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Ziagen 300 mg Film Coated Tablets

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Ziagen 300 mg Film Coated Tablets
1. Name of the medicinal product
Ziagen® 300 mg film-coated tablets
2. Qualitative and quantitative composition
Each film-coated tablet contains 300 mg of abacavir (as sulfate).
For the full list of excipients see section 6.1.
3. Pharmaceutical form
Film-coated tablet (tablets)
The scored tablets are yellow, biconvex, capsule shaped and are engraved with 'GX 623' on both sides.
The tablet can be divided into equal halves.

4. Clinical particulars
4.1 Therapeutic indications
 Ziagen is indicated in antiretroviral combination therapy for the treatment of Human Immunodeficiency Virus (HIV) infection in adults and children.
The demonstration of the benefit of Ziagen is mainly based on results of studies performed with a twice daily regimen, in treatment-naïve adult patients on combination therapy (see section 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 Ziagen 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
Ziagen should be prescribed by physicians experienced in the management of HIV infection.
Ziagen can be taken with or without food.
To ensure administration of the entire dose, the tablet(s) should ideally be swallowed without crushing.
Ziagen is also available as an oral solution for use in children over three months of age and weighing less than 14 kg and for those patients for whom the tablets are inappropriate.
Alternatively, for patients who are unable to swallow tablets, the tablet(s) may be crushed and added to a small amount of semi-solid food or liquid, all of which should be consumed immediately (see section 5.2).
Adults and adolescents (over 12 years of age): the recommended dose of Ziagen is 600 mg daily. This may be administered as either 300 mg (one tablet) twice daily or 600 mg (two tablets) once daily (see sections 4.4 and 5.1).
Patients changing to the once daily regimen should take 300 mg twice a day and switch to 600 mg once a day the following morning. Where an evening once daily regimen is preferred, 300 mg of Ziagen should be taken on the first morning only, followed by 600 mg in the evening. When changing back to a twice daily regimen, patients should complete the day's treatment and start 300 mg twice a day the following morning.
Children (under 12 years of age):
Dosing according to weight bands is recommended for Ziagen tablets. This dosing regimen for paediatric patients weighing 14-30 kg is based primarily on pharmacokinetic modelling. A pharmacokinetic overexposure of abacavir can occur since accurate dosing can not be achieved with this formulation. Therefore close safety monitoring is warranted in these patients.
Children weighing at least 30 kg: the adult dosage of 300 mg twice daily should be taken.
Children weighing > 21 kg to < 30 kg: one half of a Ziagen tablet taken in the morning and one whole tablet taken in the evening.
Children weighing 14 to 21 kg: one half of a Ziagen tablet twice daily.
Children less than three months: the experience in children aged less than three months is limited (see section 5.2).
Renal impairment: no dosage adjustment of Ziagen is necessary in patients with renal dysfunction. However, Ziagen is not recommended for patients with end-stage renal disease (see section 5.2).
Hepatic impairment: abacavir is primarily metabolised by the liver. No dose recommendation can be made in patients with mild hepatic impairment. In patients with moderate hepatic impairment, no data are available, therefore the use of abacavir is not recommended unless judged necessary. If abacavir is used in patients with mild or moderate hepatic impairment, then close monitoring is required, and if feasible, monitoring of abacavir plasma levels is recommended (see section 5.2). Abacavir is contraindicated in patients with severe hepatic impairment (see section 4.3 and 4.4).
Elderly: no pharmacokinetic data are currently available in patients over 65 years of age.
4.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. See BOXED INFORMATION ON HYPERSENSITIVITY REACTIONS in sections 4.4. and 4.8.
Severe hepatic impairment.
4.4 Special warnings and precautions for use
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 Ziagen 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 Ziagen.
• 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 Ziagen, 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 Ziagen immediately.
Ziagen, or any other medicinal product containing abacavir (e.g. Kivexa, 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, Ziagen 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 medications).
Special care is needed for those patients simultaneously starting treatment with Ziagen 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 Ziagen therap
Regardless of a patient's HLA-B*5701 status, if therapy with any abacavir containing product has been discontinued for any reason and restarting abacavir 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, Ziagen or any other medicinal product containing abacavir (e.g. Kivexa, Trizivir) must not be restarted.
Hypersensitivity reactions with rapid onset, including life-threatening reactions have occurred after restarting Ziagen 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 Ziagen. 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 Ziagen 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 Ziagen or any other medicinal product containing abacavir (e.g. Kivexa, Trizivir) again, regardless of their HLA-B*5701 status.
- in order to avoid restarting Ziagen, patients who have experienced a hypersensitivity reaction should be asked to return the remaining Ziagen tablets or oral solution to the pharmacy.
- patients who have stopped Ziagen for any reason, and particularly due to possible adverse reactions or illness, must be advised to contact their doctor before restarting.
- each patient should be reminded to read the Package Leaflet included in the Ziagen pack. They should be reminded of the importance of removing the Alert Card included in the pack, 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.
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 events 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.
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 abacavir treatment is uncertain.
Triple nucleoside therapy: in patients with high viral load (>100,000 copies/ml) the choice of a triple combination with abacavir, lamivudine and zidovudine needs special consideration (see section 5.1).
There have been reports of a high rate of virological failure and of emergence of resistance at an early stage when abacavir was combined with tenofovir disoproxil fumarate and lamivudine as a once daily regimen.
Liver disease: the safety and efficacy of Ziagen has not been established in patients with significant underlying liver disorders. Ziagen 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.
A pharmacokinetic study has been performed in patients with mild hepatic impairment. However, a definitive recommendation on dose reduction is not possible due to substantial variability of drug exposure in this patient population (see section 5.2). The clinical safety data available with abacavir in hepatically impaired patients is very limited. Due to the potential increases in exposure (AUC) in some patients, close monitoring is required. No data are available in patients with moderate or severe hepatic impairment. Plasma concentrations of abacavir are expected to substantially increase in these patients. Therefore, the use of abacavir in patients with moderate hepatic impairment is not recommended unless judged necessary and requires close monitoring of these patients.
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.
Caution should be exercised when abacavir and ribavirin are co-administered (see section 4.5).
Renal disease: Ziagen should not be administered to patients with end-stage renal disease (see section 5.2).
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 mycobacterium infections, and Pneumocystis carinii pneumonia. Any inflammatory symptoms should be evaluated and treatment instituted when necessary. Autoimmune disorders (such as Graves' disease) have also been reported to occur in the setting of immune reactivation; however, the reported time to onset is more variable and these events can occur many months after initiation of treatment.
Osteonecrosis: Although the aetiology 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 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 receiving Ziagen or any other antiretroviral therapy 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: While effective viral suppression with antiretroviral therapy has been proven to substantially reduce the risk of sexual transmission, a residual risk cannot be excluded. Precautions to prevent transmission should be taken in accordance with national guidelines.
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 Ziagen, action should be taken to try to minimize all modifiable risk factors (e.g. smoking, hypertension, and hyperlipidaemia).
4.5 Interaction with other medicinal products and other forms of interaction
Based on the results of in vitro experiments and the known major metabolic pathways of abacavir, the potential for P450 mediated interactions with other medicinal products involving abacavir is low. P450 does not play a major role in the metabolism of abacavir, and abacavir does not inhibit metabolism mediated by CYP 3A4. Abacavir has also been shown in vitro not to inhibit CYP 3A4, CYP2C9 or CYP2D6 enzymes at clinically relevant concentrations. Induction of hepatic metabolism has not been observed in clinical studies. Therefore, there is little potential for interactions with antiretroviral PIs and other medicinal products metabolised by major P450 enzymes. Clinical studies have shown that there are no clinically significant interactions between abacavir, zidovudine, and lamivudine.
Potent enzymatic inducers such as rifampicin, phenobarbital and phenytoin may via their action on UDP-glucuronyltransferases slightly decrease the plasma concentrations of abacavir.
Ethanol: the metabolism of abacavir is altered by concomitant ethanol resulting in an increase in AUC of abacavir of about 41%. These findings are not considered clinically significant. Abacavir has no effect on the metabolism of ethanol.
Methadone: in a pharmacokinetic study, co-administration of 600 mg abacavir twice daily with methadone showed a 35% reduction in abacavir Cmax and a one hour delay in tmax but the AUC was unchanged. The changes in abacavir pharmacokinetics are not considered clinically relevant. In this study abacavir increased the mean methadone systemic clearance by 22%. The induction of drug metabolising enzymes cannot therefore be excluded. Patients being treated with methadone and abacavir should be monitored for evidence of withdrawal symptoms indicating under dosing, as occasionally methadone re-titration may be required.
Retinoids: retinoid compounds are eliminated via alcohol dehydrogenase. Interaction with abacavir is possible but has not been studied.
Ribavirin: 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 potential consequence, a reduced chance of sustained virological response (SVR) for Hepatitis C (HCV) in HCV co-infected patients treated with pegylated interferon plus ribavirin. 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 anti-retroviral therapy may be at risk of a lower response rate to pegylated interferon/ribavirin therapy. Caution should be exercised when both drugs are co-administered.
4.6 Fertility, pregnancy and lactation
Pregnancy
As a general rule, when deciding to use antiretroviral agents for the treatment HIV infection in pregnant women and consequently for reducing the risk of HIV vertical transmission to the newborn, both animal data as well as clinical experience in pregnant women should be taken into account.
Animal studies have shown toxicity to the developing embryo and foetus in rats, but not in rabbits (see section 5.3). Abacavir has been shown to be carcinogenic in animal models (see section 5.3). Clinical relevance in human of these data is unknown. Placental transfer of abacavir and/or its related metabolites has been shown to occur in human.
In pregnant women, more than 800 outcomes after first trimester exposure and more than 1000 outcomes after second and third trimester exposure indicate no malformative and foeto/neonatal effect of abacavir. The malformative risk is unlikely in humans based on those data.
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).
Breast-feeding
Abacavir and its metabolites are excreted into the milk of lactating rats Abacavir is also excreted into human milk. There are no data available on the safety of abacavir when administered to babies less than three months old. It is therefore recommended that mothers do not breast-feed their babies while receiving treatment with abacavir. Additionally, it is recommended that HIV infected women do not breast-feed their infants under any circumstances in order to avoid transmission of HIV.
Fertility
Studies in animals showed that abacavir had no 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.
4.8 Undesirable effects
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.
Rash (81% vs 67% respectively) and gastrointestinal manifestations (70% vs 54% respectively) were more frequently reported in children compared to adults.
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 Ziagen 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 Ziagen regularly.
Restarting Ziagen 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 Ziagen and must never be rechallenged with Ziagen, or any other medicinal product containing abacavir (e.g. Kivexa, Trizivir).
To avoid a delay in diagnosis and minimise the risk of a life-threatening hypersensitivity reaction, Ziagen 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 medications).
Hypersensitivity reactions with rapid onset, including life-threatening reactions have occurred after restarting Ziagen 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 Ziagen. 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 Ziagen this must be done in a setting where medical assistance is readily available.
Each patient must be warned about this hypersensitivity reaction to abacavir.
For many of the other adverse reactions reported, it is unclear whether they are related to Ziagen, to the wide range of medicinal products used in the management of HIV infection or as a result of the disease process.
Many of those listed 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 Ziagen 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.
Many of the adverse reactions have not been treatment limiting. The following convention has been used for their classification: very common (>1/10), common (>1/100 to <1/10), uncommon (>1/1,000 to <1/100), rare (>1/10,000 to <1/1,000) very rare (<1/10,000).
Metabolism and nutrition disorders
Common: anorexia
Nervous system disorders
Common: headache
Gastrointestinal disorders
Common: nausea, vomiting, diarrhoea
Rare: pancreatitis
Skin and subcutaneous tissue disorders
Common: rash (without systemic symptoms)
Very rare: erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis
General disorders and administration site conditions
Common: fever, lethargy, fatigue
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 (CART) an inflammatory reaction to asymptomatic or residual opportunistic infections may arise. Autoimmune disorders (such as Graves' disease) have also been reported to occur in the setting of immune reactivation; however, the reported time to onset is more variable and these events can occur many months after initiation of treatment (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 CART. The frequency of this is unknown (see section 4.4).
Laboratory abnormalities
In controlled clinical studies laboratory abnormalities related to Ziagen treatment were uncommon, with no differences in incidence observed between Ziagen treated patients and the control arms.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.
4.9 Overdose
 Single doses up to 1200 mg and daily doses up to 1800 mg of Ziagen have been administered to patients in clinical studies. No additional adverse reactions to those reported for normal doses were reported. The effects of higher doses are not known. If overdose occurs the patient should be monitored for evidence of toxicity (see section 4.8), and standard supportive treatment applied as necessary. It is not known whether abacavir can be removed by peritoneal dialysis or haemodialysis.
5. Pharmacological properties
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: nucleoside reverse transcriptase inhibitors, ATC Code: J05AF06
Mechanism of action: Abacavir is a NRTI. It is a potent selective inhibitor of HIV-1 and HIV-2. Abacavir is metabolised intracellularly to the active moiety, carbovir 5'- triphosphate (TP). In vitro studies have demonstrated that its mechanism of action in relation to HIV is inhibition of the HIV reverse transcriptase enzyme, an event which results in chain termination and interruption of the viral replication cycle. Abacavir shows synergy in vitro in combination with nevirapine and zidovudine. It has been shown to be additive in combination with didanosine, lamivudine and stavudine.
In vitro resistance: Abacavir-resistant isolates of HIV-1 have been selected in vitro and are associated with specific genotypic changes in the reverse transcriptase (RT) codon region (codons M184V, K65R, L74V and Y115F). Viral resistance to abacavir develops relatively slowly in vitro, requiring multiple mutations for a clinically relevant increase in EC50 over wild-type virus.
In vivo resistance (Therapy naïve patients) 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%). 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%).
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): 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 abacavir 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-1 RNA [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 (p≤0.012). 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.
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. Appropriate use of abacavir can be guided using currently recommended resistance algorithms.
Cross-resistance between abacavir and antiretrovirals from other classes (e.g. PIs or NNRTIs) is unlikely.
Clinical Experience
The demonstration of the benefit of Ziagen is mainly based on results of studies performed in adult treatment-naïve patients using a regimen of Ziagen 300 mg twice daily in combination with zidovudine and lamivudine.
Twice daily (300 mg) administration:
• Therapy naïve adults
In adults treated with abacavir in combination with lamivudine and zidovudine the proportion of patients with undetectable viral load (<400 copies/ml) was approximately 70% (intention to treat analysis at 48 weeks) with corresponding rise in CD4 cells.
One randomised, double blind, placebo controlled clinical study in adults has compared the combination of abacavir, lamivudine and zidovudine to the combination of indinavir, lamivudine and zidovudine. Due to the high proportion of premature discontinuation (42% of patients discontinued randomised treatment by week 48), no definitive conclusion can be drawn regarding the equivalence between the treatment regimens at week 48. Although a similar antiviral effect was observed between the abacavir and indinavir containing regimens in terms of proportion of patients with undetectable viral load (≤400 copies/ml; intention to treat analysis (ITT), 47% versus 49%; as treated analysis (AT), 86% versus 94% for abacavir and indinavir combinations respectively), results favoured the indinavir combination, particularly in the subset of patients with high viral load (>100,000 copies/ml at baseline; ITT, 46% versus 55%; AT, 84% versus 93% for abacavir and indinavir respectively).
In a multicentre, double-blind, controlled study (CNA30024), 654 HIV-infected, antiretroviral therapy-naïve patients were randomised to receive either abacavir 300 mg twice daily or zidovudine 300 mg twice daily, both in combination with lamivudine 150 mg twice daily and efavirenz 600 mg once daily. The duration of double-blind treatment was at least 48 weeks. In the intent-to-treat (ITT) population, 70% of patients in the abacavir group, compared to 69% of patients in the zidovudine group, achieved a virologic response of plasma HIV-1 RNA ≤50 copies/ml by Week 48 (point estimate for treatment difference: 0.8, 95% CI -6.3, 7.9). In the as treated (AT) analysis the difference between both treatment arms was more noticeable (88% of patients in the abacavir group, compared to 95% of patients in the zidovudine group (point estimate for treatment difference: -6.8, 95% CI -11.8; -1.7). However, both analyses were compatible with a conclusion of non-inferiority between both treatment arms.
ACTG5095 was a randomised (1:1:1), double-blind, placebo-controlled trial performed in 1147 antiretroviral naïve HIV-1 infected adults, comparing 3 regimens: zidovudine (ZDV), lamivudine (3TC), abacavir (ABC), efavirenz (EFV) vs ZDV/3TC/EFV vs ZDV/3TC/ABC. After a median follow-up of 32 weeks, the tritherapy with the three nucleosides ZDV/3TC/ABC was shown to be virologically inferior to the two other arms regardless of baseline viral load (< or > 100 000 copies/ml) with 26% of subjects on the ZDV/3TC/ABC arm, 16% on the ZDV/3TC/EFV arm and 13% on the 4 drug arm categorised as having virological failure (HIV RNA >200 copies/ml). At week 48 the proportion of subjects with HIV RNA <50 copies/ml were 63%, 80% and 86% for the ZDV/3TC/ABC, ZDV/3TC/EFV and ZDV/3TC/ABC/EFV arms, respectively. The study Data Safety Monitoring Board stopped the ZDV/3TC/ABC arm at this time based on the higher proportion of patients with virologic failure. The remaining arms were continued in a blinded fashion. After a median follow-up of 144 weeks, 25% of subjects on the ZDV/3TC/ABC/EFV arm and 26% on the ZDV/3TC/EFV arm were categorised as having virological failure. There was no significant difference in the time to first virologic failure (p=0.73, log-rank test) between the 2 arms. In this study, addition of ABC to ZDV/3TC/EFV did not significantly improve efficacy.

• Therapy naïve children
In a study comparing the unblinded NRTI combinations (with or without blinded nelfinavir) in children, a greater proportion treated with abacavir and lamivudine (71%) or abacavir and zidovudine (60%) had HIV-1 RNA ≤400 copies/ml at 48 weeks, compared with those treated with lamivudine and zidovudine (47%)[ p=0.09, intention to treat analysis]. Similarly, greater proportions of children treated with the abacavir containing combinations had HIV-1 RNA ≤50 copies/ml at 48 weeks (53%, 42% and 28% respectively, p=0.07).
• Therapy experienced patients
In adults moderately exposed to antiretroviral therapy the addition of abacavir to combination antiretroviral therapy provided modest benefits in reducing viral load (median change 0.44 log10 copies/ml at 16 weeks).
In heavily NRTI pretreated patients the efficacy of abacavir is very low. The degree of benefit as part of a new combination regimen will depend on the nature and duration of prior therapy which may have selected for HIV-1 variants with cross-resistance to abacavir.
Once daily (600 mg) administration:
• Therapy naïve adults
The once daily regimen of abacavir 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 - Centre for Disease Control and Prevention (CDC) stage A. They were randomised to receive either abacavir 600 mg once daily or 300 mg twice daily, in combination with efavirenz and lamivudine given once daily. 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. Long term data with abacavir used as a once daily regimen (beyond 48 weeks) are currently limited.
• Therapy experienced patients
In study CAL30001, 182 treatment-experienced patients with virologic failure were randomised and received treatment with either the fixed-dose combination of abacavir/lamivudine (FDC) 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. Results indicate that the FDC group was non-inferior to the abacavir twice daily group, based on similar reductions in HIV-1 RNA as measured by average area under the curve minus baseline (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%) 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 abacavir/lamivudine FDC plus a PI or NNRTI for 48 weeks. Results indicate that the FDC 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).
Additional information:
The safety and efficacy of Ziagen in a number of different multidrug combination regimens is still not completely assessed (particularly in combination with NNRTIs).
Abacavir penetrates the cerebrospinal fluid (CSF) (see section 5.2), and has been shown to reduce HIV-1 RNA levels in the CSF. However, no effects on neuropsychological performance were seen when it was administered to patients with AIDS dementia complex.
5.2 Pharmacokinetic properties
Absorption
Abacavir is rapidly and well absorbed following oral administration. The absolute bioavailability of oral abacavir in adults is about 83%. Following oral administration, the mean time (tmax) to maximal serum concentrations of abacavir is about 1.5 hours for the tablet formulation and about 1.0 hour for the solution formulation.
At therapeutic dosages a dosage of 300 mg twice daily, the mean (CV) steady state Cmax and Cmin of abacavir are approximately 3.00 μg/ml (30%) and 0.01 µg/ml (99%), respectively. The mean (CV) AUC over a dosing interval of 12 hours was 6.02 μg.h/ml (29%), equivalent to a daily AUC of approximately 12.0 μg.h/ml. The Cmax value for the oral solution is slightly higher than the tablet. After a 600 mg abacavir tablet dose, the mean (CV) abacavir Cmax was approximately 4.26 μg/ml (28%) and the mean (CV) AUC∞ was 11.95 μg.h/ml (21%).
Food delayed absorption and decreased Cmax but did not affect overall plasma concentrations (AUC). Therefore Ziagen can be taken with or without food.
Administration of crushed tablets with a small amount of semi-solid food or liquid would not be expected to have an impact on the pharmaceutical quality, and would therefore not be expected to alter the clinical effect. This conclusion is based on the physiochemical and pharmacokinetic data, assuming that the patient crushes and transfers 100% of the tablet and ingests immediately.
Distribution
Following intravenous administration, the apparent volume of distribution was about 0.8 l/kg, indicating that abacavir penetrates freely into body tissues.
Studies in HIV infected patients have shown good penetration of abacavir into the CSF, with 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.
Plasma protein binding studies in vitro indicate that abacavir binds only low to moderately (~49%) to human plasma proteins at therapeutic concentrations. This indicates a low likelihood for interactions with other medicinal products through plasma protein binding displacement.
Biotransformation
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. The metabolites are excreted in the urine.
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.
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 (AUC24,ss + 32 %, Cmax24,ss + 99 % and Ctrough + 18 %) compared to the 300 mg twice daily regimen. Overall, these data support the use of abacavir 600 mg once daily for the treatment of HIV infected patients. Additionally, the efficacy and safety of abacavir given once daily has been demonstrated in a pivotal clinical study (CNA30021- See section 5.1 Clinical experience).
Special populations
Hepatically impaired: 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 dosage reduction is possible in patients with mild hepatic impairment due to the substantial variability of abacavir exposure.
Renally impaired: 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. Therefore no dosage reduction is required in patients with renal impairment. Based on limited experience Ziagen should be avoided in patients with end-stage renal disease.
Children: according to clinical trials performed in children abacavir is rapidly and well absorbed from an oral solution administered to children. The overall pharmacokinetic parameters in children are comparable to adults, with greater variability in plasma concentrations. The recommended dose for children from three months to 12 years taking the oral solution is 8 mg/kg twice daily. This will provide slightly higher mean plasma concentrations in children, ensuring that the majority will achieve therapeutic concentrations equivalent to 300 mg twice daily in adults.
There are insufficient safety data to recommend the use of Ziagen in infants less than three months old. The limited data available indicate that a dose of 2 mg/kg in neonates less than 30 days old provides similar or greater AUCs, compared to the 8 mg/kg dose administered to older children.
Elderly: the pharmacokinetics of abacavir have not been studied in patients over 65 years of age.
5.3 Preclinical safety data
Abacavir was not mutagenic in bacterial tests but showed activity in vitro in the human lymphocyte chromosome aberration assay, the mouse lymphoma assay, and the in vivo micronucleus test. This is consistent with the known activity of other nucleoside analogues. These results indicate that abacavir has a weak potential to cause chromosomal damage both in vitro and in vivo at high test concentrations.
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 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 carcinogenic potential in humans is unknown, these data suggest that a carcinogenic risk to humans is outweighed by the potential clinical benefit.
In pre-clinical toxicology studies, abacavir treatment 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.
In reproductive toxicity studies, embryo and foetal toxicity have been observed 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 the rat has shown that abacavir had no effect on male or female fertility.
6. Pharmaceutical particulars
6.1 List of excipients
Core:
Microcrystalline cellulose
Sodium starch glycollate
Magnesium stearate
Colloidal anhydrous silica
Coating:
Triacetin
Methylhydroxypropylcellulose
Titanium dioxide
Polysorbate 80
Iron oxide yellow
6.2 Incompatibilities
Not applicable
6.3 Shelf life
3 years
6.4 Special precautions for storage
Do not store above 30°C
6.5 Nature and contents of container
Polyvinyl chloride/foil blister packs containing 60 tablets.
6.6 Special precautions for disposal and other handling
No special requirements for disposal.
7. Marketing authorisation holder
ViiV Healthcare UK Limited
980 Great West Road
Brentford
Middlesex
TW8 9GS
United Kingdom
8. Marketing authorisation number(s)
EU/1/99/112/001
9. Date of first authorisation/renewal of the authorisation
Date of first authorisation: 8 July 1999
Date of latest renewal: 8 July 2009
10. Date of revision of the text
21 March 2014

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