Kivexa film-coated tablets

1. Name Of The Medicinal Product

Kivexa® 600 mg/300 mg film-coated tablets

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.

3. Pharmaceutical Form

Film-coated tablet (tablet).

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

4. Clinical Particulars

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).

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.

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.

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.

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.
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.
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.
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.
OPIOIDS
Methadone/Abacavir (40 to 90mg once daily for 14 days/600mg single dose, then 600mg twice daily for 14 days)	Abacavir: AUC ↔ Cmax 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.
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.

Abbreviations: ↑ = Increase;

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.

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 (see section 4.4).

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).

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.

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-B*5701 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	Comm