Potentially Fatal Reactions to Sulfonamides: Fatalities have occurred, although rarely, 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. Such reactions may occur when a sulfonamide is re-administered irrespective of the route of administration. If signs of hypersensitivity or other serious reactions occur, discontinue zonisamide immediately. Specific experience with sulfonamide-type adverse reaction to zonisamide is described below.
Serious Skin Reactions:
Consideration should be given to discontinuing zonisamide in patients who develop an otherwise unexplained rash. If the drug is not discontinued, patients should be observed frequently. 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 post-marketing 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, 6 of 269 (2.2%) zonisamide patients discontinued treatment because of rash compared to none on 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 study drug discontinuation 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.
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.
Oligohidrosis and Hyperthermia in Pediatric Patients:
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. There have been no reported deaths.
Pediatric patients appear to be at an increased risk for zonisamide-associated oligohidrosis and hyperthermia. Patients, especially pediatric patients, treated with zonisamide should be monitored closely for evidence of decreased sweating and increased body temperature, especially in warm or hot weather. Caution should be used when zonisamide 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.
The practitioner should be aware that the safety and effectiveness of zonisamide in pediatric patients have not been established, and that zonisamide is not approved for use in pediatric patients.
Suicidal Behavior and Ideation
Antiepileptic drugs (AEDs), including zonisamide, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.
Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide.
The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed.
The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5 to 100 years) in the clinical trials analyzed.
Table 3 shows absolute and relative risk by indication for all evaluated AEDs.
Table 3 Risk by indication for antiepileptic drugs in the pooled analysis
Indication
Placebo Patients with Events Per 1000 Patients
Drug Patients with Events Per 1000 Patients
Relative Risk: Incidence of Events in Drug Patients/Incidence in Placebo Patients
Risk Difference: Additional Drug Patients with Events Per 1000 Patients
Epilepsy
1.0
3.4
3.5
2.4
Psychiatric
5.7
8.5
1.5
2.9
Other
1.0
1.8
1.9
0.9
Total
2.4
4.3
1.8
1.9
The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications.
Anyone considering prescribing zonisamide or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.
Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and 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, Cognitive/Neuropsychiatric Adverse Events subsection below).
Metabolic Acidosis:
Zonisamide causes hyperchloremic, non-anion gap, metabolic acidosis (i.e., decreased serum bicarbonate below the normal reference range in the absence of chronic respiratory alkalosis) (see PRECAUTIONS, Laboratory Tests subsection). This metabolic acidosis is caused by renal bicarbonate loss due to the inhibitory effect of zonisamide on carbonic anhydrase.
Generally, zonisamide-induced metabolic acidosis occurs early in treatment, but it can develop at any time during treatment. Metabolic acidosis generally appears to be dose-dependent and can occur at doses as low as 25 mg daily.
Conditions or therapies that predispose to acidosis (such as renal disease, severe respiratory disorders, status epilepticus, diarrhea, ketogenic diet, or specific drugs) may be additive to the bicarbonate lowering effects of zonisamide.
Some manifestations of acute or chronic metabolic acidosis include hyperventilation, nonspecific symptoms such as fatigue and anorexia, or more severe sequelae including cardiac arrhythmias or stupor. Chronic, untreated, metabolic acidosis may increase the risk for nephrolithiasis or nephrocalcinosis. Nephrolithiasis has been observed in the clinical development program in 4 % of adults treated with zonisamide, has also been detected by renal ultrasound in 8 % of pediatric treated patients who had at least one ultrasound prospectively collected, and was reported as an adverse event in 3 % (4/133) of pediatric patients (see PRECAUTIONS, Kidney Stones subsection).
Chronic, untreated metabolic acidosis may result in osteomalacia (referred to as rickets in pediatric patients) and/or osteoporosis with an increased risk for fracture. Of potential relevance, zonisamide treatment was associated with reductions in serum phosphorus and increases in serum alkaline phosphatase, changes that may be related to metabolic acidosis and osteomalacia (see PRECAUTIONS, Laboratory Tests subsection).
Chronic, untreated metabolic acidosis in pediatric patients may reduce growth rates. A reduction in growth rate may eventually decrease the maximal height achieved. The effect of zonisamide on growth and bone-related sequelae has not been systematically investigated.
Measurement of baseline and periodic serum bicarbonate during treatment is recommended. If metabolic acidosis develops and persists, consideration should be given to reducing the dose or discontinuing zonisamide (using dose tapering). If the decision is made to continue patients on zonisamide in the face of persistent acidosis, alkali treatment should be considered.
Serum bicarbonate was not measured in the adjunctive controlled trials of adults with epilepsy. However, serum bicarbonate was studied in three clinical trials for indications which have not been approved: a placebo-controlled trial for migraine prophylaxis in adults, a controlled trial for monotherapy in epilepsy in adults, and an open label trial for adjunctive treatment of epilepsy in pediatric patients (3 to 16 years). In adults, mean serum bicarbonate reductions ranged from approximately 2 mEq/L at daily doses of 100 mg to nearly 4 mEq/L at daily doses of 300 mg. In pediatric patients, mean serum bicarbonate reductions ranged from approximately 2 mEq/L at daily doses from above 100 mg up to 300 mg, to nearly 4 mEq/L at daily doses from above 400 mg up to 600 mg.
In two controlled studies in adults, the incidence of a persistent treatment-emergent decrease in serum bicarbonate to less than 20 mEq/L (observed at 2 or more consecutive visits or the final visit) was dose-related at relatively low zonisamide doses. In the monotherapy trial of epilepsy, the incidence of a persistent treatment-emergent decrease in serum bicarbonate was 21% for daily zonisamide doses of 25 mg or 100 mg, and was 43% at a daily dose of 300 mg. In a placebo-controlled trial for prophylaxis of migraine, the incidence of a persistent treatment-emergent decrease in serum bicarbonate was 7% for placebo, 29% for 150 mg daily, and 34% for 300 mg daily. The incidence of persistent markedly abnormally low serum bicarbonate (decrease to less than 17 mEq/L and more than 5 mEq/L from a pretreatment value of at least 20 mEq/L in these controlled trials was 2% or less.
In the pediatric study, the incidence of persistent, treatment-emergent decreases in serum bicarbonate to levels less than 20 mEq/L was 52% at doses up to 100 mg daily, was 90% for a wide range of doses up to 600 mg daily, and generally appeared to increase with higher doses. The incidence of a persistent markedly abnormally low serum bicarbonate value was 4 % at doses up to 100 mg daily, was 18% for a wide range of doses up to 600 mg daily, and generally appeared to increase with higher doses. Some patients experienced moderately severe serum bicarbonate decrements down to a level as low as 10 mEq/L.
The relatively high frequencies of varying severities of metabolic acidosis observed in this study of pediatric patients (compared to the frequency and severity observed in various clinical trial development programs in adults) suggest that pediatric patients may be more likely to develop metabolic acidosis than adults.
Seizures on Withdrawal:
As with other AEDs, abrupt withdrawal of zonisamide in patients with epilepsy may precipitate increased seizure frequency or status epilepticus. Dose reduction or discontinuation of zonisamide should be done gradually.
Teratogenicity:
Women of child bearing potential who are given zonisamide should be advised to use effective contraception. Zonisamide was teratogenic in mice, rats, and dogs and embryolethal in monkeys when administered during the period of organogenesis. A variety of fetal abnormalities, including cardiovascular defects, and embryo-fetal deaths occurred at maternal plasma levels similar to or lower than therapeutic levels in humans. These findings suggest that the use of zonisamide during pregnancy in humans may present a significant risk to the fetus (see PRECAUTIONS, Pregnancy subsection). Zonisamide should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Cognitive/ Neuropsychiatric Adverse Events:
Use of zonisamide was frequently associated with central nervous system-related adverse events. The most significant of these can be classified into three general categories: 1) psychiatric symptoms, including depression and psychosis, 2) psychomotor slowing, difficulty with concentration, and speech or language problems, in particular, word-finding difficulties, and 3) somnolence or fatigue.
In placebo-controlled trials, 2.2% of patients discontinued zonisamide or were hospitalized for depression compared to 0.4% of placebo patients. Among all epilepsy patients treated with zonisamide, 1.4% were discontinued and 1.0% were hospitalized because of reported depression or suicide attempts. In placebo-controlled trials, 2.2% of patients discontinued zonisamide or were hospitalized due to psychosis or psychosis-related symptoms compared to none of the placebo patients. Among all epilepsy patients treated with zonisamide, 0.9% were discontinued and 1.4% were hospitalized because of reported psychosis or related symptoms.
Psychomotor slowing and difficulty with concentration occurred in the first month of treatment and were associated with doses above 300 mg/day. Speech and language problems tended to occur after 6 to 10 weeks of treatment and at doses above 300 mg/day. Although in most cases these events were of mild to moderate severity, they at times led to withdrawal from treatment.
Somnolence and fatigue were frequently reported CNS adverse events during clinical trials with zonisamide. Although in most cases these events were of mild to moderate severity, they led to withdrawal from treatment in 0.2% of the patients enrolled in controlled trials. Somnolence and fatigue tended to occur within the first month of treatment. Somnolence and fatigue occurred most frequently at doses of 300 to 500 mg/day. Patients should be cautioned about this possibility and special care should be taken by patients if they drive, operate machinery, or perform any hazardous task.
Zonisamide USP is an antiseizure drug chemically classified as a sulfonamide and unrelated to other antiseizure agents. The active ingredient is zonisamide USP, 1,2-benzisoxazole-3-methanesulfonamide. The empirical formula is C8H8N2O3S with a molecular weight of 212.23. Zonisamide USP is a white powder, pKa = 10.2, and is moderately soluble in water (0.80 mg/mL) and 0.1 N HCl (0.50 mg/mL).
The chemical structure is:
Zonisamide is supplied for oral administration as capsules containing 100 mg zonisamide USP. Each capsule contains the labeled amount of zonisamide USP plus the following inactive ingredients: microcrystalline cellulose, hydrogenated vegetable oil, gelatin and colorants. Components of gelatin capsules (For 100 mg: titanium dioxide, gelatin and FDA/E172 red iron oxide). Imprint ink dye (Black SW- 9008/SW-9009).
Zonisamide is recommended as adjunctive therapy for the treatment of partial seizures in adults. Safety and efficacy in pediatric patients below the age of 16 have not been established. Zonisamide should be administered once or twice daily, using 25 mg or 100 mg capsules. Zonisamide is given orally and can be taken with or without food. Capsules should be swallowed whole.
Adults over Age 16: The prescriber should be aware that, because of the long half-life of zonisamide, up to two weeks may be required to achieve steady state levels upon reaching a stable dose or following dosage adjustment. Although the regimen described below is one that has been shown to be tolerated, the prescriber may wish to prolong the duration of treatment at the lower doses in order to fully assess the effects of zonisamide at steady state, noting that many of the side effects of zonisamide are more frequent at doses of 300 mg per day and above. Although there is some evidence of greater response at doses above 100 to 200 mg/day, the increase appears small and formal dose-response studies have not been conducted.
The initial dose of zonisamide should be 100 mg daily. After two weeks, the dose may be increased to 200 mg/day for at least two weeks. It can be increased to 300 mg/day and 400 mg/day, with the dose stable for at least two weeks to achieve steady state at each level. Evidence from controlled trials suggests that zonisamide doses of 100 to 600 mg/day are effective, but there is no suggestion of increasing response above 400 mg/day (see CLINICAL PHARMACOLOGY, Clinical Studies subsection). There is little experience with doses greater than 600 mg/day.
Patients with Renal or Hepatic Disease: Because zonisamide is metabolized in the liver and excreted by the kidneys, patients with renal or hepatic disease should be treated with caution, and might require slower titration and more frequent monitoring (see CLINICAL PHARMACOLOGY and PRECAUTIONS).
Nicotine Transdermal System Step 1 | Novartis Consumer Health, Inc.
If you are under 18 years of age, ask a doctor before use
before using this product, read the enclosed self-help guide for complete directions and other information
stop smoking completely when you begin using the patch
if you smoke more than 10 cigarettes per day, use the following schedule below:
if you smoke 10 or less cigarettes per day, start with Step 2 for 6 weeks, then Step 3 for 2 weeks and then stop
apply one new patch every 24 hours on skin that is dry, clean and hairless
remove backing from patch and immediately press onto skin. Hold for 10 seconds.
wash hands after applying or removing patch. Save pouch to use for patch disposal. Dispose of the used patches by folding sticky ends together and putting in pouch.
the used patch should be removed and a new one applied to a different skin site at the same time each day
if you have vivid dreams, you may remove the patch at bedtime and apply a new one in the morning
do not wear more than one patch at a time
do not cut patch in half or into smaller pieces
do not leave patch on for more than 24 hours because it may irritate your skin and loses strength after 24 hours
to avoid possible burns, remove patch before undergoing any MRI (magnetic resonance imaging) procedures
stop using the patch at the end of 8 weeks. If you still feel the need to use the patch talk to your doctor.
Nicotine Transdermal System Step 1 | Physicians Total Care, Inc.
If you are under 18 years of age, ask a doctor before use
before using this product, read the enclosed self-help guide for complete directions and other information
stop smoking completely when you begin using the patch
if you smoke more than 10 cigarettes per day, use the following schedule below:
if you smoke 10 or less cigarettes per day, start with Step 2 for 6 weeks, then Step 3 for 2 weeks and then stop
apply one new patch every 24 hours on skin that is dry, clean and hairless
remove backing from patch and immediately press onto skin. Hold for 10 seconds.
wash hands after applying or removing patch. Save pouch to use for patch disposal. Dispose of the used patches by folding sticky ends together and putting in pouch.
the used patch should be removed and a new one applied to a different skin site at the same time each day
if you have vivid dreams, you may remove the patch at bedtime and apply a new one in the morning
do not wear more than one patch at a time
do not cut patch in half or into smaller pieces
do not leave patch on for more than 24 hours because it may irritate your skin and loses strength after 24 hours
to avoid possible burns, remove patch before undergoing any MRI (magnetic resonance imaging) procedures
stop using the patch at the end of 8 weeks. If you still feel the need to use the patch talk to your doctor.
Nicotine Transdermal System Step 1 | Preferred Plus (kinray)
if you are under 18 years of age, ask a doctor before use
before using this product, read the enclosed self-help guide for complete directions and other information
stop smoking completely when you begin using the patch
if you smoke more than 10 cigarettes per day, use the following schedule:
if you smoke 10 or less cigarettes per day, start with Step 2 for 6 weeks, then Step 3 for 2 weeks and then stop
apply one new patch every 24 hours on skin that is dry, clean and hairless
remove backing from patch and immediately press onto skin. Hold for 10 seconds.
wash hands after applying or removing patch. Save pouch to use for patch disposal. Dispose of used patch by folding sticky ends together and putting in pouch.
the used patch should be removed and a new one applied to a different skin site at the same time each day
if you have vivid dreams, you may remove the patch at bedtime and apply a new one in the morning
do not wear more than one patch at a time
do not cut patch in half or into smaller pieces
do not leave patch on for more than 24 hours because it may irritate your skin and loses strength after 24 hours
stop using the patch at the end of 8 weeks. If you still feel the need to use the patch talk to your doctor.
Nicotine Transdermal System Step 1 | Chain Drug Marketing Association Inc.
if you are under 18 years of age, ask a doctor before use
before using this product, read the enclosed self-help guide for complete directions and other information
stop smoking completely when you begin using the patch
if you smoke more than 10 cigarettes per day, use the following schedule:
if you smoke 10 or less cigarettes per day, start with Step 2 for 6 weeks, then Step 3 for 2 weeks and then stop
apply one new patch every 24 hours on skin that is dry, clean and hairless
remove backing from patch and immediately press onto skin. Hold for 10 seconds.
wash hands after applying or removing patch. Save pouch to use for patch disposal. Dispose of used patch by folding sticky ends together and putting in pouch.
the used patch should be removed and a new one applied to a different skin site at the same time each day
if you have vivid dreams, you may remove the patch at bedtime and apply a new one in the morning
do not wear more than one patch at a time
do not cut patch in half or into smaller pieces
do not leave patch on for more than 24 hours because it may irritate your skin and loses strength after 24 hours
stop using the patch at the end of 8 weeks. If you still feel the need to use the patch talk to your doctor.
swallow tablet(s) with a glass of water
swallow tablet(s) whole, do not crush, break, or chew
adults and children 12 years of age and older
take 2 tablets once or twice daily
children 6 to under 12 years of age
take 1 tablet once or twice daily
children under 6 years of age
ask a doctor
Nicotine Transdermal System Step 1 | Mckesson (sun Mark)
•
if you are under 18 years of age, ask a doctor before use
•
before using this product, read the enclosed self-help guide for complete directions and other information
•
begin using the patch on your quit day
•
if you smoke
more than 10 cigarettes per day, use the following schedule below:
STEP 1
STEP 2
STEP 3
Use one 21 mg patch/day
Use one 14 mg patch/day
Use one 7 mg patch/day
Weeks 1-4
Weeks 5-6
Weeks 7-8
•
if you smoke
10 or less cigarettes per day, start with
Step 2 for 6 weeks, then
Step 3 for 2 weeks
•
apply one new patch every 24 hours on skin that is dry, clean and hairless
•
remove backing from patch and immediately press onto skin. Hold for 10 seconds.
•
wash hands after applying or removing patch. Save pouch to use for patch disposal. Dispose of the used patches by folding sticky ends together and putting in pouch.
•
the used patch should be removed and a new one applied to a different skin site at the same time each day
•
if you have vivid dreams, you may remove the patch at bedtime and apply a new one in the morning
•
do not wear more than one patch at a time
•
do not cut patch in half or into smaller pieces
•
do not leave patch on for more than 24 hours because it may irritate your skin and loses strength after 24 hours
•
to avoid possible burns, remove patch before undergoing any MRI (magnetic resonance imaging) procedures
•
It is important to complete treatment. If you feel you need to use the patch for a longer period to keep from smoking, talk to your health care provider.