KELFER

Deferiprone is an oral iron chelator used as a second line agent in thalassemia syndromes when iron overload from blood transfusions occurs.

Thalassemias are a type of hereditary anaemia due a defect in the production of hemoglobin.

As a result, erythropoiesis, the production of new red blood cells, is impaired.

FDA approved on

October 14, 2011.

Deferiprone is indicated in thalassemia syndromes when first line chelation agents are not adequate to treat transfusional iron overload.

Deferiprone is a chelating agent with an affinity for ferric ions (iron III).

Deferiprone binds with ferric ions to form neutral 3:1 (deferiprone:iron) complexes that are stable at physiological pH. 12.2 Pharmacodynamics No clinical studies were performed to assess the relationship between the dose of deferiprone and the amount of iron eliminated from the body.

At the maximum approved recommended dose, deferiprone does not prolong the QT interval to any clinically relevant extent. 12.3 Pharmacokinetics Deferiprone Tablets (three times a day), 1,000 mg and 500 mg 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.

Deferiprone appeared in the blood within to 10 minutes after oral administration.

Peak serum concentration of deferiprone was reached approximately to 2 hours after a single dose.

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

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

Metabolism Deferiprone is metabolized primarily by

The major metabolite of deferiprone is the 3.

• O -glucuronide, which lacks iron binding capability.

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

No clinically significant differences in the pharmacokinetics of deferiprone were observed based on sex, race/ethnicity, body weight, mild to severe (eGFR to 89 mL/min/1.73 m 2 ) 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.

UGTIA6 Inhibitors: Phenylbutazone (UGT1A6 inhibitor) decreased glucuronidation of deferiprone by up to 78%.

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

Deferiprone is absorbed in the upper gastrointestinal tract.

Absorption is rapid with maximum plasma concentrations occurring after 1 hour in the fasted state and after 2 hours in the fed state.

In healthy patients, the volume of distribution is 1 L/kg, and in thalassemia patients, the volume of distribution is 1.6 L/kg.

Deferiprone is mainly metabolized by

UGT1A6 to the 3-O-glucuronide metabolite.

This metabolite cannot chelate iron.

Within 5-6 hours of administration, more than 90% of deferiprone is eliminated from the plasma. 75-90% of deferiprone is excreted in the urine as the metabolite.

The half-life is 1.9 hours.

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Agranulocytosis and neutropenia may occur, which can lead to fatal infections.

Hepatoxicity is also possible.

Most common side effects that lead to discontinuation of therapy were the gastrointestinal adverse effects (diarrhea, ulcer, nausea, gastrointestinal disturbances).

Deferiprone is contraindicated in patients with known hypersensitivity to deferiprone or to any of the excipients in the formulations.

The following reactions have been reported in association with the administration of deferiprone: Henoch-Schönlein purpura; urticaria; and periorbital edema with skin rash.

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

Deferiprone tablets are available in two formulations.

A 1,000 mg formulation and a 500 mg formulation, which have different dosing regimens to achieve the same total daily dosage.

To prevent medication errors, before prescribing and dispensing, ensure that the tablet formulation is appropriate for the dosing regimen.

Each tablet has distinct identifying characteristics.

Deferiprone tablets (three times a day), 1,000 mg: Starting oral dosage: 75 mg/kg/day (actual body weight) in three divided doses Maximum oral dosage: 99 mg/kg/day (actual body weight) in three divided doses Deferiprone tablets (three times a day), 500 mg: Starting oral dosage: 75 mg/kg/day (actual body weight) in three divided doses Maximum oral dosage: 99 mg/kg/day (actual body weight) in three divided doses 2.1 Important Dosage and Administration Information Deferiprone tablets are available in a 1,000 mg formulation and a 500 mg formulation, which have different oral dosing regimens to achieve the same total daily dosage.

Deferiprone tablets (three times a day).

• given three times a day Deferiprone tablets.

• given three times a day To prevent medication errors, before prescribing and dispensing, ensure that the tablet formulation is appropriate for the dosing regimen.

For patients who have trouble swallowing tablets, consider the use of oral solution.

Due to the risk of agranulocytosis, monitor ANC before and during deferiprone therapy.

ANC prior to start of deferiprone therapy and monitor on the following schedule during treatment: First six months of therapy: Monitor ANC weekly; Next six months of therapy: Monitor ANC once every two weeks; After one year of therapy: Monitor ANC every two to four weeks (or at the patient's blood transfusion interval in patients that have not experienced an interruption due to any decrease in ANC. Due to the risk of hepatic transaminase elevations, monitor ALT before and monthly during deferiprone therapy. Due to the risk of zinc deficiency, monitor zinc levels before and regularly during deferiprone therapy. 2.3 Recommended Dosage for 1,000 mg Deferiprone Tablets (three times a day) for Adult Patients with Transfusional Iron Overload due to Thalassemia Syndromes Starting Dosage for Three Times a Day Tablets The recommended starting oral dosage of deferiprone tablets (three times a day) is 75 mg/kg/day (actual body weight), in three divided doses per day. Table 3 describes the number of deferiprone tablets (three times a day) needed to achieve the 75 mg/kg/day total starting dosage).

Round dose to the nearest 500 mg (half-tablet).

Table 3: Number of Deferiprone 1,000 mg Tablets (three times a day) Needed to Achieve the Total Starting Daily Dosage of 75 mg/kg (rounded to the nearest half-tablet) Body Weight (kg) Morning Midday Evening 20 0.5 0.5 0.5 30 1 0.5 1 40 1 1 1 50 1.5 1 1.5 60 1.5 1.5 1.5 70 2 1.5 2 80 2 2 2 90 2.5 2 2.5 To minimize gastrointestinal upset when first starting therapy, dosing can start at 45 mg/kg/day and increase weekly by 15 mg/kg/day increments until the full prescribed dose is achieved.

Dosage Adjustments for Three Times Daily Tablets Tailor dosage adjustments for deferiprone tablets (three times a day) to the individual patient's response and therapeutic goals (maintenance or reduction of body iron burden).

The maximum oral dosage is 99 mg/kg/day (actual body weight), in three divided doses per day. Table 4 describes the number of deferiprone tablets (three times a day) needed to achieve the 99 mg/day total maximum daily dosage.

Table 4: Number of Deferiprone 1,000 mg Tablets (three times a day) Needed to Achieve the Maximum Total Daily Dosage of 99 mg/kg (rounded to the nearest half-tablet) Body Weight (kg) Morning Midday Evening 20 0.5 0.5 1 30 1 1 1 40 1.5 1 1.5 50 1.5 1.5 2 60 2 2 2 70 2.5 2 2.5 80 2.5 2.5 3 90 3 3 3 Pediatric use information is approved for Chiesi USA, Inc.'s FERRIPROX® (deferiprone) tablets.

However, due to Chiesi USA, Inc.'s marketing exclusivity rights, this drug product is not labeled with that information. 2.4 Recommended Dosage for 500 mg Deferiprone Tablets (three times a day) for Adult Patients with Transfusional Iron Overload due to Thalassemia Syndromes Starting Dosage for Three Times a Day Tablets The recommended starting oral dosage of deferiprone tablets (three times a day) is 75 mg/kg/day (actual body weight), in three divided doses per day. Table 5 describes the number of deferiprone tablets (three times a day) needed to achieve the 75 mg/kg/day total starting dosage.

Round dose to the nearest 250 mg (half-tablet).

Table 5: Number of Deferiprone 500 mg Tablets (three times a day) Needed to Achieve the Total Starting Daily Dosage of 75 mg/kg dose (rounded to the nearest half-tablet) Body Weight (kg) Morning Midday Evening 20 1 1 1 30 1.5 1.5 1.5 40 2 2 2 50 2.5 2.5 2.5 60 3 3 3 70 3.5 3.5 3.5 80 4 4 4 90 4 4 4 To minimize gastrointestinal upset when first starting therapy, dosing can start at 45 mg/kg/day and increase weekly by 15 mg/kg/day increments until the full prescribed dose is achieved.

Tailor dosage adjustments for deferiprone tablets (three times a day) to the individual patient's response and therapeutic goals (maintenance or reduction of body iron burden).

The maximum oral dosage is 99 mg/kg/day (actual body weight), in three divided doses per day. Table 6 describes the number of deferiprone tablets (three times a day) needed to achieve the 99 mg/day total maximum daily dosage.

Table 6: Number of Deferiprone 500 mg Tablets (three times a day) Needed to Achieve the Maximum Total Daily Dosage of 99 mg/kg dose (rounded to the nearest half-tablet) Body Weight (kg) Morning Midday Evening 20 1.5 1 1.5 30 2 2 2 40 3 2 3 50 3.5 3 3.5 60 4 4 4 70 5 4.5 4.5 80 5.5 5 5.5 90 6 6 6 Pediatric use information is approved for Chiesi USA, Inc.'s FERRIPROX® (deferiprone) tablets.

However, due to Chiesi USA, Inc.'s marketing exclusivity rights, this drug product is not labeled with that information. 2.5 Monitoring Ferritin Levels to Assess Efficacy Monitor serum ferritin concentration every two to three months to assess the effect of deferiprone on body iron stores.

If the serum ferritin is consistently below 500 mcg/L, consider temporarily interrupting deferiprone therapy until serum ferritin rises above 500 mcg/L. 2.6 Dosage Modification for Drug Interactions Allow at least a 4-hour interval between administration of deferiprone and other drugs or supplements containing polyvalent cations such as iron, aluminum, or zinc.

Tablets (three times a day), 1,000 mg White, film-coated, oval shaped tablets; imprinted with "T" score "1 K" on one side and plain on the other.

The tablets can be broken in half along the score line.

They are provided in

HDPE bottles. 1,000 mg film-coated tablets, 50 tablets NDC 51672-4237-4 Keep the bottle tightly closed to protect from moisture.

Store at 20°C to 25°C (68°F to 77°F) ; .

Tablets, 500 mg White to pinkish-white, capsule-shaped tablets; scored on one side, engraved "T" on the left of the score line and "5" on the right and plain on the other side.

They are provided in a 100 count HDPE bottle with a child-resistant cap. 500 mg tablets, 100 tablets NDC 51672-4196-1 Store at 20° to 25°C (68° to 77°F) .

Store at 20°C to 25°C (68°F to 77°F) ; .

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.

The limited available data from deferiprone use in pregnant women are insufficient to inform a drug-associated risk of major birth defects and miscarriage.

Based on evidence and developmental toxicity in animal studies, deferiprone 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 to 4% and to 20%, respectively.

Post-marketing data available from 39 pregnancies of deferiprone-treated patients and 10 pregnancies of partners of deferiprone-treated patients are as follows: Of the 39 pregnancies in deferiprone-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 deferiprone-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.

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 and 80 mg/kg/day, approximately 5% and 13% of the MHRD, respectively.

Safety and effectiveness of deferiprone tablets have not been established in pediatric patients with chronic iron overload due to blood transfusions who are less than 8 years of age.

Pediatric use information is approved for Chiesi USA, Inc.'s FERRIPROX® (deferiprone) tablets.

However, due to Chiesi USA, Inc.'s marketing exclusivity rights, this drug product is not labeled with that information.

Clinical studies of deferiprone did not include sufficient numbers of subjects aged 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.