Primidone

(BAN, rINN)
Primidone Chemical formula
Synonyms: Desoxifenobarbitona; Hexamidinum; Primaclona; Primaclone; Primidon; Primidona; Primidonas; Primidoni; Primidonum; Prymidon. 5-Ethyl-5-phenylperhydropyrimidine-4,6-dione.
Cyrillic synonym: Примидон.

💊 Chemical information

Chemical formula: C12H14N2O2 = 218.3.
CAS — 125-33-7.
ATC — N03AA03.
ATC Vet — QN03AA03.

Pharmacopoeias.

In Chin., Eur., Jpn, and US.

Ph. Eur. 6.2

(Primidone). A white or almost white, crystalline powder. Very slightly soluble in water; slightly soluble in alcohol. It dissolves in alkaline solutions.

USP 31

(Primidone). A white, odourless, crystalline powder. Soluble 1 in 2000 of water and 1 in 200 of alcohol; very slightly soluble in most organic solvents.

💊 Adverse Effects, Treatment, and Precautions

As for Phenobarbital. Adverse effects may be more frequent than with phenobarbital. Most patients rapidly develop tolerance to the adverse effects of primidone, including ataxia, dizziness, drowsiness, headache, nausea and vomiting, nystagmus, skin rashes, and visual disturbances. Care is required when withdrawing primidone therapy—see also Uses and Administration, below.

Effects on the blood.

For a report of delayed agranulocytosis in a patient treated with phenytoin and primidone.

Effects on the endocrine system.

For mention of the effects of antiepileptics on sexual function in male epileptic patients, see under Phenytoin.

Overdosage.

Crystalluria has been reported1 after acute overdosage of primidone and 7 other reported cases were also reviewed. Based on these few reports, crystalluria appears to be associated with serum-primidone concentrations in excess of 80 micrograms/mL. There is evidence from 2 reports of renal damage associated with crystal formation in vivo. Vigorous hydration is recommended in patients at risk, in order to lessen the potential for renal toxicity and improve elimination.
1. Lehmann DF. Primidone crystalluria following overdose: a report of a case and an analysis of the literature. Med Toxicol 1987; 2: 383–7.

Porphyria.

Primidone has been associated with acute attacks of porphyria and is considered unsafe in porphyric patients.

Tre m o r.

It was noted that patients receiving primidone for essential tremor have a high incidence of acute adverse reactions after small initial doses.1 This could be due to the absence of induced hepatic enzymes in these patients previously not exposed to antiepileptics.
1. Findley LJ, et al. Primidone in essential tremor of the hands and head: a double blind controlled clinical study. J Neurol Neurosurg Psychiatry 1985; 48: 911–15.

💊 Interactions

Primidone is metabolised in the body in part to phenobarbital, and interactions recorded for phenobarbital might potentially occur in patients receiving primidone. In addition, enzyme-inducing drugs enhance this metabolism and have the potential to produce elevated phenobarbital concentrations.

Antiepileptics.

Both phenytoin1 and carbamazepine2 have been reported to enhance the metabolism of primidone to phenobarbital and when primidone was combined with phenytoin there have been instances of phenobarbital toxicity.3 Vigabatrin has been reported4 to lower plasma concentrations of primidone in some patients, although it is unlikely that dosage changes would be necessary. Va l p ro a t e may increase plasma concentrations of primidone and phenobarbital, but patient response seems to be inconsistent.5-7
1. Reynolds EH, et al. Interaction of phenytoin and primidone. BMJ 1975; 2: 594–5
2. Baciewicz AM. Carbamazepine drug interactions. Ther Drug Monit 1986; 8: 305–17
3. Galdames D, et al. Interacción fenitoína-primidona: intoxicación por fenobarbital, en un adulto tratado con ambas drogas. Rev Med Chil 1980; 108: 716–20
4. Browne TR, et al. A multicentre study of vigabatrin for drugresistant epilepsy. Br J Clin Pharmacol 1989; 27 (suppl 1): 95S–100S
5. Windorfer A, et al. Elevation of diphenylhydantoin and primidone serum concentration by addition of dipropylacetate, a new anticonvulsant drug. Acta Paediatr Scand 1975; 64: 771–2
6. Bruni J. Valproic acid and plasma levels of primidone and derived phenobarbital. Can J Neurol Sci 1981; 8: 91–2
7. Yukawa E, et al. The effect of concurrent administration of sodium valproate on serum levels of primidone and its metabolite phenobarbital. J Clin Pharm Ther 1989; 14: 387–92.

💊 Pharmacokinetics

Primidone is readily absorbed from the gastrointestinal tract and is reported to have a plasma half-life ranging from 10 to 15 hours, which is shorter than those of its principal metabolites phenylethylmalonamide and phenobarbital, both of which are active. Therapeutic plasma concentrations of primidone have been suggested to be between 5 and 12 micrograms/mL. It is excreted in urine as unchanged drug (40%) and metabolites. Primidone is widely distributed but is only partially bound to plasma proteins; it has been suggested that it exhibits variable binding of up to about 20%. It crosses the placenta and is distributed into breast milk. The pharmacokinetics of primidone may be affected by use with other antiepileptics (see under Interactions, above).

💊 Uses and Administration

Primidone is an antiepileptic that is partially metabolised to phenobarbital, but is also considered to have some antiepileptic activity in its own right. It may be given to control partial and generalised tonic-clonic seizures. Primidone is also used in the management of essential tremor. In the treatment of epilepsy the dose of primidone should be adjusted according to response; a limited correlation with plasma concentrations has suggested that concentrations of 5 to 12 micrograms/mL (23 to 55 micromoles/litre) are usually necessary, but the BNF recommends monitoring of phenobarbital concentrations instead. Recommended initial oral doses in the UK are 125 mg at bedtime increased, if necessary, by 125 mg every 3 days to a total of 500 mg daily given in 2 divided doses. If necessary, the daily dose may be increased further every 3 days by 250 mg up to a maximum of 1.5 g daily given in divided doses. Usual maintenance doses are 0.75 to 1.5 g daily; maintenance doses are usually given as 2 divided doses. Dosage recommendations in the USA are generally similar although a maximum daily dose of 2 g is permitted. For doses in children, see below. As with other antiepileptics, withdrawal of primidone or transition to or from another type of antiepileptic therapy should be made gradually to avoid precipitating an increase in the frequency of seizures. For a discussion on whether or not to withdraw antiepileptic therapy in seizure-free patients. For essential tremor primidone is usually started at daily oral doses of 50 mg as the syrup or 62.5 mg as the tablet, increased gradually over 2 to 3 weeks if necessary, to a maximum of 750 mg daily.

Administration in children.

Children may be given primidone to control partial and generalised tonic-clonic seizures. Recommended initial oral doses in the UK are 125 mg at bedtime, increased if necessary, by 125 mg every 3 days to the following usual maintenance daily doses (given in 2 divided doses) according to age:
up to 2 years: 250 to 500 mg
2 to 5 years: 500 to 750 mg
6 to 9 years: 750 to 1000 mg Children aged over 9 years may be given the usual adult dose (see above). In the USA, a lower initial oral dose of 50 mg daily is recommended. This is doubled every 3 days, to reach a usual maintenance dose of 125 to 250 mg 3 times daily (10 to 25 mg/kg daily in divided doses) after 10 or more days. Children over 8 years of age may be given the usual adult dose as above.

Epilepsy.

Primidone, like its metabolite phenobarbital, is used in the treatment of epilepsy for partial seizures with or without secondary generalisation and for primary generalised tonic-clonic seizures. However, because of problems of sedation, it is usually reserved for use in cases unresponsive to other antiepileptics. It has been suggested that it may be suitable for use in patients with QT-interval prolongation.1
1. Christidis D, et al. Is primidone the drug of choice for epileptic patients with QT-prolongation? A comprehensive analysis of literature. Seizure 2006; 15: 64–6.

Neonatal apnoea.

Results from a preliminary study suggested that adjunctive treatment with primidone1 might be of value in neonatal apnoea resistant to first-line therapy with xanthines alone, but subsequent confirmatory studies seem to be lacking.
1. Miller CA, et al. The use of primidone in neonates with theophylline-resistant apnea. Am J Dis Child 1993; 147: 183–6.

Neonatal seizures.

Primidone has been tried in the management of neonatal seizures.

Tre m o r.

A beta blocker is often the first drug used in patients with essential tremor who require regular treatment but primidone1 may also be tried. A high incidence of acute adverse reactions has been reported after initial doses (see Tremor, under Adverse Effects, above). There has been concern that long-term use may produce tolerance to primidone’s effects, although a small study has found a reduced response in only a few patients.2A later study3 found a dose of 250 mg daily to be as or more effective than 750 mg daily without there being evidence of loss of efficacy during a 12-month follow-up.
1. Koller WC, Royse VL. Efficacy of primidone in essential tremor. Neurology 1986; 36: 121–4
2. Sasso E, et al. Primidone in the long-term treatment of essential tremor: a prospective study with computerized quantitative analysis. Clin Neuropharmacol 1990; 13: 67–76
3. Serrano-Dueñas M. Use of primidone in low doses (250 mg/day) versus high doses (750 mg/day) in the management of essential tremor: double-blind comparative study with one-year followup. Parkinsonism Relat Disord 2003; 10: 29–33.

💊 Preparations

BP 2008: Primidone Oral Suspension; Primidone Tablets; USP 31: Primidone Oral Suspension; Primidone Tablets.

Proprietary Preparations

Arg.: Mysoline; Austral.: Mysoline; Austria: Cyral; Mysoline; Belg.: Mysoline†; Braz.: Epidona†; Mysoline; Canad.: Mysoline†; Chile: Mysoline†; Cz.: Liskantin; Denm.: Mysoline†; Fin.: Mysoline†; Fr.: Mysoline†; Ger.: Liskantin; Mylepsinum; Resimatil; Gr.: Mysoline; Hung.: Sertan; India: Mysoline†; Irl.: Mysoline; Israel: Prysoline; Ital.: Mysoline; Mex.: Mysoline; Neth.: Mysoline; Norw.: Mysoline†; Pol.: Mizodin; Port.: Mysoline; Rus.: Hexamidin (Гексамидин); S.Afr.: Mysoline; Spain: Mysoline; Swed.: Mysoline†; Switz.: Mysoline; Turk.: Mysoline; UK: Mysoline; USA: Mysoline; Venez.: Mutigan†. Multi-ingredient: Cz.: Mysoline†.
Published November 20, 2018.