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/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 99mg/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.
`(5.3)
`
`•
`
`-----------------------------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-----------------------
`•
`Special care must be taken with Ferriprox use in patients with renal or
`hepatic impairment since no specific studies have been conducted to
`evaluate its safety and efficacy in patients with these conditions. (8.6,
`8.7)
`Nursing mothers: Discontinue the use of Ferriprox or discontinue
`nursing. (8.3)
`See 17 for PATIENT COUNSELING INFORMATION and
`MEDICATION GUIDE.
`
`•
`
`Revised: 10/2011
`
`_____________________________________________________________________________________________________________________________________
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`WARNING: AGRANULOCYTOSIS/ NEUTROPENIA
`1
`INDICATIONS AND USAGE
`2 DOSAGE AND ADMINISTRATION
`
`2.1
`Interactions with Foods, Vitamins and Antacids
`3 DOSAGE FORMS AND STRENGTHS
`4 CONTRAINDICATIONS
`5 WARNINGS AND PRECAUTIONS
`
`5.1 Agranulocytosis/Neutropenia
`
`5.2 Cardiac QT Syndrome
`
`5.3
`Embryofetal toxicity
`
`5.4
`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
`_____________________________________________________________________________________________________________________________________
`
`
`
`Pregnancy
`8.1
`
`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
`
`12.6 QT/QTc Prolongation
`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
`
`

`

`
`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.
`Dose (mg)
`Number of tablets
`
`
`
`
`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.
`Dose (mg)
`Number of tablets
`
`
`
`Body
`Weight
`(kg)
`1.5
`660
`20
`2
`990
`30
`2.5
`1320
`40
`3.5
`1650
`50
`4
`1980
`60
`4.5
`2310
`70
`5.5
`2640
`80
`6
`2970
`90
`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.
`2.1
`Interactions with Foods, Vitamins and Antacids
`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)].
`
`
`
`
`2
`
`

`

`DOSAGE FORMS AND STRENGTHS
`3
`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
`Post Marketing Experience (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 the ANC weekly on therapy [see Boxed Warning].
`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.
`5.2
`Cardiac QT Syndrome
`A thorough QT study has not been conducted with Ferriprox. One patient with a history of QT prolongation experienced Torsades de Pointes during therapy with
`Ferriprox. Administer Ferriprox with caution to patients who may be at increased risk of prolongation of the cardiac QT interval (e.g., those with congestive heart
`failure, bradycardia, use of a diuretic, cardiac hypertrophy, hypokalemia or hypomagnesemia). Instruct any patient taking Ferriprox who experiences symptoms
`suggestive of an arrhythmia (such as palpitations, dizziness, lightheadedness, syncope, or seizures) to seek medical attention immediately.
`5.3
`Embryofetal toxicity
`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
`5.4
`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
`(5.4), Torsades de Pointes (5.2), Decreased plasma zinc concentrations (5.4).
`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.
`
`
`
`
`3
`
`

`

`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
`
`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.
`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
`9.8
` Arthralgia
`2.0
` Back pain
`1.9
` Pain in extremity
`1.4
` Arthropathy
`
`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.
`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.
`
`
`
`% Subjects
`
`
`4
`
`

`

`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 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)].
`7.2
`UDP-glucuronosyltransferases (UGTs)
`Deferiprone is primarily eliminated via metabolism to the 3-O-glucuronide. In vitro studies suggest that UDP glucuronosyltransferase (UGT) 1A6 is primarily
`responsible for the glucuronidation of deferiprone. The significance of coadministration of Ferriprox with the UGT 1A6 inhibitor (e.g. silymarin (milk thistle)) on
`systemic exposure to deferiprone has not been evaluated. Closely monitor patients for adverse reactions that may require downward dose titration or interruption when
`Ferriprox is concomitantly administered with a UGT 1A6 inhibitor.
`7.3
`Polyvalent cations
`Concurrent use of Ferriprox with foods, mineral supplements, and antacids that contain polyvalent cations has not been studied. However, since 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)].
`
`USE IN SPECIFIC POPULATIONS
`8
`Pregnancy
`8.1
`Pregnancy Category D [see Warnings and Precautions (5.3), Nonclinical Toxicology (13.1)]
`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. 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
`taking Ferriprox, the patient should be apprised of the potential hazard to the fetus.
`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
`surface area. No maternal toxicity was evident at these doses.
`Embryofetal lethality and maternal toxicity occurred in pregnant rabbits given 100 mg/kg/day deferiprone orally during the period of organogenesis. This dose is
`equivalent to 32% of the MRHD based on body surface area.
`8.3
`Nursing Mothers
`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
`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
`the mother.
`8.4
`Pediatric Use
`The safety and effectiveness of Ferriprox tablets for oral use in pediatric patients have not been established.
`8.5
`Geriatric Use
`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
`end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
`8.6
`Renal Impairment
`Ferriprox has not been evaluated in patients with renal impairment.
`8.7
`Hepatic Impairment
`Ferriprox has not been conclusively evaluated in patients with hepatic impairment.
`
`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.
`
`
`
`
`5
`
`

`

`DESCRIPTION
`11
`Ferriprox (deferiprone) tablets contain 500 mg deferiprone (3-hydroxy-1,2-dimethylpyridin-4-one), a synthetic, orally active, iron-chelating agent. Deferiprone has the
`following structural formula:
`
`O
`
`N
`
`OH
`
`CH3
`
`
`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.
`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. Each tablet contains 500 mg deferiprone and the following inactive ingredients: Tablet core - microcrystalline cellulose, magnesium stearate,
`colloidal silicon dioxide; Coating - hydroxypropyl methyl cellulose, polyethylene glycol, titanium dioxide.
`
`CH3
`
`CLINICAL PHARMACOLOGY
`12
`Mechanism of Action
`12.1
`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.
`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 Cmax of deferiprone by 38% and the AUC by 10%. While a food effect cannot be ruled out, the magnitude of the exposure
`change does not warrant dose adjustment.
`In healthy subjects, the mean maximum concentration (Cmax) of deferiprone in serum was 20 mcg/mL, and the mean total area under the concentration-time curve
`(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
`of 25 to 33 mg/kg three times per day (75 to 100 mg/kg per day) has not been studied. The elimination half life (t1/2) of deferiprone was 1.9 hours. The accumulation of
`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
`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%.
`In humans, the majority of the deferiprone is metabolized, primarily by UGT 1A6. 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. Peak serum concentration of the glucuronide occurs 2 to 4 hours after
`administration of deferiprone in fasting subjects.
`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
`first 24 hours, primarily as metabolite.
`Special 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.
`12.6
`QT/QTc Prolongation
`No clinical studies of the effects of Ferriprox on the cardiac QT interval have been performed in human subjects [see Warnings and Precautions (5.2)].
`
`NONCLINICAL TOXICOLOGY
`Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`13
`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.
`
`
`
`
`6
`
`

`

`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%.
` 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.
`
` A
`
`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 a 100 count HDPE bottle with a child-resistant cap.
`500 mg film-coated tablets, 100 tablets
`NDC 52609-6000-6-1
`Store at 20º to 25ºC (68º to 77ºF); excursions permitted to 15º to 30ºC (59º to 86ºF) [see USP Controlled Room Temperature].
`Keep Ferriprox out of the reach and sight of children.
`
`17
`PATIENT COUNSELING INFORMATION
`See FDA-Approved Patient Labeling (Medication Guide)
`•
`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.
`
`•
`•
`
`•
`•
`
`•
`
`Advise patients that the amount of Ferriprox prescribed is based on body weight and on the therapeutic goal (reduction or stabilization of the body iron load).
`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 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 the iron-deferiprone complex. This is a very common sign of the
`desired effect of Ferriprox, and it is not harmful.
`Counsel women of reproductive potential to avoid pregnancy while taking Ferriprox. Advise patients to immediately notify their physician if they become
`pregnant, or if they plan to become pregnant during therapy.
`Inform patients that they should not breast feed while taking Ferriprox.
`
`Inform patients that if they experience palpitations, dizziness, lightheadedness, syncope, or seizures to immediately seek medical attention.
`
`•
`•
`
`Manufactured for ApoPharma USA, Inc., Rockville, MD, United States of
`America, 20850. Manufactured by Apotex Inc., Toronto, Ontario, Canada,
`M9L 1T9.
`
`
`
`
`
`7
`
`