Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/1861
Predicate | Object |
---|---|
rdf:type | |
rdfs:label |
EPIVIR (Tablet)
|
dailymed-instance:dosage |
Adults: The recommended oral dose of EPIVIR for adults is 300 mg
daily, administered as either 150 mg twice daily or 300 mg once
daily, in combination with other antiretroviral agents (see DESCRIPTION OF
CLINICAL STUDIES, PRECAUTIONS, MICROBIOLOGY, and CLINICAL PHARMACOLOGY). If
lamivudine is administered to a patient dually infected with HIV and HBV,
the dosage indicated for HIV therapy should be used as part of an appropriate
combination regimen (see WARNINGS).<br/>Pediatric Patients:<br/>Infants/Children/Adolescents: The recommended oral dose of EPIVIR for HIV-infected pediatric
patients 3 months up to 16 years of age is 4 mg/kg twice daily
(up to a maximum of 150 mg twice a day), administered in combination
with other antiretroviral agents.<br/>Dose Adjustment: It is recommended that doses of EPIVIR be adjusted in accordance
with renal function (see Table 9) (see CLINICAL PHARMACOLOGY). No additional dosing of EPIVIR is required after routine
(4-hour) hemodialysis or peritoneal dialysis. Although
there are insufficient data to recommend a specific dose adjustment of EPIVIR
in pediatric patients with renal impairment, a reduction in the dose and/or
an increase in the dosing interval should be considered.
|
dailymed-instance:descripti... |
EPIVIR (also known as
3TC) is a brand name for lamivudine, a synthetic nucleoside analogue with
activity against HIV-1 and HBV. 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. 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. EPIVIR
Tablets are for oral administration. Each 150-mg film-coated tablet
contains 150 mg of lamivudine and the inactive ingredients hypromellose,
magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate
80, sodium starch glycolate, and titanium dioxide. Each
300-mg film-coated tablet contains 300 mg of lamivudine and the inactive
ingredients black iron oxide, hypromellose, magnesium stearate, microcrystalline
cellulose, polyethylene glycol, polysorbate 80, sodium starch glycolate, and
titanium dioxide. EPIVIR
Oral Solution is for oral administration. One milliliter (1 mL)
of EPIVIR Oral Solution contains 10 mg of lamivudine (10 mg/mL)
in an aqueous solution and the inactive ingredients artificial strawberry
and banana flavors, citric acid (anhydrous), methylparaben, propylene glycol,
propylparaben, sodium citrate (dihydrate), and sucrose (200 mg).
|
dailymed-instance:clinicalP... |
Pharmacokinetics in Adults: 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; however, Cwas 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 AUCand C;
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. The
pharmacokinetic properties of lamivudine have been studied in asymptomatic,
HIV-infected adult patients after administration of single intravenous (IV)
doses ranging from 0.25 to 8 mg/kg, as well as single and multiple (twice-daily
regimen) oral doses ranging from 0.25 to 10 mg/kg. The
pharmacokinetic properties of lamivudine have also been studied as single
and multiple oral doses ranging from 5 mg to 600 mg/day administered
to HBV-infected patients.<br/>Absorption and Bioavailability: Lamivudine was rapidly absorbed after oral administration
in HIV-infected patients. Absolute bioavailability in 12 adult patients
was 86%��16% (mean��SD) for the 150-mg tablet
and 87%��13% for the oral solution. After oral administration
of 2 mg/kg twice a day to 9 adults with HIV, the peak serum lamivudine
concentration (C) was 1.5��0.5 mcg/mL (mean��SD).
The area under the plasma concentration versus time curve (AUC) and Cincreased
in proportion to oral dose over the range from 0.25 to 10 mg/kg. An
investigational 25-mg dosage form of lamivudine was administered orally to
12 asymptomatic, HIV-infected patients on 2 occasions, once in the
fasted state and once with food (1,099 kcal; 75 grams fat, 34 grams
protein, 72 grams carbohydrate). Absorption of lamivudine was slower
in the fed state (T: 3.2��1.3 hours) compared
with the fasted state (T: 0.9��0.3 hours);
Cin the fed state was 40%��23% (mean��SD)
lower than in the fasted state. There was no significant difference in systemic
exposure (AUC���) in the fed and fasted states; therefore, EPIVIR Tablets
and Oral Solution may be administered with or without food. The
accumulation ratio of lamivudine in HIV-positive asymptomatic adults with
normal renal function was 1.50 following 15 days of oral administration
of 2 mg/kg twice daily.<br/>Distribution: The apparent volume of distribution after IV administration
of lamivudine to 20 patients was 1.3��0.4 L/kg,
suggesting that lamivudine distributes into extravascular spaces. Volume of
distribution was independent of dose and did not correlate with body weight. Binding
of lamivudine to human plasma proteins is low (<36%). In vitro studies
showed that, over the concentration range of 0.1 to 100 mcg/mL, the amount
of lamivudine associated with erythrocytes ranged from 53% to 57% and was
independent of concentration.<br/>Metabolism: Metabolism of lamivudine is a minor route of elimination.
In man, the only known metabolite of lamivudine is the trans-sulfoxide metabolite.
Within 12 hours after a single oral dose of lamivudine in 6 HIV-infected
adults, 5.2%��1.4% (mean��SD) of the dose
was excreted as the trans-sulfoxide metabolite in the urine. Serum concentrations
of this metabolite have not been determined.<br/>Elimination: The majority of lamivudine is eliminated unchanged in urine
by active organic cationic secretion. In 9 healthy subjects given a single
300-mg oral dose of lamivudine, renal clearance was 199.7��56.9 mL/min
(mean��SD). In 20 HIV-infected patients given a single
IV dose, renal clearance was 280.4��75.2 mL/min (mean��SD),
representing 71%��16% (mean��SD) of total
clearance of lamivudine. In most single-dose studies
in HIV-infected patients, HBV-infected patients, or healthy subjects with
serum sampling for 24 hours after dosing, the observed mean elimination
half-life (t��) ranged from 5 to 7 hours. In HIV-infected patients,
total clearance was 398.5��69.1 mL/min (mean��SD).
Oral clearance and elimination half-life were independent of dose and body
weight over an oral dosing range from 0.25 to 10 mg/kg.<br/>Special Populations:<br/>Adults With Impaired Renal Function: The pharmacokinetic properties of lamivudine have been determined
in a small group of HIV-infected adults with impaired renal function (Table 1). Exposure (AUC���), C, and half-life
increased with diminishing renal function (as expressed by creatinine clearance).
Apparent total oral clearance (Cl/F) of lamivudine decreased as creatinine
clearance decreased. Twas not significantly affected by renal
function. Based on these observations, it is recommended that the dosage of
lamivudine be modified in patients with renal impairment (see DOSAGE AND ADMINISTRATION). Based
on a study in otherwise healthy subjects with impaired renal function, hemodialysis
increased lamivudine clearance from a mean of 64 to 88 mL/min; however,
the length of time of hemodialysis (4 hours) was insufficient to significantly
alter mean lamivudine exposure after a single-dose administration. Continuous
ambulatory peritoneal dialysis and automated peritoneal dialysis have negligible
effects on lamivudine clearance. Therefore, it is recommended, following correction
of dose for creatinine clearance, that no additional dose modification be
made after routine hemodialysis or peritoneal dialysis. It
is not known whether lamivudine can be removed by continuous (24-hour) hemodialysis. The
effects of renal impairment on lamivudine pharmacokinetics in pediatric patients
are not known.<br/>Adults With Impaired Hepatic Function: The pharmacokinetic properties of lamivudine have been determined
in adults with impaired hepatic function. Pharmacokinetic parameters were
not altered by diminishing hepatic function; therefore, no dose adjustment
for lamivudine is required for patients with impaired hepatic function. Safety
and efficacy of lamivudine have not been established in the presence of decompensated
liver disease.<br/>Pediatric Patients: For pharmacokinetic properties of lamivudine in pediatric
patients, see PRECAUTIONS: Pediatric Use.<br/>Gender: There are no significant gender differences in lamivudine
pharmacokinetics.<br/>Race: There are no significant racial differences in lamivudine
pharmacokinetics.<br/>Drug Interactions: 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). Lamivudine
and trimethoprim/sulfamethoxazole (TMP/SMX) were coadministered to 14 HIV-positive
patients in a single-center, open-label, randomized, crossover study. Each
patient received treatment with a single 300-mg dose of lamivudine and TMP
160 mg/SMX 800 mg once a day for 5 days with concomitant administration
of lamivudine 300 mg with the fifth dose in a crossover design. Coadministration
of TMP/SMX withlamivudine resulted in an increase of 43%��23%
(mean��SD) in lamivudine AUC���, a decrease of 29%��13%
in lamivudine oral clearance, and a decrease of 30%��36% in
lamivudine renal clearance. The pharmacokinetic properties of TMP and SMX
were not altered by coadministration with lamivudine. Lamivudine
and zalcitabine may inhibit the intracellular phosphorylation of one another.
Therefore, use of lamivudine in combination with zalcitabine is not recommended. There
was no significant pharmacokinetic interaction between lamivudine and interferon
alfa in a study of 19 healthy male subjects.<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).
|
dailymed-instance:activeIng... | |
dailymed-instance:contraind... |
EPIVIR Tablets and Oral
Solution are contraindicated in patients with previously demonstrated clinically
significant hypersensitivity to any of the components of the products.
|
dailymed-instance:supply |
EPIVIR Tablets, 150 mg,
are white, modified diamond-shaped, film-coated tablets engraved with���GX
CJ7���on one side and plain on the reverse side. Bottle
of 60 tablets (NDC 0173-0470-01) with child-resistant closure. EPIVIR Tablets, 300 mg, are gray, modified
diamond-shaped, film-coated tablets engraved with���GX EJ7���on
one side and plain on the reverse side. Bottle of
30 tablets (NDC 0173-0714-00) with child-resistant closure. Store at 25��C (77��F); excursions permitted to
15��to 30��C (59��to 86��F) [see USP Controlled Room Temperature]. EPIVIR Oral Solution, a clear, colorless
to pale yellow, strawberry-banana flavored liquid, contains 10 mg of
lamivudine in each 1 mL. Plastic bottle of 240 mL
(NDC 0173-0471-00) with child-resistant closure. This product does not require
reconstitution. Store in
tightly closed bottles at 25��C (77��F) [see USP Controlled Room Temperature]. GlaxoSmithKline Research
Triangle Park, NC 27709 Manufactured under agreement
from Shire Pharmaceuticals
Group plc Basingstoke, UK ��2006,
GlaxoSmithKline. All rights reserved. October
2006 RL-2317
|
dailymed-instance:genericDr... | |
dailymed-instance:boxedWarn... |
WARNING: LACTIC ACIDOSIS AND SEVERE HEPATOMEGALY
WITH STEATOSIS, INCLUDING FATAL CASES, HAVE BEEN REPORTED WITH THE USE OF
NUCLEOSIDE ANALOGUES ALONE OR IN COMBINATION, INCLUDING LAMIVUDINE AND OTHER
ANTIRETROVIRALS (SEE WARNINGS). EPIVIR
TABLETS AND ORAL SOLUTION (USED TO TREAT HUMAN IMMUNODEFICIENCY VIRUS [HIV]
INFECTION) CONTAIN A HIGHER DOSE OF THE ACTIVE INGREDIENT (LAMIVUDINE) THAN
EPIVIR-HBV TABLETS AND ORAL SOLUTION (USED TO TREAT CHRONIC HEPATITIS B).
PATIENTS WITH HIV INFECTION SHOULD RECEIVE ONLY DOSING FORMS APPROPRIATE FOR
TREATMENT OF HIV (SEE WARNINGS AND PRECAUTIONS). SEVERE ACUTE EXACERBATIONS OF HEPATITIS B HAVE BEEN REPORTED
IN PATIENTS WHO ARE CO-INFECTED WITH HEPATITIS B VIRUS (HBV) AND HIV AND HAVE
DISCONTINUED EPIVIR. HEPATIC FUNCTION SHOULD BE MONITORED CLOSELY WITH BOTH
CLINICAL AND LABORATORY FOLLOW-UP FOR AT LEAST SEVERAL MONTHS IN PATIENTS
WHO DISCONTINUE EPIVIR AND ARE CO-INFECTED WITH HIV AND HBV. IF APPROPRIATE,
INITIATION OF ANTI-HEPATITIS B THERAPY MAY BE WARRANTED (SEE WARNINGS).
|
dailymed-instance:activeMoi... | |
dailymed-instance:inactiveI... | |
dailymed-instance:possibleD... | |
dailymed-instance:precautio... |
Patients With Impaired Renal Function: Reduction of the dosage
of EPIVIR is recommended for patients with impaired renal function (see CLINICAL
PHARMACOLOGY and DOSAGE AND ADMINISTRATION).<br/>Patients With HIV and Hepatitis B Virus Co-Infection:<br/>infection: 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.
Posttreatment exacerbations of hepatitis have also been reported (see WARNINGS).<br/>Immune Reconstitution Syndrome: Immune reconstitution syndrome has been reported in patients
treated with combination antiretroviral therapy, including EPIVIR. 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/>Differences Between Dosing Regimens: Trough levels of lamivudine in plasma and of intracellular
lamivudine triphosphate were lower with once-daily dosing than with twice-daily
dosing (see CLINICAL PHARMACOLOGY). The clinical significance of this observation
is not known.<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: EPIVIR 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 EPIVIR. Patients should be advised that the use of EPIVIR has not
been shown to reduce the risk of transmission of HIV to others through sexual
contact or blood contamination. Patients should be
advised that EPIVIR Tablets and Oral Solution contain a higher dose of the
same active ingredient (lamivudine) as EPIVIR-HBV Tablets and Oral Solution.
If a decision is made to include lamivudine in the HIV treatment regimen of
a patient dually infected with HIV and HBV, the formulation and dosage of
lamivudine in EPIVIR (not EPIVIR-HBV) should be used. 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. Patients
should be advised that the long-term effects of EPIVIR are unknown at this
time. EPIVIR Tablets and Oral Solution are for oral
ingestion only. Patients should be advised of the importance
of taking EPIVIR with combination therapy on a regular dosing schedule and
to avoid missing doses. Parents or guardians should
be advised to monitor pediatric patients for signs and symptoms of pancreatitis. Patients
should be informed 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. Diabetic
patients should be advised that each 15-mL dose of EPIVIR Oral Solution contains
3 grams of sucrose.<br/>Drug Interactions: Lamivudine is predominantly eliminated in the urine by active
organic cationic secretion. The possibility of interactions with other drugs
administered concurrently should be considered, particularly when their main
route of elimination is active renal secretion via the organic cationic transport
system (e.g., trimethoprim). TMP 160 mg/SMX 800 mg
once daily has been shown to increase lamivudine exposure (AUC) by 43% (see
CLINICAL PHARMACOLOGY). No change in dose of either drug is recommended. There
is no information regarding the effect on lamivudine pharmacokinetics of higher
doses of TMP/SMX such as those used to treat PCP. No data are available regarding
interactions with other drugs that have renal clearance mechanisms similar
to that of lamivudine. Lamivudine and zalcitabine
may inhibit the intracellular phosphorylation of one another. Therefore, use
of lamivudine in combination with zalcitabine is not recommended.<br/>Carcinogenesis, Mutagenesis, and Impairment of Fertility: 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. Lamivudine was not active in a microbial
mutagenicity screen or an in vitro cell transformation assay, but showed
weak in vitro mutagenic activity in a cytogenetic assay using cultured
human lymphocytes and in the mouse lymphoma assay. However, lamivudine showed
no evidence of in vivo genotoxic activity in the rat at oral doses of up to
2,000 mg/kg, producing plasma levels of 35 to45 times those
in humans at the recommended dose for HIV infection. In a study of reproductive
performance, lamivudine administered to rats at doses up to 4,000 mg/kg/day,
producing plasma levels 47 to 70 times those in humans, revealed no evidence
of impaired fertility and no effect on the survival, growth, and development
to weaning of the offspring.<br/>Pregnancy: Pregnancy Category
C. Reproduction studies have been performed in rats and rabbits at orally
administered 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. Studies in
pregnant rats and rabbits showed that lamivudine is transferred to the fetus
through the placenta. In 2 clinical studies conducted
in South Africa, pharmacokinetic measurements were performed on samples from
pregnant women who received lamivudine beginning at Week 38 of gestation (10 women
who received 150 mg twice daily in combination with zidovudine and 10
who received lamivudine 300 mg twice daily without other antiretrovirals)
or beginning at Week 36 of gestation (16 women who received lamivudine
150 mg twice daily in combination with zidovudine). These studies were
not designed or powered to provide efficacy information. Lamivudine pharmacokinetics
in the pregnant women were similar to those obtained following birth and in
non-pregnant adults. Lamivudine concentrations were generally similar in maternal,
neonatal, and cord serum samples. In a subset of subjects from whom amniotic
fluid specimens were obtained following natural rupture of membranes, amniotic
fluid concentrations of lamivudine ranged from 1.2 to 2.5 mcg/mL (150 mg
twice daily) and 2.1 to 5.2 mcg/mL (300 mg twice daily) and were
typically greater than 2 times the maternal serum levels. See the ADVERSE
REACTIONS section for the limited late-pregnancy safety information available
from these studies. Lamivudine should be used during pregnancy only if the
potential benefits outweigh the risks.<br/>Antiretroviral Pregnancy Registry: To monitor maternal-fetal outcomes of pregnant women exposed
to lamivudine, a 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. A
study in lactating rats administered 45 mg/kg of lamivudine showed that
lamivudine concentrations in milk were slightly greater than those in plasma.
Lamivudine is also excreted in human milk. 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. 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 lamivudine.<br/>Pediatric Use:<br/>HIV: Limited, uncontrolled pharmacokinetic and safety data are
available from administration of lamivudine (and zidovudine) to 36 infants
up to 1 week of age in 2 studies in South Africa. In these studies,
lamivudine clearance was substantially reduced in 1-week-old neonates relative
to pediatric patients (>3 months of age) studied previously. There is
insufficient information to establish the time course of changes in clearance
between the immediate neonatal period and the age-ranges>3 months old.
See the ADVERSE REACTIONS section for the limited safety information available
from these studies. The safety and effectiveness of
twice-daily EPIVIR in combination with other antiretroviral agents have been
established in pediatric patients 3 months of age and older. In
Study A2002, pharmacokinetic properties of lamivudine were assessed in a subset
of 57 HIV-infected pediatric patients (age range: 4.8 months to
16 years, weight range: 5 to 66 kg) after oral and IV administration
of 1, 2, 4, 8, 12, and 20 mg/kg/day. In the 9 infants and children
(range: 5 months to 12 years of age) receiving oral solution 4 mg/kg
twice daily (the usual recommended pediatric dose), absolute bioavailability
was 66%��26% (mean��SD), which was less than
the 86%��16% (mean��SD) observed in adults.
The mechanism for the diminished absolute bioavailability of lamivudine in
infants and children is unknown. Systemic clearance
decreased with increasing age in pediatric patients, as shown in Figure 2.<br/>HBV: See the complete prescribing information for EPIVIR-HBV
Tablets and Oral Solution for additional information on the pharmacokinetics
of lamivudine in HBV-infected children.<br/>Geriatric Use: Clinical studies of EPIVIR did not include sufficient numbers
of subjects aged 65 and over to determine whether they respond differently
from younger subjects. 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. In
particular, because lamivudine is substantially excreted by the kidney and
elderly patients are more likely to have decreased renal function, renal function
should be monitored and dosage adjustments should be made accordingly (see
PRECAUTIONS: Patients with Impaired Renal Function and DOSAGE AND ADMINISTRATION).
|
dailymed-instance:overdosag... |
There is no known antidote
for EPIVIR. One case of an adult ingesting 6 g of EPIVIR was reported;
there were no clinical signs or symptoms noted and hematologic tests remained
normal. Two cases of pediatric overdose were reported in ACTG300. One case
was a single dose of 7 mg/kg of EPIVIR; the second case involved use
of 5 mg/kg of EPIVIR twice daily for 30 days. There were no clinical
signs or symptoms noted in either case. 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. If overdose
occurs, the patient should be monitored, and standard supportive treatment
applied as required.
|
dailymed-instance:genericMe... |
lamivudine
|
dailymed-instance:fullName |
EPIVIR (Tablet)
|
dailymed-instance:adverseRe... |
Clinical Trials in HIV:<br/>Adults: Selected clinical adverse events with a���5% frequency
during therapy with EPIVIR 150 mg twice daily plus RETROVIR 200 mg
3 times daily compared with zidovudine are listed in Table 5. *Either zidovudine monotherapy or
zidovudine in combination with zalcitabine. The types
and frequencies of clinical adverse events reported in patients receiving
EPIVIR 300 mg once daily or EPIVIR 150 mg twice daily (in 3-drug
combination regimens in EPV20001 and EPV40001) were similar. The most common
adverse events in both treatment groups were nausea, dizziness, fatigue and/or
malaise, headache, dreams, insomnia and other sleep disorders, and skin rash. Pancreatitis
was observed in 9 of the 2,613 adult patients (0.3%) who received EPIVIR
in the controlled clinical trials EPV20001, NUCA3001, NUCB3001, NUCA3002,
NUCB3002, and B3007. Selected laboratory abnormalities
observed during therapy are summarized in Table 6. * The median duration on study was
12 months. ���Either
zidovudine monotherapy or zidovudine in combination with zalcitabine. ���Current therapy was either zidovudine, zidovudine
plus didanosine, or zidovudine plus zalcitabine. ULN = Upper
limit of normal. ND = Not
done. In small, uncontrolled studies in which pregnant
women were given lamivudine alone or in combination with zidovudine beginning
in the last few weeks of pregnancy (see PRECAUTIONS: Pregnancy), reported
adverse events included anemia, urinary tract infections, and complications
of labor and delivery. In postmarketing experience, liver function abnormalities
and pancreatitis have been reported in women who received lamivudine in combination
with other antiretroviral drugs during pregnancy. It is not known whether
risks of adverse events associated with lamivudine are altered in pregnant
women compared to other HIV-infected patients. The
frequencies of selected laboratory abnormalities reported in patients receiving
EPIVIR 300 mg once daily or EPIVIR 150 mg twice daily (in 3-drug
combination regimens in EPV20001 and EPV40001) were similar.<br/>Pediatric Patients: Selected clinical adverse events and physical findings with
a���5% frequency during therapy with EPIVIR 4 mg/kg twice daily
plus RETROVIR 160 mg/m3 times daily compared with didanosine
in therapy-naive (���56 days of antiretroviral therapy) pediatric
patients are listed in Table 7. Includes pain, discharge,
erythema, or swelling of an ear. Selected laboratory
abnormalities experienced by therapy-naive (���56 days of antiretroviral
therapy) pediatric patients are listed in Table 8. ULN = Upper limit of normal. Pancreatitis,
which has been fatal in some cases, has been observed in antiretroviral nucleoside-experienced
pediatric patients receiving EPIVIR alone or in combination with other antiretroviral
agents. In an open-label dose-escalation study (A2002), 14 patients (14%)
developed pancreatitis while receiving monotherapy with EPIVIR. Three of these
patients died of complications of pancreatitis. In a second open-label study
(A2005), 12 patients (18%) developed pancreatitis. In Study ACTG300,
pancreatitis was not observed in 236 patients randomized to EPIVIR plus
RETROVIR. Pancreatitis was observed in 1 patient in this study who received
open-label EPIVIR in combination with RETROVIR and ritonavir following discontinuation
of didanosine monotherapy. Paresthesias and peripheral
neuropathies were reported in 15 patients (15%) in Study A2002, 6 patients
(9%) in Study A2005, and 2 patients (<1%) in Study ACTG300. Limited
short-term safety information is available from 2 small, uncontrolled studies
in South Africa in neonates receiving lamivudine with or without zidovudine
for the first week of life following maternal treatment starting at Week 38
or 36 of gestation (see PRECAUTIONS: Pediatric Use). Adverse events reported
in these neonates included increased liver function tests, anemia, diarrhea,
electrolyte disturbances, hypoglycemia, jaundice and hepatomegaly, rash, respiratory
infections, sepsis, and syphilis; 3 neonates died (1 from gastroenteritis
with acidosis and convulsions, 1 from traumatic injury, and 1 from unknown
causes). Two other nonfatal gastroenteritis or diarrhea cases were reported,
including 1 with convulsions; 1 infant had transient renal insufficiency associated
with dehydration. The absence of control groups further limits assessments
of causality, but it should be assumed that perinatally exposed infants may
be at risk for adverse events comparable to those reported in pediatric and
adult HIV-infected patients treated with lamivudine-containing combination
regimens. Long-term effects of in utero and infant lamivudine exposure are
not known.<br/>Lamivudine in Patients With Chronic Hepatitis B: Clinical trials in chronic hepatitis B used a lower
dose of lamivudine (100 mg daily) than the dose used to treat HIV. The
most frequent adverse events with lamivudine versus placebo were ear, nose,
and throat infections (25% versus 21%); malaise and fatigue (24% versus 28%);
and headache (21% versus 21%), respectively. The most frequent laboratory
abnormalities reported with lamivudine were elevated ALT, elevated serum lipase,
elevated CPK, and posttreatment elevations of liver functiontests. Emergence
of HBV viral mutants during lamivudine treatment, associated with reduced
drug susceptibility and diminished treatment response, was also reported (also
see WARNINGS and PRECAUTIONS). Please see the complete prescribing information
for EPIVIR-HBV Tablets and Oral Solution for more information.<br/>Observed During Clinical Practice: In addition to adverse events reported from clinical trials,
the following events have been identified during post-approval use of 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 lamivudine.<br/>Body as a Whole: Redistribution/accumulation of body fat (see PRECAUTIONS:
Fat Redistribution).<br/>Digestive: Stomatitis.<br/>Endocrine and Metabolic: Hyperglycemia.<br/>General: Weakness.<br/>Hemic and Lymphatic: Anemia (including pure red cell aplasia and severe anemias
progressing on therapy), lymphadenopathy, splenomegaly.<br/>Hepatic and Pancreatic: Lactic acidosis and hepatic steatosis, pancreatitis, posttreatment
exacerbation of hepatitis B (see WARNINGS and PRECAUTIONS).<br/>Hypersensitivity: Anaphylaxis, urticaria.<br/>Musculoskeletal: Muscle weakness, CPK elevation, rhabdomyolysis.<br/>Nervous: Paresthesia, peripheral neuropathy.<br/>Respiratory: Abnormal breath sounds/wheezing.<br/>Skin: Alopecia, rash, pruritus.
|
dailymed-instance:warning |
In pediatric patients with a history
of prior antiretroviral nucleoside exposure, a history of pancreatitis, or
other significant risk factors for the development of pancreatitis, EPIVIR
should be used with caution. Treatment with EPIVIR should be stopped immediately
if clinical signs, symptoms, or laboratory abnormalities suggestive of pancreatitis
occur (see ADVERSE REACTIONS).<br/>Lactic Acidosis/Severe Hepatomegaly with Steatosis: Lactic acidosis and severe hepatomegaly with steatosis,
including fatal cases, have been reported with the use of nucleoside analogues
alone or in combination, including 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 EPIVIR 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 EPIVIR 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).<br/>Important Differences Among Lamivudine-Containing Products: EPIVIR Tablets and Oral Solution contain a higher dose of
the same active ingredient (lamivudine) than in EPIVIR-HBV Tablets and Oral
Solution. EPIVIR-HBV was developed for patients with chronic hepatitis B.
The formulation and dosage of lamivudine in EPIVIR-HBV are not appropriate
for patients dually infected with HIV and HBV. Lamivudine has not been adequately
studied for treatment of chronic hepatitis B in patients dually infected
with HIV and HBV. If treatment with EPIVIR-HBV is prescribed for chronic hepatitis
B for a patient with unrecognized or untreated HIV infection, rapid emergence
of HIV resistance is likely to result because of the subtherapeutic dose and
the inappropriateness of monotherapy HIV treatment. If a decision is made
to administer lamivudine to patients dually infected with HIV and HBV, EPIVIR
Tablets, EPIVIR Oral Solution, COMBIVIR (lamivudine/zidovudine)
Tablets, or EPZICOM(abacavir sulfate and lamivudine) Tablets
should be used as part of an appropriate combination regimen. COMBIVIR (a
fixed-dose combination tablet of lamivudine and zidovudine) should not be
administered concomitantly with EPIVIR, EPIVIR-HBV, EPZICOM, RETROVIR, or
TRIZIVIR.<br/>Posttreatment Exacerbations of Hepatitis: In clinical trials in non-HIV-infected patients treated
with lamivudine for chronic hepatitis B, 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 followup 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.<br/>Use With Interferon- and Ribavirin-Based Regimens: In vitro studies have shown ribavirin can reduce the
phosphorylation of pyrimidine nucleoside analogues such as lamivudine. Although
no evidence of a pharmacokinetic or pharmacodynamic interaction (e.g., loss
of HIV/HCV virologic suppression) was seen when ribavirin was coadministered
with lamivudine in HIV/HCV co-infected patients (see CLINICAL PHARMACOLOGY:
Drug Interactions), hepatic decompensation (some
fatal) has occurred in HIV/HCV co-infected patients receiving combination
antiretroviral therapy for HIV and interferon alfa with or without ribavirin. Patients receiving interferon alfa with or without ribavirin and
EPIVIR should be closely monitored for treatment-associated toxicities, especially
hepatic decompensation. Discontinuation of EPIVIR should be considered as
medically appropriate. Dose reduction or discontinuation of interferon alfa,
ribavirin, or both should also be considered if worsening clinical toxicities
are observed, including hepatic decompensation (e.g., Childs Pugh>6) (see
the complete prescribing information for interferon and ribavirin).
|
dailymed-instance:indicatio... |
EPIVIR in combination with other
antiretroviral agents is indicated for the treatment of HIV infection (see
Description of Clinical Studies).<br/>Clinical Studies: The use of EPIVIR is based on the results of clinical studies
in HIV-infected patients in combination regimens with other antiretroviral
agents. Information from trials with clinical endpoints or a combination of
CD4+ cell counts and HIV-1 RNA measurements is included below as documentation
of the contribution of lamivudine to a combination regimen in controlled trials.<br/>Clinical Endpoint Study in Adults: B3007 (CAESAR) was a multi-center, double-blind, placebo-controlled
study comparing continued current therapy (zidovudine alone [62% of patients]
or zidovudine with didanosine or zalcitabine [38% of patients]) to the addition
of EPIVIR or EPIVIR plus an investigational non-nucleoside reverse transcriptase
inhibitor (NNRTI), randomized 1:2:1. A total of 1,816 HIV-infected adults
with 25 to 250 CD4+ cells/mm(median = 122 cells/mm)
at baseline were enrolled: median age was 36 years, 87% were male, 84%
were nucleoside-experienced, and 16% were therapy-naive. The median duration
on study was 12 months. Results are summarized in Table 2. An investigational non-nucleoside
reverse transcriptase inhibitor not approved in the United States.<br/>Surrogate Endpoint Studies in Adults: Dual Nucleoside Analogue Studies: Principal clinical trials in the initial development of
lamivudine compared lamivudine/zidovudine combinations against zidovudine
monotherapy or against zidovudine plus zalcitabine. These studies demonstrated
the antiviral effect of lamivudine in a 2-drug combination. More recent uses
of lamivudine in treatment of HIV infection incorporate it into multiple-drug
regimens containing at least 3 antiretroviral drugs for enhanced viral suppression.<br/>Dose Regimen Comparison Surrogate Endpoint Studies in Therapy-Naive
Adults: EPV20001 was a multi-center, double-blind, controlled study
in which patients were randomized 1:1 to receive EPIVIR 300 mg once daily
or EPIVIR 150 mg twice daily, in combination with zidovudine 300 mg
twice daily and efavirenz 600 mg once daily. A total of 554 antiretroviral
treatment-naive HIV-infected adults enrolled: male (79%), Caucasian (50%),
median age of 35 years, baseline CD4+ cell counts of 69 to 1,089 cells/mm(median = 362 cells/mm),
and median baseline plasma HIV-1 RNA of 4.66 logcopies/mL.
Outcomes of treatment through 48 weeks are summarized in Figure 1 and
Table 3. Roche
AMPLICOR HIV-1 MONITOR. Responders at each visit are
patients who had achieved and maintained HIV-1 RNA<400 copies/mL
without discontinuation by that visit. * Achieved confirmed plasma HIV-1
RNA<400 copies/mL and maintained through 48 weeks. ���Achieved suppression but rebounded by Week 48,
discontinued due to virologic failure, insufficient viral response according
to the investigator, or never suppressed through Week 48. ���Includes consent withdrawn, lost to followup,
protocol violation, data outside the study-defined schedule, and randomized
but never initiated treatment. The proportions of patients
with HIV-1 RNA<50 copies/mL (via Roche Ultrasensitive assay) through
Week 48 were 61% for patients receiving EPIVIR 300 mg once daily and
63% for patients receiving EPIVIR 150 mg twice daily. Median increases
in CD4+ cell counts were 144 cells/mmat Week 48 in patients
receiving EPIVIR 300 mg once daily and 146 cells/mmfor
patients receiving EPIVIR 150 mg twice daily. A
small, randomized, open-label pilot study, EPV40001, was conducted in Thailand.
A total of 159 treatment-naive adult patients (male 32%, Asian 100%,
median age 30 years, baseline median CD4+ cell count 380 cells/mm,
median plasma HIV-1 RNA 4.8 logcopies/mL) were enrolled.
Two of the treatment arms in this study provided a comparison between lamivudine
300 mg once daily (n = 54) and lamivudine 150 mg twice
daily (n = 52), each in combination with zidovudine 300 mg
twice daily and abacavir 300 mg twice daily. In intent-to-treat analyses
of 48-week data, the proportions of patients with HIV-1 RNA below 400 copies/mL
were 61% (33/54) in the group randomized to once-daily lamivudine and 75%
(39/52) in the group randomized to receive all 3 drugs twicedaily; the proportions
with HIV-1 RNA below 50 copies/mL were 54% (29/54) in the once-daily
lamivudine group and 67% (35/52) in the all-twice-daily group; and the median
increases in CD4+ cell counts were 166 cells/mmin the once-daily
lamivudine group and 216 cells/mmin the all-twice-daily
group.<br/>Clinical Endpoint Study in Pediatric Patients: ACTG300 was a multi-center, randomized, double-blind study
that provided for comparison of EPIVIR plus RETROVIR (zidovudine) to didanosine
monotherapy. A total of 471 symptomatic, HIV-infected therapy-naive (���56 days
of antiretroviral therapy) pediatric patients were enrolled in these 2 treatment
arms. The median age was 2.7 years (range 6 weeks to 14 years),
58% were female, and 86% were non-Caucasian. The mean baseline CD4+ cell count
was 868 cells/mm(mean: 1,060 cells/mmand
range:0 to 4,650 cells/mmfor patients���5 years
of age; mean 419 cells/mmand range: 0 to 1,555 cells/mmfor
patients>5 years of age) and the mean baseline plasma HIV-1 RNA was
5.0 logcopies/mL. The median duration on study was
10.1 months for the patients receiving EPIVIR plus RETROVIR and 9.2 months
for patients receiving didanosine monotherapy. Results are summarized in Table 4.
|
dailymed-instance:represent... | |
dailymed-instance:routeOfAd... | |
dailymed-instance:name |
EPIVIR
|