Trizivir

Separate preparations of abacavir, lamivudine and zidovudine should be administered where dosage adjustment is necessary. In these cases the physician should refer to the individual Product Monographs.

No clinically significant changes to pharmacokinetic parameters were observed for abacavir, lamivudine or zidovudine when administered together. As TRIZIVIR (abacavir sulphate/lamivudine/zidovudine) contains abacavir, lamivudine and zidovudine, any interactions that have been identified with these agents individually may occur with TRIZIVIR. The interactions listed below should not be considered exhaustive but are representative of the classes of medicinal products where caution should be exercised.

The possibility of interactions with other drugs administered concurrently should be considered, particularly when the main route of elimination is renal.

It is recommended that separate doses of abacavir, lamivudine and zidovudine be administered to patients with reduced renal function (see Warnings and Precautions), patients who weigh less than 50 kg or patients requiring dosing adjustments due to adverse events. See complete prescribing information for abacavir, lamivudine and zidovudine for dosage adjustments.

The recommended oral dose of TRIZIVIR (abacavir sulfate/lamivudine/zidovudine) is one tablet twice daily.

TRIZIVIR can be taken with or without food.

If you forget to take your medicine, take it as soon as you remember. Then continue as before. Do not take a double dose to make up for forgotten individual doses.

oral mucosal pigmentation.

The following events have been identified during use of TRIZIVIR in clinical practice. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to either their seriousness, frequency of reporting, potential causal connection to TRIZIVIR, or a combination of these factors.

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

stomatitis.

A patient with a diagnosis of AIDS dementia and a history of seizure disorder experienced a seizure 3 days after stopping abacavir therapy. In the absence of an autopsy, a definitive diagnosis could not be adequately made, and a possible relationship to abacavir therefore could not be ruled out.

gynecomastia, asthenia.

redistribution/accumulation of body fat (see Warnings and Precautions, Endocrine and Metabolism).

abnormal breath sounds/wheezing, respiratory failure.

Anemia (which may require transfusions), neutropenia, leucopenia and aplastic anemia occurred more frequently at higher dosages (1200-1500 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. Dosage reduction or cessation of therapy may become necessary (see Warnings and Precautions).

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

Pancreatitis, which has been fatal in some cases, has been observed in antiretroviral nucleoside-experienced pediatric patients receiving 3TC alone or in combination with other antiretroviral agents. In an open-label dose-escalation study (NUCA2002), 14 patients (14%) developed pancreatitis while receiving monotherapy with 3TC. Three of these patients died of complications of pancreatitis. In a second open-label study (NUCA2005), 12 patients (18%) developed pancreatitis. In study ACTG300, pancreatitis was not observed in 236 patients randomized to 3TC plus RETROVIR (AZT). Pancreatitis was observed in one patient in this study who received open-label 3TC in combination with RETROVIR (AZT) and ritonavir following discontinuation of didanosine monotherapy.

aplastic anemia, anemia, neutropenia, leucopenia, lymphadenopathy, pure red cell aplasia, splenomegaly.

Many of the adverse events listed above for abacavir (nausea, vomiting, diarrhea, fever, fatigue, rash) occur commonly as part of abacavir hypersensitivity. Therefore, patients with any of these symptoms should be carefully evaluated for the presence of this hypersensitivity reaction.

severe hepatomegaly with steatosis, cytolytic hepatitis, pancreatitis, posttreatment exacerbation of hepatitis B.

sensitization reactions (including anaphylaxis), urticaria.

myalgia, arthralgia, CPK elevation, rhabdomyolysis.

Fatal hypersensitivity reactions have been associated with therapy with abacavir sulfate. Therapy with TRIZIVIR or any medicinal product containing abacavir, must not be restarted following a hypersensitivity reaction because more severe symptoms will recur within hours and may include life-threatening hypotension and death. Patients developing signs or symptoms of hypersensitivity should discontinue treatment as soon as a hypersensitivity reaction is first suspected, and must seek medical evaluation immediately. To avoid a delay in diagnosis and minimize the risk of a life-threatening hypersensitivity reaction, TRIZIVIR should 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). TRIZIVIR, or any other medicinal product containing abacavir should not be restarted even if a recurrence of symptoms occurs following rechallenge with alternative medication(s).

Severe or fatal hypersensitivity reactions can occur within hours after TRIZIVIR re-introduction in patients who have no identified history or unrecognized symptoms of hypersensitivity during their initial period of use of TRIZIVIR (see Warnings and Precautions).

Regardless of a patient’s HLA-B*5701 status, if therapy with TRIZIVIR or any other medicinal product containing abacavir has been discontinued and restarting therapy is under consideration, the reason for discontinuation should be evaluated to ensure that the patient did not have symptoms of a hypersensitivity reaction. If a hypersensitivity reaction can not be ruled out TRIZIVIR or any other medicinal product containing abacavir (e.g. ZIAGEN, KIVEXA) should not be restarted.

Several serious adverse events have been reported with use of zidovudine in clinical practice. Reports of pancreatitis, sensitization reactions (including anaphylaxis in one patient), vasculitis and seizures have been rare. These adverse events, except for sensitization, have also been associated with HIV disease. Changes in skin and nail pigmentation have been associated with the use of zidovudine.

Coadministration of zidovudine with other drugs metabolized by glucuronidation should be avoided because the toxicity of either drug may be potentiated (see Drug Interactions).

Several serious adverse events have been reported with use of lamivudine in clinical practice. Reports of anaphylaxis, rhabdomyolysis and peripheral neuropathy have been rare (<1 in 1000).

lactic acidosis, hyperglycemia, hyperlactemia.

TRIZIVIR (abacavir sulphate/lamivudine/zidovudine) contains abacavir, lamivudine and zidovudine. The adverse events associated with these compounds listed in Table 1 may therefore be expected following treatment with TRIZIVIR. For many of these adverse events, it is unclear whether they are related to the active substance, the wide range of other medicinal products used in the management of HIV disease, or whether they are a result of the underlying disease process. The assessment of the safety profile of TRIZIVIR in clinical studies is not yet available.

alopecia, erythema multiforme, Stevens-Johnson Syndrome, toxic epidermal necrolysis.

paresthesia, peripheral neuropathy, seizures.

cardiomyopathy.

Patients with impaired renal function may be at a greater risk of toxicity from TRIZIVIR due to decreased renal clearance of lamivudine and zidovudine. Therefore a dosage adjustment of lamivudine and zidovudine may be necessary. The pharmacokinetic properties of abacavir have not been determined in patients with impaired renal function. Other drugs that are eliminated by acyl glucuronide formation are known to accumulate in patients with renal impairment, therefore it is possible the 5'glucuronide and 5'-carboxylic acid metabolites of abacavir might accumulate in patients with impaired renal function.

It is recommended that TRIZIVIR not be used in patients with reduced renal function (creatinine clearance ≤50 mL/min). For these patients, it is recommended that abacavir, lamivudine and zidovudine be administered. The individual Product Monographs for abacavir, lamivudine and zidovudine should be consulted for appropriate dosage adjustments.

TRIZIVIR is contraindicated in patients with end-stage renal disease (see Contraindications).

Since TRIZIVIR contains zidovudine, TRIZIVIR should be used with extreme caution in patients who have bone marrow compromise evidenced by granulocyte count <1000 cells/mm³ or hemoglobin <9.5 g/dL. In all of the placebo-controlled studies, but most frequently in patients with advanced symptomatic disease, anemia and granulocytopenia was the most significant adverse events observed (see Adverse Reactions). There have been reports of pancytopenia associated with the use of zidovudine, which was reversible in most instances after discontinuation of the drug.

Very rare occurrences of pure red cell aplasia have been reported with lamivudine or zidovudine use. Discontinuation of lamivudine and/or zidovudine has resulted in normalization of hematologic parameters in patients with suspected lamivudine or zidovudine induced pure red cell aplasia.

Anemia, neutropenia and leucopenia (usually secondary to neutropenia) can be expected to occur in patients receiving zidovudine. These occurred more frequently at higher zidovudine dosages (1200 to 1500 mg/day) and in patients with poor bone marrow reserve prior to treatment, particularly with advanced HIV disease. Hematological parameters should therefore be carefully monitored in patients receiving TRIZIVIR (see Contraindications).

These hematological effects are not usually observed before four to six weeks therapy. For patients with advanced symptomatic HIV disease, it is generally recommended that blood tests are performed at least every two weeks for the first three months of therapy and at least monthly thereafter. In patients with early HIV disease hematological adverse reactions are infrequent. Depending on the overall condition of the patient, blood tests may be performed less often, for example every one to three months.

Additionally dosage adjustment of zidovudine may be required if severe anemia or myelosuppression occurs during treatment with TRIZIVIR, or in patients with pre-existing bone marrow compromise e.g. haemoglobin less than 9 g/dL (5.59 mmol/L) or neutrophil count less than 1.0×10⁹/L (see Dosage and Administration). As dosage adjustment of TRIZIVIR is not possible separate preparations of zidovudine, abacavir and lamivudine should be used.

A warning card with information for the patient about this hypersensitivity reaction is included in the TRIZIVIR pack (see Information for the Patient, Warning Card).

Studies have shown that carriage of the HLA-B*5701 allele is associated with a significantly increased risk of a hypersensitivity reaction to abacavir. CNA106030 (PREDICT-1), a randomized, double blind study, evaluated the clinical utility of prospective HLA-B*5701 screening on the incidence of abacavir hypersensitivity reaction in abacavir-naïve HIV-1 infected adults (n=1650). In this study, use of pre-therapy screening for the HLA-B*5701 allele and exclusion of subjects with this allele reduced the incidence of clinically suspected abacavir hypersensitivity reactions from 7.8% (66/847) to 3.4% (27/803) (p<0.0001). Based on this study, it is estimated that 61% of patients with the HLA-B*5701 allele will develop a clinically suspected hypersensitivity reaction during the course of abacavir treatment compared with 4% of patients who do not have the HLA-B*5701 allele.

Screening for carriage of the HLA-B*5701 allele is recommended prior to initiating treatment with abacavir. Screening is also recommended prior to re-initiating abacavir in patients of unknown HLA-B*5701 status who have previously tolerated abacavir. For HLA-B*5701-positive patients, initiating or re-initiating treatment with an abacavir containing regimen is not recommended and should be considered only with close medical supervision and under exceptional circumstances where potential benefit outweighs the risk.

Skin patch testing is used as a research tool and should not be used to aid in the clinical diagnosis of abacavir hypersensitivity.

In any patient treated with abacavir, the clinical diagnosis of a hypersensitivity reaction must remain the basis of clinical decision making. Even in the absence of the 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.

Abacavir induced chromosomal aberrations both in the presence and absence of metabolic activation in an in vitro cytogenetic study in human lymphocytes. Abacavir was mutagenic in the absence of metabolic activation, although it was not mutagenic in the presence of metabolic activation in an L5178Y mouse lymphoma assay.

At systemic exposures approximately nine times higher than that in humans at the therapeutic dose, abacavir was clastogenic in males and not clastogenic in females in an in vivo mouse bone marrow micronucleus assay.

Abacavir was not mutagenic in bacterial mutagenicity assays in the presence and absence of metabolic activation.

Carcinogenicity studies with orally administered abacavir in mice and rats showed an increase in the incidence of malignant and non-malignant tumors. Malignant tumors occurred in the preputial gland of males and the clitoral gland of females of both species, and in the liver, urinary bladder, lymph nodes and subcutis of female rats. The majority of these tumors occurred at the highest abacavir dose in mice and rats, which correspond to 24-32 times the expected systemic exposure in humans.

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of antiretroviral nucleoside analogues either alone or in combination, including abacavir, lamivudine and zidovudine. A majority of these cases have been in women.

Clinical features which may be indicative of the development of lactic acidosis include generalized weakness, anorexia, and sudden unexplained weight loss, gastrointestinal symptoms and respiratory symptoms (dyspnea and tachypnea).

Obesity and prolonged nucleoside exposure may be risk factors. Particular caution should be exercised when administering TRIZIVIR to any patient with known risk factors for liver disease; however, cases have also been reported in patients with no known risk factors. Treatment with TRIZIVIR should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations).

In clinical trials, patients with prolonged prior nucleoside reverse transcriptase inhibitor (NRTI) exposure or who had HIV-1 isolates that contained multiple mutations conferring resistance to NRTIs had limited response to abacavir. The potential for cross-resistance between abacavir and other NRTIs should be considered when choosing new therapeutic regimens in therapy experienced patients.

In heavily pre-treated NRTI patients, the reduction in viral load with abacavir sulfate was very low. The degree of viral load reduction as part of a new combination regimen will depend on the nature and duration of prior therapy which may have selected for HIV-1 variants with cross-resistance to abacavir.

Severe respiratory symptoms, some indicative of adult respiratory distress syndrome (ARDS), occur in a small proportion of hypersensitivity reaction cases. ARDS or respiratory failure appear more likely to occur in a re-challenge situation.

TRIZIVIR is not recommended in children. There are no data on the use of TRIZIVIR in pediatric patients.

The safety of TRIZIVIR in human pregnancy has not been established.

Lamivudine, abacavir and zidovudine have been associated with findings in animal reproductive studies. Therefore, administration of TRIZIVIR in pregnancy should be considered only if the benefit to the mother outweighs the possible risk to the fetus.

There have been reports of mild, transient elevations in serum lactate levels, which may be due to mitochondrial dysfunction, in neonates and infants exposed in utero or peri-partum to nucleoside reverse transcriptase inhibitors (NRTIs). The clinical relevance of transient elevations in serum lactate is unknown. There have also been very rare reports of developmental delay, seizures and other neurological disease.

However, a causal relationship between these events and NRTI exposure in utero or peri-partum has not been established. These findings do not affect current recommendations to use antiretroviral therapy in pregnant women to prevent vertical transmission of HIV.

To monitor maternal-fetal outcomes of pregnant women exposed to TRIZIVIR, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling GlaxoSmithKline's Drug Surveillance Department (1-800-387-7374).

Exacerbation of anemia due to ribavirin has been reported when zidovudine is part of the regimen used to treat HIV although the exact mechanism remains to be elucidated. Therefore, the co-administration of ribavirin and zidovudine is not advised and consideration should be given to replacing zidovudine in a combination ART regimen if this is already established. This is particularly important in patients with a known history of zidovudine induced anemia.

Clinical trial and marketed use of lamivudine, have shown that some patients with chronic hepatitis B virus (HBV) disease may experience clinical or laboratory evidence of recurrent hepatitis upon discontinuation of lamivudine, which may have more severe consequences in patients with decompensated liver disease. If TRIZIVIR is discontinued in a patient with HIV and HBV co-infection, periodic monitoring of both liver function tests and markers of HBV replication should be considered.

Clinical studies of TRIZIVIR did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy.

Myopathy and myositis with pathological changes similar to that produced by HIV disease have been associated with prolonged use of zidovudine and therefore may occur with TRIZIVIR therapy.

In vitro studies have shown ribavirin can reduce the phosphorylation of pyrimidine nucleoside analogues such as lamivudine, a component of TRIZIVIR. Although no evidence of a pharmacokinetic or pharmacodynamic interaction (e.g., loss of HIV/HCV virologic suppression) was seen when ribavirin was coadministered with lamivudine in HIV/HCV co infected patients (see Drug Interactions), hepatic decompensation (some fatal) has occurred in HIV/HCV co infected patients receiving combination antiretroviral therapy for HIV and interferon alfa with or without ribavirin. Patients receiving interferon alfa with or without ribavirin and TRIZIVIR should be closely monitored for treatment associated toxicities, especially hepatic decompensation. Discontinuation of TRIZIVIR should be considered as medically appropriate. Dose reduction or discontinuation of interferon alfa, ribavirin, or both should also be considered if worsening clinical toxicities are observed, including hepatic decompensation.

During the initial phase of treatment, patients responding to antiretroviral therapy may develop an inflammatory response to indolent or residual opportunistic infections (such as MAC, CMV, PCP, and TB) which may necessitate further evaluation and treatment.

Patients receiving TRIZIVIR or any other antiretroviral therapy may continue to develop opportunistic infections and other complications of HIV infection. Therefore, patients should remain under close observation by physicians experienced in the treatment of patients with HIV associated diseases.

TRIZIVIR is contraindicated for use in hepatically impaired patients (see Contraindications). There are no data available on the use of TRIZIVIR in hepatically impaired patients. Abacavir is contraindicated in patients with moderate to severe hepatic impairment and dose reduction is required in some patients with mild hepatic impairment. Because TRIZIVIR is a fixed dose combination and cannot be dose adjusted, TRIZIVIR is contraindicated for patients with hepatic impairment.

Abacavir is metabolized primarily by the liver. The pharmacokinetics of abacavir have been studied in patients with mild hepatic impairment (Child-Pugh score 5-6) who had confirmed cirrhosis.

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. Dosage reduction of abacavir is therefore required in patients with mild hepatic impairment. The pharmacokinetics of abacavir have not been studied in patients with moderate or severe hepatic impairment.

Limited data in patients with cirrhosis suggest that accumulation of zidovudine may occur, because of decreased glucuronidation. Data obtained in patients with moderate to severe hepatic impairment show that lamivudine pharmacokinetics are not significantly affected by hepatic dysfunction.

TRIZIVIR is a fixed dose combination of abacavir sulfate, lamivudine and zidovudine. TRIZIVIR should not be administered concomitantly with either abacavir, lamivudine or zidovudine. The complete prescribing information for all agents being considered for use with TRIZIVIR should be consulted before combination therapy with TRIZIVIR is initiated.

The incidence of adverse reactions appears to increase with disease progression and patients should be monitored carefully, especially as disease progression occurs.

Serious and sometimes fatal hypersensitivity reactions have been associated with therapy with abacavir sulfate, one of the three active ingredients of TRIZIVIR. Patients who carry the HLA-B*5701 allele are at a significantly increased risk for experiencing a hypersensitivity reaction to abacavir. Other less common signs or symptoms of hypersensitivity include fever, skin rash, fatigue, myolysis, edema, paresthesia, anaphylaxis, liver failure, renal failure, hypotension, adult respiratory distress syndrome, respiratory failure, and death have occurred in association with hypersensitivity reactions, gastrointestinal symptoms, such as nausea, vomiting, diarrhea or abdominal pain, and respiratory signs and symptoms such as pharngitis, dyspnea, cough and abnormal chest x-ray findings predominantly infiltrates, which can be localized.

Physical findings associated with hypersensitivity to abacavir in some patients include lymphadenopathy, mucous membrane lesions (conjunctivitis and mouth ulcerations), and rash. The rash usually appears maculopapular or urticarial, but may be variable in appearance. There have been reports of erythema multiforme. Hypersensitivity reactions have occurred without rash.

Laboratory abnormalities associated with hypersensitivity to abacavir in some patients include elevated liver function tests, elevated creatine phosphokinase, elevated creatinine, and lymphopenia.

The diagnosis of a hypersensitivity reaction should be carefully considered for patients presenting with symptoms of acute onset respiratory diseases, even if alternative respiratory diagnoses (pneumonia, bronchitis, pharyngitis or flu-like illness) are possible. TRIZIVIR or any other medicinal product containing abacavir must never be restarted following a hypersensitivity reaction, as more severe symptoms will recur within hours and may include life-threatening hypotension and death.

To avoid a delay in diagnosis and minimize the risk of a life-threatening hypersensitivity reaction, TRIZIVIR should 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). TRIZIVIR or any other medicinal product containing abacavir should not be re-started, even if a recurrence of symptoms occurs following rechallenge with alternative medication(s).

Severe or fatal hypersensitivity reactions can occur within hours after TRIZIVIR re-introduction in patients who have no identified history or unrecognized symptoms of hypersensitivity during their initial period of use of TRIZIVIR.

Regardless of a patient’s HLA-B*5701 status, if therapy with TRIZIVIR or any other medicinal product containing abacavir has been discontinued and restarting therapy is under consideration, the reason for discontinuation should be evaluated to ensure that the patient did not have symptoms of a hypersensitivity reaction. If a hypersensitivity reaction cannot be ruled out, TRIZIVIR, or any other medicinal product containing abacavir (e.g. ZIAGEN, KIVEXA) should not be restarted.

If symptoms consistent with hypersensitivity are not identified, reintroduction can be undertaken with continued monitoring for symptoms of a hypersensitivity reaction. Make patients aware that a hypersensitivity reaction can occur with reintroduction of TRIZIVIR or any other abacavir containing product and that reintroduction of TRIZIVIR or introduction of any other abacavir containing product needs to be undertaken only if medical care can be readily accessed by the patient or others.

Overall, in clinical trials conducted before the introduction of screening for the HLA-B*5701 allele, hypersensitivity to abacavir was reported in approximately 8% of 2670 patients (n=206) in 9 clinical trials (range: 2% to 9%) with enrolment from November 1999 to February 2002. Data on time to onset and symptoms of suspected hypersensitivity were collected on a detailed data collection module. This reaction is characterised by the appearance of symptoms indicating multi-organ/body-system involvement. Symptoms can occur at any time during therapy, however they usually appear within the first 6 weeks (median time to onset 11 days) of initiation of treatment with TRIZIVIR (see Adverse Reactions). See Figure 1.

Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (“buffalo hump”), peripheral wasting, facial wasting, breast enlargement, and “cushingoid appearance” have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.

It is recommend that HIV-infected women do not breast-feed their infants under any circumstances in order to avoid transmission of HIV. It is therefore recommended that mothers do not breast-feed their babies while receiving treatment with TRIZIVIR.

Both lamivudine and zidovudine are excreted in human milk at similar concentrations to those found in serum. It is expected that abacavir will also be secreted into human milk, although this has not been confirmed.

The results of a prospective, observational, epidemiological study designed to investigate the rate of myocardial infarction in patients on combination antiretroviral therapy (N=33 347) suggest that current or recent use (within the past 6 months) of abacavir may be associated with a potential increased risk of myocardial infarction. This elevated risk does not appear to increase further over time, and no excess risk was present in patients who had stopped taking abacavir more than 6 months previously. The relative risk of myocardial infarction was estimated to be 1.9 (95% CI 1.47-2.45). The absolute myocardial infarction rate was 6.1/1000 patient years of exposure for those recently exposed to abacavir compared to an absolute myocardial infarction rate of 2.6/1000 patient years of exposure for those not recently exposed. In addition, the absolute myocardial infarction rate ranged from 3.4 to 3.7/1000 patient years of exposure for patients recently exposed to other NRTIs (i.e. zidovudine, stavudine and lamivudine).

In a pooled analysis of GSK sponsored clinical trials (N=9639), no increased risk of myocardial infarction was observed with abacavir use. At this time, though the available data do not allow a definitive conclusion regarding the association between the use of abacavir and an increased risk of myocardial infarction, it is recommended that physicians discuss the potential benefits and risks of abacavir with their patients.

As a precaution, the underlying risk of coronary heart disease should be considered when prescribing antiretroviral therapies, including abacavir, and action taken to minimize all modifiable risk factors (e.g. hypertension, hyperlipidemia, diabetes mellitus and smoking).

Abacavir sulfate is rapidly and well absorbed following oral administration. The absolute bioavailability of oral abacavir sulfate in adults is about 83%. Following oral administration, the mean time (t_max) to maximal serum concentrations of abacavir is about 1.5 hours for the tablet formulation and about 1.0 hour for the solution formulation. There are no differences observed between the AUC for the tablet or solution. At therapeutic dosages (300 mg twice daily), the steady state C_max of abacavir sulfate tablets is approximately 3 μg/mL, and the AUC over a dosing interval of 12 hours is approximately 6 μg·h/mL. The C_max value for the oral solution is slightly higher than the tablet. Food delayed absorption and decreased C_max but did not affect overall plasma concentrations (AUC). Therefore abacavir can be taken with or without food. The pharmacokinetic properties of lamivudine have been studied in asymptomatic, HIV-infected adult patients after administration of single oral, multiple oral and intravenous (IV) doses ranging from 0.25 to 10 mg/kg. After oral administration lamivudine is well absorbed from the gut. The bioavailability of lamivudine in adults is normally between 80 and 85% and the mean time (t_max) to maximal serum concentrations (C_max) is about an hour. After oral administration of 2 mg/kg, the peak plasma lamivudine concentration (C_max) was 1.5±0.5 μg/mL (mean±S.D.) and half-life was 2.6±0.5 hours. There were no significant differences in half-life across the range of single doses (0.25 to 8 mg/kg). The area under the plasma concentration versus time curve (AUC) and C_max increased in proportion to dose over the range from 0.25 to 10 mg/kg.

Pharmacokinetic studies of zidovudine following intravenous dosing in adults indicate dose-independent kinetics over the range of 1 to 5 mg/kg with a mean zidovudine half-life of 1.1 hours. Zidovudine is rapidly metabolized in the liver to 3'-azido-3'-deoxy-5'-O-β-D-glucopyranuronosylthymidine (GZDV, formerly called GAZT), and both are rapidly eliminated by the kidney. A second metabolite, 3'-amino-3'-deoxythymidine (AMT) has been identified in the plasma following single dose intravenous administration of zidovudine. After oral dosing in adults, zidovudine is rapidly absorbed from the gastrointestinal tract with peak serum concentrations occurring within 0.5 to 1.5 hours, with an average oral bioavailability of 65%.

Abacavir sulfate, lamivudine and zidovudine are inhibitors of HIV-1 and HIV-2 replication in vitro. Abacavir is a synthetic carbocyclic nucleoside analogue. Lamivudine is the (-) enantiomer of a dideoxy analogue of cytidine. Zidovudine is a thymidine analogue in which the 3'-hydroxy (-OH) group is replaced by an azido (-N3) group. Intracellularly, abacavir, lamivudine and zidovudine are phosphorylated to their active 5'-triphosphate metabolites, carbovir-triphosphate, lamivudine triphosphate and zidovudine triphosphate. The principal mode of action of carbovir, lamivudine and zidovudine triphosphate is inhibition of HIV reverse transcription (RT) via viral DNA chain termination. Carbovir, lamivudine and zidovudine triphosphate show significantly less affinity for host cell DNA polymerases.