FDA label b02c7ef0-b683-ea13-bcb4-30be2a740fd7

WARNING: AGRANULOCYTOSIS AND NEUTROPENIA FERRIPROX can cause agranulocytosis that can lead to serious infections and death. Neutropenia may precede the development of agranulocytosis. [see Warnings and Precautions (5.1) ] Measure the absolute neutrophil count (ANC) before starting FERRIPROX therapy and monitor weekly while on therapy. Interrupt FERRIPROX therapy if neutropenia develops. [see Warnings and Precautions (5.1) ] Interrupt FERRIPROX if infection develops, and monitor the ANC more frequently. [see Warnings and Precautions (5.1) ] Advise patients taking FERRIPROX to report immediately any symptoms indicative of infection. [see Warnings and Precautions (5.1) ] WARNING: AGRANULOCYTOSIS AND NEUTROPENIA See full prescribing information for complete boxed warning. FERRIPROX can cause agranulocytosis that can lead to serious infections and death. Neutropenia may precede the development of agranulocytosis. (5.1) Measure the absolute neutrophil count (ANC) before starting FERRIPROX and monitor weekly while on therapy. (5.1) Interrupt FERRIPROX if infection develops and monitor the ANC more frequently. (5.1) Advise patients taking FERRIPROX to report immediately any symptoms indicative of infection. (5.1)

5 WARNINGS AND PRECAUTIONS Liver Enzyme Elevations: Monitor monthly and discontinue for persistent elevations. ( 5.2 ) Zinc Deficiency: Monitor during therapy and supplement for deficiency. ( 5.3 ) Embryo-Fetal Toxicity: Can cause fetal harm. ( 5.4 ) 5.1 Agranulocytosis and Neutropenia Fatal agranulocytosis can occur with FERRIPROX use. FERRIPROX can also cause neutropenia, which may foreshadow agranulocytosis. Measure the absolute neutrophil count (ANC) before starting FERRIPROX therapy and monitor it weekly while on therapy. Interrupt FERRIPROX therapy if neutropenia develops (ANC < 1.5 x 10 9 /L). Interrupt FERRIPROX if infection develops and monitor the ANC frequently. Advise patients taking FERRIPROX to immediately interrupt therapy and report to their physician if they experience any symptoms indicative of infection. In pooled clinical trials, the incidence of agranulocytosis was 1.7% of patients. The mechanism of FERRIPROX-associated agranulocytosis is unknown. Agranulocytosis and neutropenia usually resolve upon discontinuation of FERRIPROX, but there have been reports of agranulocytosis leading to death. Implement a plan to monitor for and to manage agranulocytosis and neutropenia prior to initiating FERRIPROX treatment. For agranulocytosis (ANC < 0.5 x 10 9 /L): Consider hospitalization and other management as clinically appropriate. Do not resume FERRIPROX in patients who have developed agranulocytosis unless potential benefits outweigh potential risks. Do not rechallenge patients who have developed neutropenia with FERRIPROX unless potential benefits outweigh potential risks. For neutropenia (ANC < 1.5 x 10 9 /L and > 0.5 x 10 9 /L): Instruct the patient to immediately discontinue FERRIPROX and all other medications with a potential to cause neutropenia. 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 x 10 9 /L). 5.2 Liver Enzyme Elevations In clinical studies, 7.5% of 642 patients treated with FERRIPROX developed increased ALT values. Four (0.62%) FERRIPROX-treated subjects discontinued the drug due to increased serum ALT levels and 1 (0.16%) due to an increase in both ALT and AST. Monitor serum ALT values monthly during therapy with FERRIPROX and consider interruption of therapy if there is a persistent increase in the serum transaminase levels. 5.3 Zinc Deficiency Decreased plasma zinc concentrations have been observed on FERRIPROX therapy. Monitor plasma zinc, and supplement in the event of a deficiency. 5.4 Embryo-Fetal Toxicity Based on findings from animal reproduction studies and evidence of genotoxicity, FERRIPROX can cause fetal harm when administered to a pregnant woman. The available data on the use of FERRIPROX in pregnant women are insufficient to inform risk. 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. Advise pregnant women and females of reproductive potential of the potential risk to the fetus [see Use in Specific Populations ( 8.1 )] . Advise females of reproductive potential to use an effective method of contraception during treatment with FERRIPROX and for at least six months after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with FERRIPROX and for at least three months after the last dose [see Use in Specific Populations ( 8.1 , 8.3 )] .

5.1 Agranulocytosis and Neutropenia Fatal agranulocytosis can occur with FERRIPROX use. FERRIPROX can also cause neutropenia, which may foreshadow agranulocytosis. Measure the absolute neutrophil count (ANC) before starting FERRIPROX therapy and monitor it weekly while on therapy. Interrupt FERRIPROX therapy if neutropenia develops (ANC < 1.5 x 10 9 /L). Interrupt FERRIPROX if infection develops and monitor the ANC frequently. Advise patients taking FERRIPROX to immediately interrupt therapy and report to their physician if they experience any symptoms indicative of infection. In pooled clinical trials, the incidence of agranulocytosis was 1.7% of patients. The mechanism of FERRIPROX-associated agranulocytosis is unknown. Agranulocytosis and neutropenia usually resolve upon discontinuation of FERRIPROX, but there have been reports of agranulocytosis leading to death. Implement a plan to monitor for and to manage agranulocytosis and neutropenia prior to initiating FERRIPROX treatment. For agranulocytosis (ANC < 0.5 x 10 9 /L): Consider hospitalization and other management as clinically appropriate. Do not resume FERRIPROX in patients who have developed agranulocytosis unless potential benefits outweigh potential risks. Do not rechallenge patients who have developed neutropenia with FERRIPROX unless potential benefits outweigh potential risks. For neutropenia (ANC < 1.5 x 10 9 /L and > 0.5 x 10 9 /L): Instruct the patient to immediately discontinue FERRIPROX and all other medications with a potential to cause neutropenia. 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 x 10 9 /L).

5.2 Liver Enzyme Elevations In clinical studies, 7.5% of 642 patients treated with FERRIPROX developed increased ALT values. Four (0.62%) FERRIPROX-treated subjects discontinued the drug due to increased serum ALT levels and 1 (0.16%) due to an increase in both ALT and AST. Monitor serum ALT values monthly during therapy with FERRIPROX and consider interruption of therapy if there is a persistent increase in the serum transaminase levels.

5.3 Zinc Deficiency Decreased plasma zinc concentrations have been observed on FERRIPROX therapy. Monitor plasma zinc, and supplement in the event of a deficiency.

6 ADVERSE REACTIONS 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 are (incidence ≥ 5%) nausea, vomiting and abdominal pain, alanine aminotransferase increased, arthralgia and neutropenia. ( 5.1 , 6 ) To report SUSPECTED ADVERSE REACTIONS, contact ApoPharma at: Telephone: 1-866-949-0995 or FDA at 1-800-FDA-1088 Email: medicalsafety@apopharma.com 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. Adverse reaction information for FERRIPROX represents the pooled data collected from 642 patients who participated in single arm or active-controlled clinical trials. The most serious adverse reaction reported in clinical trials with FERRIPROX was agranulocytosis [see Warnings and Precautions (5.1) ] . The most common adverse reactions reported during clinical trials were nausea, vomiting, abdominal pain, alanine aminotransferase increased, arthralgia and neutropenia. The table below lists the adverse drug reactions that occurred in at least 1% of patients treated with FERRIPROX in clinical trials. Table 2: Adverse drug reactions occurring in ≥ 1% of FERRIPROX-treated patients Body System (N=642) Adverse Reaction % Subjects BLOOD AND LYMPHATIC SYSTEM DISORDERS Neutropenia 6 Agranulocytosis 2 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 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. 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, 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.

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. Adverse reaction information for FERRIPROX represents the pooled data collected from 642 patients who participated in single arm or active-controlled clinical trials. The most serious adverse reaction reported in clinical trials with FERRIPROX was agranulocytosis [see Warnings and Precautions (5.1) ] . The most common adverse reactions reported during clinical trials were nausea, vomiting, abdominal pain, alanine aminotransferase increased, arthralgia and neutropenia. The table below lists the adverse drug reactions that occurred in at least 1% of patients treated with FERRIPROX in clinical trials. Table 2: Adverse drug reactions occurring in ≥ 1% of FERRIPROX-treated patients Body System (N=642) Adverse Reaction % Subjects BLOOD AND LYMPHATIC SYSTEM DISORDERS Neutropenia 6 Agranulocytosis 2 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 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.

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, 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.

<table width="100%"> <caption>Table 2: Adverse drug reactions occurring in &#x2265; 1% of FERRIPROX-treated patients</caption> <colgroup width="5%"/> <colgroup width="75%"/> <colgroup width="20%"/> <tbody> <tr> <th align="left" colspan="2"> <content styleCode="bold">Body System</content> </th> <th valign="middle"> <content styleCode="none">(N=642)</content> </th> </tr> <tr> <th align="left"> <content styleCode="bold"/> </th> <th align="left"> Adverse Reaction</th> <th valign="middle"> <content styleCode="bold">% Subjects</content> </th> </tr> <tr> <td colspan="3" styleCode="Toprule"> <content styleCode="bold">BLOOD AND LYMPHATIC SYSTEM DISORDERS</content> </td> </tr> <tr> <td> </td> <td align="left">Neutropenia</td> <td align="center" rowspan="1">6</td> </tr> <tr> <td colspan="1"/> <td align="left" colspan="1">Agranulocytosis</td> <td align="center" colspan="1">2</td> </tr> <tr> <td colspan="3"> <content styleCode="bold">GASTROINTESTINAL DISORDERS</content> </td> </tr> <tr> <td colspan="1" rowspan="1"> </td> <td align="left" colspan="1" rowspan="1">Nausea</td> <td align="center" colspan="1" rowspan="1">13</td> </tr> <tr> <td colspan="1" rowspan="1"> </td> <td align="left" colspan="1" rowspan="1">Abdominal pain/discomfort</td> <td align="center" colspan="1" rowspan="1">10</td> </tr> <tr> <td colspan="1" rowspan="1"> </td> <td align="left" colspan="1" rowspan="1"> Vomiting</td> <td align="center" colspan="1" rowspan="1">10</td> </tr> <tr> <td colspan="1" rowspan="1"> </td> <td align="left" colspan="1" rowspan="1">Diarrhea</td> <td align="center" colspan="1" rowspan="1">3</td> </tr> <tr> <td colspan="1" rowspan="1"> </td> <td align="left" colspan="1" rowspan="1">Dyspepsia</td> <td align="center" colspan="1" rowspan="1">2</td> </tr> <tr> <td colspan="3" rowspan="1"> <content styleCode="bold">INVESTIGATIONS</content> </td> </tr> <tr> <td colspan="1" rowspan="1"> </td> <td align="left" colspan="1" rowspan="1">Alanine Aminotransferase increased</td> <td align="center" colspan="1" rowspan="1">7</td> </tr> <tr> <td colspan="1" rowspan="1"> </td> <td align="left" colspan="1" rowspan="1">Weight increased</td> <td align="center" colspan="1" rowspan="1">2</td> </tr> <tr> <td colspan="1" rowspan="1"> </td> <td align="left" colspan="1" rowspan="1">Aspartate Aminotransferase increased</td> <td align="center" colspan="1" rowspan="1">1</td> </tr> <tr> <td colspan="3" rowspan="1"> <content styleCode="bold">METABOLISM AND NUTRITION DISORDERS</content> </td> </tr> <tr> <td colspan="1" rowspan="1"> </td> <td align="left" colspan="1" rowspan="1">Increased appetite</td> <td align="center" colspan="1" rowspan="1">4</td> </tr> <tr> <td colspan="1" rowspan="1"> </td> <td align="left" colspan="1" rowspan="1">Decreased appetite</td> <td align="center" colspan="1" rowspan="1">1</td> </tr> <tr> <td colspan="3" rowspan="1"> <content styleCode="bold">MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS</content> </td> </tr> <tr> <td colspan="1" rowspan="1"> </td> <td align="left" colspan="1" rowspan="1">Arthralgia</td> <td align="center" colspan="1" rowspan="1">10</td> </tr> <tr> <td colspan="1" rowspan="1"> </td> <td align="left" colspan="1" rowspan="1">Back pain</td> <td align="center" colspan="1" rowspan="1">2</td> </tr> <tr> <td colspan="1" rowspan="1"> </td> <td align="left" colspan="1" rowspan="1">Pain in extremity</td> <td align="center" colspan="1" rowspan="1">2</td> </tr> <tr> <td colspan="1" rowspan="1"> </td> <td align="left" colspan="1" rowspan="1">Arthropathy</td> <td align="center" colspan="1" rowspan="1">1</td> </tr> <tr> <td colspan="3" rowspan="1"> <content styleCode="bold">NERVOUS SYSTEM DISORDERS</content> </td> </tr> <tr> <td colspan="1" rowspan="1"> </td> <td align="left" colspan="1" rowspan="1">Headache</td> <td align="center" colspan="1" rowspan="1">2</td> </tr> </tbody> </table>