zonisade

Important safety information

Potentially Fatal Reactions to Sulfonamides: Fatalities have occurred as a result of severe reactions to sulfonamides (zonisamide is a sulfonamide) including Stevens-Johnson syndrome, toxic epidermal necrolysis, fulminant hepatic necrosis, agranulocytosis, aplastic anemia, and other blood dyscrasias ( 5.1 ). • Serious Skin Reactions: Discontinue ZONISADE at the first sign of rash unless clearly not drug related ( 5.2 ). • Serious Hematologic Events: Aplastic anemia and agranulocytosis have been reported with zonisamide treatment ( 5.3 ). • Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multi-Organ Hypersensitivity: DRESS, also known as multiorgan hypersensitivity, has occurred with zonisamide ( 5.4 ). • Oligohidrosis and Hyperthermia in Pediatric Patients: Oligohidrosis, sometimes resulting in heat stroke and hospitalization, is seen in association with zonisamide in pediatric patients ( 5.5 ). • Acute Myopia and Secondary Angle Closure Glaucoma: If occurs, primary treatment is discontinuation of ZONISADE ( 5.6 ). • Suicidal Behavior and Ideation: Monitor patients for suicidal behavior or ideation ( 5.7 ). • Metabolic Acidosis: Baseline and periodic measurement of serum bicarbonate is recommended; consider dose reduction or discontinuation if appropriate ( 5.8 ). • Seizures on Withdrawal of Antiepileptic Drugs: Withdraw ZONISADE gradually ( 5.9 ). • Teratogenicity: Based on animal data, may cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to use an effective method of contraception during ZONISADE treatment and for one month after discontinuation ( 5.10 , 8.1 , 8.3 ). 5.1 Potentially Fatal Reactions to Sulfonamides Fatalities have occurred as a result of severe reactions to sulfonamides (zonisamide is a sulfonamide) including Stevens-Johnson syndrome, toxic epidermal necrolysis, fulminant hepatic necrosis, agranulocytosis, aplastic anemia, and other blood dyscrasias [see Warnings and Precautions ( 5.2 , 5.3 , 5.4 )] . Such reactions may occur when a sulfonamide is readministered irrespective of the route of administration. If signs of hypersensitivity or other serious reactions occur, discontinue ZONISADE immediately. Specific experience with sulfonamide-type adverse reaction to zonisamide is described below. 5.2 Serious Skin Reactions Seven deaths from severe rash [i.e., Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN)] were reported in the first 11 years of marketing in Japan. All of the patients were receiving other drugs in addition to zonisamide. In postmarketing experience from Japan, a total of 49 cases of SJS or TEN have been reported, a reporting rate of 46 per million patient-years of exposure. Although this rate is greater than background, it is probably an underestimate of the true incidence because of under-reporting. There were no confirmed cases of SJS or TEN in the US, European, or Japanese development programs. In the US and European randomized controlled trials [see Clinical Studies ( 14 )] , 6 of 269 (2.2%) patients who received zonisamide discontinued treatment because of rash compared to no patients who received placebo. Across all trials during the US and European development, rash that led to discontinuation of zonisamide was reported in 1.4% of patients (12.0 events per 1000 patient-years of exposure). During Japanese development, serious rash or rash that led to discontinuation of zonisamide was reported in 2.0% of patients (27.8 events per 1000 patient-years). Rash usually occurred early in treatment, with 85% reported within 16 weeks in the US and European studies and 90% reported within two weeks in the Japanese studies. There was no apparent relationship of dose to the occurrence of rash. Discontinue ZONISADE at the first sign of rash, unless the rash is clearly not drug-related. If signs or symptoms suggest SJS/TEN, use of ZONISADE should not be resumed and alternative therapy should be considered. 5.3 Serious Hematologic Events Two confirmed cases of aplastic anemia and one confirmed case of agranulocytosis were reported in the first 11 years of marketing in Japan, rates greater than generally accepted background rates. There were no cases of aplastic anemia and two confirmed cases of agranulocytosis in the US, European, or Japanese development programs. There is inadequate information to assess the relationship, if any, between dose and duration of treatment and these events. 5.4 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multi-Organ Hypersensitivity Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as multi-organ hypersensitivity, has occurred with zonisamide, the active ingredient in ZONISADE. Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy and/or facial swelling, in association with other organ system involvement, such as hepatitis, nephritis, hematologic abnormalities, myocarditis, or myositis, sometimes resembling an acute viral infection. Eosinophilia is often present. This disorder is variable in its expression, and other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity (e.g., fever, lymphadenopathy) may be present even though rash is not evident. If such signs or symptoms are present, the patient should be evaluated immediately. ZONISADE should be discontinued if an alternative etiology for the signs or symptoms cannot be established. 5.5 Oligohidrosis and Hyperthermia in Pediatric Patients ZONISADE is not approved for use in patients below 16 years of age. Oligohidrosis, sometimes resulting in heat stroke and hospitalization, is seen in association with zonisamide in pediatric patients. During the pre-approval development program in Japan, one case of oligohidrosis was reported in 403 pediatric patients, an incidence of 1 case per 285 patient-years of exposure. While there were no cases reported in the US or European development programs, fewer than 100 pediatric patients participated in these trials. In the first 11 years of marketing in Japan, 38 cases were reported, an estimated reporting rate of about 1 case per 10,000 patient-years of exposure. In the first year of marketing in the US, 2 cases were reported, an estimated reporting rate of about 12 cases per 10,000 patient-years of exposure. These rates are underestimates of the true incidence because of under-reporting. There has also been one report of heat stroke in an 18-year-old patient in the US. Decreased sweating and an elevation in body temperature above normal characterized these cases. Many cases were reported after exposure to elevated environmental temperatures. Heat stroke, requiring hospitalization, was diagnosed in some cases. Pediatric patients appear to be at an increased risk for zonisamide-associated oligohidrosis and hyperthermia. Patients, especially pediatric patients, treated with ZONISADE should be monitored closely for evidence of decreased sweating and increased body temperature, especially in warm or hot weather. Caution should be used when ZONISADE is prescribed with other drugs that predispose patients to heat-related disorders; these drugs include, but are not limited to, carbonic anhydrase inhibitors and drugs with anticholinergic activity. 5.6 Acute Myopia and Secondary Angle Closure Glaucoma Acute myopia and secondary angle closure glaucoma have been reported in patients receiving zonisamide, the active ingredient in ZONISADE. Elevated intraocular pressure can lead to serious sequelae, including permanent vision loss, if left untreated. Symptoms in reported cases have included acute onset of decreased visual acuity and/or ocular pain. Ophthalmologic findings can include myopia, anterior chamber shallowing, ocular hyperemia (redness), and increased intraocular pressure. Mydriasis may or may not be present. This syndrome may be associated…