Composition

Deferiprone Biomed Film coated tablets: Each tablet contains:500mg Deferiprone
Deferiprone Biomed oral solution: each ml contains 100 mg Deferiprone

Pharmacodynamic properties

Deferiprone is effective in promoting iron excretion and that a dose of 25 mg/kg three times per day can prevent the progression of iron accumulation as assessed by serum ferritin, in patients with transfusion-dependent thalassaemia. However, chelation therapy may not necessarily protect against iron-induced organ damage.

Pharmacokinetic properties

Absorption
Deferiprone is rapidly absorbed from the upper part of the gastrointestinal tract. Peak serum concentration is reported to occur 45 to 60 minutes following a single dose in fasted patients.
This may be extended to 2 hours in fed patients. Following a dose of 25 mg/kg, lower peak serum concentrations have been detected in patients in the fed state (85 µmol/l) than in the fasting state (126 µmol/l), although there was no decrease in the amount of deferiprone absorbed when it was given with food.

Biotransformation
Deferiprone is metabolised predominantly to a glucuronide conjugate. This metabolite lacks iron-binding capability due to inactivation of the 3-hydroxy group of deferiprone. Peak serum concentrations of the glucuronide occur 2 to 3 hours after administration of deferiprone.

Elimination
Deferiprone is eliminated mainly via the kidneys; 75% to 90% of the ingested dose is reported as being recovered in the urine in the first 24 hours, in the form of free deferiprone, the glucuronide metabolite and the iron-deferiprone complex. A variable amount of elimination via the faeces has been reported. The elimination half-life in most patients is 2 to 3 hours.

Therapeutic indications

Ferriprox is indicated for the treatment of iron overload in patients with thalassaemia major when deferoxamine therapy is contraindicated or inadequate.

Contraindications

- Hypersensitivity to the active substance or to any of the excipients.
- History of recurrent episodes of neutropenia.
- History of agranulocytosis.
- Pregnancy or breast-feeding.

Due to the unknown mechanism of deferiprone-induced neutropenia, patients must not take medicinal products known to be associated with neutropenia or those that can cause agranulocytosis .

Special warnings and precautions for use

-Neutropenia/Agranulocytosis

Deferiprone has been shown to cause neutropenia, including agranulocytosis. The patient’s neutrophil count should be monitored every week.

Neutropenia and agranulocytosis resolved once therapy withdrawn. If the patient develops an infection while on deferiprone, therapy should be interrupted and the neutrophil count monitored more frequently. Patients should be advised to report immediately to their physician any symptoms indicative of infection such as fever, sore throat and flu-like symptoms.

In the event of neutropenia:

Instruct the patient to immediately discontinue deferiprone and all other medicinal products with a potential to cause neutropenia. The patient should be advised to limit contact with other individuals in order to reduce the risk of infection. Obtain a complete blood cell (CBC) count, with a white blood cell (WBC) count, a neutrophil count, and a platelet count immediately upon diagnosing the event and then repeat daily. It is recommended that following recovery from neutropenia, weekly CBC, WBC, neutrophil and platelet counts  continue to be obtained for three consecutive weeks, to ensure that the patient recovers fully. Should any evidence of infection develop concurrently with the neutropenia, the appropriate cultures and diagnostic procedures should be performed and an appropriate therapeutic regimen instituted.

In the event of severe neutropenia or agranulocytosis:

Follow the guidelines above and administer appropriate therapy such as granulocyte colony stimulating factor, beginning the same day that the event is identified; administer daily until the condition resolves. Provide protective isolation and if clinically indicated, admit patient to the hospital.

in the event of neutropenia, rechallenge is not recommended. In the event of agranulocytosis, a rechallenge is contraindicated.

-Serum ferritin concentration/plasma Zn2+ concentration

It is recommended that serum ferritin concentrations, or other indicators of body iron load, be monitored every two to three months to assess the long-term effectiveness of the chelation regimen in controlling the body iron load. Interruption of therapy with deferiprone should be considered if serum

ferritin measurements fall below 500 ìg/l.

Monitoring of plasma Zn2+ concentration, and supplementation in case of a deficiency, is

recommended.

-HIV positive or other immune compromised patients

therapy in immune compromised patients should not be initiated unless potential benefits outweigh potential

risks.

-Renal or hepatic impairment and liver fibrosis

Since deferiprone is eliminated mainly via the kidneys, there may be an increased risk of

complications in patients with impaired renal function. Similarly, as deferiprone is metabolised in the

liver, caution must be exercised in patients with hepatic dysfunction. Renal and hepatic function

should be monitored in this patient population during deferiprone therapy. If there is a persistent

increase in serum alanine aminotransferase (ALT), interruption of deferiprone therapy should be

considered.

In thalassaemia patients there is an association between liver fibrosis and iron overload and/or

hepatitis C. Special care must be taken to ensure that iron chelation in patients with hepatitis C is

optimal. In these patients careful monitoring of liver histology is recommended.

-Discoloration of urine

Patients should be informed that their urine may show a reddish/brown discoloration due to the

excretion of the iron-deferiprone complex.

-Chronic overdose and neurological disorders

Neurological disorders have been observed in children treated with 2.5 to 3 times the recommended

dose for several years. doses above 100 mg/kg/day are not recommended.

Interaction with other medicinal products and other forms of interaction

-Since deferiprone binds to metallic cations, the potential exists for interactions between deferiprone and trivalent cation-dependent medicinal products such as aluminium-based antacids. Therefore, it is not recommended to concomitantly ingest aluminium-based antacids and deferiprone.
-Caution should be used when administering deferiprone and vitamin C concurrently.
-Due to the unknown mechanism of deferiprone induced neutropenia, patients must not take medicinal products known to be associated with neutropenia or those that can cause agranulocytosis.

Pregnancy and lactation

Pregnancy
Women of childbearing potential must be advised to avoid pregnancy due to the teratogenic properties of the medicinal product. These women advised to immediately stop taking deferiprone if they become pregnant.

Lactation
Deferiprone must not be used by breast-feeding mothers.

Undesirable effects

The most serious adverse reaction reported in clinical trials with deferiprone is agranulocytosis (neutrophils <0.5x109/l), the less severe form is neutropenia (neutrophils <1.5x109/l) . Episodes of diarrhoea, mostly mild and transient, have been reported in patients treated with deferiprone. Gastrointestinal effects are more frequent at the beginning of therapy and resolve in most patients within a few weeks without the discontinuation of treatment. In some patients it may be beneficial to reduce the dose of deferiprone and then scale it back up to the former dose. Arthropathy events, which ranged from mild pain in one or more joints to severe arthritis with effusion and significant disability, have also been reported in patients treated with deferiprone. Mild arthropathies are generally transient.

Increased levels of serum liver enzymes have been reported in patients taking deferiprone. In the majority of these patients, the increase was asymptomatic and transient, and returned to baseline without discontinuation or decreasing the dose of deferiprone (see section 4.4). Some patients experienced progression of fibrosis associated with an increase in iron overload or hepatitis C.
Low plasma zinc levels have been associated with deferiprone, in a minority of patients. The levels normalised with oral zinc supplementation.

Adverse reaction frequencies:

Very common(≥1/10): Reddish/Brown Urine, Nausea Abdominal Pain,  Vomiting

Common(≥1/100 to <1/10): Neutropenia, Diarrhoea, Arthralgia, Increased Appetite,  Increased liver enzymes.

Uncommon(≥1/1,000 to <1/100): Agranulocytosis.

Posology and method of administration

Deferiprone therapy should be initiated and maintained by a physician experienced in the treatment ofpatients with thalassaemia.
Deferiprone is usually given as 25 mg/kg body weight, orally, three times a day for a total daily doseof 75 mg/kg body weight.

Doses above 100 mg/kg/day are not recommended because of the potentially increased risk of adversereactions; chronic administration of more than 2.5 times the maximum recommended dose has beenassociated with neurological disorders Due to the serious nature of agranulocytosis, that can occur with the use of deferiprone, special monitoring is required for all patients. Cation must be used when the patients abosolute neutrophil count (ANC) is low, as well as when treating patients with renal insufficiency or hepatic dysfunction.

To obtain a dose of about 75 mg/kg/day, use the volume of oral solution suggested in the following table for the body weight of the patient.

Body weight	Total daily dose	Dose	ml of oral solution	Number of tablets (three times/day)
20	1500	500	5.0	1.0
30	2250	750	7.5	1.5
40	3000	1000	10.0	2.0
50	3750	1250	12.5	2.5
60	4500	1500	15.0	3.0
70	5250	1750	17.5	3.5
80	6000	2000	20.0	4.0
90	6750	2250	22.5	4.5

Overdose

neurological disorders (such as cerebellar symptoms, diplopia, lateral nystagmus, psychomotor slowdown, hand movements and axial hypotonia) have been observed in children who had been voluntarily prescribed more than 2.5 times the maximum recommended dose of 100 mg/kg/day for several years. The neurological disorders progressively

regressed after deferiprone discontinuation. In case of overdose, close clinical supervision of the patient is required.

Presentation

Deferiprone Biomed tablets: 30 film coated tablet
Deferiprone Biomed oral solution: bottle contains 100 ml