Ferriprox Special 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 Neutropenia and agranulocytosis resolved once therapy was withdrawn.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).