2.1 Recommended Dosage

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).

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.

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)].

5.1 Agranulocytosis and Neutropenia

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.

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).

5.2 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.

5.3 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)].

6.1 Clinical Trial Experience

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.

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.

Vascular disorders:hypotension, hypertension.

7.1 Drugs Associated with Neutropenia or Agranulocytosis

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)].

8.1 Pregnancy

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.

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 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.

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.

12.2 Pharmacodynamics

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).

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

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.