Jaderox

COMPOSITION AND EXCIPIENTS

• Active ingredient:

Each film coated tablet of Jaderox 90 contains Deferasirox 90 mg.

Each film coated tablet of Jaderox 180 contains Deferasirox 180 mg.

Each film coated tablet of Jaderox 360 contains Deferasirox 360 mg.

• Excipients:

Microcrystalline cellulose, Crospovidone, Povidone, Magnesium stearate, Colloidal anhydrous silica,

Hypromellose, Titanium dioxide, Macrogol, Talc, FD&C Blue (For Jaderox 180).

MECHANISM OF ACTION

Deferasirox is an orally active chelator that is highly selective for iron (III). It is a tridentate ligand that binds iron with high affinity in a 2:1 ratio. Deferasirox promotes excretion of iron, primarily in the faeces. Deferasirox has low affinity for zinc and copper, and does not cause constant low serum levels of these metals.

PHARMACOKINETIC PROPERTIES

Absorption: Deferasirox (dispersible tablet formulation) is absorbed following oral administration with a median time to maximum plasma concentration (t max) of about 1.5 to 4 hours. The absolute bioavailability (AUC) of deferasirox (dispersible tablet formulation) is about 70% compared to an intravenous dose.

Distribution: Deferasirox is highly (99%) protein bound to plasma proteins, almost exclusively serum albumin, and has a small volume of distribution of approximately 14 liters in adults.

Biotransformation: Glucuronidation is the main metabolic pathway for deferasirox, with subsequent biliary excretion. the administration of cholestyramine after a single dose of deferasirox resulted in a 45% decrease in deferasirox exposure (AUC).

Elimination: Deferasirox and its metabolites are primarily excreted in the faeces (84% of the dose). Renal excretion of deferasirox and its metabolites is minimal (8% of the dose). The mean elimination half-life (t1/2) ranged from 8 to 16 hours.

INDICATIONS

– Deferasirox is indicated for the treatment of 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.

-Deferasirox is also indicated for the treatment of chronic iron overload due to blood transfusions when deferoxamine therapy is contraindicated or inadequate in the following patient groups:

• In paediatric 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 adult and paediatric 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 adult and paediatric patients with other anaemias aged 2 years and older.

Deferasirox is also indicated for the treatment of 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.

CONTRAINDICATIONS

• Hypersensitivity to the active substance or to any of the excipients.
• Combination with other iron chelator therapies as the safety of such combinations has not been established.
• Patients with estimated creatinine clearance <60 ml/min.

WARNINGS AND PRECAUTIONS

WARNING

RENAL FAILURE, HEPATIC FAILURE, AND GASTROINTESTINAL HEMORRHAGE

Renal Failure:

• Deferasirox can cause acute renal failure and death, particularly in patients with co morbidities and those who are in the advanced stages of their hematologic disorders.
• Measure serum creatinine and determine creatinine clearance (CLCr) prior to initiation of therapy and monitor renal function at least monthly thereafter. For patients with baseline renal impairment or increased risk of acute renal failure, monitor creatinine weekly for the first month, then at least monthly. Consider dose reduction, interruption, or discontinuation based on increases in serum creatinine.

Hepatic Failure:

• Deferasirox can cause hepatic injury including hepatic failure and death.
• Measure serum transaminases and bilirubin in all patients prior to initiating treatment, every 2 weeks during the first month, and at least monthly thereafter.
• Avoid use of Deferasirox in patients with severe (Child-Pugh C) hepatic impairment and reduce the dose in patients with moderate (Child-Pugh B) hepatic impairment .

Gastrointestinal Hemorrhage:

• Deferasirox can cause gastrointestinal (GI) hemorrhages, which may be fatal, especially in elderly patients who have advanced hematologic malignancies and/or low platelet counts.
• Monitor patients and discontinue Deferasirox for suspected GI ulceration or hemorrhage .

There have been post-marketing reports of metabolic acidosis occurring during treatment with deferasirox. The majority of these patients had renal impairment, renal tubulopathy (Fanconi syndrome) or diarrhoea, or conditions where acid-base imbalance is a known complication. Acid-base balance should be monitored as clinically indicated in these populations. Interruption of therapy should be considered in patients who develop metabolic acidosis.

Dose reduction or interruption may be also considered if abnormalities occur in levels of markers of renal tubular function and/or as clinically indicated:

• Proteinuria (test should be performed prior to therapy and monthly thereafter).
• Glycosuria in non-diabetics and low levels of serum potassium, phosphate, magnesium or urate, phosphaturia, aminoaciduria (monitor as needed).

Renal tubulopathy has been mainly reported in children and adolescents with beta-thalassaemia treated with deferasirox.

Patients should be referred to a renal specialist, and further specialized investigations (such as renal biopsy) may be considered if the following occur despite dose reduction and interruption:

• Serum creatinine remains significantly elevated and
• Persistent abnormality in another marker of renal function (e.g. proteinuria, Fanconi Syndrome(..

Skin disorders:

Skin rashes may appear during deferasirox treatment. The rashes resolve spontaneously in most cases.

When interruption of treatment may be necessary, treatment may be reintroduced after resolution of the rash, at a lower dose followed by gradual dose escalation. In severe cases this reintroduction could be conducted in combination with a short period of oral steroid administration. Severe cutaneous adverse reactions (SCARs) including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis(TEN) and drug reaction with eosinophilia and systemic symptoms (DRESS), which could be life-threatening or fatal, have been reported. If any SCAR is suspected, deferasirox should be discontinued immediately and should not be reintroduced. At the time of prescription, patients should be advised of the signs and symptoms of severe skin reactions, and be closely monitored.

Hypersensitivity reactions:

Cases of serious hypersensitivity reactions (such as anaphylaxis and angioedema) have been reported in patients receiving deferasirox, with the onset of the reaction occurring in the majority of cases within the first month of treatment .If such reactions occur, deferasirox should be discontinued and appropriate medical intervention instituted. Deferasirox should not be reintroduced in patients who have experienced a hypersensitivity reaction due to the risk of anaphylactic shock.

Vision and hearing:

Auditory (decreased hearing) and ocular (lens opacities) disturbances have been reported. Auditory and ophthalmic testing (including fundoscopy) is recommended before the start of treatment and at regular intervals thereafter (every 12 months). If disturbances are noted during thetreatment, dose reduction or interruption may be considered.

Blood disorders:

There have been post-marketing reports of leukopenia, thrombocytopenia or pancytopenia (or aggravation of these cytopenias) and of aggravated anaemia in patients treated with deferasirox.

Most of these patients had pre-existing haematological disorders that are frequently associated with bone marrow failure. However, a contributory or aggravating role cannot be excluded. Interruption of treatment should be considered in patients who develop unexplained cytopenia. Other considerations Monthly monitoring of serum ferritin is recommended in order to assess the patient’s response to therapy. If serum ferritin falls consistently below 500 μg/l (in transfusional iron overload) or below 300 μg/l (in non-transfusion-dependent thalassaemia syndromes), an interruption of treatment should be considered.

The results of the tests for serum creatinine, serum ferritin and serum transaminases should be recorded and regularly assessed for trends.

Cardiac dysfunction is a known complication of severe iron overload. Cardiac function should be monitored in patients with severe iron overload during long-term treatment with deferasirox.

INTERACTION WITH OTHER MEDICINAL PRODUCTS

Agents that may decrease Deferasirox systemic exposure:

Deferasirox metabolism depends on UGT enzymes, the concomitant use of Deferasirox with potent UGT inducers (e.g. rifampicin, carbamazepine, phenytoin, phenobarbital, ritonavir) may result in a decrease in Deferasirox efficacy.

The patient’s serum ferritin should be monitored during and after thecombination, and the dose of Deferasirox adjusted if necessary.

Cholestyramine significantly reduced the deferasirox exposure in a mechanistic study to determine the degree of enterohepatic recycling.

Interaction with midazolam and other agents metabolised by CYP3A4:

the concomitant administration of deferasirox dispersible tablets and midazolam (a CYP3A4 probe substrate) resulted in a decrease of midazolam exposure by 17%, due to a possible decrease in efficacy, caution should be exercised when deferasirox is combined with substances metabolized through CYP3A4 (e.g. ciclosporin, simvastatin, hormonal contraceptive agents, bepridil, ergotamine).

Interaction with repaglinide and other agents metabolised by CYP2C8:

the concomitant administration of deferasirox as a moderate CYP2C8 inhibitor (30 mg/kg daily, dispersible tablet formulation), with repaglinide, a CYP2C8 substrate ,given as a single dose of 0.5 mg, increased repaglinide AUC and Cmax about 2.3 –foldSince the interaction has not beenestablished with dosages higher than 0.5 mg for repaglinide, the concomitant use of deferasirox with repaglinide should be avoided. If the combination appears necessary, careful clinical and bloodglucose monitoring should be performed.

Interaction with theophylline and other agents metabolised by CYP1A2:

the concomitant administration of deferasirox as a CYP1A2 inhibitor(repeated dose of 30 mg/kg/day, dispersible tablet formulation) and the CYP1A2 substrate theophylline (single dose of 120 mg) resulted in an increase of theophylline AUC by 84%Therefore, the concomitant use of deferasirox with theophylline is notrecommended. If deferasirox and theophylline are used concomitantly, monitoring of theophyllineconcentration and theophylline dose reduction should be considered. An interaction between deferasirox and other CYP1A2 substrates cannot be excluded. For substances that are predominantly metabolized by CYP1A2 and that have a narrow therapeutic index (e.g. clozapine, tizanidine), the same recommendations apply as for theophylline.

Other information:

Although deferasirox has a lower affinity for aluminium than for iron, it is not recommended to take deferasirox tablets with aluminium-containing antacid preparations. The concomitant administration of deferasirox with substances that have known ulcerogenic potential ,such as NSAIDs (including acetylsalicylic acid at high dosage), corticosteroids or oral bisphosphonates may increase the risk of gastrointestinal toxicity .The concomitant administration of deferasirox with anticoagulants may also increase the risk of gastrointestinal haemorrhage.

Pregnancy:

No clinical data on exposed pregnancies are available for deferasirox. 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 deferasirox is not used during pregnancy unless clearly necessary.

Deferasirox may decrease the efficacy of hormonal contraceptives. Women of childbearing potential are recommended to use additional or alternative non-hormonal methods of contraception when using deferasirox.

Breast-feeding:

It is not known if deferasirox is secreted into human milk.

Breast-feeding while taking deferasirox is not recommended.

Effects on ability to drive and use machines:

Deferasirox has minor influence on the ability to drive and use machines. Patients experiencing the uncommon adverse reaction of dizziness should exercise caution when driving or operating machines

Undesirable effects

The most frequent reactions reported during chronic treatment with deferasirox dispersible tablets in adult and paediatric patients include gastrointestinal disturbances (mainly nausea, vomiting, diarrhea or abdominal pain) and skin rash. Diarrhoea is reported more commonly in paediatric patients aged 2to 5 years and in the elderly. These reactions are dose-dependent, mostly mild to moderate, generally transient and mostly resolve even if treatment is continued.

dose-dependent increases in serum creatinine occurred in about 36% of patients, though most remained within the normal range. Decreases in mean creatinine clearance havebeen observed in both paediatric and adult patients with beta-thalassemia and iron overload during the

first year of treatment, Elevations of liver transaminases have been reported.

Nervous system disorders:

Common: Headache.

Uncommon: Dizziness.

Psychiatric disorders:

Uncommon: Anxiety, sleep disorder.

Eye disorders:

Uncommon: Cataract, maculopathy.

Ear and labyrinth disorders:

Uncommon: Deafness.

Respiratory, thoracic and mediastinal disorders:

Uncommon: Laryngeal pain.

Gastrointestinal disorders:

Common: Diarrhoea, constipation, vomiting, nausea, abdominal pain,abdominal distension, dyspepsia.

Uncommon: Gastrointestinal haemorrhage, gastric ulcer (including multipleulcers), duodenal ulcer, gastritis.

Hepatobiliary disorders:

Common: Transaminases increased.

Uncommon: Hepatitis, cholelithiasis.

Skin and subcutaneous tissue disorders:

Common: Rash, pruritus.

Uncommon: Pigmentation disorder.

Renal and urinary disorders:

Very common: Blood creatinine increased.

Common: Proteinuria.

Uncommon: Renal tubular disorder (acquired Fanconi syndrome), glycosuria.

General disorders and administration site conditions:

Uncommon: Pyrexia, oedema, fatigue.

Paediatric population:

Diarrhoea is reported more commonly in paediatric patients aged 2 to 5 years than in older patients.

Renal tubulopathy has been mainly reported in children and adolescents with beta-thalassaemia treated with deferasirox. In post-marketing reports, a high proportion of cases of metabolic acidosisoccurred in children in the context of Fanconi syndrome.

Acute pancreatitis has been reported, particularly in children and adolescents.

POSOLOGY AND METHOD OF ADMINISTRATION

The corresponding doses for both formulations are shown in the table below.

Table 1 Recommended doses for transfusional iron overload:

Table 2 Recommended doses for non-transfusion-dependent thalassaemia syndromes

*LIC is the preferred method of iron overload determination.

Patients With Baseline Hepatic Impairment:

Mild (Child-Pugh A) hepatic impairment: No dose adjustment is necessary.

Moderate (Child-Pugh B) hepatic impairment: Reduce the starting dose by 50%.

Severe (Child-Pugh C) hepatic impairment: Avoid treatment .

Patients With Baseline Renal Impairment:

For patients with renal impairment (ClCr 40–60 mL/min), reduce the starting dose by 50%. Do not use Deferasirox in patients with serum creatinine greater than 2 times the upper limit of normal (ULN) or creatinine clearance less than 40 mL/min.

Dose Modifications For Increases In Serum Creatinine On Deferasirox:

For serum creatinine increases while receiving Deferasirox modify the dose as follows:

• Transfusional Iron Overload Adults and Adolescents (ages 16 years and older) :

If the serum creatinine increases by 33% or more above the average baseline measurement, repeat the serum creatinine within 1 week, and if still elevated by 33% or more, reduce the dose by 10 mg per kg.

• Pediatric Patients (ages 2-15 years):

Reduce the dose by 10 mg per kg if serum creatinine increases to greater than 33% above the average baseline measurement and greater than the age appropriate ULN.

• All Patients (regardless of age):

Discontinue therapy for serum creatinine greater than 2 times the age-appropriate ULN or for creatinine clearance less than 40 mL/min.

• Non-Transfusion-Dependent Thalassemia SyndromesAdults and Adolescents (ages 16 years andolder):

If the serum creatinine increases by 33% or more above the average baseline measurement, repeat the serum creatinine within 1 week, and if still elevated by 33% or more, interrupt therapy if the dose is 5 mg per kg, or reduce by 50% if the dose is 10 or 20 mg per kg.

• Pediatric Patients (ages 10-15 years):

Reduce the dose by 5 mg per kg if serum creatinine increases to greater than 33% above the average baseline measurement and greater than the age appropriate ULN.

• All Patients (regardless of age):

Discontinue therapy for serum creatinine greater than 2 times the age-appropriate ULN or for creatinine clearance less than 40 mL/min .

Elderly patients (≥65 years of age):

In clinical studieselderly patients experienced a higher frequency of adverse reactions than younger patients (inparticular, diarrhoea) and should be monitored closely for adverse reactions that may require a dose adjustment.

Paediatric population:

Transfusional iron overload:

The dosing recommendations for paediatric patients aged 2 to 17 years with transfusional ironoverload are the same as for adult patients. Changes in weight of paediatric patients over time must be taken into account when calculating the dose.

In children with transfusional iron overload aged between 2 and 5 years, exposure is lower than in

Adults. This age group may therefore require higher doses than are necessary inadults.

Non-transfusion-dependent thalassaemia syndromes:

In paediatric patients with non-transfusion-dependent thalassaemia syndromes, dosing should not

exceed 10 mg/kg. In these patients, closer monitoring of LIC and serum ferritin is essential to avoid

overchelation: in addition to monthly serum ferritin assessments, LIC should be monitored every three

months when serum ferritin is ≤800 μg/l.

Children from birth to 23 months:

The safety and efficacy in children from birth to 23 months of age have not been established. No data are available.

Method of administration

For oral use.

dispersible tablets must be taken once daily on an empty stomach at least 30 minutes before

food, preferably at the same time each day .

The dispersible tablets are 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 .

OVERDOSE

Cases of overdose (2-3 times the prescribed dose for several weeks) have been reported. In one case ,this resulted in subclinical hepatitis which resolved after a dose interruption. Single doses of 80 mg/kg of the deferasirox dispersible tablet formulation in iron-overloaded thalassaemic patients caused mild nausea and diarrhoea.

Acute signs of overdose may include nausea, vomiting, headache and diarrhoea. Overdose may be treated by induction of emesis or by gastric lavage, and by symptomatic treatment.

STORAGE CONDITIONS

Store at temperature between 15° and 30°, away from moisture.

PACKAGING

Jaderox (90 – 180 – 360) mg is supplied as blister strips (Aluminum – Clear P.V.D.C),each strip contains 10 F.C. Tablets and each pack contains 1 or 3 strips with enclosed leaflet ( 10 or 30 F.C. Tablets per pack).