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  • CLASSES

    Nucleoside and Nucleotide Reverse Transcriptase Inhibitors (NRTI)s

    DEA CLASS

    Rx

    DESCRIPTION

    Synthetic guanosine nucleoside reverse transcriptase inhibitor (NRTI)
    Indicated for the treatment of human immunodeficiency virus (HIV) infection
    Associated with fatal hypersensitivity reactions during initial treatment and with reintroduction of therapy

    COMMON BRAND NAMES

    Ziagen

    HOW SUPPLIED

    Abacavir/Abacavir Sulfate/Ziagen Oral Sol: 1mL, 20mg
    Abacavir/Abacavir Sulfate/Ziagen Oral Tab: 300mg

    DOSAGE & INDICATIONS

    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 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. 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 for more than 24 weeks.

    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 for more than 24 weeks.

    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 for more than 24 weeks.

    Oral dosage (oral solution)
    Adults

    300 mg PO twice daily or 600 mg once daily.

    Adolescents

    300 mg PO twice daily or 600 mg 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. 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 for more than 24 weeks.

    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).

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    600 mg/day PO.

    Geriatric

    600 mg/day PO.

    Adolescents

    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.

    Children

    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.

    Infants

    >= 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.
    < 3 months: Safety and efficacy have not been established.

    Neonates

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    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.

    Renal Impairment

    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.

    ADMINISTRATION

    Oral Administration

    May be administered without regard to meals.

    Oral Liquid Formulations

    The oral solution may turn brown over time.

    STORAGE

    Ziagen:
    - Do not freeze
    - May be refrigerated
    - Store at controlled room temperature (between 68 and 77 degrees F)

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    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 1-2 days) is necessary, 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 range from less than 1 week to more than 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.[46638] [42452]

    Abacavir hypersensitivity, serious hypersensitivity reactions or anaphylaxis

    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).

    Cardiac disease, myocardial infarction

    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).
     

    Alcoholism, females, hepatic disease, hepatotoxicity or lactic acidosis, obesity

    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.
     

    Pregnancy

    Antiretroviral therapy should be provided to all women 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. In treatment-naive women, begin HAART as soon as pregnancy is recognized or HIV is diagnosed, without waiting for the results of resistance testing; subsequent modifications to the treatment regimen should be made once the test results are available. Women who are currently receiving antiretroviral treatment when pregnancy is recognized should continue their treatment regimen if it is currently effective in suppressing viral replication; consider resistance testing if HIV RNA concentrations greater than 500 copies/mL. For women not currently receiving HAART, but who have previously received treatment, obtain a complete and accurate history of all prior antiretroviral regimens used and results of prior resistance testing, and perform resistance testing if HIV RNA concentrations more than 500 copies/mL; treatment should be initiated prior to receiving resistance test results. Abacavir has been shown to cross the placenta, with drug concentrations in neonatal plasma at birth being essentially equal to those in the maternal plasma at the time of delivery. Available data from the Antiretroviral Pregnancy Registry, which includes more than 1,100 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 2.83% (32 out of 1,131 births; 95% CI: 1.94, 3.97). 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 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 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 and at least every 3 months during pregnancy; consideration may be given to monitoring every 6 months in patients on HAART with consistently suppressed viral loads and a CD4 count well above the opportunistic infection threshold. Monitor plasma HIV RNA concentrations at the initial visit, 2 to 4 weeks after initiating or changing therapy, monthly until undetectable, then at least every 3 months during pregnancy, and at 34 to 36 weeks gestation. Perform antiretroviral resistance assay (genotypic testing) at baseline in all women with HIV RNA concentrations greater than 500 copies/mL, unless they have already been tested for resistance. First trimester ultrasound is recommended to confirm gestational age and provide accurate estimation of gestational age at deliver. 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 women 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 women with high-risk factors for glucose intolerance. All pregnant women 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 woman decides to discontinue therapy, a consultation with an HIV specialist is recommended. It is strongly recommended that health care providers report cases of antenatal antiretroviral drug exposure to the Antiretroviral Pregnancy Registry; telephone 800-258-4263; fax 800-800-1052; the Antiretroviral Pregnancy Registry is also accessible via the Internet.[27468] [29710] [23512]

    Breast-feeding

    To reduce the risk of postnatal transmission, HIV-infected mothers within the United States are advised by the Centers for Disease Control and Prevention to avoid breast-feeding. This recommendation applies to both untreated women and women who are receiving antiretroviral therapy, including abacavir. 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 one 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. Other antiretroviral medications whose passage into human breast milk have been evaluated include nevirapine, zidovudine, lamivudine, and nelfinavir.

    Infants, neonates

    The safety and effectiveness of abacavir have not been established in neonates and infants < 3 months.

    Human immunodeficiency virus (HIV) infection resistance

    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. In high-income countries (e.g., US, some European countries, Australia, Japan), approximately 10% to 17% of treatment-naive individuals have resistance mutations to at least 1 antiretroviral drug; up to 8% (but generally less than 5%) of transmitted viruses will exhibit resistance to drugs from more than 1 class. 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 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 nucleoside reverse transcriptase inhibitor (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.

    Geriatric

    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.

    Autoimmune disease, Graves' disease, Guillain-Barre syndrome, immune reconstitution syndrome

    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.

    Hepatitis B and HIV coinfection

    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 with emtricitabine 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.

    Hepatitis C and HIV coinfection

    HIV treatment guidelines recommend all patients presenting with HIV infection undergo testing for hepatitis C, with continued annual screening advised for those persons considered high risk for acquiring hepatitis C. If hepatitis C and HIV coinfection is identified, consider treating both viral infections concurrently. For most patients, the benefits of concurrent therapy outweighs the potential risks (i.e., drug-induced hepatic injury, complex drug interactions, overlapping toxicities); therefore, it is recommended to initiate a fully suppressive antiretroviral (ARV) therapy and a hepatitis C regimen in all coinfected patients regardless of CD4 count. However, for antiretroviral naive patients with CD4 counts greater than 500 cells/mm3, consideration may be given to deferring ARV until the hepatitis C treatment regimen has been completed. Conversely, for patients with CD4 counts less than 200 cells/mm3, consider delaying initiation of the hepatitis C treatment regimen until the patient is stable on fully suppressive ARV regimen. Instruct coinfected patients to avoid consuming alcohol, and offer vaccinations against hepatitis A and hepatitis B as appropriate.

    ADVERSE REACTIONS

    Severe

    diarrhea / Early / 2.0-2.0
    pancreatitis / Delayed / Incidence not known
    lactic acidosis / Delayed / Incidence not known
    hepatotoxicity / Delayed / Incidence not known
    erythema multiforme / Delayed / Incidence not known
    toxic epidermal necrolysis / Delayed / Incidence not known
    Stevens-Johnson syndrome / Delayed / Incidence not known
    myocardial infarction / Delayed / Incidence not known
    hepatic failure / Delayed / Incidence not known
    renal failure (unspecified) / Delayed / Incidence not known
    azotemia / Delayed / Incidence not known
    rhabdomyolysis / Delayed / Incidence not known
    serious hypersensitivity reactions or anaphylaxis / Rapid / Incidence not known
    respiratory arrest / Rapid / Incidence not known
    acute respiratory distress syndrome (ARDS) / Early / Incidence not known

    Moderate

    migraine / Early / 7.0-13.0
    gastritis / Delayed / 6.0-6.0
    elevated hepatic enzymes / Delayed / 6.0-6.0
    hypertriglyceridemia / Delayed / 2.0-6.0
    depression / Delayed / 6.0-6.0
    neutropenia / Delayed / 2.0-5.0
    hyperamylasemia / Delayed / 2.0-4.0
    hyperglycemia / Delayed / 0-1.0
    thrombocytopenia / Delayed / 1.0-1.0
    leukopenia / Delayed / 0-1.0
    anemia / Delayed / 0-1.0
    hepatomegaly / Delayed / Incidence not known
    steatosis / Delayed / Incidence not known
    lipodystrophy / Delayed / Incidence not known
    hypotension / Rapid / Incidence not known
    conjunctivitis / Delayed / Incidence not known
    edema / Delayed / Incidence not known
    oral ulceration / Delayed / Incidence not known
    lymphadenopathy / Delayed / Incidence not known
    dyspnea / Early / Incidence not known
    lymphopenia / Delayed / Incidence not known

    Mild

    nausea / Early / 7.0-19.0
    headache / Early / 7.0-13.0
    malaise / Early / 7.0-12.0
    fatigue / Early / 7.0-12.0
    vomiting / Early / 2.0-10.0
    nightmares / Early / 10.0-10.0
    insomnia / Early / 10.0-10.0
    fever / Early / 6.0-9.0
    chills / Rapid / 6.0-9.0
    rash / Early / 5.0-7.0
    abdominal pain / Early / 6.0-6.0
    dizziness / Early / 6.0-6.0
    musculoskeletal pain / Early / 5.0-6.0
    anxiety / Delayed / 5.0-5.0
    infection / Delayed / 4.0-5.0
    paresthesias / Delayed / Incidence not known
    maculopapular rash / Early / Incidence not known
    urticaria / Rapid / Incidence not known
    lethargy / Early / Incidence not known
    pharyngitis / Delayed / Incidence not known
    arthralgia / Delayed / Incidence not known
    myalgia / Early / Incidence not known
    cough / Delayed / Incidence not known

    DRUG INTERACTIONS

    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) Because abacavir is metabolized via alcohol dehydrogenase, ethanol decreases the elimination of abacavir causing an increase in overall exposure to abacavir. In a study involving HIV-infected men, coadministration of ethanol 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 ethanol; this interaction has not been studied in females. Abacavir has no effect on the pharmacokinetic properties of ethanol (alcohol).
    Food: (Moderate) The pharmacokinetic parameters of anti-retroviral medications (anti-retroviral non-nucleoside reverse transcriptase inhibitors (NNRTIs), anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs), anti-retroviral nucleotide reverse transcriptase inhibitors, and anti-retroviral protease inhibitors) metabolized through the CYP isoenzyme system are slightly altered by smoked and oral marijuana. Despite this interaction, marijuana is not expected to adversely affect anti-retroviral efficacy. However, the incidence of marijuana associated adverse effects may change following coadministration with anti-retroviral drugs. Many anti-retrovirals are inhibitors of CYP3A4, an isoenzyme partially responsible for the metabolism of marijuana's most psychoactive compound, delta-9-tetrahydrocannabinol (Delta-9-THC). When given concurrently with anti-retrovirals, the amount of Delta-9-THC converted to the active metabolite 11-hydroxy-delta-9-tetrahydrocannabinol (11-OH-THC) may be reduced. These changes in Delta-9-THC and 11-OH-THC plasma concentrations may result in an altered marijuana adverse event profile.
    Interferon 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.
    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-2b; Ribavirin: (Major) The concomitant use of ribavirin and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) should be done with caution. The co-treatment of human immunodeficiency virus (HIV) and hepatitis C virus (HCV) has the potential to result in complex drug interactions. In a study of 14 patients with chronic, cirrhotic HCV co-infected with HIV, patients receiving NRTIs and alpha interferons, with or without ribavirin, appeared to be at increased risk for the development of hepatic decompensation (e.g., Childs-Pugh >= 6) compared to patients not receiving HAART. Additionally, NRTIs have been associated with fatal and nonfatal lactic acidosis and hepatomegaly with or without steatosis and should be used cautiously in patients with hepatic disease. Didanosine and stavudine are most frequently involved in liver-related mitochondrial toxicity. Additionally, the long-term use of didanosine is an independent factor for developing advanced liver fibrosis in HIV-positive patients in whom other causes of liver damage were excluded. Overall, the HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation. While ribavirin inhibits the phosphorylation reactions required to activate lamivudine, stavudine, d4T, and zidovudine, no evidence of a pharmacokinetic or pharmacodynamic interaction was seen. (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 Alfacon-1: (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: (Minor) Lopinavir; ritonavir induces glucuronidation and therefore has the potential to reduce abacavir plasma concentrations during concurrent therapy. 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.
    Orlistat: (Major) 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: (Major) The concomitant use of ribavirin and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) should be done with caution. The co-treatment of human immunodeficiency virus (HIV) and hepatitis C virus (HCV) has the potential to result in complex drug interactions. In a study of 14 patients with chronic, cirrhotic HCV co-infected with HIV, patients receiving NRTIs and alpha interferons, with or without ribavirin, appeared to be at increased risk for the development of hepatic decompensation (e.g., Childs-Pugh >= 6) compared to patients not receiving HAART. Additionally, NRTIs have been associated with fatal and nonfatal lactic acidosis and hepatomegaly with or without steatosis and should be used cautiously in patients with hepatic disease. Didanosine and stavudine are most frequently involved in liver-related mitochondrial toxicity. Additionally, the long-term use of didanosine is an independent factor for developing advanced liver fibrosis in HIV-positive patients in whom other causes of liver damage were excluded. Overall, the HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation. While ribavirin inhibits the phosphorylation reactions required to activate lamivudine, stavudine, d4T, and zidovudine, no evidence of a pharmacokinetic or pharmacodynamic interaction was seen.
    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.

    PREGNANCY AND LACTATION

    Pregnancy

    Antiretroviral therapy should be provided to all women 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. In treatment-naive women, begin HAART as soon as pregnancy is recognized or HIV is diagnosed, without waiting for the results of resistance testing; subsequent modifications to the treatment regimen should be made once the test results are available. Women who are currently receiving antiretroviral treatment when pregnancy is recognized should continue their treatment regimen if it is currently effective in suppressing viral replication; consider resistance testing if HIV RNA concentrations greater than 500 copies/mL. For women not currently receiving HAART, but who have previously received treatment, obtain a complete and accurate history of all prior antiretroviral regimens used and results of prior resistance testing, and perform resistance testing if HIV RNA concentrations more than 500 copies/mL; treatment should be initiated prior to receiving resistance test results. Abacavir has been shown to cross the placenta, with drug concentrations in neonatal plasma at birth being essentially equal to those in the maternal plasma at the time of delivery. Available data from the Antiretroviral Pregnancy Registry, which includes more than 1,100 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 2.83% (32 out of 1,131 births; 95% CI: 1.94, 3.97). 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 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 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 and at least every 3 months during pregnancy; consideration may be given to monitoring every 6 months in patients on HAART with consistently suppressed viral loads and a CD4 count well above the opportunistic infection threshold. Monitor plasma HIV RNA concentrations at the initial visit, 2 to 4 weeks after initiating or changing therapy, monthly until undetectable, then at least every 3 months during pregnancy, and at 34 to 36 weeks gestation. Perform antiretroviral resistance assay (genotypic testing) at baseline in all women with HIV RNA concentrations greater than 500 copies/mL, unless they have already been tested for resistance. First trimester ultrasound is recommended to confirm gestational age and provide accurate estimation of gestational age at deliver. 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 women 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 women with high-risk factors for glucose intolerance. All pregnant women 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 woman decides to discontinue therapy, a consultation with an HIV specialist is recommended. It is strongly recommended that health care providers report cases of antenatal antiretroviral drug exposure to the Antiretroviral Pregnancy Registry; telephone 800-258-4263; fax 800-800-1052; the Antiretroviral Pregnancy Registry is also accessible via the Internet.[27468] [29710] [23512]

    To reduce the risk of postnatal transmission, HIV-infected mothers within the United States are advised by the Centers for Disease Control and Prevention to avoid breast-feeding. This recommendation applies to both untreated women and women who are receiving antiretroviral therapy, including abacavir. 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 one 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. Other antiretroviral medications whose passage into human breast milk have been evaluated include nevirapine, zidovudine, lamivudine, and nelfinavir.

    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.
     
    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.[29710] 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.[50430]

    PHARMACOKINETICS

    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: None

    Oral Route

    Following 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.