Zonisamide

Class: Anticonvulsants, Miscellaneous
VA Class: CN400
Chemical Name: 1,2-Benzisoxazole-3-methanesulfonamide
Molecular Formula: C₈H₈N₂O₃S
CAS Number: 68291-97-4
Brands: Zonegran

REMS:

FDA approved a REMS for zonisamide to ensure that the benefits of a drug outweigh the risks. However, FDA later rescinded REMS requirements. See the FDA REMS page () or the ASHP REMS Resource Center ().

Introduction

Anticonvulsant; a sulfonamide.^{1 2 3}

Uses for Zonisamide

Seizure Disorders

Management (in combination with other anticonvulsants) of partial seizures in adults with epilepsy.^{1 2 3 8}

Zonisamide Dosage and Administration

General

• 
  

  Zonisamide therapy should not be discontinued abruptly; dosage reduction or discontinuance of the drug should be done gradually.¹

  
  


• 
  

  Closely monitor for marked changes in behavior that could indicate emergence or worsening of suicidal thoughts or behavior or depression.^{1 14 15 16 21} (See Suicidality Risk under Cautions.)

  
  

Administration

Oral Administration

Administer orally without regard to meals.^{1 2 3} Patients should be encouraged to drink 6–8 glasses of water each day while receiving the drug.¹

Administer initial dosage (100 mg daily) once daily; following dosage adjustment, administer once or twice daily.^{1 2 3}

Swallow capsules whole.¹

Dosage

Adults

Seizure Disorders

Partial Seizures

Oral

Adults >16 years of age: Initially, 100 mg daily.^{1 2 3 9}

After 2 weeks, dosage may be increased to 200 mg daily.^{1 3} Dosage can be further increased to 300 and 400 mg daily;^{1 2 3 9} allow ≥2 weeks between dosage changes (to achieve steady state at each dosage level).^{1 2 3 9} Some clinicians may prefer to administer lower dosages for longer periods (in order to fully assess safety at steady state).¹

Dosages >400 mg daily may not be associated with increased therapeutic benefit.¹

Adverse effects occur more frequently at dosages ≥300 mg daily.¹

Prescribing Limits

Adults

Seizure Disorders

Partial Seizures

Oral

Limited experience with dosages >600 mg daily.¹

Special Populations

Hepatic Impairment

Titrate dosage slowly in patients with hepatic disease.¹

Renal Impairment

Titrate dosage slowly in patients with renal disease.^{1 2} Do not use in patients with renal failure (GFR <50 mL/minute).¹

Geriatric Patients

No specific dosage recommendations for zonisamide; however, select dosage cautiously, usually starting at the lower end of the dosage range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant diseases or other drug therapy in this population.¹

Cautions for Zonisamide

Contraindications

• 
  

  Known hypersensitivity to zonisamide, sulfonamides, or any ingredient in the formulation.^{1 2}

  
  

Warnings/Precautions

Warnings

Hematologic Effects

Aplastic anemia and agranulocytosis reported rarely; causal relationship between these events and dosage or duration of therapy not established.^{1 2}

Oligohidrosis and Hyperthermia

Oligohidrosis (a reduction in sweating) and hyperthermia reported in patients receiving zonisamide, particularly in pediatric patients.^{1 13 26} Closely monitor patients receiving zonisamide for evidence of decreased sweating and increased body temperature, particularly in warm or hot weather.^{1 13 26} Consider risk of hyperthermia when zonisamide is used concomitantly with other drugs that predispose patients to heat-related disorders.^{1 13} (See Pediatric Use under Cautions, Drugs Predisposing to Heat-related Disorders under Interactions, and Advice to Patients.)

Suicidality Risk

Increased risk of suicidality (suicidal ideation or behavior) observed in an analysis of studies using various anticonvulsants, including zonisamide, in patients with epilepsy, psychiatric disorders (e.g., bipolar disorder, depression, anxiety), and other conditions (e.g., migraine, neuropathic pain); risk in patients receiving anticonvulsants (0.43%) was approximately twice that in patients receiving placebo (0.24%).^{1 14 15 16 21} Increased suicidality risk was observed ≥1 week after initiation of anticonvulsant therapy and continued through 24 weeks.^{14 15 16} Risk was higher for patients with epilepsy compared with those receiving anticonvulsants for other conditions.^{1 14 15 16}

Closely monitor all patients currently receiving or beginning anticonvulsant therapy for changes in behavior that may indicate emergence or worsening of suicidal thoughts or behavior or depression.^{1 14 15 16 21} Anxiety, agitation, hostility, hypomania, and mania may be precursors to emerging suicidality.¹⁵

Balance risk of suicidality with the risk of untreated illness.^{1 15} Epilepsy and other illnesses treated with anticonvulsants are themselves associated with morbidity and mortality and an increased risk of suicidality.^{1 21} If suicidal thoughts or behavior emerge during anticonvulsant therapy, consider whether these symptoms may be related to the illness itself.^{1 21} (See Advice to Patients.)

Metabolic Acidosis

Zonisamide can cause metabolic acidosis, characterized by hyperchloremia and decreased serum bicarbonate concentrations.¹⁹ Often asymptomatic, but signs and symptoms of persistent metabolic acidosis may include hyperventilation, fatigue, and anorexia; more severe symptoms may include cardiac arrhythmias and stupor.¹⁹ Generally occurs early in treatment, but may occur at any time during therapy.¹⁹

Risk of developing metabolic acidosis appears greater at higher dosages of zonisamide, but it can occur with dosages ≤25 mg daily.¹⁹ Renal disease, severe respiratory disorders, diarrhea, surgery, ketogenic diets, or other drugs (e.g., acetazolamide) may predispose patients to acidosis.¹⁹ Also appears to be more frequent and severe in younger patients.¹⁹ (See Pediatric Use under Cautions.)

Decreases in serum bicarbonate levels are usually mild to moderate (average decrease of approximately 2 mEq/L) in adults; however, some adults have experienced severe decreases (as much as 10 mEq/L below their baseline).¹⁹ Chronic, untreated metabolic acidosis may increase the risk for renal calculi (kidney stones), nephrocalcinosis, and bone abnormalities (e.g., osteoporosis, osteomalacia, rickets in children) with an increased risk of fractures.¹⁹ (See Renal Calculi under Cautions.)

FDA recommends that clinicians measure serum bicarbonate levels prior to and periodically during zonisamide therapy, even in the absence of clinical symptoms, as well as if signs or symptoms of metabolic acidosis are observed.¹⁹ If metabolic acidosis develops and persists, consider reducing the zonisamide dosage or discontinuing the drug (by slowly reducing the dosage) and modifying the patient’s anticonvulsant drug regimen as appropriate.¹⁹ If the decision is made to continue patients with metabolic acidosis on zonisamide, consider alkali treatment.¹⁹

Withdrawal Seizures

Abrupt withdrawal may result in increased seizure frequency or status epilepticus; withdraw zonisamide gradually and reduce dosage slowly.¹

Cognitive/Neuropsychiatric Effects

Possible somnolence or fatigue, psychiatric symptoms (e.g., depression, psychosis), and impaired psychomotor or cognitive performance (e.g., difficulties in concentrating, language, speech, and word finding).^{1 3 5 15 17} (See Suicidality Risk under Cautions.)

Status Epilepticus

In controlled studies, status epilepticus occurred in 1.1 or 0% of patients receiving zonisamide or placebo, respectively.¹ In all (uncontrolled and controlled) clinical studies of zonisamide therapy, the incidence of status epilepticus was 1%.¹

Sensitivity Reactions

Dermatologic and Sensitivity Reactions

Fatalities resulting from severe reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, have occurred following zonisamide use.^{1 2 7}

Fatalities resulting from fulminant hepatic necrosis, agranulocytosis, aplastic anemia, or other blood dyscrasias rarely have been caused by sulfonamides.^{1 2}

Discontinue immediately if signs or symptoms of hypersensitivity occur.¹ Consider drug discontinuance if unexplained rash occurs; if drug is not discontinued, observe patient frequently.¹

General Precautions

Renal Calculi

Clinically possible or confirmed renal calculi (kidney stones), composed of calcium or urate salts, reported.^{1 2 3 4 8 9 12}

In general, increasing fluid intake and urine output may reduce the risk of kidney stone formation, particularly in patients with predisposing risk factors; not known whether these measures reduce the risk of kidney stone formation in patients receiving zonisamide.¹

Other Renal Effects

Substantial increases in S_cr and BUN reported;¹ such increases appeared to persist over time but were not progressive.¹ Consider periodically monitoring renal function during zonisamide therapy.¹

Discontinue use in patients who develop acute renal failure or clinically important, sustained increases in S_cr and BUN.¹

Sudden, Unexplained Deaths in Epilepsy

Higher incidence of sudden and unexplained deaths than would be expected in a healthy (nonepileptic) population; however, incidence is within range of estimates for patients with refractory epilepsy.¹

Specific Populations

Pregnancy

Category C.¹

North American Antiepileptic Drug Pregnancy Registry at 888-233-2334 (for patients).¹

FDA warns that zonisamide may cause metabolic acidosis;¹⁹ if metabolic acidosis occurs during pregnancy, may affect fetal development (i.e., decreased fetal growth, decreased fetal oxygenation, and fetal death) and the ability of the fetus to tolerate labor.¹⁹

The effect of zonisamide on labor and delivery is unknown.¹

Physiologic changes during pregnancy may affect plasma zonisamide concentrations and/or therapeutic effect.¹ (See Special Populations under Pharmacokinetics: Elimination.) Some clinicians recommend closely monitoring zonisamide concentrations and adjusting zonisamide dosage as necessary in pregnant women.²⁰

Lactation

Distributes into human milk.^{18 19} Due to potential risk in nursing infant, discontinue nursing or the drug.¹

Pediatric Use

Safety and efficacy of zonisamide not established in children <16 years of age and the drug is not approved for use in pediatric patients in the US.^{1 19} However, the drug has been used in some pediatric patients† for the treatment of epilepsy to date and is approved for pediatric use in Japan.^{19 22 23 24 25 26 27}

Oligohidrosis and hyperthermia, characterized by decreased sweating and abnormally high body temperatures, reported in pediatric patients (1.6–17 years of age) receiving zonisamide and sometimes have resulted in heat stroke and hospitalization.^{1 2 3 11 13}

Closely monitor children receiving the drug for evidence of decreased sweating and increased body temperature, especially in warm or hot weather.^{1 13 26} Consider risk of hyperthermia when zonisamide is used concomitantly with other drugs that predispose patients to heat-related disorders.^{1 13} (See Oligohidrosis and Hyperthermia under Cautions, Drugs Predisposing to Heat-related Disorders under Interactions, and Advice to Patients.)

Pediatric patients may be at increased risk for zonisamide-induced metabolic acidosis; may be more severe in younger patients.¹⁹ Specific effects of zonisamide on growth and bone not studied; chronic metabolic acidosis may reduce growth rates in pediatric patients, resulting in a reduction in the maximal height achieved.¹⁹ (See Metabolic Acidosis under Cautions, Specific Drugs under Interactions, and Advice to Patients.)

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether they respond differently than younger adults.¹

Hepatic Impairment

Use with caution in patients with hepatic disease; slower dosage titration and more frequent monitoring may be necessary.¹ (See Hepatic Impairment under Dosage and Administration.)

Renal Impairment

Use with caution in patients with renal disease; slower dosage titration and more frequent monitoring may be necessary.¹

Because of insufficient experience concerning dosage and toxicity, do not use in patients with renal failure (GFR <50 mL/minute).¹ (See Renal Impairment under Dosage and Administration.)

Common Adverse Effects

Abdominal pain, anorexia, diarrhea, nausea, dyspepsia, constipation, dry mouth, taste perversion, headache, dizziness, ataxia, nystagmus, paresthesia, confusion, difficulty concentrating, impaired memory, mental slowing, speech abnormalities, difficulty in verbal expression, agitation and/or irritability, depression, insomnia, anxiety, nervousness, schizophrenic and/or schizophreniform behavior, somnolence, fatigue, tiredness, flu-like syndrome, ecchymosis, rhinitis, weight loss, rash, diplopia.^{1 2 3 8 9}

Interactions for Zonisamide

Does not appear to inhibit CYP isoenzymes in vitro;^{1 2 3} metabolic pathways include metabolism by CYP3A4.¹

Drugs Metabolized by or Affecting Hepatic Microsomal Enzymes

Potential pharmacokinetic interaction (altered serum concentrations of zonisamide) with inhibitors or inducers of CYP3A4.^{1 2}

Does not appear to interfere with metabolism of drugs metabolized by CYP isoenzymes.^{1 2 3}

Anticonvulsants

Other anticonvulsants may alter pharmacokinetics of zonisamide.^{1 2} (See Specific Drugs under Interactions.)

Drugs Predisposing to Heat-related Disorders

Increased risk of oligohidrosis and hyperthermia with drugs that predispose to heat-related disorders (e.g., carbonic anhydrase inhibitors, drugs with anticholinergic activity).^{1 13 26}

Specific Drugs

Drug	Interaction	Comments
Acetazolamide and other carbonic anhydrase inhibitors	Possible increased risk of developing metabolic acidosis and heat-related disorders during concurrent administration1 13 19 26
Carbamazepine	Possible decrease in plasma zonisamide concentrations;1 2 3 no change in steady-state plasma carbamazepine concentrations1 2 8	Increase in zonisamide dosage may be required2
Oral contraceptives	Pharmacokinetic interaction unlikely28
Phenobarbital	Zonisamide half-life decreased1
Phenytoin	Possible decrease in plasma zonisamide concentrations;1 2 3 no change in steady-state plasma phenytoin concentrations1 2 8	Increase in zonisamide dosage may be required2
Valproic acid	No change in steady-state plasma concentrations of valproic acid1 2 8

Zonisamide Pharmacokinetics

Absorption

Bioavailability

Rapidly and almost completely absorbed following oral administration, with nearly 100% oral bioavailability.^{2 3} Peak plasma concentrations attained within 2–6 hours after oral administration.¹

Food

Food delays the time to peak plasma concentration but does not affect bioavailability.¹

Distribution

Extent

Extensively binds to erythrocytes, resulting in an 8-fold higher concentration of zonisamide in erythrocytes than in plasma.¹

Crosses the placenta;¹⁸ distributed into breast milk.^{18 19}

Plasma Protein Binding

Approximately 40%.¹

Elimination

Metabolism

Undergoes acetylation to form N-acetyl zonisamide, subsequent reduction to form 2-sulfamoylacetyl phenol, and further glucuronide conjugation.^{1 3} The reduction of N-acetyl zonisamide is mediated by CYP3A4.^{1 2 3}

Does not induce own metabolism.¹

Elimination Route

Excreted principally in urine as unchanged drug and a glucuronide metabolite.^{1 2 3}

Half-life

About 63 hours.^{1 3}

Special Populations

In patients with marked renal impairment (Cl_cr≤ 20 mL/minute), AUC was increased by 35%.¹ Renal clearance decreases with decreasing renal function.¹

In patients with hepatic impairment, pharmacokinetics not studied to date.¹

Clearance of zonisamide may be increased at the end of the second trimester in pregnant women.²⁰

Pharmacokinetics were similar in geriatric and young healthy volunteers in single-dose studies.¹ (See Geriatric Patients under Dosage and Administration.)

Stability

Storage

Oral

Capsules

Dry place at 25°C (may be exposed to 15–30°C); protect from light.¹

Actions

• 
  

  Exact mechanism of action is not known; anticonvulsant activity may be associated with the drug’s sodium- and calcium-channel blocking activities.^{1 2 3 9}

  
  


• 
  

  May potentiate dopaminergic and serotonergic neurotransmission^{1 2 3} but does not appear to potentiate the synaptic activity of GABA.¹

  
  


• 
  

  Exhibits weak inhibition of carbonic anhydrase activity;^{1 2 3} not thought to contribute substantially to anticonvulsant activity.¹

  
  

Advice to Patients

• 
  

  Importance of providing copy of written patient information (medication guide) each time zonisamide is dispensed.^{1 21}

  
  


• 
  

  Risk of serious skin rash that can cause death; these skin reactions are more likely to happen within the first 4 months of starting therapy, but may occur later.¹ Importance of immediately contacting clinician if skin rash occurs.¹

  
  


• 
  

  Importance of patients being aware that zonisamide can prevent sweating, which makes it harder for the body to cool down when it gets very hot; this is more likely to occur in warmer weather, in children, and during physical exercise.^{1 13 26} Importance of avoiding exposure to heat, maintaining adequate hydration, and informing clinicians immediately if fever or increased body temperature and/or decreased sweating occurs, particularly in children or in hot weather.^{1 13 26}

  
  


• 
  

  Risk of blood cell abnormalities such as reduced RBC and WBC counts.¹ Importance of contacting clinician if fever, sore throat, sores in the mouth, or unusual bruising occurs.¹

  
  


• 
  

  Risk of suicidality (anticonvulsants, including zonisamide, may increase risk of suicidal thoughts or actions in about 1 in 500 people).^{1 15 21} Importance of patients, family, and caregivers being alert to day-to-day changes in mood, behavior, and actions and immediately informing clinician of any new or worrisome behaviors (e.g., talking or thinking about wanting to hurt oneself or end one’s life, withdrawing from friends and family, becoming depressed or experiencing worsening of existing depression, becoming preoccupied with death and dying, giving away prized possessions).^{1 15}

  
  


• 
  

  Importance of patients being aware that zonisamide may cause metabolic acidosis.¹⁹ Importance of patients being aware that blood tests to measure serum bicarbonate levels may be performed.¹⁹ Symptoms of metabolic acidosis include breathing fast (hyperventilation), fatigue, and loss of appetite; more severe symptoms include an irregular heart beat or unconsciousness.¹⁹

  
  


• 
  

  May cause drowsiness, especially at higher dosages.¹ Avoid driving or operating machinery while taking zonisamide until experience with the drug’s effects has been established.¹

  
  


• 
  

  Risk of kidney stones.¹ Importance of informing patients that increasing fluid intake (i.e., by drinking 6–8 glasses of water a day) and urine output may reduce the risk of stone formation, particularly in those with predisposing factors.¹ Importance of immediately reporting symptoms of kidney stones (e.g., sudden back pain, abdominal pain, and/or blood in urine) to clinician.¹

  
  


• 
  

  Importance of immediately reporting worsening of seizures and severe muscle pain and/or weakness to clinician.¹

  
  


• 
  

  Importance of women informing clinicians if they are or plan to become pregnant.^{1 19} Importance of informing women who are or plan to become pregnant that zonisamide may cause metabolic acidosis, which may negatively affect fetal development during pregnancy.¹⁹ Importance of clinicians informing women about the existence of and encouraging enrollment in pregnancy registries (see Pregnancy under Warnings/Precautions: Specific Populations, in Cautions).¹

  
  


• 
  

  Importance of informing nursing women and those who plan to breast-feed that zonisamide can appear in the breast milk, and that the effects of this exposure on the infant are unknown.¹⁹ Importance of women informing clinicians if they plan to breast-feed.^{1 19}

  
  


• 
  

  Importance of swallowing zonisamide capsules whole and not biting into or breaking into the capsules; zonisamide may be taken with or without food.¹

  
  


• 
  

  Importance of informing patients not to stop taking zonisamide without talking to their clinician since stopping the drug suddenly can cause serious problems, including seizures.¹

  
  


• 
  

  Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription drugs, OTC drugs, and special diets (e.g., ketogenic diet), as well as any concomitant illnesses (e.g., liver disease, kidney disease, severe lung disorders, diarrhea, surgery, depression, bipolar disorder) or family history of suicidality or bipolar disorder.^{1 13 19}

  
  


• 
  

  Importance of informing patients of other important precautionary information.¹ (See Cautions.)

  
  

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Zonisamide

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Capsules	25 mg*	Zonegran	Eisai
			Zonisamide Capsules
		50 mg*	Zonisamide Capsules
		100 mg*	Zonegran	Eisai
			Zonisamide Capsules

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 10/2011. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Zonegran 100MG Capsules (EISAI): 30/$131.99 or 90/$380.98

Zonegran 25MG Capsules (EISAI): 30/$39.99 or 90/$97.97

Zonisamide 100MG Capsules (GLENMARK PHARMACEUTICALS): 30/$59.99 or 90/$169.97

Zonisamide 25MG Capsules (GLENMARK PHARMACEUTICALS): 100/$49.99 or 300/$139.98

Zonisamide 50MG Capsules (GLENMARK PHARMACEUTICALS): 100/$91.99 or 300/$259.98

Disclaimer

This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.

The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.

AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions October 27, 2011. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

1. Elan Pharma International Ltd, (manufacturer) and Eisai Inc. (distributor). Zonegran (zonisamide) capsules prescribing information. Woodcliff Lake, NJ; 2009 Apr.

2. Anon. Zonisamide (Zonegran) for epilepsy. Med Lett Drugs Ther. 2000; 42:94-5. [PubMed 11015160]

3. Schachter SC. The next wave of anticonvulsants: focus on levetiracetam, oxcarbazepine and zonisamide. Drugs. 2000; 14:229-49.

4. Leppik IE, Willmore LJ, Homan RW et al. Efficacy and safety of zonisamide: results of a multicenter study. Epilepsy Res. 1993; 14:165-73. [PubMed 8453952]

5. Berent S, Sackellares JC, Giordani B et al. Zonisamide (CI-912) and cognition: results from preliminary study. Epilepsia. 1987; 28:61-7. [PubMed 3098556]

6. Sackellares JC, Donofrio PD, Wagner JG et al. Pilot study of zonisamide (1,2-benzisoxazole-3-methanesulfonamide) in patients with refractory partial seizures. Epilepsia. 1985; 26:206-11. [PubMed 3924586]

7. Wilensky AJ, Friel PN, Ojemann LM Et al. Zonisamide in epilepsy: a pilot study. Epilepsia. 1985; 26:212-20. [PubMed 4006880]

8. Schmidt D, Jacob R, Loiseau P et al. Zonisamide for add-on treatment of refractory partial epilepsy: a European double-blind trial. Epilepsy Res. 1993 May; 15:67-73.

9. Oommen KJ, Mathews S. Zonisamide: a new antiepileptic drug. Clin Neuropharmacol. 1999; 22:192-200. [PubMed 10442247]

10. Leppik IE. Zonisamide. Epilepsia. 1999; 40(Suppl 5):S23-9. [IDIS 435526] [PubMed 10530691]

11. Okumura A, Hayakawa F, Kuno K et al. Oligohidrosis caused by zonisamide. No To Hattatsu. 1996; 28:44-7. [PubMed 8579857]

12. Kubota M, Nishi-Nagase M, Sakakihara Y et al. Zonisamide-induced urinary lithiasis in patients with intractable epilepsy. Brain Dev. 2000; 22:230-3. [PubMed 10838109]

13. O’Brien C. Dear doctor letter regarding oligohidrosis and hyperthermia in pediatric patients. San Diego, CA: Elan Pharmaceuticals; 2002. From the FDA website.

14. Food and Drug Administration. FDA Alert: Suicidality and antiepileptic drugs. Rockville, MD; 2008 Jan 31. From the FDA website.

15. Food and Drug Administration. FDA Alert: Information for healthcare professionals: suicidality and antiepileptic drugs. Rockville, MD; 2008 Jan 31. From the FDA website.

16. Food and Drug Administration. FDA News: FDA alerts health care providers to risk of suicidal thoughts and behavior with antiepileptic medications. Rockville, MD; 2008 Jan 31. From the FDA website.

17. Kalinin VV. Suicidality and antiepileptic drugs: is there a link?. Drug Saf. 2007; 30:123-42. [PubMed 17253878]

18. Kawada K, Itoh S, Kusaka T et al. Pharmacokinetics of zonisamide in perinatal period. Brain Dev. 2002; 24:95-7. [PubMed 11891100]

19. Food and Drug Administration. FDA Alert: Information for healthcare professionals: zonisamide (marketed as Zonegran, and generics). Rockville, MD; 2009 Feb 23. From the FDA website.

20. Oles KS, Bell WL. Zonisamide concentrations during pregnancy. Ann Pharmacother. 2008; 42:1139-41. [PubMed 18577760]

21. Food and Drug Administration. Suicidal behavior and ideation and antiepileptic drugs: update 5/5/2009. Rockville, MD; 2009 May 5. From the FDA website.

22. Lee YJ, Kang HC, Seo JH et al. Efficacy and tolerability of adjunctive therapy with zonisamide in childhood intractable epilepsy. Brain Dev. 2009; Mar 20:[epub ahead of print].

23. Coppola G, Grosso S, Verrotti A et al. Zonisamide in children and young adults with refractory epilepsy: an open label, multicenter Italian study. Epilepsy Res. 2009; 83:112-6. [PubMed 19081227]

24. Santos CC, Brotherton T. Use of zonisamide in pediatric patients. Pediatr Neurol. 2005; 33:12-4. [PubMed 15876518]

25. Wilfong AA. Zonisamide monotherapy for epilepsy in children and young adults. Pediatr Neurol. 2005; 32:77-80. [PubMed 15664764]

26. Low PA, James S, Peschel T et al. Zonisamide and associated oligohidrosis and hyperthermia. Epilepsy Res. 2004; 62:27-34. [PubMed 15519129]

27. Shinnar S, Pellock JM, Conry JA. Open-label, long-term safety study of zonisamide administered to children and adolescents with epilepsy. Eur J Paediatr Neurol. 2009; 13:3-9. [PubMed 18343174]

28. Griffith SG, Dai Y. Effect of zonisamide on the pharmacokinetics and pharmacodynamics of a combination ethinyl estradiol-norethindrone oral contraceptive in healthy women. Clin Ther.. 2004; 26:2056-65.

More Zonisamide resources

• Zonisamide Side Effects (in more detail)
• Zonisamide Dosage
• Zonisamide Use in Pregnancy & Breastfeeding
• Drug Images
• Zonisamide Drug Interactions
• Zonisamide Support Group
• 20 Reviews for Zonisamide - Add your own review/rating

• Zonisamide MedFacts Consumer Leaflet (Wolters Kluwer)


• Zonisamide Professional Patient Advice (Wolters Kluwer)


• zonisamide Advanced Consumer (Micromedex) - Includes Dosage Information


• Zonegran Prescribing Information (FDA)


• Zonegran Consumer Overview

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Glyset

miglitol

Dosage Form: tablet, film coated
Glyset® miglitol tablets

For Oral Use

Glyset Description

Glyset Tablets contain miglitol, an oral alpha-glucosidase inhibitor for use in the management of non-insulin-dependent diabetes mellitus (NIDDM). Miglitol is a desoxynojirimycin derivative, and is chemically known as 3,4,5-piperidinetriol, 1-(2-hydroxyethyl)-2-(hydroxymethyl)-, [2R-(2α,3β,4α, 5β)]-. It is a white to pale-yellow powder with a molecular weight of 207.2. Miglitol is soluble in water and has a pKa of 5.9. Its empirical formula is C8H17NO5 and its chemical structure is as follows:

Glyset is available as 25 mg, 50 mg and 100 mg tablets for oral use. The inactive ingredients are starch, microcrystalline cellulose, magnesium stearate, hypromellose, polyethylene glycol, titanium dioxide, and polysorbate 80.

Glyset - Clinical Pharmacology

Miglitol is a desoxynojirimycin derivative that delays the digestion of ingested carbohydrates, thereby resulting in a smaller rise in blood glucose concentration following meals. As a consequence of plasma glucose reduction, Glyset Tablets reduce levels of glycosylated hemoglobin in patients with Type II (non-insulin-dependent) diabetes mellitus. Systemic nonenzymatic protein glycosylation, as reflected by levels of glycosylated hemoglobin, is a function of average blood glucose concentration over time.

Mechanism of Action

In contrast to sulfonylureas, Glyset does not enhance insulin secretion. The antihyperglycemic action of miglitol results from a reversible inhibition of membrane-bound intestinal α-glucoside hydrolase enzymes. Membrane-bound intestinal α-glucosidases hydrolyze oligosaccharides and disaccharides to glucose and other monosaccharides in the brush border of the small intestine. In diabetic patients, this enzyme inhibition results in delayed glucose absorption and lowering of postprandial hyperglycemia.

Because its mechanism of action is different, the effect of Glyset to enhance glycemic control is additive to that of sulfonylureas when used in combination. In addition, Glyset diminishes the insulinotropic and weight-increasing effects of sulfonylureas.

Miglitol has minor inhibitory activity against lactase and consequently, at the recommended doses, would not be expected to induce lactose intolerance.

Pharmacokinetics

Absorption

Absorption of miglitol is saturable at high doses: a dose of 25 mg is completely absorbed, whereas a dose of 100 mg is only 50% – 70% absorbed. For all doses, peak concentrations are reached in 2–3 hours. There is no evidence that systemic absorption of miglitol contributes to its therapeutic effect.

Distribution

The protein binding of miglitol is negligible (<4.0%). Miglitol has a volume of distribution of 0.18 L/kg, consistent with distribution primarily into the extracellular fluid.

Metabolism

Miglitol is not metabolized in man or in any animal species studied. No metabolites have been detected in plasma, urine, or feces, indicating a lack of either systemic or pre-systemic metabolism.

Excretion

Miglitol is eliminated by renal excretion as unchanged drug. Thus, following a 25-mg dose, over 95% of the dose is recovered in the urine within 24 hours. At higher doses, the cumulative recovery of drug from urine is somewhat lower due to the incomplete bioavailability. The elimination half-life of miglitol from plasma is approximately 2 hours.

Special Populations

Renal Impairment

Because miglitol is excreted primarily by the kidneys, accumulation of miglitol is expected in patients with renal impairment. Patients with creatinine clearance <25 mL/min taking 25 mg 3 times daily exhibited a greater than two-fold increase in miglitol plasma levels as compared to subjects with creatinine clearance >60 mL/min. Dosage adjustment to correct the increased plasma concentrations is not feasible because miglitol acts locally. Little information is available on the safety of miglitol in patients with creatinine clearance <25 mL/min.

Hepatic impairment

Miglitol pharmacokinetics were not altered in cirrhotic patients relative to healthy control subjects. Since miglitol is not metabolized, no influence of hepatic function on the kinetics of miglitol is expected.

Gender

No significant difference in the pharmacokinetics of miglitol was observed between elderly men and women when body weight was taken into account.

Race

Several pharmacokinetic studies were conducted in Japanese volunteers, with results similar to those observed in Caucasians. A study comparing the pharmacodynamic response to a single 50-mg dose in Black and Caucasian healthy volunteers indicated similar glucose and insulin responses in both populations.

Clinical Studies

Clinical Experience in Non-Insulin-Dependent Diabetes Mellitus (NIDDM) Patients on Dietary Treatment Only

Glyset Tablets were evaluated in two U.S. and three non-U.S. controlled, fixed-dose, monotherapy studies, in which 735 patients treated with Glyset were evaluated for efficacy analyses (see Table 1).

In Study 1, a one-year study in which Glyset was evaluated as monotherapy and also as combination therapy, there was a statistically significantly smaller increase in mean glycosylated hemoglobin (HbA1c) over time in the miglitol 50 mg 3 times daily monotherapy arm compared to placebo. Significant reductions in mean fasting and postprandial plasma glucose levels and in mean postprandial insulin levels were observed in patients treated with Glyset compared with the placebo group.

In Study 2, a 14-week study, there was a significant decrease in HbA1c in patients receiving Glyset 50 mg 3 times daily or 100 mg 3 times daily compared to placebo. In addition, there were significant reductions in postprandial plasma glucose and postprandial serum insulin levels compared to placebo.

Study 3 was a 6-month dose-ranging trial evaluating Glyset at doses from 25 mg 3 times daily to 200 mg 3 times daily. Glyset produced a greater reduction in HbA1c than placebo at all doses, although the effect was statistically significant only at the 100 mg 3 times daily and 200 mg 3 times daily doses. In addition, all doses of Glyset produced significant reductions in postprandial plasma glucose and postprandial insulin levels compared to placebo.

Studies 4 and 5 were 6-month studies evaluating Glyset at 50 and 100 mg 3 times daily, and 100 mg 3 times daily, respectively. As compared to placebo, Glyset produced significant reductions in HbA1c, as well as a significant reduction in postprandial plasma glucose in both studies at the doses employed.

Table 1 Results of Monotherapy Study with Glyset

		HbA1c (%)		1-hour Postprandial Glucose (mg/dL)
Study	Treatment	Mean Change from Baseline*	Treatment Effect†	Mean Change from Baseline	Treatment Effect†
* Mean baseline ranged from 7.54 to 8.72% in these studies. † The result of subtracting the placebo group average. ‡ t.i.d. = 3 times daily § p≤ 0.05 ¶ Although results for the 200 mg 3 times daily are presented for completeness, the maximum recommended dosage of Glyset is 100 mg 3 times daily.
1 (U.S.)	Placebo	+0.71	---	+24	---
	Glyset 50 mg t.i.d.‡	+0.13	-0.58§	-39	-63§
2 (U.S.)	Placebo	+0.47	---	+15	---
	Glyset 50 mg t.i.d.	-0.22	-0.69§	-52	-67§
	Glyset 100 mg t.i.d.	-0.28	-0.75§	-59	-74§
3 (non-U.S.)	Placebo	+0.18	---	+2	---
	Glyset 25 mg t.i.d.	-0.08	-0.26	-33	-35§
	Glyset 50 mg t.i.d.	-0.22	-0.40	-45	-47§
	Glyset 100 mg t.i.d.	-0.63	-0.81§	-62	-64§
	Glyset 200 mg t.i.d. ¶	-0.84	-1.02§	-85	-87§
4 (non-U.S.)	Placebo	+0.01	---	+8	---
	Glyset 50 mg t.i.d.	-0.35	-0.36§	-20	-28§
	Glyset 100 mg t.i.d.	-0.57	-0.58§	-25	-33§
5 (non-U.S.)	Placebo	+0.32	---	+17	---
	Glyset 100 mg t.i.d.	-0.43	-0.75§	-38	-55§

Clinical Experience in NIDDM Patients Receiving Sulfonylureas

Glyset was studied as adjunctive therapy to a background of maximal or near-maximal sulfonylurea (SFU) treatment in three large, double-blind, randomized studies (two U.S. and one non-U.S.) in which 471 patients treated with Glyset were evaluated for efficacy (see Table 2).

Study 6 included patients under treatment with maximal doses of SFU at entry. At the end of this 14-week study, the mean treatment effects on glycosylated hemoglobin (HbA1c) were -0.82% and -0.74% for patients receiving Glyset 50 mg 3 times daily plus SFU, and Glyset 100 mg 3 times daily plus SFU, respectively.

Study 7 was a one-year study in which Glyset at 25, 50 or 100 mg 3 times daily was added to a maximal dose of glyburide (10 mg twice daily). At the end of this study, the mean treatment effects on HbA1c of Glyset when added to maximum glyburide therapy were -0.30%, -0.62%, and -0.73% with the 25, 50 and 100 mg 3 times daily dosages of Glyset, respectively.

In Study 8, the addition of Glyset 100 mg 3 times daily to a background of treatment with glyburide produced an additional mean treatment effect on HbA1c of -0.66%.

Table 2 Results of Combination Therapy with Glyset Plus Sulfonylurea (SFU)

		HbA1c (%)		1-hour Postprandial Glucose (mg/dL)
Study	Treatment	Mean Change from Baseline*	Treatment Effect†	Mean Change from Baseline	Treatment Effect†
* Mean baseline ranged from 8.56 to 9.16% in these studies. † The result of subtracting the placebo group average. ‡ t.i.d. = 3 times daily § p≤ 0.05
6 (U.S.)	Placebo + SFU	+0.33	---	-1	---
	Glyset 50 mg t.i.d.‡ + SFU	-0.49	-0.82§	-69	-68§
	Glyset 100 mg t.i.d. + SFU	-0.41	-0.74§	-73	-72§
7 (U.S.)	Placebo + SFU	+1.01	---	48	---
	Glyset 25 mg t.i.d. + SFU	+0.71	-0.30	-2	-50§
	Glyset 50 mg t.i.d. + SFU	+0.39	-0.62§	-13	-61§
	Glyset 100 mg t.i.d. + SFU	+0.28	-0.73§	-33	-81§
8 (non-U.S.)	Placebo + SFU	+0.16	---	+10	---
	Glyset 100 mg t.i.d. + SFU	-0.50	-0.66§	-36	-46§

Dose-Response

Results from controlled, fixed-dose studies of Glyset as monotherapy or as combination treatment with a sulfonylurea were combined to derive a pooled estimate of the difference from placebo in the mean change from baseline in glycosylated hemoglobin (HbA1c) and postprandial plasma glucose as shown in Figures 1 and 2:

Because of its mechanism of action, the primary pharmacologic effect of miglitol is manifested as a reduction in postprandial plasma glucose, as shown previously in all of the major clinical trials. Glyset was statistically significantly different from placebo at all doses in each of the individual studies with respect to effect on mean one-hour postprandial plasma glucose, and there is a dose response from 25 to 100 mg 3 times daily for this efficacy parameter.

Indications and Usage for Glyset

Glyset is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

Contraindications

Glyset Tablets are contraindicated in patients with:

• Diabetic ketoacidosis


• Inflammatory bowel disease, colonic ulceration, or partial intestinal obstruction, and in patients predisposed to intestinal obstruction


• Chronic intestinal diseases associated with marked disorders of digestion or absorption, or with conditions that may deteriorate as a result of increased gas formation in the intestine


• Hypersensitivity to the drug or any of its components.

Precautions

Macrovascular Outcomes

There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with Glyset or any other anti-diabetic drug.

General

Hypoglycemia

Because of its mechanism of action, Glyset when administered alone should not cause hypoglycemia in the fasted or postprandial state. Sulfonylurea agents may cause hypoglycemia. Because Glyset Tablets given in combination with a sulfonylurea will cause a further lowering of blood glucose, it may increase the hypoglycemic potential of the sulfonylurea, although this was not observed in clinical trials. Oral glucose (dextrose), whose absorption is not delayed by Glyset, should be used instead of sucrose (cane sugar) in the treatment of mild-to-moderate hypoglycemia. Sucrose, whose hydrolysis to glucose and fructose is inhibited by Glyset, is unsuitable for the rapid correction of hypoglycemia. Severe hypoglycemia may require the use of either intravenous glucose infusion or glucagon injection.

Loss of Control of Blood Glucose

When diabetic patients are exposed to stress such as fever, trauma, infection, or surgery, a temporary loss of control of blood glucose may occur. At such times, temporary insulin therapy may be necessary.

Renal Impairment

Plasma concentrations of Glyset in renally impaired volunteers were proportionally increased relative to the degree of renal dysfunction. Long-term clinical trials in diabetic patients with significant renal dysfunction (serum creatinine >2.0 mg/dL) have not been conducted. Therefore, treatment of these patients with Glyset is not recommended.

Information for Patients

The following information should be provided to patients:

• Glyset should be taken orally three times a day at the start (with the first bite) of each main meal. It is important to continue to adhere to dietary instructions, a regular exercise program, and regular testing of urine and/or blood glucose.


• Glyset itself does not cause hypoglycemia even when administered to patients in the fasted state. Sulfonylurea drugs and insulin, however, can lower blood sugar levels enough to cause symptoms or sometimes life-threatening hypoglycemia. Because Glyset given in combination with a sulfonylurea or insulin will cause a further lowering of blood sugar, it may increase the hypoglycemic potential of these agents. The risk of hypoglycemia, its symptoms and treatment, and conditions that predispose to its development should be well understood by patients and responsible family members. Because Glyset prevents the breakdown of table sugar, a source of glucose (dextrose, D-glucose) should be readily available to treat symptoms of low blood sugar when taking Glyset in combination with a sulfonylurea or insulin.


• If side effects occur with Glyset, they usually develop during the first few weeks of therapy. They are most commonly mild-to-moderate dose-related gastrointestinal effects, such as flatulence, soft stools, diarrhea, or abdominal discomfort, and they generally diminish in frequency and intensity with time. Discontinuation of drug usually results in rapid resolution of these gastrointestinal symptoms.

Physician Counseling Information for Patients

In initiating treatment for type 2 diabetes, diet should be emphasized as the primary form of treatment. Caloric restriction and weight loss are essential in the obese diabetic patient. Proper dietary management alone may be effective in controlling the blood glucose and symptoms of hyperglycemia. The importance of regular physical activity should also be stressed, and cardiovascular risk factors should be identified and corrective measures taken where possible. Use of Glyset or other antidiabetic medications must be viewed by both the physician and patient as a treatment in addition to diet and not as a substitution or as a convenient mechanism for avoiding dietary restraint. Furthermore, loss of blood glucose control on diet alone may be transient, thus requiring only short-term administration of Glyset or other antidiabetic medications. Maintenance or discontinuation of Glyset or other antidiabetic medications should be based on clinical judgment using regular clinical and laboratory evaluations.

Laboratory Tests

Therapeutic response to Glyset may be monitored by periodic blood glucose tests. Measurement of glycosylated hemoglobin levels is recommended for the monitoring of long-term glycemic control.

Drug Interactions

Several studies investigated the possible interaction between miglitol and glyburide. In six healthy volunteers given a single dose of 5-mg glyburide on a background of 6 days treatment with miglitol (50 mg 3 times daily for 4 days followed by 100 mg 3 times daily for 2 days) or placebo, the mean Cmax and AUC values for glyburide were 17% and 25% lower, respectively, when glyburide was given with miglitol. In a study in diabetic patients in which the effects of adding miglitol 100 mg 3 times daily × 7 days or placebo to a background regimen of 3.5 mg glyburide daily were investigated, the mean AUC value for glyburide was 18% lower in the group treated with miglitol, although this difference was not statistically significant. Further information on a potential interaction with glyburide was obtained from one of the large U.S. clinical trials (Study 7) in which patients were dosed with either miglitol or placebo on a background of glyburide 10 mg twice daily. At the 6-month and 1-year clinic visits, patients taking concomitant miglitol 100 mg 3 times daily exhibited mean Cmax values for glyburide that were 16% and 8% lower, respectively, compared to patients taking glyburide alone. However, these differences were not statistically significant. Thus, although there was a trend toward lower AUC and Cmax values for glyburide when co-administered with Glyset, no definitive statement regarding a potential interaction can be made based on the foregoing three studies.

The effect of miglitol (100 mg 3 times daily × 7 days) on the pharmacokinetics of a single 1000-mg dose of metformin was investigated in healthy volunteers. Mean AUC and Cmax values for metformin were 12% to 13% lower when the volunteers were given miglitol as compared with placebo, but this difference was not statistically significant.

In a healthy volunteer study, co-administration of either 50 mg or 100 mg miglitol 3 times daily together with digoxin reduced the average plasma concentrations of digoxin by 19% and 28%, respectively. However, in diabetic patients under treatment with digoxin, plasma digoxin concentrations were not altered by co-administration of miglitol 100 mg 3 times daily × 14 days.

Other healthy volunteer studies have demonstrated that miglitol may significantly reduce the bioavailability of ranitidine and propranolol by 60% and 40%, respectively. No effect of miglitol was observed on the pharmacokinetics or pharmacodynamics of either warfarin or nifedipine.

Intestinal adsorbents (e.g., charcoal) and digestive enzyme preparations containing carbohydrate-splitting enzymes (e.g., amylase, pancreatin) may reduce the effect of Glyset and should not be taken concomitantly.

In 12 healthy males, concomitantly administered antacid did not influence the pharmacokinetics of miglitol.

Carcinogenesis, Mutagenesis, and Impairment of Fertility

Miglitol was administered to mice by the dietary route at doses as high as approximately 500 mg/kg body weight (corresponding to greater than 5 times the exposure in humans based on AUC) for 21 months. In a two-year rat study, miglitol was administered in the diet at exposures comparable to the maximum human exposures based on AUC. There was no evidence of carcinogenicity resulting from dietary treatment with miglitol.

In vitro, miglitol was found to be nonmutagenic in the bacterial mutagenesis (Ames) assay and the eukaryotic forward mutation assay (CHO/HGPRT). Miglitol did not have any clastogenic effects in vivo in the mouse micronucleus test. There were no heritable mutations detected in dominant lethal assay.

A combined male and female fertility study conducted in Wistar rats treated orally with miglitol at dose levels of 300 mg/kg body weight (approximately 8 times the maximum human exposure based on body surface area) produced no untoward effect on reproductive performance or capability to reproduce. In addition, survival, growth, development, and fertility of the offspring were not compromised.

Pregnancy

Teratogenic Effects

Pregnancy Category B

The safety of Glyset in pregnant women has not been established. Developmental toxicology studies have been performed in rats at doses of 50, 150 and 450 mg/kg, corresponding to levels of approximately 1.5, 4, and 12 times the maximum recommended human exposure based on body surface area. In rabbits, doses of 10, 45, and 200 mg/kg corresponding to levels of approximately 0.5, 3, and 10 times the human exposure were examined. These studies revealed no evidence of fetal malformations attributable to miglitol. Doses of miglitol up to 4 and 3 times the human dose (based on body surface area), for rats and rabbits, respectively, did not reveal evidence of impaired fertility or harm to the fetus. The highest doses tested in these studies, 450 mg/kg in the rat and 200 mg/kg in the rabbit promoted maternal and/or fetal toxicity. Fetotoxicity was indicated by a slight but significant reduction in fetal weight in the rat study and slight reduction in fetal weight, delayed ossification of the fetal skeleton and increase in the percentage of non-viable fetuses in the rabbit study. In the peri-postnatal study in rats, the NOAEL (No Observed Adverse Effect Level) was 100 mg/kg (corresponding to approximately four times the exposure to humans, based on body surface area). An increase in stillborn progeny was noted at the high dose (300 mg/kg) in the rat peri-postnatal study, but not at the high dose (450 mg/kg) in the delivery segment of the rat developmental toxicity study. Otherwise, there was no adverse effect on survival, growth, development, behavior, or fertility in either the rat developmental toxicity or peri-postnatal studies. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Nursing Mothers

Miglitol has been shown to be excreted in human milk to a very small degree. Total excretion into milk accounted for 0.02% of a 100-mg maternal dose. The estimated exposure to a nursing infant is approximately 0.4% of the maternal dose. Although the levels of miglitol reached in human milk are exceedingly low, it is recommended that Glyset not be administered to a nursing woman.

Pediatric Use

Safety and effectiveness of Glyset in pediatric patients have not been established.

Geriatric Use

Of the total number of subjects in clinical studies of Glyset in the United States, patients valid for safety analyses included 24% over 65, and 3% over 75. No overall differences in safety and effectiveness were observed between these subjects and younger subjects. The pharmacokinetics of miglitol were studied in elderly and young males (n=8 per group). At the dosage of 100 mg 3 times daily for 3 days, no differences between the two groups were found.

Adverse Reactions

Gastrointestinal

Gastrointestinal symptoms are the most common reactions to Glyset Tablets. In U.S. placebo-controlled trials, the incidences of abdominal pain, diarrhea, and flatulence were 11.7%, 28.7%, and 41.5% respectively in 962 patients treated with Glyset 25–100 mg 3 times daily, whereas the corresponding incidences were 4.7%, 10.0%, and 12.0% in 603 placebo-treated patients. The incidence of diarrhea and abdominal pain tended to diminish considerably with continued treatment.

Dermatologic

Skin rash was reported in 4.3% of patients treated with Glyset compared to 2.4% of placebo-treated patients. Rashes were generally transient and most were assessed as unrelated to Glyset by physician-investigators.

Abnormal Laboratory Findings

Low serum iron occurred more often in patients treated with Glyset (9.2%) than in placebo-treated patients (4.2%) but did not persist in the majority of cases and was not associated with reductions in hemoglobin or changes in other hematologic indices.

Overdosage

Unlike sulfonylureas or insulin, an overdose of Glyset Tablets will not result in hypoglycemia. An overdose may result in transient increases in flatulence, diarrhea, and abdominal discomfort. Because of the lack of extra-intestinal effects seen with Glyset, no serious systemic reactions are expected in the event of an overdose.

Glyset Dosage and Administration

There is no fixed dosage regimen for the management of diabetes mellitus with Glyset Tablets or any other pharmacologic agent. Dosage of Glyset must be individualized on the basis of both effectiveness and tolerance while not exceeding the maximum recommended dosage of 100 mg 3 times daily. Glyset should be taken three times daily at the start (with the first bite) of each main meal. Glyset should be started at 25 mg, and the dosage gradually increased as described below, both to reduce gastrointestinal adverse effects and to permit identification of the minimum dose required for adequate glycemic control of the patient.

During treatment initiation and dose titration (see below), one-hour postprandial plasma glucose may be used to determine the therapeutic response to Glyset and identify the minimum effective dose for the patient. Thereafter, glycosylated hemoglobin should be measured at intervals of approximately three months. The therapeutic goal should be to decrease both postprandial plasma glucose and glycosylated hemoglobin levels to normal or near normal by using the lowest effective dose of Glyset, either as monotherapy or in combination with a sulfonylurea.

Initial Dosage

The recommended starting dosage of Glyset is 25 mg, given orally three times daily at the start (with the first bite) of each main meal. However, some patients may benefit by starting at 25 mg once daily to minimize gastrointestinal adverse effects, and gradually increasing the frequency of administration to 3 times daily.

Maintenance Dosage

The usual maintenance dose of Glyset is 50 mg 3 times daily, although some patients may benefit from increasing the dose to 100 mg 3 times daily. In order to allow adaptation to potential gastrointestinal adverse effects, it is recommended that Glyset therapy be initiated at a dosage of 25 mg 3 times daily, the lowest effective dosage, and then gradually titrated upward to allow adaptation. After 4 – 8 weeks of the 25 mg 3 times daily regimen, the dosage should be increased to 50 mg 3 times daily for approximately three months, following which a glycosylated hemoglobin level should be measured to assess therapeutic response. If, at that time, the glycosylated hemoglobin level is not satisfactory, the dosage may be further increased to 100 mg 3 times daily, the maximum recommended dosage. Pooled data from controlled studies suggest a dose-response for both HbA1c and one-hour postprandial plasma glucose throughout the recommended dosage range. However, no single study has examined the effect on glycemic control of titrating patients' doses upwards within the same study. If no further reduction in postprandial glucose or glycosylated hemoglobin levels is observed with titration to 100 mg 3 times daily, consideration should be given to lowering the dose. Once an effective and tolerated dosage is established, it should be maintained.

Maximum Dosage

The maximum recommended dosage of Glyset is 100 mg 3 times daily. In one clinical trial, 200 mg 3 times daily gave additional improved glycemic control but increased the incidence of the gastrointestinal symptoms described above.

Patients Receiving Sulfonylureas

Sulfonylurea agents may cause hypoglycemia. There was no increased incidence of hypoglycemia in patients who took Glyset in combination with sulfonylurea agents compared to the incidence of hypoglycemia in patients receiving sulfonylureas alone in any clinical trial. However, Glyset given in combination with a sulfonylurea will cause a further lowering of blood glucose and may increase the risk of hypoglycemia due to the additive effects of the two agents. If hypoglycemia occurs, appropriate adjustments in the dosage of these agents should be made.

How is Glyset Supplied

Glyset Tablets are available as 25 mg, 50 mg, and 100 mg white, round, film-coated tablets. The tablets are debossed with the word "Glyset" on one side and the strength on the other side, as indicated below.

		Tablet Identification
Strength	NDC	Front	Back
Bottles of 100:
25 mg	0009-5012-01	Glyset	25
50 mg	0009-5013-01	Glyset	50
100 mg	0009-5014-01	Glyset	100

Store at 25°C (77°F); excursions permitted to 15°–30°C (59°–86°F) [see USP Controlled Room Temperature].

Rx only

Bayer HealthCare Pharmaceuticals Inc.

Made in Germany

Glyset is a registered trademark of Bayer HealthCare Pharmaceuticals Inc. used under license.

LAB-0167-8.0

September 2009

PRINCIPAL DISPLAY PANEL - 25 mg Tablet Bottle Label

NDC 0009-5012-01

100 Tablets

Rx only

Glyset®

miglitol tablets

25 mg

Pfizer

Distributed by

Pharmacia & Upjohn Co

Division of Pfizer Inc, NY, NY 10017

PRINCIPAL DISPLAY PANEL - 50 mg Tablet Bottle Label

NDC 0009-5013-01

100 Tablets

Rx only

Glyset®

miglitol tablets

50 mg

Pfizer

Distributed by

Pharmacia & Upjohn Co

Division of Pfizer Inc, NY, NY 10017

PRINCIPAL DISPLAY PANEL - 100 mg Tablet Bottle Label

NDC 0009-5014-01

100 Tablets

Rx only

Glyset®

miglitol tablets

100 mg

Pfizer

Distributed by

Pharmacia & Upjohn Co

Division of Pfizer Inc, NY, NY 10017

Glyset  miglitol  tablet, film coated

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 0009-5012 Route of Administration ORAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength miglitol (miglitol) miglitol 25 mg

Inactive Ingredients Ingredient Name Strength cellulose, microcrystalline   magnesium stearate   hypromellose   polyethylene glycol   titanium dioxide   polysorbate 80

Product Characteristics Color WHITE Score no score Shape ROUND Size 6mm Flavor Imprint Code Glyset;25 Contains

Packaging # NDC Package Description Multilevel Packaging 1 0009-5012-01 100 TABLET In 1 BOTTLE None

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
NDA	NDA020682	12/18/1996

Glyset  miglitol  tablet, film coated

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 0009-5013 Route of Administration ORAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength miglitol (miglitol) miglitol 50 mg

Inactive Ingredients Ingredient Name Strength cellulose, microcrystalline   magnesium stearate   hypromellose   polyethylene glycol   titanium dioxide   polysorbate 80

Product Characteristics Color WHITE Score no score Shape ROUND Size 7mm Flavor Imprint Code Glyset;50 Contains

Gentasol

Generic Name: gentamicin (Ophthalmic route)

jen-ta-MYE-sin

Commonly used brand name(s)

In the U.S.

• Garamycin


• Genoptic


• Genoptic S.O.P.


• Gentacidin


• Gentafair


• Gentak


• Gentasol


• Ocu-Mycin

Available Dosage Forms:

• Solution


• Ointment

Therapeutic Class: Antibiotic

Chemical Class: Aminoglycoside

Uses For Gentasol

Gentamicin belongs to the family of medicines called antibiotics. Gentamicin ophthalmic preparations are used to treat infections of the eye.

Gentamicin is available only with your doctor's prescription.

Before Using Gentasol

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For this medicine, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

There is no specific information comparing use of this medicine in babies up to one month of age with use in other age groups.

Geriatric

Many medicines have not been studied specifically in older people. Therefore, it may not be known whether they work exactly the same way they do in younger adults or if they cause different side effects or problems in older people. There is no specific information comparing use of this medicine in the elderly with use in other age groups.

Pregnancy

	Pregnancy Category	Explanation
All Trimesters	D	Studies in pregnant women have demonstrated a risk to the fetus. However, the benefits of therapy in a life threatening situation or a serious disease, may outweigh the potential risk.

Breast Feeding

Studies in women suggest that this medication poses minimal risk to the infant when used during breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking this medicine, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using this medicine with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Alcuronium


• Atracurium


• Cidofovir


• Cisatracurium


• Colistimethate Sodium


• Decamethonium


• Doxacurium


• Ethacrynic Acid


• Fazadinium


• Furosemide


• Gallamine


• Hexafluorenium


• Lysine


• Metocurine


• Mivacurium


• Pancuronium


• Pipecuronium


• Rapacuronium


• Rocuronium


• Succinylcholine


• Tacrolimus


• Tubocurarine


• Vancomycin


• Vecuronium

Using this medicine with any of the following medicines may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Indomethacin


• Methoxyflurane


• Polygeline

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.

Proper Use of gentamicin

This section provides information on the proper use of a number of products that contain gentamicin. It may not be specific to Gentasol. Please read with care.

For patients using the eye drop form of this medicine:

• The bottle is only partially full to provide proper drop control.


• To use:
  
  • First, wash your hands. Tilt the head back and with the index finger of one hand, press gently on the skin just beneath the lower eyelid and pull the lower eyelid away from the eye to make a space. Drop the medicine into this space. Let go of the eyelid and gently close the eyes. Do not blink. Keep the eyes closed for 1 or 2 minutes, to allow the medicine to come into contact with the infection.
  
  


• If you think you did not get the drop of medicine into your eye properly, use another drop.


• Avoid wearing contact lenses during treatment


• To keep the medicine as germ-free as possible, do not touch the applicator tip to any surface (including the eye). Also, keep the container tightly closed.

For patients using the eye ointment form of this medicine:

• First, wash your hands. Tilt the head back and with the index finger of one hand, press gently on the skin just beneath the lower eyelid and pull the lower eyelid away from the eye to make a space. Squeeze a thin strip of ointment into this space. A 1-cm (approximately ⅓-inch) strip of ointment is usually enough unless otherwise directed by your doctor. Let go of the eyelid and gently close the eyes and keep them closed for 1 or 2 minutes, to allow the medicine to come into contact with the infection.


• To keep the medicine as germ-free as possible, do not touch the applicator tip to any surface (including the eye). After using gentamicin eye ointment, wipe the tip of the ointment tube with a clean tissue and keep the tube tightly closed.

To help clear up your infection completely, keep using this medicine for the full time of treatment, even if your symptoms have disappeared. Do not miss any doses.

Dosing

The dose of this medicine will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of this medicine. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

• For ophthalmic ointment dosage form:
  
  • For eye infections:
    
    • Adults and children—Use every eight to twelve hours.
    
    
  
  


• For ophthalmic solution (eye drops) dosage form:
  
  • For mild to moderate eye infections:
    
    • Adults and children—One to two drops every four hours.
    
    
  
  
  • For severe eye infections:
    
    • Adults and children—One to two drops as often as once every hour as directed by your doctor.
    
    
  
  

Missed Dose

If you miss a dose of this medicine, apply it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule.

Storage

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Precautions While Using Gentasol

If your symptoms do not improve within a few days, or if they become worse, check with your doctor.

Gentasol Side Effects

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur:

Less common

• Itching, redness, swelling, or other sign of irritation not present before use of this medicine


• redness of eye, eyelid, or inner lining of eyelid

Rare

• Black, tarry stools; blood in urine or stools; or unusual bleeding or swelling


• blurred vision, eye pain, sensitivity to light, and/or tearing


• seeing, hearing, or feeling things that are not there

• hallucinations

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

Less common

• Burning or stinging

After application, eye ointments usually cause your vision to blur for a few minutes.

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

See also: Gentasol side effects (in more detail)

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More Gentasol resources

• Gentasol Side Effects (in more detail)
• Gentasol Use in Pregnancy & Breastfeeding
• Gentasol Support Group
• 0 Reviews for Gentasol - Add your own review/rating

• Gentasol Concise Consumer Information (Cerner Multum)


• Gentasol Drops MedFacts Consumer Leaflet (Wolters Kluwer)


• Genoptic Concise Consumer Information (Cerner Multum)


• Gentak Prescribing Information (FDA)


• Gentak eent Monograph (AHFS DI)


• Gentak Cream MedFacts Consumer Leaflet (Wolters Kluwer)

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