ABAVIR

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.

Viral load > 100,000 copies/ml RNA Co-infection HBV-HIV HCV-HIV co-infection Severe immune deficiency Pregnancy Chronic hepatitis Hepatitis Hepatic impairment End-stage renal impairment Infant under 3 months Newborn exposed in utero to the medicine Elderly Subject at risk of cardiovascular disease Extended treatment.

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.

Mechanism of action

Abacavir is a nucleoside reverse transcriptase inhibitor (INTI).

It is a potent selective inhibitor active on human immunodeficiency viruses of types and 2 (HIV-1 and HIV-2).

Abacavir is metabolised intracellularly to its active metabolite, carbovir 5'-triphosphate (TP).

In vitro studies have shown that its mechanism of action on HIV is related to enzyme inhibition, by blocking DNA chain elongation (deoxyribonucleic acid) at the level of reverse transcriptase and interruption of the viral replication cycle.

Synergic activity has been demonstrated in vitro when abacavir is associated with nevirapine or zidovudine.

An additive effect was observed when abacavir was combined with didanosine, lamivudine and stavudine.

• Liver status (abnormality) (Very common)
• Hyperglycaemia Hyperlipidaemia Blood creatinine (increase)
• KPC (increase)
• Rash (Very common)
• Stevens-Johnson Syndrome (Very rare)
• Lyell's syndrome (Very rare)
• Polymorphic Erythema (Very rare)
• Maculopapulous eruption Urticaria eruption Fever (Very common)
• Fatigue (Common)
• Post-infection inflammatory reaction Edema Basedow disease Lymphopenia
• Lymphadenopathy Hepatic impairment Autoimmune hepatitis Hepatitis Immune restoration syndrome
• Autoimmune disease Anaphylactic reaction Hypersensitivity Opportunistic infection
• Anorexia (Common)
• Lactic acidosis (Very rare)
• Weight (increase)
• Conjunctivitis Oral ulceration
• Pharyngitis Lethargy (Very common)
• Malaise Hypotension Nausea (Very common)
• Diarrhoea (Very common)
• Abdominal pain (Very common)
• Vomiting (Very common)
• Pancreatitis (Rare)
• Digestive disorder
• Muscle pain (Very common)
• Osteonecrosis Joint pain Rhabdomyolysis Headache (Very common)
• Paraesthesia Cough (Very common)
• Dyspnoea (Very common)
• Respiratory impairment Acute respiratory distress syndrome
• Renal impairment.

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.