Transcript Deferasirox in treatment of chronic iron overload

Deferasirox in
treatment of chronic
iron overload
Mohammadreza Bordbar
Pediatric Hematologist, SUMS
Jan. 2016
Traditional iron chelators

Deferoxamine (Desferal)

Deferiprone (L1)
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
OH
O
In packs of 28 tablets

Each dispersible tablet contains 136, 272, 544 mg lactose
respectively
N N
N
OH HO

EXJADE, Novartis

Osveral, Osvah pharmaceutical
Mechanism of action
- 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
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
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-transfusiondependent thalassaemia syndromes aged 10 years and older.
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).
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
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

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
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
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
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
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
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

Monitoring
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

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
Fertility, pregnancy and lactation

Fertility:
- 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
A new oral formulation of Deferasirox (Jadenu)
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 3.5-7 mg/kg increments

Once oral daily dose

Fewer GI disturbance, better taste, and better tolerability
Thanks for your kind attention
[email protected]