Summary Basis of Decision for Signifor

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:

Drug

Summary Basis of Decision (SBD) documents provide information related to the original authorization of a product. The SBD for Signifor is located below.

Recent Activity for Signifor

The SBDs written for eligible drugs (as outlined in Frequently Asked Questions: Summary Basis of Decision [SBD] Project: Phase II) approved after September 1, 2012 will be updated to include post-authorization information. This information will be compiled in a Post-Authorization Activity Table (PAAT). The PAAT will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada's decisions were negative or positive. The PAATs will be updated regularly with post-authorization activity throughout the product life cycle.

Post-Authorization Activity Table (PAAT) for Signifor

Updated: 2024-09-05

 

The following table describes post-authorization activity for Signifor, a product which contains the medicinal ingredient pasireotide (as pasireotide diaspartate). For more information on the type of information found in PAATs, please refer to the Frequently Asked Questions: Summary Basis of Decision (SBD) Project: Phase II and to the List of abbreviations found in Post-Authorization Activity Tables (PAATs).

 

For additional information about the drug submission process, refer to the Guidance Document: The Management of Drug Submissions and Applications.

 

Drug Identification Number (DIN):

  • DIN 02413299 - 0.3 mg/mL pasireotide, solution, subcutaneous injection
  • DIN 02413302 - 0.6 mg/mL pasireotide, solution, subcutaneous injection
  • DIN 02413310 - 0.9 mg/mL pasireotide, solution, subcutaneous injection

 

Post-Authorization Activity Table (PAAT)

 

Activity/Submission Type, Control Number

Date Submitted

Decision and Date

Summary of Activities

SNDS # 260471

2022-01-18

Issued NOC 2023-05-17

Submission filed as a Level I – Supplement for the addition of an alternate drug product manufacturing site. The submission was reviewed and considered acceptable, and an NOC was issued.

SNDS # 234503

2019-12-13

Issued NOC 2020-07-09

Submission filed as a Level I – Supplement for a change in the storage conditions (temperature range) of the drug product. The submission was reviewed and considered acceptable, and an NOC was issued.

NDS # 237286

2020-03-18

Issued NOC 2020-05-21

Submission filed to transfer ownership of the drug product from Novartis Pharmaceuticals Canada Inc. to Recordati Rare Diseases Canada Inc. An NOC was issued.

NC # 236660

2020-02-28

Issued NOL 2020-04-30

Submission filed as a Level II (90 day) Notifiable Change to update the PM with new safety information. As a result of the NC, modifications were made to the Warnings and Precautions and Adverse Reactions sections of the PM, and corresponding changes were made to Part III: Patient Medication Information. The submission was reviewed and considered acceptable, and an NOL was issued.

SNDS # 193942

2016-04-06

Issued NOC

2017-03-23

Submission filed as a Level I – Supplement to update the PM with pharmacokinetic and safety information. As a result of the review of the submission, changes were made to the Warnings and Precautions, and Dosage and Administration sections of the PM. Corresponding changes were made to the PM Part III: Consumer Information. The submission was reviewed and considered acceptable, and a Notice of Compliance was issued.

SNDS # 173213

2014/03/21

Issued NOC 2015/02/23

Submission filed as a Level I – Supplement to update the Product Monograph (PM) based on non‑clinical studies, pharmacokinetic data, a drug interaction study, a cardiac safety report, and literature articles. As a result of the review of the submission, changes were made to the Serious Warnings and Precautions Box, and the Contraindications, Warnings and Precautions, Adverse Reactions, Drug Interactions, and Dosage and Administration sections of the PM. Corresponding changes were made to the PM Part III: Consumer Information. The submission was reviewed and considered acceptable, and a Notice of Compliance was issued.

Drug product (DINs 02413299, 02413302, 02413310) market notification

Not applicable

Date of first sale: 2013/11/26

The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.

NDS # 145005

2011/02/08

Issued NOC 2013/09/23

Notice of Compliance issued for New Drug Submission.
Summary Basis of Decision (SBD) for Signifor

Date SBD issued: 2013-11-08

The following information relates to the New Drug Submission for Signifor.

Pasireotide (as pasireotide diaspartate)
0.3 mg/mL, 0.6 mg/mL, and 0.9 mg/mL, solution, subcutaneous injection

Drug Identification Number (DIN):

  • DIN 02413299 - 0.3 mg/mL
  • DIN 02413302 - 0.6 mg/mL
  • DIN 02413310 - 0.9 mg/mL

Novartis Pharmaceuticals Canada Inc.

New Drug Submission Control Number: 145005

 

On September 23, 2013, Health Canada issued a Notice of Compliance to Novartis Pharmaceuticals Canada Inc. for the drug product, Signifor.

The market authorization was based on quality (chemistry and manufacturing), non-clinical (pharmacology and toxicology), and clinical (pharmacology, safety, and efficacy) information submitted. Based on Health Canada's review, the benefit/risk profile of Signifor is favourable for the treatment of adult patients with Cushing's disease for whom surgery is not an option or for whom surgery has failed, as long as clinical benefit or normalization of urinary-free cortisol (UFC) or >50% decrease in UFC are derived.

Signifor should be prescribed and supervised by a qualified physician. To receive Signifor, the patient must be enrolled in the Access Program for Signifor.

 

1 What was approved?

 

Signifor (pasireotide), a synthetic analogue of somatostatin, was authorized for  the treatment of adult patients with Cushing's disease for whom surgery is not an option or for whom surgery has failed, as long as clinical benefit or normalization of urinary-free cortisol (UFC) or >50% decrease in UFC are derived.

Signifor should be prescribed and supervised by a qualified physician. To receive Signifor, the patient must be enrolled in the Access Program for Signifor.

Data on Cushing's disease patients older than 65 years are limited, but there is no evidence to suggest a dose adjustment is required in these patients.

Signifor should not be used in children. No studies have been performed in pediatric patients.

Signifor is contraindicated in

  • patients with a known hypersensitivity to pasireotide or to any of the excipients.
  • patients with moderate or severe hepatic impairment (Child Pugh B or C).
  • patients with uncontrolled diabetes (≥8% hemoglobin A1c).
  • patients with the following cardiovascular conditions:
    • New York Heart Association (NYHA) Class III to IV heart failure
    • Cardiogenic shock
    • Second or third degree atrioventricular block, sinoatrial block, or sick sinus syndrome (unless patient has a functioning pacemaker)
    • Severe bradycardia
    • Congenital long QT syndrome or baseline QTc interval ≥500 ms

Signifor was approved for use under the conditions stated in the Signifor Product Monograph taking into consideration the potential risks associated with the administration of this drug product.

Signifor [0.3 mg/mL, 0.6 mg/mL, and 0.9 mg/mL pasireotide (as pasireotide diaspartate)] is a solution for subcutaneous injection. In addition to the medicinal ingredient, pasireotide diaspartate, the solution contains mannitol, tartaric acid, sodium hydroxide and water for injection.

For more information, refer to the Clinical, Non-Clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.

Additional information may be found in the Signifor Product Monograph, approved by Health Canada and available through the Drug Product Database.

 

2 Why was Signifor approved?

 

Health Canada considers that the benefit/risk profile of Signifor is favourable for the treatment of adult patients with Cushing's disease for whom surgery is not an option or for whom surgery has failed, as long as clinical benefit or normalization of urinary-free cortisol (UFC) or >50% decrease in UFC are derived.

Cushing's disease is a rare, debilitating, and life-threatening disease that is caused by an adrenocorticotropic hormone (ACTH)-secreting pituitary adenoma most commonly affecting adult females. Patients with Cushing's disease have increased morbidity and a mortality rate higher than age- and gender-matched subjects. Pituitary resection of the adenoma is the current first-line therapy for Cushing's disease, however surgical failures sometime occur. Repeat pituitary surgery may be performed if the disease persists after the initial surgery. Currently, there are no approved drug therapies for Cushing's disease.

Signifor was shown to be efficacious in adult patients with Cushing's disease for whom surgery was not an option or for whom surgery had failed. The market authorization was based on a Phase III, multicentre, randomized, double-blind study that evaluated the safety and efficacy of two dose levels of Signifor [0.6 mg twice a day (BID) and 0.9 mg BID] over a 6-month treatment period in Cushing's disease patients with persistent or recurrent disease or de novo patients for whom surgery was not indicated or who refused surgery. In both dose groups, Signifor treatment resulted in a decrease in the mean UFC after 1 month of treatment which was maintained until the end of the study (Month 12). At Month 6, normalization of mean UFC levels was observed in 14.6% and 26.3% of patients randomized to Signifor 0.6 mg BID and 0.9 mg BID, respectively.

The proportion of patients experiencing at least one adverse event (AE) was 97.6% and 98.8% in the 0.6 mg BID and 0.9 mg BID groups, and 47.6% and 50.0% respectively, had at least one AE of Grade 3 or 4. The most common AEs requiring clinical intervention were metabolism/nutrition adverse reactions related to hyperglycemia, gastrointestinal-related events (abdominal pain, diarrhea, nausea), adrenal insufficiency, and cholelithiasis. The most frequent serious adverse events (SAEs) were diabetes mellitus, hyperglycemia, and cholelithiasis.

The main safety concerns were hepatotoxicity, cardiovascular-related adverse events, and hyperglycemia. Elevations in liver aminotransferases were commonly observed with Signifor and there were 4 cases meeting the biochemical criteria for Hy's Law reported in the clinical studies. Signifor was shown to be able to cause bradycardia and atrioventricular block, and prolong the QTc interval. Also, Signifor caused frequent, significant alterations in blood glucose levels in healthy volunteers and Cushing's Disease patients.

In December 2012, the sponsor was issued a Notice of Non-Compliance (NON) for Signifor. The major issues in the NON focused on the lack of risk mitigation plans for several serious safety concerns; hyperglycaemia, hepatotoxicity, and cardiovascular safety. In the response to the NON, the sponsor updated the Signifor Product Monograph and Risk Management Plan (RMP) to adequately address the risk management of these concerns.

In the updated Signifor Product Monograph, the indication was restricted to treatment of adult patients with Cushing's disease for whom surgery is not an option or for whom surgery has failed, as long as clinical benefit or normalization of UFC or >50% decrease are derived, adding that it should be prescribed and supervised by a qualified physician and that patients must be enrolled in an Access Program to receive Signifor. Furthermore, the labelling was updated with the addition of contraindications for uncontrolled diabetes, moderate and severe hepatic impairment and in patients with history of, or high risk for cardiovascular disease. Also included were boxed warnings for the risk of hepatotoxicity, hyperglycemia, and cardiovascular-related adverse events, increased monitoring for therapeutic response as well as safety parameters, and recommendations for discontinuation.

In the updated RMP, in order to receive Signifor, Canadian patients will be required to enrol in the restricted Access Program which includes an informed consent, patient and physician education, restricted distribution, and adverse event reporting. The sponsor will also create a global patient registry which will include several Canadian centres. The sponsor has committed to providing the details of the registry for review once they are finalized.

With the modifications to the labelling and the RMP, the benefit/risk assessment is considered positive. The results of the pivotal study demonstrated clinically meaningful results in a relatively small proportion of the population. The updated labelling, and revised RMP with the implementation of the restricted Access Program and patient registry are sufficient to communicate and mitigate the safety risks of Signifor.

This 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. For more information, refer to the Clinical, Non-Clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.

 

3 What steps led to the approval of Signifor?

 

A New Drug Submission (NDS) for Signifor was filed with Health Canada in February 8, 2011. Due to quality issues in the chemistry and manufacturing of the prefilled syringe, a Notice of Deficiency (NOD) was issued for Signifor on October 24, 2011. The sponsor submitted a response to the NOD and all of the quality concerns that led to the NOD were satisfactorily addressed. In December 2012, the NDS for Signifor received a Notice of Non-Compliance (NON). The major issues in the NON focused on the lack of risk mitigation plans for several serious safety concerns, including hyperglycaemia, hepatotoxicity and cardiovascular safety. In the response to the NON, the sponsor addressed the risks listed in the NON and the absence of an established system for enhanced vigilance in Canada. The updated labelling and revised Risk Management Plan with the implementation of a restricted Access Program and patient registry were considered sufficient to communicate and mitigate the safety risks of Signifor, and a Notice of Compliance was issued on September 23, 2013.

 

Submission Milestones: Signifor

Submission Milestone Date
Submission filed: 2011-02-08
Screening 1  
Screening Acceptance Letter issued: 2011-03-31
Review 1  
Quality Evaluation complete: 2011-10-14
Notice of Deficiency (NOD) issued by Director General (quality issues): 2011-10-24
Response filed: 2012-01-17
Screening 2  
Screening Acceptance Letter issued: 2012-03-02
Review 2  
Quality Evaluation complete: 2012-12-12
Clinical Evaluation complete: 2012-12-21
Biostatistics Evaluations complete: 2012-11-05 - 2012-12-24
Notice of Non-Compliance (NON) issued by Director General (safety issues): 2012-12-24
Response filed: 2013-03-13
Screening 3  
Screening Acceptance Letter issued: 2013-04-26
Review 3  
Clinical Evaluation complete: 2013-09-20
Labelling complete: 2013-09-23
Notice of Compliance issued by Director General: 2013-09-23

 

The Canadian regulatory decision on the clinical review of Signifor was based on a critical assessment of the Canadian data package. The foreign reviews completed by the European Union's centralized procedure European Medicines Agency (EMA) and the United States Food and Drug Administration (FDA) were used as an added reference.

For additional information about the drug submission process, refer to the Management of Drug Submissions Guidance.

 

4 What follow-up measures will the company take?

 

Requirements for post-market commitments are outlined in the Food and Drugs Act and Regulations.

 

5 What post-authorization activity has taken place for Signifor?

 

Summary Basis of Decision documents (SBDs) for eligible drugs authorized after September 1, 2012 will include post-authorization information in a table format. The Post-Authorization Activity Table (PAAT) will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada's decision was negative or positive. The PAAT will continue to be updated during the product's lifecycle.

The PAAT for Signifor is found above.

For the latest advisories, warnings and recalls for marketed products, see MedEffect Canada.

 

6 What other information is available about drugs?

 

Up to date information on drug products can be found at the following links:

 

7 What was the scientific rationale for Health Canada's decision?
7.1 Clinical Basis for Decision

 

Clinical Pharmacology

Pasireotide, the medicinal ingredient of Signifor, exerts its pharmacological activity by binding to somatostatin receptors. Somatostatin receptors are expressed in many tissues, especially in neuroendocrine tumours where hormones are excessively secreted including adrenocorticotropic hormone (ACTH) in Cushing's disease.

The clinical pharmacology studies for Signifor included data on the safety, tolerability, pharmacokinetics, and pharmacodynamics in humans.

Pasireotide is eliminated mainly via hepatic clearance (biliary excretion) with a small contribution from the renal route. In subjects with moderate and severe hepatic impairment, significant increases in systemic drug exposure were reported. Four reports of hepatotoxicity or meeting the biochemical criteria for Hy's Law cases were reported out of 462 subjects in the Phase I studies when multiple doses (5-14 days) of pasireotide were administered. The risk of hepatoxicity is clearly labelled. Signifor is contraindicated in patients with moderate or severe hepatic impairment, and appropriate warnings and precautions are in the Signifor Product Monograph.

Two electrocardiogram (ECG) studies assessed the effects of Signifor on cardiac electrophysiology. Signifor was associated with statistically significant QTc prolongation, reductions in heart rate, and prolongation of the PR interval. Warnings and precautions regarding risk of cardiovascular-related adverse events are included in the Signifor Product Monograph.

Overall, the data from the submitted clinical pharmacology studies are considered sufficient and there are no major concerns to prevent the market authorization of Signifor for the specified indication.

For further details, please refer to the Signifor Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

The clinical efficacy and safety of Signifor were evaluated in a Phase III, multicentre, randomized study over a 6-month treatment period in Cushing's disease patients with persistent or recurrent disease or de novo patients for whom surgery was not indicated or who refused surgery. This pivotal study enrolled 162 patients with a baseline urinary-free cortisol (UFC) >1.5 times the upper limit of normal (ULN) who were randomized in a 1:1 ratio to receive a subcutaneous (SC) injection of either 0.6 mg twice a day (BID) or 0.9 mg BID of Signifor. There was no control treatment used in the study as there are no approved drug therapies for Cushing's disease.

After three months of treatment, patients who had a mean 24-hour UFC ≤2 times the ULN and below or equal to their baseline values continued blinded treatment at the randomized dose until Month 6. Patients who did not meet these criteria were unblinded and the dose was increased by 0.3 mg BID. After the initial 6 months in the study, patients entered an additional 6-month open-label treatment period. The dosage could be reduced by 0.3 mg BID at any time during the study for intolerability. The median exposure to the treatment was 10.4 months with 68% of patients having at least 6 months of treatment.

The primary efficacy endpoint was the proportion of patients in each group who achieved normalization of mean 24-hour UFC levels (UFC ≤ULN) after 6 months of treatment and who did not have a dose increase (relative to randomized dose) during this period.

The results of the pivotal study demonstrated clinically meaningful results in a relatively small proportion of patients. The percentage of responders that achieved the primary endpoint was greater in the 0.9 mg BID group than in the 0.6 mg BID group. Twenty-one of 80 patients (26.3%) and 12 of 82 patients (14.6%) met the response criteria for mean UFC ≤ULN at Month 6 in the 0.9 mg BID group and 0.6 mg BID group, respectively. The lower limit of the 95% confidence interval for the Signifor 0.9 mg BID group was greater than the pre-specified null hypothesis of 15%, therefore the 0.9 mg BID dose is considered to have met the primary efficacy endpoint. While the 0.6 mg BID group did not meet the pre-specified primary endpoint, this group had a higher baseline UFC, which may have contributed to the wide range in efficacy. Meaningful clinical differences were seen with the secondary endpoint of a decrease of 50% UFC from baseline, even when treatment did not result in UFC normalization. When the primary efficacy endpoint definition was expanded to include this secondary endpoint, the proportion of responders was 34% and 41% in the 0.6 mg BID group and 0.9 mg BID group, respectively.

For more information, refer to the Signifor Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

A total of 162 patients with Cushing's disease were treated with Signifor in the pivotal Phase III study, described in the Clinical Efficacy section.

In the pivotal Phase III study, the proportion of patients experiencing at least one adverse event (AE) was 97.6% and 98.8% in the 0.6 mg BID group and 0.9 mg BID group, respectively. The most frequent adverse events (AEs) were diarrhea, nausea, hyperglycemia, and cholelithiasis.

Overall, 28 (17.3%) patients discontinued due to an AE. The AEs that led to discontinuation of 5 responders were: increased levels of gamma-glutamyltransferase (GGT), nausea, diarrhea, adrenal insufficiency and pregnancy. In the 23 non-responders, the AEs that led to the discontinuation included hyperglycemia-related AE (10 patients), elevated liver enzymes (5 patients), gastrointestinal-related AEs (3 patients), gallbladder-related AEs (1 patient), pituitary tumour progression with cranial nerve paralysis (1 patient), prolongation of the QT interval (1 patient), asthenia (1 patient), urticarial rash (1 patient, who also had hypotension and elevated immunoglobulin E). Of these 23 non-responders who discontinued due to an AE, 16 patients were discontinued prior to 6 months of treatment. The most common AEs leading to dose adjustment or interruption of study drug were nausea, diarrhea, hyperglycemia and adrenal insufficiency.

The rates of serious adverse events (SAEs) were comparable between the two groups with a tendency for more drug-related SAEs in the higher dose group (0.9 mg BID group). A total of 23.2% and 26.3% in the 0.6 mg and 0.9 mg BID groups, respectively, experienced at least one SAE. No deaths were reported within the study period. Pituitary-dependent Cushing's syndrome was the most common SAE in both dose groups. Pituitary-dependent Cushing's syndrome, pituitary tumour benign or secretory adenoma of pituitary was reported as a SAE in 9 patients and 8 of these had surgical interventions (pituitary surgery or bilateral adrenalectomy). Serious adverse events included cholelithiasis, diabetes mellitus and hyperglycemia which were reported in 4 (2.5%) patients each. Adrenal insufficiency, disease progression, drug ineffective, uterine polyp and hypotension were each reported in 2 (1.2%) patients.

Three significant safety concerns emerged from the clinical studies: the risk of hepatotoxicity; hyperglycemia; and cardiovascular-related adverse events.

Hepatoxicity

During the pivotal Phase III study, mild and transient elevations in liver enzymes were common, without a dose-dependent effect. Eight (5.1%) patients had elevations of alanine transaminase (ALT) or aspartate aminotransaminase (AST) >3 times the ULN. There were four cases meeting the biochemical criteria for Hy's Law reported (3 in healthy volunteers and one in a patient who also developed jaundice) in subjects treated with Signifor. In addition, there was another borderline case of Hy's Law in another healthy volunteer (total bilirubin was 1.97 and therefore not reported as meeting the biochemical criteria for Hy's Law). The presentation of these cases was atypical, with early concurrent liver enzyme increases, which returned to normal levels within a few weeks following discontinuation. Despite the atypical presentation, the potential for hepatotoxicity still exists, the severity of which is not fully characterized or understood. The absence of Hy's Law cases in the small Phase II and Phase III studies does not rule out the potential for hepatotoxicity with Signifor.

Hyperglycemia

In the pivotal study, hyperglycemia-related AEs were dose-dependent, reported frequently (72.8%), and were mostly considered study drug-related. Adverse events associated with disturbances in glucose metabolism included hyperglycemia (40.1%), diabetes mellitus (17.9%), increased glycosylated haemoglobin (11.1%) and type 2 diabetes mellitus (9.3%). At baseline, the majority of the patients were not receiving anti-diabetic interventions (79.6%); however, during the course of the study 53 patients (32.7%) started anti-diabetic interventions. Data indicate that both diabetic and non-diabetic patients had an increase in HbA1c which plateaued at approximately 2 months with the increase and initiation of treatment with anti-diabetic drugs. Following treatment with anti-diabetic medication, fasting plasma glucose levels showed a decrease while haemoglobin A1c (HbA1C) stabilized.

Cardiovascular-related Events

Signifor was associated with mean decreases in heart rate from baseline at all timepoints from 1.5 months to 10 months in the pivotal study. The proportion of patients with on-treatment heart rate values <50 bpm was high in the 0.6 mg BID and 0.9 mg BID groups (32.1% and 25.0%, respectively). The 0.9 mg BID group was associated with increases in QTcF (QT prolongation corrected using Fridericia's formula) from baseline of up to 8 ms at most timepoints up to 9 months. No consistent QTc prolongation tendency was observed in the 0.6 mg BID group. QTcF values >480 ms were reported for 4.1% of patients receiving 0.9 mg BID. Signifor was associated with mean 1-6 ms increases from baseline in the PR interval at all timepoints up to 10 months. Although frequent electrocardiogram (ECG) monitoring was performed in this study, the ECGs were collected before the Signifor morning injection when the drug concentrations would be at trough levels, such that the data are expected to under-estimate the maximum treatment-related changes.

Conclusion

Several serious safety concerns (hyperglycemia, hepatotoxicity, and cardiovascular safety) were identified in the Signifor clinical studies. As a result, there were several risk management goals for the sponsor: (a) to minimize drug exposure in patients that do not demonstrate a therapeutic response as well as in those with higher risk factors; (b) to provide recommendations on monitoring safety parameters as well as therapeutic responses; (c) to clearly communicate the potential benefits and risks of Signifor treatment, and obtain the patient's informed consent through the registration in the Access Program; and, (d) to actively collect safety information from all patients exposed to Signifor post-market.

Overall, the updated Signifor Product Monograph and Risk Management Plan have adequately addressed the major risk management goals. The indication has been restricted, the Signifor Product Monograph has been updated with contraindications, warnings, increased monitoring of safety concerns, and recommendations for discontinuation. The restricted Access Program includes mandatory enrolment, informed consent, physician and patient education, restricted distribution and adverse event reporting. Further, the sponsor will be incorporating Canadian patients into the international Cushing's disease patient registry.

Overall, despite the important safety concerns associated with Signifor, the safety profile of Signifor is acceptable and manageable for the treatment of adult patients with Cushing's disease for whom surgery is not an option or for whom surgery has failed, as long as clinical benefit or normalization of urinary-free cortisol (UFC) or >50% decrease in UFC are derived.

For more information, refer to the Signifor Product Monograph, approved by Health Canada and available through the Drug Product Database.

 

 

 

7.2 Non-Clinical Basis for Decision

 

Non-clinical studies investigating the pharmacology, pharmacokinetics, and toxicity of pasireotide were reviewed.

The pharmacodynamic studies have shown that pasireotide binds with high affinity to somatostatin receptor subtypes, sst 1, 2, 3 and sst 5, as compared to octreotide. Pasireotide has also been shown to inhibit ACTH secretion in cell cultures of pituitary adenomas obtained from patients with Cushing's disease.

The main targets of toxicity in both rats and monkeys included local effects in the skin after subcutenous administration, decreased body weights and food consumptions, as well as morphological changes in the endocrine organs, pituitary, thyroid, and adrenal. All systemic findings are considered to be exaggerated pharmacological effects of pasireotide.

The results of the non-clinical studies as well as the potential risks to humans have been included in the Signifor Product Monograph. In view of the intended use of Signifor, there are no pharmacological/toxicological issues within this submission which preclude authorization of the product.

For more information, refer to the Signifor Product Monograph, approved by Health Canada and available through the Drug Product Database.

 

 

7.3 Quality Basis for Decision

 

The Chemistry and Manufacturing information submitted for Signifor 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. Changes to the manufacturing process and formulation made throughout the pharmaceutical development are considered acceptable upon review. Based on the stability data submitted, the proposed shelf-life is considered acceptable.

Proposed limits of drug-related impurities are considered adequately qualified; that is, within International Conference on Harmonisation (ICH) limits and/or qualified from toxicological studies.

All sites involved in production are compliant with Good Manufacturing Practices.

All non-medicinal ingredients (excipients) found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations. The excipients used in the drug product formulation are not of animal or human origin.

 

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