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Brand Name: Epzicom  |
Drug Class: Nucleoside Reverse Transcriptase Inhibitors
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Drug Description |
| Abacavir sulfate/lamivudine (Epzicom) is a fixed-dose tablet containing two nucleoside reverse transcriptase inhibitors (NRTIs): abacavir sulfate and lamivudine. Each tablet contains abacavir sulfate 600 mg and lamivudine 300 mg.[1] |
HIV/AIDS-Related Uses |
| Epzicom was approved by the FDA on August 2, 2004, for combined use with other antiretroviral agents in the treatment of HIV-1 infection. When used as part of a three-drug HIV treatment regimen, Epzicom should be used with antiretroviral agents from different pharmacologic classes rather than with other NRTIs.[2][3] |
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Dosing Information |
Mode of Delivery |
| Oral.[4] |
Dosage Form |
Film-coated tablet containing abacavir sulfate 600 mg and lamivudine 300 mg.
Because it is a fixed-dose tablet, Epzicom should not be prescribed for patients requiring dosage adjustment.[5] |
Storage |
| Store at 25 C (77 F); excursions permitted at 15 C to 30 C (59 F to 86 F).[6] |
Pharmacology |
Both of the nucleoside analogues contained in Epzicom inhibit HIV reverse transcriptase (RT), an enzyme essential for HIV replication. Abacavir, a carbocyclic synthetic nucleoside analogue, is phosphorylated intracellularly to the active metabolite carbovir triphosphate, an analogue of deoxyguanosine-5'-triphophate (dGTP). Carbovir triphosphate inhibits the activity of HIV-1 RT by competing with dGTP for incorporation into viral DNA, resulting in termination of the DNA chain. Lamivudine, also a synthetic nucleoside analogue, is phosphorylated intracellularly to the active metabolite lamivudine triphosphate (L-TP), which inhibits HIV DNA synthesis in a manner analogous to abacavir.[7]
Following oral administration, abacavir is rapidly absorbed and extensively distributed. After administration of a single oral dose of abacavir 600 mg, the peak plasma concentration (Cmax) is 4.26 mcg/ml, and the area under the plasma concentration-time curve (AUC) is 11.95 mcg (hr)/ml. Binding to plasma proteins is approximately 50% and is independent of concentration. Abacavir distributes readily into erythrocytes. The primary routes of abacavir elimination are metabolism by alcohol dehydrogenase to form the 5'-carboxylic acid and by glucuronyl transferase to form 5'-glucuronide.[8]
Following oral administration, lamivudine is also rapidly absorbed and extensively distributed. After multiple-dose oral administration of lamivudine 300 mg once daily for 7 days in healthy individuals, steady-state Cmax was 2.04 mcg/ml and the 24-hour, steady-state AUC was 8.87 mcg (hr)/ml. Binding to plasma protein is low. Approximately 70% of an IV dose of lamivudine is recovered unchanged in urine; metabolism is a minor route of elimination.[9]
Results of a bioavailability study comparing administration of one Epzicom tablet to simultaneous administration of two 300 mg abacavir tablets and two 150 mg lamivudine tablets in healthy subjects showed no difference in absorption, as measured by AUC and Cmax.[10]
Epzicom is in FDA Pregnancy Category C. No adequate or well-controlled studies have been done in pregnant women. Studies in rats have shown that abacavir crosses the placenta. Fetal malformations and developmental toxicity occur in rats given a dose of abacavir equivalent to 35 times the recommended human exposure. In rabbits, no developmental toxicity or increased fetal malformations occurred at doses equivalent to 8.5 times the recommended human exposure. Studies of lamivudine in rats have shown that the drug crosses the placenta. No lamivudine-associated teratogenicity was observed in rats or in rabbits given doses equivalent to 35 times the recommended human exposure. Evidence of early embryolethality was seen in rabbits at exposure levels similar to the recommended human exposure; however, no embryolethality was observed in rats at exposure levels up to 35 times the recommended human dose. An Antiretroviral Pregnancy Registry has been established to monitor the outcomes of pregnant women exposed to antiretroviral agents, including Epzicom.[11] Physicians may register patients by calling 1-800-258-4263 or online at http://www.APRegistry.com.[12]
Abacavir is secreted into the milk of lactating rats, and lamivudine is excreted into milk in rats and humans. Because of the potential for HIV transmission and for serious adverse drug effects in breastfed infants, women who are receiving Epzicom should be instructed not to breastfeed.[13]
HIV-1 isolates with reduced susceptibility to the combination of abacavir and lamivudine have been selected in vitro and have also been obtained from patients failing abacavir/lamivudine-containing regimens. Genotypic characterization of abacavir/lamivudine-resistant viruses selected in vitro identified the following amino acid substitutions in HIV-1 RT: M184V/I, K65R, L74V, and Y115F. In a study of treatment-naive adults who received abacavir 600 mg once daily or 300 mg twice daily with a background regimen of both lamivudine 300 mg and efavirenz 600 mg once daily, the abacavir- and lamivudine-associated resistance mutation M184V/I was the most commonly observed.[14]
Cross resistance has been observed among NRTIs. Viruses that contain abacavir and lamivudine resistance-associated mutations, namely K65R, L74V, M184V, and Y115F, exhibit cross resistance to didanosine, emtricitabine, lamivudine, stavudine, tenofovir, and zalcitabine both in vitro and in patients. The K65R mutation can confer resistance to abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir, and zalcitabine; the L74V mutation can confer resistance to abacavir, didanosine, and zalcitabine; and the M184V mutation can confer resistance to abacavir, didanosine, emtricitabine, lamivudine, and zalcitabine. Viruses with the K65R mutation (with or without the M184V/I mutation), the L74V plus M184V/I mutation, and the M184V/I mutation plus thymidine analogue mutations (TAMs) M41L, D67N, K70R, L210W, T215Y/F, and K219E/R/H/Q/N have demonstrated decreased susceptibility to Epzicom. An increasing number of TAMs are associated with a progressive reduction in abacavir susceptibility.[15] |
Adverse Events/Toxicity |
Epzicom contains abacavir sulfate, which has been associated with serious and sometimes fatal hypersensitivity reactions. In clinical studies, hypersensitivity to abacavir was reported in approximated 8% of patients. Symptoms usually appear within the first 6 weeks of treatment but may occur at any time during therapy. Hypersensitivity to abacavir is a multiorgan syndrome usually characterized by at least two of the following manifestations: fever; rash; malaise, fatigue, or achiness; gastrointestinal symptoms of nausea, vomiting, diarrhea, or abdominal pain; and respiratory symptoms of dyspnea, cough, or pharyngitis. Less common signs and symptoms of hypersensitivity include lethargy, myolysis, edema, abnormal chest x-ray, and paresthesia. Anaphylaxis, liver failure, renal failure, hypotension, adult respiratory distress syndrome, respiratory failure, and death have occurred in association with hypersensitivity reactions.[16] In one study, once-daily dosing of abacavir was associated with more severe hypersensitivity reactions.[17] Physical findings associated with abacavir hypersensitivity include lymphadenopathy, mucous membrane lesions, and a rash that is usually maculopapular or urticarial. There have also been reports of erythema multiforme with abacavir use.[18] Suspected Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported in patients receiving abacavir in combination with other medications associated with SJS and TEN. Because the clinical signs and symptoms of abacavir hypersensitivity overlap with those of SJS and TEN, and because some patients may have multiple drug sensitivities, patients with suspected SJS or TEN should discontinue Epzicom treatment.[19] Laboratory abnormalities associated with abacavir hypersensitivity include elevated liver function tests, elevated creatine phosphokinase, elevated creatinine, and lymphopenia.[20] An Abacavir Hypersensitivity Registry has been established to facilitate reporting of hypersensitivity reactions. Physicians should register patients by calling 1-800-270-0425.[21]
Recently, the genetic HLA B*5701 allele variant has been associated with an increased likelihood of abacavir hypersensitivity reaction. New research indicates that a positive result in a genetic test for this variant accurately predicts the hypersensitivity reaction of patients to abacavir, which therefore allows these patients to avoid abacavir use (and hypersensitivity reaction risk) altogether. In the PREDICT-1 study, in which 5.6% of participants were positive for the HLA B*5701 allele, the screening test had a 100% negative predictive value. Screening for HLA B*5701 and removing positive-testing participants from the abacavir treatment arm completely eliminated hypersensitivity reactions in that arm (0% vs. 2.7% in the non-tested control group; p < 0.001). An additional study suggests that, although the variant is more common in white than black patients, genetic screening is equally useful in both populations; all five black patients who had confirmed hypersensitivity reactions were positive for the HLA B*5701 allele, which supports the use of testing in this population for the prevention of hypersensitivity reaction.[22][23] The current recommendation from the DHHS Panel on Antiretroviral Guidelines for Adults and Adolescents is to administer genetic testing for the HLA B*5701 variant before beginning treatment with abacavir in HIV infected patients.[24]
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues (alone or in combination), including abacavir and lamivudine. Female gender, obesity, and prolonged nucleoside analogue exposure may be risk factors. Caution should be exercised in any patient with known risk factors for liver disease; however, liver problems have been reported in patients with no known risk factors. Treatment with Epzicom should be suspended in any patient who develops clinical or laboratory findings that suggest lactic acidosis or pronounced hepatotoxicity. Exacerbation of hepatitis has occurred in patients treated for chronic hepatitis B infection after discontinuation of lamivudine therapy.[25]
Immune reconstitution syndrome has been reported with the use of combination anti-HIV therapy, including abacavir/lamivudine. Patients who develop immune system responses to anti-HIV therapy may develop an inflammatory response to residual opportunistic infections (e.g.Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia, tuberculosis).[26]
Other reported adverse effects of abacavir and lamivudine include redistribution of body fat, stomatitis, hyperglycemia, generalized weakness, aplastic anemia, other anemias, lymphadenopathy, splenomegaly, pancreatitis, muscle weakness, rhabdomyolysis, paresthesia, peripheral neuropathy, seizures, abnormal breath sounds and wheezing, and alopecia.[27] |
Drug And Food Interactions |
Epzicom may be administered with or without food. Administration of Epzicom with a high-fat meal does not change the bioavailability of lamivudine. Food does not alter the extent of systemic exposure to abacavir, but the rate of absorption decreases by approximately 24% compared with fasted conditions.[28]
Abacavir and lamivudine are not significantly metabolized by the cytochrome P 450 enzymes, nor do they inhibit or induce this enzyme system; therefore, it is unlikely that clinically significant drug interactions will occur with drugs metabolized through these pathways.[29] Abacavir administered at twice the recommended dose increased methadone clearance by 22%. A small number of patients receiving both Epzicom and methadone may need a methadone dosage adjustment. Consumption of alcohol may cause an increase in abacavir exposure. The AUC of lamivudine was increased by 43% when coadministered with sulfamethoxazole/trimethoprim. Concurrent administration of lamivudine and nelfinavir resulted in a 10% increase in the AUC of lamivudine.[30]
Results of in vitro studies indicate that ribavirin reduces the phosphorylation of pyrimidine nucleoside analogues, including lamivudine. Liver decompensation has occurred in patients coinfected with HIV and hepatitis C virus receiving combination antiretroviral therapy for HIV and interferon alfa with or without ribavirin.[31]
Epzicom contains fixed doses of abacavir and lamivudine and should not be administered concomitantly with other abacavir- or lamivudine-containing products.[32] |
Contraindications |
| Epzicom is contraindicated in patients with previously demonstrated hypersensitivity to abacavir or to any other component of the product. After a hypersensitivity reaction to abacavir, patients should never restart Epzicom or any other abacavir-containing product. Fatal reactions have been associated with readministration of abacavir to patients who have a history of abacavir hypersensitivity.[33] Recent research has concluded that positivity for the HLA B*5701 genetic allele is a marker for abacavir hypersensitivity; patients who test positive for this variant are at risk for developing hypersensitivity reaction and should not receive abacavir.[34][35] Epzicom is also contraindicated in patients with hepatic impairment and in patients who have creatinine clearance less than 50 ml/min.[36] |
Clinical Trials |
| Click here to search ClinicalTrials.gov for trials that use Abacavir/Lamivudine. |
Chemistry |
CAS Name |
| Abacavir sulfate: (1S,4R)-4-[2-Amino- 6-(cyclopropylamino)-9H-purin-9-yl]-2- cyclopentene-1-methanol sulfate[37]Lamivudine: 2(1H)-Pyrimidinone, 4-amino-1-[2-(hydroxymethyl)-1,3- oxathiolan-5-yl]-,(2R-cis)[38] |
CAS Number |
| Abacavir sulfate: 188062-50-2[39]Lamivudine: 134678-17-4[40] |
Molecular Formula |
| Abacavir sulfate: C14-H18-N6-O.1/2H2-O4-S / Lamivudine: C8-H11-N3-O3-S[41] |
Elemental Composition |
| Abacavir sulfate: C50.1%, H5.7%, N25.1%, O14.3%, S4.8% / Lamivudine: C41.91%, H4.84%, N18.33%, O20.94%, S13.99%[42] |
Molecular Weight |
| Abacavir sulfate: 670.76 / Lamivudine: 229.26[43] |
Melting Point |
| Abacavir: 165 C / Lamivudine: 160 to 162 C[44] |
|
Physical Description |
Abacavir sulfate: white to off-white solid.[45]
Lamivudine: white to off-white crystalline solid.[46] |
|
Solubility |
Abacavir sulfate: 77 mg/ml in distilled water at 25 C.[47]
Lamivudine: 70 mg/ml in water at 20 C.[48] |
Other Names |
Abacavir sulfate/Lamivudine[49]
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Further Reading |
Epzicom Prescribing Information from the FDA Web site [PDF]. A more current version may be available on the manufacturer's Web site.
PMID/16944966 Castillo SA, Hernandez JE, Brothers CH. Long-term safety and tolerability of the lamivudine/abacavir combination as components of highly active antiretroviral therapy. Drug Saf. 2006;29(9):811-26.
PMID/15631548 Dando TM, Scott LJ. Abacavir plus lamivudine: a review of their combined use in the management of HIV infection. Drugs. 2005;65(2):285-302. Review.
PMID/15307010 DeJesus E, McCarty D, Farthing CF, Shortino DD, Grinsztejn B, Thomas DA, Schrader SR, Castillo SA, Sension MG, Gough K, Madison SJ; EPV20001 International Study Team. Once-daily versus twice-daily lamivudine, in combination with zidovudine and efavirenz, for the treatment of antiretroviral-naive adults with HIV infection: a randomized equivalence trial. Clin Infect Dis. 2004 Aug 1;39(3):411-8. Epub 2004 Jul 15.
PMID/17150010 Waters L, Moyle G. Abacavir/lamividune combination in the treatment of HIV-1 infection: a review. Expert Opin Pharmacother. 2006 Dec;7(18):2571-80.
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Manufacturer Information |
Abacavir/Lamivudine
GlaxoSmithKline
5 Moore Drive
Research Triangle Park, NC 27709
(888) 825-5249
Epzicom
GlaxoSmithKline
5 Moore Drive
Research Triangle Park, NC 27709
(888) 825-5249
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References |
[1] GlaxoSmithKline - Epzicom Prescribing Information, March 2006, pp. 1-2, 21. Available at: http://us.gsk.com/products/assets/us_epzicom.pdf. Accessed 07/01/08.
[2] GlaxoSmithKline - Epzicom Prescribing Information, March 2006, pp. 8-9. Available at: http://us.gsk.com/products/assets/us_epzicom.pdf. Accessed 07/01/08.
[3] FDA - Drugs@FDA, Epzicom Label and Approval History. Available at: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm. Accessed 07/01/08.
[4] GlaxoSmithKline - Epzicom Prescribing Information, March 2006, p. 2. Available at: http://us.gsk.com/products/assets/us_epzicom.pdf. Accessed 07/01/08.
[5] GlaxoSmithKline - Epzicom Prescribing Information, March 2006, pp. 2, 21. Available at: http://us.gsk.com/products/assets/us_epzicom.pdf. Accessed 07/01/08.
[6] GlaxoSmithKline - GlaxoSmithKline - Epzicom Prescribing Information, March 2006, p. 21. Available at: http://us.gsk.com/products/assets/us_epzicom.pdf. Accessed 07/01/08.
[7] GlaxoSmithKline - Epzicom Prescribing Information, March 2006, p. 3. Available at: http://us.gsk.com/products/assets/us_epzicom.pdf. Accessed 07/01/08.
[8] GlaxoSmithKline - Epzicom Prescribing Information, March 2006, p. 5. Available at: http://us.gsk.com/products/assets/us_epzicom.pdf. Accessed 07/01/08.
[9] GlaxoSmithKline - Epzicom Prescribing Information, March 2006, p. 5. Available at: http://us.gsk.com/products/assets/us_epzicom.pdf. Accessed 07/01/08.
[10] GlaxoSmithKline - Epzicom Prescribing Information, March 2006, p. 5. Available at: http://us.gsk.com/products/assets/us_epzicom.pdf. Accessed 07/01/08.
[11] GlaxoSmithKline - Epzicom Prescribing Information, March 2006, pp. 17-8. Available at: http://us.gsk.com/products/assets/us_epzicom.pdf. Accessed 07/01/08.
[12] GlaxoSmithKline - Epzicom Prescribing Information, March 2006, p. 18. Available at: http://us.gsk.com/products/assets/us_epzicom.pdf. Accessed 07/01/08.
[13] GlaxoSmithKline - Epzicom Prescribing Information, March 2006, p. 18. Available at: http://us.gsk.com/products/assets/us_epzicom.pdf. Accessed 07/01/08.
[14] GlaxoSmithKline - Epzicom Prescribing Information, March 2006, p. 4. Available at: http://us.gsk.com/products/assets/us_epzicom.pdf. Accessed 07/01/08.
[15] GlaxoSmithKline - Epzicom Prescribing Information, March 2006, p. 5. Available at: http://us.gsk.com/products/assets/us_epzicom.pdf. Accessed 07/01/08.
[16] GlaxoSmithKline - Epzicom Prescribing Information, March 2006, pp. 10-2. Available at: http://us.gsk.com/products/assets/us_epzicom.pdf. Accessed 07/01/08.
[17] GlaxoSmithKline - Epzicom Prescribing Information, March 2006, p. 18. Available at: http://us.gsk.com/products/assets/us_epzicom.pdf. Accessed 07/01/08.
[18] GlaxoSmithKline - Epzicom Prescribing Information, March 2006, p. 12. Available at: http://us.gsk.com/products/assets/us_epzicom.pdf. Accessed 07/01/08.
[19] GlaxoSmithKline - Epzicom Prescribing Information, March 2006, p. 20. Available at: http://us.gsk.com/products/assets/us_epzicom.pdf. Accessed 07/01/08.
[20] GlaxoSmithKline - Epzicom Prescribing Information, March 2006, p. 12. Available at: http://us.gsk.com/products/assets/us_epzicom.pdf. Accessed 07/01/08.
[21] GlaxoSmithKline - Epzicom Prescribing Information, March 2006, pp. 13, 21. Available at: http://us.gsk.com/products/assets/us_epzicom.pdf. Accessed 07/01/08.
[22] HIV and Hepatitis.com - HLA-B*5701 Screening for Abacavir (Ziagen) Hypersensitivity. Available at: http://www.hivandhepatitis.com/recent/2008/022608_c.html. Accessed 07/01/08.
[23] Clin Infect Dis - 2008;46:1111-1118. Available at: http://www.journals.uchicago.edu/doi/pdf/10.1086/529382. Accessed 07/01/08.
[24] Panel on Antiretroviral Guidelines for Adult and Adolescents - Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services, p. 10. January 29, 2008; 1-128. Available at http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Accessed 07/01/08.
[25] GlaxoSmithKline - Epzicom Prescribing Information, March 2006, p. 13. Available at: http://us.gsk.com/products/assets/us_epzicom.pdf. Accessed 07/01/08.
[26] GlaxoSmithKline - Epzicom Prescribing Information, March 2006, p. 15. Available at: http://us.gsk.com/products/assets/us_epzicom.pdf. Accessed 07/01/08.
[27] GlaxoSmithKline - Epzicom Prescribing Information, March 2006, p. 20. Available at: http://us.gsk.com/products/assets/us_epzicom.pdf. Accessed 07/01/08.
[28] GlaxoSmithKline - Epzicom Prescribing Information, March 2006, p. 6. Available at: http://us.gsk.com/products/assets/us_epzicom.pdf. Accessed 07/01/08.
[29] GlaxoSmithKline - Epzicom Prescribing Information, March 2006, p. 7. Available at: http://us.gsk.com/products/assets/us_epzicom.pdf. Accessed 07/01/08.
[30] GlaxoSmithKline - Epzicom Prescribing Information, March 2006, pp. 7-8. Available at: http://us.gsk.com/products/assets/us_epzicom.pdf. Accessed 07/01/08.
[31] GlaxoSmithKline - Epzicom Prescribing Information, March 2006, p. 14. Available at: http://us.gsk.com/products/assets/us_epzicom.pdf. Accessed 07/01/08.
[32] GlaxoSmithKline - Epzicom Prescribing Information, March 2006, p. 14. Available at: http://us.gsk.com/products/assets/us_epzicom.pdf. Accessed 07/01/08.
[33] GlaxoSmithKline - Epzicom Prescribing Information, March 2006, p. 10. Available at: http://us.gsk.com/products/assets/us_epzicom.pdf. Accessed 07/01/08.
[34] HIV and Hepatitis.com - HLA B*5701 Genetic Test Predicts Abacavir Hypersensitivity in Black as well as White HIV Patients. Available at: http://www.hivandhepatitis.com/recent/2008/050208_b.html. Accessed 07/01/08.
[35] Clin Infect Dis - 2008;46:1111-1118. Available at: http://www.journals.uchicago.edu/doi/pdf/10.1086/529382. Accessed 07/01/08.
[36] GlaxoSmithKline - Epzicom Prescribing Information, March 2006, p. 10. Available at: http://us.gsk.com/products/assets/us_epzicom.pdf. Accessed 07/01/08.
[37] ChemIDplus - Available at: http://chem.sis.nlm.nih.gov/chemidplus/chemidlite.jsp. Accessed 07/01/08.
[38] ChemIDplus - Available at: http://chem.sis.nlm.nih.gov/chemidplus/chemidlite.jsp. Accessed 07/01/08.
[39] ChemIDplus - Available at: http://chem.sis.nlm.nih.gov/chemidplus/chemidlite.jsp. Accessed 07/01/08.
[40] ChemIDplus - Available at: http://chem.sis.nlm.nih.gov/chemidplus/chemidlite.jsp. Accessed 07/01/08.
[41] ChemIDplus - Available at: http://chem.sis.nlm.nih.gov/chemidplus/chemidlite.jsp. Accessed 07/01/08.
[42] Merck Index - 2006; pp. 1, 927
[43] Merck Index - 2006; pp. 1, 927
[44] Merck Index - 2006; pp. 1, 928
[45] GlaxoSmithKline - Epzicom Prescribing Information, March 2006, p. 2. Available at: http://us.gsk.com/products/assets/us_epzicom.pdf. Accessed 07/01/08.
[46] GlaxoSmithKline - Epzicom Prescribing Information, March 2006, p. 3. Available at: http://us.gsk.com/products/assets/us_epzicom.pdf. Accessed 07/01/08.
[47] GlaxoSmithKline - Epzicom Prescribing Information, March 2006, p. 2. Available at: http://us.gsk.com/products/assets/us_epzicom.pdf. Accessed 05/29/07.
[48] GlaxoSmithKline - Epzicom Prescribing Information, March 2006, p. 3. Available at: http://us.gsk.com/products/assets/us_epzicom.pdf. Accessed 07/01/08.
[49] Expert Rev Anti Infect Ther - 2005 Dec;3(6):871-83
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Updated July 17, 2008
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