Source: Health Products and Food Branch (CA) Revision Year: 2020
Pharmacokinetic/pharmacodynamic studies between ziprasidone and other drugs that prolong the QT interval have not been performed. An additive effect of ziprasidone and other drugs that prolong the QT interval cannot be excluded. Therefore, ziprasidone should not be given with dofetilide, sotalol, quinidine, other Class Ia and III anti-arrhythmias, mesoridazine, thioridazine, chlorpromazine, droperidol, pimozide, sparfloxacin, gatifloxacin, moxifloxacin, halofantrine, mefloquine, pentamidine, arsenic trioxide, levomethadyl acetate, dolasetron mesylate, probucol or tacrolimus. Ziprasidone is also contraindicated with drugs that have demonstrated QT prolongation as one of their pharmacodynamic effects and have this effect described in their respective Product Monograph as a contraindication or a warning (see WARNINGS AND PRECAUTIONS).
ZELDOX (ziprasidone hydrochloride) is associated with moderate QT/QTC interval prolongation, as described in the subsections below.
Many drugs that cause QT/QTc prolongation are suspected to increase the risk of a rare, potentially fatal polymorphic ventricular tachyarrhythmia known as torsades de pointes. Generally, the risk of torsades de pointes increases with magnitude of the QT/QTc prolongation produced by the drug.
Torsades may be asymptomatic or experienced by the patient as dizziness, palpitations, syncope or seizures. If sustained, torsades de pointes can progress to ventricular fibrillation and sudden cardiac death.
As per Health Canada’s QT/QTc Guidelines, in the general population, certain circumstances may increase the risk of the occurrence of torsades de pointes in association with the use of drugs that prolong the QT/QTc interval, including (1) bradycardia; (2) electrolyte disturbances (e.g., hypokalemia, hypomagnesemia, or hypocalcemia); (3) concomitant use of other drugs that prolong the QT/QTc interval; (4) presence of congenital prolongation of the QT interval; (5) family history of sudden cardiac death at <50 years; (6) personal history of cardiac disease or arrhythmias; (7) acute neurological events, e.g., stroke; (8) being female or 65 years of age or older; (9) nutritional deficits e.g., eating disorders; (10) diabetes mellitus.
Therefore:
a) Comparative study (128-054): Six antipsychotics
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 (n=28-35 per drug). 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 co-administered with an inhibitor of the CYP450 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 makes adjustments for the effect of heart rate on the QT interval. The mean increase in QTc from baseline for ziprasidone (baseline correction) at 160 mg/day was 15.9 msec, which was approximately 9 to 14 msec greater than for four of the comparator drugs (haloperidol at 15 mg/day [7.1 msec], quetiapine at 750 mg/day [5.7 msec], risperidone at 16 mg/day [3.6 msec], and olanzapine at 20 mg /day [1.7 msec], but was approximately 14 msec less than the prolongation observed for thioridazine at 300 mg/day [30.1 msec].
In the second phase of the study, the effect of ziprasidone on QTc length (16.6 msec) was not augmented by the presence of a metabolic inhibitor (ketoconazole 200 mg BID). The mean increase for the other comparator drugs was haloperidol [13.3 msec], quetiapine [8.0 msec], olanzapine [3.0 msec], and risperidone [2.6 msec], compared to thioridazine [29.6 msec].
b) QT Effects at 2x maximum recommended ziprasidone dose
A study examining the effect of 3 doses of orally administered ziprasidone (including twice the recommended clinical dose, n=29) and haloperidol (the highest dose level was comparably high, n=30) on the QTc interval was conducted in clinically stable patients with schizophrenia and schizoaffective disorder. The study comprised 4 consecutive periods, including drug tapering (phase 1), wash out (phase 2), drug therapy (phase 3) followed by the study drug wash out and initiation of outpatient drug therapy (phase 4). Serial baseline electrocardiograms (ECGs) were collected under controlled conditions on the last day (day 0) of period 2 at times matched to those collected during study drug administration (phase 3) at the time of estimated peak drug exposure. At each steady-state dose level, three ECGs and a pharmacokinetic sample were collected at the predicted time of peak exposure to administered drug (Tmax). One of the three ECGs was collected at Tmax and the other two were collected one hour on either side of Tmax.
The mean increase in QTc from baseline for ziprasidone at 40 mg/day was 4.5 msec, and at 160 mg/day was 19.5 msec (comparable to the study described above). A further increase in dose to 320 mg/day (twice the maximum recommended clinical dose) led to an increase in QTc of 22.5 msec, which was only 3 msec more than after 160 mg/day in this study, suggesting a plateau. In comparison, there was no mean QTc increase apparent at the lowest haloperidol dose (2.5 mg/day). At the 2 higher doses of haloperidol, (15 and 30 mg/day), mean QTc increases ranged from 6.6 to 7.2 msec. No subject in either treatment group experienced a QTc interval ≥450 msec or an increase from baseline of ≥75 msec.
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, which was the basis for subsequent QT-specific studies. The clinical trial data for ziprasidone did not reveal an excess risk of mortality for ziprasidone compared to other antipsychotic drugs or placebo.
Electrocardiogram readings revealing QTc intervals exceeding the potentially clinically relevant threshold of 500 msec in clinical trials with ziprasidone occurred in: 2/3266 (0.06%) patients receiving ZELDOX (ziprasidone hydrochloride) and 1/538 (0.19%) patients receiving placebo. 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, who was receiving ziprasidone for more than 6.5 years without interruption, had a QTc of 503 msec at week 189, and 435 msec 19 weeks later, while maintained on the same oral dose of ziprasidone. There were confounding factors that contributed to the occurrence of these cases.
Torsades de Pointes
There have been rare post-marketing reports of torsades de pointes (in the presence of multiple confounding factors) (see ADVERSE REACTIONS; Post-Market Adverse Drug Reactions). Torsades de pointes have not been observed in association with the use of ziprasidone at recommended doses in clinical trials, but experience is too limited to rule out increased risk.
Analysis of Post-Marketing Data
In view of the clinical trial data demonstrating a moderate QT prolongation effect of ZELDOX, a review of 5-year, post-marketing spontaneous data from the FDA AERS database was conducted using a set of heart-related search terms.
Small elevations in spontaneous reporting rates were observed for ziprasidone compared with two other atypical antipsychotics, for both fatal cases, and “all” cases (i.e., fatal plus non-fatal).
Accumulated case reports should not be used as a basis for determining the incidence of a reaction or estimating risk for a particular product, as neither the total number of reactions occurring, nor the number of patients exposed to the health product is known. Because of the multiple factors that influence reporting, quantitative comparisons of health product safety cannot be made from the data. Comparison of reporting rates cannot be employed to confirm or refute a hypothesis, due to well-known, inherent limitations with spontaneous reporting of adverse events.
Disruption of the body’s ability to reduce core body temperature has been attributed to antipsychotic agents. Appropriate care is advised when prescribing ziprasidone 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.
For animal data, see Part II: TOXICOLOGY.
See also CONTRAINDICATIONS; and WARNINGS AND PRECAUTIONS, QT Prolongation.
Ziprasidone may induce orthostatic hypotension associated with dizziness, tachycardia and, in some patients, syncope, especially during the initial dose-titration period, probably reflecting its α1-adrenergic antagonist properties. Syncope was reported in 0.6% (22/3834) 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), cerebrovascular disease or conditions which would predispose patients to hypotension (dehydration, hypovolemia and treatment with antihypertensive medications). Patients with a history of clinically significant cardiac disorders were excluded from the trials.
ZELDOX has not been systematically studied, in animals or humans, for its potential for abuse, tolerance or physical dependence. While clinical trials did not reveal any tendency for drug-seeking behaviour, these observations were not systematic and it is not possible to predict on the basis of this limited experience the extent to which ZELDOX will be misused, diverted and/or abused once marketed. Consequently, patients should be evaluated carefully for a history of drug abuse, and such patients should be observed closely for signs of ZELDOX misuse or abuse (e.g., development of tolerance, increases in dose, drug-seeking behaviour).
As with some other antipsychotics, hyperglycemia, exacerbation of pre-existing diabetes, and diabetic coma have been reported very rarely during the use of ZELDOX. However, no causal relationship with ZELDOX has been established (see ADVERSE REACTIONS, Post-Market Adverse Drug Reactions). Diabetic ketoacidosis (DKA) has occurred in patients with no reported history of hyperglycemia. Patients should have baseline and periodic monitoring of blood glucose and body weight.
Assessment of the relationship between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population. Given these confounders, and that there is no data in drug-naïve patients, the relationship between atypical antipsychotic use and hyperglycemia-related adverse events is not completely understood. However, epidemiological studies, which did not include ZELDOX, suggest an increased risk of treatmentemergent hyperglycemia-related adverse events in patients treated with the atypical antipsychotics. Because ZELDOX was not marketed at the time these studies were performed, it is not known if ZELDOX is associated with this increased risk. Precise risk estimates for hyperglycemia-related adverse events in patients treated with atypical antipsychotics are not available.
Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia, including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics should undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of anti-diabetic treatment despite discontinuation of the suspect drug. Patients with risk factors for diabetes mellitus (e.g., obesity, family history of diabetes) who are starting treatment with atypical antipsychotics should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Patients with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics should be monitored regularly for worsening of glucose control.
As with other drugs that antagonize dopamine D2 receptors and/or serotonin 5-HT2 receptors, ZELDOX may elevate prolactin levels in humans. Elevations associated with ZELDOX treatment are generally mild and may decline during administration.
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 TOXICOLOGY, Carcinogenicity).
Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactindependent in vitro, ZELDOX should only be administered to patients with previously detected breast cancer if the benefits outweigh the potential risks.
Although disturbances such as galactorrhea, amenorrhea, gynecomastia, and impotence have been reported with prolactin-elevating compounds, the clinical significance of elevated serum prolactin levels is unknown for most patients. Long-standing hyperprolactinemia when associated with hypogonadism may lead to decreased bone mineral density in both female and male subjects. Caution should be exercised when considering ziprasidone treatment in patients with pituitary tumors. Neither clinical studies nor epidemiological 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.
Patients should be advised of the risk of severe constipation during ZELDOX treatment, and that they should tell their doctor if constipation occurs or worsens, as they may need laxatives (see ADVERSE REACTIONS, Post Market Adverse Drug Reactions).
Rare cases of priapism have been reported with antipsychotic use, such as ZELDOX. This adverse reaction, as with other psychotropic drugs, did not appear to be dose-dependent and did not correlate with duration of treatment. The likely mechanism of action of priapism is a relative decrease in sympathetic tone. Severe priapism may require surgical intervention.
Venous thromboembolism (VTE), including fatal pulmonary embolism, has been reported with antipsychotic drugs, including ZELDOX, in case reports and/or observational studies. When prescribing ZELDOX, all possible risk factors for VTE should be identified before and during treatment with ZELDOX and preventive measures undertaken.
Neutropenia, granulocytopenia, and agranulocytosis have been reported during antipsychotic use (see ADVERSE REACTIONS, Post Market Adverse Drug Reactions). Therefore, it is recommended that patients have their complete blood count (CBC) tested prior to starting ZELDOX and then periodically throughout treatment.
Possible risk factors for leukopenia/neutropenia include pre-existing low white blood cell count (WBC) and history of drug induced leukopenia/neutropenia. Patients with a pre-existing low WBC or a history of drug induced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and ZELDOX should be discontinued at the first sign of decline in WBC, in the absence of other causative factors.
Patients with neutropenia should be carefully monitored for fever or other symptoms or signs of infection and treated promptly if such symptoms or signs occur. Patients with severe neutropenia (absolute neutrophil count <1 × 109/L) should discontinue ZELDOX and have their WBC followed until recovery.
See WARNINGS AND PRECAUTIONS, Special Populations, Hepatic Impairment.
A potentially fatal symptom complex sometimes referred to as NMS has been reported in association with the administration of antipsychotic drugs, including ZELDOX.
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, myoglobinuria (rhabdomyolysis), and acute renal failure.
In arriving at a diagnosis, it is important to identify 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 toxicity, heat stroke, drug fever, and primary central nervous system pathology.
The management of NMS should include: 1) immediate discontinuation of antipsychotic drugs including ZELDOX 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 uncomplicated 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.
A syndrome consisting of potentially irreversible, involuntary and disabling dyskinetic movements may develop in patients treated with antipsychotic drugs. Although the prevalence of the tardive dyskinesia 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 tardive dyskinesia 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 antipsychotic drugs administered to the patient increase. However, the syndrome can develop, although much less commonly, after relatively brief 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 tardive dyskinesia syndrome and thereby may possibly mask the underlying process. The effect that symptomatic suppression has upon the long-term course of the tardive dyskinesia syndrome is unknown.
Given these considerations, ZELDOX should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia. Chronic antipsychotic treatment should generally be reserved for patients who 1) suffer from a chronic illness that 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 dyskinesia appear in a patient on ZELDOX, drug discontinuation should be considered. However, some patients may require treatment with ZELDOX despite the presence of the tardive dyskinesia syndrome.
Antipsychotic drugs (which includes ziprasidone) may cause somnolence, postural hypotension, and motor and sensory instability, which could lead to falls and, consequently, fractures or other injuries. For patients with diseases, conditions, or medications that could exacerbate these effects, a fall risk assessment should be completed when initiating antipsychotic treatment and recurrently for patients on long-term antipsychotic therapy.
Somnolence was a commonly reported adverse event in patients treated with ZELDOX. In the 4- and 6- week placebo-controlled trials in patients with schizophrenia, somnolence was reported in 14% of patients on ziprasidone compared to 7% of patients on placebo (see ADVERSE REACTIONS). 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 ziprasidone therapy does not affect them adversely.
During clinical trials, 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. Nevertheless, 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. Conditions that lower the seizure threshold may be more prevalent in a population of 65 years or older.
Serotonin syndrome is a rare and potentially life-threatening event in which signs and symptoms include high fever, seizures, arrhythmias, and unconsciousness observed in patients taking multiple serotonergic agents or who have had considerable exposure to a single serotonin-augmenting drug. In isolated cases, there have been reports of serotonin syndrome temporally associated with the therapeutic use of ziprasidone in combination with other serotonergic medicinal products such as SSRIs (see ADVERSE REACTIONS, Post Market Adverse Drug Reactions). The features of serotonin syndrome can include confusion, agitation, fever, sweating, ataxia, hyperreflexia, myoclonus and diarrhea, hyperthermia, rigidity, and autonomic instability with possible rapid fluctuations of vital signs and symptoms can progress to delirium and coma. Management of serotonin syndrome includes withdrawal of the offending medication and supportive care for mild cases; hospitalization is required for moderate to severe cases
The possibility of a suicide attempt is inherent in psychotic illness; thus, close supervision and appropriate clinical management of high-risk patients should accompany drug 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.
Dose adjustments are not required for patients with renal impairment (see ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions, Renal Insufficiency).
Drug reaction with eosinophilia and systemic symptoms (DRESS) has been reported with ziprasidone exposure. DRESS consists of a 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.
Other severe cutaneous adverse reactions, such as Stevens-Johnson syndrome, have been reported with ziprasidone exposure (see ADVERSE REACTIONS, Post Market Adverse Drug Reactions).
Severe cutaneous adverse reactions are sometimes fatal. Discontinue ziprasidone if severe cutaneous adverse reactions occur.
In pre-marketing trials with ziprasidone, about 5% of patients developed rash (173/3834) and/or urticaria (12/3834), with discontinuation 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 white blood cells (WBC). 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 etiology cannot be identified, ziprasidone should be discontinued.
There are no adequate and well-controlled studies in pregnant women. Women of childbearing potential receiving ziprasidone should therefore be counselled on the need to use an effective method of contraception during treatment with ZELDOX.
Patients should be advised to notify their physician if they become pregnant or intend to become pregnant. ZELDOX should not be used during pregnancy unless the expected benefits to the mother markedly outweigh the potential risks to the fetus.
Fertility:
There are no adequate and well-controlled studies in women and men exposed to ziprasidone.
Teratogenic effects:
In animal studies, ziprasidone demonstrated developmental toxicity, including possible teratogenic effects at doses similar to human therapeutic doses. When ziprasidone was administered to pregnant rabbits during the period of organogenesis, an increased incidence of fetal structural abnormalities (ventricular septal defects and other cardiovascular malformations and kidney alterations) was observed at a dose of 30 mg/kg/day (3 times the maximum recommended human dose (MRHD) of 200 mg/day on a mg/m² basis). There was no evidence to suggest that these developmental effects were secondary to maternal toxicity. The developmental no-effect dose was 10 mg/kg/day (equivalent to the MRHD on an mg/m² basis).
In rats, embryofetal toxicity (decreased fetal weights, delayed skeletal ossification) was observed following administration of 10 to 160 mg/kg/day (0.5 to 8 times the MRHD on a mg/m² basis) during organogenesis or throughout gestation, but there was no evidence of teratogenicity. Doses of 40 and 160 mg/kg/day (2 and 8 times the MRHD on a mg/m² basis) were associated with maternal toxicity. The developmental no-effect dose was 5 mg/kg/day (0.2 times the MRHD on a mg/m² basis).
There was an increase in the number of pups born dead and a decrease in postnatal survival through the first 4 days of lactation among the offspring of female rats treated during gestation and lactation with doses of 10 mg/kg/day (0.5 times the MRHD on a mg/m² basis) or greater. Offspring developmental delays and neurobehavioral functional impairment were observed at doses of 5 mg/kg/day (0.2 times the MRHD on a mg/m² basis) or greater. A no-effect level was not established for these effects.
Non teratogenic effects:
Neonates exposed to antipsychotic drugs (including ZELDOX) during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress and feeding disorder in these neonates. These complications have varied in severity; while in some cases symptoms have been selflimited, in other cases neonates have required intensive care unit support and prolonged hospitalization.
ZELDOX should not be used during pregnancy unless the expected benefits to the mother markedly outweigh the potential risks to the fetus.
The effect of ZELDOX on labor and delivery in humans is not known.
There are no adequate and well-controlled studies in lactating women. Limited data indicate that ziprasidone is excreted into breast milk at very low levels. It is recommended that women taking ZELDOX should not breast-feed.
The safety and efficacy of ZELDOX in children under the age of 18 years have not been established and its use is not recommended.
Weight gain has been observed with atypical antipsychotic use in pediatric and adolescent patient populations. Independent of any drug-specific effects, weight gain can be associated with adverse changes in other metabolic parameters (e.g., glucose and lipid metabolism). Abnormal childhood weight and metabolic status can have adverse effects on cardiovascular outcomes in adulthood. Weight gain and adverse effects on other metabolic parameters associated with atypical antipsychotics can be more frequent or more severe in pediatric and adolescent patients than in the adult patients.
The following adverse events in the two studies in pediatrics are of note because they are not typical of the adult population treated with ziprasidone: abnormally decreased bicarbonate values; elevations in testosterone, elevations in insulin, total neutrophils, monocytes and ALT; fatigue; abdominal pain, insomnia; restlessness. There are also adverse events of note due to a greater incidence rate compared to adults, or a greater differential over placebo: blurred vision; extrapyramidal symptoms (aggregated); sedation/somnolence; nausea; vomiting; and elevations in serum prolactin (See ADVERSE REACTIONS, Adverse Drug Reactions in Pediatrics).
The long-term safety, including cardiometabolic effects and effects on growth, maturation and behavioural development in patients under 18 years of age has not been systematically evaluated.
The ZELDOX pediatric study in schizophrenia was terminated by Pfizer due to lack of efficacy (Placebocontrolled study A1281134, and open-label extension 1135).
The number of patients 65 years or older with schizophrenia or related disorders, exposed to ZELDOX during clinical trials was limited (n=109). In general, there was no indication of any different tolerability of ziprasidone or for reduced clearance of ziprasidone in the elderly compared to younger adults. Nevertheless, geriatric patients generally have decreased cardiac, hepatic and renal function, and more frequent use of concomitant medication. The presence of multiple factors that might increase the pharmacodynamic response to ziprasidone, or cause poorer tolerance or orthostasis, should lead to consideration of a lower starting dose, slower titration, and careful monitoring during the initial dosing period for elderly patients.
Overall Mortality:
Elderly patients with dementia treated with atypical antipsychotic drugs have an increased mortality compared to placebo in a meta-analysis of 13 controlled trials of various atypical antipsychotic drugs. ZELDOX is not indicated in elderly patients with dementia (e.g., dementiarelated psychosis) (see WARNINGS AND PRECAUTIONS, Serious Warnings and Precautions).
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 advanced Alzheimer’s dementia. Ziprasidone and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia.
Cerebrovascular Adverse Events (CVAEs), including Stroke in Elderly Patients with Dementia:
In placebo-controlled trials with some atypical antipsychotics, there was a higher incidence of cerebrovascular adverse events (cerebrovascular accidents and transient ischemic attacks) including fatalities compared to placebo-treated subjects. ZELDOX is not indicated for the treatment of patients with dementia (e.g., dementia-related psychosis). (see WARNINGS AND PRECAUTIONS, Serious Warnings and Precautions).
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 risks of QT/QTc prolongation and orthostatic hypotension with ziprasidone, caution should be observed in cardiac patients (see CONTRAINDICATIONS, as well as WARNINGS AND PRECAUTIONS, QT Prolongation and Cardiovascular, Orthostatic Hypotension).
In patients with hepatic insufficiency, lower doses should be considered (see DOSAGE AND ADMINISTRATION, Hepatic Impairment and ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions, Hepatic Insufficiency).
Dose adjustments are not required for patients with renal impairment (see ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions, Renal Insufficiency).
ZELDOX capsules contain lactose. This should be considered when prescribing to patients with rare hereditary problems of galactose intolerance, lactase deficiency or glucose-galactose malabsorption.
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 AND PRECAUTIONS, QT Prolongation).
The stated frequencies of adverse events represent the proportion of individuals who experienced, at least once, a treatment-emergent adverse event of the type listed. An event was considered treatment-emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation.
Because clinical trials are conducted under very specific conditions, the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.
The following findings are based on a pool of two 6-week, and two 4-week placebo-controlled trials for schizophrenia and a pool of three 3-week flexible dose trials for bipolar mania in which ziprasidone was administered in doses ranging from 10 to 200 mg/day.
A total of 4.1% (29/702) of patients treated with ZELDOX (ziprasidone hydrochloride) in short-term, placebo-controlled studies discontinued treatment due to an adverse event, compared with 2.2% (6/273) on placebo and 8.2% (7/85) on the active control drug. The most common event associated with dropout was rash, including 7 dropouts for rash among ziprasidone patients (1%) compared to no placebo patients (see WARNINGS AND PRECAUTIONS, SKIN, Rash).
Table 1 enumerates the incidence, rounded to the nearest percent, of treatment-emergent adverse events that occurred during acute therapy (up to 6 weeks) in predominantly schizophrenic patients, including only those events that occurred in 1% or more of patients treated with ziprasidone and for which the incidence in patients treated with ziprasidone was greater than the incidence in placebo-treated patients.
Table 1. Treatment-Emergent Adverse Event Incidence in Short-Term Placebo-Controlled Trials – Schizophrenia:
| Body System | Percentage of patients reporting | |
|---|---|---|
| ZELDOX (n = 702) | Placebo (n = 273) | |
| Body as a Whole | ||
| Asthenia | 5 | 3 |
| Accidental Injury | 4 | 2 |
| Chest Pain | 3 | 2 |
| Cardiovascular | ||
| Tachycardia | 2 | 1 |
| Postural Hypotension | 1 | 0 |
| Digestive | ||
| Nausea | 10 | 7 |
| Constipation | 9 | 8 |
| Dyspepsia | 8 | 7 |
| Diarrhea | 5 | 4 |
| Dry Mouth | 4 | 2 |
| Anorexia | 2 | 1 |
| Musculoskeletal | ||
| Myalgia | 1 | 0 |
| Nervous | ||
| Extrapyramidal Symptoms* | 14 | 8 |
| Somnolence | 14 | 7 |
| Akathisia | 8 | 7 |
| Dizziness** | 8 | 6 |
| Respiratory | ||
| Respiratory Tract Infection | 8 | 3 |
| Rhinitis | 4 | 2 |
| Cough Increased | 3 | 1 |
| Skin and Appendages | ||
| Rash | 4 | 3 |
| Fungal Dermatitis | 2 | 1 |
| Special Senses | ||
| Abnormal Vision | 3 | 2 |
* Extrapyramidal Symptoms includes the following adverse event terms: extrapyramidal syndrome, hypertonia, dystonia, dyskinesia, hypokinesia, tremor, paralysis and twitching. None of these adverse events occurred individually at an incidence greater than 5% in schizophrenia trials.
** Dizziness includes the adverse event terms dizziness and lightheadedness
Explorations for interactions on the basis of gender did not reveal any clinically meaningful differences in the adverse event occurrence on the basis of this demographic factor.
In the schizophrenia studies, the most commonly observed adverse events associated with the use of ziprasidone (incidence of 5% or greater) and observed at a rate on ziprasidone at least twice that of placebo were somnolence (14%), extrapyramidal symptoms (14%), and respiratory tract infection (8%).
An analysis for dose response in the schizophrenia 4-study pool revealed an apparent relation of adverse event to dose for the following events: asthenia, postural hypotension, anorexia, dry mouth, increased salivation, arthralgia, anxiety, dizziness, dystonia, hypertonia, somnolence, tremor, rhinitis, rash, and abnormal vision.
The incidence of reported EPS for ziprasidone-treated patients in the short-term, placebo-controlled trials was 14% vs. 8% for placebo. Medications to treat EPS and movement disorders were allowed; but if clinically meaningful movement disorder side effects were observed by the clinician or volunteered by the subject, or if a clinically meaningful movement disorder, present at screening, increased in severity or required the administration of anticholinergics or propanolol, these symptoms and their severity were recorded as adverse event. Objectively collected data from those trials on the Simpson Angus Rating Scale (for EPS) and the Barnes Akathisia Scale (for akathisia) did not generally show a difference between ziprasidone and placebo.
Table 2. Treatment-Emergent Extrapyramidal Symptoms Assessed by Adverse Events Incidence in Short-Term, Schizophrenia Placebo-Controlled Trials:
| &nbp; | Percentage of Subjects Reporting Event | |
|---|---|---|
| Extrapyramidal Symptoms | ZELDOX N=702 | Placebo N=273 |
| Dystonic events1 | 4.0% | 2.2% |
| Parkinsonism events2 | 10.7% | 5.1% |
| Akathisia events3 | 8.4% | 7.0% |
| Dyskinetic events4 | 1.9% | 2.9% |
| Residual events5 | 0.3% | 0.4% |
| Any extrapyramidal event | 21.7% | 15% |
1 Patients with the following COSTART terms were counted in this category: dystonia, oculogyric crisis
2 Patients with the following COSTART terms were counted in this category: abnormal gait, akinesia, cogwheel rigidity, extrapyramidal syndrome, hypokinesia, muscular hypertonia, tremor
3 Patients with the following COSTART terms were counted in this category: akathisia
4 Patients with the following COSTART terms were counted in this category: dyskinesia, paralysis, tardive dyskinesia
5 Patients with the following COSTART terms were counted in this category: twitching
Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include: spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur at low doses, they occur more frequently and with greater severity with high potency and at higher doses of first generation antipsychotic drugs. An elevated risk of acute dystonia is observed in males and younger age groups.
ZELDOX is associated with orthostatic hypotension (see WARNINGS AND PRECAUTIONS, Cardiovascular, Orthostatic Hypotension).
Ziprasidone is associated with an increase in the QTc interval (see WARNINGS AND PRECAUTIONS, QT Prolongation). In schizophrenia trials, ziprasidone was associated with a mean increase in heart rate of 1.4 beats per minute compared to a 0.2 beats per minute decrease among placebo patients.
The proportions of patients meeting a weight gain criterion of >7% of body weight were compared in a pool of four 4- and 6-week placebo-controlled schizophrenia clinical trials, revealing a statistically significantly greater incidence of weight gain for ziprasidone (10%) compared to placebo (4%). A median weight gain of 0.5 kg was observed in ziprasidone patients compared to no median weight change in placebo patients. In this set of clinical trials, weight gain was reported as an adverse event in 0.4% of ziprasidone and 0.4% of placebo patients.
During long-term therapy with ziprasidone, a categorization of patients at baseline on the basis of body mass index (BMI) revealed the greatest mean weight gain and highest incidence of clinically significant weight gain (>7% of body weight) in patients with low BMI (<23) compared to normal (23-27) or overweight patients (>27). There was a mean weight gain of 1.4 kg for those patients with a “low” baseline BMI, no mean change for patients with a “normal” BMI, and a 1.3 kg mean weight loss for patients who entered the program with a “high” BMI.
All reported treatment-emergent events are included except those already listed in Table 1 or in other sections. It is important to emphasize that, although the events reported occurred during treatment with ZELDOX capsules, they were not necessarily caused by the therapy.
The adverse events are categorized by body system and listed in order of decreasing frequency according to the following definitions: frequent adverse events are those occurring in at least 1/100 patients (only those not already listed in the tabulated results from placebo-controlled trials appear in this listing); infrequent adverse events are those occurring in 1/100 to 1/1000 patients; rare events are those occurring in fewer than 1/1000 patients.
Body As a Whole – Frequent: abdominal pain, flu syndrome, fever, accidental fall, face edema, chills, photosensitivity reaction, flank pain, hypothermia, motor vehicle accident; Rare: feeling hot.
Cardiovascular System – Frequent: hypertension; Infrequent: bradycardia, angina pectoris, atrial fibrillation; Rare: first degree AV block, bundle branch block, phlebitis, pulmonary embolus, cardiomegaly, cerebral infarct, cerebrovascular accident, deep thrombophlebitis, myocarditis, thrombophlebitis.
Digestive System – Frequent: vomiting; Infrequent: rectal hemorrhage, dysphagia, tongue edema; Rare: gum hemorrhage, jaundice, fecal impaction, gamma glutamyl transpeptidase increased, hematemesis, cholestatic jaundice, hepatitis, hepatomegaly, leukoplakia of mouth, fatty liver deposit, melena.
Endocrine – Rare: hypothyroidism, hyperthyroidism, thyroiditis.
Hemic and Lymphatic System – Infrequent: anemia, ecchymosis, leukocytosis, leukopenia, eosinophilia, lymphadenopathy; Rare: thrombocytopenia, hypochromic anemia, lymphocytosis, monocytosis, basophilia, lymphedema, polycythemia, thrombocythemia.
Metabolic and Nutritional Disorders – Infrequent: thirst, transaminase increased, peripheral edema, hyperglycemia, creatine phosphokinase increased, alkaline phosphatase increased, hypercholesteremia, dehydration, lactic dehydrogenase increased, albuminuria, hypokalemia; Rare: BUN increased, creatinine increased, hyperlipemia, hypocholesteremia, hyperkalemia, hypochloremia, hypoglycemia, hyponatremia, hypoproteinemia, glucose tolerance decreased, gout, hyperchloremia, hyperuricemia, hypocalcemia, hypoglycemic reaction, hypomagnesemia, ketosis, respiratory alkalosis.
Musculoskeletal System – Infrequent: tenosynovitis; Rare: myopathy.
Nervous System – Frequent: agitation, tremor, dyskinesia, hostility, paresthesia, confusion, vertigo, hypokinesia, hyperkinesia, abnormal gait, oculogyric crisis, hypesthesia, ataxia, amnesia, cogwheel rigidity, delirium, hypotonia, akinesia, dysarthria, withdrawal syndrome, buccoglossal syndrome, choreoathetosis, diplopia, incoordination, neuropathy; Rare: myoclonus, nystagmus, torticollis, circumoral paresthesia, opisthotonos, reflexes increased, trismus.
Respiratory System – Frequent: dyspnea; Infrequent: pneumonia, epistaxis; Rare: hemoptysis, laryngismus.
Skin and Appendages – Infrequent: maculopapular rash, urticaria, alopecia, eczema, exfoliative dermatitis, contact dermatitis, vesiculobullous rash. Drug reaction with eosinophilia and systemic symptoms (DRESS)
Special Senses – Infrequent: conjunctivitis, dry eyes, tinnitus, blepharitis, cataract, photophobia; Rare: eye hemorrhage, visual field defect, keratitis, keratoconjunctivitis.
Urogenital System – Infrequent: impotence, abnormal ejaculation, amenorrhea, hematuria, menorrhagia, female lactation, polyuria, urinary retention, metrorrhagia, male sexual dysfunction, anorgasmia, glycosuria; Rare: gynecomastia, vaginal hemorrhage, nocturia, oliguria, female sexual dysfunction, uterine hemorrhage.
For ziprasidone-treated subjects in short-term, placebo controlled studies 5.5% (25/457) discontinued treatment due to adverse events, compared with 3.1% (7/224) on placebo. The most common events associated with dropout (>0.5%) in the ziprasidone-treated patients were events affecting the nervous system (17/457; 3.7%), the digestive system (5/457; 1.1%), and body as a whole (4/457; 0.9%).
Table 3 enumerates the incidence of treatment-emergent adverse events that occurred during therapy in bipolar patients, including only those events that occurred in 2% or more of patients treated with ziprasidone and for which the incidence in patients treated with ziprasidone was greater than the incidence in placebo-treated patients.
Table 3. Treatment-Emergent, Adverse Event Incidence in Short-Term (up to 3 weeks), PlaceboControlled Trials – Bipolar Mania:
| Body System and COSTART Preferred Term | Ziprasidone (n=457) | Placebo (n=224) |
|---|---|---|
| Body as a whole | ||
| Headache | 67 (14.7%) | 31 (13.8%) |
| Asthenia | 21 (4.6%) | 3 (1.3%) |
| Pain | 15 (3.3%) | 5 (2.2%) |
| Accidental Injury | 14 (3.1%) | 3 (1.3%) |
| Cardiovascular | ||
| Hypertension | 10 (2.2%) | 3 (1.3%) |
| Digestive | ||
| Nausea | 32 (7.0%) | 13 (5.8%) |
| Dyspepsia | 30 (6.6%) | 11 (4.9%) |
| Constipation | 25 (5.5%) | 11 (4.9%) |
| Diarrhea | 17 (3.7%) | 7 (3.1%) |
| Vomiting | 17 (3.7%) | 5 (2.2%) |
| Tooth Disorder | 17 (3.7%) | 5 (2.2%) |
| Dry mouth | 16 (3.5%) | 6 (2.7%) |
| Increased salivation | 12 (2.6%) | 1 (0.4%) |
| Nervous | ||
| Somnolence | 104 (22.8%) | 19 (8.5%) |
| Extrapyramidal Syndrome | 62 (13.6%) | 11 (4.9%) |
| Akathisia | 59 (12.9%) | 10 (4.5%) |
| Dizziness | 49 (10.7%) | 9 (4.0%) |
| Dystonia | 32 (7.0%) | 3 (1.3%) |
| Tremor | 23 (5.0%) | 6 (2.7%) |
| Hypertonia | 22 (4.8%) | 3 (1.3%) |
| Agitation | 19 (4.2%) | 9 (4.0%) |
| Anxiety | 17 (3.7%) | 6 (2.7%) |
| Dyskinesia | 11 (2.4%) | 1 (0.4%) |
| Respiratory | ||
| Pharyngitis | 10 (2.2%) | 1 (0.4%) |
| Skin and Appendages | ||
| Pruritus | 15 (3.3%) | 5 (2.2%) |
| Special senses | ||
| Abnormal vision | 18 (3.9%) | 4 (1.8%) |
In bipolar mania clinical trials, the most common adverse events associated with the use of ziprasidone (incidence of 5% or greater) and observed at a rate on ziprasidone at least twice that of placebo were somnolence, akathisia, dizziness, dystonia, and extrapyramidal syndrome.
Ziprasidone is associated with an increase in the QTc interval (see WARNINGS AND PRECAUTIONS, QT Prolongation).
The incidence of reported extrapyramidal syndrome and other EPS-related adverse events in the shortterm, placebo-controlled trials was greater for ziprasidone-treated patients. Medications to treat EPS and movement disorders were allowed; but if clinically meaningful movement disorder side effects were observed by the clinician or volunteered by the subject, or if a clinically meaningful movement disorder present at screening increased in severity or required the administration of anticholinergics or propanolol, these symptoms and their severity were recorded as adverse events. EPS-related adverse events in all studies were usually mild, dose-related and reversible upon dose reduction and/or administration of antiparkinsonian medication. Objectively collected data from those trials on the Simpson Angus Rating Scale (for EPS) and the Barnes Akathisia Scale (for akathisia) did not generally show a difference between ziprasidone and placebo.
Table 4. Treatment-Emergent Extrapyramidal Symptoms Assessed by Adverse Events Incidence in Short-Term, Bipolar Mania Placebo-Controlled Trials:
| Percentage of Subjects Reporting Event | ||
|---|---|---|
| Extrapyramidal Symptoms | ZELDOX N=457 | Placebo N=224 |
| Dystonic events1 | 8.3% | 1.8% |
| Parkinsonism events2 | 23.6% | 8.9% |
| Akathisia events3 | 13.1% | 4.5% |
| Dyskinetic events4 | 3.9% | 0.9% |
| Residual events5 | 0.4% | 0.9% |
| Any extrapyramidal event | 40.3% | 15.6% |
1 Patients with the following COSTART terms were counted in this category: dystonia, myoclonus, oculogyric crisis, torticollis, trismus.
2 Patients with the following COSTART terms were counted in this category: abnormal gait, extrapyramidal syndrome, hypertonia, hypokinesia, muscular hypertonia, tremor
3 Patients with the following COSTART terms were counted in this category: akathisia, hyperkinesia
4 Patients with the following COSTART terms were counted in this category: dyskinesia, paralysis, tardive dyskinesia
5 Patients with the following COSTART terms were counted in this category: twitching
All reported treatment-emergent events are included except those already listed in Table 3 or in other sections. It is important to emphasize that, although the events reported occurred during treatment with ZELDOX capsules, they were not necessarily caused by the therapy.
The adverse events are categorized by body system and listed in order of decreasing frequency according to the following definitions: frequent adverse events are those occurring in at least 1/100 patients (only those not already listed in the tabulated results from placebo-controlled trials appear in this listing); infrequent adverse events are those occurring in 1/100 to 1/1000 patients; rare events are those occurring in fewer than 1/1000 patients.
Body As A Whole – Frequent: abdominal pain, back pain, neck pain; Infrequent: chest pain, infection, abscess, face edema, fever, flu syndrome, hot flushes, allergic reaction, cellulitis, chest pain substernal, chills infection bacterial, lab test abnormal, suicidal ideation.
Cardiovascular System – Infrequent: hypotension, tachycardia, palpitation, bundle branch block, migraine, bradycardia, hemorrhage, pallor, postural hypotension, QT interval prolonged, syncope.
Digestive System – Frequent: gastritis, flatulence, tongue edema, dysphagia, anorexia; Infrequent: increased appetite, gastroenteritis, duodenitis, fecal impaction, gingivitis, gum hemorrhage, mouth ulceration, periodontitis, stomach ulcer.
Hemic and Lymphatic System – Infrequent: bruise, leukopenia.
Metabolic and Nutritional Disorders – Infrequent: edema, peripheral edema, thirst, hypocalcemia, respiratory alkalosis, SGPT increased, weight gain, weight loss.
Musculoskeletal System – Frequent: myalgia; Infrequent: arthralgia, joint disorder, leg cramps, myasthenia, bone pain, arthrosis, bone fracture accidental, myopathy, painful swelling.
Nervous System – Frequent: Insomnia, paralysis, depression, speech disorder, abnormal dreams, abnormal gait, hypesthesia, oculogyric crisis; Infrequent: manic reaction, muscular hypertonia, thinking abnormal, hypokinesia, withdrawal syndrome, bipolar affective disorder – manic, grand mal convulsion, nervousness, twitching, vertigo, amnesia, apathy, ataxia, bipolar affective disorder – depressive, confusion, delusions, depersonalization, hallucinations, hyperkinesia, manic depressive reaction, paresthesia, personality disorder, sleep disorder, torticollis, trismus.
Respiratory System – Frequent: respiratory tract infection, dyspnea, rhinitis, cough increased, respiratory disorder; Infrequent: asthma, sinusitis, bronchitis, hiccup, hypoxia.
Skin And Appendages – Frequent: rash, fungal dermatitis. Infrequent: sweating, acne, maculopapular rash, dry skin, urticaria, alopecia, dermatitis, exfoliative dermatitis, herpes simplex, skin disorder.
Special Senses – Frequent: ear pain; Infrequent:photophobia, conjunctivitis, tinnitus, ear disorder, otitis media, dry eyes, otitis externa.
Urogenital System – Frequent: vaginitis, dysmenorrhea; Infrequent: urinary frequency, polyuria, urinary tract infection, dyspareunia, female lactation, mastitis female, uterine spasm, dysuria, penile erection, urinary incontinence, anorgasmia, breast pain.
The safety and efficacy of ZELDOX in children under the age of 18 years have not been established and its use is not recommended (see WARNINGS AND PRECAUTIONS, Special Populations, Pediatrics) All of the adverse events described above for adults with bipolar disorder and schizophrenia should be considered in the case of children and adolescents taking ZELDOX. Additional adverse events of note from each of the two studies in the pediatric population, are summarized in the following tables. The listed events are those that are either i) worse in children than in adults (greater frequency rates compared to studies in adults of the same disorder, or greater difference from placebo rates, or greater severity), or ii) identified only in pediatric populations, and for which drug rates are greater than placebo.
Table 5. Adverse Events during short-term (4 weeks) treatment of children and adolescents with Bipolar Disorder (ages 10-17 years), that were identified as worse in children compared to adults or unique to children, and greater than placebo:
| Body System and MedDRA term | Percentage of Subjects With Adverse events | |
|---|---|---|
| ZELDOX (n=149) | Placebo (n=88) | |
| Eye Disorders | ||
| Vision blurred | 6% | 1% |
| Gastrointestinal Disorder | ||
| Nausea | 14% | 7% |
| Vomiting | 8% | 1% |
| Abdominal paina | 13% | 7% |
| General Disorders | ||
| Fatigue | 15% | 7% |
| Investigations | ||
| Prolactin increasedb | 11% 6% (male) 17% (female) | 1% 3% (male) 0% (female) |
| Insulin increasedc | 6% | 0% |
| Total neutrophils (Abs) increasedd | 4% | 0% |
| Increased ALTe | 2% | 0% |
| Increased Testosterone (females)f | 17% | 3% |
| Nervous system disorders | ||
| Extrapyramidal Symptomsg | 30% | 7% |
| Sedation, Somnolence | 56% | 14% |
| Respiratory, thoracic and mediastinal disorders | ||
| Upper respiratory tract infection | 5% | 0% |
| Psychiatric Disorders | ||
| Insomnia | 9% | 3% |
| Restlessness | 5% | 1% |
Includes data up to 6 days after last dose of study drug.
Subjects were counted only once per treatment in each row.
Medical Dictionary for Regulatory Activities (v14.0) coding applied
a Abdominal pain includes the following adverse reaction terms: abdominal discomfort, abdominal pain, abdominal pain upper, abdominal pain lower
b Prolactin levels: >19.47 μg/L males (>1.1 ULN=17.7 μg/L); >32.12 μg/L females (>1.1 ULN=29.2 μg/L) at any time. Two subjects had an increased prolactin level greater than 60 μg/L (females, on ziprasidone, 64 ug/L and 101 ug/L).For the term prolactin, "n' for ZELDOX = 114 and for placebo = 71
c Insulin levels: >32.4 UU/ml (>1.2 ULN=27 UU/ml) at any time. The maximum value observed was 56 UU/ml. For the term insulin, "n' for ZELDOX = 88, and for placebo = 54
d Total neutrophils (abs) levels: > 9360 per μL (>1.2 ULN=7800 per μL ) at any time. Values ranged up to 15600 per μL For the term total neutrophils (abs), “n” for ZELDOX = 107 and for placebo = 74
e ALT levels >3 X ULN = 30 U/L males and 20 U/L females. For the term ALT, “n” for ZELDOX = 132, and for placebo = 84.
f Testosterone: >1.2 X ULN = 40 ng/dL and >1.2 X baseline in subjects with abnormal baseline (ie, 4 of 8 females in the ziprasidone group and 1 or 1 female in the placebo group). Increased Testosterone (females), “n” for ZELDOX = 46, and for placebo = 29.
g “Extrapyramidal symptoms” includes the following adverse reaction terms: akathesia, musculoskeletal stiffness, tremor, extrapyramidal disorder, dystonia, drooling, dyskinesia, muscle twitching, tic, muscle spasms, cogwheel rigidity, gait disturbance, torticollis.
Table 6. Adverse Events during short-term (6 weeks) treatment of children and adolescents with Schizophrenia (ages 13 -17 years), that were identified as worse in children compared to adults or unique to children, and greater than placebo:
| Body System and MedDRA term | Percentage of Subjects With Adverse events | |
|---|---|---|
| ZELDOX (n=193) | Placebo (n=90) | |
| Gastrointestinal Disorder | ||
| Nausea | 10% | 2% |
| Vomiting | 6% | 3% |
| General Disorders | ||
| Fatigue | 9% | 4% |
| Investigations | ||
| Prolactin increaseda | 20% 24% (male) 14% (female) | 5% 8% (male) 0% (female) |
| Bicarbonate decreasedb | 17% | 6% |
| Monocytes increasedc | 7% | 2% |
| Nervous system disorders | ||
| Extrapyramidal Symptomsd | 25% | 7% |
| Sedation, Somnolence | 24% | 7% |
| Dizziness | 9% | 1% |
Includes data up to 6 days after last dose of study drug. Subjects were counted only once per treatment in each row. Medical Dictionary for Regulatory Activities (v14.0) coding applied
a Prolactin levels: >19.47 μg/L males (>1.1 ULN=17.7 μg/L); >32.12 μg/L females (>1.1 ULN=29.2 μg/L) at any time. One subject had an increased prolactin level greater than 60 μg/L (female, on ziprasidone, 98.3 ug/L). For the term prolactin increased, “n” for ZELDOX = 50 and for placebo = 20
b Bicarbonate levels: < 19.8 mEq/L (<0.9 LLN= 22 per μL ) at any time. Lowest observed ZELDOX value was 15 mEq/L. For the term bicarbonate decreased, “n” for ZELDOX = 95 and for placebo = 49
c Monocyte levels: >11% (>1.2 ULN=9-10%) at any time. Highest observed ZELDOX value was 17% . For the term monocytes increased, “n” for ZELDOX = 172 and for placebo = 84
d “Extrapyramidal symptoms” includes the following adverse reaction terms: gait disturbance, muscle rigidity, muscle spasms, muscle twitching, torticollis, musculoskeletal stiffness, akathisia, drooling, dyskinesia, dystonia, extrapyramidal disorder, hypokinesia, parkinsonian rest tremor, tremor, masked facies.
In one 4-week, placebo-controlled trial in child and adolescent patients (10-17 years of age) with bipolar disorder, the mean increase in body weight was 0.7 kg in the ziprasidone group and 0.8 kg in the placebo group. Of ZELDOX treated patients, 6.9 % gained ≥7% of their bodyweight, compared to 3.7% of placebo-treated patients.
In the open-label study that enrolled patients from the above bipolar trial, 41% of patients (67/169) completed 26 weeks of therapy with ziprasidone. After 26 weeks of treatment, the mean increase in body weight was 3.9 kg, and 30% of the patients gained ≥7% of their body weight in completers, not adjusted for normal growth. In order to adjust for normal growth over 26 weeks, an increase of at least 0.5 standard deviation from baseline in BMI Z-score was used as a measure of a clinically significant change; 16% of patients on ZELDOX met this criterion after 26 weeks of treatment.
In one 6-week, placebo-controlled trial in adolescent patients (13-17 years of age) with schizophrenia, the mean change in body weight was -0.1 kg in the ziprasidone group and 0.0 kg in the placebo group. Of ZELDOX treated patients 4% gained >7% of their bodyweight, compared to 0% of placebo-treated patients.
In the open-label study that enrolled patients from the above schizophrenia trial, 34% of patients (76/221) completed 26 weeks of therapy with ziprasidone, and 13 % of the patients gained ≥7% of their body weight, not adjusted for normal growth After 26 weeks of treatment, the mean increase in body weight was 1.7 kg. In order to adjust for normal growth over 26 weeks an increase of at least 0.5 standard deviation from baseline in BMI Z-score was used as a measure of a clinically significant change; 8% of patients on ZELDOX met this criterion after 26 weeks of treatment.
The pediatric EPS data are from one short-term placebo controlled, monotherapy study in each of bipolar patient population (4 week duration; 10-17 years of age) and schizophrenic population (6 week duration; 13-17 years of age). Across the two placebo-controlled studies, the incidences of adverse events potentially related to EPS showed a greater differential between ziprasidone and placebo compared to trials of adults with these indications (Incidence of EPS on ZELDOX was 30% and 25% for bipolar and schizophrenia respectively, compared to 7% for placebo in both studies). The identified events included akathisia, drooling, dyskinesia, dystonia, gait disturbance, extrapyramidal disorder, muscle spasms/twitching, musculoskeletal stiffness, tremor, and torticollis.
Bipolar Open-label Data: In the 26-week open label extension study, a total of 18% (29 /162) experienced EPS during that period. All reported EPS events were of mild or moderate severity. Of the subjects experiencing EPS 21% (6/29) had dose reductions, and 7% (2/29) were discontinued from drug. In the pediatric bipolar patient population, EPS events of note in addition to those mentioned above include: tic, cogwheel rigidity, restless legs syndrome, and dysarthria.
Schizophrenia Open-label Data: In the 26-week, open label extension study that enrolled subjects from the placebo-controlled schizophrenia trial, a total of 15% (34/221) experienced EPS during that period. Of these, 8% (3 /34) experienced an EPS event as severe. Of the subjects experiencing EPS 30% (10 /34) had dose reductions, and none were discontinued from drug. In the schizophrenia patient population, EPS events of note in addition to the aggregated events listed above include: tardive dyskinesia, restless legs syndrome, masked facies and oculogyric crisis.
While the majority of extrapyramidal adverse events resolved within the duration of each study period, there were cases in which the events remained unresolved at the end of both the controlled and open-label trials.
Ziprasidone was associated with a mild to moderate dose-related prolongation of the QT interval in the pediatric bipolar and schizophrenia clinical trials. There are insufficient data to determine whether this population is more vulnerable than adults to QT prolongation effects from ZELDOX.
The laboratory abnormalities observed during the double-blind phase of the two pediatric studies are presented in Tables 5 and 6 (bipolar mania and schizophrenia respectively). Of note in the open-label phases, an ALT value of 763 U/L was observed in a patient , along with akathesia and fatigue, and an elevated AST value. No follow-up information is available. Decreased bicarbonate was reported at 32% (44/136) in the open-label bipolar study, and 23% (47/ 201) in the open-label schizophrenia study. Increased prolactin was reported at 7% (10/134) and 20% (17/86) respectively. One subject in the openlabel schizophrenia study had an adverse event of increased prolactin of moderate severity.
In the ziprasidone pediatric studies, periodic searches were conducted of the adverse event database of each study to identify all possibly suicide-related adverse events (PSRAEs). These were reviewed by a blinded independent panel of experts and classified according to the C-CASA suicidality classification system (Columbia Classification Algorithm for Suicide Assessment) The incidence rates below exclude events classified as overdose due to dosing error.
In one 4-week, placebo-controlled trial in child and adolescent patients (10-17 years of age) with bipolar disorder, the incidence of PSRAEs was 5.4% (8/149) for ziprasidone and 5.9% (5/88) for placebo. In the 26-week, open-label study that enrolled patients from the above trial (N=162), the incidence of PSRAEs was 9.3% (15/162).
In one 6-week, placebo-controlled trial in adolescent patients (13-17 years of age) with schizophrenia, the incidence of PSRAEs was 2.3% (5/193) for ziprasidone and 2.2% (2/90) for placebo. In the 26-week, open-label study that enrolled patients from the above trial (N=221). The incidence of PSRAEs was 4.1% (9/221).There was one completed suicide (a 17 year old female with a diagnosis of schizophrenia, disorganized type, receiving 160 mg ziprasidone).
The safety and efficacy of ZELDOX in children under the age of 18 years have not been established and its use is not recommended.
Adverse event reports not listed above that have been received from spontaneous post-marketing reports for ZELDOX since market introduction are shown below (no causal relationship with ziprasidone has been established).
Cardiac Disorders: Tachycardia, torsades de pointes (in the presence of multiple confounding factors – see WARNINGS AND PRECAUTIONS, QT Prolongation);
Gastrointestinal Disorders: Dysphagia, swollen tongue, severe constipation (see WARNINGS AND PRECAUTIONS, Gastrointestinal).
Hemic and Lymphatic System: neutropenia, granulocytopenia and agranulocytosis.
Immune System Disorders: Allergic
Metabolic and Nutritional Disorders: diabetic coma, lipids abnormal
Nervous System Disorders: Facial droop, neuroleptic malignant syndrome, serotonin syndrome (alone or in combination with serotonergic medicinal products), tardive dyskinesia;
Psychiatric Disorders: Insomnia, mania/hypomania;
Renal and Urinary Disorders: Enuresis, urinary incontinence;
Reproductive System and Breast Disorders: Galactorrhea, priapism;
Skin and subcutaneous Tissue Disorders: Angioedema, rash; Stevens Johnson Syndrome, Drug reaction with eosinophilia and systemic symptoms (DRESS);
Vascular Disorders: Postural hypotension, syncope.
Sleep-related Disorders: Atypical antipsychotic drugs, including ziprasidone, have been reported with cases of sleep apnoea, with or without concomitant weight gain. In patients who have a history of or are at risk for sleep apnoea, ZELDOX should be prescribed with caution.
Risks of somnambulism (sleep walking) and sleep-related eating disorder have been reported with the use of atypical antipsychotics including ziprasidone.
Drug-drug interactions can be pharmacodynamic (combined pharmacologic effects) or pharmacokinetic (alteration of plasma levels). The risks of using ziprasidone in combination with other drugs have been evaluated as described below. Based upon the pharmacodynamic and pharmacokinetic profile of ziprasidone, possible interactions could be anticipated:
Ketoconazole:
Ketoconazole, a potent inhibitor of CYP3A4, at a dose of 400 mg per day for 5 days, increased the AUC and Cmax of ziprasidone (80 mg BID) by approximately 35-40%. The serum concentration of S-methyldihydroziprasidone, at the expected Tmax of ziprasidone, was increased by 55% during ketoconazole treatment. No additional QTc prolongation was observed. Other potent inhibitors of CYP3A4 would be expected to have similar effects.
Coadministration of potent CYP3A4 inhibitors has the potential of increasing ziprasidone serum concentrations. The clinical importance of this potential has not been clearly defined.
Carbamazepine:
Carbamazepine is an inducer of CYP3A4; administration of 200 mg BID for 25 days resulted in a decrease of approximately 36% in the AUC of ziprasidone (20 mg BID). This effect may be greater when higher doses of carbamazapine are administered.
Valproate, Lamotrigine:
Ziprasidone has not been studied for drug interaction with valproate or lamotrigine.
Cimetidine:
Cimetidine at a dose of 800 mg QD for 2 days did not affect pharmacokinetics of ziprasidone (single 40 mg dose).
Antacids:
The coadministration of 30 mL of MAALOX with ziprasidone (single 40 mg dose) did not affect the pharmacokinetics of ziprasidone.
Benztropine, Propranolol, or Lorazepam:
Population pharmacokinetic analysis of schizophrenic patients enrolled in controlled clinical trials has not revealed evidence of clinically significant pharmacokinetic interaction with benztropine, propranolol, or lorazepam.
Potential for Effect on Cytochrome P450:
In vitro studies revealed little potential for ziprasidone to interfere with the metabolism of drugs cleared primarily by CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4. Consistent with these in vitro results, studies in normal healthy volunteers showed that ziprasidone did not alter the metabolism of dextromethorphan, a CYP2D6 model substrate, nor of ethinyl estradiol, a CYP3A4 substrate. Thus, ziprasidone is unlikely to cause clinically important drug interactions mediated by these enzymes (see ACTION AND CLINICAL PHARMACOLOGY, Pharmacokinetics).
Protein Binding:
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 appears to be minimal.
Dextromethorphan:
Consistent with in vitro results, a study in normal healthy volunteers showed that ziprasidone did not alter the metabolism of dextromethorphan, a CYP2D6 model substrate, to its major metabolite, dextrorphan. There was no statistically significant change in the urinary dextromethorphan/dextrorphan ratio.
Oral Contraceptives:
Ziprasidone, at a dose of 20 mg BID, did not affect the pharmacokinetics of concomitantly administered oral contraceptives, ethinylestradiol (0.03 mg), a CYP3A4 substrate, or levonorgestrel (0.15 mg) progesterone components.
Lithium:
Ziprasidone, at a dose of 40 mg BID, administered concomitantly with lithium at a dose of 450 mg BID for 7 days did not affect the steady-state level or renal clearance of lithium. As ziprasidone and lithium are associated with cardiac conduction changes, the combination may pose a risk for pharmacodynamic interaction, including arrhythmias.
CNS Drugs/Alcohol:
Given the primary CNS effects of ziprasidone, caution should be used when it is taken in combination with other centrally acting drugs, including alcohol.
The absorption of ziprasidone is increased up to two-fold in the presence of food.
Interactions with herbal products have not been established.
Interactions with laboratory tests have not been established.
Smoking:
Based on in vitro studies utilizing human liver enzymes, ziprasidone is a substrate for CYP1A2, however, the contribution of this pathway is minor. Consistent with these in vitro results, population pharmacokinetic evaluation has not revealed any significant differences in ziprasidone pharmacokinetics between smokers and nonsmokers.
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