2.1 Important Dosage and Administration Information

•

Deferiprone Tablets (three times a day) - 1,000 mg - given three times a day [see Dosage and Administration (2.3)]

To prevent medication errors, before prescribing and dispensing, ensure that the tablet formulation is appropriate for the dosing regimen. Each tablet has distinct identifying characteristics [see Dosage Forms and Strengths (3)].

Monitoring for Safety:

Due to the risk of agranulocytosis, monitor ANC before and during deferiprone tablets therapy.

Test ANC prior to start of deferiprone tablets therapy and monitor on the following schedule during treatment:

•

First six months of therapy: Monitor ANC weekly;

•

Next six months of therapy: Monitor ANC once every two weeks;

•

After one year of therapy: Monitor ANC every two to four weeks (or at the patient’s blood transfusion interval in patients that have not experienced an interruption due to any decrease in ANC [see Warnings and Precautions (5.1)].

Due to the risk of hepatic transaminase elevations, monitor ALT before and monthly during deferiprone tablets therapy [see Warnings and Precautions (5.2)].

Due to the risk of zinc deficiency, monitor zinc levels before and regularly during deferiprone tablets therapy [see Warnings and Precautions (5.3)].

2.3 Recommended Dosage for 1,000 mg Deferiprone Tablets (three times a day) for Adult Patients with Transfusional Iron Overload due to Thalassemia Syndromes

Starting Dosage for Three Times a Day Tablets:

The recommended starting oral dosage of deferiprone tablets (three times a day) is 75 mg/kg/day (actual body weight), in three divided doses per day. Table 3 describes the number of deferiprone tablets (three times a day) needed to achieve the 75 mg/kg/day total starting dosage. Round dose to the nearest 500 mg (half-tablet).

To minimize gastrointestinal upset when first starting therapy, dosing can start at 45 mg/kg/day and increase weekly by 15 mg/kg/day increments until the full prescribed dose is achieved.

Dosage Adjustments for Three Times Daily Tablets:

Tailor dosage adjustments for deferiprone tablets (three times a day) to the individual patient’s response and therapeutic goals (maintenance or reduction of body iron burden). The maximum oral dosage is 99 mg/kg/day (actual body weight), in three divided doses per day. Table 4 describes the number of deferiprone tablets (three times a day) needed to achieve the 99 mg/day total maximum daily dosage.

Pediatric use information is approved for Chiesi USA, Inc.’s FERRIPROX® (deferiprone) tablets. However, due to Chiesi USA, Inc.’s marketing exclusivity rights, this drug product is not labeled with that information.

2.5 Monitoring Ferritin Levels to Assess Efficacy

Monitor serum ferritin concentration every two to three months to assess the effect of deferiprone tablets on body iron stores. If the serum ferritin is consistently below 500 mcg/L, consider temporarily interrupting deferiprone tablets therapy until serum ferritin rises above 500 mcg/L.

2.6 Dosage Modification for Drug Interactions

Allow at least a 4-hour interval between administration of deferiprone tablets 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 deferiprone tablets use. Deferiprone tablets can also cause neutropenia, which may foreshadow agranulocytosis. Measure the absolute neutrophil count (ANC) before starting deferiprone tablets therapy and monitor it regularly while on therapy [see Dosage and Administration (2.1)].

Reduction in the frequency of ANC monitoring should be considered on an individual patient basis, according to the health care provider’s assessment of the patient’s understanding of the risk minimization measures required during therapy.

Interrupt deferiprone tablets therapy if neutropenia develops (ANC < 1.5 x 109/L).

Interrupt deferiprone tablets if infection develops and monitor the ANC frequently.

Advise patients taking deferiprone tablets to immediately interrupt therapy and report to their physician if they experience any symptoms indicative of infection.

The incidence of agranulocytosis was 1.7% of patients in pooled clinical trials of 642 patients with thalassemia syndromes. The mechanism of deferiprone-associated agranulocytosis is unknown. Agranulocytosis and neutropenia usually resolve upon discontinuation of deferiprone tablets, 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 deferiprone tablets treatment.

For agranulocytosis (ANC < 0.5 x 109/L):

Consider hospitalization and other management as clinically appropriate.

Do not resume deferiprone tablets in patients who have developed agranulocytosis unless potential benefits outweigh potential risks. Do not rechallenge patients who have developed neutropenia with deferiprone tablets 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 deferiprone tablets 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 pooled clinical trials, 7.5% of 642 patients with thalassemia syndromes treated with deferiprone tablets developed increased ALT values. Four (0.62%) deferiprone tablet-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 deferiprone tablets and consider interruption of therapy if there is a persistent increase in the serum transaminase levels [see Dosage and Administration (2.1)].

5.3 Zinc Deficiency

Decreased plasma zinc concentrations have been observed on deferiprone tablets therapy. Monitor plasma zinc annually, and supplement in the event of a deficiency [see Dosage and Administration (2.1)].

5.4 Embryo-Fetal Toxicity

Based on findings from animal reproduction studies and evidence of genotoxicity, deferiprone tablets can cause fetal harm when administered to a pregnant woman. The available data on the use of deferiprone tablets in pregnant women are insufficient to inform risk. In animal studies, administration of deferiprone during the period of organogenesis resulted in embryo-fetal 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 deferiprone tablets 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 deferiprone tablets 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.

The following adverse reaction information represents the pooled data collected from single arm or active-controlled clinical trials with deferiprone tablets (three times a day).

Thalassemia Syndromes:

The safety of deferiprone tablets was evaluated in the pooled clinical trial database [see Clinical Studies (14.1)]. Patients received deferiprone tablets (three times a day). Deferiprone tablets were administered orally three times a day (total daily dose either 50, 75, or 99 mg/kg), N=642. Among 642 patients receiving deferiprone tablets, 492 (76.6%) were exposed for 6 months or longer and 365 (56.9%) were exposed for greater than one year.

The median age of patients who received deferiprone tablets was 19 years (range 1, 77 years); 50.2% female; 71.2% White, 17.8% Asian, 9.2% Unknown, 1.2% Multi-racial and 0.6% Black.

The most serious adverse reaction reported in clinical trials with deferiprone tablets was agranulocytosis [see Warnings and Precautions (5.1)].

The most common adverse reactions (≥6%) reported during clinical trials were nausea, vomiting, abdominal pain, arthralgia, alanine aminotransferase increased and neutropenia.

The table below lists the adverse drug reactions that occurred in at least 1% of patients treated with deferiprone tablets in clinical trials in patients with thalassemia syndromes.

Table 7: Adverse reactions occurring in ≥ 1% of deferiprone tablets-treated patients with thalassemia syndromes

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 deferiprone tablets 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 deferiprone tablets. 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, 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 deferiprone tablets 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 Deferiprone Tablets

UDP-Glucuronosyltransferases (UGTs):

Avoid use of UGT1A6 inhibitors (e.g., diclofenac, probenecid, or silymarin (milk thistle)) with deferiprone tablets [see Dosage and Administration (2.2), Adverse Reactions (6.1), 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 deferiprone tablets 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 available data from deferiprone use in pregnant women are insufficient to inform a drug-associated risk of major birth defects and miscarriage. Based on evidence and developmental toxicity in animal studies, deferiprone tablets 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 deferiprone-treated patients and 10 pregnancies of partners of deferiprone-treated patients are as follows:

Of the 39 pregnancies in deferiprone-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 deferiprone-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 deferiprone tablets, 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 deferiprone tablets.

Contraception:

Females:

Deferiprone tablets 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 deferiprone tablets 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 deferiprone tablets and for at least 3 months after the last dose [see Nonclinical Toxicology (13.1)].

8.4 Pediatric Use

Safety and effectiveness of deferiprone tablets have not been established in pediatric patients with chronic iron overload due to blood transfusions who are less than 8 years of age.

Pediatric use information is approved for Chiesi USA, Inc.’s FERRIPROX® (deferiprone) tablets. However, due to Chiesi USA, Inc.’s marketing exclusivity rights, this drug product is not labeled with that information.

8.5 Geriatric Use

Clinical studies of deferiprone 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 with an affinity for ferric ions (iron III). Deferiprone binds with ferric ions to form neutral 3:1 (deferiprone:iron) complexes that are stable at physiological pH.

12.2 Pharmacodynamics

No clinical studies were performed to assess the relationship between the dose of deferiprone and the amount of iron eliminated from the body.

Cardiac Electrophysiology:

At the maximum approved recommended dose, deferiprone does not prolong the QT interval to any clinically relevant extent.

12.3 Pharmacokinetics

Deferiprone Tablets (three times a day), 1,000 mg:

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: 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.

14.1 Transfusional Iron Overload in Patients with Thalassemia Syndromes

In a prospective, planned, pooled analysis of patients with thalassemia syndromes from several studies, the efficacy of deferiprone 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 deferiprone. Deferiprone 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 (range 2 to 62; 91 patients were <17).

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.