Summary Basis of Decision for Tavalisse

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 Tavalisse is located below.

Recent Activity for Tavalisse

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.

The following table describes post-authorization activity for Tavalisse, a product which contains the medicinal ingredient fostamatinib (supplied as fostamatinib disodium). 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 AnchorAnchorManagement of Drug Submissions and Applications Guidance.

Updated: 2023-07-10

Drug Identification Number (DIN):

  • DIN 02508052 ‑ 100 mg fostamatinib, tablet, oral administration
  • DIN 02508060 ‑ 150 mg fostamatinib, tablet, oral administration

Post-Authorization Activity Table (PAAT)

Activity/submission type, control number Date submitted Decision and date Summary of activities
Drug product (DIN 02508052) market notification Not applicable Date of first sale: 2022-08-15 The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.
Drug product (DIN 02508060) market notification Not applicable Date of first sale: 2022-07-04 The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.
NDS # 253525 2021-06-09 Issued NOC 2021-07-15 Submission filed to transfer ownership of the drug product from Rigel Pharmaceuticals Inc. to Medison Pharma Canada Inc. An NOC was issued.
Drug product (DINs 02508052, 02508060) market notification Not applicable Date of first sale: 2020-12-10 The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.
NDS # 232078 2019-09-30 Issued NOC 2020-11-19 NOC issued for New Drug Submission.
Summary Basis of Decision (SBD) for Tavalisse

Date SBD issued: 2021-03-31

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

Fostamatinib (supplied as fostamatinib disodium)

Drug Identification Number (DIN):

  • DIN 02508052 ‑ 100 mg fostamatinib, tablet, oral administration
  • DIN 02508060 ‑ 150 mg fostamatinib, tablet, oral administration

Rigel Pharmaceuticals Inc.

New Drug Submission Control Number: 232078

 

On November 19, 2020, Health Canada issued a Notice of Compliance to Rigel Pharmaceuticals Inc. for the drug product Tavalisse.

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 Tavalisse is favourable for the treatment of thrombocytopenia in adult patients with chronic immune thrombocytopenia (ITP) who have had an insufficient response to other treatments.

Tavalisse treatment should be initiated and the patient should remain under the supervision of a physician who is experienced in the treatment of hematological diseases.

1 What was approved?

Tavalisse, an antihemorrhagic, was authorized for the treatment of thrombocytopenia in adult patients with chronic immune thrombocytopenia (ITP) who have had an insufficient response to other treatments.

Tavalisse treatment should be initiated and the patient should remain under the supervision of a physician who is experienced in the treatment of hematological diseases.

Tavalisse is not indicated for use in patients less than 18 years of age and young adults until growth is complete.

The incidence of adverse events was higher in the geriatric population (65 years of age and older). No overall differences in effectiveness were observed in geriatric patients compared to younger patients.

Tavalisse is contraindicated:

  • in patients who are hypersensitive to this drug or to any ingredient in the formulation, including any non‑medicinal ingredient, or component of the container.
  • during pregnancy.

Tavalisse 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.

Tavalisse (100 mg and 150 mg fostamatinib, supplied as fostamatinib disodium) is presented as tablets. In addition to the medicinal ingredient, the tablets contain magnesium stearate, mannitol, polyethylene glycol 3350, polyvinyl alcohol, povidone, red iron oxide, sodium bicarbonate, sodium starch glycolate, talc, titanium dioxide, and yellow iron oxide.

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

2 Why was Tavalisse approved?

Health Canada considers that the benefit-harm-uncertainty profile of Tavalisse is favourable for the treatment of thrombocytopenia in adult patients with chronic immune thrombocytopenia (ITP) who have had an insufficient response to other treatments.

Tavalisse treatment should be initiated and the patient should remain under the supervision of a physician who is experienced in the treatment of hematological diseases.

Immune thrombocytopenia is an autoimmune disorder manifested by immune‑mediated platelet destruction and a risk of bleeding. Antibody‑antigen complexes induce activation of Fc and B‑cell receptors, which in turn activate spleen tyrosine kinase (SYK), an important component of the signalling pathways in the immune process that leads to platelet destruction in ITP. Primary ITP is defined by a platelet count lower than 100 × 109 platelets/L, in the absence of other causes. Immune thrombocytopenia can also be secondary to other disorders.

The clinical severity of ITP is inversely proportional to the patient's platelet count. Platelet counts higher than 50,000 platelets/µL are rarely associated with bleeding, and are only threatening with interruption of vascular integrity (e.g., surgery, trauma). Nearly all major bleeding occurs with platelet counts lower than 30,000 platelets/µL. The rate of non‑intracerebral severe bleeding is estimated at 10%, with 0.02 to 0.04 cases per adult patient‑year for fatal hemorrhage. The predicted five‑year mortality rate is 2% in patients less than 40 years of age, and increases to 48% in patients older than 60 years of age. The decision to start treatment is determined by bleeding risk and a platelet count lower than 30,000 platelets/µL, with the goal of preventing major bleeding rather than normalizing the platelet count.

First‑line treatment options include corticosteroids, with the addition of intravenous immunoglobulin for substantial bleeding or for rapid platelet increases before procedures. First‑line treatments lead to durable remission in approximately 15% of newly diagnosed adults with ITP. Second‑line treatments are variable, with some treatments used once to induce long‑term remission (splenectomy, rituximab) and others used long‑term (steroids, immunosuppressive agents, and thrombopoietin receptor agonists).

Fostamatinib, the medicinal ingredient in Tavalisse, is an orally administered prodrug. Following administration, it is converted to the active metabolite R406, which is a relatively selective SYK inhibitor. The R406 metabolite inhibits signal transduction through Fc‑activating receptors and B‑cell receptors, thereby reducing antibody‑mediated platelet destruction. Fostamatinib also impairs vasorelaxation and inhibits vascular endothelial growth factor receptor 2 (VEGFR‑2), which leads to increased vascular resistance and hypertension.

The market authorization of Tavalisse was based primarily on results from two Phase III clinical studies of identical design, FIT‑1 and FIT‑2. Both studies were double‑blind and placebo‑controlled, and collectively enrolled 150 adult patients with ITP who have had an insufficient response to previous treatments. In the FIT‑1 study, 51 patients were randomized to the Tavalisse group and 25 patients were randomized to the placebo group. In the FIT‑2 study, 50 patients were randomized to the Tavalisse group and 24 patients were randomized to the placebo group.

The primary efficacy endpoint in the FIT‑1 and FIT‑2 studies was stable platelet response, defined as at least 50 × 109 platelets/L on at least 4 of the 6 visits between Weeks 14 to 24. In FIT‑1, 9 of the 51 patients treated with Tavalisse (17.6%; p = 0.03) and none of the patients that received the placebo achieved a stable platelet response. In FIT‑2, 9 of the 50 patients treated with Tavalisse (18%) and 1 of the 24 patients that received the placebo (4.2%) achieved a stable platelet response. Findings from secondary endpoints were generally consistent with those of the primary endpoint analysis. The difference in the percentage of patients with a platelet count of at least 50,000 platelets/µL between the Tavalisse and placebo groups at Week 24, which was a secondary endpoint, was of 15.7% in FIT‑1 and 11.8% in FIT‑2.

The FIT‑3 study is an ongoing, open‑label, Phase III extension study designed to assess safety, that included patients who completed 24 weeks of either the FIT‑1 or FIT‑2 studies or who discontinued one of these studies after 12 weeks due to lack of response. A total of 123 patients were enrolled in the FIT‑3 study, of which 44 patients had originally received placebo treatment in FIT‑1 or FIT‑2 and crossed over to receive Tavalisse in FIT‑3. Overall, 10 of the 44 placebo‑treated patients (22.7%) who crossed over from FIT‑1 and FIT‑2 achieved a stable platelet response, including one patient who had previously responded while on placebo (2.3%), for a treatment difference of 20.4% favouring Tavalisse.

The safety profile of Tavalisse in patients with ITP is based primarily on integrated data from the placebo‑controlled studies, FIT‑1 and FIT‑2. Supportive data was provided through the FIT‑3 study.

In FIT‑1 and FIT‑2, treatment‑related adverse events were reported in 59% of patients treated with Tavalisse and 27% of patients treated with the placebo. The most common treatment‑related adverse events in the Tavalisse and placebo groups, respectively, were: diarrhea (31%, 15%), hypertension (28%, 13%), nausea (19%, 8%), epistaxis (16%, 10%), respiratory tract infection (14%, 6%), increased alanine aminotransferase (ALT) levels (11%, 0%), increased aspartate aminotransferase (AST) levels (9%, 0%), dizziness (11%, 8%), neutropenia (7%, 0%), and decreased neutrophil count (11%, 0%). Severe adverse reactions were reported in 13% of patients.

In patients treated with Tavalisse, the incidences of adverse events, serious adverse events, and adverse events leading to discontinuation or death were all higher in patients 65 years of age and older than in younger patients. Overall, 20% of patients treated with Tavalisse required intervention for hypertension. A trend was observed for higher systolic blood pressure in patients receiving anti‑hypertensive medications at baseline.

Adverse events led to dose reductions in 10% of patients that received Tavalisse and 2% of patients that received the placebo. Treatment‑emergent adverse events led to dose interruption in 18% of patients who received Tavalisse and 10% of patients that received the placebo. Adverse events leading to discontinuation occurred in 10% of patients treated with Tavalisse and 8% of patients that received the placebo. Sixty percent (60%) of patients in the Tavalisse group and 85% of patients in the placebo group discontinued due to a lack of response after 12 weeks. Overall, the safety profile in the extension study was consistent with the results from the placebo-controlled period.

A Risk Management Plan (RMP) for Tavalisse was submitted by Rigel Pharmaceuticals 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.

The submitted inner and outer labels, package insert and Patient Medication Information section of the Tavalisse Product Monograph meet the necessary regulatory labelling, plain language and design element requirements.

A review of the submitted brand name assessment was conducted. This included testing for look‑alike sound‑alike attributes. The proposed name Tavalisse was accepted.

Tavalisse has an acceptable safety profile based on the non‑clinical data and clinical studies. The identified safety issues can be managed through labelling and adequate monitoring. Appropriate warnings and precautions are in place in the Tavalisse Product Monograph to address the identified safety concerns.

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 Tavalisse?

Submission Milestones: Tavalisse

Submission Milestone Date
Pre-submission meeting 2018-11-13
Submission filed 2019-09-30
Screening  
Screening Deficiency Notice issued 2019-11-15
Response filed 2019-12-30
Screening Acceptance Letter issued 2020-01-24
Review  
Review of Risk Management Plan complete 2020-08-28
Biostatistics Evaluation complete 2020-10-23
Quality Evaluation complete 2020-11-16
Clinical/Medical Evaluation complete 2020-11-17
Labelling Review complete 2020-11-17
Notice of Compliance issued by Director General, Therapeutic Products Directorate 2020-11-19

The Canadian regulatory decision on the review of Tavalisse 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 Guidance Document: Management of Drug Submissions and Applications.

4 What follow-up measures will the company take?

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

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

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 decisions were negative or positive. The PAAT will continue to be updated during the product life cycle.

The PAAT for Tavalisse 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

Fostamatinib is a tyrosine kinase inhibitor with demonstrated activity against spleen tyrosine kinase (SYK). The primary metabolite of fostamatinib, R406, reduces the antibody‑mediated destruction of platelets by inhibiting signal transduction of Fc‑activating receptors and B-cell receptors.

The clinical pharmacology program was conducted in 724 healthy subjects, in which fostamatinib was administered orally at daily doses ranging from 50 mg to 600 mg. Headache was the most common treatment‑emergent adverse event. Gastrointestinal events including diarrhea, nausea, and abdominal pain were also common, and were more frequent with the administration of multiple doses. Increases in blood pressure were also observed, and appeared to be dose‑dependent.

A Phase I study was conducted in healthy subjects to determine the concentration of R406 required to inhibit SYK signalling in vivo. Single oral doses were administered ranging from 80 mg to 600 mg, and multiple doses were administered at 100 mg to 300 mg twice daily. The results of this study provided support for a dosage regimen of 100 mg to 150 mg twice daily. Over the range of doses studied in the clinical pharmacology program, dose‑dependent and treatment‑related increases in blood pressure were observed, which were variable among subjects and generally resolved within one week of discontinuing treatment.

The pharmacokinetic profile of fostamatinib was linear and exposure was approximately dose‑proportional up to 200 mg twice daily dosing. Twice daily dosing at a range of 100 mg to 160 mg led to an approximately 2‑fold to 3‑fold accumulation in levels of R406. After oral administration of fostamatinib, the absolute bioavailability of R406 was 55% with high variability, ranging from 30% to 85%. The time at which the maximum concentration of R406 (tmax) was observed ranged from 1 hour to 4 hours, with a median tmax of approximately 1.5 hours. Findings from in vitro studies showed that R406 was 98.3% protein‑bound in human plasma. At steady‑state, the mean volume of distribution was 256 L. Fostamatinib is metabolized in the gut by alkaline phosphatase to R406, and R406 is extensively metabolized through cytochrome P450 (CYP)‑mediated oxidation and glucuronidation pathways. The mean terminal half‑life of R406 is approximately 15 hours. Following an oral dose, approximately 80% of the R406 metabolite is eliminated in the feces, and approximately 20% is eliminated in the urine.

Based on findings from drug‑drug interaction studies, the dose of Tavalisse should be reduced if it is co‑administered with a strong CYP3A4 inhibitor, as co‑administration significantly increases exposure to R406. Co‑administration of Tavalisse with strong CYP3A4 inducers should be avoided, as this led to a significant decrease in exposure to R406. Additionally, fostamatinib significantly increased the concentrations of certain substrates of CYP3A4, breast cancer resistance protein (BCRP), and P‑glycoprotein (P‑gp). Due to potentially significant interactions with anticoagulants with a narrow therapeutic index, the Tavalisse Product Monograph also includes instructions to monitor the international normalized ratio (INR) when these drugs are administered concomitantly with Tavalisse.

The pharmacokinetics of fostamatinib and R406 were examined in subjects with hepatic impairment. A high variability in pharmacokinetic parameters was observed in a dedicated hepatic impairment study. Clinical experience in patients with significant hepatic disease is limited. Consequently, a warning is included in the Tavalisse Product Monograph stating that Tavalisse should not be used in patients with severe hepatic impairment.

Warnings have also been included in the Tavalisse Product Monograph regarding the use of Tavalisse in patients with very low heart rate and the concomitant use of Tavalisse with bradycardic or PR interval‑prolonging agents. These warnings are based on results from a dedicated electrocardiographic assessment study in healthy subjects which showed a mild decrease in heart rate and uncorrected PR interval prolongation. No clinically significant effects were detected on the QTcF interval in subjects receiving 100 mg or 300 mg fostamatinib twice daily.

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

Clinical Efficacy

The clinical efficacy of Tavalisse (fostamatinib) was evaluated in two Phase III studies of identical design, FIT‑1 (C788‑047) and FIT‑2 (C788‑048). Patients who completed 24 weeks in either FIT‑1 or FIT‑2, as well as patients who did not respond to treatment after 12 weeks, were eligible to enroll in the open‑label extension study, FIT‑3, described in the Clinical Safety section.

Both FIT‑1 and FIT‑2 were double‑blind, placebo‑controlled, 24‑week studies, which collectively enrolled 150 adult patients who had an insufficient response to previous treatments. In both studies, patients were randomized in a 2:1 ratio to receive either Tavalisse or placebo. Groups were stratified based on prior splenectomy and severity of thrombocytopenia. Patients received 100 mg Tavalisse twice daily, or matching placebo. Based on platelet count and tolerability, the dose was increased to 150 mg twice daily (or matching placebo) in 88% of patients at Week 4 or later. Stable concurrent ITP therapy and rescue therapy were permitted. The mean patient age differed by 7 years between the two treatment arms, and therefore the populations were not completely comparable.

The primary efficacy endpoint in the FIT‑1 and FIT‑2 studies was stable platelet response, defined as measurements of at least 50 × 109 platelets/L on at least 4 of the 6 visits between Weeks 14 to 24.

FIT‑1 (Study C788‑047)

The FIT‑1 study was conducted in 76 patients, with 51 patients randomized to the Tavalisse group and 25 patients randomized to the placebo group. In the Tavalisse group, the median baseline platelet count was 17,000 platelets/µL, and 30 patients previously had a splenectomy. At baseline, 34 patients (45%) had previously received ITP therapy. The median number of prior therapies was 3 (range: 1‑9). Twelve patients completed the study, of which 10 patients continued in the extension study (FIT‑3). Twenty‑eight patients discontinued due to lack of response after 12 weeks, of which 26 patients continued in the extension study. In the placebo group, one patient completed the study and 22 patients discontinued after 12 weeks due to a lack of response. All 23 patients continued in the extension study.

The primary endpoint was met, as 9 of the 51 patients (17.6%; p = 0.03) treated with Tavalisse and none of the patients that received placebo achieved a stable platelet response.

Findings from secondary endpoints were generally consistent with those of the primary endpoint analysis. At Week 24, 8 out of 51 patients (15.7%) treated with Tavalisse and none of the patients that received the placebo had a platelet count of 50,000 platelets/µL or higher. Platelet response was observed within 6 weeks in 6 out of 9 responders, and within 8 to 10 weeks for all responders.

FIT‑2 (Study C788‑048)

The FIT‑2 study was conducted with 74 patients. Fifty patients were randomized to the Tavalisse group and 24 patients were randomized to the placebo group. The median baseline platelet count was 13,500 platelets/µL.

In the Tavalisse group, 28% of patients previously had a splenectomy and 49% of patients had received ITP therapy at baseline. The median number of prior therapies was 3 (range: 1‑10). Thirteen patients completed the study, of which 11 patients continued in the extension study. Thirty‑three patients discontinued due to lack of response after 12 weeks, of which 32 patients continued in the extension study. In the placebo group, two patients completed the study, 19 patients discontinued after 12 weeks due to lack of response, and 21 patients continued in the extension study.

The primary endpoint of stable platelet response was achieved in 18% of patients treated with Tavalisse (9 out of 50) and 4.2% of patients who received the placebo (1 out of 24). The difference in the percentage of patients with a platelet count of at least 50,000 platelets/µL between the Tavalisse and placebo groups at Week 24, which was a secondary endpoint, was of 15.7% in FIT‑1 and 11.8% in FIT‑2. This value was determined to be 11.8%, as this endpoint was achieved by 16.0% of patients treated with Tavalisse (8 out of 50) and 4.2% of patients who received the placebo (1 out of 24).

Indication

Sponsor's proposed indication Health Canada-approved indication
Tavalisse is indicated for the treatment of thrombocytopenia in adult patients with chronic immune thrombocytopenia (ITP) who have had an insufficient response to a previous treatment. Tavalisse is indicated for the treatment of thrombocytopenia in adult patients with chronic immune thrombocytopenia (ITP) who have had an insufficient response to other treatments.

To more accurately reflect the patient populations in the clinical studies, which included patients who have had a median of three prior ITP therapies, the approved indication specifies adult patients who have had an insufficient response to other treatments (rather than a previous treatment, as was originally proposed).

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

Clinical Safety

The safety profile of Tavalisse in patients with ITP is based primarily on integrated data from the placebo‑controlled studies (FIT‑1 and FIT‑2, described in the Clinical Efficacy section). The supportive data from this set was provided by 102 patients treated with Tavalisse and 48 patients who received the placebo. In addition, supportive data was provided through the open‑label extension study, FIT‑3.

The primary objective of the FIT‑3 study is to assess the long‑term safety of Tavalisse. In this study, patients remain blinded to their treatment assignment from the previous study (Tavalisse or placebo), and starting doses are based on the patient's final platelet count from FIT‑1 or FIT‑2. Patients designated as responders in FIT‑1 or FIT‑2 continued in FIT‑3 at their current dose and regimen. Patients who entered the FIT‑3 study as non‑responders receive 100 mg Tavalisse twice daily, regardless of their dose and regimen in the previous study.

Adverse events of interest identified from animal studies and through previous clinical studies included gastrointestinal adverse events (nausea, vomiting, diarrhea, and abdominal pain), hypertension, hepatotoxicity, neutropenia, and infection. These adverse events are consistent with the mechanism of action of fostamatinib (the medicinal ingredient in Tavalisse), and have the potential to become serious. Based on its mechanism of action, fostamatinib may cause elevated levels of unconjugated bilirubin, especially in patients with Gilbert's genotype.

In the placebo‑controlled studies (FIT‑1 and FIT‑2), treatment‑related adverse events were reported in 59% of patients treated with Tavalisse and 27% of patients treated with the placebo. The most common treatment‑related adverse events (in patients that received Tavalisse and the placebo, respectively) were diarrhea (31%, 15%), hypertension (28%, 13%), nausea (19%, 8%), epistaxis (16%, 10%), respiratory tract infection (14%, 6%), increased alanine aminotransferase (ALT) levels (11%, 0%), increased aspartate aminotransferase (AST) levels (9%, 0%), dizziness (11%, 8%), neutropenia (7%, 0%), and decreased neutrophil count (11%, 0%). Severe adverse reactions were reported in 13% of patients in the Tavalisse groups. Dyspnea and hypertension were reported in 2% of patients in each treatment group. Neutropenia, chest pain, diarrhea, dizziness, pneumonia, and hypoxia were reported in 1% of patients in each treatment group. Serious adverse drug reactions occurred in 13% of patients treated with Tavalisse, including febrile neutropenia, diarrhea, pneumonia, and hypertensive crisis, which were each reported in 1% of patients.

In patients treated with Tavalisse, the incidence of adverse events, serious adverse events, and adverse events leading to discontinuation or death were all higher in patients 65 years of age and older than in younger patients. Overall, 20% of patients treated with Tavalisse required intervention for hypertension. A trend was observed for higher systolic blood pressure in patients receiving anti‑hypertensive medications at baseline.

Adverse events led to dose reductions in 10% of patients who received Tavalisse. Diarrhea, hypertension, and increased transaminase each led to dose reductions in 2% of patients. In addition, decreased neutrophil count, febrile neutropenia, and chest pain each led to dose reductions in 1% of patients. Dose reduction was also used to manage adverse events in 2% of patients who received the placebo. Treatment‑emergent adverse events led to dose interruption in 18% of patients who received Tavalisse, including increased ALT levels (5%), diarrhea (3%), hypertension (2%), influenza‑like illness (2%), and increased bilirubin, decreased neutrophil count, dyspnea, and epistaxis in 1% of patients each. Treatment‑emergent adverse events were also managed through dose interruption in 10% of patients who received the placebo. Adverse events leading to discontinuation occurred in 10% of patients treated with Tavalisse. Reasons for discontinuation included pneumonia, abdominal pain, increased ALT levels, chest pain, diarrhea, neutropenia, headache, plasma cell myeloma, syncope, and thrombocytopenia. Adverse events leading to discontinuation were also reported for 8% of patients who received placebo treatment. Sixty percent (60%) of patients in the Tavalisse group and 85% of patients in the placebo group discontinued due to a lack of response after 12 weeks. Overall, the safety profile in the extension study was consistent with the results from the placebo‑controlled period.

Health Canada has determined that appropriate risk management measures are in place to address the safety concerns identified for Tavalisse, and to promote its safe and effective use. For more information, refer to the Tavalisse Product Monograph, approved by Health Canada and available through the Drug Product Database.

7.2 Non-Clinical Basis for Decision

Fostamatinib, the medicinal ingredient in Tavalisse, is an orally available prodrug. Upon administration, it is rapidly and extensively converted to its primary active metabolite, R406.

Primary and secondary pharmacodynamic studies revealed that R406 acts as a reversible adenosine triphosphate (ATP) competitive inhibitor of spleen tyrosine kinase (SYK) activity (Ki = 30 nM). Fostamatinib/R406 is a potentially broad immunomodulatory agent as it inhibits Fc receptor and B‑cell receptor signalling pathways. In biochemical assays, R406 exhibited broad activity across various kinase targets, including inhibition of the rearranged during transfection (RET) kinase and inhibition of auto‑phosphorylation of the vascular endothelial growth factor receptor‑2 (VEGFR‑2) kinase in vitro. Other than the kinase target class, R406 had very few off‑target activities.

Non‑clinical pharmacokinetic studies were conducted in mice, rats, rabbits, and monkeys, in which fostamatinib was administered orally and R406 was administered intravenously. The results of these studies indicate that common pathways existed in all species tested. Additionally, R406 was highly bound to plasma proteins in all species tested. It was distributed preferentially to red blood cells, but not to monocytes, in the in vitro studies. Metabolism of R406 occurred mainly through cytochrome P450 (CYP)‑mediated para‑O‑demethylation in all species, and was primarily metabolized by CYP3A4. Direct N‑glucuronidation also contributed to the metabolism of R406 in humans, monkeys, and rats.

The non‑clinical safety pharmacology studies provided evidence that fostamatinib and R406 were unlikely to cause biologically significant undesirable effects at clinical doses. Fostamatinib did not display signs of genotoxicity, carcinogenicity, or immunotoxicity in in vivo and in vitro toxicology models, including a two‑year carcinogenicity study in mice and rats.

Safety concerns considered relevant to humans were also identified through non‑clinical studies. Significant increases in blood pressure were observed in rodents, even when low doses of fostamatinib were administered. Prolongation of the PR and QA intervals and reductions in heart rate and mean arterial blood flow were also detected in rodents treated with fostamatinib or R406. Human microsomal studies revealed that R406 is a potent inhibitor of uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1). Chondrodystrophy (growth plate thickening) was observed in mice, rats, and rabbits, mainly in actively growing bones. Thickening of the growth plates was characterized by increased numbers of hypertrophic chondrocytes, likely caused by the inhibition of angiogenesis. Adverse developmental outcomes were identified in in vivo embryo‑fetal development studies, including a statistically significant increase in embryo‑fetal mortality (post‑implantation loss), alterations to growth (lower fetal weights), and percentage of nonviable embryos per litter. Fetal malformations were also observed, primarily affecting the kidneys and associated tissues and organs, and vessel development from the aorta.

Based on the outcomes of the non‑clinical studies, Tavalisse is contraindicated for use in pregnancy. Additionally, statements were included in the labelling to specify that it is not indicated in patients younger than 18 years of age and young adults until growth is complete, and should not be used during lactation. The Tavalisse Product Monograph also includes a warning regarding the use of Tavalisse in patients with very low heart rate, and sections addressing the effects of fostamatinib on cardiac safety and the potential for drug interactions between Tavalisse and UGT1A1 substrates/inhibitors.

Overall, the non‑clinical pharmacology and toxicology profile of fostamatinib supports its proposed clinical use. The results of the non‑clinical studies as well as the potential risks to humans have been included in the Tavalisse Product Monograph. Considering the intended use of Tavalisse, there are no pharmacological or toxicological issues within this submission which preclude authorization of the product.

For more information, refer to the Tavalisse 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 Tavalisse 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 48 months is acceptable when the drug product is stored at room temperature (15 ºC to 30 ºC).

Proposed limits of drug-related impurities are considered adequately qualified from toxicological studies.

All 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.

None of the excipients used in the formulation of Tavalisse are of human or animal origin.

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