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)
`
`
`
`
`
`•
`
`
`
`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 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)
`
`
`
`•
`
`
`•
`
`------------------------WARNINGS AND PRECAUTIONS----------------------­
`
`
`Embryofetal Toxicity: Advise women of the potential hazard to the fetus
`
`
`
`
`
`
`•
`and to avoid pregnancy while on this drug. (5.2)
`
`
`
`Liver Enzyme Elevations: Monitor monthly and discontinue for
`
`
`persistent elevations. (5.3)
`
`Zinc Deficiency: Monitor during therapy and supplement for deficiency.
`
`(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-----------------------------­
`
`
`Avoid 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)
`
`
`Avoid use of UGT1A6 inhibitors with FERRIPROX. (7.2)
`
`
`Allow at least a 4-hour interval between FERRIPROX and mineral
`
`
`supplements or antacids that contain polyvalent cations (e.g., iron,
`
`
`aluminum, or zinc). (7.3)
`
`
`
`•
`
`•
`
`------------------------USE IN SPECIFIC POPULATIONS----------------------­
`
`Lactation: Advise women not to breastfeed. (8.2)
`
`
`•
`See 17 for PATIENT COUNSELING INFORMATION and Medication
`
`
`
`Guide.
`
`
`
`
`----------------------------RECENT MAJOR CHANGES--------------------------
`Dosage and Administration, Dosing (2.1)
`07/2019
`
`
`
`
`
`
`
`-----------------------------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).
`
`
`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 body weight, orally, three times per day, for a
`
`
`
`•
`total daily dose of 75 mg/kg to 99 mg/kg body weight. (2.1)
`
`
`
`
`
`
`Revised: 07/2019
`_______________________________________________________________________________________________________________________________________
`8 USE IN SPECIFIC POPULATIONS
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`8.1
`Pregnancy
`
`
`
`WARNING: AGRANULOCYTOSIS/NEUTROPENIA
`
`
`8.2
`Lactation
`
`
`
`INDICATIONS AND USAGE
`1
`
`
`8.3
`Females and Males of Reproductive Potential
`
`
`
`
`2 DOSAGE AND ADMINISTRATION
`
`
`8.4
`Pediatric Use
`
`
`
`
`8.5 Geriatric Use
`
`
`
`2.1 Dosing
`
`
`10 OVERDOSAGE
`
`
`2.2
`Interactions with Foods, Vitamins and Drugs
`
`
`
`11 DESCRIPTION
`
`
`3 DOSAGE FORMS AND STRENGTHS
`
`
`12 CLINICAL PHARMACOLOGY
`
`
`4 CONTRAINDICATIONS
`
`
`5 WARNINGS AND PRECAUTIONS
`
`
`12.1 Mechanism of Action
`
`
`
`5.1 Agranulocytosis/Neutropenia
`
`
`
`12.2 Pharmacodynamics
`
`
`
`5.2
`Embryofetal Toxicity
`
`
`
`12.3 Pharmacokinetics
`
`
`
`13 NONCLINICAL TOXICOLOGY
`
`
`5.3
`Liver Enzyme Elevations
`
`
`
`5.4
`Zinc Deficiency
`
`
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`
`
`
`6 ADVERSE REACTIONS
`
`
`14 CLINICAL STUDIES
`
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`
`
`6.1 Clinical Trial Experience
`
`
`
`17 PATIENT COUNSELING INFORMATION
`
`
`6.2
`Postmarketing Experience
`
`
`
`7 DRUG INTERACTIONS
`
`
`
`7.1 Drugs Associated with Neutropenia or Agranulocytosis
`
`
`
`* Sections or subsections omitted from the full prescribing information are not
`
`
`7.2 UDP-Glucuronosyltransferases (UGTs)
`
`
`
`listed.
`
`7.3
`Polyvalent Cations
`
`
`
`_____________________________________________________________________________________________________________________________________
`
`
`
` 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 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® (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)].
`
`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
`
`
`Dosing
`2.1
`
`Starting Dose
`
`
`
`The recommended initial dose of FERRIPROX is 25 mg/kg, orally, three times per day for a total of 75 mg/kg/day. Round dose to the
`
`nearest 500 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.
` Number of 1,000 mg tablets
`
`
` Midday
`
` 0.5
`
` 0.5
`
` 1
`
` 1
`
` 1.5
`
` 1.5
`
` 2
`
` 2
`
`
`
` Body Weight
`
` (kg)
`
` 20
`
` 30
`
` 40
`
` 50
`
` 60
`
` 70
`
` 80
`
` 90
`
`
` Morning
`
` 0.5
`
` 1
`
` 1
`
` 1.5
`
` 1.5
`
` 2
`
` 2
` 2.5
`
`
`
` Evening
`
` 0.5
`
` 1
`
` 1
`
` 1.5
`
` 1.5
`
` 2
`
` 2
` 2.5
`
`
`
`
`
`
` 2
`
`

`

` Table 1b: Tablet requirement to achieve a 33 mg/kg dose (rounded to the nearest half-
`
`
`
` tablet) for administration three times a day.
` Number of 1,000 mg tablets
`
`
` Midday
`
` 0.5
`
` 1
`
` 1
`
` 1.5
`
` 2
`
` 2
`
` 2.5
`
` 3
`
`
` Morning
`
` 0.5
`
` 1
`
` 1.5
`
` 1.5
`
` 2
`
` 2.5
`
` 2.5
`
` 3
`
`
` Evening
`
` 1
`
` 1
`
` 1.5
`
` 2
`
` 2
`
` 2.5
`
` 3
`
` 3
`
`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, three times per day for a total of 99 mg/kg/day.
`
`
`
`
`
`
` Body Weight
`
` (kg)
`
` 20
`
` 30
`
` 40
`
` 50
`
` 60
`
` 70
`
` 80
`
` 90
`
`
`
`
`Monitor serum ferritin concentration every two to three months to assess the effects 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.
`
`
`Interactions with Foods, Vitamins and Drugs
`2.2
`
`
`Allow at least a 4-hour interval between FERRIPROX and other medications or supplements containing polyvalent cations such as
`
`
`iron, aluminum, or zinc. Avoid use of UGT1A6 inhibitors (e.g. diclofenac, probenecid, or silymarin (milk thistle)) with FERRIPROX
`
`
`
`[see Drug Interactions (7.2 and 7.3), Clinical Pharmacology (12.3)].
`
`
`DOSAGE FORMS AND STRENGTHS
`3
`
`
`1,000 mg film-coated tablets with functional scoring.
`
`
`
`
`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/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/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.
`
`
`
`
`
`3
`
`

`

`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. The limited 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 of the potential risk to the fetus [see Use in Specific Populations (8.1, 8.3)]. Advise females of reproductive
`
`
`
`potential to use highly effective contraception during treatment with FERRIPROX. Six months of contraception is recommended after
`
`
`
`cessation of therapy. Advise males of reproductive potential to use effective contraception during treatment with FERRIPROX. Three
`
`
`months of contraception is recommended after cessation of therapy [see Use in Specific Populations (8.1)].
`
`
`5.3
`Liver Enzyme Elevations
`
`
`
`In clinical studies, 7.5% of 642 patients treated with FERRIPROX developed increased ALT values. Four (0.62%) FERRIPROX-
`
`
`
`treated subjects discontinued the drug due to increased serum ALT levels and 1 (0.16%) due to an increase in both ALT and AST.
`
`
`
`
`Monitor serum ALT values monthly during therapy with FERRIPROX, and consider interruption of therapy if there is a persistent
`
`increase in the serum transaminase levels.
`
`
`5.4
`Zinc Deficiency
`Decreased plasma zinc concentrations have been observed on FERRIPROX therapy. Monitor plasma zinc, and supplement in the
`
`event of a deficiency.
`
`
`
`ADVERSE REACTIONS
`6
`
`
`The following clinically significant adverse reactions are described below and elsewhere in the labeling:
`
`
`
`• Agranulocytosis/Neutropenia [see Warnings and Precautions (5.1)]
`
`
`
`• Liver Enzyme Elevations [see Warnings and Precautions (5.3)]
`
`
`• Zinc Deficiency [see Warnings and Precautions (5.4)]
`
`
`
`
`
`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.
`
`
`4
`
`

`

`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`The table below lists the adverse drug reactions that occurred in at least 1% of patients treated with FERRIPROX in clinical trials.
`
`
`Table 2:Adverse drug reactions occurring in ≥ 1% of FERRIPROX-treated patients
`
`
`
`
`
`
`
`
` Body System
` (N=642)
`
` Adverse Reaction
` % Subjects
`
`
`
` BLOOD AND LYMPHATIC SYSTEM
` DISORDERS
`
` Neutropenia
`
`
`
`
` 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.
`
`
`
` 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.
`
`
`
`
` 6
`
` 2
`
`
` 13
`
` 10
`
` 10
`
` 3
`
` 2
`
`
` 7
`
` 2
`
` 1
`
`
`
` 4
`
` 1
`
`
`
`
`5
`
`

`

`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.
`
`
`
`
` DRUG INTERACTIONS
` 7
`
`
` Drugs Associated with Neutropenia or Agranulocytosis
`
`
` 7.1
`
`
` Avoid use of FERRIPROX with other drugs known to be associated with neutropenia or agranulocytosis; however, if this is not
` possible, monitor the absolute neutrophil count more frequently [see Warnings and Precautions (5.1)].
`
`
`
`
`
`
` UDP-Glucuronosyltransferases (UGTs)
`
`
` 7.2
` Avoid use of UGT1A6 inhibitors (e.g., diclofenac, probenecid, or silymarin (milk thistle)) with FERRIPROX [see Dosage and
`
`
` Administration (2.2), Adverse Reactions (6.1), Clinical Pharmacology (12.3)].
` Polyvalent Cations
`
`
` 7.3
`Deferiprone has the potential to bind polyvalent cations (e.g., iron, aluminum, and zinc), allow at least a 4-hour interval between
`
`
` FERRIPROX and other medications (e.g., antacids), or supplements containing these polyvalent cations [see Dosage and
`
` Administration (2.2)].
`
`
`
`
`
`
`
`
`
`
`
` USE IN SPECIFIC POPULATIONS
` 8
`
`
` Pregnancy
`
` 8.1
`
` Risk Summary
`
`
`
`
` Limited available data with FERRIPROX use in pregnant women are insufficient to inform a drug-associated risk of major birth
`
` defects and miscarriage. FERRIPROX can cause fetal harm when administered to a pregnant woman based on genotoxicity and
`
`
`
` developmental toxicity in animal studies (see Data).
`
`
`
` In animal reproduction studies, administration of deferiprone to pregnant animals during the period of organogenesis resulted in
` adverse developmental outcomes including embryofetal death and malformations in rats and rabbits at doses much lower than the
`
`
`
`
`
`
`
` MRHD (maximum recommended human dose) based on body surface area (see Data). Advise women of the risk to the 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
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`6
`
`

`

`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 (absent eye bulge, cranial meningocele, domed head, limb malrotation, protruding tongue,
`
`
`anal atresia, cleft palate, internal hydrocephaly, anophthalmia, misshapen bones of the face and naso-pharyngeal tract, and fused bones
`
`
`in the axial skeleton). 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.
`
`
`8.2
`Lactation
`
`
`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, including the potential for tumorigenicity shown for deferiprone in animal
`
`
`
`
`
`studies, advise patients not to breastfeed during FERRIPROX treatment and for 2 weeks after the last dose.
`
`
`
`
`Females and Males of Reproductive Potential
`8.3
`
`
`FERRIPROX can cause fetal harm when administered to a pregnant female.
`
`
`
`Pregnancy Testing
`
`Verify the pregnancy status of females of reproductive potential prior to initiating FERRIPROX therapy.
`
`
`Contraception
`
`Females
`
`Advise females of reproductive potential to avoid pregnancy during treatment with FERRIPROX and 6 months of contraception is
`
`
`
`
`recommended after cessation of therapy. Advise females to immediately report pregnancy [see Use in Specific Populations (8.1)].
`
`
`
`
`Males
`
`Advise males with female sexual partners of reproductive potential to use effective contraception during treatment with FERRIPROX
`
`
`
`
`and 3 months of contraception is recommended after cessation of therapy [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.
`
`
`7
`
`
`

`

`DESCRIPTION
`11
`
`
`FERRIPROX (deferiprone) tablets contain 1,000 mg deferiprone (3-hydroxy-1,2-dimethylpyridin-4-one), a synthetic, orally active,
`
`iron-chelating agent. The molecular formula for deferiprone is C7H9NO2 and its molecular weight is 139.15 g/mol. Deferiprone has
`
`
`
`
`
`the following structural formula:
`
`O
`
`OH
`
`N
`
`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 “1000” on one side and plain on
`
`
`the other. The tablets can be broken in half along the score line. Each tablet contains 1,000 mg deferiprone and the following inactive
`
`
`
`
`ingredients: Tablet core: methylcellulose, crospovidone, and magnesium stearate. Coating: hypromellose, hydroxypropyl cellulose,
`
`
`
`
`macrogol, and titanium dioxide.
`
`
`CLINICAL PHARMACOLOGY
`12
`
`
`12.1 Mechanism of Action
`
`
`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 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.
`
`12.2
`Pharmacodynamics
`
`
`No clinical studies were performed to assess the relationship between the dose of FERRIPROX and the amount of iron eliminated
`
`
`from the body.
`
`Cardiac Electrophysiology
`
`At a dose 1.5 times the maximum recommended dose, FERRIPROX does not prolong the QT interval to any clinically relevant extent.
`
`12.3
`Pharmacokinetics
`
`
`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 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. Administration with food decreased the maximum concentration (Cmax ) of deferiprone
`
`
`
`
`
`by 38% and the area under the concentration-time curve (AUC) by 10%. The magnitude of the exposure change does not warrant dose
`
`adjustment.
`
`
`
`
`
`
`
`
`In healthy subjects, the mean Cmax of deferiprone in serum was about 20 mcg/mL, and the mean AUC was about 50 mcg∙h/mL
`
`
`
`
`
`
`
`following oral administration of a 1,500 mg dose of FERRIPROX tablets or oral solution in the fasting state. Dose proportionality
`
`
`
`
`over the labeled dosage range 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 of deferiprone is approximately 2 hours. Following oral administration, 75% to 90% of the administered dose
`
`
`
`
`
`is recovered in the urine in the first 24 hours, primarily as metabolite. In humans, the majority of the deferiprone is metabolized,
`
`
`
`primarily by UGT1A6. The contribution of extrahepatic (e.g., renal) UGT1A6 is unknown. The major metabolite of deferiprone is the
`
`
`
`3-O-glucuronide, which lacks iron binding capability.
`
`Specific Populations
`
`
`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.
`
`Patients with Renal Impairment
`
`
`
`The pharmacokinetics of deferiprone were not significantly influenced in subjects with mild renal impairment (eGFR
`
`
`
`
`
`60 - 89 mL/min/1.73 m2), moderate renal impairment (eGFR 30 - 59 mL/min/1.73 m2), or severe renal impairment (eGFR
`
`
`
`
`
`
`
`
`
`
`
`
`15 - 29 mL/min/1.73 m2), compared with healthy subjects (eGFR ≥ 90 mL/min/1.73 m2), given a single oral dose of FERRIPROX
`
`
`33 mg/kg.
`
`
`8
`
`

`

`
`Patients with Hepatic Impairment
`
`
`
`The pharmacokinetics of deferiprone and deferiprone 3-O-glucuronide were not influenced in subjects with mild hepatic impairment
`
`
`
`
`
`(Child Pugh Class A: 5-6 points) or moderate hepatic impairment (Child Pugh Class B: 7-9 points), compared with healthy subjects
`
`
`given a single oral dose of FERRIPROX 33 mg/kg. The pharmacokinetics of deferiprone and deferiprone 3-O-glucuronide have not
`
`
`been evaluated in subjects with severe hepatic impairment (Child Pugh Class C: 10-15 points).
`Drug Interactions
`
`
`
`
`Deferiprone is primarily eliminated via metabolism to the 3-O-glucuronide. In vitro UGT1A6 is primarily responsible for the
`
`
`
`glucuronidation of deferiprone which can be reduced up to 78% in the presence of the UGT1A6 inhibitor phenylbutazone.
`
`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.
`
`
`
`
`
`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 based on body surface area.
`
`
`
`CLINICAL STUDIES
`14
`
`
`
`
`
`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 “1000” on one side and are plain on the other. They are provided in HDPE bottles.
`
`
`1,000 mg film-coated tablets, 50 tablets NDC 52609-0007-5
`
`
`
`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]. Keep the bottle tightly closed to protect from moisture.
`
`
`
`9
`
`
`

`

`
`•
`
`
`
`PATIENT COUNSELING INFORMATION
`17
`
`
`Advise the patient to read the FDA-approved patient labeling (Medication Guide)
`
`
`
`Instruct patients and their caregivers to store FERRIPROX in the originally