Ziprasidone

Class: Atypical Antipsychotics
VA Class: CN709
Chemical Name: 5-[2-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]ethyl]-6-chloro-1,3-dihydro-2H-indol-2-one monohydrochloride monohydrate
Molecular Formula: C₂₁H₂₁ClN₄OS•HCl•H₂OC₂₁H₂₁ClN₄OS•CH₄O₃S•3H₂O
CAS Number: 138982-67-9
Brands: Geodon

Special Alerts:

[Posted 02/22/2011] ISSUE: FDA notified healthcare professionals that the Pregnancy section of drug labels for the entire class of antipsychotic drugs has been updated. The new drug labels now contain more and consistent information about the potential risk for abnormal muscle movements (extrapyramidal signs or EPS) and withdrawal symptoms in newborns whose mothers were treated with these drugs during the third trimester of pregnancy.

The symptoms of EPS and withdrawal in newborns may include agitation, abnormally increased or decreased muscle tone, tremor, sleepiness, severe difficulty breathing, and difficulty in feeding. In some newborns, the symptoms subside within hours or days and do not require specific treatment; other newborns may require longer hospital stays.

BACKGROUND: Antipsychotic drugs are used to treat symptoms of psychiatric disorders such as schizophrenia and bipolar disorder.

RECOMMENDATION: Healthcare professionals should be aware of the effects of antipsychotic medications on newborns when the medications are used during pregnancy. Patients should not stop taking these medications if they become pregnant without talking to their healthcare professional, as abruptly stopping antipsychotic medications can cause significant complications for treatment. For more information visit the FDA website at: and .

• Increased Mortality in Geriatric Patients


• 
  

  Substantially higher mortality rate (4.5%) in geriatric patients with dementia-related psychosis† receiving atypical antipsychotic agents (e.g., aripiprazole, olanzapine, quetiapine, risperidone) compared with those receiving placebo (2.6%).^{1 68}

  
  


• 
  

  Most fatalities resulted from cardiac-related events (e.g., heart failure, sudden death) or infections (mostly pneumonia).^{1 68}

  
  


• 
  

  Atypical antipsychotics are not approved for the treatment of dementia-related psychosis.^{1 68} (See Increased Mortality in Geriatric Patients with Dementia-related Psychosis under Cautions.)

  
  

Introduction

Atypical or second-generation antipsychotic agent.^{1 4 10 11 29}

Uses for Ziprasidone

Schizophrenia

Symptomatic management of schizophrenia.¹

Should be reserved for patients whose disease fails to respond adequately to appropriate courses of other antipsychotic agents because of a greater capacity to prolong the QT/QT_c-interval compared with that of several other antipsychotic agents.¹ (See Prolongation of QT Interval under Cautions)

IM injection used for rapid control of behaviors that interfere with diagnosis and care (e.g., threatening behaviors, escalating or urgently distressing behavior, self-exhausting behavior).¹

Bipolar Disorder

Treatment of acute manic and mixed epsiodes (with or without psychotic features) associated with bipolar 1 disorder.^{1 73 74}

Ziprasidone Dosage and Administration

Administration

Administer orally or by IM injection.¹

Concomitant use of oral and IM ziprasidone not recommended by manufacturer.¹

Oral Administration

Administer orally twice daily with food.¹

IM Administration

Vials are for single use only.¹

Reconstitution

Reconstitute vial containing 20 mg with 1.2 mL of sterile water for injection to provide a solution containing 20 mg/mL.¹ Do not use other solutions to reconstitute the injection, and do not admix with other drugs.¹ Shake vigorously to ensure complete dissolution.¹

Observe strict aseptic technique since the drug contains no preservative.¹ Discard unused portions.¹

Dosage

Available as ziprasidone hydrochloride or ziprasidone mesylate; oral dosage expressed in terms of hydrochloride monohydrate and IM dosage expressed in terms of ziprasidone.^{1 12}

Adults

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Schizophrenia

Oral

Initially, 20 mg twice daily.¹

Dosage may be increased after a minimum of 2 days.^{1 12} Observe patients for several weeks prior to upward titrations of dosage to ensure use of the lowest effective dosage.¹

In patients responding to ziprasidone therapy, continue the drug as long as clinically necessary and tolerated, but at lowest possible effective dosage;¹² periodically reassess need for continued therapy.¹ Efficacy maintained for up to 52 weeks in clinical trials, but optimum duration of therapy currently is not known.¹

Acute Agitation in Schizophrenia

IM

Initially, 10–20 mg given as a single dose.¹

Repeat doses of 10 mg every 2 hours or 20 mg every 4 hours, up to a maximum cumulative dosage of 40 mg daily.¹

Oral therapy should replace IM therapy as soon as possible; safety and efficacy of administering ziprasidone IM injection for longer than 3 consecutive days not evaluated.¹

Bipolar Disorder

Oral

Initially, 40 mg twice daily on day 1.¹ Increase dosage to 60 or 80 mg twice daily on the second day.¹

Subsequent dosage adjustments based on efficacy and tolerability may be made within a dosage range of 40–80 mg twice daily.¹

Efficacy for long-term use (i.e., >3 weeks) or for prophylactic use in patients with bipolar disorder not systematically evaluated.¹ If used for extended periods, periodically reevaluate the long-term risks and benefits for the individual patient.¹

Prescribing Limits

Adults

Schizophrenia

Oral

Maximum 80 mg twice daily.^{1 12}

Acute Agitation

IM

Maximum cumulative dosage of 40 mg daily.

Bipolar Disorder

Oral

Maximum 80 mg twice daily.¹

Cautions for Ziprasidone

Contraindications

• 
  

  Known history of QT interval prolongation (including congenital long QT syndrome), recent AMI, or uncompensated heart failure.¹ (See Prolongation of QT Interval under Cautions.)

  
  


• 
  

  Concomitant therapy with other drugs that prolong the QT interval (e.g., class Ia and III antiarrhythmics, arsenic trioxide, chlorpromazine, dofetilide, dolasetron mesylate, droperidol, gatifloxacin, halofantrine, levomethadyl acetate, mefloquine, mesoridazine, moxifloxacin, pentamidine, pimozide, probucol, quinidine, sotalol, sparfloxacin, tacrolimus, thioridazine).¹ Ziprasidone also is contraindicated in patients receiving drugs shown to cause QT prolongation as an effect and for which this effect is described in the full prescribing information as a contraindication or a boxed or bolded warning.¹

  
  


• 
  

  Known hypersensitivity to ziprasidone.¹

  
  

Warnings/Precautions

Warnings

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Increased Mortality in Geriatric Patients with Dementia-related Psychosis

Possible increased risk of death with use of atypical antipsychotics in geriatric patients with dementia-related psychosis.^{1 68} (See Boxed Warning and see Geriatric Use under Cautions.)

Atypical antipsychotics are not approved for the treatment of dementia-related psychosis.^{1 68}

Prolongation of QT Interval

Greater capacity to prolong the QT/QT_c interval compared with that of several other antipsychotic agents.¹

Experience is too limited to rule out the possibility that ziprasidone may be associated with a greater risk of ventricular arrhythmias (e.g., torsades de pointes) and/or sudden death than other antipsychotic agents.¹

Patients at particular risk of torsades de pointes include those with bradycardia, hypokalemia, or hypomagnesemia, those receiving concomitant therapy with other drugs that prolong the QT_c interval, and those with congenital prolongation of QT_c interval.¹ (See Contraindications under Cautions.) Avoid ziprasidone therapy in patients with history of cardiac arrhythmias.¹

Determine baseline serum potassium and magnesium concentrations in patients at risk for substantial electrolyte disturbances, particularly those receiving concomitant diuretic therapy.¹ Correct hypokalemia or hypomagnesemia prior to initiating ziprasidone.¹

Clinical and ECG monitoring of cardiac function, including appropriate ambulatory ECG monitoring (e.g., Holter monitoring), is recommended during ziprasidone therapy in patients with symptoms that could indicate torsades de pointes (e.g., dizziness, palpitations, syncope).¹

Discontinue ziprasidone if the QT_c interval exceeds 500 msec.¹

Neuroleptic Malignant Syndrome

Neuroleptic malignant syndrome (NMS), a potentially fatal syndrome requiring immediate discontinuance of the drug and intensive symptomatic treatment, may occur in patients receiving antipsychotic agents.^{1 12}

Tardive Dyskinesia

Tardive dyskinesia, a syndrome of potentially irreversible, involuntary, dyskinetic movements, has been reported.¹ Consider discontinuance of ziprasidone.¹

Hyperglycemia and Diabetes Mellitus

Severe hyperglycemia, sometimes associated with ketoacidosis, hyperosmolar coma, or death, reported in patients receiving atypical antipsychotic agents.^{1 13 14 15 16 17 18 19 20 21 22 23 24 25 26 40 41 42 43 47} Closely monitor patients with preexisting diabetes mellitus for worsening of glucose control, and perform fasting glucose tests at baseline and periodically for patients with risk factors for diabetes (e.g., obesity, family history of diabetes).^{1 13 14 16 17 18 19 20 21 22 23 24 25} If manifestations of hyperglycemia occur, test for diabetes mellitus.^{1 13 14 16 17 18 19 20 21 22 23 24 25}

Sensitivity Reactions

Rash

Rash and/or urticaria, possibly related to dose and/or duration of therapy, reported.¹ Adjunctive treatment with antihistamines or steroids and/or drug discontinuance may be required.¹ Discontinue ziprasidone if alternative etiology of rash cannot be identified.¹

General Precautions

Cardiovascular Effects

Orthostatic hypotension reported, particularly during initial dosage titration period.¹ Use with caution in patients with known cardiovascular or cerebrovascular disease and/or conditions that would predispose patients to hypotension (e.g., dehydration, hypovolemia, concomitant antihypertensive therapy).¹

Nervous System Effects

Possible risk of seizures;¹ use with caution in patients with a history of seizures or with conditions known to lower the seizure threshold (e.g., dementia of the Alzheimer’s type, geriatric patients).¹

Disruption of ability to reduce core body temperature possible; use caution in patients exposed to conditions that may contribute to an elevation in core body temperature (e.g., dehydration, extreme heat, strenuous exercise, concomitant use of anticholinergic agents).¹

Somnolence reported.¹ Potential impairment of judgment, thinking, or motor skills.¹

GI Effects

Esophageal dysmotility and aspiration possible; use with caution in patients at risk for aspiration pneumonia (e.g., geriatric patients, those with advanced Alzheimer’s dementia).¹ (See Boxed Warning and see Increased Mortality in Geriatric Patients with Dementia-related Psychosis under Cautions.)

Suicide

Attendant risk with psychotic illnesses; closely supervise high-risk patients.¹ Prescribe in the smallest quantity consistent with good patient management to reduce the risk of overdosage.¹

Sexual Dysfunction

Priapism possible.¹

Endocrine Effects

Elevated prolactin concentrations possible.⁷

Metabolic Effects

Weight gain possible.^{1 7} May cause less weight gain than clozapine, olanzapine, quetiapine, or risperidone.^{4 10 11 12}

Specific Populations

Pregnancy

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Category C.¹

Lactation

Not known whether ziprasidone is distributed into milk.¹ Women receiving ziprasidone should not breast-feed.¹

Pediatric Use

Safety and efficacy not established in children <18 years of age.¹

Geriatric Use

No substantial differences in safety of oral ziprasidone relative to younger adults.¹

Lower initial dosages, slower titration, and careful monitoring during the initial dosing period may be advisable in some geriatric patients.¹

IM ziprasidone mesylate not systematically evaluated in geriatric patients.¹

Possible increased risk of death in geriatric patients with dementia-related psychosis.^{1 68} Substantial (1.6- to 1.7-fold) increase in mortality rate reported in geriatric patients with dementia who received atypical antipsychotic agents (e.g., aripiprazole, olanzapine, quetiapine, risperidone) for treatment of behavioral disorders; most fatalities resulted from cardiac-related events (e.g., heart failure, sudden death) or infections (mostly pneumonia).^{1 68}

Atypical antipsychotics are not approved for the treatment of dementia-related psychosis.^{1 68} (See Boxed Warning and see Increased Mortality in Geriatric Patients with Dementia-related Psychosis under Cautions.)

Renal Impairment

Commercially available ziprasidone mesylate injections contain sulfobutylether β-cyclodextrin sodium, an excipient that is cleared by renal filtration; use with caution.¹

Common Adverse Effects

Oral therapy for schizophrenia: somnolence, respiratory tract infection.¹

Oral therapy for bipolar mania: somnolence, extrapyramidal symptoms, dizziness, akathisia, abnormal vision, asthenia, vomiting.^{1 73 74}

IM therapy for acute agitation in schizophrenia: somnolence, headache, nausea.¹

Interactions for Ziprasidone

Ziprasidone is metabolized by the CYP3A4 isoenzyme; CYP1A2 also may contribute but to a much lesser extent.¹ Little inhibitory effect on CYP isoenzymes 1A2, 2C9, 2C19, 2D6, or 3A4; pharmacokinetic interaction unlikely with drugs metabolized by these isoenzymes.¹

Drugs Affecting Hepatic Microsomal Enzymes

Potential pharmacokinetic interactions (altered metabolism) with inhibitors or inducers of CYP3A4.¹

Pharmacokinetic interaction with inhibitors or inducers of CYP1A2, CYP2C9, CYP2C19, or CYP2D6 are unlikely.¹

Drugs That Prolong QT Interval

Potential pharmacologic interaction (additive effect on QT interval prolongation; concomitant use contraindicated) when used with drugs that prolong the QT_c interval.¹ Ziprasidone also is contraindicated in patients receiving drugs shown to cause QT prolongation as an effect and for which this effect is described in the full prescribing information as a contraindication or a boxed or bolded warning.¹ (See Contraindications and Prolongation of QT Interval under Cautions.)

Specific Drugs

Drug	Interaction	Comments
Antacids	No effects on ziprasidone pharmacokinetics1
Antiarrhythmics (class Ia and III)	Increased risk of QT interval prolongation1	Concomitant use contraindicated1
Arsenic trioxide	Increased risk of QT interval prolongation1	Concomitant use contraindicated1
Benztropine	Pharmacokinetic interaction unlikely1
Carbamazepine	Increased ziprasidone metabolism1
Chlorpromazine	Increased risk of QT interval prolongation1	Concomitant use contraindicated1
Cimetidine	No change observed in ziprasidone pharmacokinetics1
CNS agents	Additive sedative effects12
Dextromethorphan	No change observed in dextromethorphan metabolism1
Dofetilide	Increased risk of QT interval prolongation1	Concomitant use contraindicated1
Dolasetron mesylate	Increased risk of QT interval prolongation1	Concomitant use contraindicated1
Dopamine agonists	Antagonistic effects1
Droperidol	Increased risk of QT interval prolongation1	Concomitant use contraindicated1
Gatifloxacin	Increased risk of QT interval prolongation1	Concomitant use contraindicated1
Halofantrine	Increased risk of QT interval prolongation1	Concomitant use contraindicated1
Hypotensive agents	Additive hypotensive effects1	Use with caution1
Ketoconazole	Increased plasma ziprasidone concentrations1
Levodopa	Antagonistic effects1
Levomethadyl acetate	Increased risk of QT interval prolongation1	Concomitant use contraindicated1
Lithium	No change observed in lithium clearance1
Lorazepam	Pharmacokinetic interaction unlikely1
Mefloquine	Increased risk of QT interval prolongation1	Concomitant use contraindicated1
Mesoridazine	Increased risk of QT interval prolongation1	Concomitant use contraindicated1
Moxifloxacin	Increased risk of QT interval prolongation1	Concomitant use contraindicated1
Oral contraceptives	No change observed in estradiol or levonorgestrel pharmacokinetics1
Pentamidine	Increased risk of QT interval prolongation1	Concomitant use contraindicated1
Pimozide	Increased risk of QT interval prolongation1	Concomitant use contraindicated1
Probucol	Increased risk of QT interval prolongation1	Concomitant use contraindicated1
Protein-bound drugs (e.g., propranolol, warfarin)	Pharmacokinetic interaction unlikely1
Quinidine	Increased risk of QT interval prolongation1	Concomitant use contraindicated1
Sotalol	Increased risk of QT interval prolongation1	Concomitant use contraindicated1
Sparfloxacin	Increased risk of QT interval prolongation1	Concomitant use contraindicated1
Tacrolimus	Increased risk of QT interval prolongation1	Concomitant use contraindicated1
Thioridazine	Increased risk of QT interval prolongation1	Concomitant use contraindicated1

Ziprasidone Pharmacokinetics

Absorption

Bioavailability

Absolute bioavailability is approximately 60% following a 20 mg oral dose under fed conditions.¹

Peak plasma concentrations occur 6–8 hours after oral administration or about 1 hour after IM injection.¹

Food

Food increases the absorption up to twofold.¹

Distribution

Extent

Not known whether the drug is distributed into milk in humans.¹

Plasma Protein Binding

>99% bound to plasma proteins, principally to albumin and α₁-acid glycoprotein.¹

Elimination

Metabolism

Extensively metabolized in the liver principally via reduction by aldehyde oxidase; about one-third of metabolic clearance is mediated by CYP isoenzymes, principally CYP3A4.¹

Elimination Route

Approximately 20% of a dose is excreted in the urine and about 66% in feces, principally as metabolites.¹ Not removed by hemodialysis.¹

Half-life

Mean terminal half-life following oral administration is about 7 hours;¹ following IM administration, the half-life is 2–5 hours.¹

Special Populations

In patients with clinically important (Child-Pugh class A or B) cirrhosis, half-life increased by 2.3 hours compared with that of patients in the control group.¹

Stability

Storage

Oral

Capsules

15–30°C.¹

Parenteral

Powder for Injection

15–30°C.¹

Following reconstitution, store at 15–30°C protected from light for up to 24 hours or at 2–8°C for up to 7 days.¹

ActionsActions

• 
  

  Exact mechanism of antipsychotic action has not been fully elucidated; may involve antagonism of central type 2 serotonergic (5-HT₂) receptors and central dopamine D₂ receptors.^{1 8 9}

  
  


• 
  

  Precise mechanism of antimanic action has not been fully elucidated.¹

  
  


• 
  

  Antagonism of other receptors (e.g., histamine H₁ receptors, α₁-adrenergic receptors) may contribute to other therapeutic and adverse effects (e.g., orthostatic hypotension, somnolence).¹

  
  

Advice to Patients

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

• 
  

  Importance of taking medication exactly as prescribed by the clinician.¹

  
  


• 
  

  Importance of avoiding driving, operating machinery, or performing hazardous tasks until gain experience with the drug’s effects.¹

  
  


• 
  

  Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription or OTC drugs, dietary supplements, and herbal products, as well as any concomitant illnesses (e.g., diabetes mellitus, seizures, dementia).¹

  
  


• 
  

  Importance of avoiding alcohol during ziprasidone therapy.¹

  
  


• 
  

  Importance of avoiding overheating or dehydration.¹

  
  


• 
  

  Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.¹

  
  


• 
  

  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.

Ziprasidone Hydrochloride

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Capsules	20 mg	Geodon	Pfizer
		40 mg	Geodon	Pfizer
		60 mg	Geodon	Pfizer
		80 mg	Geodon	Pfizer

Ziprasidone Mesylate

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Parenteral	For injection, for IM use only	20 mg (of ziprasidone) per mL	Geodon (with sulfobutylether β-cyclodextrin sodium 294 mg/mL)	Pfizer

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 04/2011. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Geodon 20MG Capsules (PFIZER U.S.): 60/$478.01 or 180/$1402.96

Geodon 40MG Capsules (PFIZER U.S.): 60/$482.99 or 180/$1407.94

Geodon 60MG Capsules (PFIZER U.S.): 60/$574.97 or 180/$1687.92

Geodon 80MG Capsules (PFIZER U.S.): 60/$574.97 or 180/$1687.92

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 March 15, 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.

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41. Ananth J, Johnson KM, Levander EM et al. Diabetic ketoacidosis, neuroleptic malignant syndrome, and myocardial infarction in a patient taking risperidone and lithium carbonate. J Clin Psychiatry. 2004; 65:724. [IDIS 516345] [PubMed 15163265]

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44. Koro CE, Fedder DO, L’Italien GJ et al. Assessment of independent effect of olanzapine and risperidone on risk of diabetes among patients with schizophrenia: population based nested case-control study. BMJ. 2002; 325:243. [IDIS 485916] [PubMed 12153919]

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46. Anon. Which atypical antipsychotic for schizophrenia?. Drug Ther Bull. 2004; 42:57-60. [PubMed 15310154]

47. Anon. Atypical antipsychotics and hyperglycaemia. Aust Adv Drug React Bull. 2004; 23:11-2.

48. Sussman N. The implications of weight changes with antipsychotic treatment. J Clin Psychopharmacol. 2003; 23 (Suppl 1):S21-6.

49. Gianfrancesco F, Grogg A, Mahmoud R et al. Differential effects of antipsychotic agents on the risk of development of type 2 diabetes mellitus in patients with mood disorders. Clin Ther. 2003; 25:1150-71. [IDIS 497269] [PubMed 12809963]

50. Bushe C, Leonard B. Association between atypical antipsychotic agents and type 2 diabetes: review of prospective clinical data. Br J Psychiatry Suppl. 2004; 47:S87-93. [PubMed 15056600]

51. Cavazzoni P, Mukhopadhyay N, Carlson C et al. Retrospective analysis of risk factors in patients with treatment-emergent diabetes during clinical trials of antipsychotic medications. Br J Psychiatry Suppl. 2004; 47:s94-101. [PubMed 15056601]

52. Gianfrancesco FD, Grogg AL, Mahmoud RA et al. Differential effects of risperidone, olanzapine, clozapine, and conventional antipsychotics on type 2 diabetes: findings from a large health plan database. J Clin Psychiatry. 2002; 63:920-30. [IDIS 488480] [PubMed 12416602]

53. Etminan M, Streiner DL, Rochon PA. Exploring the association between atypical neuroleptic agents and diabetes mellitus in older adults. Pharmacotherapy. 2003; 23:1411-15. [IDIS 510498] [PubMed 14620387]

54. Leslie DL, Rosenheck RA. Incidence of newly diagnosed diabetes attributable to atypical antipsychotic medications. Am J Psychiatry. 2004; 161:1709-11. [IDIS 522186] [PubMed 15337666]

55. Sernyak MJ, Leslie DL, Alarcon RD et al. Association of diabetes mellitus with use of atypical neuroleptics in the treatment of schizophrenia. Am J Psychiatry. 2002; 159:561-6. [IDIS 494206] [PubMed 11925293]

56. Geller WK, MacFadden W. Diabetes and atypical neuroleptics. Am J Psychiatry. 2003; 160:388. [IDIS 513919] [PubMed 12562601]

57. Gianfrancesco FD. Diabetes and atypical neuroleptics. Am J Psychiatry. 2003; 160:388-9; author reply 389. [IDIS 513920] [PubMed 12562599]

58. Lamberti JS, Crilly JF, Maharaj K. Prevalence of diabetes mellitus among outpatients with severe mental disorders receiving atypical antipsychotic drugs. J Clin Psychiatry. 2004; 65:702-6. [IDIS 516341] [PubMed 15163259]

59. Lee DW, Fowler RB. Olanzapine/risperidone and diabetes risk. J Clin Psychiatry. 2003; 64:847-8; author reply 848. [IDIS 500324] [PubMed 12934988]

60. Reviewer Comments (personal observations).

61. Bristol-Myers Squibb., Princeton, NJ: Personal communication.

62. AstraZeneca. Wayne, PA: Personal communication.

63. Eli Lilly and Company. Indianapolis, IN: Personal communication.

64. Novartis Pharmaceuticals Corporation. East Hanover, NJ: Personal communication.

65. Janssen Pharmaceuticals. Titusville, NJ: Personal communicat

Zanaflex

Pronunciation: tye-ZAN-i-deen
Generic Name: Tizanidine
Brand Name: Zanaflex

Zanaflex is used for:

Treating muscle spasms. It may also be used for other conditions as determined by your doctor.

Zanaflex is a skeletal muscle relaxant. It works by blocking nerves that stimulate muscles to contract.

Do NOT use Zanaflex if:

• you are allergic to any ingredient in Zanaflex


• you are taking ciprofloxacin or fluvoxamine

Contact your doctor or health care provider right away if any of these apply to you.

Before using Zanaflex:

Some medical conditions may interact with Zanaflex. Tell your doctor or pharmacist if you have any medical conditions, especially if any of the following apply to you:

• if you are pregnant, planning to become pregnant, or are breast-feeding


• if you are taking any prescription or nonprescription medicine, herbal preparation, or dietary supplement


• if you have allergies to medicines, foods, or other substances


• if you have liver or kidney problems or prostate problems

Some MEDICINES MAY INTERACT with Zanaflex. Tell your health care provider if you are taking any other medicines, especially any of the following:

• Acyclovir, antiarrhythmics (eg, amiodarone, mexiletine, propafenone), cimetidine, famotidine, fluvoxamine, hormonal contraceptives (eg, birth control pills), quinolone antibiotics (eg, ciprofloxacin), ticlopidine, verapamil, or zileuton because they may increase the risk of Zanaflex's side effects

This may not be a complete list of all interactions that may occur. Ask your health care provider if Zanaflex may interact with other medicines that you take. Check with your health care provider before you start, stop, or change the dose of any medicine.

How to use Zanaflex:

Use Zanaflex as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• Take Zanaflex by mouth.


• Food can change the way your body absorbs and uses Zanaflex. Be sure to discuss this with your doctor to determine the best way to take your dose, especially when changes to your dose are being considered, or if you are being prescribed a different dose form of Zanaflex (eg, tablets or capsules).


• Do not suddenly stop taking Zanaflex. If you need to stop Zanaflex, your doctor will gradually lower your dose to prevent symptoms of withdrawal, including high blood pressure, fast heartbeat, tremor, anxiety, and muscle tension.


• If you miss a dose of Zanaflex, take it as soon as possible. If it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not take 2 doses at once.

Ask your health care provider any questions you may have about how to use Zanaflex.

Important safety information:

• Zanaflex may cause drowsiness, dizziness, lightheadedness, or fainting. These effects may be worse if you take it with alcohol or certain medicines. Use Zanaflex with caution. Do not drive or perform other possibly unsafe tasks until you know how you react to it.


• Do not drink alcohol or use medicines that may cause drowsiness (eg, sleep aids, muscle relaxers) while you are using Zanaflex; it may add to their effects. Ask your pharmacist if you have questions about which medicines may cause drowsiness.


• Zanaflex may cause dizziness, lightheadedness, or fainting; alcohol, hot weather, exercise, or fever may increase these effects. To prevent them, sit up or stand slowly, especially in the morning. Sit or lie down at the first sign of any of these effects.


• Do not switch between the tablet and capsule forms of Zanaflex unless your doctor tells you to. You may have an increased risk of side effects if you start to take one form and then switch to another. Check with your doctor or pharmacist before you take Zanaflex if you receive a different form than what you have previously been taking.


• Tell your doctor or dentist that you take Zanaflex before you receive any medical or dental care, emergency care, or surgery.


• Do not take more than the recommended dose or use for longer than prescribed without checking with your doctor.


• Lab tests, such as liver tests, may be performed while you use Zanaflex. These tests may be used to monitor your condition or check for side effects. Be sure to keep all doctor and lab appointments.


• Use Zanaflex with caution in the ELDERLY; they may be more sensitive to its effects.


• Zanaflex should not be used in CHILDREN; safety and effectiveness in children have not been confirmed.


• PREGNANCY and BREAST-FEEDING: It is not known if Zanaflex can cause harm to the fetus. If you become pregnant, contact your doctor. You will need to discuss the benefits and risks of using Zanaflex while you are pregnant. It is not known if Zanaflex is found in breast milk. If you are or will be breast-feeding while you use Zanaflex, check with your doctor. Discuss any possible risks to your baby.

Possible side effects of Zanaflex:

All medicines may cause side effects, but many people have no, or minor side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome:

Constipation; dizziness; drowsiness; dry mouth; flushing; tiredness; weakness.

Seek medical attention right away if any of these SEVERE side effects occur:

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); change in emotions, mood, or behavior; hallucinations; increased muscle spasms; muscle weakness; slow heartbeat; trouble urinating or lack of bladder control; urinary tract infection; yellowing of the skin or eyes.

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

See also: Zanaflex side effects (in more detail)

If OVERDOSE is suspected:

Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center (http://www.aapcc.org ), or emergency room immediately. Symptoms may include fainting; loss of consciousness; severe drowsiness; trouble breathing.

Proper storage of Zanaflex:

Store Zanaflex at 77 degrees F (25 degrees C). Brief storage at temperatures between 59 and 86 degrees F (15 and 30 degrees C) is permitted. Store away from heat, moisture, and light. Do not store in the bathroom. Keep Zanaflex out of the reach of children and away from pets.

General information:

• If you have any questions about Zanaflex, please talk with your doctor, pharmacist, or other health care provider.


• Zanaflex is to be used only by the patient for whom it is prescribed. Do not share it with other people.


• If your symptoms do not improve or if they become worse, check with your doctor.


• Check with your pharmacist about how to dispose of unused medicine.

This information is a summary only. It does not contain all information about Zanaflex. If you have questions about the medicine you are taking or would like more information, check with your doctor, pharmacist, or other health care provider.

Issue Date: February 1, 2012

Database Edition 12.1.1.002

Copyright © 2012 Wolters Kluwer Health, Inc.

More Zanaflex resources

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

• Zanaflex Prescribing Information (FDA)


• Zanaflex Consumer Overview


• Zanaflex Monograph (AHFS DI)


• Zanaflex Advanced Consumer (Micromedex) - Includes Dosage Information


• Tizanidine Prescribing Information (FDA)

Compare Zanaflex with other medications

• Cluster Headaches
• Muscle Spasm

Exelon Patch

Generic Name: rivastigmine

Dosage Form: patch, extended release
FULL PRESCRIBING INFORMATION

 INDICATIONS AND USAGE

Alzheimer’s Disease

Exelon Patch (rivastigmine transdermal system) is indicated for the treatment of mild to moderate dementia of the Alzheimer’s type.

Parkinson’s Disease Dementia

Exelon Patch (rivastigmine transdermal system) is indicated for the treatment of mild to moderate dementia associated with Parkinson’s disease.

The dementia of Parkinson’s disease is purportedly characterized by impairments in executive function, memory retrieval, and attention in patients with an established diagnosis of Parkinson’s disease. The diagnosis of dementia of Parkinson’s disease can be made reliably in patients in whom a progressive dementia syndrome occurs (without the necessity to document the specific deficits described above) at least 2 years after a diagnosis of Parkinson’s disease has been made, and in whom other causes of dementia have been ruled out.

 DOSAGE AND ADMINISTRATION

Alzheimer’s Disease

Table 1: Patch Size, Drug Content and Nominal Delivery Rate

Rivastigmine Nominal Dose	Rivastigmine Content per Exelon Patch	Exelon Patch Size
4.6 mg/24 hours	9 mg	5 cm2
9.5 mg/24 hours	18 mg	10 cm2

Initial Dose

Treatment is started with Exelon Patch 4.6 mg/24 hours.

After a minimum of 4 weeks of treatment and if well tolerated, this dose should be increased to Exelon Patch 9.5 mg/24 hours, which is the recommended effective dose.

Maintenance Dose

Dose increases should occur only after a minimum of 4 weeks at the previous dose, and only if the previous dose has been well tolerated. The maximum recommended dose is 9.5 mg/24 hours. Higher doses confer no appreciable additional benefit, and are associated with significant increase in the incidence of adverse events [see Adverse Reactions (6)].

If adverse effects (e.g., nausea, vomiting, diarrhea, loss of appetite) cause intolerance during treatment, the patient should be instructed to discontinue treatment for three or more days and then restart at the same or next lower dose level. If treatment is interrupted for longer than three days, treatment should be reinitiated with the lowest daily dose and titrated as described above [also see Warnings and Precautions (5)].

Switching from Capsules or Oral Solution

Patients treated with Exelon capsules or oral solution may be switched to Exelon Patch as follows:

A patient who is on a total daily dose of <6 mg of oral rivastigmine can be switched to Exelon Patch 4.6 mg/24 hours.

A patient who is on a total daily dose of 6-12 mg of oral rivastigmine may be directly switched to Exelon Patch 9.5 mg/24 hours.

It is recommended to apply the first patch on the day following the last oral dose.

Method of Administration

Exelon Patch is intended for transdermal use (on intact skin) only. The patch should not be used if the pouch seal is broken or the patch is cut, damaged, or changed in any way.

Exelon Patch should be applied once a day to clean, dry, hairless, intact healthy skin in a place that will not be rubbed against by tight clothing. The upper or lower back is recommended as the site of application because the patch is less likely to be removed by the patient; however, when sites on the back are not accessible the patch can be applied to the upper arm or chest. The patch should not be applied to skin that is red, irritated, or cut. It is recommended that the site of patch application be changed daily to avoid potential irritation, although consecutive patches can be applied to the same anatomic site (e.g., another spot on the upper back).

The patch should be pressed down firmly until the edges stick well. The patch can be used in situations that include bathing and hot weather.

The patch should be replaced with a new one every 24 hours. Only one patch should be worn at a time [see Overdosage (10)].  Do not apply a new patch to that same spot for at least 14 days. The previous day’s patch must be removed before applying a new patch. Patients and caregivers should be instructed accordingly [see Patient Counseling Information (17)].

Used patches should be placed in the previously saved pouch and discarded safely in the trash, away from pets or children.

Incompatibilities

To prevent interference with the adhesive properties of the patch, the patch should not be applied to a skin area where cream, lotion or powder has recently been applied.

Special Populations

Hepatic Impairment

Dosage adjustment is not necessary in hepatically impaired patients, as the dose of drug is individually titrated to tolerability.

Renal Impairment

No dose adjustment is necessary for patients with renal impairment.

Low Body Weight

Patients with body weight below 50 kg may experience more adverse events and may be more likely to discontinue due to adverse events. Particular caution should be exercised in titrating these patients above the recommended maintenance dose of Exelon Patch 9.5 mg/24 hours.

Parkinson’s Disease Dementia

See Dosage and Administration (2.1).

 DOSAGE FORMS AND STRENGTHS

Dosage Form

Patch.

Each patch is a thin, matrix-type transdermal system consisting of three layers when worn by the patient. A fourth layer, the release liner, covers the adhesive layer prior to use and is removed at the time the system is applied to the skin.

The outside of the backing layer is beige and labeled for each dose as follows:

- “EXELON® PATCH “4.6 mg/24 hours” and “AMCX”

- “EXELON® PATCH “9.5 mg/24 hours” and “BHDI”

Dosage Strengths

Table 1 summarizes the available strengths and quantity of rivastigmine provided in each patch:

• Each 5 cm2 patch contains 9 mg rivastigmine base, with in-vivo release rate of 4.6 mg/24 hours.
  
  


• Each 10 cm2 patch contains 18 mg rivastigmine base, with in-vivo release rate of 9.5 mg/24 hours.

For a full list of excipients, see Description (11).

 CONTRAINDICATIONS

Hypersensitivity

Exelon Patch (rivastigmine transdermal system) is contraindicated in patients with known hypersensitivity to rivastigmine, other carbamate derivatives, or other components of the formulation [see Description (11)].

 WARNINGS AND PRECAUTIONS

 Medication Errors Resulting in Overdose 

Medication errors with Exelon Patches have resulted in serious adverse events; some cases have required hospitalization, and rarely, led to death. The majority of medication errors have involved not removing the old patch when putting on a new one and the use of multiple patches at one time. Patients and caregivers must be given proper instruction on the dosage and administration of Exelon Patches.

Gastrointestinal Adverse Reactions

At higher than recommended doses, Exelon Patch (rivastigmine transdermal system) use is associated with significant gastrointestinal adverse reactions, including nausea, vomiting, diarrhea, anorexia/decreased appetite and weight loss. For this reason, patients administered Exelon Patch should always be started at a dose of 4.6 mg/24 hours and titrated to the maintenance dose of 9.5 mg/24 hours. If treatment is interrupted for longer than three days, treatment should be reinitiated with the lowest daily dose [see Dosage and Administration (2)] to reduce the possibility of severe vomiting and its potentially serious sequelae (e.g., there has been one post-marketing report of severe vomiting with esophageal rupture following inappropriate reinitiation of treatment with a 4.5-mg dose of an oral formulation after 8 weeks of treatment interruption).

At higher than recommended doses, caregivers should be advised of the high incidence of nausea and vomiting associated with the use of Exelon Patch along with the possibility of anorexia and weight loss. Caregivers should be encouraged to monitor for these adverse events and inform the physician if they occur. It is critical to inform caregivers that if therapy has been interrupted for more than three days, the next dose should not be administered until they have discussed this with the physician.

Nausea and Vomiting

In the controlled clinical trial, 7% of patients treated with Exelon Patch 9.5 mg/24 hours developed nausea, as compared to 23% of patients who received the Exelon capsule at doses up to 6 mg BID and 5% of those who received placebo. In the same clinical trial, 6% of patients treated with Exelon Patch 9.5 mg/24 hours developed vomiting, as compared with 17% of patients who received the Exelon capsule at doses up to 6 mg BID and 3% of those who received placebo. The proportion of patients who discontinued treatment on account of vomiting was 0% of the patients who received Exelon Patch 9.5 mg/24 hours as well as 2% of patients who received the Exelon capsule at doses up to 6 mg BID and 0% of those who received placebo. Vomiting was severe in 0% of patients who received Exelon Patch 9.5 mg/24 hours and 1% of patients who received the Exelon capsule at doses up to 6 mg BID and 0% of those who received placebo.

In the same clinical trial, 21% of patients treated with the higher dose of Exelon Patch 17.4 mg/24 hours developed nausea, 19% developed vomiting, and the proportion of these patients who discontinued treatment on account of vomiting was 2%. Vomiting was severe in 1% of patients treated with Exelon Patch 17.4 mg/24 hours.

Weight Loss

In the controlled clinical trial, the proportion of patients who had weight loss equal to or greater than 7% of their baseline weight was 8% of those treated with Exelon Patch 9.5 mg/24 hours, 11% of patients who received the Exelon capsule at doses up to 6 mg BID and 6% of those who received placebo.

In the same clinical trial, 12% of those treated with 17.4 mg/24 hours had weight loss equal to or greater than 7% of their baseline weight. It is not clear how much of the weight loss was associated with anorexia, nausea, vomiting, and the diarrhea associated with the drug.

Diarrhea

In the controlled clinical trial, 6% of patients treated with Exelon Patch 9.5 mg/24 hours developed diarrhea, as compared with 5% of patients who received the Exelon capsule at doses up to 6 mg BID, 10% of those treated with 17.4 mg/24 hours and 3% of those who received placebo.

Anorexia/Decreased Appetite

In the controlled clinical trial, 3% of patients treated with Exelon Patch 9.5 mg/24 hours were recorded as developing decreased appetite or anorexia, as compared with 9% of patients who received the Exelon capsule at doses up to 6 mg BID, 9% of those treated with Exelon Patch 17.4 mg/24 hours and 2% of those who received placebo.

Peptic Ulcers/Gastrointestinal Bleeding

Because of their pharmacological action, cholinesterase inhibitors may be expected to increase gastric acid secretion due to increased cholinergic activity. Therefore, patients should be monitored closely for symptoms of active or occult gastrointestinal bleeding, especially those at increased risk for developing ulcers, e.g., those with a history of ulcer disease or those receiving concurrent nonsteroidal anti-inflammatory drugs (NSAIDs). Clinical studies of Exelon have shown no significant increase, relative to placebo, in the incidence of either peptic ulcer disease or gastrointestinal bleeding.

Anesthesia

Exelon, as a cholinesterase inhibitor, is likely to exaggerate succinylcholine-type muscle relaxation during anesthesia.

Cardiovascular Conditions

Drugs that increase cholinergic activity may have vagotonic effects on heart rate (e.g., bradycardia). The potential for this action may be particularly important to patients with sick sinus syndrome or other supraventricular cardiac conduction conditions. In clinical trials, Exelon was not associated with any increased incidence of cardiovascular adverse events, heart rate or blood pressure changes, or ECG abnormalities.

Genitourinary Conditions

Although this was not observed in clinical trials of Exelon, drugs that increase cholinergic activity may cause urinary obstruction.

Neurological Conditions

Seizures

Drugs that increase cholinergic activity are believed to have some potential for causing seizures. However, seizure activity also may be a manifestation of Alzheimer's disease.

Extrapyramidal Symptoms

Like other cholinomimetics, rivastigmine may exacerbate or induce extrapyramidal symptoms. Worsening of parkinsonian symptoms, particularly tremor, has been observed in patients with dementia associated with Parkinson’s disease who were treated with Exelon capsules.

Pulmonary Conditions

Like other drugs that increase cholinergic activity, Exelon should be used with care in patients with a history of asthma or obstructive pulmonary disease.

Effects on Ability to Drive and Use Machines

Dementia may cause gradual impairment of driving performance or compromise the ability to use machinery. The administration of rivastigmine may also result in adverse events that are detrimental to these functions. Thus, the ability to continue driving or operating machinery should be routinely evaluated by the treating physician.

Special Populations

Low Body Weight

Patients with body weight below 50 kg may experience more adverse events and may be more likely to discontinue due to adverse events. Particular caution should be exercised in titrating these patients above the recommended maintenance dose of the Exelon Patch 9.5 mg/24 hours.

 ADVERSE REACTIONS

Significant gastrointestinal adverse reactions including nausea, vomiting, anorexia, and weight loss have been reported with the Exelon Patch at higher than recommended doses [see Warnings and Precautions (5.1)].

Incidence in Controlled Clinical Trial in Alzheimer’s Disease

Associated with Discontinuation of Treatment

In the single controlled clinical trial of Exelon Patch [see Clinical Studies (14)], which randomized a total of 1195 patients, the proportions of patients in the Exelon Patch 9.5 mg/24 hours, Exelon Patch 17.4 mg/24 hours, Exelon capsules 6 mg BID, and placebo groups who discontinued treatment due to adverse events were 9.6%, 8.6%, 8.1%, and 5.0%, respectively.

The most common adverse events in the Exelon Patch-treated groups that led to treatment discontinuation in this study were nausea and vomiting. The proportions of patients who discontinued treatment due to nausea were 0.7%, 1.7%, 1.7%, and 1.3% in the Exelon Patch 9.5 mg/24 hours, Exelon Patch 17.4 mg/24 hours, Exelon capsules 6 mg BID, and placebo groups, respectively. The proportions of patients who discontinued treatment due to vomiting were 0%, 1.7%, 2.0%, and 0.3% in the Exelon Patch 9.5 mg/24 hours, Exelon Patch 17.4 mg/24 hours, Exelon capsules 6 mg BID, and placebo groups, respectively.

Most Commonly Observed Adverse Events

The most commonly observed adverse events seen in patients administered Exelon Patch in the controlled clinical trial, defined as those occurring at a frequency of at least 5% in the 9.5 mg/24 hours group and at a frequency at least as high as in the placebo group are largely predicted by the cholinergic effects of Exelon. These are nausea, vomiting, and diarrhea. All these events were more common at the higher Exelon Patch dose of 17.4 mg/24 hours than at a dose of 9.5 mg/24 hours.

Adverse Events Observed at an Incidence of ≥2%

The following table lists treatment-emergent adverse events that were seen at an incidence of ≥2% in either Exelon Patch-treated group in the controlled clinical trial and for which the rate of occurrence was greater for patients treated with that dose of Exelon Patch than for those treated with placebo. The prescriber should be aware that these frequencies cannot be used to predict the frequency of adverse events in the course of usual medical practice when patient characteristics and other factors may differ from those prevailing during clinical studies. Similarly, the cited frequencies cannot be directly compared with frequencies obtained from other clinical investigations involving different treatments, uses, or investigators. An inspection of these frequencies, however, does provide the prescriber with one basis by which to estimate the relative contribution of drug and non-drug factors to the adverse event incidences in the population studied.

Table 2: Adverse Events Observed with a Frequency of ≥2% and Occurring with a Rate Greater Than Placebo

	Exelon Patch 9.5 mg/ 24 hours n (%)	Exelon Patch 17.4 mg/ 24 hours n (%)	Exelon capsule 6 mg BID n (%)	Placebo n (%)
Total Patients Studied	291	303	294	302
Total Number of Patients with AEs	147 (51)	200 (66)	186 (63)	139 (46)
Nausea	21 (7)	64 (21)	68 (23)	15 (5)
Vomiting	18 (6)	57 (19)	50 (17)	10 (3)
Diarrhea	18 (6)	31 (10)	16 (5)	10 (3)
Depression	11 (4)	12 (4)	13 (4)	4 (1)
Headache	10 (3)	13 (4)	18 (6)	5 (2)
Anxiety	9 (3)	8 (3)	5 (2)	4 (1)
Anorexia/ Decreased Appetite	9 (3)	27 (9)	26 (9)	6 (2)
Weight Decreased	8 (3)	23 (8)	16 (5)	4 (1)
Dizziness	7 (2)	21 (7)	22 (7)	7 (2)
Abdominal Pain	7 (2)	11 (4)	4 (1)	2 (1)
Urinary Tract Infection	6 (2)	5 (2)	4 (1)	3 (1)
Asthenia	5 (2)	9 (3)	17 (6)	3 (1)
Fatigue	5 (2)	7 (2)	2 (1)	4 (1)
Insomnia	4 (1)	12 (4)	6 (2)	6 (2)
Abdominal Pain Upper	3 (1)	8 (3)	6 (2)	6 (2)
Vertigo	0 (0)	7 (2)	4 (1)	3 (1)

Incidence of Application Site Reactions

The vast majority of patients participating in the controlled clinical trial had either no observed skin irritation or mild to moderate skin reactions. Among the skin reactions reported were the following: application site reactions, application site dermatitis, application site irritation and application site eczema. The incidence of severe reactions was very low regardless of administered dosage.

 Other Adverse Events Observed During Clinical Trials

Exelon Patch has been administered to 1071 patients with Alzheimer’s disease during clinical trials worldwide. Of these, 869 patients have been treated for at least 3 months, 706 patients have been treated for at least 6 months, and 212 patients have been treated for 1 year.

Treatment-emergent signs and symptoms that occurred during 1 controlled and 4 open-label trials in North America, Europe, Latin America, Asia and Japan were recorded as adverse events by the clinical investigators using terminology of their own choosing.

To provide an overall estimate of the proportion of individuals having similar types of events, the events were grouped into a smaller number of standardized categories using the MedDRA dictionary, and event frequencies were calculated across all studies. These categories are used in the listing below. The frequencies represent the proportion of 1071 patients from these trials who experienced that event while receiving Exelon Patch. All patch doses are pooled.

All adverse events occurring in at least 1 patient (approximately 0.1%) are included, except for those already listed elsewhere in labeling, too general to be informative, or relatively minor events.

Events are classified by system organ class and listed using the following definitions: Frequent – those occurring in at least 1/100 patients; Infrequent – those occurring in 1/100 to 1/1000 patients. These adverse events are not necessarily related to Exelon Patch treatment and in most cases were observed at a similar frequency in placebo-treated patients in the controlled studies.

Blood and Lymphatic System Disorders: Frequent: Anemia.

Cardiac Disorders: Infrequent: Angina pectoris, cardiac failure, bradycardia, atrial fibrillation, supraventricular extrasystoles, myocardial infarction, tachycardia, arrhythmia, atrioventricular block.

Ear and Labyrinth Disorders: Infrequent: Tinnitus.

Eye Disorders: Infrequent: Cataract, glaucoma, vision blurred.

Gastrointestinal System: Frequent: Constipation, gastritis. Infrequent: Gastroesophageal reflux disease, hematochezia, peptic ulcer, hematemesis, pancreatitis, salivary hypersecretion.

General Disorders and Administration Site Conditions: Infrequent: Application site dermatitis, application site irritation, peripheral edema, chest pain, application site eczema, hyperpyrexia.

Hepatobiliary Disorders: Infrequent: Cholecystitis.

Infections and Infestations: Frequent: Nasopharyngitis, pneumonia. Infrequent: Diverticulitis.

Injury, Poisoning and Procedural Complications: Frequent: Fall. Infrequent: Hip fracture, subdural hematoma.

Investigations: Infrequent: Blood creatine phosphokinase increased, lipase increased, blood amylase increased, electrocardiogram QT prolonged.

Metabolic and Nutritional Disorders: Frequent: Dehydration. Infrequent: Hyperlipidemia, hypokalemia, hyponatremia.

Musculoskeletal and Connective Tissue Disorders: Infrequent: Arthralgia, muscle spasms, myalgia.

Nervous System Disorders: Frequent: Tremor. Infrequent: Migraine, parkinsonism, epilepsy.

Psychiatric Disorders: Infrequent: Delusion.

Renal and Urinary Disorders: Frequent: Urinary incontinence. Infrequent: Pollakiuria, hematuria, nocturia, renal failure.

Reproductive System and Breast Disorders: Infrequent: Benign prostatic hyperplasia.

Respiratory, Thoracic, and Mediastinal Disorders: Infrequent: Dyspnea, bronchospasm, chronic obstructive pulmonary disease.

Skin and Subcutaneous Tissue Disorders: Frequent: Pruritus. Infrequent: Erythema, eczema, dermatitis, rash erythematous, skin ulcer.

Vascular Disorders: Infrequent: Hypotension.

Post-Introduction Reports

The following additional adverse reactions have been identified based on post-marketing spontaneous reports and are not listed above. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. 

Hypertension, application site hypersensitivity, urticaria, blister, dermatitis allergic, seizure, worsening of Parkinson’s disease in patients with Parkinson’s disease who were treated with Exelon Patches.

Additional Adverse Reactions Reported

The following additional adverse reactions have been observed with Exelon capsules/oral solution.

Confusion, abnormal liver function tests, duodenal ulcers.

DRUG INTERACTIONS

No specific interaction studies have been conducted with Exelon Patch (rivastigmine transdermal system).

Effect of Exelon on the Metabolism of Other Drugs

Rivastigmine is primarily metabolized through hydrolysis by esterases. Minimal metabolism occurs via the major cytochrome P450 isoenzymes. Based on in-vitro studies, no pharmacokinetic drug interactions with drugs metabolized by the following isoenzyme systems are expected: CYP1A2, CYP2D6, CYP3A4/5, CYP2E1, CYP2C9, CYP2C8, or CYP2C19.

No pharmacokinetic interaction was observed between rivastigmine taken orally and digoxin, warfarin, diazepam or fluoxetine in studies in healthy volunteers. The increase in prothrombin time induced by warfarin is not affected by administration of rivastigmine.

Effect of Other Drugs on the Metabolism of Exelon

Drugs that induce or inhibit CYP450 metabolism are not expected to alter the metabolism of rivastigmine.

Population PK analysis with a database of 625 patients showed that the pharmacokinetics of rivastigmine taken orally were not influenced by commonly prescribed medications such as antacids (n=77), antihypertensives (n=72), ß-blockers (n=42), calcium channel blockers (n=75), antidiabetics (n=21), nonsteroidal anti-inflammatory drugs (n=79), estrogens (n=70), salicylate analgesics (n=177), antianginals (n=35) and antihistamines (n=15).

Use with Anticholinergics, Cholinomimetics and Other Cholinesterase Inhibitors

In view of its pharmacodynamic effects, rivastigmine should not be given concomitantly with other cholinomimetic drugs and might interfere with the activity of anticholinergic medications. A synergistic effect may be expected when cholinesterase inhibitors are given concurrently with succinylcholine, similar neuromuscular blocking agents or cholinergic agonists such as bethanechol.

 USE IN SPECIFIC POPULATIONS

Pregnancy

Pregnancy Category B

There are no adequate or well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, Exelon Patch should be used during pregnancy only if the potential benefit outweighs the potential risk to the fetus. No dermal reproduction studies in animals have been conducted. Oral reproduction studies conducted in pregnant rats at doses up to 2.3 mg base/kg/day and in pregnant rabbits at doses up to 2.3 mg base/kg/day revealed no evidence of teratogenicity. Studies in rats showed slightly decreased fetal/pup weights, usually at doses causing some maternal toxicity.

Nursing Mothers

Milk transfer studies in animals have not been conducted with dermal rivastigmine. In rats given rivastigmine orally, concentrations of rivastigmine plus metabolites were approximately two times higher in milk than in plasma. It is not known whether rivastigmine is excreted in human breast milk. Exelon Patch (rivastigmine transdermal system) has no indication for use in nursing mothers.

Pediatric Use

There are no adequate and well-controlled trials documenting the safety and efficacy of Exelon in any illness occurring in children.

Geriatric Use

Age had no impact on the exposure to rivastigmine in Alzheimer’s disease patients treated with Exelon Patch.

Hepatic Disease 

No pharmacokinetic study was conducted with Exelon Patch in subjects with hepatic impairment. Following a single 3-mg dose, mean oral clearance of rivastigmine was 60% lower in hepatically impaired patients (n=10, biopsy proven) than in healthy subjects (n=10). After multiple 6-mg BID oral dosing, the mean clearance of rivastigmine was 65% lower in mild (n=7, Child-Pugh score 5-6) and moderate (n=3, Child-Pugh score 7-9) hepatically impaired patients (biopsy proven, liver cirrhosis) than in healthy subjects (n=10). Dosage adjustment is not necessary in hepatically impaired patients as the dose of drug is individually titrated to tolerability.

Renal Disease 

No study was conducted with Exelon Patch in subjects with renal impairment. Following a single 3-mg dose, mean oral clearance of rivastigmine is 64% lower in moderately impaired renal patients (n=8, GFR=10-50 mL/min) than in healthy subjects (n=10, GFR≥60 mL/min); Cl/F=1.7 L/min (cv=45%) and 4.8 L/min (cv=80%), respectively. In severely impaired renal patients (n=8, GFR<10 mL/min), mean oral clearance of rivastigmine is 43% higher than in healthy subjects (n=10, GFR≥60 mL/min); Cl/F=6.9 L/min and 4.8 L/min, respectively. For unexplained reasons, the severely impaired renal patients had a higher clearance of rivastigmine than moderately impaired patients. However, dosage adjustment may not be necessary in renally impaired patients as the dose of the drug is individually titrated to tolerability.

Low Body Weight

Rivastigmine exposure is higher in subjects with low body weight. Compared to a patient with a body weight of 65 kg, the rivastigmine steady-state concentrations in a patient with a body weight of 35 kg would be approximately doubled, while for a patient with a body weight of 100 kg the concentrations would be approximately halved. This suggests special attention should be given to patients with very low body weight during up-titration [see Dosage and Administration (2)].

Gender and Race

No specific pharmacokinetic study was conducted to investigate the effect of gender and race on the disposition of Exelon, but a population pharmacokinetic analysis indicates that gender (n=277 males and 348 females) and race (n=575 White, 34 Black, 4 Asian, and 12 Other) did not affect the clearance of Exelon administered orally. Similar results were seen with analyses of pharmacokinetic data obtained after the administration of Exelon Patch.

Nicotine Use

Population pharmacokinetic analysis showed that nicotine use increases the oral clearance of rivastigmine by 23% (n=75 Smokers and 549 Nonsmokers). No dose adjustment is necessary as the dose of the drug is individually titrated to tolerability.

 OVERDOSAGE

Because strategies for the management of overdose are continually evolving, it is advisable to contact a Poison Control Center to determine the latest recommendations for the management of an overdose of any drug. As in any case of overdose, general supportive measures should be utilized.

As rivastigmine has a plasma half-life of about 3.4 hours after patch administration and a duration of acetylcholinesterase inhibition of about 9 hours, it is recommended that in cases of asymptomatic overdose the patch should be immediately removed and no further patch should be applied for the next 24 hours.

As in any case of overdose, general supportive measures should be utilized. Overdosage with cholinesterase inhibitors can result in cholinergic crisis characterized by severe nausea, vomiting, salivation, sweating, bradycardia, hypotension, respiratory depression, collapse and convulsions. Increasing muscle weakness is a possibility and may result in death if respiratory muscles are involved. Atypical responses in blood pressure and heart rate have been reported with other drugs that increase cholinergic activity when coadministered with quaternary anticholinergics such as glycopyrrolate. Due to the short plasma elimination half-life of rivastigmine after patch administration, dialysis (hemodialysis, peritoneal dialysis, or hemofiltration) would not be clinically indicated in the event of an overdose.

In overdose accompanied by severe nausea and vomiting, the use of antiemetics should be considered. In a documented case of an oral 46-mg overdose with Exelon, the patient experienced vomiting, incontinence, hypertension, psychomotor retardation, and loss of consciousness. The patient fully recovered within 24 hours and conservative management was all that was required for treatment.

Overdose with Exelon Patch has been reported in the post-marketing setting. Overdoses have occurred due to application of more than one patch at one time and not removing the previous day’s patch before applying a new patch. The symptoms reported in these overdose cases are similar to those seen in cases of overdose associated with Exelon oral formulations.

 DESCRIPTION

Exelon Patch (rivastigmine transdermal system) is a reversible cholinesterase inhibitor and is known chemically as (S)- 3-[1-(dimethylamino) ethyl]phenyl ethylmethylcarbamate. It has an empirical formula of C14H22N2O2 as the base and a molecular weight of 250.34 (as the base). Rivastigmine is a viscous, clear, and colorless to yellow to very slightly brown liquid that is sparingly soluble in water and very soluble in ethanol, acetonitrile, n-octanol and ethyl acetate.

The distribution coefficient at 37°C in n-octanol/phosphate buffer solution pH 7 is 4.27.

Exelon Patch is for transdermal administration. The patch comprises a four-layer laminate containing the backing layer, drug matrix, adhesive matrix and overlapping release liner. The release liner is removed and discarded prior to use. See Figure 1 for a detailed illustration.

Figure 1: Cross Section of the Patch

Layer 1	Backing Film
Layer 2	Drug Product (Acrylic) Matrix
Layer 3	Adhesive (Silicone) Matrix
Layer 4	Release Liner (removed at time of use)

Excipients within the formulation include acrylic copolymer, poly(butylmethacrylate, methylmethacrylate), silicone adhesive applied to a flexible polymer backing film, silicone oil, and vitamin E.

 CLINICAL PHARMACOLOGY

Mechanism of Action

Pathological changes in dementia of the Alzheimer’s type and dementia associated with Parkinson’s disease involve cholinergic neuronal pathways that project from the basal forebrain to the cerebral cortex and hippocampus. These pathways are thought to be intricately involved in memory, attention, learning, and other cognitive processes. While the precise mechanism of action for rivastigmine is unknown, it is postulated to exert its therapeutic effect by enhancing cholinergic function. This is accomplished by increasing the concentration of acetylcholine through reversible inhibition of its hydrolysis by cholinesterase. If this proposed mechanism is correct, the effect of rivastigmine may lessen as the disease process advances and fewer cholinergic neurons remain functionally intact. There is no evidence that rivastigmine alters the course of the underlying dementing process.

Pharmacodynamics

After a 6-mg oral dose of rivastigmine in humans, anticholinesterase activity is present in CSF for about 10 hours, with a maximum inhibition of about 60% 5 hours after dosing.

In-vitro and in-vivo studies demonstrate that the inhibition of cholinesterase by rivastigmine is not affected by the concomitant administration of memantine, an N-methyl-D-aspartate receptor antagonist.

Pharmacokinetics

Absorption

After the first dose, there is a lag time of 0.5-1 hour in the absorption of rivastigmine from Exelon Patch (rivastigmine transdermal system). Concentrations then rise slowly typically reaching a maximum after 8 hours, although maximum values (Cmax) are often reached at later times as well (10-16 hours). After the peak, plasma concentrations slowly decrease over the remainder of the 24-hour period of application. At steady state, trough levels are approximately 60-80% of peak levels. Fluctuation (between Cmax and Cmin) is lower for Exelon Patch than for the oral formulation. Exelon Patch 9.5 mg/24 hours exhibited exposure approximately the same as that provided by an oral dose of 6 mg twice daily (i.e., 12 mg/day).

Figure 2: Rivastigmine Plasma Concentrations Following Dermal 24-Hour Patch Application

Inter-subject variability in exposure was lower (43-49%) for the Exelon Patch formulation as compared with the oral formulations (73-103%).

A relationship between drug exposure at steady state (rivastigmine and metabolite NAP226-90) and body weight was observed in Alzheimer’s dementia patients. Compared to a patient with a body weight of 65 kg, the rivastigmine steady-state concentrations in a patient with a body weight of 35 kg are approximately doubled, while for a patient with a body weight of 100 kg the concentrations are approximately halved. The effect of body weight on drug exposure suggests special attention to patients with very low body weight during up-titration [see Dosage and Administration (2)].

Over a 24-hour dermal application, approximately 50% of the drug load is released from the system.

Exposure (AUC∞) to rivastigmine (and metabolite NAP266-90) was highest when the patch was applied to the upper back, chest, or upper arm. Two other sites (abdomen and thigh) could be used if none of the three other sites is available, but the practitioner should keep in mind that the rivastigmine plasma exposure associated with these sites was approximately 20-30% lower.

There was no relevant accumulation of rivastigmine or the metabolite NAP226-90 in plasma in patients with Alzheimer’s disease upon multiple dosing.

Distribution

Rivastigmine is weakly bound to plasma proteins (approximately 40%) over the therapeutic range. It readily crosses the blood-brain barrier, reaching CSF peak concentrations in 1.4-2.6 hours. It has an apparent volume of distribution in the range of 1.8-2.7 L/kg.

Metabolism

Rivastigmine is extensively metabolized primarily via cholinesterase-mediated hydrolysis to the decarbamylated metabolite NAP226-90. In-vitro, this metabolite shows minimal inhibition of acetylcholinesterase (<10%). Based on evidence from in-vitro and animal studies, the major cytochrome P450 isoenzymes are minimally involved in rivastigmine metabolism.

The metabolite-to-parent AUC∞ ratio was about 0.7 after Exelon Patch application versus 3.5 after oral administration, indicating that much less metabolism occurred after dermal treatment. Less NAP226-90 is formed following patch application, presumably because of the lack of presystemic (hepatic first pass) metabolism. Based on in-vitro studies, no unique metabolic routes were detected in human skin.

Elimination

Renal excretion of the metabolites is the major route of elimination. Unchanged rivastigmine is found in trace amounts in the urine. Following administration of 14C-rivastigmine, renal elimination was rapid and essentially complete (>90%) within 24 hours. Less than 1% of the administered dose is excreted in the feces. The apparent elimination half-life in plasma is approximately 3 hours after patch removal. Renal clearance was approximately

2.1-2.8 L/hr.

 NONCLINICAL TOXICOLOGY

Carcinogenesis, Mutagenesis, Impairment of Fertility

In oral carcinogenicity studies conducted at doses up to 1.1 mg base/kg/day in rats and 1.6 mg base/kg/day in mice, rivastigmine was not carcinogenic.

In a dermal carcinogenicity study conducted at doses up to 0.75 mg base/kg/day in mice, rivastigmine was not carcinogenic. The mean rivastigmine plasma exposure (AUC) at this dose was 0.3-0.4 times that observed in Alzheimer’s disease patients at the recommended clinical dose (one Exelon Patch 9.5 mg/24 hours).

Rivastigmine was clastogenic in two in-vitro assays in the presence, but not the absence, of metabolic activation. It caused structural chromosomal aberrations in V79 Chinese hamster lung cells and both structural and numerical (polyploidy) chromosomal aberrations in human peripheral blood lymphocytes. Rivastigmine was not genotoxic in three in-vitro assays: the Ames test, the unscheduled DNA synthesis (UDS) test in rat hepatocytes (a test for induction of DNA repair synthesis), and the HGPRT test in V79 Chinese hamster cells. Rivastigmine was not clastogenic in the in-vivo mouse micronucleus test.

No fertility or reproduction studies have been conducted in animals treated with dermal rivastigmine. Rivastigmine had no effect on fertility or reproductive performance in rats at oral doses up to 1.1 mg base/kg/day.

 CLINICAL STUDIES

The effectiveness of the Exelon Patch (rivastigmine transdermal system) in Alzheimer’s disease and dementia associated with Parkinson’s disease was based on the results of a single controlled trial in patients with Alzheimer’s disease (see below) as well as on three controlled trials of the immediate-release capsule in Alzheimer’s disease and one controlled trial in dementia associated with Parkinson’s disease (see package insert for the Exelon capsules and oral solution for details).

International 24-Week Study of Exelon Patch (rivastigmine transdermal system)

This was a randomized double-blind clinical investigation in patients with Alzheimer’s disease [diagnosed by NINCDS-ADRDA and DSM-IV criteria, Mini-Mental Status Examination (MMSE) score ≥10 and ≤20]. The mean age of patients participating in this trial was 74 years with a range of 50-90 years. Approximately 67% of patients were women and 33% were men. The racial distribution was Caucasian 75%, Black 1%, Oriental 9% and Other Races 15%.

Study Outcome Measures

The effectiveness of the Exelon Patch (rivastigmine transdermal system) was evaluated in this study using a dual outcome assessment strategy.

The ability of the Exelon Patch to improve cognitive performance was assessed with the cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS-Cog), a multi-item instrument that has been extensively validated in longitudinal cohorts of Alzheimer’s disease patients. The ADAS-Cog examines selected aspects of cognitive performance including elements of memory, orientation, attention, reasoning, language and praxis. The ADAS-Cog scoring range is from 0-70, with higher scores indicating greater cognitive impairment. Elderly normal adults may score as low as 0 or 1, but it is not unusual for non-demented adults to score slightly higher.

The ability of the Exelon Patch to produce an overall clinical effect was assessed using the Alzheimer’s Disease Cooperative Study - Clinical Global Impression of Change (ADCS-CGIC). The ADCS-CGIC is a more standardized form of CIBIC-Plus and is also scored as a seven-point categorical rating, ranging from a score of 1, indicating “markedly improved”, to a score of 4, indicating “no change” to a score of 7, indicating “marked worsening”.

Study Results

In this study, 1195 patients were randomized to one of the following 4 treatments: Exelon Patch 9.5 mg/24 hours, Exelon Patch 17.4 mg/24 hours, Exelon capsules in a dose of 6 mg BID, or placebo. This 24-week study was divided into a 16-week titration phase followed by an 8-week maintenance phase. In the active treatment arms of this study, doses below the target dose were permitted during the maintenance phase in the event of poor tolerability.

Effects on the ADAS-Cog

Figure 3 illustrates the time course for the change from baseline in ADAS-Cog scores for all 4 treatment groups over the 24-week study. At 24 weeks, the mean differences in the ADAS-Cog change scores for the Exelon-treated patients, compared to the patients on placebo, were 1.8, 2.9, and 1.8 units for the Exelon Patch 9.5 mg/24 hours, Exelon Patch 17.4 mg/24 hours, and Exelon capsule 6 mg BID groups, respectively. The difference between each of these groups and placebo was statistically significant.

Effects on the ADCS-CGIC

Figure 4 is a histogram of the distribution of patients’ scores on the ADCS-CGIC for all 4 treatment groups.

At 24 weeks, the mean difference in the ADCS-CGIC scores for the comparison of patients in each of the Exelon-treated groups with the patients on placebo was 0.2 units. The difference between each of these groups and placebo was statistically significant.

Observed at Each Time Point

Figure 4: Distribution of ADCS-CGIC Scores for Patients Completing the Study

 HOW SUPPLIED/STORAGE AND HANDLING

Patch 4.6 mg/24 hours

Each patch of 5 cm2 contains 9 mg rivastigmine base with in-vivo release rate of 4.6 mg/24 hours.

Carton of 30………………………NDC 0078-0501-15

Patch 9.5 mg/24 hours

Each patch of 10 cm2 contains 18 mg rivastigmine base with in-vivo release rate of 9.5 mg/24 hours.

Carton of 30………………………..NDC 0078-0502-15

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

Keep Exelon Patch (rivastigmine transdermal system) in the individual sealed pouch until use.

Used systems should be folded, with the adhesive surfaces pressed together, and discarded safely.

Each pouch contains one patch.

 PATIENT COUNSELING INFORMATION

 General

Patient information is printed in section 17.8. To assure safe and effective use of Exelon Patch, this information and instructions provided in the patient information secti