiviral activity is through incorporation of the monophosphate form into the viral DNAchain, resulting in chain termination. Abacavir and lamivudine triphosphates show significantly lessaffinity for host cell DNA polymerases.

No antagonistic effects in vitro were seen with lamivudine and other antiretrovirals (tested agents:didanosine, nevirapine and zidovudine). The antiviral activity of abacavir in cell culture was notantagonized when combined with the nucleoside reverse transcriptase inhibitors (NRTIs) didanosine,emtricitabine, stavudine, tenofovir or zidovudine, the non-nucleoside reverse transcriptase inhibitor(NNRTI) nevirapine, or the protease inhibitor (PI) amprenavir.

Antiviral Activity in vitro

Both abacavir and lamivudine have been shown to inhibit replication of laboratory strains and clinicalisolates of HIV in a number of cell types, including transformed T cell lines, monocyte/macrophagederived lines and primary cultures of activated peripheral blood lymphocytes (PBLs) andmonocyte/macrophages. The concentration of drug necessary to effect viral replication by 50% (EC50)or 50% inhibitory concentration (IC50) varied according to virus and host cell type.

The mean EC50 for abacavir against laboratory strains of HIV-1IIIB and HIV-1HXB2 ranged from 1.4to 5.8 µM. The median or mean EC50 values for lamivudine against laboratory strains of HIV-1 rangedfrom 0.007 to 2.3 µM. The mean EC50 against laboratory strains of HIV-2 (LAV2 and EHO) rangedfrom 1.57 to 7.5 µM for abacavir and from 0.16 to 0.51 µM for lamivudine.

The EC50 values of abacavir against HIV-1 Group M subtypes (A-G) ranged from 0.002 to 1.179 µM,against Group O from 0.022 to 1.21 µM, and against HIV-2 isolates, from 0.024 to 0.49 µM. Forlamivudine, the EC50 values against HIV-1 subtypes (A-G) ranged from 0.001 to 0.170 µM, against

Group O from 0.030 to 0.160 µM and against HIV-2 isolates from 0.002 to 0.120 µM in peripheralblood mononuclear cells.

Baseline HIV-1 samples from therapy-naive subjects with no amino acid substitutions associated withresistance have been evaluated using either the multi-cycle Virco Antivirogram™ assay (n=92 from

COL40263) or the the single cycle Monogram Biosciences PhenoSense™ assay (n=138 from

ESS30009). These resulted in median EC50 values of 0.912 µM (range: 0.493 to 5.017 µM) and 1.26µM (range 0.72 to 1.91 µM) respectively for abacavir, and median EC50 values of 0.429 µM (range:0.200 to 2.007 µM) and 2.38 µM (1.37 to 3.68 µM) respectively for lamivudine.

Phenotypic susceptibility analyses of clinical isolates from antiretroviral-naïve patients with HIV-1

Group M non-B subtypes in three studies have each reported that all viruses were fully susceptible toboth abacavir and lamivudine; one study of 104 isolates that included subtypes A and A1 (n=26),

C (n=1), D (n=66), and the circulating recombinant forms (CRFs) AD (n=9), CD (n=1), and a complexinter-subtype recombinant_cpx (n=1) a second study of 18 isolates including subtype G (n=14) and

CRF_AG (n=4) from Nigeria, and a third study of six isolates (n=4 CRF_AG, n=1 A and n=1undetermined) from Abidjan (Côte d'Ivoire).

HIV-1 isolates (CRF01_AE, n=12; CRF02_AG, n=12; and Subtype C or CRF_AC, n=13) from 37untreated patients in Africa and Asia were susceptible to abacavir (IC50 fold changes <2.5), andlamivudine (IC50 fold changes<3.0), except for two CRF02_AG isolates with fold-changes of 2.9 and3.4 for abacavir. Group O isolates from antiviral naïve patients tested for lamivudine activity werehighly sensitive.

The combination of abacavir and lamivudine has demonstrated antiviral activity in cell culture againstnon-subtype B isolates and HIV-2 isolates with equivalent antiviral activity as for subtype B isolates.

In vivo resistance

Abacavir-resistant isolates of HIV-1 have been selected in-vitro in wild-type strain HIV-1 (HXB2) andare associated with specific genotypic changes in the RT codon region (codons M184V, K65R, L74Vand Y115). Selection for the M184V mutation occurred first and resulted in a two fold increase in IC50.

Continued passage in increasing concentrations of drug resulted in selection for double RT mutants65R/184V and 74V/184V or triple RT mutant 74V/115Y/184V. Two mutations conferred a 7- to 8-foldchange in abacavir susceptibility and combinations of three mutations were required to confer morethan an 8-fold change in susceptibility. Passage with a zidovudine resistant clinical isolate RTMC alsoselected for the 184V mutation.

HIV-1 resistance to lamivudine involves the development of a M184I or, more commonly, M184Vamino acid change close to the active site of the viral RT. Passage of HIV-1 (HXB2) in the presence ofincreasing 3TC concentrations results in high-level (>100 to >500-fold) lamivudine-resistant virusesand the RT M184I or V mutation is rapidly selected. The IC50 for wild-type HXB2 is 0.24 to 0.6 µM,while the IC50 for M184V containing HXB2 is >100 to 500 µM.

Antiviral therapy According to Genotypic/Phenotypic Resistance

In vivo resistance (Therapy-naïve patients)

The M184V or M184I variants arise in HIV-1 infected patients treated with lamivudine-containingantiretroviral therapy.

Isolates from most patients experiencing virological failure with a regimen containing abacavir inpivotal clinical trials showed either no NRTI-related changes from baseline (45%) or only M184V or

M184I selection (45%). The overall selection frequency for M184V or M184I was high (54%), and lesscommon was the selection of L74V (5%), K65R (1%) and Y115F (1%) (see table below). Theinclusion of zidovudine in the regimen has been found to reduce the frequency of L74V and K65Rselection in the presence of abacavir (with zidovudine: 0/40, without zidovudine: 15/192, 8%).

Abacavir + Abacavir +

Therapy Abacavir + lamivudine + lamivudine +

PI (or Total

Combivir1 NNRTI PI/ritonavir)

Number of

Subjects 282 1094 909 2285

Number of

Virological 43 90 158 306

Failures

Number of On-

Therapy 40 (100%) 51 (100%)2 141 (100%) 232 (100%)

Genotypes

K65R 0 1 (2%) 2 (1%) 3 (1%)

L74V 0 9 (18%) 3 (2%) 12 (5%)

Y115F 0 2 (4%) 0 2 (1%)

M184V/I 34 (85%) 22 (43%) 70 (50%) 126 (54%)

TAMs3 3 (8%) 2 (4%) 4 (3%) 9 (4%)1. Combivir is a fixed dose combination of lamivudine and zidovudine2. Includes three non-virological failures and four unconfirmed virological failures.3. Number of subjects with ≥1 Thymidine Analogue Mutations (TAMs).

TAMs might be selected when thymidine analogs are associated with abacavir. In a meta-analysis ofsix clinical trials, TAMs were not selected by regimens containing abacavir without zidovudine(0/127), but were selected by regimens containing abacavir and the thymidine analogue zidovudine(22/86, 26%).

In vivo resistance (Therapy experienced patients)

The M184V or M184I variants arise in HIV-1 infected patients treated with lamivudine-containingantiretroviral therapy and confer high-level resistance to lamivudine. In vitro data tend to suggest thatthe continuation of lamivudine in anti-retroviral regimen despite the development of M184V mightprovide residual anti-retroviral activity (likely through impaired viral fitness). The clinical relevance ofthese findings is not established. Indeed, the available clinical data are very limited and preclude anyreliable conclusion in the field. In any case, initiation of susceptible NRTIs should always be preferredto maintenance of lamivudine therapy. Therefore, maintaining lamivudine therapy despite emergenceof M184V mutation should only be considered in cases where no other active NRTIs are available.

Clinically significant reduction of susceptibility to abacavir has been demonstrated in clinical isolatesof patients with uncontrolled viral replication, who have been pre-treated with and are resistant to othernucleoside inhibitors. In a meta-analysis of five clinical trials where ABC was added to intensifytherapy, of 166 subjects, 123 (74%) had M184V/I, 50 (30%) had T215Y/F, 45 (27%) had M41L, 30(18%) had K70R and 25 (15%) had D67N. K65R was absent and L74V and Y115F were uncommon(≤3%). Logistic regression modelling of the predictive value for genotype (adjusted for baseline plasma

HIV-1RNA [vRNA], CD4+ cell count, number and duration of prior antiretroviral therapies) showedthat the presence of 3 or more NRTI resistance-associated mutations was associated with reducedresponse at Week 4 (p=0.015) or 4 or more mutations at median Week 24 (p≤0.012). In addition, the 69insertion complex or the Q151M mutation, usually found in combination with A62V, V75I, F77L and

F116Y, cause a high level of resistance to abacavir.

Week 4

Baseline Reverse (n = 166)

Transcriptase Median

Mutation n Change vRNA Percent with(log c/mL) <400 copies/mL vRNA

None 15 -0.96 40%

M184V alone 75 -0.74 64%

Any one NRTImutation 82 -0.72 65%

Any two NRTI-associated mutations 22 -0.82 32%

Any three NRTI-associated mutations 19 -0.30 5%

Four or more NRTI-associated mutations 28 -0.07 11%

Phenotypic resistance and cross-resistance

Phenotypic resistance to abacavir requires M184V with at least one other abacavir-selected mutation,or M184V with multiple TAMs. Phenotypic cross-resistance to other NRTIs with M184V or M184Imutation alone is limited. Zidovudine, didanosine, stavudine and tenofovir maintain their antiretroviralactivities against such HIV-1 variants. The presence of M184V with K65R does give rise to cross-resistance between abacavir, tenofovir, didanosine and lamivudine, and M184V with L74V gives riseto cross-resistance between abacavir, didanosine and lamivudine. The presence of M184V with Y115Fgives rise to cross-resistance between abacavir and lamivudine. Readily available genotypic drugresistance interpretation algorithms and commercially available susceptibility tests have establishedclinical cut offs for reduced activity for abacavir and lamivudine as separate drug entities that predictsusceptibility, partial susceptibility or resistance based upon either direct measurement of susceptibilityor by calculation of the HIV-1 resistance phenotype from the viral genotype. Appropriate use ofabacavir and lamivudine can be guided using these currently recommended resistance algorithms.

Cross-resistance between abacavir or lamivudine and antiretrovirals from other classes e.g. PIs or

NNRTIs is unlikely.

Clinical experience with the combination of abacavir and lamivudine as a once daily regimen is mainlybased on four studies in treatment-naïve subjects, CNA30021, EPZ104057 (HEAT study), ACTG5202,and CNA109586 (ASSERT study) and two studies in treatment-experienced subjects, CAL30001 and

ESS30008.

Therapy-naïve patients

The combination of abacavir and lamivudine as a once daily regimen is supported by a 48 weeksmulti-centre, double-blind, controlled study (CNA30021) of 770 HIV-infected, therapy-naïve adults.

These were primarily asymptomatic HIV infected patients (CDC stage A). They were randomised toreceive either abacavir (ABC) 600 mg once daily or 300 mg twice daily, in combination withlamivudine 300 mg once daily and efavirenz 600 mg once daily. The results are summarised bysubgroup in the table below:

Efficacy Outcome at Week 48 in CNA30021 by baseline HIV-1 RNA and CD4 Categories (ITTe

TLOVR ART naïve subjects).

ABC QD ABC BID +3TC+EFV+3TC+EFV (n=386)(n=384)

ITT-E Population Proportion with HIV-1 RNA <50 copies/mL

TLOVR analysis

All Subjects 253/384 (66%) 261/386 (68%)

Baseline RNA category 141/217 (65%) 145/217 (67%)<100,000 copies/mL

Baseline RNA category 112/167 (67%) 116/169 (69%)>=100,000 copies/mL

Baseline CD4 category <50 3 / 6 ( 5 0 % ) 4 /6 (67%)

Baseline CD4 category 50-100 2 1 /4 0 ( 5 3 % ) 2 3 /37 (62%)

Baseline CD4 category 101-200 5 7 / 8 5 ( 6 7 % ) 4 3 / 67 (64%)

Baseline CD4 category 201-350 1 0 1 /1 4 3 ( 7 1 % ) 1 1 4/170 (67%)

Baseline CD4 category >350 7 1 /1 0 9 ( 6 5 % ) 7 6 /105 (72%)>1 log reduction in HIV RNA or 372/384 (97%) 373/386 (97%)<50 cp/mL

All Patients

Similar clinical success (point estimate for treatment difference: -1.7, 95% CI -8.4, 4.9) was observedfor both regimens. From these results, it can be concluded with 95% confidence that the true differenceis no greater than 8.4% in favour of the twice daily regimen. This potential difference is sufficiently smallto draw an overall conclusion of non-inferiority of abacavir once daily over abacavir twice daily.

There was a low, similar overall incidence of virologic failure (viral load > 50 copies/mL) in both theonce and twice daily treatment groups (10% and 8% respectively). In the small sample size forgenotypic analysis, there was a trend toward a higher rate of NRTI-associated mutations in the oncedaily versus the twice daily abacavir regimens. No firm conclusion could be drawn due to the limiteddata derived from this study.

There are conflicting data in some comparative studies with Kivexa i.e. HEAT, ACTG5202 and

ASSERT:

EPZ104057 (HEAT study) was a randomised, double-blind, placebo-matched, 96 week, multi-centrestudy with the primary objective of evaluating the relative efficacy of abacavir/lamivudine (ABC/3TC,600mg/300mg) and tenofovir /emtricitabine (TDF/FTC, 300mg/200mg), each given once-daily incombination with lopinavir/ritonavir (LPV/r, 800mg/200mg) in HIV-infected, therapy-naive adults.

The primary efficacy analysis was performed at week 48 with study continuation to week 96 anddemonstrated non-inferiority. The results are summarised below:

Virologic Response Based on Plasma HIV-1 RNA < 50 copies/mL

ITT-Exposed Population M=F switch included

ABC/3TC +LPV/r TDF/FTC + LPV/r

Virologic Response (N = 343) (N = 345)

Week 48 Week 96 Week 48 Week 96

Overall response (stratified by 231/343 205/343 232/345 200/345baseline HIV-1 RNA) (68%) (60%) (67%) (58%)

Response by Baseline HIV-1 RNA 134/188 118/188 141/205 119/205<100,000 c/mL (71%) (63%) (69%) (58%)

Response by Baseline HIV-1 RNA 97/155 87/155 91/140 81/140≥100,000 c/mL (63%) (56%) (65%) (58%)

A similar virologic response was observed for both regimens (point estimate for treatment difference atweek 48: 0.39%, 95% CI: -6.63, 7.40).

ACTG 5202 study was a, multi-centre, comparative, randomised study of double-blindabacavir/lamivudine or emtricitabine/tenofovir in combination with open-label efavirenz oratazanavir/ritonavir in treatment-naïve HIV-1 infected patients. Patients were stratified at screeningbased on plasma HIV-1 RNA levels <100,000 and ≥100,000 copies/mL.

An interim analysis from ACTG 5202 revealed that abacavir/lamivudine was associated with astatistically significantly higher risk of virological failure as compared to emtricitabine/tenofovir(defined as viral load >1000 copies/mL at or after 16 weeks and before 24 weeks or HIV-RNA level>200 copies/mL at or after 24 weeks) in subjects with a screening viral load ≥100,000 copies/mL(estimated hazard ratio: 2.33, 95% CI: 1.46, 3.72, p=0.0003). The Data Safety Monitoring Board(DSMB) recommended that consideration be given to change in the therapeutic management of allsubjects in the high viral load stratum due to the efficacy differences observed. The subjects in the lowviral load stratum remained blinded and on-study.

Analysis of the data from subjects in the low viral load stratum showed no demonstrable differencebetween the nucleoside backbones in the proportion of patients free of virological failure at week 96.

The results are presented below:

- 88.3% with ABC/3TC vs 90.3% with TDF/FTC when taken with atazanavir/ritonavir as thirddrug, treatment difference -2.0% (95% CI -7.5%, 3.4%),

- 87.4% with ABC/3TC vs 89.2% with TDF/FTC, when taken with efavirenz as third drug,treatment difference -1.8% (95% CI -7.5%, 3.9%).

CNA109586 (ASSERT study), a multi-centre, open label, randomised study of abacavir/lamivudine(ABC/3TC, 600mg/300mg) and tenofovir/emtricitabine (TDF/FTC, 300mg/200mg), each given oncedaily with efavirenz (EFV, 600mg) in ART naïve, HLA-B*5701 negative, HIV-1 infected adults.Thevirologic results are summarised in the table below:

Virologic Response at Week 48 ITT-Exposed Population < 50 copies/mL TLOVR

ABC/3TC + EFV TDF/FTC + EFV(N =192) (N =193)

Overall response 114/192 137/193(59%) (71%)

Response by Baseline 61/95 62/83

HIV-1 RNA <100,000 (64%) (75%)c/mL

Response by Baseline 53/97 75/110

HIV-1 RNA ≥100,000 (55%) (68%)c/mL

At week 48, a lower rate of virologic response was observed for ABC/3TC compared to TDF/FTC(point estimate for the treatment difference: 11.6%, 95% CI: 2.2, 21.1).

Therapy-experienced patients

Data from two studies, CAL30001 and ESS30008 demonstrated that Kivexa once daily has similarvirological efficacy to abacavir 300 mg twice daily plus lamivudine 300 mg once daily or 150 mg twicedaily in therapy-experienced patients.

In study CAL30001, 182 treatment-experienced patients with virologic failure were randomised andreceived treatment with either Kivexa once daily or abacavir 300 mg twice daily plus lamivudine300 mg once daily, both in combination with tenofovir and a PI or an NNRTI for 48 weeks. Similarreductions in HIV-1 RNA as measured by average area under the curve minus baseline were observed,indicating that the Kivexa group was non-inferior to the abacavir plus lamivudine twice daily group(AAUCMB, -1.65 log10 copies/mL versus -1.83 log10 copies/mL respectively, 95% CI -0.13, 0.38).

Proportions with HIV-1 RNA < 50 copies/mL (50% versus 47%) and < 400 copies/mL (54% versus57%) at week 48 were also similar in each group (ITT population). However, as there were onlymoderately experienced patients included in this study with an imbalance in baseline viral load betweenthe arms, these results should be interpreted with caution.

In study ESS30008, 260 patients with virologic suppression on a first line therapy regimen containingabacavir 300 mg plus lamivudine 150 mg, both given twice daily and a PI or NNRTI, were randomisedto continue this regimen or switch to Kivexa plus a PI or NNRTI for 48 weeks. Results at 48 weeksindicated that the Kivexa group was associated with a similar virologic outcome (non-inferior)compared to the abacavir plus lamivudine group, based on proportions of subjects with HIV-1 RNA< 50 copies/mL (90% and 85% respectively, 95% CI -2.7, 13.5).

A genotypic sensitivity score (GSS) has not been established by the MAH for the abacavir/lamivudinecombination. The proportion of treatment-experienced patients in the CAL30001 study with HIV-RNA<50 copies/mL at Week 48 by genotypic sensitivity score in optimized background therapy (OBT) aretabulated The impact of major IAS-USA defined mutations to abacavir or lamivudine and multi-NRTIresistance associated mutations to the number of baseline mutations on response was also evaluated.

The GSS was obtained from the Monogram reports with susceptible virus ascribed the values ‘1-4’based upon the numbers of drugs in the regimen and with virus with reduced susceptibility ascribed thevalue ‘0’. Genotypic sensitivity scores were not obtained for all patients at baseline. Similarproportions of patients in the once-daily and twice-daily abacavir arms of CAL30001 had GSS scoresof <2 or ≥2 and successfully suppressed to <50 copies/mL by Week 48.

Proportion of Patients in CAL30001 with <50 copies/mL at Week 48 by Genotypic Sensitivity

Score in OBT and Number of Baseline Mutations

ABC/3TC FDC QD ABC BID(n=94) +3TC QD(n=88)

Number of Baseline Mutations1

Genotypic All 0-1 2-5 6+ All

SS in OBT≤2 10/24 (42%) 3/24 (13%) 7/24 (29%) 0 12/26 (46%)>2 29/56 (52%) 21/56 (38%) 8/56 (14%) 0 27/56 (48%)

Unknown 8/14 (57%) 6/14 (43%) 2/14 (14%) 0 2/6 (33%)

All 47/94 (50%) 30/94 (32%) 17/94 (18%) 0 41/88 (47%)1 Major IAS-USA defined mutations to Abacavir or Lamivudine and multi-NRTI resistance associated mutations

For the CNA109586 (ASSERT) and CNA30021 studies in treatment-naïve patients, genotype data wasobtained for only a subset of patients at screening or at baseline, as well as for those patients who metvirologic failure criteria. The partial patient subset of data available for CNA30021 is tabulated below,but must be interpreted with caution. Drug susceptibility scores were assigned for each patient’s viralgenotype utilising the ANRS 2009 HIV-1 genotypic drug resistance algorithm. Each susceptible drugin the regimen received a score of 1 and drugs for which the ANRS algorithm predicts resistance wereascribed the value ‘0’.

Proportion of Patients in CNA30021with <50 cps/mL at Week 48 by Genotypic Sensitivity Scorein OBT and Number of Baseline Mutations

ABC QD + 3TC QD + EFV QD ABC BID+(N=384) 3TC QD +

Number of Baseline Mutations1 EFV QD(N=386)

Genotypic All 0-1 2-5 6+ All

SS in OBT≤2 2/6 (33%) 2/6 (33%) 0 0 3/6 (50%)>2 58/119 (49%) 57/119 (48%) 1/119 (<1%) 0 57/114 (50%)

All 60/125 (48%) 59/125 (47%) 1/125 (<1%) 0 60/120 (50%)1 Major IAS-USA (Dec 2009) defined mutations for Abacavir or Lamivudine

A comparison of a regimen including once daily versus twice daily dosing of abacavir and lamivudinewas undertaken within a randomised, multicentre, controlled study of HIV-infected, paediatric patients.1206 paediatric patients aged 3 months to 17 years enrolled in the ARROW Trial (COL105677) andwere dosed according to the weight - band dosing recommendations in the World Health Organisationtreatment guidelines (Antiretroviral therapy of HIV infection in infants and children, 2006). After 36weeks on a regimen including twice daily abacavir and lamivudine, 669 eligible subjects wererandomised to either continue twice daily dosing or switch to once daily abacavir and lamivudine for atleast an additional 96 weeks. Within this population, 104 patients, weighing at least 25 kg, received 600mg abacavir and 300 mg lamivudine as Kivexa once daily, with a median duration of exposure of 596days.

Among the 669 subjects randomized in this study (from 12 months to ≤17 years old), theabacavir/lamivudine once daily dosing group was demonstrated to be non-inferior to the twice dailygroup according to the pre-specified non-inferiority margin of -12%, for the primary endpoint of <80c/mL at Week 48 as well as at Week 96 (secondary endpoint) and all other thresholds tested(<200c/mL, <400c/mL, <1000c/mL), which all fell well within this non-inferiority margin. Subgroupanalyses testing for heterogeneity of once versus twice daily demonstrated no significant effect of sex,age, or viral load at randomisation. Conclusions supported non-inferiority regardless of analysismethod.

Among the 104 patients who received Kivexa, including the ones who were between 40 kg and 25 kg,the viral suppression was similar

The fixed-dose combination tablet of abacavir/lamivudine (FDC) has been shown to be bioequivalentto lamivudine and abacavir administered separately. This was demonstrated in a single dose, 3-waycrossover bioequivalence study of FDC (fasted) versus 2 x 300 mg abacavir tablets plus 2 x 150 mglamivudine tablets (fasted) versus FDC administered with a high fat meal, in healthy volunteers(n = 30). In the fasted state there was no significant difference in the extent of absorption, as measuredby the area under the plasma concentration-time curve (AUC) and maximal peak concentration (Cmax),of each component. There was also no clinically significant food effect observed betweenadministration of FDC in the fasted or fed state. These results indicate that FDC can be taken with orwithout food. The pharmacokinetic properties of lamivudine and abacavir are described below.

Abacavir and lamivudine are rapidly and well absorbed from the gastro-intestinal tract following oraladministration. The absolute bioavailability of oral abacavir and lamivudine in adults is about 83% and80-85% respectively. The mean time to maximal serum concentrations (tmax) is about 1.5 hours and1.0 hour for abacavir and lamivudine, respectively. Following a single dose of 600 mg of abacavir, themean (CV) Cmax is 4.26 µg/mL (28%) and the mean (CV) AUC∞ is 11.95 µg.h/mL (21%). Followingmultiple-dose oral administration of lamivudine 300 mg once daily for seven days, the mean (CV)steady-state Cmax is 2.04 µg/mL (26%) and the mean (CV) AUC24 is 8.87 µg.h/mL (21%).

Intravenous studies with abacavir and lamivudine showed that the mean apparent volume ofdistribution is 0.8 and 1.3 l/kg respectively. Plasma protein binding studies in vitro indicate thatabacavir binds only low to moderately (~49%) to human plasma proteins at therapeutic concentrations.

Lamivudine exhibits linear pharmacokinetics over the therapeutic dose range and displays limitedplasma protein binding in vitro (< 36%). This indicates a low likelihood for interactions with othermedicinal products through plasma protein binding displacement.

Data show that abacavir and lamivudine penetrate the central nervous system (CNS) and reach thecerebrospinal fluid (CSF). Studies with abacavir demonstrate a CSF to plasma AUC ratio of between30 to 44%. The observed values of the peak concentrations are 9 fold greater than the IC50 of abacavirof 0.08 µg/mL or 0.26 µM when abacavir is given at 600 mg twice daily. The mean ratio of CSF/serumlamivudine concentrations 2-4 hours after oral administration was approximately 12%. The true extentof CNS penetration of lamivudine and its relationship with any clinical efficacy is unknown.

Abacavir is primarily metabolised by the liver with approximately 2% of the administered dose beingrenally excreted, as unchanged compound. The primary pathways of metabolism in man are by alcoholdehydrogenase and by glucuronidation to produce the 5’-carboxylic acid and 5’-glucuronide whichaccount for about 66% of the administered dose. These metabolites are excreted in the urine.

Metabolism of lamivudine is a minor route of elimination. Lamivudine is predominately cleared byrenal excretion of unchanged lamivudine. The likelihood of metabolic drug interactions withlamivudine is low due to the small extent of hepatic metabolism (5-10%).

The mean half-life of abacavir is about 1.5 hours. Following multiple oral doses of abacavir 300 mgtwice a day there is no significant accumulation of abacavir. Elimination of abacavir is via hepaticmetabolism with subsequent excretion of metabolites primarily in the urine. The metabolites andunchanged abacavir account for about 83% of the administered abacavir dose in the urine. Theremainder is eliminated in the faeces.

The observed lamivudine half-life of elimination is 18 to 19 hours. The mean systemic clearance oflamivudine is approximately 0.32 l/h/kg, predominantly by renal clearance (> 70%) via the organiccationic transport system. Studies in patients with renal impairment show lamivudine elimination isaffected by renal dysfunction. Kivexa is not recommended for use in patients with a creatinineclearance < 30 mL/min as necessary dose adjustment cannot be made (see section 4.2).

In a study of 20 HIV-infected patients receiving abacavir 300 mg twice daily, with only one 300 mgdose taken prior to the 24 hour sampling period, the geometric mean terminal carbovir-TP intracellularhalf-life at steady-state was 20.6 hours, compared to the geometric mean abacavir plasma half-life inthis study of 2.6 hours. In a crossover study in 27 HIV-infected patients, intracellular carbovir-TPexposures were higher for the abacavir 600 mg once daily regimen (AUC24,ss + 32%, Cmax24,ss + 99%and Ctrough + 18%) compared to the 300 mg twice daily regimen. For patients receiving lamivudine300 mg once daily, the terminal intracellular half-life of lamivudine-TP and the plasma lamivudinehalf-life were similar (16-19 hours and 18-19 hours respectively). In a crossover study in 60 healthyvolunteers, intracellular lamivudine-TP pharmacokinetic parameters were similar (AUC24,ss and

Cmax24,ss) or lower (Ctrough - 24%) for the lamivudine 300 mg once daily regimen compared to thelamivudine 150 mg twice daily regimen. Overall, these data support the use of lamivudine 300 mg andabacavir 600 mg once daily for the treatment of HIV-infected patients. Additionally, the efficacy andsafety of this combination given once daily has been demonstrated in a pivotal clinical study(CNA30021- See Clinical experience).

Pharmacokinetic data has been obtained for abacavir and lamivudine separately.

Abacavir is metabolised primarily by the liver. The pharmacokinetics of abacavir have been studied inpatients with mild hepatic impairment (Child-Pugh score 5-6) receiving a single 600 mg dose; themedian (range) AUC value was 24.1 (10.4 to 54.8) µg.h/mL.The results showed that there was a mean(90%CI) increase of 1.89 fold [1.32; 2.70] in the abacavir AUC, and 1.58 [1.22; 2.04] fold in theelimination half-life. No definitive recommendation on dose reduction is possible in patients with mildhepatic impairment due to substantial variability of abacavir exposure.

Data obtained in patients with moderate to severe hepatic impairment show that lamivudinepharmacokinetics are not significantly affected by hepatic dysfunction.

Based on data obtained for abacavir, Kivexa is not recommended in patients with moderate or severehepatic impairment.

Pharmacokinetic data have been obtained for lamivudine and abacavir alone. Abacavir is primarilymetabolised by the liver with approximately 2% of abacavir excreted unchanged in the urine. Thepharmacokinetics of abacavir in patients with end-stage renal disease is similar to patients with normalrenal function. Studies with lamivudine show that plasma concentrations (AUC) are increased inpatients with renal dysfunction due to decreased clearance. Kivexa is not recommended for use inpatients with a creatinine clearance < 30 mL/min as necessary dose adjustment cannot be made.

No pharmacokinetic data are available in patients over 65 years of age.

Abacavir is rapidly and well absorbed from oral formulations when administered to children. Paediatricpharmacokinetic studies have demonstrated that once daily dosing provides equivalent AUC24 to twicedaily dosing of the same total daily dose for both oral solution and tablet formulations.

The absolute bioavailability of lamivudine (approximately 58 to 66%) was lower and more variable inpaediatric patients under 12 years of age. However, paediatric pharmacokinetic studies with tabletformulations have demonstrated that once daily dosing provides equivalent AUC24 to twice dailydosing of the same total daily dose.

With the exception of a negative in vivo rat micronucleus test, there are no data available on the effectsof the combination of abacavir and lamivudine in animals.

Neither abacavir nor lamivudine were mutagenic in bacterial tests, but consistent with other nucleosideanalogues, they inhibit cellular DNA replication in in vitro mammalian tests such as the mouselymphoma assay. The results of an in vivo rat micronucleus test with abacavir and lamivudine incombination were negative.

Lamivudine has not shown any genotoxic activity in the in vivo studies at doses that gave plasmaconcentrations up to 40-50 times higher than clinical plasma concentrations. Abacavir has a weakpotential to cause chromosomal damage both in vitro and in vivo at high tested concentrations.

The carcinogenic potential of a combination of abacavir and lamivudine has not been tested. Inlong-term oral carcinogenicity studies in rats and mice, lamivudine did not show any carcinogenicpotential. Carcinogenicity studies with orally administered abacavir in mice and rats showed anincrease in the incidence of malignant and non-malignant tumours. Malignant tumours occurred in thepreputial gland of males and the clitoral gland of females of both species, and in rats in the thyroidgland of males and in the liver, urinary bladder, lymph nodes and the subcutis of females.

The majority of these tumours occurred at the highest abacavir dose of 330 mg/kg/day in mice and600 mg/kg/day in rats. The exception was the preputial gland tumour which occurred at a dose of110 mg/kg in mice. The systemic exposure at the no effect level in mice and rats was equivalent to 3and 7 times the human systemic exposure during therapy. While the clinical relevance of these findingsis unknown, these data suggest that a carcinogenic risk to humans is outweighed by the potentialclinical benefit.

In toxicology studies abacavir was shown to increase liver weights in rats and monkeys. The clinicalrelevance of this is unknown. There is no evidence from clinical studies that abacavir is hepatotoxic.

Additionally, autoinduction of abacavir metabolism or induction of the metabolism of other medicinalproducts hepatically metabolised has not been observed in man.

Mild myocardial degeneration in the heart of mice and rats was observed following administration ofabacavir for two years. The systemic exposures were equivalent to 7 to 24 times the expected systemicexposure in humans. The clinical relevance of this finding has not been determined.

In reproductive toxicity studies in animals, lamivudine and abacavir were shown to cross the placenta.

Lamivudine was not teratogenic in animal studies but there were indications of an increase in earlyembryonic deaths in rabbits at relatively low systemic exposures, comparable to those achieved inhumans. A similar effect was not seen in rats even at very high systemic exposure.

Abacavir demonstrated toxicity to the developing embryo and foetus in rats, but not in rabbits. Thesefindings included decreased foetal body weight, foetal oedema, and an increase in skeletalvariations/malformations, early intra-uterine deaths and still births. No conclusion can be drawn withregard to the teratogenic potential of abacavir because of this embryo-foetal toxicity.

A fertility study in rats has shown that abacavir and lamivudine had no effect on male or femalefertility.

Tablet Coremagnesium stearatemicrocrystalline cellulosesodium starch glycollate

Tablet Coating

Opadry Orange YS-1-13065-A containing:hypromellosetitanium dioxidemacrogol 400polysorbate 80sunset yellow FCF (E110)

Not applicable.

3 years.

Do not store above 30ºC.

30 tablets in opaque white (PVC/PVDC-Aluminium/Paper) child-resistant blister packs Multipackscontaining 90 (3 packs of 30) tablets in opaque white (PVC/PVDC-Aluminium/Paper) child-resistantblister packs.

Not all pack sizes may be marketed.

No special requirements for disposal.

ViiV Healthcare BV

Van Asch van Wijckstraat 55H3811 LP Amersfoort

Netherlands

EU/1/04/298/002

EU/1/04/298/003

Date of first authorization: 17 December 2004

Date of latest renewal: 17 November 2014

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

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