Deferiprone Drug Information

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. The following adverse reaction information represents the pooled data collected from single arm or active-controlled clinical trials with deferiprone tablets (three times a day). Thalassemia Syndromes The safety of deferiprone was evaluated in the pooled clinical trial database . Patients received deferiprone tablets (three times a day). Deferiprone was administered orally three times a day (total daily dose either 50, 75, or 99 mg/kg), N=642. Among 642 patients receiving deferiprone, 492 (76.6%) were exposed for 6 months or longer and 365 (56.9%) were exposed for greater than one year. The median age of patients who received deferiprone was 19 years (range 1, 77 years); 50.2% female; 71.2% White, 17.8% Asian, 9.2% Unknown, 1.2% Multi-racial and 0.6% Black.

The most serious adverse reaction reported in clinical trials with deferiprone 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 deferiprone in clinical trials in patients with thalassemia syndromes. Table 7: Adverse reactions occurring in ≥ 1% of deferiprone-treated patients with thalassemia syndromes Body System (N=642) Adverse Reaction % Patients BLOOD AND LYMPHATIC SYSTEM DISORDERS Neutropenia* 7 Agranulocytosis † 1 GASTROINTESTINAL DISORDERS Nausea 13 Abdominal pain/discomfort 10 Vomiting 10 Diarrhea 3 Dyspepsia 2 INVESTIGATIONS Alanine aminotransferase increased 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 *Neutropenia includes events of severe neutropenia (ANC ≥0.2 x 10 9 /L and <0.5 x 10 9 /L). †Agranulocytosis (ANC< 0.2 x 10 9 /L) 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 deferiprone therapy in 1.6% of patients.

Chromaturia (reddish/brown discoloration of the urine) is a result of the excretion of iron in the urine.

Postmarketing Experience

The following additional adverse reactions have been reported in patients receiving deferiprone. 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 Associated with Neutropenia or Agranulocytosis

Avoid co-administration of deferiprone 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 Deferiprone

UDP-Glucuronosyltransferases (UGT) Avoid use of UGT1A6 inhibitors (e.g., diclofenac, probenecid, or silymarin (milk thistle)) with deferiprone . Polyvalent Cations Deferiprone has the potential to bind polyvalent cations (e.g., iron, aluminum, and zinc); allow at least a 4-hour interval between deferiprone 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, 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 2 to 4% and 15 to 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. 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. 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.

Pediatric Use 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.

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.

No cases of acute overdose have been reported. There is no specific antidote to deferiprone 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.