Pharmacology

The chemical name of primidone is 5-ethyldihydro-5-phenyl-4,6(1H,5H pyrimidinedione) with a chemical formula as follows: Cl2H14N2O2.

Pharmacodynamics. The mechanism of action of primidone is not well understood because of its rapid conversion to phenobarbital. This can be delayed in animal models, where primidone has been shown to prevent maximal electroshock seizures but does not elevate threshold to Metrazol-induced seizures. In this action it resembles phenytoin and carbamazepine. Other studies have shown that primidone produces antiepileptic effect independent of the action of its phenobarbital metabolite.

Pharmacokinetics. Absorption of primidone from the gastrointestinal tract appears to be complete with peak levels (tmax) averaging 3 hours, with a range of 2 to 6 hours. Primidone has 2 metabolites: (1) phenobarbital and (2) phenylethylmalonamide; its distribution in the body is like that of phenobarbital. Concentrations in the brain tissues are 40% to 100% of the blood levels, but concentrations in cerebrospinal fluid lag behind those in the blood. Primidone is bound only minimally to serum albumin. Although there is significant biotransformation of primidone to its metabolites, most of it is excreted unchanged in the urine. After ingestion of high doses, gross crystalluria occurs due to poor solubility of primidone.

Therapeutic drug monitoring. Therapeutic range for primidone is between 5 and 10 mg/L (23 to 46 mmol/L). Therapeutic drug monitoring of primidone should be accompanied by the determination of phenobarbital concentrations (04).

Clinical trials

In 1985, a 5-year multicenter Veterans Administration Cooperative Study was completed that compared the efficacy and toxicity of phenobarbital, carbamazepine, phenytoin, and primidone in a double-blind prospective study design (17). There were few statistically significant differences, but carbamazepine produced the least number of adverse effects. There have been no recent trials of primidone for seizure disorder, but several clinical trials have tested the effect on essential tremor and bipolar disorder.

In a prospective randomized trial of the efficacy of add-on therapy in patients with partial epilepsy unresponsive to carbamazepine, a valproic acid-carbamazepine combination was more effective than a primidone-carbamazepine combination (18).

Indications

Primidone, either alone or used 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 anticonvulsants.

Off-label uses

Management of tremor. Primidone is still being used for the management of mild to moderate tremor. Primidone has even been recommended as one of the first-line therapies for essential tremor (16). Although tremor is not listed as an approved indication, the following are important points about its use:

Role of primidone in pain. In experimental animal studies, administration of primidone in doses lower than those required for anticonvulsive effect inhibited melastatin-related transient receptor potential (TRP) channel TRPM3, which is a nonselective cation channel expressed in nociceptive neurons and activated by heat (10). This indicated thermal exertion of antinociceptive properties of primidone.

Contraindications

Primidone is contraindicated in patients with porphyria and those who are hypersensitive to phenobarbital.

Goals and duration of treatment

Primidone is usually not the first choice in antiepileptic therapy. If patients with partial epilepsy who are treated with phenytoin or carbamazepine show adverse effects, it may be worthwhile switching to primidone. Primidone is the only antiepileptic drug that has not been associated with prolongation of Q-T interval – a cause of fatal cardiac arrhythmias. If well tolerated, it can be used for long-term therapy. The clinically effective serum level for primidone is between 5 to 12 mcg/mL. If primidone is to be discontinued, it may be replaced by its main metabolite, phenobarbital. In combination therapy with antiepileptic drugs to increase efficacy and reduce toxicity, phenobarbital plus primidone has a very low ranking.

Dosing

Patients 8 years of age and older who have received no previous treatment may be started on 100 to 125 mg of primidone at bedtime, and the dose is gradually titrated to twice daily and then 3 times daily over a period of 10 days to the maintenance dose of 250 mg tablets 3 times daily. If required, an increase to 250 mg 5 or 6 times daily may be made, but daily doses should not exceed 500 mg 4 times daily.

Special considerations

In prolonged therapy, a complete blood count and a sequential multiple analysis-12 test should be made every 6 months.

Pediatric. There are no special precautions for children.

Geriatric. Aging is associated with a greater accumulation of phenylethylmalonamide metabolite of primidone. Elderly patients excrete a reduced proportion of unchanged primidone and an increased proportion of phenylethylmalonamide in urine but it is unlikely to have a major clinical significance. Because of its sedating effect, primidone may impair cognitive function in elderly patients and has little place in the treatment of new-onset seizures in this population.

Pregnancy. The effects of primidone in human pregnancy and nursing infants are unknown. 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. Primidone is probably excreted into breast milk in clinically significant amounts. If the infant is drowsy, breastfeeding should be discontinued.

Anesthesia. There are no specific precautions for patients undergoing anesthesia who are on primidone therapy.

Interactions

Primidone is a strong inducer of cytochrome P450 and glucuronizing enzymes as well as P-glycoprotein; therefore, it can reduce the efficacy of co-administered medications such as oral anticoagulants, calcium antagonists, steroids, and antimicrobial and antineoplastic drugs through this mechanism (22). A limited number of interactions are reported between primidone and other antiepileptic drugs. Serum level of primidone is increased when it is administered concomitantly with clonazepam or carbamazepine. The ratio of derived phenobarbital to unmetabolized primidone in the serum is significantly higher in patients on a combination of primidone and phenytoin than in patients on primidone alone. Lamotrigine is eliminated mostly by glucuronidation and is susceptible to inhibition by primidone in concomitant use of these drugs.

Inhibition of 1 or both CYP2C19 and CYP3A isoforms is the likely mechanism by which isoniazid slows the elimination of coadministered primidone. Slow acetylators of isoniazid may be at greater risk for adverse drug interactions.

Nicotinamide inhibits metabolism of primidone in humans. This probably occurs by inhibition of cytochrome P-450 by nicotinamide.

Adverse effects

Initial treatment may cause somnolence during the first few days of treatment. The most frequently reported adverse effects are ataxia and vertigo, which subside with prolonged use. Life-threatening systemic side effects are rare. Depression is significantly associated with inadequate seizure control and use of primidone. There is a case report of acute suicidality following initiation of primidone for erroneously diagnosed essential tremor in a patient with Parkinson disease without risk factors for suicide, and suicidal ideation resolved after primidone was discontinued (07).

Impaired consciousness in children on phenobarbital has been reported, and over 130 μmol/L of the drug was detected in serum along with presence of primidone, although primidone had not been used (19). The explanation for this finding is that high-dose phenobarbital can convert to its prodrug primidone.

Megaloblastic anemia may occur as a rare idiosyncratic reaction to primidone. Primidone along with other hepatic enzyme-inducing antiepileptic drugs has been clearly associated with decreased bone mineral density (Pack and Morrel 2004).

Connective tissue disorders such as Dupuytren contracture have been reported after prolonged use of primidone, and drug withdrawal may result in improvement (20). In experimental studies on rats, primidone impairs male sexual behavior due to changes in erectile function (21). No such events have been reported in patients treated with primidone.

Management. Pretreatment with phenobarbital can minimize the occurrence of intolerable adverse events associated with the introduction of primidone because of a cross tolerance between the 2 drugs. If adverse effects do not subside, dosage may be reduced or the drug continued. Megaloblastic anemia can be treated with folic acid therapy after primidone is discontinued.