Abacavir oral solution

Abacavir oral solution

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• Indikationen und Verwendung
• Dosierung und Anwendung
• Darreichungsformen und Stärken
• Kontraindikationen
• Warnungen und Vorsichtsmaßnahmen
• Nebenwirkungen/Nebenwirkungen
• Wechselwirkungen mit anderen Medikamenten
• Verwendung in bestimmten Populationen
• Überdosierung
• Beschreibung
• Klinische Pharmakologie
• Nichtklinische Toxikologie
• Klinische Studien
• Wie geliefert/Lagerung und Handhabung
• Informationen zur Patientenberatung
• Leitfaden für Medikamente

Highlights of prescribing information

These highlights do not contain all of the information needed to use ABACAVIR ORAL SOLUTION safely and effectively. View full prescribing information for ABACAVIR ORAL SOLUTION.

ABACAVIR oral solution
First US approval: 1998

WARNING: HYPERSENSITIVE REACTIONS

For the full warning, see the full prescribing information.

• Unter Abacavir sind schwere und manchmal tödliche Überempfindlichkeitsreaktionen aufgetreten. (5.1)
• Überempfindlichkeit gegen Abacavir ist ein klinisches Multiorgan-Syndrom. (5.1)
• Patienten, die Träger des HLA-B sind*5701-Allel haben ein höheres Risiko, eine Überempfindlichkeitsreaktion auf Abacavir zu entwickeln. (5.1)
• Abacavir iEs ist bei Patienten mit einer früheren Überempfindlichkeitsreaktion auf Abacavir und bei HLA-B*5701-positiven Patienten kontraindiziert. (4)
• Abacavir absetzen, sobald der Verdacht einer Überempfindlichkeitsreaktion besteht. Unabhängig von HLA-B*5701-Status: Abacavir dauerhaft absetzen, wenn eine Überempfindlichkeit nicht ausgeschlossen werden kann, auch wenn andere Diagnosen möglich sind. (5.1)
• Nach einer Überempfindlichkeitsreaktion auf Abacavir darf die Einnahme von Abacavir oder einem anderen Abacavir-haltigen Produkt NIEMALS wieder aufgenommen werden. (5.1)

Indications and use of abacavir oral solution

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

Dosage and administration of abacavir oral solution

• Vor Beginn der Anwendung der Abacavir-Lösung zum Einnehmen ist ein Screening auf das HLA-B*5701-Allel durchzuführen. (2.1)
• Erwachsene: 600 mg täglich, verabreicht als entweder 300 mg zweimal täglich oder 600 mg einmal täglich. (2.2)
• Pädiatrische Patienten ab 3 Monaten: Wird entweder ein- oder zweimal täglich verabreicht. Die Dosis sollte anhand des Körpergewichts (kg) berechnet werden und 600 mg täglich nicht überschreiten. (2.3)
• Patienten mit Leberfunktionsstörung: Leichte Leberfunktionsstörung – 200 mg zweimal täglich. (2.4)

Dosage forms and strengths

Oral solution: 20 mg per ml (3)

Contraindications

• Vorhandensein des HLA-B*5701-Allels. (4)
• Vorherige Überempfindlichkeitsreaktion auf Abacavir. (4)
• Mittelschwere oder schwere Leberfunktionsstörung. (4)

Warnings and precautions

• Bei der Anwendung von Nukleosidanaloga wurde über Laktatazidose und schwere Hepatomegalie mit Steatose, einschließlich tödlicher Fälle, berichtet. (5.2)
• Bei Patienten, die mit einer antiretroviralen Kombinationstherapie behandelt wurden, wurde über ein Immunrekonstitutionssyndrom berichtet. (5.3)

Side effects/side effects

• Die am häufigsten berichteten Nebenwirkungen von mindestens mäßiger Intensität (Inzidenz größer oder gleich 10 %) in klinischen HIV-1-Studien bei Erwachsenen waren Übelkeit, Kopfschmerzen, Unwohlsein und Müdigkeit, Übelkeit und Erbrechen sowie Träume/Schlafstörungen. (6.1)
• Die am häufigsten berichteten Nebenwirkungen von mindestens mäßiger Intensität (Inzidenz größer oder gleich 5 %) in klinischen HIV-1-Studien bei Kindern waren Fieber und/oder Schüttelfrost, Übelkeit und Erbrechen, Hautausschläge und Hals-Nasen-Ohren-Infektionen. (6.2)

To report suspected side effects, contact Rising Pharmaceuticals, Inc. at 1-866-562-4597 or the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Interactions with other medications

• Methadon: Bei einer kleinen Anzahl von Patienten kann eine erhöhte Methadon-Dosis erforderlich sein. (7.1)
• Riociguat: Die Riociguat-Dosis muss möglicherweise reduziert werden. (7.2)

Use in certain populations

• Stillzeit: Mit HIV infizierte Frauen sollten angewiesen werden, wegen der Möglichkeit einer HIV-Übertragung nicht zu stillen. (8.2)

See 17 for PATIENT ADVICE INFORMATION and Medication Guide.

Revised: 11/2022

Complete Prescribing Information

WARNING: HYPERSENSITIVE REACTIONS

Serious and sometimes fatal hypersensitivity reactions involving multiple organsparticipation, occurred withAbacavir.

Patients carrying the HLA-B*5701 allele are at higher risk of a hypersensitivity reaction to abacavir; However, hypersensitivity reactions have occurred in patients who do not carry the HLA-B*5701 allele[see Warnings and Precautions (5.1)].

Abacavir is contraindicated in patients with a previous hypersensitivity reaction to abacavir and in HLA-B*5701 positive patients[see Contraindications (4), Warnings and Precautions (5.1)]. All patients should be screened for the HLA-B*5701 allele before initiating abacavir therapy or restarting abacavir therapy, unless patients have previously documented HLA-B*5701 allele assessment. If a hypersensitivity reaction is suspected, abacavir should be discontinued immediately, regardless of HLA-B*5701 status and even if other diagnoses are possible[see Contraindications (4), Warnings and Precautions (5.1)].

After a hypersensitivity reaction to abacavir, NEVER restart abacavir or any other abacavir-containing product as more severe symptoms, including death, may occur within hours. Similar serious reactions have also occurred in rare cases following reintroduction of abacavir-containing products in patients who had no history of abacavir hypersensitivity[see Warnings and Precautions (5.1)].

1. Indications and use of abacavir oral solution

Abacavir oral solution is indicated in combination with other antiretroviral drugs for the treatment of human immunodeficiency virus (HIV-1) infection.

2. Dosage and administration of abacavir oral solution

2.1 Screening for HLA-B*5701 allele before starting abacavir oral solution

Screen for the HLA-B*5701 allele prior to initiating therapy with abacavir oral solution[see Boxed Warning, Warnings and Precautions (5.1)].

2.2 Recommended dosage for adult patients

The recommended dosage of abacavir oral solution 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

The recommended dosage of abacavir oral solution in HIV-1-infected pediatric patients 3 months of age or older is 8 mg per kg orally twice daily or 16 mg per kg orally once daily (up to a maximum of 600 mg daily) in combination with other antiretroviral agents.

2.4 Recommended dosage for patients with hepatic impairment

The recommended dose of abacavir oral solution in patients with mild hepatic impairment (Child-Pugh class A) is 200 mg twice daily. To allow for dose reduction, abacavir oral solution (10 mL twice daily) should be used to treat these patients. The safety, efficacy and pharmacokinetic properties of abacavir have not been established in patients with moderate to severe hepatic impairment; Therefore, oral abacavir solution is contraindicated in these patients.

3. Dosage forms and strengths

Abacavir oral solution USP, each ml contains abacavir sulfate USP equivalent to 20 mg abacavir, is a clear to opalescent, yellowish liquid with a strawberry-banana flavor.

4. Contraindications

Abacavir oral solution is contraindicated in the following patients:

• die das HLA-B*5701-Allel haben [see Warnings and Precautions (5.1)].
• mit vorheriger Überempfindlichkeitsreaktion auf Abacavir [see Warnings and Precautions (5.1)].
• mit mittelschwerer oder schwerer Leberfunktionsstörung [see Use in Specific Populations (8.6)].

5. Warnings and Precautions

5.1 Hypersensitivity reactions

Severe and sometimes fatal hypersensitivity reactions have occurred with abacavir. These hypersensitivity reactions included multiorgan failure and anaphylaxis and typically occurred within the first 6 weeks of abacavir treatment (median time to onset was 9 days); Although abacavir hypersensitivity reactions occurred at any time during treatment[see Adverse Reactions (6.1)]. Patients carrying the HLA-B*5701 allele are at higher risk of abacavir hypersensitivity reactions; However, patients who do not carry the HLA-B*5701 allele have developed hypersensitivity reactions. Hypersensitivity to abacavir was reported in approximately 206 (8%) of 2,670 patients in 9 clinical trials of abacavir-containing products in which HLA-B*5701 screening was not performed. The incidence of suspected abacavir hypersensitivity reactions in clinical trials was 1% when subjects with the HLA-B*5701 allele were excluded. In every patient treated with abacavir, the clinical diagnosis of a hypersensitivity reaction must remain the basis for clinical decision-making.

Due to the potential for severe, serious and potentially fatal hypersensitivity reactions with abacavir:

• Alle Patienten sollten vor Beginn der Therapie mit Abacavir oder Wiederaufnahme der Therapie mit Abacavir auf das HLA-B*5701-Allel untersucht werden, es sei denn, bei den Patienten wurde zuvor eine HLA-B*5701-Allelbeurteilung dokumentiert.
• Abacavir ist bei Patienten mit einer früheren Überempfindlichkeitsreaktion auf Abacavir und bei HLA-B*5701-positiven Patienten kontraindiziert.
• Bevor Sie mit der Einnahme von Abacavir beginnen, überprüfen Sie Ihre Krankengeschichte hinsichtlich früherer Kontakte mit Abacavir-haltigen Produkten. Beginnen Sie die Behandlung mit Abacavir oder einem anderen Abacavir-haltigen Produkt NIEMALS nach einer Überempfindlichkeitsreaktion auf Abacavir, unabhängig vom HLA-B*5701-Status.
• Um das Risiko einer lebensbedrohlichen Überempfindlichkeitsreaktion unabhängig vom HLA-B*5701-Status zu verringern, brechen Sie Abacavir bei Verdacht auf eine Überempfindlichkeitsreaktion sofort ab, auch wenn andere Diagnosen möglich sind (z. B. akut auftretende Atemwegserkrankungen wie Lungenentzündung, Bronchitis, Pharyngitis oder Influenza; Gastroenteritis; oder Reaktionen auf andere Medikamente).
• Wenn eine Überempfindlichkeitsreaktion nicht ausgeschlossen werden kann, nehmen Sie die Behandlung mit Abacavir oder anderen Abacavir-haltigen Arzneimitteln nicht erneut ein, da innerhalb weniger Stunden schwerwiegendere Symptome auftreten können, die eine lebensbedrohliche Hypotonie und den Tod einschließen können.
• Wenn eine Überempfindlichkeitsreaktion ausgeschlossen ist, können Patienten die Behandlung mit Abacavir wieder aufnehmen. In seltenen Fällen traten bei Patienten, die Abacavir aus anderen Gründen als Symptomen einer Überempfindlichkeit abgesetzt hatten, innerhalb weniger Stunden nach Wiederaufnahme der Abacavir-Therapie auch lebensbedrohliche Reaktionen auf. Daher wird die Wiedereinführung von Abacavir oder anderen Abacavir-haltigen Produkten nur dann empfohlen, wenn eine medizinische Versorgung problemlos möglich ist.
• Ein Medikamentenleitfaden und eine Warnkarte, die Informationen zur Erkennung von Überempfindlichkeitsreaktionen enthalten, sollten bei jedem neuen Rezept und Nachfüllen abgegeben werden.

5.2 Lactic acidosis and severe hepatomegaly with steatosis

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues, including abacavir. The majority of these cases involved women. Female gender and obesity may be risk factors for the development of lactic acidosis and severe hepatomegaly with steatosis in patients treated with antiretroviral nucleoside analogues. Treatment with abacavir should be discontinued in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or significant hepatotoxicity, which may include hepatomegaly and steatosis, even in the absence of significant transaminase elevations.

5.3 Immune reconstitution syndrome

Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including abacavir. During the initial phase of combination antiretroviral treatment, patients whose immune system is responding may experience an inflammatory response to indolent or persistent opportunistic infections (e.gMycobacterium aviuminfection, cytomegalovirus,Pneumocystis jiroveciiPneumonia [PCP]or tuberculosis), which may require further evaluation and treatment.

The occurrence of autoimmune diseases (such as Graves' disease, polymyositis and Guillain-Barré syndrome) associated with immune reconstitution has also been reported; However, the time to onset is more variable and can occur many months after starting treatment.

5.4 Myocardial infarction

Several prospective, observational, epidemiological studies have reported an association between abacavir use and the risk of myocardial infarction (MI). Meta-analyses of randomized, controlled clinical trials have found no increased risk of MI in abacavir-treated subjects compared to controls. To date, there is no established biological mechanism that could explain a possible increase in risk. Overall, available data from observational studies and controlled clinical trials show inconsistencies; Therefore, evidence of a causal relationship between abacavir treatment and MI risk is inconclusive.

As a precautionary measure, when prescribing antiretroviral therapy, including abacavir, the underlying risk of coronary artery disease should be taken into account and measures should be taken to minimize all modifiable risk factors (e.g. hypertension, hyperlipidemia, diabetes mellitus, smoking).

6. Side effects/side effects

The following side effects are discussed in other sections of the label:

• Schwerwiegende und manchmal tödliche Überempfindlichkeitsreaktionen [see Boxed Warning, Warnings and Precautions (5.1)].
• Laktatazidose und schwere Hepatomegalie mit Steatose [see Warnings and Precautions (5.2)].
• Immunrekonstitutionssyndrom [see Warnings and Precautions (5.3)].
• Herzinfarkt [see Warnings and Precautions (5.4)].

6.1 Experience with clinical studies in adult subjects

Because clinical trials are conducted under very different conditions, the rates of adverse reactions observed in clinical trials of one drug cannot be directly compared with the rates observed in clinical trials of another drug and may not reflect the rates observed in clinical practice.

Serious and fatal abacavir-associated hypersensitivity reactions

Serious and sometimes fatal hypersensitivity reactions have occurred with abacavir in clinical trials[see Boxed Warning, Warnings and Precautions (5.1)].These reactions are characterized by 2 or more of the following signs or symptoms: (1) fever; (2) rash; (3) gastrointestinal symptoms (including nausea, vomiting, diarrhea, or abdominal pain); (4) constitutional symptoms (including general malaise, fatigue, or pain); (5) Respiratory symptoms (including shortness of breath, cough, or pharyngitis). Almost all abacavir hypersensitivity reactions include fever and/or rash as part of the syndrome.

Other signs and symptoms 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 included lymphadenopathy, mucosal lesions (conjunctivitis and mouth ulcers), and maculopapular or urticarial rash (although some patients had other types of rashes and others did not have a rash). There have been reports of erythema multiforme. Laboratory abnormalities included elevated liver enzymes, elevated creatine phosphokinase, elevated creatinine, and lymphopenia, as well as abnormal chest x-ray findings (predominantly localized infiltrates).

Additional side effects when using abacavir

Therapy-naïve adults:During therapy with abacavir 300 mg twice daily, lamivudine 150 mg twice daily, and efavirenz 600 mg daily compared with zidovudine 300, treatment-emergent clinical adverse reactions (assessed as moderate or severe by the investigator) occurred at a frequency greater than or equal to 5% Table 2 listed.

Table 2. Treatment-related (all causal) adverse reactions of at least moderate intensity (Grade 2 to 4, frequency greater than or equal to 5%) in treatment-naïve adults (CNA30024).A) over 48 weeks of treatment

AIn this study, a double-blind identification of suspected hypersensitivity reactions was performed. During the blinded portion of the study, suspected abacavir hypersensitivity was reported by investigators in 9% of 324 subjects in the abacavir group and in 3% of 325 subjects in the zidovudine group.

bTen (3%) cases with suspected drug hypersensitivity were classified as not due to abacavir after unblinding.

Treatment-emergent clinical adverse reactions (assessed by the investigator as moderate or severe) with a frequency greater than or equal to 5% during therapy with abacavir 300 mg twice daily, lamivudine 150 mg twice daily, and zidovudine 300 mg twice daily compared with indinavir 800 mg three times daily, lamivudine 150 mg twice daily, and zidovudine 300 mg twice daily from CNA3005 are shown in Table 3.

Table 3. Treatment-related (all causal) adverse reactions of at least moderate intensity (Grade 2 to 4, frequency greater than or equal to 5%) in treatment-naïve adults (CNA3005) over 48 weeks of treatment

Five subjects who received abacavir in CNA3005 experienced worsening of pre-existing depression compared to none in the indinavir arm. Background rates of pre-existing depression were similar in both treatment arms.

AbacavirOnce a day vsAbacavirTwice daily (CNA30021):During therapy with abacavir 600 mg once daily or abacavir 300 mg twice daily, both in combination with lamivudine 300 mg once daily, treatment-emergent clinical adverse reactions (rated by the investigator as at least moderate) occurred at a frequency greater than or equal to 5%, and efavirenz 600 mg once daily from CNA30021 were similar. For hypersensitivity reactions, the rate was 9% in subjects receiving abacavir once daily compared to 7% in subjects receiving abacavir twice daily. However, severe drug hypersensitivity reactions and severe diarrhea occurred significantly more frequently in subjects who received abacavir 600 mg once daily compared to subjects who received abacavir 300 mg twice daily. Five percent (5%) of subjects who received abacavir 600 mg once daily had severe drug hypersensitivity reactions, compared to 2% of subjects who received abacavir 300 mg twice daily. Two percent (2%) of subjects receiving abacavir 600 mg once daily experienced severe diarrhea, whereas none of the subjects receiving abacavir 300 mg twice daily experienced this event.

Laboratory abnormalities:Laboratory abnormalities (Grade 3 to 4) in treatment-naïve 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 shown in Table 4.

Table 4. Laboratory abnormalities (Grade 3 to 4) in treatment-naïve adults (CNA30024) over 48 weeks of treatment

ULN = upper limit of normal value.

n = number of subjects evaluated.

Laboratory abnormalities in CNA3005 are listed in Table 5.

Table 5. Treatment-related laboratory abnormalities (Grade 3 to 4) in CNA3005

ULN = upper limit of normal value.

n = number of subjects evaluated.

The frequency of treatment-related laboratory abnormalities was comparable between treatment groups in CNA30021.

6.2 Experience in clinical trials in pediatric subjects

Therapy-experienced pediatric subjects (twice daily dosage)


Treatment-emergent clinical adverse reactions (assessed by the investigator as moderate or severe) with a frequency greater than or equal to 5% during therapy with abacavir 8 mg per kg twice daily, lamivudine 4 mg per kg twice daily, and zidovudine 180 mg per day M2twice daily compared to lamivudine 4 mg per kg twice daily and zidovudine 180 mg per m2twice daily of CNA3006 are listed in Table 6.

Table 6. Treatment-related (all causality) adverse reactions of at least moderate intensity (Grade 2 to 4, greater than or equal to 5% frequency) in treatment-experienced pediatric subjects (CNA3006) over 16 weeks of treatment

Laboratory abnormalities:In CNA3006, laboratory abnormalities (anemia, neutropenia, liver function test abnormalities, and CPK elevations) were observed with similar frequency to a study in treatment-naïve adults (CNA30024). Mild elevations in blood glucose occurred more frequently in pediatric subjects receiving abacavir (CNA3006) than in adult subjects (CNA30024).


Other adverse events


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

Pediatric subjects once daily versus twice daily (COL105677):The safety of once-daily dosing of abacavir compared to twice-daily dosing was evaluated in the ARROW study. The primary safety assessment in the ARROW study was based on Grade 3 and 4 adverse events. The incidence of Grade 3 and 4 adverse events was similar in subjects randomized to once-daily dosing as in subjects randomized to twice-daily dosing. One grade 4 hepatitis event in the once-daily cohort was considered by the investigator to have uncertain causality, and all other grade 3 or 4 adverse events were considered unrelated 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 exposure.

Body as a whole

Redistribution/accumulation of body fat.

Cardiovascular system

Heart attack.

liver

lactic acidosis and liver steatosis[see Warnings and Precautions (5.2)].

skin

Suspected Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported in patients receiving abacavir primarily in combination with drugs known to be associated with SJS and TEN. Due to the overlap in clinical signs and symptoms between abacavir hypersensitivity and SJS and TEN, as well as the possibility of multiple drug hypersensitivities in some patients, abacavir treatment should be discontinued and not restarted in such cases.

There have also been reports of erythema multiforme with the use of abacavir[lakeAdverse Reactions (6.1)].

7. Drug interactions

7.1 Methadone

In a study of 11 HIV-1-infected subjects receiving methadone maintenance therapy with 600 mg abacavir twice daily (twice the currently recommended dose), oral methadone clearance increased[see Clinical Pharmacology (12.3)]. This change does not result in a change in methadone dose in most patients; However, an increased dose of methadone may be required in a small number of patients.

7.2 Riociguat

Coadministration with fixed-dose abacavir/dolutegravir/lamivudine resulted in increased riociguat exposure, which may increase the risk of riociguat adverse reactions[see Clinical Pharmacology (12.3)]. The riociguat dose may need to be reduced. View full prescribing information for ADEMPAS (riociguat).

8. Use in Specific Populations

8.1 Pregnancy

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to abacavir during pregnancy. Healthcare providers are encouraged to enroll patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263.

Risk overview

Available data from the APR show no difference in the overall risk of birth defects for abacavir compared to the background birth defect rate of 2.7% in the Metropolitan Atlanta Congenital Defects Program (MACDP) reference population.(see data).The APR uses the MACDP as the US reference population for birth defects in the general population. The MACDP evaluates women and infants from a limited geographic area and does not consider the outcomes of births that occurred at less than 20 weeks of gestation. The miscarriage rate is not reflected in the APR. The estimated background rate of miscarriage in clinically recognized pregnancies in the US general population is 15% to 20%. The background risk of major birth defects and miscarriage for the specified 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 nine times the human exposure (AUC) at the recommended clinical dose(see data).

Data

Human data:Based on prospective reports to the APR of abacavir exposures during pregnancy resulting in live births (including over 1,300 first trimester exposures and over 1,300 second/third trimester exposures), there was no difference in the overall risk of birth defects for abacavir compared to the background birth defect rate of 2.7% in the US MACDP reference population. The prevalence of live birth defects was 3.2% (95% CI: 2.3% to 4.3%) after first trimester exposure to abacavir-containing regimens and 2.9% (95% CI: 2.1% to 4.0%) after second/third trimester exposure to abacavir-containing regimens.

Abacavir was shown to cross the placenta and concentrations in neonatal plasma at birth were essentially equivalent to those in maternal plasma at delivery[see Clinical Pharmacology (12.3)].

Animal data:Abacavir was administered orally to pregnant rats (100, 300, and 1,000 mg per kg per day) and rabbits (125, 350, or 700 mg per kg per day) during organogenesis (on gestation days 6 to 17 and 6 to 20, respectively). In rats, fetal malformations (increased incidence of fetal anasarca and skeletal malformations) or developmental toxicity (decreased fetal body weight and crown-rump length) were observed 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 an exposure (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 weight) or offspring toxicities (increased incidence of stillbirths and lower body weight) occurred at doses up to 500 mg per kg per day. No developmental effects were observed in rats at a dosage of 60 mg per kg per day, resulting in an exposure (AUC) approximately four times the human exposure at the recommended daily dose. Studies in pregnant rats showed that abacavir is transmitted to the fetus via the placenta. In pregnant rabbits, there were no developmental toxicities and no increase in fetal malformations up to the highest dose evaluated, resulting in exposures (AUC) approximately nine times the human exposure at the recommended dose.

8.2 Breastfeeding

Risk overview

The Centers for Disease Control and Prevention recommends that HIV-1-infected mothers in the United States not breastfeed their infants to avoid the risk of postnatal transmission of HIV-1 infection. Abacavir is found in breast milk. There is no information about the effects of abacavir on the breast-fed infant or the effects of the drug on milk production. Because of the potential for (1) HIV-1 transmission (in HIV-negative infants), (2) development of viral resistance (in HIV-positive infants), and (3) adverse reactions in breast-fed infants, mothers should be advised not to breast-feed when receiving abacavir.

8.4 Pediatric Use

The safety and efficacy of abacavir have been demonstrated in pediatric patients aged 3 months and older. The use of abacavir is supported by pharmacokinetic studies and evidence from adequate and well-controlled studies of abacavir in adults and children[see Dosage and Administration (2.3), Adverse Reactions (6.2), Clinical Pharmacology (12.3), Clinical Studies (14.2)].

8.5 Geriatric Use

Clinical trials with abacavir did not include enough subjects aged 65 years and older to determine whether they respond differently than younger subjects. In general, caution should be exercised when using abacavir in elderly patients due to the increased frequency of decreased liver, kidney or cardiac function, as well as concomitant diseases or other drug therapies.

8.6 Patients with impaired liver function

A dose reduction is necessary in patients with mild hepatic impairment (Child-Pugh class A).[see Dosage and Administration (2.4)]. The safety, efficacy and pharmacokinetic properties of abacavir have not been established in patients with moderate or severe hepatic impairment; Therefore, abacavir is contraindicated in these patients[see Contraindications (4), Clinical Pharmacology (12.3)].

10. Overdose

There is no known specific treatment for abacavir overdose. In the event of an overdose, the patient should be monitored and standard supportive treatment administered if necessary. It is not known whether abacavir can be removed by peritoneal dialysis or hemodialysis.

11. Description of Abacavir oral solution

Abacavir sulfate is a synthetic carbocyclic nucleoside analogue with inhibitory activity against HIV-1. The chemical name of abacavir sulfate is(1S,cis)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol sulfate (salt) (2:1). Abacavir sulfate is the enantiomer with1S,4Rabsolute configuration on the cyclopentene ring. It has the molecular formula (C14H18N6o)2•H2SO4and a molecular weight of 670.76 g per mole. It has the following structural formula:

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

Abacavir oral solution USP is for oral administration. Each milliliter (1 mL) of Abacavir oral solution USP contains abacavir sulfate USP equivalent to 20 mg of abacavir (i.e. 20 mg per mL) as the active ingredient and the following inactive ingredients: artificial strawberry and banana flavors, anhydrous citric acid, methylparaben and propylparaben (added as a preservative), propylene glycol, saccharin sodium, sodium citrate (dihydrate), non-crystallizing sorbitol solution and water.

In vivoAbacavir sulfate dissociates to its free base abacavir. Dosages are expressed in abacavir.

12. Abacavir Oral Solution – Clinical Pharmacology

12.1 Mechanism of action

Abacavir is an antiretroviral drug[see Microbiology (12.4)].

12.3 Pharmacokinetics

Pharmacokinetics in adults

The pharmacokinetic properties of abacavir were dose independent in the range of 300 to 1,200 mg per day.

Absorption:Following oral administration, abacavir is rapidly absorbed and widely distributed.

The geometric mean absolute bioavailability of the tablet was 83%. The AUC of abacavir in plasma was similar after administration of the oral solution or tablets. Following oral administration of 300 mg twice daily in 20 subjects, the peak abacavir steady-state serum concentration increased (Cmax) was 3 ± 0.89 mcg per ml (mean ± SD) and AUC(0-12 hours)was 6.02 ± 1.73 µg hour per ml. After oral administration of a single dose of 600 mg abacavir to 20 volunteers, C occurredmaxwas 4.26 ± 1.19 mcg per ml (mean ± SD) and AUC∞was 11.95 ± 2.51 µg·hour per ml.


Effect of food:The bioavailability of abacavir tablets was evaluated in the fasting and non-fasting states with no significant difference in systemic exposure (AUC).∞); Therefore, Abacavir tablets can be taken with or without food. Systemic exposure to abacavir was comparable following administration of abacavir oral solution and abacavir tablets. Therefore, these products can be used interchangeably.
Distribution:The apparent volume of distribution following intravenous administration of abacavir was 0.86 ± 0.15 L per kg, suggesting that abacavir distributes to the extravascular space. In 3 subjects the CSF AUC was(0-6 hours)to plasma abacavir AUC(0-6 hours)The rate was between 27% and 33%.

Binding of abacavir to human plasma proteins is approximately 50% and was independent of concentration. Total drug-related radioactivity concentrations in blood and plasma are identical, indicating that abacavir distributes readily to erythrocytes.


Elimination:In single-dose studies, the observed elimination half-life was (t1/2) was 1.54 ± 0.63 hours. After intravenous administration, the total clearance was 0.8 ± 0.24 L per hour per kg (mean ± standard deviation).


Metabolism:In humans, abacavir is not significantly metabolized by cytochrome P450 enzymes. The main routes of elimination of abacavir are metabolism by alcohol dehydrogenase to form 5′-carboxylic acid and glucuronyltransferase to form 5′-glucuronide. The metabolites have no antiviral activity.In vitroExperiments show that abacavir does not inhibit human CYP3A4, CYP2D6, or CYP2C9 activity at clinically relevant concentrations.

Excretion:Elimination of abacavir was quantified in a mass balance study following administration of a 600 mg dose14C-Abacavir: 99% of radioactivity was recovered, 1.2% was excreted in urine as abacavir, 30% as 5′-carboxylic acid metabolite, 36% as 5′-glucuronide metabolite and 15% as unidentified minor urinary metabolites. Fecal excretion accounted for 16% of the dose.

Specific populations

Patients with kidney diseaseImpairment:The pharmacokinetic properties of abacavir have not been determined in patients with renal impairment. Renal excretion of unchanged abacavir is a minor route of elimination in humans.

patients withLiver dysfunction:The pharmacokinetics of abacavir were studied in patients with mild hepatic impairment (Child-Pugh class A). Results showed that after a single 600 mg dose of abacavir, there was an average increase in abacavir AUC of 89% and an increase in abacavir half-life of 58%. The AUCs of the metabolites were not altered by mild liver disease; However, the formation and elimination rates of the metabolites were reduced[see Contraindications (4), Use in Specific Populations (8.6)].

Pregnant woman:The pharmacokinetics of abacavir were studied in 25 pregnant women in the last trimester of pregnancy who received abacavir 300 mg twice daily. Abacavir exposure (AUC) during pregnancy was similar to postpartum and HIV-infected non-pregnant historical controls. Consistent with passive diffusion of abacavir across the placenta, abacavir concentrations in neonatal plasma samples at birth were essentially equivalent to those in maternal plasma at delivery.

Pediatric patients:The pharmacokinetics of abacavir were evaluated following single or repeated administration of abacavir in 169 pediatric subjects. Subjects receiving abacavir oral solution according to the recommended dosing regimen achieved abacavir plasma concentrations similar to those in adults. Subjects who received abacavir oral tablets achieved higher plasma concentrations of abacavir than subjects who received oral solution.

The pharmacokinetics of once-daily abacavir in HIV-1-infected pediatric subjects aged 3 months to 12 years were evaluated in 3 studies (PENTA 13). [n = 14]PENTA 15 [n = 18]and ARROW [n = 36]). All three studies were open-label, two-period crossover pharmacokinetic studies with twice-daily and once-daily dosing of abacavir and lamivudine, respectively. For both the oral solution and the tablet formulation, these three studies demonstrated that once-daily dosing provides a comparable AUC0-24up to twice daily administration of abacavir with the same total daily dose. The middle Cmaxwas approximately 1.6- to 2.3-fold higher with once-daily abacavir dosing than with twice-daily dosing.

Geriatric patients:The pharmacokinetics of abacavir have not been studied in subjects over 65 years of age.

Male and female patients: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.

Racial groups: There are no significant or clinically relevant racial differences between blacks and whites in the pharmacokinetics of abacavir.

Drug interaction studies

Effect of abacavir on the pharmacokinetics of other active substances:In vitroStudies have shown that abacavir has the potential to inhibit CYP1A1 and limited potential to inhibit CYP3A4-mediated metabolism. Abacavir did not inhibit or induce other CYP enzymes (such as CYP2C9 or CYP2D6).

Related toin vitroBased on study results, abacavir is not expected to affect the pharmacokinetics of drugs that are substrates of the following transporters during therapeutic drug exposure: 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 individuals receiving a fixed dose of abacavir/dolutegravir/lamivudine has been reported to increase the AUC of riociguat(∞)compared to the AUC of riociguat(∞)reported in healthy subjects due to CYP1A1 inhibition by abacavir. The exact magnitude of the increase in riociguat exposure has not been fully determined based on the results of two studies[see Drug Interactions (7.2)].


Effect of other active substances 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-gpin vitro; However, given the absolute bioavailability (83%), modulators of these transporters are unlikely to have a clinically relevant impact on abacavir concentrations.


Lamivudine and/or zidovudine:Fifteen HIV-1-infected subjects were enrolled in a crossover drug interaction study evaluating single doses of abacavir (600 mg), lamivudine (150 mg), and zidovudine (300 mg) alone or in combination. The analysis showed no clinically relevant changes in abacavir pharmacokinetics with the addition of lamivudine or zidovudine or the combination of lamivudine and zidovudine. Lamivudine exposure (AUC decreased by 15%) and zidovudine exposure (AUC increased by 10%) showed no clinically relevant changes when co-administered with abacavir.

Ethanol:Abacavir has no effect on the pharmacokinetic properties of ethanol. Ethanol decreases the elimination of abacavir, resulting in an increase in total exposure. Due to the shared metabolic pathways of abacavir and ethanol via alcohol dehydrogenase, the pharmacokinetic interaction between abacavir and ethanol was examined in 24 HIV-1-infected male volunteers. Each subject received the following treatments on different occasions: a single dose of 600 mg abacavir, 0.7 g per kg ethanol (equivalent to 5 alcoholic drinks) and 600 mg abacavir 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, therefore no clinically significant interaction is expected in men. This interaction has not been studied in women.

Methadone:In a study of 11 HIV-1-infected subjects receiving methadone maintenance therapy (40 mg and 90 mg daily) with abacavir 600 mg twice daily (twice the currently recommended dose), oral methadone clearance increased by 22% (90% CI). : 6% to 42%). This change does not result in a change in methadone dose in most patients; However, an increased dose of methadone may be required in a small number of patients[see Drug Interactions (7)]. The addition of methadone did not have a 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 HIV-1 reverse transcriptase (RT) activity by competing with the natural substrate dGTP and incorporating it into viral DNA.

Antiviral activity

The antiviral activity of abacavir against HIV-1 has been evaluated in a variety of cell lines, including primary monocytes/macrophages and peripheral blood mononuclear cells (PBMCs). E.C50The values ​​were between 3.7 and 5.8 micromoles (1 micromole = 0.28 micrograms per ml) and between 0.07 and 1 micromoles against HIV-1IIIBand HIV-1Balor the mean EC50The value was 0.26 ± 0.18 micromol compared to 8 clinical isolates. The middle EC50The values for 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), and 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 group AG and group O viruses (n = 3 except n = 2 for clade B). The EC50The values ​​against HIV-2 isolates (n = 4) were between 0.024 and 0.49 micromoles. The antiviral activity of abacavir in cell cultures was not antagonized in combination 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 to treat 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 were selected in cell cultures. Genotypic analysis of isolates selected in cell culture and obtained from abacavir-treated subjects showed that the amino acid substitutions K65R, L74V, Y115F and M184V/I occurred in HIV-1 RT. M184V or I substitutions resulted in an approximately 2-fold reduction in susceptibility to abacavir. Substitutions K65R, L74M, or Y115F with M184V or I resulted in a 7- to 8-fold reduction in susceptibility to abacavir, and combinations of three substitutions were required to produce a greater than 8-fold reduction in susceptibility.

Thirty-nine percent (7 of 18) of isolates from subjects who experienced virologic failure in the once-daily abacavir arm demonstrated a mean decrease in abacavir susceptibility of more than 2.5-fold with a mean decrease of 1.3-fold (range: 0.5 to 11) compared to 29% (5 of 17) of failing isolates in the twice-daily arm daily intake, with a mean 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, demonstrated cross-resistance with didanosine, emtricitabine, lamivudine, and tenofovir in cell cultures and in volunteers. Increasing numbers of thymidine analogue mutational substitutions (TAMs: M41L, D67N, K70R, L210W, T215Y/F, K219E/R/H/Q/N) are associated with a progressive reduction in abacavir susceptibility.

13. Nonclinical toxicology

13.1 Carcinogenesis, mutagenesis, impairment of fertility

Carcinogenicity

Abacavir was administered orally at three doses to separate groups of mice and rats in two-year carcinogenicity studies. The results showed an increase in the incidence of malignant and non-malignant tumors. Malignant tumors occurred in the preputial gland of males and the clitoris of females of both species, as well as in the liver of female rats. In addition, non-malignant tumors also occurred in the liver and thyroid of female rats. These observations were made at systemic exposures ranging from 6 to 32 times the human exposure at the recommended dose of 600 mg.

Mutagenicity

Abacavir induced chromosomal aberrations in both the presence and absence of metabolic activationin vitroCytogenetic study of 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. Abacavir was clastogenic in men and non-clastogenic in womenin vivoMouse bone marrow micronucleus assay.

Abacavir was not mutagenic in bacterial mutagenicity tests in the presence and absence of metabolic activation.

Impairment of fertility

Abacavir had no effect on male or female fertility in rats at a dose associated with an exposure (AUC) approximately 3.3 times (male) and 4.1 times (female), respectively, that in humans at the clinically recommended dose.

13.2 Animal toxicology and/or pharmacology

Myocardial degeneration was detected in mice and rats after two years of administration of abacavir. Systemic exposures were 7 to 24 times the expected human systemic exposure at the 600 mg dose. The clinical relevance of this finding has not been determined.

14. Clinical trials

14.1 Exams for adults

Therapy-naïve adults

CNA30024 was a multicenter, double-blind, controlled trial that randomized 649 HIV-1-infected, treatment-naïve adults to receive either abacavir (300 mg twice daily), lamivudine (150 mg twice daily), and efavirenz (600 mg once daily); or zidovudine (300 mg twice daily), lamivudine (150 mg twice daily), and efavirenz (600 mg once daily). The duration of double-blind treatment was at least 48 weeks. Study participants were male (81%), white (51%), black (21%), and Hispanic (26%). The average age was 35 years; The mean pretreatment CD4+ cell count was 264 cells per mm3and the mean plasma HIV-1 RNA level was 4.79 log10Copies per ml. The results of the randomized treatment are shown in Table 7.

Table 7. Randomized Treatment Results through Week 48 (CNA30024)

ASubjects achieved and maintained confirmed HIV-1 RNA of no more than 50 copies per mL (less than 400 copies per mL) through Week 48 (Roche AMPLICOR Ultrasensitive HIV-1 MONITOR Standard Test 1 PCR).

bIncludes viral rebound, inadequate viral response as reported by the investigator, and failure to achieve confirmed less than or equal to 50 copies per mL by Week 48.

CIncludes withdrawn consent, lack of follow-up, protocol violations, cases with missing data, clinical progress, and others.

After 48 weeks of therapy, the mean increase in CD4+ cell count from baseline was 209 cells per mm3in the group that received abacavir and 155 cells per mm3in the zidovudine group. By Week 48, clinical disease progression occurred in 8 subjects (2%) in the abacavir arm (5 CDC Class C events and 3 deaths) and 5 subjects (2%) in the zidovudine arm (3 CDC Class C events and 2 deaths).

CNA3005 was a multicenter, double-blind, controlled trial in which 562 HIV-1-infected, treatment-naïve adults were randomized to receive either abacavir (300 mg twice daily) plus COMBIVIR (lamivudine 150 mg/zidovudine 300 mg twice daily). or indinavir (800 mg three times daily) plus COMBIVIR twice daily. The study was stratified at randomization by baseline plasma HIV-1 RNA of 10,000 to 100,000 copies per ml and plasma HIV-1 RNA of more than 100,000 copies per ml. Study participants were male (87%), white (73%), black (15%), and Hispanic (9%). At the start of the study, the average age was 36 years; The mean CD4+ cell count at baseline was 360 cells per mm3and the mean baseline plasma HIV-1 RNA level was 4.8 log10Copies per ml. The proportions of subjects with plasma HIV-1 RNA less than 400 copies per ml (using the Roche AMPLICOR HIV-1 MONITOR assay) during 48 weeks of treatment are summarized in Table 8.

Table 8. Randomized Treatment Results through Week 48 (CNA3005)

ASubjects achieved and maintained confirmed HIV-1 RNA levels of less than 400 copies per ml.

bIncludes viral rebound and failure to reach confirmed less than 400 copies per ml by week 48.

CThese include withdrawal of consent, lack of follow-up, protocol violations, cases with missing data, clinical progress, and others.

Treatment response based on plasma HIV-1 RNA levels is shown in Table 9.

Table 9. Proportions of responders through week 48 by screening plasma HIV-1 RNA levels (CNA3005)

In subjects with a baseline viral load of more than 100,000 copies per ml, the percentage of subjects with HIV-1 RNA levels less than 50 copies per ml was 31% in the group receiving abacavir versus 45% in the group receiving indinavir.

By week 48, there was an overall average increase in the CD4+ cell count of around 150 cells per mm3was observed in both treatment arms. By Week 48, 9 subjects (3.4%) in the group receiving abacavir (6 CDC Class C events and 3 deaths) and 3 subjects (1.5%) in the group receiving indinavir (2 CDC Class C events and 1 death) experienced clinical disease progression.

CNA30021 was an international, multicenter, double-blind, controlled trial in which 770 HIV-1-infected, treatment-naïve adults were randomized to receive either 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. The double-blind treatment duration was at least 48 weeks. The study participants had an average age of 37 years; were male (81%), white (54%), black (27%), and Hispanic (15%). The mean CD4+ cell count at baseline was 262 cells per mm3(Range: 21 to 918 cells per mm3) and the mean baseline plasma HIV-1 RNA level was 4.89 log10Copies per ml (range: 2.6 to 6.99 log10copies per ml).

The results of the randomized treatment are shown in Table 10.

Table 10. Randomized Treatment Results through Week 48 (CNA30021)

ASubjects achieved and maintained confirmed HIV-1 RNA levels of less than 50 copies per ml (less than 400 copies per ml) through Week 48 (Roche AMPLICOR Ultrasensitive HIV-1 MONITOR standard test version 1).

bIncludes viral rebound, failure to achieve confirmed less than 50 copies per mL (less than 400 copies per mL) by Week 48, and inadequate viral load response.

CIncludes withdrawal of consent, lack of follow-up, protocol violations, clinical progression, and others.

After 48 weeks of therapy, the mean increase in CD4+ cell count from baseline was 188 cells per mm3in the group that received 600 mg of abacavir and 200 cells per mm once daily3in the group that received abacavir 300 mg twice daily. By week 48, there were 6 subjects (2%) in the group receiving 600 mg abacavir once daily (4 CDC Class C events and 2 deaths) and 10 subjects (3%) in the group receiving 300 mg abacavir twice daily (7 CDC Class C events). events and 3 deaths) there was a clinical course of the disease. None of the deaths were attributed to study drugs.

14.2 Pediatric studies

Therapy-experienced pediatric subjects

CNA3006 was a randomized, double-blind study comparing abacavir 8 mg per kg twice daily plus lamivudine 4 mg per kg twice daily plus zidovudine 180 mg per m2twice daily compared to lamivudine 4 mg per kg twice daily plus zidovudine 180 mg per m2twice a day. 205 pediatric subjects with therapy experience were included: female (56%), white (17%), black (50%), Hispanic (30%), mean age 5.4 years, baseline CD4+ cell percentage greater than 15%. (median = 27%) and mean baseline plasma HIV-1 RNA level of 4.6 log10Copies per ml. Eighty percent and 55 percent of the subjects had previously received therapy with zidovudine or lamivudine, respectively, most often in combination. The median duration of previous nucleoside analogue therapy was 2 years. At 16 weeks, the proportion of subjects who responded based on plasma HIV-1 RNA less than or equal to 400 copies per ml was significantly higher in subjects receiving abacavir plus lamivudine plus zidovudine than in subjects receiving lamivudine plus zidovudine, 13% versus 2%. respectively. Mean plasma HIV-1 RNA changes from baseline were -0.53 log10Copies per ml in the group receiving abacavir plus lamivudine plus zidovudine compared to -0.21 log10copies per ml in the group receiving lamivudine plus zidovudine. The mean increase in CD4+ cell count from baseline was 69 cells per mm3in the group that received abacavir plus lamivudine plus zidovudine and 9 cells per mm3in the group that received lamivudine plus zidovudine.

Once daily dosage

ARROW (COL105677) was a 5-year, randomized, multicenter study that examined multiple aspects of the clinical management of HIV-1 infection in pediatric subjects. HIV-1-infected, treatment-naïve subjects aged 3 months to 17 years were enrolled and treated with a first-line regimen containing abacavir and lamivudine, administered twice daily according to World Health Organization recommendations. After at least 36 weeks of treatment, subjects had the option to participate in randomization 3 of the ARROW study, which compared the safety and effectiveness of once-daily dosing with twice-daily dosing of abacavir and lamivudine in combination with a third antiretroviral drug, for an additional 96 weeks. Of the 1,206 original ARROW subjects, 669 participated in randomization 3. Virological suppression was not a requirement for participation at the start of randomization 3 (after at least 36 weeks of twice-daily treatment), 75% of subjects in the twice-daily cohort were virologically suppressed compared to 71% of subjects in the once-daily cohort.

The proportions of subjects with fewer than 80 copies per ml of HIV-1 RNA over 96 weeks are shown in Table 11. The differences between virologic responses in the two treatment arms were comparable in baseline characteristics for gender and age.

Table 11. Virological outcome of randomized treatment at week 96A(ARROW randomization 3)

16. How is Abacavir oral solution delivered?

Abacavir Oral Solution USP:It is a clear to opalescent, yellowish liquid with a strawberry-banana flavor. Each ml of solution contains abacavir sulfate USP equivalent to 20 mg abacavir. It is packaged in opaque bottles with child-resistant closures. This product does not require reconstitution.

Bottles of 240 ml NDC 64980-405-24


Store at 20° to 25°C (68° to 77°F).[see USP Controlled Room Temperature]. DO NOT FREEZE. Can be refrigerated.

17. Patient counseling information

Advise the patient to read the FDA-approved Medication Guide.

Hypersensitivity reactions

Inform patients:

• dass der Apotheker bei jedem neuen Rezept und Nachfüllen von Abacavir einen Medikamentenleitfaden und eine Warnkarte mit einer Zusammenfassung der Symptome der Abacavir-Überempfindlichkeitsreaktion und anderen Produktinformationen aushändigt und den Patienten anweist, den Medikamentenleitfaden und die Warnkarte jedes Mal zu lesen, um welche zu erhalten neue Informationen, die möglicherweise über Abacavir vorliegen. Der vollständige Text des Medikamentenleitfadens ist am Ende dieses Dokuments abgedruckt.
• die Warnkarte bei sich zu tragen.
• wie man eine Überempfindlichkeitsreaktion erkennt [see Warnings and Precautions (5.1), Medication Guide].
• dass sie, wenn sie Symptome entwickeln, die auf eine Überempfindlichkeitsreaktion hindeuten, sofort ihren Arzt anrufen sollten, um zu entscheiden, ob sie die Einnahme von Abacavir abbrechen sollten.
• dass sich eine Überempfindlichkeitsreaktion verschlimmern und zu einem Krankenhausaufenthalt oder zum Tod führen kann, wenn Abacavir nicht sofort abgesetzt wird.
• Nach einer Überempfindlichkeitsreaktion darf die Behandlung mit Abacavir oder einem anderen Abacavir-haltigen Produkt nicht wieder aufgenommen werden, da innerhalb weniger Stunden schwerwiegendere Symptome auftreten können, die zu lebensbedrohlicher Hypotonie und Tod führen können.
• dass bei einer Überempfindlichkeitsreaktion das nicht verwendete Abacavir entsorgt werden sollte, um eine erneute Einnahme von Abacavir zu vermeiden.
• dass eine Überempfindlichkeitsreaktion in der Regel reversibel ist, wenn sie rechtzeitig erkannt wird und Abacavir sofort abgesetzt wird.
• dass, wenn sie die Behandlung mit Abacavir aus anderen Gründen als den Symptomen einer Überempfindlichkeit unterbrochen haben (z. B. bei einer Unterbrechung der Medikamentenzufuhr), bei Wiederaufnahme der Einnahme von Abacavir eine schwere oder tödliche Überempfindlichkeitsreaktion auftreten kann.
• Abacavir oder ein anderes Abacavir-haltiges Produkt nicht ohne ärztliche Rücksprache und nur dann wieder einzunehmen, wenn für den Patienten oder andere Personen problemlos Zugang zu medizinischer Versorgung besteht.

Lactic acidosis/hepatomegaly with steatosis

Advise patients that lactic acidosis and severe hepatomegaly with steatosis have been reported with the use of nucleoside analogues and other antiretroviral drugs. Advise patients to discontinue abacavir if they experience clinical symptoms suggestive of lactic acidosis or significant hepatotoxicity[see Warnings and Precautions (5.2)].

Immune reconstitution syndrome

Advise patients to promptly report any signs and symptoms of infection to their healthcare provider as inflammation due to prior infection may occur soon after combination antiretroviral therapy, even when abacavir is started[see Warnings and Precautions (5.3)].

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

Advise women with HIV-1 infection not to breastfeed because HIV-1 can be passed to the baby through breast milk[see Use in Specific Populations (8.2)].

Missed dose

Advise patients to take a missed dose of abacavir 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)].

Medication Availability Guide

Instruct patients to read the Medication Guide before starting abacavir and to read it again each time the prescription is renewed. Advise patients to tell their doctor or pharmacist if they experience any unusual symptoms or if known symptoms persist or worsen.

Medication Guide

Abacavir Oral Solution USP
(a bak' a vir)

What is the most important information I should know about Abacavir oral solution?

Abacavir oral solution can cause serious side effects, including:

• Schwerwiegende allergische Reaktionen (Überempfindlichkeitsreaktion) Bei Abacavir-Lösung zum Einnehmen und anderen Abacavir-haltigen Produkten sind Nebenwirkungen aufgetreten, die zum Tod führen können. Ihr Risiko für diese allergische Reaktion ist viel höher, wenn Sie eine Genvariante namens HLA-B*5701 haben. Ihr Arzt kann mit einer Blutuntersuchung feststellen, ob Sie diese Genvariation haben.

If you experience symptoms from two or more of the following groups while taking abacavir oral solution, call your doctor immediately to find out whether you should stop taking abacavir oral solution.

A list of these symptoms can be found on the warning card provided to you by your pharmacist.Always carry this warning card with you.

If you stop taking abacavir oral solution due to an allergic reaction, never take itTake abacavir or another medicine containing abacavir (EPZICOM, TRIUMEQ or TRIZIVIR) again.

• Wenn bei Ihnen eine allergische Reaktion auftritt, entsorgen Sie nicht verwendete Abacavir-Lösung zum Einnehmen. Fragen Sie Ihren Apotheker, wie Arzneimittel ordnungsgemäß entsorgt werden.
• Wenn Sie Abacavir-Lösung zum Einnehmen oder ein anderes Abacavir-haltiges Arzneimittel erneut einnehmen, nachdem bei Ihnen eine allergische Reaktion aufgetreten ist, Innerhalb von Stunden Sie können bekommen lebensbedrohliche Symptome das kann beinhalten sehr niedriger Blutdruck oder Tod.
• Wenn Sie die Einnahme von Abacavir-Lösung zum Einnehmen aus einem anderen Grund, auch nur für ein paar Tage, abbrechen und Sie nicht allergisch gegen Abacavir-Lösung zum Einnehmen sind, sprechen Sie mit Ihrem Arzt, bevor Sie die Einnahme erneut einnehmen. Die erneute Einnahme von Abacavir Lösung zum Einnehmen kann eine schwere allergische oder lebensbedrohliche Reaktion hervorrufen, auch wenn Sie noch nie zuvor eine allergische Reaktion darauf hatten.

If your doctor tells you that you can take abacavir oral solutionRestart taking when you are near medical help or people who can call a healthcare provider if needed.

What is Abacavir oral solution?

Abacavir oral solution is a prescription human immunodeficiency virus type 1 (HIV-1) medicine used with other antiretroviral medicines to treat HIV-1 infection. HIV-1 is the virus that causes acquired immunodeficiency syndrome (AIDS).

The safety and effectiveness of abacavir oral solution have not been established in children younger than 3 months.

When used with other antiretroviral drugs to treat HIV-1 infection, abacavir oral solution may be helpful:

• Reduzieren Sie die Menge an HIV-1 in Ihrem Blut. Dies wird als „Viruslast“ bezeichnet.
• Erhöhen Sie die Anzahl der CD4+ (T)-Zellen in Ihrem Blut, die bei der Abwehr anderer Infektionen helfen.

Reducing the amount of HIV-1 and increasing the number of CD4+ (T) cells in your blood can help improve your immune system. This can reduce your risk of death or getting infections that can occur when your immune system is weakened (opportunistic infections).

Abacavir oral solution does not cure HIV-1 infection or AIDS.You must continue taking HIV-1 medications to control HIV-1 infection and reduce HIV-related illness.

Who Should Not Take Abacavir Oral Solution?

Do not take Abacavir oral solution if you:

• eine bestimmte Art von Genvariation haben, die als HLA-B*5701-Allel bezeichnet wird. Ihr Arzt wird Sie darauf testen, bevor er Ihnen eine Behandlung mit Abacavir-Lösung zum Einnehmen verschreibt.
• allergisch gegen Abacavir oder einen der Inhaltsstoffe der Abacavir-Lösung zum Einnehmen sind. Eine vollständige Liste der Inhaltsstoffe der Abacavir-Lösung zum Einnehmen finden Sie am Ende dieses Medikamentenleitfadens.
• Leberprobleme haben.

What should I tell my doctor before taking abacavir oral solution?

Before taking Abacavir oral solution, tell your doctor if you:

• getestet wurden und wissen, ob Sie eine bestimmte Genvariante namens HLA-B*5701 haben oder nicht.
• Leberprobleme haben oder hatten, einschließlich einer Hepatitis-B- oder -C-Virusinfektion.
• Herzprobleme haben, rauchen oder Krankheiten haben, die Ihr Risiko für Herzerkrankungen erhöhen, wie z. B. Bluthochdruck, hoher Cholesterinspiegel oder Diabetes.
• Alkohol trinken oder alkoholhaltige Arzneimittel einnehmen.
• schwanger sind oder eine Schwangerschaft planen. Sprechen Sie mit Ihrem Arzt, wenn Sie schwanger sind oder eine Schwangerschaft planen.

Pregnancy registry.There is a pregnancy registry for women who take antiretroviral drugs during pregnancy. The purpose of this register is to collect information about the health of you and your baby. Talk to your doctor about how you can participate in this registry.

• stillen oder planen zu stillen. Stillen Sie nicht, wenn Sie Abacavir-Lösung zum Einnehmen einnehmen.
  • Sie sollten nicht stillen, wenn Sie HIV-1 haben, da das Risiko besteht, dass HIV-1 auf Ihr Baby übertragen wird.

Tell your doctor about all the medicines you take.including prescription and over-the-counter medications, vitamins and herbal supplements.

Some medicines interact with abacavir oral solution.Keep a list of your medications to share with your doctor and pharmacist.You can ask your doctor or pharmacist for a list of medicines that interact with abacavir oral solution.Do not start taking a new medicine without telling your doctor.Your doctor can tell you whether it is safe to take abacavir oral solution with other medicines.

Tell your doctor if you take:

• jedes andere Arzneimittel zur Behandlung von HIV-1
• Methadon
• Riociguat

How should I take Abacavir oral solution?

• Nehmen Sie Abacavir-Lösung zum Einnehmen genau so, wie es Ihnen Ihr Arzt sagt.
• Ändern Sie Ihre Dosis nicht und brechen Sie die Einnahme von Abacavir-Lösung zum Einnehmen nicht ab, ohne mit Ihrem Arzt gesprochen zu haben. Wenn Sie eine Dosis Abacavir-Lösung zum Einnehmen vergessen haben, nehmen Sie sie ein, sobald Sie daran denken. Nehmen Sie nicht 2 Dosen gleichzeitig ein. Wenn Sie sich bezüglich Ihrer Dosierung nicht sicher sind, rufen Sie Ihren Arzt an.
• Bleiben Sie während der Einnahme von Abacavir Lösung zum Einnehmen in der Obhut eines Arztes.
• Abacavir Lösung zum Einnehmen kann mit oder ohne Nahrung eingenommen werden.
• Für Kinder ab 3 Monaten wird Ihr Arzt eine Dosis Abacavir-Lösung zum Einnehmen entsprechend dem Körpergewicht Ihres Kindes verschreiben.
• Informieren Sie Ihren Arzt, wenn Sie oder Ihr Kind Probleme beim Schlucken von Tabletten haben. Abacavir ist als Tablette oder als Flüssigkeit (Lösung zum Einnehmen) erhältlich.
• Lassen Sie nicht zu, dass Ihnen die Abacavir-Lösung zum Einnehmen ausgeht. Der Virusgehalt in Ihrem Blut kann zunehmen und die Behandlung des Virus kann schwieriger werden. Wenn Ihr Vorrat zur Neige geht, besorgen Sie sich Nachschub bei Ihrem Arzt oder Ihrer Apotheke.
• Wenn Sie zu viel Abacavir-Lösung zum Einnehmen eingenommen haben, rufen Sie Ihren Arzt an oder gehen Sie sofort zur nächsten Notaufnahme des Krankenhauses.

What are the possible side effects of abacavir oral solution?

• Abacavir Lösung zum Einnehmen kann schwerwiegende Nebenwirkungen verursachen, darunter:
• Siehe „Was sind die wichtigsten Informationen, die ich über Abacavir-Lösung zum Einnehmen wissen sollte?“
  • Ansammlung von Säure in Ihrem Blut (Laktatazidose). Bei einigen Menschen, die Abacavir-Lösung zum Einnehmen einnehmen, kann es zu einer Laktatazidose kommen. Laktatazidose ist ein schwerwiegender medizinischer Notfall, der zum Tod führen kann. Rufen Sie sofort Ihren Arzt an, wenn Sie eines der folgenden Symptome bemerken, die Anzeichen einer Laktatazidose sein könnten:
• sich sehr schwach oder müde fühlen
• ungewöhnliche (nicht normale) Muskelschmerzen
• Atembeschwerden
• Magenschmerzen mit Übelkeit und Erbrechen
• Kältegefühl, insbesondere in den Armen und Beinen
• sich schwindelig oder benommen fühlen
• einen schnellen oder unregelmäßigen Herzschlag haben
• Schwerwiegende Leberprobleme kann bei Personen auftreten, die Abacavir-Lösung zum Einnehmen einnehmen. In einigen Fällen können diese schwerwiegenden Leberprobleme zum Tod führen. Wenn Sie Abacavir Lösung zum Einnehmen einnehmen, kann Ihre Leber groß werden (Hepatomegalie) und es kann sich Fett in Ihrer Leber entwickeln (Steatose). Rufen Sie sofort Ihren Arzt an, wenn Sie eines der folgenden Anzeichen von Leberproblemen haben:
• Ihre Haut oder der weiße Teil Ihrer Augen verfärbt sich gelb (Gelbsucht)
• dunkler oder „teefarbener“ Urin
• heller Stuhl (Stuhlgang)
• Appetitlosigkeit für mehrere Tage oder länger
• Brechreiz
• Schmerzen, Schmerzen oder Druckempfindlichkeit auf der rechten Seite Ihres Bauchbereichs

If you are female or very overweight (obese), you may be more likely to develop lactic acidosis or severe liver problems.

• Veränderungen in Ihrem Immunsystem (Immunrekonstitutionssyndrom) kann auftreten, wenn Sie mit der Einnahme von HIV-1-Medikamenten beginnen. Ihr Immunsystem wird möglicherweise stärker und beginnt, Infektionen zu bekämpfen, die lange Zeit in Ihrem Körper verborgen waren. Informieren Sie sofort Ihren Arzt, wenn bei Ihnen nach Beginn der Einnahme von Abacavir Lösung zum Einnehmen neue Symptome auftreten.
• Herzinfarkt (Myokardinfarkt). Einige HIV-1-Arzneimittel, einschließlich Abacavir-Lösung zum Einnehmen, können Ihr Herzinfarktrisiko erhöhen.

The most common side effects of abacavir oral solutionin adults include:

• Brechreiz
• Kopfschmerzen
• Im Allgemeinen geht es mir nicht gut
• Müdigkeit
• Erbrechen
• schlechte Träume oder Schlafprobleme

The most common side effects of abacavir oral solutionin children include:

• Fieber und Schüttelfrost
• Brechreiz
• Erbrechen
• Ausschlag
• Ohren-, Nasen- oder Racheninfektionen

Tell your doctor if you experience side effects that bother you or do not go away.

These are not all of the possible side effects of abacavir oral solution. For further information, ask your doctor or pharmacist. Call your doctor for medical advice about side effects. You can report side effects to FDA at 1-800-FDA-1088.

How should I store Abacavir oral solution?

• Lagern Sie die Abacavir-Lösung zum Einnehmen bei Raumtemperatur zwischen 20 und 25 °C (68 und 77 °F).
• Abacavir-Lösung zum Einnehmen nicht einfrieren. Sie können Abacavir-Lösung zum Einnehmen im Kühlschrank aufbewahren.

Keep abacavir oral solution and all medicines out of the reach of children.

General information about the safe and effective use of abacavir oral solution

Sometimes medications are prescribed for purposes other than those listed in the medication guide. Do not use abacavir oral solution for any condition for which it has not been prescribed. Do not give Abacavir oral solution to other people, even if they have the same symptoms as you. It can harm them.

If you would like more information, contact your doctor. You can ask your doctor or pharmacist for information about abacavir oral solution intended for healthcare professionals.

For more information, call Rising Pharmaceuticals, Inc. at 1-866-562-4597.

What are the ingredients of Abacavir oral solution?

Active ingredient: abacavir

Inactive ingredients: artificial strawberry and banana flavors, anhydrous citric acid, methylparaben and propylparaben (added as a preservative), propylene glycol, saccharin sodium, sodium citrate (dihydrate), non-crystallizing sorbitol solution and water.

This medication guide has been approved by the U.S. Food and Drug Administration.

The trademarks listed are trademarks of their respective owners and are not trademarks of Aurobindo Pharma Limited. The markers of these brands are not affiliated with or endorse Aurobindo Pharma Limited or its products.

Distributed by:

Rising Pharmaceuticals, Inc.
East Brunswick, NJ 08816

Made in India

Code: TS/DROGS/19/1993

Revised: 11/2022

(front of card)

WARNING MAP

Abacavir Oral Solution USP

Patients taking abacavir oral solution may experience a serious allergic reaction (hypersensitivity reaction), which may result in death. If you experience symptoms from two or more of the following groups while taking abacavir oral solution, call your doctor immediately to find out whether you should stop taking this medicine.

Always carry this warning card with you to recognize the symptoms of this allergic reaction.

(back of card)

WARNING MAP

Abacavir Oral Solution USP

If you need to stop treatment with abacavir oral solution because you have had an allergic reaction to abacavir,NEVERTake abacavir oral solution or another medicine containing abacavir (EPZICOM).®,TRIUMEQ®,or TRIZIVIR®) again. If you experience an allergic reaction, throw away any unused abacavir oral solution. Ask your pharmacist how to properly dispose of medicines. If you take abacavir oral solution or another medicine containing abacavir again after you have had an allergic reaction,WITHIN HOURSYou can getlife-threateningSymptomsthat can includevery low blood pressureorDeath.

For more information about abacavir oral solution, see the Medication Guide.

EPZICOM®TRIUMEQ®and TRIZIVIR®are registered trademarks of the ViiV Healthcare group of companies.

Distributed by:

Rising Pharmaceuticals, Inc.
East Brunswick, NJ 08816

Made in India

Code: TS/DROGS/19/1993

Revised: 11/2022

PACKAGING LABEL - MAIN PANEL - 20 mg/ml (240 ml bottle label)

Rising®NDC 64980-405-24
PHARMACEUTICALS

Abacavir
Oral solution USP
20 mg/ml

Note for authorized dealers:
ABACAVIR ORAL SOLUTION every time
USP is dispensed, give one to the patient
attached medication guide and warning label
Card out of the box.

Only 240ml Rx

PACKAGING LABEL - MAIN PANEL - 20 mg/ml (240 ml carton label)

Rising®NDC 64980-405-24
PHARMACEUTICALS

Abacavir
Oral solution USP
20 mg/ml

Note for authorized dealers:
ABACAVIR ORAL SOLUTION every time
USP is dispensed, give one to the patient
attached medication guide and
Warning card from the box.

Only 240ml Rx