Ferriprox Information
Ferriprox ()
Ferriprox () Warning: Agranulocytosis/neutropenia
Ferriprox () Indications And Usage
Ferriprox () (deferiprone) is indicated for the treatment of patients with transfusional iron overload due to thalassemia syndromes when current chelation therapy is inadequate.
Approval is based on a reduction in serum ferritin levels. There are no controlled trials demonstrating a direct treatment benefit, such as improvement in disease-related symptoms, functioning, or increased survival .
Limitation of Use:
Ferriprox () Dosage And Administration
The recommended initial dose of Ferriprox () is 25 mg/kg, orally, three times per day for a total of 75 mg/kg/day. The maximum dose is 33 mg/kg, three times per day for a total of 99 mg/kg/day.
Dose adjustments up to 33 mg/kg, orally, three times per day should be tailored to the individual patient’s response and therapeutic goals (maintenance or reduction of body iron burden). The maximum recommended total daily dose is 99 mg/kg per day. The dose should be rounded by the prescriber to the nearest 250 mg (half-tablet).
Monitor serum ferritin concentration every two to three months to assess the effects of Ferriprox () on body iron stores. Dose adjustments should be tailored to the individual patient’s response and therapeutic goals (maintenance or reduction of body iron burden). If the serum ferritin falls consistently below 500 mcg/L, consider temporarily interrupting Ferriprox () therapy.
Ferriprox () Dosage Forms And Strengths
500 mg film-coated tablets with a functional score.
Ferriprox () Warnings And Precautions
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
Interrupt Ferriprox () if infection develops, and monitor the ANC more 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 0.5 x 10/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 10/L).
For agranulocytosis (ANC
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.
Serum liver enzyme activities
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.
Plasma Zinc concentration
Ferriprox () Adverse Reactions
The following adverse reactions are also discussed in other sections of the labeling: Agranulocytosis/Neutropenia . Elevated ALT , Torsades de Pointes , Decreased plasma zinc concentrations .
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Adverse reaction information for Ferriprox () represents the pooled data collected from 642 patients who participated in single arm or active-controlled clinical studies.
The most serious adverse reaction reported in clinical trials with Ferriprox () was agranulocytosis .
The most common adverse reactions reported during clinical trials were chromaturia, nausea, vomiting, abdominal pain, alanine aminotransferase increased, arthralgia and neutropenia.
The table below lists the adverse drug reactions that occurred in at least 1% of patients treated with Ferriprox () in clinical trials.
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.
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:
Cardiac disorders
Eye disorders
Gastrointestinal disorders
General disorders and administration site conditions
Immune system disorders:
I: cryptococcal cutaneous infection, enteroviral encephalitis, pharyngitis, pneumonia, sepsis, furuncle, infection hepatitis, rash pustular, subcutaneous abscess.
Investigations
Metabolism and nutrition disorders
Musculoskeletal and connective tissue disorders
Nervous system disorders
Psychiatric disorders:
Renal disorders:
Respiratory, thoracic and mediastinal disorders
Skin, subcutaneous tissue disorders:
Ferriprox () Use In Specific Populations
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.
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.
Ferriprox () 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.
Ferriprox () Description
Ferriprox () (deferiprone) tablets contain 500 mg deferiprone (3-hydroxy-1,2-dimethylpyridin-4-one), a synthetic, orally active, iron-chelating agent. Deferiprone has the following structural formula:
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 () tablets are white to off-white, capsule-shaped tablets, and imprinted with “APO” score “500” on one side and plain on the other. The tablets can be broken in half along the score. Each tablet contains 500 mg deferiprone and the following inactive ingredients: Tablet core - microcrystalline cellulose, magnesium stearate, colloidal silicon dioxide; Coating - hydroxypropyl methyl cellulose, polyethylene glycol, titanium dioxide.
Ferriprox () Clinical Pharmacology
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 Cmax of deferiprone by 38% and the AUC by 10%. While a food effect cannot be ruled out, the magnitude of the exposure change does not warrant dose adjustment.
In healthy subjects, the mean maximum concentration (C) of deferiprone in serum was 20 mcg/mL, and the mean total area under the concentration-time curve (AUC) was 53 mcg∙h/mL following oral administration of a 1,500 mg dose of Ferriprox () tablets in the fasting state. Dose proportionality over the labeled dosage range of 25 to 33 mg/kg three times per day (75 to 100 mg/kg per day) has not been studied. The elimination half life (t) of deferiprone was 1.9 hours. The accumulation of deferiprone and its glucuronide metabolite at the highest approved dosage level of 33 mg/kg three times per day has not been studied. The volume of distribution of deferiprone is 1.6 L/kg in thalassemia patients, and approximately 1 L/kg in healthy subjects. The plasma protein binding of deferiprone in humans is less than 10%.
In humans, the majority of the deferiprone is metabolized, primarily by UGT 1A6. 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. Peak serum concentration of the glucuronide occurs 2 to 4 hours after administration of deferiprone in fasting subjects.
More than 90% of deferiprone is eliminated from plasma within 5 to 6 hours of ingestion. Following oral administration, 75% to 90% is recovered in the urine in the first 24 hours, primarily as metabolite.
Special 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.
Ferriprox () 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.
Ferriprox () How Supplied/storage And Handling
Ferriprox () (deferiprone) tablets are white to off-white, capsule-shaped tablets, film-coated, and have a functional score imprinted with “APO” score “500” on one side and are plain on the other. They are provided in a 100 count HDPE bottle with a child-resistant cap.
500 mg film-coated tablets, 100 tablets NDC 52609-0006-1
Store at 20º to 25ºC (68º to 77ºF); excursions permitted to 15º to 30ºC (59º to 86ºF) [see USP Controlled Room Temperature].
Keep Ferriprox () out of the reach and sight of children.
Ferriprox () Patient Counseling Information
Manufactured for ApoPharma USA, Inc., Rockville, MD, United States of America, 20850. Manufactured by Apotex Inc., Toronto, Ontario, Canada, M9L 1T9
Ferriprox ()
Ferriprox () Package Label.principal Display Panel Section
