Abacavir Oral Solution

Use abacavir oral solution as ordered by your doctor. Read all information given to you. Follow all instructions closely.

• Take this medicine at the same time of day.
• Take with or without food.
• Keep taking abacavir oral solution as you have been told by your doctor or other health care provider, even if you feel well.
• It is important that you do not miss or skip a dose of this medicine during treatment.
• Measure liquid doses carefully. Use the measuring device that comes with abacavir oral solution. If there is none, ask the pharmacist for a device to measure this medicine.

What do I do if I miss a dose?

• Take a missed dose as soon as you think about it.
• If it is close to the time for your next dose, skip the missed dose and go back to your normal time.
• Do not take 2 doses at the same time or extra doses.
• If you are not sure what to do if you miss a dose, call your doctor.

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Headache.
• Upset stomach or throwing up.
• Loose stools (diarrhea).
• Not hungry.
• Not able to sleep.
• Bad dreams.
• Dizziness.
• Feeling tired or weak.

These are not all of the side effects that may occur. If you have questions about side effects, call your doctor. Call your doctor for medical advice about side effects.

You may report side effects to the FDA at 1-800-FDA-1088. You may also report side effects at http://www.fda.gov/medwatch.

• Store in the original container at room temperature or in a refrigerator.
• Do not freeze.
• Store in a dry place. Do not store in a bathroom.
• Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
• Check with your pharmacist about how to throw out unused drugs.

Do not take this medicine with any of the following medications:

• alcohol or alcohol containing products

This medicine may also interact with the following medications:

• any other medicine that contains abacavir
• methadone

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

Mechanism of Action

Abacavir is an antiretroviral agent [See Microbiology (12.4)].

Pharmacokinetics

Pharmacokinetics in Adults
The pharmacokinetic properties of abacavir were independent of dose over the range of 300 to 1,200 mg per day.
Absorption and Bioavailability: 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 (Cmax) was 3 ± 0.89 mcg per mL (mean ± SD) and AUC(0 to 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, Cmax was 4.26 ± 1.19 mcg per mL (mean ± SD) and AUC∞ was 11.95 ± 2.51 mcg•hour per mL.
Distribution: 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 to 6 h) to plasma abacavir AUC (0 to 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.
Metabolism and Elimination: 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 14C-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 trials, the observed elimination half-life (t1/2) was 1.54 ± 0.63 hours. After intravenous administration, total clearance was 0.80 ± 0.24 L per hour per kg (mean ± SD).
Effects of Food on Oral Absorption
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.
Specific Populations
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 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. The AUCs of the metabolites were not modified by mild liver disease; however, the rates of formation and elimination of the metabolites were decreased [see Contraindications (4), Use in Specific Populations (8.6)].
Pregnancy: Abacavir: 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.
Pediatric Patients: 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 to 24 to twice-daily dosing of abacavir at the same total daily dose. The mean Cmax was approximately 1.6- to 2.3-fold higher with abacavir once-daily dosing compared with twice-daily dosing.
Geriatric Patients: The pharmacokinetics of abacavir have not been studied in subjects older than 65 years.
Gender: 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.
Race: There are no significant or clinically relevant racial differences between blacks and whites in abacavir pharmacokinetics.
Drug Interactions
In human liver microsomes, abacavir did not inhibit cytochrome P450 isoforms (2C9, 2D6, 3A4). Based on these data, it is unlikely that clinically significant drug interactions will occur between abacavir and drugs metabolized through these pathways.
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.
Ethanol: 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 t1/2. 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.
Methadone: 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 [see Drug Interactions (7)]. The addition of methadone had no clinically significant effect on the pharmacokinetic properties of abacavir.

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). EC50 values ranged from 3.7 to 5.8 microM (1 microM = 0.28 mcg per mL) and 0.07 to 1 microM against HIV-1IIIB and HIV-1BaL, respectively, and the mean EC50 value was 0.26 ± 0.18 microM against 8 clinical isolates. The median EC50 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. The EC50 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.
Resistance
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. Substitutions 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 (range: 0.5 to 11) compared with 29% (5 of 17) of the failure isolates in the twice-daily arm with a median-fold decrease of 0.92 (range: 0.7 to 13).
Cross-Resistance
Cross-resistance has been observed among NRTIs. Isolates containing abacavir resistance-associated substitutions, namely, K65R, L74V, Y115F, and M184V, exhibited cross-resistance to didanosine, emtricitabine, lamivudine, and tenofovir in cell culture and in subjects. An increasing number of thymidine analogue mutation substitutions (TAMs: M41L, D67N, K70R, L210W, T215Y/F, K219E/R/H/Q/N) is associated with a progressive reduction in abacavir susceptibility.

Abacavir Oral Solution USP is a clear yellowish, strawberry-banana flavored liquid filled in 250 cc HDPE opaque bottles. Each mL of the solution contains abacavir sulfate USP equivalent to 20 mg of abacavir. They are supplied in:

Bottles of 240 mL with Induction Sealing FSE Wad (NDC 31722-562-24).
This product does not require reconstitution.
Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. DO NOT FREEZE. May be refrigerated.

Advise the patient to read the FDA-approved patient labeling (Medication Guide).
Hypersensitivity Reactions
Inform patients:
• that a Medication Guide and Warning Card summarizing the symptoms of the abacavir hypersensitivity reaction and other product information will be dispensed by the pharmacist with each new prescription and refill of Abacavir Oral Solution, and instruct the patient to read the Medication Guide and Warning Card every time to obtain any new information that may be present about abacavir. The complete text of the Medication Guide is reprinted at the end of this document.
• to carry the Warning Card with them.
• how to identify a hypersensitivity reaction [see Warnings and Precautions (5.1), Medication Guide].
• that if they develop symptoms consistent with a hypersensitivity reaction they should call their healthcare provider right away to determine if they should stop taking Abacavir Oral Solution.
• that a hypersensitivity reaction can worsen and lead to hospitalization or death if abacavir is not immediately discontinued.
• to not restart Abacavir Oral Solution or any other abacavir-containing product following a hypersensitivity reaction because more severe symptoms can occur within hours and may include life-threatening hypotension and death.
• that if they have a hypersensitivity reaction, they should dispose of any unused Abacavir Oral Solution to avoid  restarting abacavir.
• that a hypersensitivity reaction is usually reversible if it is detected promptly and Abacavir Oral Solution is stopped right away.
• that if they have interrupted Abacavir Oral Solution for reasons other than symptoms of  hypersensitivity (for example, those who have an interruption in drug supply), a serious or fatal hypersensitivity reaction may occur with reintroduction of abacavir.
• to not restart Abacavir Oral Solution or any other abacavir-containing product without medical consultation and only if medical care can be readily accessed by the patient or others.
Lactic Acidosis/Hepatomegaly with Steatosis
Advise patients that lactic acidosis and severe hepatomegaly with steatosis have been reported with use of nucleoside analogues and other antiretrovirals. Advise patients to stop taking Abacavir Oral Solution if they develop clinical symptoms suggestive of lactic acidosis or pronounced hepatotoxicity [see Boxed Warning, Warnings and Precautions (5.2)].
Immune Reconstitution Syndrome
Advise patients to inform their healthcare provider immediately of any signs and symptoms of infection as inflammation from previous infection may occur soon after combination antiretroviral therapy, including when Abacavir Oral Solution is started [see Warnings and Precautions (5.3)].
Redistribution/Accumulation of Body Fat
Inform patients that redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy and that the cause and long-term health effects of these conditions are not known at this time. [see Warnings and  Precautions (5.4)].
Pregnancy Registry
Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to abacavir during pregnancy [see Use in Specific Populations (8.1)].
Lactation
Instruct women with HIV-1 infection not to breastfeed because HIV-1 can be passed to the baby in the breast milk [see Use in Specific Populations (8.2)].
Missed Dose
Instruct patients that if they miss a dose of Abacavir Oral Solution, to take it as soon as they remember. Advise patients not to double their next dose or take more than the prescribed dose [see Dosage and Administration (2)].
Availability of Medication Guide
Instruct patients to read the Medication Guide before starting Abacavir Oral Solution and to re-read it each time the prescription is renewed. Instruct patients to inform their physician or pharmacist if they develop any unusual symptom, or if any known symptom persists or worsens.
The other brands listed are trademarks of their respective owners and are not trademarks of the Hetero Labs Limited. The makers of these brands are not affiliated with and do not endorse the Hetero Labs Limited or its products.   


Manufactured for:

Camber Pharmaceuticals, Inc.
Piscataway, NJ 08854

Manufactured by:
HETERO LABS LIMITED               
22-110, I.D.A., Jeedimetla,
Hyderabad – 500 055, India.  
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Revised: August,2017