Data from FDA - Curated by Toby Galbraith - Last updated 10 August 2017

Indication(s)

1 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 [see Clinical Studies (14)].

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

FERRIPROX® (deferiprone) is an iron chelator indicated for the treatment of patients with transfusional iron overload due to thalassemia syndromes when current chelation therapy is inadequate.

(1) 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.

(1) Limitation of Use Safety and effectiveness have not been established for the treatment of transfusional iron overload in patients with other chronic anemias.

(1)

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Advisory information

contraindications

4 CONTRAINDICATIONS 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-Sch?nlein purpura; urticaria; and periorbital edema with skin rash [see Adverse Reactions (6.2)].

Hypersensitivity to deferiprone or to any of the excipients in the formulation.

(4)

Adverse reactions

6 ADVERSE REACTIONS The most common adverse reactions are (incidence?

5 %) chromaturia, nausea, vomiting and abdominal pain, alanine aminotransferase increased, arthralgia and neutropenia.

(5.1, 6) To report SUSPECTED ADVERSE REACTIONS, contact ApoPharma Inc. at: Telephone: 1-866-949-0995 Email: [email protected] or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Clinical Trial Experience The following adverse reactions are described below and elsewhere in the labeling: Agranulocytosis/Neutropenia [see Warnings and Precautions (5.1)] Liver Enzyme Elevations [see Warnings and Precautions (5.3)] Zinc Deficiency [see Warnings and Precautions (5.4)].

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug can not 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 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.

Table 2: Adverse drug reactions occurring in?

1 % of FERRIPROX-treated patients Body System (N=642) Preferred Term % Subjects BLOOD AND LYMPHATIC SYSTEM DISORDERS Neutropenia 6 Agranulocytosis 2 GASTROINTESTINAL DISORDERS Nausea 13 Abdominal pain/discomfort 10 Vomiting 10 Diarrhea 3 Dyspepsia 2 INVESTIGATIONS Alanine Aminotransferase increased 7 Neutrophil count decreased 7 Weight increased 2 Aspartate Aminotransferase increased 1 METABOLISM AND NUTRITION DISORDERS Increased appetite 4 Decreased appetite 1 MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS Arthralgia 10 Back pain 2 Pain in extremity 2 Arthropathy 1 NERVOUS SYSTEM DISORDERS Headache 2 URINARY DISORDERS Chromaturia 15 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.

6.2 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-Sch?nlein purpura.

Vascular disorders: hypotension, hypertension.

Usage information

Dosing and administration

2 DOSAGE AND ADMINISTRATION 25 mg/kg to 33 mg/kg body weight, orally, three times per day, for a total daily dose of 75 mg/kg to 99 mg/kg body weight.

(2.1) 2.1 Dosing 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.

Table 1a: Volume of oral solution (rounded to the nearest 2.5 mL) required to achieve a 25 mg/kg dose for administration three times a day.

Body Weight (kg) Dose (mg) mL of oral solution 20 500 5 30 750 7.5 40 1,000 10 50 1,250 12.5 60 1,500 15 70 1,750 17.5 80 2,000 20 90 2,250 22.5 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. Table 1b: Volume of oral solution (rounded to the nearest 2.5 mL) required to achieve a 33 mg/kg dose for administration three times a day.

Body Weight (kg) Dose (mg) mL of oral solution 20 660 7.5 30 990 10 40 1,320 12.5 50 1,650 17.5 60 1,980 20 70 2,310 22.5 80 2,640 27.5 90 2,970 30 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 20?

to 25?C (68?

to 77?F); excursions permitted to 15?

to 30?C (59?

to 86?F) [see USP Controlled Room Temperature].

2.2 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 Drug Interactions (7.2 and 7.3), Clinical Pharmacology (12.3)].

Use in special populations

8 USE IN SPECIFIC POPULATIONS Nursing mothers: Discontinue the use of FERRIPROX or discontinue nursing.

(8.3) 8.1 Pregnancy Pregnancy Category D [see Warnings and Precautions (5.2), Nonclinical Toxicology (13.1)] 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.

8.3 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.

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

8.5 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.

8.6 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.

8.7 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).

Pregnancy and lactation
8.3 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.

Interactions

7 DRUG INTERACTIONS Avoid concomitant use with other drugs known to be associated with neutropenia or agranulocytosis; however, if this is not possible, closely monitor the absolute neutrophil count.

(7.1) Avoid concomitant use of UGT1A6 inhibitors with FERRIPROX. (7.2) Allow at least a 4-hour interval between FERRIPROX and mineral supplements, and antacids that contain polyvalent cations (e.g., iron, aluminum, and zinc).

(7.3) 7.1 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 Warnings and Precautions (5.1)].

7.2 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 and Administration (2.2), Adverse Reactions (6.1), Clinical Pharmacology (12.3)].

7.3 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 and Administration (2.2)].

More information

Category Value
Authorisation number NDA208030
Agency product number 2BTY8KH53L
Orphan designation No
Product NDC 52609-4502
Date Last Revised 15-09-2015
Type HUMAN PRESCRIPTION DRUG
RXCUI 1716268
Marketing authorisation holder ApoPharma USA, Inc.
Warnings

WARNING:

AGRANULOCYTOSIS/NEUTROPENIA 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 the ANC weekly 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)] WARNING:

AGRANULOCYTOSIS/NEUTROPENIA See full prescribing information for complete boxed warning.

FERRIPROX can cause agranulocytosis that can lead to serious infections and death.

Neutropenia may precede the development of agranulocytosis.

(5.1) Measure the absolute neutrophil count (ANC) before starting FERRIPROX and monitor the ANC weekly on therapy.

(5.1) Interrupt FERRIPROX if infection develops and monitor the ANC more frequently.

(5.1) Advise patients taking FERRIPROX to report immediately any symptoms indicative of infection.

(5.1)