Primidone

Primidone, sold under various brand names (including Mysoline), is a barbiturate medication that is used to treat partial and generalized seizures

Its common side effects include sleepiness, poor coordination, nausea, and loss of appetite. The drug’s other active metabolite is Phenylethylmalonamide (PEMA).

Primidone was approved for medical use in the United States in 1954. In 2023, it was the 239th most commonly prescribed medication in the United States, with more than 1million prescriptions.

Medical uses

Epilepsy

It is licensed for generalized tonic-clonic and complex partial seizures in the United Kingdom. In the United States, primidone is approved for adjunctive (in combination with other drugs) and monotherapy (by itself) use in generalized tonic-clonic seizures, simple partial seizures, complex partial seizures, and myoclonic seizures. The usual dose for seizure disorder is titrated from 100–125 mg/day up to a maintenance dose of 750-1,500 mg/day (maximum daily dosage is 2 g).

Open-label case series have suggested that primidone is effective in the treatment of epilepsy. Primidone has been compared to phenytoin, phenobarbital, What is known is that 10 years later, Monroe went on to publish the results of a meta-analysis of two controlled clinical trials on people displaying out-of-character and situationally inappropriate aggression, who had abnormal EEG readings, and who responded poorly to antipsychotics; one of the studies was specifically mentioned as involving psychosis patients. When they were given various anticonvulsants, not only did their EEGs improve, but so did the aggression.

In March 1993, S.G. Hayes of the University of Southern California School of Medicine reported that 9 out of 27 people (33%) with either treatment-resistant depression or treatment-resistant bipolar disorder had a permanent positive response to primidone. A plurality of subjects was also given methylphenobarbital in addition to or instead of primidone.

Adverse effects

Primidone can cause drowsiness, listlessness, ataxia, visual disturbances, nystagmus, headache, and dizziness. Transient nausea and vomiting are also common side effects.

thumb|right|Dupuytren's contracture of the fourth digit (ring finger)

Dupuytren's contracture, a disease of the fasciae in the palm and fingers that permanently bends the fingers (usually the little and ring fingers) toward the palm, was first noted to be highly prevalent in epileptic people in 1941 by a Dr. Lund, 14 years before primidone was on the market. Lund also noted that it was equally prevalent in individuals with idiopathic and symptomatic epilepsy and that the severity of the epilepsy did not matter. Only one-quarter of the women were affected, though, vs. half of the men. Critcheley et al., 35 years later, reported a correlation between how long a patient had had epilepsy and his or her chance of getting Dupuytren's contracture. They suspected that this was due to phenobarbital therapy, and that the phenobarbital was stimulating peripheral tissue growth factors. Dupuytren's contracture is almost exclusively found in Caucasians, especially those of Viking descent, and highest rates are reported in northern Scotland, Norway, Iceland, and Australia. It has also been associated with alcoholism, heavy smoking, diabetes mellitus, physical trauma (either penetrating in nature or due to manual labor), tuberculosis, and HIV. People with rheumatoid arthritis are less likely to get this, and Drs. Hart and Hooper speculate that this is also true of gout due to the use of allopurinol. This is the only susceptibility factor that is generally agreed upon. Anticonvulsants do not seem to increase the incidence of Dupuytren's contracture in people of color.

It was first reported to exacerbate hepatic porphyria in 1975. In 1981, phenobarbital, one of primidone's metabolites, was shown to only induced a significant porphyrin level at high concentrations in vitro. It can also cause elevations in hepatic enzymes such as gamma-glutamyl transferase and alkaline phosphatase. Primidone also causes exfoliative dermatitis, Stevens–Johnson syndrome, and toxic epidermal necrolysis. The populations usually said to be most at risk are institutionalized people, postmenopausal women, older men, people taking more than one anticonvulsant, and children, who are also at risk of rickets. Megaloblastic anemia is actually a group of related disorders with different causes that share morphological characteristics—enlarged red blood cells with abnormally high nuclear-cytoplasmic ratios resulting from delayed maturation of nuclei combined with normal maturation of cytoplasm, into abnormal megakaryocytes and sometimes hypersegmented neutrophils; regardless of etiology, all of the megaloblastic anemias involve impaired DNA replication. The anticonvulsant users who get this also tend to eat monotonous diets devoid of fruits and vegetables.

This antagonistic effect is not due to the inhibition of dihydrofolate reductase, the enzyme responsible for the reduction of dihydrofolic acid to tetrahydrofolic acid, but rather to defective folate metabolism.

In addition to increasing the risk of megaloblastic anemia, primidone, like other older anticonvulsants, also increases the risk of neural tube defects, and like other enzyme-inducing anticonvulsants, it increases the likelihood of cardiovascular defects, and cleft lip without cleft palate. Epileptic women are generally advised to take folic acid,

Additionally, a coagulation defect resembling vitamin K deficiency has been observed in newborns of mothers taking primidone.

Primidone, like phenobarbital and the benzodiazepines, can also cause sedation in the newborn and also withdrawal within the first few days of life; phenobarbital is the most likely out of all of them to do that. Schaffer et al. 1999 reported that one of their treatment failures, a 45-year-old woman taking 50 mg a day along with lithium 600 mg/day, clozapine 12.5 mg/day, trazodone 50 mg/day, and alprazolam 4 mg/day for three and a half months experienced auditory hallucinations that led to discontinuation of primidone. It can also cause hyperactivity in children; this most commonly occurs at low serum levels. There is one case of an individual developing catatonic schizophrenia when her serum concentration of primidone went above normal.

Primidone is one of the anticonvulsants associated with anticonvulsant hypersensitivity syndrome, with the others being carbamazepine, phenytoin, and phenobarbital. This syndrome consists of fever, rash, peripheral leukocytosis, lymphadenopathy, and occasionally hepatic necrosis.

Hyperammonemic encephalopathy was reported by Katano Hiroyuki of the Nagoya City Higashi General Hospital in early 2002 in a patient who had been stable on primidone monotherapy for five years before undergoing surgery for astrocytoma, a type of brain tumor. Additionally, her phenobarbital levels were inexplicably elevated after surgery. This is much more common with the valproates than with any of the barbiturates. A randomized, controlled trial w found that primidone was more likely to cause impotence than phenytoin, carbamazepine, or phenobarbital. Primidone can also cause vomiting; this happens in 1.0–0.1% of users. lethargy, somnolence, vomiting, nausea, and occasionally, focal neurological deficits which lessen over time. Complete recovery comes within five to seven days of ingestion. The crystals are white,

Interactions

Taking primidone with monoamine oxidase inhibitors (MAOIs) such as isocarboxazid (Marplan), phenelzine (Nardil), procarbazine (Matulane), selegiline (Eldepryl), tranylcypromine (Parnate) or within two weeks of stopping any one of them may potentiate the effects of primidone or change one's seizure patterns. Isoniazid, an antitubercular agent with MAOI properties, has been known to strongly inhibit the metabolism of primidone.

Like many anticonvulsants, primidone interacts with other anticonvulsants. Clobazam decreases clearance of primidone,

Mesuximide increases plasma levels of phenobarbital in primidone users, both primidone and phenobarbital accelerate the metabolism of carbamazepine via CYP3A4, and lamotrigine's apparent clearance is increased by primidone. In addition to being an inducer of CYP3A4, it is also an inducer of CYP1A2, which causes it to interact with substrates such as fluvoxamine, clozapine, olanzapine, and tricyclic antidepressants. It also interacts with CYP2B6 substrates such as bupropion, efavirenz, promethazine, selegiline, and sertraline; CYP2C8 substrates such as amiodarone, paclitaxel, pioglitazone, repaglinide, and rosiglitazone; and CYP2C9 substrates such as bosentan, celecoxib, dapsone, fluoxetine, glimepiride, glipizide, losartan, montelukast, nateglinide, paclitaxel, phenytoin, sulfonamides, trimethoprim, warfarin, and zafirlukast. It also interacts with estrogens. It also interferes with the metabolism of dexamethasone, a synthetic steroid hormone, to the point where its withdrawal from the regimen of a 14-year-old living in the United Kingdom made her hypercortisolemic. Tempelhoff and colleagues at the Washington University School of Medicine's Department of Anesthesiology reported in 1990 that primidone and other anticonvulsant drugs increase the amount of fentanyl needed during craniotomy based on the patient's heart rate.

Mechanism of action

The exact mechanism of primidone's anticonvulsant action is still unknown after over 50 years. It is believed to work via interactions with voltage-gated sodium channels that inhibit high-frequency repetitive firing of action potentials.

The effect of primidone in essential tremor is not mediated by Phenylethylmalonamide (PEMA).

The major metabolite, phenobarbital, is also a potent anticonvulsant in its own right and likely contributes to primidone's effects in many forms of epilepsy. According to Brenner's Pharmacology, it also increases GABA-mediated chloride flux, thereby hyperpolarizing the membrane potential. Primidone was recently shown to directly inhibit the TRPM3 ion channel; whether this effect contributes to its anticonvulsant effect is not known, but gain-of-function mutations in TRPM3 were shown to be associated with epilepsy and intellectual disability in 2021.

Pharmacokinetics

Primidone converts to phenobarbital and PEMA; it is still unknown which exact cytochrome P450 enzymes are responsible. The rate of primidone metabolism was greatly accelerated by phenobarbital pretreatment, moderately accelerated by primidone pretreatment, and reduced by PEMA pretreatment. In 1983, a new minor metabolite, p-hydroxyprimidone, was discovered.

Primidone, carbamazepine, phenobarbital, and phenytoin are among the most potent hepatic enzyme-inducing drugs in existence, which occurs at therapeutic doses. In fact, people taking these drugs have displayed the highest degree of hepatic-enzyme induction on record. CYP2C8, CYP2C19, CYP2A6, CYP3A5, CYP1E1, and the CYP2E subfamily. The gene expression of these isoenzymes is regulated by human pregnane receptor X (PXR) and constitutive androstane receptor (CAR). Phenobarbital induction of CYP2B6 is mediated by both. Primidone does not activate PXR.

The rate of metabolism of primidone into phenobarbital was inversely related to age; the highest rates were in the oldest patients (the maximum age being 55). People aged 70–81, relative to people aged 18–26, have decreased renal clearance of primidone, phenobarbital, and PEMA, in ascending order of significance, and that there was a greater proportion of PEMA in the urine. The clinical significance is unknown.

The percentage of primidone converted to phenobarbital has been estimated to be 5% in dogs and 15% in humans. Work done 12 years later found that the serum phenobarbital 0.111 mg/100 mL for every mg/kg of primidone ingested. Authors publishing a year earlier estimated that 24.5% of primidone was metabolized to phenobarbital, but the patient reported by Kappy and Buckley would have had a serum level of 44.4 mg/100 mL instead of 8.5 mg/100 mL if this were true for individuals who have ingested a large dose. The patient reported by Morley and Wynne would have had serum barbiturate levels of 50 mg/100 mL, which would have been fatal. The effectiveness of Primidone for epilepsy was first demonstrated in 1949 by Yule Bogue. He found it to have a similar anticonvulsant effect, but more specific, i.e. with fewer associated sedative effects.

It was brought to market a year later by the Imperial Chemical Industry, now known as AstraZeneca in the United Kingdom and Germany.

In 1952, it was approved in the Netherlands.

Also in 1952, Drs. Handley and Stewart demonstrated its effectiveness in the treatment of patients who failed to respond to other therapies; it was noted to be more effective in people with idiopathic generalized epilepsy than in people whose epilepsy had a known cause. That same year, it was approved in France. Primidone was introduced in 1954 under the brandname Mysoline by Wyeth in the United States.

Association with megaloblastic anemia

In 1954, Chalmers and Boheimer reported that the drug was associated with megaloblastic anemia. Between 1954 and 1957, 21 cases of megaloblastic anemia associated with primidone and/or phenytoin were reported. In most of these cases, the anemia was due to vitamin deficiencies - usually folic acid deficiency, in one case vitamin B<sub>12</sub> deficiency, This might be related to the structural similarity between folic acid, phenytoin, phenobarbital, and primidone. Folic acid had been found to alleviate the symptoms of megaloblastic anemia in the 1940s, not long after it was discovered, but the typical patient only made a full recovery—cessation of CNS and PNS symptoms as well as anemia—on B<sub>12</sub> therapy. Five years earlier, folic acid deficiency was linked to birth defects in rats. Primidone was seen by some as too valuable to withhold based on the slight possibility of this rare side effect

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Successive anticonvulsants

In Europe, until 1963, prescribing primidone and phenobarbital in combination, often with a stimulant, was not uncommon. They were believed to be the most useful for seizures occurring upon awakening, while phenytoin was the most useful for nocturnal seizures. Primidone and phenobarbital were prescribed in combination with phenytoin in diffuse epilepsies. They were third- and fourth-line agents, respectively, in the treatment of partial seizures. By 1963, carbamazepine was marketed in most of Europe. Its efficacy in generalized tonic-clonic seizures was soon found to be the same as phenytoin, and its ability to control partial seizures was superior, along with its tolerability. Sodium valproate was approved in France in 1967. Because the doses were so low (200–400 mg/day), it was viewed as a moderately effective anticonvulsant whose best quality was its nonsedating nature. In spite of the availability of carbamazepine and valproate, physicians practicing in Mediterranean countries still preferred phenobarbital. Other medications were seen as not usually necessary. Phenytoin was to be used as adjunctive therapy only. and one of two drugs (the other being sultiame) that were tried in adult patients if a combination of phenytoin and phenobarbital failed to control seizures. A review published that same year stated that carbamazepine did not live up to the claims of those who advocated its use in epilepsy.

In 1968, a Dr. Meadow encountered six babies with cleft lip and palate in addition to other congenital abnormalities whose mothers had been taking anticonvulsants. Meadow wrote a letter in The Lancet asking for cases of cleft lip and palate in babies whose mothers had taken anticonvulsants. That same year, Milunsky, Graef, and Gaynor reported cases of cleft lip and palate associated with attempted abortion with methotrexate and aminopterin, which are folic acid antagonists. That these drugs could interfere with folic acid and that folic acid supplementation might have beneficial somatic effects was widely accepted by 1969, and folic acid supplementation was believed to possibly exacerbate seizures, including the routine supplements given to pregnant women to prevent megaloblastic anemia. By 1970, the doctor had collected 32 cases, 16 of whom were born to women taking primidone. A quarter of the 32 cases had congenital heart defects; the reported rate in cleft lip and palate was 3-5%. Meadow emphasized that no proof was found of an association, the immense value of anticonvulsants, and the probably small odds of any one epileptic woman having a child with a congenital abnormality all supported its use. By the mid-1970s, it was obvious that this antagonistic effect of primidone was not due to the inhibition of dihydrofolate reductase, the enzyme responsible for the reduction of dihydrofolic acid to tetrahydrofolic acid, but rather to defective folate metabolism.

Carbamazepine was approved in the United States for the treatment of adult epilepsy in 1974. Its lack of sedating properties relative to phenobarbital and lack of somatic effects relative to phenytoin generated much interest. Within two years, primidone was no longer seen as the drug of choice for psychomotor epilepsy in the United States, because while carbamazepine and primidone are of roughly equal effectiveness, the former is less likely to cause sedation and cognitive impairment. Also, primidone has a greater tendency to cause undesirable psychiatric side effects compared with carbamazepine, which was noted to lessen pre-existing depressive symptoms. By 1978, it looked as if its superior side-effects profile would increase its use in epilepsy in the United States.

By 1980, primidone was seen as not worth mentioning as an option for childhood temporal lobe epilepsy by doctors in the United Kingdom. In January 1981, Dr. O'Brien and colleagues reported that primidone had a positive effect on the essential tremor of one of their patients. This led them to initiate a 20-person prospective study; 12 of the participants responded well. By 1984, valproic acid was the drug of choice for juvenile myoclonic epilepsy and not the equally effective primidone. However, as late as 1985, primidone was still one of the most widely used anticonvulsants. At the close of the 1980s, primidone was still the preferred anticonvulsant for complex partial seizures in Germany.

In 1990, primidone, along with phenobarbital, was a second-line agent in partial epilepsy with or without secondarily generalized tonic-clonic seizures and was one of four agents (the others being carbamazepine, phenytoin, and phenobarbital) that was used along with ethosuximide or a benzodiazepine for any absence or myoclonic seizures when valproate failed to control tonic-clonics (at least in the United States). After zonisamide, other new anticonvulsants came onto the market: felbamate, gabapentin, lamotrigine, and vigabatrin. All four were structurally distinct both from other anticonvulsants already on the market. They all had larger protective indices than conventional agents and unlike these agents, the new ones did not cause birth defects in laboratory animals or antagonize folic acid. They seemed to be relatively mild in terms of side effects. Of all of them, lamotrigine was the most similar to phenytoin in its pattern of efficacy. Felbamate was the most effective for Lennox-Gastaut syndrome and was seen as a second-line agent in juvenile myoclonic epilepsy after valproate. These new agents were aggressively marketed. In 1994, felbamate became the anticonvulsant of last resort after 10 people out of 100,000 came down with aplastic anemia.

By 1994, primidone was no longer one of the most widely used anticonvulsants. Phenytoin was still regarded as the drug of choice for partial seizures due to its long half-life and low cost; for children, though, carbamazepine was seen as the best one due to phenytoin's effects on physical appearance. On 28 February 1998, Élan Corporation, plc, bought the trademark and exclusive product distribution rights for Mysoline from Wyeth in Canada and the United States at a cost of $46 million and a royalty on future sales. The actual manufacture and distribution was done by Athena Neurosciences; their name appeared on a Mysoline package information sheet dated June 1998. On 30 November 1999, levetiracetam was approved for the adjunctive treatment of partial epilepsy in adults in the United States.

By 2000, primidone was prescribed in the event that the patient had tried all other anticonvulsants and was not a candidate for surgery in the United States. In April 2001, Élan decided to concentrate its efforts towards Zanaflex, Zonegran, Skelaxin, Abelcet, Azactam, Maxipime, Myobloc, and Cutivate. Mysoline was rationalized along with many other products that did not meet "certain commercial criteria." Yamanouchi Pharma Technologies, a Palo Alto-based subsidiary of Yamanouchi Pharmaceutical Co., Ltd, manufactured the actual drug. By 2003, most of the people taking primidone for epilepsy were elderly people who had been taking the drug for many years. In July 2004, Acorus Therapeutics Ltd. took over the manufacture and distribution of Mysoline from AstraZeneca 3 February 2005: almost four years after acquiring it from Elan, Xcel was acquired by Valeant Pharmaceuticals International. On 1 April 2005, Yamanouchi merged with Fujisawa Pharmaceutical Co., Ltd to form Astellas Pharma. As of 2005, it is widely used in the treatment of many forms of epilepsy in developing countries.

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Available forms

Primidone is available as a 250 mg/5mL suspension, and in the form of 50 mg, 125 mg, and 250 mg tablets. It is also available in a chewable tablet formulation in Canada.

It is marketed as several different brands, including Mysoline (Canada, Ireland, Japan, the United Kingdom, the United States), Prysoline (Israel, Rekah Pharmaceutical Products, Ltd.), Apo-Primidone, Liskantin (Germany, Desitin), Resimatil (Germany, Sanofi-Synthélabo GmbH), Mylepsinum (Germany, AWD.pharma GmbH & Co., KG)., and Sertan (Hungary, 250 mg tablets, ICN Pharmaceuticals Inc.[http://www.kfki.hu/chemonet/mkl/mkl98/mkl10/icn.html])

Veterinary uses

Primidone has veterinary uses, including the prevention of aggressive behavior and cannibalism in gilt pigs, and treatment of nervous disorders in dogs and other animals.