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Drug Details

ZIAGEN 300 mg Film Coated Tablets (HIV)

• Drug Class Description
  Nucleoside Reverse Transcriptase Inhibitors (NRTI's)
• Generic Name
  Abacavir
• Presentation
  Film-coated tablet The scored tablets are yellow, biconvex, capsule shaped and are engraved with GX 623 on both sides.
• Description
  Each film-coated tablet contains 300 mg of abacavir (as sulfate)
• Indications
  

  Ziagen is indicated in antiretroviral combination therapy for the treatment of Human Immunodeficiency Virus (HIV) infection.

  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.

  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.

• Adult Dosage
  

  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.

  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.

  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.

  Renal impairment: no dosage adjustment of Ziagen is necessary in patients with renal dysfunction. However, Ziagen should be avoided in patients with end-stage renal disease.

  Hepatic impairment: abacavir is primarily metabolised by the liver. No dose recommendation can be made in patients with mild hepatic impairment. No data are available in patients with moderate hepatic impairment, therefore the use of abacavir 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. Abacavir is contraindicated in patients with severe hepatic impairment.

• Child Dosage
  

  Children (under 12 years of age):

  A 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 a 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 data available on the use of Ziagen in this age group are very limited.

• Elderly Dosage
  

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

• Contra Indications
  

  Ziagen is contraindicated in patients with known hypersensitivity to abacavir or to any of the excipients of Ziagen tablets.

  See INFORMATION ON HYPERSENSITIVITY REACTIONS in Special Precautions and Adverse Reactions. Ziagen is contraindicated in patients with severe hepatic impairment.

• Special Precautions
  

  Hypersensitivity reaction (see also section 4.8): In a clinical study3.4 % 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 therapy   Regardless of a patient's HLA-B*5701 status, if therapy with Ziagen 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, 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.

  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.

  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. 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.

  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. 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.

  Renal disease: Ziagen should not be administered to patients with end-stage renal disease.

  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.

  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 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 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: patients should be advised that current antiretroviral therapy, including Ziagen, have 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 Ziagen, action should be taken to try to minimize all modifiable risk factors (e.g. smoking, hypertension, and hyperlipidaemia).

• Interactions
  

  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, coadministration of 600 mg abacavir twice daily with methadone showed a 35% reduction in abacavir C_max and a one hour delay in t_max 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.

• Adverse Drug Reactions
  

  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
  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. 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.

  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.

  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.

  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.

   

  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.