Abacavir is an oral, synthetic guanosine nucleoside reverse transcriptase inhibitor (NRTI), indicated for use in combination with other antiretroviral medications to treat HIV. Abacavir is associated with a hypersensitivity reaction that occurs in approximately 5% to 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.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Hazardous Drugs Classification
-NIOSH 2016 List: Group 2
-NIOSH (Draft) 2020 List: Table 2
-Observe and exercise appropriate precautions for handling, preparation, administration, and disposal of hazardous drugs.
-Use gloves to handle. Cutting, crushing, or otherwise manipulating tablets/capsules will increase exposure and require additional protective equipment. Oral liquid drugs require double chemotherapy gloves and protective gown; may require eye/face protection.
Route-Specific Administration
Oral Administration
-May be administered without regard to meals.
Oral Liquid Formulations
-The oral solution may turn brown over time.
In addition to gastrointestinal (GI) symptoms associated with abacavir hypersensitivity, GI adverse events experienced during clinical trials include nausea (7% to 19%), vomiting (2% to 10%), 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 women. 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 was observed in 5% to 7% of patients during clinical trials. Suspected cases of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) were reported during the postmarketing 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 postmarketing use. Due to the voluntary nature of postmarketing reports, neither a frequency nor a definitive causal relationship can be established.
Laboratory abnormalities have been reported during clinical trials with abacavir, although the reported rates were similar between abacavir and comparator groups. Reported Grade 3 and 4 laboratory abnormalities included: elevated creatine phosphokinase (greater than 4-times upper limit of normal [ULN], 7% to 8%); elevated hepatic enzymes (ALT and AST greater than 5-times ULN, 6%); neutropenia (ANC less than 750/mm3, 2% to 5%); hypertriglyceridemia (greater than 750 mg/dL, 2% to 6%); hyperamylasemia (greater than 2-times ULN, 2% to 4%); hyperglycemia (greater than 13.9 mmol/L, less than 1%); thrombocytopenia (platelets less than 50,000/mm3, 1%); leukopenia (WBC 1,500/mm3 or less, less than 1%); and anemia (Hgb 6.9 g/dL or less, less than 1%). Except for increased incidence in hyperglycemic episodes, laboratory abnormalities observed in pediatric patients were similar to those observed in adults.
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 and included abnormal dreams or nightmares (10%), insomnia (10%), headache or migraine (1% to 13%), fatigue (7% to 12%), malaise (7% to 12%), depression (6%), dizziness (6%), and anxiety (5%). In 1 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% to 5% of abacavir recipients during clinical trials. Specific infection types or sites included viral respiratory infections (5%), pneumonia (4%), and infections of the ears, nose, and throat (5%). Symptoms potentially associated with an infection include bronchitis (4%), fever (6% to 9%), and chills (6% to 9%). 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% to 6% and less than 1%, respectively, of abacavir recipients during 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. 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. Healthcare 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 (65%) and rash (61%), and 98% of cases included either fever or rash or both; rash did occur commonly as the initial symptom. Other commonly observed signs and symptoms of hypersensitivity include chills (33%), fatigue (17%), headache (40%), malaise (60%), gastrointestinal symptoms (50%) such as abdominal pain (25%), diarrhea (32%), or nausea/vomiting (48%/31%), and respiratory symptoms including pharyngitis (12%), dyspnea (25%), or cough (22%). Respiratory symptoms occur in approximately 20% of patients with abacavir hypersensitivity reactions. Other signs and symptoms include arthralgia (24%), edema, hypotension (11%), lethargy, rhabdomyolysis, myalgia (34%), 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) and 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 may 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 following 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.
During baseline evaluation of people with HIV, discuss risk reduction measures and the need for status disclosure to sexual or needle-sharing partners, especially with untreated patients who are still at high risk of HIV transmission. Include the importance of adherence to therapy to achieve and maintain a plasma HIV RNA less than 200 copies/mL. Maintaining a plasma HIV RNA less than 200 copies/mL, including any measurable value below this threshold, with antiretroviral therapy prevents sexual transmission of HIV to their partners. Patients may recognize this concept as Undetectable = Untransmittable or U=U. Instruct patients to achieve sustained viral suppression (i.e., 2 recorded measurements of plasma viral loads that are below the limits of detection and taken at least 3 months apart) before attempting to conceive a child in order to maximize their health, prevent HIV sexual transmission, and minimize the risk of HIV transmission to the infant once conception occurs. For partners with different HIV status when the person with HIV is on antiretroviral therapy and has achieved sustained viral suppression, sexual intercourse without a condom allows conception without sexual HIV transmission to the person without HIV. Expert consultation is recommended.
Unplanned antiretroviral therapy interruption may be necessary for specific situations, such as serious drug toxicity, intercurrent illness or surgery precluding oral intake (e.g., gastroenteritis or pancreatitis), severe hyperemesis gravidarum unresponsive to antiemetics, or drug non-availability. If short-term treatment interruption (i.e., less than 1 to 2 days) is necessary, in general, it is recommended that all antiretroviral agents be discontinued simultaneously, especially if the interruption occurs in a pregnant patient or is because of a 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; as stopping all simultaneously in a regimen containing drugs with differing half-lives may result in functional monotherapy of the drug with the longest half-life and may increase the risk for resistant mutations. Healthcare providers are advised to reinitiate a complete and effective antiretroviral regimen as soon as possible after an interruption of therapy. 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 on all patients before initiating treatment. Abacavir is contraindicated in any HLA-B*5701-positive patient; clearly record the positive status as an abacavir allergy in the patients' medical record. According to the manufacturer, the estimated incidence of hypersensitivity 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 who abruptly discontinued abacavir for reasons unrelated to symptoms of hypersensitivity (e.g., interruption in drug supply or 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. Further, 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. A majority of these cases occurred in females; it is unknown if pregnant women are at increased risk for this syndrome. However, because being pregnant itself can mimic some of the early symptoms of the lactic acid/hepatic steatosis syndrome or be associated with other significant disorders of liver metabolism, clinicians need to be alert for early diagnosis of this syndrome. Pregnant women receiving nucleoside analogs should have LFTs and serum electrolytes assessed more frequently during the last trimester and any new symptoms should be evaluated thoroughly. In addition, obesity may also 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.
Antiretroviral therapy should be provided to all patients during pregnancy, regardless of HIV RNA concentrations or CD4 cell count. Using highly active antiretroviral combination therapy (HAART) to maximally suppress viral replication is the most effective strategy to prevent the development of resistance and to minimize the risk of perinatal transmission. Begin HAART as soon as pregnancy is recognized, or HIV is diagnosed. HIV guidelines recommend the use of abacavir as part of a preferred 2-NRTI backbone in HLA-B*5701 negative patients WITHOUT hepatitis B virus (HBV) coinfection who are pregnant or trying to conceive. Available data from the Antiretroviral Pregnancy Registry, which includes 1,455 first trimester exposures, have shown no difference in the risk of overall major birth defects with abacavir compared to the 2.7% background rate among pregnant women in the US. When exposure to abacavir occurred in the first trimester, prevalence of defects was 3.2% (95% CI: 2.4 to 4.3). As a class, nucleoside reverse transcriptase inhibitors (NRTIs) are known to induce mitochondrial dysfunction. An association of mitochondrial dysfunction in infants and in utero antiretroviral exposure has been suggested, but not established. While the development of severe or fatal mitochondrial disease in exposed infants appears to be extremely rare, more intensive monitoring of hematologic and electrolyte parameters during the first few weeks of life is advised. Nucleoside analogs have been associated with the development of lactic acidosis, especially during pregnancy. It is unclear if pregnancy augments the incidence of lactic acidosis/hepatic steatosis in patients receiving nucleoside analogs. However, because pregnancy itself can mimic some early symptoms of the lactic acid/hepatic steatosis syndrome or be associated with other significant disorders of liver metabolism, clinicians need to be alert for early diagnosis of this syndrome. Pregnant patients receiving nucleoside analogs should have LFTs and serum electrolytes assessed more frequently during the last trimester of pregnancy and any new symptoms should be evaluated thoroughly. Regular laboratory monitoring is recommended to determine antiretroviral efficacy. Monitor CD4 counts at the initial visit. Patients who have been on HAART for at least 2 years and have consistent viral suppression and CD4 counts consistently greater than or equal to 300 cells/mm3 do not need CD4 counts monitored after the initial visit during the pregnancy. However, CD4 counts should be monitored every 3 months during pregnancy for patients on HAART less than 2 years and have CD4 counts less than 300 cells/mm3, patients with inconsistent adherence, or patients with detectable viral loads. For patients on HAART less than 2 years but have CD4 counts greater than or equal to 300 cells/mm3, monitor CD4 counts every 6 months. Monitor plasma HIV RNA at the initial visit (with review of prior levels), 2 to 4 weeks after initiating or changing therapy, monthly until undetectable, and then at least every 3 months during pregnancy. Viral load should also be assessed at approximately 36 weeks gestation, or within 4 weeks of planned delivery, to inform decisions regarding mode of delivery and optimal treatment for newborns. Patients whose HIV RNA levels are above the threshold for resistance testing (usually greater than 500 copies/mL but may be possible for levels greater than 200 copies/mL in some laboratories) should undergo antiretroviral resistance testing (genotypic testing, and if indicated, phenotypic testing). Resistance testing should be conducted before starting therapy in treatment-naive patients who have not been previously tested, starting therapy in treatment-experienced patients (including those who have received pre-exposure prophylaxis), modifying therapy in patients who become pregnant while receiving treatment, or modifying therapy in patients who have suboptimal virologic response to treatment that was started during pregnancy. DO NOT delay initiation of antiretroviral therapy while waiting on the results of resistance testing; treatment regimens can be modified, if necessary, once the testing results are known. First trimester ultrasound is recommended to confirm gestational age and provide accurate estimation of gestational age at delivery. A second trimester ultrasound can be used for both anatomical survey and determination of gestational age in those patients not seen until later in gestation. Perform standard glucose screening in patients receiving antiretroviral therapy at 24 to 28 weeks gestation, although it should be noted that some experts would perform earlier screening with ongoing chronic protease inhibitor-based therapy initiated prior to pregnancy, similar to recommendations for patients with high-risk factors for glucose intolerance. Liver function testing is recommended within 2 to 4 weeks after initiating or changing antiretroviral therapy, and approximately every 3 months thereafter during pregnancy (or as needed). All pregnant patients should be counseled about the importance of adherence to their antiretroviral regimen to reduce the potential for development of resistance and perinatal transmission. It is strongly recommended that antiretroviral therapy, once initiated, not be discontinued. If a patient decides to discontinue therapy, a consultation with an HIV specialist is recommended. There is a pregnancy exposure registry that monitors outcomes in pregnant patients exposed to abacavir; information about the registry can be obtained at www.apregistry.com or by calling 1-800-258-4263.
HIV treatment guidelines recommend clinicians provide mothers with evidence-based, patient-centered counseling to support shared decision-making regarding infant feeding. Inform patients that use of replacement feeding (i.e., formula or banked pasteurized donor human milk) eliminates the risk of HIV transmission. Advise patients who receive a diagnosis of HIV infection while breast-feeding (acute HIV) to immediately discontinue breast-feeding and switch to replacement feeding in order to reduce the risk of postnatal HIV transmission to the infant. Replacement feeding is also recommended for use when mothers with HIV are not on antiretroviral therapy (ART) or do not have suppressed viral load during pregnancy, as well as at delivery. For patients on ART who have achieved and maintained viral suppression during pregnancy (at minimum throughout the third trimester) and postpartum, the transmission risk from breast-feeding is less than 1%, but not zero. Virologically suppressed mothers who choose to breast-feed should be supported in this decision. If breast-feeding is chosen, counsel the patient about the importance of adherence to therapy and recommend that the infant be exclusively breast-fed for up to 6 months of age, as exclusive breast-feeding has been associated with a lower rate of HIV transmission as compared to mixed feeding (i.e., breast milk and formula). Promptly identify and treat mastitis, thrush, and cracked or bleeding nipples, as these conditions may increase the risk of HIV transmission through breast-feeding. Breast-fed infants should undergo immediate diagnostic and virologic HIV testing. Testing should continue throughout breast-feeding and up to 6 months after cessation of breast-feeding. For expert consultation, healthcare workers may contact the Perinatal HIV Hotline (888-448-8765). In countries where replacement feeding is unavailable, abacavir has been administered to nursing mothers as part of a regimen to decrease postnatal HIV transmission; the optimal regimen and duration of prophylaxis is undetermined. In 1 study conducted in Botswana, abacavir was found to be excreted in human breast milk; the mean breast milk-to-plasma drug ratio in the 15 women tested was 0.85. Further, an analysis of 9 breast-feeding infants found detectable plasma drug concentrations in 1 infant. In the Swiss Mother and Child HIV Cohort nested study, abacavir was measurable in 4 breast-fed infants; the relative infant dose was 0.34%. Other antiretroviral medications whose passage into human breast milk have been evaluated include nevirapine, zidovudine, lamivudine, and nelfinavir.
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. The prevalence of transmitted drug resistance (TDR) in high-income countries ranges from 9% to 14% and varies by country. In most TDR surveys, non-nucleoside reverse transcriptase inhibitor (NNRTI) resistance and nucleoside reverse transcriptase inhibitor (NRTI) resistance are the most common mutation class types detected, followed by protease inhibitor (PI) and integrase strand transfer inhibitor (INSTI) resistance mutations, respectively. 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 result kept in the patient's medical record until it becomes 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 NRTI exposure or who had HIV-1 isolates that contain multiple mutations conferring antimicrobial resistance to other NRTIs had 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.
Clinical studies of abacavir did not include sufficient numbers of patients aged 65 years or over to determine whether they respond differently from younger patients. Other reported clinical experience has not identified differences in response between geriatric and younger patients. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
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 progressive multifocal leukoencephalopathy (PML), 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 should be started on a fully suppressive antiretroviral (ARV) regimen with activity against both viruses (regardless of CD4 counts and HBV DNA concentrations). HIV treatment guidelines recommend these patients receive an ARV regimen that contains a dual NRTI backbone of tenofovir alafenamide or tenofovir disoproxil fumarate with either emtricitabine or lamivudine. If tenofovir cannot be used, entecavir should be given in combination with a fully suppressive ARV regimen (note: entecavir should not be considered part of the ARV regimen). Avoid using single-drug therapy to treat HBV (i.e., lamivudine, emtricitabine, tenofovir, or entecavir as the only active agent) as this may result in HIV resistant strains. Further, HBV treatment regimens that include adefovir or telbivudine should also be avoided, as these regimens are associated with a higher incidence of toxicities and increased rates of HBV treatment failure. Most coinfected patients should continue treatment indefinitely with the goal of maximal HIV suppression and prevention of HBV relapse. If treatment must be discontinued, monitor transaminase concentrations every 6 weeks for the first 3 months, and every 3 to 6 months thereafter. For patients who refuse a fully suppressive ARV regimen, but still requires treatment for HBV, consider 48 weeks of peginterferon alfa; do not administer HIV-active medications in the absence of a fully suppressive ARV regimen. Instruct patients to avoid consuming alcohol, and offer vaccinations against hepatitis A and hepatitis B as appropriate.
HIV treatment guidelines recommend all patients presenting with HIV infection undergo routine screening for hepatitis C virus (HCV). For HCV seronegative individuals who are at continued high risk of acquiring hepatitis C, specifically men who have sex with men (MSM) or persons who inject drugs, additional HCV screening is recommended annually or as indicated by clinical presentation (e.g., unexplained ALT elevation), risk activities, or exposure. Similarly, the AASLD/IDSA HCV guidelines and the CDC preexposure prophylaxis (PrEP) guidelines recommend HCV serologic testing at baseline and every 12 months for MSM, transgender women, and persons who inject drugs. Use an FDA-approved immunoassay licensed for detection of HCV antibodies (anti-HCV); in settings where acute HCV infection is suspected or in persons with known prior infection that cleared spontaneously or after treatment, use of nucleic acid testing for HCV RNA is recommended. If hepatitis C and HIV coinfection is identified, consider treating both viral infections concurrently. It is recommended to use a fully suppressive antiretroviral therapy and an HCV regimen in all patients with coinfection regardless of CD4 count, as lower CD4 counts do not appear to compromise the efficacy of HCV treatment. In most patients, a simplified pangenotypic HCV regimen (i.e., glecaprevir; pibrentasvir or sofosbuvir; velpatasvir) may be an appropriate choice; however, these regimens are NOT recommended for use in persons with HCV and HIV coinfection who: are treatment-experience with HCV relapse (reinfection after successful therapy is not an exclusion); have decompensated cirrhosis; on a tenofovir disoproxil fumarate containing regimen with eGFR less than 60 mL/minute; on efavirenz, etravirine, nevirapine, or boosted protease inhibitor; have untreated chronic hepatitis B; are pregnant. Patients with HCV and HIV coinfection who meet these exclusion criteria should be treated for HCV following standard approaches as described in the AASLD/IDSA HCV guidelines. 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 with HCV and HIV coinfection who have no contraindications to treatment. Instruct patients with coinfection to avoid consuming alcohol, limit ingestion of potentially hepatotoxic medications, avoid iron supplementation in the absence of documented iron deficiency, and receive vaccinations against hepatitis A and hepatitis B as appropriate.
HIV guidelines recommend screening for HLA-B*5701 before initiating an abacavir-containing regimen to reduce the risk of hypersensitivity reaction. HLA-B*5701-positive patients should not be prescribed abacavir.
NOTE: HIV guidelines recommend consideration be given to avoiding the 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 therapy for HIV infection:
-For adults, 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, including perinatal transmission and transmission to sexual partners. Starting antiretroviral therapy early is particularly important for patients with AIDS-defining conditions, those with acute or recent HIV infection, and individuals who are pregnant; delaying therapy in these subpopulations has been associated with high risks of morbidity, mortality, and HIV transmission.
-Prior to initiating treatment, obtain baseline plasma HIV RNA (viral load) and CD4 count; results do not need to be available before starting therapy.
-Antiretroviral drug-resistance testing:-Genotypic drug-resistance testing is recommended prior to initiation of therapy and prior to changing therapy for treatment failure.
--Standard genotypic drug-resistance testing in treatment-naive people should focus on testing for mutations in reverse transcriptase (RT) and protease (PR) genes.
-Testing for mutations in the integrase gene should also be performed if integrase strand transfer inhibitor (INSTI) resistance is a concern (e.g., people who acquire HIV after pre-exposure prophylaxis with long-acting cabotegravir).
-Phenotypic resistance testing may be used in conjunction with the genotypic test for patients with known or suspected complex drug-resistance mutation patterns.
-HIV-1 proviral DNA resistance testing is available for use in patients with HIV RNA concentrations below the limits of detection or with low-level viremia (i.e., less than 1,000 copies/mL), where genotypic testing is unlikely to be successful; however, the clinical utility of this assay has not been fully determined.
-It is not necessary to delay treatment until resistance test results are available; however, subsequent modifications to the treatment regimen should be made, if needed, once the test results are available.
-Pediatric guidelines are also available.
Place in therapy for HIV infection:
-For most HLA-B*5701 negative adults and adolescents WITHOUT hepatitis B virus (HBV) coinfection (including pregnant women and women who are trying to conceive), abacavir plus lamivudine is a preferred 2-NRTI backbone.
-May be considered for use in HIV-exposed neonates to reduce perinatal transmission of HIV in situations where zidovudine is unavailable or cannot be used. Initiate treatment as close to birth as possible, preferably within 6 hours; however, must confirm patient is HLA-B*5701 negative before initiating therapy.
-Pediatric guidelines are also available.
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 (tablets):
Adults: 300 mg PO twice daily or 600 mg PO once daily.
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. 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. 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 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. 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.
Oral dosage (oral solution):
Adults : 300 mg PO twice daily or 600 mg PO once daily.
Adolescents: 300 mg PO twice daily or 600 mg PO once daily.
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.
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. 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.
Infants 1 to 2 months*: 4 mg/kg/dose PO twice daily. Dosing recommendations are based on pharmacokinetic modeling and observational data supporting the safety of abacavir in infants younger than 3 months.
Neonates*: 2 mg/kg/dose PO twice daily. Dosing recommendations are based on pharmacokinetic modeling and observational data supporting the safety of abacavir in neonates.
For human immunodeficiency virus (HIV) prophylaxis* after occupational HIV exposure:
Oral dosage:
Adults: The US Public Health Service guidelines suggest abacavir 300 mg PO twice daily or 600 mg PO daily in combination with one of the following backbones (in order of preference) as acceptable alternative regimens for HIV post-exposure prophylaxis (PEP): tenofovir plus emtricitabine; tenofovir plus lamivudine; zidovudine plus lamivudine; zidovudine plus emtricitabine. Prior to administering an abacavir containing regimen, the US Public Health Service and the New York State Department of Health AIDS Institute (NYSDOH AI) recommend consultation with a clinician experienced in the management of PEP. This recommendation is due the potential for serious hypersensitivity reactions. According to PEP guidelines, individuals potentially exposed to HIV should receive a 3-drug regimen for a total of 28 days; however if tolerability is a concern, use of a 2-drug regimen may be considered and is preferred to prophylaxis discontinuation. Begin prophylaxis as soon as possible, ideally within 2 hours of exposure. If initiation of prophylaxis is delayed (beyond 36 hours or 72 hours after exposure), efficacy of the antiretroviral regimen may be diminished and treatment should be determined on a case-by-case basis. Exposures for which PEP is indicated include: skin puncture by a sharp object that has been contaminated with blood, body fluid, or other infectious material; bite from a patient with visible bleeding in the mouth which causes bleeding by the exposed worker; splash of blood, body fluid, or other infectious material onto the workers mouth, nose, or eyes; exposure of blood, body fluid, or other infectious material on a workers non-intact skin (i.e., open wound, chapped skin, abrasion, dermatitis).
For perinatal human immunodeficiency virus (HIV) prophylaxis*:
Oral dosage:
Infants 1 to 2 months: 4 mg/kg/dose PO twice daily may be considered as an alternative to zidovudine in situations where zidovudine is not available or the patient has zidovudine-associated toxicity. Due to abacavir-associated hypersensitivity, negative testing for HLA-B*5701 allele must be confirmed prior to administration. NOTE: Abacavir is not recommended as part of a presumptive HIV treatment regimen.
Neonates: 2 mg/kg/dose PO twice daily may be considered as an alternative to zidovudine in situations where zidovudine is not available or the patient has zidovudine-associated toxicity. Initiate treatment as close to birth as possible, preferably within 6 hours; however, due to abacavir-associated hypersensitivity, negative testing for HLA-B*5701 allele must be confirmed prior to administration. NOTE: Abacavir is not recommended as part of a presumptive HIV treatment regimen.
Maximum Dosage Limits:
-Adults
600 mg/day PO.
-Geriatric
600 mg/day PO.
-Adolescents
16 mg/kg/day PO (Max: 600 mg/day).
-Children
16 mg/kg/day PO (Max: 600 mg/day).
-Infants
3 to 11 months: 16 mg/kg/day PO.
1 to 2 months: Safety and efficacy have not been established; however, doses up to 8 mg/kg/day PO have been used off-label.
-Neonates
Safety and efficacy have not been established; however, doses up to 4 mg/kg/day PO have been used off-label.
Patients with Hepatic Impairment Dosing
No dosage adjustment guidelines available for pediatric patients with hepatic impairment.
In patients with mild hepatic impairment (Child-Pugh A, score 5 to 6): Decrease the dose to 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 greater than 6) 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.
Intermittent hemodialysis
It is not known if abacavir is removed by hemodialysis.
Peritoneal dialysis
It is not known if abacavir is removed by peritoneal dialysis.
*non-FDA-approved indication
Adefovir: (Major) Patients who are concurrently taking adefovir with antiretrovirals (i.e., anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs)) are at risk of developing 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 analogs alone or in combination with antiretrovirals. A majority of these cases have been in women; obesity and prolonged nucleoside exposure may also be risk factors. Particular caution should be exercised when administering nucleoside analogs to any patient with known risk factors for hepatic disease; however, cases have also been reported in patients with no known risk factors. Suspend adefovir 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).
Cabozantinib: (Minor) Monitor for an increase in cabozantinib-related adverse reactions if coadministration with abacavir is necessary. Cabozantinib is a Multidrug Resistance Protein 2 (MRP2) substrate and abacavir is an MRP2 inhibitor. MRP2 inhibitors have the potential to increase plasma concentrations of cabozantinib; however, the clinical relevance of this interaction is unknown.
Echinacea: (Moderate) Use Echinacea sp. with caution in patients taking medications for human immunodeficiency virus (HIV) infection. Some experts have suggested that Echinacea's effects on the immune system might cause problems for patients with HIV infection, particularly with long-term use. There may be less risk with short-term use (less than 2 weeks). A few pharmacokinetic studies have shown reductions in blood levels of some antiretroviral medications when Echinacea was given, presumably due to CYP induction. However, more study is needed for various HIV treatment regimens. Of the agents studied, the interactions do not appear to be significant or to require dose adjustments at the time of use. Although no dose adjustments are required, monitoring drug concentrations may give reassurance during co-administration. Monitor viral load and other parameters carefully during therapy.
Ethanol: (Major) Advise patients to avoid alcohol consumption while taking abacavir. Abacavir is metabolized via alcohol dehydrogenase. Alcohol decreases the elimination of abacavir causing an increase in overall exposure to abacavir. In a study involving HIV-infected men, coadministration of alcohol and abacavir resulted in a 41% increase in abacavir AUC and a 26% increase in abacavir half-life. In males, abacavir had no effect on the pharmacokinetic properties of alcohol; this interaction has not been studied in females. Abacavir has no effect on the pharmacokinetic properties of alcohol. (Major) Because abacavir is metabolized via alcohol dehydrogenase, alcohol decreases the elimination of abacavir causing an increase in overall exposure to abacavir. In a study involving HIV-infected men, coadministration of alcohol and abacavir resulted in a 41% increase in abacavir AUC and a 26% increase in abacavir half-life. In males, abacavir had no effect on the pharmacokinetic properties of alcohol; this interaction has not been studied in females. Abacavir has no effect on the pharmacokinetic properties of alcohol.
Interferon Alfa-2b: (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving NRTIs and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
Interferon Alfa-n3: (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving NRTIs and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
Interferon Beta-1a: (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving NRTIs and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
Interferon Beta-1b: (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving NRTIs and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
Interferon Gamma-1b: (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving NRTIs and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
Interferons: (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving NRTIs and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
Lopinavir; Ritonavir: (Moderate) Caution is advised when administering abacavir and ritonavir concurrently. Ritonavir appears to induce glucuronosyl transferase, and therefore, has the potential to reduce plasma concentrations of drugs that undergo glucuronidation, such as abacavir. The clinical significance of the potential for this interaction is unknown.
Methadone: (Moderate) In a study of 11 adult HIV-infected subjects receiving methadone maintenance therapy (40 to 90 mg/day) and abacavir 600 mg twice daily (twice the current recommended dose), methadone clearance increased by 22% (6% to 42%). While this interaction will not require dosage adjustment in the majority of patients, a small number of patients may require increased doses of methadone. In addition, a significant decrease in abacavir Cmax (34%) and increase in Tmax (67%) were noted, but no changes in overall abacavir clearance or half-life were reported. The clinical significance regarding abacavir therapy is not known.
Nirmatrelvir; Ritonavir: (Moderate) Caution is advised when administering abacavir and ritonavir concurrently. Ritonavir appears to induce glucuronosyl transferase, and therefore, has the potential to reduce plasma concentrations of drugs that undergo glucuronidation, such as abacavir. The clinical significance of the potential for this interaction is unknown.
Orlistat: (Moderate) According to the manufacturer of orlistat, HIV RNA levels should be frequently monitored in patients receiving orlistat while being treated for HIV infection with anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs). Loss of virological control has been reported in HIV-infected patients taking orlistat with atazanavir, ritonavir, tenofovir disoproxil fumarate, emtricitabine, lopinavir; ritonavir, and emtricitabine; efavirenz; tenofovir disoproxil fumarate. The exact mechanism for this interaction is not known, but may involve inhibition of systemic absorption of the anti-retroviral agent. If an increased HIV viral load is confirmed, orlistat should be discontinued.
Peginterferon Alfa-2a: (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving NRTIs and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
Peginterferon Alfa-2b: (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving NRTIs and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
Peginterferon beta-1a: (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving NRTIs and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
Ribavirin: (Moderate) Use abacavir with ribavirin and interferon with caution and closely monitor for hepatic decompensation and anemia. Dose reduction or discontinuation of interferon, ribavirin, or both should be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh greater than 6). Hepatic decompensation (some fatal) has occurred in HCV/HIV coinfected patients who received both ribavirin/interferon and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) therapies.
Riociguat: (Moderate) Monitor for an increase in riociguat-related adverse effects like hypotension if concomitant use with abacavir is necessary. Consider a riociguat dose reduction in patients who may not tolerate the hypotensive effect of riociguat. Concomitant use of riociguat and abacavir may increase riociguat exposure although the magnitude of increase is unknown. Riociguat is a CYP1A1 substrate; abacavir may inhibit CYP1A1.
Ritonavir: (Moderate) Caution is advised when administering abacavir and ritonavir concurrently. Ritonavir appears to induce glucuronosyl transferase, and therefore, has the potential to reduce plasma concentrations of drugs that undergo glucuronidation, such as abacavir. The clinical significance of the potential for this interaction is unknown.
Ropeginterferon alfa-2b: (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving NRTIs and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
Tipranavir: (Moderate) Concurrent administration of tipranavir and ritonavir with abacavir results in decreased abacavir concentrations. The clinical significance of this interaction has not been established, and no recommendations for abacavir dosage adjustments are available.
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.
In vitro and in vivo HIV-1 isolates with reduced sensitivity to abacavir have been reported. Genetic analysis of isolates from abacavir-treated patients showed point mutations in the reverse transcriptase gene that resulted in amino acid substitutions at key positions in the virus. Phenotypic analysis of HIV-1 isolates that harbor abacavir-associated mutations from 17 patients after 12 weeks of abacavir monotherapy exhibited a 3-fold decrease in susceptibility to abacavir in vitro. The clinical relevance of genotypic and phenotypic changes associated with abacavir therapy has not been established.
Cross-resistance between abacavir and other nucleoside reverse transcriptase inhibitors (i.e., tenofovir, emtricitabine, lamivudine, didanosine, and stavudine) has been observed in strains of HIV-1 containing multiple reverse transcriptase mutations. Cross-resistance between abacavir and HIV protease inhibitors is unlikely because of the different enzyme targets involved. Because of different binding sites on reverse transcriptase, cross-resistance between abacavir and non-nucleoside reverse transcriptase inhibitors is not expected.
Abacavir hypersensitivity may be related to an induced autoimmunity process related to HLA-B*5701. Human Leukocyte Antigens (HLA) 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.
Abacavir is administered orally. Once in the systemic circulation, abacavir distributes into extravascular space. Protein binding is approximately 50% and is independent of concentration. Based on radiolabeled studies, the drug readily distributes into erythrocytes. In humans, abacavir is not significantly metabolized by cytochrome P450 enzymes. The primary routes of elimination of abacavir are metabolism by alcohol dehydrogenase (to form the 5'-carboxylic acid) and glucuronyl transferase (to form the 5'glucuronide). The metabolites have no antiviral activity. In vitro experiments reveal that abacavir does not inhibit human CYP3A4, CYP2D6, or CYP2C9 activity at clinically relevant concentrations. Elimination of abacavir was quantified in a mass balance 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. In single-dose studies, the observed elimination half-life was 1.54 +/- 0.63 hours.
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.
-Route-Specific Pharmacokinetics
Oral Route
After oral administration, abacavir is rapidly and extensively absorbed. Bioavailability is about 83% for the tablets. Systemic exposure to abacavir 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.
-Special Populations
Hepatic Impairment
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, after a single oral dose of 600 mg. Abacavir pharmacokinetic parameters have not been assessed in patients with moderate or severe hepatic impairment.
Renal Impairment
Pharmacokinetic parameters of abacavir have not been studied in patients with renal impairment.
Pediatrics
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.
Neonates and Infants 1 to 3 months
Pharmacokinetic data in neonates have shown a substantially higher abacavir exposure (2- to 3-fold higher), likely due to slower drug clearance through immature enzyme pathways, compared to infants and young children. After a single abacavir dose of 8 mg/kg in 10 neonates (0 to 14 days of age), the median AUC0-8 and AUC0-inf were 26.3 (15.5 to 35.7) and 39.1 (22.3 to 50.9) mcg/hour/mL, respectively, with an apparent median clearance value of 3.5 (2.6 to 6.3) mL/minute/kg. The median Tmax and elimination half-life were 2 (1 to 4) and 3.93 (2.47 to 6.35) hours, respectively. Pharmacokinetic modeling has also predicted a slow abacavir clearance of 2.51 mL/minute/kg at birth, which doubles by 4 weeks of age. Simulations predicted that an abacavir dose of 2 mg/kg/dose twice daily in full-term neonates from birth to younger than 4 weeks and an abacavir dose of 4 mg/kg/dose twice daily in infants aged 4 to 12 weeks would achieve target AUC; however, data in low birth weight infants are lacking.
Geriatric
Pharmacokinetic parameters of abacavir have not been studied in elderly patients.
Other
Pregnancy
A population pharmacokinetic analysis of 266 samples from 36 pregnant and 114 non-pregnant females, found the pharmacokinetic parameters of abacavir to be unchanged during pregnancy. Similarly, 1 pharmacokinetic study found abacavir exposure in 25 pregnant women receiving 300 mg twice daily during the third trimester to be comparable to exposures observed in postpartum women and historical controls of non-pregnant patients with HIV. Abacavir crosses the placenta via passive diffusion, with drug concentrations in neonatal plasma cord samples at birth being essentially equal to those in the maternal plasma at the time of delivery.