Zidovudine, Lamivudine and Abacavir

Patients with a creatinine clearance between 30 and 49 mL/min receiving abacavir/lamivudine/zidovudine may experience a 1.6-to 3.3-fold higher lamivudine exposure (AUC) than patients with a creatinine clearance ≥50 mL/min. There are no safety data from randomized, controlled trials comparing abacavir/lamivudine/zidovudine fixed-dose combination to the individual components in patients with a creatinine clearance between 30 and 49 mL/min who received dose-adjusted lamivudine. In the original lamivudine registrational trials in combination with zidovudine, higher lamivudine exposures were associated with higher rates of haematologic toxicities (neutropenia and anaemia), although discontinuations due to neutropenia or anaemia each occurred in <1% of subjects. Other lamivudine-related adverse events (such as gastro-intestinal and hepatic disorders) may occur.

Patients with a sustained creatinine clearance between 30 and 49 mL/min who receive abacavir/lamivudine/zidovudine should be monitored for lamivudine-related adverse events, notably haematologic toxicities. If new or worsening neutropenia or anaemia develop, a dose adjustment of lamivudine, per lamivudine prescribing information, is indicated, which cannot be achieved with abacavir/lamivudine/zidovudine. Abacavir/lamivudine/zidovudine combination should be discontinued and the individual components should be used to construct the treatment regimen.

Whilst no dose adjustment of abacavir is necessary in patients with renal dysfunction, lamivudine and zidovudine concentrations are increased in patients with renal impairment due to decreased clearance. Therefore, as dose adjustments of these may be necessary, it is recommended that separate preparations of abacavir, lamivudine and zidovudine be administered to patients with severe renal impairment (creatinine clearance ≤30 mL/min). Physicians should refer to the individual summary of product characteristics of these medicinal products.

The safety and efficacy of abacavir/lamivudine/zidovudine combination has not been established in patients with significant underlying liver disorders. Abacavir/lamivudine/zidovudine combination is not recommended in patients with moderate or 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.

If abacavir/lamivudine/zidovudine is discontinued in patients co-infected with hepatitis B virus, periodic monitoring of both liver function tests and markers of HBV replication is recommended, as withdrawal of lamivudine may result in an acute exacerbation of hepatitis.

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.

As a general rule, when deciding to use antiretroviral agents for the treatment of HIV infection in pregnant women and consequently for reducing the risk of HIV vertical transmission to the newborn, he animal data as well as the clinical experience in pregnant women should be taken into account. In the present case, the use in pregnant women of zidovudine, with subsequent treatment of the newborn infants, has been shown to reduce the rate of maternal-foetal transmission of HIV. There are no data on the use of abacavir/lamivudine/zidovudine in pregnancy. A moderate amount of data on pregnant women taking the individual actives abacavir, lamivudine and zidovudine in combination indicates no malformative toxicity (more than 300 outcomes from first trimester exposures). A large amount of data on pregnant women taking lamivudine or zidovudine indicate no malformative toxicity (more than 3000 outcomes from first trimester exposure each, of which over 2000 outcomes involved exposure to both lamivudine and zidovudine). Moderate amount of data (more than 600 outcomes from first trimester) indicates no malformative toxicity for abacavir. The malformative risk is unlikely in humans based on the mentioned moderate amount of data.

The active ingredients of abacavir/lamivudine/zidovudine may inhibit cellular DNA replication, zidovudine has been shown to be transplacental carcinogen in one animal study and abacavir has been shown to be carcinogenic in animal models. The clinical relevance of these findings is unknown.

For patients co-infected with hepatitis who are being treated with a lamivudine containing medicinal product such as abacavir/lamivudine/zidovudine and subsequently become pregnant, consideration should be given to the possibility of a recurrence of hepatitis on discontinuation of lamivudine.

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.

Abacavir and its metabolites are excreted into the milk of lactating rats. Abacavir is also excreted into human milk.

Based on more than 200 mother/child pairs treated for HIV, serum concentrations of lamivudine in breastfed infants of mothers treated for HIV are very low (<4% of maternal serum concentrations) and progressively decrease to undetectable levels when breastfed infants reach 24 weeks of age. There are no data available on the safety of abacavir and lamivudine when administered to babies less than three months old.

After administration of a single dose of 200 mg zidovudine to HIV-infected women, the mean concentration of zidovudine was similar in human milk and serum.

It is recommended that women living with HIV do not breast-feed their infants in order to avoid transmission of HIV.

Fertility

Studies in animals showed that neither abacavir nor lamivudine nor zidovudine had any effect on fertility. Zidovudine has been shown not to affect the number of sperm, sperm morphology and motility in man.

No studies on the effects on the ability to drive and use machines have been performed. The clinical status of the patient and the adverse event profile of abacavir/lamivudine/zidovudine should be borne in mind when considering the patient’s ability to drive or operate machinery.

Summary of the safety profile

Adverse reactions have been reported with abacavir, lamivudine and zidovudine used separately or in combination for therapy of HIV disease. Because the fixed-dose combination contains abacavir, lamivudine and zidovudine, the adverse reactions associated with these compounds may be expected.

Tabulated list of adverse reactions reported with the individual substances

The adverse reactions reported with abacavir, lamivudine and zidovudine are presented in the table below. They are listed by body system, organ class and absolute frequency. Frequencies are defined as very common (>1/10), common (>1/100 to <1/10), uncommon (>1/1000 to <1/100), rare (>1/10,000 to <1/1000), very rare (<1/10,000). Care must be taken to eliminate the possibility of a hypersensitivity reaction if any of these symptoms occur.

Adverse reactions reported with the individual components of abacavir/lamivudine/zidovudine combination:

Many of the adverse reactions listed in the table 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.

Description of selected adverse reactions

Abacavir hypersensitivity

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 life-threatening 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).

Haematological adverse reactions with zidovudine

Anaemia, neutropenia and leukopenia occurred more frequently at higher doses (1,200-1,500 mg/day) and in patients with advanced HIV disease (especially when there is poor bone marrow reserve prior to treatment) and particularly in patients with CD4 cell counts less than 100/mm³. Dose reduction or cessation of therapy may become necessary. The anaemia may necessitate transfusions.

The incidence of neutropenia was also increased in those patients whose neutrophil counts, haemoglobin levels and serum vitamin B12 levels were low at the start of zidovudine therapy.

Lactic acidosis

Treatment with zidovudine has been associated with cases of lactic acidosis, sometimes fatal, usually associated with severe hepatomegaly and hepatic steatosis.

Lipoatrophy

Treatment with zidovudine has been associated with loss of subcutaneous fat which is most evident in the face, limbs and buttocks. Patients receiving abacavir/lamivudine/zidovudine should be frequently examined and questioned for signs of lipoatrophy. When such development is found, treatment with abacavir/lamivudine/zidovudine should not be continued.

Metabolic parameters

Weight and levels of blood lipids and glucose may increase during antiretroviral therapy.

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.

Osteonecrosis

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.