Taro-Deferiprone Product Monograph

RECENT MAJOR LABEL CHANGES

TABLE OF CONTENTS

Certain sections or subsections that are not applicable at the time of the preparation of the most recent authorized product monograph are not listed.

RECENT MAJOR LABEL CHANGES .................................................................................................... 2

TABLE OF CONTENTS ....................................................................................................................... 2

PART I: HEALTH PROFESSIONAL INFORMATION .............................................................................. 4

1. 1. INDICATIONS ....................................................................................................................... 4

1.1 Pediatrics .................................................................................................................................. 4

1.2 Geriatrics .................................................................................................................................. 4

1. 2. CONTRAINDICATIONS .......................................................................................................... 4
2. 3. SERIOUS WARNINGS AND PRECAUTIONS BOX ..................................................................... 5
3. 4. DOSAGE AND ADMINISTRATION ......................................................................................... 5

4.1 Dosing Considerations ............................................................................................................... 5

4.2 Recommended Dose and Dosage Adjustment ........................................................................... 6

4.4 Administration .......................................................................................................................... 7

4.5 Missed Dose .............................................................................................................................. 7

1. 5. OVERDOSAGE ...................................................................................................................... 7
2. 6. DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING .......................................... 7
3. 7. WARNINGS AND PRECAUTIONS ........................................................................................... 8

7.1 Special Populations ................................................................................................................. 11

7.1.1 Pregnant Women ......................................................................................................... 11

7.1.2 Breast-feeding ............................................................................................................. 11

7.1.3 Pediatrics ..................................................................................................................... 11

7.1.4 Geriatrics ..................................................................................................................... 11

1. 8. ADVERSE REACTIONS ......................................................................................................... 12

8.1 Adverse Reaction Overview .................................................................................................... 12

8.2 Clinical Trial Adverse Reactions ............................................................................................... 12

8.2.1 Clinical Trial Adverse Reactions – Pediatrics ................................................................ 17

8.3 Less Common Clinical Trial Adverse Reactions ........................................................................ 17

8.3.1 Less Common Clinical Trial Adverse Reactions – Pediatrics ......................................... 17

8.4 Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data17

8.5 Post-Market Adverse Reactions .............................................................................................. 17

1. 9. DRUG INTERACTIONS ........................................................................................................ 18

9.2 Drug Interactions Overview .................................................................................................... 18

9.3 Drug-Behaviour Interactions ................................................................................................... 18

9.4 Drug-Drug Interactions ............................................................................................................ 18

9.5 Drug-Food Interactions ........................................................................................................... 19

9.6 Drug-Herb Interactions............................................................................................................ 19

9.7 Drug-Laboratory Test Interactions ........................................................................................... 19

1. 10. CLINICAL PHARMACOLOGY ................................................................................................ 20

10.1 Mechanism of Action ............................................................................................................ 20

10.2 Pharmacodynamics ............................................................................................................... 20

10.3 Pharmacokinetics .................................................................................................................. 21

1. 11. STORAGE, STABILITY AND DISPOSAL ................................................................................. 24
2. 12. SPECIAL HANDLING INSTRUCTIONS ................................................................................... 24

PART II: SCIENTIFIC INFORMATION ............................................................................................... 25

1. 13. PHARMACEUTICAL INFORMATION .................................................................................... 25
2. 14. CLINICAL TRIALS ................................................................................................................ 25

14.1 Clinical Trials by Indication .................................................................................................... 25

14.3 Comparative Bioavailability Studies ...................................................................................... 30

1. 15. MICROBIOLOGY ................................................................................................................. 31
2. 16. NON-CLINICAL TOXICOLOGY .............................................................................................. 31
3. 17. SUPPORTING PRODUCT MONOGRAPHS ............................................................................ 33

PATIENT MEDICATION INFORMATION .......................................................................................... 34

PART I: HEALTH PROFESSIONAL INFORMATION

1. INDICATIONS

Taro-Deferiprone (deferiprone) is indicated for:

• the treatment of patients with transfusional iron overload due to thalassemia syndromes when current chelation therapy is inadequate.
• the treatment of patients with transfusional iron overload due to sickle cell disease or other anemias

Safety and effectiveness have not been established for the treatment of transfusional iron overload in patients with myelodysplastic syndrome or in patients with Diamond Blackfan anemia.

Taro-Deferiprone is available only through a controlled distribution program called Sun360. Under this program, only physicians and pharmacists registered with the program are able to prescribe and dispense the product. In addition, Taro-Deferiprone can be dispensed only to patients who are registered with and meet the conditions of the Sun360 program. Please call 1-833-791-3539 or log onto www.sun360psp.ca.

1.1 Pediatrics

Pediatrics (1-15 years of age): Based on the data submitted to and reviewed by Health Canada, the safety and efficacy of deferiprone in pediatric patients (1-15 years of age) with thalassemia syndromes and iron overload has been established. Therefore, Health Canada has authorized an indication for pediatric patients of 1-15 years of age with thalassemia syndromes and iron overload. In clinical trials, pediatric patients experienced a higher frequency of decreased neutrophil counts than older patients (see 7.1.3 Pediatrics).

Pediatrics (3-16 years of age): Based on the data submitted to and reviewed by Health Canada, the safety and efficacy of deferiprone in pediatric patients (3-16 years of age) with sickle cell disease or other anemias and iron overload has been established. Therefore, Health Canada has authorized an indication for pediatric patients of 3-16 years of age with sickle cell disease or other anemias and iron overload. In clinical trials, pediatric patients experienced a higher frequency of abdominal pain, decreased neutrophil counts, bone pain and oropharyngeal pain than older patients (see 7.1.3 Pediatrics).

1.2 Geriatrics

There are limited data on the use of deferiprone in this population.

2. CONTRAINDICATIONS

• Deferiprone 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. For a complete listing, see 6 DOSAGE FORMS, COMPOSITION AND PACKAGING.
• Deferiprone is contraindicated in women who are pregnant and/or breastfeeding (see 7.1.1 Pregnant Women and 7.1.2 Breast-feeding).
• Deferiprone is contraindicated in patients who have baseline severe neutropenia (absolute neutrophil count < 0.5 × 10⁹/L) (see 7 WARNINGS AND PRECAUTIONS, Hematologic).
• SERIOUS WARNINGS AND PRECAUTIONS BOX

4. DOSAGE AND ADMINISTRATION

4.1 Dosing Considerations

• Taro-Deferiprone is given three times a day (see 4.2 Dosage and Administration)

  • The effect of Taro-Deferiprone in decreasing the body iron load is directly influenced by the dose and the degree of iron overload (pre-existing iron load and amount of iron input (transfusional iron and gastrointestinal iron absorption)).
  • The long-term effectiveness of Taro-Deferiprone in controlling body iron load should be evaluated on a regular basis. 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.
  • Dose adjustments should be tailored to the individual patient’s response and therapeutic goals (maintenance or reduction of iron burden). Reduction in dose of Taro-Deferiprone should be considered if serum ferritin measurements approach normal.
  • In patients who develop gastrointestinal upset, such as nausea, vomiting and abdominal pain, the dose of Taro-Deferiprone should be decreased for one to two weeks.

Serious Warnings and Precautions

• Deferiprone can cause agranulocytosis/severe neutropenia that may lead to serious and life-threatening infections. Neutropenia may precede the development of agranulocytosis (see 8 ADVERSE REACTIONS).

  • Measure the absolute neutrophil count (ANC) before starting Taro-Deferiprone and monitor the ANC weekly on therapy (see 7 WARNINGS AND PRECAUTIONS, Hematologic and 8 ADVERSE REACTIONS sections). Interrupt Taro-Deferiprone therapy if neutropenia develops.
  • Interrupt Taro-Deferiprone therapy if infection develops and monitor the ANC more frequently (see 7 WARNINGS AND PRECAUTIONS, Hematologic).
  • Advise patients taking Taro-Deferiprone to immediately seek medical help and present their wallet card if experiencing any symptoms indicative of infection (see 7 WARNINGS AND PRECAUTIONS, Hematologic).

4.2 Recommended Dose and Dosage Adjustment

The recommended starting dosage of Taro-Deferiprone for adults and pediatric patients is 75 mg/kg actual body weight/day orally. The maximum dosage is 100 mg/kg actual body weight/day orally.

Recommended Dosage for Taro-Deferiprone (three times a day)

For Taro-Deferiprone 1000 mg tablets taken three times a day, dose per kilogram body weight should be calculated to the nearest half tablet. To obtain a dose of about

75 mg/kg/day, use the number of tablets suggested in the following tables for the body weight of the patient.

Table 1: Dosage table for Taro-Deferiprone 1000 mg tablets

*rounded to nearest half tablet

Dose Modifications for Patients with Hepatic Impairment

No adjustment of the Taro-Deferiprone dosage regimen is recommended in patients with mildly (Child-Pugh Class A) or moderately (Child-Pugh Class B) impaired hepatic function. There are no data in patients with severe (Child-Pugh Class C) hepatic impairment. Liver enzymes should be carefully monitored in this patient population during Taro-Deferiprone therapy. If there is evidence of deterioration in hepatic function, discontinuation of Taro-Deferiprone therapy should be considered (see 7 WARNINGS AND PRECAUTIONS and 10 CLINICAL PHARMACOLOGY).

Dose Modification for Patients with Renal Impairment

No adjustment of Taro-Deferiprone dosage is recommended in patients with mild, moderate or severe renal impairment. There are no data in patients with end-stage renal disease on dialysis.

4.4 Administration

Taro-Deferiprone can be taken with or without food. Taking Taro-Deferiprone with meals may reduce nausea.

Allow at least a 4-hour interval between Taro-Deferiprone and other medications or supplements containing polyvalent cations such as iron, aluminum or zinc (see 9 DRUG INTERACTIONS).

4.5 Missed Dose

If a dose of this medicine has been missed, it should be taken as soon as possible. However, if it is almost time for the next dose, the missed dose should be skipped, and the regular dosing schedule resumed. Patients should not catch up or double doses.

5. OVERDOSAGE

There is no specific antidote to deferiprone overdose.

Prolonged overdosing (at approximately 2.5 times the maximum recommended dose) has been reported to be associated with adverse neurological effects, such as cerebellar symptoms, diplopia, lateral nystagmus, psychomotor slowdown, abnormal hand movements and axial hypotonia (see 7 WARNINGS AND PRECAUTIONS). The neurological disorders regressed after deferiprone discontinuation.

6. DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING

Table 2: Dosage Forms, Strengths, Composition and Packaging

Film coated white oval shaped tablet debossed with “T” score “1K” on one side and plain on the

For the most recent information in the management of a suspected drug overdose, contact your regional poison control centre or Health Canada’s toll-free number, 1-844 POISON-X (1-844-764-7669).

other. The tablets can be broken in half along the score. Each 1000 mg tablet contains 1000 mg deferiprone. Supplied in bottles of 50 tablets.

7. WARNINGS AND PRECAUTIONS

Please see 3 SERIOUS WARNINGS AND PRECAUTIONS BOX.

Carcinogenesis and Mutagenesis

Please refer to the animal data presented in 16 NON-CLINICAL TOXICOLOGY.

Hematologic

Agranulocytosis/Severe Neutropenia

Deferiprone can cause agranulocytosis/severe neutropenia that may lead to serious and life-threatening infections. Agranulocytosis may be preceded by neutropenia (see ADVERSE REACTIONS). The mechanism of deferiprone-associated agranulocytosis is unknown.

In the pooled safety database, agranulocytosis/severe neutropenia was reported in 1.7% of patients. Agranulocytosis and neutropenia usually resolve upon discontinuation of deferiprone, but there have been post-marketing reports of agranulocytosis leading to death. Suggested management of cases of neutropenia and agranulocytosis is outlined below. It is recommended that such a management protocol be in place prior to initiating any patient on Taro-Deferiprone treatment.

Patients should avoid other medicinal products known to be associated with neutropenia or agranulocytosis. Measure the absolute neutrophil count (ANC) before starting Taro-Deferiprone therapy and monitor the ANC weekly on therapy.

Advise the patient to present the wallet card when seeing any healthcare professional for any reason as patients should avoid other medicinal products known to be associated with neutropenia or agranulocytosis.

For infection

Interrupt Taro-Deferiprone therapy if infection develops and monitor the ANC more frequently.

If patients taking Taro-Deferiprone experience any symptoms indicative of infection, advise them to immediately interrupt therapy, seek medical help and present the wallet card to the healthcare professional.

For neutropenia (ANC < 1.5 × 10⁹/L and ≥ 0.5 × 10⁹/L):

Interrupt Taro-Deferiprone therapy if neutropenia develops.

Instruct the patient to immediately discontinue Taro-Deferiprone and all other medications with a potential to cause neutropenia. The patient should be advised to limit contact with other individuals in order to reduce the risk of infection.

Obtain a complete blood cell (CBC) count, including a white blood cell (WBC) count corrected for the presence of nucleated red blood cells, an absolute neutrophil count (ANC), and a platelet count daily until recovery (ANC ≥ 1.5 × 10⁹/L). Should any evidence of infection develop concurrently with the neutropenia, the appropriate cultures and diagnostic procedures should be performed and an appropriate therapeutic regimen instituted.

For agranulocytosis/severe neutropenia (ANC < 0.5 × 10⁹/L):

Follow the above guidelines for neutropenia and if clinically indicated, admit patient to the hospital and institute other management as clinically appropriate.

Limited information is available regarding rechallenge in patients who experienced deferiprone-induced neutropenia or agranulocytosis. Deferiprone therapy has been resumed in 31 patients (3 from clinical trials and 28 in post-marketing surveillance) who previously experienced deferiprone-induced agranulocytosis, and agranulocytosis recurred in 14 (45%) of these patients. In clinical trials, rechallenge in patients with moderate or severe neutropenia was not permitted by protocol. Resumption of Taro-Deferiprone in patients who develop agranulocytosis is not recommended.

Patients with Diamond-Blackfan anemia, an unauthorized indication, may be at greater risk of deferiprone-induced agranulocytosis/severe neutropenia. Taro-Deferiprone therapy is not recommended in patients with Diamond-Blackfan anemia.

Hepatic/Biliary/Pancreatic

In the pooled safety database, 7.5% of 642 patients treated with deferiprone developed increased serum alanine aminotransferase (ALT) values. The majority of these events were transient. Four (0.6%) deferiprone-treated patients discontinued the drug due to increased serum ALT levels and 1 (0.2%) due to an increase in both ALT and aspartate aminotransferase (AST) values.

Serum ALT values should be monitored periodically during therapy with Taro-Deferiprone and interruption of therapy should be considered if there is a persistent increase in ALT levels.

Hepatic Impairment

A serious adverse event of acute liver and renal injury was seen in one subject with moderate hepatic impairment. No adjustment of the Taro-Deferiprone dosage regimen is required in patients with mildly or moderately impaired hepatic function. Liver enzymes should be carefully monitored in this patient population during Taro-Deferiprone therapy. If there is evidence of deterioration in hepatic function, discontinuation of Taro-Deferiprone should be considered (see 4.2 Dosage Recommendation).

Immune

Given that deferiprone can be associated with neutropenia and agranulocytosis, therapy in immune-compromised patients should not be initiated unless potential benefits outweigh potential risks.

Interrupt Taro-Deferiprone therapy if infection develops and monitor the ANC more frequently.

Advise patients taking Taro-Deferiprone to immediately interrupt therapy and report to their physician if they experience any symptoms indicative of infection.

Monitoring and Laboratory Tests

The long-term effectiveness of Taro-Deferiprone in controlling body iron load should be evaluated on a regular basis. 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 (see 4 DOSAGE AND ADMINISTRATION).

Absolute Neutrophil Counts

The absolute neutrophil count (ANC) should be measured before starting Taro-Deferiprone therapy and monitored weekly on therapy (see 2 CONTRAINDICATIONS and 7 WARNINGS AND PRECAUTIONS, Hematologic section above).

Hepatic function

Hepatic status should be evaluated prior to initiating Taro-Deferiprone treatment. Serum ALT values should be monitored periodically during therapy with Taro-Deferiprone. In patients with hepatic impairment, hepatic enzymes should be monitored periodically. 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.

Plasma Zinc concentration

Monitoring of plasma Zn²⁺ concentration, and supplementation in case of a deficiency, is recommended.

Neurologic

Neurological disorders such as cerebellar symptoms, diplopia, lateral nystagmus, psychomotor slowdown, abnormal hand movements and axial hypotonia, have been observed in two children treated for several months with approximately 2.5 times the maximum recommended dose, but have also been observed with standard doses of deferiprone. The neurological disorders regressed after deferiprone discontinuation (5 OVERDOSAGE).

Reproductive Health: Female and Male Potential

Women of childbearing potential must be advised to avoid pregnancy. These women should be advised to take highly effective contraceptive measures during treatment with Taro-Deferiprone and for at least six months after the last dose. Women of childbearing potential should immediately stop taking Taro-Deferiprone if they become pregnant or plan to become pregnant (See 2 CONTRAINDICATIONS and 7.1.1 Pregnant Women). Males with female partners of reproductive potential should use effective contraception during treatment with Taro-Deferiprone and for at least three months after the last dose.

• Fertility

  Deferiprone had no significant effects on fertility and reproductive performance in non- iron-loaded male and female rats dosed orally at ≤ 75 mg/kg bid prior to and through mating (males) or through early gestation (females) (see 16 NON-CLINICAL TOXICOLOGY).

7.1 Special Populations

7.1.1 Pregnant Women

Deferiprone is contraindicated in pregnancy (see 2 CONTRAINDICATIONS). No studies in pregnant women have been conducted, and relevant data from clinical use are limited. In animal studies, administration of deferiprone during the period of organogenesis resulted in embryofetal death and malformations at doses lower than equivalent human clinical doses (see 16 NON-CLINICAL TOXICOLOGY).

7.1.2 Breast-feeding

Deferiprone is contraindicated in nursing women. No studies have been conducted to determine the extent of deferiprone excretion in human milk. No prenatal and postnatal reproductive studies have been conducted in animals. If treatment is unavoidable, breast- feeding must be stopped.

7.1.3 Pediatrics

Deferiprone has been studied in 222 pediatric patients with thalassemia syndromes and iron overload participating in clinical trials, including 61 children less than 6 years old. A higher rate of the following adverse events were reported in children less than 6 years old than in older patients: decreased neutrophil count (17 (27.9%) vs 40 (6.9%)), neutropenia (7 (11.5%) vs 36 (6.2%)), increased alanine aminotransferase (10 (16.4%) vs 46 (7.9%)), and agranulocytosis (2 (3.3%) vs 9 (1.5%)).

Deferiprone has been studied in 113 pediatric patients with sickle cell disease and other anemias and iron overload participating in clinical trials. The age of these patients ranged from 3 to 16 years old (66 patients were 3 to ˂12 years, 47 patients were 12 to 16 years). Seventy- seven percent of these patients had sickle cell disease. A higher rate of the following adverse events were reported in children than in adults: abdominal pain (41 (36.3%) vs 16 (19.3%)), decreased neutrophil count (20 (17.7%) vs 4 (4.8%)), bone pain (41 (36.3%) vs 17 (20.5%)), and oropharyngeal pain (23 (20.4%) vs 8 (9.6%)).

7.1.4 Geriatrics

Clinical studies of deferiprone did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients.

8. ADVERSE REACTIONS

8.1 Adverse Reaction Overview

The most common adverse reactions reported during therapy with deferiprone in clinical trials were chromaturia, nausea, abdominal pain, vomiting, arthralgia, alanine aminotransferase increased, and neutropenia. The most serious adverse reaction reported in clinical trials with deferiprone was agranulocytosis/severe neutropenia, defined as an absolute neutrophil count of less than 0.5 × 10⁹/L, which occurred in approximately 2% of patients. Less severe episodes of neutropenia were reported in approximately 6% of patients (see 7 WARNINGS AND PRECAUTIONS). Arthropathies (including arthralgia, arthritis, and arthropathy) led to deferiprone discontinuation in 1.9% of patients. Gastrointestinal symptoms led to the discontinuation of deferiprone therapy in 1.6% of patients. Chromaturia (reddish/brown discolouration of the urine) is a result of the excretion of deferiprone-iron complex in the urine; it is an expected effect of deferiprone therapy and it is not harmful.

8.2 Clinical Trial Adverse Reactions

Clinical trials are conducted under very specific conditions. The adverse reaction rates observed in the clinical trials; therefore, may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse reaction information from clinical trials may be useful in identifying and approximating rates of adverse drug reactions in real-world use.

Thalassemia Syndromes Study LA16-0102

Adverse events described in Table 3 below reflect the safety data from Study LA16-0102, a randomized, controlled trial in which 29 patients who were treated with deferiprone for a median duration of 359 days were compared to 32 patients treated with deferoxamine for a median duration of treatment of 365 days. Therapy with deferiprone was initiated at

75 mg/kg/d and was gradually increased to 100 mg/kg/d over an approximately 8-week period. The mean dose of deferiprone during the study was 92 mg/kg/d. Adverse events reported at ≥10% incidence in either the deferiprone or deferoxamine arms are presented.

Table 3: Adverse events reported in ≥10% in either the deferiprone or deferoxamine arms in Study LA16-0102

• Treatment Emergent Adverse Events are coded with MedDRA Dictionary Version 13.0.

Study LA36-0310

LA36-0310 was prospectively designed as a pooled analysis of pre-existing data from studies that evaluated the efficacy of deferiprone. A safety evaluation was not included in the LA36- 0310 analysis.

Pooled Safety Database

The safety of deferiprone has been evaluated from a pooled safety population of

642 deferiprone-treated patients who participated in 11 single arm or active-controlled clinical studies for which safety data was collected.

Table 4 below lists the adverse drug reactions that occurred in at least 1% of patients in the deferiprone pooled safety database.

Table 4: Adverse drug reactions reported in ≥ 1% of deferiprone-treated patients from pooled safety database

Sickle Cell Disease or other Anemias

The safety of deferiprone has been evaluated in 196 patients with sickle cell disease or other anemias who participated in studies LA38-0411 and LA38-EXT.

Table 5 below lists the adverse events that occurred in at least 5% of patients treated with deferiprone in LA38-0411 subjects with sickle cell disease or other anemias.

Table 5: Adverse events reported in ≥5% of deferiprone-treated patients with sickle cell disease or other anemias (Study LA38-0411)

*Grouped term

Patients who completed the 1-year non-inferiority study LA38-0411 were offered the opportunity to take part in in the 2-year extension study LA38-EXT. Those who had been treated with deferiprone continued to receive it (N=89), while those who had been treated with deferoxamine were switched to deferiprone (N=45). The long-term safety profile of deferiprone in patients with sickle cell disease and other transfusion dependent anemias is consistent with above safety profile. Agranulocytosis rate, the deferiprone side effect of greatest concern, is comparable to the rate of between 1% and 2% seen in thalassemia patients.

8.2.1 Clinical Trial Adverse Reactions – Pediatrics

Deferiprone has been studied in 222 pediatric patients with thalassemia syndromes and iron overload participating in clinical trials, including 61 children less than 6 years old. A higher rate of the following adverse events were reported in children less than 6 years old than in older patients: decreased neutrophil count (17 (27.9%) vs 40 (6.9%)), neutropenia (7 (11.5%) vs 36 (6.2%)), increased alanine aminotransferase (10 (16.4%) vs 46 (7.9%)), and agranulocytosis (2 (3.3%) vs 9 (1.5%)).

Deferiprone has been studied in 113 pediatric patients with sickle cell disease and other anemias and iron overload participating in clinical trials. The age of these patients ranged from 3 to 16 years old (66 patients were 3 to ˂12 years, 47 patients were 12 to 16 years). Seventy- seven percent of these patients had sickle cell disease. A higher rate of the following adverse events were reported in children than in adults: abdominal pain (41 (36.3%) vs 16 (19.3%)), decreased neutrophil count (20 (17.7%) vs 4 (4.8%)), bone pain (41 (36.3%) vs 17 (20.5%)), and oropharyngeal pain (23 (20.4%) vs 8 (9.6%)).

8.3 Less Common Clinical Trial Adverse Reactions

Not applicable.

8.3.1 Less Common Clinical Trial Adverse Reactions – Pediatrics

Not applicable.

8.4 Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data

Not applicable.

8.5 Post-Market Adverse Reactions

The following additional adverse reactions have been reported in patients receiving deferiprone. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or to establish a causal relationship to drug exposure.

Blood and lymphatic system disorders: agranulocytosis, including some fatal cases, thrombocytosis, pancytopenia.

Cardiac disorders: atrial fibrillation, cardiac failure.

Congenital, familial and genetic disorders: hypospadias, congenital anomaly.

Eye disorders: diplopia, papilledema, retinal toxicity.

Gastrointestinal disorders: enterocolitis, rectal hemorrhage, gastric ulcer, pancreatitis, parotid gland enlargement.

General disorders and administration site conditions: chills, pyrexia, edema peripheral, multi- organ failure.

Hepatobiliary disorders: jaundice, hepatomegaly.

Immune system disorders: anaphylactic shock, hypersensitivity.

Infections and infestations: cryptococcal cutaneous infection, enteroviral encephalitis, pharyngitis, pneumonia, sepsis, furuncle, infectious hepatitis, rash pustular, subcutaneous abscess.

Investigations: blood bilirubin increased, blood creatinine phosphokinase increased.

Metabolism and nutrition disorders: metabolic acidosis, dehydration.

Musculoskeletal and connective tissue disorders: myositis, chondropathy, trismus

Nervous system disorders: cerebellar syndrome, cerebral hemorrhage, convulsion, gait disturbance, intracranial pressure increased, psychomotor skills impaired, pyramidal tract syndrome, somnolence.

Psychiatric disorders: bruxism, depression, obsessive-compulsive disorder.

Renal disorders: glycosuria, hemoglobinuria.

Respiratory, thoracic and mediastinal disorders: acute respiratory distress syndrome, epistaxis, hemoptysis, pulmonary embolism.

Skin, subcutaneous tissue disorders: hyperhidrosis, periorbital edema, photosensitivity reaction, pruritis, urticaria, rash, Henoch-Schönlein purpura.

Vascular disorders: hypotension, hypertension.

9. DRUG INTERACTIONS

9.2 Drug Interactions Overview

In vitro, deferiprone up to 400 µM (56 µg/mL) did not inhibit any of the CYP450 enzymes tested, i.e., CYP3A4, 2D6, 2C9, 1A2, 2E1 and 1A1. Drug-drug interactions between deferiprone and medications metabolized by cytochrome P450 enzymes are unlikely to occur.

9.3 Drug-Behaviour Interactions

Interactions with behavioural risks have not been established

9.4 Drug-Drug Interactions

Drugs associated with neutropenia or agranulocytosis

Avoid concomitant use of Taro-Deferiprone with other drugs known to be associated with neutropenia or agranulocytosis (see 7 WARNINGS AND PRECAUTIONS).

UDP-glucuronosyltransferases (UGTs) inhibitors and inducers

Deferiprone is primarily eliminated via metabolism to the 3-O-glucuronide. In vitro studies suggest that glucuronidation is catalyzed primarily by UDP glucuronosyltransferase 1A6.

Deferiprone exposure may be increased in the presence of a UGT1A6 inhibitor. An in vitro study showed a dose-dependent inhibition of deferiprone glucuronide formation by acetaminophen (up to 33%) in human UGT1A6 Supersome incubations. Deferiprone glucuronide formation was increased by omeprazole (up to 43%) in human hepatocyte cultures.

However, the clinical significance of coadministration of deferiprone with a UGT1A6 inhibitor (e.g., acetaminophen, probenecid, and valproic acid) or an inducer (e.g., omeprazole, phenobarbital, and carbamazepine) has not been determined. Closely monitor patients for adverse reactions that may require downward dose titration or interruption when Taro-Deferiprone is concomitantly administered with a UGT1A6 inhibitor.

Polyvalent cations

Concurrent use of deferiprone 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), the concurrent use may result in reduced absorption of deferiprone and mineral supplements. It is recommended to allow at least a 4- hour interval between taking Taro-Deferiprone and other medications (e.g., antacids), or supplements containing these polyvalent cations (see 4 DOSAGE AND ADMINISTRATION).

9.5 Drug-Food Interactions

Administration of deferiprone tablets with food in healthy volunteers decreased the C_max of deferiprone by 38% and the AUC by 10% (see 10 CLINICAL PHARMACOLOGY, 10.3 Pharmacokinetics).

Taro-Deferiprone can be taken with or without food. Taking Taro-Deferiprone with meals may reduce nausea.

9.6 Drug-Herb Interactions

Interactions with herbal products have not been established.

9.7 Drug-Laboratory Test Interactions

Interactions with laboratory tests have not been established.

10. CLINICAL PHARMACOLOGY

10.1 Mechanism of Action

Deferiprone is an orally active, bidentate iron(III) 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.

10.2 Pharmacodynamics

The amount of deferiprone-induced iron excretion from the body is related to the dose of deferiprone, and is also influenced by the pre-existing iron load.

Primary pharmacodynamics

Deferiprone has a high affinity for iron(III) (pFe⁺³ = 19.4) and preferentially binds trivalent cations over divalent in the order of affinity: Fe(III) > Al(III ) > Cu(II) > Zn(II) > Fe(II).

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.

Secondary Pharmacodynamics

Secondary pharmacodynamic effects of deferiprone may occur due to its binding of labile iron or other biologically important cations (e.g., Zn²⁺, Cu²⁺), which could result in depletion of cation pools required for metalloenzyme function. In vivo or in vitro studies revealed that deferiprone can inhibit the activity of the following enzymes at doses relevant to clinical exposures: tyrosine hydroxylase, tryptophan hydroxylase, hypoxia-inducible factor prolyl hydroxylase, ribonucleotide reductase, deoxyhypusine hydroxylase, catechol-O- methyl transferase, soybean LOX-1 (as a model for human 5-lipoxygenase) and heme iron- dependent cyclooxygenase. Inhibition of the non-heme iron-containing metalloenzyme ribonucleotide reductase is consistent with findings of clastogenicity, teratogenicity, and atrophy of proliferating tissues. Deferiprone was shown to reduce zinc levels and induce apoptosis in murine thymocytes.

Cardiac Electrophysiology, Electrocardiography

A study was conducted to evaluate the effect of single therapeutic (33 mg/kg) and supratherapeutic (50 mg/kg) oral doses of deferiprone 500 mg tablets 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 milliseconds (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.

Deferiprone was concluded to produce no significant prolongation of the QTc interval.

The 33 mg/kg dose of deferiprone was associated with statistically significant positive mean differences from placebo in heart rate, with a maximum mean difference of 4.9 (beats per minute) bpm (90% CI 3.2, 6.6) at 3 h. The 50 mg/kg dose of deferiprone was associated with statistically significant increases in heart rate from 2-10 h post-dosing, inclusive, with a maximum mean difference from placebo of 12.9 bpm (90% CI 10.8, 15.0) at 4 h.

The 33 mg/kg dose of deferiprone was associated with statistically significant decreases in systolic blood pressure at 0.6 h and 2 h, with a maximal mean difference from placebo of 3.0 mmHg (90% CI -5.1, -0.9). The 50 mg/kg dose of deferiprone was associated with statistically significant decreases in systolic blood pressure from 1 to 6 h, inclusive, with a maximum mean difference from placebo of -4.4 mmHg (90% CI -6.6, -2.1) at 1 h post-dosing.

The 33 mg/kg dose of deferiprone was associated with statistically significant decreases in diastolic blood pressure at 1 h, 2 h, and 6 h post-dosing, with a maximum mean difference from placebo of -3.2 mmHg (90% CI -5.0, -1.4) at 6 h. The 50 mg/kg dose of deferiprone was associated with statistically significant decreases in diastolic blood pressure at 1 h, 2 h, and 4 h post-dosing, with a maximum mean difference from placebo of -4.5 mmHg (90% CI -6.4, -2.7) at 4 h.

10.3 Pharmacokinetics

Following administration of deferiprone 500 mg tablets at doses of 33 mg/kg and 50 mg/kg in healthy volunteers, mean maximum serum deferiprone concentrations were reached at approximately 0.8 h and then declined in a multi-exponential manner. Mean apparent terminal elimination half-life was approximately 1.8 h, and the AUC0-t values were 93 and 148 μg∙h/mL for the 33 mg/kg and 50 mg/kg doses, respectively (see Table 6 below).

Exposures to deferiprone and deferiprone 3-O-glucuronide were proportional to dose, i.e., approximately 60% higher following the 50 mg/kg deferiprone dose than after the 33 mg/kg dose. The PK parameter values of T_max, half-life, CL/F, and Vz/F were similar between the

2 treatments and doses.

Table 6: Mean (SD) Deferiprone and Glucuronide Serum Pharmacokinetic Parameters in Healthy Volunteers following a Single Dose of Deferiprone 500 mg tablets under Fasting Conditions

a. T_max is presented as Median (Minimum, Maximum)

Absorption

Deferiprone is rapidly absorbed from the upper part of the gastrointestinal tract, appearing in the blood within 5 to 10 minutes of oral administration. Exposures to deferiprone are dose proportional over the dose range of 22-50 mg/kg.

Pharmacokinetic data in patients with iron overload are limited. In four adult patients with iron overload and biopsy-proven liver cirrhosis, the mean C_max was 11 µg/mL and AUC_τ 33 µg·h/mL after a 25 mg/kg dose at steady state (25 mg/kg three times per day) following a standard breakfast. After an initial delay in absorption, deferiprone serum levels rose steadily to attain their maximum concentration at approximately 2 hours post-dose. In patients with iron overload, serum deferiprone levels are lower than in healthy subjects.

Food effect

Administration with food decreased the C_max of deferiprone by 38% and the AUC by 10%. Following a single dose of 33 mg/kg in healthy subjects under fasting conditions, the mean C_max was 35 μg/mL and AUC_0-t 93 μg∙h/mL. Peak serum concentrations occurred approximately

1 hour after a single dose in fasted subjects, and up to 2 hours after a single dose in the fed state.

Distribution:

The volume of distribution of deferiprone is approximately 1 L/kg in healthy subjects and

1. 1.6 L/kg in patients with iron overload. The in vitro plasma protein binding of deferiprone is approximately 14%.

At doses lower than those used clinically, deferiprone has been shown to penetrate the blood brain barrier in rats, and to interfere with dopamine and serotonin metabolism through inhibitory effects on catechol-O-methyltransferase and tyrosine and tryptophan hydroxylases.

Metabolism:

The majority of an oral dose of deferiprone is metabolized to deferiprone 3-O-glucuronide, which lacks iron binding capacity; in vitro evidence indicates that the conjugation is catalyzed primarily by UGT1A6. Peak serum concentration of the 3-O-glucuronide occurs approximately 3 to 4 hours after administration of deferiprone in healthy subjects and in patients with iron overload. Systemic exposure to deferiprone 3-O-glucuronide was 1.4- to 2-fold (on a molar basis) that of the parent drug in patients with iron overload.

Elimination

More than 90% of deferiprone is eliminated from plasma within 8 hours of ingestion. Following oral administration, 75% to 90% is recovered in the urine in the first 24 hours, primarily as the glucuronide, while approximately 5% of the administered dose is excreted as deferiprone. The elimination half-life is approximately 1.8 hours for deferiprone and 2.5 hours for the glucuronide metabolite in fasting healthy volunteers.

Special Populations and Conditions

The influence of age, race, gender, or obesity on deferiprone pharmacokinetics has not been established.

• Pediatrics: The pharmacokinetics of deferiprone in children was assessed in 7 patients with thalassemia and iron overload aged 11 to 18 years (mean age=15 ± 2.7 years; median=16 years). These patients were on long term therapy with deferiprone and were thus considered to be at steady state. Drug concentrations were measured following administration of a dose of deferiprone, 25 mg/kg, after a standard breakfast. The exposures to deferiprone of the pediatric patients were consistent with those determined in adult patients when the drug was administered under fed conditions. Serum levels of deferiprone were maximal approximately 2 hours after dosing and declined with a half-life of 1.8 hours; levels of deferiprone glucuronide peaked at approximately 3 hours and fell with a half-life of 2.0 hours. No pharmacokinetic study has been conducted in patients <11 years of age.
• Hepatic Insufficiency: The pharmacokinetics of deferiprone and its 3-O-glucuronide metabolite following a single oral 33 mg/kg dose of deferiprone 500 mg tablets were compared in subjects with mild (Child-Pugh classification score A: 5– 6 points) or moderate (Child-Pugh classification score B: 7– 9 points) hepatic impairment to healthy volunteers. Systemic exposure to deferiprone and to its metabolite deferiprone 3-O- glucuronide was assessed by the PK parameters C_max and AUC. AUC did not differ; C_max was decreased by 20% compared to healthy volunteers. The pharmacokinetic profile of deferiprone in patients with severe hepatic impairment has not been studied.
• Renal Insufficiency: The pharmacokinetics of deferiprone and its 3-O-glucuronide metabolite following a single oral 33 mg/kg dose of deferiprone 500 mg tablets were compared in subjects with renal impairment and in healthy volunteers. Systemic exposure to deferiprone, as indicated by C_max and AUC, was not significantly altered by renal impairment. Conversely, systemic exposure to the 3-O-glucuronide metabolite increased 1.3-, 2.7- and 5.6-fold (AUC_∞) in subjects with mild, moderate and severe renal impairment, respectively, as compared to that in subjects with normal renal function. Renal clearances of both deferiprone and the 3-O-glucuronide metabolite were significantly reduced by renal impairment. Most of the dose of deferiprone was excreted in urine over the first 24 hours as the 3-O-glucuronide metabolite, irrespective of the severity of renal impairment. The pharmacokinetic profile of deferiprone in patients with end-stage renal disease on dialysis has not been studied.
• STORAGE, STABILITY AND DISPOSAL

Store at room temperature (15 to 30°C).

Keep in a safe place out of the reach and sight of children.

1. 12. SPECIAL HANDLING INSTRUCTIONS

None.

PART II: SCIENTIFIC INFORMATION

1. 13. PHARMACEUTICAL INFORMATION

Drug Substance

Proper name: deferiprone

Chemical name: 3-hydroxy-1,2-dimethylpyridin-4-one

Molecular formula and molecular mass: C₇H₉NO₂; 139.15 g/mol

Structural formula:

Physicochemical properties:

Solubility: deferiprone is slightly soluble in water and freely soluble in most polar organic solvents like methanol, ethanol and water at acidic pH (<3), practically insoluble in acetone

14. CLINICAL TRIALS

14.1 Clinical Trials by Indication

Transfusional iron overload due to Thalassemia syndromes

The efficacy of deferiprone for the treatment of patients with transfusional iron overload due to thalassemia syndromes has been evaluated in twelve clinical studies: eight clinical trials, one of which (LA16-0102) is considered pivotal, three compassionate use studies, and an investigator sponsored study. LA36-0310, a prospectively planned, pooled analysis of pre- existing data from these twelve studies, evaluated the efficacy of deferiprone 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.

Demographic characteristics for LA16-0102 and for LA36-0310 are shown in Table 7.

Table 7: Summary of patient demographics for clinical trials in Thalassemia syndromes

⁺ 29 of 31 (93.5%) of the patients were from LA16-0102

LA16-0102

Study LA16-0102 was a 12-month, multi-centre, open-label, randomized, active controlled study conducted in transfusion-dependent β-thalassemia major patients between 18 and

36 years of age. Subjects had been receiving ongoing chelation therapy with deferoxamine for at least the past 5 years and had an abnormal (<20 milliseconds (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 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 deferiprone administered three times a day (tid) orally in doses of 25 mg/kg for the first 4 weeks, increased to 28.3 mg/kg for the subsequent 4 weeks and maintained at 33.3 mg/kg for the remainder of the trial, 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 deferiprone (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 baseline demographics for age, sex, cardiac MRI T2* and liver iron concentration (LIC) were similar between the groups, although serum ferritin concentrations at baseline were higher in deferoxamine-treated patients (serum ferritin = 2,795 μg/L) compared to deferiprone- treated patients (serum ferritin = 1,790 μg/L). deferiprone-treated patients had a mean baseline cardiac MRI T2* value of 13.6 ms and LIC of 6.16 mg Fe/g dry weight (mg/g dw); corresponding values in deferoxamine-treated patients were similar at 13.9 ms and 6.32 mg Fe/g dry weight, respectively.

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

At the 12-month assessment, there was an improvement in cardiac MRI T2* of 3.5 ms (from

13.0 ms to 16.5 ms) in patients treated with deferiprone compared with a change of 1.7 ms (from 13.3 ms to 15.0 ms) in patients treated with deferoxamine, which corresponds to 27% increase and 13% increase for deferiprone and deferoxamine, respectively. The improvement in cardiac MRI T2* was significantly greater for deferiprone than deferoxamine (p = 0.02).

No significant difference (p = 0.16) in mean change of serum ferritin from baseline to

12 months between the two treatment groups was detected. In addition, the difference in mean decrease in LIC at 12 months (0.61 mg/g dw) between the 2 groups was statistically non- significant (p = 0.40). Over the same 12 months, LVEF increased from baseline by 3.1 ±

3.6 absolute units (%) in the deferiprone group and by 0.3 ± 3.4 absolute units (%) in the deferoxamine group (difference between groups; nominal p = 0.003). Results for the efficacy endpoint MRI T2* are presented in Table 8. Results for efficacy endpoints serum ferritin, LIC and LVEF are presented in Table 9.

Table 8: LA16-0102: Relative Change in MRI T2* from baseline to 12 months for deferiprone and deferoxamine treatment groups – Intent-To-Treat Population

† Geometric mean is defined as antilog of the mean of the log data

§ Coefficient of variation is defined as √[e^variance-1], where variance is the variance of the mean in log scale.

|| The ratio is defined as deferiprone mean/deferoxamine mean. At 12 months, the ratio is corrected for the difference in baseline mean between the two treatment groups by dividing it by 0.98.

¶ The Log (MRI T2*) between the deferiprone and deferoxamine treatment groups was compared by the two-sample t-test.

Table 9: LA16-0102: Change in other efficacy endpoints from baseline to 12 months for deferiprone and deferoxamine treatment groups – Intent-To-Treat Population

LA36-0310

In LA36-0310, data from 747 patients who had received deferiprone 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 deferiprone (main criterion); or liver iron concentration (LIC) of > 7 mg/g dw; or excess cardiac iron stores as demonstrated by a cardiac MRI T2* < 20 ms. Results from patients who received deferiprone in combination with other chelation therapy are excluded from the presented analysis. 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.

Deferiprone therapy was considered successful in individual patients who experienced a reduction in serum ferritin of ≥20% from baseline within one year of starting therapy (primary efficacy endpoint). Other success criteria (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 deferiprone therapy as successful for a particular measure, the lower limit of the 95% confidence interval (CI) for that efficacy measure had to be greater than 20%.

The dose of deferiprone 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.

The success rate for serum ferritin for patients on deferiprone monotherapy was 50% (95% CI:43% to 57%). Mean serum ferritin decreased by 940 μg/L within one year of therapy (p=0.0001), 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% (95% CI: 28% to 49%). For LIC, the mean decreased by 1.4 mg/g dw within one year of therapy (p=0.09), from 16.4 mg/g dw at baseline to 15.0 mg/g dw at the last observation. The overall success rate for cardiac MRI T2* was 65% (95% CI: 45% to 81%). For cardiac MRI T2* the mean increased by 3.9 ms within one year of therapy (p=0.0001), from 13.3 ms at baseline to 17.2 ms at the last observation.

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

Natural History Studies

Data from two natural history studies (Piga A, 2003; Borgna-Pignatti C, 2006) are supportive of the clinical effectiveness of deferiprone in the treatment of transfusional iron overload due to thalassemia syndromes.

Transfusional iron overload due to Sickle Cell Disease and Other Anemias

The efficacy of deferiprone for the treatment of patients with transfusional iron overload due sickle cell disease or other anemias has been evaluated in clinical trials LA38-0411 and LA38- EXT. A controlled non-inferiority study compared the efficacy of deferiprone to that of deferoxamine in patients with sickle cell disease and other transfusion-dependent anemias by evaluating liver iron concentration.

Table 10: Summary of patient demographics for LA38-0411 in transfusional Iron Overload due to Sickle Cell Disease and Other Anemias

The primary endpoint was the change in liver iron concentration from baseline after

12 months of deferiprone (75 or 99 mg/kg/day) compared to deferoxamine (20 or 40 mg/kg (children); 40 or 50 mg/kg (adults)). Patient enrollment was stopped following an interim analysis. After adjusting for the type I (alpha) error, the non-inferiority criterion was established as the upper limit of the 96.01% confidence interval for the difference between treatments being ≤2 mg/g dry weight (dw).

Data from 185 patients (122 on deferiprone and 63 on deferoxamine) were analyzed. There were no significant treatment group differences at baseline or after 12 months (p-values>0.05). Over 12 months, the Least Squares estimate of mean decrease from baseline in liver iron concentration was 4.13 ± 0.50 mg/g dw for deferiprone and 4.38 ± 0.59 mg/g dw for deferoxamine, and the non-inferiority criterion was met.

Patients who completed the 1-year non-inferiority study LA38-0411 were offered the opportunity to take part in in the 2-year extension study LA38-EXT. Those who had been treated with deferiprone continued to receive it (N=89), while those who had been treated with deferoxamine were switched to deferiprone (N=45). Liver iron concentration continued to decrease over time, with the mean value dropping from 14.93 mg/g dw at baseline to

12.30 mg/g dw after one year of treatment, to 11.19 mg/g dw after two years of treatment, and to 10.45 mg/g dw after three years of deferiprone treatment.

14.3 Comparative Bioavailability Studies

A randomized, single-dose (1 x 1000 mg), two-way crossover comparative bioavailability study of Taro- Deferiprone tablets 1000 mg (Taro Pharmaceuticals Inc.) with PrFERRIPROX tablets 1000 mg (Chiesi Canada Corp.) was conducted in healthy, adult male subjects under fasting conditions. Comparative bioavailability data from 36 subjects that were included in the statistical analysis are presented in the following table:

Table 11. Summary Table of the Comparative Bioavailability Data

¹ Taro-Deferiprone (deferiprone) tablets, 1000 mg (Taro Pharmaceuticals Inc.)

^{2 Pr}FERRIPROX (deferiprone) tablets, 1000 mg (Chiesi Canada Corp.)

³ Expressed as the median (range) only

⁴ Expressed as the arithmetic mean (CV%) only

15. MICROBIOLOGY

No microbiological information is required for this drug product.

16. NON-CLINICAL TOXICOLOGY

General Toxicology:

Acute Toxicity

The median lethal dose (LD₅₀) of deferiprone in non-iron-loaded mice and rats given a single i.p. injection was 983 and 650 mg/kg, respectively. Convulsions preceded death in mice. The oral LD₅₀ in rats was 2,000 to 3,000 mg/kg.

Subchronic and Long-Term Toxicity

In a 3-month rodent toxicology study, a minority of iron-supplemented rats given 125 mg/kg deferiprone bid orally were subject to unscheduled euthanasia during the latter two-thirds of the study, as a result of declining clinical condition, and decreased circulating RBC, platelet, and WBC counts. Microscopic examination revealed bone marrow hypocellularity, hepatic centrilobular degeneration and necrosis, and lymphocytic depletion in the thymic cortex. Bone marrow depression and non-regenerative anemia were considered to be the cause of death. Less severe effects were evident at 75 mg/kg bid, but no toxicologically relevant effects occurred at 37.5 mg/kg bid.

In a 3-month primate toxicology study, non-iron-loaded monkeys were terminated because of declining physical condition after 42-50 days’ oral administration of deferiprone, 125 mg/kg bid and later 150 mg/kg bid; animals given 50 or 100 mg/kg bid (100 or 200 mg/kg/day) survived treatment as scheduled. Moderate to severe reductions in circulating platelet, reticulocyte and white cell (all types) counts were observed. Serum levels of iron were also decreased. Intestinal degeneration and necrosis were identified as the cause of morbidity, but bone marrow hypocellularity, depletion and necrosis of thymus, spleen and lymph nodes, and liver pathology were also significant. No toxicologically relevant effects were noted at

50 mg/kg bid.

In a 12-month rodent toxicology study, following administration of deferiprone at doses of 150 or 200 mg/kg/day in 2 divided doses (75 or 100 mg/kg bid), to non-iron-loaded or iron- loaded rats, respectively, 7 of 50 non-iron-loaded and 3 of 50 iron-loaded animals were either found dead or sacrificed moribund with severe anemia and slight to moderate centrilobular degeneration and necrosis. Animals from which blood samples could be collected prior to their unscheduled termination had elevated levels of total bilirubin, aspartate aminotransferase, and/or alanine aminotransferase of up to ca. 8, 4, and 14 times their respective group mean control value. These findings could be ascribed to hypoxia due to severe anemia (hemoglobin concentration <2.5 g/dL). No findings of severe anemia with or without centrilobular degeneration and necrosis, or isolated findings of centrilobular degeneration and necrosis, were noted in non-iron-loaded or iron-loaded survivors. Relatively mild decreases in RBC and WBC counts in surviving rats partially reversed during a 4-week off-dose period following

12 months’ treatment; recovery of bone marrow hypocellularity was complete in iron-loaded, but partial in non-iron-loaded, animals. The mean relative weight of the adrenal and pituitary gland was significantly greater in non-iron-loaded rats given 75 mg/kg deferiprone bid as compared to non-iron-loaded untreated rats.

In a 12-month primate toxicology study, no treatment-related changes were detected in non- iron-loaded monkeys dosed orally with 75 mg/kg deferiprone bid. Iron loading produced increases in serum ALT activity, which may have been exacerbated by deferiprone.

Carcinogenicity:

Non-clinical carcinogenicity studies have not been conducted with deferiprone. In a 12 month rat toxicology study, reversible mammary gland hyperplasia occurred in female animals of all deferiprone-treated groups, irrespective of iron loading. The incidence of mammary tumors (1 of 65 males, 1 of 65 females) in deferiprone-treated animals was not statistically significantly different from that in controls.

However, in view of positive genotoxicity results (refer to genotoxicity information below) and the findings of mammary gland hyperplasia and mammary gland tumors in rats treated with deferiprone for 52 weeks, tumor formation in rodent carcinogenicity studies must be regarded as likely. Deferiprone was clastogenic in an in vitro mouse lymphoma cell assay and in a Chinese hamster ovary cell chromosomal aberration test. Deferiprone given orally or intraperitoneally was clastogenic in a bone marrow micronucleus assay in non-iron-loaded mice. A micronucleus test was also positive when mice predosed with iron dextran were treated with deferiprone.

Genotoxicity:

Deferiprone was not mutagenic in a bacterial reverse mutation assay. It was positive in an in vitro L5178Y/TK+/- mouse lymphoma mutagenesis assay in the absence or presence of metabolic activation. Evidence of clastogenic effect was observed in a bone marrow micronucleus test in non-iron-loaded mice and after iron loading. There was no difference in the frequencies of lymphocyte chromosomal aberrations in thalassemia patients treated with deferiprone and deferoxamine in a clinical trial conducted to a crossover design.

Reproductive and Developmental Toxicology:

Deferiprone had no significant effects on fertility and reproductive performance in non-iron- loaded male and female rats dosed orally at ≤ 75 mg/kg bid prior to and through mating (males) or through early gestation (females). In females, estrous cycle prolongation (manifested as time to confirmed mating) was noted at all doses tested.

Skeletal and soft tissue malformations occurred in offspring of rats and rabbits that received deferiprone orally during organogenesis at the lowest doses tested (25 mg/kg per day in rats; 10 mg/kg per day in rabbits). These doses were equivalent to 3% to 4% of the maximum recommended human dose (MRHD) based on body surface area. No maternal toxicity was evident at these doses.

Embryofetal lethality and maternal toxicity occurred in pregnant rabbits given 100 mg/kg/day deferiprone orally during the period of organogenesis. This dose is equivalent to 32% of the MRHD based on body surface area.

17. SUPPORTING PRODUCT MONOGRAPHS

1. 1. FERRIPROX (deferiprone tablets, 500 mg and 1000 mg; deferiprone oral solution, 100 mg/mL) and FERRIPROX MR (deferiprone extended-release tablets, 1000 mg), Submission Control No. 261912, Product Monograph, Chiesi Canada Corp., March 29, 2023.