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Abacavir

Pronunciation

Pronunciation

(a BAK a veer)

Index Terms

  • Abacavir Sulfate
  • ABC

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution, Oral:

Ziagen: 20 mg/mL (240 mL) [contains methylparaben, propylene glycol, propylparaben, saccharin sodium; strawberry-banana flavor]

Tablet, Oral:

Ziagen: 300 mg [scored]

Generic: 300 mg

Brand Names: U.S.

  • Ziagen

Pharmacologic Category

  • Antiretroviral, Reverse Transcriptase Inhibitor, Nucleoside (Anti-HIV)

Pharmacology

Nucleoside reverse transcriptase inhibitor. Abacavir is a guanosine analogue which is phosphorylated to carbovir triphosphate which interferes with HIV viral RNA-dependent DNA polymerase resulting in inhibition of viral replication.

Absorption

Rapid and extensive absorption

Distribution

Vd: 0.86 ± 0.15 L/kg; CSF to plasma AUC ratio: 27% to 33%

Metabolism

Hepatic via alcohol dehydrogenase and glucuronyl transferase to inactive carboxylate and glucuronide metabolites; not significantly metabolized by cytochrome P450 enzymes; intracellulary metabolized to carbovir triphosphate.

Excretion

Urine: ~83% (1.2% as unchanged drug, 30% as 5'-carboxylic acid metabolite, 36% as the glucuronide, and 15% as other metabolites); feces (16% total dose)

Clearance (apparent): Single dose 8 mg/kg (Hughes 1999): Pediatric patients ≥3 months to ≤13 years: 17.84 mL/minute/kg; Adults: 10.14 mL/minute/kg

Time to Peak

Pediatric patients ≥3 months to ≤13 years: Within 1.5 hours (Hughes 1999); Adults: 0.7 to 1.7 hours

Half-Life Elimination

Serum:

Pediatric patients ≥3 months to ≤13 years: 1 to 1.5 hours (Hughes 1999; Kline 1999)

Adults: 1.54 ± 0.63 hours

Hepatic impairment (mild): Increases half-life by 58%

Intracellular: 12 to 26 hours

Protein Binding

50%

Special Populations: Hepatic Function Impairment

In mild hepatic impairment (Child-Pugh score 5 to 6), AUC increased 89%.

Use: Labeled Indications

HIV-1 infection: Treatment of HIV-1 infection in combination with other antiretroviral agents

Contraindications

Hypersensitivity to abacavir or any component of the formulation; patients who are positive for the HLA-B*5701 allele; moderate to severe hepatic impairment

Dosing: Adult

HIV-1 treatment: Oral: 300 mg twice daily or 600 mg once daily in combination with other antiretroviral agents. Note: Abacavir is a component of a recommended initial regimen with dolutegravir plus lamivudine (or emtricitabine) for ART-naïve patients who are HLA-B*5701 negative (HHS [adult] 2015).

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

HIV-1 treatment: Oral:

Infants ≥3 months, Children, and Adolescents (US labeling) or Infants ≥3 months, Children and Adolescents (<25 kg) (Canadian labeling): 16 mg/kg/day in 1 or 2 divided doses (maximum: 600 mg/day) in combination with other antiretroviral agents. Note: May consider up to 20 mg/kg once-daily dosing (maximum: 600 mg/day) in stable patients with undetectable viral load and stable CD4 count for more than 6 months (HHS [pediatric] 2014)

Alternative dosing to be considered for pediatric patients ≥14 kg who are able to swallow tablets: Note: In clinical studies, data with once-daily dosing are limited to subjects transitioned from twice-daily dosing to once-daily dosing after 36 weeks of treatment.

14 to <20 kg: 300 mg once daily or 150 mg twice daily

≥20 to <25 kg: 450 mg once daily or 150 mg in the morning and 300 mg in the evening

≥25 kg: 600 mg once daily or 300 mg twice daily

Children and Adolescents (≥25 kg) (Canadian labeling): Refer to adult dosing.

Dosing: Renal Impairment

US labeling: There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied).

Canadian labeling: No dosage adjustment necessary. Use of 600 mg once daily dosing has not been studied.

Dosing: Hepatic Impairment

Mild impairment (Child-Pugh class A): 200 mg twice daily (oral solution is recommended).

Moderate to severe impairment (Child-Pugh class B or C): Use is contraindicated (has not been studied).

Administration

May be administered with or without food.

Hazardous agent; use appropriate precautions for handling and disposal (NIOSH 2014 [group 2]).

Storage

Store at 20°C to 25°C (68°F to 77°F). Oral solution may be refrigerated; do not freeze.

Drug Interactions

Cabozantinib: MRP2 Inhibitors may increase the serum concentration of Cabozantinib. Monitor therapy

Ganciclovir-Valganciclovir: May enhance the adverse/toxic effect of Reverse Transcriptase Inhibitors (Nucleoside). Hematologic toxicity with zidovudine is of particular concern. Ganciclovir-Valganciclovir may increase the serum concentration of Reverse Transcriptase Inhibitors (Nucleoside). Management: Monitor patients receiving any of these combination closely for toxicity of the reverse transcriptase inhibitor. Avoid zidovudine. Intravitreal implants would not be affected. Consider therapy modification

Methadone: May diminish the therapeutic effect of Abacavir. Abacavir may decrease the serum concentration of Methadone. Monitor therapy

Orlistat: May decrease the serum concentration of Antiretroviral Agents. Monitor therapy

Protease Inhibitors: May decrease the serum concentration of Abacavir. Monitor therapy

Ribavirin (Oral Inhalation): May enhance the hepatotoxic effect of Reverse Transcriptase Inhibitors (Nucleoside). Monitor therapy

Ribavirin (Systemic): May enhance the hepatotoxic effect of Reverse Transcriptase Inhibitors (Nucleoside). Monitor therapy

Adverse Reactions

Rates of adverse reactions were defined during combination therapy with other antiretrovirals. Frequency not always defined. *Incidence not specifically defined but reported in the range of >10%. **Incidence not specifically defined but reported in the range of 1% to 10%.

Central nervous system: Fatigue*, headache (adults: >10%; children: 1% to 10%), malaise*, abnormal dreams**, anxiety**, chills**, depression**, dizziness**, migraine**, sleep disorder**

Dermatologic: Skin rash**

Endocrine & metabolic: Hypertriglyceridemia**, increased gamma-glutamyl transferase

Gastrointestinal: Nausea*, abdominal pain**, diarrhea (increased incidence with once daily dosing)**, gastritis**, gastrointestinal disease**, increased serum amylase**, nausea and vomiting**, vomiting**, pancreatitis

Hematologic & oncologic: Neutropenia**, thrombocytopenia**

Hepatic: Increased serum ALT**, increased serum AST**

Hypersensitivity: Hypersensitivity reaction (including anaphylaxis and multiorgan failure; 8%; excluding subjects carrying the HLA-B*5701 allele: 1%)

Neuromuscular & skeletal: Increased creatinine phosphokinase**, musculoskeletal pain**

Respiratory: Bronchitis**, ENT infection**, pneumonia (children)**, viral respiratory tract infection**

Miscellaneous: Fever**

<1% (Limited to important or life-threatening): Anemia, erythema multiforme, hepatomegaly, hepatotoxicity, hyperglycemia, immune reconstitution syndrome, lactic acidosis, leukopenia, liver steatosis, myocardial infarction, pain, redistribution of body fat, renal disease, Stevens-Johnson syndrome, toxic epidermal necrolysis

ALERT: U.S. Boxed Warning

Hypersensitivity reactions:

Serious and sometimes fatal hypersensitivity reactions, with multiple organ involvement, have occurred with abacavir.

Patients who carry the HLA-B*5701 allele are at a higher risk of a hypersensitivity reaction to abacavir; although, hypersensitivity reactions have occurred in patients who do not carry HLA-B*5701 allele.

Abacavir is contraindicated in patients with a prior hypersensitivity reaction to abacavir and in HLA-B*5701–positive patients. All patients should be screened for the HLA-B*5701 allele prior to initiating therapy with abacavir or reinitiation of therapy with abacavir, unless patients have a previously documented HLA-B*5701 allele assessment. Discontinue abacavir immediately if a hypersensitivity reaction is suspected, regardless of HLA-B*5701 status and even when other diagnoses are possible.

Following a hypersensitivity reaction to abacavir, never restart abacavir or any abacavir-containing product because more severe symptoms including death, can occur within hours. Similar severe reactions have also occurred rarely following the reintroduction of abacavir-containing products in patients who have no history of abacavir hypersensitivity.

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 analogues and other antiretrovirals. Discontinue abacavir if clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity occur.

Warnings/Precautions

Concerns related to adverse effects:

• Fat redistribution: May cause redistribution of fat (eg, buffalo hump, peripheral wasting with increased abdominal girth, cushingoid appearance).

• Hypersensitivity reactions: [US Boxed Warning]: Serious and sometimes fatal hypersensitivity reactions have occurred. Patients who carry the HLA-B*5701 allele are at a higher risk for a hypersensitivity reaction to abacavir, although hypersensitivity reactions have occurred in patients who do not carry the HLA-B*5701 allele. All patients should be screened for the HLA-B*5701 allele prior to initiating or reinitiation of therapy unless patients have had a previously documented HLA-B*5701 allele assessment. Discontinue abacavir if a hypersensitivity reaction is suspected. Abacavir is contraindicated in patients who have the HLA-B*5701 allele or in patients with a prior hypersensitivity reaction to abacavir. Reintroduction of any abacavir-containing product can result in life-threatening or fatal hypersensitivity reactions, even in patients who have no history of hypersensitivity to abacavir therapy. Such reactions can occur within hours. An allergy to abacavir should be documented in the medical record of allele-positive patients. Reactions usually occur within 9 days of starting abacavir; ~90% occur within 6 weeks, although these reactions may occur at any time during therapy (HHS [adult] 2015). These reactions usually include signs or symptoms from two or more of the following: Fever, skin rash, constitutional symptoms (malaise, fatigue, aches), respiratory symptoms (eg, pharyngitis, dyspnea, cough), and GI symptoms (eg, abdominal pain, diarrhea, nausea, vomiting). Other signs and symptoms include lethargy, headache, myalgia, edema, abnormal chest x-ray findings, arthralgia and paresthesia. Anaphylaxis, liver failure, renal failure, hypotension, adult respiratory distress syndrome, respiratory failure, myolysis, and death have occurred in association with hypersensitivity reactions. Physical findings (lymphadenopathy, mucous membrane lesions, and rash [maculopapular, urticarial or variable]) may occur. Erythema multiforme has also been reported. Laboratory abnormalities (eg, elevated liver function tests, elevated creatine phosphokinase, elevated creatinine, and lymphopenia) may occur. Abacavir should be permanently discontinued if hypersensitivity cannot be ruled out, even when other diagnoses are possible and regardless of HLA-B*5701 status. Abacavir SHOULD NOT be restarted because more severe symptoms may occur within hours, including LIFE-THREATENING HYPOTENSION AND DEATH. If abacavir is restarted following an interruption in therapy not associated with symptoms of a hypersensitivity reaction, carefully evaluate the patient for previously unsuspected symptoms of hypersensitivity. Do not restart if hypersensitivity is suspected or cannot be ruled out regardless of HLA-B*5701 status. If abacavir is restarted, continually monitor for symptoms of a hypersensitivity reaction. Make the patient aware that reintroduction should only take place if medical care is readily accessible.

• Immune reconstitution syndrome: Patients may develop immune reconstitution syndrome resulting in the occurrence of an inflammatory response to an indolent or residual opportunistic infection during initial HIV treatment or activation of autoimmune disorders (eg, Graves disease, polymyositis, Guillain-Barré syndrome) later in therapy; further evaluation and treatment may be required.

• Lactic acidosis/hepatomegaly: [U.S Boxed Warning]: Lactic acidosis and severe hepatomegaly with steatosis have been reported with nucleoside analogues, including fatal cases; use with caution in patients with risk factors for liver disease (risk may be increased with female gender, obesity, pregnancy or prolonged exposure) and suspend treatment in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or hepatotoxicity (transaminase elevation may/may not accompany hepatomegaly and steatosis).

Disease-related concerns:

• Coronary heart disease: Use has been associated with an increased risk of myocardial infarction (MI) in observational studies; however, based on a meta-analysis of 26 randomized trials, the FDA has concluded there is not an increased risk. Consider using with caution in patients with risks for coronary heart disease and minimizing modifiable risk factors (eg, hypertension, hyperlipidemia, diabetes mellitus, and smoking) prior to use.

• Hepatic impairment: Use with caution and adjust dosage in patients with mild hepatic impairment (contraindicated in moderate to severe impairment).

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Dosage form specific issues:

• Propylene glycol: Some dosage forms may contain propylene glycol; large amounts are potentially toxic and have been associated hyperosmolality, lactic acidosis, seizures, and respiratory depression; use caution (AAP, 1997; Zar, 2007).

• Sorbitol: Oral solution contains sorbitol. Use oral solution with caution in patients who are fructose intolerant; may experience abdominal discomfort and/or diarrhea with administration of the oral solution.

Special handling:

• Hazardous agent: Use appropriate precautions for handling and disposal (NIOSH 2014 [group 2]).

Other warnings/precautions:

• Appropriate use: Abacavir should always be used as a component of a multidrug regimen; concomitant use with other abacavir-containing products is not recommended. Do not use abacavir/lamivudine (plus efavirenz or plus atazanavir/ritonavir) in adolescent and adult HIV-1 patients with a pre-ART HIV RNA >100,000 copies/mL (HHS [adult] 2015).

Monitoring Parameters

CBC with differential, serum creatine kinase, CD4 count, HIV RNA plasma levels, serum transaminases, triglycerides, serum amylase; HLA-B*5701 genotype status prior to initiation of therapy and prior to reinitiation of therapy in patients of unknown HLA-B*5701 status; signs and symptoms of hypersensitivity

Pregnancy Considerations

Abacavir has a high level of transfer across the human placenta. No increased risk of overall birth defects has been observed following first trimester exposure according to data collected by the antiretroviral pregnancy registry. Cases of lactic acidosis/hepatic steatosis syndrome related to mitochondrial toxicity have been reported with use of nucleoside analogues. In addition, these adverse events are similar to other rare but life-threatening syndromes which occur during pregnancy (eg, HELLP syndrome). In general nucleoside reverse transcriptase inhibitors are well tolerated and the benefits of use generally outweigh potential risk. The HHS Perinatal HIV Guidelines consider abacavir in combination with lamivudine to be a preferred NRTI backbone for use in antiretroviral-naive pregnant women (do not use in women who are positive for the HLA-B*5701 allele). This backbone is not recommended with atazanavir or efavirenz if pretreatment HIV RNA is >100,000 copies/mL. The pharmacokinetics of abacavir are not significantly changed by pregnancy and dose adjustment is not needed for pregnant women.

Combination antiretroviral therapy (cART) therapy is recommended for all HIV-infected pregnant women. The goal of therapy is to keep the viral load below the limit of detection and prevent perinatal transmission. Therapy must be individualized. In general, women who become pregnant on a stable cART regimen may continue that regimen if viral suppression is effective, contraindications for use in pregnancy are not present, and the regimen is well tolerated. For HIV infected couples planning a pregnancy, maximum viral suppression with cART is recommended prior to conception for the HIV-infected partner(s). When HIV is diagnosed during pregnancy in a woman who has never received antiretroviral therapy, cART should be considered as soon as possible after diagnosis to reduce the risk of perinatal transmission. If antiretroviral drug-resistance testing is done, treatment may be started prior to obtaining results, then adjusted accordingly. Monitoring during pregnancy is more frequent than in non-pregnant adults. If cART must be interrupted for <24 hours, stop then restart all medications simultaneously in order to decrease the chance of developing resistance. Long-term follow-up is recommended for all infants exposed to antiretroviral medications; children who develop significant organ system abnormalities (particularly of the CNS or heart) should be evaluated for potential mitochondrial dysfunction.

HIV infected women not planning a pregnancy may use any available type of contraception, considering possible drug interactions and contraindications of the specific method. In addition, consistent use of condoms is also recommended (even during pregnancy) to prevent transmission of HIV or other sexually transmitted diseases.

Health care providers are encouraged to enroll pregnant women exposed to antiretroviral medications as early in pregnancy as possible in the Antiretroviral Pregnancy Registry (1-800-258-4263 or www.APRegistry.com). Health care providers caring for HIV-infected women and their infants may contact the National Perinatal HIV Hotline (888-448-8765) for clinical consultation (HHS [perinatal] 2016).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience vomiting, dizziness, headache, nausea, diarrhea, lack of appetite, change in body fat, insomnia, or nightmares. Have patient report immediately to prescriber signs of allergic reaction with organ failure (fever, rash, fatigue, flu-like signs, nausea, vomiting, diarrhea, abdominal pain, pharyngitis, cough, or difficulty breathing), signs of lactic acidosis (fast breathing, tachycardia, abnormal heartbeat, vomiting, fatigue, shortness of breath, severe loss of strength and energy, severe dizziness, feeling cold, or muscle pain or cramps), signs of liver problems (dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or jaundice), signs of depression (suicidal ideation, anxiety, emotional instability, or confusion), angina, severe dizziness, passing out, mouth sores, enlarged lymph nodes, or signs of infection (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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