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`ATTACHMENT 1
`
`Ziprasidone
`(Ziprasidone HCI)
`
`DESCRIPTION
`
`Ziprasidone is available as Ziprasidone Capsules (Ziprasidone hydrochloride) for oral administration.
`Ziprasidone is an antipsychotic agent that is chemicaliy unrelated to phenothiazine or butyrophenone
`antipsychotic agents.
`It has a molecular weight of 4 l 2.94 (free base). with the following chemical
`name:
`
`5 - [2 - [4 - (1,2- benzisothiazol—3-yl) -l- piperazinyl] ethyl] - 6 - chloro- ] ,3-dihydro-2H—
`indol-Z-one. The empirical formula of C21H21C1N4OS (free base of Ziprasidone) represents
`the following structural formula:
`
`Ziprasidone Capsules contain a monohydrochlori de, monohydrate salt of Ziprasidone, Chemically,
`Ziprasidone hydrochloride monohydrate is 5-[2-[4-(1,2-benzisothiazol-3 -yl)-l -piperazinyl]ethyl]-6-
`chloro-l,3-dihydro-2H-indol-2-one, monohydrochloride, monohydrate The empirical formula is
`C21H21C1N4OS - HC]
`- H30 and its molecular weight is 46?.42. Ziprasidone hydrochloride
`monohydrate is a white to slightly pink powder.
`
`Ziprasidone Capsules are supplied for oral administration in 20 mg, (bluefwhite) 40 mg (bluefblue),
`60 mg (whitefwhite) and 80 mg (bluei’white) capsules. Ziprasidone Capsules contain Ziprasidone
`hydrochloride monohydrate, lactose. pregelatinized starch. and magnesium stearate.
`
`CLINICAL PHARMACOLOGY
`
`Pharmacodynamics
`
`Ziprasidone exhibited high in virro binding affinity for the dopamine D2 and D3, the serotonin SHTM,
`SHTZC, SHTM and SHTm and a,-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 H receptor (K.- = 47 nM). Ziprasidone
`functioned as an antagonist at the D; SHTM. and SHTID receptors. and as an agonist at the SHTH
`receptor. Ziprasidone inhibited synaptic reuptake of serotonin and norepinephri ne, No appreciable
`affinity was exhibited for other receptorfbinding sites tested, including the cholinergic muscarinic
`
`receptor ( 1C5“ > 1 MM).
`
`The mechanism of action of Ziprasidone as with other drugs having efficacy in schizophrenia, is
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`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 (S-HTZ) antagonism. Antagonism
`
`at receptors other than dopamine and SHTg with similar receptor affi niti es may explain some of the
`other therapeutic and side effects of ziprasidone.
`
`Ziprasidone’s antagonism of histamine [-11 receptors may explain the somnolence observed with this
`drug.
`
`Ziprasidone’s antagonism of adrenergic or] receptors may explain the orthostatic hypotension observed
`with this drug.
`
`Pharmacokinetics
`
`Ziprasidone's activity is primarily due to the parent drug. The multiple-dose pharmacokinetics of
`ziprasidone are dose—proportional within the proposed clinical dose range, and ziprasidone
`accumulation is predictable with multiple dosing. Elimination of ziprasidone is mainly via hepatic
`metabolism with a mean terminal half-life of about 7 hours within the proposed clinical dose range.
`Steady state concentrations are achieved within one to three days of dosing. The mean apparent
`systemic clearance is 7.5 mli’minr'kg. Ziprasidone is unlikely to interfere with the metabolism of dmgs
`metabolized by cytochrome P450 enzymes
`
`mm
`
`Ziprasidone is weil absorbed after oral administration, reaching peak plasma concentrations in 6
`to 8 hours. The absolute bioavailability ot‘a 20 mg dose under fed conditions is approximately
`60%. The absorption of ziprasidone is increased up to two-fold in the presence of food.
`
`Distribution
`
`Ziprasidone has a mean apparent volume of distribution of 1.5 Lfkg.
`
`It is greater than 99% bound to
`
`plasma proteins, binding primarily to albumin and 011-acld glycoprotein. The in vitro plaSma protein
`binding of ziprasidone was not altered by warfarin or propranolol, two highly protein bound drugs,
`nor did ziprasidone alter the binding of these drugs in human plasma, Thus, the potential for drug
`interactions with ziprasidone due to displacement is minimal.
`
`Metabolism and Elimination
`
`Ziprasidone is extensively metabolized after oral administration with only a small amount excreted
`in the urine (<1%) or feces (<4%) as unchanged drug. Ziprasidone is primarily cleared via three
`metabolic routes to yield four major circulating metabolites, benzisothiazole (BITP) sulphoxide, BITP
`sulphone, ziprasidone sulphoxide and S-methyldihydroziprasidone. Approximately 20% of the dose
`is excreted in the urine, with approximately 66% being eliminated in the feces. Unchanged ziprasidone
`represents about 44% of total drug-related material in serum.
`In vitro studies using human liver
`subcellular Fractions indicate that S-methy]-dihydroziprasidone is generated in two steps. The data
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`indicate that the reduction reaction is mediated by aldehyde oxidase and the subsequent methyl ation
`is mediated by thiol methyltransferase.
`In vitro studies using human liver microsomes and
`recombinant enzymes indicate that CYP3A4 is the major CYP contributing to the oxidative metabolism
`of ziprasidone. CYP1A2 may contribute to a much lesser extent. Based on in vivo abundance of
`excretory metabolites,
`less than one-third of ziprasidone metabolic clearance is mediated by
`cytochrome P450 catalyzed oxidation and approximately two-thirds via reduction by aldehyde
`oxidase. There are no known clinically relevant inhibitors or inducers of aldehyde oxidase.
`
`Population Subgroups
`
`Age and Gender Effects - 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 or between elderly
`(> 65 years) and young (18 to 45 years) subjects. Additionally, population pharmacokinetic
`evaluation of patients in controlled trials has revealed no evidence of clinically significant age or
`gender-related differences in the pharmacokinetics of ziprasidone, Dosage modifications for age or
`gender are, therefore, not recommended.
`
`Race - No specific pharrnacokinetic study was conducted to investigate the effects of race. Population
`pharrnacokinetic evaluation has revealed no evidence of clinically significant race related differences
`in the pharmacokinetics of ziprasidone. Dosage modifications for race are,
`therefore, not
`recommended.
`
`Smoking - Based on in vitro studies utilizing 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 nonsmokers.
`
`Renal Insufficiency - Because ziprasidone is highly metabolized, with less than 1% of the drug
`excreted unchanged,
`renal
`impairment alone is unlikely to have a major
`impact on the
`pharmacokinetics ofziprasidone. The pharrnacokinetics of ziprasidone following 8 days of 20 mg bid
`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 hemodialysis.
`
`Hepatic Insufficiency - 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 bid
`for 5 days in subjects (n= 13) with clinically significant (Childs-Pugh Class A and B) cirrhosis
`revealed an increase in AUCO-12 of 13% and 34% in Childs-Pugh Ciass 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.
`
`Drug-Drug Interactions
`
`An in vitro enzyme inhibition study utilizing human liver microsomes showed that ziprasidone had
`little inhibitory effect on CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4, and thus would not
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`likely interfere with the metabolism of drugs primarily metabolized by these enzymes. In vii-'0 studies
`have revealed no effect of ziprasidone on the pharmacokinetics of dextromethorphan, estrogen,
`progesterone, or lithium (See DRUG INTERACTIONS under PRECAUTIONS).
`
`In vivo studies have revealed an approximately 35% decrease in zi prasi done AUC by concomitantly
`administered carbamazepine,
`an approximately 35-40% increase in ziprasidone AUC by
`concomitantly administered ketoconazole, but no effeCt on ziprasidone-s pharmacokinetics by
`cimetidine or antacid (See DRUG INTERACTIONS under PRECAUTIONS)
`
`Clinical Trials
`
`The efficacy of ziprasi done in the treatment of schizophrenia was evaluated in 5 placebo-controlled
`studies. 4 short—term (4- and 6-week) trials and one long—term (52 week) trial. All trials were in
`inpati ents, most of whom met DSM III-R criteria for schizophrenia. Each study included 2-3 fixed
`doses of ziprasidone as well as placebo. Four of the 5 trials were able to distinguish ziprasidone
`from placebo; one short—rem": study did not. Although a single fixed dose haloperidol arm was
`included as a comparative treatment in one of the three short-term trials, this single study was
`inadequate to provide a reliable and vaiid comparison of zi prasi done and haloperidol.
`
`Several instruments were used for assessing psychiatiic signs and symptoms in these studies. The
`BriefPsychiattic Rating Scale (BPRS) and the Positive and Negative Syndrome Scale (PANSS) are
`both multi-item inventodes of general psychopathology usually used to evaluate the effects of drug
`treatment in schizophrenia. The BPRS psychosis cluster (conceptual disorganization, hallucinatory
`behavior, suspiciousness, and unusual thought content) is considered a particularly useful subset for
`assessing actively psychotic schizophrenic patients. A second widely used 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 Assessing Negative Symptoms (SANS) was employed for assessing negative symptoms in one
`trial.
`
`The results of the trials follow:
`
`(1 ) In a 4-week, placebo-controlled trial (n=139) comparing 2 fixed doses of ziprasidone (20 and 60
`mg bid) with placebo. only the 60 mg bid dose was superior to placebo on the BPRS total score and
`the CGI severity score. This higher dose group was not superior to placebo on the BPRS psychosis
`cluster or on the SANS.
`
`(2) In a 6-week, placebo-controlled trial (n=302) comparing 2 fixed doses of ziprasidone (40 and 80
`mg bid) with placebo. both dose groups were superior to placebo on the BPRS total score. the BPRS
`psychosis cluster. the CG] severity score and the PANSS total and negative subscale scores. Although
`80 mg bid had a numerically greater effect than 40 mg bid. the difference was not statistically
`significant.
`
`(3) In a 6-week. placebo-controiled tn'a] (n=419) compari mg 3 fixed doses of ziprasidone (20. 60. and
`100 mg bid) with placebo, all three dose groups were superior to placebo on the PANSS total, the
`BPRS total score. the BPRS psychosis cluster, and the CG] severity score. Only the 100 mg bid dose
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`group was superior to placebo for the PANSS negative subscale. There was no clear evidence for
`a dose response relationship within the 20 mg bid to 100 mg bid dose range.
`
`(4) In a 4-week, placebo-controlled trial (n=200) comparing 3 fixed doses of ziprasidone (5, 20 and
`40 mg bid), none of the dose groups was statistically superior to placebo on any outcome of interest.
`
`(5) A study was conducted in chronic, symptomatically stable schizophrenic inpatients (n=294)
`randomized to three fixed doses of ziprasidone (20, 40, or 80 mg bid) or placebo and followed for
`52 weeks. Patients were observed for “impending psychotic relapse,” defined as CGI—improvement
`score of 2 6 (much worse or very much worse) andfor scores 3 6 (moderately severe) on the hostility
`or uncooperativeness items of the PANSS on two consecutive days. Ziprasi done was significantly
`superior to placebo in both time to relapse and rate of relapse, with no significant difference between
`the different dose groups.
`
`There were insufficient data to examine population sub sets based on age and race. Examination of'
`population subsets based on gender did not reveal any differential responsiveness.
`
`INDICATIONS AND USAGE
`
`Ziprasidone is indicated for the treatment of schizophrenia. When deciding among the alternative
`treatments available for this condition, the prescriber should consider the finding of ziprasidone’s
`greater capacity to prolong the QTr’QTc interval compared to several other antipsychotic drugs (see
`Warnings). Prolongation of the QTc 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 torsades de pointes or increase the rate of‘ sudden death is not yet
`known (see Warnings).
`
`The efficacy of ziprasidone was established in short-term (four and six week) controlled trials of
`schizophrenic inpatients (See CLINICAL PHARMACOLOGY).
`
`In a placebo controlled trial involving the follow-up for up to 52 weeks of stable schizophrenic
`inpatients, Ziprasidone was demonstrated to deiay the time to and rate of relapse. The physician who
`elects to use Ziprasidone for extended periods should periodically re-evaluate the long-term
`usefulness of the drug for the individual patient.
`CONTRAINDICATIONS
`
`QT Prolongntion
`
`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 (see Warnings), ziprasi done should not
`be used with other drugs that prolong the QT interval, including (not a complete iist) quinidine,
`dofetiiide, pimozide, sotalol, thioridazine. moxifloxacin, and sparf'loxacin.
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`Because ziprasi done prolongs the QT interval, it is contraindicated in patients with a known history
`of QT prolongation (including congenital long QT syndrome), with recent acute myocardial infarction.
`or with uncompensated heart failure. (see Warnings).
`
`Hypersensitivity
`
`Ziprasidone is contraindicated in individuals with a known hypersensitivity to the product.
`
`WARNINGS
`
`QT Prolongation and Risk of Sudden Death
`
`A study directly comparing the QTIQTc 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.
`In the second phase of the trial, ECGs were obtained at the
`time of maximum plasma concentration while the drug was coadministered with an inhibitor of
`the CYP4503A4 metabolism of the 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 of heart 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 bid).
`
`In placebo controlled trials, ziprasidone increased the QTc interval compared to placebo by
`approximately 10 msec at the highest recommended daily dose of 160 mg. In clinical trials with
`ziprasidone, the electrocardiograms of 2r’2988 (0.06%) patients who received Ziprasidone and
`U440 (0.23%) 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. One patient had a history of prolonged QTc and a screening
`measurement of 489 msec: QTc was 503 msec during ziprasidone treatment. The other patient
`had a QTc of 391 msec at the end of treatment with ziprasidone and upon switching to
`thioridazine experienced QTc measurements of 518 and 593 msec.
`
`Some drugs that prolong the QTKQTc interval have been associated with the occurrence of
`torsades de pointes and with sudden unexplained death. The relationship of QT prolongation to
`torsades de pointes is clearest for larger increases (20 msec and greater) but it is possible that
`smaller QTIQTc prolongations may also increase risk, or increase it in susceptible individuals,
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`such as those with hypokalemia, hypomagnesemia, or genetic predisposition. Although torsade
`de pointes has not been observed in association with the use of ziprasidone at recommended
`doses in premarketing studies, experience is too limited to rule out an increased risk.
`
`As with other antipsychotic drugs and placebo, sudden unexplained deaths have been reported
`in patients taking ziprasidone at recommended doses. The premarketing experience for
`ziprasidone did not reveal an excess risk of mortality 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 com pared to several other antipsychotic drugs raises the possibility that the risk of sudden
`death may be greater for ziprasidone than for other available drugs for treating schizophrenia.
`This possibility needs to be considered ill deciding among alternative drug products. (See
`Indications and Usage).
`
`Certain circumstances may increase the risk of the occurrence of torsades de pointes andlor
`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.
`
`Ziprasidone use should be avoided in combination with other drugs that are known to prolong the
`QTc interval. Ziprasidone should also be avoided in patients with congenital long QT syndrome
`and in patients with a history of cardiac arrhythmias (see Contraindications, and see Drug
`I nteractions under Precautions).
`
`It is recommended that patients being considered for ziprasidone treatment who are at risk for
`significant electrolyte disturbances, hypokalemia in particular, have baseline serum potassium
`and magnesium measurements. Hypokalemia (anda'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 andi’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, e.g., dizziness, palpitations, or syncope, the prescriber should initiate further
`evaluation, e.g., Holter monitoring may be useful.
`
`Neuroleptic Malignant Syndrome (NMS)
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`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 of NMS are hyperpyrexia, muscle rigidity, altered mental status and evidence of
`autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis and cardiac
`dysrhythmia). Additional signs may include elevated creatinine phosphokinase, myoglobinuiia
`(rhabdomyolysis), and acute renal failure.
`
`In arriving at a diagnosis,
`The diagnostic evaluation of patients with this syndrome is complicated.
`it is important to exciude cases where the clinical presentation includes both serious medical illness
`(e. g., pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal signs
`and symptoms (EPS). Other important considerations in the differential diagnosis include central
`anticholinergic texicity, heat stroke, drug fever, and primary central nervous system (CNS) pathology.
`
`The management of NMS 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 specific 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.
`
`Tardive Dyskinesia
`
`A syndrome of potentially 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 anti psychotic treatment, which patients are likely to develop
`the syndrome. Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia
`is unknown.
`
`The risk of developing tardive dyskinesia and the likelihood that it will become irreversible are
`believed to increase as the duration of treatment and the total cumulative dose of anti psychotic drugs
`administered to the patient increase. However, the syndrome can develop, although much less
`commonly, after relatively blief treatment periods at low doses.
`
`There is no known treatment for established cases of tardive dyskinesia, although the syndrome may
`remit partially or completely, if antipsychotic treatment is withdrawn. Antipsychotic treatment, itself,
`however, may suppress (or partially suppress) the signs and symptoms of the syndrome and thereby
`may possibly mask the underlying process. The effect that symptomatic suppression has upon the long-
`tenn course of the syndrome is unknown.
`
`Given these considerations, ziprasidone should be prescribed in a manner that is most likely to
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`minimize the occurrence of tardive dyskinesia. Chronic antipsychotic treatment should generally be
`reserved for patients who suffer from a chronic illness that (1) is known to respond to antipsychotic
`drugs and (2) for whom alternative, equally effective, but potentially less harmful treatments are not
`available or appropriate.
`In patients who do require chronic treatment, the smallest dose and the
`shortest duration of treatment producing a satisfactory clinical response should be sought, The need
`for continued treatment should be reassessed periodically.
`
`If signs and symptoms of tardive dy ski nesia appear in a patient on ziprasidone, drug discontinuation
`should be considered. However. some patients may require treatment with ziprasidone despite the
`presence of the syndrome.
`
`PRECAUTIONS
`
`General
`
`Rash
`
`In premarketing trials with ziprasidone, about 5% of patients developed rash andfor urticaria, with
`discontinuation of treatment in about one-sixth of these cases. The occurrence of rash was reiated to
`
`dose ofziprasidone, 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 andtor upon discontinuation of ziprasidone, and all patients experiencing
`these events were reported to recover completely. Upon appearance of rash for which an alternative
`etiology cannot be identified, ziprasidone should be discontinued.
`
`Orthostatic Hy potension
`
`Ziprasidone may induce orthostatic hypotension associated with dizziness, tachycardia and, in some
`
`patients, syncope, especially during the initial dose-titration period, probably reflecting its on-
`adrenergic antagonist properties.
`Syncope was reported in 0.6% of the patients treated with
`ziprasidone.
`
`Ziprasidone should be used with particular caution in patients with known cardiovascular disease
`(history of myocardial infarction or ischemic heart disease, heart failure or conduction abnormalities),
`cerebrovascuiar disease or conditions that would predispose patients to hypotension (dehydration,
`hypovolernia and treatment with anti hypertensive medications).
`
`Seizures
`
`During clinical tn' ats, seizures occurred in 0.4% of patients treated with ziprasidone. There were
`confounding factors that may have contributed to the occurrence of seizures in many of these cases.
`As with other antipsychotic drugs, Ziprasidone should be used cautiously in patients with a history of
`seizures or with conditions that potentially lower the seizure threshold, e.g,, Alzheimer’s dementia.
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`Conditions that lower the seizure threshold may be more prevalent in a population of 65 years or
`older.
`
`Hyperprolactinemia
`
`As with other drugs that antagonize dopamine DZ receptors, ziprasi done elevates proiactin level s in
`humans.
`Increased prolactin levels were also observed in animal studies with this compound, and
`were associated with an increase in mammary giand neoplasia in mice; a similar effect was not
`observed in rats (see Carcinogenesis). 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.
`Although disturbances such as galactorrhea, amenorrhea, gynecomastia, and impotence have been
`reported with prolactin-elevating cempounds, the clinical significance of elevated serum prolactin
`levels is unknown for most patients. 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.
`
`Potential for Cognitive and Motor Impairment
`
`Somnolence was a commonly reported adverse event in patients treated with ziprasidone. In the 4-
`and 6-week placebo-controlled trials, somnolence was reported in 14% of patients on ziprasidone
`compared to 7% of placebo patients. Somnolence led to discontinuation in 0.3% of patients in short-
`terrn clinical trials. Since ziprasidone has the potential to impair judgment, thinking, or motor skills,
`patients should be cautioned about performing activities requiring mental alertness, such as operating
`a motor vehicle (including automobiles) or operating hazardous machinery until they are reasonably
`certain that zi prasi done therapy does not affect them adversely.
`Priapism
`One case of priapism was reported in the pre-marketing data base. While the relationship of the event
`to ziprasidone use has not been established, other drugs with alpha-adrenergic blocking effects have
`been reported to induce pri apism, and it is possible that ziprasidone may share this capacity. Severe
`pri apism may require surgical intervention.
`
`
`Body Temperature Regulation
`
`AlthOugh not reported with ziprasidone in premarketing trials, disruption of the body's ability to
`reduce core body temperature has been attributed to antipsychotic agents. Appropriate care is advised
`when prescribing ziprasi done for patients who will be experiencing conditions which may contribute
`to an elevation in core body temperature, e.g., exercising strenuously, exposure to extreme heat,
`receiving concomitant medication with anticholinergic activity, or being subject to dehydration.
`
`Dysphagia
`
`Esophageal dysmotility and aspiration have been associated with antipsychotic drug use. Aspiration
`pneumonia is a common cause of morbidity and mortality in elderly patients, in particular those with
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`
`advanced Alzheimer’s dementia. Ziprasidone and other anti psychotic drugs should be used cautiously
`in patients at risk for aspiration pneumonia.
`
`Suicide
`
`The possibility of a suicide attempt is inherent in psychotic illness and close supervision of high risk
`patients should accompany drug therapy. Prescriptions for ziprasidone should be written for the
`smallest quantity of capsules consistent with good patient management in order to reduce the risk of
`overdose.
`
`Use in Patients with Concomitant Illness
`
`Clinical experience with ziprasidone in patients with certain concomitant systemic illnesses (see
`Renal
`Impairment and Hepatic Impairment under CLINICAL PHARMACOLOGY, Special
`Populations) is limited.
`
`Ziprasidone has not been evaluated or used to any appreciable extent in patients with a recent history
`of myocardial infarction or unstable heart disease. Patients with these diagnoses were excluded from
`premarketing clinical studies. Because of the risk of QTc prolongation and orthostatic hypotensi on
`with ziprasidone, caution should be observed in cardiac patients (see QTc Prolongation in Warnings
`and Orthostatic Hypotension in Precautions).
`
`Information for Patients
`
`Please refer to the patient package insert. To assure safe and effective use of ziprasidone, the
`information and instructions provided in the patient information section should be discussed with
`patients.
`
`Laboratory Tests
`
`Patients being considered for ziprasidone treatment that are at risk of significant electrolyte
`disturbances should have baseline serum potassium and magnesium measurements. Low serum
`potassium and magnesium should be repleted before proceeding with treatment. Patients who are
`started on diuretics during ziprasidone therapy need periodic monitoring of serum potassium and
`magnesium. Ziprasidone should be discontinued in patients who are found to have persistent QTc
`measurements > 500 msec. (See Warnings)
`
`Drug Interactions
`
`effects) or
`(combined pharmacologic
`can be pharmacodynamic
`Drug-drug interactions
`pharmacokinetic (aiteration of plasma levels). The risks of using ziprasidone in combination with
`other drugs have been evaluated as described below. Based upon the phannacodynamic and
`pharmacokinetic profile of ziprasidone, possible interactions could be anticipated:
`
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`
`PIR-LUR-025177
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`NDA 20-825 Approval Letter and Labeling
`Page 15
`
`Pharmacodynarnic Interactions
`
`l.
`
`2.
`
`3.
`
`4.
`
`Ziprasidone should not be used with any drug that prolongs the QT interval
`contraindications).
`Given the primary CNS effects of ziprasidone, caution should be used when it is taken in
`combination with other centrally acting drugs.
`Because of its potential for inducing hypotension, ziprasi done may enhance the effects of certain
`antihypertensive agents.
`Ziprasidone may antagonize the effects of levodopa and dopamine agonists.
`
`(see
`
`Phannacokinetic Interactions
`
`The Effect of Other Drugs 0n Ziprasidone
`
`Carbamazepine - Carbamazepine is an inducer of CYP3A4; administration of 200 mg bid for 2i days,
`resulted in a decrease of approximately 35% in the AUC of ziprasi done. This effect may be greater
`when high er doses of carbamazepine are ad