Deferiprone

FDA Drug Information • Also known as: Deferiprone, Ferriprox

Brand Names: Deferiprone, Ferriprox
Drug Class: Iron Chelator [EPC]
Route: ORAL
Dosage Form: TABLET, FILM COATED
Product Type: HUMAN PRESCRIPTION DRUG

⚠ Boxed Warning (Black Box)

WARNING: AGRANULOCYTOSIS AND 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 regularly while on therapy. [see Warnings and Precautions ( 5.1 )] 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 AND 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 regularly while on therapy. ( 5.1 ) Interrupt FERRIPROX therapy if neutropenia develops. ( 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 )

Description

11 DESCRIPTION FERRIPROX Oral Solution (deferiprone) contains 100 mg/mL deferiprone (3-hydroxy-1,2-dimethylpyridin-4-one), a synthetic, orally active, iron-chelating agent. The molecular formula for deferiprone is C 7 H 9 NO 2 and its molecular weight is 139.15 g/mol. Deferiprone has the following structural formula: Deferiprone is a white to pinkish-white powder. It is sparingly soluble in deionized water (14.3 mg/mL) and has a melting point range of 272 °C - 278 °C. FERRIPROX Oral Solution is a clear, reddish orange colored solution. Each mL of oral solution contains 100 mg deferiprone and the following inactive ingredients: purified water, hydroxyethylcellulose, glycerin, hydrochloric acid, artificial cherry flavor, peppermint oil, FD&C Yellow No. 6, and sucralose. Structural Formula

What Is Deferiprone Used For?

1 INDICATIONS AND USAGE FERRIPROX Oral Solution is indicated for the treatment of transfusional iron overload in adult and pediatric patients 3 years of age and older with thalassemia syndromes, sickle cell disease or other anemias. FERRIPROX Oral Solution is an iron chelator indicated for the treatment of transfusional iron overload in adult and pediatric patients 3 years of age and older with thalassemia syndromes, sickle cell disease or other anemias. ( 1 ) Limitations of Use Safety and effectiveness have not been established for the treatment of transfusional iron overload in patients with myelodysplastic syndrome or in patients with Diamond Blackfan anemia. Limitations of Use Safety and effectiveness have not been established for the treatment of transfusional iron overload in patients with myelodysplastic syndrome or in patients with Diamond Blackfan anemia.

Dosage and Administration

2 DOSAGE AND ADMINISTRATION 25 mg/kg to 33 mg/kg actual body weight, orally, three times per day, for a total daily dose of 75 mg/kg to 99 mg/kg body weight. ( 2.1 ) 2.1 Important Dosage and Administration Information Monitoring for Safety Due to the risk of agranulocytosis, monitor ANC before and during FERRIPROX therapy. Test ANC prior to start of FERRIPROX therapy and monitor on the following schedule during treatment: First six months of therapy: Monitor ANC weekly; Next six months of therapy: Monitor ANC once every two weeks; After one year of therapy: Monitor ANC every two to four weeks (or at the patient's blood transfusion interval in patients that have not experienced an interruption due to any decrease in ANC [see Warnings and Precautions ( 5.1 )] . Due to the risk of hepatic transaminase elevations, monitor ALT before and monthly during FERRIPROX therapy [see Warnings and Precautions ( 5.2 )] . Due to the risk of zinc deficiency, monitor zinc levels before and regularly during FERRIPROX therapy [see Warnings and Precautions ( 5.3 )] . 2.2 Recommended Dosage for FERRIPROX Oral Solution for Adult and Pediatric Patients with Transfusional Iron Overload due to Thalassemia Syndromes, Sickle Cell Disease or Other Anemias Starting Dosage The recommended starting oral dosage of FERRIPROX Oral Solution is 25 mg/kg (actual body weight), three times per day for a total of 75 mg/kg/day. Round dose to the nearest 2.5 mL. Table 1: Volume of FERRIPROX Oral Solution in mL Needed to Achieve the Total Starting Daily Dosage of 75 mg/kg (rounded to the nearest 2.5 mL) Body Weight (kg) Morning Midday Evening 20 5 5 5 30 7.5 7.5 7.5 40 10 10 10 50 12.5 12.5 12.5 60 15 15 15 70 17.5 17.5 17.5 80 20 20 20 90 22.5 22.5 22.5 To minimize gastrointestinal upset when first starting therapy, dosing can start at 45 mg/kg/day and increase weekly by 15 mg/kg/day increments until the full prescribed dose is achieved. Dosage Adjustments Tailor dosage adjustments to the individual patient's response and therapeutic goals (maintenance or reduction of body iron burden). The maximum oral dosage is 33 mg/kg (actual body weight), three times per day for a total of 99 mg/kg/day. Table 2: Volume of FERRIPROX Oral Solution in mL Needed to Achieve the Maximum Total Daily Dosage of 99 mg/kg (rouded to the nearest 2.5 mL) Body Weight (kg) Morning Midday Evening 20 7.5 5 7.5 30 10 10 10 40 15 10 15 50 17.5 15 17.5 60 20 20 20 70 25 22.5 22.5 80 27.5 25 27.5 90 30 30 30 2.3 Monitoring Ferritin Levels to Assess Efficacy Monitor serum ferritin concentration every two to three months to assess the effect of FERRIPROX on body iron stores. If the serum ferritin is consistently below 500 mcg/L, consider temporarily interrupting FERRIPROX therapy until serum ferritin rises above 500 mcg/L. 2.4 Dosage Modification for Drug Interactions Allow at least a 4-hour interval between administration of FERRIPROX and other drugs or supplements containing polyvalent cations such as iron, aluminum, or...

Side Effects (Adverse Reactions)

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 )] The most common adverse reactions in patients with thalassemia (incidence ≥ 6%) are nausea, vomiting, abdominal pain, arthralgia, ALT increased and neutropenia. ( 6 ) The most common adverse reactions in patients with sickle cell disease or other anemias (incidence ≥6%) are pyrexia, abdominal pain, bone pain, headache, vomiting, pain in extremity, sickle cell anemia with crisis, back pain, ALT increased, AST increased, arthralgia, oropharyngeal pain, nasopharyngitis, neutrophil count decreased, cough and nausea. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Chiesi USA, Inc. at 1-888-661-9260 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 a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The following adverse reaction information represents the pooled data collected from single arm or active-controlled clinical trials with FERRIPROX Tablets (deferiprone) (three times a day) or FERRIPROX Oral Solution (deferiprone). Thalassemia Syndromes The safety of FERRIPROX was evaluated in the pooled clinical trial database [see Clinical Studies ( 14.1 )] . Patients received FERRIPROX Tablets (three times a day) or FERRIPROX Oral Solution. FERRIPROX was administered orally three times a day (total daily dose either 50, 75, or 99 mg/kg), N=642. Among 642 patients receiving FERRIPROX, 492 (76.6%) were exposed for 6 months or longer and 365 (56.9%) were exposed for greater than one year. The median age of patients who received FERRIPROX was 19 years (range 1, 77 years); 50.2% female; 71.2% White, 17.8% Asian, 9.2% Unknown, 1.2% Multi-racial and 0.6% Black. The most serious adverse reaction reported in clinical trials with FERRIPROX was agranulocytosis [see Warnings and Precautions ( 5.1 )] . The most common adverse reactions (≥6%) reported during clinical trials were nausea, vomiting, abdominal pain, arthralgia, alanine aminotransferase increased and neutropenia. The table below lists the adverse drug reactions that occurred in at least 1% of patients treated with FERRIPROX in clinical trials in patients with thalassemia syndromes. Table 3: Adverse reactions occurring in ≥ 1% of FERRIPROX-treated patients with thalassemia syndromes * Neutropenia includes events of severe neutropenia (ANC ≥0.2 x 10 9 /L and <0.5 x 10 9 /L). †Agranulocytosis (ANC< 0.2 x 10 9 /L) Body System Adverse Reaction (N=642) % Patients BLOOD AND LYMPHATIC SYSTEM DISORDERS Neutropenia * 7 Agranulocytosis † 1 GASTROINTESTINAL DISORDERS Nausea 13 Abdominal pain/discomfort 10 Vomiting 10 Diarrhea 3 Dyspepsia 2 INVESTIGATIONS Alanine aminotransferase increased 7 Weight increased 2 Aspartate aminotransferase increased 1 METABOLISM AND NUTRITION DISORDERS Increased appetite 4 Decreased appetite 1 MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS Arthralgia 10 Back pain 2 Pain in extremity 2 Arthropathy 1 NERVOUS SYSTEM DISORDERS Headache 2 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 iron in the urine. Sickle Cell Disease or Other Anemias The safety of FERRIPROX compared to deferoxamine was evaluated in LA38-0411 [see Clinical Studies ( 14.2 )] . Patients received FERRIPROX Tablets or FERRIPROX Oral Solution orally three times a day (total daily...

Drug Interactions

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 a 4-hour interval between administration of FERRIPROX 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 FERRIPROX 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 FERRIPROX UDP-Glucuronosyltransferases (UGT) Avoid use of UGT1A6 inhibitors (e.g., diclofenac, probenecid, or silymarin (milk thistle)) with FERRIPROX [see Dosage and Administration ( 2.2 ), Adverse Reactions ( 6.1 ), Clinical Pharmacology ( 12.3 )] . Polyvalent Cations Deferiprone has the potential to bind polyvalent cations (e.g., iron, aluminum, and zinc); allow at least a 4-hour interval between FERRIPROX and other medications (e.g., antacids), or supplements containing these polyvalent cations [see Dosage and Administration ( 2.2 )] .

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 )

Pregnancy and Breastfeeding

8.1 Pregnancy Risk Summary In animal reproduction studies, oral administration of deferiprone to pregnant rats and rabbits during organogenesis at doses 33% and 49%, respectively, of the maximum recommended human dose (MRHD) resulted in structural abnormalities, embryo-fetal mortality and alterations to growth (see Data ) . The limited available data from deferiprone use in pregnant women are insufficient to inform a drug-associated risk of major birth defects and miscarriage. Based on evidence and developmental toxicity in animal studies, FERRIPROX can cause fetal harm when administered to a pregnant woman. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and of miscarriage is 2-4% and 15-20%, respectively. Data Human Data Post-marketing data available from 39 pregnancies of deferiprone-treated patients and 10 pregnancies of partners of deferiprone-treated patients are as follows: Of the 39 pregnancies in deferiprone-treated patients, 23 resulted in healthy newborns, 6 ended in spontaneous abortion, 9 had unknown outcomes, and 1 infant was born with anal atresia, nephroptosis, ventricular septal defect, hemivertebra and urethral fistula. Of the 10 pregnancies in partners of deferiprone-treated patients, 5 resulted in healthy newborns, 1 resulted in a healthy newborn with slight hypospadias, 1 was electively terminated, 1 resulted in the intrauterine death of twins, and 2 had unknown outcomes. Animal Data During organogenesis, pregnant rats and rabbits received deferiprone at oral doses of 0, 30, 80 or 200 mg/kg/day, and 0, 10, 50, or 150 mg/kg/day, respectively. The daily dose was administered as two equal divided doses approximately 7 hours...

Overdosage

10 OVERDOSAGE No cases of acute overdose have been reported. There is no specific antidote to FERRIPROX 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.

How Supplied

16 HOW SUPPLIED/STORAGE AND HANDLING FERRIPROX ® Oral Solution (deferiprone) is provided in amber polyethylene terephthalate (PET) bottles with child resistant closures (polypropylene). Each pack contains one bottle of 500 mL oral solution and a graduated measuring cup (polypropylene). Oral solution, 100 mg/mL (50 g/500 mL), NDC 10122-101-50 Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Store in the original bottle and carton to protect from light. After first opening of the bottle, discard any unused portion after 35 days.

About This Information

This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.

What are side effects?

Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.

What are drug interactions?

Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.