|
Product
Antiretroviral products (Abamune)
|
Antiretroviral products (Abamune)
|
|
| |
|
Abamune Abacavir Sulfate Tablets 300 mg
COMPOSITION
Each film-coated tablet contains Abacavir 300 mg as Abacavir sulfate
DOSAGE FORM
Oral tablets
PHARMACOLOGY
Pharmacodynamics
Mechanism of Action: Abacavir is a carbocyclic synthetic nucleoside analogue. Intracellularly, abacavir is converted by cellular enzymes to the active metabolite carbovir triphosphate (CBV-TP). (CBV-TP) is an analogue of deoxyguanosine-5`-triphosphate (dGTP). (CBV-TP) inhibits the activity of HIV-1 reverse transcriptase (RT) both by competing with the natural substrate dGTP and by its incorporation into viral DNA. The lack of a 3`-OH group in the incorporated nucleoside analogue prevents the formation of the 5` to 3` phosphodiester linkage essential for DNA chain elongation, and therefore, the viral DNA growth is terminated. CBV-TP is a weak inhibitor of cellular DNA polymerases alpha, beta and gamma .
|
Pharmacokinetics
Absorption and Bioavailability: Abacavir is rapidly and extensively absorbed after oral administration. The geometric mean absolute bioavailability of the tablet is 83%. After oral administration of 300 mg twice daily in 20 patients, the steady-state peak serum abacavir concentration (C max was 3.0 ± 0.89 mcg/mL (mean ± SD) and AUC (0-12 hr) was 6.02 ± 1.73 mcg•hr/mL.
Distribution: The apparent volume of distribution after IV administration of abacavir was 0.86 ± 0.15 L/kg, suggesting that abacavir distributes into extravascular space. In 3 subjects, the CSF AUC (0-6 hr) to plasma abacavir AUC (0-6 hr) ratio ranged from 27% to 33%. Binding of abacavir to human plasma proteins is approximately 50%. Binding of abacavir to plasma proteins was independent of concentration.
Metabolism: In humans, abacavir is not significantly metabolized by cytochrome P450 enzymes. The primary routes of elimination of abacavir are metabolism by alcohol dehydrogenase (to form the 5`-carboxylic acid) and glucuronyl transferase (to form the 5`-glucuronide). The metabolites do not have antiviral activity. In vitro experiments reveal that abacavir does not inhibit human CYP3A4, CYP2D6, or CYP2C9 activity at clinically relevant concentrations.
Elimination: Elimination of abacavir was quantified in a mass balance study following administration of a 600-mg dose of 14 C-abacavir: 99% of the radioactivity was recovered, 1.2% was excreted in the urine as abacavir, 30% as the 5`-carboxylic acid metabolite, 36% as the 5`-glucuronide metabolite, and 15% as unidentified minor metabolites in the urine. Fecal elimination accounted for 16% of the dose. In single-dose studies, the observed elimination half-life (t 1/2 ) was 1.54 ± 0.63 hours.
Effects of Food on Oral Absorption: Bioavailability of abacavir tablets was assessed in the fasting and fed states. There was no significant difference in systemic exposure (AUC∞) in the fed and fasting states; therefore, ABAMUNE Tablets may be administered with or without food. Systemic exposure to abacavir was comparable after administration of abacavir oral solution and abacavir tablets. Therefore, these products may be used interchangeably.
Special population
Renal impairment: The pharmacokinetic properties of abacavir have not been determined in patients with impaired renal function. Renal excretion of unchanged abacavir is a minor route of elimination in humans.
Hepatic Impairment: The pharmacokinetics of abacavir have been studied in patients with mild hepatic impairment (Child-Pugh score 5 to 6). Results showed that there was a mean increase of 89% in the abacavir AUC, and an increase of 58% in the half-life of abacavir after a single dose of 600 mg of abacavir. The AUCs of the metabolites were not modified by mild liver disease; however, the rates of formation and elimination of the metabolites were decreased. A dose of 200 mg (provided by 10 mL of abacavir oral solution) administered twice daily is recommended for patients with mild liver disease. The safety, efficacy, and pharmacokinetics of abacavir have not been studied in patients with moderate or severe hepatic impairment, therefore ABAMUNE is contraindicated in these patients.
Pediatric Patients : The pharmacokinetics of abacavir have been studied after either single or repeat doses of abacavir in 68 pediatric patients. Following multiple-dose administration of abacavir 8 mg/kg twice daily, steady-state AUC (0-12 hr) and C max were 9.8 ± 4.56 mcg•hr/mL and 3.71 ± 1.36 mcg/mL (mean ± SD), respectively ( see WARNINGS AND PRECAUTIONS : Pediatric Use).
Geriatric Patients: The pharmacokinetics of abacavir has not been studied in patients over 65 years of age.
Gender : A population pharmacokinetic analysis in HIV-infected male (n = 304) and female (n = 67) patients showed no gender differences in abacavir AUC normalized for lean body weight.
Race : There are no significant differences between blacks and Caucasians in abacavir pharmacokinetics.
INDICATIONS
ABAMUNE 300 mg tablets are indicated for the treatment of HIV-1 infection in combination with other antiretroviral agents.
Additional important information on the use of ABAMUNE for treatment of HIV-1 infection:
Before starting ABAMUNE , review medical history for prior exposure to any abacavir containing product in order to avoid reintroduction in a patient with a history of hypersensitivity to abacavir.
DOSAGE AND ADMINISTRATION
ABAMUNE may be taken with or without food .
Adults:
The recommended oral dose of abacavir for adults is 600 mg daily administered as either 300 mg twice daily or 600 mg once daily in combination with other antiretroviral agents.
Patients with Hepatic Impairment:
The recommended dose of ABAMUNE in patients with mild hepatic impairment (Child-Pugh score 5 to 6) is 200 mg twice daily. The safety, efficacy, and pharmacokinetic properties of abacavir have not been established in patients with moderate to severe hepatic impairment, and therefore ABAMUNE is contraindicated in these patients.
CONTRAINDICATIONS
ABAMUNE tablets are contraindicated in patients with previously demonstrated hypersensitivity to abacavir or any other component of the products ( see WARNINGS and PRECAUTIONS) . Following a hypersensitivity reaction to abacavir, never restart ABAMUNE or any other abacavir-containing product. Fatal rechallenge reactions have been associated with readministration of abacavir to patients with a prior history of a hypersensitivity reaction to abacavir ( see WARNINGS and PRECAUTIONS).
ABAMUNE Tablets are contraindicated in patients with moderate or severe hepatic impairment.
WARNINGS AND PRECAUTIONS
Hypersensitivity Reactions
Serious and sometimes fatal hypersensitivity reactions have been associated with ABAMUNE and other abacavir-containing products. Patients who carry the HLA-B*5701 allele are at high risk for experiencing a hypersensitivity reaction to abacavir. Prior to initiating therapy with abacavir, screening for the HLA-B*5701 allele is recommended; this approach has been found to decrease the risk of a hypersensitivity reaction. Screening is also recommended prior to reinitiation of abacavir in patients of unknown HLA-B*5701 status who have previously tolerated abacavir. For HLA-B*5701-positive patients, treatment with an abacavir-containing regimen is not recommended and should be considered only with close medical supervision and under exceptional circumstances when the potential benefit outweighs the risk.
HLA-B*5701-negative patients may develop a hypersensitivity reaction to abacavir; however, this occurs significantly less frequently than in HLA-B*5701-positive patients. Regardless of HLA-B*5701 status, permanently discontinue ABAMUNE if hypersensitivity cannot be ruled out, even when other diagnoses are possible.
Important information on signs and symptoms of hypersensitivity, as well as clinical management, is presented below:
Signs and Symptoms of Hypersensitivity : Hypersensitivity to abacavir is a multi-organ clinical syndrome usually characterized by a sign or symptom in two or more of the following groups.
Group 1: Fever
Group 2: Rash
Group 3: Gastrointestinal (including nausea, vomiting, diarrhea, or abdominal pain)
Group 4: Constitutional (including generalized malaise, fatigue, or achiness)
Group 5: Respiratory (including dyspnea, cough, or pharyngitis)
Lactic acidosis/ Severe Hepatomegaly with Steatosis
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination, including abacavir and other antiretrovirals. A majority of these cases have been in women. Obesity and prolonged nucleoside exposure may be risk factors. Particular caution should be exercised when administering abacavir 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 abacavir 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).
Immune Reconstitution Syndrome
Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including abacavir sulfate. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia [PCP], or tuberculosis), which may necessitate further evaluation and treatment
Fat Redistribution
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.
Myocardial Infarction
In a published prospective, observational, epidemiological study designed to investigate the rate of myocardial infarction in patients on combination antiretroviral therapy, the use of abacavir within the previous 6 months was correlated with an increased risk of myocardial infarction (MI). 1 In a sponsor-conducted pooled analysis of clinical trials, no excess risk of myocardial infarction was observed in abacavir-treated subjects as compared with control subjects. In totality, the available data from the observational cohort and from clinical trials are inconclusive.
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).
Drug Interactions
Ethanol: Abacavir has no effect on the pharmacokinetic properties of ethanol. Ethanol decreases the elimination of abacavir causing an increase in overall exposure [ see PHARMACOLOGY] .
Methadone: The addition of methadone has no clinically significant effect on the pharmacokinetic properties of abacavir. In a study of 11 HIV-infected patients receiving methadone-maintenance therapy with 600 mg of abacavir twice daily (twice the currently recommended dose), oral methadone clearance increased . This alteration will not result in a methadone dose modification in the majority of patients; however, an increased methadone dose may be required in a small number of patients.
UNDESIRABLE EFFECTS
Serious and sometimes fatal hypersensitivity reactions have been associated with abacavir sulfate. In one study, once daily dosing of abacavir was associated with more severe hypersensitivity reactions ( see WARNINGS and PRECAUTIONS) .
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Postmarketing Experience
In addition to adverse reactions reported from clinical trials, the following reactions have been identified during postmarketing use of abacavir. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These reactions have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to abacavir.
Body as a Whole: Redistribution/accumulation of body fat
Cardiovascular: Myocardial infarction
Hepatic: Lactic acidosis and hepatic steatosis
Skin: 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 clinical signs and symptoms between hypersensitivity to abacavir and 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 also been reports of erythema multiforme with abacavir use.
OVERDOSAGE
There is no known antidote for abacavir.It is not known whether abacavir can be removed by peritoneal dialysis or hemodialysis.
PACKAGING INFORMATION
ABAMUNE ................................................... Container of 30 tablets
|
|
