Summary Basis of Decision for Zeldox

Review decision

The Summary Basis of Decision explains why the product was approved for sale in Canada. The document includes regulatory, safety, effectiveness and quality (in terms of chemistry and manufacturing) considerations.

Product type:


Ziprasidone hydrochloride monohydrate, 20, 40, 60, and 80 mg, Capsule, Oral

Pfizer Canada Inc.

Submission control no: 078188

Date issued: 2008-06-21


Health Canada's Summary Basis of Decision (SBD) documents outline the scientific and regulatory considerations that factor into Health Canada regulatory decisions related to drugs and medical devices. SBDs are written in technical language for stakeholders interested in product-specific Health Canada decisions, and are a direct reflection of observations detailed within the evaluation reports. As such, SBDs are intended to complement and not duplicate information provided within the Product Monograph.

Readers are encouraged to consult the 'Reader's Guide to the Summary Basis of Decision - Drugs' to assist with interpretation of terms and acronyms referred to herein. In addition, a brief overview of the drug submission review process is provided in the Fact Sheet entitled 'How Drugs are Reviewed in Canada'. This Fact Sheet describes the factors considered by Health Canada during the review and authorization process of a drug submission. Readers should also consult the 'Summary Basis of Decision Initiative - Frequently Asked Questions' document.

The SBD reflects the information available to Health Canada regulators at the time a decision has been rendered. Subsequent submissions reviewed for additional uses will not be captured under Phase I of the SBD implementation strategy. For up-to-date information on a particular product, readers should refer to the most recent Product Monograph for a product. Health Canada provides information related to post-market warnings or advisories as a result of adverse events (AE).

For further information on a particular product, readers may also access websites of other regulatory jurisdictions. The information received in support of a Canadian drug submission may not be identical to that received by other jurisdictions.

Other Policies and Guidance

Readers should consult the Health Canada website for other drug policies and guidance documents. In particular, readers may wish to refer to the 'Management of Drug Submissions Guidance'.

1 Product and submission information

Brand name:



Pfizer Canada Inc.

Medicinal ingredient:

Ziprasidone hydrochloride monohydrate

International non-proprietary Name:

Ziprasidone hydrochloride


20, 40, 60, and 80 mg

Dosage form:


Route of administration:


Drug identification number(DIN):

  • 02298597 - 20 mg
  • 02298600 - 40 mg
  • 02298619 - 60 mg
  • 02298627 - 80 mg

Therapeutic Classification:

Antipsychotic Agent

Non-medicinal ingredients:

Lactose monohydrate, magnesium stearate, pregelatinized starch

Submission type and control no:

New Drug Submission, Control No. 078188

Date of Submission:


Date of authorization:


* TM Pfizer Products Inc. Pfizer Canada Inc., licensee

2 Notice of decision

On August 27, 2007, Health Canada issued a Notice of Compliance to Pfizer Canada Inc. for the drug product, Zeldox.

Zeldox contains the medicinal ingredient ziprasidone hydrochloride monohydrate which is an antipsychotic agent.

Zeldox is indicated for the treatment of schizophrenia and related psychotic disorders. Schizophrenia is a chronic psychotic disorder with fluctuating disturbances in thinking, behaviour, and perception, with potential for significant impairment of occupational and social functioning. The mechanism of action of ziprasidone is unknown; however, it has been proposed that the efficacy of this drug in schizophrenia is mediated through a combination of dopamine type 2 and serotonin type 2 antagonism.

The market authorization was based on submitted data from quality (chemistry and manufacturing), non-clinical and clinical studies. The prescriber should consider the finding of ziprasidone's greater capacity to prolong the QT/QTc interval compared to other antipsychotic drugs. The efficacy of ziprasidone was established in short-term (4- and 6-week) controlled trials of schizophrenic inpatients. Zeldox has been shown to be effective in maintaining clinical improvement during long-term therapy (1 year). The physician who elects to use Zeldox for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient. Zeldox is not indicated in elderly patients with dementia.

Zeldox (20, 40, 60, and 80 mg/capsule, ziprasidone hydrochloride monohydrate) is presented in capsule form. Zeldox may be administered at an initial daily dose of 40 mg twice daily (BID) with food, however individual patients may benefit from an initial dose of 20 mg BID. Daily dosage may subsequently be adjusted on the basis of clinical status up to 80 mg BID. Dosage adjustments, if indicated, should generally occur at intervals of not less than 2 days, since steady-state is achieved within 1 to 3 days. Dosing guidelines are available in the Product Monograph.

Zeldox is contraindicated for patients with known history of QT prolongation (including congenital long QT syndrome), recent acute myocardial infarction, or uncompensated heart failure. Zeldox is 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. Zeldox is also contraindicated in patients who are hypersensitive to ziprasidone or to any ingredient in the formulation or component of the container. Zeldox should be administered under the conditions stated in the Product Monograph taking into consideration the potential risks associated with the administration of this drug product. Detailed conditions for the use of Zeldox are described in the Product Monograph.

Based on the Health Canada review of data on quality, safety, and effectiveness, Health Canada considers that the benefit/risk profile of Zeldox is favourable for the treatment of schizophrenia and related psychotic disorders.

3 Scientific and Regulatory Basis for Decision

In April 1997, a New Drug Submission (Control No. 050567) for ziprasidone hydrochloride monohydrate (Zeldox) was filed with Health Canada. A Notice of Non-Compliance (NON) was issued as there were safety concerns regarding QTc prolongation and other issues. The submission was refiled in June 2002 (Control No. 078188) and again the data were insufficient to support a conclusion of a positive benefit/risk profile. Data from a dedicated QTc study was provided by the sponsor; however the extent of the clinical impact of the QT prolongation on cardiac impact remained unclear. Following interactions with the sponsor, additional information was submitted and in August 2007, Health Canada granted Zeldox a Notice of Compliance (NOC). The detailed timeline of the drug submission is reported in 4 Submission Milestones. A discussion regarding QTc Prolongation appears in section 3.3.4 Clinical Safety.

3.1 Quality Basis for Decision

3.1.1 Drug Substance (Medicinal Ingredient)

General Information

Ziprasidone hydrochloride monohydrate, the medicinal ingredient of Zeldox, is a member of the atypical antipsychotic class with typical dopamine and serotonin binding activities (antagonism and agonism). The drug is indicated for the treatment of schizophrenia and related psychotic disorders.

Note that ziprasidone hydrochloride monohydrate may also be referred to by its USAN name, ziprasidone hydrochloride.

Manufacturing Process and Process Controls

Ziprasidone hydrochloride is manufactured via a multi-step synthesis. Each step of the manufacturing process is considered to be controlled within acceptable limits:

  • The sponsor has provided information on the quality and controls for all materials used in the manufacture of the drug substance.
  • The drug substance specifications are found to be satisfactory. Impurity limits meet ICH requirements.
  • The processing steps have been evaluated and the appropriate ranges for process parameters have been established.

Detailed characterization studies were performed to provide assurance that ziprasidone hydrochloride consistently exhibits the desired characteristic structure.

Control of the impurities and degradation products is considered acceptable. Impurities and degradation products arising from manufacturing and/or storage were reported and characterized. The proposed limits are considered adequately qualified (i.e. within ICH limits and/or qualified from toxicological studies).

Control of Drug Substance

Copies of the analytical methods and, where appropriate, validation reports are considered satisfactory for all analytical procedures used for release and stability testing of ziprasidone hydrochloride.

The specifications are considered acceptable for the drug substance. Data from batch analyses were reviewed and are within the proposed acceptance criteria.

The drug substance packaging is considered acceptable.


Based on the long-term and accelerated stability data submitted, the proposed retest period and storage conditions for the drug substance are supported and considered to be satisfactory.

3.1.2 Drug Product

Description and Composition

Zeldox is presented as opaque, hard gelatin capsules. Each capsule contains ziprasidone hydrochloride monohydrate equivalent to 20, 40, 60 or 80 mg of ziprasidone. The non-medicinal ingredients include: lactose monohydrate, pregelatinized starch, magnesium stearate.

All capsule strengths (20 mg, 40 mg, 60 mg and 80 mg) are available in high-density polyethylene (HDPE) bottles of 100 capsules, and blisters of seven capsules.

Each strength has a different coloured capsule imprinted with black ink. The 20 mg capsules are blue/white capsules, imprinted with "Pfizer" and "396" or "ZDX 20". The 40 mg capsules are blue/blue capsules, imprinted with "Pfizer" and "397" or "ZDX 40". The 60 mg capsules are white/white capsules, imprinted with "Pfizer" and "398" or "ZDX 60". The 80 mg capsules are blue/white capsules, imprinted with "Pfizer" and "399" or "ZDX 80".

All non-medicinal ingredients (excipients) found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations. The compatibility of ziprasidone hydrochloride with the excipients is demonstrated by the stability data presented on the proposed commercial formulation.

Pharmaceutical Development

Changes to the manufacturing process and formulation made throughout the pharmaceutical development are considered acceptable upon review.

Manufacturing Process and Process Controls

The process for the manufacture of Zeldox follows conventional pharmaceutical practices and unit processes. The validated process is capable of consistently generating product that meets release specifications. The manufacturing process is considered to be adequately controlled within justified limits.

Control of Drug Product

Copies of the analytical methods and, where appropriate, validation reports are considered satisfactory for all analytical procedures used for release and stability testing of Zeldox. The proposed limits are considered adequately qualified (i.e. within ICH limits and/or qualified from toxicological studies). Control of the impurities and degradation products is therefore considered acceptable.

Data from final batch analyses were reviewed and are considered to be acceptable according to the specifications of the drug product.


Based on the long term and accelerated stability study data submitted, the proposed shelf-life and storage conditions for the drug product were supported and considered to be satisfactory.

3.1.3 Facilities and Equipment

The design, operations, and controls of the facilities and equipment that are involved in the production are considered suitable for the activities and products manufactured.

All of the proposed manufacturing sites comply with the requirements of Division 2 of the Food and Drug Regulations.

All sites are compliant with Good Manufacturing Practices (GMP).

3.1.4 Adventitious Agents Safety Evaluation

Not applicable. There are no excipients of human or animal origin.

3.1.5 Conclusion

The Chemistry and Manufacturing information submitted for Zeldox has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications. Proper development and validation studies were conducted, and adequate controls are in place for the commercial processes.

3.2 Non-Clinical Basis for Decision

3.2.1 Pharmacodynamics

Ziprasidone was found to be a dopamine antagonist in vitro and in vivo. Ziprasidone enhanced the release of dopamine in rat prefrontal cortex. Its most potent action was antagonism of serotonin 5-HT2A receptors. Ziprasidone also had high affinity for the 5-HT1A (agonist), 5-HT1D (antagonist), and 5-HT2C (antagonist) serotonin receptor subtypes, and blocked the neuronal reuptake of norepinephrine and serotonin with moderate affinity.

The antipsychotic efficacy and mechanism of action were analyzed in animal studies to obtain a more extensive characterization of ziprasidone on various organ systems. In general, ziprasidone was well tolerated in animals at doses that produced effective dopamine receptor antagonism in the brain. Cardiovascular changes in the dog were limited to mild increases in heart rate after oral doses of ziprasidone that achieved 2- to 4-fold higher plasma levels than the maximum plasma drug concentration associated with the maximum recommended human dose.

3.2.2 Pharmacokinetics

Oral bioavailability was <40% in mice, rats, and dogs. The low oral bioavailability was partly due to incomplete absorption as shown by the >50% recovery of the dose in feces as unchanged drug.

Serum protein binding of ziprasidone was very high in various animal species (>99% in rats, rabbits, and dogs; 95% in mice).

The half-life of ziprasidone in rodents was considerably shorter than in dogs. This was probably partly due to the larger volume of distribution and slower clearance in dogs.

The metabolites that were observed in the excretia collected from dogs, rats, and mice were the same as those observed in humans.

3.2.3 Toxicology

Single-Dose Toxicity

No definitive target organs of toxicity were identified, however, clinical signs indicative of effects on the central nervous system were observed (especially sedation).

Repeat-Dose Toxicity

In mice and rats, dose-related decreases in activity and decreases in body weight were reported. Stress-related or secondary changes such as adrenal hypertrophy were observed at the higher doses in both species.

In dogs, all treatment-related effects were consistent with the pharmacologic properties of the drug. Significant weight loss occurred in the high-dose males (20 mg/kg/day). In all dogs that received 40 mg/kg/day, cholestatis of mild to moderate severity was reported.


The genetic toxicology studies were generally negative; however, a slight increase in mutation frequency in Salmonella typhimurium TA 1537 was seen at the highest level tested. Gene mutation assays were negative in mammalian cells in vitro, and chromosomal mutation induction was negative in mammalian cells in vivo and in vitro.


In mice, dose-related increases in the incidence of hyperplasia and neoplasia in the pituitary gland and secondary changes in the mammary gland, ovaries, and uterus were observed at doses having a systemic exposure approximately 1-4 times greater than that recommended for humans. Proliferative changes in the pituitary and mammary glands are not unexpected findings in rodents following treatment with this class of drugs, and are associated with increased prolactin concentrations. In the rat studies, ziprasidone showed no carcinogenic potential.

Reproductive and Developmental Toxicity

An increased incidence of fetal structural abnormalities (ventricular septal defects and other cardiovascular malformations and kidney alterations) was observed in pregnant rabbits that received 30 mg/kg/day ziprasidone (3 times the maximum recommended human dose (MRHD) of 200 mg/day on a mg/m2 basis) during the period of organogenesis. The developmental no-effect dose was 10 mg/kg/day (equivalent to the MRHD on a 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).

Studies showed an increase in the number of pups born dead and a decrease in postnatal survival among the offspring of 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.

3.2.4 Summary and Conclusion

The non-clinical studies for this drug submission are considered acceptable. Ziprasidone demonstrated effects in the non-clinical studies predictive of antipsychotic activity.

In the animal studies, ziprasidone demonstrated developmental toxicity, including possible teratogenic effects at doses similar to human therapeutic doses. Appropriate warnings and precautionary measures are in place in the Product Monograph to address the identified safety concerns.

3.3 Clinical basis for decision

3.3.1 Pharmacodynamics

Ziprasidone is a member of the atypical antipsychotic class, with typical dopamine and serotonin binding (antagonist at D2, 5-HT2A, and 5-HT1D, receptors; agonism at 5-HT1A receptors). Antagonism was shown at histamine H1 and α1 adrenergic receptors, associated with somnolence and orthostatic hypotension, respectively.

Four Positron Emission Tomography (PET) studies were conducted in male volunteers. The studies indicated that ziprasidone occupied both the brain D2 receptors and 5-HT2 receptors. The receptor occupancy was high and was related to the serum levels of the drug.

3.3.2 Pharmacokinetics


Dose-proportionality was demonstrated in the 20 to 80 mg BID (twice a day) dose range. Food greatly enhanced the bioavailability of ziprasidone.The mean absolute bioavailability of ziprasidone when administered as a 20 mg capsule with food was approximately 60%. Drug exposure values (AUC and Cmax) were higher when the drug was given with food compared to administration two hours after food. The Product Monograph states that the drug should be taken with food.


The recommended dosing of twice daily generally leads to attainment of steady state within 1-3 days.

Serum protein binding of ziprasidone was very high (>99%) in humans. Ziprasidone binds to both α1-acid glycoprotein and serum albumin. The in vitro plasma protein binding of ziprasidone was not affected by either propranolol (a drug that exhibits high binding to α1-acid glycoprotein or by warfarin (a drug that exhibits high binding to serum albumin). Similarly, ziprasidone did not affect the plasma protein binding of either warfarin or propranolol.


Ziprasidone was metabolized extensively after oral administration, with only a small amount (<5%) excreted as unchanged drug in urine and feces. Twelve metabolites were identified. Based on in vivo abundance of excretatory metabolites, the majority of metabolic clearance occurred via reduction by aldehyde oxidase, and cytochrome P450 catalyzed oxidation.

Ziprasidone was not a substrate for the cytochrome enzymes CYP1A2, CYP2C9 and CYP2C19. However, the drug inhibited the metabolism of substrates for CYP2D6 and CYP3A4.


Approximately 20% of the ziprasidone dose was excreted in the urine and 66% of the dose was excreted in the feces. The mean terminal phase half-life after multiple dosing was between 6 and 10 hours, with a range of individual values from 3 to 18 hours.

Special Populations

There were no clinically significant differences in the pharmacokinetics of ziprasidone in adults due to gender, age or renal insufficiency.

In patients with hepatic impairment, the drug exposure (AUC) and the half-life were significantly greater compared to subjects with normal hepatic function. Lower doses should be considered for hepatic insufficiency.

Drug Interactions

Pharmacodynamic interactions:
The primary potential safety concern in pharmacodynamic interactions is QT prolongation. Ziprasidone is contraindicated in drugs known to have QT prolongation effect

Pharmacokinetic interactions:
Drug interaction studies were conducted in healthy volunteers; the doses of ziprasidone were generally lower than the clinically recommended doses. The following results were reported:

  • Ziprasidone, 40 mg BID, did not affect lithium concentrations or clearance.
  • Ziprasidone, 20 mg BID, did not affect plasma levels of the components of an oral contraceptive, namely ethinylestradiol and levonorgestrel.
  • In the presence of carbamazepine (200 mg BID), steady-state ziprasidone AUC and Cmax decreased significantly. The effect is due to the induction of CYP3A4 by carbamazepine, the enzyme being responsible for the metabolism of ziprasidone.
  • Ketoconazole, a potent inhibitor of CYP3A4 increased the AUC and Cmax of ziprasidone by approximately 35-40%.
  • Neither cimetidine (a non-specific CYP3A4 inhibitor), nor an antacid (Maalox) affected the pharmacokinetics of ziprasidone (a single dose of 40 mg, taken as 2 x 20 mg).
  • Ziprasidone did not alter the ratio of dextromethorphan/dextrorphan in extensive metabolizers, indicating that it does not inhibit the metabolism of drugs that utilize CYP2D6.

The potential consequences of interaction with each of carbamazapine and ketaconzole are described in the Product Monograph.

3.3.3 Clinical Efficacy

Clinical Program

Zeldox (ziprasidone) was evaluated for the treatment of schizophrenia in 5 placebo-controlled studies (including 2 to 3 fixed doses of ziprasidone): 4 short-term (4-6 week) trials and one long-term (52-week) trial. In one of the studies, the effects of ziprasidone were compared to placebo and haloperidol. Additional data was requested and provided to assess the safety and efficacy of the drug in 4 longer term studies (8-28 week duration using flexible doses of ziprasidone as well as active comparator arms; e.g. risperidone, amisulpride). In some of the studies, the doses of ziprasidone extended beyond those that would be recommended in the Product Monograph (40 to 80 mg BID), namely doses of 20 and 100 BID were also evaluated.

The pre-marketing development program for ziprasidone included over 5400 patients and/or normal subjects exposed to one or more doses of ziprasidone. Over 4500 patients participated in multiple-dose effectiveness trials, and their experience corresponded to approximately 1733 patient years. A total of 1616 patients were enrolled in the nine clinical studies. Of these, 681 patients took part in short-term studies (4 to 6 weeks), 716 in longer-term studies (8 to 28 weeks) and 219 in the 1-year study. Males consitituted the majority of patients. Patients suffered from chronic or sub-chronic schizophrenia (majority) or schizoaffective disorder (minority).

Several instruments were used for assessing psychiatric signs and symptoms, among them the Brief Psychiatric Rating Scale (BPRS) and the Positive and Negative Syndrome Scale (PANSS). Assessments in regard to overall clinical state of the patient were provided by Clinical Global Impression (CGI) scores. The Scale for the Assessment of Negative Symptoms (SANS) was also employed in some clinical studies.

The rates of completion in ziprasidone-treated patients were comparable among the studies, and were also comparable between ziprasidone and groups treated with standard antipsychotic drugs. In the placebo-treated groups, slightly fewer patients completed the studies.

Efficacy Results

Baseline scores reflected disease severity and the baseline scores were comparable between studies which enrolled patients with similar conditions.

The studies have shown that:

  • Ziprasidone is an effective antipsychotic drug that was shown to be statistically superior to placebo in 3 of 4 short-term, fixed-dose trials.
  • Ziprasidone maintained a clinical response for up to one year in hospitalized chronic schizophrenic patients. Ziprasidone was significantly superior to placebo in both time to relapse and rate of relapse.
  • In the three flexible dose studies, the final doses of ziprasidone ranged between 116 mg/day and 131 mg/day, which corresponded approximately to the 60 mg BID dose. Examination of the distribution of patients that received 40, 60 or 80 mg BID doses (recommended dose range), indicated that approximately 60% of patients were on the low and mid doses of the drug.
  • In a 6-week placebo-controlled study, the 20 mg BID (40 mg/day) dose of ziprasidone demonstrated some efficacy in acutely exacerbated patients. In addition, this dose was significantly better than placebo in preventing relapse. Consequently, the Product Monograph indicates that the 20 mg BID dose may be efficacious in some patients.
  • In two of the studies (6-week placebo-controlled and 12-week flexible-dose study) ziprasidone was given at a 100 mg BID (200 mg/day) dose. While the drug may be somewhat more efficacious at this dose, the incidence of adverse events is also higher. Thus, the 100 mg BID dose should not be a recommended dose. Nevertheless, the fact that a total of 216 patients received the 100 mg BID dose, contributes to the safety of the drug.

An analysis of the effect of ziprasidone on patients with clinically significant depressive symptoms (Montgomery-Asberg Depression Rating Scale, MADRS) ≥14 was conducted in two multicentre placebo-controlled studies in acute schizophrenia. A statistically significant improvement versus placebo (p < 0.05) in the MADRS was observed in the sub-set of patients with doses at the high end of the recommended range (i.e., 60 mg and 80 mg BID). However, the validity of this scale in patients with schizophrenia is not established. In addition, the baseline depression scores were low, i.e., patients with such scores would not qualify to enter a clinical trial for the treatment of depression.

3.3.4 Clinical Safety

The most common adverse drug reactions (ADRs) associated with the use of ziprasidone in the short-term placebo studies (up to 6 weeks), and observed at a rate at least 2x that of placebo were somnolence (14%), extrapyramidal symptoms (14%), and respiratory tract infection (8%). The Product Monograph includes the ADRs that occurred in the eight pivotal studies (described in section 3.3.3 Clinical Efficacy), as well as ADRs from the post-marketing reports.

The following ADRs are of particular importance for ziprasidone (and are in addition to the standard class concerns for atypical anti-psychotics, such as tardive dyskinesia, neuroleptic malignant syndrome, hyperprolactinemia, priapism).

Rash occurred at a rate of 4% with ziprasidone vs 3% for placebo, and was found to have an apparent dose relationship. Rash was the most common ADR associated with dropout, including 7 dropouts for ziprasidone patients, as compared to 0 for placebo.

Weight Change
The data provided were inadequate to support a regulatory conclusion that ziprasidone has an advantage over other atypical antipsychotic drugs with regard to weight gain and/or hyperglycemia, or lipid regulation, with the exception of short-term data supporting an advantage over Zyprexa.

QTc prolongation
Review of the pivotal trials concluded that ziprasidone had the potential to prolong QT intervals, and that there were insufficient numbers of patients available in the ziprasidone clinical database for an appropriate evaluation of safety. In response, the sponsor submitted a dedicated QTc study. On review, several deficiencies were identified.

  • Both the clinical safety database and the multi-comparator QTc prolongation indicated that administration of ziprasidone within the therapeutic dose range caused a potentially clinically significant plasma level-related prolongation of mean QTc intervals as compared to other atypical antipsychotic drugs. It is well established that a number of drugs which prolong the QTc interval are associated with an increased occurrence of both torsades de pointes and sudden unexplained death. Although torsades de pointes had not been observed in the pre-marketing trials in association with the use of Zeldox at the recommended dose, experience was currently too limited to rule out an increased cardiac risk.
  • There are no consistent, reliable clinical warning signs of QT prolongation, nor is routine ECG monitoring regarded as an effective detection procedure; thus, this cardiac risk cannot be managed by early detection.

In response to the deficiencies identified above, additional QTc-related data were submitted: consisting of Dose Response Studies and three years of post-marketing reports from the US and parts of the EU. Data from the Dose Response Studies suggested that there may be a plateau of mean QTc prolongation at twice the maximum recommended dose; the data from the studies and 3 years of post-marketing reports were insufficient to allow a conclusion that the known QTc effect did not translate to increased risk of clinically significant cardiac-related harm compared to other anti-psychotics. At this point, an appeal process was denied by the Office of Science in Health Canada for reasons that additional data was required to clarify the magnitude of risk and to explore the purpoted advantages of ziprasidone.

A four-member appeal panel consisting of external experts was convened to review the data. They concluded that there was sufficient evidence that ziprasidone "demonstrated distinct advantages over the atypical antipsychotics not only in terms of weight gain but Type 2 diabetes and hypertriglyceridemia as well". They further concluded that "the indicated benefits of this compound in terms of weight gain/metabolic disturbance are much more compelling than the more nebulous implications of its risk of QTc prolongation". The panel noted that there was an indication in the post-marketing data that there was the possibility of an increased cardiovascular risk over other antipsychotics but that this risk could not be estimated relative to the other antipsychotics at that time. To help answer this question, they suggested an analysis of the five-year adverse drug reaction (ADR) data and the creation of a registry to create more data.

The sponsor submitted a review of 5-year post-marketing spontaneous data from the FDA Adverse Events Reporting System (AERS) database conducted using a set of heart-related search terms as well as Periodic Safety Update Report information. Small elevations in spontaneous reporting rates of cardiac related adverse events were observed for ziprasidone compared to two other atypical antipsychotics. The observation did not preclude approval, but its inclusion and acknowledgement in the Product Monograph was requested. The text was incorporated as requested with sponsor's reservations about the known limitations of post-marketing spontaneous report data. With this disclosure, along with text as per Health Canada's QT/QTc Guidelines in the Contraindications and Warnings sections of the Product Monograph, Zeldox was granted a Notice of Compliance in August 2007.

3.4 Benefit/Risk Assessment and Recommendation

3.4.1 Benefit/Risk assessment

The 5-year comparator analysis of comparative reporting rates of post-market reporting of cardiac-related adverse events, represented at this time to Health Canada, an estimate as to whether the QTc prolongation effect of Zeldox translates into cardiac harm with real world use. This supported the overall assessment of the benefit/risk profile of Zeldox, as well as adequate labelling.

The findings of the analysis are considered to provide reassurance that the relative rates of Zeldox reporting of cardiac-related adverse events were not so high as to preclude approvability. The recommendations regarding risk factors for QT prolongation are included in the Product Monograph.

Based on the totality of submitted data, it is judged that the potential risks of Zeldox are acceptable, under the specified conditions of use, and with the agreed-upon approach of full disclosure to prescribers in the label.

Full disclosure in the label includes:

  1. QTc labelling as per the Health Canada guidance document, including recommendations on risk factors, and
  2. Contextualized disclosure of the post-market findings in the label.

3.4.2 Recommendation

Based on the Health Canada review of data on quality, safety, and effectiveness, Health Canada considers that the benefit/risk profile of Zeldox is favourable in the treatment of schizophrenia and related psychotic disorders. The New Drug Submission complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has granted the Notice of Compliance pursuant to section C.08.004 of the Food and Drug Regulations.

4 Submission Milestones

Submission Milestones: Zeldox

Submission MilestoneDate
Control No. 050567
Submission filed1997-04-23
Screening 1
Screening Acceptance Letter issued1997-06-05
Review 1
Clinical Evaluation complete1998-03-26
NOD issued by Director General (safety issues)1998-03-27
Response filed1998-06-08
Screening 2
Screening Acceptance Letter issued1998-07-13
Review 2
Quality Evaluation complete1999-10-25
Clinical Evaluation complete1999-11-07
Biopharmaceutics Evaluation complete2000-02-15
NON issued by Director General (safety issues)2000-02-24
Response filed2000-04-17
Screening 3
Screening Acceptance Letter issued2000-05-24
Review 3
Clinical Evaluation started2000-09-06
Quality Evaluation complete2001-01-24
Cancellation Letter received2001-04-26
Control No. 078188
Submission filed2002-06-12
Screening 1
Screening Acceptance Letter issued2002-07-18
Review 1
Quality Evaluation complete2003-07-31
Clinical Evaluation complete2004-05-21
NON issued by Director General (safety issues)2004-06-03
Level 1 Appeal
Rejection issued by Director BCANS2004-12-22
Level 2 Appeal
Appeal partially granted2006-07-18
Appeal granted2007-01-26
Review 2
Biostatistics Evaluation complete2007-03-26
Quality Evaluation complete2007-07-24
Labelling Review complete2007-08-03
Clinical Evaluation complete2007-08-09
NOC issued by Director General2007-08-27