Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/1533
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TRIZIVIR (Tablet)
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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 TRIZIVIR for adults and adolescents is 1 tablet
twice daily.TRIZIVIR is not recommended
in adolescents who weigh less than 40 kg because it is a fixed-dose tablet.<br/>Dose Adjustment: Because it is a fixed-dose tablet, TRIZIVIR should not be
prescribed for patients requiring dosage adjustment such as those with creatinine
clearance<50 mL/min, patients with hepatic impairment, or patients
experiencing dose-limiting adverse events.
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| dailymed-instance:descripti... |
TRIZIVIR: TRIZIVIR Tablets contain the following 3 synthetic nucleoside
analogues: abacavir sulfate (ZIAGEN), lamivudine (also known
as EPIVIR or 3TC), and zidovudine (also known as RETROVIR,
azidothymidine, or ZDV) with inhibitory activity against HIV. TRIZIVIR
Tablets are for oral administration. Each film-coated tablet contains the
active ingredients 300 mg of abacavir as abacavir sulfate, 150 mg
of lamivudine, and 300 mg of zidovudine, and the inactive ingredients
magnesium stearate, microcrystalline cellulose, and sodium starch glycolate.
The tablets are coated with a film (Opadry green 03B11434)
that is made of FD&C Blue No. 2, hypromellose, polyethylene glycol, titanium
dioxide, and yellow iron oxide.<br/>Abacavir Sulfate: 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 (CHNO)HSOand a molecular weight of 670.76 daltons. It has the following structural
formula: 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. In this insert,
all dosages for ZIAGEN (abacavir sulfate) are expressed in terms of abacavir.<br/>Lamivudine: 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 CHNOS
and a molecular weight of 229.3 daltons. It has the following structural formula: Lamivudine
is a white to off-white crystalline solid with a solubility of approximately
70 mg/mL in water at 20��C.<br/>Zidovudine: The chemical name of zidovudine is 3���-azido-3���-deoxythymidine.
It has a molecular formula of CHNOand
a molecular weight of 267.24 daltons. It has the following structural formula: Zidovudine
is a white to beige, crystalline solid with a solubility of 20.1 mg/mL
in water at 25��C.
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Pharmacokinetics in Adults:<br/>TRIZIVIR: In a single-dose,
3-way crossover bioavailability study of 1 TRIZIVIR Tablet versus 1 ZIAGEN
Tablet (300 mg), 1 EPIVIR Tablet (150 mg), plus 1 RETROVIR
Tablet (300 mg) administered simultaneously in healthy subjects (n = 24),
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
(C), of all 3 components.One TRIZIVIR Tablet was bioequivalent to 1 ZIAGEN Tablet (300 mg),
1 EPIVIR Tablet (150 mg), plus 1 RETROVIR Tablet (300 mg)
following single-dose administration to fasting healthy subjects (n = 24).<br/>Abacavir: Following oral administration, abacavir is rapidly absorbed
and extensively distributed. Binding of abacavir to human plasma proteins
is approximately 50%. Binding of abacavir to plasma proteins 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.<br/>Lamivudine: Following oral administration, lamivudine is rapidly absorbed
and extensively distributed. Binding to plasma protein is low. Approximately
70% of an intravenous 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).<br/>Zidovudine: Following oral
administration, zidovudine is rapidly absorbed and extensively distributed.
Binding to plasma protein is low. Zidovudine is eliminated primarily by hepatic
metabolism. The major metabolite of zidovudine is 3���-azido-3���-deoxy-5���-O-��-D-glucopyranuronosylthymidine
(GZDV). GZDV area under the curve (AUC) is about 3-fold greater than the zidovudine
AUC. Urinary recovery of zidovudine and GZDV accounts for 14% and 74% of the
dose following oral administration, respectively. A second metabolite, 3���-amino-3���-deoxythymidine
(AMT), has been identified in plasma. The AMT AUC was one fifth of the zidovudine
AUC. In humans,
abacavir, lamivudine, and zidovudine are not significantly metabolized by
cytochrome P450 enzymes. The pharmacokinetic properties
of abacavir, lamivudine, and zidovudine in fasting patients are summarized
in Table 1. *Data presented as mean��standard
deviation except where noted. Approximate
range.<br/>Effect of Food on Absorption of TRIZIVIR: TRIZIVIR may be administered with
or without food. Administration with food in a single-dose bioavailability
study resulted in lower C, similar to results observed previously
for the reference formulations. The average [90% CI] decrease in abacavir,
lamivudine, and zidovudine Cwas 32% [24% to 38%], 18% [10%
to 25%], and 28% [13% to 40%], respectively, when administered with a high-fat
meal, compared to administration under fasted conditions. Administration of
TRIZIVIR with food did not alter the extent of abacavir, lamivudine, and zidovudine
absorption (AUC), as compared to administration under fasted conditions (n = 24).<br/>Special Populations:<br/>Impaired Renal Function:<br/>Impaired Hepatic Function:<br/>Pregnancy: See PRECAUTIONS:
Pregnancy.<br/>Nursing Mothers: See PRECAUTIONS:
Nursing Mothers.<br/>Pediatric Patients:<br/>Geriatric Patients: The pharmacokinetics
of abacavir, lamivudine, and zidovudine have not been studied in patients
over 65 years of age.<br/>Gender:<br/>Race:<br/>Drug Interactions: See PRECAUTIONS: Drug Interactions. The drug interactions
described are based on studies conducted with the individual nucleoside analogues.
In humans, abacavir, lamivudine, and zidovudine are not significantly metabolized
by cytochrome P450 enzymes; therefore, it is unlikely that clinically significant
drug interactions will occur with drugs metabolized through these pathways.<br/>Abacavir: Due to the common
metabolic pathways of abacavir and zidovudine via glucuronyl transferase,
15 HIV-infected patients were enrolled in a crossover 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 mg and 90 mg daily), with 600 mg of ZIAGEN twice daily
(twice the currently recommended dose), oral methadone clearance increased
22% (90% CI 6% to 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.<br/>Lamivudine and Zidovudine: 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 q 12 hr). ���= Increase;���= Decrease;���= no
significant change; AUC = area under the concentration versus time curve;
CI = confidence interval. *See PRECAUTIONS:Drug Interactions for additional information on drug interactions. Estimated
range of percent difference.<br/>Ribavirin: In vitro data indicate ribavirin reduces phosphorylation
of lamivudine, stavudine, and zidovudine. However, no pharmacokinetic (e.g.,
plasma concentrations or intracellular triphosphorylated active metabolite
concentrations) or pharmacodynamic (e.g., loss of HIV/HCV virologic suppression)
interaction was observed when ribavirin and lamivudine (n = 18),
stavudine (n = 10), or zidovudine (n = 6) were coadministered
as part of a multi-drug regimen to HIV/HCV co-infected patients (see WARNINGS).
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TRIZIVIR 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 TRIZIVIR 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). TRIZIVIR Tablets are contraindicated
in patients with hepatic impairment (see CLINICAL PHARMACOLOGY).
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TRIZIVIR is available
as tablets. Each tablet contains 300 mg of abacavir as abacavir sulfate,
150 mg of lamivudine, and 300 mg of zidovudine. The tablets are
blue-green capsule-shaped, film-coated, and imprinted with GX LL1 on one side
with no markings on the reverse side. They are packaged as follows: Bottles
of 60 Tablets (NDC 0173-0691-00). Store
at 25��C (77��F); excursions permitted to 15��to 30��C (59��to 86��F) (see USP Controlled Room Temperature).
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WARNINGS: TRIZIVIR contains 3 nucleoside
analogues (abacavir sulfate, lamivudine, and zidovudine) and is intended only
for patients whose regimen would otherwise include these 3 components.<br/>Hypersensitivity Reactions: Serious and sometimes fatal hypersensitivity
reactions have been associated with abacavir sulfate, a component of TRIZIVIR.
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
TRIZIVIR as soon as a hypersensitivity reaction is suspected. Permanently
discontinue TRIZIVIR if hypersensitivity cannot be ruled out,
even when other diagnoses are possible. Following a hypersensitivity reaction to abacavir, NEVER
restart TRIZIVIR or any other abacavir-containing product because more severe
symptoms can occur within hours and may include life-threatening hypotension
and death. Reintroduction
of TRIZIVIR 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).<br/>Hematologic Toxicity: Zidovudine has been associated
with hematologic toxicity including neutropenia and severe anemia, particularly
in patients with advanced Human Immunodeficiency Virus (HIV) disease (see
WARNINGS). Prolonged use of zidovudine has been associated with symptomatic
myopathy.<br/>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,
zidovudine, and other antiretrovirals (see WARNINGS).<br/>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) and have discontinued lamivudine,
which is one component of TRIZIVIR. Hepatic function should be monitored closely
with both clinical and laboratory follow-up for at least several months in
patients who discontinue TRIZIVIR and are co-infected with HIV and HBV. If
appropriate, initiation of anti-hepatitis B therapy may be warranted (see
WARNINGS).
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dailymed-ingredient:FD&C_Blue_No._2,
dailymed-ingredient:hypromellose,
dailymed-ingredient:magnesium_stearate,
dailymed-ingredient:microcrystalline_cellulose,
dailymed-ingredient:polyethylene_glycol,
dailymed-ingredient:sodium_starch_glycolate,
dailymed-ingredient:titanium_dioxide,
dailymed-ingredient:yellow_iron_oxide
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Therapy-Experienced Patients:<br/>Abacavir: 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 MICROBIOLOGY: Cross-Resistance).<br/>Patients With HIV and Hepatitis B Virus Co-infection:<br/>Lamivudine: 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<br/>Patients With Impaired Renal Function:<br/>TRIZIVIR: Since TRIZIVIR 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 TRIZIVIR.<br/>Patients With Impaired Hepatic Function:<br/>TRIZIVIR: TRIZIVIR is contraindicated
in patients with hepatic impairment since it is a fixed-dose tablet and the
dosage of the individual components cannot be altered.<br/>Immune Reconstitution Syndrome: Immune reconstitution syndrome has been reported in patients
treated with combination antiretroviral therapy, including TRIZIVIR. During
the initial phase of combination antiretroviral treatment, patients whose
immune system responds may develop an inflammatory response to indolent or
residual opportunistic infections (such as Mycobacterium
avium infection, cytomegalovirus, Pneumocystis
jirovecii pneumonia [PCP], or tuberculosis), which may necessitate
further evaluation and treatment.<br/>Fat Redistribution: 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.<br/>Information for Patients:<br/>Abacavir:<br/>Lamivudine: 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.<br/>Zidovudine: Patients should be informed that the important toxicities
associated with zidovudine are neutropenia and/or anemia. They should be told
of the extreme importance of having their blood counts followed closely while
on therapy, especially for patients with advanced HIV disease.<br/>TRIZIVIR: Inform patients that some HIV medicines, including TRIZIVIR
can cause a rare, but serious condition called lactic acidosis with liver
enlargement (hepatomegaly). TRIZIVIR 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 TRIZIVIR. Advise patients that the
use of TRIZIVIR has not been shown to reduce the risk of transmission of HIV
to others through sexual contact orblood 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. TRIZIVIR
Tablets are for oral ingestion only. Patients should
be advised of the importance of taking TRIZIVIR exactly as it is prescribed.<br/>Drug Interactions:<br/>TRIZIVIR: No clinically significant changes to pharmacokinetic parameters
were observed for abacavir, lamivudine, or zidovudine when administered together.<br/>Abacavir: 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 mg and 90 mg
daily), with 600 mg of ZIAGEN twice daily (twice the currently recommended
dose), oral methadone clearance increased 22% (90% CI 6% to 42%).This alteration willnot 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.<br/>Lamivudine: Trimethoprim (TMP) 160 mg/sulfamethoxazole
(SMX) 800 mg once daily has been shown to increase lamivudine exposure
(AUC). 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 TRIZIVIR in combination with zalcitabine is not recommended.<br/>Zidovudine: Coadministration
of ganciclovir, interferon-alfa, and other bone marrow suppressive or cytotoxic
agents may increase the hematologic toxicity of zidovudine.Concomitant use of zidovudine with stavudine should be avoided since
an antagonistic relationship has been demonstrated in vitro. In addition,
concomitant use of zidovudine with doxorubicin or ribavirin should be avoided
because an antagonistic relationship has alsobeen demonstrated in vitro. See
CLINICAL PHARMACOLOGY for additional drug interactions.<br/>Carcinogenesis, Mutagenesis, and Impairment of Fertility:<br/>Carcinogenicity:<br/>Mutagenicity:<br/>Impairment of Fertility:<br/>Pregnancy: Pregnancy Category C. There are no adequate and well-controlled
studies of TRIZIVIR in pregnant women. Reproduction studies with abacavir,
lamivudine, and zidovudine have been performed in animals (see Abacavir, Lamivudine,
and Zidovudine sections below). TRIZIVIR should be used during pregnancy only
if the potential benefits outweigh the risks.<br/>Abacavir: 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.<br/>Lamivudine: Studies in pregnant
rats and rabbits 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 up to 4,000 mg/kg/day and
1,000 mg/kg/day, respectively, producing plasma levels up to approximately
35 times that for the 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
those in humans.<br/>Zidovudine: Reproduction
studies with orally administered zidovudine in the rat and in the rabbit at
doses up to 500 mg/kg/day revealed no evidence of teratogenicity with
zidovudine. Zidovudine treatment resulted in embryo/fetal toxicity as evidenced
by an increase in the incidence of fetal resorptions in rats given 150 or
450 mg/kg/day and rabbits given 500 mg/kg/day. The doses used in
the teratology studies resulted in peak zidovudine plasma concentrations (after
one half of the daily dose) in rats 66 to 226 times, and in rabbits 12
to 87 times, mean steady-state peak human plasma concentrations (after
one sixth of the daily dose) achieved with the recommended daily dose (100 mg
every 4 hours). In an additional teratology study in rats, a dose of
3,000 mg/kg/day (very near the oral median lethal dose in rats of approximately
3,700 mg/kg) caused marked maternal toxicity and an increase in the incidence
of fetal malformations. This dose resulted in peak zidovudine plasma concentrations
350 times peak human plasma concentrations. No evidence of teratogenicity
was seen in this experiment at doses of 600 mg/kg/day or less. Two rodent
carcinogenicity studies were conducted (see Carcinogenesis, Mutagenesis, and
Impairment of Fertility).<br/>Antiretroviral Pregnancy Registry: To monitor maternal-fetal outcomes of pregnant women exposed
to TRIZIVIR or other antiretroviral agents, an Antiretroviral Pregnancy Registry
has been established. Physicians are encouraged to register patients by calling
1-800-258-4263.<br/>Nursing Mothers: The Centers for Disease Control
and Prevention recommend that HIV-infected mothers not breastfeed their infants
to avoid risking postnatal transmission of HIV infection.<br/>Abacavir, Lamivudine, and Zidovudine: Lamivudine and zidovudine are excreted in human breast milk;
abacavir and lamivudine are secreted 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 TRIZIVIR.<br/>Pediatric Use: TRIZIVIR is not intended for use in pediatric patients.
TRIZIVIR should not be administered to adolescents who weigh less than 40 kg
because it is a fixed-dose tablet that cannot be adjusted for this patient
population.<br/>Therapy-Experienced Pediatric Patients: A randomized, double-blind study, CNA3006, compared ZIAGEN
plus lamivudine and zidovudine versus lamivudine and zidovudine in pediatric
patients, most of whom were extensively pretreated with nucleoside analogue
antiretroviral agents. Patients in this study had a limited response to abacavir.<br/>Geriatric Use: Clinical studies of abacavir, lamivudine, and zidovudine
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. TRIZIVIR is not recommended for patients with impaired
renal function(i.e., creatinine clearance<50 mL/min; see PRECAUTIONS:
Patients with Impaired Renal Function and DOSAGE AND ADMINISTRATION).
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Abacavir: There is no known antidote for abacavir. It is not known
whether abacavir can be removed by peritoneal dialysis or hemodialysis.<br/>Lamivudine: One case of an adult ingesting 6 grams of lamivudine
was reported; there were no clinical signs or symptoms noted and hematologic
tests remained normal. Because a negligible amount of lamivudine was removed
via (4-hour) hemodialysis, continuous ambulatory peritoneal dialysis, and
automated peritoneal dialysis, it is not known if continuous hemodialysis
would provide clinical benefit in a lamivudine overdose event.<br/>Zidovudine: Acute overdoses of zidovudine have been reported in pediatric
patients and adults. These involved exposures up to 50 grams. The only
consistent findings were nausea and vomiting. Other reported occurrences included
headache, dizziness, drowsiness, lethargy, and confusion. Hematologic changes
were transient. All patients recovered. Hemodialysis and peritoneal dialysis
appear to have a negligible effect on the removal of zidovudine, while elimination
of its primary metabolite, GZDV, is enhanced.
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| dailymed-instance:genericMe... |
abacavir sulfate, lamivudine, and zidovudine
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TRIZIVIR (Tablet)
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Hypersensitivity Reaction: Serious and sometimes fatal hypersensitivity
reactions have been associated with abacavir sulfate, a component of TRIZIVIR
(see WARNINGS and PRECAUTIONS: Information for Patients). Treatment-emergent
clinical adverse reactions (rated by the investigator as moderate or severe)
with a���5% frequency during therapy with abacavir 300 mg twice
daily, lamivudine 150 mg twice daily, and zidovudine 300 mg twice
daily compared with indinavir 800 mg 3 times daily, lamivudine 150 mg
twice daily, and zidovudine 300 mg twice daily from CNA3005 are listed
in Table 5. Five patients receiving abacavir in study CNA3005 experienced
worsening of pre-existing depression compared to none in the indinavir arm.
The background rates of pre-existing depression were similar in the 2 treatment
arms.<br/>Laboratory Abnormalities: Laboratory abnormalities in study CNA3005 are listed in
Table 6. ULN = Upper limit of normal. n = Number of patients assessed.<br/>Other Adverse Events: In addition to adverse
reactions in Tables 5 and 6, other adverse events observed in the expanded
access program for abacavir were pancreatitis and increased GGT.<br/>Observed During Clinical Practice: The following events have been identified during post-approval
use of abacavir, lamivudine, and/or zidovudine. 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 lamivudine and/or zidovudine.<br/>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.<br/>Abacavir, Lamivudine, and/or Zidovudine:
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TRIZIVIR contains 3 nucleoside
analogues (abacavir sulfate, lamivudine, and zidovudine) and is intended only
for patients whose regimen would otherwise include these 3 components.<br/>Hypersensitivity Reactions: Serious and sometimes fatal hypersensitivity
reactions have been associated with abacavir sulfate, a component of TRIZIVIR.
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
TRIZIVIR as soon as a hypersensitivity reaction is suspected. Permanently
discontinue TRIZIVIR if hypersensitivity cannot be ruled out,
even when other diagnoses are possible. Following a hypersensitivity reaction to abacavir, NEVER
restart TRIZIVIR or any other abacavir-containing product because more severe
symptoms can occur within hours and may include life-threatening hypotension
and death. Reintroduction
of TRIZIVIR 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).<br/>Hematologic Toxicity: Zidovudine has been associated
with hematologic toxicity including neutropenia and severe anemia, particularly
in patients with advanced Human Immunodeficiency Virus (HIV) disease (see
WARNINGS). Prolonged use of zidovudine has been associated with symptomatic
myopathy.<br/>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,
zidovudine, and other antiretrovirals (see WARNINGS).<br/>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) and have discontinued lamivudine,
which is one component of TRIZIVIR. Hepatic function should be monitored closely
with both clinical and laboratory follow-up for at least several months in
patients who discontinue TRIZIVIR and are co-infected with HIV and HBV. If
appropriate, initiation of anti-hepatitis B therapy may be warranted (see
WARNINGS).
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TRIZIVIR is indicated in combination
with other antiretrovirals or alone for the treatment of HIV-1 infection. Additional important
information on the use of TRIZIVIR for treatment of HIV-1 infection:<br/>Description of Clinical Studies:<br/>TRIZIVIR: The following study was conducted with the individual components
of TRIZIVIR (see CLINICAL PHARMACOLOGY for information about bioequivalence
of TRIZIVIR). CNA3005 was
a multicenter, double-blind, controlled study in which 562 HIV-infected,
therapy-naive adults were randomized to receive either ZIAGEN (300 mg
twice daily) plus COMBIVIR (lamivudine 150 mg/zidovudine
300 mg twice daily), or indinavir (800 mg 3 times a day) plus
COMBIVIR twice daily. The study was stratified at randomization by pre-entry
plasma HIV-1 RNA 10,000 to 100,000 copies/mL and plasma HIV-1RNA>100,000 copies/mL.
Study participants were male (87%), Caucasian (73%), black (15%), and Hispanic
(9%). At baseline the median age was 36 years, the median pretreatment
CD4+ cell count was 360 cells/mm, and median plasma
HIV-1 RNA was 4.8 logcopies/mL.Proportions of patients with plasma HIV-1 RNA<400 copies/mL
(using Roche AMPLICOR HIV-1 MONITOR Test) through 48 weeks
of treatment are summarized in Table 3. * Patients achieved and maintained
confirmed HIV-1 RNA<400 copies/mL. Includes
viral rebound and failure to achieve confirmed<400 copies/mL by Week
48. Includes
consent withdrawn, lost to follow up, protocol violations, those with missing
data, clinical progression, and other. Treatment response
by plasma HIV-1 RNA strata is shown in Table 4. In subjects with baseline viral load>100,000 copies/mL,
percentages of patients with HIV-1 RNA levels<50 copies/mL were 31%
in the group receiving abacavir vs. 45% in the group receiving indinavir. Through Week 48, an overall mean increase
in CD4+ cell count of about 150 cells/mmwas observed in
both treatment arms. Through Week 48, 9 subjects (3.4%) in the group
receiving abacavir sulfate (6 CDC classification C events and 3 deaths)
and 3 subjects (1.5%) in the group receiving indinavir (2 CDC classification
C events and 1 death) experienced clinical disease progression.
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TRIZIVIR
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