Summary Basis of Decision for Odomzo
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:
Summary Basis of Decision (SBD) documents provide information related to the original authorization of a product. The SBD for Odomzo is located below.
Recent Activity for Odomzo
SBDs written for eligible drugs 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. PAATs will be updated regularly with post-authorization activity throughout the product's life cycle.
Post-Authorization Activity Table (PAAT) for Odomzo
Updated:
The following table describes post-authorization activity for Odomzo, a product which contains the medicinal ingredient sonidegib (supplied as sonidegib phosphate). 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 that are found in PAATs.
For additional information about the drug submission process, refer to the Management of Drug Submissions and Applications Guidance.
Drug Identification Number (DIN):
- DIN 02500337 - 200 mg sonidegib, capsule, oral administration
Post-Authorization Activity Table (PAAT)
| Activity/submission type, control number | Date submitted | Decision and date | Summary of activities |
|---|---|---|---|
| NDS # 259210 | 2021-12-02 | Issued NOC2022-01-04 | Submission filed to transfer ownership of the drug product from Sun Global FZE to Sun Pharmaceutical Industries Limited. An NOC was issued. |
| Drug product (DIN 02500337) market notification | Not applicable | Date of first sale:2020-12-23 | The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations. |
| NDS # 229407 | 2019-07-04 | Issued NOC2020-06-12 | NOC issued for New Drug Submission. |
Summary Basis of Decision (SBD) for Odomzo
Date SBD issued: 2020-08-11
The following information relates to the new drug submission for Odomzo.
Sonidegib (supplied as sonidegib phosphate)
Drug Identification Number (DIN):
- DIN 02500337 - 200 mg sonidegib, capsule, oral administration
Sun Pharma Global FZE
New Drug Submission Control Number: 229407
On June 12, 2020, Health Canada issued a Notice of Compliance to Sun Pharma Global FZE for the drug product Odomzo.
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-harm-uncertainty profile of Odomzo is favourable for the treatment of adult patients with histologically confirmed locally advanced basal cell carcinoma that is not amenable to radiation therapy or curative surgery.
1 What was approved?
Odomzo, an antineoplastic agent, was authorized for the treatment of adult patients with histologically confirmed locally advanced basal cell carcinoma that is not amenable to radiation therapy or curative surgery. This indication was granted authorization based on the objective response rate demonstrated in a non-comparative Phase II clinical trial. Overall survival benefit in this trial could not be confirmed.
Odomzo is only available through a controlled distribution program, called the Odomzo Pregnancy Prevention Program. Under this program, only prescribers and pharmacies registered with the program are able to prescribe and dispense the product, respectively. In addition, Odomzo may only be dispensed to patients who are registered and meet all the conditions of the program.
Based on the data submitted to and reviewed by Health Canada, the safety and efficacy of Odomzo in pediatric patients (younger than 18 years of age) have not been established. Therefore, Health Canada has not authorized an indication for pediatric use. Moreover, given that Odomzo can cause irreversible premature fusion of the epiphyses in pediatric patients, it is contraindicated for use in this population (as listed below).
No overall differences in the effectiveness of Odomzo were observed between geriatric patients (65 years of age or older) and younger patients. However, there was a higher incidence of serious adverse reactions, grade 3 and grade 4 adverse reactions, and adverse reactions requiring dose interruptions or discontinuations in elderly patients compared with younger patients. This was not attributed to an increase in any specific adverse event.
Odomzo is contraindicated in:
- female patients who are pregnant and females at risk of becoming pregnant
- breastfeeding female patients
- female patients of childbearing potential who do not comply with the Odomzo Pregnancy Prevention Program
- male patients who do not comply with the contraceptive measures of the Odomzo Pregnancy Prevention Program
- children and adolescents under 18 years of age
- patients who are hypersensitive to sonidegib or to any ingredient in the formulation
Odomzo was approved for use under the conditions stated in its Product Monograph, taking into consideration the potential risks associated with the administration of this drug product.
Odomzo (200 mg sonidegib, supplied as sonidegib phosphate) is presented as a capsule. In addition to the medicinal ingredient, the capsule (including the hard-capsule shell and the printing ink) contains colloidal silicon dioxide, crospovidone, lactose monohydrate, magnesium stearate, poloxamer, sodium lauryl sulfate, gelatin, red iron oxide, titanium dioxide, ammonium hydroxide, black iron oxide, propylene glycol, and shellac.
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 Odomzo Product Monograph, approved by Health Canada and available through the Drug Product Database.
2 Why was Odomzo approved?
Health Canada considers that the benefit-harm-uncertainty profile of Odomzo is favourable for the treatment of adult patients with histologically confirmed locally advanced basal cell carcinoma that is not amenable to radiation therapy or curative surgery. This indication has been granted authorization on the basis of objective response rate demonstrated in a non-comparative Phase II clinical trial. Overall survival benefit in this trial could not be confirmed.
Locally advanced basal cell carcinoma not amenable to radiation therapy or curative surgery is a serious disease. Local tissue invasion and destruction by the tumour results in considerable morbidities, including disfigurement. Most basal cell carcinomas contain genetic alterations in the hedgehog signalling pathway, resulting in aberrant pathway activation and uncontrolled proliferation of basal cells. Most commonly, these alterations cause loss of function of the protein patched 1, which normally acts to inhibit the signalling activity of smoothened, a transmembrane protein. Vismodegib, a first-in-class small-molecule inhibitor of the hedgehog signalling pathway, is currently the only systemic therapy authorized in Canada for the treatment of adult patients with histologically confirmed locally advanced basal cell carcinoma inappropriate for surgery or radiotherapy.
Another selective small-molecule inhibitor of the hedgehog signalling pathway is sonidegib, the medicinal ingredient in Odomzo, which acts by binding to smoothened.
The market authorization of Odomzo was based on efficacy and safety data derived from one Phase II pivotal clinical trial (BOLT). Sixty-six patients with locally advanced basal cell carcinoma received Odomzo 200 mg once daily. Based on the primary (6-month) analysis, the objective response rate was 47% (95% confidence interval [CI]: 35%, 60%), as determined by blinded central review according to the modified Response Evaluation Criteria in Solid Tumours (mRECIST). The median duration of response was not estimable. At the 42-month analysis, the objective response rate was 56% (95% CI: 43%, 68%), and the median duration of response was 26.1 months. The objective response rate, supported by the duration of response, is considered clinically meaningful.
The most common adverse reactions occurring in at least 10% of patients treated with Odomzo 200 mg once daily were muscle spasms, alopecia, fatigue, dysgeusia, nausea, musculoskeletal pain, diarrhea, decreased weight, decreased appetite, myalgia, abdominal pain, headache, pain, vomiting, and pruritus.
The most common severe adverse reactions reported in at least 2% of the patients were fatigue, decreased weight, muscle spasms, and hypotension.
Increased levels of serum creatine phosphokinase (CPK) were found in 61% (48/79) of patients. Grade 3 or 4 serum CPK elevations occurred in 8% (6/79) of patients.
The adverse reactions were generally manageable by close monitoring, symptomatic treatment, and treatment interruption or discontinuation.
Odomzo can cause amenorrhea (absence of menstrual periods) in female patients of reproductive age. It is not known if the reported amenorrhea is permanent. Based on non-clinical studies, Odomzo may irreversibly impair fertility. Accordingly, the Odomzo Product Monograph contains recommendations that fertility preservation strategies should be discussed with female patients of childbearing potential prior to starting treatment with Odomzo.
Odomzo was also shown to be embryotoxic, fetotoxic, and teratogenic in animal studies at maternal exposures below the recommended human dose of 200 mg. Therefore, female patients of childbearing potential must not be given Odomzo until pregnancy is excluded. To avoid the risk of embryo-fetal toxicity, Odomzo is only available through a controlled distribution program, called the Odomzo Pregnancy Prevention Program. Under this program, only prescribers and pharmacies registered with the program are able to prescribe and dispense the product, respectively. Moreover, Odomzo may only be dispensed to patients who are registered and meet all the conditions of the program. It is contraindicated in women of childbearing potential who do not comply with the requirements of this program and in male patients who do not comply with the contraceptive measures of the program.
Epiphyseal disorders, including premature fusion of the epiphyses have been reported in pediatric patients exposed to Odomzo in a clinical trial published in the literature. In some cases, pediatric patients treated with other hedgehog pathway inhibitors have experienced progression of epiphyseal fusion despite discontinuation of the hedgehog pathway inhibitor. Precocious puberty has been reported with other hedgehog pathway inhibitors. Due to these safety concerns, Odomzo is contraindicated for use in children and adolescents under the age of 18 years.
A Serious Warnings and Precautions box has been included in the Odomzo Product Monograph to highlight the risks of embryo-fetal death or severe birth defects, the risk of irreversible premature fusion of the epiphyses in pediatric patients, and the fact that Odomzo has not been studied in patients with severe renal impairment. It emphasizes that the use of Odomzo should be initiated and monitored only under the supervision of a physician qualified in the use of cancer therapies, and with a full understanding of the risks of Odomzo therapy and the monitoring requirements. It also emphasizes that Odomzo is available only through a controlled distribution program, the Odomzo Pregnancy Prevention Program.
A Risk Management Plan (RMP) for Odomzo was submitted by Sun Pharma Global FZE to Health Canada. Upon review, the RMP was considered to be acceptable. The RMP is designed to describe known and potential safety issues, to present the monitoring scheme and when needed, to describe measures that will be put in place to minimize risks associated with the product.
The submitted bottle label, patient alert card, package outsert, and Patient Medication Information section of the Odomzo Product Monograph meet the necessary regulatory labelling, plain language and design element requirements.
A Look-alike Sound-alike brand name assessment was performed and the proposed name, Odomzo, was accepted.
Based on clinical and non-clinical studies, the benefit-harm-uncertainty profile of Odomzo is considered favourable for the treatment of adult patients with histologically confirmed locally advanced basal cell carcinoma not amenable to radiation therapy or curative surgery. The identified safety concerns associated with the use of Odomzo have been appropriately addressed in the Odomzo Product Monograph through specified contraindications, warnings and precautions including a Serious Warnings and Precautions box, relevant monitoring requirements, and recommendations on dose modifications. The Odomzo Pregnancy Prevention Program is an important additional risk minimization measure designed to avoid embryo-fetal exposure to Odomzo. Educational materials regarding this program have been developed for patients and health care professionals.
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 Odomzo?
Submission Milestones: Odomzo
| Submission Milestone | Date |
|---|---|
| Pre-submission meetings: | 2014-05-22 - 2018-12-05 |
| Submission filed: | 2019-07-04 |
| Screening | |
| Screening Acceptance Letter issued: | 2019-08-20 |
| Review | |
| Biopharmaceutics Evaluation complete: | 2020-06-08 |
| Quality Evaluation complete: | 2020-06-09 |
| Review of Risk Management Plan complete: | 2020-06-10 |
| Clinical/Medical Evaluation complete: | 2020-06-11 |
| Labelling Review complete, including Look-alike Sound-alike brand name assessment: | 2020-06-11 |
| Notice of Compliance issued by Director General, Therapeutic Products Directorate: | 2020-06-12 |
The Canadian regulatory decision on the review of Odomzo was based on a critical assessment of the data package submitted to Health Canada. The foreign reviews completed by the European Medicines Agency (EMA) and the United States Food and Drug Administration (FDA) were used as added references.
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.
6 What other information is available about drugs?
Up to date information on drug products can be found at the following links:
- See MedEffect Canada for the latest advisories, warnings and recalls for marketed products.
- See the Notice of Compliance (NOC) Database for a listing of the authorization dates for all drugs that have been issued an NOC since 1994.
- See the Drug Product Database (DPD) for the most recent Product Monograph. The DPD contains product-specific information on drugs that have been approved for use in Canada.
- See the Notice of Compliance with Conditions (NOC/c)-related documents for the latest fact sheets and notices for products which were issued an NOC under the Notice of Compliance with Conditions (NOC/c) Guidance Document, if applicable. Clicking on a product name links to (as applicable) the Fact Sheet, Qualifying Notice, and Dear Health Care Professional Letter.
- See the Patent Register for patents associated with medicinal ingredients, if applicable.
- See the Register of Innovative Drugs for a list of drugs that are eligible for data protection under C.08.004.1 of the Food and Drug Regulations, if applicable.
7 What was the scientific rationale for Health Canada's decision?
7.1 Clinical basis for decision
Clinical Pharmacology
The clinical pharmacology data support the use of Odomzo for the specified indication.
Sonidegib has been investigated in pharmacokinetic, dose-escalation, and drug-drug interaction studies conducted in healthy subjects, patients with advanced solid tumours (including basal cell carcinoma) or patients with hepatic impairment. The clinical pharmacology data also included in vitro studies, exposure-response, and population pharmacokinetic analysis reports.
Administration of sonidegib with food significantly increases sonidegib bioavailability and systemic exposures. The food effect is minimized when sonidegib is taken at least one hour before or two hours after a meal, as recommended in the Odomzo Product Monograph.
Following repeated doses of sonidegib once daily, the steady state was achieved approximately 4 months after commencing treatment. The estimated accumulation at steady state was 19-fold. Sonidegib is highly bound to plasma proteins and extensively distributed in the human body. It is metabolized primarily by cytochrome P450 (CYP) 3A4. The parent drug contributes to the majority of the overall pharmacological activity. The absorbed sonidegib is eliminated exclusively by metabolism. No detectable parent drug is found in the urine. Almost 90% of the administered dose is eliminated via feces as an unchanged drug. The estimated half-life of sonidegib is approximately 28 days.
There were no clinically relevant increases in exposures of sonidegib in subjects with mild, moderate or severe hepatic impairment following a single dose administration. Therefore, no initial dose adjustments in patients with hepatic impairment is needed. However, the half-life of sonidegib was significantly prolonged in patients with moderate or severe hepatic impairment. As a result, higher drug accumulation and exposures are expected in those patients following repeated doses. As the magnitude of the increased exposures following repeated doses is unknown, patients with baseline moderate or severe hepatic impairment should be closely monitored for signs of sonidegib toxicity and changes in hepatic function. Odomzo should be permanently discontinued if the liver function deteriorates.
Pharmacokinetic properties of sonidegib were not evaluated in patients with renal impairment, given the negligible renal excretion of the parent drug. Based on a population pharmacokinetic analysis, mild to moderate renal impairment had no clinically meaningful effect on sonidegib steady-state exposure. The effect of severe renal impairment on the pharmacokinetic properties of sonidegib is unknown.
Concomitant use of a strong CYP3A4 inhibitor or inducer significantly altered sonidegib exposures. Accordingly, concurrent administration of sonidegib with a strong or moderate CYP3A4 inhibitor or inducer should be avoided. In addition, concomitant use of a proton pump inhibitor was shown to reduce sonidegib exposure. Patients may experience reduced efficacy when an acid reducing agent is concomitantly used with Odomzo.
Based on a population pharmacokinetic analysis, there is no clinically significant effect of age, body weight or gender on systemic exposure of sonidegib. A pharmacokinetic study in the pediatric (younger than 18 years of age) population has not been conducted.
For further details, please refer to the Odomzo Product Monograph, approved by Health Canada and available through the Drug Product Database.
Clinical Efficacy
The efficacy of Odomzo was evaluated in a multicentre, double-blind, multiple-cohort, non-comparative clinical trial, BOLT. The trial included 194 adult patients with locally advanced basal cell carcinoma not amenable to radiation therapy or curative surgery and 36 adult patients with metastatic basal cell carcinoma. Patients were randomized in a ratio of 2:1 to receive either Odomzo 800 mg or 200 mg orally, once daily, until disease progression or intolerable toxicity. No statistical analyses were planned to compare efficacy results between the two dose cohorts.
The primary efficacy endpoint was objective response rate as determined by blinded central review according to the modified Response Evaluation Criteria in Solid Tumours (mRECIST) for patients with locally advanced basal cell carcinoma or the RECIST version 1.1 for patients with metastatic basal cell carcinoma. The key secondary efficacy endpoints included duration of response and rate of complete response, as determined by blinded central review.
For patients with locally advanced basal cell carcinoma, the composite overall response determined by an independent review committee was based on integration of centrally evaluated magnetic resonance imaging (MRI) scans, digital clinical photographs, and histopathology, according to the mRECIST.
There were 66 patients with locally advanced basal cell carcinoma randomized to receive Odomzo 200 mg daily. These patients were followed for at least 42 months unless the treatment was discontinued earlier. Based on the primary (6-month) analysis, the objective response rate was 47% (95% CI: 35%, 60%), consisting of 2 (3%) complete responses and 29 (44%) partial responses. The median duration of response was not estimable (NE) (95% CI: NE). At the 42-month analysis, the objective response rate was 56% (95% CI: 43%, 68%), consisting of 3 (5%) complete responses and 34 (52%) partial responses. The median duration of response was 26.1 months (95% CI: NE).
The objective response rate, supported by the duration of response, is considered clinically meaningful for patients with histologically confirmed locally advanced basal cell carcinoma not amenable to radiation therapy or curative surgery.
Indication
The New Drug Submission for Odomzo was filed by the sponsor with the following indication:
- Odomzo (sonidegib) is indicated for the treatment of adult patients with locally advanced basal cell carcinoma that has recurred following surgery or radiation therapy, or those who are not candidates for surgery or radiation therapy.
Health Canada revised the proposed indication to reflect more accurately the patient population with locally advanced basal cell carcinoma enrolled in the submitted Phase II trial (BOLT) and to include a statement highlighting the basis of approval. Accordingly, Health Canada approved the following indication:
- Odomzo (sonidegib) is indicated for the treatment of adult patients with histologically confirmed locally advanced basal cell carcinoma (laBCC) that is not amenable to radiation therapy or curative surgery.
- The indication is granted market authorization based on objective response rate (ORR) demonstrated in a non-comparative Phase II trial. Overall survival (OS) benefit in this trial cannot be confirmed.
For more information, refer to the Odomzo Product Monograph, approved by Health Canada and available through the Drug Product Database.
Clinical Safety
The safety of Odomzo was mainly evaluated in the non-comparative clinical trial BOLT (described in the Clinical Efficacy section).
The most common adverse reactions experienced by at least 10% of patients with locally advanced basal cell carcinoma or metastatic basal cell carcinoma who received Odomzo 200 mg once daily were muscle spasms, alopecia, fatigue, dysgeusia, nausea, musculoskeletal pain, diarrhea, decreased weight, decreased appetite, myalgia, abdominal pain, headache, pain, vomiting, and pruritus.
The most common severe adverse reactions reported in at least 2% of the patients were fatigue, decreased weight, muscle spasms, and hypotension.
Increased levels of serum creatine phosphokinase (CPK) were observed in 61% (48/79) of patients. Grade 3 or 4 serum CPK elevations occurred in 8% (6/79) of patients.
The adverse reactions were generally manageable by close monitoring, symptomatic treatment, and treatment interruption or discontinuation.
Amenorrhea lasting for at least 18 months occurred in 2 out of 14 premenopausal women treated with Odomzo 200 mg or 800 mg once daily. It is not known if the reported amenorrhea is permanent.
To prevent the risk of embryo-fetal toxicity, Odomzo is only available through a controlled distribution program, called the Odomzo Pregnancy Prevention Program. Under this program, only prescribers and pharmacies registered with the program are able to prescribe and dispense the product, respectively. In addition, Odomzo may only be dispensed to patients who are registered and meet all the conditions of the program.
Appropriate warnings and precautions, including a Serious Warnings and Precautions box, are in place in the approved Odomzo Product Monograph to address the identified safety concerns.
For more information, refer to the Odomzo Product Monograph, approved by Health Canada and available through the Drug Product Database.
7.2 Non-Clinical Basis for Decision
The medicinal ingredient in Odomzo, sonidegib, is a selective inhibitor of smoothened, a transmembrane protein, which plays an important role in the hedgehog signal transduction pathway. This protein leads to the activation and nuclear localization of glioma-associated oncogene transcription factors and induction of hedgehog target genes. Many of these genes are involved in cell proliferation, survival, and differentiation. The inhibition of smoothened by sonidegib was shown to result in inhibition of cell proliferation in vitro and tumour regression in vivo.
In both rats and dogs, the primary toxicity targets of sonidegib were the bones and skin. Sonidegib induced thinning and closure of bone growth plates. Alopecia (loss of hair) was the manifestation of skin toxicity. These effects are attributed to the pharmacological mechanism of action of sonidegib on developmental pathways. The mature skeletal system and dentition of adult cancer patients are unlikely to be affected by sonidegib. However, hair loss due to the inhibition of the anagen phase (active growth phase) of the hair growth cycle would be expected in humans.
The gastrointestinal, lymphoid and reproductive systems were also shown to be toxicity targets of sonidegib in rats and dogs. These effects of sonidegib are consistent with its inhibition of the hedgehog signal transduction pathway.
Tremors and increased creatine phosphokinase levels were observed in both rats and dogs. In rats, this could be due to the off-target activity of sonidegib on the rat brain sodium channel type II. Tremors were also observed in the studies with juvenile rats.
Sonidegib is a potent teratogen in rats and rabbits and exerts toxicity in juvenile rats. It induced a complete loss of fertility in female rats, a high degree of abortions or total litter loss in rabbits, and significant signs of non-reversible toxicity in juvenile rats. Consequently, sonidegib administration to women of childbearing potential and juveniles is associated with significant risks.
At the time of this submission, carcinogenicity studies were still ongoing and data from these studies were not reviewed by Health Canada.
The results of the non-clinical studies as well as the potential risks to humans have been included in the Odomzo Product Monograph. In view of the intended use of Odomzo, no pharmacological or toxicological issues are identified within this submission to preclude authorization of the product.
Appropriate warnings and precautionary measures are in place in the Odomzo Product Monograph to address the identified safety concerns.
For more information, refer to the Odomzo 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 Odomzo 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. The drug product is stored at room temperature (15ºC to 30ºC), protected from moisture.
Proposed limits of drug-related impurities are considered adequately qualified, i.e., within International Council for Harmonisation limits and/or qualified from toxicological studies.
The sites involved in production are compliant with Good Manufacturing Practices.
All non-medicinal ingredients (described earlier) found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations. The excipient lactose monohydrate is derived from milk obtained from healthy animals under the same conditions as milk collected for human consumption. The gelatin used in the capsule shells for sonidegib phosphate 200 mg capsules is of bovine origin. Satisfactory information has been provided to establish that these excipients do not pose a risk of contamination with transmissible spongiform encephalopathy agents.
Related Drug Products
| Product name | DIN | Company name | Active ingredient(s) & strength |
|---|---|---|---|
| ODOMZO | 02500337 | SUN PHARMACEUTICAL INDUSTRIES LIMITED | SONIDEGIB (SONIDEGIB PHOSPHATE) 200 MG |