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ViiV Healthcare UK Ltd
Stockley Park West, Uxbridge, Middlesex,, UB11 1BT, UK Telephone: +44 (0)800 221 441 Fax: +44 (0)208 990 4328 Before you contact this company: often several companies will market medicines with the same active ingredient. Please check that this is the correct company before contacting them. Why?

Summary of Product Characteristics last updated on the eMC: 11/11/2011

SPC	Kivexa film-coated tablets

Table of Contents

1. NAME OF THE MEDICINAL PRODUCT
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
3. PHARMACEUTICAL FORM
4. CLINICAL PARTICULARS
4.1 Therapeutic indications
4.2 Posology and method of administration
4.3 Contraindications
4.4 Special warnings and precautions for use
4.5 Interaction with other medicinal products and other forms of interaction
4.6 Pregnancy and lactation
4.7 Effects on ability to drive and use machines
4.8 Undesirable effects
4.9 Overdose
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
5.2 Pharmacokinetic properties
5.3 Preclinical safety data
6. PHARMACEUTICAL PARTICULARS
6.1 List of excipients
6.2 Incompatibilities
6.3 Shelf life
6.4 Special precautions for storage
6.5 Nature and contents of container
6.6 Special precautions for disposal and other handling
7. MARKETING AUTHORISATION HOLDER
8. MARKETING AUTHORISATION NUMBER(S)
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
10. DATE OF REVISION OF THE TEXT

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1. NAME OF THE MEDICINAL PRODUCT

Kivexa® 600 mg/300 mg film-coated tablets

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2. QUALITATIVE AND QUANTITATIVE COMPOSITION

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

Excipient: sunset yellow (E110) 1.7 mg per tablet

For a full list of excipients see section 6.1.

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3. PHARMACEUTICAL FORM

Film-coated tablet (tablet).

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

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4. CLINICAL PARTICULARS

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4.1 Therapeutic indications

Kivexa is a fixed-dose combination of two nucleoside analogues (abacavir and lamivudine). It is indicated in antiretroviral combination therapy for the treatment of Human Immunodeficiency Virus (HIV) infection in adults and adolescents from 12 years of age (see sections 4.4 and 5.1).

Before initiating treatment with abacavir, screening for carriage of the HLA-B*5701 allele should be performed in any HIV-infected patient, irrespective of racial origin. Screening is also recommended prior to re-initiation of abacavir in patients of unknown HLA-B*5701 status who have previously tolerated abacavir (see “Management after an interruption of Kivexa therapy”). Abacavir should not be used in patients known to carry the HLA-B*5701 allele, unless no other therapeutic option is available in these patients, based on the treatment history and resistance testing (see section 4.4 and 4.8).

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4.2 Posology and method of administration

Posology

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

The recommended dose of Kivexa in adults and adolescents is one tablet once daily.

Kivexa should not be administered to adults or adolescents who weigh less than 40 kg because it is a fixed-dose tablet that cannot be dose reduced.

Kivexa can be taken with or without food.

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 dose adjustment of one of the active substances is indicated. In these cases the physician should refer to the individual product information for these medicinal products.

Renal impairment: Kivexa is not recommended for use in patients with a creatinine clearance < 50 ml/min (see section 5.2).

Hepatic impairment: No data are available in patients with moderate hepatic impairment, therefore the use of Kivexa is not recommended unless judged necessary. In patients with mild and moderate hepatic impairment close monitoring is required, and if feasible, monitoring of abacavir plasma levels is recommended (see sections 4.4 and 5.2). Kivexa is contraindicated in patients with severe hepatic impairment (see section 4.3).

Elderly: No pharmacokinetic data are currently available in patients over 65 years of age. Special care is advised in this age group due to age associated changes such as the decrease in renal function and alteration of haematological parameters.

Paediatric population: Kivexa is not recommended for the treatment of children less than 12 years of age as the necessary dose adjustment cannot be made.

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4.3 Contraindications

Hypersensitivity to the active substances or to any of the excipients. See BOXED INFORMATION ON ABACAVIR HYPERSENSITIVITY REACTIONS in section 4.4 and section 4.8.

Patients with severe hepatic impairment.

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4.4 Special warnings and precautions for use

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 reaction (see also section 4.8 )

In a clinical study , 3.4 % of subjects with a negative HLA-B*5701 status receiving abacavir developed a hypersensitivity reaction.

Studies have shown that carriage of the HLA-B*5701 allele is associated with a significantly increased risk of a hypersensitivity reaction to abacavir. Based on the prospective study CNA106030 (PREDICT-1), use of pre-therapy screening for the HLA-B*5701 allele and subsequently avoiding abacavir in patients with this allele significantly reduced the incidence of abacavir hypersensitivity reactions. In populations similar to that enrolled in the PREDICT-1 study, it is estimated that 48% to 61% of patients with the HLA-B*5701 allele will develop a hypersensitivity reaction during the course of abacavir treatment compared with 0% to 4% of patients who do not have the HLA-B*5701 allele.

These results are consistent with those of prior retrospective studies.

As a consequence, before initiating treatment with abacavir, screening for carriage of the HLA-B*5701 allele should be performed in any HIV-infected patient, irrespective of racial origin. Screening is also recommended prior to re-initiation of abacavir in patients of unknown HLA-B*5701 status who have previously tolerated abacavir (see “Management after an interruption of Kivexa therapy”). Abacavir should not be used in patients known to carry the HLA-B*5701 allele, unless no other therapeutic option is available based on the treatment history and resistance testing (see section 4.1).

In any patient treated with abacavir, the clinical diagnosis of suspected hypersensitivity reaction must remain the basis of clinical decision-making. It is noteworthy that among patients with a clinically suspected hypersensitivity reaction, a proportion did not carry HLA-B*5701. Therefore, even in the absence of HLA-B*5701 allele, it is important to permanently discontinue abacavir and not rechallenge with abacavir if a hypersensitivity reaction cannot be ruled out on clinical grounds, due to the potential for a severe or even fatal reaction.

Skin patch testing was used as a research tool for the PREDICT-1 study but has no utility in the clinical management of patients and therefore should not be used in the clinical setting.

• Clinical Description

Hypersensitivity reactions are characterised by the appearance of symptoms indicating multi-organ system involvement. Almost all hypersensitivity reactions will have fever and/or rash as part of the syndrome.

Other signs and symptoms may include respiratory signs and symptoms such as dyspnoea, sore throat, cough, and abnormal chest x-ray findings (predominantly infiltrates, which can be localised), gastrointestinal symptoms, such as nausea, vomiting, diarrhoea, or abdominal pain, and may lead to misdiagnosis of hypersensitivity as respiratory disease (pneumonia, bronchitis, pharyngitis), or gastroenteritis. Other frequently observed signs or symptoms of the hypersensitivity reaction may include lethargy or malaise and musculoskeletal symptoms (myalgia, rarely myolysis, arthralgia).

The symptoms related to this hypersensitivity reaction worsen with continued therapy and can be life- threatening. These symptoms usually resolve upon discontinuation of abacavir.

• Clinical Management

Hypersensitivity reaction symptoms usually appear within the first six weeks of initiation of treatment with abacavir, although these reactions may occur at any time during therapy. Patients should be monitored closely, especially during the first two months of treatment with abacavir, with consultation every two weeks.

Regardless of their HLA-B*5701 status, patients who are diagnosed with a hypersensitivity reaction whilst on therapy MUST discontinue Kivexa immediately.

Kivexa, or any other medicinal product containing abacavir (e.g. Ziagen or Trizivir), MUST NEVER be restarted in patients who have stopped therapy due to a hypersensitivity reaction. Restarting abacavir following a hypersensitivity reaction results in a prompt return of symptoms within hours. This recurrence is usually more severe than on initial presentation, and may include life-threatening hypotension and death.

To avoid a delay in diagnosis and minimise the risk of a life-threatening hypersensitivity reaction, Kivexa must be permanently discontinued if hypersensitivity cannot be ruled out, even when other diagnoses are possible (respiratory diseases, flu-like illness, gastroenteritis or reactions to other medicinal products).

Special care is needed for those patients simultaneously starting treatment with Kivexa and other medicinal products known to induce skin toxicity (such as non-nucleoside reverse transcriptase inhibitors - NNRTIs). This is because it is currently difficult to differentiate between rashes induced by these products and abacavir related hypersensitivity reactions.

• Management after an interruption of Kivexa therapy

Regardless of a patient's HLA-B*5701 status, if therapy with Kivexa has been discontinued for any reason and restarting therapy is under consideration, the reason for discontinuation must be established to assess whether the patient had any symptoms of a hypersensitivity reaction. If a hypersensitivity reaction cannot be ruled out, Kivexa or any other medicinal product containing abacavir (e.g. Ziagen or Trizivir) must not be restarted.

Hypersensitivity reactions with rapid onset, including life-threatening reactions have occurred after restarting abacavir in patients who had only one of the key symptoms of hypersensitivity (skin rash, fever, gastrointestinal, respiratory or constitutional symptoms such as lethargy and malaise) prior to stopping abacavir. The most common isolated symptom of a hypersensitivity reaction was a skin rash. Moreover, on very rare occasions hypersensitivity reactions have been reported in patients who have restarted therapy, and who had no preceding symptoms of a hypersensitivity reaction (i.e. patients previously considered to be abacavir tolerant). In both cases if a decision is made to restart abacavir this must be done in a setting where medical assistance is readily available.

Screening for carriage of the HLA B*5701 allele is recommended prior to re-initiation of abacavir in patients of unknown HLA-B*5701 status who have previously tolerated abacavir. Re-initiation of abacavir in such patients who test positive for the HLA B*5701 allele is not recommended and should be considered only under exceptional circumstances where potential benefit outweighs the risk and with close medical supervision.

• Essential patient information

Prescribers must ensure that patients are fully informed regarding the following information on the hypersensitivity reaction:

- Patients must be made aware of the possibility of a hypersensitivity reaction to abacavir that may result in a life-threatening reaction or death and that the risk of a hypersensitivity reaction is increased if they are HLA-B*5701 positive.

- Patients must also be informed that a HLA-B*5701 negative patient can also experience an abacavir hypersensitivity reaction. Therefore, ANY patient who develops signs or symptoms consistent with a possible hypersensitivity reaction to abacavir MUST CONTACT THEIR DOCTOR IMMEDIATELY.

- Patients who are hypersensitive to abacavir should be reminded that they must never take Kivexa or any other medicinal product containing abacavir (e.g. Ziagen or Trizivir) again, regardless of their HLA-B*5701 status. .

- In order to avoid restarting abacavir, patients who have experienced a hypersensitivity reaction should dispose of their remaining Kivexa tablets in their possession in accordance with the local requirements, and ask their doctor or pharmacist for advice.

- Patients who have stopped Kivexa for any reason, and particularly due to possible adverse reactions or illness, must be advised to contact their doctor before restarting.

- Patients should be advised of the importance of taking Kivexa regularly.

- Each patient should be reminded to read the Package Leaflet included in the Kivexa package.

- They should be reminded of the importance of removing the Alert Card included in the package, and keeping it with them at all times.

Lactic acidosis: lactic acidosis, usually associated with hepatomegaly and hepatic steatosis, has been reported with the use of nucleoside analogues. Early symptoms (symptomatic hyperlactatemia) include benign digestive symptoms (nausea, vomiting and abdominal pain), non-specific malaise, loss of appetite, weight loss, respiratory symptoms (rapid and/or deep breathing) or neurological symptoms (including motor weakness).

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

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

Treatment with nucleoside analogues should be discontinued in the setting of symptomatic hyperlactatemia and metabolic/lactic acidosis, progressive hepatomegaly, or rapidly elevating aminotransferase levels.

Caution should be exercised when administering nucleoside analogues to any patient (particularly obese women) with hepatomegaly, hepatitis or other known risk factors for liver disease and hepatic steatosis (including certain medicinal products and alcohol). Patients co-infected with hepatitis C and treated with alpha interferon and ribavirin may constitute a special risk.

Patients at increased risk should be followed closely.

Lipodystrophy: combination antiretroviral therapy has been associated with the redistribution of body fat (lipodystrophy) in HIV patients. The long-term consequences of these events are currently unknown. Knowledge about the mechanism is incomplete. A connection between visceral lipomatosis and protease inhibitors (PIs) and lipoatrophy and nucleoside reverse transcriptase inhibitors (NRTIs) has been hypothesised. A higher risk of lipodystrophy has been associated with individual factors such as older age, and with drug related factors such as longer duration of antiretroviral treatment and associated metabolic disturbances. Clinical examination should include evaluation for physical signs of fat redistribution. Consideration should be given to the measurement of fasting serum lipids and blood glucose. Lipid disorders should be managed as clinically appropriate (see section 4.8).

Pancreatitis: 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 of emergence of resistance at an early stage when abacavir and lamivudine were combined with tenofovir disoproxil fumarate as a once daily regimen.

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

Liver disease: The safety and efficacy of Kivexa has not been established in patients with significant underlying liver disorders. Kivexa is contraindicated in patients with severe hepatic impairment (see section 4.3).

Patients with pre-existing liver dysfunction, including chronic active hepatitis have an increased frequency of liver function abnormalities during combination antiretroviral therapy, and should be monitored according to standard practice. If there is evidence of worsening liver disease in such patients, interruption or discontinuation of treatment must be considered.

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

If lamivudine is being used concomitantly for the treatment of HIV and HBV, additional information relating to the use of lamivudine in the treatment of hepatitis B infection can be found in the Summary of Product Characteristics of products such as Zeffix.

If Kivexa is discontinued in patients co-infected with hepatitis B virus, periodic monitoring of both liver function tests and markers of HBV replication is recommended, as withdrawal of lamivudine may result in an acute exacerbation of hepatitis (see the Summary of Product Characteristics for a product such as Zeffix).

As abacavir and ribavirin share the same phosphorylation pathways, a possible intracellular interaction between these drugs has been postulated, which could lead to a reduction in intracellular phosphorylated metabolites of ribavirin and, as a possible consequence, a reduced chance of sustained virological response (SVR) for Hepatitis C (HCV) in HCV co-infected patients treated with pegylated interferon plus RBV. Conflicting clinical findings are reported in literature on co-administration between abacavir and ribavirin. Some data suggest that HIV/HCV co-infected patients receiving abacavir-containing ART may be at risk of a lower response rate to pegylated interferon/ribavirin therapy. Caution should be exercised when both drugs are co-administered. (see section 4.5).

Mitochondrial dysfunction: nucleoside and nucleotide analogues have been demonstrated in vitro and in vivo to cause a variable degree of mitochondrial damage. There have been reports of mitochondrial dysfunction in HIV-negative infants exposed in utero and/or post-natally to nucleoside analogues. The main adverse reactions reported are haematological disorders (anaemia, neutropenia), metabolic disorders (hyperlactatemia, hyperlipasemia). These reactions are often transitory. Some late-onset neurological disorders have been reported (hypertonia, convulsion, abnormal behaviour). Whether the neurological disorders are transient or permanent is currently unknown. Any child exposed in utero to nucleoside and nucleotide analogues, even HIV-negative children, should have clinical and laboratory follow-up and should be fully investigated for possible mitochondrial dysfunction in case of relevant signs or symptoms. These findings do not affect current national recommendations to use antiretroviral therapy in pregnant women to prevent vertical transmission of HIV.

Immune Reactivation Syndrome: in HIV-infected patients with severe immune deficiency at the time of institution of combination antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic pathogens may arise and cause serious clinical conditions, or aggravation of symptoms. Typically, such reactions have been observed within the first few weeks or months of initiation of CART. Relevant examples are cytomegalovirus retinitis, generalised and/or focal mycobacterial infections, and Pneumocystis carinii pneumonia. Any inflammatory symptoms should be evaluated and treatment instituted when necessary.

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

Opportunistic infections: patients should be advised that Kivexa or any other antiretroviral therapy does not cure HIV infection and 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 the treatment of these associated HIV diseases.

Transmission of HIV: patients should be advised that current antiretroviral therapy, including Kivexa, has not been proven to prevent the risk of transmission of HIV to others through sexual contact or blood contamination. Appropriate precautions should continue to be taken.

Myocardial infarction: Observational studies have shown an association between myocardial infarction and the use of abacavir. Those studied were mainly antiretroviral experienced patients. Data from clinical trials showed limited numbers of myocardial infarction and could not exclude a small increase in risk. Overall the available data from observational cohorts and from randomised trials show some inconsistency so can neither confirm nor refute a causal relationship between abacavir treatment and the risk of myocardial infarction. To date, there is no established biological mechanism to explain a potential increase in risk. When prescribing Kivexa, action should be taken to try to minimize all modifiable risk factors (e.g. smoking, hypertension, and hyperlipidaemia).

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

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

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4.5 Interaction with other medicinal products and other forms of interaction

Kivexa contains abacavir and lamivudine, therefore any interactions identified for these individually are relevant to Kivexa. Clinical studies have shown that there are no clinically significant interactions between 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 through alcohol dehydrogenase could alter abacavir exposure. Lamivudine is cleared renally. Active renal secretion of lamivudine in the urine is mediated through organic cation transporters (OCTs); co-administration of lamivudine with OCT inhibitors may increase lamivudine exposure.

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

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

Drugs by Therapeutic Area	Interaction Geometric mean change (%) (Possible mechanism)	Recommendation concerning co-administration
ANTIRETROVIRAL MEDICINAL PRODUCTS
Didanosine /Abacavir	Interaction not studied.	No dosage adjustment necessary.
Didanosine/Lamivudine	Interaction not studied.
Zidovudine/Abacavir	Interaction not studied
Zidovudine/Lamivudine Zidovudine 300 mg single dose Lamivudine 150 mg single dose	Lamivudine: AUC ↔ Zidovudine : AUC ↔
ANTI-INFECTIVE PRODUCTS
Trimethoprim/sulfamethoxazole (Co-trimoxazole)/Abacavir	Interaction not studied.	No Kivexa dosage adjustment necessary, unless patient has renal impairment (See Section 4.2). When concomitant administration with co-trimoxazole is warranted, patients should be monitored clinically. High doses of trimethoprim/ sulfamethoxazole for the treatment of Pneumocystis jirovecii pneumonia (PCP) and toxoplasmosis have not been studied and should be avoided.
Trimethoprim/sulfamethoxazole (Co-trimoxazole)/Lamivudine (160mg/800mg once daily for 5 days/300mg single dose)	Lamivudine: AUC ↑40% Trimethoprim: AUC ↔ Sulfamethoxazole: AUC ↔ (organic cation transporter inhibition)
ANTIMYCOBACTERIALS
Rifampicin/Abacavir	Interaction not studied. Potential to slightly decrease abacavir plasma concentrations through UGT induction.	Insufficient data to recommend dosage adjustment.
Rifampicin/Lamivudine	Interaction not studied.	Insufficient data to recommend dosage adjustment.
ANTICONVULSANTS
Phenobarbital/Abacavir	Interaction not studied. Potential to slightly decrease abacavir plasma concentrations through UGT induction.	Insufficient data to recommend dosage adjustment.
Phenobarbital/Lamivudine	Interaction not studied.	Insufficient data to recommend dosage adjustment.
Phenytoin/Abacavir	Interaction not studied. Potential to slightly decrease abacavir plasma concentrations through UGT induction.	Insufficient data to recommend dosage adjustment. Monitor phenytoin concentrations.
Phenytoin/Lamivudine	Interaction not studied.
ANTIHISTAMINES (HISTAMINE H1 RECEPTOR ANTAGONISTS)
Ranitidine/Abacavir	Interaction not studied.	No dosage adjustment necessary.
Ranitidine/Lamivudine	Interaction not studied. Clinically significant interaction unlikely. Ranitidine eliminated only in part by renal organic cation transport system.	No dosage adjustment necessary.
Cimetidine/Abacavir	Interaction not studied.	No dosage adjustment necessary.
Cimetidine/Lamivudine	Interaction not studied. Clinically significant interaction unlikely. Cimetidine eliminated only in part by renal organic cation transport system.	No dosage adjustment necessary.
OPIOIDS
Methadone/Abacavir (40 to 90mg once daily for 14 days/600mg single dose, then 600mg twice daily for 14 days)	Abacavir: AUC ↔ Cmax 35% Methadone: CL/F ↑22%	No Kivexa dosage adjustment necessary. Methadone dosage adjustment unlikely in majority of patients; occasionally methadone re-titration may be required.
Methadone/Lamivudine	Interaction not studied.
RETINOIDS
Retinoid compounds (e.g. isotretinoin)/Abacavir	Interaction not studied. Possible interaction given common pathway of elimination via alcohol dehydrogenase.	Insufficient data to recommend dosage adjustment.
Retinoid compounds (e.g. isotretinoin)/Lamivudine No drug interaction studies	Interaction not studied.	Insufficient data to recommend dosage adjustment.
ANTIVIRALS
Ribavirin/Abacavir	Interaction not studied. Theoretical potential to reduce intracellular phosphorylated metabolites.	Caution should be exercised when both drugs are co-administered (see section 4.4).
MISCELLANEOUS
Ethanol/Abacavir (0.7 g/kg single dose/600mg single dose)	Abacavir: AUC ↑41% Ethanol: AUC ↔ (Inhibition of alcohol dehydrogenase)	No dosage adjustment necessary.
Ethanol/Lamivudine	Interaction not studied.	No dosage adjustment necessary.

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

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4.6 Pregnancy and lactation

Pregnancy

As a general rule, when deciding to use antiretroviral agents for the treatment of HIV infection in pregnant women and consequently for reducing the risk of HIV vertical transmission to the newborn, the animal data as well as the clinical experience in pregnant women should be taken into account. There are no data on the use of Kivexa in pregnancy. A moderate amount of data on pregnant women taking the individual actives abacavir and lamivudine in combination indicates no malformative toxicity (more than 400 outcomes from first trimester exposures). Concerning lamivudine, a large amount of data (more than 3000 outcomes from first trimester) indicates no malformative toxicity. Moderate amount of data (more than 600 outcomes from first trimester) indicates no malformative toxicity for abacavir. The malformative risk is unlikely in humans based on the mentioned moderate amount of data.

The active ingredients of Kivexa may inhibit cellular DNA replication and abacavir has been shown to be carcinogenic in animal models (see section 5.3). The clinical relevance of these findings is unknown.

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

Breastfeeding

Lamivudine is excreted in human milk at similar concentrations to those found in serum. It is expected that abacavir will also be excreted into human milk, although this has not been confirmed. As a general rule it is recommended that mothers infected with HIV do not breast-feed their infants under any circumstances in order to avoid transmission of HIV.

Fertility

Studies in animals showed that neither abacavir nor lamivudine had any effect on fertility (see section 5.3).

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4.7 Effects on ability to drive and use machines

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

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4.8 Undesirable effects

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

Abacavir hypersensitivity (see also section 4.4) In a clinical study, 3.4 % of subjects with a negative HLA-B5701 status receiving abacavir developed a hypersensitivity reaction. In clinical studies with abacavir 600 mg once daily the reported rate of hypersensitivity remained within the range recorded for abacavir 300 mg twice daily. Some hypersensitivity reactions were life-threatening and resulted in fatal outcome despite taking precautions. This reaction is characterised by the appearance of symptoms indicating multi-organ/body-system involvement. Almost all patients developing hypersensitivity reactions will have fever and/or rash (usually maculopapular or urticarial) as part of the syndrome, however reactions have occurred without rash or fever. The signs and symptoms of this hypersensitivity reaction are listed below. These have been identified either from clinical studies or post marketing surveillance. Those reported in at least 10% of patients* with a hypersensitivity reaction are in bold text.
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
Some patients with hypersensitivity reactions were initially thought to have gastroenteritis, respiratory disease (pneumonia, bronchitis, pharyngitis) or a flu-like illness. This delay in diagnosis of hypersensitivity has resulted in abacavir being continued or re-introduced, leading to more severe hypersensitivity reactions or death. Therefore, the diagnosis of hypersensitivity reaction should be carefully considered for patients presenting with symptoms of these diseases. Symptoms usually appeared within the first six weeks (median time to onset 11 days) of initiation of treatment with abacavir, although these reactions may occur at any time during therapy. Close medical supervision is necessary during the first two months, with consultations every two weeks. It is likely that intermittent therapy may increase the risk of developing sensitisation and therefore occurrence of clinically significant hypersensitivity reactions. Consequently, patients should be advised of the importance of taking Kivexa regularly. Restarting abacavir following a hypersensitivity reaction results in a prompt return of symptoms within hours. This recurrence of the hypersensitivity reaction is usually more severe than on initial presentation, and may include life-threatening hypotension and death. Regardless of their HLA-B*5701 status, patients who develop this hypersensitivity reaction must discontinue Kivexa and must never be rechallenged with Kivexa, or any other medicinal product containing abacavir (Ziagen or Trizivir). To avoid a delay in diagnosis and minimise the risk of a life-threatening hypersensitivity reaction, abacavir must be permanently discontinued if hypersensitivity cannot be ruled out, even when other diagnoses are possible (respiratory diseases, flu-like illness, gastroenteritis or reactions to other medicinal products). Hypersensitivity reactions with rapid onset, including life-threatening reactions have occurred after restarting abacavir in patients who had only one of the key symptoms of hypersensitivity (skin rash, fever, gastrointestinal, respiratory or constitutional symptoms such as lethargy and malaise) prior to stopping abacavir. The most common isolated symptom of a hypersensitivity reaction was a skin rash. Moreover, on very rare occasions hypersensitivity reactions have been reported in patients who have restarted therapy and who had no preceding symptoms of a hypersensitivity reaction. In both cases, if a decision is made to restart abacavir this must be done in a setting where medical assistance is readily available. Each patient must be warned about this hypersensitivity reaction to abacavir.

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 these symptoms should be carefully evaluated for the presence of this hypersensitivity reaction. If Kivexa has been discontinued in patients due to experiencing any one of these symptoms and a decision is made to restart a medicinal product containing abacavir, this must be done in a setting where medical assistance is readily available (see section 4.4). Very rarely cases of erythema multiforme, Stevens-Johnson syndrome or toxic epidermal necrolysis have been reported where abacavir hypersensitivity could not be ruled out. In such cases medicinal products containing abacavir should be permanently discontinued.

The adverse reactions considered at least possibly related to abacavir or lamivudine are listed by body system, organ class and absolute frequency. Frequencies are defined as very common (> 1/10), common (> 1/100 to < 1/10), uncommon (> 1/1000 to < 1/100), rare (> 1/10,000 to < 1/1000), very rare (< 1/10,000).

Body system	Abacavir	Lamivudine
Blood and lymphatic systems disorders		Uncommon: Neutropenia and anaemia (both occasionally severe), thrombocytopenia Very rare: Pure red cell aplasia
Immune system disorders	Common: hypersensitivity
Metabolism and nutrition disorders	Common: anorexia
Nervous system disorders	Common: headache	Common: Headache, insomnia. Very rare: Cases of peripheral neuropathy (or paraesthesia) have been reported
Respiratory, thoracic and mediastinal disorders		Common: Cough, nasal symptoms
Gastrointestinal disorders	Common: nausea, vomiting, diarrhoea Rare: pancreatitis has been reported, but a causal relationship to abacavir treatment is uncertain	Common: Nausea, vomiting, abdominal pain or cramps, diarrhoea Rare : Rises in serum amylase. Cases of pancreatitis have been reported
Hepatobiliary disorders		Uncommon: Transient rises in liver enzymes (AST, ALT), Rare: Hepatitis
Skin and subcutaneous tissue disorders	Common: rash (without systemic symptoms) Very rare: erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis	Common: Rash, alopecia
Musculoskeletal and connective tissue disorders		Common : Arthralgia, muscle disorders Rare: Rhabdomyolysis
General disorders and administration site conditions	Common: fever, lethargy, fatigue.	Common: fatigue, malaise, fever.

Cases of lactic acidosis, sometimes fatal, usually associated with severe hepatomegaly and hepatic steatosis, have been reported with the use of nucleoside analogues (see section 4.4).

Combination antiretroviral therapy has been associated with redistribution of body fat (lipodystrophy) in HIV patients including the loss of peripheral and facial subcutaneous fat, increased intra-abdominal and visceral fat, breast hypertrophy and dorsocervical fat accumulation (buffalo hump).

Combination antiretroviral therapy has been associated with metabolic abnormalities such as hypertriglyceridaemia, hypercholesterolaemia, insulin resistance, hyperglycaemia and hyperlactataemia (see section 4.4).

In HIV-infected patients with severe immune deficiency at the time of initiation of combination antiretroviral therapy, an inflammatory reaction to asymptomatic or residual opportunistic infections may arise (see section 4.4).

Cases of osteonecrosis have been reported, particularly in patients with generally acknowledged risk factors, advanced HIV disease or long-term exposure to combination antiretroviral therapy (CART). The frequency of this is unknown (see section 4.4).

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4.9 Overdose

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

If overdose occurs the patient should be monitored for evidence of toxicity (see section 4.8), and standard supportive treatment applied as necessary. Since lamivudine is dialysable, continuous haemodialysis could be used in the treatment of overdose, although this has not been studied. It is not known whether abacavir can be removed by peritoneal dialysis or haemodialysis.

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5. PHARMACOLOGICAL PROPERTIES

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5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antivirals for systemic use, antivirals for treatment of HIV infections, combinations. ATC code: J05AR02.

Mechanism of action: Abacavir and lamivudine are NRTIs, and are potent selective inhibitors of HIV-1 and HIV-2 (LAV2 and EHO). Both abacavir and lamivudine 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 of abacavir) 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 DNA chain, resulting in chain termination. Abacavir and lamivudine triphosphates show significantly less affinity for host cell DNA polymerases.

Lamivudine has been shown to be highly synergistic with zidovudine, inhibiting the replication of HIV in cell culture. Abacavir shows synergy in vitro in combination with amprenavir, nevirapine and zidovudine. It has been shown to be additive in combination with didanosine, stavudine and lamivudine.

Antiviral Activity in vitro

Both abacavir and lamivudine have been shown to inhibit replication of laboratory strains and clinical isolates of HIV in a number of cell types, including transformed T cell lines, monocyte/macrophage derived lines and primary cultures of activated peripheral blood lymphocytes (PBLs) and monocyte/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 EC₅₀for abacavir against laboratory strains of HIV-1IIIB and HIV-1HXB2 ranged from 1.4 to 5.8 μM. The median or mean EC₅₀ values for lamivudine against laboratory strains of HIV-1 ranged from 0.007 to 2.3 μM. The mean EC₅₀ against laboratory strains of HIV-2 (LAV2 and EHO) ranged from 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. For lamivudine, the EC₅₀values 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 peripheral blood mononuclear cells.

Baseline HIV-1 samples from therapy-naive subjects with no amino acid substitutions associated with resistance 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 1.26 µM (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 to both 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 complex inter-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=1 undetermined) 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 37 untreated patients in Africa and Asia were susceptible to abacavir (IC₅₀ fold changes <2.5), and lamivudine (IC₅₀ fold changes<3.0), except for two CRF02_AG isolates with fold-changes of 2.9 and 3.4 for abacavir. Group O isolates from antiviral naïve patients tested for lamivudine activity were highly sensitive.

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

Resistance

In-vivo resistance:

Abacavir-resistant isolates of HIV-1 have been selected in-vitro in wild-type strain HIV-1 (HXB2) and are associated with specific genotypic changes in the RT codon region (codons M184V, K65R, L74V and 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 mutants 65R/184V and 74V/184V or triple RT mutant 74V/115Y/184V. Two mutations conferred a 7- to 8-fold change in abacavir susceptibility and combinations of three mutations were required to confer more than an 8-fold change in susceptibility. Passage with a zidovudine resistant clinical isolate RTMC also selected for the 184V mutation.

HIV-1 resistance to lamivudine involves the development of a M184I or, more commonly, M184V amino acid change close to the active site of the viral RT.

Passage of HIV-1 (HXB2) in the presence of increasing 3TC concentrations results in high-level (>100 to >500-fold) lamivudine-resistant viruses and 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-containing antiretroviral therapy.

Isolates from most patients experiencing virological failure with a regimen containing abacavir in pivotal 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 less common was the selection of L74V (5%), K65R (1%) and Y115F (1%) (see table below). The inclusion of zidovudine in the regimen has been found to reduce the frequency of L74V and K65R selection in the presence of abacavir (with zidovudine: 0/40, without zidovudine: 15/192, 8%).

Therapy	Abacavir + Combivir¹	Abacavir + lamivudine + NNRTI	Abacavir + lamivudine + PI (or PI/ritonavir)	Total
Number of Subjects	282	1094	909	2285
Number of Virological Failures	43	90	158	306
Number of On-Therapy Genotypes	40 (100%)	51 (100%)²	141 (100%)	232 (100%)
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 zidovudine

2.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 of six 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-containing antiretroviral therapy and confer high-level resistance to lamivudine. In vitro data tend to suggest that the continuation of lamivudine in anti-retroviral regimen despite the development of M184V might provide residual anti-retroviral activity (likely through impaired viral fitness). The clinical relevance of these findings is not established. Indeed, the available clinical data are very limited and preclude any reliable conclusion in the field. In any case, initiation of susceptible NRTIs should always be preferred to maintenance of lamivudine therapy. Therefore, maintaining lamivudine therapy despite emergence of M184V mutation should only be considered in cases where no other active NRTIs are available.

Clinically significant reduction of susceptibility to abacavir has been demonstrated in clinical isolates of patients with uncontrolled viral replication, who have been pre-treated with and are resistant to other nucleoside inhibitors. In a meta-analysis of five clinical trials where ABC was added to intensify therapy, 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) showed that the presence of 3 or more NRTI resistance-associated mutations was associated with reduced response at Week 4 (p=0.015) or 4 or more mutations at median Week 24 (p0.012). In addition, the 69 insertion complex or the Q151M mutation, usually found in combination with A62V, V75I, F77L and F116Y, cause a high level of resistance to abacavir.

Baseline Reverse Transcriptase Mutation	Week 4 (n = 166)
Baseline Reverse Transcriptase Mutation	n	Median Change vRNA (log₁₀ c/mL)	Percent with <400 copies/mL vRNA
None	15	-0.96	40%
M184V alone	75	-0.74	64%
Any one NRTI mutation	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 M184I mutation alone is limited. Zidovudine, didanosine, stavudine and tenofovir maintain their antiretroviral activities 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 rise to cross-resistance between abacavir, didanosine and lamivudine. The presence of M184V with Y115F gives rise to cross-resistance between abacavir and lamivudine. Readily available genotypic drug resistance interpretation algorithms and commercially available susceptibility tests have established clinical cut offs for reduced activity for abacavir and lamivudine as separate drug entities that predict susceptibility, partial susceptibility or resistance based upon either direct measurement of susceptibility or by calculation of the HIV-1 resistance phenotype from the viral genotype. Appropriate use of abacavir 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

Clinical experience with the combination of abacavir and lamivudine as a once daily regimen is mainly based 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 weeks multi-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 to receive either abacavir (ABC) 600 mg once daily or 300 mg twice daily, in combination with lamivudine 300 mg once daily and efavirenz 600 mg once daily. The results are summarised by subgroup 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 +3TC+EFV (n=384)	ABC BID +3TC+EFV (n= 386)
ITT-E Population TLOVR analysis	Proportion with HIV-1 RNA <50 copies/ml
All Subjects	253/384 (66%)	261/386 (68%)
Baseline RNA category <100,000 copies/mL	141/217 (65%)	145/217 (67%)
Baseline RNA category >=100,000 copies/mL	112/167 (67%)	116/169 (69%)
Baseline CD4 category <50	3/ 6 (50%)	4/6 (67%)
Baseline CD4 category 50-100	21/ 40 (53%)	23/37 (62%)
Baseline CD4 category 101-200	57/ 85 (67%)	43/67 (64%)
Baseline CD4 category 201-350	101/143 (71%)	114/170 (67%)
Baseline CD4 category >350	71/109 (65%)	76/105 (72%)
>1 log reduction in HIV RNA or <50 cp/mL All Patients	372/384 (97%)	373/386 (97%)

Similar clinical success (point estimate for treatment difference: -1.7, 95% CI –8.4, 4.9) was observed for both regimens. From these results, it can be concluded with 95% confidence that the true difference is no greater than 8.4% in favour of the twice daily regimen. This potential difference is sufficiently small to 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 the once and twice daily treatment groups (10% and 8% respectively). In the small sample size for genotypic analysis, there was a trend toward a higher rate of NRTI-associated mutations in the once daily versus the twice daily abacavir regimens. No firm conclusion could be drawn due to the limited data 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-centre study 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 in combination 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 and demonstrated 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

Virologic Response	ABC/3TC +LPV/r (N = 343)		TDF/FTC + LPV/r (N = 345)
Virologic Response	Week 48	Week 96	Week 48	Week 96
Overall response (stratified by baseline HIV-1 RNA)	231/343 (68%)	205/343 (60%)	232/345 (67%)	200/345 (58%)
Response by Baseline HIV-1 RNA <100,000 c/ml	134/188 (71%)	118/188 (63%)	141/205 (69%)	119/205 (58%)
Response by Baseline HIV-1 RNA 100,000 c/ml	97/155 (63%)	87/155 (56%)	91/140 (65%)	81/140 (58%)

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

ACTG 5202 study was a, multi-centre, comparative, randomised study of double-blind abacavir/lamivudine or emtricitabine/tenofovir in combination with open-label efavirenz or atazanavir/ritonavir in treatment-naïve HIV-1 infected patients. Patients were stratified at screening based 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 a statistically 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 all subjects in the high viral load stratum due to the efficacy differences observed. The subjects in the low viral load stratum remained blinded and on-study.

Analysis of the data from subjects in the low viral load stratum showed no demonstrable difference between 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/ritonovir as third drug, 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 once daily with efavirenz (EFV, 600mg) in ART naïve, HLA-B*5701 negative, HIV-1 infected adults.The virologic results are summarised in the table below:

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

ABC/3TC + EFV

(N =192)

TDF/FTC + EFV

(N =193)

Overall response

114/192

(59%)

137/193

(71%)

Response by Baseline HIV-1 RNA <100,000 c/mL

61/95

(64%)

62/83

(75%)

Response by Baseline HIV-1 RNA 100,000 c/mL

53/97

(55%)

75/110

(68%)

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 similar virological efficacy to abacavir 300 mg twice daily plus lamivudine 300 mg once daily or 150 mg twice daily in therapy-experienced patients.

In study CAL30001, 182 treatment-experienced patients with virologic failure were randomised and received treatment with either Kivexa once daily or abacavir 300 mg twice daily plus lamivudine 300 mg once daily, both in combination with tenofovir and a PI or an NNRTI for 48 weeks. Similar reductions 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% versus 57%) at week 48 were also similar in each group (ITT population). However, as there were only moderately experienced patients included in this study with an imbalance in baseline viral load between the arms, these results should be interpreted with caution.

In study ESS30008, 260 patients with virologic suppression on a first line therapy regimen containing abacavir 300 mg plus lamivudine 150 mg, both given twice daily and a PI or NNRTI, were randomised to continue this regimen or switch to Kivexa plus a PI or NNRTI for 48 weeks. Results at 48 weeks indicated 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/lamivudine combination. 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) are tabulated The impact of major IAS-USA defined mutations to abacavir or lamivudine and multi-NRTI resistance 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 the value '0'. Genotypic sensitivity scores were not obtained for all patients at baseline. Similar proportions of patients in the once-daily and twice-daily abacavir arms of CAL30001 had GSS scores of <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 (n=94) Number of Baseline Mutations¹				ABC BID +3TC QD (n=88)
Genotypic SS in OBT	All	0-1	2-5	6+	All
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 was obtained for only a subset of patients at screening or at baseline, as well as for those patients who met virologic 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 viral genotype utilising the ANRS 2009 HIV-1 genotypic drug resistance algorithm. Each susceptible drug in the regimen received a score of 1 and drugs for which the ANRS algorithm predicts resistance were ascribed the value '0'.

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

	ABC QD + 3TC QD + EFV QD (N=384) Number of Baseline Mutations¹				ABC BID+ 3TC QD + EFV QD (N=386)
Genotypic SS in OBT	All	0-1	2-5	6+	All
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

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5.2 Pharmacokinetic properties

The fixed-dose combination tablet of abacavir/lamivudine (FDC) has been shown to be bioequivalent to lamivudine and abacavir administered separately. This was demonstrated in a single dose, 3-way crossover bioequivalence study of FDC (fasted) versus 2 x 300 mg abacavir tablets plus 2 x 150 mg lamivudine 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 measured by the area under the plasma concentration-time curve (AUC) and maximal peak concentration (C_max), of each component. There was also no clinically significant food effect observed between administration of FDC in the fasted or fed state. These results indicate that FDC can be taken with or without food. The pharmacokinetic properties of lamivudine and abacavir are described below.

Absorption

Abacavir and lamivudine are rapidly and well absorbed from the gastro-intestinal tract following oral administration. The absolute bioavailability of oral abacavir and lamivudine in adults is about 83% and 80-85% respectively. The mean time to maximal serum concentrations (t_max) is about 1.5 hours and 1.0 hour for abacavir and lamivudine, respectively. Following a single dose of 600 mg of abacavir, the mean (CV) C_max is 4.26 µg/ml (28%) and the mean (CV) AUC is 11.95 µg.h/ml (21%). Following multiple-dose oral administration of lamivudine 300 mg once daily for seven days, the mean (CV) steady-state C_max is 2.04 µg/ml (26%) and the mean (CV) AUC₂₄ is 8.87 µg.h/ml (21%).

Distribution

Intravenous studies with abacavir and lamivudine showed that the mean apparent volume of distribution is 0.8 and 1.3 l/kg respectively. Plasma protein binding studies in vitro indicate that abacavir binds only low to moderately (~49%) to human plasma proteins at therapeutic concentrations. Lamivudine exhibits linear pharmacokinetics over the therapeutic dose range and displays limited plasma protein binding in vitro (< 36%). This indicates a low likelihood for interactions with other medicinal products through plasma protein binding displacement.

Data show that abacavir and lamivudine penetrate the central nervous system (CNS) and reach the cerebrospinal fluid (CSF). Studies with abacavir demonstrate a CSF to plasma AUC ratio of between 30 to 44%. The observed values of the peak concentrations are 9 fold greater than the IC₅₀ of abacavir of 0.08 µg/ml or 0.26 µM when abacavir is given at 600 mg twice daily. The mean ratio of CSF/serum lamivudine concentrations 2-4 hours after oral administration was approximately 12%. The true extent of CNS penetration of lamivudine and its relationship with any clinical efficacy is unknown.

Metabolism

Abacavir is primarily metabolised by the liver with approximately 2% of the administered dose being renally excreted, as unchanged compound. The primary pathways of metabolism in man are by alcohol dehydrogenase and by glucuronidation to produce the 5'-carboxylic acid and 5'-glucuronide which account 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 by renal excretion of unchanged lamivudine. The likelihood of metabolic drug interactions with lamivudine is low due to the small extent of hepatic metabolism (5-10%).

Elimination

The mean half-life of abacavir is about 1.5 hours. Following multiple oral doses of abacavir 300 mg twice a day there is no significant accumulation of abacavir. Elimination of abacavir is via hepatic metabolism with subsequent excretion of metabolites primarily in the urine. The metabolites and unchanged abacavir account for about 83% of the administered abacavir dose in the urine. The remainder is eliminated in the faeces.

The observed lamivudine half-life of elimination is 5 to 7 hours. The mean systemic clearance of lamivudine is approximately 0.32 l/h/kg, predominantly by renal clearance (> 70%) via the organic cationic transport system. Studies in patients with renal impairment show lamivudine elimination is affected by renal dysfunction. Dose reduction is required for patients with creatinine clearance < 50 ml/min (see section 4.2).

Intracellular pharmacokinetics

In a study of 20 HIV-infected patients receiving abacavir 300 mg twice daily, with only one 300 mg dose taken prior to the 24 hour sampling period, the geometric mean terminal carbovir-TP intracellular half-life at steady-state was 20.6 hours, compared to the geometric mean abacavir plasma half-life in this study of 2.6 hours. In a crossover study in 27 HIV-infected patients, intracellular carbovir-TP exposures were higher for the abacavir 600 mg once daily regimen (AUC_24,ss + 32 %, C_max24,ss + 99 % and C_trough + 18 %) compared to the 300 mg twice daily regimen. For patients receiving lamivudine 300 mg once daily, the terminal intracellular half-life of lamivudine-TP was prolonged to 16-19 hours, compared to the plasma lamivudine half-life of 5-7 hours. In a crossover study in 60 healthy volunteers, intracellular lamivudine-TP pharmacokinetic parameters were similar (AUC_24,ssand C_max24,ss) or lower (C_trough - 24 %) for the lamivudine 300 mg once daily regimen compared to the lamivudine 150 mg twice daily regimen. Overall, these data support the use of lamivudine 300 mg and abacavir 600 mg once daily for the treatment of HIV-infected patients. Additionally, the efficacy and safety of this combination given once daily has been demonstrated in a pivotal clinical study (CNA30021- See Clinical experience).

Special populations

Hepatically impaired: There are no data available on the use of Kivexa in hepatically impaired patients. Pharmacokinetic data has been obtained for abacavir and lamivudine alone.

Abacavir is metabolised primarily by the liver. The pharmacokinetics of abacavir have been studied in patients with mild hepatic impairment (Child-Pugh score 5-6) receiving a single 600 mg dose. The results showed that there was a mean increase of 1.89 fold [1.32; 2.70] in the abacavir AUC, and 1.58 [1.22; 2.04] fold in the elimination half-life. No recommendation on dose reduction is possible in patients with mild hepatic impairment due to substantial variability of abacavir exposure.

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

Renally impaired: Pharmacokinetic data have been obtained for lamivudine and abacavir alone. Abacavir is primarily metabolised by the liver with approximately 2% of abacavir excreted unchanged in the urine. The pharmacokinetics of abacavir in patients with end-stage renal disease is similar to patients with normal renal function. Studies with lamivudine show that plasma concentrations (AUC) are increased in patients with renal dysfunction due to decreased clearance. Dose reduction is required for patients with creatinine clearance of < 50 ml/min.

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

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5.3 Preclinical safety data

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

Mutagenicity and carcinogenicity

Neither abacavir nor lamivudine were mutagenic in bacterial tests, but consistent with other nucleoside analogues, inhibit cellular DNA replication in in vitro mammalian tests such as the mouse lymphoma assay. The results of an in vivo rat micronucleus test with abacavir and lamivudine in combination were negative.

Lamivudine has not shown any genotoxic activity in the in vivo studies at doses that gave plasma concentrations up to 40-50 times higher than clinical plasma concentrations. Abacavir has a weak potential 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. In long-term oral carcinogenicity studies in rats and mice, lamivudine did not show any carcinogenic potential. Carcinogenicity studies with orally administered abacavir in mice and rats showed an increase in the incidence of malignant and non-malignant tumours. Malignant tumours occurred in the preputial gland of males and the clitoral gland of females of both species, and in rats in the thyroid gland 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 and 600 mg/kg/day in rats. The exception was the preputial gland tumour which occurred at a dose of 110 mg/kg in mice. The systemic exposure at the no effect level in mice and rats was equivalent to 3 and 7 times the human systemic exposure during therapy. While the clinical relevance of these findings is unknown, these data suggest that a carcinogenic risk to humans is outweighed by the potential clinical benefit.

Repeat-dose toxicity

In toxicology studies abacavir was shown to increase liver weights in rats and monkeys. The clinical relevance 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 medicinal products hepatically metabolised has not been observed in man.

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

Reproductive toxicology

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 early embryonic deaths in rabbits at relatively low systemic exposures, comparable to those achieved in humans. 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. These findings included decreased foetal body weight, foetal oedema, and an increase in skeletal variations/malformations, early intra-uterine deaths and still births. No conclusion can be drawn with regard 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 female fertility.

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6. PHARMACEUTICAL PARTICULARS

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6.1 List of excipients

Core:

magnesium stearate

microcrystalline cellulose

sodium starch glycollate.

Coating:

Opadry Orange YS-1-13065-A containing:

hypromellose