Continuing Education Activity

Primidone, an aromatic anticonvulsant, holds a pivotal role in the comprehensive management of complex, partial, and generalized seizures prevalent in individuals who have epilepsy. This program delves into crucial facets essential for adept clinical application: indications, contraindications, pharmacological activity, and adverse events associated with primidone. The curriculum is designed to impart indispensable knowledge to members of an interprofessional healthcare team, fostering their ability to navigate the nuanced landscape of epilepsy management. Emphasis is placed on elucidating primidone's clinical attributes, shedding light on its indications, limitations, and potential adverse effects across diverse seizure types. By highlighting essential elements such as contraindications, adverse reactions, and therapeutic activity, this educational initiative seeks to empower healthcare professionals, augmenting their proficiency in harnessing primidone's therapeutic potential within the intricate realm of epilepsy management.

Objectives:

• Identify suitable seizure types and epilepsy conditions warranting primidone therapy based on clinical assessments and diagnostic criteria.

• Implement primidone in treatment plans based on evidence-based guidelines and patient-centric approaches for optimal seizure management.

• Assess patient response and monitor adverse effects regularly to evaluate primidone's efficacy, allowing adjustments for therapeutic optimization.

• Implement strategies with neurologists, pharmacists, and healthcare professionals to integrate primidone into comprehensive epilepsy management strategies.

Indications

Primidone is a first-generation barbiturate type antiepileptic medication developed to treat seizures, commonly for partial and generalized seizures. Primidone is not currently prescribed as a first choice to treat psychomotor, grand mal, and focal epileptic. This drug can also be utilized in the management of tremors. Since the 1980s, it has been considered a valid alternative to propranolol in treating essential tremors.[1][2] However, its use for this purpose is not recommended as first-line therapy.

The drug was developed by Carrington and Yule Bogue in 1949. On March 8th, 1954, the Food and Drugs Administration (FDA) endorsed primidone for treating epilepsy.[3] Nevertheless, with the subsequent marketing of carbamazepine in 1974 and the introduction of phenytoin, zonisamide, felbamate, gabapentin, lamotrigine, and vigabatrin, the role of primidone in the treatment of epilepsies has been further reduced. Its use is relegated to treating forms resistant to other therapies. In particular, its indications include the treatment of grand mal and psychomotor epilepsy (temporal lobe epilepsy). 

The high efficacy of primidone in these forms has also been clinically documented in patients resistant to other therapies who have idiopathic, post-traumatic forms associated with clear signs of brain injury or with specific modifications of the EEG trace. This antiepileptic drug can also be used in the therapy of focal or Jacksonian seizures, myoclonic, and akinetic seizures.

Although primidone is not a first-choice drug, its pharmacokinetic and pharmacodynamic properties must be well known to clinicians, as the drug can be particularly effective in specific clinical settings. For instance, QT-prolongation is a potentially fatal form of ventricular arrhythmia with an increased incidence among patients who have epilepsy. This complication may be precipitated by antiepileptic treatment. Because primidone has a favorable profile on QT-prolongation, it offers an alternative in managing epilepsy and essential tremors when accounting for special arrhythmogenic considerations. Nevertheless, it is still unclear if the drug may be beneficial in QT-interval shortening.[4]

Primidone has also been studied for other clinical purposes. In the 1990s, researchers investigated using it in cases of theophylline-resistant neonatal apnea. Some studies showed a possible role as an adjuvant in preventing apnea.[5] Historically, primidone was used as an antipsychotic, antidepressant, and anxiolytic drug, as well as against insomnia.[6] The limited data produced in the literature does not allow for the drawing of definitive conclusions about the use of the drug in these particular clinical conditions.[7] On the other hand, it seems that primidone is associated with interictal depression in patients with epilepsy.[8]

FDA-Approved Indications

Seizure disorder, including grand mal, psychomotor, and focal epileptic seizures.

Off-Label Uses

Essential tremor

Mechanism of Action

The mechanism of action of primidone is not well-known, but it appears to bind centrally with voltage-gated sodium channels and inhibits the monotonous firing of action potentials.[9] Primidone also activates gamma-aminobutyric acid (GABA)-A receptor complex with chloride ionophore, which extends the frequency of opening of the chloride channel, causing hyperpolarization by altering the electrical activity of the nerve cell membrane.[10] The effect of primidone in treating essential tremor is not mediated by the active metabolite PEMA.[11] Because in vivo investigations proved that primidone inhibits TRPM3 and attenuates thermal nociception, this drug could have a role in pain medicine.[12]

Pharmacokinetics

Absorption: Primidone is rapidly and completely absorbed from the gastrointestinal tract with a blood peak reached in about 3 hours; it shows a half-life of approximately 10 to 15 hours, shorter than the 2 metabolites while achieving a steady state within 1 to 2 days.[13] The half-life in patients older than 75 likely increases due to metabolic deficits. The half-life in neonates is longer than in children/adults, probably due to a larger apparent volume of distribution and a lower metabolic capacity of these subjects.

Distribution: The volume of distribution (Vd) is 0.8 L/kg, while the plasma concentrations of primidone are between 5 and 12 μg/mL; it is rapidly distributed in the tissues and shows a partial serum protein binding (about 35%); the therapeutic range is between 23 to 55 mg/mL. Primidone crosses the blood-brain and placental barriers and is also distributed in breast milk.

Metabolism: In addition to the primary active metabolites (PEMA and phenobarbital), the drug has a minor metabolite, p-hydroxyprimidone. However, primidone cannot be considered a prodrug because it has intrinsic pharmacological activity. Primidone is subject to 2 main metabolic processes:

• Oxidation in C2 with the formation of phenobarbital
• Cleavage of the ring in C2 with the formation of PEMA. Which isoform of CYP450 is involved in primidone's metabolism is not yet known.

The percentage of primidone metabolized to phenobarbital fluctuates between 15% and 25%.

Elimination: Primidone is excreted unchanged in the urine (64%). The drug's half-life is 10 to 15 hours.

Administration

Dosage Forms

Primidone is a white crystalline powder; it is practically insoluble in water (1/2000), slightly soluble in alcohol (1/200), and soluble in alkaline solutions. The basic skeleton of primidone comprises pyrimidinedione, which converts into phenobarbital and phenylethylmalonamide (PEMA) after metabolism. The chemical structure of primidone differs from phenobarbital due to the substitution in the C2 position of the carbonyl group with the methylene bridge. This chemical modification of the molecule led to a product with a robust anti-convulsive effect and less sedation.

Primidone is available in 50 and 250 mg tablets in different generic and branded formulations. This drug should start at the lowest possible dose, with dosing increasing stepwise to minimize adverse effects.

Adult Dosing

Seizure disorder: 250 mg orally 3 or 4 times daily

• Start 100 to 125 mg orally at bedtime for 3 days, then 100 to 125 mg orally twice daily for 3 days, then 100 to 125 mg orally 3 times daily for 3 days, then 250 mg orally 3 or 4 times daily.
• The maximum daily dose should not exceed 2 g daily. 
• Adjust dose based on response and serum levels; gradual dose tapering is necessary to discontinue therapy.

Essential tremor: 50 to 250 mg orally at bedtime

• Start 12.5 to 25 mg orally at bedtime for 3 days, then increase by 12.5 to 25 mg daily or weekly.
• The maximum daily dose should not exceed 750 mg; divide doses >250 mg daily. 
• Gradual dose tapering is necessary to discontinue therapy.[10]

Special Patient Populations

Hepatic impairment: Hepatic impairment dosing is undefined; caution is advised.

Renal impairment

• CrCl >50: give the usual dose every 12 hours
• CrCl from 10 to 50: give the usual dose every 12 to 24 hours
• CrCl <10: give the dose every 24 hours; adjust dosing based on treatment response and serum levels.

Pregnancy considerations: Primidone is an FDA pregnancy category D drug. Clinicians should weigh the risk vs benefit during pregnancy; there is a risk of teratogenicity and vitamin K deficiency-associated bleeding based on limited human data. There is also a risk of neonatal respiratory depression, lethargy, hypotonia, and withdrawal symptoms derived from human data with phenobarbital. Patients are encouraged to enroll in the North American Antiepileptic Drug Pregnancy Registry.[14]

Breastfeeding considerations: There is a risk of infant CNS depression based on limited human data; clinicians must weigh the risks vs benefits in breastfeeding females. There are no known adverse effects on milk production.

Pediatric patients:

Younger than 8: 250 mg orally 3 or 4 times daily

• Start 10 to 25 mg/kg/d orally at bedtime, then 50 mg orally twice daily for 3 days, then 100 mg orally twice daily for 3 days.
• The maximum daily dose should not exceed 2 g daily. 
• Adjust dose based on response and serum levels; gradual dose tapering is necessary to discontinue therapy.

Eight and older: 250 mg orally at bedtime

• Start 100 to 125 mg orally at bedtime for 3 days, then 100 to 125 mg orally twice daily for 3 days, then 100 to 125 mg orally 3 times daily for 3 days, then 250 mg orally 3 or 4 times daily.
• The maximum daily dose should not exceed 2 g. 
• Adjust dose based on response and serum levels; gradual dose tapering is necessary to discontinue therapy.

Older patients: No data exist on the relationship between age and the effects of primidone in older patients. However, atypical excitement or restlessness may manifest in older patients, who are typically more sensitive to the effects of primidone than younger patients.[15]

Adverse Effects

The most common adverse effects of primidone therapy are sedation and drowsiness. Ataxia, diplopia, and nystagmus occur at the initiation of treatment. Other adverse reactions include dizziness, vertigo, epigastric pain, megaloblastic anemia, respiratory depression, polyuria, skin rash, and facial edema. Hypersensitivity reactions tend to occur more frequently in patients with a history of asthma, urticaria, or angioedema. Agranulocytosis and thrombocytopenia are rare.

Long-term use of barbiturates is associated with the following:

• Connective tissue disorder
• A higher risk of decreased bone mineral density may lead to weakened or brittle bones; in such cases, the prescriber should consider discontinuing primidone.
• An increased risk of rickets and osteomalacia (phenobarbital) due to increased vitamin D metabolism.[16]
• Folate deficiency can also lead to megaloblastic anemia.
• There have been instances of hyperhomocysteinemia secondary to reduced folate levels, with elevated cholesterol and apoprotein A and B levels.[17]
• Newborns of mothers on primidone therapy have demonstrated a coagulation defect that is similar to vitamin K deficiency.[18] Primidone is an FDA pregnancy category D drug.

Drug-Drug Interactions

Using primidone with any of the following drugs is not recommended:

• Atazanavir
• Boceprevir
• Cobicistat
• Darunavir
• Delamanid
• Elvitegravir
• Maraviroc
• Mavacamten
• Nirmatrelvir
• Paritaprevir
• Ranolazine
• Rilpivirine
• Ritonavir
• Rivaroxaban
• Telaprevir
• Tenofovir
• Voriconazole

Numerous other medications can interact with primidone and may require dose adjustments. Thorough medication reconciliation is necessary.

Contraindications

Several clinical conditions contraindicate the use of primidone.

• Primidone is contraindicated in patients who are known to be hypersensitive to barbituric acid derivatives.
• Contraindications to primidone include patients with a history of porphyria. By inducing the enzymes responsible for porphyrin synthesis, barbiturates may worsen acute porphyria.
• This drug is also contraindicated in patients with severe respiratory depression or pulmonary insufficiency, hepatic impairment, alcoholism, renal impairment, sleep apnea, suicidal potential, drug dependence, or in the presence of uncontrolled pain.[19]

Monitoring

Baseline labs for primidone therapy include Cr, CBC, comprehensive metabolic panel every 6 months, serum drug level, and folate levels. The therapeutic range for primidone is between 5 and 12 mg/L. Suicidal ideation and activity have occurred in many cases of patients treated with antiepileptic agents. All patients treated with antiepileptic medications, regardless of indication, should be monitored for signs of suicidal ideation and behavior, and consideration should be given to appropriate treatment. Patients (and patient caregivers) should be encouraged to seek medical advice should there be signs of suicidal ideation or behavior.

The deficiency of folic acid is known to occur during pregnancy and can lead to an increased occurrence of congenital disabilities in the offspring of women with treated epilepsy. As with many other antiepileptic medications, primidone may lead to or aggravate the deficiency of folic acid. Supplementation with folic acid is advisable before and during pregnancy.[20]

Metabolism of primidone occurs slowly within the liver to produce phenobarbital and PEMA. Phenobarbital induces UGT enzymes CYP2C and CYP3A; the efficacy of some drugs, such as anticoagulants, adrenal steroids, antibiotics, oral contraceptives, and anticonvulsants such as phenytoin can be reduced by the metabolic acceleration. Immediate withdrawal of the drug may cause status epilepticus; reduce dosage slowly. Again, barbiturates hinder the ability to perform mental-conscious activities such as driving.

Finally, a complete blood count and liver function test are necessary every 6 months, and primidone therapy can be monitored by phenobarbital concentration if required.[1]

Toxicity

Primidone toxicity has been studied in numerous animal species and was found to be exceptionally low. Toxic levels are >15 μg/mL. Nevertheless, hepatotoxicity and behavioral problems with primidone are more common than phenobarbital. The ALT and ALP serum levels are more elevated for patients undergoing chronic primidone therapy than for any other widely used anticonvulsant. Additionally, there is documentation that hepatic cirrhosis secondary to chronic primidone use may also occur. Idiosyncratic reactions to primidone may also occur, which include hepatotoxicity and megaloblastic anemia. Dosing adjustments should be according to clinical response and biological monitoring in patients with renal impairment.

Moreover, several studies demonstrated that primidone could have significant toxicity, including:

• Genotoxicity: While the antiepileptic agent showed mutagenic proprieties in one strain of Salmonella typhimurium strain and genotoxicity during in vivo experiments, the real risk of genotoxicity to humans is unclear.[21][22] 
• Carcinogenicity: Studies demonstrated an increased incidence of hepatocellular neoplasms in mice, thyroid neoplasms in both mice and rats, and an increased incidence of renal carcinomas in male rats at clinical doses. Nevertheless, the risk of carcinogenicity to humans is unknown.[23]
• Teratogenicity: Teratogenic effects in rodents included palatal defects, enlargement of cerebral ventricles, club foot, open eyes, and subarachnoid hemorrhage. The drug also showed memory impairment and effects on fertility in animals.[24] 

Primidone Overdose

Patients who have had a primidone overdose may present with hypotension, coma, CNS depression, suppressed response to pain, suppressed reflexes, respiratory depression, and decreased urine output. Overdose requires management with symptomatic and supportive treatment, including the removal of any unabsorbed drug. Urine alkalinization and forced diuresis may enhance excretion. Hemodialysis may be necessary.[10]

Enhancing Healthcare Team Outcomes

Management of primidone therapy, and especially possible overdose, requires an interprofessional team of healthcare professionals, including nurses, pharmacists, laboratory technologists, and several physicians and advanced practice practitioners in various specialties. Without proper treatment, the morbidity and mortality from primidone overdose are high. Patients who have consumed primidone in excess often require hemodynamic and respiratory support; this could include ventilation, intubation, boluses of isotonic IV fluids, and inotropic infusions. Once the airway of a patient is protected, activated charcoal should be administered to minimize the absorption of orally administered primidone; multiple doses of activated charcoal improve phenobarbital clearance, although no evidence exists that it improves clinical outcomes. Urinary alkalinization also enhances phenobarbital clearance in patients with normal cardiac and renal function. Urinary alkalinization has not been shown to improve clinical outcomes, either.

A consultation with a mental health professional to evaluate the patient to determine if it was an intentional act and if the patient may be at continued risk for self-harm may be appropriate. The pharmacist should make sure that there are no drug interactions and that the risk of possible drug overdose requires monitoring, open communication, and coordinated action from the clinical team.[25]