PRODUCT INFORMATION
`ZELDOX(cid:147)(cid:147) (ziprasidone hydrochloride)
`
`NAME OF THE MEDICINE
`
`The chemical name for ziprasidone hydrochloride is 5-[2-[4-(1,2-benzisothiazol-3-yl)-1-
`piperazinyl]ethyl]-6-chloro-1,3-dihydro-2H-indol-2-one, monohydrochloride monohydrate.
`
`Australian Approved Names: Ziprasidone (C21H21CIN4OS) and Ziprasidone hydrochloride
`(C21H21CIN4OS.HCl.H2O).
`
`The structural formula of ziprasidone hydrochloride is shown below:
`
`is C21H21CIN4OS.HCl.H2O.
`formula of ziprasidone hydrochloride
`The molecular
`Ziprasidone hydrochloride has a molecular weight of 467.42 and the free base has a
`molecular weight of 412.94.
`
`The CAS Registry Numbers are 146939-27-7 (ziprasidone) and 138982-67-9 (ziprasidone
`hydrochloride).
`
`DESCRIPTION
`Ziprasidone is an antipsychotic agent for oral administration. It is chemically unrelated to
`phenothiazine or butyrophenone antipsychotic agents.
`
`Ziprasidone is a white to slightly pink powder. The measured solubility of ziprasidone
`hydrochloride is 0.0075% w/v in water at 37oC and 0.0041% w/v in a pH 3.0 buffer at 25oC.
`
`is supplied for oral administration as capsules containing ziprasidone
`ZELDOX
`hydrochloride monohydrate equivalent to 20 mg, 40 mg, 60 mg and 80 mg ziprasidone, and
`contains the following inactive ingredients: lactose, starch-pregelatinised maize, magnesium
`stearate, gelatin, titanium dioxide and indigo carmine CI73015 (20 mg, 40 mg and 80 mg
`capsules only), TekPrint SW-9008 Black Ink.
`
`PHARMACOLOGY
`
`Pharmacodynamics
`Ziprasidone exhibited high in vitro binding affinity for the dopamine D2 and D3, the serotonin
`5HT2A, 5HT2C, 5HT1A and 5HT1D and (cid:68)1-adrenergic receptors (Kis of 4.8, 7.2, 0.4, 1.3, 3.4, 2,
`and 10 nM, respectively) and moderate affinity for the histamine H1 receptor (Ki=47 nM).
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`Ziprasidone functioned as an antagonist at the D2, 5HT2A, and 5HT1D receptors, and as an
`agonist at the 5HT1A receptor. Ziprasidone inhibited synaptic reuptake of serotonin and
`noradrenaline. No appreciable affinity was exhibited for the other receptor/binding sites
`tested, including the cholinergic muscarinic receptor (IC50>1μM).
`
`The mechanism of action of ziprasidone, as with other drugs having efficacy in
`schizophrenia, is unknown. However, it has been proposed that this drug’s efficacy in
`schizophrenia is mediated through a combination of dopamine type 2 (D2) and serotonin
`type 2 (5HT2) antagonism. As with other drugs having efficacy in bipolar disorder, the
`mechanism of action of ziprasidone in bipolar disorder is unknown.
`
`Antagonism at receptors other than dopamine and 5HT2 with similar receptor affinities may
`explain some of the other therapeutic and side effects of ziprasidone. Ziprasidone’s
`antagonism of histamine H1 receptors may explain the somnolence observed with this drug.
`Ziprasidone’s antagonism of adrenergic (cid:68)1 receptors may explain the orthostatic hypotension
`observed with this drug.
`
`Positron Emission Tomography Studies
`At 12 hours following a 40 mg dose of ziprasidone, receptor blockade was greater than 80%
`for 5HT2A and greater than 50% for D2 using positron emission tomography (PET).
`
`Pharmacokinetics
`Absorption
`Following oral administration of multiple doses of ziprasidone with food, peak serum
`concentrations typically occur 6 to 8 hours post-dose. Ziprasidone demonstrates linear
`kinetics over the therapeutic dose range of 40-80 mg twice daily in fed subjects. The
`absolute bioavailability of a 20 mg dose is 60% in the fed state.
`
`Pharmacokinetic studies have demonstrated that the bioavailability of ziprasidone is
`significantly increased by up to 100% in the presence of food. It is therefore recommended
`that ziprasidone should be taken with food.
`
`Distribution
`Ziprasidone is greater than 99% protein bound, binding primarily to albumin and (cid:68)1-acid
`glycoprotein. Twice daily dosing generally leads to attainment of steady state within one to
`three days. Systemic exposures at steady state are related to dose. Ziprasidone has a volume
`of distribution of approximately 1.1 L/kg when administered intravenously.
`
`Metabolism
`Ziprasidone is extensively metabolised after oral administration with only a small amount
`excreted in the urine (<1%) or faeces (<4%) as unchanged drug. Ziprasidone is primarily
`cleared via three metabolic routes to yield four major circulating metabolites, benzisothiazole
`piperazine
`(BITP)
`sulphoxide, BITP
`sulphone,
`ziprasidone
`sulphoxide
`and
`S-methyl-dihydroziprasidone. Approximately 20% of the dose is excreted in the urine, with
`approximately 66% being eliminated in the faeces. Unchanged ziprasidone represents about
`44% of total drug-related concentration in serum.
`
`In vitro studies indicate that CYP3A4 is the major cytochrome catalysing the oxidative
`metabolism of
`ziprasidone with
`some potential
`contribution
`from CYP1A2.
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`S-methyl-dihydroziprasidone is generated in two steps catalysed by aldehyde oxidase and
`thiol methyltransferase.
`
`Ziprasidone, S-methyl-dihydroziprasidone, and ziprasidone sulphoxide, when tested in vitro,
`share properties which may predict a QTc-prolonging effect. S-methyl-dihydroziprasidone is
`mainly eliminated by biliary excretion and CYP3A4 catalysed metabolism. The sulphoxide
`is eliminated through renal excretion and by secondary metabolism catalysed by CYP3A4
`(see INTERACTIONS WITH OTHER MEDICINES).
`
`Excretion
`The mean terminal phase half-life after multiple dosing in normal volunteers and
`schizophrenic patients is between 6 and 10 hours, with a range of individual values from 3 to
`18 hours.
`
`Mean systemic clearance of ziprasidone administered intravenously is approximately
`5 mL/min/kg.
`
`Special Populations
`Elderly (>65 years)
`
`There are no clinically significant differences in the pharmacokinetics of ziprasidone in
`young adults and elderly.
`
`In a multiple-dose (8 days of treatment) study involving 32 subjects, there was no difference
`in the pharmacokinetics of ziprasidone between elderly (>65 years) and young (18 to 45
`years) adult subjects. Additionally, population pharmacokinetic evaluation of patients in
`controlled trials has revealed no evidence of clinically significant age-related differences in
`the pharmacokinetics of ziprasidone. Dosage modifications for age are, therefore, not
`recommended.
`
`Children and Adolescents
`
`Ziprasidone has not been systematically evaluated in subjects under 18 years of age.
`
`Gender
`
`In a multiple-dose (8 days of treatment) study involving 32 subjects, there was no difference
`in the pharmacokinetics of ziprasidone between men and women. Additionally, population
`pharmacokinetic evaluation of patients in controlled trials has revealed no evidence of
`clinically significant gender-related differences in the pharmacokinetics of ziprasidone.
`Dosage modifications for gender are, therefore, not recommended.
`
`Race
`
`No specific pharmacokinetic study was conducted to investigate the effects of race.
`Population pharmacokinetic evaluation has revealed no evidence of clinically significant
`race-related differences in the pharmacokinetics of ziprasidone. Dosage modifications for
`race are, therefore, not recommended.
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`Smoking
`
`Based on in vitro studies utilising human liver enzymes, ziprasidone is not a substrate for
`CYP1A2; smoking should therefore not have an effect on the pharmacokinetics of
`ziprasidone. Consistent with these in vitro results, population pharmacokinetic evaluation
`has not revealed any significant pharmacokinetic differences between smokers and non-
`smokers.
`
`Renal Impairment
`
`Because ziprasidone is highly metabolised, with less than 1% of the drug excreted
`unchanged, renal
`impairment alone
`is unlikely
`to have a major
`impact on
`the
`pharmacokinetics of ziprasidone. The pharmacokinetics of ziprasidone following 8 days of
`20 mg twice daily dosing were similar among subjects with varying degrees of renal
`impairment (n=27), and subjects with normal renal function, indicating that dosage
`adjustment based upon the degree of renal impairment is not required. Ziprasidone is not
`removed by haemodialysis.
`
`No marked differences in the pharmacokinetics of ziprasidone have been observed in patients
`with decreased kidney function (creatinine clearance >10 mL/min).
`
`Hepatic Impairment
`
`As ziprasidone is cleared substantially by the liver, the presence of hepatic impairment would
`be expected to increase the AUC of ziprasidone; a multiple-dose study at 20 mg twice daily
`for 5 days in subjects (n=13) with clinically significant (Child Pugh Class A and B) cirrhosis
`revealed an increase in AUC 0-12 of 13% and 34% in Child Pugh Class A and B, respectively,
`compared to a matched control group (n=14). A half-life of 7.1 hours was observed in
`subjects with cirrhosis compared to 4.8 hours in the control group.
`
`CLINICAL TRIALS
`
`Schizophrenia
`The efficacy of ziprasidone in the management of the manifestations of psychotic disorders
`was established in three short-term (4- and 6-week) and one long-term (52 week) controlled
`trials of psychotic inpatients who met DSM-III-R criteria for schizophrenia or schizoaffective
`disorder. Several instruments were used for assessing psychiatric signs and symptoms in
`these studies, among them the Brief Psychiatric Rating Scale (BPRS) and the Positive and
`Negative Syndrome Scale (PANSS), both multi-item inventories of psychopathology
`traditionally used to evaluate the effects of drug treatment in psychosis.
`
`Another traditional assessment, the Clinical Global Impression (CGI), reflects the impression
`of a skilled observer, fully familiar with the manifestations of schizophrenia, about the
`overall clinical state of the patient. In addition, the Scale for the Assessment of Negative
`Symptoms (SANS) and the Montgomery-Asberg Depression Rating Scale (MADRS) were
`employed in some clinical trials.
`
`In the 52-week, placebo-controlled maintenance trial (N=294), ziprasidone doses of 20, 40
`and 80 mg twice daily were statistically superior to placebo in the prevention of recurrent
`exacerbation of the illness, as well as in the BPRS total and psychosis cluster, the CGI, the
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`subscale, and Global Assessment of Functioning.
`total and negative
`PANSS
`Discontinuations due to adverse events were 7-10% in the ziprasidone groups and 15% in the
`placebo group.
`
`An analysis of the effect of ziprasidone on patients with clinically significant depressive
`symptoms (MADRS) (cid:116)14 was conducted in two multicentre placebo-controlled studies in
`acute schizophrenia. A statistically significant improvement versus placebo (p<0.05) in the
`MADRS was observed in patients receiving ziprasidone 60 mg twice daily in one study and
`80 mg twice daily in another study.
`
`Bipolar Mania
`The efficacy of ziprasidone in mania was established in two placebo-controlled, double-
`blind, 3-week studies which compared ziprasidone with placebo and one double-blind, 12-
`week study, which compared ziprasidone to haloperidol and placebo. These studies included
`850 patients meeting DSM-IV criteria for Bipolar I Disorder with an acute manic or mixed
`episode with or without psychotic features. Primary rating instruments used for assessing
`manic symptoms in these trials were: (1) the Mania Rating Scale (MRS), which is derived
`from the Schedule for Affective Disorders and Schizophrenia-Change Version (SADS-CB)
`with items grouped as the Manic Syndrome subscale (elevated mood, less need for sleep,
`excessive energy, excessive activity, grandiosity), the Behaviour and Ideation subscale
`(irritability, motor hyperactivity, accelerated speech, racing thoughts, poor judgment) and
`impaired insight; and (2) the Clinical Global Impression – Severity of Illness Scale (CGI-S),
`which was used to assess the clinical significance of treatment response.
`
`In a 3-week placebo-controlled, double-blind trial (n=210), the dose of ziprasidone was
`40 mg twice daily on Day 1 and 80 mg twice daily on Day 2. Titration within the range of
`40-80 mg twice daily (in 20 mg twice daily increments) was permitted for the duration of the
`study. Ziprasidone was significantly more effective than placebo in reduction of the MRS
`total score and the CGI-S score (p(cid:100)0.01).
`
`In a second 3-week placebo-controlled, double blind trial (n=205), the dose of ziprasidone
`was 40 mg twice daily on Day 1. Titration within the range of 40-80 mg twice daily (in
`20 mg twice daily increments) was permitted for the duration of study (beginning on Day 2).
`Ziprasidone was significantly more effective than placebo in reduction of the MRS total score
`and the CGI-S score (p(cid:100)0.01 and p(cid:100)0.001 respectively).
`
`In the 12-week placebo-controlled, double-blind, double-dummy trial (n=437), patients were
`randomised to ziprasidone, haloperidol, or placebo in a ratio of 2:2:1. Patients randomised to
`ziprasidone or haloperidol took their assigned drug for the 12-week study period. Patients
`randomised to placebo took placebo for the first 3 weeks of treatment and were then switched
`to ziprasidone for the remaining 9 weeks of the study. During the first 3 weeks of
`randomised study medication, the dose of ziprasidone was within the range of 40-80 mg
`twice daily and the dose of haloperidol was within the range of 4-15 mg twice daily. During
`the last 9 weeks of treatment, drug dosages could be reduced to as low as 20 mg twice daily
`for ziprasidone and 2 mg twice daily for haloperidol. Ziprasidone was significantly more
`effective than placebo in reduction of the MRS total score (p<0.001) and CGI-S score
`(p=0.002) at Week 3. In ziprasidone treated patients, significant treatment differences were
`shown in MRS total score at Day 2 (p=0.001) and maintained at Day 7 (p=0.016) and Day 14
`(p=0.001) and in CGI-S scores starting at Day 14 (p<0.001). Haloperidol was also
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`significantly more effective than placebo in reduction of the MRS total score (p(cid:100)0.01) and
`CGI-S score (p(cid:100)0.01) at Week 3.
`
`Mean and LS Mean Change in MRS (LOCF): Monotherapy Studies
`
`Study 1 (3 week) Study 2 (3 week) Study 3 (12 week)
`
`Zeldox
`Placebo
`Zeldox
`Placebo
`Zeldox
`Haloperidol
`N=131
`N=66
`N=137
`N=65
`N=176
`N=170
`
`Baseline
`Mean (SD)
`
`26.67
`(6.99)
`26.88
`
`26.19
`(7.19)
`27.09
`
`26.42
`(7.54)
`27.22
`
`29.57
`(8.01)
`28.93
`
`30.72
`(7.36)
`30.12
`
`Placebo
`N=88
`
`31.32
`(7.65)
`30.67
`
`27.48
`(7.78)
`26.74
`LS Mean
`Change at Last Visita
`-7.77
`Mean (SD)
`-12.4
`(12.91)
`(12.00)
`-6.66
`-12.27
`-5.61 (-9.26, -1.96)
`
`LS Mean
`LS Mean Diff
`(95% CI)
`P value
`
`-5.62
`-11.12
`(9.64)
`(11.46)
`-5.78
`-11.16
`-5.38 (-8.46, -2.30)
`
`0.003
`
`0.001
`
`-6.10
`-15.93
`-10.41
`(9.94)
`(10.61)
`(11.07)
`-6.39
`-16.55
`-11.35
`Zip vs Pbo: -4.96 (-7.58, -2.35)
`Hal vs Pbo: -10.16 (-12.76, -7.55)
`Zip vs Pbo: <0.001
`Hal vs Pbo: <0.001
`Note: p-values for pairwise comparisons against placebo based on ANCOVA model for post-baseline time
`points
`Key: SD = standard deviation; LOCF = last observation carried forward
`a Day 21/Week 3 (or early discontinuation)
`
` Last Visita
`
`Mean Change (SD) in CGI-S (LOCF): Monotherapy Studies
`Study 3 (12 week)
`
`Study 1 (3 week) Study 2 (3 week)
`
`Zeldox Placebo Zeldox Placebo Zeldox Haloperidol Placebo
`CGI-S
` Baseline
`
`4.89
`(0.87)
`-1.29
`(1.51)
`
`4.54
`(0.64)
`-1.09
`(1.29)
`
`4.97
`4.83
`4.77
`4.60
`4.92
`(0.79)
`(0.75)
`(0.79)
`(0.79)
`(0.73)
`-0.51
`-1.32
`-0.89
`-0.43
`-0.88
`(1.06)
`(1.15)
`(1.16)
`(1.40)
`(1.61)
`-
`<0.001
`0.002
`<0.001
`0.008
`P value
`Note: p-values for pairwise comparisons against placebo based on ANCOVA model for post-baseline time
`points
`Key: SD = standard deviation; LOCF = last observation carried forward
`a Day 21/Week 3 (or early discontinuation)
`
`
`Maintenance of effect over the 12-week period was observed for both ziprasidone and
`haloperidol treated groups. 92.5% of the subjects who responded (subjects with at least a
`50% decrease from baseline in the MRS at any given visit) in the ziprasidone treated group at
`the end of week 3 were still in response by week 12. Subjects in ziprasidone and haloperidol
`treatment groups had similar percents of responders at each visit through week 12.
`
`Based on the MADRS derived scores through week 4-12, more subjects in the haloperidol
`treatment group (5.0%) switched to depression than subjects in the ziprasidone treatment
`group.
`
`An additional randomised, placebo controlled study (n=205) compared the efficacy,
`tolerability and safety of ziprasidone and placebo in the presence of adjunctive lithium. All
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`patients were either already receiving lithium or initiated treatment with lithium on Day 1.
`Patients were randomized to either ziprasidone or placebo in a ratio of 1:1. The dose of
`ziprasidone was 40 mg twice daily on Day 1 and 80 mg twice daily on Day 2, and adjusted
`within the range 40-80 mg twice daily thereafter. Lithium treatment in patients not already
`receiving lithium was initiated at 900 mg daily on Day 1. Lithium was dosed as needed
`thereafter to maintain a serum level of 0.8 to 1.2 mEq/L, but serum levels were not
`mandatory during the study. Treatment with ziprasidone plus lithium was not more
`efficacious than placebo plus lithium, based upon the lack of a statistically significant
`difference in the rate of change in MRS or CGI-S from Baseline to Day 14.
`
`The efficacy of ziprasidone when used in combination with mood stabilisers such as lithium,
`carbamazepine, sodium valproate or lamotrigine has not been established in the treatment of
`acute mania.
`
`There are no long term clinical studies investigating the efficacy of ziprasidone in the
`prevention of recurrence of manic/depressive symptoms.
`
`Results of a Large Post-Marketing Safety Study (Zodiac Study)
`A randomised post approval study of 18,239 patients with observational follow-up for 1 year
`was conducted to determine whether ziprasidone is associated with an increased risk of non-
`suicide mortality in patients with schizophrenia compared to olanzapine. This study, which
`was conducted in naturalistic clinical practice settings, showed no significant difference in its
`primary endpoint of the rate of non-suicide mortality between ziprasidone and olanzapine
`treatments (risk ratio 1.02; 95%CI 0.76-1.39. All cause mortality also did not differ between
`the two treatment groups (risk ratio 1.01; 95%CI 0.77-1.33).
`
`INDICATIONS
`
`ZELDOX (ziprasidone) is indicated:
`
`(cid:120)
`
`(cid:120)
`
`for the treatment of schizophrenia, related psychoses, prevention of relapse and for
`maintenance of clinical improvement during continuation therapy;
`
`as monotherapy for the short term treatment of acute manic or mixed episodes associated
`with bipolar I disorder.
`
`CONTRAINDICATIONS
`
`(cid:120) Known hypersensitivity to any ingredient of the product
`
`(cid:120) Recent acute myocardial infarction
`
`(cid:120) Uncompensated heart failure
`
`(cid:120) Conditions with a potential to increase QT interval:
`o QT-interval prolongation or history of QT prolongation
`o Congenital long QT syndrome
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`o Use with other drugs known to increase the QT interval
`o Arrhythmias
`III
`treated with Class
`IA
`and
`(see INTERACTIONS WITH OTHER MEDICINES).
`
`antiarrhythmic
`
`drugs
`
`PRECAUTIONS
`
`QT Prolongation and Pro-arrhythmias
`Ziprasidone causes a mild to moderate prolongation of the QT interval.
`
`A study directly comparing the QT/QTc prolonging effect of ziprasidone with several other
`drugs effective in the treatment of schizophrenia was conducted in patient volunteers. In the
`first phase of the trial, ECGs were obtained at the time of maximum plasma concentration
`when the drug was administered alone. The mean change in QTc from baseline was
`calculated using a sample-based correction that removes the effect of heart rate on the QT
`interval. The mean increase in QTc from baseline for oral 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 trial, ECGs were obtained at the time of maximum plasma
`concentration while the drug was coadministered with the appropriate inhibitor(s) of the
`CYP450 metabolism specific for each drug. The effect of oral ziprasidone on QTc length
`was not augmented by the presence of a metabolic inhibitor (ketoconazole 200 mg twice
`daily).
`
`In placebo-controlled schizophrenia trials, ziprasidone increased the QTc interval compared
`to placebo by approximately 10 msec at the highest recommended daily dose of 160 mg. In
`schizophrenia clinical trials with ziprasidone, the electrocardiograms of 3/3266 (0.1%)
`patients who received ziprasidone and 1/538 (0.2%) patients who received placebo revealed
`QTc intervals exceeding the potentially clinically relevant threshold of 500 msec. In the
`ziprasidone-treated patients, neither case suggested a role of ziprasidone.
`
`Comparable findings were observed in the bipolar mania clinical trials. In the placebo
`controlled bipolar mania studies, ziprasidone increased the QTc interval (QTcF) compared
`with placebo by 8 msec. No subject in these studies experienced a QTcF >480 msec. The
`mean daily dose in these studies was 120 mg.
`
`Some drugs that prolong the QT/QTc interval greater than 500 msec have been associated
`with
`the occurrence of
`torsade de pointes and with sudden unexplained death
`(see INTERACTIONS WITH OTHER MEDICINES). There have been rare post-
`marketing reports of torsade de pointes in patients with multiple confounding risk factors
`taking ziprasidone. A causal relationship with ziprasidone has not been established.
`
`As with other antipsychotic drugs and placebo, sudden unexplained deaths have been
`reported in patients taking ziprasidone at recommended doses. Experience with ziprasidone
`has not revealed an excess risk of mortality for ziprasidone compared to other antipsychotic
`drugs or placebo.
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`Certain circumstances may increase the risk of torsade de pointes and/or sudden death in
`association with the use of drugs that prolong the QTc interval, including (1) bradycardia;
`(2) electrolyte imbalances (especially hypokalaemia or hypomagnesaemia); (3) concomitant
`use of other drugs that prolong the QTc interval; and (4) presence of congenital prolongation
`of the QT interval (see CONTRAINDICATIONS).
`
`It is recommended that patients being considered for ziprasidone treatment who are at risk for
`significant electrolyte disturbances, hypokalaemia in particular, have baseline serum
`potassium and magnesium measurements. Hypokalaemia may result from diuretic therapy,
`diarrhoea, 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 (see CONTRAINDICATIONS).
`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, e.g. dizziness, palpitations, syncope or seizures, the prescriber should
`initiate further evaluation, e.g. Holter monitoring, may be useful. The possibility of a
`malignant cardiac arrhythmia should also be considered and a cardiac evaluation including an
`ECG should be performed. If the QTc interval is >500 msec, then it is recommended that the
`treatment should be stopped (see CONTRAINDICATIONS).
`
`Venous Thromboembolism
`Cases of venous thromboembolism (VTE) have been reported with antipsychotic drugs.
`Since patients treated with antipsychotics often present with acquired risk factors for VTE, all
`possible risk factors for VTE should be identified before and during treatment with
`ziprasidone and preventive measures undertaken.
`
`Increased Mortality in Elderly Patient with Dementia-Related Psychosis
`Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an
`increased risk of death compared with placebo. Analyses of seventeen placebo controlled
`trials (modal duration of 10 weeks) in these patients revealed a risk of death in the drug-
`treated patients of between 1.6 to 1.7 times that seen 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 (e.g. pneumonia) in nature. Ziprasidone is not approved for the
`treatment of elderly patients with dementia-related psychosis.
`
`Cerebrovascular Adverse Events, including Stroke, in Elderly Patients with Dementia
`An approximately 3-fold increased risk of cerebrovascular adverse events has been seen in
`randomised placebo-controlled clinical trials in the dementia population with some atypical
`antipsychotics. The mechanism for this increased risk is not known. An increased risk
`cannot be excluded for other antipsychotics or other patient populations. Ziprasidone should
`be used with caution in patients with risk factors for stroke.
`
`Version: pfpzeldc10216
`
`
`Supersedes: pfpzeldc10515
`Page 9 of 23
`
`Par Pharm., Inc.
`Exhibit 1061
`Page 009
`
`

`

`Neuroleptic Malignant Syndrome (NMS)
`Neuroleptic malignant syndrome, a potentially fatal complex, has been reported in
`association with antipsychotic drugs, including ziprasidone. The clinical manifestations are
`hyperthermia, muscle rigidity, altered mental status and signs of autonomic instability such as
`irregular pulse and blood pressure, tachycardia, cardiac arrhythmias and diaphoresis.
`Additional features may include elevated creatine phosphokinase, rhabdomyolysis and acute
`renal failure. If a patient develops signs and symptoms indicative of NMS, or presents with
`unexplained high fever without additional clinical manifestations of NMS, all antipsychotic
`drugs, including ziprasidone, should be discontinued.
`
`Severe Cutaneous Adverse Reactions
`Drug reaction with eosinophilia and systemic symptoms (DRESS) has been reported with
`ziprasidone exposure. DRESS consists of a combination of: a) three or more of the
`following: cutaneous reaction (such as rash or exfoliative dermatitis), eosinophilia, fever,
`lymphadenopathy; and b) one or more systemic complications (such as hepatitis, nephritis,
`pneumonitis, myocarditis, and pericarditis).
`
`Other severe cutaneous adverse reactions (SCARs), such as Stevens-Johnson syndrome, have
`also been reported with ziprasidone exposure. SCARs are sometimes fatal and ziprasidone
`should be discontinued if SCARs occur.
`
`Tardive Dyskinesia
`In fixed-dose, placebo-controlled trials, in patients with schizophrenia, of up to six weeks
`duration, the incidence of treatment emergent tardive dyskinesia was comparable in patients
`receiving ziprasidone and placebo and lower than patients treated with active comparator
`(0.4% ziprasidone, 1.2% haloperidol and 0.7% placebo). In a 52-week, placebo-controlled
`trial in patients with schizophrenia, only one out of 219 patients treated with ziprasidone
`experienced tardive dyskinesia. However, as with other antipsychotic agents, the risk of
`tardive dyskinesia and other tardive extrapyramidal syndromes may increase with long term
`exposure and therefore if signs or symptoms of tardive dyskinesia appear in a patient on
`ziprasidone, a dose reduction or drug discontinuation should be considered. These symptoms
`can temporally deteriorate or even arise after discontinuation of treatment.
`
`Rash
`In premarketing schizophrenia trials with ziprasidone, about 5% of patients developed rash
`and/or urticaria, with discontinuation of treatment in about one-sixth of these cases. The
`occurrence of rash was related to dose of ziprasidone, although the finding might also be
`explained by the longer exposure time in the higher dose patients. Several patients with rash
`had signs and symptoms of associated systemic illness, e.g. elevated WBCs. Most patients
`improved promptly with adjunctive treatment with antihistamines or steroids and/or upon
`discontinuation of ziprasidone, and all patients experiencing these events were reported to
`recover completely. Upon appearance of rash for which an alternative aetiology cannot be
`identified, ziprasidone should be discontinued.
`
`Orthostatic Hypotension
`Ziprasidone may induce orthostatic hypotension associated with dizziness, tachycardia, and,
`in some patients, syncope, especially during the initial dose-titration period, probably
`
`Version: pfpzeldc10216
`
`
`Supersedes: pfpzeldc10515
`Page 10 of 23
`
`Par Pharm., Inc.
`Exhibit 1061
`Page 010
`
`

`

`reflecting its (cid:68)1-adrenergic antagonist properties. Syncope was reported in 0.6% of the
`patients treated with ziprasidone in schizophrenia clinical trials.
`
`Ziprasidone should be used with particular caution in patients with known cardiovascular
`disease, cerebrovascular disease or conditions which would predispose patients to
`hypotension.
`
`Suicide
`The possibility of a suicide attempt is inherent in schizophrenia and bipolar disorder, and
`close supervision of high-risk patients should accompany therapy. Prescriptions for
`ZELDOX should be written for the smallest quantity of capsules consistent with good patient
`management, in order to reduce the risk of overdose.
`
`Akathisia
`The presentation of akathisia may be variable and comprises subjective complaints of
`restlessness and an overwhelming urge to move and either distress or motor phenomena such
`as pacing, swinging of the legs while seated, rocking from foot to foot, or both. Particular
`attention should be paid to the monitoring for such symptoms and signs as, left untreated;
`akathisia is associated with poor compliance and an increased risk of relapse.
`
`CNS Drugs/Alcohol
`Given the primary CNS effects of ziprasidone, caution should be used when it is taken in
`combination with other centrally acting agents, including alcohol and drugs acting on the
`dopaminergic and serotonergic systems.
`
`Seizures
`As with other antipsychotics, caution is recommended when treating patients with a history of
`seizures.
`
`Hyperprolactinaemia
`As with other drugs that antagonise dopamine D2 receptors, ziprasidone elevates prolactin
`levels in humans. Increased prolactin levels were also observed in animal studies with this
`compound, and were associated with an increase in mammary gland neoplasia in mice; a
`similar effect was not observed in rats (see PRECAUTIONS, Carcinogenicity). Tissue
`culture experiments indicate that approximately one-third of human breast cancers are
`prolactin-dependent in vitro, a factor of potential importance if the prescription of these drugs
`is contemplated in a patient with previously detected breast cancer. Neither clinical studies
`nor epidemiologic studies conducted to date have shown an association between chronic
`administration of this class of drugs and tumorigenesis in humans; the available evidence is
`considered too limited to be conclusive at this time. Although disturbances such as
`galactorrhoea, amenorrhoea, gynaecomastia, and impotence have