FEMALES & MALES OF REPRODUCTIVE POTENTIAL SECTION.

8.3 Females and Males of Reproductive Potential. Pregnancy TestingPregnancy testing is recommended for females of reproductive potential prior to initiating deferiprone.. Contraception. FemalesDeferiprone can cause embryo-fetal harm when administered to pregnant woman [see Use in Specific Populations (8.1)]. Advise female patients of reproductive potential to use effective contraception during treatment with deferiprone and for at least months after the last dose.. MalesBased on genotoxicity findings, advise males with female partners of reproductive potential to use effective contraception during treatment with deferiprone and for at least months after the last dose [see Nonclinical Toxicology (13.1)].

GERIATRIC USE SECTION.

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.

ADVERSE REACTIONS SECTION.

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)] 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)] The most common adverse reactions are (incidence >= 5%) nausea, vomiting and abdominal pain, alanine aminotransferase increased, arthralgia and neutropenia. (5.1, 6)To report SUSPECTED ADVERSE REACTIONS, contact Taro Pharmaceuticals U.S.A., Inc. at 1-866-923-4914 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trial Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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 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 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 in clinical trials.Table 2: Adverse drug reactions occurring in >= 1% of deferiprone-treated patientsBody System(N=642) Adverse Reaction% SubjectsBLOOD AND LYMPHATIC SYSTEM DISORDERS Neutropenia6 Agranulocytosis2GASTROINTESTINAL DISORDERS Nausea13 Abdominal pain/discomfort10 Vomiting10 Diarrhea3 Dyspepsia2INVESTIGATIONS Alanine Aminotransferase increased7 Weight increased2 Aspartate Aminotransferase increased1METABOLISM AND NUTRITION DISORDERS Increased appetite4 Decreased appetite1MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS Arthralgia10 Back pain2 Pain in extremity2 Arthropathy1NERVOUS SYSTEM DISORDERSHeadache2Gastrointestinal 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 therapy in 1.6% of patients.Chromaturia (reddish/brown discoloration of the urine) is 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. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or to establish 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-Schonlein purpura.Vascular disorders: hypotension, hypertension.

BOXED WARNING SECTION.

WARNING: AGRANULOCYTOSIS AND NEUTROPENIA. Deferiprone 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 therapy and monitor weekly while on therapy. Interrupt deferiprone therapy if neutropenia develops. [see Warnings and Precautions (5.1)] Interrupt deferiprone if infection develops and monitor the ANC more frequently. [see Warnings and Precautions (5.1)] Advise patients taking deferiprone to report immediately any symptoms indicative of infection. [see Warnings and Precautions (5.1)] Deferiprone 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 therapy and monitor weekly while on therapy. Interrupt deferiprone therapy if neutropenia develops. [see Warnings and Precautions (5.1)] Interrupt deferiprone if infection develops and monitor the ANC more frequently. [see Warnings and Precautions (5.1)] Advise patients taking deferiprone to report immediately any symptoms indicative of infection. [see Warnings and Precautions (5.1)] WARNING: AGRANULOCYTOSIS AND NEUTROPENIASee full prescribing information for complete boxed warning.Deferiprone can cause agranulocytosis that can lead to serious infections and death. Neutropenia may precede the development of agranulocytosis. (5.1)Measure the absolute neutrophil count (ANC) before starting deferiprone and monitor weekly while on therapy. (5.1)Interrupt deferiprone if infection develops and monitor the ANC more frequently. (5.1)Advise patients taking deferiprone to report immediately any symptoms indicative of infection. (5.1). Deferiprone can cause agranulocytosis that can lead to serious infections and death. Neutropenia may precede the development of agranulocytosis. (5.1). Measure the absolute neutrophil count (ANC) before starting deferiprone and monitor weekly while on therapy. (5.1). Interrupt deferiprone if infection develops and monitor the ANC more frequently. (5.1). Advise patients taking deferiprone to report immediately any symptoms indicative of infection. (5.1).

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

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 mouse lymphoma cell assay in vitro. Deferiprone was clastogenic in an in vitro chromosomal aberration test in mice and in chromosomal aberration test in Chinese Hamster Ovary cells. Deferiprone given orally or intraperitoneally was clastogenic in bone marrow micronucleus assay in non-iron-loaded mice. 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.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Deferiprone is chelating agent that binds with ferric ions (iron III) to form neutral 3:1 (deferiprone:iron) complexes that are stable over wide range of pH values. Deferiprone has 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 ElectrophysiologyAt dose 1.5 times the maximum approved recommended dosage, deferiprone does not prolong the QT interval to any clinically relevant extent.. 12.3 Pharmacokinetics. The mean Cmax and AUC of deferiprone was 20 mcg/mL and 50 mcgh/mL, respectively, in healthy subjects. The dose proportionality of deferiprone over the approved recommended dosage range is unknown.. AbsorptionDeferiprone appeared in the blood within to 10 minutes after oral administration. Peak serum concentration of deferiprone was reached approximately to hours after single dose.. Effect of FoodNo clinically significant differences in the pharmacokinetics of deferiprone were observed following administration with food.. EliminationThe elimination half-life of deferiprone is approximately hours.. MetabolismDeferiprone is metabolized primarily by UGT1A6. The major metabolite of deferiprone is the 3-O-glucuronide, which lacks iron binding capability.. ExcretionFollowing oral administration, 75% to 90% of the administered dose was recovered in urine (primarily as metabolite) in the first 24 hours.. Specific PopulationsNo 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).

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. Transfusional Iron OverloadIn prospective, planned, pooled analysis of patients 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 to 99 mg/kg/day) was considered successful in individual patients who experienced >= 20% decline in serum ferritin within one year of starting therapy.Data from 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 20% reduction in serum ferritin was met in 50% (of 236 subjects), with 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 mean at baseline of 11.8 +- 4.9 ms to mean of 15.1 +- 7.0 ms after approximately one year of treatment. The clinical significance of this observation is not known.

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. Deferiprone Tablets, 500 mg are white to pinkish-white, capsule-shaped tablets; scored on one side, engraved T on the left of the score line and 5 on the right and plain on the other side. They are provided in 100 count HDPE bottle with child-resistant cap.500 mg tablets, 100 tablets NDC 51672-4196-1. Store at 20 to 25C (68 to 77F) [see USP Controlled Room Temperature]. Keep the bottle tightly closed to protect from moisture.

CLINICAL TRIALS EXPERIENCE SECTION.

6.1 Clinical Trial Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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 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 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 in clinical trials.Table 2: Adverse drug reactions occurring in >= 1% of deferiprone-treated patientsBody System(N=642) Adverse Reaction% SubjectsBLOOD AND LYMPHATIC SYSTEM DISORDERS Neutropenia6 Agranulocytosis2GASTROINTESTINAL DISORDERS Nausea13 Abdominal pain/discomfort10 Vomiting10 Diarrhea3 Dyspepsia2INVESTIGATIONS Alanine Aminotransferase increased7 Weight increased2 Aspartate Aminotransferase increased1METABOLISM AND NUTRITION DISORDERS Increased appetite4 Decreased appetite1MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS Arthralgia10 Back pain2 Pain in extremity2 Arthropathy1NERVOUS SYSTEM DISORDERSHeadache2Gastrointestinal 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 therapy in 1.6% of patients.Chromaturia (reddish/brown discoloration of the urine) is result of the excretion of iron in the urine.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. Deferiprone is 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-Schonlein purpura; urticaria; and periorbital edema with skin rash [see Adverse Reactions (6.2)]. Hypersensitivity to deferiprone or to any of the excipients in the formulation. (4).

DESCRIPTION SECTION.

11 DESCRIPTION. Deferiprone tablets contain 500 mg deferiprone (3-hydroxy-1,2-dimethylpyridin-4-one), 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 white to pinkish-white powder. It is sparingly soluble in deionized water and has melting point range of 272 to 278 C.Deferiprone tablets are white to pinkish-white, capsule-shaped tablets; scored on one side, engraved T on the left of the score line and 5 on the right and plain on the other side. The tablets can be broken in half along the score line. Each tablet contains 500 mg deferiprone and the following inactive ingredients: colloidal silicon dioxide, magnesium stearate, and microcrystalline cellulose.. Chemical Structure.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. 25 mg/kg to 33 mg/kg actual body weight, orally, three times per day, for total daily dose of 75 mg/kg to 99 mg/kg body weight. (2.1). 2.1 Recommended Dosage. Starting DoseThe recommended initial dose of deferiprone is 25 mg/kg actual body weight, orally, three times per day for total of 75 mg/kg/day. Round dose to the nearest 250 mg (half-tablet).Table 1a: Tablet requirement to achieve 25 mg/kg dose (rounded to the nearest half-tablet) for administration three times day.Body Weight (kg)Dose (mg)Number of 500 mg tablets205001307501.5401,0002501,2502.5601,5003701,7503.5802,0004902,2504.5. Dose AdjustmentsTailor dose adjustments to the individual patients 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 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 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 on body iron stores. If the serum ferritin is consistently below 500 mcg/L, consider temporarily interrupting deferiprone therapy until serum ferritin rises above 500 mcg/L.. 2.2 Dosage Modification for Drug Interactions. Allow at least 4-hour interval between administration of deferiprone and other drugs or supplements containing polyvalent cations such as iron, aluminum, or zinc [see Drug Interactions (7.2), Clinical Pharmacology (12.3)].

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. Tablets, 500 mg are white to pinkish-white, capsule-shaped tablets; scored on one side, engraved T on the left of the score line and 5 on the right and plain on the other side.. Tablets: 500 mg with functional scoring. (3).

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. Drugs Associated with Neutropenia or Agranulocytosis: Avoid co-administration. If co-administration is unavoidable, closely monitor the absolute neutrophil count. (7.1)UGT1A6 inhibitors: Avoid co-administration. (7.2)Polyvalent Cations: Allow at least 4-hour interval between administration of deferiprone and drugs or supplements containing polyvalent cations (e.g., iron, aluminum, or zinc). (2.2, 7.2). Drugs Associated with Neutropenia or Agranulocytosis: Avoid co-administration. If co-administration is unavoidable, closely monitor the absolute neutrophil count. (7.1). UGT1A6 inhibitors: Avoid co-administration. (7.2). Polyvalent Cations: Allow at least 4-hour interval between administration of deferiprone and drugs or supplements containing polyvalent cations (e.g., iron, aluminum, or zinc). (2.2, 7.2). 7.1 Drugs Associated with Neutropenia or Agranulocytosis. Avoid co-administration of deferiprone 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. UDP-Glucuronosyltransferases (UGTs)Avoid co-administration of deferiprone with 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 CationsDeferiprone has the potential to bind polyvalent cations (e.g., iron, aluminum, and zinc); allow at least 4-hour interval between administration of deferiprone and other medications (e.g., antacids) or supplements containing these polyvalent cations [see Dosage and Administration (2.2)].

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. Deferiprone is indicated for the treatment of patients with transfusional iron overload due to thalassemia syndromes when current chelation therapy is inadequate.Approval is based on reduction in serum ferritin levels. There are no controlled trials demonstrating direct treatment benefit, such as improvement in disease-related symptoms, functioning, or increased survival [see Clinical Studies (14)]. Deferiprone is an iron chelator indicated for the treatment of patients with transfusional iron overload due to thalassemia syndromes when current chelation therapy is inadequate. (1)Approval is based on reduction in serum ferritin levels. There are no controlled trials demonstrating direct treatment benefit, such as improvement in disease-related symptoms, functioning, or increased survival. (1)Limitations of UseSafety and effectiveness have not been established for the treatment of transfusional iron overload in patients with other chronic anemias. (1). Limitations of UseSafety and effectiveness have not been established for the treatment of transfusional iron overload in patients with other chronic anemias.. Safety and effectiveness have not been established for the treatment of transfusional iron overload in patients with other chronic anemias.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling (Medication Guide)Instruct patients and their caregivers to store deferiprone at 20C to 25C (68F to 77F) [see USP Controlled Room Temperature]. Instruct patients and their caregivers to store deferiprone 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. zinc supplement may be prescribed if zinc levels are low.Advise patients to take the first dose of deferiprone in the morning, the second dose at midday, and the third dose in the evening. Clinical experience suggests that taking deferiprone with meals may reduce nausea. If 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 reddish/brown discoloration due to the excretion of iron. This is very common sign of the desired effect of deferiprone, and it is not harmful.. Instruct patients and their caregivers to store deferiprone at 20C to 25C (68F to 77F) [see USP Controlled Room Temperature]. Instruct patients and their caregivers to store deferiprone 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. zinc supplement may be prescribed if zinc levels are low.. Advise patients to take the first dose of deferiprone in the morning, the second dose at midday, and the third dose in the evening. Clinical experience suggests that taking deferiprone with meals may reduce nausea. If 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 reddish/brown discoloration due to the excretion of iron. This is very common sign of the desired effect of deferiprone, and it is not harmful.. Embryo-Fetal toxicityAdvise pregnant women and females of reproductive potential of the potential risk to fetus. Advise females to inform their healthcare provider of 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 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)].. LactationAdvise females not to breastfeed during treatment with deferiprone and for at least weeks after the last dose [see Use in Specific Populations (8.2)].

LACTATION SECTION.

8.2 Lactation. Risk SummaryThere 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, and for at least weeks after the last dose.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. Deferiprone is chelating agent that binds with ferric ions (iron III) to form neutral 3:1 (deferiprone:iron) complexes that are stable over wide range of pH values. Deferiprone has lower binding affinity for other metals (e.g., copper, aluminum and zinc) than for iron.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 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 mouse lymphoma cell assay in vitro. Deferiprone was clastogenic in an in vitro chromosomal aberration test in mice and in chromosomal aberration test in Chinese Hamster Ovary cells. Deferiprone given orally or intraperitoneally was clastogenic in bone marrow micronucleus assay in non-iron-loaded mice. 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.

OVERDOSAGE SECTION.

10 OVERDOSAGE. No cases of acute overdose have been reported. There is no specific antidote to deferiprone 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 times the recommended dose for more than one year. The neurological disorders progressively regressed after deferiprone discontinuation.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANEL 500 mg Tablet Bottle Label. NDC 51672-4196-1 100 TabletsDeferiprone Tablets 500 mgPHARMACIST: Dispense Medication Guide to each patient. Print Medication Guides at: www.taro.comTARORx only. PRINCIPAL DISPLAY PANEL 500 mg Tablet Bottle Label.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. The safety and effectiveness of deferiprone in pediatric patients have not been established.

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. Deferiprone exposure-response relationships and the time course of pharmacodynamics response are unknown.. Cardiac ElectrophysiologyAt dose 1.5 times the maximum approved recommended dosage, deferiprone does not prolong the QT interval to any clinically relevant extent.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. The mean Cmax and AUC of deferiprone was 20 mcg/mL and 50 mcgh/mL, respectively, in healthy subjects. The dose proportionality of deferiprone over the approved recommended dosage range is unknown.. AbsorptionDeferiprone appeared in the blood within to 10 minutes after oral administration. Peak serum concentration of deferiprone was reached approximately to hours after single dose.. Effect of FoodNo clinically significant differences in the pharmacokinetics of deferiprone were observed following administration with food.. EliminationThe elimination half-life of deferiprone is approximately hours.. MetabolismDeferiprone is metabolized primarily by UGT1A6. The major metabolite of deferiprone is the 3-O-glucuronide, which lacks iron binding capability.. ExcretionFollowing oral administration, 75% to 90% of the administered dose was recovered in urine (primarily as metabolite) in the first 24 hours.. Specific PopulationsNo 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).

POSTMARKETING EXPERIENCE SECTION.

6.2 Postmarketing Experience. The following additional adverse reactions have been reported in patients receiving deferiprone. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or to establish 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-Schonlein purpura.Vascular disorders: hypotension, hypertension.

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryIn 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 use in pregnant women are insufficient to inform drug-associated risk of major birth defects and miscarriage. Based on evidence of genotoxicity and developmental toxicity in animal studies, deferiprone can cause fetal harm when administered to pregnant woman. Advise pregnant women and females of reproductive potential of the potential risk to fetus.The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have 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 to 4% and 15 to 20%, respectively.. Data. Human DataPost-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, ended in spontaneous abortion, had unknown outcomes, and infant was born with anal atresia, nephroptosis, ventricular septal defect, hemivertebra and urethral fistula.Of the 10 pregnancies in partners of deferiprone-treated patients, resulted in healthy newborns, resulted in healthy newborn with slight hypospadias, was electively terminated, resulted in the intrauterine death of twins, and had unknown outcomes.. Animal DataDuring 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 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.

SPL MEDGUIDE SECTION.

Dispense with Medication Guide available at: https://www.taro.com/usa-medication-guides Medication Guide Deferiprone (de-fer-ip-rone) TabletsThis Medication Guide has been approved by the U.S. Food and Drug Administration.Revised: 3/2020What is the most important information should know about deferiproneDeferiprone can cause serious side effects, including very low white blood cell count. One type of white blood cell that is important for fighting infections is called neutrophil. If your neutrophil count is low (neutropenia), you may be at risk of developing serious infection that can lead to death. Neutropenia is common with deferiprone 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 blood test before you start deferiprone 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 if you develop neutropenia or infection.Stop taking deferiprone and get medical help right away if you develop any of these symptoms of infection:feversore throat or mouth soresflu-like symptomschills and severe shaking.See What are the possible side effects of deferiprone for more information about side effects.What is deferiproneDeferiprone is 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 is 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 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 problemsare pregnant or plan to become pregnant. Deferiprone can harm your unborn baby. You should avoid becoming pregnant during treatment with deferiprone. Tell your healthcare provider right away if you become pregnant during treatment with deferiprone. Females who are able to become pregnant: Your healthcare provider should do pregnancy test before you start treatment with deferiprone.You should use effective birth control during treatment with deferiprone and for at least months after the last dose. Males with female partners who are able to become pregnant: You should use effective birth control during treatment with deferiprone and for at least 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 and for 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 take deferiproneTake deferiprone exactly as your healthcare provider tells you.Your healthcare provider will prescribe deferiprone based on your body weight.Your healthcare provider will check your body iron level during treatment with deferiprone and may change your dose if needed. Your healthcare provider may also change your dose of deferiprone if you have certain side effects. Do not change your dose of deferiprone unless your healthcare provider tells you to.Take deferiprone 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 with meals may help reduce nausea.If you must take medicine to treat indigestion (antacid), or mineral supplements that contain iron, aluminum, or zinc during treatment with deferiprone, allow at least hours between taking deferiprone and these products.If you take too much deferiprone, call your healthcare provider.If you miss 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 doses at the same time to make up for missed dose.What are the possible side effects of deferiproneDeferiprone can cause serious side effects, including:See What is the most important information should know about deferiproneIncreased liver enzyme levels in your blood. Your healthcare provider should do monthly blood tests to check your liver function during treatment with deferiprone.Decreased levels of zinc in your blood. Your healthcare provider will do blood tests to check your zinc levels during treatment with deferiprone and may prescribe zinc supplement for you if your zinc levels are low.The most common side effects of deferiprone include:nauseavomitingstomach-area (abdominal) painjoint painDeferiprone may cause change in urine color to reddish-brown. This is not harmful and is expected during treatment with deferiprone.These are not all the possible side effects of deferiprone.Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How should store deferiprone tabletsStore deferiprone tablets at room temperature, 68F to 77F (20C to 25C) [see USP Controlled Room Temperature].Keep deferiprone and all medicines out of the reach of children.General information about the safe and effective use of deferiprone.Medicines are sometimes prescribed for purposes other than those listed in Medication Guide. Do not use deferiprone for condition for which it was not prescribed. Do not give deferiprone 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 that is written for health professionals.What are the ingredients in deferiprone tabletsActive ingredient: deferiproneInactive ingredients: colloidal silicon dioxide, magnesium stearate, and microcrystalline cellulose.Mfd. by: Taro Pharmaceutical Industries Ltd., Haifa Bay, Israel, 2624761Dist. by: Taro Pharmaceuticals U.S.A., Inc., Hawthorne, NY, 10532Revised: March 2020 20872-0320-1For more information, call 1-866-923-4914 or visit www.taro.com.. fever. sore throat or mouth sores. flu-like symptoms. chills and severe shaking.. to treat iron overload due to blood transfusions in people with any other type of anemia that is long lasting (chronic). in children. have liver problems. are pregnant or plan to become pregnant. Deferiprone can harm your unborn baby. You should avoid becoming pregnant during treatment with deferiprone. Tell your healthcare provider right away if you become pregnant during treatment with deferiprone. Females who are able to become pregnant: Your healthcare provider should do pregnancy test before you start treatment with deferiprone.You should use effective birth control during treatment with deferiprone and for at least months after the last dose. Males with female partners who are able to become pregnant: You should use effective birth control during treatment with deferiprone and for at least months after the last dose. Your healthcare provider should do pregnancy test before you start treatment with deferiprone.. You should use effective birth control during treatment with deferiprone and for at least months after the last dose.. You should use effective birth control during treatment with deferiprone and for at least 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 and for weeks after the last dose.. Take deferiprone exactly as your healthcare provider tells you.. Your healthcare provider will prescribe deferiprone based on your body weight.. Your healthcare provider will check your body iron level during treatment with deferiprone and may change your dose if needed. Your healthcare provider may also change your dose of deferiprone if you have certain side effects. Do not change your dose of deferiprone unless your healthcare provider tells you to.. Take deferiprone 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 with meals may help reduce nausea.. If you must take medicine to treat indigestion (antacid), or mineral supplements that contain iron, aluminum, or zinc during treatment with deferiprone, allow at least hours between taking deferiprone and these products.. If you take too much deferiprone, call your healthcare provider.. If you miss 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 doses at the same time to make up for missed dose.. See What is the most important information should know about deferiprone. Increased liver enzyme levels in your blood. Your healthcare provider should do monthly blood tests to check your liver function during treatment with deferiprone.. Decreased levels of zinc in your blood. Your healthcare provider will do blood tests to check your zinc levels during treatment with deferiprone and may prescribe zinc supplement for you if your zinc levels are low.. nausea. vomiting. stomach-area (abdominal) pain. joint pain. Store deferiprone tablets at room temperature, 68F to 77F (20C to 25C) [see USP Controlled Room Temperature].

SPL UNCLASSIFIED SECTION.

Limitations of UseSafety and effectiveness have not been established for the treatment of transfusional iron overload in patients with other chronic anemias.. Safety and effectiveness have not been established for the treatment of transfusional iron overload in patients with other chronic anemias.

STORAGE AND HANDLING SECTION.

Store at 20 to 25C (68 to 77F) [see USP Controlled Room Temperature]. Keep the bottle tightly closed to protect from moisture.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Lactation: Advise not to breastfeed. (8.2). 8.1 Pregnancy. Risk SummaryIn 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 use in pregnant women are insufficient to inform drug-associated risk of major birth defects and miscarriage. Based on evidence of genotoxicity and developmental toxicity in animal studies, deferiprone can cause fetal harm when administered to pregnant woman. Advise pregnant women and females of reproductive potential of the potential risk to fetus.The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have 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 to 4% and 15 to 20%, respectively.. Data. Human DataPost-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, ended in spontaneous abortion, had unknown outcomes, and infant was born with anal atresia, nephroptosis, ventricular septal defect, hemivertebra and urethral fistula.Of the 10 pregnancies in partners of deferiprone-treated patients, resulted in healthy newborns, resulted in healthy newborn with slight hypospadias, was electively terminated, resulted in the intrauterine death of twins, and had unknown outcomes.. Animal DataDuring 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 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 SummaryThere 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, and for at least weeks after the last dose.. 8.3 Females and Males of Reproductive Potential. Pregnancy TestingPregnancy testing is recommended for females of reproductive potential prior to initiating deferiprone.. Contraception. FemalesDeferiprone can cause embryo-fetal harm when administered to pregnant woman [see Use in Specific Populations (8.1)]. Advise female patients of reproductive potential to use effective contraception during treatment with deferiprone and for at least months after the last dose.. MalesBased on genotoxicity findings, advise males with female partners of reproductive potential to use effective contraception during treatment with deferiprone and for at least months after the last dose [see Nonclinical Toxicology (13.1)].. 8.4 Pediatric Use. The safety and effectiveness of deferiprone in pediatric patients have not been established.. 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.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Liver Enzyme Elevations: Monitor monthly and discontinue for persistent elevations. (5.2)Zinc Deficiency: Monitor during therapy and supplement for deficiency. (5.3)Embryo-Fetal Toxicity: Can cause fetal harm. (5.4). Liver Enzyme Elevations: Monitor monthly and discontinue for persistent elevations. (5.2). Zinc Deficiency: Monitor during therapy and supplement for deficiency. (5.3). Embryo-Fetal Toxicity: Can cause fetal harm. (5.4). 5.1 Agranulocytosis and Neutropenia. Fatal agranulocytosis can occur with deferiprone use. Deferiprone can also cause neutropenia, which may foreshadow agranulocytosis. Measure the absolute neutrophil count (ANC) before starting deferiprone therapy and monitor it weekly while on therapy. Interrupt deferiprone therapy if neutropenia develops (ANC 1.5 109/L). Interrupt deferiprone if infection develops and monitor the ANC frequently. Advise patients taking deferiprone 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-associated agranulocytosis is unknown. Agranulocytosis and neutropenia usually resolve upon discontinuation of deferiprone, but there have been reports of agranulocytosis leading to death.Implement plan to monitor for and to manage agranulocytosis and neutropenia prior to initiating deferiprone treatment.. For agranulocytosis (ANC 0.5 109/L):Consider hospitalization and other management as clinically appropriate.Do not resume deferiprone in patients who have developed agranulocytosis unless potential benefits outweigh potential risks. Do not rechallenge patients who have developed neutropenia with deferiprone unless potential benefits outweigh potential risks.. For neutropenia (ANC 1.5 109/L and 0.5 109/L):Instruct the patient to immediately discontinue deferiprone and all other medications with potential to cause neutropenia.Obtain complete blood cell (CBC) count, including white blood cell (WBC) count corrected for the presence of nucleated red blood cells, an absolute neutrophil count (ANC), and platelet count daily until recovery (ANC >= 1.5 109/L).. 5.2 Liver Enzyme Elevations. In clinical studies, 7.5% of 642 patients treated with deferiprone developed increased ALT values. Four (0.62%) deferiprone-treated subjects discontinued the drug due to increased serum ALT levels and (0.16%) due to an increase in both ALT and AST.Monitor serum ALT values monthly during therapy with deferiprone and consider interruption of therapy if there is persistent increase in the serum transaminase levels.. 5.3 Zinc Deficiency. Decreased plasma zinc concentrations have been observed on deferiprone therapy. Monitor plasma zinc, and supplement in the event of deficiency.. 5.4 Embryo-Fetal Toxicity. Based on findings from animal reproduction studies and evidence of genotoxicity, deferiprone can cause fetal harm when administered to pregnant woman. The available data on the use of deferiprone 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 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 and for at least three months after the last dose [see Use in Specific Populations (8.1, 8.3)].

RECENT MAJOR CHANGES SECTION.

Dosage and Administration, Important Dosage and Administration Information (2.1)11/2021Warnings and Precautions, Agranulocytosis and Neutropenia (5.1)11/2021.