HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use
`GEODON safely and effectively. See full prescribing information for
`GEODON.
`
`GEODON® (ziprasidone HCl) capsules
`GEODON® (ziprasidone mesylate) injection for intramuscular use
`Initial U.S. Approval: 2001
`WARNING: INCREASED MORTALITY 1N ELDERLY PATIENTS
`WITH DEMENTIA-RELATED PSYCHOSIS
`Seefullprescribing injbrrmitionjbr complete boxed warning
`Elderly patients with dementia -rclated psychosis treated with
`antipsychotic drugs are at an increased risk of death compared to
`placebo treatment (5.1)
`-
`GEODON is not approved for elderly patients with dementia—
`
`related psychosis (5.1)
`
`0
`
`————————————————————————————RECENT MAJOR CHANGES—--————-—»———--————--————
`Warnings and Precautions (5.9)
`2/2017
`————————————————————————INDICATIONS AND USAGE———————————————————————————————
`GEODON is an atypical antipsychotic. In choosing among treatments,
`prescribers should be aware of the capacity ofGEODON to prolong the QT
`interval and may consider the use of other drugs first (5.2)
`GEODON is indicated as an oral formulation for the:
`Treatment of schizophrenia. (l .1)
`0
`Adults: Efficacy was established in four 4-6 week trials and one
`maintenance trial in adult patients with schizophrenia. (14.1)
`Acute treatment as monotherapy of manic or mixed episodes associated with
`bipolar l disorder. (1.2)
`0
`Adults: Efficacy was established in two 3—week trials in adult
`patients with manic or mixed episodes. (14.2)
`Maintenance treatment of bipolar l disorder as an adjunct to lithium or
`valproate. (1.2)
`0
`Adults: Efficacy was established in one maintenance trial in adult
`patients. (14.2)
`GEODON as an intramuscular injection is indicated for the.
`Acute treatment of agitation in schizophrenic patients. (1.3)
`I
`Adults. Efficacy was established in two short—term trials in agitated
`patients with schizophrenia. (l .3)
`----------------------DOSAGE AND ADMINISTRATION-----------------------
`Give oral doses with food.
`- Schizophrenia: Initiate at 20 mg twice daily. Daily dosage may be adjusted
`up to 80 mg twice daily. Dose adjustments should occur at intervals of not less
`than 2 days. Safety and efficacy has been demonstrated in doses up to 100 mg
`twice daily. The lowest effective dose should be used. (2.1)
`' Acute treatment ofmanic/niixed episodes of bipolar l disorder: Initiate at 40
`mg twice daily. Increase to 60 mg or 80 mg twice daily on day 2 of treatment.
`Subsequent dose adjustments should be based on tolerability and efficacy
`within the range of 40—80 mg twice daily. (22)
`- Maintenance treatment of bipolar I disorder as an adjunct to lithium or
`valproate. Continue treatment at the same dose on which the patient was
`initially stabili7ed, within the range of40—80 mg twice daily. (2.2)
`' Acute treatment of agitation associated with schizophrenia (intramuscular
`administration): 10 rug—20 mg up to a maximum dose of40 mg per day. Doses
`of 10 mg maybe administered every 2 hours. Doses of20 mg may be
`administered every 4 hours. ( 2.3)
`—————————————————————DOSAGE FORMS AND srRENGrHs
`O
`Capsules: 20 mg, 40 mg, 60 mg, and 80 mg (3)
`o
`Intramuscular injection: 20 mg/mL Single-use vials (5)
`———————————————————————————————CONTRAINDICATIONS-—-——-—————--—-———---———---———
`Do not use in patients with a known history of QT prolongation (4.1)
`Do not use in patients with recent acute myocardial infarction (4.1)
`Do not rise in patients with uncompensated heart failure (4.1)
`Do not use in combination with other drugs that have demonstrated QT
`prolongation (4.1)
`Do not use in patients with known hypersensitivity to ziprasidone (4.2)
`
`........................WARNINGS AND PRECAUTIONS-————---——---————---—
`a
`QT Interval Prolongation: GEODON use should be avoided in patients
`with bradycardia, hypokalcmia or hypornagnesemia, congenital
`
`Reference ID: 4060023
`
`o
`
`0
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`-
`0
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`-
`
`-
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`-
`o
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`o
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`O
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`prolongation of the QT interval, or in combination with other drugs that
`have demonstrated QT prolongation. (5.2)
`Neu miepric Malignant Syndrome (NMS): Potentially fatal symptom
`complex has been reported with antipsychotic drugs. Manage with
`immediate discontinuation of drug and close monitoring. (5.3)
`Severe Cutaneouszldverse Reactions, such as Drug Reaction with
`Eosinophilia and Systemic Symptoms (DRESS) and Stevens—Johnson
`syndrome has been reported with ziprasidone exposure. DRESS and
`other Severe Cutaneous Adverse Reactions (SCAR) are sometimes fatal.
`Discontinue GEODON if DRESS or SCAR are suspected.(5.4)
`Z'urdive Dru/cinema: May develop acutely or chronically. (5.5)
`ill/graham Changer: Atypical antipsychotic drugs have been associated
`with metabolic changes that may increase cardiovascular/
`cerebrovascular risk. These metabolic changes include hyperglycemia,
`dyslipidcmia, and weight gain. (5.6)
`Hyperglycemia andi. iabeiasMellitus (DM): Monitor all patients for
`symptoms of hyperglycemia including polydipsia, polyuria, polyphagia,
`and weakness. Patients with DM risk factors should undergo blood
`glucose testing before and during treatment. (5.6)
`Dyslipic/emia: Undesirable alterations have been observed in patients
`treated with atypical antipsychotics. (5 .6)
`ll’eigm Gain: Weight gain has been reported. Monitor weight gain. (5.6)
`Rash: Discontinue in patients who develop a rash without an identified
`cause. (5.7)
`Orflrostatzc [imatenszom Use with caution in patients with known
`cardiovascular or cerebrovascular disease. (5.8)
`Leulropenta, Neutropmza, andAgramu’oqvtosrs has been reported with
`antipsychotics. Patients with a pre—exi sting low white blood cell count
`(WBC) or a history of leukopenia/neutropenia should have their
`complete blood count (CBC) monitored frequently during the first few
`months of therapy and should discontinue Geodon at the first sign of a
`decline in WBC in the absence of other causative factors. (5.10)
`Seizures: Use cautiously in patients with a history of seizures or with
`conditions that lower seizure threshold. (5.11)
`Potentialfor Cognitive andfttowr impairment: Patients should use
`caution when operating machinery. (5.14)
`Suicide: Closely supervise high-risk patients. (5.17)
`~
`——————————————————————————————ADVERSE REACTIONS—--———---————---—————---—-—----
`Commonly observed adverse reactions (incidence 259/6 and at least twice the
`incidence for placebo) were:
`-
`Schizophrenia: Somnolence, respiratory tract infection. (61)
`O
`it/ILzrrict undid/fixed Episodes A ssociated with Bipolar Disorder:
`Somnolence. extrapyramidal symptoms, dizziness. akathisia, abnormal
`vision, asthenia, vomiting. (6.1)
`Intramuscular administration (1:594) and at least twice the lowest
`intramuscular ziprasidone group): Headache, nausea, somnolencc. (6.1)
`
`I
`
`-
`
`0
`
`To report SL'SPECTED ADVERSE REACTIONS, contact Pfizer Inc at
`1-800—438—1985 or FDA at 1—800-FDA-1088 or www. [do gruwmedwatclz.
`——————————————————————————————DRUG INTERACTIONS———————————————————————————————
`-
`Ziprasidone should not be used in combination with other drugs that
`have demonstrated QT prolongation. (4.1, 7.3)
`The absorption ofziprasrdone is increased up to two-fold in the presence
`of food. (7.9)
`The full prescribing information contains additional drug
`interactions. (7).
`———————————————————————USE IN SPECIFIC POP!TI.ATIONS—----------------------
`-
`Pregnancy: Ziprasi done should be used during pregnancy only if the
`potential henetitjustifies the potential risk. (8.1)
`Nursing/trainers: Breast feeding is not recommended. (8.3)
`Pediatric: Use: Safety and effectiveness for pediatric patients has not
`been establidied. (8.4)
`Renal Impairment: Intramuscular Ziprasidone should be administered
`with caution to patients with impaired renal function as the cyclodextrin
`excipient is cleared by renal filtration. (8.10)
`See 17 for PATIENT COUNSELING INFORMATION and
`FDA-approved patient labeling.
`
`-
`
`.
`
`0
`0
`
`0
`
`Revised: 2/2017
`
`LATUDA04358298
`
`Exhibit 2025
`
`Slayback v. Sumitomo
`|PR2020—01053
`
`1
`
`Exhibit 2025
`Slayback v. Sumitomo
`IPR2020-01053
`
`

`

`
`
`8
`
`10
`
`11
`12
`
`In Vitro Studies
`7.2
`Pliairnacodynarnic Interactions
`7.3
`7.4 Pharmacokinetic Interactions
`7.5 Lithium
`7.6 Oral Contraceptives
`7.7 Dextromethorphan
`7.8 Valproate
`7.9 Other Concomitant Drug Therapy
`’7 .10 Food Interaction
`USE IN SPECIFIC POPULATIONS
`8.1
`Pregnancy
`8.2 Labor and Delivery
`8.3 Nursing Mothers
`8.4 Pediatric Use
`8.5 Geriatric Use
`8.6 Renal Impairment
`8.7 Hepatic Impairment
`8.8 Age and Gender Effects
`8.9 Smoking
`DRUG ABUSE AND DEPENDENCE
`9.3 Dependence
`OVERDOSAGE
`0.1 Human Experience
`0.2 Management of Overdosage
`DESCRIPTION
`CLIV'ICAI. PHARMACOLOGY
`2.1 Mechanism of Action
`2.2 Pharmacodynamics
`2.3 Pharmacokinetics
`NONCLINICAL TOXICOLOGY
`3.1 Carcinogenesis, h’lillagcncsis, Impairment of Fertility
`CLINICAL STUDIES
`4.1 Schizophrenia
`4.2 Bipolar I Disorder (Acute Mixed or Manic Episodes and
`Maintenance Treatment as an Adjunct to Iithium or Valproate)
`4.3 Acute Treatment ongitation in Schizophrenia
`IIOW SUPPLIED/STORAGE AND IIANDLING
`16
`/ PATIENT COUNSELING INFORIVIATION
`7.1 Administration with Food
`7.2 Q'l‘c Prolongation
`7.3 Severe Cutaneous Adverse Reactions
`7.4 FDA Approved Patient Labeling
`
`13
`
`14
`
`
`
`*Sections or sub sections omitted from the full prescribing information are not
`listed.
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`£393
`
`(II
`
`\VARNING — INCREASED MORTALITY IN ELDERLY PATIENTS
`WTTH DEMENTIA-RELATED PSYCHOSIS
`1
`INDICATIONS AND USAGE
`1 .1
`Schizophrenia
`1.2 Bipolar I Disorder (Acute Mixed or Manic Episodes and
`Maintenance Treatment as an Adjunct to Lithium or Valproate)
`l .3 Acute Treatment of Agitation in Schizophrenia
`DOSAGE AND ADMINISTRATION
`2.1
`Schizophrenia
`2.2 Bipolar I Disorder (Acute Mixed or Manic Episodes and
`Maintenance Treatment as an Adjunct to Lithium or Valproate)
`2.3 Acute Treatment of Agitation in Schizophrenia
`2.4 Dosing in Special Populations
`DOSAGE FORMS AND STRENGTHS
`CONTRAINDICATIONS
`4 .1 QT Prolongation
`4.2 Hypersensitivity
`‘VARNINGS AND PRECAUTIONS
`5.1
`Increased Mortality in Elderly Patients with Dementia-Related
`Psychosis
`5.2 QT Prolongation and Risk of Sudden Death
`5.3 Neuroleptic Malignant Syndrome (NMS)
`5.4
`Severe Cutaneous Adverse Reactions
`5.5 Tardive Dyskinesia
`5.6 Metabolic Changes
`5.7 Rash
`5.8 Orthostatic Hypotcn si on
`5.9 Falls
`5.] 0 Leukopcnia Neutropcnia, and Agranulocytosi s
`5.11 Seizures
`5.12 Dysphagia
`5.13 Hypcrprolactincmia
`5.14 Potential for Cognitive and Motor Impairment
`5.l 5 Priapi sm
`5.16 Body Temperature Regulation
`5.17 Suicide
`5.18 Patients With Concomitant Illness
`5.19 Iaboratory Tests
`ADVERSE REACTIONS
`6.1 Clinical Trials Experience
`6.2 Postinarketing Experience
`DRUG INTERACTIONS
`7.1 Metabolic Pathway
`
`6 7
`
`Reference ID: 4060023
`
`LATUDAO4358299
`
`2
`
`

`

`
`
`FULL PRESCRIBING INFORMATION
`
`W'ARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA—RELATED PSYCHOSIS
`
`Elderly patients with dementia—related psychosis treated with antipsychotic drugs are at an increased risk of death. Analyses of
`seventeen placebo—controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed
`a risk of death in drug—treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated patients. Over the course of
`a typical 10—week controlled trial, the rate of death in drug—treated patients was about 4.5%, compared to a rate of about 2.6% in
`the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart
`failure, sudden death) or infectious (c.g., pneumonia) in nature. Observational studies suggest that, similar to atypical
`antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality. The extent to which the findings of
`increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) ot‘
`
` 1
`
`INDICATIONS AiVI) USAGE
`UEUDUN is indicated for the treatment of schizophrenia, as monotherapy for the acute treatment of bipolar manic or mixed episodes, and as an adjunct to
`lithium or valproate for the maintenance treatment of bipolar disorder. GEODDN intramuscular is indicated for acute agitation in schizophrenic patients. When deciding
`among the alternative treatments available for the condition needing treatment, the prescriber should consider the finding ofziprasidonds greater capaCity to prolong
`the QT/Ql‘c interval compared to several other antipsychotic drugs [see Warnings andPrecciuli-ons (5.2)]. Prolongation ofthe Q'l‘c interval is associated in some other
`drugs With the ability to cause torsade de pointes-type arrhythmia, a potentially fatal polymorphic ventricular tachycardia, and sudden death. In many cases this would
`lead to the conclusion that other drugs should be tried first. Whether ziprasidone will cause torsade de pointes or increase the rate of sudden death is not yet known [see
`War/rings undPrecuiitions {5. 2)]
`1.1
`Schizophrenia
`Geodon is indicated for the treatment of schizophrenia. The efficacy of oral ziprasidone was established in four short—tenn (4— and 6-week) controlled trials
`ofadult schizophrenic inpatients and in one maintenance trial of stable adult schizophrenic inpatients [see Clinical Studies (14.1)].
`1.2 Bipolar I Disorder (Acute Mixed or Manic Episodes and Maintenance Treatment as an Adjunct to Lithium or Valproate)
`Geodon is indicated as monotherapy for the acute treatment of manic or mixed episodes associated with bipolar l disorder. Efficacy was established in two
`3-week monotherapy studies in adult patients [see Clinical Studies (14.2)].
`Geodoii is indicated as an adjunct to lithium or valproate for the maintenance treatment ofbipolar I disorder. Efficacy was established in a maintenance trial in adult
`patients. The efficacy of Geodon as monotherapy for the maintenance treatment of bipolar l disorder has not been systematically evaluated in controlled clinical trials
`[see Clinical Studies (14. 2)].
`1.3 Acute Treatment of Agitation in Schizophrenia
`GEODON intramuscular is indicated for the treatment of acute agitation in schizophrenic patients for whom treatment with ziprasidone is appropriate and
`who need intramuscular antipsychotic medication for rapid control of agitation. The efficacy of intramuscular ziprasidone for acute agitation in schizophrenia was
`established in single day controlled trials of agitated schizophrenic inpatients [see Clinical Trials (14.1)]
`“Psychomotor agitation" is defined in DSM—IV as “excessive motor activity associated with a feeling of inner tension”. Schizophrenic patients experiencing
`agitation often manifest behaviors that interfere with their diagnosis and care, e.g. threatening behaviors, escalating or urgently distressing behavior, or self-exhausting
`behavior, leading clinicians to the use of intramuscular antipsychotic medications to achieve immediate control of the agitation.
`Since there is no experience regarding the safety of administering ziprasidone intramuscular to schizophrenic patients already taking oral ziprasidone, the
`practice ofco—adininistration is not recommended.
`Ziprasidone intramuscular is intended for intramuscular use only and should not be administered intravenously.
`
`2 DOSAGE AND ADMINISTRATION
`2.1 Schizophrenia
`Dose Selection
`GEODON Capsules should be administered at an initial daily dose of 20 mg twice daily with food. In some patients, daily dosage may subsequently be
`adjusted on the basis of individual clinical status up to 80 mg twice daily. Dosage adjustments. if indicated, should generally occur at intervals of not less than 2 days, as
`steady—state is achieved within 1 to 3 days. ln order to ensure use ofthe lowest effective dose, patients should ordinarily be observed for improvement for several weeks
`before upward dosage adjustment.
`Efficacy in schizophrenia was demonstrated in a dose range of 20 mg to 100 mg twice daily in short-term, placebo-controlled clinical trials. There were trends
`toward dose response within the range of 20 mg to 80 mg twice daily, but results were not consistent. An increase to a dose greater than 80 mg twice daily is not
`generally recommended. The safety of doses above 100 mg twice daily has not been systematically evaluated in clinical trials [see Clinical Studies (14.1)].
`Maintenance Treatment
`\Vhile there is no body of evidence available to answer the question of how long a patient treated with ziprasidone should remain on it, a maintenance study in
`patients who had been symptomatically stable and then randomized to continue ziprasidone or switch to placebo demonstrated a delay in time to relapse for patients
`receiving Geodon [see Clinical Studies (14.1)]. No additional benefit was demonstrated for doses above 20 mg twice daily. l'aticnts should be periodically reassessed to
`determine the need for maintenance treatment.
`2.2 Bipolar I Disorder (Acute Mixed or Manic. Episodes and Maintenance Treatment as an Adjunct to lithium or Valproate)
`
`Acute Treatment of Manic or Mixed Episodes
`Dose Selection-Oral ziprasidone should be administered at an initial daily dose of-tt) mg twice daily with food. The dose may then be increased to 60 mg or
`80 mg twice daily on the second day of treatment and subsequently adjusted on the basis oftolerance and efficacy within the ran go 40 trig—8t) mg tvvicc daily. In the
`flexible—dose clinical trials, the mean daily dose administered was approximately 120 mg [see Clinical Studies (14. 2)].
`
`Maintenance Treatment (as an adjunct to lithium or valproate)
`Continue treatment at the same dose on which the patient was initially stabilized, within the range of 40 mg-SU mg twice daily With food Patients should be
`periodically reassessed to detennine the need for maintenance treatment [see Clinical Studies (14.2)].
`2.3 Acute Treatment of Agitation in Schizophrenia
`Intramuscular Dosing
`The recommended dose is 10 mg to 20 mg administered as required up to a maXimuin dose of 40 mg per day. Doses of 10 mg maybe administered every two
`hours, doses of 20 mg may be administered every four hours up to a maximum of40 mg/day. Intramuscular administration ofzipraSidone for more than three
`consecutive days has not been studied.
`lflong-term therapy is indicated, oral ziprasidone hydrochloride capsules should replace the intramuscular administration as soon as possible.
`
`Reference ID: 4060023
`
`LATUDAO4358300
`
`3
`
`

`

`Since there is no experience regarding the safety of administering ziprasidone intramuscular to schizophrenic patients already taking oral ziprasidone, the
`practice ofCit—administration is not recommended.
`Ziprasidorre intramuscular is intended for intrarriuscular use only aird should not be administered intravenously.
`
`Intramuscular Preparation for Administration
`GEODON for [nj ectiorr (ziprasidone mesylate) should only be administered by intramuscular injection and should not be administered intravenously.
`Single-dose vials require reconstitution prior to administration.
`Add l.2 mL of Sterile Water for Injection to the vial and shake vigorously until all the drug is dissolved. Each mL of reconstituted solution contains 20 mg
`ziprasidone. To administer a l0 mg dose, draw up 0.5 rnL of the reconstituted solution. To administer a 20 mg dose, draw up 1.0 mL ofthe reconstituted solution Any
`unused portion should be discarded. Since no preservative or bacteriostatic agent is present in this product. aseptic technique must be used in preparation of the filial
`solution. This medicinal product must not be mixed with other medicinal products or solvents other than Sterile Water for Injection. Parenteral drug products should be
`inspected visual] y for particulate matter and discoloration prior to administration, whenever solution and container permit.
`2.4 Dosing in Special Populations
`@: Dosage adjustments are generally not required on the basis of age. gender. race. or renal or hepatic impairment. Geodon is not approved for use in
`children or adolescents.
`Intramuscular: Ziprasidone intramuscular has not been systematically evaluated in elderly patients or in patients with hepatic or renal impairment. As the
`cyclodextrin excipient is cleared by renal filtration, ziprasidone intramuscular should be administered with caution to patients with impaired renal function. Dosing
`adjustments are not required on the basis of gender or race [see Use in Specific Populations (8)].
`
`3 DOSAGE FORMS AND STRENGTHS
`GEODON Capsules are differentiated by capsule color/size and are imprinted in black ink with “Pfizer and ZDX [dosage strength]“ or “Pfizer" and a unique
`number. GEODON Capsules are supplied for oral administration in 20 mg (blue/white). 40 mg (blue/blue). 60 mg (white/white), and 80 mg (blue/white) capsules. They
`are supplied in the following strengths and package configurations;
`
`GEODON Capsules
`Capsule Strength (mg)
`Imprint
`20
`ZDX 20
`40
`ZDX 4t)
`60
`ZDX 60
`80
`ZDX 80
`
`OR
`
`GEODON Capsules
`Capsule Strength (mg)
`Imprint
`20
`396
`40
`397
`60
`398
`80
`399
`
`(‘rFODON for Injection is available in a single-dose vial as 7iprasidone mesylate (20 mg ziprasidone/mL when reconstituted according to label instructions)
`[see Dosage andrtdminisrralmn (2.3)]. Each ml] of ziprasidone mesylate for injection (when reconstituted) affords a colorless to pale pink solution that contains 20 m g
`ofziprasidonc and 4.7 mg of methanesulfonic acid solubilized by 204 mg of sulfobutylethcr B—cyclodextrin sodium (SBECD).
`4
`CONTRAINDICATIONS
`4.1 QT Prolongation
`Because of ziprasidone’s dose-related prolongation of the QT interval and the known association of fatal arrhythmias with QT prolongation by some other
`drugs, Ziprasidorie is contraindicated:
`o
`in patients with a known history of QT prolongation (including congenital long QT syndrome)
`0
`in patients with recent acute myocardial infarction
`o
`in patients with uncompensated heart failure
`Pharmacokinetici’phannacodynamic studies between Ziprasidone and other drugs that prolong the QT interval have not been perfomied. An additive effect of
`Ziprasi done and other drugs that prolong the QT interval cannot be excluded. Therefore. Ziprasi done should not be given with:
`-
`dofetilide, sotalol. quinidine, other Class Ia and III anti-arrhythmics, mesoridazine. thioridazine, chlorpromazine, droperidol, pimOZide, spariloxacin,
`gatifloxacin, moxifloxacin, halofantrine, mefloquine, pentamidine, arsenic trioxide, levomethadyl acetate, dolasetron mesylate, probucol or tacrolinius.
`other drugs that have demonstrated QT prolongation as one of their pharmacodynamic effects and have this effect described in the full prescribing
`information as a contraindication or a boxed or bolded warning [see Warnings andPrecautimzs (5.2)].
`4.2 Hypersensitiw‘ty
`Ziprasidone is contraindicated in individuals with a known hypersensitivity to the product.
`
`0
`
`5 WARNINGS AND PRECAUTIONS
`5.1
`Increased Mortality in Elderly Patients with Dementia—Related Psychosis
`Elderly patients with dementia—related psychosis treated with antipsychotic drugs are at an increased risk of death. GEODON is not approved for the
`treatment of denientia—related psychosis. [see Boxer! Warning]
`5.2
`QT Prolongation and Risk of Sudden Death
`Ziprasidone use should be avoided in combination with other drugs that are known to prolong the QTc interval [see Contraindications (4.1), Drug
`Interactions (7.4)]. Additionally. clinicians should be alert to the identification of other drugs that have been consistently observed to prolong the QTc interval. Such
`drugs should not be prescribed with zipra sidone. Ziprasidone should also be avoided in patients with congenital long QT syndrome and in patients with a history of
`cardiac arrhythmias [see Cormaindicanons (4)].
`A study directly comparing the QT/QTc prolonging effect of oral ziprasidone with several oth er drugs effective in the treatment of schizophrenia was
`conducted in patient volunteers. In the first phase ofthe trial, ECGs were obtained at the time of maximum plasma concentration when the drug was administered alone.
`In the second phase of the trial, ECGs were obtained at the time ofmaximum plasma concentration while the drug was co—administered with an inhibitor of the
`CYP4503A4 metabolism ofthe drug.
`In the first phase of the study, the mean change in QTc from baseline was calculated for each drug, using a sample—based correction that removes the effect
`ofheart rate on the QT interval. The mean increase in QTc from baseline for ziprasidone ranged from approximately 9 to 14 msec greater than for four of the
`comparator drugs (risperidone, olanzapine, quetiapine, and haloperidol), but was approximately 14 msec less than the prolongation observed for thioridazine,
`In the second phase of the study, the effect of ziprasidone on QTc length was not augmented by the presence of a metabolic inhibitor (ketoconazole 200 mg
`twi cc daily).
`In placebo—controlled trials, oral ziprasidonc increased the QTc interval compared to placebo by approximately l0 msec at the higdiest recommended daily
`dose of 160 mg. In clinical trials with oral Ziprasidonc, the electrocardiograms of 2/2988 (006%) patients who received GEODON and 1/440 (023%) patients who
`received placebo revealed QTc intervals exceeding the potentially clinically relevant threshold of 500 mscc. In the ziprasidone—treated patients, neither case suggested a
`role of zipra sidone. One patient had a history of prolonged QTc and a screening measurement of 489 msec; Q'I‘c was 503 msec during Ziprasidone treatment. The other
`patient had a QTc of 391 msec al the end of treatment with ziprasidone and upon switching to thioridazine experienced QTc measurements of 5 l8 and 593 nisec.
`Some drugs that prolong the QT/QTe interval have been associated with the occurrence oftorsade de pointes and with sudden unexplained death. The
`relationship of QT prolongation to torsade de pointes is clearest for larger increases (20 nisec and greater) but it is possible that smaller QT/QTC prolongations may also
`increase risk, or increase it in susceptible individuals. Although torsade de pointes has not been observed in association With the use ofziprasidone in premarketing
`
`Reference ID: 4060023
`
`LATUDAO4358301
`
`4
`
`

`

`studies and experience is too limited to rule out an increased risk, there have been rare post-marketing reports (in the presence of multiple confounding factors) [see
`Adverse Reactions (6. 2)].
`A study evaluating the QT/QTc prolonging effect of intramuscular ziprasidone, with intramuscular haloperidol as a control, was conducted in patient
`volunteers. In the trial, ECGs were obtained at the time ofmaximum plasma concentration following two injections of ziprasidone (20 mg then 30 mg) or lraloperidol
`(7.5 mg then 10 mg) given four hours apart. Note that a 30 mg dose of intramuscular ziprasidone is 50% higher than the recommended therapeutic dose. The mean
`change in QTc from baseline was calculated for each drug, using a sample-based correction that removes the effect ofheart rate on the QT interval. The mean increase
`in QTc from baseline for ziprasidone was 4.6 rnsec following the first injection and 12.8 rnsec following the second injection. The mean increase in QTc from baseline
`for haloperidol was 6.0 rnsec following the first injection and 14.7 rnsec following the second injection. In this study. no patients had a QTc interval exceeding 500
`msec.
`
`As with other antipsychotic drugs and placebo, sudden unexplained deaths have been reported in patients taking Aiprasidone at recommended doses. The
`premarketing experience for ziprasidone did not reveal an excess risk ofmortality for ziprasidone compared to other antipsychotic drugs or placebo, but the extent of
`exposure was limited, especially for the drugs used as active controls and placebo. Nevertheless. ziprasidone‘s larger prolongation of QTc length compared to several
`other antipsychotic drugs raises the possibility that the risk of sudden death maybe greater for ziprasidone than for other available drugs for treating schizophrenia. This
`possibility needs to be considered in deciding among alternative drug products [see Indications and Usage (1)].
`Certain circumstances may increase the risk ofthe occurrence oftorsade de pointes and/or sudden death in association with the use of drugs that prolong the
`QTc interval, including (1) bradycardia‘. (2) hypokalemia or hypomagnesemia; (3) concomitant use of other drugs that prolong the QTc interval; and (4) presence of
`congenital prolongation of the QT interval.
`It is recommended that patients being considered for ziprasidone treatment who are at risk for signifith electrolyte disturbances, hypokalemia in particular.
`have baseline serum potassium and magnesium measurements. Hypokalemia (and/or hypomagnesemia) may increase the risk of QT prolongation and arrhythmia.
`Hypokalemia may result from diuretic therapy, diarrhea. and other causes. Patients with low serum potassium and/or magnesium should be repleted with those
`electrolytes before proceeding with treatment. It is essential to periodically monitor serum electrolytes in patients for whom diuretic therapy is introduced during
`ziprasidone treatment. Persistently prolonged QTc intervals may also increase the risk of further prolongation and arrhythmia but it is not clear that routine screening
`ECG measures are effective in detecting such patients. Rather, ziprasidone should be avoided in patients with histories of significant cardiovascular illness, e.g.. QT
`prolongation, recent acute myocardial infarction, uncompensated heart failure, or cardiac arrhythmia. ziprasidone should be discontinued in patients who are found to
`have persistent QTc measurements >500 msec.
`For patients taking ziprasidone who experience symptoms that could indicate the occurrence of torsade de pointes, eg , dizziness, palpitations, or syncope,
`the prescriber should initiate further evaluation, e.g., Holter monitoring may be useful.
`5.3
`Neurolepfic Malignant Syndrome (NM$
`A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with administration
`of antipsychotic drugs. Clinical manifestations ofNMS arc ltypcrpyrcxi a, muscle rigidity, altered mental status, and cvidcncc of autonomic in stability (irregular pulse or'
`blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additional signs may include elevated creatinine phosphokinase, niyoglobinuria (rhabdomyolysis),
`and acute renal failure.
`The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a diagnosis, it is important to exclude cases where the clinical
`presentation irrclu dos both serious medical illness (cg, pneumonia, systemic infection, etc.) and untreated or inadequately treated cxtrapyramidal signs and symptoms
`(FPS). Other important considerations in thc differential diagnosis include central anticbolinergic toxicity, hcat stroke, drug fever, and primary central nervous systcm
`(CNS) pathology.
`The management ofNMS should include: (1) immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy; (2)
`intensive symptomatic treatment and medical monitoring; and (3) treatment of any concomitant serious medical problems for which specific treatments are available.
`There is no general agreement about spectfic pharmacological treatment regimens for NMS.
`If a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of drug therapy should be carefully considered. The
`patient should be carefully monitored, since recurrences of NMS have been reported.
`Severe Cutaneous Adverse Rarctiom
`5.4
`
`Drug Reaction with liosinoplrilia and Systemic Symptoms (DRESS)
`Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported with Ziprasidonc exposure. DRESS conststs ofa combination of three
`or more of the following: cutaneous reaction (such as rash or exfoliative dermatitis), eosinophilia, fever, lymphadenopathy and one or more systemic complications
`such as hepatitis, nephritis, pneumonitis, myocarditis, and pericarditis. DRESS 18 sometimes fatal. Discontinue zi prasrdone if DRESS is suspected.
`Other severe cutaneous adverse reactions
`Other severe cutaneous adverse reactions, such as Stevens-Johnson syndrome, have been reported with ziprasidone exposure. Severe cutaneous adverse
`reactions are sometimes fatal. Discontinue ziprasidone if severe cutaneous adverse reactions are suspected.
`5.5
`Tar'dive Dyskirresia
`A syndrome ofpotentially irreversible, involuntary, dyskinetic movements may develop in patients undergoing treatment with antipsychotic drugs. Although
`the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to rely upon prevalence estimates to predict, at the
`inception of antipsychotic treatment, which patients are likely to develop the syndrome.