Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/682
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EPIVIR-HBV (Tablet, Coated)
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Adults: The recommended oral dose of EPIVIR-HBV for treatment
of chronic hepatitis B in adults is 100 mg once daily (see paragraph
below and WARNINGS). Safety and effectiveness of treatment beyond
1 year have not been established and the optimum duration of
treatment is not known (see PRECAUTIONS). The formulation and dosage of lamivudine in EPIVIR-HBV
are not appropriate for patients dually infected with HBV and HIV.
If lamivudine is administered to such patients, the higher dosage
indicated for HIV therapy should be used as part of an appropriate
combination regimen, and the prescribing information for EPIVIR as
well as EPIVIR-HBV should be consulted.<br/>Pediatric Patients: The recommended oral dose of EPIVIR-HBV for pediatric
patients 2 to 17 years of age with chronic hepatitis B is 3 mg/kg
once daily up to a maximum daily dose of 100 mg. Safety and effectiveness
of treatment beyond 1 year have not been established and the
optimum duration of treatment is not known (see PRECAUTIONS). EPIVIR-HBV is available in a 5-mg/mL oral solution when
a liquid formulation is needed. (Please see information above regarding
distinctions between different lamivudine-containing products.)<br/>Dose Adjustment: It is recommended that doses of EPIVIR-HBV be adjusted
in accordance with renal function (Table 8) (see CLINICAL PHARMACOLOGY:
Special Populations). No additional dosing of EPIVIR-HBV is required
after routine (4-hour) hemodialysis or peritoneal dialysis. Although there are insufficient data to recommend a specific
dose adjustment of EPIVIR-HBV in pediatric patients with renal impairment,
a dose reduction should be considered.
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dailymed-instance:descripti... |
EPIVIR-HBV is a brand name for lamivudine, a synthetic
nucleoside analogue with activity against hepatitis B virus (HBV)
and HIV. Lamivudine was initially developed for the treatment of HIV
infection as EPIVIR. Please see the complete prescribing information
for EPIVIR Tablets and Oral Solution for additional information. 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-HBV
Tablets are for oral administration. Each tablet contains
100 mg of lamivudine and the inactive ingredients hypromellose,
macrogol 400, magnesium stearate, microcrystalline cellulose, polysorbate
80, red iron oxide, sodium starch glycolate, titanium dioxide, and
yellow iron oxide. EPIVIR-HBV Oral Solution is for oral administration. One
milliliter (1 mL) of EPIVIR-HBV Oral Solution contains 5 mg
of lamivudine (5 mg/mL) in an aqueous solution and the inactive
ingredients artificial strawberry and banana flavors, citric acid
(anhydrous), methylparaben, propylene glycol, propylparaben, sodiumcitrate (dihydrate), and sucrose (200 mg).
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Pharmacokinetics in Adults: The pharmacokinetic properties of lamivudine have
been studied as single and multiple oral doses ranging from 5 to 600 mg
per day administered to HBV-infected patients. The pharmacokinetic properties of lamivudine have also 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.<br/>Absorption and Bioavailability: Lamivudine was rapidly absorbed after oral administration
in HBV-infected patients and in healthy subjects. Following single
oral doses of 100 mg, the peak serum lamivudine concentration
(C) in HBV-infected patients (steady state) and healthy
subjects (single dose) was 1.28��0.56 mcg/mL
and 1.05��0.32 mcg/mL (mean��SD),
respectively, which occurred between 0.5 and 2 hours after administration.
The area under the plasma concentration versus time curve (AUC) following 100 mg lamivudine oral single
and repeated daily doses to steady state was 4.3��1.4
(mean��SD) and 4.7��1.7 mcg���hr/mL,
respectively. The relative bioavailability of the tablet and solution
were then demonstrated in healthy subjects. Although the solution
demonstrated a slightly higher peak serum concentration (C), there was no significant difference in systemic exposure (AUC���)
between the solution and the tablet. Therefore, the solution and the
tablet may be used interchangeably. After oral
administration of lamivudine once daily to HBV-infected adults, the
AUC and Cincreased in proportion to dose over the range
from 5 mg to 600 mg once daily. The
100-mg tablet was administered orally to 24 healthy subjects on 2 occasions,
once in the fasted state and once with food (standard meal: 967 kcal;
67 grams fat, 33 grams protein, 58 grams carbohydrate).
There was no significant difference in systemic exposure (AUC���)
in the fed and fasted states; therefore, EPIVIR-HBV Tablets and Oral
Solution may be administered with or without food. 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 10-mg/mL oral solution.<br/>Distribution: The apparent volume of distribution after IV administration
of lamivudine to 20 asymptomatic HIV-infected 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%) and independent of dose. 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. In 9 healthy subjects receiving 300 mg of lamivudine
as single oral doses, a total of 4.2% (range 1.5% to 7.5%) of the
dose was excreted as the trans-sulfoxide metabolite in the urine,
the majority ofwhich was excreted in the first 12 hours. Serum concentrations of the trans-sulfoxide 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- or 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 healthy subjects and in subjects with impaired
renal function, with and without hemodialysis (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). Hemodialysis
increases 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 peritonealdialysis. It is
not known whether lamivudine can be removed by continuous (24-hour)
hemodialysis. The effect of renal impairment
on lamivudine pharmacokinetics in pediatric patients with chronic
hepatitis B is not known.<br/>Adults With Impaired Hepatic
Function: The pharmacokinetic properties of lamivudine have
been determined in adults with impaired hepatic function (Table 2).
Patients were stratified by severity of hepatic functional impairment. 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 EPIVIR-HBV have not been established in the presence of
decompensated liver disease (see PRECAUTIONS).<br/>Post-Hepatic Transplant: Fourteen HBV-infected patients received liver transplant
following lamivudine therapy and completed pharmacokinetic assessments
at enrollment, 2 weeks after 100-mg once-daily dosing (pre-transplant),
and 3 months following transplant; there were no significant
differences in pharmacokinetic parameters. The overall exposure of
lamivudine is primarily affected by renal dysfunction; consequently,
transplant patients with reduced renal function had generally higher
exposure than patients with normal renal function. Safety and efficacy
of EPIVIR-HBV have not been established in this population (see PRECAUTIONS).<br/>Pediatric Patients: Lamivudine pharmacokinetics were evaluated in a
28-day dose-ranging study in 53 pediatric patients with chronic
hepatitis B. Patients aged 2 to 12 years were randomized to receive
lamivudine 0.35 mg/kg twice daily, 3 mg/kg once daily, 1.5 mg/kg
twice daily, or 4 mg/kg twice daily. Patients aged 13 to 17 years
received lamivudine 100 mg once daily. Lamivudine was rapidly
absorbed (T0.5 to 1 hour). In general, both Cand exposure (AUC) showed dose proportionality in the dosing
range studied. Weight-corrected oral clearance was highest at age
2 and declined from 2 to 12 years, where values were then similar
to those seen in adults. A dose of 3 mg/kg given once daily produced
a steady-state lamivudine AUC (mean 5,953 ng���hr/mL��1,562
SD) similar to that associated with a dose of 100 mg/day in adults.<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: Multiple doses of lamivudine and a single dose of
interferon were coadministered to 19 healthy male subjects in a pharmacokinetics
study. Results indicated a small (10%) reduction in lamivudine AUC,
but no change in interferon pharmacokinetic parameters when the 2
drugs were given in combination. All other pharmacokinetic parameters
(C, T, and t) were unchanged.
There was no significant pharmacokinetic interaction between lamivudine
and interferon alfa in this study. Lamivudine
and zidovudine were coadministered to 12 asymptomatic HIV-positive
adult patients in a single-center, open-label, randomized, crossover
study. No significant differences were observed in AUC���or
total clearance for lamivudine or zidovudine when the 2 drugs were
administered together. Coadministration of lamivudine with zidovudine
resulted in an increase of 39%��62% (mean��SD)
in Cof zidovudine. 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
with lamivudine resulted in an increase of 44%��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 (see PRECAUTIONS: Drug Interactions). Lamivudine and zalcitabine may inhibit the intracellular phosphorylation
of one another. Therefore, use of lamivudine in combination with zalcitabine
is not recommended.
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EPIVIR-HBV Tablets and EPIVIR-HBV Oral Solution
are contraindicated in patients with previously demonstrated clinically
significant hypersensitivity to any of the components of the products.
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dailymed-instance:supply |
EPIVIR-HBV Tablets, 100 mg, are butterscotch-colored,
film-coated, biconvex, capsule-shaped tablets imprinted with���GX
CG5���on one side. Bottles of 60 tablets
(NDC 0173-0662-00) with child-resistant closures. Store at 25��C (77��F), excursions
permitted to 15��to 30��C (59��to 86��F) [see USP
Controlled Room Temperature]. EPIVIR-HBV
Oral Solution, a clear, colorless to pale yellow, strawberry-banana-flavored
liquid, contains 5 mg of lamivudine in each 1 mL in plastic
bottles of 240 mL. Bottles of 240 mL (NDC
0173-0663-00) with child-resistant closures. This product does not
require reconstitution. Store at controlled room temperature of 20��to 25��C (68��to 77��F) (see USP) in tightly closed bottles.
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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). HUMAN IMMUNODEFICIENCY VIRUS
(HIV) COUNSELING AND TESTING SHOULD BE OFFERED TO ALL PATIENTS BEFORE
BEGINNING EPIVIR-HBV AND PERIODICALLY DURING TREATMENT (SEE WARNINGS),
BECAUSE EPIVIR-HBV TABLETS AND ORAL SOLUTION CONTAIN A LOWER DOSE
OF THE SAME ACTIVE INGREDIENT (LAMIVUDINE) AS EPIVIR TABLETS AND ORAL SOLUTION USED TO TREAT HIV INFECTION. 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 BECAUSE OF SUBTHERAPEUTIC DOSE AND INAPPROPRIATE
MONOTHERAPY. SEVERE ACUTE EXACERBATIONS OF HEPATITIS B HAVE BEEN REPORTED IN
PATIENTS WHO HAVE DISCONTINUED ANTI-HEPATITIS B THERAPY (INCLUDING
EPIVIR-HBV). HEPATIC FUNCTION SHOULD BE MONITORED CLOSELY WITH BOTH
CLINICAL AND LABORATORY FOLLOW-UP FOR AT LEAST SEVERAL MONTHS IN PATIENTS
WHO DISCONTINUE ANTI-HEPATITIS B THERAPY. IF APPROPRIATE,INITIATION
OF ANTI-HEPATITIS B THERAPY MAY BE WARRANTED (SEE WARNINGS).
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dailymed-ingredient:hypromellose,
dailymed-ingredient:macrogol_400,
dailymed-ingredient:magnesium_stearate,
dailymed-ingredient:microcrystalline_cellulose,
dailymed-ingredient:polysorbate_80,
dailymed-ingredient:red_iron_oxide,
dailymed-ingredient:sodium_starch_glycolate,
dailymed-ingredient:titanium_dioxide,
dailymed-ingredient:yellow_iron_oxide
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General: Patients should be assessed before beginning treatment
with EPIVIR-HBV by a physician experienced in the management of chronic
hepatitis B.<br/>Emergence of Resistance-Associated
HBV Mutations: In controlled clinical trials, YMDD-mutant HBV were
detected in patients with on-lamivudine re-appearance of HBV DNA after
an initial decline below the solution-hybridization assay limit (see
MICROBIOLOGY: Drug Resistance). These mutations can be detected by
a research assay and have been associated with reduced susceptibility
to lamivudine in vitro. Lamivudine-treated patients (adult and pediatric)
with YMDD-mutant HBV at 52 weeks showed diminished treatment
responses in comparison to lamivudine-treated patients without evidence
of YMDD mutations, including lower rates of HBeAg seroconversion and
HBeAg loss (no greater than placebo recipients), more frequent return
of positive HBV DNA by solution-hybridization or branched-chain DNA
assay, and more frequent ALT elevations. In the controlled trials,
when patients developed YMDD-mutant HBV, they had a rise in HBV DNA
and ALT from their own previous on-treatment levels. Progression of
hepatitis B, including death, has been reported in some patients with
YMDD-mutant HBV, including patients from the liver transplant setting
and from other clinical trials. In clinicalpractice, monitoring of
ALT and HBV DNA levels during lamivudine treatment may aid in treatment
decisions if emergence of viral mutants is suspected.<br/>Limitations of Populations Studied: Safety and efficacy of EPIVIR-HBV have not been
established in patients with decompensated liver disease or organ
transplants; pediatric patients<2 years of age; patients
dually infected with HBV and HCV, hepatitis delta, or HIV; or other
populations not included in the principal phase III controlled studies.
There are no studies in pregnant women and no data regarding effect
on vertical transmission, and appropriate infant immunizations should
be used to prevent neonatal acquisition of HBV.<br/>Assessing Patients During Treatment: Patients should be monitored regularly during treatment
by a physician experienced in the management of chronic hepatitis
B. The safety and effectiveness of treatment with EPIVIR-HBV beyond
1 year have not been established. During treatment, combinations
of such events such as return of persistently elevated ALT, increasing
levels of HBV DNA over time after aninitial decline below assay limit,
progression of clinical signs or symptoms of hepatic disease, and/or
worsening of hepatic necroinflammatory findings may be considered
as potentially reflecting loss of therapeutic response. Such observations
should be taken into consideration when determining the advisability
of continuing therapy with EPIVIR-HBV. The
optimal duration of treatment, the durability of HBeAg seroconversions
occurring during treatment, and the relationship between treatment
response and long-term outcomes such as hepatocellular carcinoma or
decompensated cirrhosis are not known.<br/>Patients With Impaired Renal Function: Reduction of the dosage of EPIVIR-HBV is recommended
for patients with impaired renal function (see CLINICAL PHARMACOLOGY
and DOSAGE AND ADMINISTRATION).<br/>Information for Patients: A Patient Package Insert (PPI) for EPIVIR-HBV is
available for patient information. Patients
should remain under the care of a physician while taking EPIVIR-HBV.
They should discuss any new symptoms or concurrent medications with
their physician. Patients should be advised
that EPIVIR-HBV is not a cure for hepatitis B, that the long-term
treatment benefits of EPIVIR-HBV are unknown at this time, and, in
particular, that the relationship of initial treatment response to
outcomes such as hepatocellular carcinoma and decompensated cirrhosis
is unknown. Patients should be informed that deterioration of liver
disease has occurred in some cases when treatment was discontinued.
Patients should be advised to discuss any changes in regimen with
their physician. Patients should be informed
that emergence of resistant hepatitis B virus and worsening of disease
can occur during treatment, and they should promptly report any new
symptoms to their physician. Patients should
be counseled on the importance of testing for HIV to avoid inappropriate
therapy and development of resistant HIV, and HIV counseling and testing
should be offered before starting EPIVIR-HBV and periodically during
therapy. Patients should be advised that EPIVIR-HBV Tablets and EPIVIR-HBV
Oral Solution contain a lower dose of the same active ingredient (lamivudine)
as EPIVIR Tablets, EPIVIR Oral Solution, COMBIVIR Tablets, EPZICOM
Tablets, and TRIZIVIR Tablets. EPIVIR-HBV should not be taken concurrently
with EPIVIR, COMBIVIR, EPZICOM, or TRIZIVIR (see WARNINGS). Patients
infected with both HBV and HIV who are planning to change their HIV
treatment regimen to a regimen that does not include EPIVIR, COMBIVIR,
EPZICOM, or TRIZIVIR should discuss continued therapy for hepatitis
B with their physician. Patients should be
advised that treatment with EPIVIR-HBV has not been shown to reduce
the risk of transmission of HBV to others through sexual contact or
blood contamination (see Pregnancy section). Diabetic patients should be advised that each 20-mL dose of EPIVIR-HBV
Oral Solution contains 4 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 44% (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 Pneumocystis carinii pneumonia. 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: Lamivudine long-term carcinogenicity studies in
mice and rats showed no evidence of carcinogenic potential at exposures
up to 34 times (mice) and 200 times (rats) those observed
in humans at the recommended therapeutic dose for chronic hepatitis
B. 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 60 to 70 times those in humans at
the recommended dose for chronic hepatitis B. In a study of reproductive
performance, lamivudine administered to rats at doses up to 4,000 mg/kg/day,
producing plasma levels 80 to 120 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 60 times that for the adult
HBV 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 exposures up to 60 times that in humans.
Studies in pregnant rats and rabbits showed that lamivudine is transferred
to the fetus through the placenta. There are no adequate and well-controlled
studies in pregnant women. Because animal reproductive toxicity studies
are not always predictive of human response, lamivudine should be
used during pregnancy only if the potential benefits outweigh the
risks. Lamivudine has not been shown to affect
the transmission of HBV from mother to infant, and appropriate infant
immunizations should be used to prevent neonatal acquisition of HBV.<br/>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: 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 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/>HBV: Safety and efficacy of lamivudine for treatment
of chronic hepatitis B in children have been studied in pediatric
patients from 2 to 17 years of age in a controlled clinical trial
(see CLINICAL PHARMACOLOGY, INDICATIONS AND USAGE, and DOSAGE AND
ADMINISTRATION). Safety and efficacy in pediatric
patients<2 years of age have not been established.<br/>HIV: See the complete prescribing information for EPIVIR
Tablets and Oral Solution for additional information on pharmacokinetics
of lamivudine in HIV-infected children.<br/>Geriatric Use: Clinical studies of EPIVIR-HBV 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 concomitantdisease 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).
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There is no known antidote for EPIVIR-HBV. 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. 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.
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lamivudine
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EPIVIR-HBV (Tablet, Coated)
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dailymed-instance:adverseRe... |
Several serious adverse events reported with lamivudine
(lactic acidosis and severe hepatomegaly with steatosis, posttreatment
exacerbations of hepatitis B, pancreatitis, and emergence of viral
mutants associated with reduced drug susceptibility and diminished
treatment response) are also described in WARNINGS and PRECAUTIONS.<br/>Clinical Trials In Chronic Hepatitis
B:<br/>Adults: Selected clinical adverse events observed with a���5% frequency during therapy with EPIVIR-HBV compared with
placebo are listed in Table 5. Frequencies of specified laboratory
abnormalities during therapy with EPIVIR-HBV compared with placebo
are listed in Table 6. In patients followed for up to 16 weeks after
discontinuation of treatment, posttreatment ALT elevations were observed
more frequently in patients who had received EPIVIR-HBV than in patients
who had received placebo. A comparison of ALT elevations between Weeks
52 and 68 in patients who discontinued EPIVIR-HBV at Week 52 and patients
in the same studies who received placebo throughout the treatment
course is shown in Table 7.<br/>Lamivudine in Patients With HIV: In HIV-infected patients, safety information reflects
a higher dose of lamivudine (150 mg b.i.d.) than the dose used
to treat chronic hepatitis B in HIV-negative patients. In clinical
trials using lamivudine as part of a combination regimen for treatment
of HIV infection, several clinical adverse events occurred more often
in lamivudine-containing treatment arms than in comparator arms. These
included nasal signs and symptoms (20% vs. 11%), dizziness (10% vs.
4%), and depressive disorders (9% vs. 4%). Pancreatitis was observed
in 9 of the 2,613 adult patients (<0.5%) who received EPIVIR
in controlled clinical trials. Laboratory abnormalities reported more
often in lamivudine-containing arms included neutropenia and elevations
of liver function tests (also more frequent in lamivudine-containing
arms for a retrospective analysis of HIV/HBV dually infected patients
in one study), and amylase elevations. Please see the complete prescribing
information for EPIVIR Tablets and Oral Solution for more information.<br/>Pediatric Patients With Hepatitis
B: Most commonly observed adverse events in the pediatric
trials were similar to those in adult trials; in addition, respiratory
symptoms (cough, bronchitis, and viral respiratory infections) were
reported in both lamivudine and placebo recipients. Posttreatment
transaminase elevations were observed in some patients followed after
cessation of lamivudine.<br/>Pediatric Patients With HIV Infection: In early open-label studies of lamivudine in children
with HIV, peripheral neuropathy and neutropenia were reported, and
pancreatitis was observed in 14% to 15% of patients.<br/>Observed During Clinical Practice: The following events have been identified during
post-approval use of lamivudine in clinical practice. 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 either their seriousness, frequency of reporting, potential
causal connection to lamivudine, or a combination of these factors.
Post-marketing experience with lamivudine at this time is largely
limited to use in HIV-infected patients.<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 steatosis, pancreatitis, posttreatment
exacerbation of hepatitis (see WARNINGS and PRECAUTIONS).<br/>Hypersensitivity: Anaphylaxis, urticaria.<br/>Musculoskeletal: Rhabdomyolysis.<br/>Nervous: Paresthesia, peripheral neuropathy.<br/>Respiratory: Abnormal breath sounds/wheezing.<br/>Skin: Alopecia, pruritus, rash.
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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. Most of these
reports have described patients receiving nucleoside analogues for
treatment of HIV infection, but there have been reports of lactic
acidosis in patients receiving lamivudine for hepatitis B. Particular
caution should be exercised when administering EPIVIR or EPIVIR-HBV
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 or EPIVIR-HBV 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 Between Lamivudine-Containing
Products, HIV Testing, and Risk of Emergence of Resistant HIV: EPIVIR-HBV Tablets and Oral Solution contain a lower
dose of the same active ingredient (lamivudine) as EPIVIR Tablets
and Oral Solution, COMBIVIR (lamivudine/zidovudine)
Tablets, EPZICOM (abacavir sulfate and lamivudine)
Tablets, and TRIZIVIR (abacavir, lamivudine, and
zidovudine) Tablets used to treat HIV infection. The formulation and
dosage of lamivudine in EPIVIR-HBV are not appropriate for patients
dually infected with HBV and HIV. If a decision is made to administer
lamivudine to such patients, the higher dosage indicated for HIV therapy
should be used as part of an appropriate combination regimen, and
the prescribing information for EPIVIR, COMBIVIR, EPZICOM, or TRIZIVIR
as well as for EPIVIR-HBV should be consulted. HIV counseling and
testing should be offered to all patients before beginning EPIVIR-HBV
and periodically during treatment because of the risk of rapid emergence
of resistant HIV and limitation of treatment options if EPIVIR-HBV
is prescribed to treat chronic hepatitis B in a patient who has unrecognized
or untreated HIV infection or acquires HIV infection during treatment.<br/>Posttreatment Exacerbations of Hepatitis: Clinical and laboratory evidence of exacerbations
of hepatitis have occurred after discontinuation of EPIVIR-HBV (these
have been primarily detected by serum ALT elevations, in addition
to the re-emergence of HBV DNA commonly observed after stopping treatment;
see Table 7 for more information regarding frequency ofposttreatment
ALT elevations). Although most events appear to have been self-limited,
fatalities have been reported in some cases. 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 therapy alters the
course of posttreatment exacerbations of hepatitis.<br/>Pancreatitis: Pancreatitis has been reported in patients receiving
lamivudine, particularly in HIV-infected pediatric patients with prior
nucleoside exposure.
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EPIVIR-HBV is indicated for the treatment of chronic
hepatitis B associated with evidence of hepatitis B viral replication
and active liver inflammation. This indication is based on 1-year
histologic and serologic responses in adult patients with compensated
chronic hepatitis B, and more limited information from a study in
pediatric patients ages 2 to 17 years (see Descriptionof Clinical
Studies below).<br/>Description of Clinical Studies:<br/>Adults: The safety and efficacy of EPIVIR-HBV were
evaluated in 4 controlled studies in 967 patients
with compensated chronic hepatitis B. All patients were 16 years
of age or older and had chronic hepatitis B virus infection (serum
HBsAg positive for at least 6 months) accompanied by evidence
of HBV replication (serum HBeAg positive and positive for serum HBV
DNA, as measured by a research solution-hybridization assay) and persistently
elevated ALT levels and/or chronic inflammation on liver biopsy compatible
with a diagnosis of chronic viral hepatitis. Three of these studies
provided comparisons of EPIVIR-HBV 100 mg once daily versus placebo,
and results of these comparisons are summarized below. Principal endpoint comparisons for the histologic
and serologic outcomes in lamivudine (100 mg daily) and placebo
recipients in placebo-controlled studies are shown in the following
tables. Normalization of serum ALT levels was more frequent
with lamivudine treatment compared with placebo in Studies 1-3. The majority of lamivudine-treated patients showed a
decrease of HBV DNA to below the assay limit early in the course of
therapy. However, reappearance of assay-detectable HBV DNA during
lamivudine treatment was observed in approximately one third of patients
after this initial response.<br/>Pediatrics: The safety and efficacy of EPIVIR-HBV were evaluated
in a double-blind clinical trial in 286 patients ranging from
2 to 17 years of age, who were randomized (2:1) to receive 52 weeks
of lamivudine (3 mg/kg once daily to a maximum of 100 mg
once daily) or placebo. All patients had compensated chronic hepatitis
B accompanied by evidence of hepatitis B virus replication (positive
serum HBeAg and positive for serum HBV DNA by a research branched-chain
DNA assay) and persistently elevated serum ALT levels. The combination
of loss of HBeAg and reduction of HBV DNA to below the assay limit
of the research assay, evaluated at Week 52, was observed in 23% of
lamivudine subjects and 13% of placebo subjects. Normalization of
serum ALT was achieved and maintained to Week 52 more frequently in
patients treated withEPIVIR-HBV compared with placebo (55% versus
13%). As in the adult controlled trials, most lamivudine-treated subjects
had decreases in HBV DNA below the assay limit early in treatment,
but about one third of subjects with this initial response had reappearance
of assay-detectable HBV DNA during treatment. Adolescents (ages 13
to 17 years) showed less evidence of treatment effect than younger
children.
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EPIVIR-HBV
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