Chemical formula: C₁₄H₁₈N₆O Molecular mass: 286.332 g/mol PubChem compound: 441300
Abacavir interacts in the following cases:
Abacavir is primarily metabolised by the liver. No definitive dose recommendation can be made in patients with mild hepatic impairment (Child-Pugh score 5-6). In patients with moderate or severe hepatic impairment, no clinical data are available, therefore the use of abacavir is not recommended unless judged necessary. If abacavir is used in patients with mild hepatic impairment, then close monitoring is required, including monitoring of abacavir plasma levels if feasible.
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.
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.
Retinoid compounds are eliminated via alcohol dehydrogenase. Interaction with abacavir is possible but has not been studied.
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.
Potent enzymatic inducers such as rifampicin, phenobarbital and phenytoin may via their action on UDP-glucuronyltransferases slightly decrease the plasma concentrations of abacavir.
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-∞) when compared to historical riociguat AUC(0-∞) reported in healthy subjects. Riociguat dose may need to be reduced. Consult the riociguat prescribing information for dosing recommendations.
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.
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. Abacavir has been shown to be carcinogenic in animal models. 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 foetal/neonatal effect of abacavir. The malformative risk is unlikely in humans based on those data.
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 HIVnegative infants exposed in utero and/or post-natally to nucleoside analogues.
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 recommended that HIV infected women do not breast-feed their infants under any circumstances in order to avoid transmission of HIV.
Studies in animals showed that abacavir had no effect on fertility.
No studies on the effects on ability to drive and use machines have been performed.
For many adverse reactions reported, it is unclear whether they are related to abacavir, to the wide range of medicinal products used in the management of HIV infection or as a result of the disease process. Many of the adverse reactions 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. 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).
Common: anorexia
Very rare: lactic acidosis
Common: headache
Common: nausea, vomiting, diarrhoea
Rare: pancreatitis
Common: rash (without systemic symptoms)
Very rare: erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis
Common: fever, lethargy, fatigue
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.
Restarting abacavir following an abacavir HSR results in a prompt return of symptoms within hours. This recurrence of the HSR is usually more severe than on initial presentation, and may include lifethreatening hypotension and death. Similar reactions have also occurred infrequently after restarting abacavir in patients who had only one of the key symptoms of hypersensitivity (see above) prior to stopping abacavir; and on very rare occasions have also been seen in patients who have restarted therapy with no preceding symptoms of a HSR (i.e. patients previously considered to be abacavir tolerant).
Weight and levels of blood lipids and glucose may increase during antiretroviral therapy.
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.
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.
In controlled clinical studies laboratory abnormalities related to abacavir treatment were uncommon, with no differences in incidence observed between abacavir treated patients and the control arms.
1206 HIV-infected paediatric patients aged 3 months to 17 years were enrolled in the ARROW Trial (COL105677), 669 of whom received abacavir and lamivudine either once or twice daily. No additional safety issues have been identified in paediatric subjects receiving either once or twice daily dosing compared to adults.
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