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)].

5.1 Agranulocytosis/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 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)].

5.4 Laboratory Tests

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.

6.1 Clinical Trial Experience

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.

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.

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, infection 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 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)].

8.1 Pregnancy

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 Ferriprox 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.

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.

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)].

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 based on body surface area.