PRIMIDONE

Chemistry - An analog of phenobarbital, primidone occurs as a white, odorless, slightly bittertasting, crystalline powder with a melting point of 279°-284°C. One gram is soluble in approximately 2000 ml of water or 200 ml of alcohol.

Storage, Stability, Compatibility

Tablets should be stored in well-closed containers preferablyat room temperature. The oral suspension should be stored in tight, light-resistant containerspreferably at room temperature; avoid freezing. Commercially available suspension and tabletsgenerally have expiration dates of 5 years after manufacture.

Pharmacology - PRIMIDONE

Primidone and its active metabolites, phenylethamalonamide (PEMA) and phenobarbital have similar anticonvulsant actions. While the exact mechanisms for this activity areunknown, these agents raise seizure thresholds or alter seizure patterns.

Uses, Indications

Primidone is indicated for seizure control (idiopathic epilepsy, epileptiformconvulsions) in the dog. Because it is rapidly converted into phenobarbital in this species (seepharmacokinetics below), there is some question as to whether it has any advantages over usingphenobarbital alone. However, many clinicians feel that some animals not responding to phenobarbital do benefit from primidone therapy, perhaps as a result that PEMA has been demonstratedto potentiate the anticonvulsant activity of phenobarbital in animals. When compared withphenobarbital, increased incidence of hepatotoxicity associated with primidone is considered to bethe major limitation to long-term therapy with this agent. Primidone is considered to be more toxicin rabbits and cats than in humans or dogs.

Pharmacokinetics - PRIMIDONE

Primidone is slowly absorbed after oral administration in the dog, with peaklevels occurring 2-4 hours after dosing. The bioavailability of primidone in humans has been reported as 60-80%.
Primidone is rapidly converted to PEMA and phenobarbital in the dog. Serum half-lives ofprimidone, PEMA, and phenobarbital have been reported to be 1.85 hrs, 7.1 hrs, and 41 hours, respectively (Yeary 1980)
Primidone, like phenobarbital (possibly due to the phenobarbital?), can induce hepatic microsomalenzymes which can increase the rate of metabolism of itself and other drugs.
For more information on the pharmacokinetics of phenobarbital, refer to its monograph earlier inthis section.
Contraindications/Precautions - Many clinicians and the veterinary manufacturers of primidonefeel that primidone is contraindicated in cats, other clinicians dispute this, but it is recommended thatprimidone be used in cats only with extreme caution. Use cautiously in patients who arehypovolemic, anemic, have borderline hypoadrenal function, or cardiac or respiratory disease. Largedoses are contraindicated in patients with nephritis or severe respiratory dysfunction. Primidone iscontraindicated in patients with severe liver disease or who have demonstrated previoushypersensitivity reactions to them.

Adverse Effects, Warnings

Adverse effects in dogs are similar for both primidone and phenobarbital. Dogs may exhibit increased symptoms of anxiety and agitation when initiating therapy.
These effects may be transitory in nature and often will resolve with small dosage increases.
Occasionally, dogs will exhibit profound depression at lower dosage ranges (and plasma levels).
Polydipsia, polyuria, and polyphagia are also quite commonly displayed at moderate to high serumlevels. They are best controlled by limiting intake of both food and water. Sedation and/or ataxiaoften become significant concerns as serum levels reach the higher ends of the therapeutic range.
Increases in liver enzymes (ALT, ALP, glutamate dehydrogenase) and decreased serum albuminwith chronic therapy are common (up to 70% of dogs treated), and is more prevalent than withphenobarbital. Hepatic lipidosis, hepatocellular hypertrophy and necrosis, and extramedullaryhematopoiesis can be seen after 6 months of therapy. Serious hepatic injury probably occurs inapproximately 6-14% of dogs treated.
In dogs, anorexia, tachycardia, dermatitis, episodic hyperventilation, and rarely megaloblasticanemia have also been reported with primidone therapy.
Overdosage - Because primidone is rapidly metabolized to phenobarbital in dogs, similarsymptoms (sedation to coma, anorexia, vomiting, nystagmus) are seen and corresponding procedures should be used for the treatment of acute primidone overdose. This includes the removal ofingested product from the gut if appropriate and offering respiratory and cardiovascular support.
Activated charcoal has been demonstrated to be of considerable benefit in enhancing the clearanceof phenobarbital, even when the drug was administered parenterally. Charcoal acts as a "sink" forthe drug to diffuse from the vasculature back into the gut. Forced alkaline diuresis can be ofconsiderable benefit in augmenting the elimination of phenobarbital in patients with normal renalfunction. Peritoneal or hemodialysis mayalso be helpful in severe intoxications or in anuric patients.

Drug Interactions

Oral acetozolamide may decrease the GI absorption of primidone.
Because the primary active metabolite for primidone is phenobarbital, these drug interactions maybe of significance: The following drugs may increase the effect of phenobarbital: Other CNSdepressants (narcotics, phenothiazines, antihistamines, etc), valproic acid, and chloramphenicol. The interaction with chloramphenicol may be of especial significance in the dog.
Phenobarbital may decrease the effect of the following drugs: oral anticoagulants, corticosteroids, beta blockers (propranolol), quinidine, theophylline, metronidazole.
Phenobarbital with furosemide may cause or increase postural hypotension. Barbiturates mayeffect the metabolism of phenytoin, monitoring of blood levels may be indicated.
Phenobarbital may decrease the absorption of griseofulvin; avoid giving simultaneously.
Drug/Lab Interactions - Barbiturates may cause increased retention of bromosulfopthalein (BSP;sulfobromopthalein) and give falsely elevated results. It is recommended that barbiturates (includingprimidone) not be administered within the 24 hours before BSP retention tests, or if they must, (e.g., for seizure control) the results be interpreted accordingly.