Abacavir Sulfate

Name: Abacavir Sulfate

Introduction

Antiretroviral; HIV nucleoside reverse transcriptase inhibitor (NRTI).1 2 3 46 200

Abacavir Sulfate Dosage and Administration

General

Screen all patients for HLA-B*5701 allele before initiating or reinitiating abacavir or fixed combination containing abacavir.1 200 201 228 229 240 Abacavir and abacavir-containing preparations contraindicated in HLA-B*5701-positive individuals.1 200 201 228 229 240 (See Hypersensitivity Reactions under Cautions.)

Administration

Oral Administration

Abacavir (Ziagen): Administer orally once or twice daily without regard to meals.1 Use oral solution in pediatric patients or when solid oral dosage form is inappropriate.1 Use scored 300-mg tablets in adults, adolescents, and children weighing ≥14 kg who can reliably swallow tablets.1 Use in conjunction with other antiretrovirals for treatment of HIV-1.1

Abacavir/lamivudine (Epzicom): Administer orally once daily without regard to meals.228 Use in conjunction with other antiretrovirals for treatment of HIV-1.228

Abacavir/dolutegravir/lamivudine (Triumeq): Administer orally once daily without regard to meals.240 Use alone as a complete treatment regimen or in conjunction with other antiretrovirals for treatment of HIV-1.240

Abacavir/lamivudine/zidovudine (Trizivir): Administer orally twice daily without regard to meals.229 Use alone as a complete treatment regimen or in conjunction with other antiretrovirals for treatment of HIV-1.229

Do not use abacavir, abacavir/lamivudine, abacavir/dolutegravir/lamivudine, abacavir/lamivudine/zidovudine concomitantly with any other abacavir-containing preparation.1 228 229 240

Because antiretrovirals in the fixed combinations also are available in single-entity or other fixed-combination preparations, take care to ensure that therapy is not duplicated when a fixed combination is used in conjunction with other antiretrovirals.228 229 240 (See Precautions Related to Use of Fixed Combinations under Cautions.)

Dosage

Available as abacavir sulfate;1 dosage expressed in terms of abacavir.1

Pediatric Patients

Treatment of HIV Infection Oral

Abacavir (Ziagen oral solution) in children and adolescents ≥3 months of age: 8 mg/kg (up to 300 mg) twice daily or 16 mg/kg (up to 600 mg) once daily. 1 201 When oral solution used for initial therapy, experts recommend twice-daily regimen initially;201 then, based on response, consider switching to once-daily regimen after approximately 24 weeks of therapy.201

Abacavir (Ziagen tablets) in children weighing ≥14 kg able to swallow tablets: See Table 1 and Table 2.1 Although once- or twice-daily regimen can be used, experts recommend once-daily regimen.201

Table 1. Twice-daily Regimen in Children and Adolescents Weighing ≥14 kg Able to Swallow Tablets (Ziagen 300-mg Tablets)1

Weight (kg)

AM dose

PM dose

14 to <20

150 mg (half tablet)

150 mg (half tablet)

20 to <25

150 mg (half tablet)

300 mg

≥25

300 mg

300 mg

Table 2. Once-daily Regimen in Children and Adolescents Weighing ≥14 kg Able to Swallow Tablets (Ziagen 300-mg Tablets)1

Weight (kg)

Once-daily dose

14 to <20

300 mg

20 to <25

450 mg (one and one-half tablets)

≥25

600 mg (2 tablets)

Abacavir/lamivudine (Epzicom) in children and adolescents weighing ≥25 kg: 1 tablet (abacavir 600 mg and lamivudine 300 mg) once daily.228

Abacavir/lamivudine/zidovudine (Trizivir) in pediatric patients weighing ≥40 kg: 1 tablet (abacavir 300 mg, lamivudine 150 mg, and zidovudine 300 mg) twice daily.200 229

Adults

Treatment of HIV Infection Oral

Abacavir (Ziagen): 300 mg twice daily or 600 mg once daily.1

Abacavir/lamivudine (Epzicom): 1 tablet (abacavir 600 mg and lamivudine 300 mg) once daily.228

Abacavir/dolutegravir/lamivudine (Triumeq): 1 tablet (600 mg of abacavir, 50 mg of dolutegravir, and 300 mg of lamivudine) once daily.240

Abacavir/lamivudine/zidovudine (Trizivir): 1 tablet (abacavir 300 mg, lamivudine 150 mg, and zidovudine 300 mg) twice daily.229

Postexposure Prophylaxis of HIV following Occupational Exposure (PEP)† Oral

Abacavir (Ziagen): 600 mg once daily.199 Use in conjunction with other antiretrovirals (see Postexposure Prophylaxis following Occupational Exposure to HIV under Uses).199

Initiate PEP as soon as possible following occupational exposure to HIV (preferably within hours); continue for 4 weeks, if tolerated.199

Prescribing Limits

Pediatric Patients

Treatment of HIV Infection Oral

Abacavir (Ziagen) in children ≥3 months of age: Maximum 300 mg twice daily or 600 mg once daily.1

Special Populations

Hepatic Impairment

Treatment of HIV Infection Oral

Abacavir (Ziagen) in adults with mild hepatic impairment (Child-Pugh score 5–6): 200 mg twice daily (i.e., 10 mL of oral solution twice daily).1 Contraindicated in those with moderate or severe hepatic impairment.1

Abacavir/lamivudine, abacavir/dolutegravir/lamivudine, abacavir/lamivudine/zidovudine: Not recommended in patients with mild hepatic impairment.228 229 240 Contraindicated in those with moderate or severe hepatic impairment.228 229 240

Renal Impairment

Treatment of HIV Infection

Abacavir (Ziagen): Dosage recommendations not available for patients with impaired renal function.1 45 46 Some experts state dosage adjustments not needed.200

Abacavir/lamivudine, abacavir/dolutegravir/lamivudine, abacavir/lamivudine/zidovudine: Not recommended in patients with Clcr <50 mL/minute.228 229 240

Geriatric Patients

Abacavir (Ziagen): Select dosage with caution because of age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.1

Abacavir/lamivudine, abacavir/dolutegravir/lamivudine, abacavir/lamivudine/zidovudine: Use with caution.228 229 240 (See Geriatric Use under Cautions.)

Cautions for Abacavir Sulfate

Contraindications

  • Abacavir, abacavir/lamivudine, abacavir/dolutegravir/lamivudine, abacavir/lamivudine/zidovudine: HLA-B*5701-positive patients.1 228 229 240 (See Hypersensitivity Reactions under Cautions.)

  • Abacavir, abacavir/lamivudine, abacavir/dolutegravir/lamivudine, abacavir/lamivudine/zidovudine: Previous hypersensitivity reaction to abacavir or any ingredient in the formulation.1 228 229 240 (See Hypersensitivity Reactions under Cautions.)

  • Abacavir, abacavir/lamivudine, abacavir/dolutegravir/lamivudine, abacavir/lamivudine/zidovudine: Moderate or severe hepatic impairment.1 228 229 240

  • Abacavir/dolutegravir/lamivudine: Concomitant use with dofetilide.240

Warnings/Precautions

Warnings

Hypersensitivity Reactions

Serious, sometimes fatal, hypersensitivity reactions reported with abacavir or fixed combinations containing abacavir (abacavir/lamivudine, abacavir/dolutegravir/lamivudine, abacavir/lamivudine/zidovudine).1 228 229 240

Hypersensitivity manifestations usually involve ≥2 of the following groups: fever, rash, GI (e.g., nausea, vomiting, diarrhea, abdominal pain), constitutional (e.g., generalized malaise, fatigue, achiness), and respiratory (e.g., pharyngitis, dyspnea, cough).1 47 228 229 240 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) also may occur.1 47 228 229 240

Usually apparent within first 6 weeks of abacavir therapy (median time to onset is 9 days), but may occur at any time during therapy.1 50 228 229 240 Incidence may be greater in those receiving once-daily abacavir than in those receiving twice-daily abacavir.1 80 81

Patients carrying the HLA-B*5701 allele are at higher risk for abacavir hypersensitivity,1 71 85 86 87 89 228 229 240 although hypersensitivity reactions also reported in those who do not carry the HLA-B*5701 allele.1 228 229 240 Negative result on HLA-B*5701 testing does not absolutely rule out possibility of some form of hypersensitivity reaction.71 86 87 90 98

Screen all patients for HLA-B*5701 allele prior to initiating or reinitiating abacavir or fixed combination containing abacavir.1 200 201 228 229 240

Abacavir and abacavir-containing preparations contraindicated in patients positive for HLA-B*5701 allele and in those with history of prior hypersensitivity reactions to abacavir.1 200 201 228 229 240

Immediately discontinue abacavir or abacavir-containing preparation as soon as a hypersensitivity reaction is first suspected.1 228 229 240 Monitor clinical status, including liver function tests, and initiate appropriate therapy.1 228 229 240 Never reinitiate abacavir or abacavir-containing preparation following a hypersensitivity reaction, regardless of HLA-B*5701 allele status and even when other diagnoses are possible (e.g., acute-onset respiratory disease, gastroenteritis, reactions to other drugs).1 228 229 240 If hypersensitivity is ruled out, manufacturer states abacavir or other abacavir-containing preparation may be reinitiated, but only if medical care is readily accessible.1 228 229 240 Severe or fatal hypersensitivity reactions can occur within hours after reintroduction of the drug in patients with no identified history of abacavir hypersensitivity or with unrecognized manifestations of hypersensitivity to the drug.1 65 69 228 229 240

Stevens-Johnson syndrome and toxic epidermal necrolysis reported during postmarketing experience in patients receiving abacavir concomitantly with other drugs known to be associated with these severe adverse effects.1 228 229 240 In such cases, discontinue abacavir and do not reinitiate the drug because patient may have multiple drug sensitivities.1 228 229 240 Manifestations of Stevens-Johnson syndrome and toxic epidermal necrolysis are similar to those of abacavir hypersensitivity.1 228 229 240 Erythema multiforme also reported with abacavir.1 228 229 240

Lactic Acidosis and Severe Hepatomegaly with Steatosis

Lactic acidosis and severe hepatomegaly with steatosis (sometimes fatal) reported in patients receiving HIV NRTIs (including abacavir) alone or in conjunction with other antiretrovirals.1 228 229 240 Reported most frequently in women; obesity and long-term NRTI therapy also may be risk factors.1 Has been reported in patients with no known risk factors.1

Use particular caution in patients with known risk factors for liver disease.1

Discontinue abacavir or abacavir-containing preparation if there are 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).1 228 229 240

Other Warnings and Precautions

Cardiovascular Effects

MI reported in some patients receiving abacavir.1

In response to conflicting data regarding a possible association between abacavir and MI,1 102 106 108 228 229 240 FDA conducted a meta-analysis of 26 randomized clinical trials that evaluated use of abacavir in adults.107 109 This meta-analysis did not identify an increased risk of MI in patients receiving abacavir.1 107 109 228 229 240 FDA recommends that clinicians continue to prescribe abacavir according to approved labeling1 107 and that patients not discontinue abacavir without consulting their clinician.107

As a precaution in patients receiving antiretroviral therapy (including abacavir), consider patient’s underlying risk of CHD and minimize any modifiable risk factors (e.g., hypertension, hyperlipidemia, diabetes mellitus, smoking).1 228 229 240

Precautions Related to Use of Fixed Combinations

Abacavir/lamivudine, abacavir/dolutegravir/lamivudine, abacavir/lamivudine/zidovudine: Consider cautions, precautions, contraindications, and drug interactions associated with each drug in the fixed combination.228 229 240 Consider cautionary information applicable to specific populations (e.g., pregnant or nursing women, individuals with hepatic or renal impairment, geriatric patients) for each drug.228 229 240

Because the antiretrovirals contained in abacavir/lamivudine, abacavir/dolutegravir/lamivudine, and abacavir/lamivudine/zidovudine also are available in single-entity or other fixed-combination preparations, take care to ensure that therapy not duplicated when a fixed combination is used in conjunction with other antiretrovirals.228 229 240

Do not use multiple abacavir-containing preparations concomitantly.1 228 229 240

Do not use abacavir/lamivudine concomitantly with any preparation containing abacavir or lamivudine.228 In addition, do not use concomitantly with any preparation containing emtricitabine.228

Do not use abacavir/dolutegravir/lamivudine concomitantly with any preparation containing abacavir or lamivudine.240 In addition, do not use concomitantly with any preparation containing emtricitabine.240

Do not use abacavir/lamivudine/zidovudine concomitantly with any preparation containing abacavir, lamivudine, or zidovudine.229 In addition, do not use concomitantly with any preparation containing emtricitabine.229

Adipogenic Effects

Possible redistribution or accumulation of body fat, including central obesity, dorsocervical fat enlargement (“buffalo hump”), peripheral wasting, breast enlargement, and general cushingoid appearance.1 228 229 240

Mechanisms and long-term consequences of adipogenic effects unknown;1 228 229 240 causal relationship not established.1 228 229 240

Immune Reconstitution Syndrome

During initial treatment, patients who 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]); this may necessitate further evaluation and treatment.1 228 229 240

Autoimmune disorders (e.g., Graves' disease, polymyositis, Guillain-Barré syndrome) also reported in the setting of immune reconstitution; time to onset is more variable and can occur many months after initiation of antiretroviral therapy.1 228 229 240

Specific Populations

Pregnancy

Antiretroviral Pregnancy Registry at 800-258-4263 or .1 202 228 229 240

Data from the Antiretroviral Pregnancy Registry show no difference in the risk of overall major birth defects for abacavir compared with background rate for major birth defects.1 202 228

Experts state that abacavir and lamivudine is a preferred dual NRTI option for initial antiretroviral regimens in antiretroviral-naive pregnant women, but use only in those negative for HLA-B*5701.202

A triple NRTI regimen of abacavir, lamivudine, and zidovudine not recommended for initial treatment in antiretroviral-naive pregnant women because of inferior virologic efficacy.202

Lactation

Abacavir distributed into human milk and has been detected in plasma of at least 1 breast-feeding child.202 (See Distribution under Pharmacokinetics.)

Instruct HIV-infected women not to breast-feed because of risk of HIV transmission and risk of adverse effects in the infant.1 202

Pediatric Use

Abacavir (Ziagen): Safety and efficacy not established in neonates and infants <3 months of age.1 Adverse effects reported in children similar to those reported in adults (e.g., hypersensitivity reactions, GI effects).1 6 23 34

Abacavir/lamivudine (Epzicom): Do not use in pediatric patients weighing <25 kg.228

Abacavir/lamivudine/zidovudine (Trizivir): Do not use in pediatric patients or in adolescents weighing <40 kg.229

Abacavir/dolutegravir/lamivudine (Triumeq): Safety and efficacy not established in pediatric patients <18 years of age.240

Geriatric Use

Abacavir (Ziagen): Insufficient experience in those ≥65 years of age to determine whether they respond differently than younger adults.1 Select dosage with caution because of age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.1 228 229 240

Abacavir/lamivudine, abacavir/dolutegravir/lamivudine, abacavir/lamivudine/zidovudine: Insufficient experience in those ≥65 years of age to determine whether they respond differently than younger adults.228 229 240 Use with caution because of age-related decreases in hepatic, renal, and/or cardiac function and potential for concomitant disease and drug therapy.228 229 240

Hepatic Impairment

Abacavir (Ziagen): Use with caution in those with known risk factors for liver disease.1 Dosage adjustment necessary in adults with mild hepatic impairment.1 (See Hepatic Impairment under Dosage and Administration.) Contraindicated in those with moderate or severe hepatic impairment.1

Abacavir/lamivudine, abacavir/dolutegravir/lamivudine, abacavir/lamivudine/zidovudine: Not recommended in patients with mild hepatic impairment.228 229 240 Contraindicated in patients with moderate or severe hepatic impairment.228 229 240

Renal Impairment

Abacavir (Ziagen): Pharmacokinetics not fully determined in patients with impaired renal function;1 renal excretion of unchanged abacavir only a minor route of elimination.1

Abacavir/lamivudine, abacavir/dolutegravir/lamivudine, abacavir/lamivudine/zidovudine: Do not use in patients with Clcr <50 mL/minute.228 229 240

Common Adverse Effects

Hypersensitivity reactions, GI effects (nausea, vomiting, diarrhea, anorexia), insomnia, fever and/or chills, headache, malaise, fatigue.1

Abacavir Sulfate Pharmacokinetics

Absorption

Bioavailability

Mean absolute oral bioavailability of abacavir is 83%.1 46 Rapidly absorbed following oral administration.1 2 6 19 23 43

Commercially available abacavir tablets and oral solution are bioequivalent.46

Fixed-combination tablet containing abacavir 600 mg and lamivudine 300 mg (abacavir/lamivudine; Epzicom) is bioequivalent to two 300-mg tablets of abacavir and two 150-mg tablets of lamivudine given simultaneously.228

Fixed-combination tablet containing abacavir 600 mg, dolutegravir 50 mg, and lamivudine 300 mg (abacavir/dolutegravir/lamivudine; Triumeq) is bioequivalent to a 50-mg tablet of dolutegravir administered simultaneously with a fixed-combination tablet containing 600 mg of abacavir and 300 mg of lamivudine.240

Fixed-combination tablet containing abacavir 300 mg, lamivudine 150 mg, and zidovudine 300 mg (abacavir/lamivudine/zidovudine; Trizivir) is bioequivalent to a 300-mg abacavir tablet, 150-mg lamivudine tablet, and 300-mg zidovudine tablet given simultaneously.229 68

Food

Food does not have a clinically important effect on abacavir bioavailability.1 46 68

Abacavir/lamivudine, abacavir/lamivudine/zidovudine: Food does not affect AUC of abacavir, lamivudine, or zidovudine when the drugs are given as fixed combinations.68 228 229

Abacavir/dolutegravir/lamivudine: Administration with high-fat meal increases dolutegravir peak plasma concentrations and AUC by 37 and 48%, respectively, compared with administration in fasting state;240 abacavir peak plasma concentrations decreased by 23%;240 lamivudine exposures not affected.240

Special Populations

Pediatric patients: Plasma concentrations attained with abacavir oral solution are similar to those observed in adults;1 plasma concentrations attained with abacavir oral tablets are higher than those observed in pediatric patients receiving the oral solution.1

HIV-1-infected pediatric patients 3 months to 12 years of age: AUC of abacavir reported with once-daily regimen of oral solution or tablets is comparable to AUC of abacavir reported with twice-daily regimen of oral solution or tablets.1 Mean peak plasma concentrations 1.6- to 2.3-fold higher when abacavir is administered once daily compared with administration twice daily.1

Mild hepatic impairment (Child-Pugh score 5–6): AUC of abacavir is 89% higher than in those with normal hepatic function.1

Pregnant women: Pharmacokinetics similar to that in nonpregnant women;202 AUC in pregnant women similar to that reported in women 6–12 weeks postpartum and in nonpregnant individuals.202

Distribution

Extent

Abacavir is extensively distributed following oral administration.1

Abacavir is distributed into CSF following oral administration.1 6 20 46 62 84

Abacavir crosses human placenta.82 83 Concentrations in cord blood at time of delivery generally similar to maternal serum concentrations.82

Abacavir is distributed into human milk.202 In a study in 15 women receiving abacavir at 1 month postpartum, milk-to-plasma ratio was 0.85 and the drug was detected in the plasma of at least 1 breast-feeding child.202

Plasma Protein Binding

Abacavir is 50% bound to plasma proteins; binding independent of drug concentrations.1

Elimination

Metabolism

Abacavir is metabolized in the liver by alcohol dehydrogenase and glucuronyltransferase to inactive metabolites.1

Intracellularly, abacavir is phosphorylated and then converted to the active carbovir triphosphate by cellular kinases.1 3 6 Intracellular (host cell) conversion to carbovir triphosphate is necessary for the antiviral activity of the drug.1 2 3 4 6 7 8 9

Elimination Route

82.2% of abacavir oral dose excreted in urine; 16% excreted in feces.1 46

Half-life

About 1.5 hours.1 6 7 46

Special Populations

Half-life of abacavir increased 58% in patients with mild hepatic impairment (Child-Pugh score 5–6).1

Half-life was 1.33 hours in 1 patient with renal failure (GFR <10 mL/minute) undergoing peritoneal dialysis.18

Stability

Storage

Oral

Solution

Abacavir (Ziagen): 20–25°C.1 May be refrigerated;1 do not freeze.1

Tablets

Abacavir (Ziagen): 20–25°C.1

Abacavir/lamivudine (Epzicom): 25°C (may be exposed to 15–30°C).228

Abacavir/dolutegravir/lamivudine (Triumeq): 25°C (may be exposed to 15–30°C).240 Store and dispense in original package;240 do not remove desiccant;240 protect from moisture.240

Abacavir/lamivudine/zidovudine (Trizivir): 25°C (may be exposed to 15–30°C).229

Indications

ZIAGEN tablets and oral solution, in combination with other antiretroviral agents, are indicated for the treatment of human immunodeficiency virus (HIV-1) infection.

Warnings

Included as part of the PRECAUTIONS section.

Overdose

There is no known specific treatment for overdose with ZIAGEN. If overdose occurs, the patient should be monitored and standard supportive treatment applied as required. It is not known whether abacavir can be removed by peritoneal dialysis or hemodialysis.

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