Summary Basis of Decision for Tasigna
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:
Tasigna
Nilotinib hydrochloride monohydrate, 200 mg, Capsule, Oral
Novartis Pharmaceuticals Canada Inc.
Submission control no: 110305
Date issued: 2009-05-04
Foreword
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:
Manufacturer/sponsor:
Medicinal ingredient:
International non-proprietary Name:
Strength:
Dosage form:
Route of administration:
Drug identification number(DIN):
- 02315874
Therapeutic Classification:
Non-medicinal ingredients:
Shell: gelatin, titanium dioxide, iron oxide yellow, and the printing ink includes red iron oxide.
Submission type and control no:
Date of Submission:
Date of authorization:
PrTASIGNA* (nilotinib capsules) is a registered trademark
2 Notice of decision
On September 9, 2008, Health Canada issued a Notice of Compliance under the Notice of Compliance with Conditions (NOC/c) Policy to Novartis Pharmaceuticals Canada Inc. for the drug product Tasigna*. The product was authorized under the NOC/c Policy on the basis of the promising nature of the clinical evidence, and the need for further follow-up to confirm the clinical benefit. Patients should be advised of the fact that the market authorization was issued with conditions.
Tasigna* contains the medicinal ingredient nilotinib (as nilotinib hydrochloride monohydrate) which is a protein-tyrosine kinase inhibitor.
Tasigna* is indicated for the treatment of accelerated phase (AP) Philadelphia chromosome-positive chronic myeloid leukemia (CML) in adult patients resistant to or intolerant of at least one prior therapy including imatinib.
Tasigna* is a potent inhibitor of the Abl tyrosine kinase activity of the Bcr-Abl oncoprotein both in cell lines and in primary Philadelphia chromosome-positive leukemia cells. As a result, Tasigna* selectively inhibits the proliferation and induces apoptosis in primary Philadelphia-chromosome-positive leukemia cells from CML patients.
The market authorization was based on submitted data from quality (chemistry and manufacturing), non-clinical, and clinical studies. The clinical efficacy and safety data submitted consisted of the Phase II component of an ongoing open-label multicentre study. In the interim analysis, 28% of CML-AP patients treated with Tasigna* (number [n]= 105) achieved the primary efficacy endpoint of overall confirmed hematologic response, defined as either a complete hematologic response, or no evidence of leukemia. The majority of Tasigna* treated patients experienced adverse reactions at some time. Most reactions were mild to moderate. Discontinuation for adverse events regardless of causality was observed in 14% of CML-AP patients. Further follow-up is needed to confirm the clinical effectiveness of Tasigna*.
Tasigna* 200 mg nilotinib (as nilotinib hydrochloride monohydrate) is presented as capsules. The recommended dose of Tasigna* is 400 mg twice daily. Dosing recommendations are available in the approved Product Monograph.
Tasigna* is contraindicated for patients with long QT syndrome, and patients with known hypersensitivity to nilotinib or to any of the excipients. Tasigna* should be administered under the conditions stated in the approved Product Monograph taking into consideration the potential
risks associated with the administration of this drug product (myelosuppression, QT-interval prolongation, hepatotoxicity, sudden deaths, drug-drug and drug-food interactions). Detailed conditions for the use of Tasigna* are described in the approved Product Monograph.
Based on the Health Canada review of data on quality, safety, and effectiveness, Health Canada considers that the benefit/risk profile of Tasigna* is favourable for the treatment of accelerated phase Philadelphia chromosome-positive chronic myeloid leukemia in adult patients resistant to or intolerant of at least one prior therapy including imatinib.
3 Scientific and Regulatory Basis for Decision
The Advance Consideration Notice of Compliance with Conditions (NOC/c) New Drug Submission (NDS) for Tasigna* (Control Number 110305) was originally submitted on December 5, 2006 in order to obtain marketing authorization for the treatment of adult patients with imatinib-resistant or imatinib-intolerant, Philadelphia positive (Ph+) chronic myelogenous leukemia (CML) in accelerated phase (AP). During the review, a number of efficacy and safety issues were identified, and it was determined that a more complete dataset was required for an accurate benefit/risk assessment. Therefore, a Notice of Non-Compliance (NON) was issued on July 13, 2007. In response to the NON, the sponsor submitted A 120-day Efficacy and Safety Update report in patients with CML-AP treated with Tasigna*, in addition to longer-term safety data (median duration of exposure 6.3 months for CML-AP patients and 11.4 months for CML patients in the chronic phase). Subsequent review led to the decision to issue the sponsor market authorization under the NOC/c Policy, in recognition of the promising but unconfirmed evidence of clinical effectiveness in the submission. This authorization is conditional upon further confirmation of clinical benefit.
3.1 Quality Basis for Decision
3.1.1 Drug Substance (Medicinal Ingredient)
General Information
Nilotinib (as nilotinib hydrochloride monohydrate), the medicinal ingredient of Tasigna*, is a kinase inhibitor. Nilotinib is a potent inhibitor of the Abl tyrosine kinase activity of the Bcr-Abl oncoprotein both in cell lines and in primary Philadelphia chromosome-positive leukemia cells. As a result, nilotinib selectively inhibits the proliferation and induces apoptosis in cell lines and in primary Philadelphia-chromosome positive leukemia cells from CML patients.
Manufacturing Process and Process Controls
Nilotinib hydrochloride monohydrate 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 International Conference on Harmonisation (ICH) recommended acceptance criteria or have been qualified through toxicological studies.
- The processing steps have been evaluated and the appropriate ranges for process parameters have been established.
Characterization
The structure of nilotinib hydrochloride monohydrate is considered to be adequately elucidated and the representative spectra have been provided. Physical and chemical properties have been described and are found to be satisfactory.
Impurities and degradation products arising from manufacturing and/or storage were reported and characterized. These products were found to be within ICH established limits and/or were qualified from batch analysis, and toxicological studies and therefore, are considered to be acceptable.
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 nilotinib hydrochloride monohydrate.
Batch analysis results were reviewed and all results comply with the specifications and demonstrate consistent quality of the batches produced.
The drug substance packaging is considered acceptable.
Stability
Stability study results based on accelerated and long-term testing show that nilotinib hydrochloride monohydrate is a stable compound when packaged as proposed over the proposed storage period.
3.1.2 Drug Product
Description and Composition
Tasigna* (nilotinib capsules) is available as 200 mg hard capsules. Each capsule contains 200 mg nilotinib base (as nilotinib hydrochloride monohydrate). White to slightly yellowish powder is contained in a light yellow, opaque, hard gelatin capsule (size 0) with a red axial imprint "NVR/TKI". The capsules are packaged in blister packs (2 strips of 14 blisters/card, 4 cards/carton).
The non-medicinal ingredients are listed below:
- Capsule content: Colloidal silicon anhydrous; crospovidone; lactose monohydrate; poloxamer 188; magnesium stearate
- Capsule shell: Gelatin; titanium dioxide; iron oxide, yellow. The printing ink includes red iron oxide.
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 nilotinib 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 method of manufacturing is considered acceptable and the process is considered adequately controlled within justified limits.
Control of Drug Product
Tasigna* is tested to verify that the identity, appearance, content uniformity, dissolution, and levels of degradation products and microbiological impurities are within acceptance criteria. The test specifications and analytical methods are considered acceptable. Analytical methods and, where appropriate, validation reports are considered satisfactory for all analytical procedures used for release and stability testing of Tasigna*.
Stability
Based on the long-term and accelerated stability data submitted, the proposed 24-month shelf-life at 15-30°C for Tasigna* is considered acceptable.
The compatibility of the drug product with the container closure system was demonstrated through compendial testing and stability studies.
3.1.3 Facilities and Equipment
The design, operations and controls of the facility and equipment that are involved in the production are considered suitable for the activities and products manufactured.
All sites are compliant with Good Manufacturing Practices (GMP).
3.1.4 Adventitious Agents Safety Evaluation
The excipients, lactose monohydrate and gelatin, in the capsule shell are of animal origin. Letters of attestation confirming that the materials are not from a bovine spongiform encephalopathy and transmissible spongiform encephalopathy (BSE/TSE) affected country/area have been provided for this product indicating that it is considered to be safe for human use.
3.1.5 Conclusion
The Chemistry and Manufacturing information submitted for Tasigna* 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
Based on the sponsor-provided experimental data and publications, nilotinib inhibits the tyrosine kinase activity of Bcr-Abl in cells, leading to reduced phosphorylation of downstream signaling pathways and apoptosis in Bcr-Abl dependent cells. The cytotoxic effect of nilotinib on Bcr-Abl expressing cells has been described. The efficacy of nilotinib in the animal disease models was consistent with a cytotoxic effect.
The safety pharmacology studies demonstrated that nilotinib and its metabolites have inhibitory activities on the adenosine 3 receptor and adenosine transporter at the µM level. Also, studies on cloned hERG channels showed that nilotinib can exert inhibition with a 50% inhibitory concentration (IC50) of 0.13 µM. This concentration is significantly lower in comparison to the plasma concentration of 400 mg twice a day (BID) nilotinib evaluated at 2 µM in a clinical trial. Therefore, nilotinib was considered to have demonstrated a pre-clinical signal for QT prolongation. Additional non-clinical studies were initiated to further assess the non-clinical cardiac safety profile of nilotinib.,
3.2.2 Pharmacokinetics
Absorption
Oral administration of nilotinib demonstrated moderate absorption and bioavailability in mice, rats, rabbits, and monkeys.
Distribution
In vitro plasma protein binding of nilotinib was high (approximately 97-99%) and independent of the concentration tested in rats, dogs, mice, and monkeys.
Nilotinib was widely distributed in rats, with highest concentrations observed in the stomach glandular, adrenal, liver, and bile. The drug had a high affinity to melanin as indicated by a high retention in pigmented skin and uveal tract.
In pregnant rats, nilotinib was moderately distributed from the mother to the fetus. In the lactating rats, nilotinib and its metabolites were detected in the rat milk.
Metabolism
In vitro studies indicate that nilotinib is primarily metabolized by the cytochrome P450 enzyme CYP3A4, and may therefore alter the pharmacokinetic profile of concomitantly administered drugs that are CYP3A4 substrates. Nilotinib could act as an inhibitor of CYP2C8, CYP2C9, CYP2D6, CYP3A4, and CYP3A5 activity in the clinical setting, and possibly, but less likely, for CYP2C19.
Nilotinib was also shown to be a substrate and inhibitor for P-glycoprotein (P-gp). The appropriate information regarding possible drug-drug interactions is included in the Product Monograph.
Excretion
In all of the species tested (rats, mice, rabbits, and monkeys), nilotinib was extensively metabolized and the dominant excretion was recovered in the feces. Renal excretion was minor.
3.2.3 Toxicology
Single-Dose Toxicity
Oral single-dose toxicity studies were not conducted. In the intravenous single-dose study with rats, the administration of 9 mg/kg nilotinib did not induce any toxicologically relevant changes and therefore this dose was considered to be the No-Observed-Adverse-Effect-Level (NOAEL).
Repeat-Dose Toxicity
Oral administration of repeat doses of nilotinib was conducted in mice, rats, dogs, and monkeys. In monkeys that received nilotinib for a duration of 39 weeks, hepatoxicity was observed (increased alanine aminotransferase and alkaline phosphatase, as well as histopathological changes). The liver damage showed signs of sinusoidal cell aggregation of hyperplastic and hypertrophic Kupffer cells, in addition to bile duct hyperplasia, peripheral fibrosis, and increased liver weight. Biological changes included increased bilirubin and cholesterol levels, leukocyte inflammation, and changes in red blood cell parameters.
Genotoxicity/Mutagenicity
No evidence of mutagenic potential was observed in bacterial in vitro systems and in mammalian in vitro and in vivo systems with and without metabolic activation.
Carcinogenicity
Carcinogenicity studies were not performed. The sponsor has agreed to submit the results of a two-year carcinogenicity study in rats.
Reproductive and Developmental Toxicity
Oral administration of nilotinib at doses of ≥ 30 mg/kg/day in rats produced maternal and embryo-lethality/fetal effects.
Nilotinib 300 mg/kg/day administered to pregnant rabbits orally via gavage once daily from gestation days 7-20 resulted in embryotoxicity, maternal toxicity, and increased resorption of fetuses. Fetal skeletal variations were also increased at this dose in the presence of maternal toxicity.
3.2.4 Conclusion
The results of the non-clinical studies as well as the potential risks to humans have been included in the Product Monograph. In view of the intended use of Tasigna, there are no pharmacological/toxicological issues within this submission which preclude authorization of the product for the requested indication.
Additional non-clinical studies were initiated to further assess the non-clinical cardiac safety profile of nilotinib. 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
Based on the provided publication and experimental clinical data, nilotinib inhibits downstream signaling pathways such as PI3K/AKT, STAT5, and Crkl, and induces apoptosis of Bcr-Abl positive cells. Preliminary findings of a study to analyze the post-treatment changes in p-Crkl by Western blot showed reductions of p-Crkl in 16 out of 19 patients.
3.3.2 Pharmacokinetics
Absorption
Following a single oral dose of nilotinib in healthy volunteers, absorption of nilotinib was estimated to be approximately 30%.
The absorption of nilotinib was significantly increased when taken with food. The percent increase in the maximum drug concentration in plasma (Cmax) and area under the curve (AUC) was related to the fat content of the food and the time of food intake relative to nilotinib administration.
Distribution
Nilotinib was highly bound to human plasma proteins (~98%), human serum proteins (~99%), human serum albumin (~94%), and to α1-acid glycoprotein (~94%) The protein binding was independent of the drug concentration tested.
Metabolism
In vitro studies suggest that CYP3A4 is the principle enzyme responsible for nilotinib metabolism.
Fifteen metabolites were characterized, however, nilotinib accounted for 87.5 ± 9.2% of the total serum exposure from 0-48 hours; none of the metabolites demonstrated a significant pharmacological activity.
Excretion
Greater than 90% of the administered dose was recovered within seven days post-dose, with 93% recovered in the feces. This implies that there was no significant tissue accumulation of nilotinib or its metabolites after single dosing. The average amount of unchanged drug in the feces was 68.5% of the dose.
Drug Interaction Studies
Co-administration of nilotinib with midazolam (both metabolized by CYP3A4) indicated that a drug interaction may occur between nilotinib and other concurrently administered drugs metabolized via a similar pathway.
Co-administration of nilotinib with the known CYP3A4 inhibitor ketoconazole resulted in increased nilotinib exposure and a corresponding higher incidence of headache.
In the non-clinical studies, nilotinib was shown to be a substrate and inhibitor of P-gp.
Non-clinical studies indicated that nilotinib could likely inhibit CYP2C8 and CYP3A4/5 in humans at the steady-state Cmax of 4.3 μM. Although a study was performed with midazolam (verifying the nilotinib inhibition of CYP3A4), no clinical studies were performed to evaluate the effects of nilotinib on CYP2C8. The sponsor plans a clinical drug interaction study with a substrate of CYP2C9 at clinically relevant concentrations of nilotinib. If the results show clinically relevant interaction, the sponsor will conduct an additional clinical study with a CYP2C8 substrate accordingly.
Special Populations
A population pharmacokinetic (PK) study was conducted to study covariate influences on the PK of nilotinib. Bioavailability of nilotinib was approximately 20% higher in female patients, whereas age, body weight, and concomitant medications did not show relevant influences on PK.
3.3.3 Clinical Efficacy
The clinical efficacy of Tasigna* was based on interim analysis of the Phase II component of Study 2101 conducted in patients with Philadelphia chromosome-positive (Ph+) accelerated phase (AP) chronic myeloid leukemia (CML) who are resistant or intolerant to imatinib. Resistance to imatinib included failure to achieve a complete hematologic response (by 3 months), cytogenetic response (by 6 months) or major cytogenetic response (by 12 months), or progression of the disease after a previous cytogenetic or hematologic response. Imatinib intolerance included patients who discontinued imatinib because of toxicity and were not in major cytogenetic response at the time of study entry. Overall, 73% of the patients were imatinib-resistant while 27% were imatinib-intolerant. The majority of patients had a long history of CML that included extensive prior treatment with other antineoplastic agents such as imatinib, hydroxyurea, interferon, or failed stem cell transplant.
The Tasigna* dose for the Phase II component was 400 mg twice a day (BID). Patients may have had a dose escalation to 600 mg BID according to escalation criteria if there had been no previous dose reductions due to toxicities, in the absence of severe adverse drug reactions and severe non-leukemia related hematologic toxicities. PK studies showed no dose-proportionality in nilotinib exposure between patients administered the 400 BID dose or the 600 mg BID dose. Primary efficacy was based on a composite endpoint of overall confirmed hematologic response (HR), consisting of complete hematologic response (CHR), marrow response/no evidence of leukemia, and return to chronic phase (RTC).
The initial efficacy analysis was based on data submitted from the first 64 CML-AP patients who completed 4-months treatment with Tasigna* 400 mg BID. Of the 64 patients, 51.7% of the patients had a prior dose of imatinib ≥ 800 mg as their highest dose, and 33.7% of the patients had a prior dose of 600-800 mg imatinib as their highest dose. A total of 84.3% of the patients were imatinib-resistant, while 15.7% were imatinib-intolerant. Primary efficacy results showed that 43.8% of the patients achieved an overall HR. The median duration of HR was 10.2 months, and the median time to response was 1 month. The overall cytogenetic response rate was a secondary endpoint, with 31.3% of the patients responding with a median time to response of 2 months. Although 44% of the treated patients achieved HR, the clinical relevance of the composite HR definition was questionable. A longer exposure time (closer to that of the median duration of response) were required to make an adequate risk/benefit assessment.
In response, the sponsor submitted a 120-day Efficacy and Safety Update report. This included 4 months of follow-up data from the 64CML-AP patients previously mentioned, as well as 4-month data from 41 additional CML-AP patients (enrolled since the original submission). A total of 105 CML-AP patients were treated orally with Tasigna* 400 mg BID; 24 of these patients were dose-escalated to 600 mg BID. The primary endpoint in the CML-AP patients was overall confirmed hematologic response (HR), defined as either a complete hematologic response (CHR), or no evidence of leukemia (NEL). With the 105 patients (64 and 41 patients in the primary and additional enrolments, respectively) the overall HR rate was 26%. The median exposure was 190.5 days. Two patients lost NEL type of response and none of the 19 patients who achieved confirmed CHR had a loss of CHR. The duration of CHR ranged from 2.8 months to 14.0 months.
In the first 64 consecutively enrolled CML-AP patients, the median duration of response was not reached, with 68% of responders maintaining their response at 8 months. In both groups, the median progression-free survival was not reached.
The cytogenetic response was one of several secondary endpoints. The unconfirmed major cytogenetic response (MCyR) rate was 23.4% (15/64 patients) and 17% (4/41 patients) for the primary and additional enrolment CML-AP patients, respectively. The overall unconfirmed MCyR rate was 21%.
After reviewing additional data provided, it was concluded that Tasigna* has shown promising evidence of clinical effectiveness for CML-AP patients resistant or intolerant to imatinib. The sponsor has agreed to submit the final efficacy data from Study 2101.
3.3.4 Clinical Safety
The safety profile of Tasigna* was based on interim analysis of the ongoing Phase II component of Study 2101. The data was primarily evaluated from chronic phase (CP) and accelerated phase (AP) CML patients resistant/intolerant to imatinib. The standard dose was 400 mg BID. For more information about Study 2101, see section 3.3.3 Clinical Efficacy.
The initial safety analysis was based on 371 patients (84% were classified as Caucasian) and the median duration of exposure was 4.8 months. The most frequently non-hematologic adverse events (AEs) were rash, nausea, headache, pruritus, fatigue, constipation, and diarrhea. The most frequent Grade 3 or 4 AEs were thrombocytopenia (22.4%), neutropenia (15.6%), anemia (7.3%) and increased lipase levels (5.4%). Overall, the most frequent serious adverse events (SAEs) were related to the blood and lymphatic system disorders (6.7%; thrombocytopenia, neutropenia, febrile neutropenia, anemia, leucopenia). In CML-AP patients, 19.1% experienced SAEs related to the blood and lymphatic system disorders, and 5.1% experienced a cardiac disorder (myocardial infarction, angina pectoris, atrial fibrillation, pericardial effusion, pericarditis, ventricular dysfunction). Abnormal levels of albumin, aspartate aminotransferase, alanine transaminase, serum alkaline phosphatase, and total bilirubin suggested clinically significant hepatotoxic side effects of Tasigna*. Elevation in serum lipase has been observed. Few of these elevations were associated with abdominal pain or pancreatitis. Tasigna* treatment resulted in dose-dependent QT prolongation. To further evaluate these toxicities, data from a longer duration of exposure and a larger study population were required.
In response, the sponsor submitted the 120-day Efficacy and Safety Update report. An additional 4 months of data for all the safety parameters presented in the original submission were reported from a larger number of patients (n=318 for CML-CP and n=120 for CML-AP). At the time of data cut-off, 46% of the CML-CP patients and 30.8% of the CML-AP patients had a duration of exposure of 6 to <12 months. The median dose intensity was 796.6 mg/day corresponding to the indicated dose of 400 mg BID.
The updated safety information in the additional report was consistent with the original submission data. Overall, the most frequent AEs included gastrointestinal disorders, skin and subcutaneous tissue disorders, nervous system disorders, and blood and lymphatic system disorders.
The overall incidence of drug-related AEs for the CML-CP and CML-AP populations were 90.9% and 79.2%, respectively. The most frequent drug-related AEs observed for CML-CP patients were rash (28.3%), thrombocytopenia (25.8%), pruritis (23.6%), nausea (22.3%), fatigue (19.8%), headache (17.6%), neutropenia (13.8%), and lipase increase (11.9%). The most frequent drug-related AEs observed for CML-AP patients were thrombocytopenia (31.7%), rash (20.8%), neutropenia (20%), pruritis (17.5%), anemia (15%), lipase increase (11.8%), and constipation (10.8%). Pancreatitis occurred in 0.9% and 0.8% of CML-CP and CML-AP patients, respectively.
Patients experiencing Grade 3 or 4 AEs were 69.5% for the CML-CP population and 67.5% for the CML-AP patients. The most frequent Grade 3 or 4 AEs for the CML-CP population included thrombocytopenia (25.3%), neutropenia (16.7%), anemia (8.7%), and increased lipase (7.5%). For the CML-AP patients, Grade 3 or 4 AEs included thrombocytopenia (34.2%), neutropenia (20%), anemia (13.3%), and increased lipase (9.2%) and additionally, leucopenia (6.7%), pneumonia (4.2%) and decreased hemoglobin (4.2%).
The most frequent SAEs were related to blood and lymphatic system disorders (7.3%), cardiac disorders (5.7%), infections and infestations (5.5%), general disorders and administration site conditions (5.3%), gastrointestinal disorders (4.6%).
The most frequently newly occurring or worsening Grade 3 or 4 hematological abnormalities for the CML-CP population concerned platelet counts (28.5%), neutrophils (28.3%), and absolute lymphocytes (24%). For the CML-AP population, the Grade 3 or 4 hematological abnormalities were seen in platelet counts (37.4%), neutrophils (37.1%), absolute lymphocytes (35.1%), white blood cell count (30.5%), and hemoglobin (22.9%).
The most frequently newly occurring or worsening Grade 3 or 4 chemistry abnormalities for the CML-CP population were lipase increases (15.1%), hyperglycemia (10.7%), hypophosphatemia (9.7%), and total bilirubin increases (8.6%). In the CML-AP population, the reports showed lipase increases (16.8%), total bilirubin increases (10.3%), hypophosphatemia (9.7%), and hyperglycemia (4.4%).
Tasigna* has been demonstrated to prolong cardiac ventricular repolarization measured by the QT interval. It was observed that a number of patients experienced a QTcF prolongation from baseline of >30 msec (33% of CML-CP patients, 40.8% of CML-AP patients). QTcF increases of >60 msec were reported in 1.9% of the CML-CP patients and 2.5% of the CML-AP patients. In the CML-CP population, cardiac AEs leading to discontinuation were myocardial infarction, acute myocardial infarction, angina pectoris, and coronary artery arteriosclerosis (one patient each). Only two cardiac AEs, myocardial infarction and atrial fibrillation (one patient each), resulted in discontinuation in the CML-AP population. In both study populations, no episodes of torsades de pointes or death due to arrhythmias were noted.
Tasigna* has been shown to be a QT-interval prolonger and sudden deaths have been reported in patients receiving Tasigna* (10/2800 patients). Therefore, the drug is contraindicated in patients with long QT syndrome. Tasigna* will be restricted in patients who are at significant risk of QT-interval prolongation, for example (e.g.) patients taking drugs that are known QT-prolongers, and also in patients with electrolyte abnormalities.
Treatment with Tasigna* may result in increased levels of bilirubin, hepatic transaminase enzymes, and alkaline phosphatase. In addition, elevations of lipase and amylase levels have been observed. Tasigna* needs to be used with caution in patients with hepatic impairment or previous history of pancreatitis. Appropriate warnings and precautions are in place in the approved Product Monograph to address the identified safety concerns. In order to verify clinical benefit of Tasigna* further studies are going to be required.
3.3.5 Additional Issues
In keeping with the provisions outlined in the Notice of Compliance with Conditions (NOC/c) Policy, the sponsor has agreed to provide the following reports:
- Final efficacy data in patients with imatinib-resistant or intolerant CML-AP and combined safety data from Study 2101.
- A clinical study report to assess the use of Tasigna* in patients with hepatic impairment.
- A clinical drug interaction study with a substrate of CYP2C9 at clinically relevant concentrations of nilotinib. If the results show a clinically relevant interaction, an additional clinical study with a CYP2C8 substrate should be submitted.
- A non-clinical nilotinib cardiac safety assessment (in vivo and in vitro studies).
- A two-year, nilotinib long-term carcinogenicity study in rats.
3.4 Benefit/Risk Assessment and Recommendation
3.4.1 Benefit/Risk Assessment
Tasigna* has been shown to be efficacious in CML-AP patients who are resistant or intolerant to imatinib and at a high risk for disease progression to blast crisis. The market authorization with conditions was based on the interim analysis of the confirmed hematologic response rate in Study 2101. This primary endpoint was achieved in 28% of the 105 CML-AP patients at the time of data cut-off.
Treatment-emergent hematologic toxicities included thrombocytopenia (27%), neutropenia (15%), and anemia (13%). Pleural and pericardial effusions as well as complications of fluid retention occurred in 1% of patients receiving Tasigna*. Congestive heart failure was observed in 1% of patients.Gastrointestinal and central nervous system hemorrhage was reported in 3% and 1% of patients, respectively.
The most frequent non-hematologic drug-related adverse events were rash, pruritus, nausea, fatigue, headache, constipation and diarrhea. Most of these adverse events were mild to moderate in severity. Bone pain, arthralgia, muscle spasms, and peripheral edema were observed less commonly and have been of mild to moderate severity.
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 Tasigna* is favourable for the treatment of accelerated phase Philadelphia chromosome-positive chronic myeloid leukemia in adult patients resistant to or intolerant to at least one prior therapy including imatinib.
This New Drug Submission (NDS) qualifies for authorization under the Notice of Compliance with Conditions (NOC/c) Policy. 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.
In keeping with the provisions outlined in the Notice of Compliance with Conditions (NOC/c) Policy, the sponsor has agreed to provide the following reports:
- Final efficacy data in patients with imatinib-resistant or intolerant CML-AP and combined safety data from Study 2101.
- A clinical study report to assess the use of Tasigna* in patients with hepatic impairment.
- A clinical drug interaction study with a substrate of CYP2C9 at clinically relevant concentrations of nilotinib. If the results show a clinically relevant interaction, an additional clinical study with a CYP2C8 substrate should be submitted.
- A non-clinical nilotinib cardiac safety assessment (in vivo and in vitro studies).
- A two-year, nilotinib long-term carcinogenicity study in rats.
4 Submission Milestones
Submission Milestones: Tasigna
| Submission Milestone | Date |
|---|---|
| Advance consideration Notice of Compliance with Conditions granted for CML-AP: | 2006-11-10 |
| Submission filed: | 2006-12-05 |
| Screening 1 | |
| Screening Acceptance Letter issued: | 2006-12-28 |
| Review 1 | |
| Quality Evaluation complete: | 2007-07-12 |
| Clinical Evaluation complete: | 2007-07-03 |
| Notice of Non-compliance issued by Director General (safety and effectiveness issues): | 2007-07-13 |
| Response filed: | 2007-10-03 |
| Screening 2 | |
| Screening Acceptance Letter issued: | 2007-10-26 |
| Review 2 | |
| Quality Evaluation complete: | 2008-01-22 |
| Clinical Evaluation complete: | 2008-09-05 |
| Labelling Review complete: | 2008-09-05 |
| Notice of Compliance with Conditions-Qualifying Notice issued: | 2008-07-04 |
| Response filed: | 2008-08-13 |
| Notice of Compliance issued by Director General under the NOC/c Policy: | 2008-09-09 |
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| Product name | DIN | Company name | Active ingredient(s) & strength |
|---|---|---|---|
| TASIGNA | 02315874 | NOVARTIS PHARMACEUTICALS CANADA INC | NILOTINIB (NILOTINIB HYDROCHLORIDE MONOHYDRATE) 200 MG |