Summary Basis of Decision for Pomalyst

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 Pomalyst is located below.

Recent Activity for Pomalyst

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 Pomalyst

Updated: 2023-04-14

The following table describes post-authorization activity for Pomalyst, a product which contains the medicinal ingredient pomalidomide. 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 02419580 - 1 mg pomalidomide, capsule, oral administration
  • DIN 02419599 - 2 mg pomalidomide, capsule, oral administration
  • DIN 02419602 - 3 mg pomalidomide, capsule, oral administration
  • DIN 02419610 - 4 mg pomalidomide, capsule, oral administration

Post-Authorization Activity Table (PAAT)

Activity/submission type, control number Date submitted Decision and date Summary of activities
Summary Safety Review Not applicable Posted 2021-05-27 Summary Safety Review posted for Pomalyst and Thalomid (Assessing the potential risk of progressive multifocal leukoencephalopathy).
SNDS # 243491 2020-08-31 Issued NOC 2021-02-02 Submission filed as a Level II – Supplement (Safety) to update the PM with new safety information related to progressive multifocal leukoencephalopathy (PML), and migrate it to the 2016 format. The submission was reviewed and considered acceptable. As a result of the SNDS, 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. An NOC was issued.
New safety and effectiveness review Not applicable Started between 2020-08-01and 2020-08-31 Health Canada started a safety and effectiveness review for Pomalyst and Thalomid related to progressive multifocal leukoencephalopathy (a serious brain infection).
NC # 229243 2019-07-04 Issued NOL 2019-08-23 Submission filed as a Level II (90 day) Notifiable Change to update the PM with new safety information related to anaphylaxis and hypothyroidism. As a result of the NC, modifications were made to the Serious Warnings and Precautions Box, Warnings and Precautions, Adverse Reactions, and Dosage and Administration sections of the PM. Corresponding changes were made to Part III: Consumer Information. The submission was reviewed and considered acceptable, and an NOL was issued.
SNDS # 219719 2018-08-31 Issued NOC 2019-07-30 Submission filed as a Level I – Supplement to update the PM with data from study PBTC-043. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Dosage and Administration and Action and Clinical Pharmacology sections of the PM. An NOC was issued.
SNDS # 218459 2018-07-20 Issued NOC 2019-07-02 Submission filed as a Level I – Supplement for a new indication. The indication authorized was: in combination with dexamethasone and bortezomib, the treatment of adult patients with multiple myeloma who have received at least one prior treatment regimen including lenalidomide. The submission was reviewed and considered acceptable, and an NOC was issued.
NC # 210498 2017-10-23 Issued NOL
2018-02-01		 Submission filed as a Level II (90 day) Notifiable Change (Risk Management Change) to update the PM with new safety information. As a result of the NC, modifications were made to the Warnings and Precautions, Adverse Reactions, and Dosage and Administration sections of the PM, and corresponding changes were made to the PM Part III: Consumer Information. The submission was reviewed and considered acceptable, and an NOL was issued.
SNDS # 194902 2016-05-09 Issued NOC
2017-04-11		 Submission filed as a Level I - Supplement to update the PM. As a result of the SNDS, modifications were made to the, Warnings and Precautions, Drug Interactions, and Dosage and Administration sections of the PM, and corresponding changes were made to the PM Part III: Consumer Information. The submission was reviewed and considered acceptable, and an NOC was issued.
NC # 195645 2016-06-02 Issued No Objection Letter
2016-09-13		 Submission filed as a Level II (90 day) Notifiable Change (Risk Management Change) to update the Product Monograph (PM) with new safety information regarding risks associated with Pomalyst use: reactivation of Hepatitis B, gastrointestinal hemorrhage, and non-melanoma skin malignancies (basal cell and squamous cell carcinoma). As a result of the NC, additions were made to the Warnings and Precautions, and Adverse Reactions sections of the PM. Corresponding changes were made to the PM Part III: Consumer Information. The submission was reviewed and considered acceptable, and a No Objection Letter was issued.
NC # 190764 2015-12-21 Issued No Objection Letter
2016-04-11		 Submission filed as a Level II (90 day) Notifiable Change (Risk Management Change) to update the Product Monograph (PM) with new safety information related to co-administration of Pomalyst with a strong CYP1A2 inhibitor. As a result of the NC, additions were made to the Drug Interactions, and Dosage and Administration sections of the PM. The submission was reviewed and considered acceptable, and a No Objection Letter was issued.
NC # 185962 2015-07-02 Issued No Objection Letter
2015-10-27		 Submission filed as a Level II (90 day) Notifiable Change (Safety Change) for Product Monograph (PM) changes associated with hepatotoxicity and interstitial lung disease. As a result of the Notifiable Change (NC), revisions were made to the Warnings and Precautions, Adverse Reactions, and Dosage and Administration sections of the PM, and corresponding changes were made to the PM Part III: Patient Medication Information. The submission was reviewed and a No Objection Letter was issued.
NC # 181932 2015-02-05 Issued No Objection Letter
2015-05-20		 Submission filed as a Level II (90 day) Notifiable Change (Safety Change) for Product Monograph (PM) changes associated with the risk of drug hypersensitivity. As a result of the Notifiable Change (NC), revisions were made to the Warnings and Precautions, Adverse Reactions, and Dosage and Administration sections of the PM, and corresponding changes were made to the PM Part III: Consumer Information. The submission was reviewed and a No Objection Letter was issued.
NC # 179574 2015-01-07 Issued No Objection Letter
2015-04-09		 Submission filed as a Level II (90 day) Notifiable Change (Safety Change) for Product Monograph (PM) and labelling changes associated with avoiding embryo-fetal exposure to the drug. As a result of the Notifiable Change (NC), revisions were made to the packaging and changes were made to the PM Part III: Consumer Information. The submission was reviewed and a No Objection Letter was issued.
NC # 175333 2014-06-02 Issued No Objection Letter
2014-09-10		 Submission filed as a Level II (90 day) Notifiable Change (Safety Change) for Product Monograph (PM) changes associated with tumour lysis syndrome and pancytopenia. As a result of the Notifiable Change (NC), revisions were made to the Warnings and Precautions and Adverse Reactions sections of the PM, and corresponding changes were made to the PM Part III: Consumer Information. The submission was reviewed and a No Objection Letter was issued.
SNDS # 176450 2014-07-14 Submission cancelled
2014-09-03		 Submission filed as a Level I - Supplement to provide a clinical study report analysing the pharmacokinetics of pomalidomide. No changes to the Product Monograph were proposed and therefore this information will be reviewed outside the scope of a Supplemental New Drug Submission (SNDS). The SNDS was therefore cancelled by the sponsor at the request of Health Canada.
Drug product (DIN(s) 02419580, 02419599, 02419602, 02419610) market notification Not applicable Date of first sale:
2014-02-24		 The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.
NDS # 165891 2013-04-24 Issued NOC
2014-01-20		 Notice of Compliance issued for New Drug Submission.
Summary Basis of Decision (SBD) for Pomalyst

Date SBD issued: 2014-03-10

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

Pomalidomide, 1 mg, 2 mg, 3 mg, and 4 mg, capsules, oral

Drug Identification Number (DIN):

  • 02419580 - 1 mg
  • 02419599 - 2 mg
  • 02419602 - 3 mg
  • 02419610 - 4 mg

Celgene Inc.

New Drug Submission Control Number: 165891

 

On January 20, 2014, Health Canada issued a Notice of Compliance to Celgene Inc. for the drug product Pomalyst. 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 Pomalyst is considered favourable, in combination with dexamethasone (Pomalyst+LD-dex), for patients with multiple myeloma (MM) for whom both bortezomib and lenalidomide have failed and who have received at least two prior treatment regimens and have demonstrated disease progression on the last regimen.

1 What was approved?

Pomalyst, an antineoplastic agent and immunomodulatory agent, was authorized, in combination with dexamethasone (Pomalyst+LD-dex), for patients with multiple myeloma (MM) for whom both bortezomib and lenalidomide have failed and who have received at least two prior treatment regimens and have demonstrated disease progression on the last regimen.

Pomalyst is only available through a controlled distribution program called RevAid. Under this program, only prescribers and pharmacists registered with the program are able to prescribe and dispense the product. In addition, Pomalyst can only be dispensed to patients who are registered and meet all the conditions of the RevAid program.

No dosage adjustment is required for Pomalyst based on age. The concomitant administration of dexamethasone may increase the risk of infection, particularly pneumonia, in patients >65 years of age treated with Pomalyst. Dexamethasone dosing may need to be reduced or interrupted in these patients in case of infection.

There is limited information on the safety of Pomalyst in combination with dexamethasone in patients >75 years of age. The concomitant dexamethasone dose should be reduced by half in patients >75 years of age.

The safety and effectiveness of Pomalyst in children and adolescents have not been established.

Pomalyst is contraindicated:

  • in patients who are hypersensitive to pomalidomide, the active ingredient in Pomalyst, or to thalidomide, lenalidomide or to any ingredient in the formulation or component of the container;
  • in pregnant women and women at risk of becoming pregnant; if Pomalyst is taken during pregnancy, it may cause severe birth defects or death of the fetus;
  • in breast feeding women;
  • in male patients unable to follow or comply with the required contraceptive measures.

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

Pomalyst (1 mg, 2 mg, 3 mg, and 4 mg pomalidomide) is presented as a capsule. In addition to the medicinal ingredient, the capsule contains mannitol, pregelatinized starch, and sodium stearyl fumarate. The additional composition of the different capsule strengths is as follows: gelatin; titanium dioxide; FD&C blue #2; FD&C blue #1 (4 mg capsule only); yellow iron oxide (1 mg, 2 mg, and 3 mg capsules); and FD&C red #3 (2 mg capsule only).

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 Pomalyst Product Monograph, approved by Health Canada and available through the Drug Product Database.

2 Why was Pomalyst approved?

Health Canada considers that the benefit/risk profile of Pomalyst is favourable, in combination with dexamethasone (Pomalyst+LD-dex) for patients with multiple myeloma (MM) for whom both bortezomib and lenalidomide have failed and who have received at least two prior treatment regimens and have demonstrated disease progression on the last regimen.

MM is a malignant neoplasm of plasma cells that accumulate in bone marrow, leading to bone destruction and marrow failure. Normal immunoglobulin production is compromised, affecting the normal immune response, which predisposes patients to recurrent infections. MM is typically sensitive to a variety of cytotoxic drugs, both as initial treatment or as treatment of relapsed disease. However, responses are transient, and MM is not considered curable with current approaches. The indication requested in this drug submission is for a subgroup of patients for whom treatment with both bortezomib and lenalidomide have failed and who have received at least two prior treatment regimens and have demonstrated disease progression on the last regimen. In Canada, there are currently no drugs or drug combinations with a market authorization for the treatment of patients with relapsed and refractory multiple myeloma to both lenalidomide and bortezomib.

Pomalyst has been shown to be efficacious in patients with MM for whom both bortezomib and lenalidomide have failed, and who have received at least two prior treatment regimens and have demonstrated disease progression on the last regimen.

The market authorization was based on one pivotal Phase III, multicentre, randomized, open-label study (CC04047-MM-003)which compared the efficacy and safety of Pomalyst in combination with low-dose dexamethasone (Pomalyst+LD-dex) versus (vs.) high-dose dexamethasone (HD-dex) in patients with refractory or relapsed MM. The study was conducted in a total of 455 patients; 302 patients were enrolled in the Pomalyst+LD-dex arm and 153 patients were enrolled in the HD-dex arm.

The pivotal study met its primary study endpoint of progression-free survival (PFS) by International Myeloma Working Group (IMWG) criteria. The median PFS time was 15.7 weeks [95% confidence interval (CI): 13.0, 20.1] in the Pomalyst+LD-dex arm vs. 8.0 weeks (95% CI: 7.0, 9.0) in the HD-dex arm. The hazard ratio (HR) was 0.45 (95% CI: 0.35, 0.59, p<0.001). The median overall survival (OS), one of the key secondary endpoints, was 55.4 weeks (95% CI 45.3, 67.3) in the Pomalyst+LD-dex arm and 35.1 weeks (95% CI 29.9, 47.1) in the HD-dex arm (HR = 0.74, log-rank p = 0.028). The study results were considered statistically significant and clinically relevant for the intended indication and the targeted population.

The most commonly reported adverse events (AEs) in patients receiving Pomalyst+LD-dex were related to blood and lymphatic system disorders (anemia, neutropenia and thrombocytopenia), general disorders and administration site conditions (fatigue, pyrexia and edema peripheral), and infections and infestations (pneumonia).

Pomalyst, structurally related to thalidomide, is considered to have the potential to cause teratogenic effects in humans. There is a potential risk for human birth defects, stillbirths, and spontaneous abortions if Pomalyst is administered to a pregnant woman. In addition, Pomalyst is present in the semen of male patients. Therefore, there is a potential risk of fetal harm during unprotected intercourse between male patients and pregnant women or females of child-bearing potential. These risks, along with the risk of neutropenia, thrombocytopenia, deep vein thrombosis and pulmonary embolism have been included in a Serious Warnings and Precautions Box in the Product Monograph for Pomalyst.

A Risk Management Plan (RMP) for Pomalyst was submitted by Celgene Inc. 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.

Overall, the efficacy findings seen in the pivotal study showed that Pomalyst+LD-dex is clinically beneficial for the intended indication. It significantly improved PFS and OS and is associated with a higher response rate compared to HD-dex. The treatment is associated with considerable toxicity, but the toxicity appears to be manageable and is well captured in the product monograph. Appropriate warnings and precautions are in place in the Pomalyst Product Monograph to address the identified safety concerns. The recommended dose and schedule is fully supported by the pivotal study data. The overall results from the clinical development program support the recommended indication and conditions of use. Controlled distribution of Pomalyst via the RevAid program will be implemented as a means to prevent the risk of exposure of embryos and fetuses to pomalidomide. The overall benefit-risk assessment for Pomalyst is favorable.

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 Pomalyst?

The drug submission for Pomalyst was reviewed under the Priority Review Policy. Pomalyst demonstrated a significant increase in effectiveness with an improved benefit/risk profile compared to existing therapies for progressive multiple myeloma (MM), a condition that is not adequately managed by a drug marketed in Canada.

A Look-alike Sound-alike brand name assessment was performed and the proposed name Pomalyst has been deemed appropriate and acceptable.

 

Submission Milestones: Pomalyst

Submission Milestone Date
Pre-submission meeting: 2013-02-19
Request for priority status  
Filed: 2013-04-24
Approval issued by Director, Bureau of Metabolism, Oncology and Reproductive Sciences: 2013-05-30
Submission filed: 2013-06-20
Screening  
Screening Acceptance Letter issued: 2013-07-25
Review  
Quality Evaluation complete: 2013-12-19
Clinical Evaluation complete: 2014-01-17
Biostatistics Evaluation complete: 2013-10-18
Labelling Review complete: 2014-01-17
Notice of Compliance issued by Director General: 2014-01-20

 

The Canadian regulatory decision on the non-clinical and clinical review of Pomalyst 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 Stated 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?

As part of the marketing authorization for Pomalyst, Health Canada requested, and the sponsor agreed to several commitments to be addressed post-market. In addition to requirements outlined in the Food and Drugs Act and Regulations, commitments include (but are not limited to):

  • In order to prevent the risk of exposure of embryos and fetuses to pomalidomide, Pomalyst will be only available through a controlled distribution program (RevAid). Celgene will submit confirmation of the final implementation of the revised RevAid Physician-Patient Agreement Form.
5 What post-authorization activity has taken place for Pomalyst?

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 Pomalyst 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

The medicinal ingredient in Pomalyst, pomalidomide, is an immunomodulatory agent with antineoplastic activity. It is an analogue of thalidomide. Pomalyst exerts its action in the bone marrow to slow down the growth of cancerous myeloma cells. In in vitro cellular assays, pomalidomide inhibited proliferation and induced apoptosis of hematopoietic tumor cells.

The clinical pharmacology included reports on the human pharmacodynamic and pharmacokinetic studies. The results showed that Pomalyst is extensively metabolized via cytochrome P450 (CYP) isozymes (mainly CYP3A4 and CYP1A2) and non CYP hydrolysis. The co administration of a strong CYP1A2 inhibitor with Pomalyst in the presence of a strong CYP3A4 inhibitor should be avoided as it may result in increased exposure to Pomalyst. The co administration of pomalidomide with dexamethasone in patients with multiple myeloma (MM) did not result in any changes in the pharmacokinetic parameters.

Pharmacology Safety

Pomalidomide is structurally related to thalidomide, a known human teratogen that causes severe and life-threatening birth defects. In nonclinical studies, pomalidomide induced malformations in rats and rabbits similar to those described with thalidomide. If Pomalidomide (Pomalyst) is taken during pregnancy, it may cause severe birth defects or death to the fetus. Female patients of child bearing potential and male patients must comply with required contraceptive measures. For more information, please refer to the Clinical Safety section of this document.

Overall, the clinical pharmacological data support the use of Pomalyst for the specified indication. Appropriate warnings and precautions are in place in the Pomalyst Product Monograph to address the identified safety concerns.

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

Clinical Efficacy

The efficacy of Pomalyst was evaluated in one pivotal Phase III multicentre, randomized, open-label study (CC-4047-MM-003). The study compared the efficacy and safety of Pomalyst in combination with low-dose dexamethasone (Pomalyst+LD-dex) versus (vs.) high-dose dexamethasone (HD-dex) in previously treated adult patients with relapsed and refractory multiple myeloma, who had received at least two prior treatment regimens, had failed both lenalidomide and bortezomib, and had demonstrated disease progression on the last regimen.

A total of 455 patients were enrolled in the study. Patients were randomized in a 2:1 ratio to one of two treatment arms. A total of 302 patients were randomized in the Pomalyst+LD-dex arm (Pomalyst 4 mg/day on Days 1-21 and dexamethasone 40 mg on Days 1, 8, 15, and 22 of a 28-day cycle). A total of 153 patients were randomized in the HD-dex arm (40 mg on Days 1 through 4, 9 through 12, and 17 through 20 of a 28-day cycle. In both arms, patients over the age of 75 received dexamethasone 20 mg).

The primary endpoint of the study was progression-free survival (PFS). The PFS was reviewed by an Independent Response Adjudication Committee (IRAC) based on International Myeloma Working Group (IMWG) criteria. A key secondary study endpoint was overall survival (OS). Study treatment was continued until patients showed disease progression. Patients who did not progress, who were intolerant to treatment, or no longer wished to receive study treatment remained in the PFS follow-up period of the treatment phase. Patients on the HD-dex arm following disease progression had the option to receive Pomalyst alone or with dexamethasone in a companion study.

The PFS and OS were evaluated in several relevant subgroups: gender, age, Eastern Cooperative Oncology Group (ECOG) performance status, cytogenetic risk, creatinine clearance, baseline albumin levels, and microglobulin. The median PFS time was 15.7 weeks [95% confidence interval (CI): 13.0, 20.1] in the Pomalyst+LD-dex arm vs. 8.0 weeks (95% CI: 7.0, 9.0) in the HD-dex arm. The hazard ratio (HR) was 0.45 (95% CI: 0.35, 0.59, p<0.001). The median overall survival (OS) observed in the pivotal study was 55.4 weeks (95% CI 45.3, 67.3) in the Pomalyst+LD-dex arm and 35.1 weeks (95% CI 29.9, 47.1) in the HD-dex arm (HR = 0.74, log-rank p = 0.028). Regardless of the subgroup evaluated, PFS and OS were generally consistent with that observed in the intent-to-treat (ITT) population for both treatment groups. The efficacy findings of the pivotal study are supported by the efficacy finding from two non-pivotal studies. The study results were considered statistically significant and clinically relevant for the intended indication.

It should be noted that there is a potential risk that cigarette smoking may reduce the efficacy of the treatment by decreasing the exposure to pomalidomide due to CYP1A2 induction.

The original indication proposed with the New Drug Submission (NDS) was as follows: Pomalyst (pomalidomide) in combination with dexamethasone is indicated for patients with relapsed multiple myeloma or refractory multiple myeloma for whom both Revlimid (lenalidomide) and bortezomib have failed.

Following review of the submission, Health Canada revised the indication to: Pomalyst (pomalidomide) in combination with dexamethasone (Pomalyst+LD-dex) is indicated for patients with multiple myeloma for whom both bortezomib and lenalidomide have failed and who have received at least two prior treatment regimens and have demonstrated disease progression on the last regimen.

Overall, the data obtained from the clinical pivotal study demonstrated that Pomalyst+LD-dex is clinically beneficial for the approved indication. It significantly improves PFS and OS and is associated with a higher response rate compared to HD-dex.

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

Clinical Safety

The clinical safety of Pomalyst (pomalidomide) was based on data from the pivotal study previously described in the Clinical Efficacy section.

Results from the pivotal study showed that approximately 24% of patients in the Pomalyst+LD-dex arm had pomalidomide dose reductions, most of which were due to blood disorders, including neutropenia (7.7%), thrombocytopenia (6.3%), and febrile neutropenia (1.3%). Also, 61.3% of patients had pomalidomide dose interruptions which were due to neutropenia (21.0%), thrombocytopenia (8%), pneumonia (4%), febrile neutropenia, general physical health deterioration (3.7%), pyrexia (3.7%), fatigue (2.3%), and anemia (2%).

The most commonly reported adverse events (AEs) in patients receiving Pomalyst+LD-dex were related to blood and lymphatic system disorders (anemia, neutropenia, and thrombocytopenia), general disorders and administration site conditions (fatigue, pyrexia, and edema peripheral), and infections and infestations (pneumonia). The most commonly reported Grade 3 or 4 AEs were neutropenia, anemia, thrombocytopenia, pneumonia, fatigue, pyrexia, and edema peripheral.

The most commonly reported serious adverse events (SAEs) were pneumonia and febrile neutropenia and thrombocytopenia. Among patients with thrombocytopenia in the pivotal study, the majority of patients in both treatments groups had no concurrent hemorrhage or bleeding. Nevertheless, there is a potential increased risk of hemorrhage in patients treated with Pomalyst.

Pomalidomide, the medicinal ingredient in Pomalyst, is considered to have the potential to cause teratogenic effects in humans. There is a risk of fetal harm if Pomalyst is administered to a pregnant woman. Pomalidomide is also present in the semen of male patients. Therefore, there is a potential risk of fetal harm during unprotected intercourse between male patients and pregnant women or females of child-bearing potential. Females of child-bearing potential may be treated with Pomalyst provided that adequate contraception, with two simultaneous effective methods of contraception, is used to prevent fetal exposure to the drug. The choice of the two simultaneously effective contraceptive methods will necessitate a risk/benefit discussion between the patient and a qualified physician experienced in the use of contraceptive methods. Male patients must also comply with the required contraceptive measures.

The use of Pomalyst in combination with LD-dex resulted in an increased risk of venous thromboembolic events (VTE), such as deep vein thrombosis (DVT) and pulmonary embolism (PE). Moreover, the risk of thromboembolic events may be increased with the simultaneous use of Pomalyst with erythropoietic agents, hormone replacement therapy, or hormonal contraceptives.

The risk of infections in MM patients is further increased with administration of Pomalyst. The initiation of Pomalyst in patients with active infections or requiring immunosuppressive treatments may increase the risk of developing serious infections. The concomitant administration of dexamethasone with Pomalyst may increase the risk of infection, particularly pneumonia, in patients >65 years of age. The appropriate dexamethasone dose reduction for the geriatric population has not been thoroughly studied. In order to reduce the risk of infection, it is recommended to reduce the starting dose of dexamethasone by half in patients >75 years of age.

Development of peripheral neuropathy is an identified risk with use of pomalidomide. In addition, cardiac failure, cardiac arrhythmia, and tumor lysis syndrome are immunomodulatory agent class effects that have also been identified as potential risks with use of Pomalyst; but these were not observed during the pivotal Phase III clinical study (CC-4047-MM-003).

Second primary malignancies have been reported in patients receiving Pomalyst. However, the role of Pomalyst in the development of second primary malignancies is unclear.

Several potential risks associated with the use of Pomalyst remain unknown, such as, interactions with other drugs, the safe use of Pomalyst during lactation, the safe use of Pomalyst in patients with significant cardiac dysfunction, hepatic impairment or renal impairment, and the effects of Pomalyst+LD-dex on electrocardiogram parameters.

It should also be noted that the ability to operate machinery or driving may be altered in patients taking Pomalyst, due to confusion, fatigue, depressed level of consciousness, and dizziness.

Given these potential safety risks, appropriate warnings and precautions have been put in place in the approved Pomalyst Product Monograph to address the identified safety concerns.

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

7.2 Non-Clinical Basis for Decision

The non-clinical pharmacology and toxicology studies were considered appropriate to support the use of Pomalyst, in combination with dexamethasone (Pomalyst+LD-dex), for patients with MM for whom both bortezomib and lenalidomide have failed and who have received at least two prior treatment regimens and have demonstrated disease progression on the last regimen.

Pomalidomide, the medicinal ingredient in Pomalyst, is not anticipated to cause clinically relevant pharmacokinetic drug-drug interactions due to cytochrome P450 (CYP) inhibition, induction or transporter inhibition when co-administered with substrates of these enzymes or transporters.

In toxicological studies, pomalidomide showed a low order of general toxicity in rats, whereas in the monkey, repeated dosing resulted in immunosuppressive effects on the hematopoietic/lymphoreticular systems and secondary consequences that generally occurred at decreasing doses with increased duration of dosing. The effects in monkeys included one case of acute myeloid leukemia which was attributed to chronic treatment-related immunosuppression. The clinical and anatomic pathology findings in monkeys were fully to partially reversible after 8 weeks. Systemic pomalidomide exposure in monkeys, based on area under the curve from 0 to 24 h (AUC0-24h), at the 0.1 mg/kg/day low dose considered a no observed adverse effect level (NOAEL) in the 9-month monkey study, was about half the maximal human recommend dose. The observations in monkeys are considered relevant for human safety.

Pomalidomide was not genotoxic in a standard battery of tests. Pomalidomide was negative in the human Ether-à-go-go-related gene (hERG) assay and did not elicit cardiovascular effects in dog and monkey cardiovascular safety pharmacology studies or repeated dose toxicology studies in monkeys. Pomalidomide administered during organogenesis resulted in increased post-implantation loss and dose-dependent increased incidences of malformations and variations at all dose levels in rats and rabbits. Similar findings, including malformations, were elicited by thalidomide, a human teratogen used as a positive control in the rabbit study.

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

For more information, refer to the Pomalyst 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 Pomalyst 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 of 30 months is 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 (previously described) in the drug product are acceptable for use in drugs according to the Food and Drug Regulations.

Bovine gelatin is used to manufacture capsule shell of Pomalyst. A certificate of suitability confirming that the substance meets the criteria described in the current version of the monograph Products with risk of transmitting agents of animal spongiform encephalopathies (No. 1483) of the European Pharmacopoeia was provided.

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