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Pegarin®
(ethotoin tablets, USP)
PEGARIN - ethotoin tablet
Taj Pharmaceuticals Limited.
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PEGARIN® 250 mg
(ethotoin tablets, USP)
Rx Only
DESCRIPTION
PEGARIN (ethotoin tablets, USP) is an oral antiepileptic of the
hydantoin series and is chemically identified as
3-ethyl-5-phenyl-2,4-imidazolidinedione. It is represented by
the following structural formula:
PEGARIN
tablets are available in a dosage strength of 250 mg.
Inactive Ingredients: Acacia, lactose, sodium
carboxymethylcellulose, stearic acid and talc.
CLINICAL PHARMACOLOGY
PEGARIN (ethotoin tablets, USP) exerts an antiepileptic
effect without causing general central nervous system
depression. The mechanism of action is probably very similar to
that of phenytoin. The latter drug appears to stabilize rather
than to raise the normal seizure threshold, and to prevent the
spread of seizure activity rather than to abolish the primary
focus of seizure discharges.
Ethotoin is fairly rapidly absorbed; the extent of oral
absorption is not known. The drug exhibits saturable metabolism
with respect to the formation of N-deethyl and p-hydroxyl-ethotoin,
the major metabolites. Where plasma concentrations are below
about 8 µg/mL, the elimination half-life of ethotoin is in the
range of 3 to 9 hours. A study comparing single doses of 500
mg, 1000 mg, and 1500 mg of PEGARIN (ethotoin tablets, USP)
demonstrated that ethotoin, and to a lesser extent
5-phenylhydantoin, a major metabolite, exhibits substantial
nonlinear kinetics. The degree of nonlinearity with multiple
dosing may be increased over that seen after a single dose,
given the likelihood of plasma accumulation based on a reported
elimination half-life of 6 to 9 hours and a dosing interval of 4
to 6 hours. Experience suggests that therapeutic plasma
concentrations fall in the range of 15 to 50 µg/mL;
however, this range is not as extensively documented as those
quoted for other antiepileptics.
In laboratory animals, the drug was found effective against
electroshock convulsions, and to a lesser extent, against
complex partial (psychomotor) and pentylenetetrazol-induced
seizures. In mice, the duration of antiepileptic activity was
prolonged by hepatic injury but not by bilateral nephrectomy;
the drug is apparently biotransformed by the liver.
INDICATIONS AND USAGE
PEGARIN (ethotoin tablets, USP) is indicated for the
control of tonic-clonic (grand mal) and complex partial
(psychomotor) seizures.
CONTRAINDICATIONS
PEGARIN (ethotoin tablets, USP) is contraindicated in
patients with hepatic abnormalities or hematologic disorders.
WARNINGS
Suicidal Behavior and Ideation:
Antiepileptic drugs (AEDs), including PEGARIN, increase the risk
of suicidal thoughts or behavior in patients taking these drugs
for any indication. Patients treated with any AED for any
indication should be monitored for the emergence or worsening of
depression, suicidal thoughts or behavior, and/or any unusual
changes in mood or behavior.
Pooled analyses of 199 placebo-controlled clinical trials (mono-
and adjunctive therapy) of 11 different AEDs showed that
patients randomized to one of the AEDs had approximately twice
the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of
suicidal thinking or behavior compared to patients randomized to
placebo. In these trials, which had a median treatment duration
of 12 weeks, the estimated incidence rate of suicidal behavior
or ideation among 27,863 AED-treated patients was 0.43%,
compared to 0.24% among 16,029 placebo-treated patients,
representing an increase of approximately one case of suicidal
thinking or behavior for every 530 patients treated. There were
four suicides in drug-treated patients in the trials and none in
placebo-treated patients, but the number is too small to allow
any conclusion about drug effect on suicide.
The increased risk of suicidal thoughts or behavior with AEDs
was observed as early as one week after starting drug treatment
with AEDs and persisted for the duration of treatment
assessed. Because most trials included in the analysis did not
extend beyond 24 weeks, the risk of suicidal thoughts or
behavior beyond 24 weeks could not be assessed.
The risk of suicidal thoughts or behavior was generally
consistent among drugs in the data analyzed. The finding of
increased risk with AEDs of varying mechanisms of action and
across a range of indications suggests that the risk applies to
all AEDs used for any indication. The risk did not vary
substantially by age (5-100 years) in the clinical trials
analyzed. Table 1 shows absolute and relative risk by indication
for all evaluated AEDs.
|
Table1: Risk by indication for antiepileptic drugs
in the pooled analysis |
|
Indication |
Placebo
Patients
with
Events Per
1000
Patients |
Drug
Patients
with
Events Per
1000
Patients |
Relative Risk:
Incidence of
Events in Drug
Patients/Incidence
in Placebo
Patients |
Risk Difference:
Additional
Drug Patients
with Events
Per 1000
Patients |
|
Epilepsy |
1.0 |
3.4 |
3.5 |
2.4 |
|
Psychiatric |
5.7 |
8.5 |
1.5 |
2.9 |
|
Other |
1.0 |
1.8 |
1.9 |
0.9 |
|
Total |
2.4 |
4.3 |
1.8 |
1.9 |
The relative risk for suicidal thoughts or behavior was higher
in clinical trials for epilepsy than in clinical trials for
psychiatric or other conditions, but the absolute risk
differences were similar for the epilepsy and psychiatric
indications.
Anyone considering prescribing PEGARIN or any other
AED must balance the risk of suicidal thoughts or behavior
with the risk of untreated illness. Epilepsy and many other
illnesses for which AEDs are prescribed are themselves
associated with morbidity and mortality and an increased risk of
suicidal thoughts and behavior. Should suicidal thoughts and
behavior emerge during treatment, the prescriber needs to
consider whether the emergence of these symptoms in any given
patient may be related to the illness being treated.
Patients, their caregivers, and families should be informed that
AEDs increase the risk of suicidal thoughts and behavior and
should be advised of the need to be alert for the emergence
or worsening of the signs and symptoms of depression, any
unusual changes in mood or behavior, or the emergence of
suicidal thoughts, behavior, or thoughts about self-harm.
Behaviors of concern should be reported immediately to
healthcare providers.
Use in Pregnancy:
PEGARIN (ethotoin tablets, USP) can cause fetal harm
when administered to a pregnant woman. There are multiple
reports in the clinical literature which indicate that the use
of antiepileptic drugs during pregnancy results in an increased
incidence of birth defects in the offspring. Although data are
more extensive with respect to phenytoin
and phenobarbital, reports indicate a possible similar
association with the use of other antiepileptic drugs.
Therefore, antiepileptic drugs should be administered to women
of child-bearing potential only if they are clearly shown
to be essential in the management of their seizures.
Antiepileptic drugs should not be discontinued in patients in
whom the drug is administered to prevent major seizures because
of the strong possibility of precipitating status epilepticus
with attendant hypoxia and risk to both mother and the unborn
child. Consideration should, however, be given to
discontinuation of antiepileptics prior to and during pregnancy
when the nature, frequency and severity of the seizures do not
pose a serious threat to the patient. It is not, however, known
whether even minor seizures constitute some risk to the
developing embryo or fetus.
Reports have suggested that the maternal ingestion of
antiepileptic drugs, particularly barbiturates, is associated
with a neonatal coagulation defect that may cause bleeding
during the early (usually within 24 hours of birth) neonatal
period. The possibility of the occurrence of this defect
with the use of PEGARIN should be kept in mind. The defect is
characterized by decreased levels of vitamin k-dependent
clotting factors, and prolongation of either the prothrombin
time or the partial thromboplastin time, or both. It has been
suggested that vitamin k be given prophylactically to the
mother one month prior to and during delivery, and the infant,
intravenously, immediately after birth.
If PEGARIN is used during pregnancy, or if the patient becomes
pregnant while taking this drug, the patient should be apprised
of the potential hazard to the fetus.
To provide information regarding the effects of in utero
exposure to PEGARIN, physicians are advised to recommend that
pregnant patients taking PEGARIN enroll in the North American
Antiepileptic Drug (NAAED) Pregnancy Registry. This can be done
by calling the toll- free number 1-888-233-2334, and must be
done by patients themselves. Information on the registry can
also be found at the website
http://www.aedpregnancyregistry.org/.
PRECAUTIONS
General:
Blood dyscrasias have been reported in patients receiving
PEGARIN. Although the etiologic role of PEGARIN has not been
definitely established, physicians should be alert for general
malaise, sore throat and other symptoms indicative of possible
blood dyscrasia.
There is some evidence suggesting that hydantoin-like compounds
may interfere with folic acid metabolism, precipitating a
megaloblastic anemia. If this should occur during gestation,
folic acid therapy should be considered.
Information for Patients:
Patients should be advised to report immediately such signs and
symptoms as sore throat, fever, malaise, easy bruising,
petechiae, epistaxis, skin rash or others that may be indicative
of an infection or bleeding tendency.
Patients, their caregivers, and families should be counseled
that AEDs, including PEGARIN, may increase the risk of
suicidal thoughts and behavior and should be advised of the need
to be alert for the emergence or worsening of symptoms of
depression, any unusual changes in mood or behavior, or the
emergence of suicidal thoughts, behavior, or thoughts of
self-harm. Behaviors of concern should be reported immediately
to healthcare providers.
Patients should be encouraged to enroll in the NAAED Pregnancy
Registry if they become pregnant. This registry is collecting
information about the safety of antiepileptic drugs during
pregnancy. To enroll, patients can call the toll-free number
1-888-233-2334 (see
Use In Pregnancy).
Laboratory Tests:
Liver function tests should be performed if clinical evidence
suggests the possibility of hepatic dysfunction. Signs of liver
damage are an indication for withdrawal of the drug.
It is recommended that blood counts and urinalyses be performed
when therapy is begun and at monthly intervals for several
months thereafter. As in patients receiving other hydantoin
compounds and other antiepileptic drugs, blood dyscrasias
have been reported in patients receiving PEGARIN (ethotoin
tablets, USP). Marked depression of the blood count is
indication for withdrawal of the drug.
Drug Interactions:
PEGARIN used in combination with other drugs known to adversely
affect the hematopoietic system should be avoided if possible.
A two-way interaction between the hydantoin antiepileptic,
phenytoin, and the coumarin anticoagulants has been suggested.
Presumably, phenytoin acts as a stimulator of coumarin
metabolism and has been reported to cause decreased serum levels
of the coumarin anticoagulants and increased
prothrombin-proconvertin concentrations. Conversely, the
coumarin anticoagulants have been reported to increase the serum
levels and prolong the serum half-life of phenytoin by
inhibiting its metabolism. Although there is no documentation of
such, a similar interaction between ethotoin and the coumarin
anticoagulants may occur. Caution is therefore advised when
administering PEGARIN to patients receiving coumarin
anticoagulants.
Carcinogenesis, Mutagenesis, Impairment of Fertility:
No data are available on long-term potential for carcinogenicity
in animals or humans.
Pregnancy:
Pregnancy Category D. See “WARNINGS”
section.
Nonteratogenic Effects:
Reports have suggested that the maternal ingestion of
antiepileptic drugs, particularly barbiturates, is associated
with a neonatal coagulation defect that may cause bleeding
during the early (usually within 24 hours of birth) neonatal
period. The possibility of the occurrence of this defect with
the use of PEGARIN should be kept in mind. See “WARNINGS”
section.
Nursing Mothers:
Ethotoin is excreted in breast milk. Because of the potential
for serious adverse reactions in nursing infants from ethotoin,
a decision should be made whether to discontinue nursing or to
discontinue the drug, taking into account the importance of the
drug to the mother.
Pediatric Use:
Safety and effectiveness in the pediatric population were
established on the basis of open-label, uncontrolled experience
in patients down to the age of one with various types of
seizures.
Geriatric Use:
Clinical studies of PEGARIN 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, usually starting at
the low end of the dosing range, reflecting the greater
frequency of decreased hepatic, renal, or cardiac function, and
of concomitant disease or other drug therapy.
ADVERSE REACTIONS
Adverse reactions associated with PEGARIN, in decreasing order
of severity, are:
Isolated cases of lymphadenopathy and systemic lupus
erythematosus have been reported in patients taking hydantoin
compounds, and lymphadenopathy has occurred with PEGARIN.
Withdrawal of therapy has resulted in remission of the clinical
and pathological findings. Therefore, if a lymphoma-like
syndrome develops, the drug should be withdrawn and the patient
should be closely observed for regression of signs and symptoms
before treatment is resumed.
Ataxia and gum hypertrophy have occurred only rarely—usually
only in patients receiving an additional hydantoin derivative.
It is of interest to note that ataxia and gum hypertrophy have
subsided in patients receiving other hydantoins when PEGARIN (ethotoin
tablets, USP) was given as a substitute antiepileptic.
Occasionally, vomiting or nausea after ingestion of PEGARIN has
been reported, but if the drug is administered after meals, the
incidence of gastric distress is reduced. Other side effects
have included chest pain, nystagmus, diplopia, fever, dizziness,
diarrhea, headache, insomnia, fatigue, numbness, skin rash, and
Stevens-Johnson syndrome.
OVERDOSAGE
Symptoms of acute overdosage include drowsiness, visual
disturbance, nausea and ataxia. Coma is possible at very high
dosage.
Treatment should be begun by inducing emesis; gastric lavage may
be considered as an alternative. General supportive measures
will be necessary. A careful evaluation of blood-forming organs
should be made following recovery.
DOSAGE AND ADMINISTRATION
PEGARIN
(ethotoin tablets, USP) is administered orally in 4 to 6
divided doses daily. The drug should be taken after food, and
doses should be spaced as evenly as practicable. Initial dosage
should be conservative. For adults, the initial daily dose
should be 1 g or less, with subsequent gradual dosage increases
over a period of several days. The optimum dosage must be
determined on the basis of individual response. The usual adult
maintenance dose is 2 to 3 g daily. Less than 2 g daily has been
found ineffective in most adults.
Pediatric dosage depends upon the age and weight of the patient.
The initial dose should not exceed 750 mg daily. The usual
maintenance dose in children ranges from 500 mg to 1 g daily,
although occasionally 2 or (rarely) 3 g daily may be necessary.
If a patient is receiving another antiepileptic drug, it should
not be discontinued when PEGARIN therapy is begun. The dosage of
the other drug should be reduced gradually as that of PEGARIN is
increased. PEGARIN may eventually replace the other drug or the
optimal dosage of both antiepileptics may be established.
In tonic-clonic (grand mal) seizures, use of the drug with
phenobarbital may be beneficial.
HOW SUPPLIED
PEGARIN (ethotoin tablets, USP) 250 mg
grooved, white tablets bearing the letters OV on one side and
the number 61 on the other and are supplied in bottles of 100 (NDC
67386-601-01).
Recommended storage: Store below 77°F (25°C). Dispense in a
tight light-resistant container, as defined in the USP, with a
child-resistant cap.
Taj Pharmaceuticals Limited., Mumbai., India
®Trademark of Taj Pharmaceuticals Limited.
Revised: March 2011
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