General Administration Information
For storage information, see the specific product information within the How Supplied section.
-May be administered without regard to meals.
Oral Liquid Formulations
-The oral solution may turn brown over time.
The safety profile of once-daily abacavir dosing has been shown to be comparable to that of twice-daily dosing. In a randomized multicenter trial (ARROW), the frequency of Grade 3 and 4 adverse events was similar in patients who received once-daily dosing compared with patients who received twice-daily dosing.
In addition to gastrointestinal (GI) symptoms associated with abacavir hypersensitivity, nausea and vomiting were reported in 9% of pediatric patients. Other GI adverse events experienced during adult clinical trials include diarrhea (7%, severe 2%), abdominal pain (6%), and gastritis (6%). GI adverse reactions reported during the expanded access program include pancreatitis and increased gamma-glutamyl transpeptidase (GGT).
Lactic acidosis and severe hepatotoxicity (i.e., fatal cases of hepatomegaly with steatosis) have been reported with the use of nucleoside analogs, including abacavir, when used alone or in combination. A majority of these cases have been in adult women; it is not clear if this increased risk translates over to the pediatric population. Obesity and prolonged nucleoside exposure may be risk factors. 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).
While more commonly associated with protease inhibitor therapy, a lipodystrophy syndrome, consisting of redistribution/accumulation of body fat, has been reported in patients receiving long-term highly active antiretroviral therapy (HAART) that includes abacavir.
In addition to hypersensitivity-associated dermatologic reactions, rash (unspecified) was observed in 7% of pediatric patients during clinical trials. Suspected cases of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) were reported during the post-marketing period in patients receiving abacavir primarily in combination with medications known to be associated with SJS or 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 post-marketing use.
Laboratory abnormalities have been reported during clinical trials with abacavir, although the reported rates were similar between abacavir and comparator groups. With the exception of increased incidence in hyperglycemic episodes, laboratory abnormalities observed in pediatric patients were similar to those observed in adults. Reported Grade 3/4 laboratory abnormalities in adults included: elevated creatine phosphokinase (> 4x upper limit of normal [ULN], 7-8%); elevated hepatic enzymes (ALT and AST > 5x ULN, 6%); neutropenia (ANC < 750/mm3, 2-5%); hypertriglyceridemia (> 750 mg/dL, 2-6%); hyperamylasemia (> 2x ULN, 2-4%); hyperglycemia (> 13.9 mmol/L, < 1%); thrombocytopenia (platelets < 50,000/mm3, 1%); leukopenia (WBC <= 1500/mm3, < 1%); and anemia (Hgb <= 6.9 g/dL, < 1%).
Neurologic adverse events were reported by patients receiving treatment with abacavir during clinical trials. These events were distinct from neurologic symptoms associated with abacavir hypersensitivity. Headache was reported in 1% of pediatric patients during clinical trials. Other adverse events reported in adult trials include abnormal dreams or nightmares (10%), insomnia (10%), headache or migraine (7-13%), fatigue (7-12%), malaise (7-12%), depression (6%), dizziness (6%), and anxiety (5%). In one trial, 5 abacavir-treated patients (1.9%) experienced worsening of pre-existing depression compared with none in the comparator arm; the background rates for pre-existing depression was similar in both treatment arms.
Cases of infection were reported by 4-5% of abacavir recipients during clinical trials. Specific infection types/sites reported in pediatric patients included pneumonia (4%) and infections of the ears, nose, and throat (5%). Fever and/or chills was also reported in 9% of pediatric patients. Of note, fever and chills are also symptoms associated with abacavir hypersensitivity and, thus, should be evaluated closely.
Musculoskeletal pain and generalized pain were reported in 5-6% and < 1%, respectively, of abacavir recipients during adult clinical trials.
Abacavir treatment was linked with the development of myocardial infarction (MI) in several prospective, observational, epidemiologic trials. In contrast to these observational trials, a sponsor-conducted, pooled analysis of clinical trials showed no excess risk of MI in abacavir-treated subjects as compared with control subjects. Furthermore, a meta-analysis of 26 randomized clinical trials conducted by the FDA failed to reveal an association between treatment with abacavir-containing regimens and development of MI (OR = 1.02; 95% CI 0.56 to 1.84). In light of the conflicting data, caution is advised when prescribing abacavir to patients with pre-existing coronary heart disease. Further, health care providers are encouraged to minimize a patient's modifiable risk factors (e.g., hypertension, hyperlipidemia, diabetes mellitus, and smoking) prior to prescribing.
Serious hypersensitivity reactions or anaphylaxis, including fatal reactions, have occurred in patients receiving abacavir. In clinical trials, the incidence of hypersensitivity reactions to abacavir was 8% when HLA-B*5701 screening was not performed; the incidence was 1% when HLA-B*5701-positive patients were excluded. The most common symptoms are fever and rash; rash occurred commonly as the initial symptom. Other observed signs and symptoms of hypersensitivity include chills, fatigue, headache, malaise, abdominal pain, diarrhea, nausea, vomiting, pharyngitis, dyspnea, cough, arthralgia, edema, hypotension, lethargy, rhabdomyolysis, myalgia, and paresthesias. Physical findings include lymphadenopathy, mucous membrane lesions (conjunctivitis and oral ulceration), and rash. The rash, if present, usually appears as a maculopapular rash or urticarial rash (urticaria). There have been reports of erythema multiforme, but the rash may be variable in appearance. Laboratory findings include elevated hepatic enzymes, increased creatine phosphokinase, increased creatinine/BUN (azotemia), and lymphopenia; radiologic findings may include abnormal chest x-rays (predominantly infiltrates, which can be localized). Deaths have been reported in patients receiving abacavir who were initially diagnosed with an acute respiratory disease (pneumonia, bronchitis, or flu-like illness) who were later recognized to have had a hypersensitivity reaction to abacavir that included respiratory symptoms. A delay in diagnosis of abacavir hypersensitivity can result in abacavir being continued or reintroduced, leading to more severe hypersensitivity reactions including life-threatening hypotension, acute respiratory distress syndrome (ARDS), respiratory arrest, anaphylactoid reactions, hepatic failure, renal failure (unspecified), and death. Symptoms usually appear within the first 6 weeks of treatment, although these reactions can occur at any time during therapy. Hypersensitivity reactions have been reported upon reintroduction of abacavir therapy that has been discontinued for other medical reasons. In a minority of patients, hypersensitivity has occurred days or weeks after reintroduction of abacavir treatment. Symptoms worsen with continued therapy but often resolve upon discontinuation of the drug. In clinical trials comparing once daily to twice daily abacavir treatment regimens, patients taking the once daily regimen experienced a significantly higher incidence of severe drug hypersensitivity reactions (5% vs. 2%, respectively). Patients developing signs or symptoms of hypersensitivity should discontinue use of abacavir as soon as a hypersensitivity reaction is suspected. In patients presenting with symptoms of acute respiratory disease and other symptoms associated with hypersensitivity to abacavir, a hypersensitivity reaction should be suspected even if alternative respiratory diagnoses (i.e., pneumonia, bronchitis, pharyngitis, or flu-like illness) are possible. If the clinical presentation of an acute illness cannot be clearly differentiated from a hypersensitivity reaction, abacavir should be permanently discontinued. Patients should never be restarted on any abacavir-containing product (i.e., Ziagen, Epzicom, Trizivir) after a hypersensitivity reaction because more severe symptoms will recur within hours of administration and may include life-threatening hypotension and death. To facilitate reporting of hypersensitivity reactions and collection of information on each case, health care professionals should report all hypersensitivity reactions to the FDA MedWatch program at (800) FDA-1088.
Unplanned antiretroviral therapy interruption may be necessary in specific situations, such as serious drug toxicity, intercurrent illness or surgery precluding oral intake (e.g., gastroenteritis or pancreatitis), or drug non-availability. If short-term treatment interruption is necessary (i.e., less than 1 to 2 days), in general, it is recommended that all antiretroviral agents be discontinued simultaneously, especially if the interruption is because of serious toxicity. However, if a short-term treatment interruption is anticipated in the case of elective surgery, the pharmacokinetic properties and food requirements of specific drugs should be considered. When the antiretroviral regimen contains drugs with differing half-lives, stopping all drugs simultaneously may result in functional monotherapy of the drug with the longest half-life. For example, after discontinuation, the duration of detectable drug concentrations of efavirenz and nevirapine ranges from < 1 week to > 3 weeks. Simultaneously stopping all drugs in a regimen containing these agents may result in functional monotherapy with the NNRTI and may increase the risk of NNRTI-resistant mutations. Planned long-term treatment interruptions are not recommended due to the potential for HIV disease progression (i.e., declining CD4 counts, viral rebound, acute viral syndrome), development of minor HIV-associated manifestations or serious non-AIDS complications, development of drug resistance, increased risk of HIV transmission, and increased risk for opportunistic infections. If therapy must be discontinued, counsel patient on the potential risks and closely monitor for any clinical or laboratory abnormalities.
Abacavir has been associated with serious hypersensitivity reactions or anaphylaxis (some cases have been fatal); to reduce the risk, perform HLA-B*5701 testing before initiating treatment in all patients. Abacavir is contraindicated in all HLA-B*5701-positive patients; clearly record the positive status as an abacavir allergy in the patient's medical record. According to the manufacturer, the incidence of hypersensitivity reactions to abacavir was 8% when HLA-B*5701 screening was not performed; the incidence was 1% when HLA-B*5701-positive patients were excluded. Racial background may help identify those at higher risk for carrying the HLA-B*5701 gene, as in the United States approximately 8% of Caucasian patients, 2.5% of Black patients, and 1% of Asian patients are carriers. Regardless of HLA-B*5701 status, immediately discontinue treatment in patients developing or with suspected signs or symptoms of abacavir hypersensitivity, including those presenting with 2 or more of the following: fever, rash, gastrointestinal (e.g., nausea, vomiting, diarrhea, abdominal pain), constitutional (generalized malaise, fatigue, achiness), or respiratory (dyspnea, cough, pharyngitis). Permanently discontinue abacavir if the clinical presentation of an acute illness cannot be clearly differentiated from a hypersensitivity reaction. NEVER reinitiate an abacavir-containing product in a patient who experiences a hypersensitivity reaction as more severe symptoms will recur within hours of administration and may include life-threatening hypotension and death. Severe or fatal hypersensitivity reactions may also occur within hours after abacavir reintroduction in patients without an identified history of hypersensitivity but abruptly discontinued abacavir for reasons unrelated to symptoms of hypersensitivity (e.g., interruption in drug supply or drug discontinuation while treating other medical conditions). In some cases, symptoms consistent with hypersensitivity may have been present before abacavir was discontinued, but may have been attributed to other medical conditions (e.g., acute onset respiratory diseases, gastroenteritis, or reactions to other medications). In a minority of cases, hypersensitivity reactions occurred days to weeks after abacavir reintroduction. If abacavir has been discontinued for reasons other than symptoms of hypersensitivity and if reinitiation is being considered, re-evaluate the reason for discontinuation and ensure that the patient did not have any suspected symptoms of hypersensitivity. If hypersensitivity symptoms are suspected upon review, do not reinitiate abacavir. If symptoms consistent with hypersensitivity are not identified and the patient is HLA-B*5701-negative, undertake reintroduction with caution. If HLA-B*5701 status is unknown, screening should occur prior to restarting therapy. Health care professionals should report all hypersensitivity reactions to the FDA MedWatch program (800-FDA-1088).
Conflicting data have been published regarding the potential for increased risk of myocardial infarction (MI) in persons receiving treatment with abacavir-containing regimens. As a precaution, the FDA-approved product labeling for abacavir recommends considering the underlying risk of cardiac disease and taking action to minimize all modifiable risk factors (e.g., hypertension, hyperlipidemia, diabetes mellitus, and smoking) when prescribing antiretroviral therapies, including abacavir. The HIV guidelines recommend consideration be given to avoiding use of abacavir-containing regimens in patients with known high cardiovascular risk. Several prospective, observational, epidemiological studies have reported an association with the use of abacavir and the risk of MI. Patients in these studies who started abacavir for the first time had worse initial cardiovascular risk profiles than observed with the other nucleoside reverse transcriptase inhibitor (NRTI) agents; therefore, it cannot be ruled out that some of these results could be the result of channeling bias. The authors of these studies speculate that the underlying mechanism for increased risk of cardiovascular disease may be due to an increased propensity for subclinical atherosclerosis to manifest itself clinically as a consequence of the pro-inflammatory potential of abacavir; however, a biological mechanism to explain the potential increase in risk has not been definitely established. In contrast to the observational trials, a sponsor-conducted, pooled analysis of clinical trials showed no excess risk of MI in abacavir-treated subjects as compared with control subjects. Furthermore, a meta-analysis of 26 randomized clinical trials conducted by the FDA failed to reveal an association between treatment with abacavir-containing regimens and development of MI (OR = 1.02; 95% CI 0.56 to 1.84).
Abacavir is contraindicated in patients with moderate (Child-Pugh Class B) or severe (Child-Pugh Class C) hepatic disease. A dose reduction of abacavir is required in patients with mild hepatic impairment. Use abacavir with caution in those with known risk factors for hepatic disease (e.g., alcoholism). Hepatotoxicity or lactic acidosis, including fatal cases, has been reported with the use of nucleoside analogs, including abacavir. Adult females appear to be at a higher risk for lactic acidosis; it is not clear whether this increased risk also applies to pediatric females. In addition, obesity may be a risk factor for nucleoside analog-induced lactic acidosis and hepatotoxicity. Discontinue treatment 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 increases in transaminases.
Testing for human immunodeficiency virus (HIV) infection resistance is recommended in all antiretroviral treatment-naive patients at the time of HIV diagnosis, regardless of whether treatment will be initiated. Additionally, perform resistance testing prior to initiating or changing any HIV treatment regimen. Transmission of drug-resistant HIV strains has been both well documented and associated with suboptimal virologic response to initial antiretroviral therapy. Therefore, resistance testing at baseline can help optimize treatment and, thus, virologic response. In the absence of therapy, resistant viruses may decline over time to less than the detection limit of standard resistance tests, but may still increase the risk of treatment failure when therapy is eventually initiated. Thus, if therapy is deferred, resistance testing should still be performed during acute HIV infection with the genotypic resistance test results kept in the patient's medical record until they become clinically useful. Additionally, because of the possibility of acquisition of another drug-resistant virus before treatment initiation, repeat resistance testing at the time therapy is initiated would be prudent. Patients with prolonged prior nucleoside reverse transcriptase inhibitor (NRTI) exposure or who have HIV-1 isolates that contain multiple mutations conferring resistance to other NRTIs have limited response to abacavir. The potential for cross-resistance between abacavir and other NRTIs should be considered when choosing new therapeutic regimens in previously treated patients. Abacavir should not be added as a single agent when antiretroviral regimens are changed due to loss of virologic response.
Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy. During the initial phase of HIV treatment, patients whose immune system responds to abacavir therapy may develop an inflammatory response to indolent or residual opportunistic infections (such as mycobacterium avium complex (MAC), cytomegalovirus (CMV), Pneumocystis carinii pneumonia (PCP), or tuberculosis (TB)), which may necessitate further evaluation and treatment. In addition, autoimmune disease (including Graves' disease, Guillain-Barre syndrome, and polymyositis) may also develop; the time to onset is variable and may occur months after treatment initiation.
Perform hepatitis B virus (HBV) screening in any patient who presents with HIV-infection to assure appropriate treatment. Patients with hepatitis B and HIV coinfection who require treatment for either infection should be started on a fully suppressive antiretroviral regimen that contains NRTIs with activity against both viruses. Avoid using single-drug therapy to treat HBV (i.e., lamivudine, emtricitabine, or tenofovir as the only active agent) due to the risk of developing resistant strains of HIV. The HIV guidelines recommend that coinfected pediatric patients 2 years and older receive an antiretroviral regimen that contains tenofovir in combination with either lamivudine or emtricitabine as the dual NRTI backbone. If tenofovir cannot be used, another agent with anti-HBV activity should be used in combination with lamivudine or emtricitabine to assure adequate treatment of HBV infection. Management of HIV should be continued with the goal of maximal suppression.
Perform hepatitis C virus (HCV) screening in any child whose mother is known to have HCV infection and all HIV-infected adolescents. Treatment of HCV infection in children younger than 3 years is not usually recommended; however, treatment should be considered for all children 3 years and older and adolescents with hepatitis C and HIV coinfection who have no contraindications to treatment. For antiretroviral-naive adolescent patients with CD4 counts greater than 500 cells/mm3, consideration may be given to deferring ARV therapy until the hepatitis C treatment regimen has been completed. Conversely, for adolescent patients with CD4 counts less than 200 cells/mm3, consider delaying initiation of the hepatitis C treatment regimen until the patient is stable on a fully suppressive ARV regimen. All HIV-infected children and adolescents, regardless of HIV and HCV status, should receive standard vaccination with hepatitis A and B vaccines. Additionally, HIV/HCV-coinfected adolescents should be counseled to avoid alcohol.
Description: Abacavir is an oral, synthetic guanosine nucleoside reverse transcriptase inhibitor (NRTI). When used as part of a recommended combination treatment regimen, abacavir is a potent NRTI. Abacavir is associated with a hypersensitivity reaction that occurs in approximately 5-10% of patients. This hypersensitivity reaction, characterized by fever, skin rash, fatigue, gastrointestinal symptoms, and, sometimes, respiratory symptoms, can be life-threatening; when a hypersensitivity reaction cannot be ruled out, abacavir treatment is permanently discontinued and rechallenge is contraindicated. Abacavir is FDA-approved in pediatric patients as young as 3 months.
NOTE: Screen patients for the HLA-B*5701 allele before initiating an abacavir-containing regimen to assess the risk of hypersensitivity reaction. HLA-B*5701-positive patients should not be prescribed abacavir.
NOTE: The HIV guidelines recommend consideration be given to avoiding use of abacavir-containing regimens in patients at high risk for cardiovascular adverse events. Although a definitive correlation has not been established, recent (within 6 months) or current use of abacavir has been associated with an increased risk of myocardial infarction.
Initiation of HIV therapy
-Antiretroviral drug resistance testing (preferably genotypic testing) is recommended prior to initiation of therapy in antiretroviral treatment-naive patients and prior to changing therapy for treatment failure.
-Infants and Children-Initiation of treatment immediately (or as soon as possible) after HIV diagnosis is recommended in all pediatric patients. The urgency of rapid treatment initiation is especially critical for all children younger than 1 year, who carry the highest risk of rapid disease progression and mortality. If therapy is deferred for certain circumstances, closely monitor the child's virologic, immunologic, and clinical status at least every 3 to 4 months. If therapy is deferred, treatment should be initiated when HIV RNA concentrations increase, CD4 count or percentage values decline (i.e., approaching CDC Stage 2 or 3), the child develops new HIV-related clinical symptoms, or the ability of the caregiver and child to adhere to the prescribed regimen has improved.
-Adolescents-Initiation of treatment immediately (or as soon as possible) after HIV diagnosis is recommended in all patients to reduce the risk of disease progression and to prevent the transmission of HIV. Starting antiretroviral therapy early is particularly important for patients with AIDS-defining conditions and those with acute or recent HIV infection; delaying therapy in these subpopulations has been associated with high risks of morbidity, mortality, and HIV transmission.
Place in therapy for HIV
-For treatment-naive children and adolescents 3 months and older, abacavir is one of the preferred nucleoside reverse transcriptase inhibitors (NRTIs) to be included as a part of a 2-NRTI backbone regimen. The 2-NRTI backbone should be used in combination with a non-nucleoside reverse transcriptase inhibitor (NNRTI), protease inhibitor (PI), or integrase strand transfer inhibitor (INSTI). Specific recommendations vary depending on age.
Per the manufacturer, this drug has been shown to be active against most strains of the following microorganisms either in vitro and/or in clinical infections: human immunodeficiency virus (HIV)
NOTE: The safety and effectiveness in treating clinical infections due to organisms with in vitro data only have not been established in adequate and well-controlled clinical trials.
For the treatment of human immunodeficiency virus (HIV) infection in combination with other antiretroviral agents:
Oral dosage (oral solution):
Infants and Children 3 months to 2 years: 8 mg/kg/dose PO twice daily or 16 mg/kg/dose PO once daily. Data regarding the efficacy of once-daily dosing are limited to patients who transitioned from twice-daily dosing to once-daily dosing after 36 weeks of treatment. The HIV guidelines recommend that infants and young children should be initiated with twice-daily dosing of the oral solution. A switch to once-daily dosing may be considered for clinically stable patients with undetectable viral loads and stable CD4 counts.
Children 3 to 12 years: 8 mg/kg/dose PO twice daily or 16 mg/kg/dose PO once daily (Max: 600 mg/day). Data regarding the efficacy of once-daily dosing are limited to patients who transitioned from twice-daily dosing to once-daily dosing after 36 weeks of treatment.
Adolescents: 300 mg PO twice daily or 600 mg PO once daily.
Oral dosage (tablets):
Children weighing 14 to 19 kg: 150 mg PO twice daily or 300 mg PO once daily. Data regarding the efficacy of once-daily dosing are limited to patients who transitioned from twice-daily dosing to once-daily dosing after 36 weeks of treatment. The HIV guidelines state that therapy can be initiated with once-daily dosing in those able to take pill formulations. However, if therapy was initiated with twice-daily abacavir solution, twice-daily dosing should be used with consideration to switching to once-daily dosing in clinically stable patients with undetectable viral loads and stable CD4 counts.
Children weighing 20 to 24 kg: 150 mg PO once daily in the morning and 300 mg PO once daily in the evening or 450 mg PO once daily. Data regarding the efficacy of once-daily dosing are limited to patients who transitioned from twice-daily dosing to once-daily dosing after 36 weeks of treatment. The HIV guidelines state that therapy can be initiated with once-daily dosing in those able to take pill formulations. However, if therapy was initiated with twice-daily abacavir solution, twice-daily dosing should be used with consideration to switching to once-daily dosing in clinically stable patients with undetectable viral loads and stable CD4 counts.
Children and Adolescents weighing 25 kg or more: 300 mg PO twice daily or 600 mg PO once daily. Data regarding the efficacy of once-daily dosing are limited to patients who transitioned from twice-daily dosing to once-daily dosing after 36 weeks of treatment. The HIV guidelines state that therapy can be initiated with once-daily dosing in those able to take pill formulations. However, if therapy was initiated with twice-daily abacavir solution, twice-daily dosing should be used with consideration to switching to once-daily dosing in clinically stable patients with undetectable viral loads and stable CD4 counts.
Maximum Dosage Limits:
Safety and efficacy have not been established.
< 3 months: Safety and efficacy have not been established.
>= 3 months: 16 mg/kg/day PO is FDA-approved maximum dosage; however, doses up to 20 mg/kg/dose PO once daily are recommended in HIV guidelines as part of a once-daily regimen for stable patients.
16 mg/kg/day PO (Max: 600 mg/day) is FDA-approved maximum dosage; however, doses up to 20 mg/kg/dose PO once daily (Max: 600 mg/day) are recommended in HIV guidelines as part of a once-daily regimen for stable patients.
16 mg/kg/day PO (Max: 600 mg/day) is FDA-approved maximum dosage; however, doses up to 20 mg/kg/dose PO once daily (Max: 600 mg/day) are recommended in HIV guidelines as part of a once-daily regimen for stable patients.
Patients with Hepatic Impairment Dosing
No dosage adjustment guidelines are available for pediatric patients with hepatic impairment.
In adult patients with mild hepatic impairment (Child-Pugh A, score 5 to 6), the recommended dose is 200 mg PO twice daily; abacavir oral solution (10 mL PO twice daily) can be used to enable this dose reduction. Abacavir is contraindicated in patients with moderate to severe hepatic impairment (Child-Pugh B or C, score 6 or greater), as safety, efficacy, and pharmacokinetic parameters have not yet been established.
Patients with Renal Impairment Dosing
Dosing in patients with renal impairment has not been studied. Renal excretion of unchanged abacavir is a minor route of elimination in humans.
It is not known if abacavir is removed by hemodialysis.
It is not known if abacavir is removed by peritoneal dialysis.
Monograph content under development
Mechanism of Action: Abacavir inhibits viral reverse transcriptase. Intracellularly, abacavir is converted by cellular enzymes to the active metabolite carbovir triphosphate. Carbovir triphosphate is an analog of deoxyguanosine-5'-triphosphate (dGTP). Carbovir triphosphate inhibits the activity of HIV-1 reverse transcriptase (RT) both by competing with the natural substrate dGTP and by its incorporation into viral DNA. The lack of a 3'-hydroxyl group in the incorporated nucleoside analog prevents the formation of the 5' to 3' phosphodiester linkage essential for DNA chain elongation, and therefore, the viral DNA growth is inhibited.
Abacavir hypersensitivity may be related to an induced autoimmunity process related to HLA-B*5701. Human Leukocyte Antigens (HLAs) help the body to distinguish "self" versus "foreign" proteins (peptides). A study determined that abacavir alters the quantity and quality of self-peptide loading into HLA-B*5701. These self-peptides are then presented for the first time and because the body has not previously recognized them, it mistakenly treats them as foreign, resulting in a polyclonal T-cell autoimmune response and multi-organ systemic toxicity. Once the drug is discontinued, reactive T-cells would be reduced and then differentiate into T memory cells. Re-exposure would again generate these peptides leading to a rapid expansion of T memory cells which could cause severe and potentially life-threatening reactions.
Pharmacokinetics: Abacavir is administered orally. Once in the systemic circulation, it distributes into extravascular space. Protein binding is approximately 50% and is independent of concentration. Based on radiolabeled studies, the drug readily distributes into erythrocytes. The primary routes of elimination are metabolism by alcohol dehydrogenase (to form the 5'-carboxylic acid) and glucuronyl transferase (to form the 5'glucuronide). The metabolites have no antiviral activity. Elimination was quantified in a mass balance study following administration of a 600-mg dose of (14)C-abacavir: 83% of the radioactivity was recovered in urine, 1.2% as unchanged drug, 30% as the 5'-carboxylic acid metabolite, 36% as the 5'-glucuronide metabolite, and 15% as unidentified minor metabolites. Fecal elimination accounted for 16% of the dose.
Affected cytochrome P450 isoenzymes and drug transporters: CYP1A1, CYP3A4
Data from in vitro studies show abacavir has the potential to inhibit CYP1A1 and the limited potential to inhibit CYP3A4. Other CYP isoenzymes (e.g., CYP2C9 and CYP2D6) are not inhibited or induced by abacavir. Similarly, abacavir at therapeutic drug exposures is not expected to affect the pharmacokinetics of substrates of the following drug transporters: organic anion transporter polypeptide (OATP)1B1/3, breast cancer resistance protein (BCRP), P-glycoprotein (P-gp), organic cation transporter (OCT)1, OCT2, or multidrug and toxic extrusion protein (MATE)1 and MATE2-K.
Following oral administration, abacavir is rapidly and extensively absorbed. Bioavailability is about 83% for the tablets. Systemic exposure was comparable after administration of the solution, therefore, the solution and the tablets may be used interchangeably. There is no significant difference in systemic exposure during fed or fasted states.
Infants 3 months and older, Children, and Adolescents
Pharmacokinetic parameters of abacavir, after single or repeated doses, have been studied in 169 pediatric patients. Pediatric patients receiving the oral solution according to the recommended dosage regimen attained plasma concentrations similar to those seen in adults. Higher plasma concentrations were observed in patients receiving the tablet formulation compared with those receiving the oral solution. Clearance is faster in children and slows down in adolescents and young adults to approximately the clearance noted in adults. Studies in pediatric patients with clinically stable HIV have shown that once-daily dosing provides comparable exposure as twice-daily dosing for both the oral solution and tablet formulations. The mean Cmax was approximately 1.6- to 2.3-fold higher with abacavir once-daily dosing compared with twice-daily dosing.
Patients with mild hepatic impairment (Child Pugh score 5 to 6) show a mean increase in abacavir half-life and AUC of 58% and 89%, respectively, following a single oral dose of 600 mg. A reduced dose is recommended in patients with mild hepatic impairment. Pharmacokinetic parameters have not been assessed in patients with moderate or severe hepatic impairment, and use in these patients is contraindicated.
Pharmacokinetic parameters of abacavir have not been studied in patients with renal impairment; however, minimal parent drug is excreted in the urine.