Ethosuximide

Zarontin is the brand name used in the United States, Canada, the UK, Australia, and some other countries for ethosuximide.

Zarontin has been used since about 1960 as a first-line medication for the treatment of generalized absence seizures.

Zarontin
Tablet
Zarontin 250mg

250-mg orange-colored gelatin capsule

Liquid Solution

250 mg/5 mL (raspberry-flavored)

Indications

Zarontin is used to treat absence seizures, particularly in young children. It has no effect against (or may even worsen) partial and tonic-clonic seizures.

Forms

Zarontin is marketed in the United States by Parke-Davis (a division of Pfizer). The name or appearance may differ in other places. These descriptions apply to the U.S. versions:

Dosing

Please see package insert.

How to take and store Ethosuximide?

Zarontin can be taken either with food or without food, but many people find that stomach upset is less of a problem if the medicine is taken with meals.

Zarontin capsules should be swallowed whole, not chewed or broken open. They are stored at room temperature.

Remind patients using the syrup to use an accurate measuring device and to store it at room temperature, protected from freezing and away from light.

Remind all patients to keep Zarontin out of the reach of children.

Missed Doses

Advise patients to take a forgotten dose immediately. If it is almost time for the next dose, they should delay that dose for a few hours, instead of taking two doses very close together. Patients who take Zarontin only once a day could be advised to wait about 12 hours between doses and then resume a 24-hour schedule the next day.

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

Mechanisms of actions of Ethosuximide

The exact mechanism of action of ethosuximide is not entirely understood. Ethosuximide inhibits NADPH-linked aldehyde reductase necessary for the formation of gamma-hydroxybutyrate, which has been associated with the induction of absence seizures. Ethosuximide also appears to inhibit the sodium-potassium ATPase system. Ethosuximide can decrease the burst firing of thalamocortical neurons. This action may explain the anti-absence activity of the drug.

Ethosuximide also has been shown to decrease non-inactivating Na currents in thalamocortical neurons, as well as blocking Ca dependent K channels.

It does not appear to alter brain GABA concentrations.

Clinical Pharmacology of Ethosuximide

Absorption
Peak plasma levels are reached in 3 to 5 hours for both children and adults if capsules are taken. The time is somewhat shorter if the syrup is used, but the total amount absorbed will be about the same. Absorption is virtually complete.

Some generic forms of ethosuximide are now available in the United States. They may not be exactly equivalent to Zarontin pharmacologically.

Distribution and metabolism
Ethosuximide is not bound to plasma proteins. It is distributed through total body water and metabolized in the liver.

The half-life of ethosuximide is about 30 to 40 hours in children and 50 to 60 hours in adults.

Because ethosuximide is metabolized in the liver, people with liver disease should be treated with great caution. They may have to be started at a lower dose and have their dosage increased more slowly.

Steady state
In children, steady state is reached after 6 days of taking a stable dose of Zarontin. For adults, the equivalent period is 12 days. A patient's dosage should not be increased until steady state has been reached (or some time later), so that the effects of the previous dosage can be assessed.

Efficacy of Ethosuximide

Zarontin (ethosuximide) generally is used only for absence seizures. It is highly effective and safe for treating childhood absence epilepsy, which occurs in 8% of children with epilepsy between ages 5 and 14 years. This disorder usually begins between ages 4 and 8 in children without previous brain disorders. Often there is a family history of the same disorder. These seizures almost always can be provoked in the office by having the child hyperventilate for a few minutes. Although these seizures usually will stop when the child gets older, children who have them need effective treatment to avoid learning problems and accidental injuries.

Zarontin is often the first-line medication for childhood absence epilepsy. In one early study, 95% of patients had the number of seizures reduced by at least half, and about half the patients had them reduced by at least 90%.

Some children who have absence seizures have more complicated disorders that are harder to treat and may not be outgrown, such as atypical absence or juvenile myoclonic epilepsy.These children may also have other types of seizures, are often older when the absence seizures begin, and have a different EEG pattern than children with typical childhood absence epilepsy. Zarontin is also effective in controlling absence seizures in many of these children, but other medications often are needed to control other types of seizures. Depakote and other valproate medications will control absence seizures, so it may be used instead of Zarontin. Some children do best with a combination of these two.

Zarontin can also be used in combination therapy for patients who have both absences and other kinds of seizures. No single combination of antiepileptic medications is perfect for everyone. Sometimes, a series of combinations must be tried before finding what is best for the individual patient. Adding Zarontin usually does not affect the level of other seizure medicines in the body, but some adjustment of the Zarontin dosage may be needed if other medications are added.

Common side effects of Ethosuximide

Dose-related side effects

In early studies of ethosuximide, a minority of subjects reported adverse effects. The most common adverse effects were gastrointestinal:

  • nausea
  • abdominal discomfort
  • vomiting
  • anorexia
  • diarrhea


These problems are usually mild. If they do not diminish within several days, a reduction in the dose of Zarontin may be required. Another effective technique to resolve such problems is to divide the daily dosage into smaller doses to be taken with meals.

Less common were other adverse effects:

  • drowsiness
  • dizziness
  • hiccups
  • behavioral changes (irritability, mood change, aggressiveness)


These effects generally respond to dose reduction.

Some children taking ethosuximide develop persistent headaches, which do not appear to be dose-related.

Other patients notice a pinkish or brownish discoloration of their urine. This is unlikely to represent a serious problem.

Idiosyncratic reactions

The most common idiosyncratic reaction to ethosuximide is a mild rash, which often disappears if the medication is stopped. Some patients need steroid therapy.

Serious Side effects of Ethosuximide

A small percentage of people who take ethosuximide experience serious reactions. Alert patients to call immediately if they notice any of the following symptoms:

  • Rash
  • Sore throat, fever, sores in the mouth, or easy bruising (blood dyscrasias)
  • Fever, rash, arthritis, swelling in the lymph nodes (systemic lupus erythematosus or lupuslike syndrome)
  • Depression, anxiety, or aggressiveness
  • Hallucinations, hearing "voices" or losing contact with reality (psychosis)

As with many seizure medicines, skin rashes (including the very rare Stevens-Johnson syndrome, which can be fatal) have been a problem for a small number of patients. Most rashes are much less serious and will disappear if ethosuximide is withdrawn.

Similarly, Zarontin carries a very small risk of blood abnormalities. Checking the blood cell count within 2 to 12 weeks after the Zarontin is started and every 4 to 12 months after that is often recommended, but reminding patients to report symptoms promptly is probably more effective in early recognition of blood disorders.

One effect that has been studied extensively is an allergic reaction to Zarontin that might bring about some of the symptoms and blood test results found in systemic lupus erythematosus (SLE). Sometimes patients with these symptoms have a lupuslike syndrome from which they fully recover when ethosuximide is stopped, though recovery may take some time.

Behavioral changes occasionally occur shortly after patients start taking Zarontin. Hallucinations, paranoia, and other signs of psychosis have been reported in a few patients, mostly adolescents or young adults with a history of previous emotional problems or psychiatric disease. These problems may be more likely if high doses are given.

Tests of liver and kidney function are also recommended. Zarontin should be given to patients with liver or kidney disease only with extreme caution.

A complete list of all reactions to Zarontin can be found in the package insert.

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.

Impact of Ethosuximide on bone health

See package insert. 

Other Uses of Ethosuximide

Besides childhood absence epilepsy, Zarontin has shown itself to be effective against atypical absence seizures and absence status (at high levels). It is also a useful adjunctive medication for patients with juvenile myoclonic epilepsy and Lennox-Gastaut syndrome.

It also has shown efficacy in controlling negative myoclonus, a rare type of partial seizures seen in some epilepsy syndromes in children. Unlike the more common brisk jerks of positive myoclonus, negative myoclonus involves a brief loss of postural tone. This loss occurs at the same time as spike-and-wave complexes in the contralateral cerebral hemisphere.

Ethosuximide Contraindications

Patients who are allergic to succinimides should not take Zarontin. Besides ethosuximide, the other common succinimide is Celontin (methsuximide).

Ethosuximide should be administered with extreme caution to patients with known liver or kidney disease.

Ethosuximide Interactions with other medications

Zarontin is less likely than many other antiepileptic drugs to interact with other medications. Nevertheless, it's advisable to question patients or family members about the use of prescription and OTC medications, herbal products, vitamins, alcohol, and other substances when prescribing Zarontin. Usually all necessary medications can be used, but the dosages may need to be adjusted to achieve therapeutic levels.

Effects of Zarontin (ethosuximide) on other drugs

Zarontin has little effect on other medications. It may elevate blood levels of phenytoin (Dilantin, Phenytek) somewhat, but the clinical significance is unclear.

Effects of other drugs on Zarontin (ethosuximide)

Valproate (Depakote, Depakene, valproic acid) may slightly increase blood levels of ethosuximide, but it is unclear whether the effect is clinically significant. The combination of these two medications is often beneficial.

Administering ethosuximide along with isoniazid, ritonavir, or erythromycin may elevate serum levels of ethosuximide to a greater extent because of their inhibitory effects on enzymes responsible for its metabolism in the liver.

The level of ethosuximide is reduced if it is taken concurrently with enzyme-inducing medications, including:

  • carbamazepine (Tegretol, Carbatrol)
  • phenytoin (Dilantin, Phenytek)
  • primidone (Mysoline)
  • phenobarbital
  • rifampin

AED Interaction Sheets:

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

Interaction sheet for ethosuximide (Zarontin)

Ethosuximide effects on Children

Ethosuximide has been used for many years to treat children with absence seizures. Side effects are usually mild, most often gastrointestinal upsets that can be minimized by taking doses with meals, up to three times a day.

The initial dose for patients 3 to 6 years of age is one capsule or one teaspoon of syrup (250 mg) per day. Children over 6 years can start with two capsules or two teaspoons of syrup (500 mg) per day. The dose thereafter must be individualized by small increments according to the patient's response. One useful method is to increase the daily dose by 250 mg every 4 to 7 days until control is achieved with minimal side effects.

The optimal daily dose for most children is 20 mg/kg. This dose has given average plasma levels within the accepted therapeutic range of 40 to 100 mcg/mL.

Ethosuximide and Pregnancy

The U.S. Food and Drug Administration (FDA) lists Zarontin in Pregnancy Category C. This indicates that caution is advised, but the benefits of the medication may outweigh the potential risks.

The babies of women taking antiepileptic drugs (AEDs) generally are more likely to have birth defects, although a large majority are normal. The risk of defects is higher for women who take more than one AED and for women with a family history of birth defects. The reasons for these differences are uncertain, since factors other than medication, such as genetics and seizures, also may play a role.

There is little solid evidence indicating whether particular AEDs are more teratogenic than others. We do know that ethosuximide crosses the placenta and plasma levels in neonates are similar to those of the mother.

Advise women who are capable of becoming pregnant 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.

About 20% to 35% of women have seizures more often during pregnancy because of changes in hormones or changes in how their medication is handled by the body. Check the blood levels of ethosuximide regularly during pregnancy so that the dosage can be adjusted as needed.

Ethosuximide appears in breast milk. Estimates are that a nursing infant might receive a dose of 13 to 38 mg per day. The effect of this dose on an infant is unknown. Discuss the options with women taking ethosuximide who are interested in breast-feeding, including staying with ethosuximide, switching to a different AED, or discontinuing their medication.

Ethosuximide effects on Seniors

Absence seizures are much more common in childhood, so not many seniors take Zarontin. As with most other medications, low initial doses and caution in titration is advised. Patients with reduced liver function must be treated with particular caution.

Some common side effects of Zarontin, such as drowsiness or dizziness, may exacerbate pre-existing problems of seniors, and their greater risk of injury from falls or other accidents makes this an area of concern.

Ethosuximide Dosing and titration

For children ages 3 to 6 years with absence seizures, the usual starting dose is 1 capsule or 1 teaspoon (5 mL) of the syrup per day. This is often given as half a teaspoon (2.5 mL) twice a day.

The initial daily dose for older children is often 2 capsules or 2 teaspoons of syrup, which can be increased after about a week.

Most children do best at about 20 mg/kg per day. The dose is usually divided, with doses given two or three times a day.

A therapeutic serum level of ethosuximide is generally considered to be 40-100 mcg/mL, but adjustments should depend on clinical response. Because Zarontin has a long half-life, blood levels do not fluctuate much, so the time when tests are done is not important. Levels in saliva are very similar to plasma levels and also can be used to monitor therapy.

Special Concerns for Ethosuximide

Please see package insert.

Ethosuximide 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 Zarontin (ethosuximide) 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."

Ethosuximide References for Professionals

Abstracts of articles related to Zarontin (ethosuximide) are available through PubMed, a service of the National Library of Medicine:

Here is a link to one article about Zarontin:

Browne TR, Dreifuss FE, Dyken PR, et al. Ethosuximide in the treatment of absence (petit mal) seizures Neurology 1975 Jun;25(6):515-24. PMID: 805382.

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