ABAVIR OS

Abacavir sulfate is a synthetic carbocyclic nucleoside analogue with inhibitory activity against HIV-1.

The chemical name of abacavir sulfate is ( 1 S,cis).

• 4-[2-amino-6-(cyclopropylamino)-9 H -purin-9-yl]-2-cyclopentene-1-methanol sulfate (salt) (2:1).

Abacavir sulfate is the enantiomer with 1S, 4R absolute configuration on the cyclopentene ring.

It has a molecular formula of (C 14 H 18 N 6 O) 2 •H 2 SO and a molecular weight of 670.76 g per mol.

It has the following structural formula

Abacavir sulfate USP is a white to off-white solid and is soluble in water.

Abacavir tablets

USP are for oral administration.

Each tablet contains abacavir sulfate

USP equivalent to 300 mg of abacavir as active ingredient and the following inactive ingredients: colloidal silicon dioxide, magnesium stearate, microcrystalline cellulose, and sodium starch glycolate.

The tablets are coated with a film that is made of hypromellose, iron oxide yellow, polysorbate 80, titanium dioxide, and triacetin.

In vivo, abacavir sulfate dissociates to its free base, abacavir.

Dosages are expressed in terms of abacavir.

Abacavir tablets, in combination with other antiretroviral agents, are indicated for the treatment of human immunodeficiency virus (HIV-1) infection.

Abacavir tablets, a nucleoside analogue human immunodeficiency virus (HIV-1) reverse transcriptase inhibitor, are indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection.

Abacavir is an antiretroviral agent. 12.3 Pharmacokinetics Pharmacokinetics in Adults The pharmacokinetic properties of abacavir were independent of dose over the range of to 1,200 mg per day. Absorption: Following oral administration, abacavir is rapidly absorbed and extensively distributed.

The geometric mean absolute bioavailability of the tablet was 83%.

Plasma abacavir

AUC was similar following administration of the oral solution or tablets.

After oral administration of 300 mg twice daily in 20 subjects, the steady-state peak serum abacavir concentration (C max ) was 3 ± 0.89 mcg per mL (mean ± SD) and AUC (0-12 h) was 6.02 ± 1.73 mcg•hour per mL.

After oral administration of a single dose of 600 mg of abacavir in 20 subjects, C max was 4.26 ± 1.19 mcg per mL (mean ± SD) and AUC ∞ was 11.95 ± 2.51 mcg•hour per mL.

Bioavailability of abacavir tablets was assessed in the fasting and fed states with no significant difference in systemic exposure (AUC ∞ ); therefore, abacavir 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.

The apparent volume of distribution after IV administration of abacavir was 0.86 ± 0.15 L per kg, suggesting that abacavir distributes into extravascular space.

In 3 subjects, the CSF AUC (0-6 h) to plasma abacavir AUC (0-6 h) ratio ranged from 27% to 33%.

Binding of abacavir to human plasma proteins is approximately 50% and was independent of concentration.

Total blood and plasma drug-related radioactivity concentrations are identical, demonstrating that abacavir readily distributes into erythrocytes.

In single-dose trials, the observed elimination half-life (t 1/2 ) was 1.54 ± 0.63 hours.

After intravenous administration, total clearance was 0.8 ± 0.24 L per hour per kg (mean ± SD).

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 of abacavir was quantified in a mass balance trial 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.

Specific Populations Patients with 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.

The pharmacokinetics of abacavir have been studied in subjects with mild hepatic impairment (Child-Pugh Class A).

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.

AUCs of the metabolites were not modified by mild liver disease; however, the rates of formation and elimination of the metabolites were decreased.

Abacavir pharmacokinetics were studied in 25 pregnant women during the last trimester of pregnancy receiving abacavir 300 mg twice daily.

Abacavir exposure (AUC) during pregnancy was similar to those in postpartum and in HIV-infected non-pregnant historical controls.

Consistent with passive diffusion of abacavir across the placenta, abacavir concentrations in neonatal plasma cord samples at birth were essentially equal to those in maternal plasma at delivery.

The pharmacokinetics of abacavir have been studied after either single or repeat doses of abacavir in 169 pediatric subjects.

Subjects receiving abacavir oral solution according to the recommended dosage regimen achieved plasma concentrations of abacavir similar to adults.

Subjects receiving abacavir oral tablets achieved higher plasma concentrations of abacavir than subjects receiving oral solution.

The pharmacokinetics of abacavir dosed once daily in HIV-1-infected pediatric subjects aged 3 months through 12 years was evaluated in 3 trials (PENTA 13 [n = 14], PENTA 15 [n = 18], and ARROW [n = 36]).

All 3 trials were 2-period, crossover, open-label pharmacokinetic trials of twice-versus once-daily dosing of abacavir and lamivudine.

For the oral solution as well as the tablet formulation, these 3 trials demonstrated that once-daily dosing provides comparable AUC 0-24 to twice-daily dosing of abacavir at the same total daily dose.

The mean

C max was approximately 1.6.

• to 2.3-fold higher with abacavir once-daily dosing compared with twice-daily dosing.

The pharmacokinetics of abacavir have not been studied in subjects older than 65 years.

A population pharmacokinetic analysis in HIV-1-infected male (n = 304) and female (n = 67) subjects showed no gender differences in abacavir AUC normalized for lean body weight.

There are no significant or clinically relevant racial differences between blacks and whites in abacavir pharmacokinetics.

Drug Interaction Studies Effect of Abacavir on the Pharmacokinetics of Other Agents: In vitro studies have shown that abacavir has potential to inhibit CYP1A1 and limited potential to inhibit metabolism mediated by CYP3A4.

Abacavir did not inhibit or induce other CYP enzymes (such as CYP2C9, or CYP2D6).

Based on in vitro study results, abacavir at therapeutic drug exposures is not expected to affect the pharmacokinetics of drugs that are substrates of the following transporters: organic anion transporter polypeptide (OATP)1B1/3, breast cancer resistance protein (BCRP) or P-glycoprotein (P-gp), organic cation transporter (OCT)1, OCT2, or multidrug and toxic extrusion protein (MATE)1 and MATE2-K. Riociguat: Coadministration of a single dose of riociguat (0.5 mg) to HIV-1–infected subjects receiving fixed-dose abacavir/dolutegravir/lamivudine is reported to increase riociguat AUC (∞) compared with riociguat AUC (∞) reported in healthy subjects due to CYP1A1 inhibition by abacavir.

The exact magnitude of increase in riociguat exposure has not been fully characterized based on findings from two studies.

Effect of Other Agents on the Pharmacokinetics of Abacavir: In vitro, abacavir is not a substrate of OATP1B1, OAP1B3, OCT1, OCT2, OAT1, MATE1, MATE2-K, multidrug resistance-associated protein (MRP)2 or MRP4; therefore, drugs that modulate these transporters are not expected to affect abacavir plasma concentrations.

Abacavir is a substrate of BCRP and P-gp in vitro; however, considering its absolute bioavailability (83%), modulators of these transporters are unlikely to result in a clinically relevant impact on abacavir concentrations.

Lamivudine and/or Zidovudine: Fifteen HIV-1-infected subjects were enrolled in a crossover-designed drug interaction trial evaluating single doses of abacavir (600 mg), lamivudine (150 mg), and zidovudine (300 mg) alone or in combination.

Analysis showed no clinically relevant changes in the pharmacokinetics of abacavir with the addition of lamivudine or zidovudine or the combination of lamivudine and zidovudine.

Lamivudine exposure (AUC decreased 15%) and zidovudine exposure (AUC increased 10%) did not show clinically relevant changes with concurrent abacavir.

Abacavir has no effect on the pharmacokinetic properties of ethanol.

Ethanol decreases the elimination of abacavir causing an increase in overall exposure.

Due to the common metabolic pathways of abacavir and ethanol via alcohol dehydrogenase, the pharmacokinetic interaction between abacavir and ethanol was studied in 24 HIV-1-infected male subjects.

Each subject received the following treatments on separate occasions: a single 600 mg dose of abacavir, 0.7 g per kg ethanol (equivalent to 5 alcoholic drinks), and abacavir 600 mg plus 0.7 g per kg ethanol.

Coadministration of ethanol and abacavir resulted in a 41% increase in abacavir AUC ∞ and a 26% increase in abacavir t 1/2.

Abacavir had no effect on the pharmacokinetic properties of ethanol, so no clinically significant interaction is expected in men.

This interaction has not been studied in females.

In a trial of 11 HIV-1-infected subjects receiving methadone-maintenance therapy (40 mg and 90 mg daily), with 600 mg of abacavir twice daily (twice the currently recommended dose), oral methadone clearance increased 22% (90% CI: 6% to 42%).

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.

The addition of methadone had no clinically significant effect on the pharmacokinetic properties of abacavir. 12.4 Microbiology Abacavir is a carbocyclic synthetic nucleoside analogue.

Abacavir is converted by cellular enzymes to the active metabolite, carbovir triphosphate (CBV-TP), 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.

Antiviral Activity The antiviral activity of abacavir against HIV-1 was assessed in a number of cell lines including primary monocytes/macrophages and peripheral blood mononuclear cells (PBMCs).

EC 50 values ranged from 3.7 to 5.8 microM (1 microM = 0.28 mcg per mL) and 0.07 to 1 microM against HIV-1 IIIB and HIV-1 BaL, respectively, and the mean EC 50 value was 0.26 ± 0.18 microM against 8 clinical isolates.

The median

EC 50 values of abacavir were 344 nM (range: 14.8 to 676 nM), 16.9 nM (range: 5.9 to 27.9 nM), 8.1 nM (range: 1.5 to 16.7 nM), 356 nM (range: 35.7 to 396 nM), 105 nM (range: 28.1 to 168 nM), 47.6 nM (range: 5.2 to 200 nM), 51.4 nM (range: 7.1 to 177 nM), and 282 nM (range: 22.4 to 598 nM) against HIV-1 clades A-G and group O viruses (n = 3 except n = 2 for clade B), respectively.

EC 50 values against HIV-2 isolates (n = 4), ranged from 0.024 to 0.49 microM.

The antiviral activity of abacavir in cell culture was not antagonized when combined with the nucleoside reverse transcriptase inhibitors (NRTIs) didanosine, emtricitabine, lamivudine, stavudine, tenofovir, zalcitabine or zidovudine, the non-nucleoside reverse transcriptase inhibitor (NNRTI) nevirapine, or the protease inhibitor (PI) amprenavir.

Ribavirin (50 microM) used in the treatment of chronic HCV infection had no effect on the anti-HIV–1 activity of abacavir in cell culture.

HIV-1 isolates with reduced susceptibility to abacavir have been selected in cell culture.

Genotypic analysis of isolates selected in cell culture and recovered from abacavir-treated subjects demonstrated that amino acid substitutions K65R, L74V, Y115F, and M184V/I emerged in HIV-1 RT.

M184V or I substitutions resulted in an approximately 2-fold decrease in susceptibility to abacavir.

K65R, L74M, or Y115F with M184V or I conferred a 7-to 8-fold reduction in abacavir susceptibility, and combinations of three substitutions were required to confer more than an 8-fold reduction in susceptibility.

Thirty-nine percent (7 of 18) of the isolates from subjects who experienced virologic failure in the abacavir once-daily arm had a greater than 2.5-fold mean decrease in abacavir susceptibility with a median-fold decrease of 1.3 (ran.

The following adverse reactions are discussed in other sections of the labeling: Serious and sometimes fatal hypersensitivity reactions.

Lactic acidosis and severe hepatomegaly with steatosis.

Immune reconstitution syndrome.

Myocardial infarction.

The most commonly reported adverse reactions of at least moderate intensity (incidence greater than or equal to 10%) in adult HIV-1 clinical trials were nausea, headache, malaise and fatigue, nausea and vomiting, and dreams/sleep disorders.

The most commonly reported adverse reactions of at least moderate intensity (incidence greater than or equal to 5%) in pediatric HIV-1 clinical trials were fever and/or chills, nausea and vomiting, skin rashes, and ear/nose/throat infections.

To report SUSPECTED ADVERSE

REACTIONS, contact Aurobindo Pharma USA, Inc.fda.gov/medwatch. 6.1 Clinical Trials Experience in Adult Subjects 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 clinical practice.

Serious and Fatal Abacavir-Associated Hypersensitivity Reactions

In clinical trials, serious and sometimes fatal hypersensitivity reactions have occurred with abacavir.

These reactions have been characterized by 2 or more of the following signs or symptoms: fever; rash; gastrointestinal symptoms (including nausea, vomiting, diarrhea, or abdominal pain); constitutional symptoms (including generalized malaise, fatigue, or achiness); respiratory symptoms (including dyspnea, cough, or pharyngitis).

Almost all abacavir hypersensitivity reactions include fever and/or rash as part of the syndrome.

Other signs and symptoms have included lethargy, headache, myalgia, edema, arthralgia, and paresthesia.

Anaphylaxis, liver failure, renal failure, hypotension, adult respiratory distress syndrome, respiratory failure, myolysis, and death have occurred in association with these hypersensitivity reactions.

Physical findings have included lymphadenopathy, mucous membrane lesions (conjunctivitis and mouth ulcerations), and maculopapular or urticarial rash (although some patients had other types of rashes and others did not have a rash).

There were reports of erythema multiforme.

Laboratory abnormalities included elevated liver chemistries, elevated creatine phosphokinase, elevated creatinine, and lymphopenia, and abnormal chest x-ray findings (predominantly infiltrates, which were localized).

Additional Adverse Reactions with Use of Abacavir Therapy-Naive Adults: Treatment-emergent clinical adverse reactions (rated by the investigator as moderate or severe) with a greater than or equal to 5% frequency during therapy with abacavir 300 mg twice daily, lamivudine 150 mg twice daily, and efavirenz 600 mg daily compared with zidovudine 300 mg twice daily, lamivudine 150 mg twice daily, and efavirenz 600 mg daily from CNA30024 are listed in Table 2.

Table 2.

Treatment-Emergent (All Causality) Adverse Reactions of at Least Moderate Intensity (Grades to 4, Greater than or Equal to 5% Frequency) in Therapy-Naive Adults (CNA30024 This trial used double-blind ascertainment of suspected hypersensitivity reactions. During the blinded portion of the trial, suspected hypersensitivity to abacavir was reported by investigators in 9% of 324 subjects in the abacavir group and 3% of 325 subjects in the zidovudine group). through 48 Weeks of Treatment Adverse Reaction Abacavir plus Lamivudine plus Efavirenz (n = 324) Zidovudine plus Lamivudine plus Efavirenz (n = 325) Dreams/sleep disorders 10% 10% Drug hypersensitivity 9% <1% Ten (3%) cases of suspected drug hypersensitivity were reclassified as not being due to abacavir following unblinding.

Headaches/migraine 7% 11% Nausea 7% 11% Fatigue/malaise 7% 10% Diarrhea 7% 6% Rashes 6% 12% Abdominal pain/gastritis/gastrointestinal signs and symptoms 6% 8% Depressive disorders 6% 6% Dizziness 6% 6% Musculoskeletal pain 6% 5% Bronchitis 4% 5% Vomiting 2% 9% Treatment-emergent clinical adverse reactions (rated by the investigator as moderate or severe) with a greater than or equal to 5% frequency during therapy with abacavir 300 mg twice daily, lamivudine 150 mg twice daily, and zidovudine 300 mg twice daily compared with indinavir 800 mg 3 times daily, lamivudine 150 mg twice daily, and zidovudine 300 mg twice daily from CNA3005 are listed in Table 3.

Table 3.

Treatment-Emergent (All Causality) Adverse Reactions of at Least Moderate Intensity (Grades to 4, Greater than or Equal to 5% Frequency) in Therapy-Naive Adults (CNA3005) through 48 Weeks of Treatment Adverse Reaction Abacavir plus Lamivudine/Zidovudine (n = 262) Indinavir plus Lamivudine/Zidovudine (n = 264) Nausea 19% 17% Headache 13% 9% Malaise and fatigue 12% 12% Nausea and vomiting 10% 10% Hypersensitivity reaction 8% 2% Diarrhea 7% 5% Fever and/or chills 6% 3% Depressive disorders 6% 4% Musculoskeletal pain 5% 7% Skin rashes 5% 4% Ear/nose/throat infections 5% 4% Viral respiratory infections 5% 5% Anxiety 5% 3% Renal signs/symptoms <1% 5% Pain (non-site-specific) <1% 5% Five subjects receiving abacavir in CNA3005 experienced worsening of pre-existing depression compared with none in the indinavir arm.

The background rates of pre-existing depression were similar in the 2 treatment arms.

Abacavir Once Daily versus Abacavir Twice

Daily (CNA30021): Treatment-emergent clinical adverse reactions (rated by the investigator as at least moderate) with a greater than or equal to 5% frequency during therapy with abacavir 600 mg once daily or abacavir 300 mg twice daily, both in combination with lamivudine 300 mg once daily and efavirenz 600 mg once daily from CNA30021, were similar.

For hypersensitivity reactions, subjects receiving abacavir once daily showed a rate of 9% in comparison with a rate of 7% for subjects receiving abacavir twice daily.

However, subjects receiving abacavir 600 mg once daily experienced a significantly higher incidence of severe drug hypersensitivity reactions and severe diarrhea compared with subjects who received abacavir 300 mg twice daily.

Five percent (5%) of subjects receiving abacavir 600 mg once daily had severe drug hypersensitivity reactions compared with 2% of subjects receiving abacavir 300 mg twice daily.

Two percent (2%) of subjects receiving abacavir 600 mg once daily had severe diarrhea while none of the subjects receiving abacavir 300 mg twice daily had this event.

Laboratory abnormalities (Grades to 4) in therapy-naive adults during therapy with abacavir 300 mg twice daily, lamivudine 150 mg twice daily, and efavirenz 600 mg daily compared with zidovudine 300 mg twice daily, lamivudine 150 mg twice daily, and efavirenz 600 mg daily from CNA30024 are listed in Table 4.

Table 4.

Abnormalities (Grades to 4) in Therapy-Naive Adults (CNA30024) through 48 Weeks of Treatment ULN = Upper limit of normal. n = Number of subjects assessed.

Grade 3/4 Laboratory Abnormalities Abacavir plus Lamivudine plus Efavirenz (n = 324) Zidovudine plus Lamivudine plus Efavirenz (n = 325) Elevated CPK (>4 X ULN) 8% 8% Elevated ALT (>5 X ULN) 6% 6% Elevated AST (>5 X ULN) 6% 5% Hypertriglyceridemia (>750 mg/dL) 6% 5% Hyperamylasemia (>2 X ULN) 4% 5% Neutropenia (ANC <750/mm 3 ) 2% 4% Anemia (Hgb ≤6.9 gm/dL) <1% 2% Thrombocytopenia (Platelets <50,000/mm 3 ) 1% <1% Leukopenia (WBC ≤1,500/mm 3 ) <1% 2% Laboratory abnormalities in CNA3005 are listed in Table 5.

Table 5.

Abnormalities (Grades to 4) in CNA3005 ULN = Upper limit of normal. n = Number of subjects assessed.

Grade 3/4 Laboratory Abnormalities Abacavir plus Lamivudine/Zidovudine (n = 262) Indinavir plus Lamivudine/Zidovudine (n = 264) Elevated CPK (>4 x ULN) 18 (7%) 18 (7%) ALT (>5 x ULN) 16 (6%) 16 (6%) Neutropenia (<750/mm 3 ) 13 (5%) 13 (5%) Hypertriglyceridemia (>750 mg/dL) 5 (2%) 3 (1%) Hyperamylasemia (>2 x ULN) 5 (2%) 1 (<1%) Hyperglycemia (>13.9 mmol/L) 2 (<1%) 2 (<1%) Anemia (Hgb ≤6.9 g/dL) 0 (0%) 3 (1%) The frequencies of treatment-emergent laboratory abnormalities were comparable between treatment groups in CNA30021. 6.2 Clinical Trials Experience in Pediatric Subjects Therapy-Experienced Pediatric Subjects (Twice-Daily Dosing) Treatment-emergent clinical adverse reactions (rated by the investigator as moderate or severe) with a greater than or equal to 5% frequency during therapy with abacavir 8 mg per kg twice daily, lamivudine 4 mg per kg twice daily, and zidovudine 180 mg per m 2 twice daily compared with lamivudine 4 mg per kg twice daily and zidovudine 180 mg per m 2 twice daily from CNA3006 are listed in Table 6.

Table 6.

Treatment-Emergent (All Causality) Adverse Reactions of at Least Moderate Intensity (Grades to 4, Greater than or Equal to 5% Frequency) in Therapy-Experienced Pediatric Subjects (CNA3006) through 16 Weeks of Treatment Adverse Reaction Abacavir plus Lamivudine plus Zidovudine (n = 102) Lamivudine plus Zidovudine (n = 103) Fever and/or chills 9% 7% Nausea and vomiting 9% 2% Skin rashes 7% 1% Ear/nose/throat infections 5% 1% Pneumonia 4% 5% Headache 1% 5% Laboratory Abnormalities: In CNA3006, laboratory abnormalities (anemia, neutropenia, liver function test abnormalities, and CPK elevations) were observed with similar frequencies as in a trial of therapy-naive adults (CNA30024).

Mild elevations of blood glucose were more frequent in pediatric subjects receiving abacavir (CNA3006) as compared with adult subjects (CNA30024).

In addition to adverse reactions and laboratory abnormalities reported in Tables 2, 3, 4, 5, and 6, other adverse reactions observed in the expanded access program were pancreatitis and increased GGT.

Pediatric Subjects Once-Daily versus Twice-Daily

Dosing (COL105677): The safety of once-daily compared with twice-daily dosing of abacavir was assessed in the ARROW trial.

Primary safety assessment in the ARROW trial was based on Grade and Grade 4 adverse events.

The frequency of

Grade and 4 adverse events was similar among subjects randomized to once-daily dosing compared with subjects randomized to twice-daily dosing.

One event of

Grade 4 hepatitis in the once-daily cohort was considered as uncertain causality by the investigator and all other Grade 3 or 4 adverse events were considered not related by the investigator. 6.3 Postmarketing Experience The following adverse reactions have been identified during postmarketing use of abacavir.

Because these reactions are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposures.

Body as a Whole

Redistribution/accumulation of body fat.

Lactic acidosis and hepatic steatosis.

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.

There is no known specific treatment for overdose with abacavir.

If overdose occurs, the patient should be monitored and standard supportive treatment applied as required.

It is not known whether abacavir can be removed by peritoneal dialysis or hemodialysis.

Abacavir tablets are contraindicated in patients: who have the HLA-B*5701 allele. with prior hypersensitivity reaction to abacavir. with moderate or severe hepatic impairment.

Presence of

HLA-B*5701 allele.

Prior hypersensitivity reaction to abacavir.

Moderate or severe hepatic impairment.

Before initiating abacavir, screen for the HLA-B*5701 allele.

Adults: 600 mg daily, administered as either 300 mg twice daily or 600 mg once daily.

Aged 3 Months and Older: Administered either once or twice daily.

Dose should be calculated on body weight (kg) and should not exceed 600 mg daily.

Mild hepatic impairment – 200 mg twice daily. 2.1 Screening for HLA-B5701 Allele prior to Starting Abacavir Tablets Screen for the HLA-B5701 allele prior to initiating therapy with abacavir tablets. 2.2 Recommended Dosage for Adult Patients The recommended dosage of abacavir tablets for adults is 600 mg daily, administered orally as either 300 mg twice daily or 600 mg once daily, in combination with other antiretroviral agents. 2.3 Recommended Dosage for Pediatric Patients Abacavir tablets are available as scored tablet for HIV-1-infected pediatric patients weighing greater than or equal to 14 kg for whom a solid dosage form is appropriate.

Before prescribing abacavir tablets, children should be assessed for the ability to swallow tablets.

If a child is unable to reliably swallow abacavir tablets, the oral solution formulation should be prescribed.

The recommended oral dosage of abacavir tablets for HIV-1-infected pediatric patients is presented in Table 1.

Table 1.

Dosing Recommendations for Abacavir Scored Tablets in Pediatric Patients Weight (kg) Once-Daily Dosing Regimen Data regarding the efficacy of once-daily dosing is limited to subjects who transitioned from twice-daily dosing to once-daily dosing after 36 weeks of treatment.

Twice-Daily Dosing Regimen AM Dose PM Dose Total Daily Dose to <20 1 tablet (300 mg) ½ tablet (150 mg) ½ tablet (150 mg) 300 mg > 20 to <25 1½ tablets (450 mg) ½ tablet (150 mg) 1 tablet (300 mg) 450 mg ≥ 25 2 tablets (600 mg) 1 tablet (300 mg) 1 tablet (300 mg) 600 mg 2.4 Recommended Dosage for Patients with Hepatic Impairment The recommended dose of abacavir tablets in patients with mild hepatic impairment (Child-Pugh Class A) is 200 mg twice daily.

To enable dose reduction, abacavir oral solution (10 mL twice daily) should be used for the treatment of these patients.

The safety, efficacy, and pharmacokinetic properties of abacavir have not been established in patients with moderate to severe hepatic impairment; therefore, abacavir tablets are contraindicated in these patients.

Abacavir tablets

USP, containing abacavir sulfate equivalent to 300 mg abacavir, are yellow colored, biconvex, capsule shaped, coated tablet, debossed with ‘D’ and ‘88’ on either side of the score line on one side and plain with a score line on other side.

They are packaged as follows

Unit dose packages of 30 (3 x 10) NDC 68084-021-21 Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) .

Do not use if blister is torn or broken.

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to abacavir during pregnancy.

Healthcare Providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263.

Risk Summary Available data from the

APR show no difference in the overall risk of birth defects for abacavir compared with the background rate for birth defects of 2.7% in the Metropolitan Atlanta Congenital Defects Program (MACDP) reference population.

The APR uses the MACDP as the U.S. reference population for birth defects in the general population.

MACDP evaluates women and infants from a limited geographic area and does not include outcomes for births that occurred at less than 20 weeks’ gestation.

The rate of miscarriage is not reported in the APR.

The estimated background rate of miscarriage in clinically recognized pregnancies in the U.S. general population is 15% to 20%.

The background risk for major birth defects and miscarriage for the indicated population is unknown.

In animal reproduction studies, oral administration of abacavir to pregnant rats during organogenesis resulted in fetal malformations and other embryonic and fetal toxicities at exposures 35 times the human exposure (AUC) at the recommended clinical daily dose.

However, no adverse developmental effects were observed following oral administration of abacavir to pregnant rabbits during organogenesis, at exposures approximately 9 times the human exposure (AUC) at the recommended clinical dose.

Based on prospective reports to the APR of exposures to abacavir during pregnancy resulting in live births (including over 1,300 exposed in the first trimester and over 1,300 exposed in second/third trimester), there was no difference between the overall risk of birth defects for abacavir compared with the background birth defect rate of 2.7% in the U.S. reference population of the MACDP.

The prevalence of defects in live births was 3.2% (95% CI: 2.3% to 4.3%) following first trimester exposure to abacavir-containing regimens and 2.9% (95% CI: 2.1% to 4%) following second/third trimester exposure to abacavir-containing regimens.

Abacavir has been shown to cross the placenta and concentrations in neonatal plasma at birth were essentially equal to those in maternal plasma at delivery.

Abacavir was administered orally to pregnant rats (at 100, 300, and 1,000 mg per kg per day) and rabbits (at 125, 350, or 700 mg per kg per day) during organogenesis (on Gestation Days 6 through and 6 through 20, respectively).

Fetal malformations (increased incidences of fetal anasarca and skeletal malformations) or developmental toxicity (decreased fetal body weight and crown-rump length) were observed in rats at doses up to 1,000 mg per kg per day, resulting in exposures approximately 35 times the human exposure (AUC) at the recommended daily dose.

No developmental effects were observed in rats at 100 mg per kg per day, resulting in exposures (AUC) 3.5 times the human exposure at the recommended daily dose.

In a fertility and early embryo-fetal development study conducted in rats (at 60, 160, or 500 mg per kg per day), embryonic and fetal toxicities (increased resorptions, decreased fetal body weights) or toxicities to the offspring (increased incidence of stillbirth and lower body weights) occurred at doses up to 500 mg per kg per day. No developmental effects were observed in rats at 60 mg per kg per day, resulting in exposures (AUC) approximately 4 times the human exposure at the recommended daily dose.

Studies in pregnant rats showed that abacavir is transferred to the fetus through the placenta.

In pregnant rabbits, no developmental toxicities and no increases in fetal malformations occurred at up to the highest dose evaluated, resulting in exposures (AUC) approximately 9 times the human exposure at the recommended dose.

The safety and effectiveness of abacavir have been established in pediatric patients aged 3 months and older.

Use of abacavir is supported by pharmacokinetic trials and evidence from adequate and well-controlled trials of abacavir in adults and pediatric subjects.

Clinical trials of abacavir did not include sufficient numbers of subjects aged and over to determine whether they respond differently from younger subjects.

In general, caution should be exercised in the administration of abacavir in elderly patients reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.