Adco Abacavir 20 mg/ml Oral Solution

ADCO ABACAVIR SOLUTION is indicated for the treatment of Human Immunodeficiency Virus (HIV) infected adults and children in combination with other antiretroviral agents.

Before initiating treatment with ADCO ABACAVIR SOLUTION, screening for carriage of the HLA-8*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-8*5701 status who have previously tolerated abacavir. ADCO ABACAVIR SOLUTION should not be used in patients known to carry the HLA-8*5701 allele, unless no other therapeutic option is available in these patients, based on the treatment history and resistance testing. The oral solution is available for use in children and for those patients in whom the tablet dosage form is inappropriate. Therapy should be initiated by a medical practitioner experienced in the management of HIV infection.

Adults and children over 12 years: The recommended dose of ADCO ABACAVIR SOLUTION is 600 mg daily (30 ml). Shake the bottle before use.

Paediatric population: Children from 3 months to 12 years: The recommended dosage is 8 mg/kg twice daily up to a maximum of 600 mg (30 ml) daily.

Method of administration: Oral. ADCO ABACAVIR SOLUTION can be taken with or without food.

ADCO ABACAVIR SOLUTION is contra-indicated in:

• Patients with a known hypersensitivity to abacavir or any of the inactive ingredients listed in section 6.1.
• Patients with hepatic impairment (such as those infected with hepatitis B virus) should not use ADCO ABACAVIR SOLUTION.
• ADCO ABACAVIR SOLUTION should not be used in pregnancy or lactation.

Hypersensitivity reactions (see also section 4.8): Cases of fatal hypersensitivity reactions (HSR) have occurred in patients receiving ADCO ABACAVIR SOLUTION. This hypersensitivity reaction is characterised by the emergence of symptoms indicating multi-organ/body-system involvement. Patients should discontinue ADCO ABACAVIR SOLUTION if they develop a hypersensitivity reaction and MUST not be rechallenged with ADCO ABACAVIR SOLUTION or any other abacavir containing medicinal product (see section 4.8).

Lactic acidosis/severe hepatomegaly with steatosis: Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of antiretroviral nucleoside analogues alone or in combination, including abacavir in the treatment of HIV infection (see section 4.8).

ADCO ABACAVIR SOLUTION should be discontinued immediately if symptoms associated with hypersensitivity occur and should never be recommenced in patients who have stopped therapy due to a hypersensitivity reaction. Patients should be closely monitored for signs of hypersensitivity during the first two months of treatment, although hypersensitivity reactions can occur at any time. Patients restarting therapy after an interruption are at particular risk even if they have not previously shown symptoms of hypersensitivity. Since intermittent therapy may increase the risk of hypersensitivity developing, patients should be advised of the importance of regular dosing. The patients should be reminded to keep the Alert Card with them all the time.

ADCO ABACAVIR SOLUTION should be avoided in patients with end-stage renal disease.

Before initiating treatment with ADCO ABACAVIR SOLUTION, screening for carriage of the HLA-8*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-8*5701 status who have previously tolerated abacavir. ADCO ABACAVIR SOLUTION should not be used in patients known to carry the HLA-8*5701 allele, unless no other therapeutic option is available in these patients, based on the treatment history and resistance testing.

Lipodystrophy and metabolic abnormalities: Redistribution/accumulation of body fat, including central obesity, dorsocervical fat enlargement [buffalo hump], peripheral wasting, facial wasting, breast enlargement, elevated serum lipid and blood glucose levels have been observed either separately or together in some patients receiving combination antiretroviral therapy. Whilst all members of the Protease Inhibitor and NRTI classes of medicinal products have been associated with one or more of these specific adverse events, linked to a general syndrome commonly referred to as lipodystrophy, data indicate that there are differences in the risk between individual members of the respective therapeutic classes. In addition, the lipodystrophy syndrome has a multi-factorial aetiology with for example HIV disease status, older age and duration of antiretroviral treatment all playing important, possibly synergistic roles. The long-term consequences of these events are currently unknown. Clinical examination should include evaluation to physical signs of fat re-distribution. Consideration should be given to the measurement of serum lipids and blood glucose. Lipid disorders should be managed as clinically appropriate. Patients with evidence of lipodystrophy should have a thorough cardiovascular risk assessment.

Opportunistic Infections: Patients receiving ADCO ABACAVIR SOLUTION may still develop opportunistic infections and other complications of HIV infections. Therefore patients should remain under close clinical observation by medical practitioners experienced in the treatment of these associated HIV diseases. Regular monitoring of viral load and CD4 counts needs to be done.

The risk of HIV transmission to others: Patients should be advised that antiretroviral therapy with ADCO ABACAVIR SOLUTION 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 employed.

Pancreatitis: Pancreatitis has been observed in some patients receiving ADCO ABACAVIR SOLUTION. Pancreatitis must be considered whenever a patient develops abdominal pain, nausea, vomiting or elevated biochemical markers. Discontinue use of ADCO ABACAVIR SOLUTION until diagnosis of pancreatitis is excluded.

Lactic acidosis/hyperlactataemia: Use of ADCO ABACAVIR SOLUTION can result in potentially fatal lactic acidosis as a consequence of mitochondrial dysfunction. Clinical features are non-specific, and include nausea, vomiting, abdominal pain, dyspnoea, fatigue and weight loss. Suspicious biochemical features include mild raised transaminases, raised lactate dehydrogenase (LOH) and/or creatine kinase. In patients with suspicious symptoms or biochemistry, measure the venous lactate level (normal< 2 mmol/litre) and the serum bicarbonate respond as follows:

• Lactate 2-5 mmol/litre with minimum symptoms: switch to agents that are less likely to cause lactic acidosis monitor regularly, and be alert for clinical signs.
• Lactate 5-10 mmol/litre without symptoms: monitor closely.
• Lactate 5-10 mmol/litre with symptoms and/or with reduced standard bicarbonate: STOP NRTIs and change treatment option. Once lactate has settled, use medicines that are less likely to cause lactic acidosis. Exclude other causes, (e.g. sepsis, uraemia, diabetic ketoacidosis, thyrotoxicosis, (lymphoma) and hyperthyroidism.
• Lactate > 10 mmol/litre: STOP all therapy (80 % mortality in case studies).

The above lactate values may not be applicable to paediatric patients. Caution should be exercised when administering ADCO ABACAVIR SOLUTION to patients with known risk factors for liver disease. Treatment with ADCO ABACAVIR SOLUTION should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or hepatotoxicity.

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. Apart from lactic acidosis/hyperlactataemia (see above) other manifestations of mitochondrial dysfunction include haematological disorders (anaemia, neutropenia), and peripheral neuropathy. Some late-onset neurological disorders have been reported (hypertonia, convulsion, abnormal behavior). It is not known whether the neurological disorders are transient or permanent. Any foetus exposed in utero to nucleoside and nucleotide analogues, even HIV negative infants/children, should have clinical and laboratory follow-up and should be fully investigated for possible mitochondrial dysfunction in case of relevant sign and symptoms.

Immune Reconstitution Inflammatory Syndrome: Immune reconstitution inflammatory syndrome (IRIS) is an immunopathological response resulting from the rapid restoration of pathogen-specific immune responses to pre-existing antigens combined with immune dysregulation, which occurs shortly after starting combination Anti-Retroviral Therapy (cART). Typically, such reaction presents by paradoxical deterioration of opportunistic infections being treated or with unmasking of an asymptomatic opportunistic disease, often with an atypical inflammatory presentation. IRIS usually develops within the first three months of initiation of ART and occurs more commonly in patients with low CD4 counts. Common examples of IRIS reactions to opportunistic diseases are tuberculosis, cytomegalovirus retinitis, and cryptococcal meningitis. Appropriate treatment of the opportunistic disease should be instituted or continued, and ART continued. Inflammatory manifestations generally subside after a few weeks. Severe cases may respond to glucocorticoids, but there is only limited evidence for this in patients with tuberculosis IRIS. Autoimmune disorders (such as Graves' disease) have also been reported as IRIS reactions; 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), There have been reports of osteonecrosis, particularly in patients with advanced HIV disease 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.

Excipients: Fructose intolerance: ADCO ABACAVIR SOLUTION contains 344.4 mg/ml of sorbitol which is metabolised to fructose and is therefore not suitable for patients who have hereditary fructose intolerance. Sorbitol can have a mild laxative effect. The calorific value of sorbitol is 2.6 kcal/g. ADCO ABACAVIR SOLUTION also contains methyl parahydroxybenzoate and propyl parahydroxybenzoate which may cause allergic reactions (possibly delayed). This medicine contains less than 1 mmol sodium (23 mg) per dosage unit, that is to say it is essentially u2018sodium-freeu2019.

The potential for P450 mediated interactions with other medicinal products involving abacavir is low. In vitro studies have shown that abacavir has potential to inhibit cytochrome P450 1A1 (CYP1A1). P450 does not play a major role in the metabolism of abacavir, and abacavir shows limited potential to inhibit metabolism mediated by CYP 3A4. Abacavir has also been shown in vitro not to inhibit 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: Administration of ADCO ABACAVIR SOLUTION with alcohol may result in decreased elimination of abacavir, and an increase in the area under the plasma concentration time curve 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 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 increases the systemic clearance of oral methadone by 22%. The induction of drug metabolising enzymes cannot therefore be excluded. Patients should be monitored for signs 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.

Riociguat: In vitro, abacavir inhibits CYP1A1. Concomitant administration of a single dose of riociguat (0.5 mg) to HIV patients receiving the combination of abacavir/dolutegravir/lamivudine (600mg/50mg/300mg once daily) led to an approximately three-fold higher riociguat AUC(0-u221e) when compared to historical riociguat AUC(0 - u221e) reported in healthy subjects. Riociguat dose may need to be reduced. Consult the riociguat prescribing information for dosing recommendations.

ADCO ABACAVIR SOLUTION is contraindicated in pregnancy and lactation.

Pregnancy: ADCO ABACAVIR SOLUTION has not been studied in pregnant women. However, animal studies have shown teratogenicity and other problems. ADCO ABACAVIR SOLUTION must not be used in pregnancy or if planning pregnancy.

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: It is not known whether ADCO ABACAVIR SOLUTION is excreted into breast milk. Due to the potential for adverse events in the infant, patients on ADCO ABACAVIR SOLUTION treatment should not breast feed. In addition, breast feeding is not recommended for patients with HIV infection due to the risk of passing HIV on to the infant.

Fertility: No data available.

No data available.

a. Summary of safety profile: Severe hypersensitivity reactions, sometimes fatal, have occurred in about 4 % of patients receiving ADCO ABACAVIR SOLUTION, especially (but not exclusively) during the first six weeks of treatment, or during intermittent therapy. This hypersensitivity reaction is characterised by symptoms of multiorgan involvement. Symptoms of hypersensitivity commonly include fever, rash, cough, dyspnoea, lethargy, malaise, headache, myalgia, elevated liver function tests and gastrointestinal disturbances, particularly nausea and vomiting, diarrhoea, and abdominal pain. Anaphylaxis has been reported. 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.

b) Tabulated list of adverse reactions: MedDRA System Organ Class Description and frequency:

• Immune system disorders: Frequent: Hypersensitivity reactions. Frequency not known: Anaphylaxis
• Metabolism and nutrition disorders: Frequent: Anorexia. Less frequent: Lactic acidosis. Frequency unknown: Elevated blood glucose and triglyceride concentrations, fat redistribution/accumulation of body fat.
• Nervous system disorders: Frequent: headache
• Gastrointestinal disorders: Frequent: Nausea and vomiting, diarrhoea, abdominal pain. Less frequent: Pancreatitis.
• Skin and subcutaneous tissue disorders: Frequent: Rash. Less frequent: Erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis.
• General disorders and administration site conditions: Frequent: lethargy, fatigue, fever, malaise

c. Description of Selected Adverse Reactions: Abacavir hypersensitivity reactions: The signs and symptoms of this HSR 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. 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. Other key symptoms include gastrointestinal, respiratory or constitutional symptoms such as lethargy and malaise.

Skin Rash: (usually maculopapular or urticarial) Gastrointestinal tract: Nausea, vomiting, diarrhoea, abdominal pain, mouth ulceration Respiratory tract: Dyspnoea, cough, sore throat, adult respiratory distress syndrome, respiratory failure Miscellaneous: Fever, lethargy, malaise, oedema, lymphadenopathy, hypotension, conjunctivitis, anaphylaxis Neurological/Psychiatry: Headache, paraesthesia Haematological: Lymphopenia Liver/pancreas: Elevated liver function tests, hepatitis, hepatic failure Musculoskeletal: Myalgia, rarely myolysis, arthralgia, elevated creatine phosphokinase Urology: Elevated creatinine, renal failure Symptoms related to this HSR worsen with continued therapy and can be life-threatening and in rare instance, have been fatal. Caution is needed as hypersensitivity may be misdiagnosed as influenza, respiratory disease, or gastroenteritis. Misdiagnosis may lead to continued or re-introduction of ADCO ABACAVIR SOLUTION which may lead to a more severe hypersensitivity reaction and even death. Symptoms worsen with continued therapy, and will usually resolve once therapy is discontinued. Restarting ADCO ABACAVIR SOLUTION after a hypersensitivity reaction has occurred will result in a return of the symptoms within hours. This return of the hypersensitivity reaction may be more severe than the initial reaction and it is possible that it may result in life-threatening hypotension and death.

Metabolic parameters: Weight and levels of blood lipids and glucose may increase during antiretroviral therapy (see section 4.4)

Immune reactivation syndrome: 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 and autoimmune hepatitis) have also been reported to occur in the setting of immune reactivation; however, the reported time to onset is more variable and these events can occur many months after initiation of treatment (see section 4.4).

Osteonecrosis: 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).

Reporting of suspected adverse reactions: Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Healthcare providers are asked to report any suspected adverse reactions to SAHPRA via the Med Safety APP (Medsafety X SAHPRA) and eReporting platform (who-umc.org) found on SAHPRA website.

Refer to undesirable effects (section 4.8) for symptoms of overdose. Treatment is symptomatic and supportive. 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.