Mysoline

Pronunciation

Generic Name: Primidone
Class: Barbiturates
VA Class: CN400
Chemical Name: 5-ethyldihydro-5-phenyl-4,6(1H, 5H)-pyrimidinedione
CAS Number: 125-33-7

Warning(s)

REMS:

FDA approved a REMS for primidone to ensure that the benefits of a drug outweigh the risks. However, FDA later rescinded REMS requirements. See the FDA REMS page () or the ASHP REMS Resource Center ().

Introduction

Anticonvulsant; a structural analog of phenobarbital; related to barbiturate-derivative anticonvulsants.a b c d

Uses for Mysoline

Used alone or with other anticonvulsants (e.g., phenytoin, phenobarbital); a c d however, some clinicians do not recommend concurrent use of primidone and phenobarbital because of possible increased sedation.a

Slideshow: Flashback: FDA Drug Approvals 2013

Generalized Seizures

Prophylactic management of tonic-clonic (grand mal) seizures, particularly those refractory to other anticonvulsant therapy.a c d

Prophylactic management of other partial seizures (e.g., those with autonomic symptoms), including atonic (also known as akinetic) seizures.a b

Partial Seizures

Prophylactic management of partial seizures with complex symptomatology (psychomotor seizures).a c d

Prophylactic management of other partial seizures, including focal seizures.a b c d

Mysoline Dosage and Administration

General

  • Closely monitor patients receiving anticonvulsant therapy for notable changes in behavior that could indicate emergence or worsening of suicidal thoughts or behavior or depression.d g h i (See Suicidality Risk under Cautions.)

  • When primidone therapy is discontinued, withdraw the drug slowly to avoid precipitating seizures or status epilepticus.a b c d

  • When a patient is transferred to primidone from another anticonvulsant, gradually increase primidone dosage over a period of at least 2 weeks while gradually decreasing dosage of the other anticonvulsant, to maintain adequate seizure control.a c

Administration

Oral Administration

Administer orally.a c d

Dosage

Adjust dosage carefully according to individual requirements and response.a c d In some cases, determination of blood concentrations of the drug may be needed to achieve optimal dosage adjustment.c d

May require several weeks of therapy before therapeutic efficacy can be assessed.c d

Pediatric Patients

Generalized and Partial Seizures
Oral

Anticonvulsant-naive children <8 years of age: Initially, 50 mg at bedtime (days 1–3), increase to 50 mg twice daily (days 4–6), then increase to 100 mg twice daily (days 7–9).a c d Follow with a maintenance dosage of 125–250 mg 3 times daily or 10–25 mg/kg daily given in divided doses.a c d Alternatively, some clinicians recommend 1.25 g/m2 daily in 2–4 divided doses.a

Anticonvulsant-naive children ≥8 years of age: Initially, 100–125 mg at bedtime (days 1–3), increase to 100–125 mg twice daily (days 4–6), then increase to 100–125 mg 3 times daily (days 7–9).a c d Follow with a maintenance dosage of 250 mg 3 or 4 times daily.a c d Do not exceed 500 mg 4 times daily.a c d

Children ≥8 years of age receiving other anticonvulsants: Initially, 100–125 mg (primidone) at bedtime; increase dosage (primidone) slowly to maintenance level while gradually decreasing dosage of other anticonvulsant.c d Continue this regimen until satisfactory dosage achieved with the combination, or the other drug is withdrawn.c d If primidone monotherapy is the objective, gradually increase primidone dosage while decreasing dosage of the drug being discontinued over a period of at least 2 weeks.a c d

Adults

Generalized and Partial Seizures
Oral

Anticonvulsant therapy-naive adults: Initially, 100–125 mg at bedtime (days 1–3), increase to 100–125 mg twice daily (days 4–6), then increase to 100–125 mg 3 times daily (days 7–9).a c d Follow with a maintenance dosage of 250 mg 3 or 4 times daily.a c d Do not exceed 500 mg 4 times daily.a c d

Adults receiving other anticonvulsants: Initially, 100–125 mg (primidone) at bedtime; increase dosage (primidone) slowly to maintenance level while gradually decreasing dosage of other anticonvulsant.c d Continue this regimen until satisfactory dosage is achieved with the combination, or the other drug is withdrawn.c d If primidone monotherapy is the objective, gradually increase primidone dosage while decreasing dosage of the drug being discontinued over a period of at least 2 weeks.a c d

Prescribing Limits

Pediatric Patients

Generalized and Partial Seizures
Oral

Children ≥8 years of age: Maximum 2 g daily given in divided doses (e.g., 500 mg 4 times daily).a c d

Adults

Generalized and Partial Seizures
Oral

Maximum 2 g daily given in divided doses (e.g., 500 mg 4 times daily).a c d

Special Populations

No special population dosage recommendations at this time.c d

Cautions for Mysoline

Contraindications

  • Porphyria.c d

  • Known hypersensitivity to phenobarbital.c d

Warnings/Precautions

Warnings

Shares the toxic potentials of the barbiturate-derivative anticonvulsants; observe the usual precautions of anticonvulsant therapy.a

Suicidality Risk

Increased risk of suicidality (suicidal ideation or behavior) observed in an analysis of studies using various anticonvulsants in patients with epilepsy, psychiatric disorders (e.g., bipolar disorder, depression, anxiety), and other conditions (e.g., migraine, neuropathic pain); risk in patients receiving anticonvulsants (0.43%) was approximately twice that in patients receiving placebo (0.24%).d g h i j Increased suicidality risk was observed ≥1 week after initiation of anticonvulsant therapy and continued through 24 weeks.d g h j Risk was higher for patients with epilepsy compared with those receiving anticonvulsants for other conditions.d g h j

Closely monitor all patients currently receiving or beginning anticonvulsant therapy for changes in behavior that may indicate emergence or worsening of suicidal thoughts or behavior or depression.d g h i j Anxiety, agitation, hostility, hypomania, and mania may be precursors to emerging suicidality.g

Balance risk of suicidality with the risk of untreated illness.d g Epilepsy and other illnesses treated with anticonvulsants are themselves associated with morbidity and mortality and an increased risk of suicidality.d g If suicidal thoughts or behavior emerge during anticonvulsant therapy, consider whether these symptoms may be related to the illness itself.d i (See Advice to Patients.)

Withdrawal Effects

Abrupt withdrawal may result in increased seizure frequency or status epilepticus.a b c d

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm.c d

Reports suggest an association between use of anticonvulsants in pregnant, epileptic women and an increased incidence of birth defects in children born to these women; however, causal relationship to many anticonvulsants not established.c d f

Neurologic manifestations (overactivity, tumors) reported in neonates whose mothers received primidone during pregnancy.f

Do not discontinue anticonvulsants in pregnant women in whom the drugs are administered to prevent major seizures because of the strong possibility of precipitating status epilepticus with attendant hypoxia and threat to life.c d

Carefully weigh these considerations when treating or counseling epileptic women of childbearing potential.c d

Neonatal hemorrhage (with a coagulation defect resembling vitamin K deficiency) reported in newborns whose mothers were receiving primidone during pregnancy.b c d f Administer prophylactic vitamin K to pregnant women taking primidone for one month prior to and during delivery.b c d Additionally, administer vitamin K to the neonate immediately after birth.b f

General Precautions

Laboratory Monitoring

Perform baseline CBC and a sequential multiple analysis-12 (SMA-12) test every 6 months during primidone therapy.a c d

Hematologic Effects

Granulocytopenia, agranulocytosis, red-cell hypoplasia and aplasia rarely reported; may require discontinuance of primidone.c d

Megaloblastic anemia may occur as a rare idiosyncrasy.c d Administer folic acid.c d

Specific Populations

Pregnancy

Category D.f Safety during pregnancy not established.a c d (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

North American Antiepileptic Drug (NAAED) Pregnancy Registry at 888-233-2334 (for patients); registry information also available on the website .d

Lactation

Distributed into milk.a c d f Discontinue nursing or drug if excessive somnolence or drowsiness is observed in nursing infants of women receiving the drug.a c d

Pediatric Use

Safety and efficacy established in pediatric patients.c d

Possible paradoxical excitement and hyperactivity or an exacerbation of existing hyperactivity in children.b

Geriatric Use

Possible excitement, confusion, or depression.b

Common Adverse Effects

Drowsiness, ataxia, vertigo, lethargy, anorexia, nausea, vomiting.a c d

Interactions for Mysoline

Specific Drugs

Drug

Interaction

Comments

Contraceptives (oral)

Possible increased metabolism of both the estrogenic and progestinic components of oral contraceptivesb

Consider alternate methods of contraceptionb

Phenobarbital

Possible increased sedationa b

Use with caution,a if at all b

Phenytoin

Possible increase in amount of primidone converted to phenobarbital and increased sedationb

Valproic acid

Increased plasma phenobarbital concentrations and excessive somnolenceb

Observe patient for possible neurologic toxicity and monitor plasma concentrations of phenobarbital; decrease dosage of primidone if neededb

Mysoline Pharmacokinetics

Absorption

Bioavailability

Approximately 60–80% absorbed from GI tract.a

Onset

Following oral administration, peak serum concentrations are reached in about 4 hours.a

Plasma Concentrations

Limited data indicate that serum primidone concentrations should be maintained at 5–12 mcg/mL to adequately control seizures and minimize risk of adverse effects.a c d

Distribution

Extent

Distributed into milk in substantial quantities.a c d

Elimination

Metabolism

Slowly metabolized by the liver.a Approximately 15–25% of an oral dose metabolized to phenobarbital.a

Elimination Route

Slowly excreted in urine as phenylethylmalonamide (PEMA), phenobarbital, and p-hydroxyphenobarbital.a

During chronic therapy, approximately 15–25% excreted in urine unchanged and approximately 50–70% excreted as PEMA.a

Half-life

Primidone: One manufacturer stated 21 hours; other clinicians suggested 10–12 hours.a

PEMA: 24–48 hours.a

Special Populations

Removed by hemodialysis.a

Stability

Storage

Oral

Tablets

Tight, light-resistant containers at 20–25°C.c d

Actions

  • Shares the actions of barbiturate-derivative anticonvulsants and has sedative properties similar to phenobarbital.a

  • Exact mechanism of antiepileptic action is unknown; primidone and its metabolites (phenobarbital and PEMA) have anticonvulsant activity.c d

  • Effective in subhypnotic doses.a

Advice to Patients

  • Risk of suicidality (anticonvulsants may increase risk of suicidal thoughts or actions in about 1 in 500 people).d g h i j Importance of patients, family, and caregivers being alert to day-to-day changes in mood, behavior, and actions and immediately informing clinician of any new or worrisome behaviors (e.g., talking or thinking about wanting to hurt oneself or end one’s life, withdrawing from friends and family, becoming depressed or experiencing worsening of existing depression, becoming preoccupied with death and dying, giving away prized possessions).d g h j

  • Importance of informing patients that several weeks of therapy may be required before therapeutic efficacy can be assessed.c d

  • Importance of informing patients not to stop primidone therapy abruptly; may precipitate seizures or status epilepticus.a b c d

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and herbal products, as well as any concomitant illnesses.c

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed; advise pregnant women of possible risk to fetus.a d f Importance of clinicians informing women about the existence of and encouraging enrollment in pregnancy registries (see Pregnancy under Cautions).d

  • Importance of informing patients of other important precautionary information.c d (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Primidone

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets

50 mg*

Mysoline (scored)

Valeant

Primidone Tablets

250 mg*

Mysoline (scored)

Valeant

Primidone Tablets

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 02/2014. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Mysoline 250MG Tablets (VALEANT): 30/$218.98 or 90/$633.99

Mysoline 50MG Tablets (VALEANT): 90/$179.99 or 270/$519.96

Primidone 250MG Tablets (AMNEAL PHARMACEUTICALS): 90/$69.99 or 270/$191.98

Primidone 50MG Tablets (LANNETT): 90/$39.99 or 270/$109.97

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions October 27, 2011. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

a. AHFS drug information 2007. McEvoy GK, ed. Primidone. Bethesda, MD: American Society of Health-System Pharmacists; 2008.

b. AHFS drug information 2007. McEvoy GK, ed. Anticonvulsants General Statement. Bethesda, MD: American Society of Health-System Pharmacists; 2008:2254-8.

c. Mutual Pharmaceuticals. Primidone tablets prescribing information. Philadelphia, PA; 2006 Nov.

d. Valeant Pharmaceuticals North America. Mysoline (primidone) tablets prescribing information. Aliso Viejo, CA; 2009 May.

e. Food and Drug Administration. Drugs or vaccines used in registries for specific diseases. From the FDA web site. Rockville, MD; Undated. Accessed 2008 Mar 20.

f. Primidone. In: Briggs GG, Freeman RK, Yaffe SJ. Drug in pregnancy and lactation: a reference guide to fetal and neonatal risk. 8th ed. Philadelphia: Lippincott Williams & Wilkins; 2008;1525-8.

g. US Food and Drug Administration. Information for healthcare professionals: suicidality and antiepileptic drugs. Rockville, MD; 2008 Jan 31. From the FDA web site.

h. US Food and Drug Administration. FDA News: FDA alerts health care providers to risk of suicidal thoughts and behavior with antiepileptic medications. Rockville, MD; 2008 Jan 31. From the FDA website.

i. US Food and Drug Administration. Suicidal behavior and ideation and antiepileptic drugs: update 5/5/2009. Rockville, MD; 2009 May 5. From the FDA website. Accessed 2009 Oct 21.

j. US Food and Drug Administration. FDA Alert: Suicidality and antiepileptic drugs. Rockville, MD; 2008 Jan 31. From the FDA website.

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