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Pronunciation:

(PRI mi done)

U.S. Brand Names:

Mysoline®

Synonyms:

Desoxyphenobarbital; Primaclone

Generic Available:

Yes

Canadian Brand Names:

Apo-Primidone®; Mysoline®

Use:

Management of grand mal, psychomotor, and focal seizures

Use - Unlabeled/Investigational:

Benign familial tremor (essential tremor)

Pregnancy Risk Factor:

Pregnancy Implications:

Crosses the placenta. Dysmorphic facial features; hemorrhagic disease of newborn due to fetal vitamin K depletion, maternal folic acid deficiency may occur. Epilepsy itself, number of medications, genetic factors, or a combination of these probably influence the teratogenicity of anticonvulsant therapy. Benefit:risk ratio usually favors continued use during pregnancy.

Lactation:

Enters breast milk/not recommended (AAP recommends use "with caution")

Contraindications:

Hypersensitivity to primidone, phenobarbital, or any component of the formulation; porphyria; pregnancy

Warnings/Precautions:

Use with caution in patients with renal or hepatic impairment, pulmonary insufficiency; abrupt withdrawal may precipitate status epilepticus. Potential for drug dependency exists. Do not administer to patients in acute pain. Use caution in elderly, debilitated, or pediatric patients - may cause paradoxical responses. May cause CNS depression, which may impair physical or mental abilities. Patients must cautioned about performing tasks which require mental alertness (eg, operating machinery or driving). Effects with other sedative drugs or ethanol may be potentiated. Use with caution in patients with depression or suicidal tendencies, or in patients with a history of drug abuse. Tolerance or psychological and physical dependence may occur with prolonged use. Primidone's metabolite, phenobarbital, has been associated with cognitive deficits in children. Use with caution in patients with hypoadrenalism.

Adverse Reactions:

Frequency not defined.

Central nervous system: Drowsiness, vertigo, ataxia, lethargy, behavior change, fatigue, hyperirritability

Dermatologic: Rash

Gastrointestinal: Nausea, vomiting, anorexia

Genitourinary: Impotence

Hematologic: Agranulocytopenia, agranulocytosis, anemia

Ocular: Diplopia, nystagmus

Overdosage/Toxicology:

Symptoms of overdose include unsteady gait, slurred speech, confusion, jaundice, hypothermia, fever, hypotension, coma, and respiratory arrest. Assure adequate hydration and renal function. Urinary alkalinization with I.V. sodium bicarbonate also helps to enhance elimination. Repeat oral doses of activated charcoal significantly reduce the half-life of primidone through nonrenal elimination. Hemodialysis or hemoperfusion is of uncertain value. Patients in stage IV coma due to high serum drug levels may require charcoal hemoperfusion.

Drug Interactions:

Metabolized to phenobarbital; Induces CYP1A2 (strong), 2B6 (strong), 2C8/9 (strong), 3A4 (strong)

Acetaminophen: Barbiturates may enhance the hepatotoxic potential of acetaminophen overdoses

Antiarrhythmics: Barbiturates may increase the metabolism of antiarrhythmics, decreasing their clinical effect; includes disopyramide, propafenone, and quinidine

Anticonvulsants: Barbiturates may increase the metabolism of anticonvulsants; includes ethosuximide, felbamate (possibly), lamotrigine, phenytoin, tiagabine, topiramate, and zonisamide; does not appear to affect gabapentin or levetiracetam

Antineoplastics: Limited evidence suggests that enzyme-inducing anticonvulsant therapy may reduce the effectiveness of some chemotherapy regimens (specifically in ALL); teniposide and methotrexate may be cleared more rapidly in these patients

Antipsychotics: Barbiturates may enhance the metabolism (decrease the efficacy) of antipsychotics; monitor for altered response; dose adjustment may be needed

Beta-blockers: Metabolism of beta-blockers may be increased and clinical effect decreased; atenolol and nadolol are unlikely to interact given their renal elimination

Calcium channel blockers: Barbiturates may enhance the metabolism of calcium channel blockers, decreasing their clinical effect

Chloramphenicol: Barbiturates may increase the metabolism of chloramphenicol and chloramphenicol may inhibit barbiturate metabolism; monitor for altered response

Cimetidine: Barbiturates may enhance the metabolism of cimetidine, decreasing its clinical effect

CNS depressants: Sedative effects and/or respiratory depression with barbiturates may be additive with other CNS depressants; monitor for increased effect. Includes ethanol, sedatives, antidepressants, narcotic analgesics, and benzodiazepines

Corticosteroids: Barbiturates may enhance the metabolism of corticosteroids, decreasing their clinical effect

Cyclosporine: Levels may be decreased by barbiturates; monitor

CYP1A2 substrates: Primidone may decrease the levels/effects of CYP1A2 substrates. Example substrates include aminophylline, estrogens, fluvoxamine, mirtazapine, ropinirole, and theophylline.

CYP2B6 substrates: Primidone may decrease the levels/effects of CYP2B6 substrates. Example substrates include bupropion, efavirenz, promethazine, selegiline, and sertraline.

CYP2C8/9 substrates: Primidone may decrease the levels/effects of CYP2C8/9 substrates. Example substrates include amiodarone, fluoxetine, glimepiride, glipizide, losartan, nateglinide, phenytoin, pioglitazone, rosiglitazone, sertraline, sulfonamides, warfarin, and zafirlukast.

CYP3A4 substrates: Primidone may decrease the levels/effects of CYP3A4 substrates. Example substrates include benzodiazepines, calcium channel blockers, clarithromycin, cyclosporine, erythromycin, estrogens, mirtazapine, nateglinide, nefazodone, nevirapine, protease inhibitors, tacrolimus, and venlafaxine.

Doxycycline: Barbiturates may enhance the metabolism of doxycycline, decreasing its clinical effect; higher dosages may be required

Estrogens: Barbiturates may increase the metabolism of estrogens and reduce their efficacy

Felbamate may inhibit the metabolism of barbiturates and barbiturates may increase the metabolism of felbamate

Griseofulvin: Barbiturates may impair the absorption of griseofulvin, and griseofulvin metabolism may be increased by barbiturates, decreasing clinical effect

Guanfacine: Effect may be decreased by barbiturates

Immunosuppressants: Barbiturates may enhance the metabolism of immunosuppressants, decreasing its clinical effect; includes both cyclosporine and tacrolimus

Loop diuretics: Metabolism may be increased and clinical effects decreased; established for furosemide, effect with other loop diuretics not established

MAO inhibitors: Metabolism of barbiturates may be inhibited, increasing clinical effect or toxicity of the barbiturates

Methadone: Barbiturates may enhance the metabolism of methadone resulting in methadone withdrawal

Methoxyflurane: Barbiturates may enhance the nephrotoxic effects of methoxyflurane

Oral contraceptives: Barbiturates may enhance the metabolism of oral contraceptives, decreasing their clinical effect; an alternative method of contraception should be considered

Theophylline: Barbiturates may increase metabolism of theophylline derivatives and decrease their clinical effect

Tricyclic antidepressants: Barbiturates may increase metabolism of tricyclic antidepressants and decrease their clinical effect; sedative effects may be additive

Valproic acid: Metabolism of barbiturates may be inhibited by valproic acid; monitor for excessive sedation; a dose reduction may be needed

Warfarin: Barbiturates inhibit the hypoprothrombinemic effects of oral anticoagulants via increased metabolism; this combination should generally be avoided

Ethanol/Nutrition/Herb Interactions:

Ethanol: Avoid ethanol (may increase CNS depression).

Food: Protein-deficient diets increase duration of action of primidone.

Herb/Nutraceutical: Avoid valerian, St John's wort, kava kava, gotu kola (may increase CNS depression).

Stability:

Protect from light

Mechanism of Action:

Decreases neuron excitability, raises seizure threshold similar to phenobarbital; primidone has two active metabolites, phenobarbital and phenylethylmalonamide (PEMA); PEMA may enhance the activity of phenobarbital

Pharmacodynamics/Kinetics:

Distribution: Adults: Vd: 2-3 L/kg

Protein binding: 99%

Metabolism: Hepatic to phenobarbital (active) and phenylethylmalonamide (PEMA)

Bioavailability: 60% to 80%

Half-life elimination (age dependent): Primidone: 10-12 hours; PEMA: 16 hours; Phenobarbital: 52-118 hours

Time to peak, serum: ~4 hours

Excretion: Urine (15% to 25% as unchanged drug and active metabolites)

Dosage:

Oral:

Children <8 years: Initial: 50-125 mg/day given at bedtime; increase by 50-125 mg/day increments every 3-7 days; usual dose: 10-25 mg/kg/day in divided doses 3-4 times/day

Children 8 years and Adults: Initial: 125-250 mg/day at bedtime; increase by 125-250 mg/day every 3-7 days; usual dose: 750-1500 mg/day in divided doses 3-4 times/day with maximum dosage of 2 g/day

Adults: Essential tremor (unlabeled use): 750 mg early in divided doses

Dosing interval in renal impairment:

Clcr 50-80 mL/minute: Administer every 8 hours

Clcr 10-50 mL/minute: Administer every 8-12 hours

Clcr<10 mL/minute: Administer every 12-24 hours

Hemodialysis: Moderately dialyzable (20% to 50%); administer dose postdialysis or administer supplemental 30% dose

Monitoring Parameters:

Serum primidone and phenobarbital concentration, CBC, neurological status. Due to CNS effects, monitor closely when initiating drug in elderly. Monitor CBC at 6-month intervals to compare with baseline obtained at start of therapy. Since elderly metabolize phenobarbital at a slower rate than younger adults, it is suggested to measure both primidone and phenobarbital levels together.

Reference Range:

Therapeutic: Children <5 years: 7-10 mcg/mL (SI: 32-46 mol/L); Adults: 5-12 mcg/mL (SI: 23-55 mol/L); toxic effects rarely present with levels <10 mcg/mL (SI: 46 mol/L) if phenobarbital concentrations are low. Dosage of primidone is adjusted with reference mostly to the phenobarbital level; Toxic: >15 mcg/mL (SI: >69 mol/L)

Dietary Considerations:

Folic acid: Low erythrocyte and CSF folate concentrations. Megaloblastic anemia has been reported. To avoid folic acid deficiency and megaloblastic anemia, some clinicians recommend giving patients on anticonvulsants prophylactic doses of folic acid and cyanocobalamin.

Patient Education:

Take exactly as directed; do not increase dose or frequency or discontinue without consulting prescriber. Drug may cause physical and/or psychological dependence. While using this medication, do not use alcohol and other prescription or OTC medications (especially pain medications, sedatives, antihistamines, or hypnotics) without consulting prescriber. Maintain adequate hydration (2-3 L/day of fluids) unless instructed to restrict fluid intake. You may experience drowsiness, dizziness, or blurred vision (use caution when driving or engaging in tasks requiring alertness until response to drug is known); nausea, vomiting, or loss of appetite (small, frequent meals, frequent mouth care, chewing gum, or sucking lozenges may help); or impotence (reversible). Wear identification of epileptic status and medications. Report behavioral or CNS changes (confusion, depression, increased sedation, excitation, headache, insomnia, or lethargy); muscle weakness, or tremors; unusual bruising or bleeding (mouth, urine, stool); or worsening of seizure activity or loss of seizure control. Pregnancy/breast-feeding precautions: Do not get pregnant while taking this drug; use appropriate contraceptive measures. Consult prescriber if breast-feeding.

Nursing Implications:

Observe patient for excessive sedation; institute safety measures

Dental Health: Effects on Dental Treatment:

No significant effects or complications reported

Dental Health: Vasoconstrictor/Local Anesthetic Precautions:

No information available to require special precautions

Dosage Forms:

Tablet: 50 mg, 250 mg [generic tablet may contain sodium benzoate]

International Brand Names:

Apo-Primidone® (CA, NZ); Cyral® (AT); Epidona® (BR); Hexamidin® (RU); Liskantin® (CZ, DE, LU); Mizodin® (PL); Mylepsinum® (DE); Mysoline® (AR, AT, AU, BE, BR, CA, CH, CL, CY, CZ, DK, EG, ES, FR, GB, HK, ID, IE, IN, IT, JO, KW, LB, LU, MT, MX, NL, NO, NZ, PT, SE, SY, TR, ZA); Primidona® (BR); Primidona L.CH.® (CL); Primidon Era® (DK); Primidon Holsten® (DE); Primidon® (HR, RO, SI); Prysoline® (IL); Resimatil® (DE); Sertan® (HU); Wyeth Pirimidona® (BR)

References

"American Academy of Pediatrics Committee on Drugs. The Transfer of Drugs and Other Chemicals Into Human Milk,"Pediatrics, 2001, 108(3):776-89.

Lane GP, Lewis CG, and Zail SC, "Macroscopic Crystalluria After Primidone Overdosage,"Med J Aust, 1987, 147(11-12):624-5.

Schwankhaus JD, Kattah JC, Lux WE, et al, "Primidone/Phenobarbital-Induced Periodic Alternating Nystagmus,"Ann Ophthalmol, 1989, 21(6):230-2.

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