1. Deferasirox in treatment of chronic iron overload
Mohammadreza Bordbar
Pediatric Hematologist, SUMS
Jan. 2016

10. Traditional iron chelators
Deferoxamine (Desferal)
Deferiprone (L1)

11. Deferasirox (ICL 670) a novel orally active iron chelator
eliminate the need for 8 hour infusion 5-7 days/week
improves patients compliance
Dispersible Tablets: 125, 250 and 500 mg
In packs of 28 tablets
Each dispersible tablet contains 136, 272, 544 mg lactose respectively O OH HO N

12. EXJADE, Novartis
Osveral, Osvah pharmaceutical

13. Mechanism of action - tridentate ligand binding iron with 2:1 ratio
- highly selective for iron (III)
- tridentate ligand binding iron with 2:1 ratio
- promotes iron excretion primarily from feces
- low affinity for Zinc and Copper

14. Pharmacokinetic properties
Absorption:
- median time to maximum plasma concentration of about 1.5 to 4 hours
- bioavailability moderately (approx. 13–25%) elevated when taken 30 minutes before meals with normal or high fat content
Distribution:
- highly protein bound (99%)
- small volume of distribution
Elimination:
- primarily excreted in the faeces (84% of the dose)
- minimal renal excretion (8% of the dose)
- mean elimination half-life (t1/2) ranged from 8 to 16 hours

15. Therapeutic indications
chronic iron overload due to frequent blood transfusions (≥7 ml/kg/month of packed red blood cells) in patients with beta thalassaemia major aged 6 years and older
treatment of chronic iron overload due to blood transfusions when deferoxamine therapy is contraindicated or inadequate in the following patient groups:
- in patients with beta thalassaemia major with iron overload due to frequent blood transfusions (≥ 7 ml/kg/month of packed red blood cells) aged 2 to 5 years,
- in patients with beta thalassaemia major with iron overload due to infrequent blood transfusions (<7 ml/kg/month of packed red blood cells) aged 2 years and older,
- in patients with other anaemias aged 2 years and older.
- chronic iron overload requiring chelation therapy when deferoxamine therapy is contraindicated or inadequate in patients with non-transfusion- dependent thalassaemia syndromes aged 10 years and older.

16. posology
treatment started after the transfusion of approximately 20 units (about 100 ml/kg) of packed red blood cells or
evidence from clinical monitoring that chronic iron overload is present (e.g. serum ferritin >1,000 μg/l)
Doses (in mg/kg) must be calculated and rounded to the nearest whole tablet size
The recommended initial daily dose of EXJADE is 20 mg/kg body weight.
An initial daily dose of 30 mg/kg for patients who require reduction of elevated body iron levels and receiving more than 14 ml/kg/month of packed red blood cells (approximately >4 units/month for an adult).

17. Dose adjustment Dose adjusted every 3-6 months based on serum ferritin
Steps of 5-10 ml/kg
therapeutic goals :maintenance or reduction of iron burden
If serum ferritin levels persistently above 2500 μg/l and not showing a decreasing trend over time, doses of up to 40 mg/kg may be considered.
when serum ferritin level has reached the target (usually between 500 and 1000 μg/l), dose reductions in steps of 5 to 10 mg/kg should be considered to maintain serum ferritin levels within the target range

18. Special population Elderly patients (≥ 65 years):
- higher frequency of adverse reaction (specially diarrhea)
- may need more frequent monitoring and dose adjustment
Pediatric patients:
-consider changes in weight over time when calculating the doses
- children aged 2-5 years have lower exposure than adults and may require higher doses
- initial dose the same; individual titration
- the safety and efficacy in children below 2 years old not established

19. Renal impairment:
contraindicated in creatinine clearance ˂ 60ml/min
Hepatic impairment:
- not recommended in patients with severe hepatic impairment
(Child-Pugh Class C)
- dose should be considerably reduced in moderate hepatic impairment
(Child-Pugh Class B), with progressive increase up to 50% dose
- hepatic function monitored before treatment, every 2 weeks in the first month and then monthly

20. Method of administration
EXJADE must be taken once daily on an empty stomach at least 30 minutes before food, preferably at the same time each day
The tablets dispersed by stirring in a glass of water or orange or apple juice (100 to 200 ml) until a fine suspension is obtained
After the suspension has been swallowed, any residue must be resuspended in a small volume of water or juice and swallowed
The tablets must not be chewed or swallowed whole

21. Adverse reactions Gastrointestinal disorders
- Common: Diarrhea, constipation, vomiting, nausea, abdominal pain, abdominal distension, dyspepsia
- Uncommon: Gastrointestinal haemorrhage, gastric ulcer (including multiple ulcers), duodenal ulcer, gastritis , Oesophagitis, Gastrointestinal perforation
Skin and subcutaneous tissue disorders
- Common: Rash, pruritus
- Uncommon: Pigmentation disorder , Stevens-Johnson syndrome, leukocytoclastic vasculitis, urticaria, erythema multiforme, alopecia

22. Adverse reactions Renal and urinary disorders
-Common: Blood creatinine increased, Proteinuria
- Uncommon: Renal tubulopathy (acquired Fanconi’s syndrome), glycosuria, Acute renal failure, tubulointerstitial nephritis, nephrolithiasis, renal tubular necrosis
Hepatobiliary disorders
- Common: Transaminases increased
- Uncommon: Hepatitis, cholelithiasis, Hepatic failure

23. Adverse reactions Blood and lymphatic system disorders
-Pancytopenia, thrombocytopenia, anemia aggravated, neutropenia
Immune system disorders
-Hypersensitivity reactions (including anaphylaxis and angioedema)
Metabolism and nutrition disorders
-Metabolic acidosis
Psychiatric disorders
- Anxiety, sleep disorder
Eye disorders
- Early cataract, maculopathy ,Optic neuritis

24. Adverse reactions Ear and labyrinth disorders -Hearing loss
Respiratory, thoracic and mediastinal disorders
- Pharyngolaryngeal pain
General disorders
- Pyrexia, oedema, fatigue
Nervous system disorders
- Headache (common) ;Dizziness

25. Monitoring

26. Drug interaction
Substances with GI ulcerogenic potential such as NSAIDS, anticoagulants, corticosteroids and oral bisphosphonates increase the risk of GI toxicities
UGT inducers : rifampicin, carbamazepine, phenytoin, phenobarbital, ritonavir
decrease EXJADE efficacy, serum ferritin should be monitored frequently and EXJADE dose adjusted accordingly
Cholestyramine: significantly reduces the deferasirox exposure
substances metabolised through CYP3A4 (e.g. ciclosporin, simvastatin, hormonal contraceptive agents, bepridil, ergotamine, midazolam) :
the efficacy of mentioned drugs decrease and their dose may need to be increased

27. Repaglinide: a CYP2C8 substrate
EXJADE as a moderate CYP2C8 inhibitor decrease its efficacy and their concomitant administration should be avoided. Otherwise, close monitoring of blood glucose is advised.
substances metabolised by CYP1A2 (e.g. clozapine, tizanidine, theophylin)
EXJADE inhibits the enzyme and increase the drug level

28. Fertility, pregnancy and lactation
- No fertility data is available for humans. In animals, no adverse effects on male or female fertility were found
Pregnancy:
- Studies in animals have shown some reproductive toxicity at maternally toxic doses . The potential risk for humans is unknown.
-As a precaution, it is recommended that EXJADE is not used during pregnancy unless clearly necessary.
Breast feeding:
- In animal studies, deferasirox was found to be rapidly and extensively secreted into maternal milk. No effect on the offspring was noted.
- Breast-feeding while taking EXJADE is not recommended

29. A new oral formulation of Deferasirox (Jadenu)

30. Jadenu
90, 180, 270 mg tablets
Can be swallowed (not dispersed) with empty stomach or a light-fat meal
The same indications and precautions as EXJADE
Starting dose is 14mg/kg (equal to 20 mg/kg EXJADE)
Increase up to 28 mg/kg with mg/kg increments
Once oral daily dose
Fewer GI disturbance, better taste, and better tolerability

31. Thanks for your kind attention