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  • CLASSES

    Antidotes, Systemic
    Chelating Agents

    BOXED WARNING

    Agranulocytosis, infection, neutropenia

    Deferiprone may cause agranulocytosis which can lead to serious infection and death. Neutropenia may precede the development of agranulocytosis. Neutropenia and agranulocytosis usually resolve after discontinuation of therapy; however, there have been fatal cases of agranulocytosis associated with deferiprone. The mechanism for agranulocytosis due to the drug is not known. The absolute neutrophil count (ANC) should be monitored prior to initiation of deferiprone and regularly during therapy according to the following schedule: monitor ANC weekly during the first 6 months of therapy, monitor ANC every 2 weeks during the next 6 months of therapy, and monitor ANC every 2 to 4 weeks (or at the patient's blood transfusion interval in patients that have not experienced an interruption due to any decrease in ANC) after 1 year of therapy. Reduction in the frequency of ANC monitoring should be considered on an individual patient basis, according to the health care provider's assessment of the patient's understanding of the risk minimization measures required during therapy. Interrupt deferiprone therapy if neutropenia develops (i.e., ANC between 0.5 to 1.5 x 109/L) and obtain a complete blood cell (CBC) count, an ANC, and a platelet count daily until the white blood cell (WBC) count recovers. If agranulocytosis develops (i.e., ANC less than 0.5 x 109/L), consider hospitalization and other management as clinically appropriate. Do not resume deferiprone therapy in patients who develop agranulocytosis unless potential benefits outweigh potential risks. Do not rechallenge patients who have developed neutropenia unless potential benefits outweigh potential risks. Therapy should also be interrupted if an infection develops, and the ANC should then be monitored more frequently. Advise patients to immediately interrupt therapy and talk to their health care provider if they experience any symptoms of infection (e.g., fever, chills, sore throat, mouth sores, or flu-like symptoms).[46163] [60360]

    DEA CLASS

    Rx

    DESCRIPTION

    Iron chelator
    Used for transfusional iron overload due to thalassemia syndromes, sickle cell disease, or other anemias in adults and pediatric patients 3 years and older
    May cause agranulocytosis

    COMMON BRAND NAMES

    Ferriprox

    HOW SUPPLIED

    Deferiprone/Ferriprox Oral Tab: 500mg, 1000mg
    Ferriprox Oral Sol: 1mL, 100mg

    DOSAGE & INDICATIONS

    For the treatment of transfusional iron overload due to thalassemia syndromes, sickle cell disease, or other anemias.
    NOTE: Safety and efficacy have not been established for the treatment of transfusional iron overload in patients with myelodysplastic syndrome or Diamond Blackfan anemia.
    Oral dosage (oral solution)
    Adults

    Initially, 25 mg/kg/dose PO 3 times daily for a total of 75 mg/kg/day. To minimize gastrointestinal upset, dosing can be initiated at 15 mg/kg/dose PO 3 times daily for a total of 45 mg/kg/day and increased weekly by 15 mg/kg/day increments until the full prescribed dose is achieved. Titrate dose up to 33 mg/kg/dose PO 3 times daily (99 mg/kg/day maximum) based on response and therapeutic goals (reduction or maintenance of iron burden). Round dose to the nearest 2.5 mL. Monitor serum ferritin concentration every 2 to 3 months. If serum ferritin is consistently less than 500 mcg/L, consider interrupting therapy until serum ferritin rises above 500 mcg/L.

    Children and Adolescents 3 to 17 years

    Initially, 25 mg/kg/dose PO 3 times daily for a total of 75 mg/kg/day. To minimize gastrointestinal upset, dosing can be initiated at 15 mg/kg/dose PO 3 times daily for a total of 45 mg/kg/day and increased weekly by 15 mg/kg/day increments until the full prescribed dose is achieved. Titrate dose up to 33 mg/kg/dose PO 3 times daily (99 mg/kg/day maximum) based on response and therapeutic goals (reduction or maintenance of iron burden). Round dose to the nearest 2.5 mL. Monitor serum ferritin concentration every 2 to 3 months. If serum ferritin is consistently less than 500 mcg/L, consider interrupting therapy until serum ferritin rises above 500 mcg/L.

    Oral dosage (3 times a day tablets [500 mg or 1,000 mg tablets])

    NOTE: Before prescribing and dispensing, ensure the formulation used is appropriate for the dosing regimen. The 1,000 mg tablets are available in 2 different formulations, which have different dosing regimens to achieve the same total daily dosage (i.e., twice a day tablet and 3 times a day tablet).

    Adults

    Initially, 25 mg/kg/dose PO 3 times daily for a total of 75 mg/kg/day. To minimize gastrointestinal upset, dosing can be initiated at 15 mg/kg/dose PO 3 times daily for a total of 45 mg/kg/day and increased weekly by 15 mg/kg/day increments until the full prescribed dose is achieved. Titrate dose up to 33 mg/kg/dose PO 3 times daily (99 mg/kg/day maximum) based on response and therapeutic goals (reduction or maintenance of iron burden). Round dose to the nearest 250 or 500 mg (half-tablet). Monitor serum ferritin concentration every 2 to 3 months. If serum ferritin is consistently less than 500 mcg/L, consider interrupting therapy until serum ferritin rises above 500 mcg/L.

    Children and Adolescents 8 to 17 years

    Initially, 25 mg/kg/dose PO 3 times daily for a total of 75 mg/kg/day. To minimize gastrointestinal upset, dosing can be initiated at 15 mg/kg/dose PO 3 times daily for a total of 45 mg/kg/day and increased weekly by 15 mg/kg/day increments until the full prescribed dose is achieved. Titrate dose up to 33 mg/kg/dose PO 3 times daily (99 mg/kg/day maximum) based on response and therapeutic goals (reduction or maintenance of iron burden). Round dose to the nearest 250 or 500 mg (half-tablet). Monitor serum ferritin concentration every 2 to 3 months. If serum ferritin is consistently less than 500 mcg/L, consider interrupting therapy until serum ferritin rises above 500 mcg/L.

    Oral dosage (twice a day tablets [1,000 mg tablets])

    NOTE: Before prescribing and dispensing, ensure the formulation used is appropriate for the dosing regimen. The 1,000 mg tablets are available in 2 different formulations, which have different dosing regimens to achieve the same total daily dosage (i.e., twice a day tablet and 3 times a day tablet).

    Adults

    Initially, 75 mg/kg/day PO in 2 divided doses (taken approximately 12 hours apart) with food. To minimize gastrointestinal upset, dosing can be initiated at 45 mg/kg/day PO in 2 divided doses (taken approximately 12 hours apart) and increased weekly by 15 mg/kg/day increments until the full prescribed dose is achieved. Titrate the dose based on response and therapeutic goals (reduction or maintenance of iron burden) to a maximum dose of 99 mg/kg/day PO in 2 divided doses (approximately 12 hours apart) with food. Round dose to the nearest 500 mg (half-tablet). Monitor serum ferritin concentration every 2 to 3 months. If serum ferritin is consistently less than 500 mcg/L, consider interrupting therapy until serum ferritin rises above 500 mcg/L.

    Children and Adolescents 8 to 17 years

    Initially, 75 mg/kg/day PO in 2 divided doses (taken approximately 12 hours apart) with food. To minimize gastrointestinal upset, dosing can be initiated at 45 mg/kg/day PO in 2 divided doses (taken approximately 12 hours apart) and increased weekly by 15 mg/kg/day increments until the full prescribed dose is achieved. Titrate the dose based on response and therapeutic goals (reduction or maintenance of iron burden) to a maximum dose of 99 mg/kg/day PO in 2 divided doses (approximately 12 hours apart) with food. Round dose to the nearest 500 mg (half-tablet). Monitor serum ferritin concentration every 2 to 3 months. If serum ferritin is consistently less than 500 mcg/L, consider interrupting therapy until serum ferritin rises above 500 mcg/L.

    MAXIMUM DOSAGE

    Adults

    99 mg/kg/day PO.

    Geriatric

    99 mg/kg/day PO.

    Adolescents

    99 mg/kg/day PO.

    Children

    3 to 12 years: 99 mg/kg/day PO.
    1 to 2 years: Safety and efficacy have not been established.

    Infants

    Safety and efficacy have not been established.

    Neonates

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are necessary.

    Renal Impairment

    Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are necessary.

    ADMINISTRATION

     
    NOTE: The 1,000 mg tablets are available in 2 different formulations, which have different dosing regimens to achieve the same total daily dosage (i.e., a twice a day tablet and 3 times a day tablet). Each tablet has different identifying characteristics to prevent medication errors. Before prescribing and dispensing a 1,000 mg tablet, ensure the formulation is appropriate for the dosing regimen.

    Oral Administration

    Administer the 1,000 mg twice a day tablet with food; other formulations may be administered with or without food.
    Allow at least a 4-hour interval between the administration of deferiprone and other medications or supplements containing polyvalent cations such as iron, aluminum, and zinc.

    Oral Solid Formulations

    Tablets have a functional score and are designed for half tablet dosing to meet individual patient dosage requirements.

    Oral Liquid Formulations

    Calculate the dose based on the patient's actual body weight. The dose should be rounded by the prescriber to the nearest 2.5 mL.
    Pour the calculated dose into the provided measuring cup.
    After administering the measured dose, add about 10 to 15 mL of water to the measuring cup and gently swirl to mix the water and any remaining deferiprone solution left in the cup. Drink all the mixture in the measuring cup.
    Storage: After the initial opening, discard any unused contents of the bottle after 35 days.

    STORAGE

    Ferriprox:
    - Protect from direct sunlight
    - Protect from moisture
    - Store at controlled room temperature (between 68 and 77 degrees F)
    - Store in a dry, well ventilated place
    - Store in original container

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Deferiprone is contraindicated in patients with a hypersensitivity to deferiprone or any excipients in the formulation.

    Agranulocytosis, infection, neutropenia

    Deferiprone may cause agranulocytosis which can lead to serious infection and death. Neutropenia may precede the development of agranulocytosis. Neutropenia and agranulocytosis usually resolve after discontinuation of therapy; however, there have been fatal cases of agranulocytosis associated with deferiprone. The mechanism for agranulocytosis due to the drug is not known. The absolute neutrophil count (ANC) should be monitored prior to initiation of deferiprone and regularly during therapy according to the following schedule: monitor ANC weekly during the first 6 months of therapy, monitor ANC every 2 weeks during the next 6 months of therapy, and monitor ANC every 2 to 4 weeks (or at the patient's blood transfusion interval in patients that have not experienced an interruption due to any decrease in ANC) after 1 year of therapy. Reduction in the frequency of ANC monitoring should be considered on an individual patient basis, according to the health care provider's assessment of the patient's understanding of the risk minimization measures required during therapy. Interrupt deferiprone therapy if neutropenia develops (i.e., ANC between 0.5 to 1.5 x 109/L) and obtain a complete blood cell (CBC) count, an ANC, and a platelet count daily until the white blood cell (WBC) count recovers. If agranulocytosis develops (i.e., ANC less than 0.5 x 109/L), consider hospitalization and other management as clinically appropriate. Do not resume deferiprone therapy in patients who develop agranulocytosis unless potential benefits outweigh potential risks. Do not rechallenge patients who have developed neutropenia unless potential benefits outweigh potential risks. Therapy should also be interrupted if an infection develops, and the ANC should then be monitored more frequently. Advise patients to immediately interrupt therapy and talk to their health care provider if they experience any symptoms of infection (e.g., fever, chills, sore throat, mouth sores, or flu-like symptoms).[46163] [60360]

    Pregnancy

    Data are limited regarding use of deferiprone during pregnancy; however, based on animal studies deferiprone may cause fetal harm when administered to a pregnant woman. In studies involving rats and rabbits, administration of deferiprone during organogenesis at doses 33% and 49%, respectively, of the maximum recommended human dose (MRHD) resulted in embryo-fetal death, skeletal and soft tissue malformations, and alterations to growth. Available human data include postmarketing reports from 39 pregnancies of deferiprone-treated females and 10 pregnancies of partners of deferiprone-treated males. Of the 39 pregnancies in drug-exposed females, 23 resulted in healthy newborns, 6 ended in spontaneous abortions, 9 had unknown outcomes, and 1 infant was born with anal atresia, nephroptosis, ventricular septal defect, hemivertebral, and urethral fistula. Of the 10 pregnancies of partners of drug-exposed males, 5 resulted in healthy newborns, 1 resulted in a healthy newborn with slight hypospadias, 1 was electively terminated, 1 resulted in intrauterine death of twins, and 2 had unknown outcomes. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Instruct drug recipients to immediately report a known or suspected pregnancy to their health care provider.

    Breast-feeding

    Advise patients that breast-feeding is not recommended during treatment with deferiprone, and for at least 2 weeks after the last dose, due to the potential for serious adverse reactions in the breastfed child, including the potential for tumorigenicity shown for deferiprone in animal studies. There is no information regarding the presence of deferiprone in human milk, the effects on the breastfed child, or the effects on milk production. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    Contraception requirements, male-mediated teratogenicity, pregnancy testing, reproductive risk

    Counsel patients about the reproductive risk and contraception requirements during deferiprone treatment. Deferiprone can cause fetal harm when administered to pregnant females; therefore, all females of childbearing potential should undergo pregnancy testing prior to initiating treatment. Advise female drug recipients to use effective contraception during treatment and for 6 months after cessation of therapy. The drug has also been associated with male-mediated teratogenicity; thus, contraception requirements are also recommended for deferiprone-treated males with female sexual partners of reproductive potential. Instruct males to use contraception during treatment and for 3 months after cessation of therapy.

    ADVERSE REACTIONS

    Severe

    agranulocytosis / Delayed / 1.5-1.7
    pancreatitis / Delayed / Incidence not known
    enterocolitis / Delayed / Incidence not known
    GI bleeding / Delayed / Incidence not known
    peptic ulcer / Delayed / Incidence not known
    acute cerebellar syndrome / Early / Incidence not known
    increased intracranial pressure / Early / Incidence not known
    seizures / Delayed / Incidence not known
    pancytopenia / Delayed / Incidence not known
    anaphylactic shock / Rapid / Incidence not known
    retinopathy / Delayed / Incidence not known
    papilledema / Delayed / Incidence not known
    heart failure / Delayed / Incidence not known
    atrial fibrillation / Early / Incidence not known
    pulmonary embolism / Delayed / Incidence not known
    acute respiratory distress syndrome (ARDS) / Early / Incidence not known

    Moderate

    bone pain / Delayed / 25.0-25.0
    neutropenia / Delayed / 6.0-8.0
    elevated hepatic enzymes / Delayed / 8.0-8.0
    glycosuria / Early / Incidence not known
    depression / Delayed / Incidence not known
    teeth grinding (bruxism) / Delayed / Incidence not known
    thrombocytosis / Delayed / Incidence not known
    ocular inflammation / Early / Incidence not known
    hepatitis / Delayed / Incidence not known
    jaundice / Delayed / Incidence not known
    hepatomegaly / Delayed / Incidence not known
    hyperbilirubinemia / Delayed / Incidence not known
    zinc deficiency / Delayed / Incidence not known
    trismus / Delayed / Incidence not known
    dehydration / Delayed / Incidence not known
    metabolic acidosis / Delayed / Incidence not known
    hypotension / Rapid / Incidence not known
    hypertension / Early / Incidence not known
    hemoptysis / Delayed / Incidence not known
    peripheral edema / Delayed / Incidence not known
    furunculosis / Delayed / Incidence not known

    Mild

    fever / Early / 28.0-28.0
    abdominal pain / Early / 10.0-26.0
    headache / Early / 2.0-20.0
    vomiting / Early / 10.0-19.0
    nausea / Early / 7.0-13.0
    back pain / Delayed / 2.0-13.0
    arthralgia / Delayed / 10.0-10.0
    pharyngitis / Delayed / 9.0-9.0
    cough / Delayed / 8.0-8.0
    diarrhea / Early / 3.0-5.0
    appetite stimulation / Delayed / 4.0-4.0
    dyspepsia / Early / 2.0-2.0
    weight gain / Delayed / 2.0-2.0
    arthropathy / Delayed / 1.0-1.0
    anorexia / Delayed / 1.0-1.0
    urine discoloration / Early / Incidence not known
    drowsiness / Early / Incidence not known
    psychomotor impairment / Early / Incidence not known
    infection / Delayed / Incidence not known
    rash / Early / Incidence not known
    hyperhidrosis / Delayed / Incidence not known
    purpura / Delayed / Incidence not known
    urticaria / Rapid / Incidence not known
    photosensitivity / Delayed / Incidence not known
    diplopia / Early / Incidence not known
    epistaxis / Delayed / Incidence not known
    chills / Rapid / Incidence not known

    DRUG INTERACTIONS

    Aluminum Hydroxide: (Moderate) Concurrent use of deferiprone with food, mineral supplements, and antacids that contain polyvalent (trivalent) 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 deferiprone and other medications or dietary supplements containing these polyvalent cations. Such medications can include antacids, iron salts, aluminum hydroxide, dietary supplements containing polyvalent minerals, and zinc salts.
    Aluminum Hydroxide; Magnesium Carbonate: (Moderate) Concurrent use of deferiprone with food, mineral supplements, and antacids that contain polyvalent (trivalent) 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 deferiprone and other medications or dietary supplements containing these polyvalent cations. Such medications can include antacids, iron salts, aluminum hydroxide, dietary supplements containing polyvalent minerals, and zinc salts.
    Aluminum Hydroxide; Magnesium Hydroxide: (Moderate) Concurrent use of deferiprone with food, mineral supplements, and antacids that contain polyvalent (trivalent) 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 deferiprone and other medications or dietary supplements containing these polyvalent cations. Such medications can include antacids, iron salts, aluminum hydroxide, dietary supplements containing polyvalent minerals, and zinc salts.
    Aluminum Hydroxide; Magnesium Hydroxide; Simethicone: (Moderate) Concurrent use of deferiprone with food, mineral supplements, and antacids that contain polyvalent (trivalent) 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 deferiprone and other medications or dietary supplements containing these polyvalent cations. Such medications can include antacids, iron salts, aluminum hydroxide, dietary supplements containing polyvalent minerals, and zinc salts.
    Aluminum Hydroxide; Magnesium Trisilicate: (Moderate) Concurrent use of deferiprone with food, mineral supplements, and antacids that contain polyvalent (trivalent) 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 deferiprone and other medications or dietary supplements containing these polyvalent cations. Such medications can include antacids, iron salts, aluminum hydroxide, dietary supplements containing polyvalent minerals, and zinc salts.
    Carbetapentane; Guaifenesin; Phenylephrine: (Moderate) Concurrent use of deferiprone with food, mineral supplements, and antacids that contain polyvalent (trivalent) 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 deferiprone and other medications or dietary supplements containing these polyvalent cations. Such medications can include antacids, iron salts, aluminum hydroxide, dietary supplements containing polyvalent minerals, and zinc salts.
    Carbetapentane; Phenylephrine: (Moderate) Concurrent use of deferiprone with food, mineral supplements, and antacids that contain polyvalent (trivalent) 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 deferiprone and other medications or dietary supplements containing these polyvalent cations. Such medications can include antacids, iron salts, aluminum hydroxide, dietary supplements containing polyvalent minerals, and zinc salts.
    Chlorpheniramine; Pseudoephedrine: (Moderate) Concurrent use of deferiprone with food, mineral supplements, and antacids that contain polyvalent (trivalent) 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 deferiprone and other medications or dietary supplements containing these polyvalent cations. Such medications can include antacids, iron salts, aluminum hydroxide, dietary supplements containing polyvalent minerals, and zinc salts.
    Clozapine: (Major) Avoid concomitant use of deferiprone with other drugs known to be associated with neutropenia or agranulocytosis, such as clozapine; however, if this is not possible, closely monitor the absolute neutrophil count and interrupt deferiprone therapy if neutropenia develops.
    Deferasirox: (Major) Although the potential benefits of combination iron chelation therapy have been mentioned in the literature, deferasirox should not be combined with other iron chelator therapies (e.g., deferiprone) as the safety of such combinations has not been established.
    Deferoxamine: (Major) Although the potential benefits of combination iron chelation therapy have been mentioned in the literature, deferiprone should not be combined with other iron chelator therapies (e.g., deferoxamine) as the safety of such combinations has not been established.
    Dichlorphenamide: (Moderate) Use dichlorphenamide and deferiprone together with caution. Metabolic acidosis is associated with the use of dichlorphenamide and has been reported with the postmarketing use of deferiprone. Concurrent use may increase the severity of metabolic acidosis. Measure sodium bicarbonate concentrations at baseline and periodically during dichlorphenamide treatment. If metabolic acidosis occurs or persists, consider reducing the dose or discontinuing dichlorphenamide therapy.
    Diclofenac: (Major) Avoid the concomitant use of deferiprone and diclofenac. Deferiprone is a UDP glucuronosyltransferase (UGT) 1A6 substrate, and diclofenac inhibits UGT1A6. The in vitro glucuronidation of deferiprone was reduced by 78% in the presence of another UGT1A6 inhibitor. Side effects, such as nausea, increased liver enzymes, or risk for neutropenia may be increased.
    Diclofenac; Misoprostol: (Major) Avoid the concomitant use of deferiprone and diclofenac. Deferiprone is a UDP glucuronosyltransferase (UGT) 1A6 substrate, and diclofenac inhibits UGT1A6. The in vitro glucuronidation of deferiprone was reduced by 78% in the presence of another UGT1A6 inhibitor. Side effects, such as nausea, increased liver enzymes, or risk for neutropenia may be increased.
    Ethanol: (Major) Advise patients to avoid alcohol while taking deferiprone twice a day tablets. Consumption of alcohol while taking deferiprone twice a day tablets may result in more rapid release of deferiprone. At 40% (v/v) alcohol concentration in vitro dissolution studies, there was 88% release of deferiprone from a 1,000 mg deferiprone tablet (twice a day) within two hours compared to 4% release of deferiprone within 2 hours in the absence of alcohol.
    Felbamate: (Major) Avoid concomitant use of deferiprone with other drugs known to be associated with neutropenia or agranulocytosis, such as felbamate; however, if this is not possible, closely monitor the absolute neutrophil count and interrupt deferiprone therapy if neutropenia develops.
    Ferric carboxymaltose: (Major) Deferiprone chelates iron. Therapeutically, it is typically illogical for a patient to receive both iron supplementation (e.g., iron salts, iron dextran, ferric carboxymaltose, ferric citrate, sodium ferric gluconate complex, iron sucrose, sucroferric oxyhydroxide or polysaccharide-iron complex) and deferiprone simultaneously. Concurrent use of deferiprone with iron supplements has not been studied. Since deferiprone has the potential to bind polyvalent cations (e.g., iron), allow at least a 4-hour interval between deferiprone and other oral medications or dietary supplements containing these polyvalent cations when they are used together.
    Ferric Derisomaltose: (Major) Deferiprone chelates iron. Therapeutically, it is typically illogical for a patient to receive both iron supplementation (e.g., iron salts, iron dextran, ferric carboxymaltose, ferric citrate, sodium ferric gluconate complex, iron sucrose, sucroferric oxyhydroxide or polysaccharide-iron complex) and deferiprone simultaneously. Concurrent use of deferiprone with iron supplements has not been studied. Since deferiprone has the potential to bind polyvalent cations (e.g., iron), allow at least a 4-hour interval between deferiprone and other oral medications or dietary supplements containing these polyvalent cations when they are used together.
    Ferric Maltol: (Major) Deferiprone chelates iron. Therapeutically, it is typically illogical for a patient to receive both iron supplementation (e.g., iron salts, iron dextran, iron sucrose, sodium ferric gluconate complex, or polysaccharide-iron complex) and deferiprone simultaneously. Concurrent use of deferiprone with iron supplements has not been studied. However, since deferiprone has the potential to bind polyvalent cations (e.g., iron), allow at least a 4-hour interval between deferiprone and other oral medications or dietary supplements containing these polyvalent cations when they are used.
    Ferumoxytol: (Major) Deferiprone chelates iron. Therapeutically, it is typically illogical for a patient to receive both iron supplementation (e.g., iron salts, iron dextran, ferric carboxymaltose, ferric citrate, sodium ferric gluconate complex, iron sucrose, sucroferric oxyhydroxide or polysaccharide-iron complex) and deferiprone simultaneously. Concurrent use of deferiprone with iron supplements has not been studied. Since deferiprone has the potential to bind polyvalent cations (e.g., iron), allow at least a 4-hour interval between deferiprone and other oral medications or dietary supplements containing these polyvalent cations when they are used together.
    Iron - Injectable Only: (Major) Deferiprone chelates iron. Therapeutically, it is typically illogical for a patient to receive both iron supplementation (e.g., iron salts, iron dextran, ferric carboxymaltose, ferric citrate, sodium ferric gluconate complex, iron sucrose, sucroferric oxyhydroxide or polysaccharide-iron complex) and deferiprone simultaneously. Concurrent use of deferiprone with iron supplements has not been studied. Since deferiprone has the potential to bind polyvalent cations (e.g., iron), allow at least a 4-hour interval between deferiprone and other oral medications or dietary supplements containing these polyvalent cations when they are used together.
    Iron Dextran: (Major) Deferiprone chelates iron. Therapeutically, it is typically illogical for a patient to receive both iron supplementation (e.g., iron salts, iron dextran, ferric carboxymaltose, ferric citrate, sodium ferric gluconate complex, iron sucrose, sucroferric oxyhydroxide or polysaccharide-iron complex) and deferiprone simultaneously. Concurrent use of deferiprone with iron supplements has not been studied. Since deferiprone has the potential to bind polyvalent cations (e.g., iron), allow at least a 4-hour interval between deferiprone and other oral medications or dietary supplements containing these polyvalent cations when they are used together.
    Iron Salts: (Major) Deferiprone chelates iron. Therapeutically, it is typically illogical for a patient to receive both iron supplementation (e.g., iron salts, iron dextran, iron sucrose, sodium ferric gluconate complex, or polysaccharide-iron complex) and deferiprone simultaneously. Concurrent use of deferiprone with iron supplements has not been studied. However, since deferiprone has the potential to bind polyvalent cations (e.g., iron), allow at least a 4-hour interval between deferiprone and other oral medications or dietary supplements containing these polyvalent cations when they are used.
    Iron Sucrose, Sucroferric Oxyhydroxide: (Major) Deferiprone chelates iron. Therapeutically, it is typically illogical for a patient to receive both iron supplementation (e.g., iron salts, iron dextran, ferric carboxymaltose, ferric citrate, sodium ferric gluconate complex, iron sucrose, sucroferric oxyhydroxide or polysaccharide-iron complex) and deferiprone simultaneously. Concurrent use of deferiprone with iron supplements has not been studied. Since deferiprone has the potential to bind polyvalent cations (e.g., iron), allow at least a 4-hour interval between deferiprone and other oral medications or dietary supplements containing these polyvalent cations when they are used together.
    Iron: (Major) Deferiprone chelates iron. Therapeutically, it is typically illogical for a patient to receive both iron supplementation (e.g., iron salts, iron dextran, iron sucrose, sodium ferric gluconate complex, or polysaccharide-iron complex) and deferiprone simultaneously. Concurrent use of deferiprone with iron supplements has not been studied. However, since deferiprone has the potential to bind polyvalent cations (e.g., iron), allow at least a 4-hour interval between deferiprone and other oral medications or dietary supplements containing these polyvalent cations when they are used.
    Methimazole: (Major) Avoid concomitant use of deferiprone with other drugs known to be associated with neutropenia or agranulocytosis, such as methimazole; however, if this is not possible, closely monitor the absolute neutrophil count and interrupt deferiprone therapy if neutropenia develops.
    Milk Thistle, Silybum marianum: (Major) Avoid the concomitant use of deferiprone and Milk Thistle (Silymarin). Deferiprone is a UDP glucuronosyltransferase (UGT) 1A6 substrate, and milk thistle may inhibit UGT1A6. The in vitro glucuronidation of deferiprone was reduced by 78% in the presence of another UGT1A6 inhibitor. Side effects, such as nausea, increased liver enzymes, or risk for neutropenia may be increased.
    Norethindrone Acetate; Ethinyl Estradiol; Ferrous fumarate: (Major) Deferiprone chelates iron. Therapeutically, it is typically illogical for a patient to receive both iron supplementation (e.g., iron salts, iron dextran, iron sucrose, sodium ferric gluconate complex, or polysaccharide-iron complex) and deferiprone simultaneously. Concurrent use of deferiprone with iron supplements has not been studied. However, since deferiprone has the potential to bind polyvalent cations (e.g., iron), allow at least a 4-hour interval between deferiprone and other oral medications or dietary supplements containing these polyvalent cations when they are used.
    Norethindrone; Ethinyl Estradiol; Ferrous fumarate: (Major) Deferiprone chelates iron. Therapeutically, it is typically illogical for a patient to receive both iron supplementation (e.g., iron salts, iron dextran, iron sucrose, sodium ferric gluconate complex, or polysaccharide-iron complex) and deferiprone simultaneously. Concurrent use of deferiprone with iron supplements has not been studied. However, since deferiprone has the potential to bind polyvalent cations (e.g., iron), allow at least a 4-hour interval between deferiprone and other oral medications or dietary supplements containing these polyvalent cations when they are used.
    Polysaccharide-Iron Complex: (Major) Deferiprone chelates iron. Therapeutically, it is typically illogical for a patient to receive both iron supplementation (e.g., iron salts, iron dextran, iron sucrose, sodium ferric gluconate complex, or polysaccharide-iron complex) and deferiprone simultaneously. Concurrent use of deferiprone with iron supplements has not been studied. However, since deferiprone has the potential to bind polyvalent cations (e.g., iron), allow at least a 4-hour interval between deferiprone and other oral medications or dietary supplements containing these polyvalent cations when they are used.
    Probenecid: (Major) Avoid the concomitant use of deferiprone and probenecid. Deferiprone is a UDP glucuronosyltransferase (UGT) 1A6 substrate, and probenecid inhibits this enzyme. The in vitro glucuronidation of deferiprone is reduced by 78% in the presence of phenylbutazone, another UGT1A6 inhibitor. Similar results may be seen when deferiprone and probenecid are administered concomitantly.
    Probenecid; Colchicine: (Major) Avoid the concomitant use of deferiprone and probenecid. Deferiprone is a UDP glucuronosyltransferase (UGT) 1A6 substrate, and probenecid inhibits this enzyme. The in vitro glucuronidation of deferiprone is reduced by 78% in the presence of phenylbutazone, another UGT1A6 inhibitor. Similar results may be seen when deferiprone and probenecid are administered concomitantly.
    Propylthiouracil, PTU: (Major) Avoid concomitant use of deferiprone with other drugs known to be associated with neutropenia or agranulocytosis, such as propylthiouracil, PTU; however, if this is not possible, closely monitor the absolute neutrophil count and interrupt deferiprone therapy if neutropenia develops.
    Sodium Ferric Gluconate Complex; ferric pyrophosphate citrate: (Major) Deferiprone chelates iron. Therapeutically, it is typically illogical for a patient to receive both iron supplementation (e.g., iron salts, iron dextran, iron sucrose, sodium ferric gluconate complex, or polysaccharide-iron complex) and deferiprone simultaneously. Concurrent use of deferiprone with iron supplements has not been studied. However, since deferiprone has the potential to bind polyvalent cations (e.g., iron), allow at least a 4-hour interval between deferiprone and other oral medications or dietary supplements containing these polyvalent cations when they are used.
    Zinc Salts: (Moderate) Concurrent use of deferiprone with food, mineral supplements, and antacids that contain polyvalent (trivalent) 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 deferiprone and other medications or dietary supplements containing these polyvalent cations. Such medications can include antacids, iron salts, aluminum hydroxide, dietary supplements containing polyvalent minerals, and zinc salts.
    Zinc: (Moderate) Concurrent use of deferiprone with food, mineral supplements, and antacids that contain polyvalent (trivalent) 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 deferiprone and other medications or dietary supplements containing these polyvalent cations. Such medications can include antacids, iron salts, aluminum hydroxide, dietary supplements containing polyvalent minerals, and zinc salts.

    PREGNANCY AND LACTATION

    Pregnancy

    Data are limited regarding use of deferiprone during pregnancy; however, based on animal studies deferiprone may cause fetal harm when administered to a pregnant woman. In studies involving rats and rabbits, administration of deferiprone during organogenesis at doses 33% and 49%, respectively, of the maximum recommended human dose (MRHD) resulted in embryo-fetal death, skeletal and soft tissue malformations, and alterations to growth. Available human data include postmarketing reports from 39 pregnancies of deferiprone-treated females and 10 pregnancies of partners of deferiprone-treated males. Of the 39 pregnancies in drug-exposed females, 23 resulted in healthy newborns, 6 ended in spontaneous abortions, 9 had unknown outcomes, and 1 infant was born with anal atresia, nephroptosis, ventricular septal defect, hemivertebral, and urethral fistula. Of the 10 pregnancies of partners of drug-exposed males, 5 resulted in healthy newborns, 1 resulted in a healthy newborn with slight hypospadias, 1 was electively terminated, 1 resulted in intrauterine death of twins, and 2 had unknown outcomes. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Instruct drug recipients to immediately report a known or suspected pregnancy to their health care provider.

    Advise patients that breast-feeding is not recommended during treatment with deferiprone, and for at least 2 weeks after the last dose, due to the potential for serious adverse reactions in the breastfed child, including the potential for tumorigenicity shown for deferiprone in animal studies. There is no information regarding the presence of deferiprone in human milk, the effects on the breastfed child, or the effects on milk production. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    MECHANISM OF ACTION

    Deferiprone is an orally active chelating agent with an affinity for Fe3+. It binds with ferric ions to form neutral complexes (3:1 deferiprone to iron) that are stable in a wide range of pH values. Deferiprone has a high affinity for iron with a lower affinity for other trivalent metals such as copper, aluminum, and zinc.

    PHARMACOKINETICS

    Deferiprone is administered orally. Once in the systemic circulation, the apparent mean volume of distribution is 97 +/- 28 L. Deferiprone is primarily metabolized by UGT1A6. The major metabolite is 3-O-glucuronide, which lacks iron-binding capacity. The half-life of deferiprone is approximately 2 hours. The majority (more than 90%) of deferiprone is eliminated from the plasma within 5 to 6 hours, and 75% to 90% is recovered in the urine in the first 24 hours (primarily as the metabolite).[46163]
     
    Affected cytochrome P450 isoenzymes and drug transporters: UDP-Glucuronosyltransferase (UGT1A6)
    Deferiprone is primarily metabolized by UGT1A6. Inhibitors of UGT1A6 can reduce the metabolism of deferiprone by up to 78%.[46163]

    Oral Route

    Three times a day formulations: Deferiprone is rapidly absorbed from the upper gastrointestinal tract, with drug concentrations appearing in the blood within 5 to 10 minutes post-dose. Following a single oral dose, peak serum concentrations (Cmax) are achieved in approximately 1 to 2 hours. In healthy subjects, the mean Cmax and AUC of deferiprone were 20 mcg/mL and 50 mcg x hour/mL, respectively. Administration with food produces no clinically significant differences in the pharmacokinetics of deferiprone.[46163] [60360]
    Twice a day formulation: In fasted subjects, peak serum concentrations (Cmax) are achieved approximately 2 hours after a single dose. Compared with fasted conditions, administration with a high-fat meal does not alter the Cmax and AUC of deferiprone. In healthy subjects receiving a 1,000 mg (twice a day) tablet dose with food, the mean Cmax and AUC of deferiprone were 6 +/- 2 mcg/mL and 28 +/- 7 mcg x hour/mL, respectively. In vitro dissolution studies found that alcohol at concentrations of 40% (V/V) caused an 88% release of deferiprone from the twice a day tablet formulation within 2 hours; there was only a 4% release in the absence of alcohol.[46163]