Zonisamide

Zonisamide (zoh-NIH-sah-mide) is the generic name (non-brand name) used in the United States for a widely used seizure medicine. The common brand name for Zonisamide is Zonegran (ZAHN-uh-gran).

Zonisamide was first used in Japan in 1972 to treat psychiatric diseases, and it has been widely used to treat epilepsy in Japan and Korea since at least 1990. The Food and Drug Administration (FDA) approved it for use in the United States in March 2000, suggesting that it be used along with other seizure medicines (as adjunctive or add-on therapy) in the treatment of partial seizures in adults.

Zonegran
Tablet
Zonegran

100-mg
White capsule with red cap, printed with company logo and "ZONEGRAN 100"

50-mg
White capsule with gray cap, printed with company logo and "ZONEGRAN 50"

25-mg
White capsule with white cap, printed with company logo and "ZONEGRAN 25"

Indications

The FDA has approved zonisamide as adjunctive therapy for partial seizures in adults with epilepsy. Clinical research and experience with patients suggests that it also may be effective for other types of epilepsy and epilepsy syndromes, including:

  • simple partial seizures
  • complex partial seizures 
  • myoclonic seizures
  • primary generalized tonic clonic seizures
  • secondarily generalized seizures 
  • Lennox-Gastaut syndrome
  • infantile spasms (West syndrome)
  • progressive myoclonic epilepsy (PME)

Forms

Zonisamide is marketed in the United States by several manufacturers. The name or appearance may differ in other places.

Dosing

Please see package insert.

How to take and store Zonisamide?

Advise patients to:

  • Swallow each capsule whole and not to bite it or break it open.
  • Take Zonegran with or without food (being consistent from day to day).
  • Drink plenty of liquids each day, to lessen the risk of renal stones.
  • Store Zonegran in a dry environment at room temperature, away from light.
Missed Doses

In general, tell patients that if they forget a dose, they should take it as soon as they remember. 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. If the patient is on a once-a-day regimen, suggest allowing an interval of about 12 hours before taking the second dose, and then resuming 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 Zonisamide

Zonisamide is chemically classified as a sulfonamide. It is not chemically related to any other seizure medicines.

The primary mechanisms of action of zonisamide appear related to blockage of voltage-dependent sodium and T-type (but not L-type) calcium channels. Zonisamide is a less potent carbonic anhydrase inhibitor than acetazolamide and therefore this effect is probably not a major contributor to its mechanism of action. Zonisamide is a broad-spectrum anti-epileptic drug (AED) in animal models.

Clinical Pharmacology of Zonisamide

Absorption
Zonisamide is absorbed rapidly and evenly distributed. Peak plasma levels of zonisamide are reached 2 to 4 hours after the capsules are taken. (These levels are 2 to 5 micrograms per milliliter if two to four 100-mg capsules are used.) If the capsules are taken with food, peak levels are not reached for 4 to 6 hours, but the availability of the medication is not affected.

Distribution and metabolism
Zonisamide binds to red blood cells and is found in a much higher concentration in red blood cells than in plasma. The concentration in plasma is greater at higher doses, perhaps because the red cells become saturated. Zonisamide is approximately 40% bound to plasma proteins. This rate is unaffected by the presence of therapeutic concentrations of phenytoin, phenobarbital or carbamazepine. Daily dosages and plasma concentrations are linearly related in adults and children.

Zonisamide is excreted primarily in the urine, so people with kidney disease should be treated with caution. The time required for the concentration of zonisamide in the blood to be reduced to half the peak level, its half-life, is about 50 to 68 hours for plasma and 105 hours for red blood cells. This is considered a long half-life. It is shortened by the presence of some other medications, however.

Because zonisamide is metabolized in the liver, people with liver disease should be treated with caution. The dose may have to be increased more slowly.

Zonisamide does not induce its own metabolism or inhibit hepatic metabolism.

Steady state
Steady state (equilibrium), when the amount of drug taken is equal to the amount being metabolized and excreted, is reached after about 14 days of taking a stable dose of zonisamide. Levels in the blood then can be expected to be fairly constant. The dose that a patient takes should not be increased until steady state has been reached (or some time later), so that the effects of the previous dose can be assessed.

Efficacy of Zonisamide

Zonegran is proven effective for partial epilepsy in adults.

The FDA-approved information on Zonegran focuses on three studies involving a total of 499 patients who had frequent partial-onset seizures (with or without secondary generalization) uncontrolled by multiple drugs. During the 3 months that each study lasted, the patients were given increasing doses of either Zonegran or a placebo (an inactive substance), in addition to the medication they were previously taking. The researchers measured the average (median) percent reduction in the frequency of partial seizures. They also looked at the percentage of patients whose seizures were reduced more than 50% ("responders"). Here are the results:

Study Median % Reduction in partial seizures % Responders(at least 50% fewer seizures)
Zonegran Placebo Zonegran Placebo
Study1 40.5% 9.0% 41.8% 22.2%
Study2 29.6% -3.2% 29.0% 15.0%
Study3 27.2% -1.1% 28.0% 12.0%

The patients taking Zonegran had a significant reduction in the number of seizures, and more of them had at least 50% fewer seizures, compared to the patients who received the placebo.

Recent small studies have shown that Zonegran has potential benefits for a broad spectrum of other types of epilepsy, such as Lennox-Gastaut syndrome, infantile spasms, and progressive myoclonus epilepsy (PME), though further research is needed.

Common side effects of Zonisamide

The most commonly reported side effects in clinical trials were:

  • somnolence
  • ataxia
  • anorexia   
  • confusion
  • abnormal thinking
  • nervousness
  • fatigue
  • dizziness
  • weight loss

Other side effects are weight loss, agitation/irritability, nausea, and headache.

Most side effects are mild to moderate in severity.

Serious Side effects of Zonisamide

Among 505 Zonegran-exposed subjects in the U.S. and European studies, 13 (2.6%) developed kidney stones, as compared to 2 patients out of 1,008 (0.2%) in Japanese studies. Stones are urate or calcium. They can develop slowly and may resolve spontaneously. They may be more likely in patients taking Zonegran for at least 6 months and those with a family history of nephrolithiasis.

In the same Japanese cohort, 17 patients were discontinued because of leukopenia or abnormal liver enzymes.

Oligohidrosis occurs rarely in children, typically presenting as decreased sweating and high fever.

Rash occurs in under 5% of patients. This reaction usually occurs within the first four months of therapy, and is especially likely in patients with a history of sulfa allergy (which is therefore a contraindication). The rash associated with Zonegran may take various forms, from small red spots or blotches on the surface of the skin to large blisters. It may be preceded or accompanied by itchiness. If severe, it may require treatment with an antihistamine or steroid.

In studies in which Zonegran was compared with a placebo, 2.2% of patients taking Zonegran stopped taking it or were hospitalized because of depression, versus 0.4% of those given the placebo. Similarly, 2.2% of the patients given Zonegran in these studies experienced psychosis or psychosis-related symptoms. None of the patients receiving a placebo had this experience.

On 2/23/2009, the US Food and Drug Administration issued a warning that the antiepileptic medication zonisamide (Zonegran) can cause metabolic acidosis in some patients. Metabolic acidosis is a condition of excess acidity (low pH) in the blood. The condition can manifest with a variety of symptoms, including chest pains, heart racing, rapid breathing, stomach upset, kidney stones, confusion and other symptoms. People who are already prone to have metabolic acidosis from kidney disease or drugs such as acetazolamide (Diamox), certain diabetes drugs or the ketogenic diet may be more prone to develop zonisamide-induced metabolic acidosis. Young people are also more likely to develop the condition. Metabolic acidosis is detected by measuring blood levels of bicarbonate (worrisome if less than 17 mEq/L), sometimes along with arterial blood gas measurement for levels of oxygen, carbon dioxide and acidity. Once diagnosed, the condition usually is treatable, most directly by stopping zonisamide. The FDA recommended that healthcare professionals measure serum bicarbonate before starting treatment and regularly thereafter.

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 Zonisamide

Research and experience with patients suggests that zonisamide also may be effective for other types of epilepsy and epilepsy syndromes, including:

  • Lennox-Gastaut syndrome
  • infantile spasms (West syndrome)
  • progressive myoclonic epilepsy (PME)
Zonisamide Contraindications

Zonisamide is contraindicated in patients who have demonstrated hypersensitivity to sulfonamides or Zonegran.

Zonisamide Interactions with other medications

Effects of zonisamide on other drugs
Zonisamide has no appreciable effect on the steady state plasma concentrations of other AEDs.

Effects of other drugs on zonisamide
In the presence of enzyme-inducing AEDs, zonisamide half-life decreases by approximately 50% and plasma concentration at steady state decreases.

Zonisamide is not affected by cimetidine.

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

Zonisamide effects on Children

Efficacy
Although the FDA has not officially approved zonisamide for children, a number of research studies in children of various ages (even infants) have shown generally good results. It has been effective in reducing many types of seizures, especially primarily generalized seizures, absence seizures, infantile spasms, and myoclonic seizures.

Side effects
If the dosage is carefully controlled, side effects should not be a problem for most children. In one large study that included children as young as 1 month, side effects were reported for fewer than 20% of children who took zonisamide alone and about 30% who took it along with one or more other seizure medicines. The most common side effects in this study involved problems with thinking or behavior, followed by stomach upset. One dangerous side effect, decreased sweating with fever, occasionally affects young children, but not adults, leading to high fever and possible heatstroke. Advise parents whose children are given zonisamide also to watch for the other symptoms of rare but serious reactions that are listed in the package insert.

Dosage
Standard dosing recommendations in children are to start zonisamide at 2 to 4 mg/kg per day. The dosage is increased by a similar amount every 2 weeks, depending on how well the child's seizures are controlled and whether any side effects have appeared. Most children do best at about 8 mg/kg per day. The highest dose recommended is 12 mg/kg per day.

In the past, administering low doses to children was difficult, since zonisamide was available only as 100-mg capsules. Smaller capsules, 25 mg and 50 mg, became available in the United States in December 2003.

Zonisamide and Pregnancy

The U.S. Food and Drug Administration (FDA) has labeled zonisamide as "Pregnancy Category C" and recommends that women who could possibly become pregnant should use effective birth control while using zonisamide. Recognizing that seizures in the mother also may be hazardous to a fetus, however, they conclude that the risks and benefits must be weighed in considering the use of zonisamide during pregnancy.

The use of zonisamide by pregnant women hasn't been fully studied. A prospective study of pregnancy outcomes in zonisamide-treated women at member hospitals of the Japanese Epilepsy Society between 1989 and 1994 identified 26 offspring, including 4 children born to women on zonisamide monotherapy. Among the 22 offspring exposed to AED polytherapy, malformations occurred in two (anencephaly in one and atrial septal defect in the other). No malformations occurred in children exposed to zonisamide monotherapy. Because of the small sample size, these results should be interpreted with caution.

When zonisamide was given to pregnant mice, rats, and dogs early in pregnancy, there were high rates of fetal abnormalities, especially heart defects and skeletal malformations. After it was given to monkeys during certain stages of pregnancy, many of the fetuses died, possibly because of malformations. All of these effects occurred at doses (and blood levels in the mother) that were equivalent to the amounts used to treat epilepsy in humans, or sometimes even lower. There was also a higher rate of death among the offspring of rats who were given zonisamide late in their pregnancy.

Advise women who are capable of becoming pregnant to take at least 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 an AED is metabolized. Though specific effects of pregnancy on zonisamide are not known, serum levels should be checked regularly during pregnancy so that the dosage can be adjusted as needed.

It is not known whether zonisamide is found in human milk. The effect on labor and delivery also is unknown.

Studies in rats showed decreases in fertility when zonisamide was given. Its effect on human fertility is unknown.

Zonisamide effects on Seniors

Most studies of zonisamide have not included enough seniors (over 65) to determine whether they respond in a different way than younger adults. Tests in which healthy volunteers of various ages were given one dose didn't find any important differences in the way their bodies absorbed and eliminated zonisamide. However, zonisamide doses should be reduced in elderly patients with renal dysfunction.

Zonisamide Dosing and titration

The recommended initial daily dose of zonisamide is 100 to 200 mg for adults and 2 to 4 mg/kg per day for children. Because steady state is reached within 14 days, dosages should be increased at 2-week intervals to a target maintenance dose of 400 to 600 mg/day in adults and 4 to 8 mg/kg per day in children. These amounts are usually given in two divided doses, but some patients may take zonisamide once a day. Higher dosages may be tolerable and necessary in selected patients. Serum concentrations of 10-40 mcg/mL are usually achieved.

A blood level of approximately 10-40 mcg/mL is generally considered to be therapeutic (lower for seniors), but adjustments should depend on clinical response.

Zonisamide 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 Zonegran (zonisamide) 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."

Zonisamide References for Professionals

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

Here are links to some articles relevant to this subject:

Kyllerman M, Ben-Menachem E: Zonisamide for progressive myoclonus epilepsy: long-term observations in seven patients. Epilepsy Res 29: 109-114, 1998. PMID 9477142.

Leppik IE: Zonisamide. Epilepsia 40(suppl 5): S23, 1999. PMID 10530691.

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