Treatment of Chronic Iron Overload Due to Blood Transfusions (Transfusional Iron Overload)
FERASIRO is indicated for the treatment of chronic iron overload due to blood transfusions (transfusional hemosiderosis) in patients 2 years of age and older.

Treatment of Chronic Iron Overload in Non-Transfusion-Dependent Thalassemia Syndromes
FERASIRO is indicated for the treatment of chronic iron overload in patients 10 years of age and older with non-transfusion-dependent thalassemia (NTDT) syndromes and with a liver iron concentration (LIC) of at least 5 milligrams of iron per gram of liver dry weight (mg Fe/g dw) and a serum ferritin greater than 300 mcg/L.

Limitations of Use

The safety and efficacy of FERASIRO when administered with other iron chelation therapy have not been established.

Transfusional Iron Overload

FERASIRO therapy should only be considered when a patient has evidence of chronic transfusional iron overload. The evidence should include the transfusion of at least 100 mL/kg of packed red blood cells (e.g., at least 20 units of packed red blood cells for a 40 kg person or more in individuals weighing more than 40 kg), and a serum ferritin consistently greater than 1000 mcg/L.

Prior to starting therapy, or increasing dose, evaluate:

•  Serum ferritin level
•  Baseline renal function:

·    Obtain serum creatinine in duplicate (due to variations in measurements)

·    Calculate the estimated glomerular filtration rate (eGFR). Use a prediction equation appropriate for adultpatients (e.g., CKD-EPI, MDRD method) and in pediatric patients (e.g., Schwartz equations).

·    Obtain urinalyses and serum electrolytes to evaluate renal tubular function (see section 4.2  and section 4.4).

• Serum transaminases and bilirubin (see section 4.2 and section 4.4).
• Baseline auditory and ophthalmic examinations (see section 4.4).

 Initiating Therapy:

The recommended initial dose of FERASIRO for patients 2 years of age and older with eGFR greater than 60 mL/min/1.73 m² is 14 mg per kg body weight orally, once daily. Calculate doses (mg per kg per day) to the nearest whole tablet or nearest whole sachet content for granules. Changes in weight of pediatric patients overtime must be taken into account when calculating the dose.

During Therapy:

·    Monitor serum ferritin monthly and adjust the dose of FERASIRO, if necessary, every 3 to 6 months based on serum ferritin trends.

·    Use the minimum effective dose to achieve a trend of decreasing ferritin.

·    Make dose adjustments in steps of 3.5 or 7 mg per kg and tailor adjustments to the individual patient’s response and therapeutic goals.

·    In patients not adequately controlled with doses of 21 mg per kg (e.g., serum ferritin levels persistently above 2500 mcg/L and not showing a decreasing trend over time), doses of up to 28 mg per kg may be considered. Doses above 28 mg per kg are not recommended (see section 4.4).

·    Adjust dose based on serum ferritin levels

-  If the serum ferritin falls below 1000 mcg/L at 2 consecutive visits, consider dose reduction, especially if the FERASIRO dose is greater than 17.5 mg/kg/day (see section 4.8).

-  If the serum ferritin falls below 500 mcg/L, interrupt FERASIRO therapy and continue monthly monitoring.

-  Evaluate the need for ongoing chelation therapy for patients whose conditions no longer require regular blood transfusions.

-  Use the minimum effective dose to maintain iron burden in the target range (see section 4.4).

·    Monitor blood counts, liver function, renal function and ferritin monthly (see section 4.4)

·    Interrupt FERASIRO for pediatric patients who have acute illnesses, which can cause volume depletion, such as vomiting, diarrhea, or prolonged decreased oral intake, and monitor more frequently. Resume therapy as appropriate, based on assessments of renal function, when oral intake and volume status are normal (seesection 4.2, section 4.4 and section 5).

Iron Overload in Non-Transfusion-Dependent Thalassemia Syndromes

FERASIRO therapy should only be considered when a patient with NTDT syndrome has an LIC of at least 5 mg Fe/g dw and a serum ferritin greater than 300 mcg/L.

Prior to starting therapy, obtain:

•     LIC by liver biopsy
•    Baseline renal function:

-       Obtain serum creatinine in duplicate (due to variations in measurements)

-       Calculate the estimated glomerular filtration rate (eGFR). Use a prediction equation appropriate for adult patients (e.g., CKD-EPI, MDRD method) and in pediatric patients (e.g., Schwartz equations).

-       Obtain urinalyses and serum electrolytes to evaluate renal tubular function (see section 4.2 and section 4.4)

•  Serum transaminases and bilirubin (see section 4.2 and section 4.4)
•  Baseline auditory and ophthalmic examinations (see section 4.4) 

·  Initiating Therapy:

·  The recommended initial dose of FERASIRO for patients with eGFR greater than 60 mL/min/1.73 m² is 7 mgper kg body weight orally once daily. Calculate doses (mg per kg per day) to the nearest whole tablet or nearest whole sachet content for granules.

·  If the baseline LIC is greater than 15 mg Fe/g dw, consider increasing the dose to 14 mg/kg/day after 4 weeks.

During Therapy:

·    Monitor serum ferritin monthly. Interrupt treatment when serum ferritin is less than 300 mcg/L and obtain an LIC to determine whether the LIC has fallen to less than 3 mg Fe/g dw.

·    Use the minimum effective dose to achieve a trend of decreasing ferritin.

·    Monitor LIC every 6 months.

·    After 6 months of therapy, if the LIC remains greater than 7 mg Fe/g dw, increase the dose of deferasirox to a maximum of 14 mg/kg/day. Do not exceed a maximum of 14 mg/kg/day.

·    If after 6 months of therapy, the LIC is 3 to 7 mg Fe/g dw, continue treatment with deferasirox at no more than 7 mg/kg/day.

·    When the LIC is less than 3 mg Fe/g dw, interrupt treatment with deferasirox and continue to monitor the LIC.

·    Monitor blood counts, liver function, renal function and ferritin monthly (see section 4.4).

·    Increase monitoring frequency for pediatric patients who have acute illness, which can cause volume depletion, such as vomiting, diarrhea, or prolonged decreased oral intake. Consider dose interruption until oral intake andvolume status are normal. (see section 4.2, section 4.4 and section 5)
Restart treatment when the LIC rises again to more than 5 mg Fe/g dw.

Administration

Swallow FERASIRO tablets once daily with water or other liquids, preferably at the same time each day.

Take FERASIRO tablets on an empty stomach or with a light meal (contains less than 7% fat content andapproximately 250 calories). Examples of light meals include 1 whole wheat English muffin, 1 packet jelly (0.5 ounces), and skim milk (8 fluid ounces) or a turkey sandwich (2 oz. turkey on whole wheat bread w/ lettuce, tomato, and 1 packet mustard). Do not take FERASIRO tablets with aluminum-containing antacid products (see section 4.5). For patients who have difficulty swallowing whole tablets, FERASIRO tablets may be crushed andmixed with soft foods (e.g., yogurt or applesauce) immediately prior to use and administered orally. Commercial crushers with serrated surfaces should be avoided for crushing a single 90 mg tablet. The dose should be immediately and completely consumed and not stored for future use.

For patients who are currently on chelation therapy with Deferasirox tablets for oral suspension and converting toDeferasirox (film-coated tablets), the dose should be about 30% lower, rounded to the nearest whole tablet. Thetable below provides additional information on dosing conversion to Deferasirox (film-coated tablets).

Use in Patients with Baseline Hepatic or Renal Impairment

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 FERASIRO tablets. (see section 4.4)

Patients with Baseline Renal Impairment

Do not use FERASIRO in adult or pediatric patients with eGFR less than 40 mL/min/1.73 m² (see section 4.4)

For patients with renal impairment (eGFR 40-60 mL/min/1.73 m²), reduce the starting dose by 50%.

Exercise caution in pediatric patients with eGFR between 40 and 60 mL/minute/1.73 m². If treatment is needed, use the minimum effective dose and monitor renal function frequently. Individualize dose titration based on improvement in renal injury.

Dose Modifications for Decreases in Renal Function While on FERASIRO

FERASIRO is contraindicated in patients with eGFR less than 40 mL/minute/1.73 m² (see section 4.3).

For decreases in renal function while receiving FERASIRO (see section 4.4), modify the dose as follows:

Transfusional Iron Overload

Adults:

·    If the serum creatinine increases by 33% or more above the average baseline measurement, repeat the serumcreatinine within 1 week, and if still elevated by 33% or more, reduce the dose by 7 mg per kg.

Pediatric Patients (ages 2 years–17 years):

·      Reduce the dose by 7 mg per kg if eGFR decreases by greater than 33% below the average baseline measurement and repeat eGFR within 1 week

·      Interrupt FERASIRO for acute illnesses, which can cause volume depletion, such as vomiting, diarrhea, orprolonged decreased oral intake, and monitor more frequently.

Resume therapy as appropriate, based on assessments of renal function, when oral intake and volume status are normal.

Avoid use of other nephrotoxic drugs (see section 4.4).

·      In the setting of decreased renal function, evaluate the risk benefit profile of continued FERASIRO use. Use theminimum effective FERASIRO dose and monitor renal function more frequently, by evaluating tubular and glomerular function. Titrate dosing based on renal injury. Consider dose reduction or interruption and less nephrotoxic therapies until improvement of renal function. If signs of renal tubular or glomerular injury occur in the presence of other risk factors such as volume depletion, reduce or interrupt FERASIRO to prevent severe and irreversible renal injury (see section 4.4).

All Patients (regardless of age):

·      Discontinue therapy for eGFR less than 40 mL/min/1.73 m² (see section 4.3).

Non-Transfusion-Dependent Thalassemia Syndromes

Adults:

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 3.5 mg per kg, or reduce by 50% if the dose is 7 or 14 mg per kg.

Pediatric Patients (ages 10 years–17 years):

·      Reduce the dose by 3.5 mg per kg if eGFR decreases by greater than 33% below the average baseline measurement and repeat the eGFR within 1 week.

·      Increase monitoring frequency for pediatric patients who have acute illnesses, which can cause volume depletion, such as vomiting, diarrhea, or prolonged decreased oral intake. Consider dose interruption until oral intake and volume status are normal. Avoid use of other nephrotoxic drugs (see section 4.4).

·      In the setting of decreased renal function, evaluate the risk benefit profile of continued FERASIRO use. Use theminimum effective FERASIRO dose and monitor renal function more frequently, by evaluating tubular and glomerular function. Titrate dosing based on renal injury. Consider dose reduction or interruption and less nephrotoxic therapies until improvement of renal function. If signs of renal tubular or glomerular injury occur in the presence of other risk factors such as volume depletion, reduce or interrupt FERASIRO to prevent severe and irreversible renal injury (see section 4.4).

All Patients (regardless of age):

·      Discontinue therapy for eGFR less than 40 mL/min/1.73 m² (see section 4.3).

Dose Modifications Based on Concomitant Medications

UDP-glucuronosyltransferases (UGT) Inducers

Concomitant use of UGT inducers decreases systemic exposure. Avoid the concomitant use of strong UGT inducers (e.g., rifampicin, phenytoin, phenobarbital, ritonavir). If you must administer FERASIRO tablets with a strongUGT inducer, consider increasing the initial dose by 50%, and monitor serum ferritin levels and clinical responsesfor further dose modification (see section 4.2 and section 4.5).

Bile Acid Sequestrants

Concomitant use of bile acid sequestrants decreases systemic exposure. Avoid the concomitant use of bile acid sequestrants (e.g., cholestyramine, colesevelam, colestipol). If you must administer FERASIRO tablets with a bileacid sequestrant, consider increasing the initial dose by 50%, and monitor serum ferritin levels and clinicalresponses for further dose modification (see section 4.2 and section 4.5).

Acute Kidney Injury, Including Acute Renal Failure Requiring Dialysis and Renal Tubular Toxicity Including Fanconi Syndrome

FERASIRO is contraindicated in patients with eGFR less than 40 mL/min/1.73 m². Exercise caution in pediatricpatients with eGFR between 40 and 60 mL/minute/1.73 m². If treatment is needed, use the minimum effective dose and monitor renal function frequently. Individualize dose titration based on improvement in renal injury. For patientswith renal impairment (eGFR 40-60 mL/min/1.73 m²) reduce the starting dose by 50% (see section 4.2).

FERASIRO can cause acute kidney injury including renal failure requiring dialysis that has resulted in fatal outcomes. Based on postmarketing experience, most fatalities have occurred in patients with multiple comorbiditiesand who were in advanced stages of their hematological disorders. In the clinical trials, adults and pediatric deferasirox-treated patients with no preexisting renal disease experienced dose-dependent mild, non-progressive increases in serum creatinine and proteinuria.

Pre-existing renal disease and concomitant use of other nephrotoxic drugs may increase the risk of acute kidney injury in adult and pediatric patients. Acute illnesses associated with volume depletion and overchelation may increase the risk of acute kidney injury in pediatric patients. In pediatric patients, small decreases in eGFR can result in increases in deferasirox (tablets for oral suspension) exposure, particularly in younger patients with bodysurface area typical of patients less than age 7 years. This can lead to a cycle of worsening renal function andfurther increases in deferasirox exposure, unless the dose is reduced or interrupted. Renal tubular toxicity, including acquired Fanconi syndrome, has been reported in patients treated with deferasirox, most commonly in pediatricpatients with beta-thalassemia and serum ferritin levels less than 1,500 mcg/L. (see section 4.4, section 4.8 and section 5).

Evaluate renal glomerular and tubular function before initiating therapy or increasing the dose. Use prediction equations validated for use in adult and pediatric patients to estimate GFR. Obtain serum electrolytes and urinalysis in all patients to evaluate renal tubular function (see setion 4.2)

Monitor all patients for changes in eGFR and for renal tubular toxicity weekly during the first month after initiationor modification of therapy and at least monthly thereafter. Monitor serum ferritin monthly to evaluate for over chelation. Use the minimum dose to establish and maintain a low iron burden.

Monitor renal function more frequently in patients with preexisting renal disease or decreased renal function. In pediatric patients, interrupt FERASIRO during acute illnesses, which can cause volume depletion such as vomiting, diarrhea, or prolonged decreased oral intake, and monitor renal function more frequently. Promptly correct fluiddeficits to prevent renal injury. Resume therapy as appropriate, based on assessments of renal function, when oral intake and volume status are normal (see section 4.4, section 4.8 and section 5).

Hepatic Toxicity and Failure

FERASIRO can cause hepatic injury, fatal in some patients. In Study 1, 4 patients (1.3%) discontinued deferasirox because of hepatic toxicity (drug-induced hepatitis in 2 patients and increased serum transaminases in 2 additional patients). Hepatic toxicity appears to be more common in patients greater than 55 years of age. Hepatic failure wasmore common in patients with significant comorbidities, including liver cirrhosis and multiorgan failure (see section 4.8).

Acute liver injury and failure, including fatal outcomes, have occurred in pediatric deferasirox- treated patients. Liver failure occurred in association with acute kidney injury in pediatric patients at risk for over chelation during a volume-depleting event. Interrupt FERASIRO therapy when acute liver injury or acute kidney injury is suspected and during volume depletion. Monitor liver and renal function more frequently in pediatric patients who are receiving FERASIRO in the 14-28 mg/kg/day range and when iron burden is approaching normal. Use theminimum effective dose to achieve and maintain a low iron burden (see section 4.2, section 4.4 and section 4.8).

Measure transaminases (AST and ALT) and bilirubin in all patients before the initiation of treatment and every 2 weeks during the first month and at least monthly thereafter. Consider dose modifications or interruption of treatment for severe or persistent elevations.

Avoid the use of FERASIRO in patients with severe (Child-Pugh C) hepatic impairment. Reduce the starting dose in patients with moderate (Child-Pugh B) hepatic impairment (see section 4.2). Patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment may be at higher risk for hepatic toxicity.

Gastrointestinal (GI) Ulceration, Hemorrhage, and Perforation

GI hemorrhage, including deaths, has been reported, especially in elderly patients who had advanced hematologic malignancies and/or low platelet counts. Nonfatal upper GI irritation, ulceration and hemorrhage have beenreported in patients, including children and adolescents, receiving deferasirox (see section 4.8). Monitor for signs and symptoms of GI ulceration and hemorrhage during FERASIRO therapy, and promptly initiate additional evaluation and treatment if a serious GI adverse event is suspected. The risk of gastrointestinal hemorrhage may be increased when administering FERASIRO in combination with drugs that have ulcerogenic or hemorrhagicpotential, such as nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, oral bisphosphonates, or anticoagulants. There have been reports of ulcers complicated with gastrointestinal perforation (including fatal outcome) (see section 4.8).

Bone Marrow Suppression

Neutropenia, agranulocytosis, worsening anemia, and thrombocytopenia, including fatal events, have been reported in patients treated with deferasirox. Preexisting hematologic disorders may increase this risk. Monitor blood countsin all patients. Interrupt treatment with deferasirox in patients who develop cytopenias until the cause of the cytopenia has been determined. FERASIRO is contraindicated in patients with platelet counts below 50 x 10 /L.

Age-Related Risk of Toxicity

Elderly Patients

Deferasirox (film-coated tablets) has been associated with serious and fatal adverse reactions in the postmarketingsetting among adults, predominantly in elderly patients. Monitor elderly patients treated with Deferasirox (film-coated tablets) more frequently for toxicity.

Pediatric Patients

Deferasirox (film-coated tablets) has been associated with serious and fatal adverse reactions in pediatric patients inthe postmarketing setting. These events were frequently associated with volume depletion or with continued deferasirox (tablets for oral suspension) doses in the 20- 40 mg/kg/day range equivalent to 14-28 mg/kg/day deferasirox (film-coated tablets) when body iron burden was approaching or in the normal range. Interrupt deferasirox (film-coated tablets) in patients with volume depletion, and resume deferasirox (film-coated tablets) when renal function and fluid volume have normalized. Monitor liver and renal function more frequently during volume depletion and in patients receiving deferasirox (film-coated tablets) in the 14-28 mg/kg/day range when iron burden is approaching the normal range. Use the minimum effective dose to achieveand maintain a low iron burden (see section 4.2 and section 4.4).

Overchelation

For patients with transfusional iron overload, measure serum ferritin monthly to assess for possible over chelation of iron. An analysis of pediatric patients treated with deferasirox (tablets for oral suspension) in pooled clinical trials (n =158), found a higher rate of renal adverse events (AEs) among patients receiving doses greater than 25 mg/kg/day equivalent to

17.5 mg/kg/day deferasirox (film-coated tablets) while their serum ferritin values were less than 1000 mcg/L. Consider dose reduction or closer monitoring of renal and hepatic function, and serum ferritin levels during these periods. Use the minimum effective dose to maintain a low-iron burden. (see section 4.8)

If the serum ferritin falls below 1000 mcg/L at 2 consecutive visits, consider dose reduction, especially if thedeferasirox (film-coated tablets) dose is greater than 17.5 mg/kg/day (see section 4.8). If the serum ferritin falls below 500 mcg/L, interrupt therapy with deferasirox (film-coated tablets) and continue monthly monitoring.

Evaluate the need for ongoing chelation for patients whose conditions do not require regular blood transfusions.Use the minimum effective dose to maintain iron burden in the target range. Continued administration of deferasirox(film-coated tablets) in the 14 to 28 mg/kg/day range, when the body iron burden is approaching or within the normal range can result in life threatening adverse events (see section 4.2)

For patients with NTDT, measure serum ferritin monthly, and if the serum ferritin falls below 300 mcg/L, interrupt deferasirox (film-coated tablets) and obtain a confirmatory LIC e.g Biopsy.

Hypersensitivity

Deferasirox (film-coated tablets) may cause serious hypersensitivity reactions (such as anaphylaxis and angioedema), with the onset of the reaction usually occurring within the first month of treatment (see section 4.8). If reactions are severe, discontinue Deferasirox (film- coated tablets) and institute appropriate medical intervention.Deferasirox (film-coated tablets) is contraindicated in patients with known hypersensitivity to deferasirox productsand should not be reintroduced in patients who have experienced previous hypersensitivity reactions on deferasirox products due to the risk of anaphylactic shock.

Severe Skin Reactions

Severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS), toxic epidermalnecrolysis (TEN) and drug reaction with eosinophilia and systemic symptoms (DRESS) which could be life-threatening or fatal have been reported during deferasirox therapy (see section 4.8). Cases of erythema multiforme have been observed. Advise patients of the signs and symptoms of severe skin reactions, and closely monitor. If any severe skin reactions are suspected, discontinue Deferasirox (film-coated tablets) immediately and do not reintroduce deferasirox therapy.

Skin Rash

Rashes may occur during deferasirox (film-coated tablets) treatment (see section 4.8). For rashes of mild-tomoderate severity, deferasirox (film-coated tablets) may be continued without dose adjustment, since the rash often resolves spontaneously. In severe cases, interrupt treatment with deferasirox. Reintroduction at a lower dose with escalation may be considered after resolution of the rash.

Auditory and Ocular Abnormalities

Auditory disturbances (high frequency hearing loss, decreased hearing), and ocular disturbances (lens opacities,cataracts, elevations in intraocular pressure, and retinal disorders) were reported at a frequency of less than 1% with deferasirox therapy in the clinical studies. The frequency of auditory adverse events irrespective of causality was increased among pediatric patients, who received deferasirox (tablets for oral suspension) doses greater than 25 mg/kg/day equivalent to 17.5 mg/kg/day deferasirox (film-coated tablets) when serum ferritin was less than 1000 mcg/L. (see section 4.4)

The safety of deferasirox in combination with other iron chelators has not been established. Therefore, it must not be combined with other iron chelator therapies (see section 4.3).

Interaction with food

The Cmax of deferasirox film-coated tablets was increased (by 29%) when taken with a high- fat meal. Deferasirox film-coated tablets may be taken either on an empty stomach or with a light meal, preferably at the same time each day (see sections 4.2 and 5.2).

Agents that may decrease Deferasirox systemic exposure

Deferasirox metabolism depends on UGT enzymes. In a healthy volunteer study, the concomitant administration of deferasirox (single dose of 30 mg/kg,) and the potent UGT inducer, rifampicin, (repeated dose of 600 mg/day) resulted in a decrease of deferasirox exposure by 44% (90% CI: 37% - 51%). Therefore, the concomitant use ofDeferasirox tablets 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 the combination, 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 (see section 5.2).

Interaction with midazolam and other agents metabolised by CYP3A4

In a healthy volunteer study, the concomitant administration of deferasirox and midazolam (a CYP3A4 probesubstrate) resulted in a decrease of midazolam exposure by 17% (90% CI: 8%

- 26%). In the clinical setting, this effect may be more pronounced. Therefore, due to a possible decrease in efficacy, caution should be exercised when deferasirox is combined with substances metabolised through CYP3A4 (e.g. ciclosporin, simvastatin, hormonal contraceptive agents, bepridil, ergotamine).

Interaction with repaglinide and other agents metabolised by CYP2C8

In a healthy volunteer study, the concomitant administration of deferasirox as a moderate CYP2C8 inhibitor (30 mg/kg daily), with repaglinide, a CYP2C8 substrate, given as a single dose of 0.5 mg, increased repaglinide AUCand Cmax about 2.3-fold (90% CI [2.03-2.63]) and 1.6-fold (90% CI [1.42-1.84]), respectively. Since the interactionhas not been established with dosages higher than 0.5 mg for repaglinide, the concomitant use of deferasirox withrepaglinide should be avoided. If the combination appears necessary, careful clinical and blood glucose monitoring should be performed (see section 4.4). An interaction between deferasirox and other CYP2C8 substrates like paclitaxel cannot be excluded.

Interaction with theophylline and other agents metabolised by CYP1A2

In a healthy volunteer study, the concomitant administration of deferasirox as a CYP1A2 inhibitor (repeated dose of30 mg/kg/day) and the CYP1A2 substrate theophylline (single dose of 120 mg) resulted in an increase of theophylline AUC by 84% (90% CI: 73% to 95%). The single dose Cmax was not affected, but an increase of

theophylline Cmax is expected to occur with chronic dosing. Therefore, the concomitant use of deferasirox with theophylline is not recommended. If deferasirox and theophylline are used concomitantly, monitoring of theophylline concentration and theophylline dose reduction should be considered. An interaction betweendeferasirox and other CYP1A2 substrates cannot be excluded. For substances that are predominantly metabolised by CYP1A2 and that have a narrow therapeutic index (e.g. clozapine, tizanidine), the same recommendations apply as for theophylline.

Other information

The concomitant administration of deferasirox and aluminium-containing antacid preparations has not been formally studied. Although deferasirox has a lower affinity for aluminium than for iron, it is not recommended to takedeferasirox 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 (see section 4.4). The concomitant administration of deferasirox with anticoagulants may also increase the risk of gastrointestinal haemorrhage. Close clinical monitoring is required when deferasirox is combined with these substances.

Concomitant administration of deferasirox and busulfan resulted in an increase of busulfan exposure (AUC), butthe mechanism of the interaction remains unclear. If possible, evaluation of the pharmacokinetics (AUC, clearance)of a busulfan test dose should be performed to allow dose adjustment.

Pregnancy

No clinical data on exposed pregnancies are available for deferasirox. Studies in animals have shown some reproductive toxicity at maternally toxic doses (see section 5.3). The potential risk for humans is unknown.

As a precaution, it is recommended that FERASIRO is not used during pregnancy unless clearly necessary.

Deferasirox may decrease the efficacy of hormonal contraceptives (see section 4.5). Women of childbearing potential are recommended to use additional or alternative non-hormonal methods of contraception when using Deferasirox.

Breast-feeding

In animal studies, deferasirox was found to be rapidly and extensively secreted into maternal milk. No effect on the offspring was noted. It is not known if deferasirox is secreted into human milk. Breast-feeding while taking FERASIRO is not recommended.

Fertility

No fertility data is available for humans. In animals, no adverse effects on male or female fertility were found (see section 5.3).

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 (see section 4.8).

Summary of the safety profile

The most frequent reactions reported during chronic treatment in clinical studies conducted with deferasirox inadult and paediatric patients include gastrointestinal disturbances (mainly nausea, vomiting, diarrhoea or abdominal pain) and skin rash. Diarrhoea is reported more commonly in paediatric patients aged 2 to 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.

During clinical studies dose-dependent increases in serum creatinine occurred in about 36% of patients, though most remained within the normal range. Decreases in mean creatinine clearance have been observed in bothpaediatric and adult patients with beta-thalassemia and iron overload during the first year of treatment, but there is evidence that this does not decrease further in subsequent years of treatment. Elevations of liver transaminases have been reported. Safety monitoring schedules for renal and liver parameters are recommended. Auditory (decreased hearing) and ocular (lens opacities) disturbances are uncommon, and yearly examinations are also recommended (see section 4.4).

Severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) and drug reaction with eosinophilia and systemic symptoms (DRESS) have been reported with the use of Deferasirox (see section 4.4).

Tabulated list of adverse reactions

Adverse reactions are ranked below using the following convention: very common (≥1/10); common (≥1/100 to<1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); not known (cannotbe estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 5

¹ Adverse reactions reported during post-marketing experience. These are derived from spontaneous reports for which it is not always possible to reliably establish frequency or a causal relationship to exposure to the medicinal product.

² Severe forms associated with changes in consciousness in the context of hyperammonaemic encephalopathy have been reported.

Description of selected adverse reactions

Gallstones and related biliary disorders were reported in about 2% of patients. Elevations of liver transaminases were reported as an adverse reaction in 2% of patients. Elevations of transaminases greater than 10 times the upper limit of the normal range, suggestive of hepatitis, were uncommon (0.3%). During post-marketing experience, hepatic failure, sometimes fatal, has been reported with the deferasirox, especially in patients with preexisting liver cirrhosis (see section 4.4). There have been post-marketing reports of metabolic acidosis. The majority of these patients had renal impairment, renal tubulopathy (Fanconi syndrome) or diarrhoea, or conditions where acid-base imbalance is a known complication (see section 4.4). Cases of serious acute pancreatitis were observed without documented underlying biliary conditions. As with other iron chelator treatment, high- frequency hearing loss and lenticular opacities (early cataracts) have been uncommonly observed in patients treated with deferasirox (see section 4.4).

Creatinine clearance in transfusional iron overload

In a retrospective meta-analysis of 2,102 adult and paediatric beta-thalassaemia patients with transfusional iron overload treated with deferasirox in two randomised and four open label studies of up to five years' duration, a mean creatinine clearance decrease of 13.2% in adult patients (95% CI: -14.4% to -12.1%; n=935) and 9.9%(95% CI: -11.1% to -8.6%; n=1,142)

in paediatric patients was observed during the first year of treatment. In 250 patients who were followed for up to five years, no further decrease in mean creatinine clearance levels was observed.

Clinical study in patients with non-transfusion-dependent thalassaemia syndromes

In a 1-year study in patients with non-transfusion-dependent thalassaemia syndromes and iron overload (at a doseof 10 mg/kg/day), diarrhoea (9.1%), rash (9.1%), and nausea (7.3%) were the most frequent study drug-related adverse events. Abnormal serum creatinine and creatinine clearance values were reported in 5.5% and 1.8% of patients, respectively. Elevations of liver transaminases greater than 2 times the baseline and 5 times the upper limit of normal were reported in 1.8% of patients.

Paediatric population

In two clinical studies, growth and sexual development of paediatric patients treated with deferasirox for up to 5 years were not affected (see section 4.4).

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 acidosis occurred in children in the context of Fanconi syndrome.

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

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked toreport any suspected adverse reactions to the competent authority in Saudi Arabia as per details below:

To report any side effect(s):

•   Saudi Arabia

The National Pharmacovigilance and Drug Safety Centre (NPC)

-     Fax: +966-11-205-7662

-     Call NPC at +966-11-2038222, Ext 2317-2356-2340

-      SFDA Call Center: 19999

-      E-mail: npc.drug@sfda.gov.sa

-     Website: https://ade.sfda.gov.sa/

•   Other GCC States:

-     Please contact the relevant competent authority.

Early signs of acute overdose are digestive effects such as abdominal pain, diarrhoea, nausea and vomiting. Hepaticand renal disorders have been reported, including cases of liver enzyme and creatinine increased withrecovery after treatment discontinuation. An erroneously administered single dose of 90 mg/kg led to Fanconi syndrome which resolved after treatment.

There is no specific antidote for deferasirox. Standard procedures for management of overdose may be indicated as well as symptomatic treatment, as medically appropriate.

Pharmacotherapeutic group: Iron chelating agents 

ATC code: V03AC03

Mechanism of action

Deferasirox is an orally active chelator that is highly selective for iron (III). It is a tridentate ligand that binds ironwith 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.

Pharmacodynamic effects

In an iron-balance metabolic study in iron-overloaded adult thalassaemic patients, deferasirox at daily dosesof 10, 20 and 40 mg/kg induced the mean net excretion of 0.119,

0.329 and 0.445 mg Fe/kg body weight/day, respectively. Clinical efficacy and safety

Deferasirox has been investigated in 411 adult (age ≥16 years) and 292 paediatric patients (aged 2 to <16 years)with chronic iron overload due to blood transfusions. Of the paediatric patients 52 were aged 2 to 5 years. Theunderlying conditions requiring transfusion included beta-thalassaemia, sickle cell disease and other congenital and acquired anaemias (myelodysplastic syndromes, Diamond-Blackfan syndrome, aplastic anaemia and othervery rare anaemias).

Daily treatment with the deferasirox formulation at doses of 20 and 30 mg/kg for one year in frequently transfused adult and paediatric patients with beta-thalassaemia led to reductions in indicators of total body iron; liver iron concentration was reduced by about -0.4 and -8.9 mg Fe/g liver (biopsy dry weight (dw)) on average, respectively, and serum ferritin was reduced by about -36 and -926 μg/l on average, respectively. At these same doses the ratios of iron excretion: iron intake were 1.02 (indicating net iron balance) and 1.67 (indicating net iron removal), respectively.

Deferasirox induced similar responses in iron-overloaded patients with other anaemias. Daily doses of 10 mg/kg forone year could maintain liver iron and serum ferritin levels and induce net iron balance in patients receiving infrequent transfusions or exchange transfusions. Serum ferritin assessed by monthly monitoring reflectedchanges in liver iron concentration indicating that trends in serum ferritin can be used to monitor response to therapy. Limited clinical data (29 patients with normal cardiac function at baseline) using MRI indicate that treatment with deferasirox 10-30 mg/kg/day for 1 year may also reduce levels of iron in the heart (on average, MRI T2* increased from 18.3 to 23.0 milliseconds).

The principal analysis of the pivotal comparative study in 586 patients suffering from beta- thalassaemia and transfusional iron overload did not demonstrate non-inferiority of deferasirox to deferoxamine in the analysis ofthe total patient population. It appeared from a post-hoc analysis of this study that, in the subgroup of patients with liver iron concentration

≥7 mg Fe/g dw treated with deferasirox (20 and 30 mg/kg) or deferoxamine (35 to ≥50 mg/kg), the non-inferiority criteria were achieved. However, in patients with liver iron concentration <7 mg Fe/g dw treated withdeferasirox (5 and 10 mg/kg) or deferoxamine (20 to 35 mg/kg), non-inferiority was not established due to imbalance in the dosing of the two chelators. This imbalance occurred because patients on deferoxamine wereallowed to remain on their pre-study dose even if it was higher than the protocol specified dose. Fifty-six patients under the age of 6 years participated in this pivotal study, 28 of them receiving deferasirox.

It appeared from preclinical and clinical studies that deferasirox could be as active as deferoxamine when used in a dose ratio of 2:1 (i.e. a dose of deferasirox that is numerically half of the deferoxamine dose). For deferasirox film-coated tablets, a dose ratio of 3:1 can be considered (i.e. a dose of deferasirox film-coated tablets that is numerically one third of the deferoxamine dose). However, this dosing recommendation was not prospectively assessed in the clinical studies.

In addition, in patients with liver iron concentration ≥7 mg Fe/g dw with various rare anaemias or sickle cell disease, deferasirox up to 20 and 30 mg/kg produced a decrease in liver iron concentration and serum ferritincomparable to that obtained in patients with beta- thalassaemia.

In a 5-year observational study in which 267 children aged 2 to <6 years (at enrollment) with transfusional haemosiderosis received deferasirox, there were no clinically meaningful differences in the safety and tolerability profile of Deferasirox in paediatric patients aged 2 to <6 years compared to the overall adult and older paediatricpopulation, including increases in serum creatinine of >33% and above the upper limit of normal on ≥2 consecutive occasions (3.1%), and elevation of alanine aminotransferase (ALT) greater than 5 times the upper limit of normal (4.3%). Single events of increase in ALT and aspartate aminotransferase were reported in 20.0% and 8.3%, respectively, of the 145 patients who completed the study.

In a study to assess the safety of deferasirox film-coated and dispersible tablets, 173 adult and paediatricpatients with transfusion dependent thalassaemia or myelodysplastic syndrome were treated for 24 weeks. A comparable safety profile for film-coated and dispersible tablets was observed.

In patients with non-transfusion-dependent thalassaemia syndromes and iron overload, treatment with deferasirox dispersible tablets was assessed in a 1-year, randomised, double- blind, placebo-controlled study. The studycompared the efficacy of two different deferasirox dispersible tablet regimens (starting doses of 5 and 10 mg/kg/day, 55 patients in each arm) and of matching placebo (56 patients). The study enrolled 145 adult and 21 paediatric patients. The primary efficacy parameter was the change in liver iron concentration (LIC) from baseline after 12 months of treatment. One of the secondary efficacy parameters was the change in serum ferritin between baseline and fourth quarter. At a starting dose of 10 mg/kg/day, deferasirox dispersible tablets led toreductions in indicators of total body iron. On average, liver iron concentration decreased by 3.80 mg Fe/g dw in patients treated with deferasirox dispersible tablets (starting dose 10 mg/kg/day) and increased by 0.38 mg Fe/g dw in patients treated with placebo (p<0.001). On average, serum ferritin decreased by 222.0 μg/l in patients treated with deferasirox dispersible tablets (starting dose 10 mg/kg/day) and increased by 115 μg/l in patients treated with placebo (p<0.001).

Deferasirox film-coated tablets demonstrate higher bioavailability compared to the Deferasirox dispersible tabletformulation. After adjustment of the strength, the film-coated tablet formulation (360 mg strength) was equivalent to Deferasirox dispersible tablets (500 mg strength) with respect to the mean area under the plasma concentrationtime curve (AUC) under fasting conditions. The Cmax was increased by 30% (90% CI: 20.3% - 40.0%); however, a clinical exposure/response analysis revealed no evidence of clinically relevant effects of such an increase.

Absorption

Deferasirox is absorbed following oral administration with a median time to maximum plasma concentration (tmax) of about 1.5 to 4 hours. The absolute bioavailability (AUC) of deferasirox is about 70% compared to an intravenous dose.
The absolute bioavailability of the film-coated tablet formulation has not been determined. Bioavailability of deferasirox film-coated tablets was 36% greater than that with dispersible tablets.

A food-effect study involving administration of the film-coated tablets to healthy volunteers under fasting conditions and with a low-fat (fat content <10% of calories) or high-fat (fat content >50% of calories) meal indicated that the AUC and Cmax were slightly decreased after a low-fat meal (by 11% and 16%, respectively). After a high-fat meal, AUC and Cmax were increased (by 18% and 29%, respectively). The increases in Cmax due to the change in formulation and due to the effect of a high-fat meal may be additive and therefore, it is recommended that the film-coated tablets should be taken either on an empty stomach or with a light meal.

Distribution

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

Biotransformation

Glucuronidation is the main metabolic pathway for deferasirox, with subsequent biliary excretion. Deconjugation of glucuronidates in the intestine and subsequent reabsorption (enterohepatic recycling) is likely to occur: in a healthy volunteer study, the administration of cholestyramine after a single dose of deferasirox resulted in a 45%decrease in deferasirox exposure (AUC).

Deferasirox is mainly glucuronidated by UGT1A1 and to a lesser extent UGT1A3. CYP450- catalysed (oxidative) metabolism of deferasirox appears to be minor in humans (about 8%). No inhibition of deferasirox metabolism by hydroxyurea was observed in vitro.

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. The transporters MRP2 and MXR (BCRP) are involved in the biliary excretion of deferasirox.

Linearity / non-linearity

The Cmax and AUC0-24h of deferasirox increase approximately linearly with dose under steady-state conditions.Upon multiple dosing exposure increased by an accumulation factor of 1.3 to 2.3.

Characteristics in patients

Paediatric patients

The overall exposure of adolescents (12 to ≤17 years) and children (2 to <12 years) to deferasirox after single and multiple doses was lower than that in adult patients. In children younger than 6 years old exposure was about 50% lower than in adults. Since dosing is individually adjusted according to response this is not expected to have clinical consequences.

Gender

Females have a moderately lower apparent clearance (by 17.5%) for deferasirox compared to males. Since dosing is individually adjusted according to response this is not expected to have clinical consequences.

Elderly patients

The pharmacokinetics of deferasirox have not been studied in elderly patients (aged 65 or older).

Renal or hepatic impairment

The pharmacokinetics of deferasirox have not been studied in patients with renal impairment. The pharmacokinetics of deferasirox were not influenced by liver transaminase levels up to 5 times the upper limit of the normal range.

In a clinical study using single doses of 20 mg/kg deferasirox, the average exposure was increased by 16% in subjects with mild hepatic impairment (Child-Pugh Class A) and by 76% in subjects with moderate hepatic impairment (Child-Pugh Class B) compared to subjects with normal hepatic function. The average Cmax ofdeferasirox in subjects with mild or moderate hepatic impairment was increased by 22%. Exposure was increased 2.8-fold in one subject with severe hepatic impairment (Child-Pugh Class C) (see sections 4.2 and 4.4).

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity or carcinogenic potential. The main findings were kidney toxicity and lensopacity (cataracts). Similar findings were observed in neonatal and juvenile animals. The kidney toxicity is considered mainly due to iron deprivation in animals that were not previously overloaded with iron.

Tests of genotoxicity in vitro were negative (Ames test, chromosomal aberration test) while deferasirox caused formation of micronuclei in vivo in the bone marrow, but not liver, of non-iron-loaded rats at lethal doses. No such effects were observed in iron-preloaded rats. Deferasirox was not carcinogenic when administered to rats in a2-year study and transgenic p53+/- heterozygous mice in a 6-month study.

The potential for toxicity to reproduction was assessed in rats and rabbits. Deferasirox was not teratogenic but caused increased frequency of skeletal variations and stillborn pups in rats at high doses that were severely toxic to the non-iron-overloaded mother. Deferasirox did not cause other effects on fertility or reproduction.

Microcrystalline Cellulose

Croscaramellose Sodium

Low-substituted Hydroxypropyl cellulose

Poloxamer 188

Povidone K 30 

Lactose Monohydrate

Colloidal Silicon Dioxide

Sodium stearyl fumarate

Hydrogenated Castor oil 

Opadry Yellow 03H520019

Not applicable.

Do not store above 30°C. Keep out of sight and reach of children.

10 Tablets of FERASIRO 90/180/360 are sealed with Plain Lid Coated Aluminium Foil on one side and clear PVC/PE/PVdC film on another side in the form of a Alu-PVC/PE/PVdC blister pack and such 1 (1x10) or 3 (3x10) blisters are further packed in printed carton along with instructions for use.

No special requirements.