Reference ID: 4563476
`
`HIGHLIGHTS OF PRESCRIBING INFORMATION
`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 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)
`
`•
`
`•
`
`-----------------------------INDICATIONS AND USAGE--------------------------
`FERRIPROX® 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).
`Limitations 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 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)
`
`-----------------------DOSAGE FORMS AND STRENGTHS--------------------
`Tablets: 500 mg film-coated, with functional scoring. (3)
`
`------------------------------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 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
`
`-------------------------------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.
`
`Revised: MM/2020
`
`_______________________________________________________________________________________________________________________________________
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`WARNING: AGRANULOCYTOSIS AND NEUTROPENIA
`1
`INDICATIONS AND USAGE
`2 DOSAGE AND ADMINISTRATION
`
`2.1 Recommended Dosage
`
`2.2 Dosage Modification for Drug Interactions
`3 DOSAGE FORMS AND STRENGTHS
`4 CONTRAINDICATIONS
`5 WARNINGS AND PRECAUTIONS
`
`5.1 Agranulocytosis and Neutropenia
`
`5.2
`Liver Enzyme Elevations
`
`5.3
`Zinc Deficiency
`
`5.4
`Embryo-Fetal Toxicity
`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
`Effect of Other Drugs on FERRIPROX
`
`_____________________________________________________________________________________________________________________________________
`
`8 USE IN SPECIFIC POPULATIONS
`
`8.1
`Pregnancy
`
`8.2
`Lactation
`
`8.3
`Females and Males of Reproductive Potential
`
`8.4
`Pediatric Use
`
`8.5 Geriatric Use
`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.
`
`
`
`1
`
`

`

`Reference ID: 4563476
`
`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)]
`
`•
`
`INDICATIONS AND USAGE
`1
`FERRIPROX® 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)].
`Limitations 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
`Recommended Dosage
`2.1
`Starting Dose
`The recommended initial dose of FERRIPROX is 25 mg/kg actual body weight, orally, 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
`Dose (mg) Number of 500 mg
`Weight
`tablets
`(kg)
`20
`30
`40
`50
`60
`70
`80
`90
`
`500
`750
`1,000
`1,250
`1,500
`1,750
`2,000
`2,250
`
`1
`1.5
`2
`2.5
`3
`3.5
`4
`4.5
`
`
`
`2
`
`

`

`Reference ID: 4563476
`
`Dose Adjustments
`Tailor dose adjustments to the individual patient’s response and therapeutic goals (maintenance or reduction of body iron burden). The
`maximum dose is 33 mg/kg actual body weight, three times per day for a total of 99 mg/kg/day.
`
`
`Tablet requirement to
`Table 1b:
`achieve a 33 mg/kg dose (rounded to the
`nearest half-tablet) for administration three
`times a day.
`Dose (mg) Number of 500 mg
`tablets
`
`Body
`Weight
`(kg)
`1.5
`660
`20
`2
`990
`30
`2.5
`1,320
`40
`3.5
`1,650
`50
`4
`1,980
`60
`4.5
`2,310
`70
`5.5
`2,640
`80
`6
`2,970
`90
`Monitor serum ferritin concentration every two to three months to assess the effect of FERRIPROX on body iron stores. If the serum
`ferritin is consistently below 500 mcg/L, consider temporarily interrupting FERRIPROX therapy until serum ferritin rises above
`500 mcg/L.
`2.2
`Dosage Modification for Drug Interactions
`Allow at least a 4-hour interval between administration of FERRIPROX and other drugs or supplements containing polyvalent cations
`such as iron, aluminum, or zinc [see Drug Interactions (7.2), Clinical Pharmacology (12.3)].
`
`DOSAGE FORMS AND STRENGTHS
`3
`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.
`
`CONTRAINDICATIONS
`4
`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)].
`
`WARNINGS AND PRECAUTIONS
`5
`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.
`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.
`
`
`
`3
`
`

`

`Reference ID: 4563476
`
`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 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)].
`
`ADVERSE REACTIONS
`6
`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)]
`Clinical Trial Experience
`6.1
`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
`(N=642)
`Body System
` Adverse Reaction
`% Subjects
`BLOOD AND LYMPHATIC SYSTEM
`
`DISORDERS
` Neutropenia
` Agranulocytosis
`
`6
`2
`
`
`
`4
`
`

`

`Reference ID: 4563476
`
`
`4
`1
`
`
`13
`10
`10
`3
`2
`
`7
`2
`1
`
`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.
`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.
`
`
`
`5
`
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`

`Reference ID: 4563476
`
`Vascular disorders: hypotension, hypertension.
`
`DRUG INTERACTIONS
`7
`Drugs Associated with Neutropenia or Agranulocytosis
`7.1
`Avoid co-administration of FERRIPROX with other drugs known to be associated with neutropenia or agranulocytosis. If co-
`administration is unavoidable, closely monitor the absolute neutrophil count [see Warnings and Precautions (5.1)].
`7.2
`Effect of Other Drugs on FERRIPROX
`UDP-Glucuronosyltransferases (UGTs)
`Avoid co-administration of FERRIPROX with a UGT1A6 inhibitor (e.g., diclofenac, probenecid, or silymarin (milk thistle)) [see
`Dosage and Administration (2.2), Adverse Reactions (6.1), and Clinical Pharmacology (12.3)].
`Polyvalent Cations
`Deferiprone has the potential to bind polyvalent cations (e.g., iron, aluminum, and zinc); allow at least a 4-hour interval between
`administration of FERRIPROX and other medications (e.g., antacids) or supplements containing these polyvalent cations [see Dosage
`and Administration (2.2)].
`
`USE IN SPECIFIC POPULATIONS
`8
`Pregnancy
`8.1
`Risk Summary
`In animal reproduction studies, oral administration of deferiprone to pregnant rats and rabbits during organogenesis at doses 33% and
`49%, respectively, of the maximum recommended human dose (MRHD) resulted in structural abnormalities, embryo-fetal mortality
`and alterations to growth (see Data). The limited data from FERRIPROX use in pregnant women are insufficient to inform a drug-
`associated risk of major birth defects and miscarriage. Based on evidence of genotoxicity and developmental toxicity in animal
`studies, FERRIPROX can cause fetal harm when administered to a pregnant woman. Advise pregnant women and females of
`reproductive potential of the potential risk to a fetus.
`The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a
`background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of
`major birth defects and of miscarriage is 2-4% and 15-20%, respectively.
`Data
`Human Data
`Post-marketing data available from 39 pregnancies of FERRIPROX-treated patients and 10 pregnancies of partners of FERRIPROX-
`treated patients are as follows:
`Of the 39 pregnancies in FERRIPROX-treated patients, 23 resulted in healthy newborns, 6 ended in spontaneous abortion, 9 had
`unknown outcomes, and 1 infant was born with anal atresia, nephroptosis, ventricular septal defect, hemivertebra and urethral fistula.
`Of the 10 pregnancies in partners of FERRIPROX-treated patients, 5 resulted in healthy newborns, 1 resulted in a healthy newborn
`with slight hypospadias, 1 was electively terminated, 1 resulted in the intrauterine death of twins, and 2 had unknown outcomes.
`Animal Data
`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
`150 mg/kg/day, respectively. The daily dose was administered as two equal divided doses approximately 7 hours apart. Doses of
`200 mg/kg/day in rats and 150 mg/kg/day in rabbits, approximately 33% and 49% of the MRHD, respectively, resulted in increased
`post-implantation loss and reduced fetal weights in the presence of maternal toxicity (reduced maternal body weight and body weight
`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,
`visceral and skeletal fetal malformations, such as cranial malformations, cleft palate, limb malrotation, anal atresia, internal
`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
`doses equal to or greater than 30 and 80 mg/kg/day, approximately 5% and 13% of the MHRD, respectively.
`
`
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`

`Reference ID: 4563476
`
`Lactation
`8.2
`Risk Summary
`There is no information regarding the presence of deferiprone in human milk, the effects on the breastfed child, or the effects on milk
`production.
`Because of the potential for serious adverse reactions in the breastfed child, including the potential for tumorigenicity shown for
`deferiprone in animal studies, advise patients that breastfeeding is not recommended during treatment with FERRIPROX, and for at
`least 2 weeks after the last dose.
`8.3
`Females and Males of Reproductive Potential
`Pregnancy Testing
`Pregnancy testing is recommended for females of reproductive potential prior to initiating FERRIPROX.
`Contraception
`Females
`FERRIPROX can cause embryo-fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)]. Advise
`female patients of reproductive potential to use effective contraception during treatment with FERRIPROX and for at least 6 months
`after the last dose.
`Males
`Based on genotoxicity findings, advise males with female partners of reproductive potential to use effective contraception during
`treatment with FERRIPROX and for at least 3 months after the last dose [see Nonclinical Toxicology (13.1)].
`8.4
`Pediatric Use
`The safety and effectiveness of FERRIPROX in pediatric patients have not been established.
`8.5
`Geriatric Use
`Clinical studies of FERRIPROX did not include sufficient numbers of subjects aged 65 and over to determine whether they respond
`differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly
`and younger patients.
`
`OVERDOSAGE
`10
`No cases of acute overdose have been reported. There is no specific antidote to FERRIPROX overdose.
`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.
`
`DESCRIPTION
`11
`FERRIPROX (deferiprone) tablets contain 500 mg deferiprone (3-hydroxy-1,2-dimethylpyridin-4-one), a synthetic, orally active, iron-
`chelating agent. The molecular formula for deferiprone is C7H9NO2 and its molecular weight is 139.15 g/mol. Deferiprone has the
`following structural formula:
`
`O
`
`N
`
`OH
`
`CH3
`
`CH3
`
`
`Deferiprone is a white to pinkish-white powder. It is sparingly soluble in deionized water and has a melting point range of 272 °C –
`278 °C.
`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 half along the score line. Each tablet contains 500 mg deferiprone and the following inactive
`ingredients: Tablet core - microcrystalline cellulose, magnesium stearate, colloidal silicon dioxide; Coating - hypromellose,
`polyethylene glycol, titanium dioxide.
`
`
`7
`
`

`

`Reference ID: 4563476
`
`CLINICAL PHARMACOLOGY
`12
`12.1 Mechanism of Action
`Deferiprone is a chelating agent that binds with ferric ions (iron III) to form neutral 3:1 (deferiprone:iron) complexes that are stable
`over a wide range of pH values. Deferiprone has a lower binding affinity for other metals (e.g., copper, aluminum and zinc) than for
`iron.
`Pharmacodynamics
`12.2
`Deferiprone exposure-response relationships and the time course of pharmacodynamics response are unknown.
`Cardiac Electrophysiology
`At a dose 1.5 times the maximum approved recommended dosage, FERRIPROX does not prolong the QT interval to any clinically
`relevant extent.
`12.3
`Pharmacokinetics
`The mean Cmax and AUC of deferiprone was 20 mcg/mL and 50 mcg∙h/mL, respectively, in healthy subjects. The dose proportionality
`of deferiprone over the approved recommended dosage range is unknown.
`Absorption
`Deferiprone appeared in the blood within 5 to 10 minutes after oral administration. Peak serum concentration of deferiprone was
`reached approximately 1 to 2 hours after a single dose.
`Effect of Food
`No clinically significant differences in the pharmacokinetics of deferiprone were observed following administration with food.
`Elimination
`The elimination half-life of deferiprone is approximately 2 hours.
`Metabolism
`Deferiprone is metabolized primarily by UGT1A6. The major metabolite of deferiprone is the 3-O-glucuronide, which lacks iron
`binding capability.
`Excretion
`Following oral administration, 75% to 90% of the administered dose was recovered in urine (primarily as metabolite) in the first
`24 hours.
`Specific Populations
`No clinically significant differences in the pharmacokinetics of deferiprone were observed based on sex, race/ethnicity, body weight,
`mild to severe (eGFR 15 to 89 mL/min/1.73 m2) renal impairment, or mild (Child Pugh Class A) to moderate (Child Pugh Class B)
`hepatic impairment. The effect of age, including geriatric or pediatric populations, end stage renal disease, or severe (Child Pugh Class
`C) hepatic impairment on the pharmacokinetics of deferiprone is unknown.
`Drug Interaction Studies
`In Vitro Studies
`UGT1A6 Inhibitors: Co-administration of deferiprone with phenylbutazone (UGT1A6 inhibitor) decreased glucuronidation of
`deferiprone by up to 78%.
`Polyvalent Cations: Deferiprone has the potential to bind polyvalent cations (e.g., iron, aluminum, and zinc).
`
`NONCLINICAL TOXICOLOGY
`13
`Carcinogenesis, Mutagenesis, Impairment of Fertility
`13.1
`Carcinogenicity studies have not been conducted with deferiprone. However, in view of the genotoxicity results, and the findings of
`mammary gland hyperplasia and mammary gland tumors in rats treated with deferiprone in the 52-week toxicology study, tumor
`formation in carcinogenicity studies must be regarded as likely.
`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 chromosomal aberration test in Chinese Hamster Ovary cells. Deferiprone given orally or intraperitoneally was
`clastogenic in a bone marrow micronucleus assay in non-iron-loaded mice. A micronucleus test was also positive when mice predosed
`with iron dextran were treated with deferiprone. Deferiprone was not mutagenic in the Ames bacterial reverse mutation test.
`
`
`8
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`

`

`Reference ID: 4563476
`
`A fertility and early embryonic development study of deferiprone was conducted in rats. Sperm counts, motility and morphology were
`unaffected by treatment with deferiprone. There were no effects observed on male or female fertility or reproductive function at the
`highest dose which was 25% of the MRHD.
`
`CLINICAL STUDIES
`14
`Transfusional Iron Overload
`In a prospective, planned, pooled analysis of patients from several studies, the efficacy of FERRIPROX was assessed in transfusion-
`dependent iron overload patients in whom previous iron chelation therapy had failed or was considered inadequate due to poor
`tolerance. The main criterion for chelation failure was serum 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% decline in serum
`ferritin within one year of starting therapy.
`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 analysis, 105 (47%) were male and 119 (53%) were female. The mean age of these patients was 18.2 years.
`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 57%.
`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* 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 15.1 ± 7.0 ms after approximately one year of treatment. The clinical
`significance of this observation is not known.
`
`HOW SUPPLIED/STORAGE AND HANDLING
`16
`FERRIPROX® (deferiprone) tablets are white to off-white capsule-shaped tablets, film-coated, and have a functional score imprinted
`with “APO” score “500” on one side and are plain on the other. They are provided in HDPE bottles.
`500 mg film-coated tablets, 100 tablets NDC 52609-0006-1
`Store at 20 °C to 25 °C (68 °F to 77 °F); excursions permitted to 15 °C to 30 °C (59 °F to 86 °F) [see USP Controlled Room
`Temperature].
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`PATIENT COUNSELING INFORMATION
`17
`Advise the patient to read the FDA-approved patient labeling (Medication Guide)
`Instruct patients and their caregivers to store FERRIPROX at 20 °C to 25 °C (68 °F to 77 °F); excursions permitted to 15 °C to
`•
`30 °C (59 °F to 86 °F) [see USP Controlled Room Temperature]. Instruct patients and their caregivers to store FERRIPROX out
`of the reach and sight of children.
`Inform patients of the risks of developing agranulocytosis and instruct them to immediately interrupt therapy and report to their
`physician if they experience any symptoms of infection such as fever, sore throat or flu-like symptoms.
`Inform patients that their blood will be checked to monitor liver function and zinc levels. A zinc supplement may be prescribed if
`zinc levels are low.
`• Advise patients to take the first dose of FERRIPROX in the morning, the second dose at midday, and the third dose in the
`evening. Clinical experience suggests that taking FERRIPROX with meals may reduce nausea. If a dose of this medicine has been
`missed, take it as soon as possible. However, if it is almost time for the next dose, skip the missed dose and go back to the regular
`dosing schedule. Do not catch-up or double doses.
`• Advise patients to contact their physician in the event of overdose.
`Inform patients that their urine might show a reddish/brown discoloration due to the excretion of iron. This is a very common sign
`•
`of the desired effect of FERRIPROX, and it is not harmful.
`Embryo-Fetal toxicity
`Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females to inform their
`healthcare provider of a known or suspected pregnancy [see Warnings and Precautions (5.4) and Use in Specific Populations (8.1)].
`Advise female patients of reproductive potential to use effective contraception during treatment with FERRIPROX and for at least six
`months after the last dose [see Use in Specific Populations (8.1, 8.3)]. Advise males with female partners of reproductive potential to
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`Reference ID: 4563476
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`use effective contraception during treatment with FERRIPROX and for at least three months after the last dose [see Use in Specific
`Populations (8.3) and Nonclinical Toxicology (13.1)].
`Lactation
`Advise females not to breastfeed during treatment with FERRIPROX and for at least 2 weeks after the last dose [see Use in Specific
`Populations (8.2)].
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`Distributed by ApoPharma USA, Inc., Weston, FL, United States of America, 33326. Manufactured by Apotex Inc., Toronto, Ontario,
`Canada, M9L 1T9.
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`Reference ID: 4563476
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`HIGHLIGHTS OF PRESCRIBING INFORMATION
`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
`
`
`-----------------------DOSAGE FORMS AND STRENGTHS--------------------
`Tablets: 1,000 mg film-coated, with functional scoring. (3)
`
`------------------------------CONTRAINDICATIONS-------------------------------
`Hypersensitivity to deferiprone or to any of the excipients in the formulation.
`(4)
`
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`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)
`Interru