Zonisamide (Page 3 of 6)

PRECAUTIONS

General:

Somnolence is commonly reported, especially at higher doses of zonisamide (see WARNINGS: Cognitive/Neuropsychiatric Adverse Events subsection). Zonisamide is metabolized by the liver and eliminated by the kidneys; caution should therefore be exercised when administering zonisamide to patients with hepatic and renal dysfunction (see CLINICAL PHARMACOLOGY, Specific Populations subsection).

Kidney Stones:

Among 991 patients treated during the development of zonisamide, 40 patients (4%) with epilepsy receiving zonisamide developed clinically possible or confirmed kidney stones (e.g., clinical symptomatology, sonography, etc.), a rate of 34 per 1,000 patient-years of exposure (40 patients with 1,168 years of exposure). Of these, 12 were symptomatic, and 28 were described as possible kidney stones based on sonographic detection. In nine patients, the diagnosis was confirmed by a passage of a stone or by a definitive sonographic finding. The rate of occurrence of kidney stones was 28.7 per 1,000 patient-years of exposure in the first six months, 62.6 per 1,000 patient-years of exposure between 6 and 12 months, and 24.3 per 1,000 patient-years of exposure after 12 months of use. There are no normative sonographic data available for either the general population or patients with epilepsy. Although the clinical significance of the sonographic findings may not be certain, the development of nephrolithiasis may be related to metabolic acidosis (see WARNINGS, Metabolic Acidosis subsection). The analyzed stones were composed of calcium or urate salts. In general, increasing fluid intake and urine output can help reduce the risk of stone formation, particularly in those with predisposing risk factors. It is unknown, however, whether these measures will reduce the risk of stone formation in patients treated with zonisamide.

Although not approved in pediatric patients, sonographic findings consistent with nephrolithiasis were also detected in 8 % of a subset of zonisamide treated pediatric patients who had at least one renal ultrasound prospectively performed in a clinical development program investigating open-label treatment. The incidence of kidney stone as an adverse event was 3 % (see WARNINGS, Metabolic Acidosis subsection) .

Effect on Renal Function: In several clinical studies, zonisamide was associated with a statistically significant 8% mean increase from baseline of serum creatinine and blood urea nitrogen (BUN) compared to essentially no change in the placebo patients. The increase appeared to persist over time but was not progressive; this has been interpreted as an effect on glomerular filtration rate (GFR). There were no episodes of unexplained acute renal failure in clinical development in the U.S., Europe, or Japan. The decrease in GFR appeared within the first 4 weeks of treatment. In a 30-day study, the GFR returned to baseline within 2 to 3 weeks of drug discontinuation. There is no information about reversibility, after drug discontinuation, of the effects on GFR after long-term use. Zonisamide should be discontinued in patients who develop acute renal failure or a clinically significant sustained increase in the creatinine/BUN concentration. Zonisamide should not be used in patients with renal failure (estimated GFR < 50 mL/min) as there has been insufficient experience concerning drug dosing and toxicity.

Status Epilepticus: Estimates of the incidence of treatment emergent status epilepticus in zonisamide-treated patients are difficult because a standard definition was not employed. Nonetheless, in controlled trials, 1.1% of patients treated with zonisamide had an event labeled as status epilepticus compared to none of the patients treated with placebo. Among patients treated with zonisamide across all epilepsy studies (controlled and uncontrolled), 1% of patients had an event reported as status epilepticus.

Information for Patients:

Inform patients of the availability of a Medication Guide, and instruct them to read the Medication Guide prior to taking zonisamide capsules. Instruct patients to take zonisamide capsules only as prescribed.

Advise patients as follows: (See Medication Guide)

  1. Zonisamide may produce drowsiness, especially at higher doses. Patients should be advised not to drive a car or operate other complex machinery until they have gained experience on zonisamide sufficient to determine whether it affects their performance. 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.
  2. Patients should contact their physician immediately if a skin rash develops (see WARNINGS, Serious Skin Reactions subsection).
  3. Instruct patients to seek immediate medical attention if they experience blurred vision, visual disturbances, or periorbital pain (see WARNINGS, Acute Myopia and Secondary Angle Closure Glaucoma subsection).
  4. Patients should contact their physician immediately if they develop signs or symptoms, such as sudden back pain, abdominal pain, and/or blood in the urine, that could indicate a kidney stone. Increasing fluid intake and urine output may reduce the risk of stone formation, particularly in those with predisposing risk factors for stones (see PRECAUTIONS, Kidney Stones subsection).
  5. Patients should contact their physician immediately if a child has been taking zonisamide and is not sweating as usual with or without a fever (see WARNINGS, Oligohidrosis and Hyperthermia in Pediatric Patients subsection).
  6. Because zonisamide can cause hematological complications, patients should contact their physician immediately if they develop a fever, sore throat, oral ulcers, or easy bruising (see WARNINGS, Serious Hematologic Events subsection).
  7. Counsel patients and caregivers that AEDs, including zonisamide, may increase the risk of suicidal thoughts and behavior and advise them of the need to be alert for the emergence or worsening of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers (see WARNINGS, Suicidal Behavior and Ideation subsection).
  8. Warn patients about the possible development of hyperammonemia with or without encephalopathy. Although hyperammonemia may be asymptomatic, clinical symptoms of hyperammonemic encephalopathy often include acute alterations in level of consciousness and/or cognitive function with lethargy and/or vomiting. Instruct patients to contact their physician if they develop unexplained lethargy, vomiting, or changes in mental status (see WARNINGS, Hyperammonemia and Encephalopathy subsection)
  9. Patients should contact their physician immediately if they develop fast breathing, fatigue/tiredness, loss of appetite, or irregular heart beat or palpitations, which are possible manifestations of metabolic acidosis (see WARNINGS, Metabolic Acidosis subsection).
  10. As with other AEDs, patients should contact their physician if they intend to become pregnant or are pregnant during zonisamide therapy. Patients should notify their physician if they intend to breast-feed or are breast-feeding an infant (see PRECAUTIONS, Use in Nursing Mothers subsection).
  11. Encourage patients to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry if they become pregnant. This registry is collecting information about the safety of antiepileptic drugs during pregnancy. To enroll, patients can call the toll-free number 1-888-233-2334 (see PRECAUTIONS, Pregnancy subsection).

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Laboratory Tests:

In several clinical studies, zonisamide was associated with a mean increase in the concentration of serum creatinine and blood urea nitrogen (BUN) of approximately 8% over the baseline measurement. Consideration should be given to monitoring renal function periodically (see PRECAUTIONS, Effect on Renal Function subsection).

Zonisamide increases serum chloride and alkaline phosphatase and decreases serum bicarbonate (see WARNINGS, Metabolic Acidosis subsection), phosphorus, calcium, and albumin.

Drug Interactions with CNS Depressants: Concomitant administration of zonisamide 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 zonisamide , 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 or the risk of hyperammonemia. Therefore, if zonisamide is given concomitantly with another carbonic anhydrase inhibitor, the patient should be monitored for the appearance or worsening of metabolic acidosis (see CLINICAL PHARMACOLOGY, Interactions of Zonisamide with Other Carbonic Anhydrase Inhibitors subsection and WARNINGS, Metabolic Acidosis subsection and Hyperammonemia and Encephalopathy subsection).

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