Side Effects of Zonegran (zonisamide)

Zonegran (zonisamide) is an anti-seizure medication used to treat partial-seizures.

It is unknown how exactly Zonegran works in the body. Zonegran is presumed to work on the sodium and calcium channels in the brain cells where it controls electric-currents that are responsible for seizure activity.

Common side effects of Zonegran include:

• dizziness,
• agitation,
• fatigue,
• confusion,
• loss of concentration,
• loss of appetite,
• nausea,
• diarrhea,
• stomach ache,
• headache,
• speech disturbance, and
• weight loss.

Serious side effects of Zonegran include:

• psychiatric disorders such as schizophrenia, seizures, and
• serious skin disorders such as Stevens-Johnson syndrome or toxic epidermal necrolysis.

Drug interactions of Zonegran include metformin, which when combined with Zonegran increases the risk of lactic acid build up.

Orlistat should be used with caution with Zonegran because it lowers the beneficial effects of Zonegran and increases the chances of seizures.

There are no adequate studies done on Zonegran to determine its safe and effective use in pregnant mothers. It is unknown if Zonegran is excreted in breast milk. It should be used with caution in women who are breastfeeding.

Common side effects of zonisamide are:

• Dizziness
• Agitation
• Fatigue
• Confusion
• Loss of concentration
• Loss of appetite
• Nausea
• Diarrhea
• Stomach ache
• Headache
• Speech disturbance
• Weight loss

Serious side effects of zonisamide include:

• Psychiatric disorders such as schizophrenia
• Seizures
• Serious skin disorders such as Stevens-Johnson's syndrome or toxic epidermal necrolysis.

The most common adverse reactions with Zonegran (an incidence at least 4% greater than placebo) in controlled clinical trials and shown in descending order of frequency were

• somnolence,
• anorexia,
• dizziness,
• ataxia,
• agitation/irritability, and
• difficulty with memory and/or concentration.

In controlled clinical trials, 12% of patients receiving Zonegran as adjunctive therapy discontinued due to an adverse reaction compared to 6% receiving placebo.

Approximately 21% of the 1,336 patients with epilepsy who received Zonegran in clinical studies discontinued treatment because of an adverse reaction.

The most common adverse reactions leading to discontinuation were

• somnolence,
• fatigue and/or ataxia (6%),
• anorexia (3%),
• difficulty concentrating (2%),
• difficulty with memory,
• mental slowing,
• nausea/vomiting (2%), and
• weight loss (1%).

Many of these adverse reactions were dose related.

Adverse Reaction Incidence In Controlled Clinical Trials

Table 4 lists adverse reactions that occurred in at least 2% of patients treated with Zonegran in controlled clinical trials that were numerically more common in the Zonegran group. In these studies, either Zonegran or placebo was added to the patient's current AED therapy.

Table 4. Adverse Reactions in Placebo-Controlled, Add-On Trials (Events that occurred in at least 2% of Zonegran-treated patients and occurred more frequently in Zonegran-treated than placebo-treated patients)

Other Adverse Reactions In Clinical Trials

Zonegran has been administered to 1,598 individuals during all clinical trials, only some of which were placebo-controlled. The frequencies represent the proportion of the 1,598 individuals exposed to Zonegran who experienced an event on at least one occasion.

All events are included except those already listed in the previous table or discussed in the prescribing information, trivial events, those too general to be informative, and those not reasonably associated with Zonegran.

Events are further classified within each category and listed in order of decreasing frequency as follows:

• frequent occurring in at least 1:100 patients;
• infrequent occurring in 1:100 to 1:1000 patients;
• rare occurring in fewer than 1:1000 patients.

Body As A Whole

Frequent: Accidental injury, asthenia.

Infrequent: Chest pain, flank pain, malaise, allergic reaction, face edema, neck rigidity. Rare: Lupus erythematosus.

Cardiovascular

Infrequent: Palpitation, tachycardia, vascular insufficiency, hypotension, hypertension, thrombophlebitis, syncope, bradycardia.

Rare: Atrial fibrillation, heart failure, pulmonary embolus, ventricular extrasystoles.

Digestive

Frequent: Vomiting.

Infrequent: Flatulence, gingivitis, gum hyperplasia, gastritis, gastroenteritis, stomatitis, cholelithiasis, glossitis, melena, rectal hemorrhage, ulcerative stomatitis, gastro-duodenal ulcer, dysphagia, gum hemorrhage.

Rare: Cholangitis, hematemesis, cholecystitis, cholestatic jaundice, colitis, duodenitis, esophagitis, fecal incontinence, mouth ulceration.

Hematologic And Lymphatic

Infrequent: Leukopenia, anemia, immunodeficiency, lymphadenopathy. Rare: Thrombocytopenia, microcytic anemia, petechia.

Metabolic And Nutritional

Infrequent: Peripheral edema, weight gain, edema, thirst, dehydration. Rare: Hypoglycemia, hyponatremia, lactic dehydrogenase increased, SGOT increased, SGPT increased.

Musculoskeletal

Infrequent: Leg cramps, myalgia, myasthenia, arthralgia, arthritis.

Nervous System

Frequent: Tremor, convulsion, abnormal gait, hyperesthesia, incoordination.

Infrequent: Hypertonia, twitching, abnormal dreams, vertigo, libido decreased, neuropathy, hyperkinesia, movement disorder, dysarthria, cerebrovascular accident, hypotonia, peripheral neuritis, reflexes increased.

Rare: Dyskinesia, dystonia, encephalopathy, facial paralysis, hypokinesia, hyperesthesia, myoclonus, oculogyric crisis.

Behavioral Abnormalities – Non-Psychosis -Related

Infrequent: Euphoria.

Respiratory

Frequent: Pharyngitis, cough increased.

Infrequent: Dyspnea.

Rare: Apnea, hemoptysis.

Skin And Appendages

Frequent: Pruritus.

Infrequent: Maculopapular rash, acne, alopecia, dry skin, sweating, eczema, urticaria, hirsutism, pustular rash, vesiculobullous rash.

Special Senses

Frequent: Amblyopia, tinnitus.

Infrequent: Conjunctivitis, parosmia, deafness, visual field defect, glaucoma.

Rare: Photophobia, iritis.

Urogenital

Infrequent: Urinary frequency, dysuria, urinary incontinence, hematuria, impotence, urinary retention, urinary urgency, amenorrhea, polyuria, nocturia. Rare: Albuminuria, enuresis, bladder pain, bladder calculus, gynecomastia, mastitis, menorrhagia.

Post Marketing Experience

The following serious adverse reactions have been reported since approval and use of Zonegran worldwide:

• acute pancreatitis,
• rhabdomyolysis,
• increased creatine phosphokinase, and
• drug reaction with eosinophilia and systemic symptoms (DRESS).

These reactions are reported voluntarily from a population of uncertain size; therefore, it is not possible to estimate their frequency or establish a causal relationship to drug exposure.

To report suspected adverse reactions, contact Concordia Pharmaceuticals Inc. at 1- 877-370-1142 or the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Drug Interactions With CNS Depressants

• Concomitant administration of Zonegran and alcohol or other CNS depressant drugs has not been evaluated in clinical studies.
• Because of the potential of zonisamide to cause CNS depression, as well as other cognitive and/or neuropsychiatric adverse events, zonisamide should be used with caution if used in combination with alcohol or other CNS depressants.

Other Carbonic Anhydrase Inhibitors

• Concomitant use of Zonegran, a carbonic anhydrase inhibitor, with any other carbonic anhydrase inhibitor (e.g., topiramate, acetazolamide or dichlorphenamide), may increase the severity of metabolic acidosis and may also increase the risk of kidney stone formation.
• Therefore, if Zonegran is given concomitantly with another carbonic anhydrase inhibitor, the patient should be monitored for the appearance or worsening of metabolic acidosis.

Drug Abuse And Dependence

• The abuse and dependence potential of Zonegran has not been evaluated in human studies.
• In a series of animal studies, zonisamide did not demonstrate abuse liability and dependence potential.
• Monkeys did not selfadminister zonisamide in a standard reinforcing paradigm.
• Rats exposed to zonisamide did not exhibit signs of physical dependence of the CNS-depressant type.
• Rats did not generalize the effects of diazepam to zonisamide in a standard discrimination paradigm after training, suggesting that zonisamide does not have abuse potential of the benzodiazepine-CNS depressant type.