May 29, 2016
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Ferriprox

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Ferriprox




Warnings
Precautions

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

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 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 < 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 Specific Populations and Nonclinical Toxicology].

Laboratory Tests

Serum Liver Enzyme Activities

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.

Plasma Zinc Concentration

Decreased plasma zinc concentrations have been observed on Ferriprox therapy. Monitor plasma zinc, and supplement in the event of a deficiency.

Patient Counseling Information

See FDA-Approved Patient Labeling (Medication Guide)

  • 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 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.

Nonclinical Toxicology

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 deferprone. 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.

Use In Specific Populations

Pregnancy

Pregnancy Category D [see WARNINGS AND PRECAUTIONS, Nonclinical Toxicology]

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.

Nursing Mothers

It is not known whether deferiprone is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for adverse reactions in nursing infants from Ferriprox, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

The safety and effectiveness of Ferriprox tablets for oral use 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/1.73m²), mild renal impairment (eGFR 60–89 mL/min/1.73m²), moderate renal impairment (eGFR 30–59 mL/min/1.73m²), and severe renal impairment (eGFR 15–29 mL/min/1.73m²). Systemic exposure to deferiprone and to its metabolite deferiprone 3-O-glucuronide was assessed by the PK parameters Cmax and AUC.

Regardless of the degree of renal impairment, the majority of the dose of Ferriprox was excreted in the urine over the first 24 hours as deferiprone 3-O-glucuronide. No significant effect of renal impairment was seen on systemic exposure to deferiprone. Systemic exposure to the inactive 3-O-glucuronide increased with decreasing eGFR. Based on the results of this study, no adjustment of the Ferriprox dosage regimen is required in patients with impaired renal function.

Hepatic Impairment

The influence of severe hepatic impairment on the pharmacokinetics of deferiprone and deferiprone 3-O-glucuronide has not been evaluated. Safety and efficacy of Ferriprox have not been evaluated in patients with severe hepatic impairment.

An open-label, non-randomized, parallel group clinical study was conducted to evaluate the effect of impaired hepatic function on the safety, tolerability, and pharmacokinetics of a single 33 mg/kg oral dose of Ferriprox. Subjects were categorized into 3 groups based on the Child-Pugh classification score: healthy volunteers, mild hepatic impairment (Class A: 5– 6 points), and moderate hepatic impairment (Class B: 7– 9 points). Systemic exposure to deferiprone and to its metabolite deferiprone 3-O-glucuronide was assessed by the PK parameters Cmax and AUC. The PK of both deferiprone and deferiprone 3-O-glucuronide was generally similar in all subjects, regardless of degree of liver impairment. A serious adverse event of acute liver and renal injury was seen in one subject with moderate hepatic impairment. Based on the results of this study, no adjustment of the Ferriprox dosage regimen is required in patients with mildly or moderately impaired hepatic function.

This monograph has been modified to include the generic and brand name in many instances.

Last reviewed on RxList: 3/24/2016

Warnings
Precautions

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