Summary Basis of Decision for Ferriprox

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 Ferriprox is located below.

Recent Activity for Ferriprox

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

Post-Authorization Activity Table (PAAT) for Ferriprox

Updated: 2025-03-11

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

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

Drug Identification Number (DIN)

  • DIN 02436531 - 500 mg deferiprone, tablet, oral administration
  • DIN 02436558 - 1,000 mg tablet, deferiprone, tablet, oral administration
  • DIN 02436523 - 100 mg/mL deferiprone, solution, oral administration

Post-Authorization Activity Table (PAAT)

Activity/submission type, control number Date submitted Decision and date Summary of activities
Drug product (DIN 02536579) market notification Not applicable Date of first sale 2023-06-05 The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.
SNDS # 261912 2022-03-01 Issued NOC 2023-03-30 Submission filed as a Level I – Supplement for a new dosage form (modified-release tablets, Ferriprox MR) for the 1,000 mg strength, and to migrate the PM to the 2020 format. The submission was reviewed and considered acceptable, and an NOC was issued. A new DIN (02536579) was issued for the new dosage form. A Regulatory Decision Summary was published.
SNDS # 244597 2020-09-29 Issued NOC 2021-10-13 Submission filed as a Level I – Supplement for a new indication. The indication authorized was: the treatment of patients with transfusional iron overload due to sickle cell disease or other anemias. The pivotal study LA38-0411 was a multi-center, randomized, active-controlled, open label study that compared deferiprone with deferoxamine for the treatment of patients with iron overload due to sickle cell disease or other transfusion-dependent anemias. The study met its primary endpoint and demonstrated the non-inferiority between Ferriprox and deferoxamine for the change from baseline in liver iron concentration after 12 months. The submission was reviewed and considered acceptable, and an NOC was issued.
NDS # 235993 2020-02-13 Issued NOC 2020-04-01 Submission filed to transfer ownership of the drug product from ApoPharma, a Division of Apotex Inc. to Chiesi Canada Corp. An NOC was issued.
SNDS # 223425 2019-03-18 Issued NOC 2019-07-04 Submission filed as a Level I – Supplement to update the PM. The changes were in response to an Advisement Letter issued by Health Canada, dated January 16 2019, requesting revisions related to the risk of neurological disorders. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Warnings and Precautions section of the PM. An NOC was issued.
Summary Safety Review Not applicable Posted
2019-02-25		 Summary Safety Review posted for Ferriprox (deferiprone) (Assessing the potential risk of brain and nervous system [neurological] disorders in children).
SNDS # 216743 2018-05-30 Issued NOC
2018-12-21		 Submission filed as Level I - Supplement to make updates to the manufacturing process of the drug substance. The information was reviewed and considered acceptable. An NOC was issued.
New safety review started by Health Canada Not applicable Started between
2018-05-01		 Health Canada started a safety review for Ferriprox between 2018-05-01 and 2018-05-31as shown on website.
Drug product (DIN 02436523) market notification Not applicable Date of first sale 2016-07-28 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 02436531) market notification Not applicable Date of first sale 2016-03-21 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 02436558) market notification Not applicable Date of first sale 2015-04-28 The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.
NDS # 162924 2013-02-28 Issued NOC
2015-02-13		 Notice of Compliance issued for New Drug Submission.
Summary Basis of Decision (SBD) for Ferriprox

Date SBD issued: 2015-06-10

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

Deferiprone, 500 mg and 1,000 mg; 100 mg/mL, tablets; solution, oral

Drug Identification Number (DIN):

  • DIN 02436531 - 500 mg, tablet
  • DIN 02436558 - 1,000 mg, tablet
  • DIN 02436523 - 100 mg/mL, oral solution

ApoPharma Inc.

New Drug Submission Control Number: 162924

 

On February 13, 2015, Health Canada issued a Notice of Compliance to ApoPharma Inc. for the drug product, Ferriprox.

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 Ferriprox is favourable for the treatment of patients with transfusional iron overload due to thalassemia syndromes when current chelation therapy is inadequate.

1 What was approved?

 

Ferriprox, an iron chelating agent, was authorized for the treatment of patients with transfusional iron overload due to thalassemia syndromes when current chelation therapy is inadequate.

Ferriprox should only be prescribed by a qualified physician experienced in the treatment of patients with transfusional iron overload due to thalassemia syndromes.

In the pediatric population (less than 16 years of age), patients experienced a higher frequency of decreased neutrophil counts than older patients.

In the geriatric population (>65 years of age), there are limited data on the use of Ferriprox.

Ferriprox is contraindicated as follows:

  • Patients who are hypersensitive to this drug or to any ingredient in the formulation or component of the container.
  • Women who are pregnant and/or breastfeeding.
  • Patients who have baseline severe neutropenia (an absolute neutrophil count <0.5 × 109/L).

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

Ferriprox (500 mg, 1,000 mg and 100 mg/mL, deferiprone) is presented as a tablet and also as an oral solution. In addition to the medicinal ingredient deferiprone, non-medicinal ingredients in the 500 mg tablet include: colloidal silicon dioxide, hydroxypropyl methylcellulose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, and titanium dioxide. The non-medicinal ingredients in the 1,000 mg tablet include: crospovidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, magnesium stearate, methylcellulose, polyethylene glycol, and titanium dioxide. The non-medicinal ingredients in the 100 mg/mL oral solution include: artificial cherry flavour, Sunset Yellow FCF, glycerol, hydrochloric acid, hydroxyethyl cellulose, peppermint oil, purified water, and sucralose.

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

 

2 Why was Ferriprox approved?

 

Health Canada considers that the benefit/risk profile of Ferriprox is favourable for the treatment of patients with transfusional iron overload due to thalassemia syndromes when current chelation therapy is inadequate.

Ferriprox should only be prescribed by a qualified physician experienced in the treatment of patients with transfusional iron overload due to thalassemia syndromes.

Patients with thalassemia major, a transfusion-dependent hereditary anemia, require regular and frequent blood transfusions to maintain life. Patients with other thalassemia syndromes may require repeated blood transfusions. Iron overload is a predictable and life-threatening complication of such programs of treatment as there is no natural means to remove the excess iron introduced through the transfusion of red blood cells. Without intervention to remove excess iron, death frequently occurs in the second or third decade after transfusions begin, mainly due to organ toxicity secondary to iron overload. These patients require treatment with iron chelators to prevent the morbidity and mortality induced by the iron overload.

At present, two iron chelators, parenteral deferoxamine (subcutaneous or intravenous) and oral deferasirox, are available in Canada for the treatment of iron overload. Despite the ability of deferoxamine and deferasirox to promote net iron excretion in treated populations, there remains a need for another effective and tolerable iron chelator for those patients in whom existing chelators are inadequate due either to failure to control iron levels, intolerable adverse effects, or inability to comply with parenteral therapy.

The approval of Ferriprox was based primarily on two clinical studies: Study LA16-0102, a Phase III, multicenter, randomized, open-label, active-controlled clinical study, and Study LA36-0310, a prospectively planned, pooled analysis of pre-existing data from clinical studies of Ferriprox to evaluate its efficacy in patients with iron overload for whom previous chelation therapy had been inadequate . Study LA16-0102 was designed to assess the relative efficacy of Ferriprox to that of deferoxamine in removing excess cardiac iron in transfusion-dependent thalassemia major patients. Study LA36-0310 was designed to evaluate the effect of Ferriprox on serum ferritin levels, a common indirect measure of body iron stores. Results from these pivotal studies demonstrated that Ferriprox as monotherapy reduced cardiac iron in patients with mild to moderate cardiac iron overload treated over a 12 month period and reduced serum ferritin levels within one year in patients who had failed their previous chelation therapy.

The long-term benefit (effectiveness) of Ferriprox in controlling body iron load should be evaluated on a regular basis throughout the duration of treatment. It is recommended to monitor serum ferritin concentrations every two to three months and to monitor liver and cardiac iron concentrations annually, or as clinically indicated.

The safety profile of Ferriprox is considered well established, based on clinical study reports and extensive post-marketing monitoring. Agranulocytosis and neutropenia have been identified as clinically significant adverse events (AEs). Deferiprone (medicinal ingredient of Ferriprox)-associated agranulocytosis is unpredictable, and its mechanism remains uncertain. Due to the potential seriousness of agranulocytosis and neutropenia, as well as the inability to predict patients at a higher risk of developing these AEs, neutropenia and agranulocytosis are considered to be significant risks associated with Ferriprox treatment and require risk minimization in order to manage the risk to patients. This can be sufficiently managed through a combination of Product Monograph labelling recommendations pertaining to monitoring and treatment interruptions and the controlled distribution program implemented for Ferriprox.

A Risk Management Plan (RMP) for Ferriprox was submitted by ApoPharma 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.

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

Overall, with respect to the safety and efficacy data reviewed, the therapeutic benefits demonstrated are considered to outweigh the potential risks in the treatment of patients with transfusional iron overload due to thalassemia syndromes when current chelation therapy is inadequate. Ferriprox has an acceptable safety profile based on the non-clinical data and clinical studies. The identified safety issues can be managed through adequate monitoring and labelling. Appropriate warnings and precautions are in place in the Ferriprox Product Monograph to address the identified safety concerns. The controlled distribution program, which provides for a patient wallet card in regard to the risk of agranulocytosis, is a vital component of risk mitigation.

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 Ferriprox?

 

A pre-submission meeting for the current NDS was held on June 12, 2012. The NDS was subsequently filed to Health Canada on February 28, 2013. During the clinical review of the NDS, a number of efficacy and safety issues were identified which did not allow Health Canada to undertake a benefit/risk assessment. These issues included limitations of data submitted in support of the proposed indication, extrapolation from thalassemia to other hereditary anemias, hepatic fibrosis, carcinogenicity, and potential loss of efficacy with long-term treatment. Therefore, on February 14, 2014, a Notice of Deficiency (NOD) was issued to the sponsor citing the need for revision to the proposed indication and further assessment of outstanding safety issues. The Sponsor submitted a response to Notice of Deficiency (R-NOD) on May 15, 2014 to address the major objections and other concerns outlined in the NOD which included additional evidence of the efficacy of Ferriprox, further discussion of safety issues, and a revised Product Monograph and Risk Management Plan.

 

Submission Milestones: Ferriprox

Submission Milestone Date
Pre-submission meeting: 2012-06-12
Submission filed: 2013-02-28
Screening 1  
Screening Deficiency Notice issued: 2013-05-01
Response filed: 2013-06-13
Screening Acceptance Letter issued: 2013-07-29
Review 1  
Biopharmaceutics Evaluation complete: 2013-12-23
Quality Evaluation complete: 2014-02-04
Notice of Deficiency (NOD) issued by Director General (proposed indication and outstanding safety issues): 2014-02-14
Response filed: 2014-05-15
Screening 2  
Screening Acceptance Letter issued: 2014-06-19
Review 2  
Quality Evaluation complete: 2015-02-09
Clinical Evaluation complete: 2015-01-20
Biostatistics Evaluation complete: 2015-01-12
Labelling Review complete: 2015-01-13
Notice of Compliance issued by Director General: 2015-02-13

 

The Canadian regulatory decision on the clinical review of Ferriprox was based primarily on a critical assessment of the Canadian data package. The foreign reviews completed by the European Union's centralized procedure European Medicines Agency (EMA) and the United States Food and Drug Administration (FDA) were used as an added reference. The review of Periodic Safety Update Reports (PSURs), from the International Birth Date of Ferriprox, August 25, 1999, until February 28, 2009, was covered in the Food and Drug Administration (FDA) clinical review, and Health Canada relied upon the FDA assessment for this component of the submission review.

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

 

4 What follow-up measures will the company take?

 

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

 

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

 

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 Ferriprox 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

Deferiprone is rapidly absorbed from the gastrointestinal tract following oral administration. Exposures to deferiprone are dose proportional over the dose range of 22-50 mg/kg. Deferiprone is primarily eliminated via metabolism to the 3O glucuronide. In vitro studies suggest that this biotransformation is catalyzed primarily by UDP glucuronosyltransferase 1A6 (UGT1A6). Deferiprone exposure may be increased in the presence of a UGT1A6 inhibitor. However, the clinical significance of co-administration of Ferriprox with a UGT1A6 inhibitor [for example (e.g.), acetaminophen, probenecid, and valproic acid] or an inducer (e.g., omeprazole, phenobarbital, and carbamazepine) has not been determined.

Concurrent use of Ferriprox with mineral supplements and antacids that contain polyvalent cations has not been studied. Since deferiprone has the potential to bind polyvalent cations (e.g., iron, aluminum, and zinc), concurrent use may result in reduced absorption of deferiprone and mineral supplements.

A clinical study in thalassemia patients with iron overload demonstrated a dose-response relationship for deferiprone and 24-h urinary iron excretion at daily doses of between 25 and 100 mg/kg. Iron balance studies in thalassemia patients with iron overload demonstrated a dose-response relationship for deferiprone and iron excretion at doses of between 17 and 33 mg/kg three times daily. Deferiprone at doses of 25 mg/kg given three times daily promoted iron excretion sufficient to achieve negative iron balance or to neutralize the continued transfusional iron loading in the majority of transfusion-dependent patients.

The pharmacokinetics of deferiprone have not been evaluated in patients with hepatic impairment.

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

Clinical Efficacy

The overall clinical program which assessed the efficacy of Ferriprox comprised a total of twelve clinical studies which included: eight clinical studies (one of which, LA16-0102, is considered a pivotal study) three compassionate use studies, and an investigator sponsored study. Study LA36-0310, a second pivotal study, is a prospectively planned, pooled analysis of pre-existing data derived from these twelve studies, which evaluated the efficacy of Ferriprox in transfusion-dependent iron-overloaded patients (nearly all with thalassemia) in whom previous iron chelation therapy (deferoxamine or deferasirox; mostly deferoxamine) had failed, due to an inadequate response or poor tolerance. The clinical effectiveness of Ferriprox as monotherapy is based on a demonstration of reduction in cardiac iron in patients with mild to moderate cardiac iron overload treated over a 12 month period in study LA16-0102 and on a reduction in serum ferritin levels within one year in patients who had failed their previous chelation therapy in study LA36-0310. While a randomized clinical trial to show that deferiprone therapy is associated with less cardiac disease and improved survival compared to deferoxamine therapy has not been conducted in patients with iron overload, data from two natural history studies [LA12-9907 (Piga A, 2003); Borgna-Pignatti study (Borgna-Pignatti C, 2006)] are supportive of the clinical effectiveness of Ferriprox in the treatment of transfusional iron overload due to thalassemia syndromes.

Study LA16-0102

Study LA16-0102 was a 12-month, Phase III, multicenter, randomized, open-label, active-controlled clinical study conducted in transfusion-dependent β-thalassemia major patients between 18 and 36 years of age. Patients had been receiving ongoing chelation therapy with deferoxamine for at least the past 5 years and had an abnormal (<20 ms) but not severely abnormal (>8 ms) cardiac Magnetic Resonance Imaging T2-star (MRI T2*) value, a left ventricular ejection fraction (LVEF) greater than 56% (measured by Cardiovascular Magnetic Resonance), and a left ventricular shortening fraction (LVSF) greater than 30% (measured by echocardiogram).

Patients were stratified into moderate (≥8 ms to <14 ms) or mild (≥14 ms to <20 ms) cardiac iron overload according to their baseline cardiac MRI T2* assessment and were randomized in a 1:1 ratio to receive either Ferriprox administered three times a day orally in doses of 25 mg/kg for the first four weeks, increased to 28.3 mg/kg for the subsequent four weeks and maintained at 33.3 mg/kg for the remainder of the study, or to continue with deferoxamine at a dose of 50 mg/kg/day administered by subcutaneous infusion on 5-7 days per week. A total of 61 patients were randomized and treated with Ferriprox (Number of patients, n = 29) at an average dose of 92 mg/kg/day or with deferoxamine (n = 32) at an average dose of 43 mg/kg/day for 5.7 days per week.

The primary efficacy endpoint was the patients' cardiac iron status as determined by cardiac MRI T2*; an increase in cardiac iron concentration will decrease the cardiac MRI T2* value. A cardiac MRI T2* value below 20 ms demonstrates cardiac iron overload, and lower cardiac MRI T2* values are observed with increased severity of overload. Secondary efficacy measures were the assessment of serum ferritin concentration and liver iron concentration (LIC). LIC was assessed by the Superconducting Quantum-Interference Device BioSusceptometer. A tertiary efficacy measure was the LVEF measured by Cardiovascular Magnetic Resonance.

Study results at the 12-month assessment period showed an improvement in cardiac MRI T2* of 3.5 ms in patients treated with Ferriprox compared with a change of 1.7 ms in patients treated with deferoxamine. The improvement in cardiac MRI T2* was significantly greater for Ferriprox than deferoxamine (p = 0.02). No significant difference between the treatment groups was detected in mean change of serum ferritin or mean change of LIC from baseline to 12 months.

Over the same 12 months, LVEF increased from baseline by 3.1 ± 3.6 absolute units (%) in the Ferriprox group and by 0.3 ± 3.4 absolute units (%) in the deferoxamine group (difference between groups; nominal p = 0.003).

Study LA36-0310

The LA36-0310 study was a prospectively planned, pooled analysis of pre-existing data derived from twelve studies (previously noted above) which evaluated the efficacy of Ferriprox in transfusion-dependent iron-overloaded patients (nearly all with thalassemia) in whom previous iron chelation therapy (deferoxamine or deferasirox; mostly deferoxamine) had failed, due to an inadequate response or poor tolerance.

In LA36-0310, data from 747 patients who had received Ferriprox therapy were analyzed for study eligibility. Criteria for chelation failure were defined by one or more measures of iron accumulation above a boundary level associated with an increased risk of organ damage, as follows: serum ferritin >2,500 µg/L before treatment with Ferriprox (main criterion); or LIC of >7 mg/g dry weight; or excess cardiac iron stores as demonstrated by a cardiac MRI T2* <20 ms. Results from patients who received Ferriprox in combination with other chelation therapy are excluded from the presented analysis given that the robust data supporting authorization in this single arm study setting is considered to come from those patients in whom Ferriprox was administered as monotherapy. Analysis criteria were met for serum ferritin, LIC, and cardiac MRI T2* for 236 patients, and 87 patients, and 31 patients, respectively. Most [29/31 (93.5%)] of the patients evaluated for the cardiac MRI T2* criterion were from LA16-0102.

In this study, Ferriprox therapy was considered successful in individual patients who experienced a reduction in serum ferritin of ≥20% from baseline within one year of starting therapy, which was the primary efficacy endpoint.

Other secondary efficacy endpoints were a decline in LIC of ≥20% from baseline within one year of starting therapy or a decline in cardiac iron overload, defined as an increase in cardiac MRI T2* ≥20% from baseline within one year of starting therapy. Overall success rates were calculated as the proportion of patients with a successful outcome. In order to consider Ferriprox therapy as successful for a particular measure, the lower limit of the 95% confidence interval for that efficacy measure had to be greater than 20%.

The proposed ≥20% reduction in serum ferritin or LIC was based on an understanding that it would mean a drop of a minimum of 500 μg/L or 1.4 mg Fe/g dry weight, respectively, changes which represent a meaningful improvement in iron burden based on experience with other chelators; the same criterion on percentage improvement was also employed for cardiac MRI T2*. A decrease by 20% in a year for serum ferritin or LIC, or an increase in the case of MRI T2*, suggests that chelation management is heading in the right direction in consideration of the fact that the disease is the iatrogenic iron overload.

The dose of Ferriprox ranged from 35-100 mg/kg/day, administered orally in either tablet or solution form. The majority (77%) of patients eligible for assessment for the primary efficacy endpoint were administered a dose of 75 mg/kg/day; 18% received a dose of 100 mg/kg/day and 5% received a dose of ≤50 mg/kg/day.

Results from the LA36-0310 study demonstrated that the success rate for serum ferritin for patients on Ferriprox monotherapy was 50%. Mean serum ferritin decreased by 940 μg/L within one year of therapy, that is (i.e.,) from 4,444 μg/L at baseline to 3,503 μg/L at the last observation. The overall success rate for LIC was 38%. The overall success rate for cardiac MRI T2* was 65%.

Subgroup analyses were consistent with the primary analysis in that the lower limit of the 95% confidence interval was greater than 20% for all subsets involved in analyses examining the impact of age, gender, and region.

Data are limited to one year for cardiac MRI T2* evaluation and to within one year for serum ferritin evaluation. However, data from two natural history studies are supportive of the clinical effectiveness of Ferriprox in the treatment of transfusional iron overload due to thalassemia syndromes over a longer period. Further, data for cardiac MRI T2* are limited to patients with mild to moderate cardiac iron overload. These limitations can be managed with careful monitoring of chelated patients for continued efficacy and safety by physicians familiar with thalassemia and transfusion therapy.

Although data for the evaluation of the effectiveness of Ferriprox in reducing LIC are limited, this can be adequately mitigated through labeling. Appropriate and ongoing monitoring of chelated patients should allow for careful evaluation of the effectiveness of chelation with respect to the liver, with opportunity for the treating physician to modify the chelation regimen as appropriate for each individual patient.

The dose of Ferriprox should be tailored to the individual patient's response and therapeutic goals (maintenance or reduction of iron burden). Reduction in dose of Ferriproxshould be considered if serum ferritin measurements approach normal.

Data from the ApoPharma database provide clinical evidence that deferiprone use is not associated with increased toxicity during treatment of patients with thalassemia whose serum ferritin is lower than 500 µg/L. Data presented from published literature (case reports) also suggest that deferiprone use has not been associated with increased toxicity during treatment of patients with thalassemia whose serum ferritin was <500 µg/L.

Supportive Studies

There were three clinical studies (LA-02 and LA-02/06 4-year and 7-year follow-up) submitted as support for the long-term use of Ferriprox. The efficacy data from these studies demonstrated that, at 12 months, deferiprone maintained, but did not decrease, serum ferritin at baseline levels. The 4-year data shows a non-statistically significant increase in serum ferritin, which became a statistically significant increase by 7 years. However, the study protocol specified that a fixed dose of 75 mg/kg/day deferiprone was required, regardless of the transfusion regimen of the patient. Iron balance studies demonstrated that total iron excretion increased with an increasing dose. Patients in the study whose transfusion regimen exceeded the capabilities of a 75 mg/kg/day dose to excrete iron would be expected to accumulate total body iron in a situation where a dose increase of Ferriprox was not allowed. As there are different treatment goals depending on the individual patient needs (iron maintenance or iron decrease), and transfusion regimens vary among the patient population, it is reasonable to expect that different dosages of the iron chelator would also be required in different situations. Therefore, from the perspective of efficacy (in particular, long-term efficacy) of Ferriprox, the sponsor has provided sufficient rationale to explain that the results of LA-02/06 may primarily be due to the dose of Ferriprox. It is considered that doses up to 100 mg/kg/day may be more efficacious in many patients. Considering the limited long-term efficacy data for Ferriprox, the Product Monograph recommends that the long-term effectiveness of Ferriprox in controlling body iron load should be evaluated on a regular basis. It recommends to monitor serum ferritin concentrations every two to three months and to monitor liver and cardiac iron concentrations annually or as clinically indicated. These recommendations are considered sufficient to monitor the long-term efficacy of the drug.

Study LA12-9907 was a retrospective assessment of pre-existing efficacy data from a single registry for transfusion-dependent β-thalassemia patients treated with either Ferriprox or deferoxamine for a minimum of four years conducted at the request of the EMA as a post-marketing approval study. This study was considered a supportive study rather than a pivotal clinical study because it was a non-randomized trial based on the collection of historical/retrospective data, and thus was not considered to be adequately controlled or to have adequate unbiased and reliable data. Although limited by study design, cardiac disease-free survival over a 5-year period was significantly more favourable in the Ferriprox group. Comparison of different aspects of cardiac disease between therapy groups, using New York Heart Association (NYHA) classification, demonstrated a significant difference; however, the basis of diagnosis of the newly diagnosed cardiac disease events as pertained to changes in NYHA classification remained unclear, as did their clinical relevance.

A 2006 publication (Borgna-Pignatti C, 2006), a natural history study with a total study duration of nearly nine years, reported a lower prevalence of cardiac events and cardiac deaths in those patients who switched from deferoxamine to deferiprone therapy than in those patients who continued to be chelated with deferoxamine. As per inclusion criteria, patients had not had a cardiac event prior to entry. Median duration of deferoxamine treatment was 7 years and once on deferiprone, median duration of treatment was 4.3 years. The average exposure to deferiprone therapy may not have been sufficiently long given that cardiac events and death both rely upon an extended duration of follow-up. Recognizing limitations inherent to a natural history study, results are nonetheless considered supportive of pivotal study LA16-0102 in their observation of the efficacy of Ferriprox in preventing iron-induced cardiac morbidity and mortality in transfusion-dependent thalassemia.

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

Clinical Safety

The analysis of the safety was based on safety data from study LA16-0102 and on the pooled safety data of all studies included in the submission. In addition, since Ferriprox has been approved in Europe since 1999 and in the United States since 2011, there are extensive post-market data available which also were taken into account during the safety review. The review of Periodic Safety Update Reports (PSURs), from the International Birth Date of Ferriprox, August 25, 1999 until February 28, 2009, was covered in the Food and Drug Administration (FDA) clinical review, and Health Canada relied upon the FDA assessment for this component of the submission review. Health Canada reviewed remaining available PSURs, from March 1, 2009 through August 31, 2013.

The total number of Ferriprox patients included in the pooled safety analysis was 642. The most common adverse events (AEs) were pyrexia (28.2%), arthralgia (15.7%), nausea (18.2%), vomiting (16.8%), chromaturia (14.6%), abdominal pain (12.3%), diarrhea (11.2%), alanine aminotransferase increased (8.7%), and neutropenia (6.7%).

Although overall proportions of adult and pediatric patients with at least one adverse event are not different, low neutrophil count was experienced by significantly more children than adults, which is consistent with the observed greater rate of neutropenia in children compared to adults in healthy populations. Decreased neutrophil count (p = 0.001), neutropenia (p = 0.17), increased alanine aminotransferase (p = 0.05), and agranulocytosis (p = 0.28) were reported more frequently in children less than 6 years old than in the older patients.

The most significant serious AEs observed clinically during Ferriprox therapy are agranulocytosis, defined as a confirmed absolute neutrophil count (ANC) <0.5 × 109/L, and neutropenia, defined as a confirmed ANC between 0.5 and 1.5 × 109/L.

In the ApoPharma-sponsored clinical studies, neutropenia occurred in 43 (6.7%) of 642 patients: 37 cases in 34 (6.1%) of 560 patients with thalassemia major, and 12 cases in 9 (11%) of 82 patients with other iron overload conditions. In thalassemia major patients, patients at a range of ages (2-33) developed neutropenia, and were treated with Ferriprox for a median duration of approximately 300 days before reporting neutropenia for the first time. Most clinical study protocols required treatment discontinuation in any patient reporting neutropenia (or agranulocytosis). All episodes of neutropenia resolved within 2 to 175 days, mostly upon discontinuation of Ferriprox treatment.

In Ferriprox clinical studies, agranulocytosis occurred in 11 patients (1.7%). All 11 episodes resolved upon discontinuation of Ferriprox. Most of the cases occurred within the first year of therapy initiation; the time to agranulocytosis ranged from 65 to 3,352 days. The median duration of agranulocytosis in thalassemia major patients ranged from 3 to 18 days.

There were 14 deaths following reports of agranulocytosis in post-marketing surveillance. The development of agranulocytosis is unpredictable, and the mechanism remains uncertain. These risks can be sufficiently managed through a combination of Product Monograph labelling recommendations pertaining to absolute neutrophil count monitoring and Ferriprox treatment interruptions and the restricted distribution program implemented for Ferriprox. It is recommended not to have concomitant use of medicinal products known to be associated with neutropenia or those that can cause agranulocytosis. Furthermore, Ferriprox is contraindicated in patients with baseline severe neutropenia. Further risk management involves a controlled distribution program, where patients and healthcare providers are educated on the risk of agranulocytosis associated with the drug, and in which only prescribers and pharmacists registered with the program are able to prescribe and dispense the drug. An additional component of this program is a wallet card containing information pertaining to the risk of agranulocytosis which is to be presented to any healthcare professional treating these patients for any reason.

A potential association between Ferriprox treatment and progression of hepatic fibrosis has previously been of concern. However, a body of literature, comprised of studies by independent investigators, assessed liver histology during therapy with Ferriprox. With the exception of one, these studies did not support an association between Ferriprox and progression of hepatic fibrosis in patients. There are no non-clinical data to support a role of Ferriprox in the progression of hepatic fibrosis, and no cases of liver fibrosis have been reported via post-marketing surveillance since Ferriprox's first approval in 1999. It is important to take into account the confounding factors, including the disease itself, as well as Hepatitis C status in many patients. When considered together, the available data do not indicate a risk of drug-associated progression of hepatic fibrosis in patients treated with Ferriprox.

Safety Topics of Special Interest
Thorough QT/QTC study

A study was conducted to evaluate the effect of single therapeutic (33 mg/kg) and supra-therapeutic (50 mg/kg) oral doses of deferiprone on the cardiac QT and QTc interval duration in healthy subjects. The upper bound of the 95% one-sided confidence interval for the least-squares mean difference in QTcF between placebo and either dose was <10 ms at all post-dose time points. The largest mean differences in QTcF from placebo were recorded at the 2 h time point and were 3.0 ms (95% one-sided UCL: 5.0 ms) for the 33 mg/kg dose and 5.2 ms (95% one-sided UCL: 7.2 ms) for the 50 mg/kg dose. It was concluded that Ferriprox does not produce any significant prolongation of the QTc interval.

Diamond-Blackfan anemia

Clinical trials have not been conducted to evaluate the safety and efficacy of Ferriprox in patients with Diamond-Blackfan anemia. Case reports suggest that patients with Diamond-Blackfan anemia, an unauthorized indication, are at greater risk of Ferriprox-associated agranulocytosis. Agranulocytosis events with fatal outcome have been reported post-marketing and in published literature in Diamond-Blackfan anemia patients treated with Ferriprox. Therefore, a warning was included in the Product Monograph.

Monitoring of liver enzymes in hepatitis C thalassemia patients

Based on data reviewed, fluctuations of liver enzymes may be more frequent and greater in magnitude in hepatitis C patients. Precautionary wording with regards to the need for careful monitoring in hepatitis C positive thalassemia patients undergoing chelation with Ferriprox has been incorporated into the Product Monograph. Special care must be taken to ensure that iron chelation in patients with hepatitis C is optimal. In these patients careful monitoring of liver enzymes and of liver histology is recommended.

Appropriate warnings and precautions are in place in the approved Ferriprox Product Monograph to address the identified safety concerns.

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

 

 

 

7.2 Non-Clinical Basis for Decision

 

The Canadian regulatory decision on the non-clinical review of Ferriprox was primarily based on a critical assessment of the Canadian data package. However, embryo-fetal development study review relied upon the Food and Drug Administration Pharmacology/Toxicology review.

Deferiprone (the medicinal ingredient of Ferriprox) is a chelating agent with an affinity for ferric ions (iron III), binding them in neutral 3:1 (deferiprone:iron) complexes. Deferiprone has a lower binding affinity for metal ions such as copper, aluminum, zinc and ferrous ions (iron II) than for ferric ions.

Deferiprone prevents uptake by and mobilizes iron from primary cultures of cells, including rat cardiomyocytes, rat and human hepatocytes, and mouse macrophages. Iron chelation reduces iron-mediated free radical damage and protects against iron-induced loss of activities of mitochondrial respiratory enzyme complexes I-III.

Deferiprone increases iron excretion in multiple species, including the mouse, rat, gerbil, guinea pig and monkey, and removes iron from the kidney, pancreas and liver of iron-loaded animals. Some studies have shown reduction of excess cardiac iron levels.

Deferiprone is unequivocally genotoxic and a presumed trans-species carcinogen, which implies a carcinogenic risk for humans. Short-term and long-term rodent carcinogenicity studies have not been completed. The findings of the 52-week rat toxicology study are difficult to interpret due to inadequate power and a high apparent background rate of tumorigenesis. In the absence of dedicated studies, it must be concluded that deferiprone is a carcinogen. Appropriate warnings and precautionary measures are in place in the Ferriprox Product Monograph to address the identified safety concerns.

Teratogenicity studies conducted in rabbits and rats indicated that deferiprone is a potent teratogen in both species [minimum doses tested were 25 mg/kg/day in rats and 10 mg/kg/day in rabbits, without having established a no observed adverse effect level (NOAEL)]. No studies have been done to investigate the transmission of deferiprone via lactation and no pre- or post-natal studies have been completed. Ferriprox has been contraindicated in pregnancy and during breast feeding.

For more information, refer to the Ferriprox 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 Ferriprox 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 60 months for the 500 mg tablets, 36 months for the 1,000 mg tablets, and 36 months for the 100 mg/mL oral solution 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 (described earlier) found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations.

Certificates from ApoPharma Inc. and Srini Pharmaceuticals Ltd. attesting that deferiprone is not manufactured using materials obtained from sources that are at risk of transmitting Bovine Spongiform Encephalopathy (BSE) or Transmissible Spongiform Encephalopathy (TSE) were provided by the sponsor.

 

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