Drug Facts
Composition & Profile
Identifiers & Packaging
16 HOW SUPPLIED/STORAGE AND HANDLING Abacavir Oral Solution USP: It is a clear to opalescent, yellowish, strawberry-banana-flavored liquid. Each mL of the solution contains abacavir sulfate USP equivalent to 20 mg of abacavir. It is packaged in opaque bottles with child-resistant closure. 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. May be refrigerated.; PACKAGE LABEL-PRINCIPAL DISPLAY PANEL - 20 mg/mL (240 mL Bottle Label) Rising ® NDC 64980-405-24 PHARMACEUTICALS Abacavir Oral Solution USP 20 mg/mL Notice to Authorized Dispenser: Each time ABACAVIR ORAL SOLUTION USP is dispensed, give the patient an attached Medication Guide and Warning Card from the carton. 240 mL Rx only PACKAGE LABEL-PRINCIPAL DISPLAY PANEL - 20 mg/mL (240 mL Bottle Label); PACKAGE LABEL-PRINCIPAL DISPLAY PANEL - 20 mg/mL (240 mL Carton Label) Rising ® NDC 64980-405-24 PHARMACEUTICALS Abacavir Oral Solution USP 20 mg/mL Notice to Authorized Dispenser: Each time ABACAVIR ORAL SOLUTION USP is dispensed, give the patient an attached Medication Guide and Warning Card from the carton. 240 mL Rx only PACKAGE LABEL-PRINCIPAL DISPLAY PANEL - 20 mg/mL (240 mL Carton Label)
- 16 HOW SUPPLIED/STORAGE AND HANDLING Abacavir Oral Solution USP: It is a clear to opalescent, yellowish, strawberry-banana-flavored liquid. Each mL of the solution contains abacavir sulfate USP equivalent to 20 mg of abacavir. It is packaged in opaque bottles with child-resistant closure. 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. May be refrigerated.
- PACKAGE LABEL-PRINCIPAL DISPLAY PANEL - 20 mg/mL (240 mL Bottle Label) Rising ® NDC 64980-405-24 PHARMACEUTICALS Abacavir Oral Solution USP 20 mg/mL Notice to Authorized Dispenser: Each time ABACAVIR ORAL SOLUTION USP is dispensed, give the patient an attached Medication Guide and Warning Card from the carton. 240 mL Rx only PACKAGE LABEL-PRINCIPAL DISPLAY PANEL - 20 mg/mL (240 mL Bottle Label)
- PACKAGE LABEL-PRINCIPAL DISPLAY PANEL - 20 mg/mL (240 mL Carton Label) Rising ® NDC 64980-405-24 PHARMACEUTICALS Abacavir Oral Solution USP 20 mg/mL Notice to Authorized Dispenser: Each time ABACAVIR ORAL SOLUTION USP is dispensed, give the patient an attached Medication Guide and Warning Card from the carton. 240 mL Rx only PACKAGE LABEL-PRINCIPAL DISPLAY PANEL - 20 mg/mL (240 mL Carton Label)
Overview
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 4 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 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 active ingredient and the following inactive ingredients: artificial strawberry and banana flavors, citric acid anhydrous, methylparaben and propylparaben (added as preservatives), propylene glycol, saccharin sodium, sodium citrate (dihydrate), noncrystallizing sorbitol solution, and water. In vivo , abacavir sulfate dissociates to its free base, abacavir. Dosages are expressed in terms of abacavir. Chemical Structure
Indications & Usage
Abacavir oral solution, in combination with other antiretroviral agents, is indicated for the treatment of human immunodeficiency virus (HIV-1) infection. Abacavir, a nucleoside analogue human immunodeficiency virus (HIV-1) reverse transcriptase inhibitor, is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection. ( 1 )
Dosage & Administration
Before initiating abacavir oral solution, screen for the HLA-B*5701 allele. ( 2.1 ) Adults: 600 mg daily, administered as either 300 mg twice daily or 600 mg once daily. ( 2.2 ) Pediatric Patients 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. ( 2.3 ) Patients with Hepatic Impairment: Mild hepatic impairment – 200 mg twice daily. (2.4) 2.1 Screening for HLA-B*5701 Allele prior to 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 aged 3 months and 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 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 oral solution is contraindicated in these patients.
Warnings & Precautions
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues. ( 5.2 ) Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy. ( 5.3 ) 5.1 Hypersensitivity Reactions Serious and sometimes fatal hypersensitivity reactions have occurred with abacavir. These hypersensitivity reactions have included multi-organ failure and anaphylaxis and typically occurred within the first 6 weeks of treatment with abacavir (median time to onset was 9 days); although abacavir hypersensitivity reactions have occurred any time during treatment [see Adverse Reactions (6.1) ] . Patients who carry the HLA-B*5701 allele are at a higher risk of abacavir hypersensitivity reactions; although, 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 with abacavir-containing products where HLA-B*5701 screening was not performed. The incidence of suspected abacavir hypersensitivity reactions in clinical trials was 1% when subjects carrying the HLA-B*5701 allele were excluded. In any patient treated with abacavir, the clinical diagnosis of hypersensitivity reaction must remain the basis of clinical decision making. Due to the potential for severe, serious, and possibly fatal hypersensitivity reactions with abacavir: All patients should be screened for the HLA-B*5701 allele prior to initiating therapy with abacavir or reinitiation of therapy with abacavir, unless patients have a previously documented HLA-B*5701 allele assessment. Abacavir is contraindicated in patients with a prior hypersensitivity reaction to abacavir and in HLA-B*5701-positive patients. Before starting abacavir, review medical history for prior exposure to any abacavir-containing product. NEVER restart abacavir or any other abacavir-containing product following a hypersensitivity reaction to abacavir, regardless of HLA-B*5701 status. To reduce the risk of a life-threatening hypersensitivity reaction, regardless of HLA-B*5701 status, discontinue abacavir immediately if a hypersensitivity reaction is suspected, even when other diagnoses are possible (e.g., acute onset respiratory diseases such as pneumonia, bronchitis, pharyngitis, or influenza; gastroenteritis; or reactions to other medications). If a hypersensitivity reaction cannot be ruled out, do not restart abacavir or any other abacavir-containing products because more severe symptoms which may include life-threatening hypotension and death, can occur within hours. If a hypersensitivity reaction is ruled out, patients may restart abacavir. Rarely, patients who have stopped abacavir for reasons other than symptoms of hypersensitivity have also experienced life-threatening reactions within hours of reinitiating abacavir therapy. Therefore, reintroduction of abacavir or any other abacavir-containing product is recommended only if medical care can be readily accessed. A Medication Guide and Warning Card that provide information about recognition of hypersensitivity reactions should be dispensed with each new prescription and refill. 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. A majority of these cases have been in women. Female sex 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 suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity, which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations. 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 systems respond may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia [PCP], or tuberculosis), which may necessitate further evaluation and treatment. Autoimmune disorders (such as Graves’ disease, polymyositis, and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable and can occur many months after initiation of treatment. 5.4 Myocardial Infarction Several prospective, observational, epidemiological studies have reported an association with the use of abacavir and the risk of myocardial infarction (MI). Meta-analyses of randomized, controlled, clinical trials have observed no excess risk of MI in abacavir-treated subjects as compared with control subjects. To date, there is no established biological mechanism to explain a potential increase in risk. In totality, the available data from the observational studies and from controlled clinical trials show inconsistency; therefore, evidence for a causal relationship between abacavir treatment and the risk of MI is inconclusive. As a precaution, the underlying risk of coronary heart disease should be considered when prescribing antiretroviral therapies, including abacavir, and action taken to minimize all modifiable risk factors (e.g., hypertension, hyperlipidemia, diabetes mellitus, smoking).
Boxed Warning
HYPERSENSITIVITY REACTIONS Serious and sometimes fatal hypersensitivity reactions, with multiple organ involvement, have occurred with abacavir. Patients who carry the HLA-B*5701 allele are at a higher risk of a hypersensitivity reaction to abacavir; although, 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 prior 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 prior to initiating therapy with abacavir or reinitiation of therapy with abacavir, unless patients have a previously documented HLA-B*5701 allele assessment. Discontinue abacavir immediately if a hypersensitivity reaction is suspected, regardless of HLA-B*5701 status and even when other diagnoses are possible [see Contraindications (4) , Warnings and Precautions (5.1) ]. Following a hypersensitivity reaction to abacavir, NEVER restart abacavir or any other abacavir-containing product because more severe symptoms, including death can occur within hours. Similar severe reactions have also occurred rarely following the reintroduction of abacavir-containing products in patients who have no history of abacavir hypersensitivity [see Warnings and Precautions (5.1) ] . WARNING: HYPERSENSITIVITY REACTIONS See full prescribing information for complete boxed warning. Serious and sometimes fatal hypersensitivity reactions have occurred with abacavir. ( 5.1 ) Hypersensitivity to abacavir is a multi-organ clinical syndrome. ( 5.1 ) Patients who carry the HLA-B * 5701 allele are at a higher risk of experiencing a hypersensitivity reaction to abacavir. ( 5.1 ) Abacavir i s contraindicated in patients with a prior hypersensitivity reaction to abacavir and in HLA-B*5701-positive patients. ( 4 ) Discontinue abacavir as soon as a hypersensitivity reaction is suspected. Regardless of HLA-B * 5701 status, permanently discontinue abacavir if hypersensitivity cannot be ruled out, even when other diagnoses are possible. ( 5.1 ) Following a hypersensitivity reaction to abacavir, NEVER restart abacavir or any other abacavir-containing product. ( 5.1 )
Contraindications
Abacavir oral solution is contraindicated in patients: who have the HLA-B*5701 allele [see Warnings and Precautions (5.1) ] . with prior hypersensitivity reaction to abacavir [see Warnings and Precautions (5.1) ]. with moderate or severe hepatic impairment [see Use in Specific Populations (8.6) ] . Presence of HLA-B*5701 allele. ( 4 ) Prior hypersensitivity reaction to abacavir. ( 4 ) Moderate or severe hepatic impairment. ( 4 )
Adverse Reactions
The following adverse reactions are discussed in other sections of the labeling: Serious and sometimes fatal hypersensitivity reactions [see Boxed Warning , Warnings and Precautions (5.1) ] . Lactic acidosis and severe hepatomegaly with steatosis [see Warnings and Precautions (5.2) ] . Immune reconstitution syndrome [see Warnings and Precautions (5.3) ] . Myocardial infarction [see Warnings and Precautions (5.4) ] . The most commonly reported adverse reactions of at least moderate intensity (incidence greater than or equal to 10%) in adult HIV-1 clinical trials were nausea, headache, malaise and fatigue, nausea and vomiting, and dreams/sleep disorders. (6.1) The most commonly reported adverse reactions of at least moderate intensity (incidence greater than or equal to 5%) in pediatric HIV-1 clinical trials were fever and/or chills, nausea and vomiting, skin rashes, and ear/nose/throat infections. (6.2) To report SUSPECTED ADVERSE REACTIONS, contact Rising Pharma Holdings, Inc. at 1-844-874-7464 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience in Adult Subjects Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Serious and Fatal Abacavir-Associated Hypersensitivity Reactions In clinical trials, serious and sometimes fatal hypersensitivity reactions have occurred with abacavir [see Boxed Warning , Warnings and Precautions (5.1) ]. These reactions have been 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 generalized malaise, fatigue, or achiness); (5) respiratory symptoms (including dyspnea, cough, or pharyngitis). Almost all abacavir hypersensitivity reactions include fever and/or rash as part of the syndrome. Other signs and symptoms have included lethargy, headache, myalgia, edema, arthralgia, and paresthesia. Anaphylaxis, liver failure, renal failure, hypotension, adult respiratory distress syndrome, respiratory failure, myolysis, and death have occurred in association with these hypersensitivity reactions. Physical findings have included lymphadenopathy, mucous membrane lesions (conjunctivitis and mouth ulcerations), and maculopapular or urticarial rash (although some patients had other types of rashes and others did not have a rash). There were reports of erythema multiforme. Laboratory abnormalities included elevated liver chemistries, elevated creatine phosphokinase, elevated creatinine, and lymphopenia, and abnormal chest x-ray findings (predominantly infiltrates, which were localized). Additional Adverse Reactions with Use of Abacavir Therapy-Naive Adults: Treatment-emergent clinical adverse reactions (rated by the investigator as moderate or severe) with a greater than or equal to 5% frequency during therapy with abacavir 300 mg twice daily, lamivudine 150 mg twice daily, and efavirenz 600 mg daily compared with zidovudine 300 mg twice daily, lamivudine 150 mg twice daily, and efavirenz 600 mg daily from CNA30024 are listed in Table 2. Table 2. Treatment-Emergent (All Causality) Adverse Reactions of at Least Moderate Intensity (Grades 2 to 4, Greater than or Equal to 5% Frequency) in Therapy-Naive Adults (CNA30024 a ) through 48 Weeks of Treatment Adverse Reaction Abacavir plus Lamivudine plus Efavirenz (n = 324) Zidovudine plus Lamivudine plus Efavirenz (n = 325) Dreams/sleep disorders Drug hypersensitivity Headaches/migraine Nausea Fatigue/malaise Diarrhea Rashes Abdominal pain/gastritis/gastrointestinal signs and symptoms Depressive disorders Dizziness Musculoskeletal pain Bronchitis Vomiting 10% 9% 7% 7% 7% 7% 6% 6% 6% 6% 6% 4% 2% 10% <1% b 11% 11% 10% 6% 12% 8% 6% 6% 5% 5% 9% a This trial used double-blind ascertainment of suspected hypersensitivity reactions. During the blinded portion of the trial, suspected hypersensitivity to abacavir was reported by investigators in 9% of 324 subjects in the abacavir group and 3% of 325 subjects in the zidovudine group. b Ten (3%) cases of suspected drug hypersensitivity were reclassified as not being due to abacavir following unblinding. Treatment-emergent clinical adverse reactions (rated by the investigator as moderate or severe) with a greater than or equal to 5% frequency during therapy with abacavir 300 mg twice daily, lamivudine 150 mg twice daily, and zidovudine 300 mg twice daily compared with indinavir 800 mg 3 times daily, lamivudine 150 mg twice daily, and zidovudine 300 mg twice daily from CNA3005 are listed in Table 3. Table 3. Treatment-Emergent (All Causality) Adverse Reactions of at Least Moderate Intensity (Grades 2 to 4, Greater than or Equal to 5% Frequency) in Therapy-Naive Adults (CNA3005) through 48 Weeks of Treatment Adverse Reaction Abacavir plus Lamivudine/Zidovudine (n = 262) Indinavir plus Lamivudine/Zidovudine (n = 264) Nausea Headache Malaise and fatigue Nausea and vomiting Hypersensitivity reaction Diarrhea Fever and/or chills Depressive disorders Musculoskeletal pain Skin rashes Ear/nose/throat infections Viral respiratory infections Anxiety Renal signs/symptoms Pain (non-site-specific) 19% 13% 12% 10% 8% 7% 6% 6% 5% 5% 5% 5% 5% <1% <1% 17% 9% 12% 10% 2% 5% 3% 4% 7% 4% 4% 5% 3% 5% 5% Five subjects receiving abacavir in CNA3005 experienced worsening of pre-existing depression compared with none in the indinavir arm. The background rates of pre-existing depression were similar in the 2 treatment arms. Abacavir Once Daily versus Abacavir Twice Daily (CNA30021): Treatment-emergent clinical adverse reactions (rated by the investigator as at least moderate) with a greater than or equal to 5% frequency during therapy with abacavir 600 mg once daily or abacavir 300 mg twice daily, both in combination with lamivudine 300 mg once daily and efavirenz 600 mg once daily from CNA30021, were similar. For hypersensitivity reactions, subjects receiving abacavir once daily showed a rate of 9% in comparison with a rate of 7% for subjects receiving abacavir twice daily. However, subjects receiving abacavir 600 mg once daily experienced a significantly higher incidence of severe drug hypersensitivity reactions and severe diarrhea compared with subjects who received abacavir 300 mg twice daily. Five percent (5%) of subjects receiving abacavir 600 mg once daily had severe drug hypersensitivity reactions compared with 2% of subjects receiving abacavir 300 mg twice daily. Two percent (2%) of subjects receiving abacavir 600 mg once daily had severe diarrhea while none of the subjects receiving abacavir 300 mg twice daily had this event. Laboratory Abnormalities: Laboratory abnormalities (Grades 3 to 4) in therapy-naive adults during therapy with abacavir 300 mg twice daily, lamivudine 150 mg twice daily, and efavirenz 600 mg daily compared with zidovudine 300 mg twice daily, lamivudine 150 mg twice daily, and efavirenz 600 mg daily from CNA30024 are listed in Table 4. Table 4. Laboratory Abnormalities (Grades 3 to 4) in Therapy-Naive Adults (CNA30024) through 48 Weeks of Treatment Grade 3/4 Laboratory Abnormalities Abacavir plus Lamivudine plus Efavirenz (n = 324) Zidovudine plus Lamivudine plus Efavirenz (n = 325) Elevated CPK (>4 X ULN) Elevated ALT (>5 X ULN) Elevated AST (>5 X ULN) Hypertriglyceridemia (>750 mg/dL) Hyperamylasemia (>2 X ULN) Neutropenia (ANC <750/mm 3 ) Anemia (Hgb ≤6.9 gm/dL) Thrombocytopenia (Platelets <50,000/mm 3 ) Leukopenia (WBC ≤1,500/mm 3 ) 8% 6% 6% 6% 4% 2% <1% 1% <1% 8% 6% 5% 5% 5% 4% 2% <1% 2% ULN = Upper limit of normal. n = Number of subjects assessed. Laboratory abnormalities in CNA3005 are listed in Table 5. Table 5. Treatment-Emergent Laboratory Abnormalities (Grades 3 to 4) in CNA3005 Grade 3/4 Laboratory Abnormalities Abacavir plus Lamivudine/Zidovudine (n = 262) Indinavir plus Lamivudine/Zidovudine (n = 264) Elevated CPK (>4 x ULN) ALT (>5 x ULN) Neutropenia (<750/mm 3 ) Hypertriglyceridemia (>750 mg/dL) Hyperamylasemia (>2 x ULN) Hyperglycemia (>13.9 mmol/L) Anemia (Hgb ≤6.9 g/dL) 18 (7%) 16 (6%) 13 (5%) 5 (2%) 5 (2%) 2 (<1%) 0 (0%) 18 (7%) 16 (6%) 13 (5%) 3 (1%) 1 (<1%) 2 (<1%) 3 (1%) ULN = Upper limit of normal. n = Number of subjects assessed. The frequencies of treatment-emergent laboratory abnormalities were comparable between treatment groups in CNA30021. 6.2 Clinical Trials Experience in Pediatric Subjects Therapy-Experienced Pediatric Subjects (Twice-Daily Dosing) Treatment-emergent clinical adverse reactions (rated by the investigator as moderate or severe) with a greater than or equal to 5% frequency during therapy with abacavir 8 mg per kg twice daily, lamivudine 4 mg per kg twice daily, and zidovudine 180 mg per m 2 twice daily compared with lamivudine 4 mg per kg twice daily and zidovudine 180 mg per m 2 twice daily from CNA3006 are listed in Table 6. Table 6. Treatment-Emergent (All Causality) Adverse Reactions of at Least Moderate Intensity (Grades 2 to 4, Greater than or Equal to 5% Frequency) in Therapy-Experienced Pediatric Subjects (CNA3006) through 16 Weeks of Treatment Adverse Reaction Abacavir plus Lamivudine plus Zidovudine (n = 102) Lamivudine plus Zidovudine (n = 103) Fever and/or chills Nausea and vomiting Skin rashes Ear/nose/throat infections Pneumonia Headache 9% 9% 7% 5% 4% 1% 7% 2% 1% 1% 5% 5% Laboratory Abnormalities: In CNA3006, laboratory abnormalities (anemia, neutropenia, liver function test abnormalities, and CPK elevations) were observed with similar frequencies as in a trial of therapy-naive adults (CNA30024). Mild elevations of blood glucose were more frequent in pediatric subjects receiving abacavir (CNA3006) as compared with adult subjects (CNA30024). Other Adverse Events In addition to adverse reactions and laboratory abnormalities reported in Tables 2, 3, 4, 5, and 6, other adverse reactions observed in the expanded access program were pancreatitis and increased GGT. Pediatric Subjects Once-Daily versus Twice-Daily Dosing (COL105677): The safety of once-daily compared with twice-daily dosing of abacavir was assessed in the ARROW trial. Primary safety assessment in the ARROW trial was based on Grade 3 and Grade 4 adverse events. The frequency of Grade 3 and 4 adverse events was similar among subjects randomized to once-daily dosing compared with subjects randomized to twice-daily dosing. One event of Grade 4 hepatitis in the once-daily cohort was considered as uncertain causality by the investigator and all other Grade 3 or 4 adverse events were considered not related by the investigator. 6.3 Postmarketing Experience The following adverse reactions have been identified during postmarketing use of abacavir. Because these reactions are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposures. Body as a Whole Redistribution/accumulation of body fat. Cardiovascular Myocardial infarction. Hepatic Lactic acidosis and hepatic 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 medications known to be associated with SJS and TEN, respectively. Because of the overlap of clinical signs and symptoms between hypersensitivity to abacavir and SJS and TEN, and the possibility of multiple drug sensitivities in some patients, abacavir should be discontinued and not restarted in such cases. There have also been reports of erythema multiforme with abacavir use [see Adverse Reactions (6.1) ].
Drug Interactions
Methadone: An increased methadone dose may be required in a small number of patients. ( 7.1 ) Riociguat: The riociguat dose may need to be reduced. ( 7.2 ) 7.1 Methadone In a trial of 11 HIV-1-infected subjects receiving methadone-maintenance therapy with 600 mg of abacavir twice daily (twice the currently recommended dose), oral methadone clearance increased [see Clinical Pharmacology (12.3) ] . 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. 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. See full prescribing information for ADEMPAS (riociguat).
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