Ziagen 300 mg

Based on the results of in vitro experiments and the known major metabolic pathways of abacavir sulfate, the potential for drug interactions involving abacavir sulfate is low. Abacavir sulfate shows low potential to inhibit metabolism mediated by the cytochrome P450 3A4 enzyme. It has also been shown in vitro not to interact with drugs that are metabolized by CYP3A4, CYP2C9 or CYP2D6 enzymes. Induction of hepatic metabolism has not been observed in clinical studies. Therefore, there is little potential for drug interactions with antiretroviral protease inhibitors and other drugs metabolized by major P450 enzymes. Clinical studies have shown that there are no clinically significant interactions between abacavir sulfate, zidovudine, and lamivudine.

Abacavir is primarily metabolized by the liver. The recommended dose of ZIAGEN in patients with mild hepatic impairment (Child-Pugh score 5-6) who have confirmed cirrhosis is 200 mg twice a day. To enable dose reduction ZIAGEN oral solution should be used for the treatment of these patients. ZIAGEN is contraindicated in patients with moderate or severe hepatic impairment, as the pharmacokinetics have not been studied in these patient groups. (See Contraindications and Warnings and Precautions, Impaired Hepatic Function.)

An Information for the Patient Leaflet and Warning Card that provide information about recognition of hypersensitivity reactions should be dispensed with each new prescription and refill.

ZIAGEN can be taken with or without food.

Patients changing to the once daily regimen should take 300 mg twice a day and switch to 600 mg once a day the following morning. Where an evening once daily regimen is preferred, 300 mg of ZIAGEN should be taken on the first morning only, followed by 600 mg in the evening. When changing back to a twice daily regimen, patients should complete the day's treatment and start 300 mg twice a day the following morning.

Patients, guardians and caregivers of pediatric patients must be made aware of the potential signs and symptoms of a hypersensitivity reaction to abacavir and that abacavir must be stopped and never restarted following a possible hypersensitivity reaction (see Warnings and Precautions and Adverse Reactions).

There are insufficient data to recommend the use of ZIAGEN in infants less than three months old (see Warnings and Precautions, Pediatrics).

The recommended dose of ZIAGEN is 300 mg (one tablet or 15 mL of oral solution) twice daily in combination with other antiretroviral agents.

The recommended oral dose of ZIAGEN for adolescent and pediatric patients 3 months up to 12 years of age is 8 mg/kg twice daily (up to a maximum of 300 mg twice daily) in combination with other antiretroviral agents.

The recommended oral dose of ZIAGEN for adults is 600 mg daily administered as either 300 mg twice daily or 600 mg once daily, in combination with other antiretroviral agents. The use of 600 mg once daily may be associated with a higher incidence of severe hypersensitivity reactions.

The use of once daily ZIAGEN 600 mg has not been studied in patients less than 18 years of age.

The use of once daily ZIAGEN 600 mg has not been studied in elderly patients or patients with comorbid conditions.

No dosage adjustment of ZIAGEN is necessary in patients with renal dysfunction. However, ZIAGEN should be avoided in patients with end-stage renal disease. The use of ZIAGEN 600 mg once daily has not been studied in patients with renal impairment and is not recommended for use in this population (see Warnings and Precautions, Renal).

If the patient forgets to take their medicine, they should take it as soon as they remember. Then continue as before. Patients should not take a double dose to make up for forgotten individual doses. If a patient stops therapy with ZIAGEN because of side effects or illness, they must check with their doctor before restarting therapy to make sure that symptoms of a hypersensitivity reaction have not been missed.

Common: diarrhea, nausea, vomiting. Rare: pancreatitis has been reported, but a causal relationship to ZIAGEN treatment is uncertain.

In addition to adverse events reported from clinical trials, the following events have been identified during use of abacavir 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 abacavir, or a combination of these factors.

Common: anorexia, hyperlactatemia. Rare: lactic acidosis (see Warnings and Precautions).

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.

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 patients in 9 clinical trials (range: 2% to 9%). This reaction is characterized 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 six weeks (median time to onset 11 days) of initiation of treatment with abacavir.

In controlled study (CNA30021), more patients taking ZIAGEN 600 mg once daily had severe hypersensitivity reactions than patients taking ZIAGEN 300 mg twice daily (see Warnings and Precautions and Dosage and Administration).

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.

The signs and symptoms of this hypersensitivity reaction are listed below. Those reported in at least 10% of patients with a hypersensitivity reaction are in bold text.

Treatment emergent clinical adverse reactions (rated by the investigator as at least moderate) with a ≥5% frequency during therapy with ZIAGEN 600 mg once daily and efavirenz 600 mg once daily from Study 30021 were similar. For hypersensitivity reactions, patients receiving ZIAGEN once daily showed a rate of 9% in comparison to a rate of 7% for patients receiving ZIAGEN twice daily. However, patients receiving ZIAGEN 600 mg once daily, experienced a significantly higher incidence of severe drug hypersensitivity reactions and severe diarrhea compared to patients who received ZIAGEN 300 mg twice daily. Five percent (5%) of patients receiving ZIAGEN 600 mg once daily had severe drug hypersensitivity reactions compared to 2% of patients receiving ZIAGEN 300 mg twice daily. Two percent (2%) of patients receiving ZIAGEN 600 mg once daily had severe diarrhea while none of the patients receiving ZIAGEN 300 mg twice daily had this event.

Common: fatigue, fever, lethargy.

Common: headache.

anaphylaxis, conjunctivitis, edema, fatigue, fever, hypotension, lymphadenopathy, malaise.

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

Common: rash (without systemic symptoms). Very rare: erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis.

Cases of lactic acidosis, sometimes fatal, usually associated with severe hepatomegaly and hepatic steatosis, have been reported with the use of nucleoside analogues.

In controlled clinical studies laboratory abnormalities related to ZIAGEN treatment were uncommon, with no differences in incidence observed between ZIAGEN-treated patients and the control arms.

A patient with a diagnosis of AIDS dementia and a history of seizure disorder experienced a seizure 3 days after stopping ZIAGEN 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.

adult respiratory distress syndrome, cough, dyspnea, respiratory failure, sore throat.

arthralgia, elevated creatine phosphokinase, myalgia, rarely myolysis.

Fatal hypersensitivity reactions have been associated with therapy with ZIAGEN (abacavir sulfate).

Therapy with ZIAGEN or any other 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, ZIAGEN 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). ZIAGEN 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 ZIAGEN reintroduction in patients who have no identified history or unrecognized symptoms of hypersensitivity during their initial period of use of ZIAGEN (see Warnings and Precautions).

Regardless of a patient’s HLA-B*5701 status, if therapy with ZIAGEN 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, ZIAGEN or any other medicinal product containing abacavir (e.g. KIVEXA, TRIZIVIR) should not be restarted.

elevated liver function tests, hepatic failure.

abdominal pain, diarrhea, mouth ulceration, nausea, vomiting.

Suspected Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported in patients receiving abacavir primarily in combination with medications known to be associated with SJS and TEN, respectively. Because of the overlap of the clinical signs and symptoms between hypersensitivity to abacavir, SJS and TEN, and the possibility of multiple drug sensitivities in some patients, abacavir should be discontinued and not restarted in such cases. There have been reports of erythema multiforme with abacavir use.

elevated creatinine, renal failure.

Some patients who experienced a hypersensitivity reaction were initially thought to have acute onset or worsening respiratory disease. 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, gastroenteritis or reactions to other medications are possible.

Symptoms worsen with continued therapy, and usually resolve upon discontinuation of ZIAGEN.

Restarting ZIAGEN or any other medicinal product containing abacavir following a hypersensitivity reaction results in a prompt return of symptoms within hours. This recurrence of the hypersensitivity reaction may be more severe than on initial presentation, and may include life-threatening hypotension and death. Regardless of their HLA-B*5701 status, patients who develop this hypersensitivity reaction must discontinue ZIAGEN and must never be rechallenged with ZIAGEN or any other medicinal product containing abacavir (e.g. KIVEXA, TRIZIVIR).

For many of the other adverse events reported, it is unclear whether they are related to ZIAGEN, to the wide range of medicinal products used in the management of HIV disease or as a result of the disease process.

Many of the events listed (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.

The majority of the events listed below have not been treatment limiting. Care however, must be taken to eliminate the possibility of a hypersensitivity reaction if any of these symptoms occur.

The following convention has been used for classification: very common (>1/10), common (>1/100, <1/10), uncommon (>1/1000, <1/100), rare (>1/10 000, <1/1000) very rare (<1/10 000).

lymphopenia.

lactic acidosis and hepatic steatosis (see Warnings and Precautions, Hepatic/Biliary/Pancreatic).

headache, paraesthesia.

Each mL of clear to opalescent, yellowish, strawberry-banana flavored liquid, contains: abacavir sulfate equivalent to abacavir 20 mg. Nonmedicinal ingredients: artificial strawberry and banana flavors, citric acid (anhydrous), hydrochloric acid, methylparaben, propylene glycol, propylparaben, saccharin sodium, sodium citrate (dihydrate), sodium hydroxide and sorbitol solution. Bottles of 240 mL.

Each yellow, biconvex, capsule-shaped, film-coated tablet, scored and embossed with “GX 623” on both sides, contains: abacavir sulfate equivalent to abacavir 300 mg. Nonmedicinal ingredients: colloidal silicon dioxide, hydroxypropyl methylcellulose, magnesium stearate, microcrystalline cellulose, polysorbate 80, sodium starch glycolate, titanium dioxide, triacetin and yellow iron oxide. Bottles of 60.

Preliminary data from a single dose pharmacokinetic study of ZIAGEN in 6 end-stage renal disease patients has demonstrated that abacavir concentrations were similar to those with normal renal function. The two major metabolites (5'-glucuronide and 5'-carboxylate metabolites) are likely to accumulate but are considered inactive. No dosing modification of ZIAGEN is recommended in patients with renal dysfunction. However, ZIAGEN should be avoided in patients with end-stage renal disease. Once daily ZIAGEN 600 mg dosing has not been studied in the patients with impaired renal function and is not recommended for use in this population.

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.

In controlled study (CNA 30021), more patients taking ZIAGEN 600 mg once daily had severe hypersensitivity reactions than patients taking ZIAGEN 300 mg twice daily (see Dosage and Administration). In this study, 4 patients (11%) receiving ZIAGEN 600 mg once daily experienced hypotension with a hypersensitivity reaction compared with 0 patients receiving ZIAGEN 300 mg twice daily.

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

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 tumours. Malignant tumours 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 tumours occurred at the highest abacavir dose in mice and rats, which corresponds to 24-32 times the expected systemic exposure in humans.

Abacavir is contraindicated in patients with moderate to severe hepatic impairment and dose reduction is required in patients with mild 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. The pharmacokinetics have not been studied in patients with moderate or severe hepatic impairment, therefore ZIAGEN is contraindicated in these patient groups. Once daily ZIAGEN 600 mg dosing has not been studied in the patients with impaired hepatic function and is not recommended for use in this population (see Dosage and Administration, Impaired Hepatic Function).

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

Clinical features which may be indicative of the development of lactic acidosis include generalised 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 ZIAGEN 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 ZIAGEN should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced 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 ZIAGEN 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 appears more likely to occur in a rechallenge situation.

Abacavir is rapidly and well absorbed from the oral solution when administered to children. The overall pharmacokinetic parameters in children are comparable to adults, with greater variability in plasma concentrations. The recommended dose for children from 3 months to 12 years old is 8 mg/kg twice daily. This will provide slightly higher mean plasma concentrations in children, ensuring that the majority will achieve a therapeutic concentration equivalent to 300 mg twice daily in adults. There are insufficient safety data to recommend the use of ZIAGEN in infants less than three months old.

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

There are no adequate and well controlled studies in pregnant women. ZIAGEN should be used during pregnancy only if the potential benefits outweigh the risk.

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 on 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.

Studies in pregnant rats showed that abacavir is transferred to the fetus through the placenta. Developmental toxicity (depressed fetal body weight and reduced crown-rump length) and increased incidences of fetal anasarca and skeletal malformations were observed when rats were treated with abacavir at doses of 1000 mg/kg during organogenesis. This dose produced 35 times the human exposure, based on AUC.

In a fertility study, evidence of toxicity to the developing embryo and fetuses (increased resorptions, decreased fetal body weights) occurred only at 500 mg/kg per day. The offspring of female rats treated with abacavir at 500 mg/kg (beginning at embryo implantation and ending at weaning) showed increased incidence of stillbirth and lower body weights throughout life. In the rabbit, there was no evidence of drug-related developmental toxicity and no increases in fetal malformations at doses up to 700 mg/kg (8.5 times the human exposure at the recommended dose, based on AUC).

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.

Clinical studies of ZIAGEN did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. 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. Once-daily ZIAGEN 600 mg dosing has not been studied in the elderly and is not recommended for use in this population.

A ZIAGEN 600 mg OD regimen should not be used in patients over 65 years of age, or in patients with comorbid conditions such as hepatic or renal failure, as this dosing regimen has not been studied in this population.

ZIAGEN (abacavir sulfate) should always be used in combination with other antiretroviral agents. When antiretroviral regimens are changed due to loss of virologic response, ZIAGEN should not be added as a single agent.

Serious and sometimes fatal hypersensitivity reactions have been associated with therapy with ZIAGEN (see Boxed Serious Warnings and Precautions). Patients who carry the HLA-B*5701 allele are at a significantly increased risk for experiencing a hypersensitivity reaction to abacavir.

Discontinue ZIAGEN as soon as a hypersensitivity reaction is suspected. To minimize the risk of a life-threatening hypersensitivity reaction, permanently discontinue ZIAGEN if hypersensitivity cannot be ruled out, even when other diagnoses are possible (e.g., acute onset respiratory diseases such as pneumonia, bronchitis, pharyngitis, or influenza; gastroenteritis; or reactions to other medications). 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 ZIAGEN or any other abacavir containing product and that reintroduction of ZIAGEN or any other abacavir containing product needs to be undertaken only if medical care can be readily accessed by the patient or others.

Following a hypersensitivity reaction to abacavir, never restart ZIAGEN or any other abacavir containing product because more severe symptoms can occur within hours and may include life-threatening hypotension and death.

Regardless of a patient’s HLA-B*5701 status, if therapy with ZIAGEN 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, ZIAGEN or any other medicinal product containing abacavir (e.g. KIVEXA, TRIZIVIR) should not be restarted.

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 in the nine studies were collected on a detailed data collection module. This reaction is characterized 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 ZIAGEN (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 recommended that HIV infected women do not breastfeed their infants under any circumstances in order to avoid transmission of HIV. It is therefore recommended that mothers do not breastfeed their babies while receiving treatment with ZIAGEN.

Abacavir and its metabolites are secreted into the milk of lactating rats. It is expected that these will also be secreted into human milk, although this has not been confirmed. There is no data available on the safety of ZIAGEN when administered to babies less than three months old.

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).

ZIAGEN oral solution should be stored between 15 and 25°C.

ZIAGEN tablets should be stored between 15 and 30°C.

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 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 ZIAGEN can be taken with or without food.

In a study of 20 HIV-infected patients receiving abacavir 300 mg twice daily, with only one 300 mg dose taken prior to the 24 h sampling period, the geometric mean terminal carbovir-TP intracellular half-life at steady-state was 20.6 h, compared to the geometric mean abacavir plasma half-life in this study of 2.6 h. The steady state pharmacokinetic properties of abacavir 600 mg once daily was compared to abacavir 300 mg twice daily in a crossover study in 27 HIV-infected patients. Intracellular carbovir triphosphate exposures in peripheral blood mononuclear cells were higher for abacavir 600 mg once daily with respect to AUC_24,ss (32 %, higher), C_max24,ss (99% higher) and trough values (18% higher), compared to the 300 mg twice daily regimen. These data support the use of abacavir 600 mg once daily for the treatment of HIV-infected patients. Additionally, the efficacy and safety of this combination given once daily has been demonstrated in a pivotal clinical study.

Abacavir is a nucleoside analogue reverse transcriptase inhibitor. Abacavir is metabolized intracellularly to the active moiety, carbovir 5'-triphosphate (TP), a potent, selective inhibitor of HIV-1 and HIV-2, including HIV-1 isolates with reduced susceptibility to zidovudine, lamivudine, zalcitabine, didanosine and 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 which results in chain termination and interruption of the viral replication cycle. Abacavir shows synergy in vitro in combination with nevirapine or zidovudine. It has been shown to be additive in combination with didanosine, zalcitabine, lamivudine and stavudine.