Data from FDA - Curated by Marshall Pearce - Last updated 31 December 2017

Indication(s)

1 INDICATIONS AND USAGE FERRIPROX® (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 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)]. Limitation of Use: Safety and effectiveness have not been established for the treatment of transfusional iron overload in patients with other chronic anemias. FERRIPROX® (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 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. (1) Limitation of Use Safety and effectiveness have not been established for the treatment of transfusional iron overload in patients with other chronic anemias. (1)

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Advisory information

contraindications
4 CONTRAINDICATIONS Ferriprox 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-Schönlein 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)
Adverse reactions
6 ADVERSE REACTIONS The most common adverse reactions are (incidence ≥ 5%) chromaturia, nausea, vomiting and abdominal pain, alanine aminotransferase increased, arthralgia and neutropenia. (5.1, 6) To report SUSPECTED ADVERSE REACTIONS, contact ApoPharma Inc. at: Telephone: 1-866-949-0995 Email: [email protected] or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Clinical Trial Experience The following adverse reactions are also discussed in other sections of the labeling: Agranulocytosis/Neutropenia [see Warnings and Precautions (5.1)]. Elevated ALT (5.3), Decreased plasma zinc concentrations (5.3). Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adverse reaction information for Ferriprox represents the pooled data collected from 642 patients who participated in single arm or active-controlled clinical studies. The most serious adverse reaction reported in clinical trials with Ferriprox was agranulocytosis [see Warnings and Precautions (5.1)]. The most common adverse reactions reported during clinical trials were chromaturia, nausea, vomiting, abdominal pain, alanine aminotransferase increased, arthralgia and neutropenia. The table below lists the adverse drug reactions that occurred in at least 1% of patients treated with Ferriprox in clinical trials. Table 2: Adverse drug reactions occurring in ≥ 1% of 642 Ferriprox-treated patients Body System % Subjects Preferred Term BLOOD AND LYMPHATIC SYSTEM DISORDERS Neutropenia 6.2 Agranulocytosis 1.7 GASTROINTESTINAL DISORDERS Nausea 12.6 Abdominal pain/discomfort 10.4 Vomiting 9.8 Diarrhea 3.0 Dyspepsia 2.0 INVESTIGATIONS Alanine Aminotransferase increased 7.5 Neutrophil count decreased 7.3 Weight increased 1.9 Aspartate Aminotransferase increased 1.2 METABOLISM AND NUTRITION DISORDERS Increased appetite 4.0 Decreased appetite 1.1 MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS Arthralgia 9.8 Back pain 2.0 Pain in extremity 1.9 Arthropathy 1.4 NERVOUS SYSTEM DISORDERS Headache 2.5 URINARY DISORDERS Chromaturia 14.6 Gastrointestinal symptoms such as nausea, vomiting, and abdominal pain were the most frequent adverse reactions reported by patients participating in clinical trials and led to the discontinuation of Ferriprox therapy in 1.6% of patients. Chromaturia (reddish/brown discoloration of the urine) is a result of the excretion of the iron in the urine. 6.2 Postmarketing Experience The following additional adverse reactions have been reported in patients receiving Ferriprox. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or to establish a causal relationship to drug exposure. Blood and lymphatic system disorders: thrombocytosis, pancytopenia. Cardiac disorders: atrial fibrillation, cardiac failure. Congenital, familial and genetic disorders: hypospadias. Eye disorders: diplopia, papilledema, retinal toxicity. Gastrointestinal disorders: enterocolitis, rectal hemorrhage, gastric ulcer, pancreatitis, parotid gland enlargement. General disorders and administration site conditions: chills, pyrexia, edema peripheral, multi-organ failure. Hepatobiliary disorders : jaundice, hepatomegaly. Immune system disorders: anaphylactic shock, hypersensitivity. Infections and infestations: cryptococcal cutaneous infection, enteroviral encephalitis, pharyngitis, pneumonia, sepsis, furuncle, 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.

Usage information

Dosing and administration
2 DOSAGE AND ADMINISTRATION The recommended initial dose of Ferriprox is 25 mg/kg, orally, three times per day for a total of 75 mg/kg/day. The maximum dose is 33 mg/kg, three times per day for a total of 99 mg/kg/day. Dose adjustments up to 33 mg/kg, orally, three times per day should be tailored to the individual patient’s response and therapeutic goals (maintenance or reduction of body iron burden). The maximum recommended total daily dose is 99 mg/kg per day. The dose should be rounded by the prescriber to the nearest 250 mg (half-tablet). Table 1a: Tablet requirement to achieve a 25 mg/kg (rounded to the nearest half-tablet) dose level for administration three times a day. Body Weight (kg) Dose (mg) Number of tablets 20 500 1 30 750 1.5 40 1000 2 50 1250 2.5 60 1500 3 70 1750 3.5 80 2000 4 90 2250 4.5 Table 1b: Tablet requirement to achieve 33 mg/kg (rounded to the nearest half-tablet) dose level for administration three times a day. Body Weight (kg) Dose (mg) Number of tablets 20 660 1.5 30 990 2 40 1320 2.5 50 1650 3.5 60 1980 4 70 2310 4.5 80 2640 5.5 90 2970 6 Monitor serum ferritin concentration every two to three months to assess the effects of Ferriprox on body iron stores. Dose adjustments should be tailored to the individual patient’s response and therapeutic goals (maintenance or reduction of body iron burden). If the serum ferritin falls consistently below 500 mcg/L, consider temporarily interrupting Ferriprox therapy. 25 mg/kg to 33 mg/kg body weight, orally, three times per day, for a total daily dose of 75 mg/kg to 99 mg/kg body weight. (2) 2.1 Interactions with Foods, Vitamins and Antacids Allow at least a 4-hour interval between Ferriprox and other medications or supplements containing polyvalent cations such as iron, aluminum, and zinc [see Drug Interactions (7.3)].
Use in special populations
8 USE IN SPECIFIC POPULATIONS Safety and efficacy of Ferriprox has not been evaluated in patients with severe hepatic impairment. (8.7) Nursing mothers: Discontinue the use of Ferriprox or discontinue nursing. (8.3) 8.1 Pregnancy Pregnancy Category D [see Warnings and Precautions (5.2), Nonclinical Toxicology (13.1)] Risk Summary Based on evidence of genotoxicity and developmental toxicity in animal studies, Ferriprox can cause fetal harm when administered to a pregnant woman. In animal studies, administration of deferiprone during the period of organogenesis resulted in embryofetal death and malformations at doses lower than equivalent human clinical doses. There are no studies in pregnant women, and available human data are limited. If Ferriprox is used during pregnancy or if the patient becomes pregnant while taking Ferriprox, the patient should be apprised of the potential hazard to the fetus. Animal Data Skeletal and soft tissue malformations occurred in offspring of rats and rabbits that received deferiprone orally during organogenesis at the lowest doses tested (25 mg/kg per day in rats; 10 mg/kg per day in rabbits). These doses were equivalent to 3% to 4% of the maximum recommended human dose (MRHD) based on body surface area. No maternal toxicity was evident at these doses. Embryofetal lethality and maternal toxicity occurred in pregnant rabbits given 100 mg/kg/day deferiprone orally during the period of organogenesis. This dose is equivalent to 32% of the MRHD based on body surface area. 8.3 Nursing Mothers It is not known whether deferiprone is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for adverse reactions in nursing infants from Ferriprox, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. 8.4 Pediatric Use The safety and effectiveness of Ferriprox tablets for oral use in pediatric patients have not been established. 8.5 Geriatric Use Safety and effectiveness in elderly individuals have not been established. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. 8.6 Renal Impairment An open-label, non-randomized, parallel group clinical study was conducted to evaluate the effect of impaired renal function on the safety, tolerability, and pharmacokinetics of a single 33 mg/kg oral dose of Ferriprox. Subjects were categorized into 4 groups based on estimated glomerular filtration rate (eGFR): healthy volunteers (eGFR ≥ 90 mL/min/1.73m2), mild renal impairment (eGFR 60–89 mL/min/1.73m2), moderate renal impairment (eGFR 30–59 mL/min/1.73m2), and severe renal impairment (eGFR 15–29 mL/min/1.73m2). Systemic exposure to deferiprone and to its metabolite deferiprone 3-O-glucuronide was assessed by the PK parameters Cmax and AUC. Regardless of the degree of renal impairment, the majority of the dose of Ferriprox was excreted in the urine over the first 24 hours as deferiprone 3-O-glucuronide. No significant effect of renal impairment was seen on systemic exposure to deferiprone. Systemic exposure to the inactive 3-O-glucuronide increased with decreasing eGFR. Based on the results of this study, no adjustment of the Ferriprox dosage regimen is required in patients with impaired renal function. 8.7 Hepatic Impairment The influence of severe hepatic impairment on the pharmacokinetics of deferiprone and deferiprone 3-O-glucuronide has not been evaluated. Safety and efficacy of Ferriprox have not been evaluated in patients with severe hepatic impairment. An open-label, non-randomized, parallel group clinical study was conducted to evaluate the effect of impaired hepatic function on the safety, tolerability, and pharmacokinetics of a single 33 mg/kg oral dose of Ferriprox. Subjects were categorized into 3 groups based on the Child-Pugh classification score: healthy volunteers, mild hepatic impairment (Class A: 5– 6 points), and moderate hepatic impairment (Class B: 7– 9 points). Systemic exposure to deferiprone and to its metabolite deferiprone 3-O-glucuronide was assessed by the PK parameters Cmax and AUC. The PK of both deferiprone and deferiprone 3-O-glucuronide was generally similar in all subjects, regardless of degree of liver impairment. A serious adverse event of acute liver and renal injury was seen in one subject with moderate hepatic impairment. Based on the results of this study, no adjustment of the Ferriprox dosage regimen is required in patients with mildly or moderately impaired hepatic function.
Pregnancy and lactation
8.3 Nursing Mothers It is not known whether deferiprone is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for adverse reactions in nursing infants from Ferriprox, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Interactions

7 DRUG INTERACTIONS Avoid concomitant use with other drugs known to be associated with neutropenia or agranulocytosis; however, if this is not possible, closely monitor the absolute neutrophil count. (7.1) Allow at least a 4-hour interval between Ferriprox and mineral supplements, and antacids that contain polyvalent cations (e.g., iron, aluminum, and zinc). (7.3) 7.1 Drugs Associated with Neutropenia or Agranulocytosis Avoid concomitant use of Ferriprox with other drugs known to be associated with neutropenia or agranulocytosis; however, if this is not possible, closely monitor the absolute neutrophil count [see Warnings and Precautions (5.1)]. 7.2 UDP-Glucuronosyltransferases (UGTs) Deferiprone is primarily eliminated via metabolism to the 3-O-glucuronide. In vitro studies suggest that UDP glucuronosyltransferase (UGT) 1A6 is primarily responsible for the glucuronidation of deferiprone which can be reduced up to 78% in the presence of the UGT1A6 inhibitor phenylbutazone. However, the clinical significance of coadministration of Ferriprox with a UGT1A6 inhibitor (e.g. diclofenac, probenecid, or silymarin (milk thistle)) on the systemic exposure of deferiprone has not been determined. Closely monitor patients for adverse reactions that may require downward dose titration or interruption when Ferriprox is concomitantly administered with a UGT1A6 inhibitor. 7.3 Polyvalent Cations Concurrent use of Ferriprox with foods, mineral supplements, and antacids that contain polyvalent cations has not been studied. However, since deferiprone has the potential to bind polyvalent cations (e.g., iron, aluminum, and zinc), allow at least a 4-hour interval between Ferriprox and other medications (e.g., antacids), or supplements containing these polyvalent cations [see Dosage and Administration (2)].

More information

Category Value
Authorisation number NDA021825
Agency product number 2BTY8KH53L
Orphan designation No
Product NDC 52609-0006
Date Last Revised 30-11-2017
Type HUMAN PRESCRIPTION DRUG
RXCUI 1190357
Marketing authorisation holder ApoPharma USA, Inc.
Warnings WARNING: AGRANULOCYTOSIS/NEUTROPENIA Ferriprox 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 Ferriprox therapy and monitor the ANC weekly on therapy. Interrupt Ferriprox therapy if neutropenia develops. [see Warnings and Precautions (5.1) ] Interrupt Ferriprox if infection develops, and monitor the ANC more frequently. [see Warnings and Precautions (5.1) ] Advise patients taking Ferriprox to report immediately any symptoms indicative of infection. [see Warnings and Precautions (5.1)] WARNING: AGRANULOCYTOSIS /NEUTROPENIA See full prescribing information for complete boxed warning. Ferriprox 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 Ferriprox and monitor the ANC weekly on therapy. (5.1) Interrupt Ferriprox if infection develops and monitor the ANC more frequently. (5.1) Advise patients taking Ferriprox to report immediately any symptoms indicative of infection. (5.1)