Abacavir

U.S. BRAND NAMES — Ziagen®
CANADIAN BRAND NAMES — Ziagen®
THERAPEUTIC CATEGORY Antiretroviral AgentHIV Agents (Anti-HIV Agents)Nucleoside Reverse Transcriptase Inhibitor (NRTI)
DOSING — Oral (use in combination with other antiretroviral agents):
(For additional information see "Abacavir: Drug information")
Neonates and Infants <3 months: Not approved for use
Infants 3 months, Children, and Adolescents: 8 mg/kg twice daily (maximum: 300 mg twice daily); Note: Safety and efficacy of once daily dosing have not been established in pediatric patients
Adults: 300 mg twice daily or 600 mg once daily
Dosing adjustment in hepatic impairment: Mild hepatic impairment (Child-Pugh score 5-6): Adults: 200 mg twice daily (using oral solution) Moderate to severe hepatic impairment: Drug is contraindicated
DOSAGE FORMS — Available as abacavir sulfate; mg strength refers to abacavir
Solution, oral: 20 mg/mL (240 mL) [strawberry-banana flavor]
Tablet: 300 mg
GENERIC AVAILABLE — No
ADMINISTRATION — Oral: May be administered without regard to food
USE — Treatment of HIV-1 infection in combination with other antiretroviral agents. (Note: HIV regimens consisting of three antiretroviral agents are strongly recommended)
ADVERSE REACTIONS Central nervous system: Insomnia, fever, headache, malaise, fatigue, anxiety
Dermatologic: Rash (see Warnings); erythema multiforme. Note: Suspected toxic epidermal necrolysis and Stevens-Johnson syndrome have been reported but patients also received medications known to be associated with these rashes; due to the similarities between these rashes and abacavir hypersensitivity reactions, abacavir should be discontinued and never restarted in such patients.
Endocrine & metabolic: Mild elevations of blood glucose (may be more frequent in pediatric patients), hypertriglyceridemia, lactic acidosis, fat redistribution and accumulation (see Precautions)
Gastrointestinal: Nausea, vomiting, diarrhea, anorexia; pancreatitis (rare); Note: Severe diarrhea may occur at a higher incidence in patients receiving once daily dosing
Hepatic: Hepatomegaly with steatosis; elevated liver enzymes
Neuromuscular & skeletal: Asthenia, musculoskeletal pain
Respiratory: Cough
Miscellaneous: Hypersensitivity reaction (see Warnings); immune reconstitution syndrome
CONTRAINDICATIONS — Hypersensitivity to abacavir or any component [do not rechallenge patients who have experienced hypersensitivity reactions to abacavir, potentially fatal hypersensitivity reactions may occur (see Warnings)]; moderate or severe hepatic dysfunction
PRECAUTIONS — Use with caution and decrease the dose in patients with mild hepatic dysfunction (see Contraindications). Fat redistribution and accumulation [ie, central obesity, peripheral wasting, facial wasting, breast enlargement, dorsocervical fat enlargement (buffalo hump), and cushingoid appearance] have been observed in patients receiving antiretroviral agents (causal relationship not established). Always use abacavir in combination with other antiretroviral agents; do not add abacavir as a single agent to antiretroviral regimens that are failing; resistance to abacavir develops relatively slowly, but cross resistance between abacavir and other nucleoside reverse transcriptase inhibitors (NRTIs) may occur; limited response may be seen in patients with HIV isolates containing multiple mutations conferring resistance to NRTIs or in patients with a prolonged prior NRTI exposure (see Additional Information)
Immune reconstitution syndrome (an acute inflammatory response to residual or indolent opportunistic infections) may occur in HIV patients during initial treatment with combination antiretroviral agents, including abacavir; this syndrome may require further patient assessment and therapy. Systemic exposure of abacavir at 6-32 times the normal human exposure, increased the incidence of tumors (malignant and nonmalignant) in mice and rats; myocardial degeneration was seen in mice and rats receiving abacavir for 2 years at 7-24 times the expected human exposure; the clinical relevance of these findings is currently unknown
WARNINGS — Serious and sometimes fatal hypersensitivity reactions may occur; discontinue therapy immediately in patients who show signs or symptoms of 2 or more of the following: Fever, skin rash, respiratory symptoms (including cough, dyspnea, or pharyngitis), GI symptoms (including nausea, vomiting, diarrhea, or abdominal pain), and constitutional symptoms (including fatigue, malaise, or achiness). Carefully consider the diagnosis of hypersensitivity reaction in patients who present with acute onset respiratory symptoms, even if other diagnoses, such as bronchitis, flu-like illness, pharyngitis, or pneumonia, are possible. Permanently discontinue abacavir if hypersensitivity reaction cannot be ruled out, even when other diagnoses are possible. Skin rash may be maculopapular or urticarial, but can be variable in appearance; erythema multiforme has been reported; hypersensitivity reaction may occur without a rash. Other symptoms may include edema, lethargy, myolysis, paresthesia, shortness of breath, mouth ulcerations, conjunctivitis, lymphadenopathy, and abnormal findings on chest x-ray (ie, infiltrates that can be localized). Anaphylaxis, renal failure, hepatic failure, respiratory failure, ARDS, hypotension, and death may also occur in association with hypersensitivity reactions. Laboratory abnormalities include increases in liver function tests, elevated CPK or serum creatinine, and lymphopenia.
Do not restart abacavir or any other abacavir-containing product after a hypersensitivity reaction occurs; more severe symptoms can recur within hours and may include life-threatening hypotension and death. Fatal hypersensitivity reactions have occurred following the reintroduction of abacavir in patients whose therapy was interrupted for other reasons. These patients had no identified history or had unrecognized symptoms of abacavir hypersensitivity. Reactions occurred within hours. In some cases, signs of a hypersensitivity reaction may have been previously present, but attributed to other medical conditions (acute onset respiratory diseases, gastroenteritis, reactions to other medications). If abacavir or any other abacavir-containing product is to be restarted following an interruption in therapy, the patient must first be evaluated for previously unsuspected symptoms of hypersensitivity. Do not restart abacavir or any other abacavir-containing product, if hypersensitivity is suspected or cannot be ruled out. Hypersensitivity reactions occur in ~8% of adult and pediatric patients; most hypersensitivity reactions occur within the first 6 weeks of therapy, but can occur at any time; one study reported a higher incidence of severe hypersensitivity reactions with once daily dosing compared with twice daily dosing (see product information); call the Abacavir Hypersensitivity Reaction Registry at 1-800-270-0425 to facilitate reporting and collection of information on patients experiencing abacavir hypersensitivity reactions (see Additional Information)
Cases of lactic acidosis, severe hepatomegaly with steatosis and death have been reported with the use of abacavir and other NRTIs; most of these cases have been in women; prolonged nucleoside use, obesity, and prior liver disease may be risk factors; use with extreme caution in patients with other risk factors for liver disease; discontinue abacavir in patients who develop laboratory or clinical evidence of lactic acidosis or pronounced hepatotoxicity
DRUG INTERACTIONS — Use with ethanol increases abacavir AUC by 41% and prolongs half-life by 26%; abacavir may increase the clearance of methadone by 22% (a small number of patients may require an increase in methadone dosage)
FOOD INTERACTIONS — Food does not significantly affect AUC
PREGNANCY RISK FACTOR — C (show table)
MONITORING PARAMETERS — Signs and symptoms of hypersensitivity reaction; serum glucose and triglycerides, viral load, CD4 counts
STABILITY — Store tablets and oral solution at room temperature; oral solution may be refrigerated; do not freeze
MECHANISM OF ACTION — A carbocyclic analogue that is converted within cells to the active metabolite carbovir triphosphate; carbovir triphosphate serves as an alternative substrate to deoxyguanosine-5'-triphosphate (dGTP), a natural substrate for cellular DNA polymerase and reverse transcriptase; carbovir triphosphate inhibits HIV viral reverse transcriptase by competing with natural dGTP and by becoming incorporated into viral DNA causing chain termination. Abacavir is also a weak inhibitor of cellular DNA polymerases (alpha, beta, and gamma).
PHARMACOKINETICS Absorption: Rapid and extensive
Distribution: Apparent Vd: Adults: 0.86 +/- 0.15 L/kg CSF to plasma AUC ratio: 27% to 33%
Protein binding: 50%
Metabolism: In the liver by alcohol dehydrogenase and glucuronyl transferase to inactive carboxylate and glucuronide metabolites; not significantly metabolized by cytochrome P450 enzymes
Bioavailability: Tablet: 83%; solution and tablet provide comparable AUCs
Half-life: Infants 3 months and Children 13 years: 1-1.5 hours Adults: 1.54 +/- 0.63 hours Hepatic impairment: Increases half-life by 58%
Time to peak serum concentration: Infants 3 months and Children 13 years: Within 1.5 hours
Elimination: ~83% of dose excreted in the urine (1.2% as unchanged drug, 30% as 5'-carboxylic acid metabolite, 36% as the glucuronide, and 15% as other metabolites); 16% eliminated in feces Clearance (apparent): Single dose 8 mg/kg: Infants 3 months and Children 13 years: 17.84 mL/minute/kg Adults: 10.14 mL/minute/kg
PATIENT INFORMATION — Abacavir is not a cure for HIV. Take abacavir everyday as prescribed; do not change dose or discontinue without physician's advice. If abacavir is stopped for any reason, notify physician before restarting therapy. If a dose is missed, take it as soon as possible, then return to normal dosing schedule; if a dose is skipped, do not double the next dose
(For additional information see "Abacavir: Patient drug information")
Serious and sometimes fatal allergic reactions may occur. Read the patient Medication Guide that you receive with each prescription and refill of abacavir; carry the Warning Card with you. Stop taking abacavir and notify physician immediately if 2 or more of the following sets of symptoms occur: Fever, rash, GI symptoms (nausea, vomiting, diarrhea or abdominal pain), flu-like symptoms (severe tiredness, achiness, or generally ill feeling), or respiratory symptoms (sore throat, shortness of breath, cough). If you experience an allergic (hypersensitivity) reaction to abacavir (or Ziagen®, Trizivir®, or Epzicom™), never take abacavir, Ziagen®, Trizivir®, or Epzicom™ again. If you take an abacavir-containing medication after having an allergic reaction, you may get life-threatening symptoms including very low blood pressure or death within hours.
HIV medications may cause changes in body fat, including an increase in fat in the upper back and neck, breasts, and trunk; a loss of fat from the face, arms, and legs may also occur. Some HIV medications (including abacavir) may cause a serious, but rare, condition called lactic acidosis with an increase in liver size (hepatomegaly). Before starting abacavir, inform your physician about your medical conditions, including any liver problems. Do not take Ziagen® with other abacavir-containing medications (eg, Epzicom® or Trizivir®).
NURSING IMPLICATIONS — Inform patients of the possibility of a fatal hypersensitivity reaction and the signs and symptoms (see Warnings)
ADDITIONAL INFORMATION — The patient Medication Guide, which includes written manufacturer information, should be dispensed to the patient with each new prescription and refill; the Warning Card describing the hypersensitivity reaction should be given to the patient to carry with them. A familial predisposition to the abacavir hypersensitivity reaction has been reported; use abacavir with great caution in children of parents who experience a hypersensitivity reaction to abacavir (see Peyriere, 2001). Recent studies have identified genetic markers which may help predict which patients are at risk for developing the abacavir hypersensitivity reaction; further studies are needed (see Hetherington, 2002 and Mallal, 2002).
Reverse transcriptase mutations of K65R, L74V, Y115F, and M184V have been associated with abacavir resistance; at least 2-3 mutations are needed to decrease HIV susceptibility by 10-fold. The presence of a multiple number of these abacavir resistance-associated mutations, may confer cross-resistance for other nucleoside or nucleotide reverse transcriptase inhibitors (eg, didanosine, emtricitabine, lamivudine, zalcitabine, or tenofovir). A progressive decrease in abacavir susceptibility is associated with an increasing number of thymidine analogue mutations (TAMs; M41L, D67N, K70R, L210W, T215Y/F, K219E/R/H/Q/N).
A recent multicenter study, conducted in previously untreated HIV-infected children (median age: 5.3 years; range: 0.3-16.7 years), demonstrated that abacavir-containing antiretroviral regimens were more effective than regimens containing the NRTI combination of zidovudine and lamivudine; after adjusting for use of nelfinavir and controlling for baseline factors, the NRTI combination of abacavir and lamivudine showed the largest and most durable reduction in viral load, compared to the combination of zidovudine and lamivudine or zidovudine and abacavir; further studies are needed.
A high rate of early virologic failure in therapy-naive adult HIV patients has been observed with the once daily three-drug combination therapy of abacavir, lamivudine, and tenofovir. This combination should not be used as a new treatment regimen for naive or pretreated patients. Any patient currently receiving this regimen should be closely monitored and considered for regimen modification.
Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. Briars, LA, Hilao, JJ, Kraus, DM. A Review of Pediatric Human Immunodeficiency Virus Infection. Journal of Pharmacy Practice 2004; 17:407. 2. Center for Disease, Control, Prevention. Guidelines for Using Antiretroviral Agents Among HIV-Infected Adults and Adolescents. Recommendations of the Panel on Clinical Practices for Treatment of HIV. MMWR 2002; 51:1. 3. Collura, JM, Kraus, DM. New Pediatric Antiretroviral Agents. J Pediatr Health Care 2000; 14:183. 4. Foster, RH, Faulds, D. Abacavir. Drugs 1998; 55:729. 5. Hetherington, S, Hughes, AR, Mosteller, M, et al. Genetic Variations in HLA-B Region and Hypersensitivity Reactions to Abacavir. Lancet 2002; 359:1121. 6. Hughes, W, McDowell, JA, Shenep, J, et al. Safety and Single-Dose Pharmacokinetics of Abacavir (1592U89) in Human Immunodeficiency Virus Type 1-Infected Children. Antimicrob Agents Chemother 1999; 43:609. 7. Kline, MW, Blanchard, S, Fletcher, CV, et al. A Phase I Study of Abacavir (1592U89) Alone and in Combination With Other Antiretroviral Agents in Infants and Children With Human Immunodeficiency Virus Infection. Pediatrics 1999; 103(4):e47; http://www.pediatrics.org/cgi/content/full/103/4/e47. 8. Mallal, S, Nolan, D, Witt, C, et al. Association Between Presence of HLA-B5701, HLA-DR7, and HLA-DQ3 and Hypersensitivity to HIV-1 Reverse-Transcriptase Inhibitor Abacavir. Lancet 2002; 359:727. 9. Paediatric European Network for Treatment of AIDS, (PENTA). Comparison of Dual Nucleoside-Analogue Reverse-Transcriptase Inhibitor Regimens With and Without Nelfinavir in Children with HIV-1 Who Have Not Previously Been Treated: The PENTA 5 Randomised Trial. Lancet 2002; 359:733. 10. Panel on Clinical Practices for Treatment of HIV, Infection. Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and Adolescents. October 10 2006; http://www.aidsinfo.nih.gov. 11. Peyriere, H, Nicolas, J, Siffert, M, et al. Hypersensitivity Related to Abacavir in Two Members of a Family. Ann Pharmacother 2001; 35:1291. 12. Working Group on Antiretroviral, Therapy, Medical Management of HIV-Infected, Children. Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection. October 26 2006; http://www.aidsinfo.nih.gov. 13. Working Group on Antiretroviral, Therapy, Medical Management of HIV-Infected, Children. Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection. Supplement I: Pediatric Antiretroviral Drug Information. October 26 2006; http://www.aidsinfo.nih.gov.