FDA Label for Deferiprone

Warning: Agranulocytosis And Neutropenia

• •Deferiprone tablets 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 deferiprone tablets therapy and monitor weekly while on therapy. Interrupt deferiprone tablets therapy if neutropenia develops. [see Warnings and Precautions (5.1)]
• •Interrupt deferiprone tablets if infection develops and monitor the ANC more frequently. [see Warnings and Precautions (5.1)]
• •Advise patients taking deferiprone tablets to report immediately any symptoms indicative of infection. [see Warningsand Precautions (5.1)]

1 Indications And Usage

Deferiprone tablets are 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.

2.1 Recommended Dosage

Starting Dose:

The recommended initial dose of deferiprone tablets 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).

Table 1a: Tablet requirement to achieve a 25 mg/kg dose (rounded to the nearest half-tablet) for administration three times a day.

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.

Table 1b: Tablet requirement to achieve 33 mg/kg dose (rounded to the nearest half-tablet) for administration three times a day.

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.

2.2 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)].

3 Dosage Forms And Strengths

Tablets: 500 mg film-coated, modified capsule shaped, white to off-white with functional scoring and debossed with 54 [score] 422 on one side and plain on the other.

4 Contraindications

Deferiprone tablets are 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)].

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 weekly while on therapy.

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

Interrupt deferiprone tablets therapy 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.

In pooled clinical trials, the incidence of agranulocytosis was 1.7% of patients. The mechanism of deferiprone tablets-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 clinical studies, 7.5% of 642 patients treated with deferiprone tablets developed increased ALT values. Four (0.62%) deferiprone tablets-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.

5.3 Zinc Deficiency

Decreased plasma zinc concentrations have been observed on deferiprone tablets 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, 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 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 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 Adverse Reactions

The following clinically significant adverse reactions are described below and elsewhere in the labeling:

• •Agranulocytosis and Neutropenia [see Warnings and Precautions (5.1)]
• •Liver Enzyme Elevations [see Warnings and Precautions (5.2)]
• •Zinc Deficiency [see Warnings and Precautions (5.3)]

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 deferiprone tablets 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 deferiprone tablets 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 deferiprone tablets in clinical trials.

Table 2: Adverse drug reactions occurring in ≥ 1% of deferiprone tablets-treated patients

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, 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 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 co-administration of deferiprone tablets 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 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 data from deferiprone tablets 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, 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-tablets-treated patients and 10 pregnancies of partners of deferiprone tablets-treated patients are as follows:

Of the 39 pregnancies in deferiprone tablets-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 tablets-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 tablets 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

The safety and effectiveness of deferiprone tablets in pediatric patients have not been established.

8.5 Geriatric Use

Clinical studies of deferiprone tablets 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.

10 Overdosage

No cases of acute overdose have been reported. There is no specific antidote to deferiprone tablets 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.

11 Description

Deferiprone tablets contain 500 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:

deferiprone-chem-structure.jpg - deferiprone chem structure

Deferiprone is a white crystalline powder. It is slightly soluble in deionized water and has a melting point range of 271°C - 273°C.

Deferiprone tablets are white to off-white, modified capsule shaped, biconvex, film coated tablet, debossed with 54 [score] 422 on one side and plain on the other. The tablets can be broken in half along the score line. Each tablet contains 500 mg deferiprone and the following inactive ingredients: Tablet core - colloidal silicon dioxide, crospovidone, magnesium stearate, microcrystalline cellulose; Coating - hypromellose, polyethylene glycol, polysorbate 80, titanium dioxide, and water, purified.

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, deferiprone tablets do not prolong the QT interval to any clinically relevant extent.

12.3 Pharmacokinetics

The mean C_max 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.

14 Clinical Studies

Transfusional Iron Overload:

In a prospective, planned, pooled analysis of patients from several studies, the efficacy of deferiprone tablets 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 tablets. Deferiprone tablets 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.

16 How Supplied/Storage And Handling

Deferiprone Tablets:

500 mg, white to off-white, modified capsule shaped, biconvex, film coated tablet, debossed with 54 [score] 422 on one side and plain on the other side. They are provided in a 100 count and 300 count HDPE bottle with a child-resistant cap.

NDC 0054-0576-25: Bottle of 100 Tablets

NDC 0054-0576-28: Bottle of 300 Tablets

Storage:

Store at 20° to 25°C (68° to 77°F); [see USP Controlled Room Temperature].

17 Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (Medication Guide)

• •Instruct patients and their caregivers to store deferiprone tablets at 20° to 25°C (68° to 77°F); [see USP Controlled Room Temperature]. Instruct patients and their caregivers to store deferiprone tablets out of the reach and sight of children.
• •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.
• •Inform patients that their blood will be checked to monitor liver function and zinc levels. A zinc supplement may be prescribed if zinc levels are low.
• •Advise patients to take the first dose of deferiprone tablets in the morning, the second dose at midday, and the third dose in the evening. Clinical experience suggests that taking deferiprone tablets with meals may reduce nausea. If a dose of this medicine has been missed, take it 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 iron. This is a very common sign of the desired effect of deferiprone tablets, and it is not harmful.

Embryo-Fetal toxicity:

Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions (5.4) and 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 six months after the last dose [see Use in Specific Populations (8.1, 8.3)]. Advise males with female partners of reproductive potential to use effective contraception during treatment with deferiprone and for at least three months after the last dose [see Use in Specific Populations (8.3) and Nonclinical Toxicology (13.1)].

Lactation:

Advise females not to breastfeed during treatment with deferiprone tablets and for at least 2 weeks after the last dose [see Use in Specific Populations (8.2)].

Distr. by: Hikma Pharmaceuticals USA Inc.

Berkeley Heights, NJ 07922

C50000816/01

Revised January 2021

Medication Guide

See “What are the possible side effects of deferiprone tablets?” for more information about side effects.

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins and herbal supplements.

Keep deferiprone tablets and all medicines out of the reach of children.

Package/Label Principal Display Panel

Deferiprone Tablets, 500 mg Bottle of 100 NDC 0054-0576-25

deferiprone-tabs-bl-100s - image 01

Deferiprone Tablets, 500 mg Bottle of 300 NDC 0054-0576-28