NDC 0054-0576 Deferiprone

Deferiprone

NDC Product Code 0054-0576

NDC CODE: 0054-0576

Proprietary Name: Deferiprone What is the Proprietary Name?
The proprietary name also known as the trade name is the name of the product chosen by the medication labeler for marketing purposes.

Non-Proprietary Name: Deferiprone What is the Non-Proprietary Name?
The non-proprietary name is sometimes called the generic name. The generic name usually includes the active ingredient(s) of the product.

Drug Use Information

Drug Use Information
The drug use information is a summary and does NOT have all possible information about this product. This information does not assure that this product is safe, effective, or appropriate. This information is not individual medical advice and does not substitute for the advice of a health care professional. Always ask a health care professional for complete information about this product and your specific health needs.

  • This medication is used by people with a certain type of blood disorder (thalassemia) who have too much iron in the body, caused by repeated blood transfusions. Blood transfusions help people with blood disorders but they also bring extra iron into the body. It is important to get rid of the extra iron because high levels of iron can cause health problems (such as heart failure, liver disease, diabetes, delayed growth in children). Deferiprone is used if you have trouble taking other traditional iron-removal medications or you continue to have high iron levels after taking other iron-removal medications. Deferiprone belongs to a class of drugs known as iron chelators. It works by attaching to iron which helps your body pass the extra iron out in the urine.

Product Characteristics

Color(s):
WHITE (C48325)
Shape: CAPSULE (C48336)
Size(s):
17 MM
Imprint(s):
54;422
Score: 2

NDC Code Structure

NDC 0054-0576-25

Package Description: 100 TABLET, COATED in 1 BOTTLE

NDC 0054-0576-28

Package Description: 300 TABLET, COATED in 1 BOTTLE

NDC Product Information

Deferiprone with NDC 0054-0576 is a a human prescription drug product labeled by Hikma Pharmaceuticals Usa Inc.. The generic name of Deferiprone is deferiprone. The product's dosage form is tablet, coated and is administered via oral form. The RxNorm Crosswalk for this NDC code indicates a single RxCUI concept is associated to this product: 389242.

Dosage Form: Tablet, Coated - A solid dosage form that contains medicinal substances with or without suitable diluents and is covered with a designated coating.

Product Type: Human Prescription Drug What kind of product is this?
Indicates the type of product, such as Human Prescription Drug or Human Over the Counter Drug. This data element matches the “Document Type” field of the Structured Product Listing.

Deferiprone Active Ingredient(s)

What is the Active Ingredient(s) List?
This is the active ingredient list. Each ingredient name is the preferred term of the UNII code submitted.


Inactive Ingredient(s)

About the Inactive Ingredient(s)
The inactive ingredients are all the component of a medicinal product OTHER than the active ingredient(s). The acronym "UNII" stands for “Unique Ingredient Identifier” and is used to identify each inactive ingredient present in a product.

  • MICROCRYSTALLINE CELLULOSE (UNII: OP1R32D61U)
  • CROSPOVIDONE (UNII: 2S7830E561)
  • MAGNESIUM STEARATE (UNII: 70097M6I30)
  • WATER (UNII: 059QF0KO0R)
  • HYPROMELLOSE, UNSPECIFIED (UNII: 3NXW29V3WO)
  • TITANIUM DIOXIDE (UNII: 15FIX9V2JP)
  • POLYSORBATE 80 (UNII: 6OZP39ZG8H)
  • POLYETHYLENE GLYCOL 1000 (UNII: U076Q6Q621)
  • SILICON DIOXIDE (UNII: ETJ7Z6XBU4)

Administration Route(s)

What are the Administration Route(s)?
The translation of the route code submitted by the firm, indicating route of administration.

  • Oral - Administration to or by way of the mouth.

Pharmacological Class(es)

What is a Pharmacological Class?
These are the reported pharmacological class categories corresponding to the SubstanceNames listed above.

  • Iron Chelating Activity - [MoA] (Mechanism of Action)
  • Iron Chelator - [EPC] (Established Pharmacologic Class)

Product Labeler Information

What is the Labeler Name?
Name of Company corresponding to the labeler code segment of the Product NDC.

Labeler Name: Hikma Pharmaceuticals Usa Inc.
Labeler Code: 0054
FDA Application Number: ANDA213239 What is the FDA Application Number?
This corresponds to the NDA, ANDA, or BLA number reported by the labeler for products which have the corresponding Marketing Category designated. If the designated Marketing Category is OTC Monograph Final or OTC Monograph Not Final, then the Application number will be the CFR citation corresponding to the appropriate Monograph (e.g. “part 341”). For unapproved drugs, this field will be null.

Marketing Category: ANDA - A product marketed under an approved Abbreviated New Drug Application. What is the Marketing Category?
Product types are broken down into several potential Marketing Categories, such as NDA/ANDA/BLA, OTC Monograph, or Unapproved Drug. One and only one Marketing Category may be chosen for a product, not all marketing categories are available to all product types. Currently, only final marketed product categories are included. The complete list of codes and translations can be found at www.fda.gov/edrls under Structured Product Labeling Resources.

Start Marketing Date: 06-03-2021 What is the Start Marketing Date?
This is the date that the labeler indicates was the start of its marketing of the drug product.

Listing Expiration Date: 12-31-2022 What is the Listing Expiration Date?
This is the date when the listing record will expire if not updated or certified by the product labeler.

Exclude Flag: N - NO What is the NDC Exclude Flag?
This field indicates whether the product has been removed/excluded from the NDC Directory for failure to respond to FDA"s requests for correction to deficient or non-compliant submissions ("Y"), or because the listing certification is expired ("E"), or because the listing data was inactivated by FDA ("I"). Values = "Y", "N", "E", or "I".

* Please review the disclaimer below.

Deferiprone Product Labeling Information

The product labeling information includes all published material associated to a drug. Product labeling documents include information like generic names, active ingredients, ingredient strength dosage, routes of administration, appearance, usage, warnings, inactive ingredients, etc.

Product Labeling Index

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.

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.Body Weight (kg)Dose (mg)Number of 500 mg tablets205001307501.5401,0002501,2502.5601,5003701,7503.5802,0004902,2504.5Dose 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.Body Weight (kg)Dose (mg)Number of 500 mg tablets206601.5309902401,3202.5501,6503.5601,9804702,3104.5802,6405.5902,9706Monitor 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 patientsBody System Adverse Reaction(N=642)% SubjectsBLOOD AND LYMPHATIC SYSTEM DISORDERS Neutropenia6 Agranulocytosis2GASTROINTESTINAL DISORDERS Nausea 13 Abdominal pain/discomfort 10 Vomiting10 Diarrhea 3 Dyspepsia2INVESTIGATIONS Alanine Aminotransferase increased 7 Weight increased Aspartate Aminotransferase increased1METABOLISM AND NUTRITION DISORDERS Increased appetite 4 Decreased appetite1MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS Arthralgia 10 Back pain2 Pain in extremity2 Arthropathy1NERVOUS SYSTEM DISORDERS Headache2Gastrointestinal 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 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 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.

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 TabletsNDC 0054-0576-28: Bottle of 300 TabletsStorage:Store at 20º to 25ºC (68º to 77ºF); [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 20º to 25ºC (68º to 77ºF); [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 07922C50000816/01Revised January 2021

Medication Guide

  • Deferiprone (de fer’ i prone) TabletsWhat is the most important information I should know about deferiprone tablets? Deferiprone tablets can cause serious side effects, including a very low white blood cell count. One type of white blood cell that is important for fighting infections is called a neutrophil. If your neutrophil count is low (neutropenia), you may be at risk of developing a serious infection that can lead to death. Neutropenia is common with deferiprone tablets and can become severe in some people. Severe neutropenia is known as agranulocytosis. If you develop agranulocytosis, you will be at risk of developing serious infections that can lead to death. Your healthcare provider should do a blood test before you start deferiprone tablets and weekly during treatment to check your neutrophil count. If you develop neutropenia, your healthcare provider should check your blood counts every day until your white blood cell count improves. Your healthcare provider may temporarily stop treatment with deferiprone tablets if you develop neutropenia or infection. Stop taking deferiprone tablets and get medical help right away if you develop any of these symptoms of infection: •fever •sore throat or mouth sores •flu-like symptoms •chills and severe shakingSee “What are the possible side effects of deferiprone tablets?” for more information about side effects. What are deferiprone tablets?Deferiprone tablets are a prescription medicine used to treat people with thalassemia syndromes who have iron overload from blood transfusions, when current iron removal (chelation) therapy does not work well enough. It is not known if deferiprone tablets are safe and effective: •to treat iron overload due to blood transfusions in people with any other type of anemia that is long lasting (chronic) •in childrenDo not take deferiprone tablets if you are allergic to deferiprone or any of the ingredients in deferiprone tablets. See the end of this Medication Guide for a complete list of ingredients in deferiprone tablets.Before you take deferiprone tablets, tell your healthcare provider about all of your medical conditions, including if you: •have liver problems •are pregnant or plan to become pregnant. Deferiprone tablets can harm your unborn baby. You should avoid becoming pregnant during treatment with deferiprone tablets. Tell your healthcare provider right away if you become pregnant during treatment with deferiprone tablets. Females who are able to become pregnant:oYour healthcare provider should do a pregnancy test before you start treatment with deferiprone tablets.oYou should use effective birth control during treatment with deferiprone tablets and for at least 6 months after the last dose. Males with female partners who are able to become pregnant:oYou should use effective birth control during treatment with deferiprone tablets and for at least 3 months after the last dose. •are breastfeeding or plan to breastfeed. It is not known if deferiprone passes into your breast milk. Do not breastfeed during treatment with deferiprone tablets and for 2 weeks after the last dose.Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins and herbal supplements. How should I take deferiprone tablets? •Take deferiprone tablets exactly as your healthcare provider tells you. •Your healthcare provider will prescribe deferiprone tablets based on your body weight. •Your healthcare provider will check your body iron level during treatment with deferiprone tablets and may change your dose if needed. Your healthcare provider may also change your dose of deferiprone tablets if you have certain side effects. Do not change your dose of deferiprone tablets unless your healthcare provider tells you to. •Take deferiprone tablets 3 times each day. Take your first dose in the morning, the second dose at mid-day, and the third dose in the evening. •Taking deferiprone tablets with meals may help reduce nausea. •If you must take a medicine to treat indigestion (antacid), or mineral supplements that contain iron, aluminum, or zinc during treatment with deferiprone tablets, allow at least 4 hours between taking deferiprone tablets and these products. •If you take too many deferiprone tablets, call your healthcare provider. •If you miss a dose, take it as soon as you remember. If it is almost time for your next dose, skip the missed dose and then continue with your regular schedule. Do not try to catch-up or take 2 doses at the same time to make up for a missed dose.What are the possible side effects of deferiprone tablets? Deferiprone tablets can cause serious side effects, including: •See “What is the most important information I should know about deferiprone tablets?” •Increased liver enzyme levels in your blood. Your healthcare provider should do monthly blood tests to check your liver function during treatment with deferiprone tablets. •Decreased levels of zinc in your blood. Your healthcare provider will do blood tests to check your zinc levels during treatment with deferiprone tablets and may prescribe a zinc supplement for you if your zinc levels are low.The most common side effects of deferiprone tablets include: •nausea •vomiting •stomach-area (abdominal) pain •joint painDeferiprone tablets may cause a change in urine color to reddish-brown. This is not harmful and is expected during treatment with deferiprone tablets. These are not all the possible side effects of deferiprone tablets. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How should I store deferiprone tablets? •Store deferiprone tablets at room temperature between 68ºF to 77ºF (20ºC to 25ºC).Keep deferiprone tablets and all medicines out of the reach of children. General information about the safe and effective use of deferiprone tablets. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use deferiprone tablets for a condition for which it was not prescribed. Do not give deferiprone tablets to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about deferiprone tablets that is written for health professionals. What are the ingredients in Deferiprone Tablets? Active ingredient: deferiprone Inactive ingredients: Tablet core: colloidal silicon dioxide, crospovidone, magnesium stearate, microcrystalline cellulose. Coating: hypromellose, polyethylene glycol, polysorbate 80, titanium dioxide, and water, purified.This Medication Guide has been approved by the U.S. Food and Drug Administration.Distr. by: Hikma Pharmaceuticals USA Inc.Berkeley Heights, NJ 07922C50000816/01Revised January 2021

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