HIGHLIGHTS OF PRESCRIBING INFORMATION
`
`
` These highlights do not include all the information needed to use
` FERRIPROX Tablets safely and effectively. See full prescribing
`
`
`
`
` information for FERRIPROX Tablets.
`
`
`FERRIPROX® (deferiprone) tablets, for oral use
`
`
`
`
`
`Initial U.S. Approval: 2011
`
`
`
`•
`
`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)
`
`
`
`
`
`•
`
`
`•
`
`
`----------------------------RECENT MAJOR CHANGES-------------------------­
`
`
`Indications and Usage (1)
`04/2021
`
`
`
`-----------------------------INDICATIONS AND USAGE-------------------------­
`
`
`
`
`
`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. (1.1)
`
`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 sickle cell disease or other anemias. (1.2)
`
`
`Limitations 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. (1.3)
`
`
`------------------------DOSAGE AND ADMINISTRATION---------------------­
`
`
`
`
`25 mg/kg to 33 mg/kg actual body weight, orally, three times per day, for a
`
`
`
`
`
`
`total daily dose of 75 mg/kg to 99 mg/kg body weight. (2.1)
`
`
`
`------------------------------CONTRAINDICATIONS------------------------------­
`Hypersensitivity to deferiprone or to any of the excipients in the formulation.
`
`
`
`(4)
`
`
`
`
`------------------------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)
`
`
`
`
`•
`
`
`•
`
`
`
`
`•
`
`-----------------------------ADVERSE REACTIONS-------------------------------­
`The most common adverse reactions in patients with thalassemia
`
`
`•
`(incidence ≥ 6%) are nausea, vomiting, abdominal pain, arthralgia, ALT
`
`
`
`
`increased and neutropenia. (5.1, 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. (5.1, 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
`
`
`
`-------------------------------DRUG INTERACTIONS-----------------------------­
`
`
`
`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)
`
`
`•
`
`•
`
`------------------------USE IN SPECIFIC POPULATIONS----------------------­
`
`Lactation: Advise not to breastfeed. (8.2)
`
`
`
`See 17 for PATIENT COUNSELING INFORMATION and Medication
`
`Guide.
`
`
`
`
`-----------------------DOSAGE FORMS AND STRENGTHS-------------------­
`
`
`
`
`
`Tablets: 500 mg film-coated, with functional scoring. (3)
`
`Revised: 04/2021
`_______________________________________________________________________________________________________________________________________
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`7.2
`Effect of Other Drugs on FERRIPROX
`
`
`
`
`
`8 USE IN SPECIFIC POPULATIONS
`
`
`
`
`
`
`WARNING: AGRANULOCYTOSIS AND NEUTROPENIA
`8.1
`Pregnancy
`
`
`
`
`
`1
`INDICATIONS AND USAGE
`8.2
`Lactation
`
`
`
`
`8.3
`Females and Males of Reproductive Potential
`
`
`
`
`
`
`Transfusional Iron Overload in Patients with Thalassemia
`1.1
`8.4
`Pediatric Use
`
`
`
`
`
`Syndromes
`8.5 Geriatric Use
`
`
`
`
`
`
`
`Transfusional Iron Overload in Patients with Sickle Cell Disease or
`10 OVERDOSAGE
`
`
`
`
`Other Anemias
`11 DESCRIPTION
`
`
`
`
`
`Limitations of Use
`1.3
`12 CLINICAL PHARMACOLOGY
`
`
`
`
`
`2 DOSAGE AND ADMINISTRATION
`
`
`12.1 Mechanism of Action
`
`
`
`
`
`Recommended Dosage for FERRIPROX Tablets for Adult and
`2.1
`
`
`
`12.2 Pharmacodynamics
`
`
`
`
`Pediatric Patients with Transfusional Iron Overload due to
`
`
`12.3 Pharmacokinetics
`
`
`
`
`Thalassemia Syndromes, Sickle Cell Disease or Other Anemias
`
`
`
`13 NONCLINICAL TOXICOLOGY
`
`
`2.2 Monitoring Ferritin Levels to Assess Efficacy
`
`
`
`
`2.3
`Dosage Modification for Drug Interactions
`
`
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`
`
`
`14 CLINICAL STUDIES
`
`
`3 DOSAGE FORMS AND STRENGTHS
`
`
`
`4 CONTRAINDICATIONS
`
`
`14.1 Transfusional Iron Overload in Patients with Thalassemia
`
`
`
`5 WARNINGS AND PRECAUTIONS
`
`
`Syndromes
`
`14.2 Transfusional Iron Overload in Patients with Sickle Cell Disease
`
`
`
`
`
`5.1 Agranulocytosis and Neutropenia
`
`
`
`
`and Other Anemias
`
`5.2
`Liver Enzyme Elevations
`
`
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`
`
`5.3
`Zinc Deficiency
`
`
`
`17 PATIENT COUNSELING INFORMATION
`
`
`5.4
`Embryo-Fetal Toxicity
`
`
`
`6 ADVERSE REACTIONS
`
`
`
`* Sections or subsections omitted from the full prescribing information are not
`
`
`
`6.1 Clinical Trial Experience
`
`
`
`listed.
`6.2
`Postmarketing Experience
`
`
`
`7 DRUG INTERACTIONS
`
`
`7.1 Drugs Associated with Neutropenia or Agranulocytosis
`
`
`
`
`
`
`
`
`
`
`1.2
`
`
`
`
`
`Reference ID: 4788713
`
`
`
` 1
`
`

`

`_____________________________________________________________________________________________________________________________________
`FULL PRESCRIBING INFORMATION
`
`
`
`
`
`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)]
`
`
`•
`
` 1
`
`
`
`
`INDICATIONS AND USAGE
`
`
`
`
`
`
`
`
`Transfusional Iron Overload in Patients with Thalassemia Syndromes
`1.1
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`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.
`
`
`
`
`
`
`
`
`
`
`
`Transfusional Iron Overload in Patients with Sickle Cell Disease or Other Anemias
`1.2
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`FERRIPROX Tablets are indicated for the treatment of transfusional iron overload in adult and pediatric patients 8 years of age and
`
`
`
`
`
`
`older with sickle cell disease or other anemias.
`
`
`
`Limitations of Use
`1.3
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`• 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.
`
`
`2
`
`2.1
`
`
`
`DOSAGE AND ADMINISTRATION
`
`
`
`
`
`
`
`
`
`
`
`Recommended Dosage for FERRIPROX Tablets for Adult and Pediatric Patients with Transfusional Iron Overload
`
`
`
`
`
`
`due to Thalassemia Syndromes, Sickle Cell Disease or Other Anemias
`
`
`Starting Dosage
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`The recommended starting oral dosage of FERRIPROX Tablets is 25 mg/kg (actual body weight), three times per day for a total of
`
`
`
`
`
`
`
`
`
`
`75 mg/kg/day. Round dose to the nearest 250 mg (half-tablet).
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` Table 1a:
`
`
`
` Tablet requirement to achieve a 25 mg/kg dose (rounded to the nearest half-tablet) for
` administration three times a day.
`
`
`
`
`
` Body Weight
`
` Dose (mg)
`
`
`
` Number of 500 mg tablets
` (kg)
`
`
` 500
`
` 20
`
` 1
`
` 750
`
` 30
`
` 1.5
`
` 1,000
`
` 40
`
` 2
`
` 1,250
`
` 50
`
` 2.5
`
` 1,500
`
` 60
`
` 3
`
` 1,750
`
` 70
`
` 3.5
`
` 2,000
`
` 80
`
` 4
`
`
` 2,250
`
` 90
` 4.5
`
`
`
` 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.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4788713
`
`
`
` 2
`
`

`

`
`
`
`
` Table 1b:
`
`
`
`
` Tablet requirement to achieve a 33 mg/kg dose (rounded to the nearest half-tablet) for
` administration three times a day.
`
`
`
`
`
` Body Weight
`
`
`
` Number of 500 mg tablets
`
` Dose (mg)
` (kg)
`
`
` 1.5
`
` 660
`
` 20
`
`
` 990
`
` 30
` 2
`
` 2.5
`
` 1,320
`
` 40
`
` 3.5
`
` 1,650
`
` 50
`
`
` 1,980
`
` 60
` 4
`
` 4.5
`
` 2,310
`
` 70
`
` 5.5
`
` 2,640
`
` 80
`
`
` 2,970
`
` 90
` 6
`
`
`
`
`
` For patients who have trouble swallowing tablets, consider the use of FERRIPROX Oral Solution (see the prescribing information for
`
`
` FERRIPROX Oral Solution).
`
`
`
`
`
`
` Monitoring Ferritin Levels to Assess Efficacy
`
`
` 2.2
`
`
`
`
`
`
`
`
`
`
`
`
` 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.
`
`
`
`
`
`
` Dosage Modification for Drug Interactions
`
` 2.3
`
`
`
`
`
`
`
`
` 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)].
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Dosage Adjustments
`
`
`
`
`
`
`
`
`
`
`
`
`
`Tailor dosage adjustments to the individual patient’s response and therapeutic goals (maintenance or reduction of body iron burden).
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`The maximum oral dosagee is 33 mg/kg (actual body weight), three times per day for a total of 99 mg/kg/day.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` 3
`
`
`
`
` DOSAGE FORMS AND STRENGTHS
` Tablets: 500 mg film-coated, capsule-shaped, white to off-white tablets with functional scoring, and imprinted with “APO” score
`
`
`
`
` “500” on one side and plain on the other.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` 4
`
`
` CONTRAINDICATIONS
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` FERRIPROX is contraindicated in patients with known hypersensitivity to deferiprone or to any of the excipients in the formulation.
`
`
`
`
`
` 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)].
`
`
`
`
`
`
`
`
`
`
`
` 5
`
`
` WARNINGS AND PRECAUTIONS
`
` Agranulocytosis and Neutropenia
`
`
`
`
` 5.1
`
`
`
`
`
`
`
` 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 109/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.
`
`
`
`The incidence of agranulocytosis was 1.7% of patients in pooled clinical trials of 642 patients with thalassemia syndromes and 1.5%
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`of patients in pooled clinical trials of 196 patients with sickle cell disease or other anemias. 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.
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4788713
`
`
`
` 3
`
`

`

`Implement a plan to monitor for and to manage agranulocytosis and neutropenia prior to initiating FERRIPROX treatment.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`For agranulocytosis (ANC < 0.5 x 109/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 109/L and > 0.5 x 109/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 109/L).
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Liver Enzyme Elevations
`5.2
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`In pooled clinical trials, 7.5% of 642 patients with thalassemia syndromes 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. In pooled clinical trials, 7.7% of 196 patients with sickle cell disease or other anemias treated with
`
`
`FERRIPROX developed increased ALT values.
`
`
`
`
`
`
`
`
`
`
`
`
`
`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.
`
`Zinc Deficiency
`5.3
`
`
`
`
`
`
`
`
`
`
`
`
`Decreased plasma zinc concentrations have been observed on FERRIPROX therapy. Monitor plasma zinc, and supplement in the
`
`
`
`event of a deficiency.
`
`
`
`Embryo-Fetal Toxicity
`5.4
`
`
`
`
`
`
`
`
`
`
`
`
`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 embryo-fetal death and malformations
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`at doses lower than equivalent human clinical doses. Advise pregnant women and females of reproductive potential of the potential
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`risk to the fetus [see Use in Specific Populations (8.1)].
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`Advise females of reproductive potential to use an effective method of contraception during treatment with FERRIPROX and for at
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`least six months after the last dose. Advise males with female partners of reproductive potential to use effective contraception during
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`treatment with FERRIPROX and for at least three months after the last dose [see Use in Specific Populations (8.1, 8.3)].
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`6
`ADVERSE REACTIONS
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`The following clinically significant adverse reactions are described below and elsewhere in the labeling:
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`• Agranulocytosis and Neutropenia [see Warnings and Precautions (5.1)]
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`• Liver Enzyme Elevations [see Warnings and Precautions (5.2)]
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`• Zinc Deficiency [see Warnings and Precautions (5.3)]
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`Clinical Trial Experience
`6.1
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`Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug
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`cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
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`The following adverse reaction information represents the pooled data collected from single arm or active-controlled clinical trials
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`with FERRIPROX Tablets (deferiprone) (three times a day) or FERRIPROX Oral Solution (deferiprone).
`
`Thalassemia Syndromes
`
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`The safety of FERRIPROX was evaluated in the pooled clinical trial database [see Clinical Studies (14.1)]. Patients received
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`FERRIPROX Tablets (three times a day) or FERRIPROX Oral Solution. FERRIPROX was administered orally three times a day
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`(total daily dose either 50, 75, or 99 mg/kg), N=642. Among 642 patients receiving FERRIPROX , 492 (76.6%) were exposed for
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`6 months or longer and 365 (56.9%) were exposed for greater than one year.
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`The median age of patients who received FERRIPROX was 19 years (range 1, 77 years); 50.2% female; 71.2% White, 17.8% Asian,
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`9.2% Unknown, 1.2% Multi-racial and 0.6% Black.
`
`Reference ID: 4788713
`
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` 4
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`

`

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` 6
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` 2
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` 13
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` 10
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` 10
` 3
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` 2
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` 7
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` 2
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` 1
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` 4
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` 1
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`The most serious adverse reaction reported in clinical trials with FERRIPROX was agranulocytosis [see Warnings and Precautions
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`(5.1)].
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`The most common adverse reactions (≥6%) reported during clinical trials were nausea, vomiting, abdominal pain, arthralgia, alanine
`
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`aminotransferase increased and neutropenia.
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`The table below lists the adverse drug reactions that occurred in at least 1% of patients treated with FERRIPROX in clinical trials in
`
`
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`patients with thalassemia syndromes.
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`Table 2: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
`
`
`
` Agranulocytosis
` GASTROINTESTINAL DISORDERS
`
`
`
` Nausea
`
` Abdominal pain/discomfort
`
` Vomiting
`
`
` Diarrhea
`
`
`
` Dyspepsia
` INVESTIGATIONS
`
`
` Alanine aminotransferase increased
`
` Weight increased
`
`
`
` Aspartate aminotransferase increased
` METABOLISM AND NUTRITION
`
` DISORDERS
`
`
`
` Increased appetite
`
`
`
` Decreased appetite
`
` MUSCULOSKELETAL AND
`
`
`
` CONNECTIVE TISSUE DISORDERS
`
`
` 10
`
`
` Arthralgia
` 2
`
`
`
` Back pain
`
`
` 2
`
` Pain in extremity
`
`
`
` 1
`
` Arthropathy
`
`
` NERVOUS SYSTEM DISORDERS
`
` 2
`
`
`
` Headache
`
`
`
`
`
`
`
`
`
`
` 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.
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` Chromaturia (reddish/brown discoloration of the urine) is a result of the excretion of iron in the urine.
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` Sickle Cell Disease or Other Anemias
`
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`The safety of FERRIPROX compared to deferoxamine was evaluated in LA38-0411 [see Clinical Studies (14.2)]. Patients received
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`FERRIPROX Tablets or FERRIPROX Oral Solution orally three times a day (total daily dose 75-99 mg/kg/day) n=152) or the control
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`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.
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`Among 152 patients receiving FERRIPROX, 120 (78.9%) were exposed for 6 months or longer and 17 (11.2%) were exposed for
`
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`greater than one year.
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`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
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`5.9% Multi-racial.
`
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`The most common adverse reactions (≥6%) reported during clinical trials in patients with SCD or other anemias were pyrexia,
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`abdominal pain, bone pain, headache, vomiting, pain in extremity, sickle cell anemia with crisis, back pain, alanine aminotransferase
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`(ALT) increased, aspartate aminotransferase (AST) increased, arthralgia, oropharyngeal pain, nasopharyngitis, neutrophil count
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`decreased, cough and nausea.
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`The table below lists the adverse reactions (irrespective of a causal assessment; adverse events) of interest that occurred in patients
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`treated with FERRIPROX in clinical trials in subjects with sickle cell disease or other anemias.
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`Reference ID: 4788713
`
`
`
` 5
`
`

`

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`Table 3:Adverse reactions occurring in ≥5% of FERRIPROX-treated patients with sickle cell disease or other anemias
` DEFEROXAMINE
`
`FERRIPROX
`
`
` (N=152)
` (N=76)
`
` % Patients
`
` % Patients
`
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`
`
`
`
`
`
`
`
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`
`
`
`
`
`
`
`
`
`
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` 17
`
`
` 26
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` 19
`
` 7
`
` 5
`
`
`
` 28
`
` 5
`
`
` 9
`
` 5
`
`
` 12
`
` 11
`
` 8
`
`
`
` 25
`
` 18
`
` 13
`
` 10
`
`
` 20
`
`
`
` 10
`
` 8
`
`
` 13
`
`
` 13
`
` 11
`
` 9
`
` 8
`
`
`
` 33
`
` 4
`
`
` 12
`
` 3
`
`
` 0
`
` 0
`
` 4
`
`
`
` 34
`
` 15
`
` 18
`
` 8
`
`
` 13
`
`
`
` 15
`
` 15
`
`
`Body System
`
` Adverse Reaction
`
` BLOOD AND LYMPHATIC SYSTEM
`
`
` DISORDERS
`
`
`
`
` Sickle cell anemia with crisis
`
`
`
` GASTROINTESTINAL DISORDERS
`
`
`
`
` Abdominal pain*
`
` Vomiting
`
`
` Nausea
`
`
`
` Diarrhea
` GENERAL DISORDERS AND
`
` ADMINISTRATION SITE
`
`
` CONDITIONS
`
`
` Pyrexia
`
` Pain
`
`
`
` INFECTIONS AND INFESTATIONS
`
` Nasopharyngitis
`
`
`
` Upper respiratory tract infection
`
`
` INVESTIGATIONS
`
` Alanine aminotransferase increased
`
`
` Aspartate aminotransferase increased
`
` Neutrophil count decreased
`
`
`
` MUSCULOSKELETAL AND
`
` CONNECTIVE TISSUE DISORDERS
`
`
`
`
` Bone pain
`
` Pain in extremity
`
`
`
` Back pain
`
`
`
` Arthralgia
`
` NERVOUS SYSTEM DISORDERS
`
`
`
` Headache
`
`
` RESPIRATORY, THORACIC AND
`
` MEDIASTINAL DISORDERS
`
` Oropharyngeal pain
`
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`
`
` Cough
` *Grouped term
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`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
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`increase in the following adverse reactions as compared to adults: abdominal pain, neutrophil count decreased, bone pain and
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`oropharyngeal pain.
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`Postmarketing Experience
`6.2
`
`
`
`The following additional adverse reactions have been reported in patients receiving FERRIPROX. Because these reactions are
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`reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or to establish a
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`causal relationship to drug exposure.
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`Blood and lymphatic system disorders: thrombocytosis, pancytopenia.
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`Cardiac disorders: atrial fibrillation, cardiac failure.
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`Congenital, familial and genetic disorders: hypospadias.
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`Eye disorders: diplopia, papilledema, retinal toxicity.
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`Gastrointestinal disorders: enterocolitis, rectal hemorrhage, gastric ulcer, pancreatitis, parotid gland enlargement.
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`General disorders and administration site conditions: chills, edema peripheral, multi-organ failure.
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`Reference ID: 4788713
`
`
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` 6
`
`

`

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`Hepatobiliary disorders: jaundice, hepatomegaly.
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`Immune system disorders: anaphylactic shock, hypersensitivity.
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`Infections and infestations: cryptococcal cutaneous infection, enteroviral encephalitis, pharyngitis, pneumonia, sepsis, furuncle,
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`infectious hepatitis, rash pustular, subcutaneous abscess.
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`Investigations: blood bilirubin increased, blood creatinine phosphokinase increased.
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`Metabolism and nutrition disorders: metabolic acidosis, dehydration.
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`Musculoskeletal and connective tissue disorders: myositis, chondropathy, trismus.
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`Nervous system disorders: cerebellar syndrome, cerebral hemorrhage, convulsion, gait disturbance, intracranial pressure increased,
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`psychomotor skills impaired, pyramidal tract syndrome, somnolence.
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`Psychiatric disorders: bruxism, depression, obsessive-compulsive disorder.
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`Renal disorders: glycosuria, hemoglobinuria.
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`Respiratory, thoracic and mediastinal disorders: acute respiratory distress syndrome, epistaxis, hemoptysis, pulmonary embolism.
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`Skin, subcutaneous tissue disorders: hyperhidrosis, periorbital edema, photosensitivity reaction, pruritis, urticaria, rash, Henoch-
`
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`Schönlein purpura.
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`Vascular disorders: hypotension, hypertension.
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`DRUG INTERACTIONS
`7
`
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`
`Drugs Associated with Neutropenia or Agranulocytosis
`7.1
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`Avoid co-administration of FERRIPROX with other drugs known to be associated with neutropenia or agranulocytosis. If co-
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`administration is unavoidable, closely monitor the absolute neutrophil count [see Warnings and Precautions (5.1)].
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`
`Effect of Other Drugs on FERRIPROX
`7.2
`
`
`UDP-Glucuronosyltransferases (UGT)
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`
`
`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)].
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`Polyvalent Cations
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`Deferiprone has the potential to bind polyvalent cations (e.g., iron, aluminum, and zinc); allow at least a 4-hour interval between
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`FERRIPROX and other medications (e.g., antacids), or supplements containing these polyvalent cations [see Dosage and
`
`
`
`Administration (2.2)].
`
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`
`
`USE IN SPECIFIC POPULATIONS
`8
`
`
`Pregnancy
`8.1
`
`
`Risk Summary
`
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`
`
`In animal reproduction studies, oral administration of deferiprone to pregnant rats and rabbits during organogenesis at doses 33% and
`
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`49%, respectively, of the maximum recommended human dose (MRHD) resulted in structural abnormalities, embryo-fetal mortality
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`and alterations to growth (see Data). The limited available data from deferiprone use in pregnant women are insufficient to inform a
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`drug-associated risk of major birth defects and miscarriage. Based on evidence and developmental toxicity in animal studies,
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`FERRIPROX can cause fetal harm when administered to a pregnant woman. Advise pregnant women and females of reproductive
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`
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`potential of the potential risk to a fetus.
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`The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a
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`background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of
`
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`
`
`major birth defects and of miscarriage is 2-4% and 15-20%, respectively.
`
`Data
`
`Human Data
`
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`
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`
`
`
`
`
`Post-marketing data available from 39 pregnancies of deferiprone-treated patients and 10 pregnancies of partners of deferiprone­
`
`
`
`
`treated patients are as follows:
`
`
`
` 7
`
`Reference ID: 4788713
`
`

`

`
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`
`
`Of the 39 pregnancies in deferiprone-treated patients, 23 resulted in healthy newborns, 6 ended in spontaneous abortion, 9 had
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`
`
`
`unknown outcomes, and 1 infant was born with anal atresia, nephroptosis, ventricular septal defect, hemivertebra and urethral fistula.
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`
`Of the 10 pregnancies in partners of deferiprone-treated patients, 5 resulted in healthy newborns, 1 resulted in a healthy newborn with
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`
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`slight hypospadias, 1 was electively terminated, 1 resulted in the intrauterine death of twins, and 2 had unknown outcomes.
`
`
`Animal Data
`
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`
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`
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`
`
`During organogenesis, pregnant rats and rabbits received deferiprone at oral doses of 0, 30, 80 or 200 mg/kg/day, and 0, 10, 50, or
`
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`
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`
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`150 mg/kg/day, respectively. The daily dose was administered as two equal divided doses approximately 7 hours apart. Doses of
`
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`
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`
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`
`
`200 mg/kg/day in rats and 150 mg/kg/day in rabbits, approximately 33% and 49% of the MRHD, respectively, resulted in increased
`
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`
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`post-implantation loss and reduced fetal weights in the presence of maternal toxicity (reduced maternal body weight and body weight
`
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`
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`gain in both rats and rabbits; abnormal large placenta at low incidence in rats). The 200 mg/kg/day dose in rats resulted in external,
`
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`
`
`
`
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`
`
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`
`
`
`visceral and skeletal fetal malformations such as cranial malformations, cleft palate, limb malrotation, anal atresia, internal
`
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`
`
`
`
`
`
`
`
`hydrocephaly, anophthalmia and fused bones. The dose of 150 mg/kg/day in rabbits resulted in external fetal malformations (partially
`
`opened eyes) and minor blood vessel and skeletal variations.
`
`
`
`
`
`
`In rats, malformations including micrognathia and persistent ductus arteriosus could be observed in the absence of maternal toxicity at
`
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`
`
`
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`
`
`doses equal to or greater than 30 and 80 mg/kg/day, approximately 5% and 13% of the MHRD, respectively.
`
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`
`
`
`Lactation
`8.2
`
`
`Risk Summary
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`There is no information regarding the presence of deferiprone in human milk, the effects on the breastfed child, or the effects on milk
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`production.
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`Because of the potential for serious adverse reactions in the breastfed child, including the potential for tumorigenicity shown for
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`deferiprone in animal studies, advise patients that breastfeeding is not recommended during treatment with FERRIPROX, and for at
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`least 2 weeks after the last dose.
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`Females and Males of Reproductive Potential
`8.3
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`Pregnancy Testing
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`Pregnancy testing is recommended for females of reproductive potential prior to initiating FERRIPROX.
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`Contraception
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`Females
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`FERRIPROX can cause embryo-fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)]. Advise
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`female patients of reproductive potential to use effective contraception during treatment with FERRIPROX and for at least 6 months
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