Ferriprox Solution
FDA Label NDC 10122-101

• FERRIPROX can cause agranulocytosis that can lead to serious infections and death. Neutropenia may precede the development of agranulocytosis. [see Warnings and Precautions (5.1)]

• Measure the absolute neutrophil count (ANC) before starting FERRIPROX therapy and monitor weekly while on therapy. Interrupt FERRIPROX therapy if neutropenia develops. [see Warnings and Precautions (5.1)]

• Interrupt FERRIPROX if infection develops, and monitor the ANC more frequently. [see Warnings and Precautions (5.1)]

• Advise patients taking FERRIPROX to report immediately any symptoms indicative of infection. [see Warnings and Precautions (5.1)]

FERRIPROX^® 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 [see Clinical Studies (14)].

Limitations of Use

• Safety and effectiveness have not been established for the treatment of transfusional iron overload in patients with other chronic anemias.

Starting Dose

The recommended initial dose of FERRIPROX is 25 mg/kg actual body weight, orally, three times per day for a total of 75 mg/kg/day. Round dose to the nearest 2.5 mL.

Dose Adjustments

Tailor dose adjustments to the individual patient’s response and therapeutic goals (maintenance or reduction of body iron burden). The maximum dose is 33 mg/kg actual body weight, three times per day for a total of 99 mg/kg/day.

Monitor serum ferritin concentration every two to three months to assess the effect 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.

Allow at least a 4-hour interval between administration of FERRIPROX and other drugs or supplements containing polyvalent cations such as iron, aluminum, or zinc [see Drug Interactions (7.2), Clinical Pharmacology (12.3)].

Oral Solution: 100 mg/mL (50 g/500 mL), clear, reddish orange colored 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 (6.2)].

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 it weekly while 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 and neutropenia prior to initiating FERRIPROX treatment.

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 have developed neutropenia with FERRIPROX unless potential benefits outweigh potential risks.

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).

In clinical studies, 7.5% of 642 patients 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.

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

Based on findings from animal reproduction studies and evidence of genotoxicity, FERRIPROX can cause fetal harm when administered to a pregnant woman. The available data on the use of FERRIPROX in pregnant women are insufficient to inform risk. 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. Advise pregnant women and females of reproductive potential of the potential risk to the fetus [see Use in Specific Populations (8.1)].

Advise females of reproductive potential to use an effective method of contraception during treatment with FERRIPROX and for at least six months after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with FERRIPROX and for at least three months after the last dose [see Use in Specific Populations (8.1, 8.3)].

The following clinically significant adverse reactions are described below and elsewhere in the labeling:

• Agranulocytosis and Neutropenia [see Warnings and Precautions (5.1)]
• Liver Enzyme Elevations [see Warnings and Precautions (5.2)]
• Zinc Deficiency [see Warnings and Precautions (5.3)]

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 Warnings and Precautions (5.1)].

The most common adverse reactions reported during clinical trials were 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 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: 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.

Avoid co-administration of FERRIPROX with other drugs known to be associated with neutropenia or agranulocytosis. If co-administration is unavoidable, closely monitor the absolute neutrophil count [see Warnings and Precautions (5.1)].

UDP-Glucuronosyltransferases (UGTs)

Avoid co-administration of FERRIPROX with a UGT1A6 inhibitor (e.g., diclofenac, probenecid, or silymarin (milk thistle)) [see Dosage and Administration (2.2), Adverse Reactions (6.1), and Clinical Pharmacology (12.3)].

Polyvalent Cations

Deferiprone has the potential to bind polyvalent cations (e.g., iron, aluminum, and zinc); allow at least a 4-hour interval between administration of FERRIPROX and other medications (e.g., antacids) or supplements containing these polyvalent cations [see Dosage and Administration (2.2)].

Risk Summary

In animal reproduction studies, oral administration of deferiprone to pregnant rats and rabbits during organogenesis at doses 33% and 49%, respectively, of the maximum recommended human dose (MRHD) resulted in structural abnormalities, embryo-fetal mortality and alterations to growth (see Data). The limited data from FERRIPROX use in pregnant women are insufficient to inform a drug-associated risk of major birth defects and miscarriage. Based on evidence of genotoxicity and developmental toxicity in animal studies, FERRIPROX can cause fetal harm when administered to a pregnant woman. Advise pregnant women and females of reproductive potential of the potential risk to a fetus.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and of miscarriage is 2-4% and 15-20%, respectively.

Data

Human Data

Post-marketing data available from 39 pregnancies of FERRIPROX-treated patients and 10 pregnancies of partners of FERRIPROX-treated patients are as follows:

Of the 39 pregnancies in FERRIPROX-treated patients, 23 resulted in healthy newborns, 6 ended in spontaneous abortion, 9 had unknown outcomes, and 1 infant was born with anal atresia, nephroptosis, ventricular septal defect, hemivertebra and urethral fistula.

Of the 10 pregnancies in partners of FERRIPROX-treated patients, 5 resulted in healthy newborns, 1 resulted in a healthy newborn with slight hypospadias, 1 was electively terminated, 1 resulted in the intrauterine death of twins, and 2 had unknown outcomes.

Animal Data

During organogenesis, pregnant rats and rabbits received deferiprone at oral doses of 0, 30, 80 or 200 mg/kg/day, and 0, 10, 50, or 150 mg/kg/day, respectively. The daily dose was administered as two equal divided doses approximately 7 hours apart. Doses of 200 mg/kg/day in rats and 150 mg/kg/day in rabbits, approximately 33% and 49% of the MRHD, respectively, resulted in increased post-implantation loss and reduced fetal weights in the presence of maternal toxicity (reduced maternal body weight and body weight gain in both rats and rabbits; abnormal large placenta at low incidence in rats). The 200 mg/kg/day dose in rats resulted in external, visceral and skeletal fetal malformations, such as cranial malformations, cleft palate, limb malrotation, anal atresia, internal hydrocephaly, anophthalmia, and fused bones. The dose of 150 mg/kg/day in rabbits resulted in external fetal malformations (partially opened eyes) and minor blood vessel and skeletal variations.

In rats, malformations including micrognathia and persistent ductus arteriosus could be observed in the absence of maternal toxicity at doses equal to or greater than 30 and 80 mg/kg/day, approximately 5% and 13% of the MHRD, respectively.

Risk Summary

There is no information regarding the presence of deferiprone in human milk, the effects on the breastfed child, or the effects on milk production.

Because of the potential for serious adverse reactions in the breastfed child, including the potential for tumorigenicity shown for deferiprone in animal studies, advise patients that breastfeeding is not recommended during treatment with FERRIPROX, and for at least 2 weeks after the last dose.

Pregnancy Testing

Pregnancy testing is recommended for females of reproductive potential prior to initiating FERRIPROX.

Contraception

Females

FERRIPROX can cause embryo-fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)]. Advise female patients of reproductive potential to use effective contraception during treatment with FERRIPROX and for at least 6 months after the last dose.

Males

Based on genotoxicity findings, advise males with female partners of reproductive potential to use effective contraception during treatment with FERRIPROX and for at least 3 months after the last dose [see Nonclinical Toxicology (13.1)].

The safety and effectiveness of FERRIPROX in pediatric patients have not been established.

Clinical studies of FERRIPROX did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients.

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 (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 has the following structural formula:

Deferiprone is a white to pinkish-white 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 and the following inactive ingredients: purified water, hydroxyethylcellulose, glycerin, hydrochloric acid, artificial cherry flavor, peppermint oil, FD&C Yellow No. 6, and sucralose.

Deferiprone is a chelating agent that binds with ferric ions (iron III) 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 (e.g., copper, aluminum and zinc) than for iron.

Deferiprone exposure-response relationships and the time course of pharmacodynamics response are unknown.

Cardiac Electrophysiology

At a dose 1.5 times the maximum approved recommended dosage, FERRIPROX does not prolong the QT interval to any clinically relevant extent.

The mean C_max and AUC of deferiprone was 20 mcg/mL and 50 mcg∙h/mL, respectively, in healthy subjects. The dose proportionality of deferiprone over the approved recommended dosage range is unknown.

Absorption

Deferiprone appeared in the blood within 5 to 10 minutes after oral administration. Peak serum concentration of deferiprone was reached approximately 1 to 2 hours after a single dose.

Effect of Food

No clinically significant differences in the pharmacokinetics of deferiprone were observed following administration with food.

Elimination

The elimination half-life of deferiprone is approximately 2 hours.

Metabolism

Deferiprone is metabolized primarily by UGT1A6. The major metabolite of deferiprone is the 3-O-glucuronide, which lacks iron binding capability.

Excretion

Following oral administration, 75% to 90% of the administered dose was recovered in urine (primarily as metabolite) in the first 24 hours.

Specific Populations

No clinically significant differences in the pharmacokinetics of deferiprone were observed based on sex, race/ethnicity, body weight, mild to severe (eGFR 15 to 89 mL/min/1.73 m²) renal impairment, or mild (Child Pugh Class A) to moderate (Child Pugh Class B) hepatic impairment. The effect of age, including geriatric or pediatric populations, end stage renal disease, or severe (Child Pugh Class C) hepatic impairment on the pharmacokinetics of deferiprone is unknown.

Drug Interaction Studies

In Vitro Studies

UGT1A6 Inhibitors: Co-administration of deferiprone with phenylbutazone (UGT1A6 inhibitor) decreased glucuronidation of deferiprone by up to 78%.

Polyvalent Cations: Deferiprone has the potential to bind polyvalent cations (e.g., iron, aluminum, and zinc).

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.

Transfusional Iron Overload

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^® (deferiprone) oral solution is provided in amber polyethylene terephthalate (PET) bottles with child resistant closures (polypropylene). Each pack contains one bottle of 500 mL oral solution and a graduated measuring cup (polypropylene).

Oral solution, 100 mg/mL (50 g/500 mL), NDC 10122-101-50

Store at 20 °C to 25 °C (68 °F to 77 °F); excursions permitted to 15 °C to 30 °C (59 °F to 86 °F) [see USP Controlled Room Temperature].

Store in the original bottle and carton to protect from light.

After first opening of the bottle, discard any unused portion after 35 days.

Advise the patient to read the FDA-approved patient labeling (Medication Guide and Instructions for Use)

• Instruct patients and their caregivers that FERRIPROX oral solution is light sensitive and to store FERRIPROX oral solution in the originally supplied bottle and carton. Store at 20 °C to 25 °C (68 °F to 77 °F); excursions permitted to 15 °C to 30 °C (59 °F to 86 °F) [see USP Controlled Room Temperature]. Instruct patients and their caregivers to store FERRIPROX out of the reach and sight 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.
• Inform patients that their blood will be checked to monitor liver function and zinc levels. A zinc supplement may be prescribed if zinc levels are low.
• 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 it 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 iron. This is a very common sign of the desired effect of FERRIPROX, and it is not harmful.

Embryo-Fetal toxicity

Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions (5.4) and Use in Specific Populations (8.1)]. Advise female patients of reproductive potential to use effective contraception during treatment with FERRIPROX and for at least six months after the last dose [see Use in Specific Populations (8.1, 8.3)]. Advise males with female partners of reproductive potential to use effective contraception during treatment with FERRIPROX and for at least three months after the last dose [see Use in Specific Populations (8.3) and Nonclinical Toxicology (13.1)].

Lactation

Advise females not to breastfeed during treatment with FERRIPROX and for at least 2 weeks after the last dose [see Use in Specific Populations (8.2)].

Distributed by Chiesi USA, Inc., Cary, NC 27518. Manufactured by Apotex Inc., Toronto, Ontario, Canada, M9L 1T9.

CTFD-015-0320-00-SPL

This Medication Guide has been approved by the U.S. Food and Drug Administration.

Revised: 07/2020

CTFD-016-0320-00-SPL.

FERRIPROX^® (Feh’ ri prox)

(deferiprone)

oral solution, 100 mg/mL

Read this Instructions for Use before taking FERRIPROX oral solution and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or your treatment.

Important information:

• Store FERRIPROX oral solution at room temperature, 68°F to 77°F (20°C to 25°C).
• Store FERRIPROX oral solution in the original bottle and carton to protect from light.
• After first opening, use a bottle of FERRIPROX oral solution within 35 days. After 35 days, discard the bottle and any unused FERRIPROX oral solution.

Keep FERRIPROX oral solution and all medicines out of the reach of children.

Supplies needed to measure and take a dose of FERRIPROX oral solution (See Figure A):

• 1 bottle of FERRIPROX oral solution
• 1 measuring cup (supplied with each bottle of FERRIPROX oral solution). The measuring cup has markings for teaspoons (TSP) and milliliters (mL). Note: 1 TSP is equal to 5 mL.

Figure A

If you do not receive a measuring cup with your FERRIPROX oral solution, ask your pharmacist. Only use the measuring cup that comes with FERRIPROX oral solution to make sure that you measure the right amount of medicine.

Step 1: To open the bottle of FERRIPROX oral solution, remove the outer plastic wrapper from the child-resistant cap. Push down on the child-resistant cap and turn the cap in the direction of the arrow (See Figure B).

Figure B

Step 2: Pour the prescribed dose of FERRIPROX oral solution into the measuring cup (See Figure C).

Figure C

Step 3: Put the child-resistant cap back on the FERRIPROX oral solution bottle and turn it in the direction of the arrow. (See Figure D)

Figure D

Step 4: Swallow the prescribed dose of FERRIPROX oral solution (See Figure E).

Figure E

Step 5: Add about 10 to 15 mL of water to the measuring cup (See Figure F). Gently swirl the measuring cup to mix the water and any FERRIPROX oral solution left in the measuring cup (See Figure G). Drink all the mixture in the measuring cup (See Figure H).

Figure F	Figure G	Figure H

Step 6: Hand-wash the measuring cup with water.

Step 7: Keep the measuring cup with the bottle of FERRIPROX oral solution.

This Instructions for Use has been approved by the U.S. Food and Drug Administration.

Distributed by:		Manufactured by:
Chiesi USA, Inc., Cary, NC 27518.		Apotex Inc., Toronto, Ontario, Canada, M9L 1T9.

Issued 07/2020

CTFD-021-0320-00-SPL

Chiesi USA, Inc., NDC 10122-101-50

FERRIPROX oral solution

100 mg/mL (50 g/500 mL)

Rx only

500 mL