Deferasirox
125mg /250mg/ 500mg Tablets

What Deferasirox is

ODEFERASIROX contains an active substance called deferasirox. It is an iron chelator which is a medicine used to remove the excess iron from the body (also called iron overload).

What Deferasirox is used for

Repeated blood transfusions may be necessary in patients with various types of anaemia (for example thalassaemia, sickle cell disease or myelodysplastic syndromes). However, repeated blood transfusions can cause a build-up of excess iron. This is because blood contains iron and your body does not have a natural way to remove the excess iron you get with your blood transfusions. In patients with nontransfusion- dependent thalassaemia syndromes, iron overload may also develop over time, mainly due to increased absorption of dietary iron in response to low blood cell counts. Over time, the excess iron can damage important organs such as the liver and heart. Medicines called iron chelators are used to remove the excess iron and reduce the risk of it causing organ damage.

DEFERASIROX is used to treat chronic iron overload caused by frequent blood transfusions in patients with beta thalassaemia major aged 6 years and older.

DEFERASIROX is used to treat chronic iron overload caused by frequent blood transfusions in patients with beta thalassaemia major aged 6 years and older.

DEFERASIROX is also used to treat chronic iron overload when deferoxamine therapy is contraindicated or inadequate in patients with beta thalassaemia major with iron overload caused by infrequent blood transfusions, in patients with other types of anaemias, and in children aged 2 to 5 years.

DEFERASIROX is also used when deferoxamine therapy is contraindicated or inadequate to treat patients aged 10 years or older who have iron overload associated with their thalassaemia syndromes, but who are not transfusion dependent.

How Deferasirox works
DEFERASIROX traps and removes excess iron which is then excreted mainly in the stools.

What you need to know before you take Deferasirox

Follow all the doctor’s instructions carefully. They may differ from the general information in this leaflet.

Do not take Deferasirox

• If you are allergic to deferasirox or any of the other ingredients of this medicine (listed in section 6).
• If this applies to you, tell your doctor before taking Deferasirox.
• If you think you may be allergic, ask your doctor for advice.
• If you have moderate or severe kidney disease.
• If you are currently taking another iron chelator medication.

DEFERASIROX is not recommended

• if you are at an advanced stage of myelodysplastic syndrome (MDS; decreased production of blood cells by the bone marrow) or have advanced cancer.

Warnings and precautions
Talk to your doctor or pharmacist before taking DEFERASIROX

• if you have a kidney or liver problem.
• if you have a cardiac problem due to iron overload.
• if you notice a marked decrease in your urine output (sign of kidney problem).
• if you develop a severe rash, or difficulty breathing and dizziness or swelling mainly of the face
• and throat (signs of severe allergic reaction, see also section 4 “Possible side effects”).
• if you develop a rash, reddening of the skin, blistering of lips, eyes or mouth, skin peeling, sore
• throat (signs of severe skin reaction, see also section 4 “Possible side effects”).
• if you experience a combination of drowsiness, upper right abdominal pain, yellowing or
• increased yellowing of your skin or eyes and dark urine (signs of liver problems).
• if you vomit blood and/or have black stools.
• if you experience frequent abdominal pain, particularly after eating or taking DEFERASIROX.
• if you experience frequent heartburn.
• if you have a low level of platelets or white blood cells in your blood test.
• if you have blurred vision or vomiting.
• if you have diarrhoea or vomiting.

If any of these apply to you, tell your doctor straight away.

Monitoring your Deferasirox treatment
You will have regular blood and urine tests during treatment. These will monitor the amount of iron in your body (blood level of ferritin) to see how well DEFERASIROX is working. The tests will also monitor your kidney function (blood level of creatinine, presence of protein in the urine) and liver function (blood level of transaminases). You may also have MRI (magnetic resonance imaging) tests to determine the amount of iron in your liver. Your doctor will take these tests into consideration when deciding on the dose of DEFERASIROX most suitable for you and will also use these tests to decide when you should stop taking DEFERASIROX.

You will get a booklet from your doctor which will help you to track your response to DEFERASIROX. Your doctor will write your blood tests in this booklet at each visit. Keep the booklet safe and bring it with you each time you visit your doctor.

Your eyesight and hearing will be tested each year during treatment as a precautionary measure.

Other medicines and Deferasirox
Deferasirox must not be taken with other iron chelators. Antacids (medicines used to treat heartburn) containing aluminium should not be taken at the same time of day as Deferasirox.

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines. This includes in particular:

• ciclosporin (used to prevent the body rejecting a transplanted organ or for other conditions, such as
• rheumatoid arthritis or atopic dermatitis),
• simvastatin (used to lower cholesterol),
• certain painkillers or anti-inflammatory medicines (e.g. aspirin, ibuprofen, corticosteroids),
• oral bisphosphonates (used to treat osteoporosis),
• anticoagulant medicines (used to prevent or treat blood clotting),
• hormonal contraceptive agents (birth control medicines),
• bepridil, ergotamine,
• repaglinide (used to treat diabetes),
• rifampicin (used to treat tuberculosis),
• phenytoin, phenobarbital, carbamazepine (used to treat epilepsy),
• ritonavir (used in the treatment of HIV infection),
• paclitaxel (used in cancer treatment),
• theophylline (used to treat respiratory diseases such as asthma),
• clozapine (used to treat psychiatric disorders such as schizophrenia),
• tizanidine (used as a muscle relaxant),
• cholestyramine (used to lower cholesterol levels in the blood).

Additional tests may be required to monitor the blood levels of some of these medicines.

Older people (age 65 years and over)
DEFERASIROX can be used by people aged 65 years and over at the same dose as for other adults. Elderly patients may experience more side effects (in particular diarrhoea) than younger patients. They should be monitored closely by their doctor for side effects that may require a dose adjustment.

Children and adolescents (age 2 years to 17 years)
DEFERASIROX can be used in adolescents and children receiving regular blood tranfusions aged 2 years and over and in adolescents and children not receiving regular blood transfusions aged 10 years and over. As the patient grows the doctor will adjust the dose.

Pregnancy and breast-feeding
Deferasirox is not recommended during pregnancy unless clearly necessary. If you are pregnant or think that you may be, tell your doctor who will discuss with you whether you can take DEFERASIROX during your pregnancy.

Breast-feeding is not recommended during treatment with Deferasirox. Tell your doctor if you are breastfeeding.
Ask your doctor or pharmacist for advice before taking any medicine.

Driving and using machines
If you feel dizzy after taking Deferasirox, do not drive or operate any tools or machines until you are feeling normal again.

Deferasirox contains lactose
If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicine.

How to take Deferasirox

Treatment with Deferasirox will be overseen by a doctor who is experienced in the treatment of iron overload caused by blood transfusions. Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist if you are not sure.

How much Deferasirox to take
The dose of Deferasirox is related to body weight for all patients. Your doctor will calculate the dose you need and tell you how many tablets to take each day.

• The usual daily dose at the start of the treatment is 20 mg per kilogram body weight for patients receiving regular blood transfusions. A higher or lower starting dose may be recommended by your doctor based on your individual treatment needs.
• The usual daily dose at the start of the treatment for patients not receiving regular blood transfusions is 10 mg per kilogram body weight.
• Depending on how you respond to treatment, your doctor may later adjust your treatment to a higher or lower dose.
• The maximum recommended daily dose is 40 mg per kilogram body weight for patients receiving regular blood transfusions, 20 mg per kilogram body weight for adult patients not receiving regular blood transfusions and 10 mg per kilogram body weight for paediatric patients not receiving regular blood transfusions.

When to take Deferasirox

• Take DEFERASIROX once a day, every day, at about the same time each day.
• Take the tablets on an empty stomach.
• Then wait at least 30 minutes before eating any food.

Taking DEFERASIROX at the same time each day will also help you remember when to take your tablets.

How to take DEFERASIROX:

• Drop the tablet(s) into a glass of water, or apple or orange juice (100/200 ml).
• Stir until the tablet(s) dissolve completely. The liquid in the glass will look cloudy.
• Drink everything in the glass. Then add a little water or juice to what is left in the glass, swirl the liquid around and drink that too.
• Do not dissolve the tablets in fizzy drinks or milk.
• Do not chew, break or crush the tablets.
• Do not swallow the tablets whole.

How long to take Deferasirox

Continue taking DEFERASIROX every day for as long as your doctor tells you. This is a long-term treatment, possibly lasting for months or years. Your doctor will regularly monitor your condition to check that the treatment is having the desired effect (see also section 1: “Monitoring your Deferasirox treatment”).

If you have questions about how long to take Deferasirox, talk to your doctor.

If you take more Deferasirox than you should
If you have taken too much Deferasirox, or if someone else accidentally takes your tablets, contact your doctor or hospital for advice straight away. Show them the pack of tablets. Medical treatment may be necessary.

If you forget to take DEFERASIROX
If you miss a dose, take it as soon as you remember on that day. Take your next dose as scheduled. Do not take a double dose on the next day to make up for the forgotten tablet(s).

If you stop taking DEFERASIROX
Do not stop taking DEFERASIROX unless your doctor tells you to. If you stop taking it, the excess iron will no longer be removed from your body (see also above section “How long to take DEFERASIROX”).

Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them. Most of the side effects are mild to moderate and will generally disappear after a few days to a few weeks of treatment.

Some side effects could be serious and need immediate medical attention.

These side effects are uncommon or rare.

• If you get a severe rash, or difficulty breathing and dizziness or swelling mainly of the face and throat (signs of severe allergic reaction),
• If you get a severe rash, reddening of the skin, blistering of lips, eyes or mouth, skin peeling, sore throat (signs of severe skin reaction),
• If you notice a marked decrease in your urine output (sign of kidney problem),
• If you experience a combination of drowsiness, upper right abdominal pain, yellowing or increased yellowing of your skin or eyes and dark urine (signs of liver problems),
• If you vomit blood and/or have black stools,
• If you experience frequent abdominal pain, particularly after eating or taking DEFERASIROX,
• If you experience frequent heartburn,
• If you experience partial loss of vision,

Stop taking this medicine and tell your doctor straight away.

Some side effects could become serious.
These side effects are uncommon, that is they may affect up to 1 in 100 people.

• If you get blurred or cloudy eyesight,
• If you get reduced hearing,

Tell your doctor as soon as possible.

Some side effects are very common.br> These side effects may affect more than 1 in 10 people.

• Disturbance in renal function tests.

Some side effects are common.

These side effects may affect up to 1 in 10 people.

• Gastrointestinal disorders, such as nausea, vomiting, diarrhoea, pain in the abdomen, bloating, constipation, indigestion
• Rash
• Headache
• Disturbance in liver function tests
• Itching
• Disturbance in urine test (protein in the urine)

Other side effects are uncommon.

These side effects may affect up to 1 in 100 people.

• Dizziness
• Fever
• Sore throat
• Swelling of arms or legs
• Change in the colour of the skin
• Anxiety
• Sleep disorder
• Tiredness

If any of these affects you severely, tell your doctor.

Frequency not known (cannot be estimated from the available data).

• A decrease in the number of cells involved in blood clotting (thrombocytopenia), in the number of red blood cells (anaemia aggravated) or in the number of all kinds of blood cells (pancytopenia)
• Hair loss

Reporting of side effects
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly FDA.

How to store Deferasirox

• Keep this medicine out of the sight and reach of children.
• Do not use this medicine after the expiry date which is stated on the blister and the carton. The expiry date refers to the last day of that month.
• Store in the original package in order to protect from moisture.
• Do not use any pack that is damaged or shows signs of tampering.

Contents of the pack and other information

What DEFERASIROX contains

The active substance is deferasirox.
Each tablet of 125 mg contains 125 mg deferasirox.
Each tablet of 250 mg contains 250 mg deferasirox.
Each tablet of 500 mg contains 500 mg deferasirox.

The other ingredients are lactose monohydrate, crospovidone type A, povidone, sodium laurilsulfate, microcrystalline cellulose, colloidal anhydrous silica and magnesium stearate.

What Deferasirox looks like and contents of the pack
Deferasirox is supplied as dispersible tablets. The tablets are off-white, round and flat. Each tablet contains 125 mg, 250 mg or 500 mg deferasirox:

• Deferasirox 125 mg tablets are stamped “ 125” on one side and “TAJ” on the other.
• Deferasirox 250 mg tablets are stamped “250” on one side and “TAJ” on the other.
• Deferasirox 500 mg tablets are stamped “ 500” on one side and “TAJ” on the other.

Each blister pack contains 20, 30 or 100 dispersible tablets.
Not all pack sizes or strengths may be available.

Deferasirox
125mg /250mg/ 500mg Tablets

INDICATIONS AND USAGE

Deferasirox is indicated for the treatment of chronic iron overload due to blood transfusions (transfusional hemosiderosis) in patients 2 years of age and older. This indication is based on a reduction of liver iron concentrations and serum ferritin levels. An improvement in survival or disease-related symptoms has not been established.

Deferasirox 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. This indication is based on achievement of an LIC less than 5 mg Fe/g dw. An improvement in survival or disease-related symptoms has not been established.

Controlled clinical trials of Deferasirox with myelodysplastic syndromes (MDS) and chronic iron overload due to blood transfusions have not been performed.

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

DOSAGE AND ADMINISTRATION

Deferasirox 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, obtain:

• serum ferritin level
• baseline serum creatinine in duplicate (due to variations in measurements) and determine the creatinine clearance (Cockcroft-Gault method)
• serum transaminases and bilirubin
• baseline auditory and ophthalmic examinations

The recommended initial dose of Deferasirox for patients 2 years of age and older is 20 mg per kg body weight orally, once daily. Calculate doses (mg per kg per day) to the nearest whole tablet.

After commencing therapy, monitor serum ferritin monthly and adjust the dose of Deferasirox, if necessary, every 3-6 months based on serum ferritin trends. Make dose adjustments in steps of 5 or 10 mg per kg and tailor adjustments to the individual patient’s response and therapeutic goals. In patients not adequately controlled with doses of 30 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 40 mg per kg may be considered. Doses above 40 mg per kg are not recommended.

If the serum ferritin falls consistently below 500 mcg/L, consider temporarily interrupting therapy with Deferasirox.

Deferasirox 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 or by an FDA-cleared or approved method for identifying patients for treatment with deferasirox therapy
• Serum ferritin level on at least 2 measurements 1 month apart
• Baseline serum creatinine in duplicate (due to variations in measurements) and determine the creatinine clearance (Cockcroft-Gault method)
• Serum transaminases and bilirubin
• Baseline auditory and ophthalmic examinations

Initiating therapy:

• The recommended initial dose of Deferasirox is 10 mg per kg body weight orally once daily. Calculate doses (mg per kg per day) to the nearest whole tablet.
• If the baseline LIC is greater than 15 mg Fe/g dw, consider increasing the dose to 20 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.
• 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 20 mg/kg/day. Do not exceed a maximum of 20 mg/kg/day.
• If after 6 months of therapy, the LIC is 3-7 mg Fe/g dw, continue treatment with deferasirox at no more than 10 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, hepatic function, and renal function

Restart treatment when the LIC rises again to more than 5 mg Fe/g dw.

Do not chew tablets or swallow them whole.

Take Deferasirox once daily on an empty stomach at least 30 minutes before food, preferably at the same time each day. Completely disperse tablets by stirring in water, orange juice, or apple juice until a fine suspension is obtained. Disperse doses of less than 1 g in 3.5 ounces of liquid and doses of 1 g or greater in 7 ounces of liquid. After swallowing the suspension, resuspend any residue in a small volume of liquid and swallow. Do not take Deferasirox with aluminum-containing antacid products

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 Deferasirox.

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 or creatinine clearance less than 40 mL/min.

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 upper limit of normal.

All Patients (regardless of age):

• Discontinue therapy for serum creatinine greater than 2 times the age-appropriate upper limit of normal or for creatinine clearance <40 mL/min.

Non-Transfusion-Dependent Thalassemia Syndromes
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, 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 upper limit of normal.

All Patients (regardless of age):

• Discontinue therapy for serum creatinine greater than 2 times the age-appropriate upper limit of normal or for creatinine clearance <40 mL/min.

UDP-glucuronosyltransferases (UGT) Inducers
Concomitant use of UGT inducers decreases Deferasirox systemic exposure. Avoid the concomitant use of potent UGT inducers (e.g., rifampicin, phenytoin, phenobarbital, ritonavir) with Deferasirox. If you must administer Deferasirox with 1 of these agents, consider increasing the initial dose of Deferasirox by 50%, and monitor serum ferritin levels and clinical responses for further dose modification.

Bile Acid Sequestrants
Concomitant use of bile acid sequestrants decreases Deferasirox systemic exposure. Avoid the concomitant use of bile acid sequestrants (e.g., cholestyramine, colesevelam, colestipol) with Deferasirox. If you must administer Deferasirox with 1 of these agents, consider increasing the initial dose of Deferasirox by 50%, and monitor serum ferritin levels and clinical responses for further dose modification.

DOSAGE FORMS AND STRENGTHS

• 125 mg tablets
  Off-white, round, flat tablet with beveled edge and imprinted with “J” and “125” on one side and “NVR” on the other.
• 250 mg tablets
  Off-white, round, flat tablet with beveled edge and imprinted with “J” and “250” on one side and “NVR” on the other.
• 500 mg tablets
  Off-white, round, flat tablet with beveled edge and imprinted with “J” and “500” on one side and “NVR” on the other.

CONTRAINDICATIONS

Deferasirox is contraindicated in patients with:

• Serum creatinine greater than 2 times the age-appropriate upper limit of normal or creatinine clearance less than 40 mL/min;
• Poor performance status;
• High-risk myelodysplastic syndromes;
• Advanced malignancies;
• Platelet counts <50 x 109/L;
• Known hypersensitivity to deferasirox or any component of Deferasirox.

WARNINGS AND PRECAUTIONS

Deferasirox can cause acute renal failure, fatal in some patients and requiring dialysis in others. Postmarketing experience showed that most fatalities occurred in patients with multiple comorbidities and who were in advanced stages of their hematological disorders. In the clinical trials, Deferasirox-treated patients experienced dose-dependent increases in serum creatinine. In patients with transfusional iron overload, these increases in creatinine occurred at a greater frequency compared to deferoxamine-treated patients (38% versus 14%, respectively, in Study 1 and 36% versus 22%, respectively, in Study 3)

Measure serum creatinine in duplicate (due to variations in measurements) and determine the creatinine clearance (estimated by the Cockcroft-Gault method) before initiating therapy in all patients in order to establish a reliable pretreatment baseline. Monitor serum creatinine weekly during the first month after initiation or modification of therapy and at least monthly thereafter. Monitor serum creatinine and/or creatinine clearance more frequently if creatinine levels are increasing. Dose reduction, interruption, or discontinuation based on increases in serum creatinine may be necessary

Deferasirox is contraindicated in patients with creatinine clearance less than 40 mL/minute or serum creatinine greater than 2 times the age appropriate upper limit of normal.

Renal tubular damage, including Fanconi’s Syndrome, has been reported in patients treated with Deferasirox, most commonly in children and adolescents with beta-thalassemia and serum ferritin levels <1500 mcg/L.

Intermittent proteinuria (urine protein/creatinine ratio >0.6 mg/mg) occurred in 18.6% of Deferasirox-treated patients compared to 7.2% of deferoxamine-treated patients in Study 1. In clinical trials in patients with transfusional iron overload, Deferasirox was temporarily withheld until the urine protein/creatinine ratio fell below 0.6 mg/mg. Monthly monitoring for proteinuria is recommended. The mechanism and clinical significance of the proteinuria are uncertain.

Deferasirox 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 was more common in patients with significant comorbidities, including liver cirrhosis and multiorgan failure.

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 Deferasirox in patients with severe (Child-Pugh C) hepatic impairment. Reduce the starting dose in patients with moderate (Child-Pugh B) hepatic impairment. Patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment may be at higher risk for hepatic toxicity.

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 been reported in patients, including children and adolescents, receiving Deferasirox. Monitor for signs and symptoms of GI ulceration and hemorrhage during Deferasirox 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 Deferasirox in combination with drugs that have ulcerogenic or hemorrhagic potential, such as nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, oral bisphosphonates, or anticoagulants.

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 counts in all patients. Interrupt treatment with Deferasirox in patients who develop cytopenias until the cause of the cytopenia has been determined. Deferasirox is contraindicated in patients with platelet counts below 50 x 109/L.

Deferasirox has been associated with serious and fatal adverse reactions in the postmarketing setting, predominantly in elderly patients. Monitor elderly patients treated with Deferasirox more frequently for toxicity.

Deferasirox 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 Adverse Reactions (6.2)]. If reactions are severe, discontinue Deferasirox and institute appropriate medical intervention. Deferasirox is contraindicated in patients with known hypersensitivity to Deferasirox.

Severe skin reactions, including Stevens-Johnson syndrome (SJS) and erythema multiforme, have been reported during Deferasirox therapy. If SJS or erythema multiforme is suspected, discontinue Deferasirox and evaluate.

Rashes may occur during Deferasirox treatment. For rashes of mild to moderate severity, Deferasirox 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 in combination with a short period of oral steroid administration.

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 <1% with Deferasirox therapy in the clinical studies. Perform auditory and ophthalmic testing (including slit lamp examinations and dilated fundoscopy) before starting Deferasirox treatment and thereafter at regular intervals (every 12 months). If disturbances are noted, monitor more frequently. Consider dose reduction or interruption.

For patients with transfusional iron overload, measure serum ferritin monthly to assess for possible overchelation of iron. If the serum ferritin falls below 500 mcg/L, consider interrupting therapy with Deferasirox, since overchelation may increase Deferasirox toxicity.

For patients with NTDT, measure LIC by liver biopsy or by using an FDA-cleared or approved method for monitoring patients receiving deferasirox therapy every 6 months on treatment. Interrupt Deferasirox administration when the LIC is less than 3 mg Fe/g dw. Measure serum ferritin monthly, and if the serum ferritin falls below 300 mcg/L, interrupt Deferasirox and obtain a confirmatory LIC.

ADVERSE REACTIONS

The following adverse reactions are also discussed in other sections of the labeling:

• Renal Toxicity, Renal Failure, and Proteinuria
• Hepatic Toxicity and Failure
• Gastrointestinal (GI) Hemorrhage
• Bone Marrow Suppression
• Hypersensitivity
• Severe Skin Reactions
• Skin Rash
• Auditory and Ocular Abnormalities

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Transfusional Iron Overload
A total of 700 adult and pediatric patients were treated with Deferasirox (deferasirox) for 48 weeks in premarketing studies. These included 469 patients with beta-thalassemia, 99 with rare anemias, and 132 with sickle cell disease. Of these patients, 45% were male, 70% were Caucasian and 292 patients were <16 years of age. In the sickle cell disease population, 89% of patients were black. Median treatment duration among the sickle cell patients was 51 weeks. Of the 700 patients treated, 469 (403 beta-thalassemia and 66 rare anemias) were entered into extensions of the original clinical protocols. In ongoing extension studies, median durations of treatment were 88-205 weeks.

Six hundred twenty-seven patients with MDS were enrolled across 5 uncontrolled trials. These studies varied in duration from 1 to 5 years. The discontinuation rate across studies in the first year was 46% (AEs 20%, withdrawal of consent 10%, death 8%, other 4%, lab abnormalities 3%, and lack of efficacy 1%). Among 47 patients enrolled in the study of 5-year duration, 10 remained on Deferasirox at the completion of the study.

Table 1 displays adverse reactions occurring in >5% of Deferasirox-treated beta-thalassemia patients (Study 1), sickle cell disease patients (Study 3), and patients with MDS (MDS pool). Abdominal pain, nausea, vomiting, diarrhea, skin rashes, and increases in serum creatinine were the most frequent adverse reactions reported with a suspected relationship to Deferasirox. Gastrointestinal symptoms, increases in serum creatinine, and skin rash were dose related.

In Study 1, a total of 113 (38%) patients treated with Deferasirox had increases in serum creatinine >33% above baseline on 2 separate occasions (Table 2) and 25 (8%) patients required dose reductions. Increases in serum creatinine appeared to be dose related. In this study, 17 (6%) patients treated with Deferasirox developed elevations in SGPT/ALT levels >5 times the upper limit of normal at 2 consecutive visits. Of these, 2 patients had liver biopsy proven drug-induced hepatitis and both discontinued Deferasirox therapy. An additional 2 patients, who did not have elevations in SGPT/ALT >5 times the upper limit of normal, discontinued Deferasirox because of increased SGPT/ALT. Increases in transaminases did not appear to be dose related. Adverse reactions that led to discontinuations included abnormal liver function tests (2 patients) and drug-induced hepatitis (2 patients), skin rash, glycosuria/proteinuria, Henoch Schönlein purpura, hyperactivity/insomnia, drug fever, and cataract (1 patient each).

In Study 3, a total of 48 (36%) patients treated with Deferasirox had increases in serum creatinine >33% above baseline on 2 separate occasions (Table 2). Of the patients who experienced creatinine increases in Study 3, 8 Deferasirox-treated patients required dose reductions. In this study, 5 patients in the Deferasirox group developed elevations in SGPT/ALT levels >5 times the upper limit of normal at 2 consecutive visits and 1 patient subsequently had Deferasirox permanently discontinued. Four additional patients discontinued Deferasirox due to adverse reactions with a suspected relationship to study drug, including diarrhea, pancreatitis associated with gallstones, atypical tuberculosis, and skin rash.

In the MDS pool, in the first year, a total of 229 (37%) patients treated with Deferasirox had increases in serum creatinine >33% above baseline on 2 consecutive occasions (Table 2) and 8 (3.5%) patients permanently discontinued. A total of 5 (0.8%) patients developed SGPT/ALT levels >5 times the upper limit of normal at 2 consecutive visits. The most frequent adverse reactions that led to discontinuation included increases in serum creatinine, diarrhea, nausea, rash, and vomiting. Death was reported in the first year in 52 (8%) of patients.

Non-Transfusion-Dependent Thalassemia Syndromes
In Study 4, 110 patients with NTDT received 1 year of treatment with Deferasirox 5 or 10 mg/kg/day and 56 patients received placebo in a double-blind, randomized trial. In Study 5, 130 of the patients who completed Study 4 were treated with open-label Deferasirox at 5, 10, or 20 mg/kg/day (depending on the baseline LIC) for 1 year. Table 3 displays adverse reactions occurring in >5% in any group. The most frequent adverse reactions with a suspected relationship to study drug were nausea, rash, and diarrhea.

In Study 4, 1 patient in the placebo 10 mg/kg/day group experienced an ALT increase to >5 times ULN and >2 times baseline (Table 4). Three Deferasirox-treated patients (all in the 10 mg/kg/day group) had 2 consecutive serum creatinine level increases >33% from baseline and >ULN. Serum creatinine returned to normal in all 3 patients (in 1 spontaneously and in the other 2 after drug interruption). Two additional cases of ALT increase and 2 additional cases of serum creatinine increase were observed in the 1-year extension of Study 4.

Proteinuria
In clinical studies, urine protein was measured monthly. Intermittent proteinuria (urine protein/creatinine ratio >0.6 mg/mg) occurred in 18.6% of Deferasirox-treated patients compared to 7.2% of deferoxamine-treated patients in Study 1.

Other Adverse Reactions
In the population of more than 5,000 patients with transfusional iron overload who have been treated with Deferasirox during clinical trials, adverse reactions occurring in 0.1% to 1% of patients included gastritis, edema, sleep disorder, pigmentation disorder, dizziness, anxiety, maculopathy, cholelithiasis, pyrexia, fatigue, pharyngolaryngeal pain, early cataract, hearing loss, gastrointestinal hemorrhage, gastric ulcer (including multiple ulcers), duodenal ulcer, and renal tubulopathy (Fanconi’s Syndrome). Adverse reactions occurring in 0.01% to 0.1% of patients included optic neuritis, esophagitis, and erythema multiforme. Adverse reactions which most frequently led to dose interruption or dose adjustment during clinical trials were rash, gastrointestinal disorders, infections, increased serum creatinine, and increased serum transaminases.

The following adverse reactions have been spontaneously reported during post-approval use of Deferasirox in the transfusional iron overload setting. Because these reactions are reported voluntarily from a population of uncertain size, in which patients may have received concomitant medication, it is not always possible to reliably estimate frequency or establish a causal relationship to drug exposure.

• +Skin and subcutaneous tissue disorders: Stevens-Johnson syndrome (SJS), leukocytoclastic vasculitis, urticaria, alopecia
• +Immune system disorders: hypersensitivity reactions (including anaphylaxis and angioedema)
• +Renal and urinary disorders: acute renal failure, tubulointerstitial nephritis
• +Hepatobiliary disorders: hepatic failure
• +Gastrointestinal disorders: gastrointestinal hemorrhage
• +Blood and lymphatic system disorders: worsening anemia

DRUG INTERACTIONS

The concomitant administration of Deferasirox and aluminum-containing antacid preparations has not been formally studied. Although deferasirox has a lower affinity for aluminum than for iron, avoid use of Deferasirox with aluminum-containing antacid preparations due to the mechanism of action of Deferasirox.

Deferasirox may induce CYP3A4 resulting in a decrease in CYP3A4 substrate concentration when these drugs are coadministered. Closely monitor patients for signs of reduced effectiveness when deferasirox is administered with drugs metabolized by CYP3A4 (e.g., alfentanil, aprepitant, budesonide, buspirone, conivaptan, cyclosporine, darifenacin, darunavir, dasatinib, dihydroergotamine, dronedarone, eletriptan, eplerenone, ergotamine, everolimus, felodipine, fentanyl, hormonal contraceptive agents, indinavir, fluticasone, lopinavir, lovastatin, lurasidone, maraviroc, midazolam, nisoldipine, pimozide, quetiapine, quinidine, saquinavir, sildenafil, simvastatin, sirolimus, tacrolimus, tolvaptan, tipranavir, triazolam, ticagrelor, and vardenafil).

Deferasirox inhibits CYP2C8 resulting in an increase in CYP2C8 substrate (e.g., repaglinide and paclitaxel) concentration when these drugs are coadministered. If Deferasirox and repaglinide are used concomitantly, consider decreasing the dose of repaglinide and perform careful monitoring of blood glucose levels. Closely monitor patients for signs of exposure related toxicity when Deferasirox is coadministered with other CYP2C8 substrates.

Deferasirox inhibits CYP1A2 resulting in an increase in CYP1A2 substrate (e.g., alosetron, caffeine, duloxetine, melatonin, ramelteon, tacrine, theophylline, tizanidine) concentration when these drugs are coadministered. An increase in theophylline plasma concentrations could lead to clinically significant theophylline induced CNS or other adverse reactions. Avoid the concomitant use of theophylline or other CYP1A2 substrates with a narrow therapeutic index (e.g., tizanidine) with Deferasirox. Monitor theophylline concentrations and consider theophylline dose modification if you must coadminister theophylline with Deferasirox. Closely monitor patients for signs of exposure related toxicity when Deferasirox is coadministered with other drugs metabolized by CYP1A2.

Deferasirox is a substrate of UGT1A1 and to a lesser extent UGT1A3. The concomitant use of Deferasirox with potent UGT inducers (e.g., rifampicin, phenytoin, phenobarbital, ritonavir) may result in a decrease in Deferasirox efficacy due to a possible decrease in deferasirox concentration. Avoid the concomitant use of potent UGT inducers with Deferasirox. Consider increasing the initial dose of Deferasirox if you must coadminister these agents together.

Avoid the concomitant use of bile acid sequestrants (e.g., cholestyramine, colesevelam, colestipol) with Deferasirox due to a possible decrease in deferasirox concentration. If you must coadminister these agents together, consider increasing the initial dose of Deferasirox.

USE IN SPECIFIC POPULATIONS

Pregnancy Category C
There are no adequate and well-controlled studies with Deferasirox in pregnant women. Administration of deferasirox to animals during pregnancy and lactation resulted in decreased offspring viability and an increase in renal anomalies in male offspring at exposures that were less than the recommended human exposure. Deferasirox should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

In embryofetal developmental studies, pregnant rats and rabbits received oral deferasirox during the period of organogenesis at doses up to (100 mg per kg/day in rats and 50 mg per kg/day in rabbits) 0.8 times the maximum recommended human dose (MRHD) on a mg/m2 basis. These doses resulted in maternal toxicity but no fetal harm was observed.

In a prenatal and postnatal developmental study, pregnant rats received oral deferasirox daily from organogenesis through lactation day 20 at doses (10, 30, and 90 mg per kg/day) 0.08, 0.2, and 0.7 times the MRHD on a mg/m2 basis. Maternal toxicity, loss of litters, and decreased offspring viability occurred at 0.7 times the MRHD on a mg/m2 basis, and increases in renal anomalies in male offspring occurred at 0.2 times the MRHD on a mg/m2 basis.

It is not known whether Deferasirox is excreted in human milk. Deferasirox and its metabolites were excreted in rat milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from deferasirox and its metabolites, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Of the 700 patients with transfusional iron overload who received Deferasirox during clinical studies, 292 were pediatric patients 2-<16 years of age with various congenital and acquired anemias, including 52 patients age 2-<6 years, 121 patients age 6-<12 years and 119 patients age 12-<16 years. Seventy percent of these patients had beta-thalassemia. Children between the ages of 2-<6 years have a systemic exposure to Deferasirox approximately 50% of that of adults. However, the safety and efficacy of Deferasirox in pediatric patients was similar to that of adult patients, and younger pediatric patients responded similarly to older pediatric patients. The recommended starting dose and dosing modification are the same for children and adults.

Growth and development in patients with chronic iron overload due to blood transfusions were within normal limits in children followed for up to 5 years in clinical trials.

Sixteen pediatric patients (10 to <16 years of age) with chronic iron overload and NTDT were treated with Deferasirox in clinical studies. The safety and efficacy of Deferasirox in these children was similar to that seen in the adults. The recommended starting dose and dosing modification are the same for children and adults with chronic iron overload in NTDT.

Safety and effectiveness have not been established in pediatric patients with chronic iron overload due to blood transfusions who are less than 2 years of age or pediatric patients with chronic iron overload and NTDT who are less than 10 years of age.

Four hundred thirty-one (431) patients ≥65 years of age were studied in clinical trials of Deferasirox in the transfusional iron overload setting. The majority of these patients had myelodysplastic syndrome (MDS) (n=393). In these trials, elderly patients experienced a higher frequency of adverse reactions than younger patients. Monitor elderly patients for early signs or symptoms of adverse reactions that may require a dose adjustment. Elderly patients are at increased risk for toxicity due to the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range.

For patients with renal impairment (ClCr 40-60 mL/min), reduce the starting dose by 50%. Deferasirox is contraindicated in patients with a creatinine clearance <40 mL/min or serum creatinine >2 times the age-appropriate upper limit of normal.

Deferasirox can cause renal failure. Monitor serum creatinine and calculate creatinine clearance (using Cockcroft-Gault method) during treatment in all patients. Reduce, interrupt or discontinue Deferasirox dosing based on increases in serum creatinine.

In a single dose (20 mg/kg) study in patients with varying degrees of hepatic impairment, deferasirox exposure was increased compared to patients with normal hepatic function. The average total (free and bound) AUC of deferasirox increased 16% in 6 patients with mild (Child-Pugh A) hepatic impairment, and 76% in 6 patients with moderate (Child-Pugh B) hepatic impairment compared to 6 patients with normal hepatic function. The impact of severe (Child-Pugh C) hepatic impairment was assessed in only 1 patient.

Avoid the use of Deferasirox in patients with severe (Child-Pugh C) hepatic impairment. For patients with moderate (Child-Pugh B) hepatic impairment, the starting dose should be reduced by 50%. Closely monitor patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment for efficacy and adverse reactions that may require dose titration.

OVERDOSAGE

Cases of overdose (2-3 times the prescribed dose for several weeks) have been reported. In 1 case, this resulted in hepatitis which resolved without long-term consequences after a dose interruption. Single doses up to 80 mg per kg per day in iron overloaded beta-thalassemic patients have been tolerated with nausea and diarrhea noted. In healthy volunteers, single doses of up to 40 mg per kg per day were tolerated. There is no specific antidote for Deferasirox. In case of overdose, induce vomiting and employ gastric lavage.

DESCRIPTION

Deferasirox (deferasirox) is an iron chelating agent. Deferasirox tablets for oral suspension contain 125 mg, 250 mg, or 500 mg deferasirox. Deferasirox is designated chemically as 4-[3,5-Bis (2-hydroxyphenyl)-1H-1,2,4-triazol-1-yl]-benzoic acid and its structural formula is:

Deferasirox is a white to slightly yellow powder. Its molecular formula is C21H15N3O4 and its molecular weight is 373.4.

Inactive Ingredients:
Lactose monohydrate (NF), crospovidone (NF), povidone (K30) (NF), sodium lauryl sulphate (NF), microcrystalline cellulose (NF), silicon dioxide (NF), and magnesium stearate (NF).

CLINICAL PHARMACOLOGY

Deferasirox (deferasirox) is an orally active chelator that is selective for iron (as Fe3+). It is a tridentate ligand that binds iron with high affinity in a 2:1 ratio. Although deferasirox has very low affinity for zinc and copper there are variable decreases in the serum concentration of these trace metals after the administration of deferasirox. The clinical significance of these decreases is uncertain.

Pharmacodynamic effects tested in an iron balance metabolic study showed that deferasirox (10, 20, and 40 mg per kg per day) was able to induce a mean net iron excretion (0.119, 0.329, and 0.445 mg Fe/kg body weight per day, respectively) within the clinically relevant range (0.1-0.5 mg per kg per day). Iron excretion was predominantly fecal.

Absorption
Deferasirox is absorbed following oral administration with median times to maximum plasma concentration (tmax) of about 1.5-4 hours. The Cmax and AUC of deferasirox increase approximately linearly with dose after both single administration and under steady-state conditions. Exposure to deferasirox increased by an accumulation factor of 1.3-2.3 after multiple doses. The absolute bioavailability (AUC) of deferasirox tablets for oral suspension is 70% compared to an intravenous dose. The bioavailability (AUC) of deferasirox was variably increased when taken with a meal.

Distribution
Deferasirox is highly (~99%) protein bound almost exclusively to serum albumin. The percentage of deferasirox confined to the blood cells was 5% in humans. The volume of distribution at steady state (Vss) of deferasirox is 14.37 ± 2.69 L in adults.

Metabolism
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. Deferasirox is mainly glucuronidated by UGT1A1 and to a lesser extent UGT1A3. CYP450-catalyzed (oxidative) metabolism of deferasirox appears to be minor in humans (about 8%). Deconjugation of glucuronide metabolites in the intestine and subsequent reabsorption (enterohepatic recycling) was confirmed in a healthy volunteer study in which the administration of cholestyramine 12 g twice daily (strongly binds to deferasirox and its conjugates) 4 and 10 hours after a single dose of deferasirox resulted in a 45% decrease in deferasirox exposure (AUC) by interfering with the enterohepatic recycling of deferasirox.

Excretion
Deferasirox and metabolites are primarily (84% of the dose) excreted in the feces. Renal excretion of deferasirox and metabolites is minimal (8% of the administered dose). The mean elimination half-life (t1/2) ranged from 8-16 hours following oral administration.

Drug Interactions
Midazolam: In healthy volunteers, the concomitant administration of Deferasirox and midazolam (a CYP3A4 probe substrate) resulted in a decrease of midazolam peak concentration by 23% and exposure by 17%. In the clinical setting, this effect may be more pronounced. The study was not adequately designed to conclusively assess the potential induction of CYP3A4 by deferasirox.

Repaglinide: In a healthy volunteer study, the concomitant administration of Deferasirox (30 mg per kg/day for 4 days) and the CYP2C8 probe substrate repaglinide (single dose of 0.5 mg) resulted in an increase in repaglinide systemic exposure (AUC) to 2.3-fold of control and an increase in Cmax of 62%.

Theophylline: In a healthy volunteer study, the concomitant administration of Deferasirox (repeated dose of 30 mg per kg/day) and the CYP1A2 substrate theophylline (single dose of 120 mg) resulted in an approximate doubling of the theophylline AUC and elimination half-life. The single dose Cmax was not affected, but an increase in theophylline Cmax is expected to occur with chronic dosing.

Rifampicin: In a healthy volunteer study, the concomitant administration of Deferasirox (single dose of 30 mg per kg) and the potent UDP-glucuronosyltransferase (UGT) inducer rifampicin (600 mg/day for 9 days) resulted in a decrease of deferasirox systemic exposure (AUC) by 44%.

Cholestyramine: The concomitant use of Deferasirox with bile acid sequestrants may result in a decrease in Deferasirox efficacy. In healthy volunteers, the administration of cholestyramine after a single dose of deferasirox resulted in a 45% decrease in deferasirox exposure (AUC).

In vitro studies:

• Cytochrome P450 Enzymes: Deferasirox inhibits human CYP3A4, CYP2C8, CYP1A2, CYP2A6, CYP2D6, and CYP2C19 in vitro.
• Transporter Systems: The addition of cyclosporin A (PgP/MRP1/MRP2 inhibitor) or verapamil (PgP/MRP1 inhibitor) did not influence ICL670 permeability in vitro.

Pharmacokinetics in Specific Populations

Pediatric: Following oral administration of single or multiple doses, systemic exposure of adolescents and children to deferasirox was less than in adult patients. In children <6 years of age, systemic exposure was about 50% lower than in adults.

Geriatric: The pharmacokinetics of deferasirox have not been studied in elderly patients (65 years of age or older).

Gender: Females have a moderately lower apparent clearance (by 17.5%) for deferasirox compared to males.

Renal Impairment: Compared to patients with MDS and ClCr >60 mL/min, patients with MDS and ClCr 40 to 60 mL/min (n=34) had approximately 50% higher mean deferasirox trough plasma concentrations.

The effect of 20 and 40 mg per kg per day of deferasirox on the QT interval was evaluated in a single-dose, double-blind, randomized, placebo- and active-controlled (moxifloxacin 400 mg), parallel group study in 182 healthy male and female volunteers age 18-65 years. No evidence of prolongation of the QTc interval was observed in this study.

NONCLINICAL TOXICOLOGY

A 104-week oral carcinogenicity study in Wistar rats showed no evidence of carcinogenicity from deferasirox at doses up to 60 mg per kg per day (0.48 times the MRHD on a mg/m2 basis). A 26-week oral carcinogenicity study in p53 (+/-) transgenic mice has shown no evidence of carcinogenicity from deferasirox at doses up to 200 mg per kg per day (0.81 times the MRHD on a mg/m2 basis) in males and 300 mg per kg per day (1.21 times the MRHD on a mg/m2 basis) in females.

Deferasirox was negative in the Ames test and chromosome aberration test with human peripheral blood lymphocytes. It was positive in 1 of 3 in vivo oral rat micronucleus tests.

Deferasirox at oral doses up to 75 mg per kg per day (0.6 times the MRHD on a mg/m2 basis) was found to have no adverse effect on fertility and reproductive performance of male and female rats.

CLINICAL STUDIES

Transfusional Iron Overload
The primary efficacy study, Study 1, was a multicenter, open-label, randomized, active-comparator control study to compare Deferasirox (deferasirox) and deferoxamine in patients with beta-thalassemia and transfusional hemosiderosis. Patients ≥2 years of age were randomized in a 1:1 ratio to receive either oral Deferasirox at starting doses of 5, 10, 20, or 30 mg per kg once daily or subcutaneous Desferal (deferoxamine) at starting doses of 20 to 60 mg per kg for at least 5 days per week based on LIC at baseline (2-3, >3-7, >7-14, and >14 mg Fe/g dry weight). Patients randomized to deferoxamine who had LIC values <7 mg Fe/g dry weight were permitted to continue on their prior deferoxamine dose, even though the dose may have been higher than specified in the protocol.

Patients were to have a liver biopsy at baseline and end of study (after 12 months) for LIC. The primary efficacy endpoint was defined as a reduction in LIC of ≥3 mg Fe/g dry weight for baseline values ≥10 mg Fe/g dry weight, reduction of baseline values between 7 and <10 to <7 mg Fe/g dry weight, or maintenance or reduction for baseline values <7 mg Fe/g dry weight.

A total of 586 patients were randomized and treated, 296 with Deferasirox and 290 with deferoxamine. The mean age was 17.1 years (range, 2-53 years); 52% were females and 88% were Caucasian. The primary efficacy population consisted of 553 patients (Deferasirox n=276; deferoxamine n=277) who had LIC evaluated at baseline and 12 months or discontinued due to an adverse event. The percentage of patients achieving the primary endpoint was 52.9% for Deferasirox and 66.4% for deferoxamine. The relative efficacy of Deferasirox to deferoxamine cannot be determined from this study.

In patients who had an LIC at baseline and at end of study, the mean change in LIC was -2.4 mg Fe/g dry weight in patients treated with Deferasirox and -2.9 mg Fe/g dry weight in patients treated with deferoxamine.

Reduction of LIC and serum ferritin was observed with Deferasirox doses of 20 to 30 mg per kg per day. Deferasirox doses below 20 mg per kg per day failed to provide consistent lowering of LIC and serum ferritin levels (Figure 1). Therefore, a starting dose of 20 mg per kg per day is recommended.

Figure 1. Changes in Liver Iron Concentration and Serum Ferritin Following Deferasirox (5-30 mg per kg per day) in Study 1

Study 2 was an open-label, noncomparative trial of efficacy and safety of Deferasirox given for 1 year to patients with chronic anemias and transfusional hemosiderosis. Similar to Study 1, patients received 5, 10, 20, or 30 mg per kg per day of Deferasirox based on baseline LIC.

A total of 184 patients were treated in this study: 85 patients with beta-thalassemia and 99 patients with other congenital or acquired anemias (myelodysplastic syndromes, n=47; Diamond-Blackfan syndrome, n=30; other, n=22). 19% of patients were <16 years of age and 16% were ≥65 years of age. There was a reduction in the absolute LIC from baseline to end of study (-4.2 mg Fe/g dry weight).

Study 3 was a multicenter, open-label, randomized trial of the safety and efficacy of Deferasirox relative to deferoxamine given for 1 year in patients with sickle cell disease and transfusional hemosiderosis. Patients were randomized to Deferasirox at doses of 5, 10, 20, or 30 mg per kg per day or subcutaneous deferoxamine at doses of 20-60 mg per kg per day for 5 days per week according to baseline LIC.

A total of 195 patients were treated in this study: 132 with Deferasirox and 63 with deferoxamine. 44% of patients were <16 years of age and 91% were black. At end of study, the mean change in LIC (as measured by magnetic susceptometry by a superconducting quantum interference device) in the per protocol-1 (PP-1) population, which consisted of patients who had at least 1 post-baseline LIC assessment, was -1.3 mg Fe/g dry weight for patients receiving Deferasirox (n=113) and -0.7 mg Fe/g dry weight for patients receiving deferoxamine (n=54). 

One-hundred five (105) patients with thalassemia major and cardiac iron overload were enrolled in a study assessing the change in cardiac MRI T2* value (measured in milliseconds, ms) before and after treatment with deferasirox. Cardiac T2* values at baseline ranged from 5 to <20 ms. The geometric mean of cardiac T2* in the 68 patients who completed 3 years of Deferasirox therapy increased from 11.98 ms at baseline to 17.12 ms at 3 years. Cardiac T2* values improved in patients with severe cardiac iron overload (<10 ms) and in those with mild to moderate cardiac iron overload (≥10 to <20 ms). The clinical significance of these observations is unknown.

Six hundred twenty-seven patients with MDS were enrolled across 5 uncontrolled trials. Two hundred thirty-nine of the 627 patients were enrolled in trials that limited enrollment to patients with IPSS Low or Intermediate 1 risk MDS and the remaining 388 patients were enrolled in trials that did not specify MDS risk stratification but required a life expectancy of greater than 1 year. Planned duration of treatment in these trials ranged from 1 year (365 patients) to 5 years (47 patients). These trials evaluated the effects of Deferasirox therapy on parameters of iron overload, including LIC (125 patients) and serum ferritin (627 patients). Percent of patients completing planned duration of treatment was 51% in the largest 1 year study, 52% in the 3-year study and 22% in the 5 year study. The major causes for treatment discontinuation were withdrawal of consent, adverse reaction, and death. Over 1 year of follow-up across these pooled studies, mean change in serum ferritin was -332.8 (±2615.59) mcg/L (n=593) and mean change in LIC was -5.9 (±8.32) mg Fe/g dw (n=68). Results of these pooled studies in 627 patients with MDS suggest a progressive decrease in serum ferritin and LIC beyond 1 year in those patients who are able to continue Deferasirox. No controlled trials have been performed to demonstrate that these reductions improve morbidity or mortality in patients with MDS. Adverse reactions with Deferasirox therapy occur more frequently in older patients. In elderly patients, including those with MDS, individualize the decision to remove accumulated iron based on clinical circumstances and the anticipated clinical benefit and risks of Deferasirox therapy.

Non-Transfusion Dependent Thalassemia
Study 4 was a randomized, double-blind, placebo-controlled trial of treatment with Deferasirox for patients 10 years of age or older with NTDT syndromes and iron overload. Eligible patients had an LIC of at least 5 mg Fe/g dw measured by R2 MRI and a serum ferritin exceeding 300 mcg/L at screening (2 consecutive values at least 14 days apart from each other). A total of 166 patients were randomized, 55 to the Deferasirox 5 mg/kg/day dose group, 55 to the Deferasirox 10 mg/kg/day dose group, and 56 to placebo (28 to each matching placebo group). Doses could be increased after 6 months if the LIC exceeded 7 mg Fe/g dw and the LIC reduction from baseline was less than 15%. The patients enrolled included 89 males and 77 females. The underlying disease was beta-thalassemia intermedia in 95 (57%) patients, HbE beta-thalassemia in 49 (30%) patients, and alpha-thalassemia in 22 (13%) patients. There were 17 pediatric patients in the study. Caucasians comprised 57% of the study population and Asians comprised 42%. The median baseline LIC (range) for all patients was 12.1 (2.6-49.1) mg Fe/g dw. Follow-up was for 1 year. The primary efficacy endpoint of change in LIC from baseline to Week 52 was statistically significant in favor of both Deferasirox dose groups compared with placebo (p ≤0.001) (Table 5). Furthermore, a statistically significant dose effect of Deferasirox was observed in favor of the 10 mg/kg/day dose group (10 versus 5 mg/kg/day, p=0.009). In a descriptive analysis, the target LIC (less than 5 mg Fe/g dw) was reached by 15 (27%) of 55 patients in the 10 mg/kg/day arm, 8 (15%) of 55 patients in the 5 mg/kg/day arm and 2 (4%) of 56 patients in the combined placebo groups.

Study 5 was an open-label trial of Deferasirox for the treatment of patients previously enrolled on Study 4, including cross-over to active treatment for those previously treated with placebo. The starting dose of Deferasirox in Study 5 was assigned based on the patient’s LIC at completion of Study 4, being 20 mg/kg/day for an LIC exceeding 15 mg Fe/g dw, 10 mg/kg/day for LIC 3-15 mg Fe/g dw, and observation if the LIC was less than 3 mg Fe/g dw. Patients could continue on 5 mg/kg/day if they had previously exhibited at least a 30% reduction in LIC. Doses could be increased to a maximum of 20 mg/kg/day after 6 months if the LIC was more than 7 mg Fe/g dw and the LIC reduction from baseline was less than 15%. The primary efficacy endpoint in Study 5 was the proportion of patients achieving an LIC less than 5 mg Fe/g dw. A total of 133 patients were enrolled. Twenty patients began Study 5 with an LIC less than 5 mg Fe/g dw. Of the 113 patients with a baseline LIC of at least 5 mg Fe/g dw in Study 5, the target LIC (less than 5 mg Fe/g dw) was reached by 39 (35%). The responders included 4 (10%) of 39 patients treated at 20 mg/kg/day for a baseline LIC exceeding 15 mg Fe/g dw, and 31 (51%) of 61 patients treated at 10 mg/kg/day for a baseline LIC between 5 and 15 mg Fe/g dw. The absolute change in LIC at Week 52 by starting dose is shown in Table 5 above.

HOW SUPPLIED/STORAGE AND HANDLING

Deferasirox is provided as 125 mg, 250 mg, and 500 mg tablets for oral suspension.

125 mg
Off-white, round, flat tablet with beveled edge and imprinted with “J” and “125” on one side and “NVR” on the other.
Bottles of 30 tablets

250 mg
Off-white, round, flat tablet with beveled edge and imprinted with “J” and “250” on one side and “NVR” on the other.
Bottles of 30 tablets

500 mg
Off-white, round, flat tablet with beveled edge and imprinted with “J” and “500” on one side and “NVR” on the other.
Bottles of 30 tablets

Store Deferasirox tablets at 25°C (77°F); excursions are permitted to 15°C-30°C (59°F-86°F) [see USP Controlled Room Temperature]. Protect from moisture.

PATIENT COUNSELING INFORMATION

• Advise patients to take Deferasirox once daily on an empty stomach at least 30 minutes prior to food, preferably at the same time every day. Instruct patients to completely disperse the tablets in water, orange juice, or apple juice, and drink the resulting suspension immediately. After the suspension has been swallowed, resuspend any residue in a small volume of the liquid and swallow.
• Advise patients not to chew tablets or swallow them whole.
• Caution patients not to take aluminum-containing antacids and Deferasirox simultaneously.
• Because auditory and ocular disturbances have been reported with Deferasirox, conduct auditory testing and ophthalmic testing before starting Deferasirox treatment and thereafter at regular intervals.
• Caution patients experiencing dizziness to avoid driving or operating machinery.
• Caution patients about the potential for the development of GI ulcers or bleeding when taking Deferasirox in combination with drugs that have ulcerogenic or hemorrhagic potential, such as NSAIDs, corticosteroids, oral bisphosphonates, or anticoagulants.
• Caution patients about potential loss of effectiveness of drugs metabolized by CYP3A4 (e.g., cyclosporine, simvastatin, hormonal contraceptive agents) when Deferasirox is administered with these drugs.
• Caution patients about potential loss of effectiveness of Deferasirox when administered with drugs that are potent UGT inducers (e.g., rifampicin, phenytoin, phenobarbital, ritonavir). Based on serum ferritin levels and clinical response, consider increases in the dose of Deferasirox when concomitantly used with potent UGT inducers.
• Caution patients about potential loss of effectiveness of Deferasirox when administered with drugs that are bile acid sequestrants (e.g., cholestyramine, colesevelam, colestipol). Based on serum ferritin levels and clinical response, consider increases in the dose of Deferasirox when concomitantly used with bile acid sequestrants.
• Perform careful monitoring of glucose levels when repaglinide is used concomitantly with Deferasirox. An interaction between Deferasirox and other CYP2C8 substrates like paclitaxel cannot be excluded.
• Advise patients that blood tests will be performed because Deferasirox may affect your kidneys, liver, or blood cells. The blood tests will be performed every month or more frequently if you are at increased risk of complications (e.g., preexisting kidney condition, are elderly, have multiple medical conditions, or are taking medicine that affects your organs). There have been reports of severe kidney and liver problems, blood disorders, stomach hemorrhage and death in patients taking Deferasirox .
• Skin rashes may occur during Deferasirox treatment and if severe, interrupt treatment. Serious allergic reactions (which include swelling of the throat) have been reported in patients taking Deferasirox, usually within the first month of treatment. If reactions are severe, advise patients to stop taking Deferasirox and contact their doctor immediately.