Ferriprox

Deferiprone.

Tablet: Excipients/Inactive Ingredients: Tablet Core: Microcrystalline cellulose, magnesium stearate, colloidal silicon dioxide. Coating: Hypromellose, macrogol, titanium dioxide.
Oral Solution: FERRIPROX (deferiprone) oral solution 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 C₇H₉NO₂ and its molecular weight is 139.15 g/mol.
Deferiprone is a white to pinkish-white crystalline powder. It is sparingly soluble in deionized water 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.
Excipients/Inactive Ingredients: Purified water, hydroxyethylcellulose, glycerin, hydrochloric acid, artificial cherry flavor, peppermint oil, FD&C Yellow No. 6 and sucralose.

Pharmacotherapeutic Group: Iron Chelator. ATC Code: V03AC02.
Pharmacology: Pharmacodynamics: Tablet: Deferiprone is 3-hydroxy-1,2-dimethylpyridin-4-one, a bidentate ligand which binds to iron in a 3:1 molar ratio.
Clinical studies have demonstrated that deferiprone is effective in promoting iron excretion and that a dose of 25 mg/kg 3 times daily can prevent the progression of iron accumulation as assessed by serum ferritin in patients with transfusion-dependent thalassemia. However, chelation therapy may not necessarily protect against iron-induced organ damage.
Oral Solution: No clinical studies were performed to assess the relationship between the dose of FERRIPROX and the amount of iron eliminated from the body.
Cardiac Electrophysiology: At a dose 1.5 times the maximum recommended dose, FERRIPROX does not prolong the QT interval to any clinically relevant extent.
Mechanism of Action: Deferiprone is a chelating agent with an affinity for ferric ion (iron III). Deferiprone binds with ferric ions to form neutral 3:1 (deferiprone:iron) complexes that are stable over a wide range of pH values. Deferiprone has a lower binding affinity for other metals such as copper, aluminum and zinc than for iron.
Pharmacokinetics: Tablet: Absorption: Deferiprone is rapidly absorbed from the upper part of the gastrointestinal tract. Peak serum concentration is reported to occur 45-60 min following a single dose in fasted patients. This may be extended to 2 hrs in fed patients.
Following a dose of 25 mg/kg, lower peak serum concentrations have been detected in patients in the fed state (85 micromol/L) than in the fasting state (126 micromol/L), although there was no decrease in the amount of deferiprone absorbed when it was given with food.
Biotransformation: Deferiprone is metabolized predominantly to a glucuronide conjugate. This metabolite lacks iron-binding capability due to inactivation of the 3-hydroxy group of deferiprone. Peak serum concentrations of glucuronide occur 2-3 hrs after administration of deferiprone.
Elimination: In humans, deferiprone is eliminated mainly via the kidneys; 75-90% of the ingested dose is reported to be recovered in the urine in the first 24 hrs, in the form of the free deferiprone, the glucuronide metabolite and the iron-deferiprone complex. A variable amount of elimination via the feces has been reported. The elimination half-life in most patients is 2-3 hrs.
Oral Solution: Deferiprone is rapidly absorbed from the upper part of the gastrointestinal tract, appearing in the blood within 5 to 10 minutes of oral administration. Peak serum concentrations occur approximately 1 hour after a single dose in fasted healthy subjects and patients, and up to 2 hours after a single dose in the fed state. Administration with food decreased the maximum concentration (C_max) of deferiprone by 38% and the area under the concentration-time curve (AUC) by 10%. The magnitude of the exposure change does not warrant dose adjustment.
In healthy subjects, the mean C_max of deferiprone in serum was about 20 mcg/mL, and the mean AUC was about 50 mcg∙h/mL following oral administration of a 1,500 mg dose of FERRIPROX tablets or oral solution in the fasting state. Dose proportionality over the labeled dosage range of 25 to 33 mg/kg three times per day (75 to 99 mg/kg per day) has not been studied.
The elimination half-life of deferiprone is approximately 2 hours. Following oral administration, 75% to 90% of the administered dose is recovered in the urine in the first 24 hours, primarily as metabolite. In humans, the majority of the deferiprone is metabolized, primarily by UGT1A6. The contribution of extrahepatic (e.g., renal) UGT1A6 is unknown. The major metabolite of deferiprone is the 3-O-glucuronide, which lacks iron binding capability.
In a bioequivalence study, the rate (C_max) and the extent (AUC) of drug absorption of the solution and tablet formulations were shown to be equivalent.
Specific Populations: The pharmacokinetics of deferiprone has not been studied in geriatric or pediatric populations, and the influence of race, gender, or obesity has not been established.
Drug Interactions: Deferiprone is primarily eliminated via metabolism to the 3-O-glucuronide. In vitro UGT1A6 is primarily responsible for the glucuronidation of deferiprone which can be reduced up to 78% in the presence of the UGT1A6 inhibitor phenylbutazone.
Toxicology: Tablet: Preclinical Safety Data: Preclinical studies have been conducted in animal species including mice, rats, rabbits, dogs and monkeys. The most common findings in non-iron-loaded animals at doses of ≥100 mg/kg/day were hematologic effects eg, bone marrow hypocellularity, and decreased WBC, RBC and/or platelet counts in peripheral blood.
Atrophy of the thymus, lymphoid tissues and testis, and hypertrophy of the adrenals, were reported at doses of ≥100 mg/kg/day in non-iron-loaded animals.
No carcinogenicity studies in animals have been conducted with deferiprone. The genotoxic potential of deferiprone was evaluated in a set of in vivo tests. Deferiprone did not show direct mutagenic properties; however, it did display clastogenic characteristics in vivo in animals.
Deferiprone was teratogenic and embryotoxic in reproductive studies in non-iron-loaded rats and rabbits at doses at least as low as 25 mg/kg/day. No prenatal and postnatal reproductive studies have been conducted in animals.
Oral Solution: Clinical Studies: In a prospective, planned, pooled analysis of patients from several studies, the efficacy of FERRIPROX 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 FERRIPROX. FERRIPROX therapy (35-99 mg/kg/day) was considered successful in individual patients who experienced a ≥ 20% decline in serum ferritin within one year of starting therapy.
Data from a total of 236 patients were analyzed. Of the 224 patients with thalassemia who received deferiprone monotherapy and were eligible for serum ferritin analysis, 105 (47%) were male and 119 (53%) were female. The mean age of these patients was 18.2 years.
For the patients in the analysis, the endpoint of at least a 20% reduction in serum ferritin was met in 50% (of 236 subjects), with a 95% confidence interval of 43% to 57%.
A small number of patients with thalassemia and iron overload were assessed by measuring the change in the number of milliseconds (ms) in the cardiac MRI T2* value before and after treatment with deferiprone for one year. There was an increase in cardiac MRI T2* from a mean at baseline of 11.8±4.9 ms to a mean of 15.1±7.0 ms after approximately one year of treatment. The clinical significance of this observation is not known.
Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenicity studies have not been conducted with deferiprone. However, in view of the genotoxicity results, and the findings of mammary gland hyperplasia and mammary gland tumors in rats treated with deferiprone in the 52-week toxicology study, tumor formation in carcinogenicity studies must be regarded as likely.
Deferiprone was positive in a mouse lymphoma cell assay in vitro. Deferiprone was clastogenic in an in vitro chromosomal aberration test in mice and in a chromosomal aberration test in Chinese Hamster Ovary cells. Deferiprone given orally or intraperitoneally was clastogenic in a bone marrow micronucleus assay in non-iron-loaded mice. A micronucleus test was also positive when mice predosed with iron dextran were treated with deferiprone. Deferiprone was not mutagenic in the Ames bacterial reverse mutation test.
A fertility and early embryonic development study of deferiprone was conducted in rats. Sperm counts, motility and morphology were unaffected by treatment with deferiprone. There were no effects observed on male or female fertility or reproductive function at the highest dose which was 25% of the MRHD based on body surface area.

Tablet and oral solution: Ferriprox is indicated for the treatment of iron overload in patients 1 year of age and older with thalassaemia major.
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 Pharmacology: Toxicology: Oral Solution: Clinical Studies under Actions).
Limitation of Use: Safety and effectiveness have not been established for the treatment of transfusional iron overload in patients with other chronic anemias.

Tablet: Deferiprone therapy should be initiated and maintained by a physician experienced in the treatment of patients with thalassemia.
Deferiprone is most commonly given as 25 mg/kg body weight orally 3 times a day for a total daily dose of 75 mg/kg body weight. Dosage per kilogram body weight should be calculated to the nearest half tablet.
To obtain a dose of about 75 mg/kg/day, use the number of tablets suggested: See Table 1.


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Doses ≥100 mg/kg/day are not recommended because of the potentially increased risk of adverse reactions.
Due to the serious nature of agranulocytosis that can occur with the use of deferiprone, special monitoring is required for all patients. Caution must be used when the patient's absolute neutrophil count (ANC) is low, as well as when treating patients with renal insufficiency or hepatic dysfunction.
Oral Solution: Starting Dose: The recommended initial dose of FERRIPROX is 25 mg/kg, orally, three times per day for a total of 75 mg/kg/day. (See Table 2a.)


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Dose Adjustments: Dose adjustments should be tailored to the individual patient’s response and therapeutic goals (maintenance or reduction of body iron burden). The maximum dose is 33 mg/kg, three times per day for a total of 99 mg/kg/day. The dose should be rounded by the prescriber to the nearest 2.5 mL. (See Table 2b.)


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Monitor serum ferritin concentration every two to three months to assess the effects 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.
After first opening of the bottle, use within 35 days. Store the bottle in the original carton to protect from light. Store FERRIPROX only in the original container. After 35 days, discard the contents of the bottle. Store at 20º to 25ºC (68º to 77ºF); excursions permitted to 15º to 30ºC (59º to 86ºF).
Interactions with Foods, Vitamins and Drugs: Allow at least a 4-hour interval between FERRIPROX and other medications or supplements containing polyvalent cations such as iron, aluminum, and zinc. Avoid concomitant use of UGT1A6 inhibitors (e.g. diclofenac, probenecid, or silymarin (milk thistle)) with FERRIPROX (see Pharmacology: Pharmacokinetics: Oral Solution: Drug Interactions under Actions and Interactions: Oral Solution).

Tablet: No case of overdose has been reported. In case of overdose, close clinical supervision of the patient is required.
Oral Solution: 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.

Tablet: Hypersensitivity to deferiprone or to any of the excipients of Ferriprox. History of recurrent episodes of neutropenia; history of agranulocytosis.
Due to the unknown mechanism of deferiprone-induced neutropenia, patients should not take medicinal products known to be associated with neutropenia or those that can cause agranulocytosis (see Precautions: Tablet).
Oral Solution: 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: Oral Solution).

AGRANULOCYTOSIS/NEUTROPENIA: FERRIPROX can cause agranulocytosis that can lead to serious infections and death. Neutropenia may precede the development of agranulocytosis (see Precautions).
Measure the absolute neutrophil count (ANC) before starting FERRIPROX and monitor the ANC weekly on therapy (see Precautions).
Interrupt FERRIPROX if infection develops and monitor the ANC more frequently (see Precautions).
Advise patients taking FERRIPROX to report immediately any symptoms indicative of infection (see Precautions).

Tablet: Neutropenia/Agranulocytosis: Deferiprone has been shown to cause neutropenia, including agranulocytosis. It is recommended that a patient's neutrophil count be monitored every week.
In clinical trials, weekly monitoring of the neutrophil count has been effective in identifying cases of neutropenia and agranulocytosis. Neutropenia and agranulocytosis resolved once therapy was withdrawn. If the patients develop an infection while on deferiprone, therapy should be interrupted and the neutrophil count monitored more frequently. Patients should be advised to immediately report to the physician any symptoms that indicate infection eg, fever, sore throat and flu-like symptoms.
It is recommended that such a management protocol be in place prior to initiating any patient on deferiprone treatment. Deferiprone should not be initiated to neutropenic patient. The risk of agranulocytosis and neutropenia is higher if the baseline ANC count is <1.5 x 10⁹/L.
In the Event of Neutropenia: Instruct the patient to immediately discontinue deferiprone and all other medications with a potential to cause neutropenia. The patient should be advised to limit contact with other individuals in order to reduce the risk of infection. Obtain a complete blood cell (CBC) count, with a white blood cell (WBC) count, corrected for the presence of nucleated red blood cells, a neutrophil count, and a platelet count immediately upon diagnosing event and then repeat daily. It is recommended that following recovery from neutropenia, weekly CBC, WBC and neutrophil and platelet counts continue to be obtained for 3 consecutive weeks, to ensure that the patient recovers fully. Should any evidence of infection develop concurrrently with the neutropenia, the appropriate cultures and diagnostic procedures should be performed and an appropriate therapeutic regimen instituted.
In the Event of Severe Neutropenia or Agranulocytosis: Follow previously mentioned guidelines and administer appropriate therapy eg, granulocyte colony stimulating factor, beginning the same day that the event is identified; administer daily until the condition resolves. Provide protective isolation and if clinically indicated, admit patient to the hospital.
Limited information is available regarding rechallenge. Therefore, in the event of neutropenia, rechallenge is not recommended. In the event of agranulocytosis, a rechallenge is contraindicated.
Carcinogenicity, Mutagenicity & Impairment of Fertility: In view of the genotoxicity results, a carcinogenic potential of deferiprone cannot be excluded (see Pharmacology: Toxicology: Tablet under Actions). No animal studies to evaluated the potential effects of deferiprone on fertility have been reported.
Serum Ferritin Concentration/Plasma Zinc Concentration: It is recommended that serum ferritin concentration or other indicators of body iron load, be monitored every 2-3 months to assess the long-term effectiveness of the chelation regimen in controlling the body iron load. Interruption of therapy with deferiprone should be considered if serum ferritin measurements fall <500 micro/L. Monitoring of plasma zinc concentrations and supplementation in case of a deficiency is recommended.
HIV Positive or Other Immune Compromised Patients: No data are available on the use of deferiprone in HIV positive or in other immune compromised patients. Given that deferiprone can be associated with neutropenia and agranulocytosis, therapy in immune compromised patients should not be initiated unless potential benefits outweigh potential risks.
Renal or Hepatic Impairment and Liver Fibrosis: There are no available data in patients with renal or hepatic impairment. Since deferiprone is eliminated mainly via the kidneys, there may be an increased risk of complications in patients with impaired renal function. Similarly, as deferiprone is metabolized in the liver, caution must be exercised in patients with hepatic dysfunction. Renal and hepatic function should be monitored in this patient population during deferiprone therapy. If there is a persistent increase in serum alanine aminotransferase (ALT), interruption of deferiprone therapy should be considered.
In thalassemia patients, there is an association between liver fibrosis and iron overload and/or hepatitis C. Special care must be taken to ensure that iron chelation in patients with hepatitis C is optimal. In these patients, careful monitoring of liver histology is recommended.
Discoloration of Urine: Patients should be informed that the urine may show a reddish/brown discoloration due to the excretion of the iron-deferiprone complex.
Effects on the Ability to Drive or Operate Machinery: No studies on the effect on the ability to drive and use machines have been performed.
Oral Solution: Agranulocytosis/Neutropenia: Fatal agranulocytosis can occur with FERRIPROX use. FERRIPROX can also cause neutropenia, which may foreshadow agranulocytosis. Measure the absolute neutrophil count (ANC) before starting FERRIPROX therapy and monitor the ANC weekly on therapy.
Interrupt FERRIPROX therapy if neutropenia develops (ANC < 1.5 x 10⁹/L).
Interrupt FERRIPROX if infection develops, and monitor the ANC frequently.
Advise patients taking FERRIPROX 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 FERRIPROX-associated agranulocytosis is unknown. Agranulocytosis and neutropenia usually resolve upon discontinuation of FERRIPROX, but there have been reports of agranulocytosis leading to death.
Implement a plan to monitor for and to manage agranulocytosis/neutropenia prior to initiating FERRIPROX treatment.
For Neutropenia (ANC < 1.5 x 10⁹/L and > 0.5 x 10⁹/L): Instruct the patient to immediately discontinue FERRIPROX and all other medications with a potential to cause neutropenia.
Obtain a complete blood cell (CBC) count, including a white blood cell (WBC) count corrected for the presence of nucleated red blood cells, an absolute neutrophil count (ANC), and a platelet count daily until recovery (ANC ≥ 1.5 x 10⁹/L).
For Agranulocytosis (ANC < 0.5 x 10⁹/L): Consider hospitalization and other management as clinically appropriate.
Do not resume FERRIPROX in patients who have developed agranulocytosis unless potential benefits outweigh potential risks. Do not rechallenge patients who develop neutropenia with FERRIPROX unless potential benefits outweigh potential risks.
Embryofetal Toxicity: 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. 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. Women of reproductive potential should be advised to avoid pregnancy when taking FERRIPROX (see Use in Pregnancy & Lactation: Oral Solution and Pharmacology: Toxicology: Oral Solution under Actions).
Liver Enzyme Elevations: In clinical studies, 7.5% of 642 subjects treated with FERRIPROX developed increased ALT values. Four (0.62%) FERRIPROX-treated subjects discontinued the drug due to increased serum ALT levels and 1 (0.16%) due to an increase in both ALT and AST.
Monitor serum ALT values monthly during therapy with FERRIPROX, and consider interruption of therapy if there is a persistent increase in the serum transaminase levels.
Zinc Deficiency: Decreased plasma zinc concentrations have been observed on FERRIPROX therapy. Monitor plasma zinc, and supplement in the event of a deficiency.
Pediatric Use: The safety and effectiveness of FERRIPROX in pediatric patients have not been established.
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.
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/1.73 m²), mild renal impairment (eGFR 60-89 mL/min/1.73 m²), moderate renal impairment (eGFR 30-59 mL/min/1.73 m²), and severe renal impairment (eGFR 15-29 mL/min/1.73 m²). Renal function does not influence the pharmacokinetics of deferiprone and deferiprone 3-O-glucuronide.
Hepatic Impairment: An open-label, non-randomized, parallel group clinical study was conducted to evaluate the effect of impaired hepatic function on the 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). Mild and moderate hepatic impairment do not influence the pharmacokinetics of deferiprone and deferiprone 3-O-glucuronide. One subject with moderate hepatic impairment experienced a serious adverse event of acute liver and renal injury. The pharmacokinetics of deferiprone and deferiprone 3-O-glucuronide have not been evaluated in patients with severe hepatic impairment (Child Pugh Class C; 10-15 points).

Use in pregnancy: Tablet: There is no adequate information on the use of deferiprone in pregnant women. Studies in animals have shown reproductive toxicity (see Pharmacology: Toxicology: Tablet under Actions). The potential risk for human is unknown.
Women of childbearing potential must be advised to avoid pregnancy due to the clastogenic and teratogenic properties of Ferriprox. These women should be counseled to take contraceptive measure and must be advised to immediately stop taking deferiprone if they become pregnant or plan to become pregnant.
Oral Solution: Pregnancy Category D (Precautions and Pharmacology: Toxicology: Oral Solution under Actions).
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.
Use in lactation: Tablet: It is not known whether deferiprone is excreted in human milk. No prenatal and postnatal reproductive studies have been conducted in animals. Deferiprone should not be used by nursing mothers. If treatment is unavoidable, breastfeeding must be stopped.
Oral Solution: 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.

Tablet: The most serious adverse reaction reported in clinical trials with deferiprone is agranulocytosis (neutrophils <0.5 x 10⁹/L), with an incidence of 0.8% (0.5 cases per 100 patient-years of treatment), 5.9% (2.5 cases per 100 patient-years). This rate should be considered in the context of the underlying elevated incidence of neutropenia in thalassemia patients, particularly in those with hypersplenism.
Episodes of diarrhea, mostly mild and transient, have been reported in patients treated with deferiprone. Gastrointestinal effects are more frequent at the beginning of therapy and in most patients resolve within a few weeks without discontinuation of treatment. In some patients, it may be beneficial to reduce the dose of deferiprone and then scale it back up to the former dose. Arthropathy events, which ranged from mild pain in 1 or more joints to severe arthritis with effusion and significant disability, have also been reported in patients treated with deferiprone. Mild arthropathies are generally transient.
Increased levels of serum liver enzymes have been reported in patients taking deferiprone. In the majority of these patients, the increase was asymptomatic and transient, and returned to baseline without discontinuation or decreasing the dose of deferiprone (see Precautions: Tablet).
Some patients experienced progression of fibrosis associated with an increase in iron overload or hepatitis C.
In a minority of patients, low plasma zinc levels have been associated with deferiprone. The levels normalized with oral zinc supplementation.
See Table 3.


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Oral Solution: Clinical Trial Experience: The following adverse reactions are described as follows and as previously mentioned in the labeling: Agranulocytosis/neutropenia; liver enzyme elevations; zinc deficiency (see Precautions: Oral Solution).
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 trials.
The most serious adverse reaction reported in clinical trials with FERRIPROX was agranulocytosis (see Precautions: Oral Solution).
The most common adverse reactions reported during clinical trials were chromaturia, nausea, vomiting, abdominal pain, alanine aminotransferase increased, arthralgia and neutropenia.
The table as follows lists the adverse drug reactions that occurred in at least 1% of patients treated with FERRIPROX in clinical trials. (See Table 4.)


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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.
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.

Tablet: Interactions between deferiprone and other medicinal products have not been reported. However, since deferiprone binds to metallic cations, the potential exists for interactions between deferiprone and trivalent cation-dependent medicinal products eg, aluminum-based antacids. Therefore, it is not recommended to concomitantly ingest aluminum-based antacids and deferiprone.
The safety of concurrent use of deferiprone and vitamin C has not been formally studied. Based on the reported adverse interaction that can occur between deferoxamine and vitamin C, caution should be used when administering deferiprone and vitamin C concurrently.
Incompatibilities: Not applicable.
Oral Solution: 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, monitor the absolute neutrophil count more frequently (see Precautions: Oral Solution).
UDP-Glucuronosyltransferases (UGTs): A clinical study to evaluate the effect of coadministration of UGT1A6 inhibitors with FERRIPROX on the systemic exposure of deferiprone has not been conducted. However, in the presence of the UDP glucuronosyltransferase (UGT) 1A6 inhibitor, phenylbutazone, the in vitro glucuronidation of deferiprone is reduced by 78%. Therefore, avoid concomitant use of UGT1A6 inhibitors (e.g. diclofenac, probenecid, or silymarin (milk thistle)) with FERRIPROX (see Dosage & Administration: Oral Solution, Adverse Reactions: Oral Solution, and Pharmacology: Pharmacodynamics: Oral Solution under Actions).
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 & Administration: Oral Solution).

Tablet: Do not store above 30°C.
Shelf-Life: 5 years.
Oral Solution: Store at 20º to 25ºC (68º to 77ºF); excursions permitted to 15º to 30ºC (59º to 86ºF).
Store in the original package in order to protect from light.

Oral Solution: Instruct patients and their caregivers that FERRIPROX is light sensitive and to store FERRIPROX in the originally supplied bottle and carton. Store FERRIPROX at 20º to 25ºC (68º to 77ºF); excursions permitted to 15º to 30ºC (59º to 86ºF). Instruct patients and their caregivers to store FERRIPROX out of the sight and reach 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.
Advise patients that the amount of FERRIPROX prescribed is based on body weight and on the therapeutic goal (reduction or stabilization of the body iron load). Advise patients to use the measuring cup provided with FERRIPROX to measure the volume prescribed. Instruct patients to add about 10-15 mL of water to the measuring cup and swirl it around to mix the water with any remaining medicine in the cup and drink the mixture. The measuring cup should be hand-washed with water after use.
Advise patients to take the first dose of FERRIPROX in the morning, the second dose at midday, and the third dose in the evening. Clinical experience suggests that taking FERRIPROX with meals may reduce nausea. If a dose of this medicine has been missed, take as soon as possible. However, if it is almost time for the next dose, skip the missed dose and go back to the regular dosing schedule. Do not catch-up or double doses.
Advise patients to contact their physician in the event of overdose.
Inform patients that their urine might show a reddish/brown discoloration due to the excretion of the iron-deferiprone complex. This is a very common sign of the desired effect of FERRIPROX, and it is not harmful.
Counsel women of reproductive potential to avoid pregnancy while taking FERRIPROX. Advise patients to immediately notify their physician if they become pregnant, or if they plan to become pregnant during therapy.
Inform patients that they should not breast feed while taking FERRIPROX.

Antidotes & Detoxifying Agents

V03AC02 - deferiprone ; Belongs to the class of iron chelating agents. Used in iron overload.

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