피리미돈

Pharmaceuticals -> Used in Switzerland

Pharmaceuticals

Pharmaceuticals -> Listed in ZINC15

Pharmaceuticals -> Antiepileptic

log Kow = 0.91

1.6

0.91

Practically tasteless

Slightly bitter taste

Crystals

White crystalline powder

less than 1 mg/mL at 66 °F (NTP, 1992)

In water, 480 mg/L at 30 °C

Very slightly soluble in water

Very slightly soluble in most organic solvents

1.04e+00 g/L

Breast Feeding; Lactation; Milk, Human; Anticonvulsants; Barbiturates

FDA approved drugs -> Active ingredient

FDA approved drugs -> Active ingredient

Pharmaceuticals

538 to 540 °F (NTP, 1992)

281.5 °C

MP: 281-282 °C

281.5 °C

Primaclone is an odorless white crystalline powder. Slightly bitter taste. No acidic properties. (NTP, 1992)

Solid

Danger

H302 (100%): Harmful if swallowed [Warning Acute toxicity, oral]

P203, P264, P270, P280, P301+P317, P318, P330, P405, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 49 reports by companies from 7 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

Warning

H302: Harmful if swallowed [Warning Acute toxicity, oral]

Hazard Traits - Carcinogenicity

Primidone: Does not have an individual approval but may be used under an appropriate group standard

SYMPTOMS: Symptoms of exposure to this compound via ingestion may include sleepiness, mental confusion, unsteadiness, coma, slow and shallow respiration flaccid muscles, hypotension, cyanosis, hypothermia or hyperthermia, absent reflexes, painful gums and excessive fatigue. Other symptoms of exposure through ingestion may include ataxia, vertigo, nausea, anorexia, vomiting, hyperirritability, emotional disturbances, sexual impotency, diplopia, nystagmus, morbilliform skin eruptions and possible megaloblastic anemia. Ingestion may also lead to sedation, dizziness, an acute feeling of intoxication, maculopapular rash, leukopenia, thrombocytopenia, systemic lupus erythematosus, lymphadenopathy, acute psychotic reactions, hemorrhagic disease in the neonate and osteomalacia. It can cause mental dullness, drooping of the eyelids and, rarely, blurred and narrow vision. It can also cause a coma, the duration of which is dependent on the dose. If the coma continues, moist rales are heard in the lower lung fields, indicating pulmonary edema. Atelectasis or aspiration pneumonia with signs of lung consolidation and fever can also occur. Carbon dioxide retention under these conditions causes acidosis. Death occurs most often from pneumonia, pulmonary edema or refractory hypotension. Cerebral edema contributes to the persistence of coma. Chronic symptoms of ingestion include skin rash, mental confusion, drowsiness, hangover, emotional lability or depression, irritability, poor judgment, neglect of personal appearance and other behavior disturbances. Other symptoms may include general malaise, polyuria, thyroid enlargement, epidermal necrolysis, tremors, central nervous system depression, disequilibrium, personality changes, thirst and impaired sexual function.

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including primidone, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

The Generic Animal Drug and Patent Restoration act requires that each sponsor of an approved animal drug must submit to the FDA certain information regarding patents held for the animal drug or its method of use. The Act requires that this information, as well as a list of all animal drug products approved for safety and effectiveness, be made available to the public. Primidone is included on this list.

Oral dosage form new animal drugs. Primidone. ... Indications for use. For the control of convulsions associated with idiopathic epilepsy, epileptiform convulsions, viral encephalitis, distemper, and hardpad disease that occurs as a clinically recognizable lesion in certain entities in dogs. ... Limitations. Federal law restricts this drug to use by or on the order of a licensed veterinarian.

Brodie MJ, Dichter MA; N Engl J Med 334: 168-75 (1996). A review of the practical management of epilepsy with established antiepileptic drugs is /presented/.

Dessens AB, et al; Acta Paediatr Suppl 404: 54-64 (1994). Studies on long lasting consequences of prenatal exposure to anticonvulsant drugs.

Pranzatelli MR, Nadi NS; Adv Neurol 67: 329-60 (1995). Mechanism of action of antiepileptic drugs and antimyoclonic drugs.

Pacifici GM, Nottoli R; Clin Pharm 28 (3): 235-69 (1995). Placental transfer of drugs administered to the mother.

For more Special Reports (Complete) data for Primidone (8 total), please visit the HSDB record page.

EYES: First check the victim for contact lenses and remove if present. Flush victim's eyes with water or normal saline solution for 20 to 30 minutes while simultaneously calling a hospital or poison control center. Do not put any ointments, oils, or medication in the victim's eyes without specific instructions from a physician. If symptoms (such as redness or irritation) develop, immediately transport the victim to a hospital.

Suitable extinguishing media: Use water spray, alcohol-resistant foam, dry chemical or carbon dioxide.

Advice for firefighters: Wear self contained breathing apparatus for fire fighting if necessary.

PRECAUTIONS FOR "CARCINOGENS": Storage site should be as close as practical to lab in which carcinogens are to be used, so that only small quantities required for ... expt need to be carried. Carcinogens should be kept in only one section of cupboard, an explosion-proof refrigerator or freezer (depending on chemicophysical properties ...) that bears appropriate label. An inventory ... should be kept, showing quantity of carcinogen & date it was acquired ... Facilities for dispensing ... should be contiguous to storage area. /Chemical Carcinogens/

Keep container tightly closed in a dry and well-ventilated place.

Primidone tablets should be stored in well-closed containers at a temperature less than 40 °C, preferably at 15-30 °C.

PRECAUTIONS FOR "CARCINOGENS": A high-efficiency particulate arrestor (HEPA) or charcoal filters can be used to minimize amt of carcinogen in exhausted air ventilated safety cabinets, lab hoods, glove boxes or animal rooms ... Filter housing that is designed so that used filters can be transferred into plastic bag without contaminating maintenance staff is avail commercially. Filters should be placed in plastic bags immediately after removal ... The plastic bag should be sealed immediately ... The sealed bag should be labelled properly ... Waste liquids ... should be placed or collected in proper containers for disposal. The lid should be secured & the bottles properly labelled. Once filled, bottles should be placed in plastic bag, so that outer surface ... is not contaminated ... The plastic bag should also be sealed & labelled. ... Broken glassware ... should be decontaminated by solvent extraction, by chemical destruction, or in specially designed incinerators. /Chemical Carcinogens/

ACCIDENTAL RELEASE MEASURES: Personal precautions, protective equipment and emergency procedures: Use personal protective equipment. Avoid dust formation. Avoid breathing vapors, mist or gas. Ensure adequate ventilation. Evacuate personnel to safe areas. Avoid breathing dust. Environmental precautions: Prevent further leakage or spillage if safe to do so. Do not let product enter drains. Methods and materials for containment and cleaning up: Pick up and arrange disposal without creating dust. Sweep up and shovel. Keep in suitable, closed containers for disposal.

SMALL SPILLS AND LEAKAGE: If you spill this chemical, you should dampen the solid spill material with water, then transfer the dampened material to a suitable container. Use absorbent paper dampened with water to pick up any remaining material. Seal your contaminated clothing and the absorbent paper in a vapor-tight plastic bag for eventual disposal. Wash all contaminated surfaces with a soap and water solution. Do not reenter the contaminated area until the Safety Officer (or other responsible person) has verified that the area has been properly cleaned.

SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.

PRECAUTIONS FOR "CARCINOGENS": There is no universal method of disposal that has been proved satisfactory for all carcinogenic compounds & specific methods of chem destruction ... published have not been tested on all kinds of carcinogen-containing waste. ... summary of avail methods & recommendations ... /given/ must be treated as guide only. /Chemical Carcinogens/

PRECAUTIONS FOR "CARCINOGENS": ... Incineration may be only feasible method for disposal of contaminated laboratory waste from biological expt. However, not all incinerators are suitable for this purpose. The most efficient type ... is probably the gas-fired type, in which a first-stage combustion with a less than stoichiometric air:fuel ratio is followed by a second stage with excess air. Some ... are designed to accept ... aqueous & organic-solvent solutions, otherwise it is necessary ... to absorb soln onto suitable combustible material, such as sawdust. Alternatively, chem destruction may be used, esp when small quantities ... are to be destroyed in laboratory. /Chemical Carcinogens/

PRECAUTIONS FOR "CARCINOGENS": HEPA (high-efficiency particulate arrestor) filters ... can be disposed of by incineration. For spent charcoal filters, the adsorbed material can be stripped off at high temp & carcinogenic wastes generated by this treatment conducted to & burned in an incinerator. ... LIQUID WASTE: ... Disposal should be carried out by incineration at temp that ... ensure complete combustion. SOLID WASTE: Carcasses of lab animals, cage litter & misc solid wastes ... should be disposed of by incineration at temp high enough to ensure destruction of chem carcinogens or their metabolites. /Chemical Carcinogens/

For more Disposal Methods (Complete) data for Primidone (7 total), please visit the HSDB record page.

PRECAUTIONS FOR "CARCINOGENS": Smoking, drinking, eating, storage of food or of food & beverage containers or utensils, & the application of cosmetics should be prohibited in any laboratory. All personnel should remove gloves, if worn, after completion of procedures in which carcinogens have been used. They should ... wash ... hands, preferably using dispensers of liq detergent, & rinse ... thoroughly. Consideration should be given to appropriate methods for cleaning the skin, depending on nature of the contaminant. No standard procedure can be recommended, but the use of organic solvents should be avoided. Safety pipettes should be used for all pipetting. /Chemical Carcinogens/

PRECAUTIONS FOR "CARCINOGENS": In animal laboratory, personnel should remove their outdoor clothes & wear protective suits (preferably disposable, one-piece & close-fitting at ankles & wrists), gloves, hair covering & overshoes. ... Clothing should be changed daily but ... discarded immediately if obvious contamination occurs ... /also,/ workers should shower immediately. In chemical laboratory, gloves & gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, & disposable plastic aprons might provide addnl protection. If gowns are of distinctive color, this is a reminder that they should not be worn outside of lab. /Chemical Carcinogens/

PRECAUTIONS FOR "CARCINOGENS": ... Operations connected with synth & purification ... should be carried out under well-ventilated hood. Analytical procedures ... should be carried out with care & vapors evolved during ... procedures should be removed. ... Expert advice should be obtained before existing fume cupboards are used ... & when new fume cupboards are installed. It is desirable that there be means for decreasing the rate of air extraction, so that carcinogenic powders can be handled without ... powder being blown around the hood. Glove boxes should be kept under negative air pressure. Air changes should be adequate, so that concn of vapors of volatile carcinogens will not occur. /Chemical Carcinogens/

PRECAUTIONS FOR "CARCINOGENS": Vertical laminar-flow biological safety cabinets may be used for containment of in vitro procedures ... provided that the exhaust air flow is sufficient to provide an inward air flow at the face opening of the cabinet, & contaminated air plenums that are under positive pressure are leak-tight. Horizontal laminar-flow hoods or safety cabinets, where filtered air is blown across the working area towards the operator, should never be used ... Each cabinet or fume cupboard to be used ... should be tested before work is begun (eg, with fume bomb) & label fixed to it, giving date of test & avg air-flow measured. This test should be repeated periodically & after any structural changes. /Chemical Carcinogens/

For more Preventive Measures (Complete) data for Primidone (14 total), please visit the HSDB record page.

RECOMMENDED RESPIRATOR: Where the neat test chemical is weighed and diluted, wear a NIOSH-approved half face respirator equipped with an organic vapor/acid gas cartridge (specific for organic vapors, HCl, acid gas and SO2) with a dust/mist filter. (NTP, 1992)

PRECAUTIONS FOR "CARCINOGENS": ... Dispensers of liq detergent /should be available./ ... Safety pipettes should be used for all pipetting. ... In animal laboratory, personnel should ... wear protective suits (preferably disposable, one-piece & close-fitting at ankles & wrists), gloves, hair covering & overshoes. ... In chemical laboratory, gloves & gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, & disposable plastic aprons might provide addnl protection. ... Gowns ... /should be/ of distinctive color, this is a reminder that they are not to be worn outside the laboratory. /Chemical Carcinogens/

Eye/face protection: Safety glasses with side-shields conforming to EN166. Use equipment for eye protection tested and approved under appropriate government standards such as NIOSH (US) or EN 166(EU).

Skin protection: Handle with gloves.

Body Protection: Complete suit protecting against chemicals. The type of protective equipment must be selected according to the concentration and amount of the dangerous substance at the specific workplace.

Respiratory protection: For nuisance exposures use type P95 (US) or type P1 (EU EN 143) particle respirator. For higher level protection use type OV/AG/P99 (US) or type ABEK-P2 (EU EN 143) respirator cartridges. Use respirators and components tested and approved under appropriate government standards such as NIOSH (US) or CEN (EU).

When acetaminophen in therapeutic doses is used concurrently in patients receiving chronic primidone therapy, its effects may be decreased because of increased metabolism resulting from induction of hepatic microsomal enzymes by the phenobarbital metabolite; also, risk of hepatotoxicity with single toxic doses or prolonged use of acetaminophen may be increased in chronic alcoholics or in patients regularly using hepatic-enzyme inducing agents.

Concurrent use of adrenocorticoids, glucocorticoid and mineralocorticoid; coumarin- or indandione-derivative anticoagulants; tricyclic antidepressants; chloramphenicol; oral estrogen-containing contraceptives; corticotropin (ACTH); cyclosporine; dacarbazine; digitalis glycosides, with possible exception of digoxin; disopyramide; doxycycline; levothyroxine; metronidazole; mexiletine; or quinidine with primidone may decrease the effects of these medications because of increased metabolism resulting from induction of hepatic microsomal enzymes by the barbiturate metabolite. Dosage increases may be necessary during and after primidone therapy. Use of nonhormonal method of birth control or a progestin-only oral contraceptive may be necessary during primidone therapy. Also, concurrent use of tricyclic antidepressants with primidone may enhance CNS depression, lower convulsive threshold, and decrease the effects of primidone; dosage adjustments may be necessary to control seizures.

Concurrent use of alcohol or CNS depression-producing medications may potentiate the CNS and respiratory depressant effects of either these medications or primidone; dosage adjustment of primidone may be necessary.

Concurrent use of amphetamines may cause a delay in the intestinal absorption of the phenobarbital metabolite.

For more Interactions (Complete) data for Primidone (21 total), please visit the HSDB record page.

In clinical trials in epilepsy, therapy with primidone was not associated with an increased frequency of serum aminotransferase elevations or liver toxicity. Primidone therapy can lead to increases in gamma glutamyltranspeptidase (GGT) levels. Elevations in alkaline phosphatase levels were largely due to bone isoforms of the enzyme. There have been no convincing reports of hepatotoxicity due to primidone in humans and no reports of its association with acute liver failure. Interestingly, primidone appears to cause cirrhosis in dogs. Because of its similarity in structure to phenytoin and phenobarbital (aromatic anticonvulsant), it has been suspected to cross react with those agents in causing anticonvulsant hypersensitivity syndrome, but convincing case reports have not been published.

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 140(SRC), determined from a structure estimation method(2), indicates that primidone is expected to have high mobility in soil(SRC). Volatilization of primidone from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 1.9X10-13 atm-cu m/mole(SRC), developed using a fragment constant estimation method(3). Primidone is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 3.3X10-10 mm Hg at 25 °C(SRC), determined from a fragment constant method(2). Biodegradation data in soil were not available(SRC, 2018).

AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 140(SRC), determined from a structure estimation method(2), indicates that primidone is not expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is not expected(3) based upon an estimated Henry's Law constant of 1.9X10-13 atm-cu m/mole(SRC), developed using a fragment constant estimation method(2). According to a classification scheme(4), an estimated BCF of 3(SRC), from its log Kow of 0.91(5) and a regression-derived equation(2), suggests the potential for bioconcentration in aquatic organisms is low(SRC). Biodegradation data in water were not available(SRC, 2018).

ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), primidone, which has an estimated vapor pressure of 3.3X10-10 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), is expected to exist solely in the particulate phase in the ambient atmosphere. Particulate-phase primidone may be removed from the air by wet and dry deposition(SRC). Primidone does not contain chromophores that absorb at wavelengths >290 nm(3) and, therefore, is not expected to be susceptible to direct photolysis by sunlight(SRC).

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

IDENTIFICATION AND USE: Primidone is anticonvulsant, which is used alone or concomitantly with other anticonvulsants. It is indicated in the control of grand mal, psychomotor, and focal epileptic seizures. Primidone can be used for seizure control in dogs. HUMAN STUDIES: Overdosage of primidone results in symptoms similar to those of acute barbiturate intoxication. In addition, primidone crystalluria may occur and may facilitate the diagnosis. A case was reported of a patient who developed megaloblastic anemia caused by folate deficiency during treatment with primidone. In one study, children of epileptic women on medication with primidone were of lower weight and had smaller heads than children from epileptic mothers without medication and children from parents without epilepsy. Fetal exposure to primidone was associated with Goldenhar syndrome, hemifacial microsomia, tetralogy of Fallot, aqueductal stenosis, and anterior encephalocele in male infant. There is a report of the acardiac acephalic fetus of an epileptic mother who was on primidone therapy. In vitro studies showed no chromosomal aberration in human lymphocytes. ANIMAL STUDIES: Primidone caused a significant increase in the incidence of follicular cell adenoma of the thyroid in male rats. There was a small but significant increase in the incidence of renal tubule adenoma or carcinoma. The incidence of renal tubule hyperplasia was also increased in all groups of males receiving primidone. There was no significant increase in the incidence of any neoplasm in females. In mice, primidone caused significant increases in the incidence of hepatocellular adenoma, of hepatocellular carcinoma, and of hepatocellular adenoma, hepatocellular carcinoma, and hepatoblastoma (combined) in all dosed groups of males and females compared with controls. Primidone caused significant increases in the incidence of hepatoblastoma in all dosed groups of males. In males, there was also a significant positive trend in the incidence of follicular cell adenoma of the thyroid in mice receiving pyrimidone. There was an increased incidence in follicular cell hyperplasia of the thyroid in males and females receiving primidone. In pregnant rats treated with primidone the findings were consistent with the neurobehavioral teratology of phenobarbital, including its ability to produce lesions in the hippocampus and endocrine dysfunction resulting in reproductive deficits. These results suggest that primidone produced its adverse effects as a result of its metabolism to phenobarbital, which in turn affects the limbic system. Primidone was tested in as many as 5 Salmonella typhimurium strains (TA1535, TA1537, TA97, TA98, and TA100) in the presence and absence of metabolic activation. The compound was positive in strain TA1535 without activation. Because primidone is rapidly metabolized to phenobarbital in dogs, similar clinical signs (sedation to coma, anorexia, vomiting, nystagmus) are seen and corresponding procedures should be used for the treatment of acute primidone overdose.

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

The following link will take the user to the National Toxicology Program (NTP) Test Status of Agents Search page, which tabulates the results and current status of tests such as "Short-Term Toxicity Studies", "Long-term Carcinogenicity Studies", "Developmental Studies", "Genetic Toxicology Studies", etc., performed with this chemical. Testing status for primidone is available.[Available from, as of February 1, 2019: https://ntpsearch.niehs.nih.gov/?e=True&ContentType=Testing+Status]

EPA has released the Interactive Chemical Safety for Sustainability (iCSS) Dashboard. The iCSS Dashboard provides an interactive tool to explore rapid, automated (or in vitro high-throughput) chemical screening data generated by the Toxicity Forecaster (ToxCast) project and the federal Toxicity Testing in the 21st century (Tox21) collaboration. /The title compound was tested by ToxCast and/or Tox21 assays/[USEPA; ICSS Dashboard Application; Available from, as of February 4, 2019: http://actor.epa.gov/dashboard/]

A concentration range of 11-130 ug/L was reported for primidone in Lake Mead waste water samples, USA, sampled in 2001(1). Concentrations of primidone in wastewater influent during and after a major US sporting event in 2011 were 68 and 42 g/day, respectively. Respective estimated effluent concentrations were 51 and 112 g/day(2). Primidone exhibited a removal rate range of -8 to 20% in an urban sewage treatment plant in Dresdin Germany, sampled for 10 consecutive days in January/February, 2015(3). Removal of primidone in wastewater treatment is minimal(4). Using wastewater samples from nine municipal wastewater treatment plants in the area of Zurich, Switzerland, mean primidone concentrations in influent and effluent were 0.17 and 0.18 ug/L, respectively(4). The compound was reported at mean concentrations of 122, 148 and 149 ng/L in effluent from a tertiary wastewater treatment facility in Los Angeles, CA sampled in July 2008, May 2009, and October 2009, respectively(5). Concentrations of 10.8 and 18-30 ng/L were reported in industrial waste water and sewage water, respectively, from The Netherlands in 2002(6). Primidone was present at a mean concentration of 2.5 ng/L in effluent discharged from nine wastewater treatment plants into the Han River, Seoul, South Korea, sampled on Sept 30, 2008(6).

PRECAUTIONS FOR "CARCINOGENS": Whenever medical surveillance is indicated, in particular when exposure to a carcinogen has occurred, ad hoc decisions should be taken concerning ... /cytogenetic and/or other/ tests that might become useful or mandatory. /Chemical Carcinogens/

Using a structure estimation method based on molecular connectivity indices(1), the Koc of primidone can be estimated to be 140(SRC). According to a classification scheme(2), this estimated Koc value suggests that primidone is expected to have high mobility in soil(SRC). Using a water/sediment matrix from the Elbe River, in Dresden, Germany and a flow-through column, primidone was shown to be very mobile with a log Koc of about 1.2 over pH range of 4 to 8(3). Primidone, present in recycled waste water at a range of 18-53 ng/L, was frequently discovered in leachate water at mean concentrations of 8.5 and 2.0 ng/L following application of recycled treated wastewater to turfgrass, (hybrid Bermida grass) underlaid with sandy loam or loamy sand soils, respectively, over a 6-month period(4). A pKa of 12.3 (acidic character of ionizable functional group) has been reported. In sediment column studies using sediment from an Elbe River tributary (Torgue, Germany) and flow water from the Elbe (Dresden), low retardation was observed and no pH dependence was reported. It was postulated that deprotonation of hydroxyl group due to lactam-lactim tautomerization cannot occur at pH 4 to 6 and, therefore, the molecule stays in neutral form and is very mobile because of its low Kow(5).

/SIGNS AND SYMPTOMS/ Overdosage of primidone results in symptoms similar to those of acute barbiturate intoxication. In addition, primidone crystalluria may occur and may facilitate the diagnosis.

/CASE REPORTS/ The present paper describes a patient who was in danger of dying from a massive primidone overdose. She was comatose, hypotensive and in acute renal failure with crystalluria. Because of her clinical condition and high plasma primidone level (209 mg/L) hemoperfusion was instituted. Both the calculated drug clearances and the remarkable improvement in the patient's clinical condition suggest that hemoperfusion was very effective.

/CASE REPORTS/ Seven cases of crystalluria following primidone overdose have been reported since the 1950s. An eighth case of primidone crystalluria following overdose is presented. Because of low aqueous solubility (600 mg/L at 37 degrees C) which is directly proportional to temperature, any factor increasing renal excretion of unchanged primidone predisposes to crystal formation. Renal clearance is dependent on dosage because of negligible protein binding, zero-order conversion to phenobarbitone (phenobarbital) and first-order conversion to phenylethylmalonamide. Therapy with other anticonvulsants known to induce the metabolism to phenobarbitone does not appear to be protective against crystalluria in overdose situations. The critical serum primidone concentration for crystalluria presence seems to be 80 mg/L. There is evidence for nephrotoxicity of the crystals themselves if formed in vivo (actual crystal presence during voiding). The chemical phenomenon of supersaturation of a solution is protective against in vivo crystal formation with subsequent nephrotoxicity. Vigorous hydration to augment elimination and to lessen the propensity for renal toxicity is recommended.

/CASE REPORTS/ A 7.5-year-old girl who was treated with phenobarbital (PHB) for epilepsy was admitted with decreased levels of consciousness. She had been known to have high PHB levels of unknown cause, without symptoms. Her PHB levels were very high, as expected, but primidone levels were also detected although she and her parents denied history of primidone administration. We wished to rule out intentional unprescribed use of primidone. Our retrospective review showed 3 other children with high PHB concentrations where primidone was also detected when PHB levels were over 130 umol/L. Complementary studies confirmed that high-dose PHB can convert to its prodrug primidone, which has not been reported previously.

For more Human Toxicity Excerpts (Complete) data for Primidone (16 total), please visit the HSDB record page.

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including primidone, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

The Generic Animal Drug and Patent Restoration act requires that each sponsor of an approved animal drug must submit to the FDA certain information regarding patents held for the animal drug or its method of use. The Act requires that this information, as well as a list of all animal drug products approved for safety and effectiveness, be made available to the public. Primidone is included on this list.

Oral dosage form new animal drugs. Primidone. ... Indications for use. For the control of convulsions associated with idiopathic epilepsy, epileptiform convulsions, viral encephalitis, distemper, and hardpad disease that occurs as a clinically recognizable lesion in certain entities in dogs. ... Limitations. Federal law restricts this drug to use by or on the order of a licensed veterinarian.

N03AA03

N - Nervous system

QN - Nervous system

Primidone alters sodium and calcium channel transport, reducing the frequency of nerve firing, which may be responsible for its effect on convulsions and essential tremor. Primidone has a wide therapeutic window as doses of 50-1000mg/day were effective. Patients should be counselled regarding the risk of status epilepticus with abrupt cessation of primidone.

Primidone and its metabolites, phenobarbital and phenylethylmalonamide (PEMA), are active anticonvulsants. Primidone does not directly interact with GABA-A receptors or chloride channels but phenobarbital does. Primidone alters transmembrane sodium and calcium channel transport, reducing the frequency of nerve firing, which may be responsible for the primidone’s effect on convulsions and essential tremor.

The melastatin-related transient receptor potential (TRP) channel TRPM3 is a nonselective cation channel expressed in nociceptive neurons and activated by heat. Because TRPM3-deficient mice show inflammatory thermal hyperalgesia, pharmacological inhibition of TRPM3 may exert antinociceptive properties. Fluorometric Ca influx assays and a compound library containing approved or clinically tested drugs were used to identify TRPM3 inhibitors. Biophysical properties of channel inhibition were assessed using electrophysiological methods. The nonsteroidal anti-inflammatory drug diclofenac, the tetracyclic antidepressant maprotiline, and the anticonvulsant primidone were identified as highly efficient TRPM3 blockers with half-maximal inhibition at 0.6 to 6 uM and marked specificity for TRPM3. Most prominently, primidone was biologically active to suppress TRPM3 activation by pregnenolone sulfate (PregS) and heat at concentrations markedly lower than plasma concentrations commonly used in antiepileptic therapy. Primidone blocked PregS-induced Cai influx through TRPM3 by allosteric modulation and reversibly inhibited atypical inwardly rectifying TRPM3 currents induced by coapplication of PregS and clotrimazole. In vivo, analgesic effects of low doses of primidone were demonstrated in mice, applying PregS- and heat-induced pain models, including inflammatory hyperalgesia. Thus, applying the approved drug at concentrations that are lower than those needed to induce anticonvulsive effects offers a shortcut for studying physiological and pathophysiological roles of TRPM3 in vivo.

The half life of primidone is 7-22h in adults, 5-11h in children, and 8-80h in newborns.

The pharmacokinetics and metabolism of primidone at steady-state were studied in 10 elderly patients aged 70-81 years and eight control subjects aged 18-26 years. Primidone half-lives and clearance values (mean +/- s.d.) were similar in the elderly and in the young (12.1 +/- 4.6 vs 14.7 +/- 3.5 hr and 34.8 +/- 9.0 vs 33.2 +/- 7.2 mL/kg/hr respectively. ...

In a ... study in eight epileptic patients (aged 18-26 years) receiving long-term treatment with primidone (mean daily dose, 422 +/- 115 mg per day), the half-life for primidone was 14.7 +/- 3.5 hours.

The pharmacokinetics of primidone (PRM) after oral administration of a single 500 mg dose was studied in 7 patients with acute viral hepatitis and 7 healthy control subjects. The elimination half-life and the apparent clearance of unchanged PRM in the patients were 18.0 +/- 3.1 hr and 42 +/- 14 mL/kg/hr, respectively (mean +/- SD) and did not differ significantly from the values in the controls (half-life 17.0 +/- 2.4 hr; clearance 35 +/- 8 mL/kg/hr). ...

Serum half lives of primidone, PEMA /phenylethamalonamide/, and phenobarbital have been reported to be 1.85 hr, 7.1 hr, and 41 hr, respectively.

For more Biological Half-Life (Complete) data for Primidone (6 total), please visit the HSDB record page.

Primidone is metabolized to phenobarbitol and phenylethylmalonamide (PEMA). This metabolism is largely mediated by CYP2C9, CYP2C19, and CYP2E1.

Physiologically based pharmacokinetic modeling of the parent chemical primidone and its two metabolites phenobarbital and phenylethylmalonamide (PEMA) was applied to investigate the differences of primidone metabolism among humans, rats, and mice. The model simulated previously published pharmacokinetic data of the parent chemical and its metabolites in plasma and brain tissues from separate studies of the three species. Metabolism of primidone and its metabolites varied widely among a sample of three human subjects from two separate studies. Estimated primidone metabolism, as expressed by the maximal velocity Vmax, ranged from 0 to 0.24 mg/kg/min for the production of phenobarbital and from 0.003 to 0.02 mg/kg/min for the production of PEMA among three human subjects. Further model simulations indicated that rats were more efficient at producing and clearing phenobarbital and PEMA than mice. However, the overall metabolism profile of primidone and its metabolites in mice indicated that mice were at higher risk of toxicity owing to higher residence of phenobarbital in their tissues and owing to the carcinogenic potential of phenobarbital as illustrated in long-term bioassays. ...

The placental transfer of primidone and metabolites was investigated in 14 women treated for epilepsy with primidone (and additionally phenytoin, ethosuximide or valproate in 5 women) throughout pregnancy. Primidone, PEMA /phenylethylmalonamide/, phenobarbital, and polar metabolites (p-hydroxyphenobarbital and p-hydroxyphenobarbital glucuronide) were found in similar concentrations in maternal and cord blood at birth.

The pharmacokinetics and metabolism of primidone at steady-state were studied in 10 elderly patients aged 70-81 years and eight control subjects aged 18-26 years. Primidone half-lives and clearance values (mean +/- s.d.) were similar in the elderly and in the young (12.1 +/- 4.6 vs 14.7 +/- 3.5 hr and 34.8 +/- 9.0 vs 33.2 +/- 7.2 mL/kg/hr respectively. The serum concentrations of the metabolites phenylethylmalonamide (PEMA) and phenobarbitone relative to those of parent drug were higher in the elderly than in the young, the difference being significant (P less than 0.01) in the case of PEMA. The renal clearances of primidone, phenobarbitone and PEMA were moderately decreased in the elderly but this reduction was statistically significant only for PEMA. Elderly patients excreted a reduced proportion of unchanged primidone and an increased proportion of PEMA in urine. Ageing is associated with a greater accumulation of PEMA, which is unlikely to have a major clinical significance.

Although phenobarbital was not detected after administration of single doses of primidone, long-term administration of primidone (at various doses) in 46 epilepsy patients showed serum accumulation of phenobarbital, and PEMA /phenylethylmalonamide/. Although there was significant inter-individual variability, concentrations of the two metabolites showed correlation with those of the parent drug, and concentrations of phenobarbital were consistently higher than those of PEMA. Two of the subjects had been on a daily dose of primidone (750 mg in divided doses) for more than 3 years. After a single dose of 750 mg in this study, peak serum concentrations of primidone were achieved rapidly (by 0.5 hour), and declined slowly (half-lives, 5.3 and 7.0 hours). In both subjects, peak concentrations of metabolites, PEMA (12 and 10 ug/mL) and phenobarbital (33 and 11 ug/mL), remained relatively constant. In the cerebrospinal fluid, binding to protein by PEMA and by primidone was negligible, and approximately 60% by phenobarbital.

For more Metabolism/Metabolites (Complete) data for Primidone (9 total), please visit the HSDB record page.

13AFD7670Q

PRIMIDONE

Established Pharmacologic Class [EPC] - Anti-epileptic Agent

Physiologic Effects [PE] - Decreased Central Nervous System Disorganized Electrical Activity

Primidone is an Anti-epileptic Agent. The physiologic effect of primidone is by means of Decreased Central Nervous System Disorganized Electrical Activity.

PRIMIDONE

Drugs used to prevent SEIZURES or reduce their severity.

Substances that do not act as agonists or antagonists but do affect the GAMMA-AMINOBUTYRIC ACID receptor-ionophore complex. GABA-A receptors (RECEPTORS, GABA-A) appear to have at least three allosteric sites at which modulators act: a site at which BENZODIAZEPINES act by increasing the opening frequency of GAMMA-AMINOBUTYRIC ACID-activated chloride channels; a site at which BARBITURATES act to prolong the duration of channel opening; and a site at which some steroids may act. GENERAL ANESTHETICS probably act at least partly by potentiating GABAergic responses, but they are not included here.

Oral primidone is up to 80% bioavailable with a Tmax if 2-4h. A 500mg oral dose of primidone Reaches a Cmax of 2.7±0.4µg/mL with a Tmax of 0.5-7h. Data regarding the AUC of primidone is not readily available.

Primidone is 72.9-80.6% recovered in urine.

The volume of distribution of primidone is 0.5-0.8L/kg.

Primidone is cleared at a rate of 30mL/min.

Mice were treated with a teratogenic dose of primidone (100 mg/kg) by gastric intubation at three different times during pregnancy, viz. days 6-14, days 12-14 on day 14 only. Blood samples were taken on day 14 at 1, 4, 8 and 24 hr after dosage. Primidone and its metabolites phenylethylmalondiamide (PEMA), and phenobarbitone, were assayed by GLC. There was no accumulation of the parent compound or the metabolites after repeated administration of primidone; each of the substances was cleared from the plasma within 24 hr. The rate of metabolism of primidone increased with prolonged treatment. The peak concentration of the metabolites was higher in the two multiple-dose groups than in the single dose group. The concentration of PEMA exceeded that of primidone between 3-8 hr and then began to decrease in the multiple-dose groups, a similar pattern was established for phenobarbitone also, although the concentrations were lower than those of PEMA.

The placental transfer of primidone and metabolites was investigated in 14 women treated for epilepsy with primidone (and additionally phenytoin, ethosuximide or valproate in 5 women) throughout pregnancy. Primidone, PEMA /phenylethylmalonamide/, phenobarbital, and polar metabolites (p-hydroxyphenobarbital and p-hydroxyphenobarbital glucuronide) were found in similar concentrations in maternal and cord blood at birth.

Anticonvulsants

MEDICATION (VET)

MEDICATION

Use (kg) in Switzerland (2009): >250

A solution of ethylphenylmalonamide (I) in a large molecular excess of formamide (II) is refluxed for 2 hr. The cyclization may be viewed as being brought about by a Cannizzaro type of disproportionation of II followed by a deammoniation and a dehydration between I and the highly reactive methanolamine resulting from the disproportionation.

Prepared by electrolytic production of phenobarbital or by catalytic desulfuration of the corresponding 2-thiobarbituric acid: Boon et al., United Kingdom patent 666027 (1952 to I.C.I.) ... .

Primidone is obtained by reductive desulfurization of 2-thiophenobarbital with Raney nickel or zinc and formic acid, or by ring closure of ethylphenylmalonamide with formamide or formic acid.