Zonisamide

Chemical formula: C₈H₈N₂O₃S  Molecular mass: 212.226 g/mol  PubChem compound: 5734

Interactions

Zonisamide interacts in the following cases:

CYP3A4 inducers

Zonisamide is metabolised partly by CYP3A4 (reductive cleavage), and also by N-acetyl-transferases and conjugation with glucuronic acid; therefore, substances that can induce or inhibit these enzymes may affect the pharmacokinetics of zonisamide:

Exposure to zonisamide is lower in epileptic patients receiving CYP3A4-inducing agents such as phenytoin, carbamazepine, and phenobarbitone. These effects are unlikely to be of clinical significance when zonisamide is added to existing therapy; however, changes in zonisamide concentrations may occur if concomitant CYP3A4-inducing anti-epileptic or other medicinal products are withdrawn, dose adjusted or introduced, an adjustment of the zonisamide dose may be required. Rifampicin is a potent CYP3A4 inducer. If co-administration is necessary, the patient should be closely monitored and the dose of zonisamide and other CYP3A4 substrates adjusted as needed.

CYP3A4 inhibitors

Zonisamide is metabolised partly by CYP3A4 (reductive cleavage), and also by N-acetyl-transferases and conjugation with glucuronic acid; therefore, substances that can induce or inhibit these enzymes may affect the pharmacokinetics of zonisamide:

Based upon clinical data, known specific and non-specific CYP3A4 inhibitors appear to have no clinically relevant effect on zonisamide pharmacokinetic exposure parameters. Steady-state dosing of either ketoconazole (400 mg/day) or cimetidine (1,200 mg/day) had no clinically relevant effects on the single-dose pharmacokinetics of zonisamide given to healthy subjects. Therefore, modification of zonisamide dosing should not be necessary when co-administered with known CYP3A4 inhibitors.

Hepatic impairment

Use in patients with hepatic impairment has not been studied. Therefore use in patients with severe hepatic impairment is not recommended. Caution must be exercised in treating patients with mild to moderate hepatic impairment, and a slower titration of zonisamide may be required.

Renal impairment

Caution must be exercised in treating patients with renal impairment, as there is limited information on use in such patients and a slower titration of zonisamide might be required. Since zonisamide and its metabolites are excreted renally, it should be discontinued in patients who develop acute renal failure or where a clinically significant sustained increase in serum creatinine is observed.

In subjects with renal impairment, renal clearance of single doses of zonisamide was positively correlated with creatinine clearance. The plasma AUC of zonisamide was increased by 35% in subjects with creatinine clearance <20 ml/min.

P-gp substrates

An in vitro study shows that zonisamide is a weak inhibitor of P-gp (MDR1) with an IC50 of 267 μmol/l and there is the theoretical potential for zonisamide to affect the pharmacokinetics of substances which are P-gp substrates. Caution is advised when starting or stopping zonisamide treatment or changing the zonisamide dose in patients who are also receiving medicinal products which are P-gp substrates (e.g. digoxin, quinidine).

Carbonic anhydrase inhibitors

Zonisamide should be used with caution in adult patients treated concomitantly with carbonic anhydrase inhibitors such as topiramate and acetazolamide, as there are insufficient data to rule out a possible pharmacodynamic interaction.

Zonisamide should not be used as co-medication in paediatric patients with other carbonic anhydrase inhibitors such as topiramate and acetazolamide.

Fertility

There are no clinical data available on the effects of zonisamide on human fertility. Studies in animals have shown changes in fertility parameters.

Metabolic acidosis

Hyperchloraemic, non-anion gap, metabolic acidosis (i.e. decreased serum bicarbonate below the normal reference range in the absence of chronic respiratory alkalosis) is associated with zonisamide treatment. This metabolic acidosis is caused by renal bicarbonate loss due to the inhibitory effect of zonisamide on carbonic anhydrase. Such electrolyte imbalance has been observed with the use of zonisamide in placebo-controlled clinical trials and in the post-marketing period. Generally, zonisamide-induced metabolic acidosis occurs early in treatment although cases can occur at any time during treatment. The amounts by which bicarbonate is decreased are usually small–moderate (average decrease of approximately 3.5 mEq/l at daily doses of 300 mg in adults); rarely patients can experience more severe decreases. Conditions or therapies that predispose to acidosis (such as renal disease, severe respiratory disorders, status epilepticus, diarrhoea, surgery, ketogenic diet, or medicinal products) may be additive to the bicarbonate lowering effects of zonisamide.

The risk of zonisamide induced metabolic acidosis appears to be more frequent and severe in younger patients. Appropriate evaluation and monitoring of serum bicarbonate levels should be carried out in patients taking zonisamide who have underlying conditions which might increase the risk of acidosis, in patients who are at an increased risk of adverse consequences of metabolic acidosis and in patients with symptoms suggestive of metabolic acidosis. If metabolic acidosis develops and persists, consideration should be given to reducing the dose or discontinuing zonisamide (by gradual discontinuation or reduction of a therapeutic dose) as osteopenia may develop. If the decision is made to continue patients on zonisamide in the face of persistent acidosis, alkali treatment should be considered.

Zonisamide should be used with caution in adult patients being treated concomitantly with carbonic anhydrase inhibitors such as topiramate or acetazolamide, as there are insufficient data to rule out a pharmacodynamic interaction

Pancreatitis

In patients taking zonisamide who develop the clinical signs and symptoms of pancreatitis, it is recommended that pancreatic lipase and amylase levels are monitored. If pancreatitis is evident, in the absence of another obvious cause, it is recommended that discontinuation of zonisamide be considered and appropriate treatment initiated.

Rhabdomyolysis

In patients taking zonisamide, in whom severe muscle pain and/or weakness develop either in the presence or absence of a fever, it is recommended that markers of muscle damage be assessed, including serum creatine phosphokinase and aldolase levels. If elevated, in the absence of another obvious cause such as trauma or grand mal seizures, it is recommended that zonisamide discontinuation be considered and appropriate treatment initiated.

Aplastic anaemia, agranulocytosis, thrombocytopenia, leukopenia, pancytopenia, leucocytosis

Zonisamide is a benzisoxazole derivative, which contains a sulphonamide group. Serious immune based adverse reactions that are associated with medicinal products containing a sulphonamide group include rash, allergic reaction and major haematological disturbances, including aplastic anaemia, which very rarely can be fatal.

Cases of agranulocytosis, thrombocytopenia, leukopenia, aplastic anaemia, pancytopenia and leucocytosis have been reported. There is inadequate information to assess the relationship, if any, between dose and duration of treatment and these events.

Rash, Stevens-Johnson syndrome

Serious rashes occur in association with zonisamide therapy, including cases of Stevens-Johnson syndrome.

Consideration must be given to discontinuing zonisamide in patients who develop an otherwise unexplained rash. All patients who develop a rash while taking zonisamide must be closely supervised, with additional levels of caution applied to those patients receiving concomitant antiepileptic agents that may independently induce skin rashes.

Heat stroke

Cases of decreased sweating and elevated body temperature have been reported mainly in paediatric patients. Caution should be used in adults when zonisamide is prescribed with other medicinal products that predispose patients to heat related disorders; these include carbonic anhydrase inhibitors and medicinal products with anticholinergic activity.

Acute myopia, secondary angle closure glaucoma

A syndrome consisting of acute myopia associated with secondary angle closure glaucoma has been reported in adult and paediatric patients receiving zonisamide. Symptoms include acute onset of decreased visual acuity and/or ocular pain. Ophthalmologic findings can include myopia, anterior chamber shallowing, and ocular hyperaemia (redness) and increased intraocular pressure. This syndrome may be associated with supraciliary effusion resulting in anterior displacement of the lens and iris, with secondary angle closure glaucoma. Symptoms may occur within hours to weeks of initiating therapy. Treatment includes discontinuation of zonisamide, as rapidly as possible in the judgment of the treating physician, and appropriate measures to reduce intraocular pressure. Elevated intraocular pressure of any aetiology, if left untreated, can lead to serious sequelae including permanent vision loss. Caution should be used when treating patients with history of eye disorders with zonisamide.

Suicide ideation and behaviour

Suicidal ideation and behaviour have been reported in patients treated with anti-epileptic agents in several indications. A meta-analysis of randomised placebo-controlled trials of anti-epileptic medicinal products has also shown a small increased risk of suicidal ideation and behaviour. The mechanism of this risk is not known and the available data do not exclude the possibility of an increased risk for zonisamide.

Therefore patients should be monitored for signs of suicidal ideation and behaviours and appropriate treatment should be considered. Patients (and caregivers of patients) should be advised to seek medical advice should signs of suicidal ideation or behaviour emerge.

Weight loss

Zonisamide may cause weight loss. A dietary supplement or increased food intake may be considered if the patient is losing weight or is underweight whilst on this medication. If substantial undesirable weight loss occurs, discontinuation of zonisamide should be considered. Weight loss is potentially more serious in children.

Kidney stones

Some patients, especially those with a predisposition to nephrolithiasis, may be at increased risk for renal stone formation and associated signs and symptoms such as renal colic, renal pain or flank pain. Nephrolithiasis may lead to chronic kidney damage. Risk factors for nephrolithiasis include prior stone formation, a family history of nephrolithiasis and hypercalciuria. None of these risk factors can reliably predict stone formation during zonisamide treatment. In addition, patients taking other medications associated with nephrolithiasis may be at increased risk. Increasing fluid intake and urine output may help reduce the risk of stone formation, particularly in those with predisposing risk factors.

Pregnancy

There are limited data from the use of zonisamide in pregnant women. Studies in animals have shown reproductive toxicity. In humans the potential risk of major congenital malformations and neurodevelopmental disorders is unknown.

Data from a registry study suggest an increase in the proportion of babies born at a low birth weight (LBW), pre-term or small for gestational age (SGA). These increases are from about 5% to 8% for LBW, from about 8% to 10% for pre-term birth and from about 7% to 12% for SGA, all compared with mothers treated with lamotrigine monotherapy.

Zonisamide must not be used during pregnancy unless clearly necessary and only if the potential benefit is considered to justify the risk to the foetus. If zonisamide is prescribed during pregnancy, patients should be fully informed of the potential harm to the foetus and use of the minimal effective dose is advised along with careful monitoring.

Nursing mothers

Zonisamide is excreted in human milk; the concentration in breast milk is similar to maternal plasma. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from zonisamide therapy. Due to the long retention time of zonisamide in the body, breast-feeding must not be resumed until one month after zonisamide therapy is completed.

Carcinogenesis, mutagenesis and fertility

Women of childbearing potential

Women of childbearing potential must use effective contraception during treatment with zonisamide, and for one month after discontinuation.

Zonisamide must not be used in women of childbearing potential not using effective contraception unless clearly necessary and only if the potential benefit is considered to justify the risk to the foetus. Specialist medical advice should be given to women treated with zonisamide who are of childbearing potential. The woman should be fully informed of and understand the possible effects of zonisamide on the foetus and these risks should be discussed with the patient in relation to the benefits before starting treatment. Pregnancy testing in women of childbearing potential should be considered prior to initiating treatment with zonisamide. Women planning a pregnancy should meet with their specialists to reassess treatment with zonisamide and to consider other therapeutic options prior to conception and before contraception is discontinued.

As with all antiepileptic medicines, sudden discontinuation of zonisamide should be avoided as this may lead to breakthrough seizures that could have serious consequences for the woman and the unborn child. The risk of birth defect is increased by factor 2 to 3 in the offspring of mothers treated with an antiepileptic medicinal product. The most frequently reported are cleft lip, cardiovascular malformations and neural tube defect. Multiple antiepileptic medicinal product therapy may be associated with a higher risk of congenital malformations than monotherapy.

Fertility

There are no clinical data available on the effects of zonisamide on human fertility. Studies in animals have shown changes in fertility parameters.

Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been performed. However, given that some patients may experience drowsiness or difficulty with concentration, particularly early in treatment or after a dose increase, patients must be advised to exercise caution during activities requiring a high degree of alertness, e.g., driving or operating machines.

Adverse reactions


Summary of the safety profile

Zonisamide has been administered to over 1,200 patients in clinical studies, more than 400 of whom received zonisamide for at least 1 year. In addition there has been extensive post-marketing experience with zonisamide in Japan since 1989 and in the USA since 2000.

It should be noted that zonisamide is a benzisoxazole derivative, which contains a sulphonamide group. Serious immune based adverse reactions that are associated with medicinal products containing a sulphonamide group include rash, allergic reaction and major haematological disturbances including aplastic anaemia, which very rarely can be fatal.

The most common adverse reactions in controlled adjunctive-therapy studies were somnolence, dizziness and anorexia. The most common adverse reactions in a randomised, controlled monotherapy trial comparing zonisamide with carbamazepine prolonged release were decreased bicarbonate, decreased appetite, and decreased weight. The incidence of markedly abnormally low serum bicarbonate (a decrease to less than 17 mEq/l and by more than 5 mEq/l) was 3.8%. The incidence of marked decreases in weight of 20% or more was 0.7%.

Tabulated list of adverse reactions

Adverse reactions associated with zonisamide obtained from clinical studies and post-marketing surveillance are tabulated below. The frequencies are arranged according to the following scheme:

very common ≥1/10
common ≥1/100 to <1/10
uncommon ≥1/1,000 to <1/100
rare ≥1/10,000 to <1/1,000
very rare <1/10,000
not known cannot be estimated from the available data

Table 1. Adverse reactions associated with zonisamide obtained from adjunctive use clinical studies and post-marketing surveillance:

System Organ
Class
(MedDRA
terminology)
Very
Common
Common Uncommon Very Rare
Infections and
infestation
  Pneumonia
Urinary tract
infection
 
Blood and
lymphatic
system disorders
 Ecchymosis Agranulocytosis
Aplastic anaemia
Leucocytosis
Leucopoenia
Lymphadenopathy
Pancytopenia,
Thrombocytopenia
Immune system
disorders
 Hypersensitivity Drug-induced
hypersensitivity syndrome
Drug rash with eosinophilia
and systemic symptoms
Metabolism and
nutrition
disorders
Anorexia Hypokalaemia Metabolic acidosis
Renal tubular acidosis
Psychiatric
Disorders
Agitation
Irritability
Confusional
state
Depression
Affect lability
Anxiety
Insomnia
Psychotic
disorder
Anger
Aggression
Suicidal ideation
Suicide attempt
Hallucination
Nervous system
disorders
Ataxia
Dizziness
Memory
impairment
Somnolence
Bradyphrenia
Disturbance in
attention
Nystagmus
Paraesthesia
Speech disorder
Tremor
Convulsion Amnesia
Coma
Grand mal seizure
Myasthenic syndrome
Neuroleptic malignant
syndrome
Status epilepticus
Eye disorders Diplopia  Angle closure glaucoma
Eye pain
Myopia
Vision blurred
Visual acuity reduced
Respiratory,
thoracic and
mediastinal
disorders
   Dyspnoea
Pneumonia aspiration
Respiratory disorder
Hypersensitivity-type
Pneumonitis
Gastrointestinal
disorders
 Abdominal pain
Constipation
Diarrhoea
Dyspepsia
Nausea
Vomiting Pancreatitis
Hepatobiliary
disorders
  Cholecystitis
Cholelithiasis
Hepatocellular damage
Skin and
subcutaneous
tissue disorders
 Rash
Pruritus
Alopecia
 Anhidrosis
Erythema multiforme
Stevens-Johnson syndrome
Toxic epidermal necrolysis
Musculoskeletal
and connective
tissue disorders
   Rhabdomyolysis
Renal and
urinary
disorders
 Nephrolithiasis Calculus urinary Hydronephrosis
Renal failure
Urine abnormality
General
disorders and
administration
site conditions
 Fatigue
Influenza-like
illness
Pyrexia
Oedema
peripheral
  
Investigations Decreased
bicarbonate
Weight
decreased
 Blood creatine
phosphokinase increased
Blood creatinine increased
Blood urea increased
Liver function tests
abnormal
Injury,
poisoning and
procedural
complications
   Heat stroke

In addition there have been isolated cases of Sudden Unexplained Death in Epilepsy Patients (SUDEP) receiving zonisamide.

Table 2. Adverse reactions in a randomised, controlled monotherapy trial comparing zonisamide with carbamazepine prolonged release:

System Organ Class
(MedDRA terminology)
Very Common CommonUncommon
Infections and
infestation
  Urinary tract infection
Pneumonia
Blood and lymphatic
disorders
  Leukopenia
Thrombocytopenia
Metabolism and
nutrition disorders
 Decreased appetite Hypokalaemia
Psychiatric Disorders  Agitation
Depression
Insomnia
Mood swings
Anxiety
Confusional state
Acute psychosis
Aggression
Suicidal ideation
Hallucination
Nervous system
disorders
 Ataxia
Dizziness
Memory impairment
Somnolence
Bradyphrenia
Disturbance in attention
Paraesthesia
Nystagmus
Speech disorder
Tremor
Convulsion
Eye disorders  Diplopia 
Respiratory, thoracic
and mediastinal
disorders
  Respiratory disorder
Gastrointestinal
disorders
 Constipation
Diarrhoea
Dyspepsia
Nausea
Vomiting
Abdominal pain
Hepatobiliary disorders   Cholecystitis acute
Skin and subcutaneous
tissue disorders
 Rash Pruritus
Ecchymosis
General disorders and
administration site
conditions
 Fatigue
Pyrexia
Irritability
 
Investigations Decreased
bicarbonate
Weight decreased
Blood creatinine
phosphokinase increased
Alanine aminotransferase
increased
Aspartate aminotransferase
increased
Urine analysis
abnormal

MedDRA version 13.1

Additional information on special populations

Elderly

A pooled analysis of safety data on 95 elderly subjects has shown a relatively higher reporting frequency of oedema peripheral and pruritus compared to the adult population.

Review of post-marketing data suggests that patients aged 65 years or older report a higher frequency than the general population of the following events: Stevens-Johnson syndrome (SJS) and Drug Induced Hypersensitivity syndrome (DIHS).

Paediatric population

The adverse event profile of zonisamide in paediatric patients aged 6 to 17 years in placebo-controlled clinical studies was consistent with that of adults. Among 465 subjects in the paediatric safety database (including a further 67 subjects from the extension phase of the controlled clinical trial) there were 7 deaths (1.5%; 14.6/1000 person-years): 2 cases of status epilepticus, of which one was related to severe weight loss (10% within 3 months) in an underweight subject and subsequent failure to take medication; 1 case of head injury/haematoma, and 4 deaths in subjects with pre-existing functional neurological deficits for various causes (2 cases of pneumonia-induced sepsis/organ failure, 1 SUDEP and 1 head injury). A total of 70.4% of paediatric subjects who received ZNS in the controlled study or its open label extension had at least one treatment-emergent bicarbonate measurement below 22 mmol/L. The duration of low bicarbonate measurements was also long (median 188 days).

A pooled analysis of safety data on 420 paediatric subjects (183 subjects aged 6 to 11 years, and 237 subjects aged 12 to 16 years with a mean duration of exposure of approximately 12 months) has shown a relatively higher reporting frequency of pneumonia, dehydration, decreased sweating, abnormal liver function tests, otitis media, pharyngitis, sinusitis and upper respiratory tract infection, cough, epistaxis and rhinitis, abdominal pain, vomiting, rash and eczema, and fever compared to the adult population (particularly in subjects aged below 12 years) and, at a low incidence, amnesia, creatinine increased, lymphadenopathy, and thrombocytopenia. The incidence of a decrease in body weight of 10% or more was 10.7%. In some cases of weight decrease there was a delay in transition to the next Tanner stage and in bone maturation.

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