Ethosuximide is an orally available medicine for the treatment of Absence seizures. It is available by the brand names of Zarontin among others. It is used alone or in combination with other anti-epileptic medicines for absence (petit-mal) seizures.
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Indications of Ethosuximide:
- It is recommended for management of absence (petit mal) seizures.
Ethosuximide Dose in Adults
Ethosuximide Adult dosage in the treatment of Absence (petit mal) seizures:
- Oral dose of 500 mg once daily.
- The dosage depends on the patient's response and can be increased in small increments (eg, ≤250 mg).
- Doses >1,500 mg per 24 hours divided doses should only be used under the strict supervision of a physician.
- Higher doses may be required in some cases.
Note:
Once-daily doses are shown to be more effective and well-tolerated in clinical trials (in children) and pharmacokinetic analysis.
Ethosuximide Dose in Children
Ethosuximide treatment dosage for Absence (petit mal) seizures in Children:
Note: According to the patient's tolerance, the daily dose is either divided into bi-daily or tri-daily doses in clinical practise.
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Fixed dosing:
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Children 3 to 6 years:
- An oral dose of 250 mg once daily.
- Dosage can be increased in small increments (for instance ≤250 mg) every 4 days to one week as required.
- Usual optimal daily dose: 20 mg/kg per day.
- The usual maximum daily dose: 1,500 mg once a day in divided doses/ higher doses may be necessary for some patients
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Children ≥6 years and Adolescents:
- An oral dose of 500 mg every 24 hours.
- The dose can be changed according to the patient response by increasing in small increments (eg, 250 mg) every 4 days to one week as required.
- The typical recommended dose is 20 mg/kg per day.
- Usual maximum daily dose: 1,500 mg divided into two doses per day; for some people, greater doses may be required.
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Weight-directed dosing:
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Children ≥2 years and Adolescents:
- A starting oral dose of 10 mg/kg per day, followed by weekly adjustments of 5–10 mg/kg per day until the desired response was achieved.
- Usual range: 20 to 30 mg/kg per 24 hours in 2 to 3 divided doses.
- Single doses administered every 24 hours have also been shown to be effective and tolerated.
- Doses reported in the literature range from 6.5 to 50 mg/kg per 24 hours.
- The maximum daily dose is either 2,000 mg per day or 60 mg/kg once day, whichever is less.
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Ethosuximide Pregnancy Risk Factor: D
- Ethosuximide can cross placenta.
- In some cases, infants may have birth defects.
- Teratogenicity is dependent on epilepsy, the amount of drugs or genetic factors used, or a combination thereof.
- Multi-drug therapy may increase the likelihood of congenital malformations.
- It is preferred to use a single-dose therapy that has the lowest dose of effectiveness.
- If a woman with epilepsy is planning to conceive, the baseline serum concentrations of that patient should be tested once or twice during pregnancy.
- This should take place in a time when seizure control has been at its best.
- Women with controlled seizures should be monitored for at least 4 weeks before they become pregnant.
Use of Ethosuximide during breastfeeding
- Breast milk contains ethouximide.
- The manufacturer suggests that breastfeeding mothers be cautious when prescribing Ethosuximide.
- According to the Canadian label, it is best to avoid breastfeeding while taking ethosuximide.
Ethosuximide dosage in patients with renal disease:
According to the manufacturer's labelling, there are no dosage modifications necessary. Use with the utmost care.
Ethosuximide dosage in patients with liver disease:
According to the manufacturer's labelling, there are no dosage modifications necessary. Use with the utmost care.
Ethosuximide side effects:
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Central Nervous System:
- Aggressive Behavior
- Ataxia
- Delusional Paranoid Disorder
- Depression (With Cases Of Overt Suicidal Intentions)
- Disturbed Sleep Dizziness
- Drowsiness
- Euphoria
- Fatigue
- Headache
- Hyperactivity
- Irritability
- Lack Of Concentration
- Lethargy
- Night Terrors
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Dermatologic:
- Pruritus
- Skin Rash
- Stevens-Johnson Syndrome
- Urticaria
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Endocrine & Metabolic:
- Hirsutism
- Increased Libido
- Weight Loss
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Gastrointestinal:
- Abdominal Pain
- Anorexia
- Abdominal Cramps
- Diarrhea
- Epigastric Pain
- Gastric Distress
- Gingival Hyperplasia
- Hiccups
- Nausea
- Swollen Tongue
- Vomiting
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Genitourinary:
- Occult Blood In Urine
- Vaginal Hemorrhage
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Hematologic & Oncologic:
- Agranulocytosis
- Eosinophilia
- Leukopenia
- Pancytopenia
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Hypersensitivity:
- Hypersensitivity Reaction
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Immunologic:
- DRESS Syndrome (Drug Rash With Eosinophilia And Systemic Symptoms)
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Neuromuscular & Skeletal:
- Systemic Lupus Erythematosus
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Ophthalmic:
- Myopia
Contraindication to Ethosuximide:
- Hypersensitivity to succinimides or ethosuximide, or any other component of the formulation.
Warnings and precautions
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Blood dyscrasias
- Some cases have been reported as having fatal blood dyscrasias due to ethosuximide.
- Monitoring blood counts is important once per month, especially for patients with signs of infection.
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Depression in the CNS:
- It can lead to depression in the central nervous system, which can result in impaired mental/physical abilities.
- Patients should be cautious when operating machinery or driving.
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Dermatologic reactions
- Stevens-Johnson syndrome (SJS) has been described as a severe reaction that usually manifests within 28 days, but can be seen later.
- If you experience a rash, stop using the drug immediately.
- If you suspect Steven Johson syndrome, do not take ethosuximide again. Instead, look for alternative therapies.
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Hepatic effects
- There have been reports of liver function abnormalities.
- Every month, test your liver function.
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Hypersensitivity reactions in multi-organ systems:
- Drug reactions with eosinophilia and systemic symptoms (DRESS), also known as multi-organ hypersensitivity reactions, have been reported to be lethal.
- Watch out for symptoms such as fever, rash and exfoliative dermatitis.
- If there are suspicions of DRESS syndrome, therapy should be stopped immediately
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Effects on the renal system:
- It has been reported that there is an abnormality in renal function.
- Every month, a urine test should be performed.
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Systemic lupus, erythematosus
- Systemic lupus, also known as SLE, has been reported using ethosuximide.
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Suicidal thoughts:
- A pooled analysis of antiepileptic trials (regardless the indication) revealed an increase in suicidal thoughts/behavior.
- The incidence rate was 0.43% for patients treated, compared to 0.2% for patients who received placebo.
- After starting therapy, risk can be detected within seven days. This can continue for the duration of the trial (most trials last less than 24 weeks).
- If you notice any changes in your attitude or suicidal thoughts, please alert your healthcare provider immediately.
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Hepatic impairment
- Patients with hepatic impairment should exercise extreme caution.
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Renal impairment
- Patients with impaired renal function should exercise extreme caution.
Ethosuximide: Drug Interaction
Note: Drug Interaction Categories:
- Risk Factor C: Monitor When Using Combination
- Risk Factor D: Consider Treatment Modification
- Risk Factor X: Avoid Concomitant Use
Risk Factor C (Monitor therapy) |
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| Alcohol (Ethyl) | CNS Depressants may enhance the CNS depressant effect of Alcohol (Ethyl). |
| Alizapride | May enhance the CNS depressant effect of CNS Depressants. |
| Amphetamines | May diminish the therapeutic effect of Ethosuximide. Amphetamines may decrease the serum concentration of Ethosuximide. |
| Aprepitant | May elevate CYP3A4 substrates' serum concentration (High risk with Inhibitors). |
| Bosentan | May lower the serum level of CYP3A4 substrates (High risk with Inducers). |
| Brexanolone | Brexanolone's CNS depressing effects may be amplified by other CNS depressants. |
| Brimonidine (Topical) | May enhance the CNS depressant effect of CNS Depressants. |
| Bromopride | May enhance the CNS depressant effect of CNS Depressants. |
| Cannabidiol | May enhance the CNS depressant effect of CNS Depressants. |
| Cannabis | May enhance the CNS depressant effect of CNS Depressants. |
| Chlorphenesin Carbamate | May enhance the adverse/toxic effect of CNS Depressants. |
| Clofazimine | May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). |
| CNS Depressants | May enhance the adverse/toxic effect of other CNS Depressants. |
| Cobicistat | May increase the serum concentration of Ethosuximide. |
| CYP3A4 Inducers (Moderate) | May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). |
| CYP3A4 Inhibitors (Moderate) | May decrease the metabolism of CYP3A4 Substrates (High risk with Inhibitors). |
| Deferasirox | May lower the serum level of CYP3A4 substrates (High risk with Inducers). |
| Dimethindene (Topical) | CNS depressants may have an enhanced CNS depressant impact. |
| Doxylamine | CNS depressants may have an enhanced CNS depressant impact. Management: The producer of the pregnancy-safe drug Diclegis (doxylamine/pyridoxine) particularly advises against combining it with other CNS depressants. |
| Dronabinol | May lower the serum level of CYP3A4 substrates (High risk with Inducers). |
| Duvelisib | May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). |
| Erdafitinib | May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). |
| Erdafitinib | May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). |
| Esketamine | May enhance the CNS depressant effect of CNS Depressants. |
| Fosaprepitant | May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). |
| Fosnetupitant | May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). |
| Fosphenytoin | Ethosuximide may enhance the CNS depressant effect of Fosphenytoin. Fosphenytoin may decrease the serum concentration of Ethosuximide. Ethosuximide may increase the serum concentration of Fosphenytoin. |
| HydrOXYzine | May enhance the CNS depressant effect of CNS Depressants. |
| Ivosidenib | May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). |
| Kava Kava | May enhance the adverse/toxic effect of CNS Depressants. |
| Larotrectinib | May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). |
| Lofexidine | May enhance the CNS depressant effect of CNS Depressants. Management: Drugs listed as exceptions to this monograph are discussed in further detail in separate drug interaction monographs. |
| Magnesium Sulfate | May enhance the CNS depressant effect of CNS Depressants. |
| MetyroSINE | CNS Depressants may enhance the sedative effect of MetyroSINE. |
| Mianserin | May diminish the therapeutic effect of Anticonvulsants. |
| Minocycline | May enhance the CNS depressant effect of CNS Depressants. |
| Mirtazapine | CNS Depressants may enhance the CNS depressant effect of Mirtazapine. |
| Nabilone | CNS depressants may have an enhanced CNS depressant impact. |
| Netupitant | May elevate CYP3A4 substrates' serum concentration (High risk with Inhibitors). |
| Orlistat | Could lower the serum level of anticonvulsants. |
| Palbociclib | May elevate CYP3A4 substrates' serum concentration (High risk with Inhibitors). |
| Phenytoin | Ethosuximide may enhance the CNS depressant effect of Phenytoin. Phenytoin may decrease the serum concentration of Ethosuximide. Ethosuximide may increase the serum concentration of Phenytoin. |
| Piribedil | Piribedil's CNS depressing effects may be enhanced by other CNS depressants. |
| Pramipexole | The sedative effects of pramipexole might be enhanced by CNS depressants. |
| ROPINIRole | The sedative effects of CNS depressants may increase those of ROPINIRole. |
| Rotigotine | Rotigotine's sedative effects may be boosted by CNS depressants. |
| Rufinamide | CNS depressants' harmful or toxic effects could be increased. Particularly, drowsiness and lightheadedness could be worsened. |
| Sarilumab | May lower the serum level of CYP3A4 substrates (High risk with Inducers). |
| Selective Serotonin Reuptake Inhibitors | CNS Depressants may enhance the adverse/toxic effect of Selective Serotonin Reuptake Inhibitors. Specifically, the risk of psychomotor impairment may be enhanced. |
| Siltuximab | May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). |
| Simeprevir | May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). |
| Tetrahydrocannabinol | May enhance the CNS depressant effect of CNS Depressants. |
| Tetrahydrocannabinol and Cannabidiol | May enhance the CNS depressant effect of CNS Depressants. |
| Tocilizumab | May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). |
| Trimeprazine | May enhance the CNS depressant effect of CNS Depressants. |
| Valproate Products | Ethosuximide may decrease the serum concentration of Valproate Products. Valproate Products may increase the serum concentration of Ethosuximide. |
Risk Factor D (Consider therapy modification) |
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| Blonanserin | CNS Depressants may enhance the CNS depressant effect of Blonanserin. |
| Buprenorphine | CNS Depressants may enhance the CNS depressant effect of Buprenorphine. Management: Consider reduced doses of other CNS depressants, and avoiding such drugs in patients at high risk of buprenorphine overuse/self-injection. Initiate buprenorphine patches (Butrans brand) at 5 mcg/hr in adults when used with other CNS depressants. |
| Chlormethiazole | May enhance the CNS depressant effect of CNS Depressants. Management: Monitor closely for evidence of excessive CNS depression. The chlormethiazole labeling states that an appropriately reduced dose should be used if such a combination must be used. |
| CYP3A4 Inducers (Strong) | May increase the metabolism of CYP3A4 Substrates (High risk with Inducers). Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. |
| CYP3A4 Inhibitors (Strong) | May decrease the metabolism of CYP3A4 Substrates (High risk with Inhibitors). |
| Dabrafenib | May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). |
| Droperidol | May enhance the CNS depressant effect of CNS Depressants. Management: Consider dose reductions of droperidol or of other CNS agents (eg, opioids, barbiturates) with concomitant use. Exceptions to this monograph are discussed in further detail in separate drug interaction monographs. |
| Enzalutamide | May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Concurrent use of enzalutamide with CYP3A4 substrates that have a narrow therapeutic index should be avoided. Use of enzalutamide and any other CYP3A4 substrate should be performed with caution and close monitoring. |
| Flunitrazepam | CNS Depressants may enhance the CNS depressant effect of Flunitrazepam. |
| HYDROcodone | CNS Depressants may enhance the CNS depressant effect of HYDROcodone. Management: Avoid concomitant use of hydrocodone and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. |
| Lorlatinib | May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Avoid concurrent use of lorlatinib with any CYP3A4 substrates for which a minimal decrease in serum concentrations of the CYP3A4 substrate could lead to therapeutic failure and serious clinical consequences. |
| Mefloquine | May diminish the therapeutic effect of Anticonvulsants. Mefloquine may decrease the serum concentration of Anticonvulsants. Management: Mefloquine is contraindicated for malaria prophylaxis in persons with a history of convulsions. Monitor anticonvulsant concentrations and treatment response closely with concurrent use. |
| Methotrimeprazine | CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Methotrimeprazine may enhance the CNS depressant effect of CNS Depressants. Management: Reduce adult dose of CNS depressant agents by 50% with initiation of concomitant methotrimeprazine therapy. Further CNS depressant dosage adjustments should be initiated only after clinically effective methotrimeprazine dose is established. |
| MiFEPRIStone | May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Minimize doses of CYP3A4 substrates, and monitor for increased concentrations/toxicity, during and 2 weeks following treatment with mifepristone. Avoid cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus. |
| Mitotane | May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Doses of CYP3A4 substrates may need to be adjusted substantially when used in patients being treated with mitotane. |
| Opioid Agonists | CNS Depressants may enhance the CNS depressant effect of Opioid Agonists. Management: Avoid concomitant use of opioid agonists and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. |
| OxyCODONE | CNS Depressants may enhance the CNS depressant effect of OxyCODONE. Management: Avoid concomitant use of oxycodone and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. |
| Perampanel | May enhance the CNS depressant effect of CNS Depressants. Management: Patients taking perampanel with any other drug that has CNS depressant activities should avoid complex and high-risk activities, particularly those such as driving that require alertness and coordination, until they have experience using the combination. |
| Pitolisant | May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Combined use of pitolisant with a CYP3A4 substrate that has a narrow therapeutic index should be avoided. Other CYP3A4 substrates should be monitored more closely when used with pitolisant. |
| Sodium Oxybate | May enhance the CNS depressant effect of CNS Depressants. Management: Consider alternatives to combined use. When combined use is needed, consider minimizing doses of one or more drugs. Use of sodium oxybate with alcohol or sedative hypnotics is contraindicated. |
| St John's Wort | May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. |
| Stiripentol | May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Use of stiripentol with CYP3A4 substrates that are considered to have a narrow therapeutic index should be avoided due to the increased risk for adverse effects and toxicity. Any CYP3A4 substrate used with stiripentol requires closer monitoring. |
| Suvorexant | CNS Depressants may enhance the CNS depressant effect of Suvorexant. Management: Dose reduction of suvorexant and/or any other CNS depressant may be necessary. Use of suvorexant with alcohol is not recommended, and the use of suvorexant with any other drug to treat insomnia is not recommended. |
| Tapentadol | May enhance the CNS depressant effect of CNS Depressants. Management: Avoid concomitant use of tapentadol and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. |
| Zolpidem | CNS Depressants may enhance the CNS depressant effect of Zolpidem. Management: Reduce the Intermezzo brand sublingual zolpidem adult dose to 1.75 mg for men who are also receiving other CNS depressants. No such dose change is recommended for women. Avoid use with other CNS depressants at bedtime; avoid use with alcohol. |
Risk Factor X (Avoid combination) |
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| Azelastine (Nasal) | CNS Depressants may enhance the CNS depressant effect of Azelastine (Nasal). |
| Bromperidol | May enhance the CNS depressant effect of CNS Depressants. |
| Conivaptan | May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). |
| Fusidic Acid (Systemic) | May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). |
| Idelalisib | May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). |
| Orphenadrine | CNS Depressants may enhance the CNS depressant effect of Orphenadrine. |
| Oxomemazine | May enhance the CNS depressant effect of CNS Depressants. |
| Paraldehyde | CNS Depressants may enhance the CNS depressant effect of Paraldehyde. |
| Thalidomide | CNS Depressants may enhance the CNS depressant effect of Thalidomide. |
Monitoring parameters:
- It is important to monitor:
- Seizure frequency
- The drug's trough serum levels
- Complete blood count
- Liver enzymes (monthly)
- Monthly urine test
- Dermatological signs
- Any kind of suicidal thoughts or depression.
How to administer?
It is administered without regard to meals.
Ethosuximide Mechanism of action:
This has the potential to lower the threshold for seizures and inhibit the paroxysmal spike-and-wave pattern seen in absence seizures. In motor cortex, it results in decreased neuronal transmission.
Absorption:
- Complete and fast
Metabolism:
- Hepatic (up to 3 inactive metabolites).
Half-life Elimination
- Children under 30 hours,
- Adults 50-60 hours
Time to peak serum concentration:
- 1-7 hours
Excretion
- Slowly excreted in the urine (12% to 20%)
Ethosuximide Brand Names (International):
- Zarontin
- Asamid
- Emeside
- Etomal
- Etosuximida
- Etoxin
- Fluozoid
- Jarontin
- Petimid
- Petinimid
- Petnidan
- Serontin
- Suxilep
- Suximal
- Suxinutin
- Zarondan
- Zarontil
Ethosuximide Brand Names in Pakistan:
Brands in Pakistan will be updated later.
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