Ferriprox Drug Information

Important Dosage and Administration Information FERRIPRO X

T ablets are available in two different 1,000 mg formulations, which have different oral dosing regimens to achieve the same total daily dosage. FERRIPROX Tablets (twice a day) - 1,000 mg - given two times a day FERRIPROX Tablets (three times a day) - 1,000 mg - given three times a day 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.

For patients who have trouble swallowing tablets, consider the use of FERRIPROX Oral Solution (see the prescribing information for FERRIPROX Oral Solution). Monitoring for Safety Due to the risk of agranulocytosis, monitor ANC before and during FERRIPROX therapy. Test ANC prior to start of FERRIPROX 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 FERRIPROX therapy. Due to the risk of zinc deficiency, monitor zinc levels before and regularly during FERRIPROX therapy.

Recommended Dosage for 1,000 mg FERRIPROX

T ablets ( twice a day) for Adult and Pediatric Patients with Transfusional Iron Overload due to Thalassemia Syndromes, Sickle Cell Disease or Other Anemias Starting Dos ag e for T wice a Day Tablets The recommended starting oral dosage of FERRIPROX Tablets (twice a day) is 75 mg/kg/day (actual body weight) in two divided doses per day (taken approximately 12 hours apart), with food. Round the total daily dose to the nearest 500 mg (half-tablet). Table 1 describes the number of FERRIPROX Tablets (twice a day) needed to achieve the 75 mg/kg/day total starting daily dosage.

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. Dos ag e Adjustment s for T wice a Day Tablets Tailor dosage adjustments of FERRIPROX Tablets (twice a day) to the individual patient’s response and therapeutic goals (maintenance or reduction of body iron burden). The maximum total daily oral dosage is 99 mg/kg (actual body weight) divided into two doses taken approximately 12 hours apart with food.

Table 3 describes the number of FERRIPROX Tablets (three times a day) needed to achieve the 75 mg/kg/day total starting dosage. Dosage Adjustments for Three Times Daily Tablets Tailor dosage adjustments for FERRIPROX 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 FERRIPROX Tablets (three times a day) needed to achieve the 99 mg/day total maximum daily dosage. Monitoring Ferritin Levels to Assess Efficacy 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. 2. 5 Dosage Modification for Drug Interactions 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.

Clinical Trial Experience

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. FERRIPROX Tablets (twice a day) were evaluated in trials in healthy subjects. FERRIPROX Tablets (twice a day) contain deferiprone, the same active ingredient as FERRIPROX Tablets (deferiprone) (three times a day) and FERRIPROX Oral Solution (deferiprone).

The following adverse reaction information represents the pooled data collected from single arm or active-controlled clinical trials with FERRIPROX Tablets (deferiprone) (three times a day) or FERRIPROX Oral Solution (deferiprone). Thalassemia Syndromes The safety of FERRIPROX was evaluated in the pooled clinical trial database. Patients received FERRIPROX Tablets (three times a day) or FERRIPROX Oral Solution.

FERRIPROX was administered orally three times a day (total daily dose either 50, 75, or 99 mg/kg), N=642. The most serious adverse reaction reported in clinical trials with FERRIPROX was agranulocytosis. The most common adverse reactions (≥6%) reported during clinical trials were nausea, vomiting, abdominal pain, arthralgia, alanine aminotransferase increased and neutropenia.

The table below lists the adverse drug reactions that occurred in at least 1% of patients treated with FERRIPROX in clinical trials in patients with thalassemia syndromes. Table 5: Adverse reactions occurring in ≥ 1% of FERRIPROX-treated patients with thalassemia syndromes 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.

Sickle Cell Disease or Other Anemias The safety of FERRIPROX compared to deferoxamine was evaluated in LA38-0411. The table below lists the adverse reactions (irrespective of a causal assessment; adverse events) of interest that occurred in patients treated with FERRIPROX in clinical trials in subjects with sickle cell disease or other anemias. Table 6: Adverse reactions occurring in ≥5% of FERRIPROX-treated patients with sickle cell disease or other anemias *Grouped term Clinically relevant adverse reactions in <5% of patients include neutropenia and agranulocytosis.

Pediatric Patients FERRIPROX has been studied in 86 pediatric patients with sickle cell disease or other anemias. Pediatric patients (<17 years) had an increase in the following adverse reactions as compared to adults: abdominal pain, neutrophil count decreased, bone pain and oropharyngeal pain.

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, 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.

Drugs

A ssociated with N eutropenia or A granulocytosis 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.

Effect of Other Drugs on FERRIPROX UDP-Glucuronosyltransferases (UGT) Avoid use of UGT1A6 inhibitors (e.g., diclofenac, probenecid, or silymarin (milk thistle)) with FERRIPROX. Polyvalent Cations 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.

Pregnancy 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 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, 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 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. Animal Data During organogenesis, pregnant rats and rabbits received deferiprone at oral doses of mg/kg/day, and 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.

Pediatric Use The safety and effectiveness of FERRIPROX for the treatment of transfusional iron overload due to thalassemia syndromes have been established in pediatric patients 8 years of age and older. Use of FERRIPROX for this indication is supported by evidence of efficacy from clinical trials in adult patients with thalassemia and evidence of safety in pediatric patients with sickle cell disease. The safety and effectiveness of FERRIPROX for the treatment of transfusional iron overload due to sickle cell disease or other anemias have been established in 86 pediatric patients 3 to 16 years of age, among the 152 patients treated with FERRIPROX Tablets or Oral Solution in an adequate and well-controlled study.

Seventy-six percent of these patients had sickle cell disease. The recommended starting dose and dose-modifications are the same for children and adults. The adverse reactions, including agranulocytosis, seen in the 8 year period of the registry are similar to those seen in the most recent clinical studies.

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

FERRIPROX 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.

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.