Primidone
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221215944
2008-06-23T15:34:39Z
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{{drugbox
| IUPAC_name = 5-ethyl-5-phenyl-hexahydropyrimidine-4,6-dione
| image = Primidone structure.svg
| width = 127
| CAS_number = 125-33-7
| ATC_prefix = N03
| ATC_suffix = AA03
| ATC_supplemental =
| PubChem = 4909
| DrugBank = APRD00549
| C=12 | H=14 | N=2 | O=2
| molecular_weight = 218.252 g/mol
| bioavailability = ~100%<ref name=Ochoa_2005>{{cite web | last = Ochoa | first = Juan G | coauthors = Riche, Willise. | year = 2005 | url = http://www.emedicine.com/neuro/topic692.htm | title = Antiepileptic Drugs: An Overview | work = eMedicine | publisher = eMedicine, Inc. | accessdate = 2005-07-02}}</ref>
| protein_bound = 25%<ref name=Ochoa_2005/>
| metabolism = [[Hepatic]]
| elimination_half-life = Primidone: 5-18 hours,<br>Phenobarbital: 75-120 hours,<ref name=Ochoa_2005/><br>PEMA: 16 hours<ref name=birf.info>{{cite web | author=CDER, U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES | year=2003–2005 | title=Primidone (Mysoline) | work=Pharmacology Guide for Brain Injury Treatment | publisher=Brain Injury Resource Foundation | url=http://www.birf.info/home/bi-tools/qlinks_anticon.html | accessdate=2005-07-02}}</ref><br>Time to reach steady state:<br>Primidone: 2-3 days,<br>Phenobarbital&PEMA 1-4weeks<ref name=steadystate>{{cite web | author=Yale Medical School, Department of Laboratory Medicine | year=1998 | title=Therapeutic Drug Levels| work=YNHH Laboratory Manual - Reference Documents | publisher=Yale Medical School | url=http://info.med.yale.edu/labmed/clinical/labman/D011.html | accessdate=2005-07-13}}</ref>
| excretion = [[Renal]]
| pregnancy_AU =
| pregnancy_US = D
| legal_AU =
| legal_UK = POM
| legal_US = Rx-only
| routes_of_administration = oral
}}
'''Primidone''' is an [[anticonvulsant]] of the [[pyrimidinedione]]<ref name=biam2>{{cite web | author=Biam | year=2001 |title=PRIMIDONE (French) | work=PYRIMIDINEDIONE | url=http://www.biam2.org/www/Sub2339.html | accessdaymonth=3 July | accessyear=2005}}</ref> class whose active [[metabolite]]s, [[phenobarbital]] (major) and phenylethylmalonamide (PEMA) (minor), are also anticonvulsants. It is used mainly to treat [[complex partial seizure|complex partial]], [[simple partial seizure|simple partial]]s, generalized [[tonic-clonic seizure]]s, [[myoclonus|myoclonic]], [[akinetic seizure]]s and since the 1980s it has been a valuable alternative to [[propranolol]] in the treatment of [[essential tremor]]. Unlike other anticonvulsants such as [[carbamazepine]] and [[valproic acid]], primidone is rarely used in the treatment of [[bipolar disorder]] or any other psychiatric problem. It is also not widely used in treatment of [[neuropathic pain]], [[trigeminal neuralgia]], or [[migraine]]. Primidone has been occasionally used to treat [[long QT syndrome]], [[cerebral palsy]], and [[athetosis]].
Primidone was once a mainstay anticonvulsant in the treatment of partial and generalized seizures and was the treatment of choice for secondarily generalized seizures originating in the temporal lobes, especially when combined with phenytoin, but by the early 1980s, carbamazepine had surpassed it in popularity due to the latter's lower incidence of sedation. As time passed and more and more anticonvulsants came on the market, primidone was pushed further and further away from its former place of prominence and major Western pharmaceutical corporations became less and less interested in manufacturing and selling it. It has largely fallen into disuse in the developed world as more and more anticonvulsants entered the market and has been withdrawn from markets all over the world.
Unlike many other anticonvulsants, primidone works via interactions with voltage-gated sodium channels which inhibit high-frequency repetitive firing of action potentials. It is much less toxic in overdose than phenobarbital. Along with carbamazepine, phenobarbital, and phenytoin, primidone is an inducer of metabolic enzymes in the liver, which means that it accelerates the metabolism of many other pharmaceuticals. Like other anticonvulsants that entered the market before 1989, primidone has been associated with [[hyperhomocysteinemia]], [[folate deficiency]] and its various symptoms (birth defects, depression, and [[megaloblastic anemia]]), reduced calcium absorption, and various bone diseases. It also shares with most other anticonvulsants the tendency to cause sedation.
==History==
Primidone's effectiveness for epilepsy was first demonstrated in 1949 by Dr. Yule Bogue.<ref name=Denis_Williams_1956_p589>{{cite journal | first = Denis | last = Williams | month = August | year = 1956 | title = Treatment of Epilepsy with Mysoline | journal = Proceedings of the Royal Society of Medicine | volume = 49 | issue = 8 | pages = 589–591 | pmid = 13359420 | url = http://www.pubmedcentral.nih.gov/pagerender.fcgi?artid=1889099&pageindex=7 | accessdate = 2007-10-12 }}</ref> It was introduced a year later by the Imperial Chemical Industry (ICI), now known as [[AstraZeneca]] in the United Kingdom<ref name=Morley_et_al_1957>{{cite journal | first = D. | last = Morley | coauthors = N. A. Wynne | date = [[January 12]], [[1957]] | title = Acute Primidone Poisoning in a Child | journal = British Medical Journal | volume = 1 | issue = 5010 | pages = 90 | pmid = 13383203 | url = http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=13383203 | accessdate = 2007-11-05 }}</ref><ref name=Dotevall_et_al_1957>{{cite journal | first = Gerhard | last = Dotevall | coauthors = Birger Herner | date = [[August 24]], [[1957]] | title = Treatment of Acute Primidone Poisoning with Bemegride and Amiphenazole | journal = British Medical Journal | volume = 2 | issue = 5042 | pages = 451&nash;2 | pmid = 13446511 | url = http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=13446511 | accessdate = 2007-11-05 }}</ref> and Germany.<ref name=Fazekas_et_al_1960>{{de icon}} {{cite journal | first = I. Gy. | last = Fazekas | coauthors = B. Rengei | month = January | year = 1960 | title = Tödliche Vergiftung (Selbstmord) mit Mysoline und Phenobarbiturat | journal = Archives of Toxicology | volume = 18 | issue = 4 | pages = 213–23 | format = PDF | doi = 10.1007/BF00577226 | pmid = 13698457 | url = http://www.springerlink.com/content/k38587p17347828k/fulltext.pdf | accessdate = 2007-11-05 }}</ref> In 1952, it was approved in the Netherlands.<ref name=van_Heijst_et_al_1983>{{cite journal | first = A. N. | last = van Heijst | coauthors = W. de Jong, R. Seldenrijk, A. van Dijk | month = June | year = 1983 | title = Coma and crystalluria: a massive primidone intoxication treated with haemoperfusion | journal = Journal of Toxicology. Clinical Toxicology | volume = 20 | issue = 4 | pages = 307–18 | pmid = 6655772 }}</ref> That same year, 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.<ref name=Denis_Williams_1956_p589/> Dr. Whitty noted in 1953 that it benefitted patients with psychomotor epilepsy, who were often treatment-resistant. Toxic effects were reported to be mild.<ref name=Whitty_et_al_1953>{{cite journal | first = C. W. | last = Whitty | date = [[September 5]], [[1953]] | title = Value of primidone in epilepsy | journal = British Medical Journal | volume = 2 | issue = 4835 | pages = 540–1 | pmid = 13082031 | url = http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=13082031 | accessdate = 2007-10-21}}</ref> That same year, it was approved in France.<ref name=Loiseau_et_al_1999>{{cite journal | last = Loiseau | first = Pierre Jean-Marie | month = June | year = 1999 | title = Clinical Experience with New Antiepileptic Drugs: Antiepileptic Drugs in Europe | journal = [[Epilepsia]] | volume = 40 | issue = Suppl 6 | pages = S3–8 | doi = 10.1111/j.1528-1157.1999.tb00925.x | pmid = 10530675 | url = http://www.blackwell-synergy.com/doi/pdf/10.1111/j.1528-1157.1999.tb00925.x | format = [[PDF]] | accessdate = 2007-03-26}}</ref> Primidone was introduced in 1954 under the brandname Mysoline by [[Wyeth]] in the United States.<ref name=wyeth.com>{{cite web | author = [[Wyeth]] | url = http://www.wyeth.com/aboutwyeth/history | title = Wyeth Timeline | work = About Wyeth | accessdate = 2007-11-11}}</ref>
The first report associating it with megaloblastic anemia came in 1954 from Drs. Chalmers and Boheimer.<ref name="Sumner_and_Newman_1957">{{cite science | first = M. J. D. | last = Newman | coauthors = D. W. Sumner | year = 1957 | month = February | title = Megaloblastic anemia following the use of primidone | journal = Blood | volume = 12 | issue = 2 | pages = 183–8 | pmid = 13403983 | url = http://bloodjournal.hematologylibrary.org/cgi/reprint/12/2/183 | format = [[PDF]] | abstract = http://bloodjournal.hematologylibrary.org/cgi/content/abstract/12/2/183}}</ref> Between 1954 and 1957, twenty-one cases of megalogblastic anemia associated with primidone and/or phenytoin were reported.<ref name=Kidd_et_al_1957>{{cite journal | first = Patrick | last = Kidd | coauthors = David L. Mollin | date = [[October 26]], [[1957]] | title = Megaloblastic Anaemia and Vitamin-B12 Deficiency After Anticonvulsant Therapy | journal = British Medical Journal | volume = 2 | issue = 5051 | pages = 97–976 | pmid = 13472024 | url = http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1962638 | accessdate = 2007-10-24}}</ref> Most cases were due to folic acid deficiency; however, there was one that only responded to B<sub>12</sub> therapy<ref name="Sumner_and_Newman_1957"/> and one that required Vitamin C.<ref name=Kidd_et_al_1957/> Few cases were associated with deficient diets; one patient ate mostly bread and butter,<ref name="Sumner_and_Newman_1957"/> another ate bread, buns, and hard candy, and another could rarely be persuaded to eat in the hospital.<ref name=Kidd_et_al_1957/> The idea that folic acid deficiency could cause megaloblastic anemia was not new. What was new was the idea that ''drugs'' could cause this in well-nourished people with no intestinal abnormalities.<ref name="Sumner_and_Newman_1957"/> In many cases, it was not clear which drug had caused it.<ref name=Fuld_et_al_1956>{{cite journal | first = H. | last = Fuld | coauthors = E. H. Moorhouse | date = [[May 5]], [[1956]] | title = Observations on Megaloblastic Anaemias After Primidone | journal = British Medical Journal | volume = 1 | issue = 4974 | pages = 1021–1023 | pmid = 13304415 | url = http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1979778 | accessdate = 2007-10-24}}</ref> It was speculated that this might be related to the structural similarity between folic acid, phenytoin, phenobarbital, and primidone.<ref name=Girdwood_et_al_1956>{{cite journal | first = R. H. | last = Girdwood | coauthors = J. A. R. Lenman | date = [[January 21]], [[1956]] | title = Megaloblastic Anaemia Occurring During Primidone Therapy | journal = British Medical Journal | volume = 1 | issue = 4959 | pages = 146–147 | pmid = 13276653 | url = http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=13276653 | accessdate = 2007-10-24}}</ref> 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 [[peripheral nervous system|PNS]] symptoms as well as anemia—on B<sub>12</sub> therapy.<ref name=Meyer_1947>{{cite journal | last = Meyer | first = Leo M. | year = 1947 | title = Folic Acid In The Treatment Of Pernicious Anemia | journal = Blood | volume = 2 | issue = 1 | pages = 50–62 | url = http://bloodjournal.hematologylibrary.org/cgi/reprint/2/1/50 | format = PDF | accessdate = 2007-08-27}}</ref> Five years earlier, folic acid deficiency was linked to birth defects in rats.<ref name=Nelson_et_al_1952>{{cite journal | first = Marjorie M. | last = Nelson | coauthors = C. Willet Asling, and Herbert M. Evans | month = September | year = 1952 | title = Production of multiple congenital abnormalities in young by maternal pteroylglutamic acid deficiency during gestation | journal = Journal of Nutrition | volume = 48 | issue = 1 | pages = 61–79 | pmid = 13000492 | url = http://jn.nutrition.org/cgi/reprint/48/1/61 | format = [[PDF]] | accessdate = 2008-01-06 }}
</ref> Primidone was seen by some as too valuable to withhold based on the slight possibility of this rare side effect<ref name="Sumner_and_Newman_1957"/> and by others as dangerous enough to be withheld unless phenobarbital or some other barbiturate failed to work for this and other reasons (i.e., reports of permanent psychosis.<ref name=Garland_1957>{{cite journal | first = Hugh | last = Garland | month = August | year = 1957 | title = Drugs used in the management of epilepsy | journal = Proceedings of the Royal Society of Medicine | volume = 50 | issue = 8 | pages = 611–5 | pmid = 13465742 | url = http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1889058 | accessdate = 2007-12-02 }}</ref>
In Europe, up until 1963, it was not unocmmon to prescribe primidone and phenobarbital in combination, often with a stimulant. 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. It soon became clear that its efficacy in generalized tonic-clonic seizures was the same as phenytoin, that 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.<ref name=Loiseau_et_al_1999/> In spite of these advances, primidone was still considered to be a "sheet-anchor" anticonvulsant in the [[United Kingdom]] as late as 1969, along with phenobarbital and phenytoin, for the treatment of pediatric epilepsy in spite of its side effects<ref name="Wilson1969">{{cite journal | last = Wilson | first = John | date = [[November 22]], [[1969]] | title = Drug treatment of epilepsy in childhood | journal = [[British Medical Journal]] | volume = 4 | issue = 5681 | pages = 475–477 | pmid = 4390959 | url = http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=4390959 | accessdate = 2007-02-13}}</ref> 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.<ref name="standard_treatment_of_epilepsy_1969UK">{{cite journal | last = Gibberd | first = F. B. | date = [[1 November]], [[1969]] | title = Epilepsy | journal = [[British Medical Journal]] | volume = 4 | issue = 5678 | pages = 281–284 | pmid = 4390562 | url = http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=4390562 | accessdate = 2007-09-24}}</ref>
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.<ref name=Meadow_1970>{{cite journal | first = S. R. | last = Meadow | month = January | year = 1970 | title = Congenital abnormalities and anticonvulsant drugs | journal = Proceedings of the Royal Society of Medicine | volume = 63 | issue = 1 | pages = 48–9 | pmid = 5417773 | url = http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=5417773 | accessdate = 2007-11-06 }}</ref> While it was widely accepted by 1969 that these drugs could interfere with folic acid and that folic acid supplementation might have beneficial somatic effects, it was believed that folic acid supplementation could exacerbate seizures; this included the routine supplements given to pregnant women to prevent megaloblastic anemia.<ref name=Folic_acid_1968>{{cite journal | first = Naomi | last = Baumslag | coauthors = T. Edelstein, and J. Metz | date = [[January 3]], [[1970]] | title = Reduction of Incidence of Prematurity by Folic Acid Supplementation in Pregnancy | journal = British Medical Journal | volume = 1 | issue = 5687 | pages = 16–7 | pmid = 5460838 | url = http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1700896 | accessdate = 2007-12-06}}</ref><ref name="standard_treatment_of_epilepsy_1969UK"/> By 1970, the doctor had collected thirty-two cases. Sixteen of them were born to women taking primidone. 25% of the thirty-two cases had congenital heart defects; the reported rate in cleft lip and palate was 3-5%. Meadow emphasized that there was no proof 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.<ref name=Meadow_1970/> Roman and Caratzali reported in 1971 that the offspring of mice treated with primidone had more abnormal bone [[metaphase]]s than controls; this was due to chromosomal lesions.<ref name=Roman_et_al_1971>{{cite journal | first = I. C. | last = Roman | coauthors = A. Caratzali | date = [[October 23]], [[1971]] | title = Effects of anticonvulsant drugs on chromosomes | journal = British Medical Journal | volume = 4 | issue = 5781 | pages = 234 | pmid = 5115838 | url = http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=5115838 | accessdate = 2007-11-08 }}</ref> 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 [[redox|reduction]] of [[folic acid|dihydrofolic acid]] to [[folic acid|tetrahydrofolic acid]], but rather to defective folate metabolism.<ref name=meg-1976>{{cite journal | first = R. H. | last = Girdwood | year = 1976 | title = Drug-induced anaemias | journal = Drugs | volume = 11 | issue = 5 | pages = 394–404 | pmid = 782836 | doi = 10.2165/00003495-197611050-00003}}</ref>
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.<ref name="Tegretol1978WJM">{{cite journal | last = Schain | first = Richard J. | month = March | year = 1978 | title = Pediatrics—Epitomes of Progress: Carbamazepine (Tegretol) in the Treatment of Epilepsy | journal = [[Western Journal of Medicine]] | volume = 128 | issue = 3 | pages = 231–232 | pmid = | url = http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1238063 | accessdate = 2007-03-14}}</ref> Within two years, primidone was no longer seen as the drug of choice for psychomotor epilepsy in the United States. This was due to the fact that 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.<ref name=Rodin_et_al_1976>{{cite journal | first = Ernst A. | last = Rodin | coauthors = Rim CS, Kitano H, Lewis R, Rennick PM | title = A comparison of the effectiveness of primidone versus carbamazepine in epileptic outpatients | journal = [[The Journal of Nervous and Mental Disease]] | volume = 163 | issue = 1 | year = 1976 | pages = 41–6 | pmid = 819630 | doi = 10.1097/00005053-197607000-00006}}</ref> By 1978, it looked as if its superior side effect profile would increase its use in epilepsy in the United States.<ref name="Tegretol1978WJM"/> That same year, a review was published stating that primidone and phenobarbital were used less often in the United Kingdom due to their greater tendency to cause behavior disorders and interfere with learning in young children. Valproate was heralded by some as "the greatest thing since Greta Garbo" and carbamazepine had also risen in popularity.<ref name=Addy_1978>{{cite journal | first = D. P. | last = Addy | [[September 16]], [[1979]] | title = Childhood epilepsy | journal = British Medical Journal | volume = 2 | issue = 6140 | pages = 811–2 | pmid = 698744 | url = http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=698744 | accessdate = 2007-11-13}}</ref>
By 1980, primidone was seen as not worth mentioning as an option for childhood temporal lobe epilepsy by doctors in the United Kingdom.<ref name=BMJ_1980_3_22>{{cite journal | date = [[March 22]], [[1980]] | title = Prognosis of temporal lobe epilepsy in childhood. | journal = British Medical Journal | volume = 280 | issue = 6217 | pages = 812–813 | pmid = 7370676| url = http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1600996 | accessdate = 2007-08-26}}</ref> In January of 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 twenty-person [[prospective study]]. Twelve of the participants responded well.<ref name="O'Brien_et_al_1981">{{cite journal | last = O'Brien | first = M D | coauthors = A R Upton and P A Toseland | date = [[January 17]], [[1981]] | title = Benign familial tremor treated with primidone | journal = [[British Medical Journal]] | volume = 282 | issue = 6259 | pages = 178–180 | pmid = 6779938 | url = http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=6779938 | accessdate = 2007-04-03}}</ref> By 1984, valproic acid was the drug of choice for [[juvenile myoclonic epilepsy]]<ref name=Asconapé_et_al_1984>{{cite journal | first = J. | last = Asconapé | coauthors = J. K. Penry | month = February | year = 1984 | title = Some clinical and EEG aspects of benign juvenile myoclonic epilepsy | journal = Epilepsia | volume = 25 | issue = 1 | pages = 108–14 | pmid = 6420145 | doi = 10.1111/j.1528-1157.1984.tb04163.x }}</ref> and not the equally effective primidone.<ref name=Janz_1985>{{cite journal | first = D. | last = Janz | month = November | year = 1985 | title = Epilepsy with impulsive petit mal (juvenile myoclonic epilepsy) | journal = Acta Neurologica Scandinavica | volume = 72 | issue = 5 | pages = 449–59 | pmid = 3936330 }}</ref> However, as late as 1985, primidone was still one of the most widely used anticonvulsants.<ref name=impotence>{{cite journal | author=Mattson RH, Cramer JA, Collins JF, Smith DB, Delgado-Escueta AV, Browne TR, Williamson PD, Treiman DM, McNamara JO, McCutchen CB, et al.| title=Comparison of carbamazepine, phenobarbital, phenytoin, and primidone in partial and secondarily generalized tonic-clonic seizures.| journal=New England Journal of Medicine.| volume=313| issue=3| date=[[July 8]], [[1985]]| pages=145–51. | pmid=3925335}}</ref> At the close of the 1980s, primidone was still the preferred anticonvulsant for complex partial seizures in Germany.<ref name=Loiseau_et_al_1999/> In 1989, Dainippon Pharmaceutical launched Exegran ([[zonisamide]]), the first new, chemically unique, non-benzodiazepine anticonvulsant in decades.<ref name=excegran_1989>{{cite web
| author=Dainippon Sumitomo Pharma Co., Ltd.
| year=2005 | title=Company History | work=Company Information
| publisher=Dainippon Sumitomo Co., Ltd. | url=http://www.ds-pharma.co.jp/english/profile/history.html
| accessdate = 2005-11-12}}</ref>
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 seizure|absence]] or [[myoclonus|myoclonic seizure]]s when valproate failed to control tonic-clonics (at least in the United States).<ref name=In_1990>{{cite journal | first = R. H. | last = Mattson | month = December | year = 1990 | title = Selection of drugs for the treatment of epilepsy | journal = [[Seminars in Neurology]] | volume = 10 | issue = 4 | pages = 406–13 | pmid = 2287835}}</ref> 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 indexes 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. Out 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 ten people out of 100,000 came down with [[aplastic anemia]].<ref name=Laxer_1994>{{cite journal | first = K. D. | last = Laxer | month = September | year = 1994 | title = Guidelines for treating epilepsy in the age of felbamate, vigabatrin, lamotrigine, and gabapentin. | journal = Western Journal of Medicine | volume = 161 | issue = 3 | pages = 309–314 | url = http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1011415 | accessdate = 2007-09-19 | pmid = 7975572}}</ref>
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, low cost but for children, carbamazepine was seen as the best one due to phenytoin's effects on physical appearance.<ref name=Laxer_1994/> [[Topiramate]] was approved two years later. It, along with the others, was mainly used in patients refractory to carbamazepine and valproate. These new agents were often described as having "innovative" and "selective" mechanisms of action; in reality, most of them also worked similarly to older agents.<ref name=Perucca_1996>{{cite journal | first = Emilio | last = Perucca | year = 1996 | title = The new generation of antiepileptic drugs: advantages and disadvantages | journal = British Journal of Clinical Pharmacology | volume = 42 | pages = 531–543 | pmid = 8951184 | url = http://www.blackwell-synergy.com/doi/pdf/10.1111/j.1365-2125.1996.tb00046.x | accessdate = 2007-09-24 | doi = 10.1111/j.1365-2125.1996.tb00046.x}}</ref> On [[February 28]], [[1998]], [[Élan|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.<ref name=elanmysoline>{{cite web | author = Élan Corporation, plc | url = http://www.elan.com/Images/2_1755_tcm3-4228.pdf | title = Product Acquisitions | format = PDF | work = Annual Report Pursuant to Section 13 or 15(d) of The Securities Exchange Act of 1934 for the fiscal year ended: December 31, 1998 | accessdate = 2005-07-03}}</ref> The actual manufacture and distribution was done by [[Athena Neurosciences]]; their name appeared on a Mysoline package information sheet dated June 1998.<ref name=athenamysoline>{{cite web | author = Medscape | authorlink = Medscape | url = http://www.medscape.com/content/2002/00/43/02/430209/430209_ref.html | title = "Athena Neurosciences. Mysoline (primidone) package insert. South San Francisco, CA; June 1998." | work = Medscape: References | accessdate = 2005-07-03}}</ref> On [[November 30]], [[1999]], [[levetiracetam]] was approved for the adjunctive treatment of partial epilepsy in adults in the United States.<ref name=Keppra>{{cite web | url = http://www.fda.gov/cder/foi/nda/99/21035_Keppra.htm | title = Drug Approval Package: Keppra (Levetiracetam) Tablets | accessdate = 2007-11-14 | author = U.S. Food and Drug Administration Center for Drug Evaluation and Research }}</ref>
By the year 2000, primidone was something that was prescribed in the event that the patient had tried all other anticonvulsants and was not a candidate for surgery in the United States.<ref name=Kanner_et_al_2000>{{cite journal | first = Andres M. | last = Kanner | coauthors = Jaime Parra, and Marlis Frey | month = October | year = 2000 | title = The "Forgotten" Cross-Tolerance Between Phenobarbital and Primidone: It Can Prevent Acute Primidone-Related Toxicity | journal = Epilepsia | volume = 41 | issue = 10 | pages = 1310–4 | pmid = 11051127 | url = http://www.blackwell-synergy.com/doi/pdf/10.1111/j.1528-1157.2000.tb04610.x | format = PDF | accessdate = 2007-11-12 | doi = 10.1111/j.1528-1157.2000.tb04610.x}}</ref> In April of 2001, Élan decided to concentrate its efforts towards [[tizanidine|Zanaflex]], [[zonisamide|Zonegran]], [[metaxalone|Skelaxin]], [[amphotericin B|Abelcet]], [[aztreonam|Azactam]], [[cefepime|Maxipime]], [[Botulinum toxin|Myobloc]], and [[fluticasone|Cutivate]]. Mysoline was [[Wiktionary:rationalization|rationalized]] along with many other products that did not meet "certain commercial criteria."<ref name=elanrationalise>{{cite web | author = Élan Corporation, plc | year = 2001 | url = http://www.elan.com/images/2_2592_tcm3-4377.pdf | title = 2001 Annual Report and Form 20-F | accessdate = 2005-07-03 | format = [[PDF]] | work = elan.com | pages = 25}}</ref> Yamanouchi Pharma Technologies, a [[Palo Alto]]-based [[subsidiary]] of [[Yamanouchi Pharmaceutical|Yamanouchi Pharmaceutical Co., Ltd]],<ref name=yamanouchisubsidiary>{{cite web | author = Informagen | year = 2000 | url = http://informagen.com/Resource_Informagen/report.php?mrn=11209 | title = Yamanouchi Pharma Technologies, Inc. (YPT) | work = Resource Informagen | accessdate = 2005-07-03}}</ref> manufactured the actual drug.<ref name=yamanouchimanufacture>{{cite web | url = http://www.rxlist.com/cgi/generic2/primid_ids.htm | title = Mysoline Indications, Dosage, Storage, Stability | work = Primidone - RxList Monograph | accessdate = 2005-07-03}}</ref> By 2003, most of the people taking primidone for epilepsy were elderly people who had been taking the drug for many years.<ref name=de_Haan_et_al_2003> {{nl icon}} {{cite journal | first = G. J. | last = de Haan | coauthors = J. A. Carpay, and C. A. van Donselaar | date = [[November 22]], [[2003]] | title = Anti-epilepticum primidon binnenkort uit de handel: nu medicatie herzien / Antiepileptic primidone shortly to be withdrawn from sale: change medication now | journal = Nederlands Tijdschrift voor Geneeskunde | volume = 147 | issue = 47 | pages = 2325–6 | pmid = 14669538 | url = http://www.ntvg.nl/db_artikel.asp?ID=2003123250001A&NR=2&OFF=9&fr=rs | accessdate = 2007-10-06}}</ref> In July of 2004, Acorus Therapeutics Ltd. took over the manufacture and distribution of Mysoline from AstraZeneca<ref name=astrazeneca.com>{{cite web | author = AstraZeneca | year = 2004 | url = http://www.astrazeneca.com/productbrowse/4_75.aspx | title = Mysoline, Mylepsinum (primidone) - anticonvulsant used to treat epilepsy | accessdate = 2005-07-03}}</ref> [[February 3]], [[2005]]: almost four years after acquiring it from Elan, Xcel was acquired by Valeant Pharmaceuticals International.<ref name=valeantxcel>{{cite web | author = KESQ NewsChannel 3 Palm Springs, CA | year = 2005 | url = http://www.kesq.com/Global/story.asp?S=2895353 | title = Valeant to buy Xcel Pharmaceuticals for $280 million | accessdate = 2005-07-03}}</ref> In [[April 1]], [[2005]], Yamanouchi merged with Fujisawa Pharmaceutical Co., Ltd to form [[Astellas Pharma]].<ref name=yamanouchi_fujisawa>{{cite web | url = http://www.astellas.com/ca/Astellas_Canada.pdf | title = Yamanouchi, Fujisawa Unite to Form Astellas - Canadian operation based in Markham, Ontario | format = PDF | accessdate = 2005-07-03}}</ref> [[As of 2005]], it is widely used in the treatment of many forms of epilepsy in developing countries.<ref name=Lopez-Gomez_et_al_2005>{{cite journal | first = M | last = Lopez-Gomez | coauthors = J. Ramirez-Bermudez, C. Campillo, A. L. Sosa, M. Espinola, I. Ruiz. | year = 2005 | month = May | title = Primidone is associated with interictal depression in patients with epilepsy | journal = Epilepsy & Behavior | volume = 6 | issue = 3 | pages = 413–6 | pmid = 15820351 | url = http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WDT-4FPYWP8-5&_user=10&_coverDate=05%2F31%2F2005&_alid=301001088&_rdoc=1&_fmt=full&_orig=search&_qd=1&_cdi=6775&_sort=d&_docanchor=&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=89357c80278ec360b1a64c6998eab8cf | doi = 10.1016/j.yebeh.2005.01.016}}</ref>
==Indications==
===Epilepsy===
According to the electronic Medicines Compendium, primidone is licensed for generalized tonic-clonic and complex partial seizures in the United Kingdom.<ref name=licenseduk>{{cite web | author = Acorus Therapeutics, Ltd. | year = 2005 | url = http://emc.medicines.org.uk/emc/assets/c/html/displaydoc.asp?documentid=16760 | title = Mysoline 250 mg Tablets | work = electronic Medicines Compendium | publisher = Datapharm Communications and the Association of the British Pharmaceutical Industry (ABPI) | accessdate = 2006-03-08}}</ref> 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, and complex partial seizures.<ref name=yamanouchimanufacture/> Although it is not approved for other seizure types, it is used to treat akinetic seizures, simple partial seizures, and myoclonic seizures.<ref name=licenseduk/> In [[juvenile myoclonic epilepsy]] (JME), it is a second-line therapy, reserved for when the valproates and/or lamotrigine do not work and when other second-line therapies—[[acetazolamide]], [[clonazepam]], and [[phenobarbital]]—do not work either.<ref name=jme>{{cite book | last = Broadley | first = Marissa A. | title = The Childhood Seizure e-Book | url = http://www.pediatricneurology.com/seizures.htm | accessdate = 2005-07-03 | date = 2002-06-06 | publisher = Pediatric Neurological Associates | location = Valhalla, New York | chapter = Juvenile Myoclonic Epilepsy of Janz (JME) | chapterurl = http://www.pediatricneurology.com/new_page_1.htm }}</ref>
Open-label case series have suggested that primidone is effective in the treatment of epilepsy.<ref name=Livinston_et_al_1956>{{cite journal | last = Livingston | first = Samuel | coauthors = Don Petersen | date = [[February 16]], [[1956]] | title = Primidone (mysoline) in the treatment of epilepsy; results of treatment of 486 patients and review of the literature | journal = New England Journal of Medicine | volume = 254 | issue = 7 | pages = 327–9 | pmid = 13288784 }}</ref><ref name=Smith_et_al_1953>{{cite journal | first = Bernard H. | last = Smith | coauthors = Francis L. McNaughton | month = May | year = 1953 | title = Mysoline, A new Anticonvulsant: Its Value in Refractory Cases of Epilepsy | journal = Canadian Medical Association Journal | volume = 68 | issue = 5 | pages = 464–467 | pmid = 13042720 | url = http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=13042720 | accessdate = 2007-10-12 }}</ref><ref name=Whitty_et_al_1953/><ref name=Denis_Williams_1956_p589/><ref name=neonatalseizures>{{cite journal | first = C. | last = Powell | coauthors = Painter MJ, Pippenger CE | year = 1984 | month = October | title = Primidone therapy in refractory neonatal seizures | journal = Journal of Pediatrics | volume = 105 | issue = 4 | pages = 651–4 | pmid = 6481545 | doi = 10.1016/S0022-3476(84)80442-4}}</ref><ref name=pme>{{cite journal | first = Kuriko | last = Kagitani-Shimono | coauthors = Imai Katsumi, Okamoto Nobuhiko, Ono Jiro and Okada Shintaro | month = January | year = 2002 | title = Unverricht-Lundborg disease with cystatin B gene abnormalities | journal = Pediatric Neurology | volume = 26 | issue = 1 | pages = 55–60 | pmid = 11814737 | url = http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&list_uids=11814737&dopt=ExternalLink | doi = 10.1016/S0887-8994(01)00336-8}}</ref> Primidone has been compared to carbamazepine,<ref name=Rodin_et_al_1976/><ref name=impotence/><ref name=Hermanns_et_al_1996>{{cite journal | first = Guido | last = Hermanns | coauthors = Soheyl Noachtar, Ingrid Tuxhorn, Hans Holthausen, Alois Ebner, and Peter Wolf | month = July | year = 1996 | title = Systematic Testing of Medical Intractability for Carbamazepine, Phenytoin, and Phenobarbital or Primidone in Monotherapy for Patients Considered for Epilepsy Surgery | journal = Epilepsia | volume = 37 | issue = 7 | pages = 675–679 | pmid = 8681900 | doi = 10.1111/j.1528-1157.1996.tb00632.x }}</ref><ref name=Smith_et_al_1987>{{cite journal | first = D. B. | last = Smith | coauthors = Richard H. Mattson, J. A. Cramer, J. F. Collins, R. A. Novelly, and B. Craft | year = 1987 | title = Results of a nationwide Veterans Administration Cooperative Study comparing the efficacy and toxicity of carbamazepine, phenobarbital, phenytoin, and primidone | journal = Epilepsia | volume = 28 | issue = Suppl 3 | pages = S50–8 | pmid = 3319543 | doi = 10.1111/j.1528-1157.1987.tb05778.x }}</ref> phenytoin,<ref name=Gruber_et_al_1962>{{cite journal | first = C. M., Jr. | last = Gruber | coauthors = J. T. Brock, and M. Dyken | month = January-February | year = 1962 | title = Comparison of the effectiveness of phenobarital, mephobarbital, primidone, diphenylhydantoin, ethotoin, metharbital, and methylphenylethylhydantoin in motor seizures | journal = Clinical Pharmacology and Therapeutics | volume = 3 | pages = 23–8 | pmid = 13902356 }}</ref><ref name=impotence/><ref name=Hermanns_et_al_1996/><ref name=White_et_al_1965>{{cite journal | last = White | first = P. T. | coauthors = Plott D, and Norton J | month = January | year = 1966 | title = Relative anticonvulsant potency of primidone; a double blind comparison | journal = Archives of Neurology | volume = 14 | issue = 1 | pages = 31–5 | pmid = 5320823}}</ref> phenobarbital,<ref name=Gruber_et_al_1962/><ref name=impotence/><ref name=Hermanns_et_al_1996/> [[mephobarbital]], [[ethotoin]], [[metharbital]], and [[mephenytoin]].<ref name=Gruber_et_al_1962/> Compared to carbamazepine, primidone has been found to be equally effective,<ref name=Rodin_et_al_1976/> less effective at controlling partial seizures but just as effective at controlling generalized tonic-clonics,<ref name=impotence/><ref name=Smith_et_al_1987/> less likely to cause side effects but more likely to cause side effects requiring withdrawal of the drug, half as likely to reduce seizures in patients being considered for surgery by at least 80%,<ref name=Hermanns_et_al_1996/> more likely to cause depression,<ref name=Rodin_et_al_1976/> significantly more likely cause intolerable side effects,<ref name=Smith_et_al_1987/> more likely to cause impotence and decreased libido,<ref name=impotence/> and cause more adverse effects on motor performance and attention/concentration tests.<ref name=Smith_et_al_1987/><ref name=Rodin_et_al_1976/> In adult comparison trials, primidone higher a incidence of intolerable side effects than phenytoin,<ref name=Smith_et_al_1987/> a higher incidence of decreased libido and impotence, similar control of tonic-clonic seizures, more likely to cause nausea, vomiting, dizziness, and sedation;<ref name=impotence/> twice as likely to be effective in controlling seizures in epilepsy surgery candidates,<ref name=Hermanns_et_al_1996/> more acute effects such as nausea, vomiting, dizziness, and sedation,<ref name=impotence/> and to be just as effective.<ref name=White_et_al_1965>{{cite journal | last = White | first = P. T. | coauthors = Plott D, and Norton J | month = January | year = 1966 | title = Relative anticonvulsant potency of primidone; a double blind comparison | journal = Archives of Neurology | volume = 14 | issue = 1 | pages = 31–5 | pmid = 5320823}}</ref><ref name=Gruber_et_al_1962/>
===Essential tremor===
Primidone is considered to be a first-line therapy for essential tremor along with propranolol. In terms of tremor amplitude reduction, it is just as effective as propranolol, reducing it by 50%. Both drugs are well studied for this condition, unlike other therapies, and are recommended for initial treatment. 250 mg/day (low-dose therapy) is just as good as 750 mg/day (high-dose therapy).<ref name=Zesiewicz_et_al_2005>{{cite journal | last = Zesiewicz | first = T. A. | coauthors = R. Elble, E. D. Louis, R. A. Hauser, K. L. Sullivan, R. B. Dewey, Jr, W. G. Ondo, G. S. Gronseth,and W. J. Weiner |date = [[June 28]], [[2005]] | title = Practice Parameter: Therapies for essential tremor: Report of the Quality Standards Subcommittee of the American Academy of Neurology | journal = Neurology | volume = 64 | issue = 12 | pages = 2008–20 | doi = 10.1212/01.WNL.0000163769.28552.CD) | pmid = 15972843 | url = http://www.neurology.org/cgi/content/full/64/12/2008 | accessdate = 2007-08-11 | doi_brokendate = 2008-06-23}}</ref>
Primidone is not the only anticonvulsant used for essential tremor; the others include topiramate, [[clonazepam]], and gabapentin. Other pharmacological agents include [[alprazolam]] (Xanax), [[atenolol]], [[sotalol]], [[nadolol]], [[clozapine]], [[nimodipine]], and [[Botox|botilinum toxin A]]. Many of these drugs were less effective (according to Table 1), but a few were not. Only propranolol has been compared to primidone in a clinical trial.<ref name=Zesiewicz_et_al_2005/>
===Long QT syndrome===
The first case report in which the shortening of the QT interval by primidone was documented, published in the July 1980 issue of ''[[Annals of Internal Medicine]]'', involved three patients, a 31-year-old woman, her 15-year-old nephew, and his 16-year-old sister. The woman still had [[ventricular fibrillation]], [[fainting|syncope]], and seizures even after the removal of her left [[stellate ganglion]] and a thoracic chain dissection. The woman had previously been tried on a combination of phenobarbital and phenytoin when she was thought to have only seizures, followed by phenobarbital combined phenytoin and [[procainamide]]. The procainamide was replaced with propanolol, which in turn replaced the propanolol when the latter brought the [[tachycardia]] back almost instantaneously upon the first dose. The phenobarbital and phenytoin were then combined with [[atropine]] and acetyl [[G-strophanthidin|strophanthidin]]. When this failed, the atropine and acetyl strophanthidin were replaced with [[lidocaine]] prior to the surgery. After the surgery, the QT-prolongation returned, so the phenytoin was doubled to 200 mg four times daily. A month later, she was admitted to the hospital for phenytoin toxicity, where it was found that she had slow [[EEG|spike and abortive wave activity]] in her left [[temporal lobe]]. It was after this that primidone was substituted for phenytoin. The primidone suppressed the fibrillations and lengthened the [[QT interval]] for two years and eight months in the patient. Her 16-year-old niece was started on primidone after an unsuccessful trial of phenytoin. Following this, her 15-year-old nephew, the niece's brother, was started because of family history.<ref name=longqt1980>{{cite journal | author = DeSilvey DL | coauthors = Moss AJ | month = July | year = 1980 | title = Primidone in the treatment of the long QT syndrome: QT shortening and ventricular arrhythmia suppression | journal = Annals of Internal Medicine | volume = 93 | issue = 1 | pages = 53–4 | pmid = 7396315 | url = http://openurl.epnet.com/linksvc/linking.aspx?genre=article&sid=PubMed&issn=0003-4819&title=Ann%20Intern%20Med&volume=93&issue=1&spage=53&atitle=Primidone%20in%20the%20treatment%20of%20the%20long%20QT%20syndrome:%20QT%20shortening%20and%20ventricular%20arrhythmia%20suppression.&aulast=DeSilvey&date=1980}}</ref>
The second case report, published in the December 1986 issue of ''Zhonghua Xin Xue Guan Bing Za Zhi'', describes four cases, men, women, adults and adolescents, who were put on primidone for LQTS.<ref name=longqt1986china>{{zh}} {{cite journal | first = Y. W. | last = Lan | year = 1986 | month = December | title = [Primidone in the treatment of long Q-T syndrome. Clinical analysis of 4 cases]" | journal = Zhonghua Xin Xue Guan Bing Za Zhi (Chinese Journal of Cardiovascular Diseases) | volume = 14 | issue = 6 | pages = 330–2, 380 | pmid = 3582153}}</ref> The 2002 case focuses on [[hypocalcemia]] stemming from such treatment in an adolescent male. The primidone he had been taking suppressed his hypocalcemia-induced QT prolongation.<ref name=longqt2002greece>{{cite science | first = Konstantinos | last = Loukeris | coauthors = Davide Mauri and Padelis Pazarlis | month = October | year = 2002 | title = QT length and heart function in primidone hypocalcaemia | journal = [[Acta Cardiologica]] | volume = 57 | issue = 5 | pages = 367–369 | doi = 0.2143/AC.57.5.2005455 | pmid = 12405576 | url = http://poj.peeters-leuven.be/content.php?url=article&id=2005455&journal_code=AC&download=yes | format = PDF | abstract = http://poj.peeters-leuven.be/content.php?url=article&id=2005455&journal_code=AC }}</ref>
===Psychiatric disorders===
In 1965, Monroe and Wise reported using primidone along with a [[phenothiazine]] derivative [[antipsychotic]] and [[chlordiazepoxide]] in treatment-resistant [[psychosis]].<ref name=antipsychotic>{{cite journal | first = Russell R. | last = Monroe | coauthors = Samuel P. Wise, III. | year = 1965 | month = December | title = Combined phenothiazine, chlordiazepoxide and primidone therapy for uncontrolled psychotic patients | journal = American Journal of Psychiatry | volume = 122 | issue = 6 | pages = 694–8 | doi = 10.1176/appi.ajp.122.6.694 | pmid = 5320821 | url = http://ajp.psychiatryonline.org/cgi/reprint/122/6/694 | format = [[PDF]] | accessdate = 2007-02-21 | doi_brokendate = 2008-06-23}}</ref> What is known is that ten 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 they were administered not only did their EEGs improve, but so did the aggression.<ref name=ictalaggression>{{cite journal | first = R. R. | last = Monroe | year = 1975 | month = February | title = Anticonvulsants in the treatment of aggression | journal= Journal of Nervous and Mental Disease | volume = 160 | issue = 2–1 | pages = 119–26 | pmid = 1117287}}</ref>
In March of 1993, S.G. Hayes of the University of Southern California School of Medicine reported that nine out of twenty-seven people (33%) with either treatment-resistant [[clinical depression|depression]] or treatment-resistant bipolar disorder had a permanent positive response to primidone. It should be noted that a plurality of subjects were also given [[methylphenobarbital]] in addition to or instead of primidone.<ref name=hayes1993>{{cite journal | first = S. G. | last = Hayes | year = 1993 | month = March | title = Barbiturate anticonvulsants in refractory affective disorders | journal = Annals of Clinical Psychiatry | volume = 5 | issue = 1 | pages = 35–44 | pmid = 8348197 | doi = 10.3109/10401239309148922}}</ref>
Five months later, Brown, Stone, and Rathbone published a case report titled, "Primidone and rapid cycling affective disorders" describing a 62-year-old woman who had rapid-cycling bipolar disorder starting in 1978. [[lithium salt|Lithium]] treatment was started two years later, but it only eliminated the manic swings, leaving her depressions unaffected. Between 1980 and 1989, the patient had six to ten episodes a year, each lasting between eleven and twenty-four days that left her with little energy, made tasks seem more arduous than they actually were, a smaller appetite, a tendency to sleep too much, anxious, and weepy. No antidepressant eliminated all her symptoms. At the age of fifty-eight, she was started on 125 mg/day of primidone for hand tremor. Her depression, which was resistant to all the antidepressants she tried, gradually remitted during primidone therapy; the expected depressive episode lasted three days instead of 13-17. Eight weeks later, she had an episode lasting twenty-eight days. Her last two episodes were nineteen weeks apart, lasting twenty-five and twenty-seven days, respectively. It was during the final episode, in the middle of 1990, that her dose of primidone was stabilized at 500 mg/day. She had been free of depression for two and a half years before the case report was written up.<ref name="bsr1993">{{cite journal | author = Brown GM | coauthors = Stone GH, Rathbone MP | date = [[October 9]], [[1993]] | title = Primidone and rapid cycling affective disorders | journal = Lancet | volume = 342 | issue = 8876 | pages = 925 | pmid = 8105181 | url = http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=8105181&query_hl=229&itool=pubmed_ExternalLink | doi = 10.1016/0140-6736(93)91972-O}}</ref>
In 1999, Drs. Linda C. Schaffer, Charles B. Schaffer, and J. Caretto conducted a follow-up study on those earlier reports, as no one else had done so in the six years following their publication, and found it to be roughly as (permanently) effective for refractory bipolar disorder as Hayes had reported it to be (31% vs. Hayes's 33%). All subjects with a permanent and complete treatment response were either Bipolar I or Bipolar NOS. In this study, unlike the 1993 case report, primidone had an impact on manic symptoms—especially insomnia, anxiety, and racing thoughts—and only on manic symptoms.<ref name=primidonebipolar2>{{cite journal | author = Schaffer LC | coauthors = Schaffer CB, Caretto J | month = June | year = 1999 | title = The use of primidone in the treatment of refractory bipolar disorder | journal = Annals of Clinical Psychiatry | volume = 11 | issue = 2 | pages = 61–6 | pmid = 10440522 | url = http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&list_uids=10440522&dopt=ExternalLink | doi = 10.3109/10401239909147050}}</ref>
===Other===
Unlike [[carbamazepine]], there are few case reports mentioning the use of primidone in the treatment of [[trigeminal neuralgia]]. The first, published in the October 10, 1957 issue of ''Gazette Médicale de France'', has no abstract.<ref name=trigeminal_neuralgia_1>{{fr icon}} {{cite journal | first = M. | last = Bergouignan | year = 1957 | month = October | title = [Recent developments in the medical treatment of essential trigeminal neuralgia: importance of various anti-epileptic medication.] | journal = Gazette Médicale de France | volume = 64 | issue = 19 | pages = 1571–2 passim | pmid = 13480440}}</ref> The second one was a case report of a woman taking primidone and then phenobarbital for trigeminal neuralgia. She developed [[toxic epidermal necrolysis]], as well as [[endocarditis]] and gastrointestinal [[hemorrhage]]. The second recurrence, induced by phenobarbital, killed her within five weeks of onset.<ref name=trigeminal_neuralgia_2>{{cite journal | first = G. | last = Stuttgen | month = March | year = 1973 | title = Toxic epidermal necrolysis provoked by barbiturates | journal = British Journal of Dermatology | volume = 88 | issue = 3 | pages = 291–3 | pmid = 4541299 | doi = 10.1111/j.1365-2133.1973.tb07551.x}}</ref>
Two trials of primidone for athetosis have been published. In one, small doses of primidone successfully treated eighteen out of thirty-one children. In a subsequent pilot trial in which children who experienced improvement were switched to placebo, the results were much more disappointing, with the two subjects who experienced subjective improvement also experiencing this on placebo.<ref name=Lorber_1958>{{cite journal | last = Lorber | first = John | date = [[July 26]], [[1958]] | title = Primidone Treatment of Athetosis in Children | journal = British Medical Journal | volume = 2 | issue = 5090 | pages = 208 | pmid = 13560827 | url = http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=13560827 | accessdate = 2007-11-14}}</ref>
Primidone has been used in cerebral palsy. In 1953, Plum and Sparup found that out of thirty-three patients, twenty had a favorable or moderate response. Thorn reported in 1962 that sixteen patients responded favorably to both primidone and [[chlordiazepoxide]] and four to only primidone. Nine patients responded only to chlordiazepoxide and four responded to neither drug. The best results were obtained in athetosis and rigidity.<ref name=Thorn_et_al_1962>{{cite journal | last = Thorn | first = I. | month = June | year = 1962 | title = Primidone and chlordiazepoxide in cerebral palsy | journal = Developmental Medicine and Child Neurology | volume = 4 | pages = 325–7 | pmid = 13921015 }}</ref>
Primidone has veterinary uses, including the prevention of [[savaging|aggressive behavior and cannibalism]] in [[gilt]] [[pig]]s, and treatment of nervous disorders in dogs and other animals.<ref name="noahcompendium.co.uk">{{cite web | author = National Office of Animal Health | url = http://www.noahcompendium.co.uk/Schering-Plough_Animal_Health/Mysoline_Veterinary_Tablets/-34475.html | title = Compendium of Veterinary Medicine | accessdate = 2007-03-19}}</ref><ref name="thepigsite.com">{{cite web | author = The Pig Site | url = http://www.thepigsite.com/pighealth/article/260/savaging-of-piglets-cannibalism | title = Savaging of Piglets | accessdate = 2007-03-19}}</ref>
==Mechanism of action==
The exact mechanism of primidone's anticonvulsant action is still unknown after over fifty years.<ref name=primidone_pharmacology>{{cite web | url = http://www.rxlist.com/cgi/generic/primid_cp.htm | title = Mysoline: Clinical Pharmacology | accessdate = 2007-10-07 | work = RxList }}</ref> It is believed to work via interactions with voltage-gated sodium channels which inhibit high-frequency repetitive firing of action potentials.<ref name=MacDonald_et_al_1995>{{cite journal | first = R. L. | last = MacDonald | coauthors = K. M. Kelly | year = 1995 | title = Antiepileptic drug mechanisms of action | journal = Epilepsia | volume = 36 | issue = Suppl 2 | pages = S2–12 | pmid = 8784210 | doi = 10.1111/j.1528-1157.1995.tb05996.x }}</ref>
The effect of primidone in essential tremor is not mediated by PEMA.<ref name="Calzetti_et_al_1981">{{cite journal | last = Calzetti | first = S. | coauthors = L. J. Findley, F. Pisani and A. Richens | month = October | year = 1981 | title = Phenylethylmalonamide in essential tremor. A double-blind controlled study | journal = Journal of Neurology, Neurosurgery, and Psychiatry | volume = 44 | issue = 10 | pages = 932–934 | pmid = 7031184 | url = http://jnnp.bmj.com/cgi/content/abstract/44/10/932 | accessdate = 2007-02-12}}</ref>
==Overdose==
The most common symptoms of primidone overdose are coma with loss of [[deep tendon reflex]]es and, during the recovery period, if the patient survives, disorientation, [[dysarthria]], nystagmus, and ataxia,<ref name=Kappy_et_al_1969>{{cite journal | first = Michael S. | last = Kappy | coauthors = Jerome Buckley | month = April | year = 1969 | title = Primidone intoxication in a child | journal = Archives of Disease in Childhood | volume = 44 | issue = 234 | pages = 282–4 | pmid = 5779436 }}</ref>lethargy, somnolence, vomiting, nausea, and occasionally, focal neurological deficits which lessen over time.<ref name=Brillman_et_al_1974>{{cite journal | first = J. | last = Brillman | coauthors = B. B. Gallagher, and R. H. Mattson | month = March | year = 1974 | title = Acute primidone intoxication | journal = Archives of Neurology | volume = 30 | issue = 3 | pages = 255–8 | pmid = 4812959 }}</ref> Complete recovery comes within five to seven days of ingestion.<ref name=Kappy_et_al_1969/> The symptoms of primidone poisoning have generally been attributed to its biotransformation to phenobarbital; however, primidone has toxic effects independent of its metabolites in humans.<ref name=Brillman_et_al_1974/> The massive [[crystalluria]] that sometimes occurs sets its symptom profile apart from that of phenobarbital.<ref name=Bailey_et_al_1972>{{cite journal | first = D. N. | last = Bailey | coauthors = P. I. Jatlow | month = November | year = 1972 | title = Chemical analysis of massive crystalluria following primidone overdose | journal = American Journal of Clinical Pathology | volume = 58 | issue = 5 | pages = 583–9 | pmid = 4642162 }}</ref><ref name=Turner_1980>{{cite journal | first = C. R. | last = Turner | month = October | year = 1980 | title = Primidone intoxication and massive crystalluria | journal = Clinical Pediatrics | volume = 19 | issue = 10 | pages = 706–7 | pmid = 7408374 }}</ref><ref name=van_Heijst_et_al_1983/><ref name=Kappy_et_al_1969/> The crystals are white,<ref name=Bailey_et_al_1972/><ref name=Brillman_et_al_1974/> needle-like,<ref name=van_Heijst_et_al_1983/> shimmering, hexagonal plates consisting mainly of primidone.<ref name=Bailey_et_al_1972/><ref name=Brillman_et_al_1974/>
In the Netherlands alone, there were thirty-four cases of suspected primidone poisoning between 1978 and 1982. Out of these, Primidone poisoning was much less common than phenobarbital poisoning. Twenty-seven of those adult cases were reported to the Dutch National Poison Control Centre. Out of these, one person taking it with phenytoin and phenobarbital died, twelve became drowsy and four were comatose.<ref name=van_Heijst_et_al_1983/>
Treatments for primidone overdose have included [[hemoperfusion]] with forced [[diuresis]],<ref name=van_Heijst_et_al_1983/> a combination of [[bemegride]] and [[amiphenazole]];<ref name=Dotevall_et_al_1957/> and a combination of bemegride, [[spironolactone]], caffeine, [[metrazol|pentylenetetrazol]], strophanthin, penicillin and [[streptomycin]].<ref name=Fazekas_et_al_1960/>
In the three adults who are reported to have succeeded, the doses were 20–30 g.<ref name=Kappy_et_al_1969/><ref name=Dotevall_et_al_1957/><ref name=Fazekas_et_al_1960/> However, two adult survivors ingested 30 g<ref name=Kappy_et_al_1969/> 25 g,<ref name=Dotevall_et_al_1957/> and 22.5 g.<ref name=Brillman_et_al_1974/> One woman experienced symptoms of primidone intoxication after ingesting 750 mg of her roommate's primidone.<ref name=Ajax_1965>{{cite journal | first = E. T. | last = Ajax | month = October | year = 1966 | title = An unusual case of primidone intoxication | journal = Diseases of the Nervous System | volume = 27 | issue = 10 | pages = 660–1 | pmid = 5919666 }}</ref>
==Adverse Effects==
Primidone can cause drowsiness, listless, [[ataxia]], visual disturbances, [[nystagmus]], headache, and dizziness. These side effects are the most common, occurring in more than 1% of users.<ref name=AcorusPI>{{cite web | url = http://www.acorus-therapeutics.com/pdfs/products/MysolineSPCJune%202007.pdf | title = Summary of Product Characteristics | accessdate = 2007-10-12 | date = 2007-06-01 | work = Official Acorus Therapeutics Site | publisher = Acorus Therapeutics | pages = 3-4}}</ref> Transient nausea and vomiting are also common side effects.<ref name=impotence/>
[[Image:Morbus dupuytren fcm.jpg|thumb|right|Dupuytren's contracture of the fourth digit (ring finger).]]
[[Dupuytren's contracture]], a disease of the [[fascia]]e 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, fourteen 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. However, only one quarter of the women were affected vs. half of the men.<ref name="Hart_and_Hooper2005">{{cite journal | last = Hart | first = M. G. | coauthors = G. Hooper | month = July | year = 2005 | title = Clinical associations of Dupuytren's disease. | journal = Postgraduate Medical Journal | volume = 81 | issue = 957 | pages = 425–428 | pmid = 15998816 | url = http://pmj.bmj.com/cgi/content/full/81/957/425 | accessdate = 2007-03-07 | doi = 10.1136/pgmj.2004.027425}}</ref> Thirty-five years later, Critcheley et al 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.<ref name=Critchley1976>{{cite journal | author=Critchley EM, Vakil SD, Hayward HW, Owen VM| title=Dupuytren's disease in epilepsy: result of prolonged administration of anticonvulsants| journal = Journal of Neurology, Neurosurgery, and Psychiatry | volume=39| issue=5| year=1976| pages=498–503 | pmid=932769}}</ref> 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 non-whites.<ref name="Hart_and_Hooper2005"/>
Primidone has other cardiovascular effects in beyond shortening the QT interval. Both it and phenobarbital are associated with elevated serum levels (both fasting and six hours after [[methionine]] [[loading]]) of [[homocysteine]], an [[amino acid]] derived from methionine. This is almost certainly related to the low folate levels reported in primidone users. Elevated levels of homocysteine have been linked to [[coronary heart disease]]. In 1985, both drugs were also reported to increase serum levels of [[high density lipoprotein]] (HDL) [[cholesterol]], total cholesterol, and [[apolipoprotein]]s A and B.<ref name="Schwaninger_et_al_1999">{{cite journal | last = Schwaninger | first = Markus | month = March | year = 1999 | title = Elevated plasma concentrations of homocysteine in antiepileptic drug treatment | journal = [[Epilepsia]] | volume = 40 | issue = 3 | pages = 345–350 | pmid = 10080517 | url = http://www.blackwell-synergy.com/doi/pdf/10.1111/j.1528-1157.1999.tb00716.x | format = [[PDF]] | accessdate = 2007-03-16 | doi = 10.1111/j.1528-1157.1999.tb00716.x}}</ref>
It was first reported to exacerbate hepatic [[porphyria]] in 1975. In 1981, it was shown that phenobarbital, one of primidone's metabolites, only induced a significant [[porphyrin]] at high concentrations ''in vitro''.<ref name=porphyria2>{{cite journal | last = Reynolds, Jr. | first = N. C. | coauthors = Miska, R. M. | year = 1981 | month = April | title = Safety of anticonvulsants in hepatic porphyrias | journal = Neurology | volume = 31 | issue = 4 | pages = 480–4 | pmid = 7194443}}</ref> It can also cause elevations in hepatic enzymes such as [[gamma-glutamyl transferase]] and [[alkaline phosphatase]].<ref name=AcorusPI/>
Less than 1% of primidone users will experience a rash. Compared to carbamazepine, lamotrigine, and phenytoin, this is very low. The rate is comparable to that of felbamate, vigabatrin, and topiramate.<ref name=Arif_et_al_2007>{{cite journal | first = H. | last = Arif | coauthors = R. Buchsbaum, D. Weintraub, S. Koyfman, C. Salas-Humara, C. W. Bazil, S. R. Resor, Jr, and L. J. Hirsch | date = [[May 15]], [[2007]] | title = Comparison and predictors of rash associated with 15 antiepileptic drugs | journal = Neurology | volume = 68 | issue = 20 | pages = 1701–9 | pmid = 17502552 | url = http://www.neurology.org/cgi/content/full/68/20/1701 | accessdate = 2007-09-25 | doi = 10.1212/01.wnl.0000261917.83337.db}}</ref> Primidone also causes [[exfoliative dermatitis]], [[Stevens-Johnson syndrome]], and [[toxic epidermal necrolysis]].<ref name=AcorusPI/>
[[Image:XrayRicketsLegssmall.jpg|thumb|Radiograph of a rickets sufferer|right]]
Primidone, along with phenytoin and phenobarbital, is one of the anticonvulsants most heavily associated with bone diseases such as [[osteoporosis]], [[osteopenia]] (which can precede osteoporosis), [[osteomalacia]] and fractures.<ref name=osteomalacia>{{cite journal | first = A. M. | last = Pack | coauthors = M. J. Morrell | year = 2001 | title = Adverse effects of antiepileptic drugs on bone structure: epidemiology, mechanisms and therapeutic implications | journal = CNS Drugs | volume = 15 | issue = 8 | pages = 633–42 | pmid = 11524035 }}</ref><ref name=Arora_et_al_2006>{{cite journal | last = Valsamis | first = Helen A | coauthors = Surender K Arora, Barbara Labban and Samy I McFarlane | date = [[September 6]] [[2006]] | title = Antiepileptic drugs and bone metabolism | journal = Nutrition & Metabolism | volume = 3 | issue = 36 | doi = 10.1186/1743-7075-3-36 | url = http://www.nutritionandmetabolism.com/content/3/1/36 | accessdate = 2007-03-28 | pages = 36}}</ref><ref name="Harrington_and_Hodkinson_1987">{{cite journal | last = Harrington | first = M. G. | coauthors = H. M. Hodkinson | month = July | year = 1987 | title = Anticonvulsant drugs and bone disease in the elderly | journal = Journal of the Royal Society of Medicine | volume = 80 | issue = 7 | pages = 425–427 | pmid = 3656313 | url = http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1290903 | accessdate = 2007-03-13}}</ref> 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]].<ref name=osteomalacia/> However, it has been suggested that bone demineralization in most pronounced young people (25–44 years of age)<ref name=Arora_et_al_2006/> and one 1987 study of institutionalized people found that the rate of osteomalacia in the ones taking anticonvulsants—one out of nineteen individuals taking an anticonvulsant (vs. none among the thirty-seven people taking none) —was similar to that expected in elderly people. The authors speculated that this was due to improvements in diet, sun exposure and exercise in response to earlier findings, and/or that this was because it was sunnier in London than in the Northern European countries which had earlier reported this effect.<ref name="Harrington_and_Hodkinson_1987"/> In any case, the use of more than one anticonvulsant has been associated with an increased prevalence of bone disease in institutionalized epilepsy patients versus institutionalized people who did not have epilepsy. Likewise, postmenopausal women taking anticonvulsants have a greater risk of fracture than their drug-naive counterparts.<ref name=osteomalacia/>
Anticonvulsants affect the bones in many ways. They cause [[hypophosphatemia]], [[hypocalcemia]], low Vitamin D levels, and increased [[parathyroid hormone]]. Anticonvulsants also contribute to the increased rate of fractures by causing somnolence, ataxia, and tremor which would cause gait disturbance, further increasing the risk of fractures on top of the increase due to seizures and the restrictions on activity placed on epileptic people.Increased fracture rate has also been reported for carbamazepine, valproate and clonazepam. The risk of fractures is higher for people taking enzyme-inducing anticonvulsants than for people taking non-enzyme-inducing anticonvulsants.<ref name=Arora_et_al_2006/> In addition to all of the above, primidone can cause [[arthralgia]].<ref name=AcorusPI/>
[[Granulocytopenia]], [[agranulocytosis]], and [[red-cell hypoplasia]] and aplasia, and megaloblastic anemia are rarely associated with the use of primidone.<ref name="RxList">{{cite web | url = http://www.rxlist.com/cgi/generic/primid_ad.htm | title = Mysoline | accessdate = 2007-03-11 | work = RxList | pages = 3}}</ref> Megaloblastic anemia is actually a group of related disorders with different causes that share morphological characteristics—enlarged [[red blood cell]]s with abnormally high nuclear-to-cytoplasmic ratios resulting from delayed maturation of nuclei combined with normal maturation of cytoplasm, in to abnormal [[megakaryocyte]]s and sometimes [[Wiktionary:hypersegmentation|hypersegmented]] [[neutrophil]]s; regardless of [[etiology]], all of the megaloblastic anemias involve impaired [[DNA synthesis]].<ref name=eMedicine>{{cite web | last = Schick | first = Paul | year = 2005 | url = http://www.emedicine.com/MED/topic1420.htm | title = Megaloblastic Anemia | publisher = eMedicine | accessdate = 2005-08-15}}</ref> The anticonvulsant users who get this also tend to eat monotonous diets devoid of fruits and vegetables.<ref name=Reynolds_et_al_1965>{{cite journal | first = E. H. | last = Reynolds | coauthors = J. F. Hallpike, B. M. Phillips, and D. M. Matthews | month = September | year = 1965 | title = Reversible absorptive defects in anticonvulsant megaloblastic anaemia | journal = Journal of Clinical Pathology | volume = 18 | issue = 5 | pages = 593–598 | pmid = 5835440 | url = http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=473011 | accessdate = 2007-07-15 | doi = 10.1136/jcp.18.5.593}}</ref>
This antagonistic effect is not due to the inhibition of [[dihydrofolate reductase]], the [[enzyme]] responsible for the [[redox|reduction]] of [[folic acid|dihydrofolic acid]] to [[folic acid|tetrahydrofolic acid]], but rather to defective folate metabolism.<ref name=meg-1976>{{cite journal | first = R. H. | last = Girdwood | year = 1976 | title = Drug-induced anaemias | journal = Drugs | volume = 11 | issue = 5 | pages = 394–404 | pmid = 782836 | doi = 10.2165/00003495-197611050-00003}}</ref>
In addition to increasing the risk of megaloblastic anemia, primidone, like other older anticonvulsants also increases the risk of [[neural tube defect]]s,<ref name="O'Brien_et_al_2005">{{cite journal | first = M. D. | last = O'Brien | coauthors = S. K. Gilmour-White | year = 2005 | title = Management of epilepsy in women | journal = Postgraduate Medical Journal | volume = 81 | pages = 278–285 | url = http://pmj.bmj.com/cgi/content/full/81/955/278 | accessdate = 2007-09-16 | doi = 10.1136/pgmj.2004.030221 | pmid = 15879038}}</ref> and like other enzyme-inducing anticonvulsants, it increases the likelihood of cardiovascular defects, and cleft lip without cleft palate.<ref name=birthdefects>{{cite journal | first = S | last = Hernandez-Diaz S | coauthors = Werler MM, Walker AM, Mitchell AA. | title=Folic acid antagonists during pregnancy and the risk of birth defects.| journal=New England Journal of Medicine| volume=343| issue=22| year=2000| pages=1608–14 | pmid=11096168 | url = http://content.nejm.org/cgi/content/full/343/22/1608 | doi=10.1056/NEJM200011303432204}}</ref> Epileptic women are generally advised to take folic acid,<ref name="O'Brien_et_al_2005"/> but there is conflicting evidence regarding the effectiveness of vitamin supplementation in the prevention of such defects.<ref name=Biale_et_al_1984>{{cite journal | first = Y | last = Biale | coauthors = H. Lewenthal | title = Effect of folic acid supplementation on congenital malformations due to anticonvulsive drugs. | journal = European Journal of Obstetrics, Gynecology, and Reproductive Biology | volume = 18 | issue = 4 | pages = 211–6 | pmid = 6519344 | doi = 10.1016/0028-2243(84)90119-9 | year = 1984 }}</ref><ref name=birthdefects/>
Additionally, a [[coagulation]] defect resembling [[Vitamin K]] [[deficiency]] has been observed in newborns of mothers taking primidone.<ref name="O'Brien_et_al_2005"/> Because of this, primidone is a Category D medication.<ref name="vitaminkprimidone">{{cite journal | first = M. K. | last = Bruno | coauthors = C. L. Harden | month = January | year = 2002 | title = Epilepsy in Pregnant Women | journal = Current Treatment Options in Neurology | volume = 4 | issue = 1 | pages = 31–40 | pmid = 11734102 | doi = 10.1007/s11940-002-0003-7}}</ref>
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.<ref name="O'Brien_et_al_2005"/>
In May of 2005, Dr. M. Lopez-Gomez's team reported an association between the use of primidone and [[depression (mood)|depression]] in epilepsy patients; this same study reported that inadequate seizure control, posttraumatic epilepsy, and polytherapy were also risk factors. Polytherapy was also associated with poor seizure control. Out of all of the risk factors, usage of primidone and inadequate seizure control were the greatest; with [[odds ratio|OR]]s of 4.089 and 3.084, respectively. They had been looking for factors associated with depression in epilepsy patients.<ref name=Lopez-Gomez_et_al_2005/> 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, [[trazadone]] 50 mg/day, and alprazolam 4 mg/day for three and a half months experienced auditory hallucinations that led to discontinuation of primidone.<ref name=primidonebipolar2/> It can also cause [[hyperactivity]] in children;<ref name=Stores_1976>{{cite journal | first = G. | last = Stores | year = 1975 | month = October | title = Behavioural effects of anti-epileptic drugs | journal = Developmental Medicine and Child Neurology | volume = 17 | issue = 5 | pages = 647–58 | pmid = 241674}}</ref> this most commonly occurs at low serum levels.<ref name=Herranz_et_al_1988>{{cite journal | first = J. L. | last = Herranz | coauthors = J. A. Armijo, and R. Arteaga | month = November-December | year = 1988 | title = Clinical side effects of phenobarbital, primidone, phenytoin, carbamazepine, and valproate during monotherapy in children | journal = Epilepsia | volume = 29 | issue = 6 | pages = 794–804 | pmid = 3142761 | doi = 10.1111/j.1528-1157.1988.tb04237.x }}</ref> There is one case of an individual developing catatonic schizophrenia when her serum concentration of primidone went above normal.<ref name=Sher_et_al_1983>{{cite journal | first = A. | last = Sher | coauthors = J. M. Andersen, and S. C. Bhatia | month = July-August | year = 1983 | title = Primidone-induced catatonic schizophrenia | journal = Drug Intelligence & Clinical Pharmacy | volume = 17 | issue = 7–8 | pages = 551–2 | pmid = 6872851 }}</ref>
Primidone is one of the anticonvulsants associated with [[anticonvulsant hypersensitivity syndrome]], others being carbamazepine, phenytoin, and phenobarbital. This syndrome consists of fever, rash, peripheral [[leukocytosis]], lymphadenopathy, and occasionally hepatic [[necrosis]].<ref name=primidoneAHS>{{cite journal | first = Raymond G. | last = Schlienger | coauthors = Shear, Neil H. | year = 1998 | title = Antiepileptic drug hypersensitivity syndrome | journal = Epilepsia | volume = 39 | issue = Suppl 7 | pages = S3–7 | pmid = 9798755 | url = http://www.blackwell-synergy.com/doi/pdf/10.1111/j.1528-1157.1998.tb01678.x | format = PDF | accessdate = 2007-01-20 | doi = 10.1111/j.1528-1157.1998.tb01678.x}}</ref>
[[hyperammonemia|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 post-surgery. This is much more common with the valproates than with any of the barbiturates.<ref name=he2002>{{cite journal | author=Katano H, Fukushima T, Karasawa K, Sugiyama N, Ohkura A, Kamiya K.| title=Primidone-induced hyperammonemic encephalopathy in a patient with cerebral astrocytoma.| journal=Journal of Clinical Neuroscience.| volume=9| issue=1| year=2002| pages=79–81 | pmid=11749025 | url = http://www.sciencedirect.com/science?_ob=MImg&_imagekey=B6WHP-457MDPK-N-1&_cdi=6856&_user=10&_orig=search&_coverDate=01%2F31%2F2002&_qd=1&_sk=999909998&view=c&wchp=dGLbVzz-zSkWA&md5=187493fdfe9a11cf9414ba1997a80a15&ie=/sdarticle.pdf| doi=10.1054/jocn.2001.1011}}</ref> A randomized controlled trial whose results were published in the July 1985 issue of ''[[The New England Journal of Medicine]]'' found that primidone was more likely to cause [[impotence]] than phenytoin, carbamazepine, or phenobarbital.<ref name=impotence/> Like phenytoin, primidone is rarely associated with lymphadenopathy.<ref name=Langlands_et_al_1967>{{cite journal | first = A. O. | last = Langlands | coauthors = N. Maclean, J. G. Pearson, and E. R. Williamson | date = [[January 28]], [[1967]] | title = Lymphadenopathy and megaloblastic anaemia in patient receiving primidone. | journal = British Medical Journal | volume = 1 | issue = 5534 | pages = 215–217 | url = http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1840532 | accessdate = 2007-09-19 | pmid = 4959849 }}</ref> Primidone can also cause vomiting; this happens in 1.0–0.1% of users.<ref name=AcorusPI/>
==Interactions==
Taking primidone with [[monoamine oxidase inhibitor]]s (MAOIs) such as [[isocarboxazid]] (Marplan), [[phenelzine]] (Nardil), [[procarbazine]] (Matulane), [[selegiline]] (Eldepryl), [[tranylcypromine]] (Parnate) or within two weeks of stopping any one of them may [[Wiktionary:potentiate|potentiate]] the effects of '''primidone''' or change one's seizure patterns.<ref name=merck>{{cite web | url = http://www.merck.com/mmpe/lexicomp/primidone.html | title =
Primidone | accessdate = 2007-10-04 | work = The Merck Manual's Online Medical Library | publisher = Lexi-Comp }}</ref> [[Isoniazid]], an antitubercular agent with MAOI properties, has been known to strongly inhibit the metabolism of primidone.<ref name=Desta_et_al_2001>{{cite journal | first = Zeruesenay | last = Desta | coauthors = Nadia V. Soukhova, and David A. Flockhart | month = February | year = 2001 | title = Inhibition of Cytochrome P450 (CYP450) Isoforms by Isoniazid: Potent Inhibition of CYP2C19 and CYP3A | journal = Antimicrobial Agents and Chemotherapy | volume = 45 | issue = 2 | pages = 382–392 | pmid = 11158730 | url = http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=11158730 | accessdate = 2007-10-05 | doi = 10.1128/AAC.45.2.382-392.2001}}</ref>
Like many anticonvulsants, primidone interacts with other anticonvulsants. [[Clobazam]] decreases clearance of primidone,<ref name=Theis_et_al_1997>{{cite journal | author=Theis JG, Koren G, Daneman R, Sherwin AL, Menzano E, Cortez M, Hwang P | title=Interactions of clobazam with conventional antiepileptics in children | journal=Journal of Child Neurology | volume=12 | issue=3 | year=1997 | pages=208–13 | pmid=9130097 | url = http://openurl.proquest.com/in?service=pq&issn=0883-0738&volume=12&issue=3&spage=208&pid=ipauto}}</ref>
[[Mesuximide]] increases plasma levels of phenobarbital in primidone users,<ref name=Browne_et_al_1983>{{cite journal | first = Thomas R. | last = Browne | coauthors = Robert G. Feldman, Robert A. Buchanan RA, Nancy C. Allen, L. Fawcett-Vickers, GK Szabo, GF Mattson, SE Norman, DJ Greenblatt | month = April | year = 1983 | title = Methsuximide for complex partial seizures: efficacy, toxicity, clinical pharmacology, and drug interactions | journal = Neurology | volume = 33 | issue = 4 | pages = 414–8 | pmid = 6403891}}</ref> both primidone and phenobarbital accelerate the metabolism of carbamazepine via CYP3A4,<ref name=Spina_et_al_1996>{{cite journal | first = Edoardo | last = Spina | coauthors = Francesco Pisani, and Emilio Perucca | month = September | year = 1996 | title = Clinically significant pharmacokinetic drug interactions with carbamazepine. An update. | journal = Clinical Pharmacokinetics | volume = 31 | issue = 3 | pages = 198–214 | pmid = 8877250}}</ref> and [[lamotrigine]]'s apparent clearance is increased by primidone.<ref name=lamotrigine_interaction>{{cite web | author = GlaxoSmithKline | year = 2005 | url = http://us.gsk.com/products/assets/us_lamictal.pdf | title = LAMICTAL Prescribing Information | accessdate = 2006-03-14}}</ref> 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 antidepressant]]s.<ref name=Spina_and_Perucca_2002>{{cite journal | first = Edoardo | last = Spina | coauthors = Emilio Perucca | month = February | year = 2002 | title = Clinical Significance of Pharmacokinetic Interactions Between Antiepileptic and Psychotropic Drugs | journal = Epilepsia | volume = 43 | issue = Suppl 2 | pages = 37–44 | pmid = 11903482 | url = http://www.blackwell-synergy.com/doi/full/10.1046/j.1528-1157.2002.043s2037.x | accessdate = 2007-10-07 | doi = 10.1046/j.1528-1157.2002.043s2037.x}}</ref> 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, [[sulfonamide]]s, [[trimethoprim]], [[warfarin]], and [[zafirlukast]]. It also interacts with estrogens.<ref name=merck/>
Primidone and the other enzyme-inducing anticonvulsants can cut the half-life of [[antipyrine]] roughly in half (6.2 ± 1.9 h vs. 11.2 ± 4.2 h), and increases the clearance rate by almost 70%. Phenobarbital reduces the half-life to 4.8 ± 1.3 and increases the clearance by almost 109%.<ref name="Perucca_et_al_1984">{{cite journal | last = Perucca | first = E. | coauthors = A. Hedges, K. A. Makki, M. Ruprah, J. F. Wilson, and A. Richens | year = 1984 | title = A comparative study of the relative enzyme inducing properties of anticonvulsant drugs in epileptic patients. | journal = British Journal of Clinical Pharmacology | volume = 18 | issue = 3 | pages = 401–410 | doi = 10.1111/j.1365-2125.2004.02311.x | pmid = 6435654 | url = http://www.blackwell-synergy.com/doi/pdf/10.1111/j.1365-2125.2004.02311.x | format = PDF | accessdate = 2007-03-23}}</ref> 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 [[hypercortisolemia|hypercortisolemic]].<ref name=Young_et_al_1991>{{cite journal | author=Young MC, Hughes IA | title=Loss of therapeutic control in [[congenital adrenal hyperplasia]] due to interaction between dexamethasone and primidone. | journal=Acta Paediatrica Scandinavica | volume=80 | issue=1 | year=1991 | pages=120–4 | pmid=2028784 | doi=10.1111/j.1651-2227.1991.tb11744.x}}</ref> 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.<ref name=Tempelhoff_et_al_1990>{{cite journal | first = Rene | last = Tempelhoff | coauthors = P. A. Modica and Edward L. Spitznagel, Jr. | year = 1990 | month = April | title = Anticonvulsant therapy increases fentanyl requirements during anaesthesia for craniotomy | journal = Canadian Journal of Anaesthesia / Journal Canadien D'Anesthésie | volume = 37 | issue = 3 | pages = 327–32 | pmid = 2108815}}</ref>
==Pharmacokinetics==
Primidone converts to phenobarbital and PEMA;<ref name=>{{cite book |last=Gatti |first=G. |coauthors=M. Furlanut, and E. Perrucca |editor=Gian Maria Pacifici and Olavi Pelkonen (eds.) |title=Interindividual Variability in Human Drug Metabolism |accessdate=2007-11-09 |date=2001-07-01 |publisher=CRC Press |isbn=0748408649 |pages=[http://books.google.com/books?id=mNKWjla41qUC&pg=PA168&dq=primidone+cyp2c9&sig=JesYU9mmuy6RRI-R9BuN1Ic_7pE 168] |chapter=Interindividual variability in the metabolism of anti-epileptic drugs and its clinical application}}</ref> it is still unknown which exact [[cytochrome P450]] enzymes are responsible.<ref name=Desta_et_al_2001/> The phenobarbital, in turn, is metabolized to p-hydroxyphenobarbital.<ref name=Nau_et_al_1980>{{cite journal | author=Nau H | coauthors = Jesdinsky D, Wittfoht W | title=Microassay for primidone and its metabolites phenylethylmalondiamide, phenobarbital and p-hydroxyphenobarbital in human serum, saliva, breast milk and tissues by gas chromatography—mass spectrometry using selected ion monitoring | journal = Journal of Chromatography | volume=182 | issue=1 | year=1980 | pages=71–9 | pmid = 7380904 | url = http://torpedo.nrl.navy.mil/tu/ps/openurl.html?issn=0021-9673&volume=182&issue=1&spage=71 | doi=10.1016/S0378-4347(00)81652-7}}</ref> The rate of primidone metabolism was greatly accelerated by phenobarbital pretreatment, moderately accelerated by primidone pretreatment, and reduced by PEMA pretreatment.<ref name=up-down>{{cite journal | author = Alvin J | coauthors = Goh E, Bush MT | month = July | year = 1975 | title = Study of the hepatic metabolism of primidone by improved methodology | journal = Journal of Pharmacology and Experimental Therapeutics | volume = 194 | issue = 1 | pages = 117–25 | pmid = 1151744}}</ref> In 1983, a new minor metabolite, p-hydroxyprimidone, was discovered.<ref name=Hooper_et_al_1983>{{cite journal | author = Hooper WD | coauthors = Treston AM, Jacobsen NW, Dickinson RG, Eadie MJ | month = November/December | year = 1983 | title = Identification of p-hydroxyprimidone as a minor metabolite of primidone in rat and man | journal = Drug Metabolism and Disposition | volume = 11 | issue = 6 | pages = 607–10 | pmid = 6140148 | url = http://dmd.aspetjournals.org/cgi/reprint/11/6/607}}</ref>
Primidone, carbamazepine, phenobarbital and phenytoin are among the most potent hepatic enzyme inducing drugs in existence. This enzyme induction occurs at therapeutic doses. In fact, people taking these drugs have displayed the highest degree of hepatic enzyme induction on record.<ref name="Perucca_et_al_1984"/> 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 antidepressant]]s. Its metabolite, phenobarbital, is a substrate of [[CYP2C9]],<ref name=Spina_and_Perucca_2002>{{cite journal | first = Edoardo | last = Spina | coauthors = Emilio Perucca | month = February | year = 2002 | title = Clinical Significance of Pharmacokinetic Interactions Between Antiepileptic and Psychotropic Drugs | journal = Epilepsia | volume = 43 | issue = Suppl 2 | pages = 37–44 | pmid = 11903482 | url = http://www.blackwell-synergy.com/doi/full/10.1046/j.1528-1157.2002.043s2037.x | accessdate = 2007-10-07 | doi = 10.1046/j.1528-1157.2002.043s2037.x}}</ref> [[CYP2B6]],<ref name=Lee_et_al_2006>{{cite journal | first = Anna M. | last = Lee | coauthors = Sharon Miksys, and Rachel F. Tyndale | month = July | year = 2006 | title = Phenobarbital increases monkey in vivo nicotine disposition and induces liver and brain CYP2B6 protein | journal = British Journal of Pharmacology | volume = 148 | issue = 6 | pages = 786–4 | doi = 10.1038/sj.bjp.0706787 | pmid = 16751792 | url = http://www.nature.com/bjp/journal/v148/n6/full/0706787a.html | accessdate = 2007-10-07}}</ref> [[CYP2C8]], [[CYP2C19]], [[CYP2A6]], [[CYP3A5]],<ref name=Kojima_et_al_2007>{{cite journal | first = Koki | last = Kojima | coauthors = Kiyoshi Nagata, Tsutomu Matsubara, and Yasushi Yamazoe | month = August | year = 2007 | title = Broad but distinct role of pregnane x receptor on the expression of individual cytochrome p450s in human hepatocytes | journal = Drug Metabolism & Pharmacokinetics | volume = 22 | issue = 4 | pages = 276–86 | pmid = 17827782 | url = http://www.jstage.jst.go.jp/article/dmpk/22/4/276/_pdf | accessdate = 2007-10-07 | doi = 10.2133/dmpk.22.276}}</ref> [[CYP1E1]], and the [[CYP2E]] subfamily.<ref name=Madan_et_al_2003>{{cite journal | first = Ajay | last = Madan | coauthors = Richard A. Graham, Kathleen M. Carroll, Daniel R. Mudra, L. Alayne Burton, Linda A. Krueger, April D. Downey, Maciej Czerwinski, Jameson Forster, Maria D. Ribadeneira, Liang-Shang Gan, Edward L. LeCluyse, Karl Zech, Philmore Robertson, Jr., Patrick Koch, Lida Antonian, Greg Wagner, Li Yu, and Andrew Parkinson | month = April | year = 2003 | title = Effects of Prototypical Microsomal Enzyme Inducers on Cytochrome P450 Expression in Cultured Human Hepatocytes | journal = Drug Metabolism and Disposition | volume = 31 | issue = 4 | pages = 421–31 | pmid = 12642468 | url = http://dmd.aspetjournals.org/cgi/content/full/31/4/421 | accessdate = 2007-10-07 | doi = 10.1124/dmd.31.4.421}}</ref> 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.<ref name=Kojima_et_al_2007/><ref name=Li_et_al_2007>{{cite journal | first = Chien-Chun | last = Li | coauthors = Chong-Kuei Lii, Kai-Li Liu, Jaw-Ji Yang, and Haw-Wen Chen | date = [[August 23]], [[2007]] | title = DHA down-regulates phenobarbital-induced cytochrome P450 2B1 gene expression in rat primary hepatocytes by attenuating CAR translocation | journal = Toxicology and Applied Pharmacology | doi = 10.1016/j.taap.2007.08.009 | pmid = 17904175 | volume = 225 | pages = 329 }}</ref> Primidone does not activate PXR.<ref name=Kobayashi_et_al_2004>{{cite journal | first = Kaoru | last = Kobayashi | coauthors = Saeko Yamagami, Tomoaki Higuchi, Masakiyo Hosokawa, and Kan Chiba | month = April | year = 2004 | title = Key structural features of ligands for activation of human pregnane X receptor | journal = Drug Metabolism and Disposition | volume = 32 | issue = 4 | pages = 468–72 | pmid = 15039302 | url = http://dmd.aspetjournals.org/cgi/content/full/32/4/468 | accessdate = 2007-10-07 | doi = 10.1124/dmd.32.4.468}}</ref>
The rate of metabolism of primidone into phenobarbital was [[inverse relation|inversely related]] to age; the highest rates were in the oldest patients (the maximum age being 55).<ref name=pediatric-pk>{{cite journal | author=Battino D, Avanzini G, Bossi L, Croci D, Cusi C, Gomeni C, Moise A.| title=Plasma levels of primidone and its metabolite phenobarbital: effect of age and associated therapy.| journal=Therapeutic Drug Monitoring| volume=5| issue=1| year=1983| pages=73–9 | pmid=6845402}}</ref> People aged 70-81, relative to people aged 18-26, have decreased renal clearance of primidone, phenobarbital, and PEMA, in ascending order of [[statistical significance|significance]], and that there was a greater proportion of PEMA in the urine.<ref name=geriatric-pk>{{cite journal | author=Martines C, Gatti G, Sasso E, Calzetti S, Perucca E.| title=The disposition of primidone in elderly patients.| journal=British Journal of Clinical Pharmacology| volume=30 | issue=4 | year=1990 | pages=607–11 | pmid=2291873}}</ref> 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 twelve 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. However, 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 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.<ref name=Kappy_et_al_1969/>
==Available forms==
Primidone is available as a 250 mg/5mL suspension, and in the form of 50 mg, 125 mg, and 250 tablets. It is also available in a chewable tablet formulation in Canada.<ref name=chewable>{{cite web | url = http://www.epilepsy.com/medications/b_mysoline_intro.html | title = Mysoline | accessdate = 2007-01-10 | last = Schachter | first = Steven C. | year = 2004 | month = February | work = Epilepsy.com | publisher = Epilepsy Therapy Development Project}}</ref>
The available brands include Mysoline (Canada,<ref name=valeantmysoline>{{cite web | url = http://www.valeant.com/products/index.jspf | title = Valeant Pharmaceuticals International: Products | accessdate = 2005-07-03}}</ref> Ireland,<ref name=brandnameIreland>{{cite web | url = http://www.acorus-therapeutics.com/index_Page910.htm | title = Service List | accessdaymonth = 13 March | accessyear = 2006}}</ref> Japan,<ref name=Japan_brand_names>{{cite web | author = Dainippon Sumitomo Pharma | year = 2005 | url = http://med.ds-pharma.co.jp/medicine/ryouiki/seishin/doc/primidone_tabfgr_tenpu.pdf | title = Primidone 250 mg Tablets & Primidone 99.5% Powder | format = PDF | accessmonthday = March 13 | accessyear = 2006}}</ref> the United Kingdom,<ref name=brandnameuk>{{cite web | url = http://www.acorus-therapeutics.com/index_orderinguk.htm | title = Acorus Therapeutics Ltd. - Ordering - UK | accessdate = 2005-07-04 | work = acorus-therapeutics.com | publisher = Acorus Therapeutics}}</ref> and the United States<ref name=valeantmysoline/>), Prysoline (Israel, Rekah Pharmaceutical Products, Ltd.),<ref name=Rekah_Prysoline>{{cite web | year = 2005 | url = http://www.health.gov.il/units/pharmacy/trufot/PerutTrufa.asp?Reg_Number=024%2079%2021145%2000 | title = Prysoline Tablets | work = The Israel Drug Registry | publisher = The State of Israel | accessdate = 2006-02-17 }}</ref> Apo-Primidone,<ref name=chewable/><ref name=>{{cite web | url = http://www.epilepsy.com/medications/b_mysoline_intro.html | title = APO-PRIMIDONE | accessdate = 2007-01-10 | date = 2007-01-10 | publisher = Apotex }}</ref> Liskantin (Germany, Desitin),<ref name=destinin.de>{{cite web | url = http://www.desitin.de/index.php/article/detail/766 | title = Liskantin | accessdate = 2005-07-03 | publisher = Desitin}}</ref> Resimatil (Germany, [[Sanofi-Synthélabo]] [[GmbH]]),<ref name=netdoktor.de>{{cite web | url = http://www.dkv.com/content_appl.phtml?content=http://dkv.netdoktor.de/redesign/medikamente/100001437.htm | title = Resimatil Tabletten | accessdate = 2005-07-03 | publisher = Deutsche Krankenversicherung AG }}</ref> and Mylepsinum (Germany, [[AWD.pharma]] [[GmbH]] & Co., [[Kommanditgesellschaft|KG]]).<ref name=dvk.netdoktor.de>{{cite web | url = http://www.dkv.com/content_appl.phtml?content=http://dkv.netdoktor.de/redesign/medikamente/100001217.htm | title = Mylepsinum Tabletten | accessdate = 2005-07-03 | publisher = Deutsche Krankenversicherung AG }}</ref>, Sertan (Hungary, 250mg tablets, [[ICN Pharmaceuticals Inc.]][[http://www.kfki.hu/chemonet/mkl/mkl98/mkl10/icn.html]])
It has been available in the United States as a generic drug from Lannett since 1978.<ref name=lannet>{{cite web | url = http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.Label_ApprovalHistory#apphist | title = Approval History |
work = Drugs@FDA | publisher = United States Food and Drug Administration Center for Drug Evaluation and Research | accessdaymonth = 17 February | accessyear = 2006}}</ref>
==References==
{{reflist|3}}
==Further reading==
* {{cite web | url = http://ntp.niehs.nih.gov/index.cfm?objectid=070AA2DE-BEEC-884F-558DED2D4C3BEAD6 | title = TR-476 Toxicology and Carcinogenesis Studies of Primidone (CAS No. 125-33-7) in F344/N Rats and B<sub>6</sub>C<sub>3</sub>F<sub>1</sub> Mice (Feed Studies) | publisher = Department of Health and Human Services National Toxicology Program | accessdaymonth = 2 July | accessyear = 2005}}
==External links==
* [http://www.valeant.com/ Official Website of Valeant Pharmaceuticals International]
{{Anticonvulsants}}
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[[Category:Barbiturates]]
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