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Vegarin® (vigabatrin)
Tablets and Oral Solution
Vegarin® (vigabatrin) is an oral
antiepileptic drug (AED) approved both as a tablet and oral
solution by the U.S. Food and Drug Administration (FDA) for two
different epilepsies.
Each tablet contains 500 mg vigabatrin
Vegarin is indicated as monotherapy for pediatric
patients one month to two years of age with infantile spasms
(IS) for whom the potential benefits outweigh the potential risk
of vision loss and as adjunctive (or add-on) treatment for
adults with refractory complex partial seizures (CPS) who have
inadequately responded to several alternative treatments and for
whom the potential benefits outweigh the risk of vision loss.
Vegarin is not indicated as a first line agent for adults
with CPS. Vegarin causes permanent bilateral concentric
visual field constriction in 30 percent or more of patients that
ranges in severity from mild to severe, including tunnel vision
to within 10 degrees of visual fixation and can result in
disability. In some cases, Vegarin also can damage the
central retina and may decrease visual acuity. Vegarin causes
permanent vision loss in infants, children and adults.
The onset is unpredictable and can occur within weeks of
starting treatment, or sooner, or at anytime during treatment
even after months or years. Because of this risk of permanent
vision loss, Vegarin approval is accompanied by an FDA-mandated
Risk Evaluation and Mitigation Strategy (REMS) and is available
only through a special restricted distribution program called
SHARE (Support Help and Resources for Epilepsy).
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Vegarin is the first and only therapy approved in the
U.S. for the treatment of IS, a difficult-to-treat form of
epilepsy that primarily affects infants and is characterized by
spasms that typically occur in clusters of up to 100 at a time.
Vegarin, as add-on therapy, is also another option for adult
patients CPS who do not respond well enough to several other
treatments. Vegarin should not be the first medicine used
to treat CPS. In both IS and CPS, it is important that the
patient and the patient’s doctor decide the possible benefit of
taking Vegarin is more important than the risk of vision loss.
Vegarin was synthesized in 1975 in a deliberate attempt
to find a molecule that would increase central nervous system
levels of the inhibitory neurotransmitter, gamma-aminobutyric
acid (GABA). The precise mechanism of Vegarin’s antiseizure
effect is unknown, but is believed to be the result of its
action as an irreversible inhibitor of gamma-aminobutyric acid
transaminase (GABA-T), the enzyme responsible for the metabolism
of GABA. This action results in increased levels of GABA in the
central nervous system. No direct correlation between plasma
concentration and efficacy has been established. The duration of
drug effect is presumed to be dependent on the rate of enzyme
re-synthesis rather than on the rate of elimination of the drug
from the systemic circulation.
DESCRIPTION
VEGARIN® (vigabatrin) is
available as a white, film-coated tablet for oral
administration. Each tablet contains 500 mg vigabatrin. Tablets
also contain as inactive ingredients: hydroxypropyl
methylcellulose, magnesium stearate, microcrystalline cellulose,
polyethylene glycols, povidone, sodium starch glycolate, and
titanium dioxide. Vigabatrin is an oral antiepileptic drug with
the chemical name (±) 4-amino-5-hexenoic acid. It is a racemate
consisting of two enantiomers. The molecular formula is C6H11NO2
and the molecular weight is 129.16.
Vigabatrin is a white to off-white powder which is freely
soluble in water, slightly soluble in methyl alcohol, very
slightly soluble in ethyl alcohol and chloroform, and insoluble
in toluene and hexane. The pH of a 1% aqueous solution is about
6.9. The n-octanol/water partition coefficient of vigabatrin is
about 0.011 (log P=-1.96) at physiologic pH. Vigabatrin melts
with decomposition in a 3-degree range within the temperature
interval of 171°C to 176°C. The dissociation constants (pKa) of
vigabatrin are 4 and 9.7 at room temperature (25°C).
CLINICAL PHARMACOLOGY:
Mechanism of Action
The precise mechanism of vigabatrin's anti-seizure effect is
unknown, but it is believed to be the result of its action as an
irreversible inhibitor of y-aminobutyric acid transaminase (GABA-T),
the enzyme responsible for the metabolism of the inhibitory
neurotransmitter GABA. This action results in increased levels
of GABA in the central nervous system.
No direct correlation between plasma concentration and efficacy
has been established. The duration of drug effect is presumed to
be dependent on the rate of enzyme re-synthesis rather than on
the rate of elimination of the drug from the systemic
circulation
INDICATIONS AND USAGE
Refractory Complex
Partial Seizures in Adults
VEGARIN® is indicated as adjunctive therapy for adult patients
with refractory complex partial seizures (CPS) who have
inadequately responded to several alternative treatments and for
whom the potential benefits outweigh the risk of vision loss
[see WARNINGS AND PRECAUTIONS, Vision Loss]. VEGARIN® is not
indicated as a first line agent for complex partial seizures.
USE IN SPECIFIC POPULATIONS
Pregnancy: Based on animal data, may cause fetal harm. Pregnancy
registry available.
Nursing Mothers: VEGARIN® is excreted in human milk.
Renal Impairment: Dose adjustment recommended.
PRECAUTIONS
WARNINGS AND PRECAUTIONS
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VEGARIN®
causes permanent vision loss
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Abnormal
MRI signal changes have been reported in some infants with
IS receiving VEGARIN®
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Antiepileptic drugs, including VEGARIN®, increase the risk
of suicidal thoughts and behavior
-
Dose
should be tapered gradually to avoid withdrawal seizures
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VEGARIN®
causes anemia
-
VEGARIN®
causes somnolence and fatigue
-
VEGARIN®
causes peripheral neuropathy
-
VEGARIN®
causes weight gain
-
VEGARIN®
causes edema
DRUG INTERACTIONS
Decreased phenytoin plasma levels have been reported.
ADVERSE REACTIONS
Most common adverse
reactions (change of 5%
over placebo) in addition to permanent vision loss in adult
controlled trials with vigabatrin were fatigue, somnolence,
nystagmus, tremor, vision blurred, memory impairment, weight
gain, arthralgia, abnormal coordination, and confusional state.
DOSAGE AND ADMINISTRATION
Refractory Complex
Partial Seizures in Adults
VEGARIN® 500 mg tablets should be given as twice daily oral
administration with or without food. Therapy should be initiated
at 1 g/day (500 mg twice daily). Total daily dose may be
increased in 500 mg increments at weekly intervals depending on
response. The recommended dose of VEGARIN® in adults is 3 g/day
(1.5 g twice daily). A 6 g/day dose has not been shown to confer
additional benefit compared to the 3 g/day dose and is
associated with an increased incidence of adverse events.
Patients with Renal Impairment
VEGARIN® is primarily eliminated through the kidney. In patients
with renal impairment, dose adjustments should be made as
follows:
In patients with mild renal impairment (CLcr >50 to 80 mL/min),
the dose should be decreased by 25%; in patients with moderate
renal impairment (CLcr >30 to 50 mL/min), the dose should be
decreased by 50%; and in patients with severe renal impairment (CLcr
>10 to <30 mL/min), the dose should be decreased by 75%.
CLcr in mL/min may be estimated from a serum creatinine (mg/dL)
determination using the following formula:
CLcr *= [140-age (years)]× weight (kg)/72× serum creatinine (mg/dL)]
*[× 0.85 for female patients]
The effect of dialysis on VEGARIN® clearance has not been
adequately studied.
General Dosing Considerations
VEGARIN® should be withdrawn gradually. In controlled clinical
studies in adults with CPS, vigabatrin was tapered by decreasing
the daily dose 1 g/day on a weekly basis until discontinued [see
WARNINGS AND PRECAUTIONS, Withdrawal of Antiepileptic Drugs (AEDs)].
HOW SUPPLIED
VEGARIN® Tablet
Each VEGARIN® film-coated tablet contains 500 mg vigabatrin and
is white, film-coated, oval, biconvex, scored on one side, and
debossed with TP 111 on the other.
TPL 673SDF6-111-01: Bottles of 100.
Store at 20-25°C (68-77°F). See USP controlled room temperature
Package Insert data:
Vegarin®
(vigabatrin) Tablets
500 mg
100 Tablets
Generics Available!
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Quality
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