AHFS Class:

• HIV Nucleoside and Nucleotide Reverse Transcriptase Inhibitors 8:18.08.20

Generic Name(s):

• Abacavir Sulfate

Abacavir, an antiretroviral agent, is a human immunodeficiency virus (HIV) nucleoside reverse transcriptase inhibitor (NRTI).1,2,3,200

Treatment of HIV Infection

Abacavir is used in conjunction with other antiretroviral agents for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in adults, adolescents, and pediatric patients 3 months of age or older.1,26,33,78,79,126,127,200,201,228 Abacavir is also used in conjunction with other antiretroviral agents for the treatment of HIV infection in full-term infants from birth†.202

Abacavir is commercially available as a single-entity preparation and in various fixed-combination preparations.1,228,229,240 Fixed-combination preparations containing abacavir and lamivudine (Epzicom^®); abacavir, lamivudine, and zidovudine (Trizivir^®); and abacavir, dolutegravir, and lamivudine (Triumeq^® and Triumeq PD^®) are used in the treatment of HIV; refer to separate combination product monographs for information related to the specific uses of these products.228,229,240

Abacavir is included in various antiretroviral regimens recommended in guidelines for the treatment of HIV in adults and adolescents, pediatric patients, and patients with perinatal HIV infection (only in patients who are negative for human leukocyte antigen [HLA]-B*5701).200,201,202,300

Clinical Experience

Antiretroviral-naïve Adults and Adolescents

Efficacy of a non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimen of efavirenz and the dual nucleoside reverse transcriptase inhibitor (NRTI) option of abacavir and lamivudine was evaluated in a randomized, double-blind study (study CNA30024) in 649 HIV-infected, treatment-naïve adults (median baseline CD4+ T-cell count 264/mm³, median baseline plasma HIV-1 RNA level 4.79 log₁₀ copies/mL).1,78 Patients were randomized to receive a 3-drug regimen of abacavir (300 mg twice daily), lamivudine (150 mg twice daily), and efavirenz (600 mg once daily) or a 3-drug regimen of zidovudine (300 mg twice daily), lamivudine (150 mg twice daily), and efavirenz (600 mg once daily).1,78 At week 48 (intent-to-treat analysis), about 69% of patients in both treatment groups had plasma HIV-1 RNA levels of 50 copies/mL or less.1,78 At week 48, the mean increase from baseline CD4+ T-cell count was 209/mm³ in those receiving abacavir, lamivudine, and efavirenz and 155/mm³ in those receiving zidovudine, lamivudine, and efavirenz.1,78

Efficacy of the triple NRTI regimen of abacavir, lamivudine, and zidovudine was evaluated in a randomized, double-blind study (study CNA3005) in 562 HIV-infected, treatment-naïve adults (median baseline CD4+ T-cell counts 359-360/mm³, median baseline plasma HIV-1 RNA levels 4.8-4.9 log₁₀ copies/mL).26 Patients were randomized to receive a 3-drug regimen of abacavir (300 mg twice daily) and the fixed-combination preparation containing lamivudine and zidovudine (lamivudine/zidovudine; Combivir^®; 150 mg of lamivudine and 300 mg of zidovudine twice daily) or a 3-drug regimen of indinavir (800 mg every 8 hours), lamivudine (150 mg twice daily), and zidovudine (300 mg twice daily).26 At week 48, 51% of patients in both treatment groups had plasma HIV-1 RNA levels <400 copies/mL; 40% of those receiving abacavir, lamivudine, and zidovudine and 46% of those receiving indinavir, lamivudine, and zidovudine had plasma HIV-1 RNA levels of 50 copies/mL or less (intent-to-treat analysis).26 In patients with baseline HIV-1 RNA levels exceeding 100,000 copies/mL, a greater proportion of those who received the indinavir-containing regimen (45%) had plasma HIV-1 RNA levels <50 copies/mL than those who received the abacavir-containing regimen (31%).26 The median change in CD4+ T-cell count at 48 weeks was similar in both treatment groups.26

The comparative efficacy of a once- or twice-daily abacavir regimen used with lamivudine in an NNRTI-based regimen was evaluated in a randomized, double-blind study (study CNA30021) in 770 HIV-infected, treatment-naïve adults (median baseline CD4+ T-cell count 262/mm³ and median baseline plasma HIV-1 RNA level 4.89 log₁₀ copies/mL).1,79 Patients were randomized to receive a regimen of abacavir (600 mg once daily), lamivudine (300 mg once daily), and efavirenz (600 mg once daily) or abacavir (300 mg twice daily), lamivudine (300 mg once daily), and efavirenz (600 mg once daily).1,79 At week 48 (intent-to-treat analysis), 64 or 65% of patients receiving abacavir once or twice daily, respectively, had plasma HIV-1 RNA levels <50 copies/mL.1 At week 48, the mean increase from baseline CD4+ T-cell count was 188/mm³ in those receiving abacavir once daily and 200/mm³ in those receiving abacavir twice daily.1,79

In the randomized, open-label, multicenter, Altair study, a quadruple NRTI regimen (abacavir, emtricitabine, tenofovir disoproxil fumarate [DF], zidovudine) was compared to a standard NNRTI- or protease inhibitor (PI)-based regimen in 322 adults with previously-untreated HIV.122 After 48 weeks of treatment, the abacavir-containing quadruple NRTI regimen was found to be noninferior to the NNRTI- and PI-based regimens for reduction in plasma HIV RNA from baseline.122 However, reduction in plasma HIV RNA from baseline was substantially greater with the NNRTI- and PI-based regimens than with the abacavir-containing quadruple NRTI regimen, and substantially fewer patients receiving the quadruple NRTI regimen achieved HIV-1 RNA levels below 200 copies/mL.122

Antiretroviral-experienced Adults and Adolescents

A triple NRTI regimen that includes abacavir (300 mg twice daily) and a fixed dose combination of lamivudine and zidovudine (Combivir^®; 150 mg of lamivudine and 300 mg of zidovudine twice daily) has been evaluated in a 48-week, open-label study in HIV-infected patients who previously received antiretroviral regimens that included 1 or 2 NRTIs without any other antiretroviral agents.33 At the start of the study, 34% of patients had baseline plasma HIV-1 RNA levels <400 copies/mL and 11% had levels <50 copies/mL; the median CD4+ T-cell count was 506/mm³.33 At 48 weeks, 82% of patients had plasma HIV-1 RNA levels <400 copies/mL and 56% had levels <50 copies/mL (intent-to-treat analysis).33 Patients with baseline HIV-1 RNA levels <5000 copies/mL were more likely to achieve levels <400 copies/mL at week 48 than those with baseline levels exceeding 5000 copies/mL.33 At 48 weeks, the median change from baseline CD4+ T-cell count was 66 cells/mm³.33

In the randomized, open-label, multicenter, NEFA study, 460 patients receiving a PI and 2 NRTIs who had maintained plasma HIV-1 RNA levels <200 copies/mL for at least 6 months but wished to change to a regimen that did not include a PI randomized to switch from their existing PI to abacavir, efavirenz, or nevirapine while maintaining the existing NRTIs.125 At 12 months, 13, 6, or 10% of patients switched to abacavir, efavirenz, or nevirapine, respectively, had experienced death, progression to acquired immunodeficiency syndrome (AIDS), or an increase in plasma HIV-1 RNA levels to 200 copies/mL or more (intent-to-treat analysis).125

Antiretroviral-naïve Pediatric Patients

The comparative efficacy of 3 different NRTI options was evaluated in 128 antiretroviral-naïve HIV-infected pediatric patients 3 months to 16 years of age (median age 5.4 years, median baseline CD4 percentage 22%, mean baseline HIV-1 RNA 5.1 log₁₀ copies/mL) who were randomized to receive open-label dual NRTI options of abacavir and lamivudine, abacavir and zidovudine, or zidovudine and lamivudine with or without nelfinavir (Penta 5 study).126,127 Asymptomatic patients (n=55) were randomized to receive nelfinavir or placebo, while patients with more advanced HIV disease received open-label nelfinavir.126,127 At 48 weeks, intent-to-treat analysis indicated that reductions in plasma HIV-1 RNA levels were greater in children receiving an abacavir-containing dual NRTI option (decrease of 2.19 log₁₀ copies/mL with abacavir and zidovudine or 2.63 log₁₀ copies/mL with abacavir and lamivudine) than in those receiving the option containing zidovudine and lamivudine (decrease of 1.71 log₁₀copies/mL).127 At 5 years (intent-to-treat analysis in patients randomized to receive nelfinavir), plasma HIV-1 RNA levels were <50 copies/mL in 69% of those randomized to receive abacavir and lamivudine compared with 26 or 33% of those randomized to receive abacavir and zidovudine or zidovudine and lamivudine, respectively.126

Efficacy of abacavir and lamivudine in conjunction with other antiretrovirals was evaluated in a randomized, open-label, parallel-group study in 1206 HIV-1-infected treatment-naïve infants, children, and adolescents 3 months to 17 years of age (ARROW).1,134,228 After a minimum of 36 weeks of treatment with a first-line regimen containing the dual NRTI option of abacavir and lamivudine (administered twice daily) in conjunction with a ritonavir-boosted PI or NNRTI, the comparative efficacy of a once- or twice-daily regimen of abacavir and lamivudine in conjunction with other antiretrovirals was evaluated in 669 patients weighing at least 25 kg (median age 5.5 years, 52% female, median time on twice-daily abacavir and lamivudine regimen 1.8 years).1,134,228 Patients were randomized in a 1:1 ratio to receive a once- or twice-daily regimen of abacavir and lamivudine (given as single-entity preparations or as abacavir/lamivudine) in conjunction with other antiretrovirals.1,134,228 At the time of randomization, 71% of those in the once-daily group and 75% of those in the twice-daily group were virologically suppressed.1,134,228 At 96 weeks, 67% of those receiving a once-daily regimen and 70% of those receiving a twice-daily regimen of abacavir and lamivudine achieved HIV-1 RNA levels <80 copies/mL.228

Antiretroviral-experienced Pediatric Patients

Efficacy of a triple NRTI regimen of abacavir, lamivudine, and zidovudine in antiretroviral-experienced pediatric patients has been evaluated in a phase 3, randomized, double-blind study (study CNA3006) that included 205 HIV-infected children 3 months to 13 years of age (median age: 5.4 years, 56% female, 17% white, 50% African American, 30% Hispanic, median baseline CD4+ T-cell percentage 27%, median baseline plasma HIV-1 RNA levels 4.6 log₁₀ copies/mL);1,34 more than 50% had previously received NRTI therapy for longer than 2 years.34 Children were randomized to receive a 3-drug regimen of abacavir (8 mg/kg twice daily), lamivudine (4 mg/kg twice daily), and zidovudine (180 mg/m² twice daily) or a 2-drug regimen of lamivudine (4 mg/kg twice daily) and zidovudine (180 mg/m² twice daily).1,34 At week 16, the median CD4+ T-cell count increase from baseline was 69 or 9/mm³ in those receiving the 3- or 2-drug regimen, respectively.1 At week 48, 17 or 2% of those receiving the 3- or 2-drug regimen, respectively, had plasma HIV-1 RNA levels of 400 copies/mL or less (as-treated analysis).34 The median decrease from baseline in plasma HIV-1 RNA was two- to three-fold greater in those receiving the 3-drug regimen than in those receiving the 2-drug regimen.34

Clinical Perspective

Therapeutic options for the treatment and prevention of HIV infection and recommendations concerning the use of antiretrovirals are continuously evolving.200,201,202 Antiretroviral therapy (ART) is recommended for all individuals with HIV regardless of CD4 counts, and should be initiated as soon as possible after diagnosis of HIV and continued indefinitely.200,201,202 The primary goals of ART are to achieve and maintain durable suppression of HIV viral load (as measured by plasma HIV-1 RNA levels) to a level below which drug-resistance mutations cannot emerge (i.e., below detectable limits), restore and preserve immunologic function, reduce HIV-related morbidity and mortality, improve quality of life, and prevent transmission of HIV.200,202 While the most appropriate antiretroviral regimen cannot be defined for each clinical scenario, the US Department of Health and Human Services (HHS) Panel on Antiretroviral Guidelines for Adults and Adolescents, HHS Panel on Antiretroviral Therapy and Medical Management of Children Living with HIV, and HHS Panel on Treatment of Pregnant Women with HIV Infection and Prevention of Perinatal Transmission, have developed comprehensive guidelines that provide information on selection and use of antiretrovirals for the treatment or prevention of HIV infection.200,201,202 Because of the complexity of managing patients with HIV, it is recommended that clinicians with HIV expertise be consulted when needed.200,201,202

The use of combination antiretrovial regimens that generally include 3 drugs from 2 or more drug classes is currently recommended to achieve viral suppression.200,201 In both treatment-naïve adults and children, an initial antiretroviral regimen generally consists of 2 NRTIs administered in combination with a third active antiretroviral drug from 1 of 3 drug classes: an INSTI, NNRTI, or a PI with a pharmacokinetic enhancer (also known as a booster; the 2 drugs used for this purpose are cobicistat and ritonavir).200,201,202 Selection of an initial regimen should be individualized based on factors such as virologic efficacy, toxicity, pill burden, dosing frequency, drug-drug interaction potential, resistance-test results, comorbid conditions, access, and cost.200,201,202 In patients with comorbid infections (e.g., hepatitis B, tuberculosis), regimen selection should also consider the potential for activity against other present infections and timing of initiation relative to other anti-infective regimens.200

Abacavir, an NRTI, is commonly used as part of a dual-NRTI “backbone” of a fully suppressive antiretroviral regimen.200 In the 2022 HHS adult and adolescent HIV treatment guideline, abacavir is included in various regimens.200 An abacavir-containing regimens is listed among recommended initial regimens for most people with HIV: dolutegravir/abacavir/lamivudine (onlyin patients who are negative for HLA-B*5701).200

In the 2022 HHS pediatric HIV treatment guideline, abacavir is included in various antiretroviral regimens.201 Abacavir plus lamivudine or emtricitabine is recommended as the preferred dual-NRTI combination for children aged ≥3 months and, based on observational and pharmacokinetic data, for full-term infants from birth (onlyin patients who are negative for HLA-B*5701).201

In the 2022 HHS perinatal HIV treatment guideline, abacavir is included in various antiretroviral regimens.202 Some of these abacavir-containing regimens are listed among preferred initial options for pregnant patients, and include the following regimen: dolutegravir/abacavir/lamivudine (onlyin patients who are negative for HLA-B*5701).202 Additionally, abacavir plus lamivudine is recommended as one of the preferred dual-NRTI backbones for pregnant patients.202

Postexposure Prophylaxis following Occupational Exposure to HIV

Abacavir is used in conjunction with other antiretroviral agents for postexposure prophylaxis of HIV infection following occupational exposure† (PEP) in health-care personnel and other individuals exposed via percutaneous injury (e.g., needlestick, cut with sharp object) or mucous membrane or nonintact skin (e.g., chapped, abraded, dermatitis) contact with blood, tissue, or other body fluids that might contain HIV (only in patients who are negative for HLA-B*5701).199 Abacavir is not recommended for use as postexposure prophylaxis following nonoccupational exposure to HIV due to time required for testing for HLA-B*5701.198

The US Public Health Service (USPHS) states that the preferred regimen for PEP following an occupational exposure to HIV is a 3-drug regimen of raltegravir used in conjunction with emtricitabine and tenofovir DF (may be administered as the fixed combination emtricitabine/tenofovir DF; Truvada^®).199 These experts recommend several alternative regimens that include an INSTI, NNRTI, or PI and 2 NRTIs (dual NRTIs).199 The preferred dual NRTI option for use in PEP regimens is emtricitabine and tenofovir DF (may be administered as the fixed combination emtricitabine/tenofovir DF; Truvada^®); alternative dual NRTIs are tenofovir DF and lamivudine, lamivudine and zidovudine (may be administered as the fixed combination lamivudine/zidovudine; Combivir^®), or zidovudine and emtricitabine.199 Abacavir is considered an alternative agent that should be used only in consultation with an HIV expert, as testing for HLA-B*5701 is required prior to use and may not be available or practical for initiating PEP.199

Because management of occupational exposures to HIV is complex and evolving, consultation with an infectious disease specialist, clinician with expertise in administration of antiretroviral agents, and/or the National Clinicians' Postexposure Prophylaxis Hotline (PEPline at 888-448-4911) is recommended whenever possible.199 However, initiation of PEP should not be delayed while waiting for expert consultation.199

General

Pretreatment Screening

• Screen all patients for the human leukocyte antigen (HLA)-B*5701 allele before abacavir or a fixed-combination preparation containing abacavir is initiated or reinitiated, unless there is documentation of previous HLA-B*5701 allele assessment.1,228,229,240,300 Abacavir and abacavir-containing preparations are contraindicated in HLA-B*5701-positive individuals.1,228,229,240

Administration

Abacavir sulfate is administered orally once or twice daily without regard to meals.1 If a dose of abacavir is missed, administer the dose as soon as possible.1 Do not double the next dose or take more than the prescribed dose.1

Abacavir is commercially available as a single entity preparation and in the following fixed-combination tablets for oral use: abacavir and lamivudine (Epzicom^®); abacavir, lamivudine, and zidovudine (Trizivir^®); and abacavir, dolutegravir, and lamivudine (Triumeq^® and Triumeq PD^®).1,228,229,240 Since the antiretroviral agents contained in the fixed combination preparations also may be available in single-entity or other fixed-combination preparations, exercise care to ensure that therapy is not duplicated if a fixed combination is used in conjunction with other antiretrovirals.1,228,229,240

Single-entity abacavir sulfate is commercially available as an oral solution or tablets.1

Abacavir oral solution is used in pediatric patients or when a solid oral dosage form is inappropriate.1

The scored 300-mg abacavir tablets are used in adults and may be used in children weighing 14 kg or greater who have undergone assessment demonstrating ability to reliably swallow tablets.1

Store abacavir tablets and oral solution between 20-25°C.1 The oral solution may also be refrigerated.1

Dosage

Abacavir is commercially available as abacavir sulfate; dosage is expressed in terms of abacavir.1

Pediatric Patients

Treatment of HIV Infection

The usual dosage of abacavir oral solution for the treatment of HIV-1 infection in pediatric patients 3 months of age and older is 8 mg/kg (up to 300 mg) twice daily or 16 mg/kg (up to 600 mg) once daily.1

In pediatric patients 3 months of age or older weighing 14 kg or more who can reliably swallow tablets, the usual dosage of abacavir tablets for the treatment of HIV-1 infection is based on weight.1 (See Table 1 and Table 2.)

Adults

Treatment of HIV Infection

The usual dosage of abacavir for the treatment of HIV-1 infection in adults is 600 mg once daily or 300 mg twice daily.1

Postexposure Prophylaxis following Occupational Exposure to HIV

For postexposure prophylaxis of HIV infection following occupational exposure† (PEP) in health-care personnel or other individuals, abacavir is administered in a dosage of 600 mg once daily in conjunction with other antiretrovirals.199

The PEP regimen should be initiated as soon as possible following occupational exposure to HIV (preferably within hours) and continued for 4 weeks, if tolerated.199

Special Populations

Renal Impairment

The manufacturer makes no specific dosage recommendations for single-entity abacavir in patients with renal impairment.1

Hepatic Impairment

If abacavir is used in adults with mild hepatic impairment (Child-Pugh class A), the manufacturer recommends that dosage of the drug for treatment of HIV-1 infection be reduced to 200 mg twice daily.1 To facilitate this dosage adjustment in these patients, the commercially available oral solution should be used (i.e., 10 mL twice daily).1 Abacavir is contraindicated in patients with moderate or severe hepatic impairment since safety, efficacy, and pharmacokinetics have not been established in these patients.1

Geriatric Patients

The manufacturer makes no specific dosage recommendations for single-entity abacavir in geriatric patients.1 Select dosage with caution due to age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.1

Contraindications

• Presence of the human leukocyte antigen (HLA)-B*5701 allele.1
• Moderate or severe hepatic impairment.1
• History of hypersensitivity reaction to abacavir.1

Warnings/Precautions

Warnings

A boxed warning regarding the risk of hypersensitivity reactions is included in the prescribing information of abacavir.1 Serious, sometimes fatal, hypersensitivity reactions including anaphylaxis and organ failure have been reported with abacavir or fixed-combination preparations containing abacavir (abacavir/lamivudine, abacavir/lamivudine/zidovudine).1,228,229,240 An association between presence of the HLA-B*5701 allele and abacavir hypersensitivity has been established, although hypersensitivity reactions have occurred in patients without the HLA-B*5701 allele.1 In clinical studies, hypersensitivity reactions were reported in approximately 8% of 2670 patients across 9 clinical trials receiving abacavir in conjunction with other antiretrovirals when screening for the HLA-B*5701 allele was not performed.1 When patients with the HLA-B*5701 allele were excluded from the analysis, the incidence of hypersensitivity reactions was 1%.1 The use of abacavir or fixed-combination preparations containing abacavir is considered a contraindication in patients with the HLA-B*5701 allele or a prior hypersensitivity reaction to abacavir.1,228,229,240

Manifestations of hypersensitivity usually are apparent within the first 6 weeks of abacavir therapy (median time to onset is 9 days), but may occur at any time.1 Severe hypersensitivity reactions can occur within hours following rechallenge in patients with a prior history of hypersensitivity to the drug, and these reactions may include life-threatening hypotension and death.1 There also have been reports of severe or fatal hypersensitivity reactions occurring after abacavir was reintroduced in patients with no identified history of abacavir hypersensitivity or with unrecognized manifestations of hypersensitivity to the drug.1

Hypersensitivity reactions reported in patients receiving abacavir are characterized by the appearance of manifestations indicating involvement of multiple organ and body systems; these reactions have occurred in association with anaphylaxis, liver failure, renal failure, hypotension, and death.1 The most frequent manifestations of abacavir hypersensitivity include signs or symptoms from at least 2 of the following: fever, rash, GI symptoms (including nausea, vomiting, diarrhea, abdominal pain), constitutional symptoms (including generalized malaise, fatigue, achiness), and respiratory symptoms (including pharyngitis, dyspnea, cough).1,47 Other signs and symptoms include lethargy, myalgia, chills, myolysis, headache, arthralgia, edema, tachycardia, abnormal chest radiographs (predominantly infiltrates, which may be localized), paresthesia, lymphadenopathy, and mucous membrane lesions (e.g., conjunctivitis, mouth ulceration).1,47 Adult respiratory distress syndrome and respiratory failure have occurred in association with hypersensitivity reactions.1 Hypersensitivity reactions can occur without rash; if rash occurs, it usually is maculopapular or urticarial, but may be variable in appearance.1 Erythema multiforme has been reported.1 Laboratory abnormalities reported in patients experiencing a hypersensitivity reaction to abacavir include lymphopenia and increases in serum concentrations of liver enzymes, creatine kinase (CK), creatine phosphokinase (CPK), or creatinine.1

Abacavir or fixed-combination preparations containing abacavir should be discontinued immediately in any individual who develops signs or symptoms suggesting hypersensitivity, regardless of HLA-B*5701 status and even when other diagnoses are possible.1 Clinical status, including liver function tests, should be monitored and appropriate therapy should be initiated.1 Abacavir and abacavir-containing preparations should never be reinitiated in any patient who experienced a hypersensitivity reaction while receiving the drug, regardless of the patient's HLA-B*5701 status; more severe symptoms may occur within hours and may include life-threatening hypotension and death.1 Similar severe reactions have also occurred rarely following the reintroduction of abacavir or abacavir-containing preparations in patients who have no history of abacavir hypersensitivity.1

Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported during postmarketing experience in patients receiving abacavir concomitantly with other drugs known to be associated with these severe adverse effects.1 In such cases, abacavir should be discontinued and should not be reinitiated because of the possibility that the patient may have multiple drug sensitivities and because the clinical signs and symptoms of Stevens-Johnson syndrome and toxic epidermal necrolysis are similar to those of abacavir hypersensitivity.1

Other Warnings and Precautions

Hepatic Effects and Lactic Acidosis

Lactic acidosis and severe hepatomegaly with steatosis, including some fatalities, have been reported rarely in patients receiving abacavir or fixed-combination preparations containing abacavir (abacavir/lamivudine, abacavir/dolutegravir/lamivudine, abacavir/lamivudine/zidovudine) and have also been reported in patients receiving other HIV nucleoside reverse transcriptase inhibitors (NRTIs).1,228,229,240 Female sex and obesity may be risk factors for development of lactic acidosis and severe hepatomegaly with steatosis.1 Suspend treatment with abacavir in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (e.g., hepatomegaly and steatosis even in the absence of markedly increased serum aminotransferase concentrations).1

Myocardial Infarction

Myocardial infarction (MI) has been reported in some patients receiving abacavir.1

Based on a totality of data from several prospective, observational, epidemiological studies and from controlled clinical trials, evidence to support a causal relationship between abacavir use and the risk of MI is inconclusive.1 In observational studies, an association between abacavir use and the risk of MI was reported; however, in meta-analyses of randomized clinical trials, no excess risk for MI development was observed.1 To date, there is no established biological mechanism to explain a potential increase in risk of MI.1

Consider the underlying risk of coronary heart disease prior to prescribing abacavir, and take action to reduce modifiable risk factors for heart disease (e.g., hypertension, hyperlipidemia, diabetes mellitus, smoking).1

Although the clinical importance has not been determined, myocardial degeneration was found in mice and rats following administration of abacavir for 2 years (systemic exposure equivalent to 7-24 times the expected systemic exposure in humans).1

Immune Reconstitution Syndrome

Immune reconstitution syndrome has been reported in HIV-infected patients receiving multiple-drug antiretroviral therapy, including abacavir.1 During the initial phase of treatment, HIV-infected patients whose immune systems respond to antiretroviral therapy may develop an inflammatory response to indolent or residual opportunistic infections (e.g., Mycobacterium avium complex [MAC], M. tuberculosis , cytomegalovirus [CMV], Pneumocystis jirovecii [formerly P. carinii ]); such responses may necessitate further evaluation and treatment.1

Autoimmune disorders (e.g., Graves' disease, polymyositis, Guillain-Barré syndrome) also have been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable and can occur many months after initiation of antiretroviral therapy.1

Specific Populations

Pregnancy

To monitor maternal-fetal outcomes of pregnant women exposed to antiretroviral agents, including abacavir, the Antiretroviral Pregnancy Registry (APR) was established.1 Clinicians are encouraged to contact the registry at 800-258-4263 to report cases of prenatal exposure to antiretroviral drugs.1

Based on prospective reports to the APR of exposures to abacavir during pregnancy resulting in live births (including over 1,300 exposed in the first trimester and over 1,300 exposed in the second/third trimester), there was no difference between the overall risk of birth defects for abacavir compared with the background birth defect rate of 2.7% in the U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP).1 Use of the MACDP population as the comparator group has several limitations; the MACDP assesses populations from a limited geographic area and does not include outcomes for births that occurred at <20 weeks' gestation.1 The rate of miscarriage is not reported in the APR.1

Abacavir crosses the placenta and is distributed into cord blood in concentrations similar to maternal serum concentrations.1 Concentrations in neonatal plasma at birth were essentially equal to those in maternal plasma at delivery.1 In animal reproductive studies, abacavir administration during organogenesis resulted in developmental toxicities (i.e., depressed fetal body weight, reduced crown-rump length) and fetal malformations (i.e., fetal anasarca, skeletal malformations) based on abacavir exposure 35 times the usual human exposure (based on AUC).1 No developmental effects were observed at exposures 3.5-times the usual human exposure (based on AUC).1

Lactation

Abacavir is distributed into human milk.1 The effects of abacavir on the breastfed infant, or the effects of the drug on milk production are not known.1

Because of the risk of transmission of HIV to an uninfected infant through breast milk, the US Centers for Disease Control and Prevention (CDC) and other experts recommend that HIV-infected women not breast-feed infants, regardless of antiretroviral therapy.1,202 Therefore, because of the potential for HIV transmission and the potential for serious adverse effects from abacavir if the drug were distributed into milk, women should be instructed not to breast-feed while they are receiving abacavir.1

Females and Males of Reproductive Potential

There was no evidence that abacavir affected fertility in male or female rats when exposed to approximately 3.3 and 4.1 times, respectively, the usual human exposure (based on body surface area).1

Pediatric Use

Safety and efficacy of single-entity abacavir tablets or oral solution have been established in infants and children 3 months of age and older.1 Use of abacavir in children 3 months of age and older is supported by pharmacokinetic trials and evidence from adequate and well-controlled trials in adult and pediatric patients.1 Safety and efficacy have not been established in neonates and infants less than 3 months of age.1

Geriatric Use

While clinical experience to date has not revealed age-related differences in response to abacavir, clinical studies evaluating abacavir have not included sufficient numbers of adults 65 years of age or older to determine whether geriatric patients respond differently than younger adults.1 Dosage of abacavir for geriatric patients should be selected carefully because of limited experience with the drug in this age group and because these individuals frequently have decreased hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.1

Hepatic Impairment

A reduction in dosage is recommended if abacavir is used in patients with mild hepatic impairment (Child-Pugh class A).1 Pharmacokinetic study showed a mean increase of 89% in the abacavir AUC and an increase of 58% in half-life after a single dose of 600 mg of abacavir.1 Safety, efficacy, and pharmacokinetics of abacavir have not been established in patients with moderate or severe hepatic impairment and the drug is contraindicated in such patients.1

Renal Impairment

The pharmacokinetic properties of abacavir have not been evaluated in impaired renal function; the excretion of unchanged abacavir via renal elimination is considered minor.1

Common Adverse Effects

Adverse effects of at least moderate intensity reported in 10% or more of adult patients receiving abacavir for HIV-1 infection include nausea, headache, fatigue and malaise, nausea and vomiting, and dreams/sleep disorders.1

Adverse effects of at least moderate intensity reported in 5% or more of pediatric patients receiving abacavir for HIV-1 infection include fever and/or chills, nausea and vomiting, skin rash, and ear, nose, and throat infections.1

In vitro studies indicate that abacavir has the potential to inhibit cytochrome P-450 (CYP) isoenzyme 1A1, and has limited potential to inhibit CYP3A4.1 Abacavir does not induce nor inhibit CYP2C9 or CYP2D6.1 At therapeutic exposures, abacavir is not expected to affect substrates of organic anion transporter polypeptide (OATP)1B1 or OATP1B3, 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.1

In vitro studies indicate that abacavir is a substrate of BCRP and P-gp; however, the concomitant use of modulators of these transporters is not expected to have clinically relevant effects on abacavir serum concentrations.1 In vitro studies indicate that abacavir is not a substrate of OATP1B1, OAP1B3, OCT1, OCT2, OAT1, MATE1, MATE2-K, or multidrug resistance-associated protein (MRP)2, or MRP4; therefore, the concomitant use of agents that modulate these transporters is not expected to affect abacavir serum concentrations.1

The following drug interactions are based on studies using abacavir.1 Additional drug interactions may exist for fixed-dose combinations containing abacavir and lamivudine (Epzicom^®); abacavir, lamivudine, and zidovudine (Trizivir^®); and abacavir, dolutegravir, and lamivudine (Triumeq^® and Triumeq PD^®).228,229,240 See the full prescribing information for drug interactions of each of these combination products.228,229,240

Antiretroviral Agents

HIV Nonnucleoside Reverse Transcriptase Inhibitors (NNRTIs)

In vitro studies indicate there are no antagonistic antiretroviral effects of nevirapine, a nonnucleoside reverse transcriptase inhibitor (NNRTI), on abacavir antiretroviral activity against HIV-1.1

HIV Nucleoside and Nucleotide Reverse Transcriptase Inhibitors (NRTIs)

Results of in vitro studies using HIV-1 indicate that the antiretroviral effects of abacavir are not antagonized by other nucleoside reverse transcriptase inhibitors (NRTIs), including didanosine, emtricitabine, lamivudine, tenofovir disoproxil fumarate (tenofovir DF), and zidovudine.1

Lamivudine and Zidovudine

Clinically important pharmacokinetic interactions have not been observed when abacavir, lamivudine, and zidovudine were used concurrently.1 In a crossover study evaluating concomitant use of single doses of abacavir (600 mg), lamivudine (150 mg), and zidovudine (300 mg) in HIV-infected individuals, the pharmacokinetic parameters of abacavir were unchanged when administered with lamivudine and/or zidovudine.1 The AUC of lamivudine was decreased 15% and the AUC of zidovudine increased 10% when used concomitantly with abacavir.1

HIV Protease Inhibitors (PIs)

Amprenavir

In vitro, amprenavir had no impact on the antiretroviral activity of abacavir against HIV-1.1

Alcohol

Although alcohol and abacavir are both metabolized by alcohol dehydrogenase, clinically important drug interactions are not expected between abacavir and alcohol.1 Following oral administration of a single oral dose of abacavir 600 mg and alcohol 0.7 g/kg (about 5 alcoholic drinks) in HIV-infected men, AUC) of abacavir was increased 41% and the elimination half-life of the drug was increased 26%.1 There was no change in the pharmacokinetic parameters of alcohol.1 Concomitant use of abacavir and alcohol has not been investigated in women.1

Methadone

Concomitant use of methadone and abacavir may increase clearance of methadone, but does not affect the pharmacokinetics of abacavir.1 In a limited number of HIV-infected individuals receiving maintenance therapy with methadone (40 or 90 mg daily), concomitant use of abacavir 600 mg twice daily (twice the usual recommended adult dosage) resulted in a 22% increase in methadone clearance.1

The manufacturer of abacavir states that, although an increase in methadone dosage may be required in a small number of patients because of a pharmacokinetic interaction, most patients will not need modification of methadone dosage.1

Ribavirin

In vitro, ribavirin had no effect on the antiretroviral activity of abacavir against HIV-1.1

Riociguat

Concomitant use of riociguat and abacavir may result in increased exposure to riociguat due to CYP1A1 inhibition by abacavir, thus increasing the risk for adverse reactions associated with riociguat use.1 The exact magnitude of increase in riociguat exposure is not fully characterized, and dose reductions of riociguat may be necessary.1 Consult the prescribing information for riociguat dose reduction recommendations.1

Description

Following conversion to a pharmacologically active metabolite, abacavir inhibits replication of retroviruses, including human immunodeficiency virus type 1 (HIV-1) and type 2 (HIV-2), by interfering with viral RNA-directed DNA polymerase (reverse transcriptase).1,2,3,4 The drug, therefore, exerts a virustatic effect against retroviruses by acting as a reverse transcriptase inhibitor.1,2,3,4

Like other HIV nucleoside reverse transcriptase inhibitors (NRTIs), including didanosine, emtricitabine, lamivudine, and zidovudine, the antiviral activity of abacavir is dependent upon intracellular conversion of the drug to a 5'-triphosphate metabolite.1,2,3,4 Carbovir triphosphate (carbocyclic guanosine triphosphate) appears to be the pharmacologically active form of the drug.1,2,3,4 Substantial differences exist in the rates at which human cells phosphorylate various NRTIs and in the enzymatic pathways involved.3,6

Enzymatic conversion of abacavir to carbovir triphosphate is complex and involves certain steps and enzymes that differ from those involved in the enzymatic conversion of dideoxynucleoside reverse transcriptase inhibitors.3,6 Abacavir is phosphorylated by adenosine phosphotransferase to abacavir monophosphate, which is converted to carbovir monophosphate by a cytosolic enzyme.3,6 Subsequently, carbovir monophosphate is phosphorylated by cellular kinases to carbovir triphosphate.1,3,6 Abacavir is not a substrate for enzymes (i.e., thymidine kinase, deoxycytidine kinase, adenosine kinase, mitochondrial deoxyguanosine kinase) known to phosphorylate other nucleoside analogs.3 Because phosphorylation of abacavir depends on cellular rather than viral enzymes, conversion of the drug to the active triphosphate derivative occurs in both virus-infected and uninfected cells.3 Carbovir triphosphate is a structural analog of deoxyguanosine-5'-triphosphate (dGTP), the usual substrate for viral RNA-directed DNA polymerase.1,2,3,6 Although other mechanisms may be involved in the antiretroviral activity of the drug, carbovir triphosphate appears to compete with deoxyguanosine-5'-triphosphate for viral RNA-directed DNA polymerase and incorporation into viral DNA.1,2 Following incorporation of carbovir triphosphate into the viral DNA chain instead of deoxyguanosine-5'-triphosphate, DNA synthesis is prematurely terminated because the absence of the 3'-hydroxy group on the drug prevents further 5' to 3' phosphodiester linkages.1,2

Abacavir is rapidly absorbed following oral administration, with similar AUCs observed following the use of the oral solution or tablets.1 The geometric mean absolute oral bioavailability of abacavir sulfate tablets is 83%.1 In HIV-infected adults receiving abacavir in a dosage of 300 mg twice daily (given as abacavir succinate), peak plasma concentration and AUC_{(0-12 hours)} of the drug at steady-state averaged 3 mcg/mL and 6.02 mcg•hour/mL, respectively.1 In studies in HIV-infected adults employing oral abacavir dosages of 300-1200 mg daily (given as abacavir succinate), the pharmacokinetics of the drug were independent of the dose.1 Administration of abacavir tablets either during a fasting or fed state does not significantly impact systemic exposure.1 In pediatric patients, abacavir exposure is expected to be similar regardless of whether the scored tablet or oral solution is administered.1 According to the manufacturer, abacavir tablets and oral solution can be used interchangeably.1 After single and multi-dose regimens of abacavir oral solution at recommended dosages in pediatric subjects, serum concentrations of abacavir were similar to those in adult patients.1 In crossover studies of pediatric subjects 3 months to 12 years of age receiving abacavir and lamivudine, the use of abacavir oral solution and tablets given once daily resulted in similar exposure to abacavir given twice daily when the same total daily dosage was administered.1 In these studies, the mean peak plasma concentrations of abacavir were approximately 1.6- to 2.3-fold higher when the same total daily abacavir dosage was administered once versus twice daily.1

Abacavir is about 50% bound to plasma proteins; binding of abacavir to plasma proteins is independent of drug concentration.1 Abacavir is distributed into CSF.1 Following administration of radiolabeled abacavir, total blood- and plasma-drug related radioactivity are identical; these results indicate abacavir readily distributes into erythrocytes.1 Following oral administration of a 600-mg dose of radiolabeled abacavir, 82.2% of the dose is excreted in urine and 16% of the dose is excreted in feces.1 The 5'-carboxylic acid metabolite, 5'-glucuronide metabolite, and unchanged abacavir accounted for 30, 36, and 1.2%, respectively, of recovered radioactivity in urine; unidentified minor metabolites accounted for 15% of recovered radioactivity in urine.1 Abacavir is metabolized by alcohol dehydrogenase to form the 5'-carboxylic acid and by glucuronyltransferase to form the 5'-glucuronide; these metabolites do not appear to have any antiviral activity.1 Any involvement of cytochrome P-450 isoenzymes in the metabolism of abacavir is limited.1 The plasma elimination half-life of abacavir following a single oral dose (given as abacavir sulfate) is about 1.5 hours.1 Systemic exposure of abacavir is not affected by gender or race (Black vs white patients).1

Spectrum

Abacavir has a limited spectrum of antiviral activity.1,2 Following intracellular conversion to a pharmacologically active 5'-triphosphate metabolite, abacavir is active in vitro against human and animal retroviruses, including HIV-1 and HIV-21,2 and feline immunodeficiency virus (Petaluma strain).2 Abacavir has some in vitro activity against hepatitis B virus (HBV) and cytomegalovirus (CMV), but has been inactive against other human viruses tested, including herpes simplex virus types 1 and 2, varicella-zoster virus, and influenza virus type A.2

The antiretroviral activity of abacavir has been evaluated in vitro in various cell culture systems, including lymphoblastoid cell lines, macrophage/monocyte cultures, and peripheral blood mononuclear cells.1,2,6

Retroviruses

Abacavir is active in vitro against HIV-1 and HIV-2.1,2,6 In a study evaluating the in vitro antiretroviral activity of abacavir, didanosine, and zidovudine using peripheral blood lymphocytes inoculated with clinical isolates of HIV-1 obtained from individuals who were treatment naïve (had not previously received antiretroviral agent therapy), abacavir was more active than didanosine and as active as zidovudine on a weight basis.2

When tested against HIV-1IIIb or HIV-1BaL, the concentration of abacavir required to inhibit viral replication by 50% (EC₅₀) ranged from 3.7-5.8 or 0.07-1.0 µM, respectively.1 When tested against 8 clinical isolates, the EC₅₀ of abacavir was 0.26 µM.1 The EC₅₀ of the drug ranged from 0.0015-1.05 µM against different HIV-1 clades (A-G) and 0.024-0.49 µM against HIV-2 isolates.1

Resistance

Strains of HIV-1 with reduced susceptibility to abacavir have been produced in vitro in cell culture by serial passage of the retrovirus in the presence of increasing concentrations of the drug.1,2,4,6 In addition, strains of HIV-1 with in vitro resistance to abacavir have emerged during therapy with the drug.1,2,6,16,60,61

Although the complete mechanism(s) of resistance or reduced susceptibility to abacavir has not been fully determined to date, mutation of HIV reverse transcriptase appears to be the principal mechanism.2,4,60 Acquisition of a single mutation can result in decreased susceptibility to abacavir; acquisition of multiple mutations generally is necessary for high-level resistance to the drug.1,2,4,49,60

Abacavir-resistant variants produced in vitro in the presence of increasing concentrations of the drug have contained one or more amino acid substitutions including K65R, L74V, Y115F, or M184V/I.4,16,60 These same substitutions have been identified in HIV-1 variants isolated from patients receiving abacavir in clinical studies; the substitution at amino acid position 184 is the most frequently observed change in clinical isolates.1,2,6,60,61,79 Substitutions at amino acid positions M184V or I result in an approximately two-fold decrease in abacavir susceptibility; substitutions at K65R, L74M, or Y115F with M184V or I confer a seven- to eight-fold decrease in abacavir susceptibility.1 Combinations of these substitutions result in a greater than eight-fold decrease in susceptibility.1

Cross-resistance

Cross-resistance between abacavir and other HIV NRTIs, including didanosine, emtricitabine, lamivudine, and tenofovir disoproxil fumarate (tenofovir DF) has been reported.1,4,6,16,49 There is evidence that HIV isolates that are highly resistant to multiple NRTIs also have reduced susceptibility to abacavir.6,16 Strains with the Q151M mutation (a mutation that appears to be associated with resistance against multiple NRTIs) also have reduced susceptibility to abacavir; these strains become highly resistant to abacavir when additional mutations conferring resistance to other nucleosides (e.g., V60I, K65R, V118I, M184V, T215Y) are present.16

Advice to Patients

• A medication guide and warning card must be provided to the patient each time abacavir or fixed combination containing abacavir is dispensed.1,228,229,240 The medication guide and warning card include information on symptoms of abacavir hypersensitivity reactions.1
• Advise patients to read the medication guide and warning card prior to initiating therapy and each time a prescription is refilled; advise patients to carry the warning card on their person.1
• Critical nature of compliance with HIV therapy and importance of remaining under the care of a clinician.1 Importance of taking abacavir as prescribed; do not alter or discontinue antiretroviral regimen without consulting clinician.1
• Advise patients that if they miss a dose of abacavir to take the dose as soon as they remember, and to not double their next dose.1
• Possibility of potentially fatal hypersensitivity reactions to abacavir.1 Discontinue the drug and consult clinician immediately if signs or symptoms of hypersensitivity, including fever, rash, GI symptoms (nausea, vomiting, diarrhea, abdominal pain), constitutional symptoms (generalized fatigue, malaise, achiness), or respiratory symptoms (sore throat, shortness of breath, cough) occur while receiving abacavir or abacavir-containing preparations.1,228,229,240
• Do not restart abacavir or abacavir-containing preparations after a hypersensitivity reaction since more severe symptoms may recur within hours, which may include life-threatening hypotension and death.1,228,229,240
• Advise patients that if abacavir therapy is interrupted for reasons other than hypersensitivity (e.g., interruption in drug supply), it should not be reinitiated without consulting a clinician since a severe or fatal hypersensitivity reaction can occur when the drug is reintroduced.1 Reinitiate the drug under such circumstances only if medical care is readily available.1
• Advise patients to dispose of unused abacavir after a hypersensitivity reaction occurs to avoid accidentally restarting the medication.1
• Advise patients that lactic acidosis and severe hepatomegaly have been reported.1 Advise patients to stop taking abacavir if symptoms of lactic acidosis or significant hepatotoxicity occur (e.g., yellowing of skin or eyes, nausea, dark urine, light-colored stool).1
• Advise patients to report signs and symptoms of infection as inflammation from a previous infection may occur after starting combination antiretroviral therapy including abacavir.1
• Importance of informing clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal products, and any concomitant illnesses.1
• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1 Advise HIV-infected women not to breast-feed.1
• Advise patients of other important precautionary information.1

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

1. ViiV Pharmaceuticals. Ziagen^® (abacavir sulfate) tablets and oral solution prescribing information. Research Triangle Park, NC; 2023 Sep.

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