Anticonvulsants, Dione (Systemic)

This monograph includes information on the following:

1) Paramethadione  * 
2) Trimethadione  * 

BAN:
Trimethadione—Troxidone {03}

VA CLASSIFICATION
Paramethadione
Primary: CN400

Trimethadione
Primary: CN400


Other commonly used names for trimethadione are
TMO, {07} {18} {24} trimethadionum, {05} trimethinum, {05} and troxidone . {03} {05}
Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).

*Not commercially available in the U.S.

Not commercially available in Canada.



Category:


Anticonvulsant{02}{03}

Indications

Accepted

Epilepsy, absence seizure pattern (treatment)—Paramethadione and trimethadione are indicated in the control of absence (petit mal) seizures that are refractory to treatment with other medications. {08} {09}

—Paramethadione and trimethadione should not be used unless other less toxic anticonvulsants have been ineffective in controlling seizures. {08} {09}


Pharmacology/Pharmacokinetics

Physicochemical characteristics:

Chemical group—
    Oxazolidinediones {08} {09} {18} {19}
Molecular weight—
    Paramethadione: 157.17 {02}
    Trimethadione: 143.14 {03} {18}

pKa—
    Dimethadione (DMO {24}; active metabolite of trimethadione {07} {09} {11} {18} {19}): 6.13 {18}

Mechanism of action/Effect:

Dione anticonvulsants reduce T-type calcium currents in thalamic neurons, {07} {19} including thalamic relay neurons. {07} {19} This raises the threshold for repetitive activity in the thalamus, {18} and inhibits corticothalamic transmission. {18} {19} Thus, the abnormal thalamocortical rhythmicity, which is thought to underlie the 3-Hz spike-and-wave discharge seen on electroencephalogram(EEG) with absence seizures, {07} is dampened. {19} The maximal seizure pattern in patients undergoing electroconvulsive therapy is not modified. {08} {09}

Absorption:

Rapid. {08} {09} {18}

Protein binding:

Insignificant. {18} {19} {24}

Biotransformation:

Hepatic; {18} {19} {24} both medications almost completely {06} {08} {09} {18} demethylated {08} {09} {19} {24} to active metabolites. {08} {09} {18} {19}

Half-life:

Paramethadione—12 to 24 hours {01}; active metabolite—unknown {06}.

Trimethadione—11 to 16 hours; {18} {24} active metabolite (dimethadione) {07} {09} {11} {18} {19}—about 10 days {18}.

Time to peak serum concentration

Trimethadione—30 to 60 minutes. {18}

Elimination:
    Metabolites— {06} {18} Renal (slow). {08} {09} {18}


Precautions to Consider

Cross-sensitivity and/or related problems

Patients sensitive to one dione anticonvulsant may be sensitive to the other also. {27}

Carcinogenicity

No data are available on long-term potential for carcinogenicity in animals or humans. {08}

Pregnancy/Reproduction

Pregnancy—
Use of dione anticonvulsants is not recommended during pregnancy. {08} {09} {18}

Controlled studies in humans have not been done. However, there have been reports of congenital malformations and fetal death occurring with dione anticonvulsant use in humans. {04} {15} Fetal exposure to paramethadione and trimethadione {04} {15} has been associated with ``fetal trimethadione syndrome,'' {04} {15} characterized by an increased frequency of congenital malformations including malformed ears {04} {15}, urogenital malformations {04} {15}, and skeletal abnormalities. {04} An increase in fetal deaths {04} {15} and high rates of mental retardation in surviving children {04} {15} have also been reported. Patients should be advised that an effective means of contraception should be used during therapy, and that the physician should be informed if pregnancy occurs. {08} {09}

For paramethadione: FDA Pregnancy Category D. {08}

For trimethadione: FDA pregnancy category not assigned.

Delivery—

Exposure to dione anticonvulsants prior to delivery may lead to a neonatal coagulation defect {08} {09} characterized by decreased concentrations of vitamin K–dependent coagulation factors, {08} {09} and increased prothrombin times and/or increased partial thromboplastin times {08} {09}, resulting in an increased risk of life-threatening hemorrhage in the neonate, usually within 24 hours of birth {08} {09}. Dione anticonvulsants may also produce a vitamin K deficiency in the mother, causing increased bleeding during delivery. Risk may be reduced by administering vitamin K to the mother for one month prior to, and during delivery {08} {09} and to the neonate, intramuscularly or subcutaneously {20}, immediately after birth. {08} {09}

Breast-feeding

It is not known whether dione anticonvulsants are distributed into breast milk. {08} {09} However, many medications are distributed into breast milk, and, because of the high toxicity of dione anticonvulsants, breast-feeding is not recommended. {08}

Pediatrics

Appropriate studies on the relationship of age to the effects of the dione anticonvulsants have not been performed in the pediatric population. However, no pediatrics-specific problems have been documented to date.


Geriatrics


Appropriate studies on the relationship of age to the effects of dione anticonvulsants have not been performed in the geriatric population. However, one small pharmacokinetic study of trimethadione found that metabolism may be decreased, and half-life increased in elderly patients. {24}


Dental

The leukopenic and thrombocytopenic effects of dione anticonvulsants may result in an increased incidence of microbial infection, delayed healing, and gingival bleeding. If leukopenia or thrombocytopenia occurs, dental work should be deferred until blood counts have returned to normal. {21} Patients should be instructed in proper oral hygiene during treatment, including caution in use of regular toothbrushes, dental floss, and toothpicks. {21}

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

Acetazolamide    (concurrent use may potentiate acidosis, enhance ophthalmic toxicity, and alter the distribution and excretion of the active metabolite of trimethadione {06})


» Alcohol and
» Central nervous system (CNS) depression–producing medications, other (See Appendix II )    (CNS depression may be enhanced)


Antidepressants, tricyclic,{12}{14}{17} or
Haloperidol{12}{17} or
Loxapine{12} or
Maprotiline{12} or
Molindone{06}{12}{17} or
Monoamine oxidase (MAO) inhibitors,{12}{17} including furazolidone, procarbazine, and more than 10 mg a day of selegiline, or
Phenothiazines{12}{17} or
Pimozide{12} or
Thioxanthenes{12}{17}    (concurrent use may lower the convulsive threshold, enhance CNS depression, and decrease the effects of the anticonvulsant medication; dosage adjustments may be necessary)


Phenacemide{13}    (concurrent use with dione anticonvulsants may result in additive toxicity {13})


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Risk-benefit should be considered when the following medical problems exist
» Blood dyscrasias{08}{09} or
» Hepatic function impairment{08}{09} or
Optic nerve or retinal disease{08}{09} or
» Renal function impairment{08}{09}    (risk of exacerbation of pre-existing conditions)

    (decreased metabolism with hepatic function impairment {18} {24})


Porphyria, acute intermittent{06}    (risk of exacerbation with the use of trimethadione {06})


» Sensitivity to dione anticonvulsants{08}{09}

Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

» Blood cell and platelet counts{08}{09}    (a complete blood count is recommended prior to start of treatment {08} {09} and monthly thereafter {08} {09}; if no abnormality appears within 12 months, frequency of monitoring may be decreased {08} {09}; if neutrophil count is between 2500 and 3000, blood count should be done more frequently than once a month {08} {09}; if neutrophil count is 2500 or less, withdrawal of dione anticonvulsant is indicated {08} {09} to prevent severe bone marrow depression)


» Hepatic function determinations{08}{09}    (recommended prior to initiation of dione therapy {08} {09}, monthly for several months, then every few months thereafter {27}; if jaundice or other signs of liver dysfunction occur, the medication should be withdrawn {08} {09})


Ophthalmological examinations{28}    (recommended every 6 months {27}; hemeralopia can usually be reversed by decreasing dione dosage {08} {09}; if scotomata occur, medication should be withdrawn {08} {09})


» Renal function determinations{01}    (recommended prior to initiation of therapy and, during therapy, at monthly intervals for several months, then every few months thereafter {27})


» Urinalysis{08}{09}    (recommended prior to initiation of dione therapy and monthly thereafter; {08} {09} if persistent or increasing albuminuria or other significant renal abnormality occurs, medication should be withdrawn {08} {09})




Side/Adverse Effects
The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence more frequent
    
Hemeralopia{08}{09}{19} , scotomata{08}{09} , or diplopia{08}{09}{19} (changes in vision, especially night blindness, glare or snowy image caused by bright light, or double vision)

Incidence rare
    
Allergic reaction{08}{09} (itching of skin associated with swollen lymph nodes; enlarged liver and spleen)
    
blood dyscrasias{08}{09}{18} , including agranulocytosis, aplastic anemia, eosinophilia, hypoplastic anemia, leukopenia, pancytopenia, and thrombocytopenia{08}{09} (sore throat and fever; unusual bleeding, such as recurring nosebleeds, bleeding gums, or vaginal bleeding; red or purple spots on skin; unusual tiredness or weakness)—fatalities have occurred{08}{09}
    
confusion{06}{18}
    
convulsions, tonic-clonic, precipitation of{08}{09}
    
hepatitis{08}{09} (loss of appetite; unusual tiredness; yellow eyes or skin; weight loss; fever; skin rash or itching; nausea or vomiting; dark urine; pain in abdomen and joints)
    
lymphadenopathies{08}{09} (swollen lymph nodes)
    
myasthenia gravis–like syndrome{08}{09}{10} (severe muscle weakness, including drooping eyelids; double vision; difficulty in chewing, swallowing, talking, and breathing; severe tiredness){10}{18}
    
nephrosis{08}{09} (swelling of face, hands, legs, and feet; cloudy urine{18})—fatalities have occurred{08}{09}
    
skin rash{08}{09}
    
systemic lupus erythematosus (SLE)-like syndrome{08}{09}{26} (chest pain; fever; muscle or joint pain; shortness of breath or troubled breathing; skin rash; swollen lymph nodes)
Note: If lymph node enlargement or lupus-like manifestations {08} {09} {26}, or jaundice or other symptoms of liver dysfunction {08} {09} occur, dione anticonvulsant should be withdrawn {08} {09} {26}. Patients with more severe systemic lupus-like manifestations may require moderate doses of corticosteroids until symptoms subside. {26}
If symptoms of myasthenia gravis–like syndrome occur, dione anticonvulsant should be withdrawn. {08} {09} The myasthenic reaction resolves slowly {10}, and neostigmine may be used to control weakness in the interim {10}.
Skin rash is usually acneform or morbilliform {08} {09} {18}. If skin rash appears, dione anticonvulsant should be withdrawn promptly to prevent exfoliative dermatitis or severe forms of erythema multiforme. {08} {09} After all signs of rash, even minor rash, have cleared, the dione anticonvulsant may be reinstituted cautiously. {08} {09}





Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
    
Dizziness{18}
    
drowsiness{08}{09}{18}{19}
    
headache{08}{09}
    
irritability{08}{09}
    
photophobia{08}{09}{18} (increased sensitivity of eyes to light)
Note: Drowsiness tends to diminish with continued therapy. {08} {09} However, if drowsiness continues, dosage reduction may be necessary. {08} {09} Paramethadione may have a slightly greater sedative action than trimethadione. {01}



Incidence less frequent
    
Anorexia{08}{09} (loss of appetite)
    
behavior or mood changes{08}{09}
    
blood pressure changes{08}{09}
    
gastrointestinal effects, specifically abdominal or stomach pain{08}{09} , nausea {08}{09} ,or vomiting{08}{09}
    
hair loss{08}{09}
    
hiccups{08}{09}
    
insomnia{06}{08}{09}{18} (trouble in sleeping)
    
paresthesias{08}{09} (tingling, burning, or prickly sensations)
    
unusual tiredness or weakness{08}{09}
    
unusual weight loss{08}{09}





Overdose
For more information on the management of overdose or unintentional ingestion, contact a Poison Control Center (see Poison Control Center Listing ).

Clinical effects of overdose
The following effects have been selected on the basis of their potential clinical significance(possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
Acute effects
    
Ataxia{08}{09} (clumsiness or unsteadiness)
    
coma{08}{09} —following massive overdose
    
dizziness, severe{08}{09}
    
drowsiness, severe{08}{09}
    
nausea, severe{08}{09}
    
visual disturbances{08}{09}


Treatment of overdose
To decrease absorption—Immediate evacuation of stomach by induction of emesis, lavage, or both is recommended. {08} {09}

To enhance elimination—Alkalinization of urine is reported to enhance elimination of active metabolites. {08} {09} {18}

Monitoring—Frequent monitoring of vital signs and close patient observation are required. {08} {09} Following recovery, a complete {27} blood count and a careful evaluation of hepatic and renal function should be done. {08} {09}

Supportive care—General supportive care is necessary in dione anticonvulsant overdose treatment. {08} {09} Patients in whom intentional overdose is confirmed or suspected should be referred for psychiatric consultation.


Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Anticonvulsants, Dione (Systemic).

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Sensitivity to dione anticonvulsants

Pregnancy and delivery—Risk of congenital malformations in the fetus; women of child-bearing potential advised to use an effective method of birth control during therapy, and to notify physician immediately if pregnancy occurs; bleeding problems may occur in mother during delivery and in baby immediately after delivery.
Other medications, especially CNS depressants
Other medical problems, especially blood dyscrasias, hepatic function impairment, or renal function impairment

Proper use of this medication

Proper administration:

For paramethadione capsules
Swallowing whole; not breaking, chewing, or crushing before swallowing

For trimethadione solution
Using an accurate measuring device, such as a specially marked measuring spoon, a plastic syringe, or a small graduated cup

For trimethadione tablets
Chewing, or crushing and dissolving in small amount of water

For all dosage forms
Taking with a small amount of food or milk to reduce gastric irritation
» Compliance with therapy; not taking more or less medication than prescribed

» Proper dosing
Missed dose: Taking as soon as possible; not taking if almost time for next scheduled dose; one missed dose may be added at bedtime {06} {27}

» Proper storage

Precautions while using this medication
» Regular visits to physician to check progress of therapy

» Reporting sore throat, fever, general feeling of tiredness, or any unusual bleeding or bruising to physician as soon as possible

Possible vision changes, especially intolerance to bright light; wearing sunglasses and avoiding bright light; caution when driving at night

» Avoiding use of alcohol and other CNS depressants

» Caution if drowsiness occurs; not driving or doing jobs requiring alertness

» Caution if any kind of surgery, dental treatment, or emergency treatment is required

» Informing physician as soon as possible if pregnancy occurs during therapy

» Checking with physician before discontinuing medication; gradual dosage reduction is usually needed


Side/adverse effects
Signs of potential side effects, especially hemeralopia, scotomata, or diplopia; allergic reaction; blood dyscrasias; confusion; convulsions; hepatitis; lymphadenopathies; myasthenia gravis–like syndrome; nephrosis; skin rash; and SLE–like syndrome


General Dosing Information
Because of the potential for severe adverse reactions with dione anticonvulsant use, strict medical supervision, especially during the first year of therapy, is recommended. {08} {09}

Physician should be notified immediately if signs or symptoms of infection or unusual bleeding, such as sore throat, fever, malaise, easy bruising, red or purple spots on skin, nosebleed, or bleeding gums occur. {08} {09}

When used to replace other anticonvulsant therapy, the dosage of this medication should be increased gradually while that of the other medication is gradually decreased, to maintain seizure control. {27}

Dione anticonvulsants do not modify the maximal seizure pattern in patients undergoing electroconvulsive therapy. {08} {09}

When dione anticonvulsant therapy is to be discontinued, dosage should be reduced gradually to prevent possible occurrence of absence status. {08} {09}

Diet/Nutrition
Dione anticonvulsants should be taken with a small amount {22} of food or milk to reduce gastric irritation. {27}

PARAMETHADIONE

Summary of Differences
Side/adverse effects: Slightly greater sedative action than trimethadione.


Oral Dosage Forms

PARAMETHADIONE CAPSULES

Usual adult and adolescent dose
Anticonvulsant
Oral, initially 300 mg three times a day, the dosage being increased by an additional 300 mg a day at one-week intervals until seizure control is obtained or until toxic symptoms appear. {08} The total daily dose is given in three or four divided doses. {08}


Usual adult prescribing limits
Up to 2.4 grams a day. {08}

Usual pediatric dose
Anticonvulsant
Children up to 2 years of age: Oral, 100 mg three times a day. {16}

Children 2 to 6 years of age: Oral, 200 mg three times a day. {16}

Children 6 years of age and over: Oral, 300 mg three times a day. {16}


Strength(s) usually available
U.S.—
Not commercially available.

Canada—
Not commercially available.

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 25 °C (59 and 77 °F), {08} unless otherwise specified by manufacturer. Store in a tight container.

Auxiliary labeling:
   • May cause drowsiness.
   • Do not chew or crush capsule.

Additional information:
Capsules contain an oily liquid. {08}


TRIMETHADIONE

Summary of Differences
Side/adverse effects: Slightly less sedative action than paramethadione.


Oral Dosage Forms

TRIMETHADIONE CAPSULES USP

Usual adult and adolescent dose
Anticonvulsant
Oral, initially 300 mg three times a day, the dosage being increased by an additional 300 mg a day at one-week intervals until seizure control is obtained or until toxic symptoms appear. {09} The total daily dose is given in three or four divided doses. {09}


Usual adult prescribing limits
Up to 2.4 grams a day. {09}

Usual pediatric dose
Anticonvulsant
Oral, 13 mg per kg of body weight or 335 mg per square meter of body surface three times a day; {16} or for

Children up to 2 years of age: Oral, 100 mg three times a day. {16}

Children 2 to 6 years of age: Oral, 200 mg three times a day. {16}

Children 6 years of age and over: Oral, 300 mg three or four times a day. {16}


Strength(s) usually available
U.S.—
Not commercially available.

Canada—
Not commercially available.

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 25 °C (59 and 77 F), {09} unless otherwise specified by manufacturer. Store in a tight container.

Stability:
Capsule contents may soften and shrink at elevated temperatures, but this will not alter the therapeutic effect. {25}

Auxiliary labeling:
   • May cause drowsiness.


TRIMETHADIONE ORAL SOLUTION USP

Usual adult and adolescent dose
See Trimethadione Capsules USP .

Usual pediatric dose
See Trimethadione Capsules USP .

Strength(s) usually available
U.S.—
Not commercially available.

Canada—
Not commercially available.

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a tight container. Protect from freezing.

Auxiliary labeling:
   • May cause drowsiness.

Additional information:
Use a specially marked measuring spoon, a plastic syringe, or a small marked measuring cup to measure each dose accurately.


TRIMETHADIONE TABLETS USP

Usual adult and adolescent dose
See Trimethadione Capsules USP .

Usual pediatric dose
See Trimethadione Capsules USP .

Strength(s) usually available
U.S.—
Not commercially available.

Canada—
Not commercially available.

Packaging and storage:
Store in refrigerator, preferably between 2 and 8 °C (36 and 46 °F), to minimize crystallization {09}. Store in a tight container.

Stability:
Some crystallization, not harmful to product, may occur. {09}

Auxiliary labeling:
   • Chew or crush tablets before swallowing.
   • May cause drowsiness.
   • Keep refrigerated. Do not freeze.

Additional information:
Tablets should be crushed and given in a small amount of water or chewed. {23}



Revised: 12/4/1995



References
  1. Panelist comment.
  1. Fleeger CA, editor. USP dictionary of USAN and international drug names 1995. Rockville, MD: The United States Pharmacopeial Convention, Inc., 1994: 495.
  1. Fleeger CA, editor. USP dictionary of USAN and international drug names 1995. Rockville, MD: The United States Pharmacopeial Convention, Inc., 1994: 688.
  1. Feldman GL, Weaver DD, Lovrien EW. The fetal trimethadione syndrome. Am J Dis Child 1977 Dec; 131: 1389-92.
  1. Reynolds JEF, editor. Martindale, the extra pharmacopeia. 30th ed. London: The Pharmaceutical Press, 1993: 310.
  1. Panelist comment, 7/28/87.
  1. Macdonald RL, Kelly KM. Mechanisms of action of currently prescribed and newly developed antiepileptic drugs. Epilepsia 1994; 35 Suppl 4: S41-S50.
  1. Paramethadione package insert (Paradione, Abbott—US), Rev 5/92, Rec 4/23/93.
  1. Trimethadione package insert (Tridione, Abbott—US), Rev 2/92, Rec 4/23/93.
  1. Booker HE, Chun RWM, Sanguino M. Myasthenia gravis syndrome associated with trimethadione. JAMA 1970 Jun 29; 212 (13): 2262-3.
  1. Panelist comment, 9/15/88.
  1. Reviewers' responses to Psychiatric Disease Advisory Panel Memo #6 of 9/16/91.
  1. Phenacemide package insert (Phenurone, Abbott—US), Rev 2/88, Rec 11/89.
  1. Dallos V, Heathfield K. Iatrogenic epilepsy due to antidepressant drugs. Br Med J 1969; 4: 80-2.
  1. Yerby MS. Pregnancy, teratogenesis, and epilepsy. Neurol Clin 1994 Nov; 12 (4): 749-71.
  1. Shirkey HC, editor. Pediatric therapy. 5th ed. Saint Louis: CV Mosby, 1975: 1252-3.
  1. Itil TM, Soldatos C. Epileptogenic side effects of psychotropic drugs. Practical recommendations. JAMA 1980 Sep 26; 244 (13): 1460-3.
  1. Levy R, Mattson R, Meldrum B, Penry JK, Dreifuss FE, editors. Antiepileptic drugs. 3rd ed. New York: Raven Press Ltd., 1989: 715-20.
  1. Rogawski MA, Porter RJ. Antiepileptic drugs: pharmacological mechanisms and clinical efficacy with consideration of promising developmental stage compounds. Pharmacol Rev 1990; 42(3): 223-86.
  1. Panelist comment, 1/11/90.
  1. Panelist comment, 7/19/87.
  1. Reviewer comment, 7/11/88.
  1. Tridione Dulcet tablets product label (Abbott—US), Rec 4/23/93.
  1. Tanaka E, Ishikawa A, Ono A, et al. Age-related changes in trimethadione oxidizing capacity. Br J Clin Pharmacol 1987; 23: 355-7.
  1. Tridione capsules product label (Abbott—US), Rec 4/23/93.
  1. Drory VE, Korczyn AD. Hypersensitivity vasculitis and systemic lupus erythematosus induced by anticonvulsants. Clin Neuropharmacol 1993; 16 (1): 19-29.
  1. Reviewers' responses to monograph revision of 7/95.
  1. Gilman AG, Goodman LS, editors. Goodman and Gilman's the pharmacological basis of therapeutics. 4th ed. New York: Macmillan, 1970: 217.
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