Primidone

Mysoline (MY-soh-leen) is the brand name used in the United States, Canada, and many other countries for the seizure medicine with the generic name primidone (PRIM-ih-dohn).

Mysoline was introduced for epilepsy in the 1950s. It remains a well-known medication but it is used by only a small percentage of people with epilepsy. Although it is very effective, side effects may decrease its value.

Mysoline
Tablet
Mysoline 50mg

50-mg white, square-shaped tablet embossed with "M" and "Mysoline 50"

Mysoline 250mg

250-mg yellow, square-shaped tablet embossed with "M" and "Mysoline 250"

Generic primidone made by other companies is also available in the United States, in the same doses.

Both sizes of Mysoline tablets are scored so they can be cut in half easily if 125 mg is prescribed.

In Canada, primidone is available in 125-mg chewable tablets (Apo-Primidone) (not shown).

Indications

Mysoline, used alone or concomitantly with other anticonvulsants, is indicated in the control of grand mal, psychomotor, and focal epileptic seizures in adults and children years of age and older. It may control grand mal seizures refractory to other anticonvulsant therapy.

Forms

Mysoline is manufactured in the United States by Valeant Pharmaceuticals. The name or appearance may differ in other places. These descriptions apply to the U.S. versions:

How to take and store Primidone?

Tablets should be swallowed whole; not bitten or chewed.

Mysoline can be taken either with food or without food, but patients should be consistent each day in whether they take it with food or not.

Patients should be cautioned if you write a new prescription using a different strength of Mysoline. For example, if you've been prescribing 50-mg tablets and the new prescription is for 250-mg tablets, advise the patient about how many Mysoline tablets should now be taken.

Mysoline tablets should be stored at room temperature, away from light and moisture and out of the reach of children.

Missed Doses

Missed doses of Mysoline are common because most people need to take it three of four times per day. A forgotten dose should be taken right away. Advise patients to take a forgotten dose immediately unless it is almost time for the next dose. In that case, they should skip the forgotten dose (rather than taking a double dose) or call for further instructions.

Patients who often forget doses may benefit from using a special pillbox or watch with an alarm.

Mechanisms of actions of Primidone

Mysoline in combination with one of its metabolites, phenobarbarbital, reduces high-frequency, repetitive neuronal firing.

Clinical Pharmacology of Primidone

Mysoline is metabolized in the liver to phenobarbital and another active compound, phenylethylmalonamide. It is metabolized by the hepatic P450 system. Mysoline is ~70-80% protein-bound.

Mysoline is rapidly and nearly completely absorbed following oral administration. Peak serum concentrations are reached in approximately 3 hours. When taken as monotherapy, the half-life of Mysoline is approximately 12 hours. When taken in combination with hepatic enzyme-inducing antiepileptic drugs, the half-life of Mysoline is reduced by nearly 50%.

Efficacy of Primidone

Mysoline is effective against partial seizures, secondarily generalized seizures, and tonic-clonic seizures. It is not effective against other generalized seizure types, such as absence seizures or myoclonic seizures.

Effective serum concentrations generally range from 8-12 mg/L, though lower or higher concentrations may be necessary in some individual patients.

A VA Cooperative study in adults with partial and generalized tonic-clonic seizures (Mattson et al. 1985) showed that patients were more likely to stop taking Mysoline because of intolerable side effects than carbamazepine and phenytoin. However, CBZ was as effective as phenytoin and better tolerated than phenobarbital or primidone. The patients in this study who had tonic-clonic seizures achieved similar control from Mysoline as from the other medications used in the study (phenobarbital, carbamazepine and phenytoin). Of those in this group who took primidone for a year, 63% were seizure-free.

A similar study in children-which also included valproate-focused on the rate of side effects. Only 8% of the children who were given Mysoline had to stop taking it because of side effects.

Mysoline is most often used as adjunctive therapy in adults whose seizures are not well controlled by other medications.

Common side effects of Primidone

The most common side effects of Mysoline are neurotoxic and dose-related. They include:

  • vertigo
  • irregular eye movements
  • nausea
  • vomiting
  • blurred or double vision
  • drowsiness
  • depression

The problems are mild to moderate and usually disappear with time or when the dose is reduced.

Some other less common side effects are:

  • loss of appetite
  • irritability
  • acne or other skin lesions
  • sexual impotency
  • decreased sexual desire
  • blood abnormalities
  • frozen shoulder

These side effects tend to occur within a week of initiation or dosage increase. In chronic therapy, they typically are noticeable 3-4 hours after a dose (associated with peak serum concentrations).

They can be lessened by:

  • reducing the total daily dosage
  • splitting the total daily dosage into more frequent doses
  • shifting more of the total daily dosage to bedtime, especially for patients with nocturnal or early-morning seizures

Patients who have just started taking Mysoline (or who have just started taking a larger amount) should be cautioned about possible sedation and to avoid activities that require full vigilance until the effects of the drug are fully apparent.

Serious Side effects of Primidone

Potentially serious or life-threatening reactions to Mysoline are rare. Symptoms that patients should report immediately to their doctor include:

  • An allergic reaction (difficulty breathing; closing of the throat; swelling of the lips, tongue, or face; or hives)
  • Fever, swollen glands, sore throat, or mouth sores
  • Red or purple point-like rash or blistering or peeling skin lesions
  • Easy bruising, paleness, weakness, or fatigue
  • Worsening of seizures

Patients taking Mysoline should avoid drinking alcohol because this combination can cause marked sedation or sleepiness.

On July 10, 2008, an advisory panel was convened by the Food and Drug Administration (FDA) to review data that the FDA had previously collected from drug studies showing an association between many of the antiepileptic drugs (AEDs) and suicidal ideation and behavior, which together are called suicidality. According to the FDA’s Alert, among the patients with epilepsy in these drug studies, 1 out of 1000 people taking the placebo (inactive substance) showed suicidality compared to approximately 3.5 out of 1000 people who took an AED. The FDA advisory panel voted to accept the FDA's data at its meeting on July 10.

  • Taking antiepileptic medicines may increase the risk of having suicidal thoughts or actions;
  • Do not make any changes to the medication regimen without first talking with the responsible healthcare professional;
  • Pay close attention to any day-to-day changes in mood, behavior and actions. These changes can happen very quickly so it is important to be mindful of any sudden differences.
  • Be aware of common warning signs that might be a signal for risk of suicide. Some of these are:
    • Talking or thinking about wanting to hurt yourself or end your life
    • Withdrawing from friends and family
    • Becoming depressed or having your depression get worse
    • Becoming preoccupied with death and dying
    • Giving away prized possessions

We again urge patients and families to contact their doctor before stopping an epilepsy medication because this may possibly lead to seizures and worsening of mood.

Other Uses of Primidone

Mysoline is used off-label to treat essential tremor, a common movement disorder.

Primidone Contraindications

Mysoline should not be taken by patients with a history of porphyria and by patients who are sensitive to phenobarbital.

Women who are pregnant or may become pregnant, and those who are breastfeeding should be cautious about using Mysoline. Breastfeeding may need to be discontinued if the baby is unusually sleepy.

Primidone Interactions with other medications

Effects of Mysoline on other drugs
Because Mysoline accelerates hepatic metabolism, it will increase the clearance of:

  • oral contraceptives
  • valproate
  • phenytoin
  • phenobarbital
  • carbamazepine
  • topiramate
  • lamotrigine
  • tiagabine
  • theophylline
  • warfarin
  • steroids

Effects of other drugs on Mysoline
Valproate will increase the serum concentration of phenobarbital, one of the metabolites of Mysoline, by inhibiting its hepatic metabolism.

On the other hand, drugs that accelerate hepatic metabolism will lower serum concentrations of Mysoline. These include:

  • phenytoin
  • carbamazepine
  • oxcarbazepine
  • phenobarbital
  • felbamate

AED Interaction Sheets:
Seizure drugs are often affected by drug-drug interactions. Print these informative sheets for practical help.

Primidone effects on Children

Mysoline is useful in treating seizures that occur in children. But certain types of generalized seizures are not improved by Mysoline, so a correct diagnosis is critical.

Because children metabolize and eliminate Mysoline faster than adults do, they require higher doses, relative to their weight.

See Dosing and titration of Mysoline for dosage recommendations in children.

Primidone and Pregnancy

The effects of Mysoline in human pregnancy and nursing infants are unknown. The risk of defects is higher for women who take several medicines, and for women with a family history of birth defects.

Women who are capable of becoming pregnant should be advised to take 400 mcg (0.4 mg) of folic acid (folate) daily to help prevent neural tube defects. Women at high risk, such as those with a history of a neural tube defect in a previous pregnancy, should take 4000 mcg (4 mg) daily, beginning before they become pregnant.

Check the levels of Mysoline in the woman's blood at intervals during pregnancy, since changes in her body may affect them. Dosage adjustments may be needed to prevent seizures or side effects.

During the last month of pregnancy, the woman should take 10 mg per day of vitamin K to prevent a bleeding disorder that affects some babies born to mothers who are taking anticonvulsants.

No studies have been performed to demonstrate the effect of specific AEDs during labor and delivery. Possible causes of seizures include:

  • failure or inability to take medication
  • sleep deprivation
  • hyperventilation
  • stress
  • pain

If the mother is taking Mysoline, a breast-fed newborn will receive Mysoline in the breast milk. If nursing newborns are unusually drowsy, nursing should be discontinued.

Primidone effects on Seniors

Doctors do not often prescribe Mysoline to people over 65 because seniors are at particular risk for the following:

  • More possibilities for drug interactions. Usually seniors can continue to take all their medications, including Mysoline, if the dosages are changed to compensate for the effects of interactions.
  • Greater susceptibility to side effects. Some common side effects of Mysoline, such as sleepiness or unsteadiness, may exacerbate pre-existing problems.
  • Greater danger of injury from falls or other accidents resulting from side effects.

Lower doses are generally required, because elderly patients metabolize Mysoline more slowly than younger adults.

Primidone Dosing and titration

Mysoline must be introduced gradually, and a low starting dose is advisable. Here is an example of a typical schedule for building up to the desired level of Mysoline for an older child or adult:

Days 1 to 3: 100 to 125 mg at bedtime
Days 4 to 6: 100 to 125 mg each morning and evening
Days 7 to 9: 100 to 125 mg morning, noon, and night
Days 10 and later: 250 mg morning, noon, and night

Patients aged 8 or older usually take one 250-mg Mysoline tablet three or four times a day to maintain control of their seizures. Some people need to take more tablets, but the total dose should not exceed 2000 mg per day.

For children under 8 years of age, the usual dose for controlling seizures is 125 to 250 mg three times daily. The dose is usually calculated according to the child's weight, based on 10 to 25 mg of Mysoline per day for each kilogram (about 2.2 pounds) of the child's weight. Here is an example of a schedule that may be used to start a young child on Mysoline:

Days 1 to 3: 50 mg at bedtime
Days 4 to 6: 50 mg morning and evening
Days 7 to 9: 100 mg morning and evening
Days 10 and later: 125 mg three times a day to 250 mg three times a day

No one should stop taking Mysoline or change the amount they take without talking to their doctor first because of the risk of seizure exacerbation or status epilepticus.

Primidone Package insert

In the United States, companies that manufacture medicines are required to publish certain kinds of information about each product. This document is commonly known as a “package insert” because it is usually included with each package of the medicine.

You can also read these documents (also called "prescribing information") online. The U.S. package insert for Mysoline (primidone) is found at:

Some of the information may differ in other countries.

To learn how to read and understand a package insert, see How to read a package insert.

Primidone References for Professionals

Abstracts of articles relevant to this topic are available through PubMed, a service of the National Library of Medicine:

Mattson, RH, Cramer, JA, et al. Comparison of carbamazepine, phenobarbital, phenytoin and primidone in partial and secondarily generalized tonic clonic seizures. N Engl J Med. 1985;313:145-151. PMID: 3925335.

Primidone (Mysoline) was as effective as the other medications for generalized tonic-clonic seizures in adults, but the patients who took it experienced many more intolerable side effects in the early weeks of treatment.

Herranz JL, Armijo JA, Arteaga R. Clinical side effects of phenobarbital, primidone, phenytoin, carbamazepine, and valproate during monotherapy in children. Epilepsia. 1988;29(6):794-804. PMID: 3142761.

Children taking primidone (Mysoline) had a low rate of overall side effects and a moderate rate of withdrawal from treatment due to side effects in comparison to the other medications tested.

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