Each ml contains: Abacavir Sulphate
Equivalent to Abacavir 20 mg
Hypersensitivity: In clinical studies, approximately 4% of subjects receiving Abacavir developed a hypersensitivity reaction which in rare cases proved fatal.
Description: This is characterised by the appearance of symptoms indicating multiorgan/body-system involvement. The majority of patients have fever and/or rash as part of the syndrome. The symptoms of this hypersensitivity reaction can occur at any time during treatment with Abacavir, but usually appear within the first 6 weeks of initiation of treatment with Abacavir (median time to onset 11 days), and most often include fever, gastrointestinal symptoms (nausea, vomiting, diarrhoea and abdominal pain), rash and fatigue or malaise. Other symptoms may include myalgia, arthralgia, oedema, paraesthesia and respiratory symptoms such as dyspnoea, sore throat or cough.
The symptoms worsen with continued therapy and can be life-threatening. These symptoms usually resolve upon discontinuation of Abacavir.
When patients who have discontinued Abacavir present with an indeterminate diagnosis of hypersensitivity (single symptom), the doctor should:
Assess the probability that hypersensitivity preceded the interruption
Assess the risk: benefit of reinitiating Abacavir
Select the appropriate medical setting in which to re-introduce Abacavir, if such a decision is made.
Prescribers must ensure that patients are fully informed regarding the following
Patients must be made aware of the possibility of a hypersensitivity reaction to abacavir that may result in a life-threatening reaction or death.
Patients developing signs or symptoms possibly linked with a hypersensitivity reaction MUST CONTACT their doctor IMMEDIATELY.
Patients who have stopped Abacavir for any reason, and particularly due to adverse reactions or illness, must be advised to contact their doctor before restarting.
Abacavir is a nucleoside analogue reverse transcriptase inhibitor. It is an antiviral agent against HIV-1 and HIV-2, including HIV-1 isolates that are resistant to zidovudine, lamivudine, zalcitabine, didanosine or nevirapine. In vitro studies have demonstrated that its mechanism of action in relation to HIV is inhibition of the HIV reverse transcriptase enzyme, an event that 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, zalcitabine, lamivudine and stavudine.
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 and in vivo, requiring multiple mutations to reach an eight-fold increase in IC50 over wild-type virus, which may be a clinically relevant level. Isolates resistant to abacavir may also show reduced sensitivity to lamivudine, zalcitabine and/or didanosine, but remain sensitive to zidovudine and stavudine. Cross-resistance between abacavir and protease inhibitors or non-nucleoside reverse transcriptase inhibitors is unlikely.
Abacavir is 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 1,0 hour. Food delayed absorption and decreased Cmax but did not affect overall plasma concentrations (AUC). Therefore abacavir can be taken with or without food.
Studies in HIV infected patients have shown good penetration of abacavir into the cerebrospinal fluid (CSF), with a CSF to plasma AUC ratio of between 30 to 44%. In a phase I pharmacokinetic study, the penetration of abacavir into the CSF was investigated following administration of abacavir 300 mg twice a day. The mean concentration of abacavir achieved in the CSF 1,5 hours post dose was 0,14 micrograms/mL. In a further pharmacokinetic study of 600 mg twice a day, the CSF concentration of abacavir increased over time, from approximately 0,13 micrograms/mL at 0,5 to 1 hour after dosing, to approximately 0,74 micrograms/mL after 3 to 4 hours. While peak concentrations may not have been attained by 4 hours, the observed values are 9-fold greater than the IC50 of abacavir 0,08 micrograms/mL or 0,26 microM. Plasma protein binding studies in vitro indicate that abacavir binds only moderately (~49%) to human plasma proteins at therapeutic concentrations. This indicates a low likelihood for drug interactions through plasma protein binding
Abacavir is primarily metabolised by the liver with less than 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 dose in the urine.
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 drug accumulation. 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.
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).
The results showed that there was a mean increase of 1,89-fold in the abacavir AUC, and 1,58-fold in the half-life of abacavir. The AUCs of the metabolites were not modified by the liver disease. However, the rates of formation and elimination of these were decreased. The pharmacokinetics have not been studied in patients with moderate or severe hepatic impairment, therefore abacavir is contra-indicated in these patient groups.
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.
The overall pharmacokinetic parameters in children are comparable to adults, with slightly greater variability in plasma concentrations. The recommended dose for children from 3 months to 12 years 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 a day in adults. There are insufficient safety data to recommend the use of abacavir in infants less than 3 months old.
The pharmacokinetics of abacavir has not been studied in patients over 65 years of age. When treating elderly patients consideration needs to be given to the greater frequency of decreased hepatic, renal and cardiac function, and concomitant disease or other drug therapy.
Abacavir is indicated in antiretroviral combination therapy for the treatment of Human Immunodeficiency Virus (HIV) infected adults and children.
Abacavir is contra-indicated:
in patients with known hypersensitivity to abacavir or any ingredient of the formulations (see WARNINGS)
in patients with a hereditary fructose intolerance
in patients with liver function impairment
in pregnancy and lactation (see PREGNANCY AND LACTATION)
in infants under 3 months of age
Hypersensitivity: Approximately 4% of subjects receiving Abacavir develop a hypersensitivity reaction which in rare cases has proved fatal. This is characterised by the appearance of symptoms indicating multi-organ/body-system involvement. Patients who develop a hypersensitivity reaction must discontinue Abacavir and MUST not be re-challenged with Abacavir (see SIDE-EFFECTS AND SPECIAL PRECAUTIONS).
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 SIDE-EFFECTS AND SPECIAL PRECAUTIONS).
Abacavir contains sorbitol which may cause abdominal pains and diarrhoea.
Based on the results of in vitro experiments and the known major metabolic pathways of abacavir, the potential for drug interactions involving abacavir is low. Abacavir shows no potential to inhibit metabolism mediated by the cytochrome P450 3A4 enzyme.
It has also been shown in vitro not to interact with medicines that are metabolised by CYP3A4, CYP2C9 or CYP2D6 enzymes. Induction of hepatic metabolism has not been observed in clinical studies. Therefore, there is little potential for medicine interactions with antiretroviral protease inhibitors and other medicines metabolised by major P450 enzymes. Clinical studies have shown that there are no clinically significant interactions between abacavir, zidovudine, and lamivudine.
The metabolism of abacavir is altered by concomitant ethanol resulting in an increase in AUC of abacavir of about 41%.
No dose reduction of abacavir is necessary. Abacavir has no effect on the metabolism of ethanol.
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%. This change is not considered clinically relevant for the majority of patients, however occasionally methadone re-titration may be required.
Retinoid compounds such as isotretinoin, are eliminated via alcohol dehydrogenase. Interaction with abacavir is possible
but has not been studied.
PREGNANCY AND LACTATION
Abacavir is contra-indicated in pregnancy and lactation
DOSAGE AND DIRECTIONS FOR USE:
Abacavir should be prescribed by physicians experienced in the management of HIV infection.
Abacavir can be taken with or without food.
Adults and adolescents (over 12 years of age):
for these patients groups other formulations with higher amounts of the active substance are available.
Abacavir sulphate oral solution 20mg/ml can be taken with or without food.
Children (under 12 years of age):
Amount of oral solution(ML) by weight band to be taken twice daily(approximately 12 hours apart) . Children less than three months: the experience in children aged less than three months is limited Amount of solution by weight band(twice daily):3-5.9kg 6-9.9kg 10-13.9kg 3ml 4ml 6ml.
Renal impairment: no dosage adjustment of Abacavir is necessary in patients with renal dysfunction. However, Abacavir is not recommended for 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. 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. Elderly: no pharmacokinetic data is currently available in patients over 65 years of age
SIDE EFFECTS AND SPECIAL PRECAUTIONS
Hypersensitivity: In clinical studies, approximately 4% of subjects receiving Abacavir developed a hypersensitivity reaction which in rare cases proved fatal. This 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.
Symptoms can occur at any time while being treated with Abacavir, but usually appear within the first 6 weeks of initiation of treatment with Abacavir (median time to onset 11 days).(see WARNINGS)
The signs and symptoms of this hypersensitivity reaction are listed below.
Blood and the lymphatic system disorders
Less frequent (incidence approximately 5%): lymphadenopathy, lymphopenia
Nervous system disorders
Less frequent (incidence approximately 5%): paraesthesia
Less frequent (incidence approximately 5%): conjunctivitis
Less frequent (incidence approximately 5%): hypotension
Less frequent (incidence approximately 5%): headache
Respiratory, thoracic and mediastinal disorders
Less frequent (incidence approximately 5%): dyspnoea, sore throat, cough
Less frequent (incidence approximately 5%): nausea, vomiting, diarrhoea, abdominal pain, mouth ulceration
Less frequent (incidence approximately 5%): elevated liver function tests, hepatic failure
Skin and subcutaneous tissue disorders
Less frequent (incidence approximately 5%): rash (usually maculopapular or urticarial)
Musculoskeletal, connective tissue and bone disorders
Less frequent (incidence approximately 5%): myalgia, myolysis, arthralgia, elevated creatine phosphokinase
Renal and urinary disorders
Less frequent (incidence approximately 5%): elevated creatinine, renal failure
General disorders and administrative site conditions
Less frequent (incidence approximately 5%): fever, fatigue, malaise, oedema, anaphylaxis Some patients with hypersensitivity reactions were initially thought to have respiratory disease (pneumonia, bronchitis, pharyngitis), a flu-like illness, gastroenteritis or reactions to other medications. This delay in diagnosis of hypersensitivity has resulted in Abacavir being continued or re-introduced, leading to more severe hypersensitivity reactions or death. Therefore, the diagnosis of hypersensitivity reactions should be carefully considered for patients presenting with symptoms of these diseases. Symptoms worsen with continued therapy, and usually resolve upon discontinuation of Abacavir.
Restarting Endocrine disorders
Metabolism and nutrition disorders
Frequency unknown: elevated blood glucose and triglyceride concentrations, anorexia
Frequency unknown: headache
Frequent: nausea, vomiting, diarrhoea
Skin and subcutaneous tissue disorders
Frequency unknown: skin rash (without systemic symptoms), erythema multiforma, Stevens-Johnson syndrome, toxic
General disorders and administrative site conditions
Frequent: fatigue and lethargy
Frequency unknown: fever
Rare: lactic acidosis, 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. A majority of these cases have been in women. Caution should be exercised when administering Abacavir to any patient, and particularly to those with known risk factors for liver disease. Treatment with Abacavir should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or hepatotoxicity.
Abacavir contains sorbitol which is metabolised to fructose and is therefore unsuitable for patients who have hereditary fructose intolerance (see CONTRAINDICATIONS).
No currently available data suggests that Abacavir affects the ability to drive or operate machinery. 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 is a weak clastogen 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 sub cutis of female rats. The majority of these tumours occurred at the highest dose levels equivalent to 24 to 32 times the expected systemic exposure in humans.
KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT:
Single doses up to 1200 mg and daily doses up to 1800 mg of abacavir have been administered to patients in clinical studies. No unexpected adverse reactions were reported. The effects of higher doses are not known. If overdosage occurs the patient should be monitored for evidence of toxicity (see SIDE-EFFECTS AND SPECIAL PRECAUTIONS), and standard supportive treatment applied as necessary. It is not known whether abacavir can be removed by peritoneal dialysis or haemodialysis
Clear colorless syrupy liquid contained in an Amber pet bottle.
Store below 30oC. Protect from light.
KEEP OUT OF REACH OF CHILDREN.
PACKING: Plastic bottle of 100ml or 240ml in a carton.