`
`These highlights do not include all the information needed to use
`
`
` FERRIPROX safely and effectively. See full prescribing information for
`
`
`
`
`
` FERRIPROX.
`
`
`FERRIPROX® (deferiprone) tablets, for oral use
`
`
`
`
`
`
`Initial U.S. Approval: 2011
`
`
`
`•
`
`
`
`WARNING: AGRANULOCYTOSIS/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 the ANC weekly 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)
`
`
`
`
`
`
`•
`
`
`•
`
`
`
`-----------------------------INDICATIONS AND USAGE-------------------------
`FERRIPROX® (deferiprone) is an iron chelator indicated for the treatment of
`
`
`
`
`
`
`patients with transfusional iron overload due to thalassemia syndromes when
`
`
`
`
`
`current chelation therapy is inadequate. (1)
`
`
`Approval is based on a reduction in serum ferritin levels. There are no
`
`
`
`controlled trials demonstrating a direct treatment benefit, such as
`
`
`
`improvement in disease-related symptoms, functioning, or increased survival
`
`
`
`(1).
`
`Limitation of Use
`
`
`Safety and effectiveness have not been established for the treatment of
`
`
`•
`transfusional iron overload in patients with other chronic anemias. (1)
`
`
`
`
`------------------------DOSAGE AND ADMINISTRATION---------------------
`
`25 mg/kg to 33 mg/kg body weight, orally, three times per day, for a
`
`
`
`
`
`•
`total daily dose of 75 mg/kg to 99 mg/kg body weight. (2)
`
`
`
`
`
`
`
`
`
`-----------------------DOSAGE FORMS AND STRENGTHS-------------------
`
`
`500 mg film-coated tablets with a functional score. (3)
`
`
`
`
`•
`
`------------------------------CONTRAINDICATIONS------------------------------
`
`Hypersensitivity to deferiprone or to any of the excipients in the
`
`
`
`•
`formulation. (4)
`
`
`
`
`
`------------------------WARNINGS AND PRECAUTIONS----------------------
`
`
`If infection occurs while on Ferriprox, interrupt therapy and monitor the
`
`
`
`
`
`
`
`•
`ANC more frequently. (5.1)
`
`
`Ferriprox can cause fetal harm. Women should be advised of the
`
`
`
`potential hazard to the fetus and to avoid pregnancy while on this drug.
`
`
`
`
`
`(5.2)
`
`
`
`•
`
`-----------------------------ADVERSE REACTIONS-------------------------------
`
`The most common adverse reactions are (incidence ≥ 5%) chromaturia,
`
`
`
`
`
`
`
`•
`nausea, vomiting and abdominal pain, alanine aminotransferase
`
`
`increased, arthralgia and neutropenia. (5.1, 6)
`
`
`
`
`
`To report SUSPECTED ADVERSE REACTIONS, contact ApoPharma
`
`Inc. at: Telephone: 1-866-949-0995
`
`
`
`Email: medicalsafety@apopharma.com or FDA at 1-800-FDA-1088 or
`
`
`
`www.fda.gov/medwatch
`
`
`-------------------------------DRUG INTERACTIONS-----------------------------
`
`
`Avoid concomitant use with other drugs known to be associated with
`
`
`
`
`•
`neutropenia or agranulocytosis; however, if this is not possible, closely
`
`
`monitor the absolute neutrophil count. (7.1)
`
`
`
`Allow at least a 4-hour interval between Ferriprox and mineral
`
`
`supplements, and antacids that contain polyvalent cations (e.g., iron,
`
`
`
`
`aluminum, and zinc). (7.3)
`
`
`
`
`
`•
`
`------------------------USE IN SPECIFIC POPULATIONS----------------------
`
`Safety and efficacy of Ferriprox has not been evaluated in patients with
`
`
`
`•
`severe hepatic impairment. (8.7)
`
`
`Nursing mothers: Discontinue the use of Ferriprox or discontinue
`
`nursing. (8.3)
`
`See 17 for PATIENT COUNSELING INFORMATION and Medication
`
`
`
`
`Guide.
`
`
`
`•
`
`
`
`Revised: 02/2015
`
`
`_______________________________________________________________________________________________________________________________________
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`WARNING: AGRANULOCYTOSIS/ NEUTROPENIA
`
`
`1
`INDICATIONS AND USAGE
`
`
`2 DOSAGE AND ADMINISTRATION
`
`
`Interactions with Foods, Vitamins and Antacids
`2.1
`
`
`
`3 DOSAGE FORMS AND STRENGTHS
`
`
`4 CONTRAINDICATIONS
`
`
`5 WARNINGS AND PRECAUTIONS
`
`
`5.1 Agranulocytosis/Neutropenia
`
`
`
`5.2
`Embryofetal Toxicity
`
`
`
`
`5.3
`Laboratory Tests
`
`
`
`6 ADVERSE REACTIONS
`
`
`6.1 Clinical Trial Experience
`
`
`
`6.2
`Postmarketing Experience
`
`
`
`7 DRUG INTERACTIONS
`
`
`7.1 Drugs Associated with Neutropenia or Agranulocytosis
`
`
`
`
`
`
`7.2 UDP-Glucuronosyltransferases (UGTs)
`
`
`
`7.3
`Polyvalent Cations
`
`
`
`
`8 USE IN SPECIFIC POPULATIONS
`
`
`8.1
`Pregnancy
`
`
`
`
`_____________________________________________________________________________________________________________________________________
`
`8.3 Nursing Mothers
`
`
`
`8.4
`Pediatric Use
`
`
`
`8.5 Geriatric Use
`
`
`
`8.6 Renal Impairment
`
`
`
`8.7 Hepatic Impairment
`
`
`
`10 OVERDOSAGE
`
`
`11 DESCRIPTION
`
`
`12 CLINICAL PHARMACOLOGY
`
`
`12.1 Mechanism of Action
`
`
`
`12.2 Pharmacodynamics
`
`
`
`12.3 Pharmacokinetics
`
`
`
`13 NONCLINICAL TOXICOLOGY
`
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`
`
`
`14 CLINICAL STUDIES
`
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`
`
`17 PATIENT COUNSELING INFORMATION
`
`
`
`* Sections or subsections omitted from the Full Prescribing Information are not
`
`
`
`
`listed.
`
`
`
`
`
`Reference ID: 3706686
`
`
`
` 1
`
`
`
`
`FULL PRESCRIBING INFORMATION
`
`
`
`WARNING: AGRANULOCYTOSIS/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 the ANC weekly 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)]
`
`
`
`
`
`
`
`•
`
`•
`
`INDICATIONS AND USAGE
`1
`
`
`FERRIPROX® (deferiprone) is indicated for the treatment of patients with transfusional iron overload due to thalassemia syndromes when current chelation therapy is
`
`
`
`
`
`
`
`
`
`
`inadequate.
`
`Approval is based on a reduction in serum ferritin levels. There are no controlled trials demonstrating a direct treatment benefit, such as improvement in disease-related
`
`
`
`
`
`
`
`
`symptoms, functioning, or increased survival [see Clinical Studies (14)].
`
`
`
`Limitation of Use:
`
`
`Safety and effectiveness have not been established for the treatment of transfusional iron overload in patients with other chronic anemias.
`
`
`
`
`
`
`•
`
`DOSAGE AND ADMINISTRATION
`2
`
`
`The recommended initial dose of Ferriprox is 25 mg/kg, orally, three times per day for a total of 75 mg/kg/day. The maximum dose is 33 mg/kg, three times per day for
`
`
`
`
`
`
`
`
`
`
`
`
`
`a total of 99 mg/kg/day.
`
`Dose adjustments up to 33 mg/kg, orally, three times per day should be tailored to the individual patient’s response and therapeutic goals (maintenance or reduction of
`
`
`
`
`
`
`
`body iron burden). The maximum recommended total daily dose is 99 mg/kg per day. The dose should be rounded by the prescriber to the nearest 250 mg (half-tablet).
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` Table 1a: Tablet requirement to achieve a 25 mg/kg
`
`
`
`
`
` (rounded to the nearest half-tablet) dose level for
` administration three times a day.
`
` Number of tablets
`
`
` Dose (mg)
`
` Body
`
`
` Weight
`
` (kg)
`
` 20
`
` 30
`
` 40
`
` 50
`
` 60
`
` 70
`
` 80
`
` 90
`
`
`
`
`
`
` 500
`
` 750
`
` 1000
`
` 1250
`
` 1500
`
` 1750
`
` 2000
`
` 2250
`
` 1
`
`
` 1.5
`
` 2
`
` 2.5
`
` 3
`
` 3.5
`
` 4
` 4.5
`
`
`
`
` Table 1b: Tablet requirement to achieve 33 mg/kg
`
`
`
`
`
`
` (rounded to the nearest half-tablet) dose level for
` administration three times a day.
`
` Number of tablets
`
`
` Dose (mg)
`
`
`
` Body
`
`
` Weight
`
` (kg)
`
` 1.5
`
` 660
`
` 20
`
`
` 990
`
` 30
` 2
`
` 2.5
`
` 1320
`
` 40
`
` 3.5
`
` 1650
`
` 50
`
`
` 1980
`
` 60
` 4
`
` 4.5
`
` 2310
`
` 70
`
` 5.5
`
` 2640
`
` 80
`
`
` 2970
`
` 90
` 6
`
`
`
`
` Monitor serum ferritin concentration every two to three months to assess the effects of Ferriprox on body iron stores. Dose adjustments should be tailored to the
`
` individual patient’s response and therapeutic goals (maintenance or reduction of body iron burden). If the serum ferritin falls consistently below 500 mcg/L, consider
`
`
`
`
`
`
`
` temporarily interrupting Ferriprox therapy.
`
`
`
`
` Interactions with Foods, Vitamins and Antacids
`
` 2.1
` Allow at least a 4-hour interval between Ferriprox and other medications or supplements containing polyvalent cations such as iron, aluminum, and zinc [see Drug
`
`
`
` Interactions (7.3)].
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 3706686
`
`
`
` 2
`
`
`
` 3
`
`
` DOSAGE FORMS AND STRENGTHS
`
`
` 500 mg film-coated tablets with a functional score.
`
`
`
`
` 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/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 the ANC weekly on therapy.
`
`
`Interrupt Ferriprox therapy if neutropenia develops (ANC < 1.5 x 109/L).
`
`
`
`
`
`
`
`
`
`
`
`Interrupt Ferriprox if infection develops, and monitor the ANC more 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/neutropenia prior to initiating Ferriprox treatment.
`
`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).
`
`
`
`
`
`
`
`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 develop
`
`
`
`
`
`neutropenia with Ferriprox unless potential benefits outweigh potential risks.
`
`
`
`Embryofetal Toxicity
`5.2
`
`
`
`
`
`
`
`Based on evidence of genotoxicity and developmental toxicity in animal studies, Ferriprox can cause fetal harm when administered to a pregnant woman. 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. If Ferriprox is used during pregnancy or if the patient becomes pregnant while taking Ferriprox, the patient should be apprised of the potential hazard to the fetus.
`
`
`
`
`
`Women of reproductive potential should be advised to avoid pregnancy when taking Ferriprox [see Use in Specific Populations (8.1) and Nonclinical Toxicology
`
`
`
`(13.1)].
`
`Laboratory Tests
`5.3
`
`
`
`
`Serum Liver Enzyme Activities
`
`
`
`
`
`
`
`
`
`
`
`
`In clinical studies, 7.5% of 642 subjects 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.
`
`Plasma Zinc Concentration
`
`
`
`
`
`
`
`
`
`Decreased plasma zinc concentrations have been observed on Ferriprox therapy. Monitor plasma zinc, and supplement in the event of a deficiency.
`
`
`
`ADVERSE REACTIONS
`6
`
`
`Clinical Trial Experience
`6.1
`
`
`
`
`
`
`The following adverse reactions are also discussed in other sections of the labeling: Agranulocytosis/Neutropenia [see Warnings and Precautions (5.1)]. Elevated ALT
`
`
`
`
`
`
`(5.3), Decreased plasma zinc concentrations (5.3).
`
`
`
`
`
`
`
`
`
`
`
`
`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 studies.
`
`
`
`
`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 chromaturia, 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.
`
`
`
`
`
`
` 3
`
`Reference ID: 3706686
`
`
`
`
`
`
` % Subjects
`
`
`
` 6.2
`
` 1.7
`
`
` 12.6
`
` 10.4
`
` 9.8
`
` 3.0
`
` 2.0
`
`
` 7.5
`
` 7.3
`
` 1.9
`
` 1.2
`
`
` 4.0
`
` 1.1
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Table 2: Adverse drug reactions occurring in ≥ 1% of 642 Ferriprox-treated patients
`
`
`
` Body System
`
`
` Preferred Term
`
` BLOOD AND LYMPHATIC SYSTEM
` DISORDERS
`
` Neutropenia
`
`
`
`
` Agranulocytosis
` GASTROINTESTINAL DISORDERS
`
`
` Nausea
`
` Abdominal pain/discomfort
`
`
` Vomiting
`
`
` Diarrhea
`
`
` Dyspepsia
` INVESTIGATIONS
`
`
` Alanine Aminotransferase increased
`
`
`
` Neutrophil count decreased
`
` Weight increased
`
`
`
` Aspartate Aminotransferase increased
` METABOLISM AND NUTRITION DISORDERS
`
`
` Increased appetite
`
`
` Decreased appetite
` MUSCULOSKELETAL AND CONNECTIVE
`
` TISSUE DISORDERS
`
`
`
` Arthralgia
`
` 9.8
`
` Back pain
`
`
` 2.0
`
` Pain in extremity
`
`
` 1.9
`
` Arthropathy
`
`
` 1.4
` NERVOUS SYSTEM DISORDERS
`
`
`
`
` 2.5
` Headache
` URINARY DISORDERS
`
`
`
`
` 14.6
` Chromaturia
` 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 the iron in the urine.
`
`
` Postmarketing Experience
`
`
` 6.2
`
`
`
`
`
` 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.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 3706686
`
`
`
` 4
`
`
`
`
`
`
`
`
`
`
`
` DRUG INTERACTIONS
` 7
`
`
`
`
`
` Drugs Associated with Neutropenia or Agranulocytosis
` 7.1
` Avoid concomitant use of Ferriprox with other drugs known to be associated with neutropenia or agranulocytosis; however, if this is not possible, closely monitor the
`
`
`
`
`
`
` absolute neutrophil count [see Warnings and Precautions (5.1)].
`
`
`
`
` UDP-Glucuronosyltransferases (UGTs)
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` 7.2
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` Deferiprone is primarily eliminated via metabolism to the 3-O-glucuronide. In vitro studies suggest that UDP glucuronosyltransferase (UGT) 1A6 is primarily
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` responsible for the glucuronidation of deferiprone which can be reduced up to 78% in the presence of the UGT1A6 inhibitor phenylbutazone. However, the clinical
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` significance of coadministration of Ferriprox with a UGT1A6 inhibitor (e.g. diclofenac, probenecid, or silymarin (milk thistle)) on the systemic exposure of deferiprone
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` has not been determined. Closely monitor patients for adverse reactions that may require downward dose titration or interruption when Ferriprox is concomitantly
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` administered with a UGT1A6 inhibitor.
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` Polyvalent Cations
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` 7.3
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` Concurrent use of Ferriprox with foods, mineral supplements, and antacids that contain polyvalent cations has not been studied. However, since deferiprone has the
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` 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
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` supplements containing these polyvalent cations [see Dosage and Administration (2)].
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` 8
` USE IN SPECIFIC POPULATIONS
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` Pregnancy
` 8.1
` Pregnancy Category D [see Warnings and Precautions (5.2), Nonclinical Toxicology (13.1)]
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` Risk Summary
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` Based on evidence of genotoxicity and developmental toxicity in animal studies, Ferriprox can cause fetal harm when administered to a pregnant woman. In animal
` studies, administration of deferiprone during the period of organogenesis resulted in embryofetal death and malformations at doses lower than equivalent human clinical
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` doses. There are no studies in pregnant women, and available human data are limited. If Ferriprox is used during pregnancy or if the patient becomes pregnant while
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` taking Ferriprox, the patient should be apprised of the potential hazard to the fetus.
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` Animal Data
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` 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
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` surface area. No maternal toxicity was evident at these doses.
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` Embryofetal lethality and maternal toxicity occurred in pregnant rabbits given 100 mg/kg/day deferiprone orally during the period of organogenesis. This dose is
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` equivalent to 32% of the MRHD based on body surface area.
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` Nursing Mothers
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` 8.3
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` It is not known whether deferiprone is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for adverse reactions in
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` nursing infants from Ferriprox, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to
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` the mother.
` Pediatric Use
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` 8.4
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` The safety and effectiveness of Ferriprox tablets for oral use in pediatric patients have not been established.
` Geriatric Use
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` 8.5
` Safety and effectiveness in elderly individuals have not been established. In general, dose selection for an elderly patient should be cautious, usually starting at the low
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` end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
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` 8.6
` Renal Impairment
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` An open-label, non-randomized, parallel group clinical study was conducted to evaluate the effect of impaired renal function on the safety, tolerability, and
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` pharmacokinetics of a single 33 mg/kg oral dose of Ferriprox. Subjects were categorized into 4 groups based on estimated glomerular filtration rate (eGFR): healthy
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`volunteers (eGFR ≥ 90 mL/min/1.73m2), mild renal impairment (eGFR 60–89 mL/min/1.73m2), moderate renal impairment (eGFR 30–59 mL/min/1.73m2), and severe
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`renal impairment (eGFR 15–29 mL/min/1.73m2). Systemic exposure to deferiprone and to its metabolite deferiprone 3-O-glucuronide was assessed by the PK
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`parameters C max and AUC.
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` Regardless of the degree of renal impairment, the majority of the dose of Ferriprox was excreted in the urine over the first 24 hours as deferiprone 3-O-glucuronide. No
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` significant effect of renal impairment was seen on systemic exposure to deferiprone. Systemic exposure to the inactive 3-O-glucuronide increased with decreasing
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` eGFR. Based on the results of this study, no adjustment of the Ferriprox dosage regimen is required in patients with impaired renal function.
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` Hepatic Impairment
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` 8.7
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` The influence of severe hepatic impairment on the pharmacokinetics of deferiprone and deferiprone 3-O-glucuronide has not been evaluated. Safety and efficacy of
` Ferriprox have not been evaluated in patients with severe hepatic impairment.
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` An open-label, non-randomized, parallel group clinical study was conducted to evaluate the effect of impaired hepatic function on the safety, tolerability, and
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` pharmacokinetics of a single 33 mg/kg oral dose of Ferriprox. Subjects were categorized into 3 groups based on the Child-Pugh classification score: healthy volunteers,
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` mild hepatic impairment (Class A: 5– 6 points), and moderate hepatic impairment (Class B: 7– 9 points). Systemic exposure to deferiprone and to its metabolite
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` deferiprone 3-O-glucuronide was assessed by the PK parameters C max and AUC. The PK of both deferiprone and deferiprone 3-O-glucuronide was generally similar in
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` all subjects, regardless of degree of liver impairment. A serious adverse event of acute liver and renal injury was seen in one subject with moderate hepatic impairment.
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` Based on the results of this study, no adjustment of the Ferriprox dosage regimen is required in patients with mildly or moderately impaired hepatic function.
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`Reference ID: 3706686
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` 5
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` 10
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` OVERDOSAGE
` No cases of acute overdose have been reported. There is no specific antidote to Ferriprox overdose.
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` Neurological disorders such as cerebellar symptoms, diplopia, lateral nystagmus, psychomotor slowdown, hand movements and axial hypotonia have been observed in
` children treated with 2.5 to 3 times the recommended dose for more than one year. The neurological disorders progressively regressed after deferiprone discontinuation.
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` 11
`
`
` DESCRIPTION
` Ferriprox (deferiprone) tablets contain 500 mg deferiprone (3-hydroxy-1,2-dimethylpyridin-4-one), a synthetic, orally active, iron-chelating agent. Deferiprone has the
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` following structural formula:
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`O
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`OH
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`N
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`CH3
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`Deferiprone is a white to pinkish-white crystalline powder. It is sparingly soluble in deionized water and has a melting point range of 272°C - 278°C.
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`Ferriprox tablets are white to off-white, capsule-shaped tablets, and imprinted with “APO” score “500” on one side and plain on the other. The tablets can be broken in
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`half along the score. Each tablet contains 500 mg deferiprone and the following inactive ingredients: Tablet core - microcrystalline cellulose, magnesium stearate,
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`colloidal silicon dioxide; Coating - hydroxypropyl methyl cellulose, polyethylene glycol, titanium dioxide.
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`CH3
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`CLINICAL PHARMACOLOGY
`12
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`Mechanism of Action
`12.1
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`Deferiprone is a chelating agent with an affinity for ferric ion (iron III). Deferiprone binds with ferric ions to form neutral 3:1 (deferiprone:iron) complexes that are
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`stable over a wide range of pH values. Deferiprone has a lower binding affinity for other metals such as copper, aluminum and zinc than for iron.
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`12.2
`Pharmacodynamics
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`No clinical studies were performed to assess the relationship between the dose of Ferriprox and the amount of iron eliminated from the body.
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`Cardiac Electrophysiology
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`At a dose 1.5 times the maximum recommended dose, Ferriprox does not prolong the QT interval to any clinically relevant extent.
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`12.3
`Pharmacokinetics
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`Deferiprone is rapidly absorbed from the upper part of the gastrointestinal tract, appearing in the blood within 5 to 10 minutes of oral administration. Peak serum
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`concentrations occur approximately 1 hour after a single dose in fasted healthy subjects and patients, and up to 2 hours after a single dose in the fed state.
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`Administration with food decreased the C max of deferiprone by 38% and the AUC by 10%. While a food effect cannot be ruled out, the magnitude of the exposure
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`change does not warrant dose adjustment.
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`In healthy subjects, the mean maximum concentration (C max ) of deferiprone in serum was 20 mcg/mL, and the mean total area under the concentration-time curve
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`(AUC) was 53 mcg∙h/mL following oral administration of a 1,500 mg dose of Ferriprox tablets in the fasting state. Dose proportionality over the labeled dosage range
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`of 25 to 33 mg/kg three times per day (75 to 99 mg/kg per day) has not been studied. The elimination half life (t 1/2 ) of deferiprone was 1.9 hours. The accumulation of
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`deferiprone and its glucuronide metabolite at the highest approved dosage level of 33 mg/kg three times per day has not been studied. The volume of distribution of
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`deferiprone is 1.6 L/kg in thalassemia patients, and approximately 1 L/kg in healthy subjects. The plasma protein binding of deferiprone in humans is less than 10%.
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`In humans, the majority of the deferiprone is metabolized, primarily by UGT1A6. The contribution of extrahepatic (e.g., renal) UGT1A6 is unknown. The major
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`metabolite of deferiprone is the 3-O-glucuronide, which lacks iron binding capability. Peak serum concentration of the glucuronide occurs 2 to 4 hours after
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`administration of deferiprone in fasting subjects.
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`More than 90% of deferiprone is eliminated from plasma within 5 to 6 hours of ingestion. Following oral administration, 75% to 90% is recovered in the urine in the
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`first 24 hours, primarily as metabolite.
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`Specific Populations
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`The pharmacokinetics of deferiprone has not been studied in geriatric or pediatric populations, and the influence of race, gender, or obesity has not been established.
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`NONCLINICAL TOXICOLOGY
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`Carcinogenesis, Mutagenesis, Impairment of Fertility
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`13
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`13.1
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`Carcinogenicity studies have not been conducted with deferiprone. However, in view of the genotoxicity results, and the findings of mammary gland hyperplasia and
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`mammary gland tumors in rats treated with deferiprone in the 52-week toxicology study, tumor formation in carcinogenicity studies must be regarded as likely.
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`Deferiprone was positive in a mouse lymphoma cell assay in vitro. Deferiprone was clastogenic in an in vitro chromosomal aberration test in mice and in a
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`chromosomal aberration test in Chinese Hamster Ovary cells. Deferiprone given orally or intraperitoneally was clastogenic in a bone marrow micronucleus assay in
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`non-iron-loaded mice. A micronucleus test was also positive when mice predosed with iron dextran were treated with deferiprone. Deferiprone was not mutagenic in the
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`Ames bacterial reverse mutation test.
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` 6
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`Reference ID: 3706686
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` A fertility and early embryonic development study of deferiprone was conducted in rats. Sperm counts, motility and morphology were unaffected by treatment with
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` deferiprone. There were no effects observed on male or female fertility or reproductive function at the highest dose which was 25% of the MRHD based on body
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` surface area.
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` 14
`
`
` CLINICAL STUDIES
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` In a prospective, planned, pooled analysis of patients from several studies, the efficacy of Ferriprox was assessed in transfusion-dependent iron overload patients in
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` whom previous iron chelation therapy had failed or was considered inadequate due to poor tolerance. The main criterion for chelation failure was serum
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` ferritin > 2,500 mcg/L before treatment with Ferriprox. Ferriprox therapy (35-99 mg/kg/day) was considered successful in individual patients who experienced a ≥ 20%
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` decline in serum ferritin within one year of starting therapy.
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` Data from a total of 236 patients were analyzed. Of the 224 patients with thalassemia who received deferiprone monotherapy and were eligible for serum ferritin
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` analysis, 105 (47%) were male and 119 (53%) were female. The mean age of these patients was 18.2 years.
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` For the patients in the analysis, the endpoint of at least a 20% reduction in serum ferritin was met in 50% (of 236 subjects), with a 95% confidence interval of 43% to
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` 57%.
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` A small number of patients with thalassemia and iron overload were assessed by measuring the change in the number of milliseconds (ms) in the cardiac MRI T2*
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` value before and after treatment with deferiprone for one year. There was an increase in cardiac MRI T2* from a mean at baseline of 11.8 ± 4.9 ms to a mean of
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` 15.1 ± 7.0 ms after approximately one year of treatment. The clinical significance of this observation is not known.
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` 16
` HOW SUPPLIED/STORAGE AND HANDLING
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`FERRIPROX® (deferiprone) tablets are white to off-white, capsule-shaped tablets, film-coated, and have a functional score imprinted with “APO” score “500