Abacavir Sulfate; Lamivudine (4048)
| Ingredients: |
Abacavir Sulfate; Lamivudine |
| Indications: |
Infection, human immunodeficiency virus |
| Pregnancy Category: |
C |
| FDA Approved: |
2004- 08- 01 |
| Classes: |
Antivirals; Nucleoside reverse transcriptase inhibitors |
| Brand Names: |
Epzicom
-
US
;
Kivexa
-
England, Ireland
;
|
| DEA schedules: |
(none)
|
| Cost of therapy: |
$813.55
(
HIV Infection (combination regimen) ;
Epzicom ;
600 mg; 300 mg ;
1 tablet/day ;
30 day supply
)
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BOXED WARNING
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- Epzicom contains 2 nucleoside analogues (abacavir sulfate and lamivudine) and is intended only for patients whose regimen
would otherwise include these 2 components.
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Hypersensitivity Reactions
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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. 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 the Patient ).
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Lactic Acidosis and Severe Hepatomegaly
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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 ).
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Exacerbations of Hepatitis B
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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) 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 coinfected with HIV and HBV. If appropriate, initiation of anti- hepatitis B therapy may be warranted (see WARNINGS ).
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DESCRIPTION
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NOTE: The trade name has been used throughout this monograph for clarity.
Epzicom
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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.
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.
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Abacavir Sulfate
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The chemical name of abacavir sulfate is (1 S, cis )- 4- [2- amino- 6- (cyclopropylamino)- 9 H - 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.
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.
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Lamivudine
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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.
Lamivudine is a white to off- white crystalline solid with a solubility of approximately 70 mg/ ml in water at 20°C.
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CLINICAL PHARMACOLOGY
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Microbiology
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Mechanism of Action
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Abacavir is a carbocyclic synthetic nucleoside analogue. Abacavir is converted intracellularly by cellular enzymes to the
active metabolite, carbovir triphosphate, an analogue of deoxyguanosine- 5'- triphosphate (dGTP). Carbovir triphosphate inhibits
the activity of HIV- 1 reverse transcriptase (RT) in viral DNA synthesis both by competing with the natural substrate dGTP
and by its incorporation into viral DNA resulting in chain termination. Lamivudine is a synthetic nucleoside analogue, which
is phosphorylated intracellularly to its active metabolite, lamivudine triphosphate. The principal mode of action of lamivudine
triphosphate is inhibition of RT via viral DNA chain termination after incorporation of the nucleoside analogue. Abacavir
and lamivudine are weak inhibitors of human DNA polymerases α, β, and γ.
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Antiviral Activity
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Abacavir had IC50 (50% inhibitory concentration) values ranging from 3.7- 5.8 µM and 0.07- 1.0 µM against HIV- 1IIIB in lymphoblastic cell lines and HIV- 1BaL in monocytes/ macrophages, respectively, and a mean IC50 value of 0.26 µM against 8 clinical isolates in monocytes and peripheral blood mononuclear cells. Lamivudine had IC50 values ranging from 0.0026- 15 µM against HIV- 1 in monocytes and human peripheral blood lymphocytes. The combination of abacavir
and lamivudine has demonstrated antiviral activity in vitro against nonsubtype B isolates and HIV- 2 isolates with equivalent antiviral activity as for subtype B isolates. Abacavir/
lamivudine had additive to synergistic activity in vitro 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 potency of abacavir/
lamivudine reproducibly by 2- to 6- fold in vitro.
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Resistance
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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 amino acid substitutions M184V/ I, K65R, L74V, and Y115F in HIV- 1 RT.
Genetic analysis of isolates from patients failing an abacavir- containing regimen demonstrated that amino acid substitutions
K65R, L74V, Y115F, and M184V in HIV- 1 RT contributed to abacavir resistance. Genotypic analysis of isolates recovered from
patients failing a lamivudine- containing regimen showed that the resistance was due to the M184V mutation in HIV- 1 RT. In
a study of therapy naive adults receiving Ziagen 600 mg once daily (n=384) or 300 mg twice daily (n=386) in a background regimen
of lamivudine 300 mg and efavirenz 600 mg once daily (Study CNA30021), the incidence of virologic failure at 48 weeks was
similar between the 2 groups (11% in both arms). Genotypic (n=38) and phenotypic analyses (n=35) of virologic failure isolates
from this study showed that the RT mutations that emerged during abacavir/ lamivudine once- daily and twice- daily therapy
were K65R, L74V, Y115F, and M184V/ I. The abacavir- and lamivudine- associated resistance mutation M184V/ I was the most commonly
observed mutation in virologic failure isolates from patients receiving abacavir/ lamivudine once daily (56%, 10/ 18) and
twice daily (40%, 8/ 20).
Thirty- nine percent (39%, 7/ 18) of the isolates from patients who experienced virologic failure in the abacavir once- daily
arm had a >2.5- fold decrease in abacavir susceptibility with a median- fold decrease of 1.3 (range 0.5- 11) compared with
29% (5/ 17) of the failure isolates in the twice- daily arm with a median- fold decrease of 0.92 (range 0.7- 13). Fifty- six
percent (56%, 10/ 18) of the virologic failure isolates in the once- daily abacavir group compared to 41% (7/ 17) of the failure
isolates in the twice- daily abacavir group had a >2.5- fold decrease in lamivudine susceptibility with median- fold changes
of 81 (range 0.79 to >116) and 1.1 (range 0.68 to >116) in the once- daily and twice- daily abacavir arms, respectively.
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Cross-Resistance
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Cross- resistance has been observed among nucleoside reverse transcriptase inhibitors. Viruses containing abacavir and lamivudine
resistance- associated mutations, namely, K65R, L74V, M184V, and Y115F, exhibit cross- resistance to didanosine, emtricitabine,
lamivudine, tenofovir, and zalcitabine 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.
The combination of abacavir/ lamivudine has demonstrated decreased susceptibility to viruses with the mutations K65R with
or without the M184V/ I mutation, viruses with L74V plus the M184V/ I mutation, and viruses with thymidine analog mutations
(TAMs: M41L, D67N, K70R, L210W, T215Y/ F, K219 E/ R/ H/ Q/ N) plus M184V. An increasing number of TAMs is associated with
a progressive reduction in abacavir susceptibility.
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Pharmacokinetics in Adults
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Epzicom
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In a single dose, 3- way crossover bioavailability study of 1 Epzicom tablet versus 2 Ziagen tablets (2 × 300 mg) and 2 Epivir
tablets (2 ×150 mg) administered simultaneously in healthy subjects (n=25), there was no difference in the extent of absorption,
as measured by the area under the plasma concentration- time curve (AUC) and maximal peak concentration (Cmax ), of each component.
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Abacavir
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Following oral administration, abacavir is rapidly absorbed and extensively distributed. After oral administration of a single
dose of 600 mg of abacavir in 20 patients, Cmax was 4.26 ± 1.19 µg/ ml (mean ± SD) and AUC(∞) was 11.95 ± 2.51 µg·h/ ml. Binding of abacavir to human plasma proteins is approximately
50% and was independent of concentration. Total blood and plasma drug- related radioactivity concentrations are identical,
demonstrating that abacavir readily distributes into erythrocytes. The primary routes of elimination of abacavir are metabolism
by alcohol dehydrogenase to form the 5'- carboxylic acid and glucuronyl transferase to form the 5'- glucuronide.
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Lamivudine
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Following oral administration, lamivudine is rapidly absorbed and extensively distributed. After multiple- dose oral administration
of lamivudine 300 mg once daily for 7 days to 60 healthy volunteers, steady- state Cmax (Cmax, ss ) was 2.04 ± 0.54 µg/ ml (mean ± SD) and the 24- hour steady- state AUC [AUC(24, ss)] was 8.87 ± 1.83 µg·h/ ml. Binding to
plasma protein is low. Approximately 70% of an IV dose of lamivudine is recovered as unchanged drug in the urine. Metabolism
of lamivudine is a minor route of elimination. In humans, the only known metabolite is the trans- sulfoxide metabolite (approximately
5% of an oral dose after 12 hours).
The steady- state pharmacokinetic properties of the Epivir 300- mg tablet once daily for 7 days compared to the Epivir 150-
mg tablet twice daily for 7 days were assessed in a crossover study in 60 healthy volunteers. Epivir 300 mg once daily resulted
in lamivudine exposures that were similar to Epivir 150 mg twice daily with respect to plasma AUC(24, ss); however, Cmax, ss was 66% higher and the trough value was 53% lower compared to the 150- mg twice- daily regimen. Intracellular lamivudine triphosphate
exposures in peripheral blood mononuclear cells were also similar with respect to AUC(24, ss) and Cmax24, ss ; however, trough values were lower compared to the 150- mg twice- daily regimen. Inter- subject variability was greater for
intracellular lamivudine triphosphate concentrations versus lamivudine plasma trough concentrations. The clinical significance
of observed differences for both plasma lamivudine concentrations and intracellular lamivudine triphosphate concentrations
is not known.
In humans, abacavir and lamivudine are not significantly metabolized by cytochrome P450 enzymes.
The pharmacokinetic properties of abacavir and lamivudine in fasting patients are summarized in TABLE 1 .
| TABLE 1
Pharmacokinetic Parameters* for Abacavir and Lamivudine in Adults
|
| Parameter |
Abacavir |
Lamivudine |
| Oral bioavailability (%) |
86 ± 25 (n=6) |
86 ± 16 (n=12) |
| Apparent volume of distribution (L/ kg) |
0.86 ± 0.15 (n=6) |
1.3 ± 0.4 (n=20) |
| Systemic clearance (L/ h/ kg) |
0.80 ± 0.24 (n=6) |
0.33 ± 0.06 (n=20) |
| Renal clearance (L/ h/ kg) |
.007 ± .008 (n=6) |
0.22 ± 0.06 (n=20) |
| Elimination half- life (h) |
1.45 ± 0.32 (n=20) |
5- 7† |
|
| *
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Data presented as mean ± standard deviation except where noted. |
| †
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Approximate range. |
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Effect of Food on Absorption of Epzicom
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Epzicom may be administered with or without food. Administration with a high- fat meal in a single- dose bioavailability study
resulted in no change in AUC(last), AUC(∞) and Cmax for lamivudine. Food did not alter the extent of systemic exposure to abacavir [AUC(∞)], but the rate of absorption (Cmax ) was decreased approximately 24% compared to fasted conditions (n=25). These results are similar to those from previous studies
of the effect of food on abacavir and lamivudine tablets administered separately.
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Special Populations
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Impaired Renal Function
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Epzicom
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Because lamivudine requires dose adjustment in the presence of renal insufficiency, Epzicom is not recommended for use in
patients with creatinine clearance <50 ml/ min (see PRECAUTIONS ).
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Impaired Hepatic Function
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Epzicom
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Abacavir is contraindicated in patients with moderate to severe hepatic impairment and dose reduction is required in patients
with mild hepatic impairment. Because Epzicom is a fixed- dose combination and cannot be dose adjusted, Epzicom is contraindicated
for patients with hepatic impairment.
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Nursing Mothers
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See PRECAUTIONS, Nursing Mothers .
Abacavir
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No data are available on the pharmacokinetics of abacavir in nursing mothers.
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Lamivudine
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Samples of breast milk obtained from 20 mothers receiving lamivudine monotherapy (300 mg twice daily) or combination therapy
(150 mg lamivudine twice daily and 300 mg zidovudine twice daily) had measurable concentrations of lamivudine.
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Pediatric Patients
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Epzicom
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The pharmacokinetics of Epzicom in pediatric patients are under investigation. There are insufficient data at this time to
recommend a dose (see PRECAUTIONS, Pediatric Use ).
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Geriatric Patients
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The pharmacokinetics of abacavir and lamivudine have not been studied in patients over 65 years of age.
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Gender
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Abacavir
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A population pharmacokinetic analysis in HIV- infected male (n=304) and female (n=67) patients showed no gender differences
in abacavir AUC normalized for lean body weight.
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Lamivudine
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A pharmacokinetic study in healthy male (n=12) and female (n=12) subjects showed no gender differences in lamivudine AUC(∞)
normalized for body weight.
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Race
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Abacavir
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There are no significant differences between blacks and Caucasians in abacavir pharmacokinetics.
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Lamivudine
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There are no significant racial differences in lamivudine pharmacokinetics.
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Drug Interactions
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See DRUG INTERACTIONS . The drug interactions described are based on studies conducted with the individual nucleoside analogues. In humans, abacavir
and lamivudine are not significantly metabolized by cytochrome P450 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.
Abacavir
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Fifteen (15) HIV- infected patients were enrolled in a crossover- designed drug interaction study evaluating single doses
of abacavir (600 mg), lamivudine (150 mg), and zidovudine (300 mg) alone or in combination. Analysis showed no clinically
relevant changes in the pharmacokinetics of abacavir with the addition of lamivudine or zidovudine or the combination of lamivudine
and zidovudine. Lamivudine exposure (AUC decreased 15%) and zidovudine exposure (AUC increased 10%) did not show clinically
relevant changes with concurrent abacavir.
In a study of 11 HIV- infected patients receiving methadone- maintenance therapy (40 and 90 mg daily), with 600 mg of Ziagen
twice daily (twice the currently recommended dose), oral methadone clearance increased 22% (90% CI 6- 42%). This alteration
will not result in a methadone dose modification in the majority of patients; however, an increased methadone dose may be
required in a small number of patients.
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Lamivudine
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No clinically significant alterations in lamivudine or zidovudine pharmacokinetics were observed in 12 asymptomatic HIV- infected
adult patients given a single dose of zidovudine (200 mg) in combination with multiple doses of lamivudine (300 mg q12h).
Lamivudine pharmacokinetics are not significantly affected by abacavir.
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| TABLE 2
Effect of Coadministered Drugs on Abacavir and Lamivudine AUC*
|
| Drugs That May Alter Blood Concentrations |
| Coadministered Drug and Dose |
Dose |
Concentrations |
Concentration of Coadministered Drug |
| AUC |
Variability |
| Ethanol 0.7 g/ kg (n=24) |
Single 600 mg Abacavir |
↑41% Abacavir |
90% CI: 35- 48% Abacavir |
↔ |
| Nelfinavir 750 mg q8h × 7- 10 days (n=11) |
Single 150 mg Lamivudine |
↑10% Lamivudine |
95% CI: 1- 20% Lamivudine |
↔ |
| Trimethoprim 160 mg/ sulfamethoxazole 800 mg daily × 5 days (n=14) |
Single 300 mg Lamivudine |
↑43% Lamivudine |
90% CI: 32- 55% Lamivudine |
↔ |
|
| Note:
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ROUTINE DOSE MODIFICATION OF ABACAVIR AND LAMIVUDINE IS NOT WARRANTED WITH COADMINISTRATION OF DRUGS IN TABLE 2 .
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↑ = Increase; ↔ = no significant change; AUC = area under the concentration versus time curve; CI = confidence interval. |
| *
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See DRUG INTERACTIONS for additional information on drug interactions.
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CLINICAL STUDIES
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Epzicom
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There have been no clinical trials conducted with Epzicom (see CLINICAL PHARMACOLOGY for information about bioequivalence of Epzicom). One Epzicom tablet given once daily is an alternative regimen to Epivir
tablets 300 mg once daily plus Ziagen tablets 2 × 300 mg once daily as a component of antiretroviral therapy.
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Therapy-Naive Adults
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The following study was conducted with the individual components of Epzicom: CNA30021 was an international, multicenter, double- blind, controlled study in which 770 HIV- infected, therapy- naive adults were
randomized and received either Ziagen 600 mg once daily or Ziagen 300 mg twice daily, both in combination with Epivir 300
mg once daily and efavirenz 600 mg once daily. The double- blind treatment duration was at least 48 weeks. Study participants
had a mean age of 37 years, were: male (81%), Caucasian (54%), black (27%), and American Hispanic (15%). The median baseline
CD4 + cell count was 262 cells/ mm3(range 21- 918 cells/ mm3) and the median baseline plasma HIV- 1 RNA was 4.89 log10 copies/ ml (range: 2.60- 6.99 log10 copies/ ml).
The outcomes of randomized treatment are provided in TABLE 3 .
| TABLE 3
Outcomes of Randomized Treatment Through Week 48 (CNA30021)
|
| Outcome |
Ziagen 600 mg qd plus Epivir plus Efavirenz (n=384) |
Ziagen 300 mg bid plus Epivir plus Efavirenz (n=386) |
| Responder* |
64% (71%) |
65% (72%) |
| Virologic failure† |
11% (5%) |
11% (5%) |
| Discontinued due to adverse reactions |
13% |
11% |
| Discontinued due to other reasons‡ |
11% |
13% |
|
| *
|
Patients achieved and maintained confirmed HIV- 1 RNA <50 copies/ ml (<400 copies/ ml) through Week 48 (Roche Amplicor Ultrasensitive
HIV- 1 Monitor standard test version 1.0).
|
| †
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Includes viral rebound, failure to achieve confirmed <50 copies/ ml (<400 copies/ ml) by Week 48, and insufficient viral load
response.
|
| ‡
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Includes consent withdrawn, lost to follow up, protocol violations, clinical progression, and other. |
|
After 48 weeks of therapy, the median CD4 + cell count increases from baseline were 188 cells/ mm3in the group receiving Ziagen 600 mg once daily and 200 cells/ mm3in the group receiving Ziagen 300 mg twice daily. Through Week 48, 6 subjects (2%) in the group receiving Ziagen 600 mg once
daily (4 CDC classification C events and 2 deaths) and 10 subjects (3%) in the group receiving Ziagen 300 mg twice daily (7
CDC classification C events and 3 deaths) experienced clinical disease progression. None of the deaths were attributed to
study medications.
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INDICATIONS AND USAGE
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Epzicom tablets, in combination with other antiretroviral agents, are indicated for the treatment of HIV- 1 infection.
Additional important information on the use of Epzicom for treatment of HIV- 1 infection:
| • |
Epzicom is 1 of multiple products containing abacavir. Before starting Epzicom, review medical history for prior exposure
to any abacavir- containing product in order to avoid reintroduction in a patient with a history of hypersensitivity to abacavir.
|
| • |
In one controlled study (CNA30021), more patients taking Ziagen 600 mg once daily had severe hypersensitivity reactions compared
to patients taking Ziagen 300 mg twice daily.
|
| • |
As part of a triple- drug regimen, Epzicom tablets are recommended for use with antiretroviral agents from different pharmacological
classes and not with other nucleoside/ nucleotide reverse transcriptase inhibitors.
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See WARNINGS , ADVERSE REACTIONS , and CLINICAL STUDIES .
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CONTRAINDICATIONS
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Epzicom tablets are contraindicated in patients with previously demonstrated hypersensitivity to abacavir or to any other
component of the product (see WARNINGS ). Following a hypersensitivity reaction to abacavir, NEVER restart Epzicom or any other abacavir- containing product. Fatal
rechallenge reactions have been associated with readministration of abacavir to patients with a prior history of a hypersensitivity
reaction to abacavir (see WARNINGS and PRECAUTIONS ).
Epzicom tablets are contraindicated in patients with hepatic impairment (see CLINICAL PHARMACOLOGY ).
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WARNINGS
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Hypersensitivity Reaction
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Serious and sometimes fatal hypersensitivity reactions have been associated with Epzicom and other abacavir- containing products.
To minimize the risk of a life- threatening hypersensitivity reaction, permanently discontinue Epzicom if hypersensitivity
cannot be ruled out, even when other diagnoses are possible. Important information on signs and symptoms of hypersensitivity,
as well as clinical management, is presented below.
Signs and Symptoms of Hypersensitivity
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Hypersensitivity to abacavir is a multi- organ clinical syndrome usually characterized by a sign or symptom in 2 or more of
the following groups:
- Group 1: Fever.
- Group 2: Rash.
- Group 3: Gastrointestinal (including nausea, vomiting, diarrhea, or abdominal pain).
- Group 4: Constitutional (including generalized malaise, fatigue, or achiness).
- Group 5: Respiratory (including dyspnea, cough, or pharyngitis).
Hypersensitivity to abacavir following the presentation of a single sign or symptom has been reported infrequently.
Hypersensitivity to abacavir was reported in approximately 8% of 2670 patients (n=206) in 9 clinical trials (range: 2- 9%)
with enrollment from November 1999 to February 2002. Data on time to onset and symptoms of suspected hypersensitivity were
collected on a detailed data collection module. Symptoms usually appeared within the first 6 weeks of treatment with abacavir,
although the reaction may occur at any time during therapy. Median time to onset was 9 days; 89% appeared within the first
6 weeks; 95% of patients reported symptoms from 2 or more of the 5 groups listed above.
Other less common signs and symptoms of hypersensitivity include lethargy, myolysis, edema, abnormal chest x- ray findings
(predominantly infiltrates, which can be localized), and paresthesia. Anaphylaxis, liver failure, renal failure, hypotension,
adult respiratory distress syndrome, respiratory failure, and death have occurred in association with hypersensitivity reactions.
In one study, 4 patients (11%) receiving Ziagen 600 mg once daily experienced hypotension with a hypersensitivity reaction
compared with 0 patients receiving Ziagen 300 mg twice daily.
Physical findings associated with hypersensitivity to abacavir in some patients include lymphadenopathy, mucous membrane lesions
(conjunctivitis and mouth ulcerations), and rash. The rash usually appears maculopapular or urticarial, but may be variable
in appearance. There have been reports of erythema multiforme. Hypersensitivity reactions have occurred without rash.
Laboratory abnormalities associated with hypersensitivity to abacavir in some patients include elevated liver function tests,
elevated creatine phosphokinase, elevated creatinine, and lymphopenia.
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Clinical Management of Hypersensitivity
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Discontinue Epzicom as soon as a hypersensitivity reaction is suspected. To minimize the risk of a life- threatening hypersensitivity
reaction, permanently discontinue Epzicom if hypersensitivity cannot be ruled out, even when other diagnoses are possible
( e.g., acute onset respiratory diseases such as pneumonia, bronchitis, pharyngitis, or influenza; gastroenteritis; or reactions to
other medications). 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.
When therapy with Epzicom has been discontinued for reasons other than symptoms of a hypersensitivity reaction, and if reinitiation
of Epzicom or any other abacavir- containing product is under consideration, carefully evaluate the reason for discontinuation
of Epzicom to ensure that the patient did not have symptoms of a hypersensitivity reaction. If hypersensitivity cannot be
ruled out, DO NOT reintroduce Epzicom or any other abacavir- containing product. If symptoms consistent with hypersensitivity
are not identified, reintroduction can be undertaken with continued monitoring for symptoms of a hypersensitivity reaction.
Make patients aware that a hypersensitivity reaction can occur with reintroduction of Epzicom or any other abacavir- containing
product and that reintroduction of Epzicom or introduction of any other abacavir- containing product needs to be undertaken
only if medical care can be readily accessed by the patient or others.
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Abacavir Hypersensitivity Reaction Registry
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To facilitate reporting of hypersensitivity reactions and collection of information on each case, an abacavir hypersensitivity
registry has been established. Physicians should register patients by calling 1- 800- 270- 0425.
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Lactic Acidosis/Sever Hepatomegaly With Steatosis
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| |
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 and other antiretrovirals. A majority of these cases
have been in women. Obesity and prolonged nucleoside exposure may be risk factors. Particular caution should be exercised
when administering Epzicom to any patient with known risk factors for liver disease; however, cases have also been reported
in patients with no known risk factors. Treatment with Epzicom should be suspended in any patient who develops clinical or
laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis
even in the absence of marked transaminase elevations).
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Posttreatment Exacerbations of Hepatitis
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In clinical trials in non- HIV- infected patients treated with lamivudine for chronic HBV, clinical and laboratory evidence
of exacerbations of hepatitis have occurred after discontinuation of lamivudine. These exacerbations have been detected primarily
by serum ALT elevations in addition to re- emergence of HBV DNA. Although most events appear to have been self- limited, fatalities
have been reported in some cases. Similar events have been reported from postmarketing experience after changes from lamivudine-
containing HIV treatment regimens to non- lamivudine- containing regimens in patients infected with both HIV and HBV. The
causal relationship to discontinuation of lamivudine treatment is unknown. Patients should be closely monitored with both
clinical and laboratory follow- up for at least several months after stopping treatment. There is insufficient evidence to
determine whether re- initiation of lamivudine alters the course of posttreatment exacerbations of hepatitis.
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Other
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Epzicom contains fixed doses of 2 nucleoside analogues, abacavir and lamivudine, and should not be administered concomitantly
with other abacavir- containing and/ or lamivudine- containing products (Ziagen, Epivir, Combivir, or Trizivir).
The complete prescribing information for all agents being considered for use with Epzicom should be consulted before combination
therapy with Epzicom is initiated.
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PRECAUTIONS
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Therapy-Experienced Patients
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Abacavir
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| |
In clinical trials, patients with prolonged prior NRTI exposure or who had HIV- 1 isolates that contained multiple mutations
conferring resistance to NRTIs had limited response to abacavir. The potential for cross- resistance between abacavir and
other NRTIs should be considered when choosing new therapeutic regimens in therapy- experienced patients (see CLINICAL PHARMACOLOGY, Microbiology, Cross- Resistance ).
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Patients With HIV and Hepatitis B Virus Coinfection
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Lamivudine
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Safety and efficacy of lamivudine have not been established for treatment of chronic hepatitis B in patients dually infected
with HIV and HBV. In non- HIV- infected patients treated with lamivudine for chronic hepatitis B, emergence of lamivudine-
resistant HBV has been detected and has been associated with diminished treatment response (see Epivir- HBV package insert
for additional information). Emergence of hepatitis B virus variants associated with resistance to lamivudine has also been
reported in HIV- infected patients who have received lamivudine- containing antiretroviral regimens in the presence of concurrent
infection with hepatitis B virus.
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Patients With Impaired Renal Function
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Epzicom
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Since Epzicom is a fixed- dose tablet and the dosage of the individual components cannot be altered, patients with creatinine
clearance <50 ml/ min should not receive Epzicom.
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Patients With Impaired Hepatic Function
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Epzicom
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Epzicom is contraindicated in patients with hepatic impairment since it is a fixed- dose tablet and the dosage of the individual
components cannot be altered.
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Fat Redistribution
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Redistribution/ accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral
wasting, facial wasting, breast enlargement, and “cushingoid appearance” have been observed in patients receiving antiretroviral
therapy. The mechanism and long- term consequences of these events are currently unknown. A causal relationship has not been
established.
|
Information for the Patient
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| |
Abacavir
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Hypersensitivity Reaction
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| |
Inform Patients:
| • |
That a Medication Guide and Warning Card summarizing the symptoms of the abacavir hypersensitivity reaction and other product
information will be dispensed by the pharmacist with each new prescription and refill of Epzicom, and encourage the patient
to read the Medication Guide and Warning Card every time to obtain any new information that may be present about Epzicom.
|
| • |
To carry the Warning Card with them.
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| • |
How to identify a hypersensitivity reaction (see WARNINGS and the Medication Guide provided with the prescription).
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| • |
That if they develop symptoms consistent with a hypersensitivity reaction to discontinue treatment with Epzicom and seek medical
evaluation immediately.
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| • |
That a hypersensitivity reaction can worsen and lead to hospitalization or death if Epzicom is not immediately discontinued.
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| • |
To not restart Epzicom or any other abacavir- containing product following a hypersensitivity reaction because more severe
symptoms can occur within hours and may include life- threatening hypotension and death.
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| • |
That a hypersensitivity reaction is usually reversible if it is detected promptly and Epzicom is stopped right away.
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| • |
That if they have interrupted Epzicom for reasons other than symptoms of hypersensitivity (for example, those who have an
interruption in drug supply), a serious or fatal hypersensitivity reaction may occur with reintroduction of abacavir.
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| • |
That in one study, more severe hypersensitivity reactions were seen when Ziagen was dosed 600 mg once daily.
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| • |
To not restart Epzicom or any other abacavir- containing product without medical consultation and that restarting abacavir
needs to be undertaken only if medical care can be readily accessed by the patient or others.
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Lamivudine
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Patients co- infected with HIV and HBV should be informed that deterioration of liver disease has occurred in some cases when
treatment with lamivudine was discontinued. Patients should be advised to discuss any changes in regimen with their physician.
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Epzicom
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| |
Inform patients that some HIV medicines, including Epzicom, can cause a rare, but serious condition called lactic acidosis
with liver enlargement (hepatomegaly).
Epzicom is not a cure for HIV infection and patients may continue to experience illnesses associated with HIV infection, including
opportunistic infections. Patients should remain under the care of a physician when using Epzicom. Advise patients that the
use of Epzicom has not been shown to reduce the risk of transmission of HIV to others through sexual contact or blood contamination.
Inform patients that redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy and
that the cause and long- term health effects of these conditions are not known at this time.
Epzicom tablets are for oral ingestion only.
Patients should be advised of the importance of taking Epzicom exactly as it is prescribed.
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Carcinogenesis, Mutagenesis, and Impairment of Fertility
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Carcinogenicity
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Abacavir
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Abacavir was administered orally at 3 dosage levels to separate groups of mice and rats in 2- year carcinogenicity studies.
Results showed an increase in the incidence of malignant and nonmalignant tumors. Malignant tumors occurred in the preputial
gland of males and the clitoral gland of females of both species, and in the liver of female rats. In addition, nonmalignant
tumors also occurred in the liver and thyroid gland of female rats. These observations were made at systemic exposures in
the range of 6- 32 times the human exposure at the recommended dose.
|
Lamivudine
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| |
Long- term carcinogenicity studies with lamivudine in mice and rats showed no evidence of carcinogenic potential at exposures
up to 10 times (mice) and 58 times (rats) those observed in humans at the recommended therapeutic dose for HIV infection.
It is not known how predictive the results of rodent carcinogenicity studies may be for humans.
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Mutagenicity
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Abacavir
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Abacavir induced chromosomal aberrations both in the presence and absence of metabolic activation in an in vitro cytogenetic study in human lymphocytes. Abacavir was mutagenic in the absence of metabolic activation, although it was not
mutagenic in the presence of metabolic activation in an L5178Y mouse lymphoma assay. Abacavir was clastogenic in males and
not clastogenic in females in an in vivo mouse bone marrow micronucleus assay. Abacavir was not mutagenic in bacterial mutagenicity assays in the presence and absence
of metabolic activation.
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Lamivudine
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Lamivudine was mutagenic in an L5178Y mouse lymphoma assay and clastogenic in a cytogenetic assay using cultured human lymphocytes.
Lamivudine was not mutagenic in a microbial mutagenicity assay, in an in vitro cell transformation assay, in a rat micronucleus test, in a rat bone marrow cytogenetic assay, and in an assay for unscheduled
DNA synthesis in rat liver.
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Impairment of Fertility
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| |
Abacavir or lamivudine induced no adverse effects on the mating performance or fertility of male and female rats at doses
producing systemic exposure levels approximately 8 or 130 times, respectively, higher than those in humans at the recommended
dose based on body surface area comparisons.
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Pregnancy Category C
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There are no adequate and well- controlled studies of Epzicom in pregnant women. Reproduction studies with abacavir and lamivudine
have been performed in animals (see Abacavir and Lamivudine sections below). Epzicom should be used during pregnancy only if the potential benefits outweigh the risks.
Abacavir
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| |
Studies in pregnant rats showed that abacavir is transferred to the fetus through the placenta. Fetal malformations (increased
incidences of fetal anasarca and skeletal malformations) and developmental toxicity (depressed fetal body weight and reduced
crown- rump length) were observed in rats at a dose which produced 35 times the human exposure, based on AUC. Embryonic and
fetal toxicities (increased resorptions, decreased fetal body weights) and toxicities to the offspring (increased incidence
of stillbirth and lower body weights) occurred at half of the above mentioned dose in separate fertility studies conducted
in rats. In the rabbit, no developmental toxicity and no increases in fetal malformations occurred at doses that produced
8.5 times the human exposure at the recommended dose based on AUC.
|
Lamivudine
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| |
Studies in pregnant rats showed that lamivudine is transferred to the fetus through the placenta. Reproduction studies with
orally administered lamivudine have been performed in rats and rabbits at doses producing plasma levels up to approximately
35 times that for the recommended adult HIV dose. No evidence of teratogenicity due to lamivudine was observed. Evidence of
early embryolethality was seen in the rabbit at exposure levels similar to those observed in humans, but there was no indication
of this effect in the rat at exposure levels up to 35 times that in humans.
|
Antiretroviral Pregnancy Registry
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| |
To monitor maternal- fetal outcomes of pregnant women exposed to Epzicom or other antiretroviral agents, an Antiretroviral
Pregnancy Registry has been established. Physicians are encouraged to register patients by calling 1- 800- 258- 4263.
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Nursing Mothers
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| |
The Centers for Disease Control and Prevention recommend that HIV- infected mothers not breastfeed their infants to avoid
risking postnatal transmission of HIV infection.
Abacavir
|
| |
Abacavir is secreted into the milk of lactating rats.
|
Lamivudine
|
| |
Lamivudine is excreted in human breast milk and into the milk of lactating rats.
Because of both the potential for HIV transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breastfeed if they are receiving Epzicom.
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Pediatric Use
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| |
Safety and effectiveness of Epzicom in pediatric patients have not been established.
|
Geriatric Use
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| |
Clinical studies of abacavir and lamivudine did not include sufficient numbers of patients aged 65 and over to determine whether
they respond differently from younger patients. In general, dose selection for an elderly patient should be cautious, reflecting
the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
Epzicom is not recommended for patients with impaired renal function or impaired hepatic function (see PRECAUTIONS and DOSAGE AND ADMINISTRATION ).
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DRUG INTERACTIONS
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Epzicom
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| |
No clinically significant changes to pharmacokinetic parameters were observed for abacavir or lamivudine when administered
together.
|
Abacavir
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| |
Abacavir has no effect on the pharmacokinetic properties of ethanol. Ethanol decreases the elimination of abacavir causing
an increase in overall exposure (see CLINICAL PHARMACOLOGY, Drug Interactions ).
The addition of methadone has no clinically significant effect on the pharmacokinetic properties of abacavir. In a study of
11 HIV- infected patients receiving methadone- maintenance therapy (40 and 90 mg daily), with 600 mg of Ziagen twice daily
(twice the currently recommended dose), oral methadone clearance increased 22% (90% CI 6- 42%). This alteration will not result
in a methadone dose modification in the majority of patients; however, an increased methadone dose may be required in a small
number of patients.
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Lamivudine
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| |
Trimethoprim (TMP) 160 mg/ sulfamethoxazole (SMX) 800 mg once daily has been shown to increase lamivudine exposure (AUC).
No change in dose of either drug is recommended. The effect of higher doses of TMP/ SMX on lamivudine pharmacokinetics has
not been investigated (see CLINICAL PHARMACOLOGY ).
Lamivudine and zalcitabine may inhibit the intracellular phosphorylation of one another. Therefore, use of Epzicom in combination
with zalcitabine is not recommended.
See CLINICAL PHARMACOLOGY for additional drug interactions.
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ADVERSE REACTIONS
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| |
Abacavir
|
| |
Hypersensitivity Reaction
|
| |
Serious and sometimes fatal hypersensitivity reactions have been associated with abacavir sulfate, a component of Epzicom.
In one study, once- daily dosing of Ziagen was associated with more severe hypersensitivity reactions (see WARNINGS and PRECAUTIONS, Information for the Patient ).
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Therapy-Naive Adults
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Treatment- emergent clinical adverse reactions (rated by the investigator as moderate or severe) with a ≥5% frequency during
therapy with Ziagen 600 mg once daily or Ziagen 300 mg twice daily, both in combination with lamivudine 300 mg once daily
and efavirenz 600 mg once daily are listed in TABLE 4 .
| TABLE 4
Treatment- Emergent (All Causality) Adverse Reactions of at Least Moderate Intensity (Grades 2- 4, ≥5% Frequency) in Therapy-
Naive Adults (CNA30021) Through 48 Weeks of Treatment
|
| Adverse Event |
Ziagen 600 mg qd Plus Epivir Plus Efavirenz (n=384) |
Ziagen 300 mg bid Plus Epivir Plus Efavirenz (n=386) |
| Drug hypersensitivity *†
|
9% |
7% |
| Insomnia |
7% |
9% |
| Depression/ depressed mood |
7% |
7% |
| Headache/ migraine |
7% |
6% |
| Fatigue/ malaise |
6% |
8% |
| Dizziness/ vertigo |
6% |
6% |
| Nausea |
5% |
6% |
| Diarrhea* |
5% |
6% |
| Rash |
5% |
5% |
| Pyrexia |
5% |
3% |
| Abdominal pain/ gastritis |
4% |
5% |
| Abnormal dreams |
4% |
5% |
| Anxiety |
3% |
5% |
|
| *
|
Patients receiving Ziagen 600 mg once daily, experienced a significantly higher incidence of severe drug hypersensitivity
reactions and severe diarrhea compared to patients who received Ziagen 300 mg twice daily. Five percent (5%) of patients receiving
Ziagen 600 mg once daily had severe drug hypersensitivity reactions compared to 2% of patients receiving Ziagen 300 mg twice
daily.Two percent (2%) of patients receiving Ziagen 600 mg once daily had severe diarrhea while none of the patients receiving
Ziagen 300 mg twice daily had this event.
|
| †
|
Study CNA30024 was a multicenter, double- blind, controlled study in which 649 HIV infected, therapy- naive adults were randomized and received
either Ziagen (300 mg twice daily), Epivir (150 mg twice daily), and efavirenz (600 mg once daily) or zidovudine (300 mg twice
daily), Epivir (150 mg twice daily), and efavirenz (600 mg once daily). CNA30024 used double- blind ascertainment of suspected
hypersensitivity reactions. During the blinded portion of the study, suspected hypersensitivity to abacavir was reported by investigators in 9% of 324 patients in the abacavir group and 3% of
325 patients in the zidovudine group.
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|
|
Laboratory Abnormalities
|
| |
Laboratory abnormalities observed in clinical studies of Ziagen were anemia, neutropenia, liver function test abnormalities,
and elevations of CPK, blood glucose, and triglycerides. Additional laboratory abnormalities observed in clinical studies
of Epivir were thrombocytopenia and elevated levels of bilirubin, amylase, and lipase.
The frequencies of treatment- emergent laboratory abnormalities were comparable between treatment groups in Study CNA30021.
|
Other Adverse Events
|
| |
In addition to adverse reactions listed above, other adverse events observed in the expanded access program for abacavir were
pancreatitis and increased GGT.
|
Observed During Clinical Practice
|
| |
The following reactions have been identified during post- approval use of abacavir and lamivudine. Because they are reported
voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion
due to a combination of their seriousness, frequency of reporting, or potential causal connection to abacavir and/ or lamivudine.
Abacavir
|
| |
Suspected Stevens- Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported in patients receiving abacavir
primarily in combination with medications known to be associated with SJS and TEN, respectively. Because of the overlap of
clinical signs and symptoms between hypersensitivity to abacavir and SJS and TEN, and the possibility of multiple drug sensitivities
in some patients, abacavir should be discontinued and not restarted in such cases.
There have also been reports of erythema multiforme with abacavir use.
|
Abacavir and Lamivudine
|
| |
- Body as a Whole: Redistribution/ accumulation of body fat (see PRECAUTIONS, Fat Redistribution ).
- Digestive: Stomatitis.
- Endocrine and Metabolic: Hyperglycemia.
- General: Weakness.
- Hemic and Lymphatic: Aplastic anemia, anemia (including pure red cell aplasia and severe anemias progressing on therapy), lymphadenopathy, splenomegaly.
- Hepatic and Pancreatic: Lactic acidosis and hepatic steatosis, pancreatitis, posttreatment exacerbation of hepatitis B (see WARNINGS ).
- Hypersensitivity: Sensitization reactions (including anaphylaxis), urticaria.
- Musculoskeletal: Muscle weakness, CPK elevation, rhabdomyolysis.
- Nervous: Paresthesia, peripheral neuropathy, seizures.
- Respiratory: Abnormal breath sounds/ wheezing.
- Skin: Alopecia, erythema multiforme, Stevens- Johnson syndrome.
|
|
|
OVERDOSAGE
|
| |
Abacavir
|
| |
There is no known antidote for abacavir. It is not known whether abacavir can be removed by peritoneal dialysis or hemodialysis.
|
Lamivudine
|
| |
One case of an adult ingesting 6 g of lamivudine was reported; there were no clinical signs or symptoms noted and hematologic
tests remained normal. It is not known whether lamivudine can be removed by peritoneal dialysis or hemodialysis.
|
|
DOSAGE AND ADMINISTRATION
|
| |
A Medication Guide and Warning Card that provide information about recognition of hypersensitivity reactions should be dispensed
with each new prescription and refill. To facilitate reporting of hypersensitivity reactions and collection of information on each case, an abacavir hypersensitivity
registry has been established. Physicians should register patients by calling 1- 800- 270- 0425.
The recommended oral dose of Epzicom for adults is 1 tablet daily, in combination with other antiretroviral agents (see CLINICAL STUDIES ; PRECAUTIONS ; CLINICAL PHARMACOLOGY, Microbiology ; and CLINICAL PHARMACOLOGY ).
Epzicom can be taken with or without food.
Dose Adjustment
|
| |
Because it is a fixed- dose tablet, Epzicom should not be prescribed for patients requiring dosage adjustment such as those
with creatinine clearance <50 ml/ min, those with hepatic impairment, or those experiencing dose- limiting adverse events.
Use of Epivir oral solution and Ziagen oral solution may be considered.
|
|
ANIMAL PHARMACOLOGY
|
| |
Myocardial degeneration was found in mice and rats following administration of abacavir for 2 years. The systemic exposures
were equivalent to 7- 24 times the expected systemic exposure in humans. The clinical relevance of this finding has not been
determined.
|
HOW SUPPLIED
|
| |
Epzicom is available as tablets: Each tablet contains 600 mg of abacavir as abacavir sulfate and 300 mg of lamivudine. The tablets are orange, film- coated,
modified capsule- shaped, and debossed with "GS FC2" on one side with no markings on the reverse side.
Storage: Store at 25°C (77°F); excursions permitted to 15- 30°C (59- 86°F).
|
PRODUCT LISTING - EQUIVALENTS NOT AVAILABLE
|
| |
| tablet - oral - 600 mg- 300 mg -
|
| 30.0's |
$777.03 |
Epzicom
GlaxoSmithKline
|
00173074200 |
|
|