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Zonisamide (Zonegran) - Uses, Dosages, Brands

Zonisamide (Zonegran) stabilizes the neuronal membranes and suppresses neuronal hyper synchronization through action at sodium and calcium channels without affecting the GABA receptors.

It is used to treat the following conditions:

Focal (partial) onset seizures:
- It is used as an adjunct treatment of focal (partial) onset seizures in adolescents older than 16 years of age and adults with epilepsy

Zonisamide (Zonegran) Dose in Adults

Dosage in the treatment of Focal (partial) onset seizures:

It is used for adjunctive use or off-label as monotherapy.
- Initially, 100 mg/day orally is given.
- The dose can be increased to 200 mg/day orally after 14 days.
- Further dosage can be increased to 300 mg and 400 mg/day orally.
- Dosage increment can be made with a minimum of 14 days between adjustments, in order to reach steady-state at each dosage level.
- There is no evidence of increased response with doses more than 400 mg/day.
- Doses of 300 mg/day orally and more are associated with increased side effects.

Zonisamide (Zonegran) Dose in Children

Zonisamide Dosage as an adjunct in the treatment of Partial seizures.

Infants, Children, and Adolescents ≤16 years:
- Initially 1 to 2 mg/kg/day given in two divided doses each day
- Dosage is increased as 0.5 to 1 mg/kg/day every 2 weeks
- Usual dose is 5 to 8 mg/kg/day
- Some recommend higher initial and maximum doses e.g
  - Initially, 2 to 4 mg/kg/day is given in two divided doses/day
  - Then titrate dose upwards if needed every 14 days;
- The maximum daily dose is 12 mg/kg/day.
Adolescents >16 years:
- Initially100 mg once daily is given
- The dose can be increased to 200 mg/day after 14 days
- Further increase in dose should be made as 100 mg/day and only after a minimum of 14 days between adjustments
- The usual effective dose is 100 to 600 mg/day.

Zonisamide (Zonegran) dosage in the treatment of Infantile spasms:

Faster titration of zonisamide has been extensively used to control infantile spasms.
In one trial, zonisamide monotherapy was started at doses of 3 to 5 mg/kg/day given in 2 divided doses per day
Doses were increased after every 4th day till seizures were controlled or a maximum dose of 10 mg/kg/day was given
4 out of 11 patients responded to the treatment at doses of 4 - 5 mg/kg/day.
In another trial of newly diagnosed infantile spasm, patients with zonisamide add-on or monotherapy, it was started at doses of 2 - 4 mg/kg/day given in 2 divided doses per day
Doses were then increased by 2 to 5 mg/kg every 2 to 4 days till seizures were controlled or a maximum of 10 to 20 mg/kg/day was given
9 of 27 patients gave a response at a mean effective dose of 7.8 mg/kg/day.

Vigabatrin for the treatment of infantile spasms

Pregnancy Risk Factor C

In animal reproduction studies, teratogenic effects were observed.
Zonisamide was found in the newborn after delivery.
Zonisamide therapy can cause metabolic acidosis as a side effect.
The transient metabolic acidosis in newborns who have been exposed to zonisamide in the womb should be checked.
Pregnant women who are taking zonisamide should also be examined and treated as non-pregnant patients.
Maternal polytherapy with antiepileptic drugs may increase the risk of congenital malformations. Monotherapy with the lowest dose is recommended.
Antiepileptic medication-treated newborns are more at risk for adverse events.
Pregnancy causes it to clear more quickly, so a dosage adjustment is necessary.
Effective contraception should be used during therapy for women with childbearing potential.
For epilepsy treatment in pregnant women, other agents may be used.

Use Zonisamide while breastfeeding

Zonisamide is found in breast milk in similar concentrations to that in maternal plasma. It can also be detected in infant plasma.
The manufacturer warns against nursing babies to avoid serious adverse reactions.

Zonisamide (Zonegran) dose in Renal disease:

GFR >=50mL/minute
- The manufacturer's labeling does not include any dosage adjustments.
- Patients with kidney disease should be advised to slow titration and to monitor frequently.
GFR = 50 mL/minute
- Not recommended.
- An increase of 35% in the AUC is associated with renal impairment.

Zonisamide (Zonegran) dose in Liver disease:

There are no dosage adjustments given in the manufacturer’s labeling.
But, slower titration and frequent monitoring are advised in patients with renal disease; use with caution

Frequency not always defined. Frequencies noted in patients receiving other anticonvulsants:

Common Side Effects of Zonisamide (Zonegran) Include:

Central nervous system:
- Drowsiness
- Dizziness
Gastrointestinal:
- Anorexia

Less Common Side Effects of Zonisamide (Zonegran) Include:

Cardiovascular:
- Facial Edema
Central Nervous System:
- Headache
- Agitation
- Irritability
- Fatigue
- Tiredness
- Confusion
- Depression
- Insomnia
- Lack Of Concentration
- Memory Impairment
- Speech Disturbance
- Ataxia
- Decreased Mental Acuity
- Anxiety
- Nervousness
- Schizophreniform Disorder, Convulsions
- Hyperesthesia
- Seizure
- Status Epilepticus
- Hypotonia
- Hyperthermia
Dermatologic:
- Skin Rash
- Bruising
- Pruritus
- Hypohidrosis
- Stevens-Johnson Syndrome
- Toxic Epidermal Necrolysis
Endocrine & Metabolic:
- Metabolic Acidosis
Gastrointestinal:
- Nausea
- Abdominal Pain
- Diarrhea
- Dyspepsia
- Weight Loss
- Constipation
- Dysgeusia
- Xerostomia
- Vomiting
Hematologic & Oncologic:
- Agranulocytosis
- Aplastic Anemia
Neuromuscular & Skeletal:
- Paresthesia
- Abnormal gait
- Tremor
- Weakness
Ophthalmic:
- Diplopia
- Nystagmus
- Amblyopia
Otic:
- Tinnitus
Renal:
- Nephrolithiasis
- Increased Blood Urea Nitrogen
Respiratory:
- Rhinitis
- Increased Cough
- Pharyngitis
Miscellaneous:
- Flu-Like Syndrome
- Accidental Injury

Contraindication to Zonisamide (Zonegran) Include:

Allergy reactions to zonisamide, the sulfonamides or any component of the formulation

Warnings and precautions

CNS effects
- Within the first month of treatment, significant CNS effects, such as fatigue or somnolence, psychiatric symptoms (eg depression, psychosis), and psychomotor slowing (eg difficulty with concentration or speech problems) may occur.
- Most commonly, these effects are experienced at doses greater than 300 mg/day.
- It can cause sedation that can lead to impairment of mental or physical abilities.
- It is important to inform patients about tasks that require mental alertness, such as driving or operating machinery.
Metabolic acidosis
- Some patients may develop metabolic acidosis from its use. This is usually due to the fact that it can be dose-dependent.
- Predisposing conditions/therapies include severe respiratory disease, renal failure, diarrhea, status epilepticus and ketogenic diet.
- Metabolic acidosis can occur at low doses of 25 mg daily.
- Before initiation of therapy and throughout, it is important to note serum bicarbonate.
- Consider reducing or tapering your dose if metabolic acidosis is present.
- Alkali treatment should also be administered if acidosis persists.
- Untreated metabolic acidosis may increase your risk of developing nephrolithiasis or nephrocalcinosis.
Multiorgan hypersensitivity reactions
- Sometimes, fatal drug reactions with eosinophilia or systemic symptoms (DRESS) can occur. These are also known as multiorgan hypersensitivity reactions.
- Check for symptoms such as fever, rash and facial swelling. Also, consider other organ involvement (eg myocarditis or hepatitis. Hematological abnormalities. & myositis).
- If an alternative cause is not possible, stop therapy.
Effects on the renal system:
- An increase in creatinine levels and BUN has been observed
- If acute renal failure occurs or a sustained increase in creatinine/BUN levels, monitor your kidney function and discontinue therapy.
- It has also been reported that kidney stones are possible.
Suicidal thoughts:
- Suicidal thoughts/behavior are more common.
- All patients should be monitored for any changes in behavior that may indicate depression or suicidal thoughts.
Allergy to sulfonamide ("sulfa")
- Patients who have had allergic reactions to sulfonamide in the past are advised to avoid any sulfa-containing drugs.
- Cross-reactivity between non-antibiotic sulfonamides or antibiotic sulfonamides may not occur, or at best this potential is very low.
- Nonantibiotic sulfonamides are unlikely to cause cross-reactions due to antibody production (anaphylaxis).
- Type IV T-cell-mediated reactions (eg maculopapularrash) aren't well understood so the possibility of adverse T-cell-mediated reactions may not be entirely eliminated.
Hepatic impairment
- Patients with hepatic impairment should be cautious.
Renal impairment
- Patients with severe renal impairment (GFR 50mL/minute) are not advised to use this medication.

Zonisamide: Drug Interaction

Risk Factor C (Monitor therapy)
Alcohol (Ethyl)	CNS Depressants may enhance the CNS depressant effect of Alcohol (Ethyl).
Alizapride	May enhance the CNS depressant effect of CNS Depressants.
Alpha-/Beta-Agonists (Indirect-Acting)	Carbonic Anhydrase Inhibitors may increase the serum concentration of Alpha-/Beta-Agonists (Indirect-Acting).
Amantadine	Carbonic Anhydrase Inhibitors may increase the serum concentration of Amantadine.
Amphetamines	Carbonic Anhydrase Inhibitors may decrease the excretion of Amphetamines.
Bosentan	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).
Brexanolone	CNS Depressants may enhance the CNS depressant effect of Brexanolone.
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.
CNS Depressants	May enhance the adverse/toxic effect of other CNS Depressants.
CYP3A4 Inducers (Moderate)	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).
Deferasirox	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).
Dimethindene (Topical)	May enhance the CNS depressant effect of CNS Depressants.
Doxylamine	May enhance the CNS depressant effect of CNS Depressants. Management: The manufacturer of Diclegis (doxylamine/pyridoxine), intended for use in pregnancy, specifically states that use with other CNS depressants is not recommended.
Dronabinol	May enhance the CNS depressant effect of CNS Depressants.
Erdafitinib	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).
Esketamine	May enhance the CNS depressant effect of CNS Depressants.
Flecainide	Carbonic Anhydrase Inhibitors may increase the serum concentration of Flecainide.
Fosphenytoin	May decrease the serum concentration of Zonisamide.
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.
Lacosamide	Antiepileptic Agents (Sodium Channel Blockers) may enhance the adverse/toxic effect of Lacosamide. Specifically the risk for bradycardia, ventricular tachyarrhythmias, or a prolonged PR interval may be increased.
Lithium	Carbonic Anhydrase Inhibitors may decrease the serum concentration of Lithium.
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.
Memantine	Carbonic Anhydrase Inhibitors may increase the serum concentration of Memantine.
MetFORMIN	Carbonic Anhydrase Inhibitors may enhance the adverse/toxic effect of MetFORMIN. Specifically, the risk of developing lactic acidosis may be increased.
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	May enhance the CNS depressant effect of CNS Depressants.
Orlistat	May decrease the serum concentration of Anticonvulsants.
PHENobarbital	May decrease the serum concentration of Zonisamide.
Phenytoin	May decrease the serum concentration of Zonisamide.
Piribedil	CNS Depressants may enhance the CNS depressant effect of Piribedil.
Pramipexole	CNS Depressants may enhance the sedative effect of Pramipexole.
QuiNIDine	Carbonic Anhydrase Inhibitors may decrease the excretion of QuiNIDine.
ROPINIRole	CNS Depressants may enhance the sedative effect of ROPINIRole.
Rotigotine	CNS Depressants may enhance the sedative effect of Rotigotine.
Rufinamide	May enhance the adverse/toxic effect of CNS Depressants. Specifically, sleepiness and dizziness may be enhanced.
Sarilumab	May decrease the serum concentration 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).
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.
Risk Factor D (Consider therapy modification)
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 at lower doses in patients already receiving 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.
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.
Methenamine	Carbonic Anhydrase Inhibitors may diminish the therapeutic effect of Methenamine. Management: Consider avoiding this combination. Monitor for decreased therapeutic effects of methenamine if used concomitant with a carbonic anhydrase inhibitor.
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.
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.
Salicylates	May enhance the adverse/toxic effect of Carbonic Anhydrase Inhibitors. Salicylate toxicity might be enhanced by this same combination. Management: Avoid these combinations when possible. Dichlorphenamide use with high-dose aspirin as contraindicated. If another combination is used, monitor patients closely for adverse effects. Tachypnea, anorexia, lethargy, and coma have been reported.
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.
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)
Azelastine (Nasal)	CNS Depressants may enhance the CNS depressant effect of Azelastine (Nasal).
Bromperidol	May enhance the CNS depressant effect of CNS Depressants.
Carbonic Anhydrase Inhibitors	May enhance the adverse/toxic effect of other Carbonic Anhydrase Inhibitors. The development of acid-base disorders with concurrent use of ophthalmic and oral carbonic anhydrase inhibitors has been reported. Management: Avoid concurrent use of different carbonic anhydrase inhibitors if possible. Monitor patients closely for the occurrence of kidney stones and with regards to severity of metabolic acidosis.
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.

Monitor:

Metabolic profile, namely urea and serum creatinine.
Before therapy begins and every so often during it, serum bicarbonate is taken.
suicidal behavior (eg suicidal thoughts and depression, behavioral changes)
Reduced sweating, higher body temperature, especially in hot or warm weather (mainly pediatric patients).

How to administer Zonisamide (Zonegran)?

Capsules should be swallowed as a whole.
Give once or twice daily with or without food.

Mechanism of action of Zonisamide (Zonegran):

It is a sulfuramide. It stabilizes neuronal membranes, suppresses neuronal hypersynchronization by action at calcium and sodium channels, and does not affect GABA activities.

It's fast and complete.IntakeWhen taken orally.

Distribution:

V : 1.45 L/kg
It is extremely concentrated in erythrocytes

Protein binding:

Metabolism:

Mainly via the hepatic pathway via CYP3A4
It is acetylated to N-acetyl zonisamide, and reduced via cytochrome P450 enzyme CYP3A4 or 2-sulfamoylacetylphenol.
SMAP is then conjugated with glucuronide

Eliminating half-life: