Zarontin (Ethosuximide) for Treating Seizures

Ethosuximide for preventing seizures

Zarontin (Ethosuximide) for Treating Seizures

This leaflet is about the use of ethosuximide for preventing seizures. (Seizures may be also called convulsions or fits.)

This leaflet has been written specifically for parents and carers about the use of this medicine in children. The information may differ from that provided by the manufacturer. Please read this leaflet carefully. Keep it somewhere safe so that you can read it again.

Do not stop giving ethosuximide suddenly, as your child may have more seizures.

Why is it important for my child to take this medicine?

It is important that your child takes ethosuximide regularly so that they have fewer seizures.

When should I give ethosuximide?

Ethosuximide is usually given twice each day, once in the morning and once in the evening. Ideally, these times are 10–12 hours apart, for example some time between 7 and 8 am, and between 7 and 8 pm.

Very occasionally the medicine can be given three times a day (your doctor will tell you if it needs to be given this). This should be in the morning, early afternoon and at bedtime. Ideally, these times are at least 6 hours apart, for example 8 am, 2 pm and 8 pm.

Give the medicine at about the same time(s) each day so that this becomes part of your child’s daily routine, which will help you to remember.

How much should I give?

Your doctor will work out the amount of ethosuximide (the dose) that is right for your child. The dose will be shown on the medicine label.

Your doctor will start your child on a low dose and then gradually increase it over a few days or weeks to help your child get used to the medicine. If you are not sure how much to give, check with your doctor, epilepsy nurse or pharmacist.

It is important that you follow your doctor’s instructions about how much to give.

How should I give it?

Capsules should be swallowed whole with a glass of water, milk or juice. Your child should not chew the capsule.

Liquid medicine: Measure out the right amount using an oral syringe or medicine spoon. You can get these from your pharmacist. Do not use a kitchen teaspoon as it will not give the right amount.

When should the medicine start working?

It may take a few weeks for ethosuximide to work properly, so your child may still have seizures during this time. This is because the amount of medicine has to be increased slowly.

Continue to give the medicine in the way that you have been told to by your doctor or epilepsy nurse. Ethosuximide may not stop your child’s seizures completely.

If you are worried about whether it is helping, contact your doctor but continue to give the medicine.

What if my child is sick (vomits)?

  • If your child is sick less than 30 minutes after having a dose of ethosuximide, give them the same dose again.
  • If your child is sick more than 30 minutes after having a dose of ethosuximide, you do not need to give them another dose. Wait until the next normal dose.

What if I forget to give it?

  • If you usually give it twice a day: If you remember up to 4 hours after you should have given a dose, give your child the missed dose. For example, if you usually give a dose at about 7 am, you can give the missed dose at any time up to 11 am. If you remember after that time, do not give the missed dose. Just give the next dose as usual.
  • If you usually give it three times a day: Do not give the missed dose. Just give the next dose as usual.

Never give a double dose of ethosuximide.

What if I give too much?

You are unly to do harm if you give an extra dose of ethosuximide by mistake. If you are concerned that you may have given too much, contact your doctor or NHS Direct (0845 4647 in England and Wales; 08454 24 24 24 in Scotland). Have the medicine or packaging with you if you telephone for advice.

Are there any possible side-effects?

We use medicines to make our children better, but sometimes they have other effects that we don’t want (side-effects).

Side-effects that you must do something about

If your child starts to have more fits than usual, contact your doctor or take them to hospital straight away.

If your child develops a fever (temperature above 38°C), sore throat, mouth ulcers, bruising or bleeding, contact your doctor or take them to hospital straight away.

Other side-effects you need to know about

  • Ethosuximide usually causes only mild side-effects, which should get better as your child’s body gets used to the medicine. If they are still a problem after 2 weeks, or you are worried, contact your doctor, but continue to give ethosuximide.
  • Your child may be feel sick (nausea) or be sick (vomit) or have stomach ache or diarrhoea, or go off their food.
  • Your child may have a headache or feel dizzy or sleepy (drowsy), and they may have sleep disturbances such as difficulty getting to sleep.
  • They may have hiccups.
  • Your child may seem less alert than normal, and may say they cannot think clearly, or their coordination may be affected. They may also have changes in mood or become irritable more easily.

There may, sometimes, be other side-effects that are not listed above.

If you notice anything unusual and are concerned, contact your doctor.

Can other medicines be given at the same time as ethosuximide?

  • You can give your child medicines that contain paracetamol or ibuprofen, unless your doctor has told you not to.
  • Check with your doctor or pharmacist before giving any other medicines to your child. This includes herbal or complementary medicines.

Epilepsy and pregnancy

  • Pregnancy presents a risk to both the mother with epilepsy and her unborn baby. If your daughter has sex, it is essential that she uses adequate contraception to prevent an unplanned pregnancy.
  • If your daughter thinks that she may be pregnant, it is important that she sees your family doctor as early as possible. Your daughter should keep taking her medication until she sees her doctor.

Ethosuximide and pregnancy

  • The risk of ethosuximide causing harm to an unborn baby is low but your daughter must always speak to her doctor before trying to conceive.
  • The oral contraceptive pill can be used safely by women or girls who are taking ethosuximide.

General advice about medicines for seizures

Do not suddenly stop giving any of these medicines to your child, as they may have a seizure. If you are worried, contact your doctor but carry on giving the medicine to your child as usual.

If your child seems to have more seizures than usual, contact your doctor or epilepsy nurse.

  • If your doctor decides to stop a particular medicine, they will discuss this with you. You will usually reduce the dose bit by bit.

Do not change the dose of any drug without talking to your doctor first.

  • It is best that your child always has the same brand of each medicine, as there may be differences between brands. Keep a record of which medicines your child has.
  • Try to give medicines at about the same times every day, to help you remember.
  • If you are not sure a medicine is working, contact your doctor but continue to give the medicine as usual in the meantime. Do not give extra doses, as you may do harm.
  • Only give the medicine(s) to your child. Never give them to anyone else, even if their condition appears to be the same, as this could do harm.

If you think someone else may have taken the medicine by accident, contact your doctor straight away.

  • Make sure that you always have enough medicine. Order a new prescription at least 2 weeks before you will run out.
  • Make sure that the medicines you have at home have not reached the ‘best before’ or ‘use by’ date on the packaging. Give old medicines to your pharmacist to dispose of.

Where I should keep this medicine?

  • Keep the medicine in a cupboard, away from heat and direct sunlight. It does not need to be kept in the fridge.
  • Make sure that children cannot see or reach the medicine.
  • Keep the medicine in the container it came in.

Who to contact for more information

Your doctor, pharmacist or nurse will be able to give you more information about ethosuximide and about other medicines used to treat epilepsy.


Ethosuximide, Valproic Acid, and Lamotrigine in Childhood Absence Epilepsy

Zarontin (Ethosuximide) for Treating Seizures

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Zarontin (Ethosuximide) for Treating Seizures

Ethosuximide is FDA approved for the management of absence seizures in patients over 3 years of age. Currently, there are no off label uses for ethosuximide, however, there is some evidence it may have some analgesic effects. Specifically, several studies have suggested value in the management of neuropathic pain.[1][2][3]

Ethosuximide has level A evidence for childhood absence seizures and has been known to be an effective medication in the management of absence seizures in humans since the 1960s and 1970s.

[4][5] A landmark trial in 2010 showed that ethosuximide and valproic acid were more effective than lamotrigine for the management of childhood absence seizures[6]. Seizure freedom rates for ethosuximide and valproic acid were 53% and 58% respectively.

These patients were then followed for 12 months to evaluate their long term outcomes. This data was published in 2013, showing that ethosuximide had better tolerability than valproic acid.[7] Similar data has been found in adolescents.

[8] Due to its effectiveness and relatively limited side effect profile as outlined above, ethosuximide is considered the first line therapy for absence epilepsy. If a patient continues to be refractory to ethosuximide monotherapy, valproic acid can to added to increase the lihood of seizure control. 

While ethosuximide is effective for absence seizures, it otherwise has a very narrow therapeutic profile. It has no benefit in symptomatic epilepsies or other generalized epilepsies.

If a patient has concurrent generalized tonic-clonic (GTC) seizures, valproic acid is recommended over ethosuximide as initial monotherapy since ethosuximide does not control GTC seizures and can potentially exacerbate them. 

Ethosuximide (3-ethyl-3-methyl pyrrolidine-2,5-dione) is one of three succinimides known to have anticonvulsant properties. The other two succinimides, phensuximide and methsuximide, have worse side effect profiles and are less effective than ethosuximide.[9] Studies of this class of organic compounds first took place in the 1950s in mouse models. 

Thalamocortical neurons are hypothesized to be generators of the classic 3 Hz spike-and-wave discharges seen with absence seizures and rely heavily on low threshold T-type calcium channels to do so. Ethosuximide is able to lower the threshold of T-type calcium currents and disrupt the oscillatory activity of thalamocortical circuitry by blocking T-type calcium channels.

Ethosuximide administration is via 250mg capsules or a 250mg/5mL oral suspension. The oral suspension has a faster absorption rate than the capsules. 

Dosing should start at 125mg BID for children between ages 3-6. Children above the age of 6 and adults can start at 250 mg BID. Dosing can then be increased by 250mg every 4 to 7 days to 20 mg/kg/day divided BID.

Serum concentrations of ethosuximide follow linear kinetics with increasing doses. The maximum dose is 1500 mg/day. Patients on hemodialysis may require additional doses before or after their treatments to maintain therapeutic levels.

When being discontinued, it should be tapered off slowly as abrupt withdrawal may precipitate absence status epilepticus.

Ethosuximide has excellent bioavailability (over 90%). It has negligible protein binding once it enters the bloodstream and readily crosses the blood-brain barrier.

[10] It is hepatically metabolized (80%) primarily by CYP3A4 into inactive metabolites. About 10 to 20% may be excreted unchanged in the urine. It has a relatively long half-life; 30 hours in children and 50 to 60 hours in adults.

Because of its long half-life, ethosuximide can take several days (7 to 10) to reach a steady state. 

The overall rate of adverse side effects with ethosuximide use is less than most other AEDs (26 to 46%). Gastrointestinal side effects (nausea, vomiting, diarrhea, and anorexia) are a common initial side effect which often diminishes after 1 to 2 weeks. Other common side effects include drowsiness, lethargy, insomnia, and hiccups. Headache can occur in 14% of children on ethosuximide. 

Reports exist of rare idiosyncratic reactions Stevens-Johnson syndrome, agranulocytosis, aplastic anemia, and systemic lupus erythematosus.[11][12] Discontinuation of ethosuximide is necessary if any idiosyncratic reactions occur. Recovery may take time but usually occurs with discontinuation. 

Patients with hypersensitivity to succinimides should avoid taking ethosuximide.  Its use requires caution in patients with hepatic and renal disease.

There are no guidelines for therapeutic drug monitoring of ethosuximide. Dosing can be adjusted purely on the patient's clinical response to a particular dose and electroencephalogram (EEG). Ethosuximide levels checking is done as a trough.

The therapeutic range for ethosuximide is between 40 to 100 mcg/ml. Higher levels than 100 mcg/ml are usually tolerable without toxicity. Patients in absence status epilepticus may need serum concentrations higher than 120 mcg/ml to achieve seizure control.

[10] Complete blood counts (CBC) and liver function tests (LFT) can also be checked intermittently to monitor for severe but rare hematologic dyscrasias (pancytopenia, agranulocytosis, leukopenia) despite no evidence that this is sufficient to alert physicians about this potential serious idiosyncratic reaction.

Enzyme-inducing antiepileptic drugs (AEDs) such as phenytoin, carbamazepine, and phenobarbital can reduce serum concentrations of ethosuximide by accelerating its elimination.[13] The effect of valproic acid on ethosuximide concentrations can be variable.[14][15][16][17] Ethosuximide may increase phenytoin levels, but it has no enzyme-inducing properties. 

Isoniazid may reduce ethosuximide metabolism, while rifampicin can increase ethosuximide clearance.[18][19]

Mouse models suggest symptoms of ethosuximide toxicity begin with incoordination and can progress to dyspnea, respiratory failure, and death.[20] Comparably, overdose in humans can lead to coma and respiratory depression.

Recommendations are that patients with an acute overdose of ethosuximide should be observed in an emergency room or inpatient setting, with supportive care if needed.

[21] Hemodialysis can be a safe and effective way to rapidly clear ethosuximide from the body.[22]

Ethosuximide is a category C drug (possibly unsafe in pregnancy) that is known to cross the placenta; Serum concentrations of ethosuximide in neonates are comparable to that of the mothers.

[23] Recommendations are that during pregnancy, ethosuximide should be used as monotherapy with the lowest effective dose when possible. Levels could be checked pre-pregnancy and then monitored intermittently during pregnancy.

Ethosuximide can be excreted in breastmilk at concentrations comparable to maternal serum. Because of this, breastfeeding while on ethosuximide is considered potentially hazardous.

Primary care physicians commonly are the first medical care providers to be informed about staring episodes or poor school performance suggesting absence seizures, prompting a referral to neurology.

After making a diagnosis of absence epilepsy, and initiating ethosuximide, primary care physicians and neurologists should both monitor for clinical benefit from ethosuximide therapy.

 If a patient remains seizures free for over two years while on ethosuximide, and if the patient's EEG has normalized, one could consider slowly tapering the medication off over weeks to see if the patient developed terminal remission. 

To access free multiple choice questions on this topic, click here.

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