DESCRIPTION:
Chemical name: 5-ethyldihydro-5-phenyl-4,6 (1H, 5H) pyrimidinedione.
Mysoline is a white, crystalline, highly stable substance, M.P. 279-284 deg C.
It is poorly soluble in water (60 mg per 100 mL at 37 deg C) and in most organic
solvents. It possesses no acidic properties, in contrast to its barbiturate
analog.
Mysoline 250 mg tablets contain the following inactive ingredients:
Microcrystalline Cellulose, NF; Lactose, USP; Methylcellulose, USP; Sodium
Starch Glycolate, NF; Talc, USP; Sodium Lauryl Sulfate, NF; Magnesium Stearate,
NF; Water, USP, Purified.
ACTIONS/CLINICAL PHARMACOLOGY:
Mysoline raises electro- or chemoshock seizure thresholds or alters seizure
patterns in experimental animals. The mechanism(s) of primidone's antiepileptic
action is not known.
Primidone Per Se has anticonvulsant activity as do its two metabolites,
phenobarbital and phenylethylmalonamide (PEMA). In addition to its
anticonvulsant activity, PEMA potentiates the anticonvulsant activity of
phenobarbital in experimental animals.
INDICATIONS AND USAGE:
Mysoline, used alone or concomitantly with other anticonvulsants, is indicated
in the control of grand mal, psychomotor, and focal epileptic seizures. It may
control grand mal seizures refractory to other anticonvulsant therapy.
CONTRAINDICATIONS:
Primidone is contraindicated in: 1) patients with porphyria and 2) patients who
are hypersensitive to phenobarbital (see ACTIONS/CLINICAL PHARMACOLOGY).
WARNINGS:
The abrupt withdrawal of antiepileptic medication may precipitate status
epilepticus.
The therapeutic efficacy of a dosage regimen takes several weeks before it can
be assessed.
USAGE IN PREGNANCY
The effects of Mysoline in human pregnancy and nursing infants are unknown.
Recent reports suggest an association between the use of anticonvulsant drugs by
women with epilepsy and an elevated incidence of birth defects in children born
to these women. Data are more extensive with respect to diphenylhydantoin and
phenobarbital, but these are also the most commonly prescribed anticonvulsants;
less systematic or anecdotal reports suggest a possible similar association with
the use of all known anticonvulsant drugs.
The reports suggesting an elevated incidence of birth defects in children of
drug-treated epileptic women cannot be regarded as adequate to prove a definite
cause-and-effect relationship. There are intrinsic methodologic problems in
obtaining adequate data on drug teratogenicity in humans: the possibility also
exists that other factors leading to birth defects, e.g., genetic factors or the
epileptic condition itself, may be more important than drug therapy. The
majority of mothers on anticonvulsant medication deliver normal infants. It is
important to note that anticonvulsant 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 threat to life. In individual cases where the severity and frequency
of the seizure disorders are such that the removal of medication does not pose a
serious threat to the patient, discontinuation of the drug may be considered
prior to and during pregnancy, although it cannot be said with any confidence
that even minor seizures do not pose some hazard to the developing embryo or
fetus.
The prescribing physician will wish to weigh these considerations in treating or
counseling epileptic women of childbearing potential.
Neonatal hemorrhage, with a coagulation defect resembling vitamin K deficiency,
has been described in newborns whose mothers were taking primidone and other
anticonvulsants. Pregnant women under anticonvulsant therapy should receive
prophylactic vitamin K1 therapy for one month prior to, and during, delivery.
PRECAUTIONS:
The total daily dosage should not exceed 2 g. Since Mysoline therapy generally
extends over prolonged periods, a complete blood count and a sequential multiple
analysis-12 (SMA-12) test should be made every six months.
IN NURSING MOTHERS
There is evidence that in mothers treated with primidone, the drug appears in
the milk in substantial quantities. Since tests for the presence of primidone in
biological fluids are too complex to be carried out in the average clinical
laboratory, it is suggested that the presence of undue somnolence and drowsiness
in nursing newborns of Mysoline-treated mothers be taken as an indication that
nursing should be discontinued.
ADVERSE REACTIONS:
The most frequently occurring early side effects are ataxia and vertigo. These
tend to disappear with continued therapy, or with reduction of initial dosage.
Occasionally, the following have been reported: nausea, anorexia, vomiting,
fatigue, hyperirritability, emotional disturbances, sexual impotency, diplopia,
nystagmus, drowsiness, and morbilliform skin eruptions. Granulocytopenia,
agranulocytosis and red-cell hypoplasia and aplasia, have been reported rarely.
These and, occasionally, other persistent or severe side effects may necessitate
withdrawal of the drug. Megaloblastic anemia may occur as a rare idiosyncrasy to
Mysoline and to other anticonvulsants. The anemia responds to folic acid without
necessity of discontinuing medication.
DOSAGE AND ADMINISTRATION:
ADULT DOSAGE
Patients 8 years of age and older who have received no previous treatment may be
started on Mysoline according to the following regimen using either 50 mg or
scored 250 mg Mysoline tablets.
Days 1 to 3: 100 to 125 mg at bedtime
Days 4 to 6: 100 to 125 mg b.i.d.
Days 7 to 9: 100 to 125 mg t.i.d.
Day 10 to maintenance: 250 mg t.i.d.
For most adults and children 8 years of age and over, the usual maintenance
dosage is three to four 250 mg Mysoline tablets daily in divided doses (250 mg
t.i.d. or q.i.d.). If required, an increase to five or six 250 mg tablets daily
may be made but daily doses should not exceed 500 mg q.i.d.
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INITIAL: ADULTS AND CHILDREN OVER 8
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KEY: .. =50 mg tablet -- =250 mg tablet
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DAY 1 2 3 4 5 6
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AM .. .. ..
NOON
PM .. .. .. .. .. ..
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DAY 7 8 9 10 11 12
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AM .. .. .. --
NOON .. .. .. -- Adjust to
PM .. .. .. -- Maintenance
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Dosage should be individualized to provide maximum benefit. In some cases, serum
blood level determinations of primidone may be necessary for optimal dosage
adjustment. The clinically effective serum level for primidone is between 5 to
12 mcgm/mL.
IN PATIENTS ALREADY RECEIVING OTHER ANTICONVULSANTS
Mysoline should be started at 100 to 125 mg at bedtime and gradually increased
to maintenance level as the other drug is gradually decreased. This regimen
should be continued until satisfactory dosage level is achieved for the
combination, or the other medication is completely withdrawn. When therapy with
Mysoline alone is the objective, the transition from concomitant therapy should
not be completed in less than two weeks.
PEDIATRIC DOSAGE
For children under 8 years of age, the following regimen may be used:
Days 1 to 3: 50 mg at bedtime
Days 4 to 6: 50 mg b.i.d.
Days 7 to 9: 100 mg b.i.d.
Day 10 to maintenance: 125 mg t.i.d. to 250 mg t.i.d.
For children under 8 years of age, the usual maintenance dosage is 125 to 250 mg
three times daily or, 10 to 25 mg/kg/day in divided doses.