EPZICOM- abacavir sulfate and lamivudine tablet, film coated
EPZICOM contains 2 nucleoside analogues (abacavir sulfate and lamivudine) and is intended only for patients whose regimen would otherwise include these 2 components.
Hypersensitivity Reactions: Serious and sometimes fatal hypersensitivity reactions have been associated with abacavir sulfate, a component of EPZICOM. Hypersensitivity to abacavir is a multi-organ clinical syndrome usually characterized by a sign or symptom in 2 or more of the following groups: (1) fever, (2) rash, (3) gastrointestinal (including nausea, vomiting, diarrhea, or abdominal pain), (4) constitutional (including generalized malaise, fatigue, or achiness), and (5) respiratory (including dyspnea, cough, or pharyngitis). Discontinue EPZICOM as soon as a hypersensitivity reaction is suspected.
Patients who carry the HLA-B*5701 allele are at high risk for experiencing a hypersensitivity reaction to abacavir. Prior to initiating therapy with abacavir, screening for the HLA-B*5701 allele is recommended; this approach has been found to decrease the risk of hypersensitivity reaction. Screening is also recommended prior to reinitiation of abacavir in patients of unknown HLA-B*5701 status who have previously tolerated abacavir. HLA-B*5701-negative patients may develop a suspected hypersensitivity reaction to abacavir; however, this occurs significantly less frequently than in HLA-B*5701-positive patients.
Regardless of HLA-B*5701 status, permanently discontinue EPZICOM if hypersensitivity cannot be ruled out, even when other diagnoses are possible.
Following a hypersensitivity reaction to abacavir, NEVER restart EPZICOM or any other abacavir-containing product because more severe symptoms can occur within hours and may include life-threatening hypotension and death.
Reintroduction of EPZICOM or any other abacavir-containing product, even in patients who have no identified history or unrecognized symptoms of hypersensitivity to abacavir therapy, can result in serious or fatal hypersensitivity reactions. Such reactions can occur within hours (see WARNINGS and PRECAUTIONS: Information for Patients).
Lactic Acidosis and Severe Hepatomegaly: 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, lamivudine, and other antiretrovirals (see WARNINGS).
Exacerbations of Hepatitis B: Severe acute exacerbations of hepatitis B have been reported in patients who are co-infected with hepatitis B virus (HBV) and human immunodeficiency virus (HIV-1) and have discontinued lamivudine, which is one component of EPZICOM. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who discontinue EPZICOM and are co-infected with HIV-1 and HBV. If appropriate, initiation of anti-hepatitis B therapy may be warranted (see WARNINGS).
EPZICOM Tablets contain the following 2 synthetic nucleoside analogues: abacavir sulfate (ZIAGEN� , also a component of TRIZIVIR�) and lamivudine (also known as EPIVIR� or 3TC) with inhibitory activity against HIV-1.
EPZICOM Tablets are for oral administration. Each orange, film-coated tablet contains the active ingredients 600 mg of abacavir as abacavir sulfate and 300 mg of lamivudine, and the inactive ingredients magnesium stearate, microcrystalline cellulose, and sodium starch glycolate. The tablets are coated with a film (OPADRY� orange YS-1-13065-A) that is made of FD&C Yellow No. 6, hypromellose, polyethylene glycol 400, polysorbate 80, and titanium dioxide.
The chemical name of abacavir sulfate is ( 1S,cis)- 4-[2-amino-6-(cyclopropylamino)-9H -purin-9-yl]-2-cyclopentene-1-methanol sulfate (salt) (2:1). Abacavir sulfate is the enantiomer with 1S , 4R absolute configuration on the cyclopentene ring. It has a molecular formula of (C14 H18 N6 O)2 �H2 SO4 and a molecular weight of 670.76 daltons. It has the following structural formula:
abacavir sulfate structural formula
(click image for full-size original)
Abacavir sulfate is a white to off-white solid with a solubility of approximately 77 mg/mL in distilled water at 25�C.
In vivo, abacavir sulfate dissociates to its free base, abacavir. All dosages for abacavir sulfate are expressed in terms of abacavir.
The chemical name of lamivudine is (2R,cis)-4-amino-1-(2-hydroxymethyl-1,3-oxathiolan-5-yl)-(1H)-pyrimidin-2-one. Lamivudine is the (-)enantiomer of a dideoxy analogue of cytidine. Lamivudine has also been referred to as (-)2?,3?-dideoxy, 3?-thiacytidine. It has a molecular formula of C8 H11 N3 O3 S and a molecular weight of 229.3 daltons. It has the following structural formula:
lamivudine structural formula
Lamivudine is a white to off-white crystalline solid with a solubility of approximately 70 mg/mL in water at 20�C.
Mechanism of Action:
Abacavir is a carbocyclic synthetic nucleoside analogue. Abacavir is converted by cellular enzymes to the active metabolite, carbovir triphosphate (CBV-TP), an analogue of deoxyguanosine-5?-triphosphate (dGTP). CBV-TP inhibits the activity of HIV-1 reverse transcriptase (RT) both by competing with the natural substrate dGTP and by its incorporation into viral DNA. The lack of a 3?-OH group in the incorporated nucleotide analogue prevents the formation of the 5? to 3? phosphodiester linkage essential for DNA chain elongation, and therefore, the viral DNA growth is terminated. CBV-TP is a weak inhibitor of cellular DNA polymerases ?, ?, and ?.
Lamivudine is a synthetic nucleoside analogue. Intracellularly lamivudine is phosphorylated to its active 5?-triphosphate metabolite, lamivudine triphosphate (3TC-TP). The principal mode of action of 3TC-TP is inhibition of RT via DNA chain termination after incorporation of the nucleotide analogue. CBV-TP and 3TC-TP are weak inhibitors of cellular DNA polymerases ?, ?, and ?.
The antiviral activity of abacavir against HIV-1 was evaluated against a T-cell tropic laboratory strain HIV-1IIIB in lymphoblastic cell lines, a monocyte/macrophage tropic laboratory strain HIV- 1BaL in primary monocytes/macrophages, and clinical isolates in peripheral blood mononuclear cells. The concentration of drug necessary to effect viral replication by 50 percent (EC50 ) ranged from 3.7 to 5.8 ?M (1 ?M = 0.28 mcg/mL) and 0.07 to 1.0 ?M against HIV-1IIIB and HIV-1BaL , respectively, and was 0.26 � 0.18 ?M against 8 clinical isolates. The EC50 values of abacavir against different HIV-1 clades (A-G) ranged from 0.0015 to 1.05 ?M, and against HIV-2 isolates, from 0.024 to 0.49 ?M. Ribavirin (50 ?M) had no effect on the anti�HIV-1 activity of abacavir in cell culture.
The antiviral activity of lamivudine against HIV-1 was assessed in a number of cell lines (including monocytes and fresh human peripheral blood lymphocytes) using standard susceptibility assays. EC50 values were in the range of 0.003 to 15 ?M (1 ?M = 0.23 mcg/mL). HIV-1 from therapy-naive subjects with no amino acid substitutions associated with resistance gave median EC50 values of 0.429 �M (range: 0.200 to 2.007 �M) from Virco (n = 92 baseline samples from COLA40263) and 2.35 �M (1.37 to 3.68 �M) from Monogram Biosciences (n = 135 baseline samples from ESS30009). The EC50 values of lamivudine against different HIV-1 clades (A-G) ranged from 0.001 to 0.120 �M, and against HIV-2 isolates from 0.003 to 0.120 ?M in peripheral blood mononuclear cells. Ribavirin (50 ?M) decreased the anti�HIV-1 activity of lamivudine by 3.5 fold in MT-4 cells.
The combination of abacavir and lamivudine has demonstrated antiviral activity in cell culture against non-subtype B isolates and HIV-2 isolates with equivalent antiviral activity as for subtype B isolates. Abacavir/lamivudine had additive to synergistic activity in cell culture in combination with the nucleoside reverse transcriptase inhibitors (NRTIs) emtricitabine, stavudine, tenofovir, zalcitabine, zidovudine; the non-nucleoside reverse transcriptase inhibitors (NNRTIs) delavirdine, efavirenz, nevirapine; the protease inhibitors (PIs) amprenavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir; or the fusion inhibitor, enfuvirtide. Ribavirin, used in combination with interferon for the treatment of HCV infection, decreased the anti-HIV-1 potency of abacavir/lamivudine reproducibly by 2- to 6-fold in cell culture.