FERRIPROX

FERRIPROX Tablets (deferiprone) contain 1,000 mg deferiprone (3-hydroxy-1,2-dimethylpyridin-4-one), a synthetic, orally active, iron-chelating agent. The molecular formula for deferiprone is C 7 H 9 NO 2 and its molecular weight is 139.15 g/mol. Deferiprone has the following structural formula: Deferiprone is a white to pinkish-white powder. It is sparingly soluble in deionized water (14.3 mg/mL) and has a melting point range of 272 °C - 278 °C. FERRIPROX Tablets ( twice a day) , 1,000 mg White to off-white, capsule-shaped tablets, and imprinted with “FPX” score “DR” on one side and “APO” score “1000” on the other. The tablets can be broken in half along the score line. Each tablet contains 1,000 mg deferiprone and the following inactive ingredients: Tablet core - hypromellose acetate succinate, magnesium oxide, colloidal silicon dioxide and magnesium stearate; Coating - triethyl citrate, talc, titanium dioxide, and methacrylic acid and ethyl acrylate copolymer. FERRIPROX T ablets (three times a day) , 1,000 mg White to off-white, capsule-shaped tablets, and imprinted with “APO” score “1000” on one side and plain on the other. The tablets can be broken in half along the score line. Each tablet contains 1,000 mg deferiprone and the following inactive ingredients: Tablet core - methylcellulose, crospovidone, and magnesium stearate; Coating - hypromellose, hydroxypropyl cellulose, macrogol, and titanium dioxide. structural formula

FERRIPROX Tablets are indicated for the treatment of transfusional iron overload in adult and pediatric patients 8 years of age and older with thalassemia syndromes, sickle cell disease or other anemias. Limitation s of Use • 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. FERRIPROX Tablets are an iron chelator indicated for the treatment of transfusional iron overload in adult and pediatric patients 8 years of age and older with thalassemia syndromes, sickle cell disease or other anemias. ( 1 ) Limitation s of Use 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.

FERRIPROX Tablets are available in two different 1,000 mg formulations, which have different dosing regimens to achieve the same total daily dosage. ( 2.1 ) To prevent medication errors, before prescribing and dispensing, ensure that the tablet formulation is appropriate for the dosing regimen. Each tablet has distinct identifying characteristics. ( 2.1 , 3 ) FERRIPROX Tablets (twice a day), 1,000 mg: • Starting oral dosage: 75 mg/kg/day (actual body weight) in two divided doses ( 2.2 ) • Maximum oral dosage: 99 mg/kg/day (actual body weight) in two divided doses ( 2.2 ) FERRIPROX Tablets (three times a day), 1,000 mg: ○ Starting oral dosage: 75 mg/kg/day (actual body weight) in three divided doses ( 2.2 ) ○ Maximum oral dosage: 99 mg/kg/day (actual body weight) in three divided doses ( 2.2 ) 2.1 Important Dosage and Administration Information FERRIPRO X T ablets are available in two different 1,000 mg formulations , which have different oral dosing regimens to achieve the same total daily dosage. FERRIPROX Tablets (twice a day) - 1,000 mg - given two times a day [see Dosage and Administration ( 2.2 )] FERRIPROX Tablets (three times a day) - 1,000 mg - given three times a day [see Dosage and Administration ( 2.3 )] To prevent medication errors, before prescribing and dispensing, ensure that the tablet formulation is appropriate for the dosing regimen. Each tablet has distinct identifying characteristics [see Dosage Forms and Strengths ( 3 )]. For patients who have trouble swallowing tablets, consider the use of FERRIPROX Oral Solution (see the prescribing information for FERRIPROX Oral Solution). Monitoring for Safety Due to the risk of agranulocytosis, monitor ANC before and during FERRIPROX therapy. Test ANC prior to start of FERRIPROX therapy and monitor on the following schedule during treatment: • First six months of therapy: Monitor ANC weekly; • Next six months of therapy: Monitor ANC once every two weeks; • After one year of therapy: Monitor ANC every two to four weeks (or at the patient’s blood transfusion interval in patients that have not experienced an interruption due to any decrease in ANC [see Warnings and Precautions ( 5.1 )] . Due to the risk of hepatic transaminase elevations, monitor ALT before and monthly during FERRIPROX therapy [see Warnings and Precautions ( 5.2 )] . Due to the risk of zinc deficiency, monitor zinc levels before and regularly during FERRIPROX therapy [see Warnings and Precautions ( 5.3 )] . 2.2 Recommended Dosage for 1,000 mg FERRIPROX T ablets ( twice a day) for Adult and Pediatric Patients with Transfusional Iron Overload due to Thalassemia Syndromes, Sickle Cell Disease or Other Anemias Starting Dos ag e for T wice a Day Tablets The recommended starting oral dosage of FERRIPROX Tablets (twice a day) is 75 mg/kg/day (actual body weight) in two divided doses per day (taken approximately 12 hours apart), with food. Round the total daily dose to the nearest 500 mg (half-tablet). Table 1 describes the number of FERRIPROX Tablets (twice a day) needed to achieve the 75 mg/kg/day total starting daily dosage. Table 1 : Number of FERRIPROX 1,000 mg T ablets (twice a day) Needed to Achieve the Total Starting Daily Dosage of 75 mg/k g (rounded to the nearest half-tablet) Body Weight (kg) Morning Evening 20 0.5 1 30 1 1.5 40 1.5 1.5 50 2 2 60 2 2.5 70 2.5 3 80 3 3 90 3.5 3.5 To minimize gastrointestinal upset when first starting therapy, dosing can start at 45 mg/kg/day and increase weekly by 15 mg/kg/day increments until the full prescribed dose is achieved. Dos ag e Adjustment s for T wice a Day Tablets Tailor dosage adjustments of FERRIPROX Tablets (twice a day) to the individual patient’s response and therapeutic goals (maintenance or reduction of body iron burden). The maximum total daily oral dosage is 99 mg/kg (actual body weight) divided into two doses taken approximately 12 hours apart with food. Table 2 describes the number of FERRIPROX Tablets (twice a day) needed to achieve the 99 mg/day total maximum daily dosage. Table 2 : Number of FERRIPROX 1,000 mg Tablets (twice a day) Needed to A chieve a Total Maximum Recommended Daily Dosage of 99 mg/kg (rounded to the nearest half-tablet) Body Weight (kg) Morning Evening 20 1 1 30 1.5 1.5 40 2 2 50 2.5 2.5 60 3 3 70 3.5 3.5 80 4 4 90 4.5 4.5 2 .3 Recommended Dos age for 1,000 mg FERRIPROX T ablets (three times a day) for Adult and Pediatric Patients with Transfusional Iron Overload due to Thalassemia Syndromes, Sickle Cell Disease or Other Anemias Starting Dos ag e for Three Times a Day Tablets The recommended starting oral dosage of FERRIPROX Tablets (three times a day) is 75 mg/kg/day (actual body weight), in three divided doses per day. Table 3 describes the number of FERRIPROX Tablets (three times a day) needed to achieve the 75 mg/kg/day total starting dosage). Round dose to the nearest 500 mg (half-tablet). Table 3 : Number of F ERRIPROX 1,000 mg T ablets (three times a day) Needed to Achieve the Total Starting Daily Dosage of 75 mg/kg (rounded to the nearest half-tablet) Body Weight (kg) Morning Midday Evening 20 0.5 0.5 0.5 30 1 0.5 1 40 1 1 1 50 1.5 1 1.5 60 1.5 1.5 1.5 70 2 1.5 2 80 2 2 2 90 2.5 2 2.5 To minimize gastrointestinal upset when first starting therapy, dosing can start at 45 mg/kg/day and increase weekly by 15 mg/kg/day increments until the full prescribed dose is achieved. Dosage Adjustments for Three Times Daily Tablets Tailor dosage adjustments for FERRIPROX Tablets (three times a day) to the individual patient’s response and therapeutic goals (maintenance or reduction of body iron burden). The maximum oral dosage is 99 mg/kg/day (actual body weight), in three divided doses per day. Table 4 describes the number of FERRIPROX Tablets (three times a day) needed to achieve the 99 mg/day total maximum daily dosage. Table 4: Number of FERRIPROX 1,000 mg Tablets (three times a day) Needed to Achieve the Maximum Total Daily Dosage of 99 mg/kg (rounded to the nearest half-tablet) Body Weight (kg) Morning Midday Evening 20 0.5 0.5 1 30 1 1 1 40 1.5 1 1.5 50 1.5 1.5 2 60 2 2 2 70 2.5 2 2.5 80 2.5 2.5 3 90 3 3 3 2.4 Monitoring Ferritin Levels to Assess Efficacy Monitor serum ferritin concentration every two to three months to assess the effect of FERRIPROX on body iron stores. If the serum ferritin is consistently below 500 mcg/L, consider temporarily interrupting FERRIPROX therapy until serum ferritin rises above 500 mcg/L. 2. 5 Dosage Modification for Drug Interactions Allow at least a 4-hour interval between administration of FERRIPROX and other drugs or supplements containing polyvalent cations such as iron, aluminum, or zinc [ see Drug Interactions ( 7.2 ), Clinical Pharmacology ( 12.3 ) ] .

FERRIPROX is contraindicated in patients with known hypersensitivity to deferiprone or to any of the excipients in the formulations. The following reactions have been reported in association with the administration of deferiprone: Henoch-Schönlein purpura; urticaria; and periorbital edema with skin rash [ see Adverse Reactions ( 6.2 )] . Hypersensitivity to deferiprone or to any of the excipients in the formulations. ( 4 )

The following clinically significant adverse reactions are described below and elsewhere in the labeling: Agranulocytosis and Neutropenia [see Warnings and Precautions ( 5.1 )] Liver Enzyme Elevations [ see Warnings and Precautions ( 5.2 ) ] Zinc Deficiency [see Warnings and Precautions ( 5.3 )] The most common adverse reactions in patients with thalassemia (incidence ≥ 6%) are nausea, vomiting, abdominal pain, arthralgia, ALT increased and neutropenia. ( 6 ) The most common adverse reactions in patients with sickle cell disease or other anemias (incidence ≥6%) are pyrexia, abdominal pain, bone pain, headache, vomiting, pain in extremity, sickle cell anemia with crisis, back pain, ALT increased, AST increased, arthralgia, oropharyngeal pain, nasopharyngitis, neutrophil count decreased, cough and nausea. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Chiesi USA, Inc. at 1-888-661-9260 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. FERRIPROX Tablets (twice a day) were evaluated in trials in healthy subjects. FERRIPROX Tablets (twice a day) contain deferiprone, the same active ingredient as FERRIPROX Tablets (deferiprone) (three times a day) and FERRIPROX Oral Solution (deferiprone). The following adverse reaction information represents the pooled data collected from single arm or active-controlled clinical trials with FERRIPROX Tablets (deferiprone) (three times a day) or FERRIPROX Oral Solution (deferiprone). Thalassemia Syndromes The safety of FERRIPROX was evaluated in the pooled clinical trial database [see Clinical Studies ( 14.1 )] . Patients received FERRIPROX Tablets (three times a day) or FERRIPROX Oral Solution . FERRIPROX was administered orally three times a day (total daily dose either 50, 75, or 99 mg/kg), N=642. Among 642 patients receiving FERRIPROX, 492 (76.6%) were exposed for 6 months or longer and 365 (56.9%) were exposed for greater than one year. The median age of patients who received FERRIPROX was 19 years (range 1, 77 years); 50.2% female; 71.2% White, 17.8% Asian, 9.2% Unknown, 1.2% Multi-racial and 0.6% Black. The most serious adverse reaction reported in clinical trials with FERRIPROX was agranulocytosis [see Warnings and Precautions ( 5.1 ) ] . The most common adverse reactions (≥6%) reported during clinical trials were nausea, vomiting, abdominal pain, arthralgia, alanine aminotransferase increased and neutropenia. The table below lists the adverse drug reactions that occurred in at least 1% of patients treated with FERRIPROX in clinical trials in patients with thalassemia syndromes. Table 5: Adverse reactions occurring in ≥ 1% of FERRIPROX-treated patients with thalassemia syndromes Body System (N=642) Adverse Reaction % Patients BLOOD AND LYMPHATIC SYSTEM DISORDERS Neutropenia * 7 Agranulocytosis † 1 GASTROINTESTINAL DISORDERS Nausea 13 Abdominal pain/discomfort 10 Vomiting 10 Diarrhea 3 Dyspepsia 2 INVESTIGATIONS Alanine aminotransferase increased 7 Weight increased 2 Aspartate aminotransferase increased 1 METABOLISM AND NUTRITION DISORDERS Increased appetite 4 Decreased appetite 1 MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS Arthralgia 10 Back pain 2 Pain in extremity 2 Arthropathy 1 NERVOUS SYSTEM DISORDERS Headache 2 * Neutropenia includes events of severe neutropenia (ANC ≥0.2 x 10 9 /L and <0.5 x 10 9 /L). †Agranulocytosis (ANC< 0.2 x 10 9 /L) Gastrointestinal symptoms such as nausea, vomiting, and abdominal pain were the most frequent adverse reactions reported by patients participating in clinical trials and led to the discontinuation of FERRIPROX therapy in 1.6% of patients. Chromaturia (reddish/brown discoloration of the urine) is a result of the excretion of iron in the urine. Sickle Cell Disease or Other Anemias The safety of FERRIPROX compared to deferoxamine was evaluated in LA38-0411 [see Clinical Studies ( 14.2 )] . Patients received FERRIPROX Tablets or FERRIPROX Oral Solution orally three times a day (total daily dose 75-99 mg/kg/day) n=152) or the control arm, deferoxamine, 20-40 mg/kg/day (children) or 40-50 mg/kg/day (adults), by subcutaneous infusion for 5 – 7 days per week, n=76. Among 152 patients receiving FERRIPROX, 120 (78.9%) were exposed for 6 months or longer and 17 (11.2%) were exposed for greater than one year. The median age of patients who received FERRIPROX was 15 years (range 3, 59 years); 54.6% male; 78.9% White, 15.1% Black and 5.9% Multi-racial. The most common adverse reactions (≥6%) reported during clinical trials in patients with SCD or other anemias were pyrexia, abdominal pain, bone pain, headache, vomiting, pain in extremity, sickle cell anemia with crisis, back pain, alanine aminotransferase (ALT) increased, aspartate aminotransferase (AST) increased, arthralgia, oropharyngeal pain, nasopharyngitis, neutrophil count decreased, cough and nausea. The table below lists the adverse reactions (irrespective of a causal assessment; adverse events) of interest that occurred in patients treated with FERRIPROX in clinical trials in subjects with sickle cell disease or other anemias. Table 6: Adverse reactions occurring in ≥5% of FERRIPROX-treated patients with sickle cell disease or other anemias Body System Adverse Reaction FERRIPROX (N=152) % Patients DEFEROXAMINE (N=76) % Patients BLOOD AND LYMPHATIC SYSTEM DISORDERS Sickle cell anemia with crisis 17 13 GASTROINTESTINAL DISORDERS Abdominal pain* 26 13 Vomiting 19 11 Nausea 7 9 Diarrhea 5 8 GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS Pyrexia 28 33 Pain 5 4 INFECTIONS AND INFESTATIONS Nasopharyngitis 9 12 Upper respiratory tract infection 5 3 INVESTIGATIONS Alanine aminotransferase increased 12 0 Aspartate aminotransferase increased 11 0 Neutrophil count decreased 8 4 MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS Bone pain 25 34 Pain in extremity 18 15 Back pain 13 18 Arthralgia 10 8 NERVOUS SYSTEM DISORDERS Headache 20 13 RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS Oropharyngeal pain 10 15 Cough 8 15 *Grouped term Clinically relevant adverse reactions in <5% of patients include neutropenia and agranulocytosis. Pediatric Patients FERRIPROX has been studied in 86 pediatric patients with sickle cell disease or other anemias. Pediatric patients (<17 years) had an increase in the following adverse reactions as compared to adults: abdominal pain, neutrophil count decreased, bone pain and oropharyngeal pain. 6.2 Postmarketing Experience The following additional adverse reactions have been reported in patients receiving FERRIPROX. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or to establish a causal relationship to drug exposure. Blood and lymphatic system disorders: thrombocytosis, pancytopenia. Cardiac disorders: atrial fibrillation, cardiac failure. Congenital, familial and genetic disorders: hypospadias. Eye disorders: diplopia, papilledema, retinal toxicity. Gastrointestinal disorders: enterocolitis, rectal hemorrhage, gastric ulcer, pancreatitis, parotid gland enlargement. General disorders and administration site conditions: chills, 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.

Drugs Associated with Neutropenia or Agranulocytosis: Avoid co-administration. If co-administration is unavoidable, closely monitor the absolute neutrophil count. ( 7.1 ) UGT1A6 Inhibitors: Avoid co-administration. ( 7.2 ) Polyvalent Cations: Allow at least a 4-hour interval between administration of FERRIPROX and drugs or supplements containing polyvalent cations (e.g., iron, aluminum, or zinc). ( 2.2 , 7.2 ) 7.1 Drugs A ssociated with N eutropenia or A granulocytosis Avoid co-administration of FERRIPROX with other drugs known to be associated with neutropenia or agranulocytosis. If co-administration is unavoidable, closely monitor the absolute neutrophil count [ see Warnings and Precautions ( 5.1 ) ] . 7.2 Effect of Other Drugs on FERRIPROX UDP-Glucuronosyltransferases (UGT) Avoid use of UGT1A6 inhibitors (e.g., diclofenac, probenecid, or silymarin (milk thistle)) with FERRIPROX [ see Dosage and Administration ( 2.2 ) , Adverse Reactions ( 6.1 ), Clinical Pharmacology ( 12.3 ) ] . Polyvalent Cations Deferiprone has the potential to bind polyvalent cations (e.g., iron, aluminum, and zinc); allow at least a 4-hour interval between FERRIPROX and other medications (e.g., antacids), or supplements containing these polyvalent cations [see Dosage and Administration ( 2.2 ) ] .