DESIROX Tablets

Deferasirox

Prescribing information

To be sold by retail on prescription of Specialists only

Black Box Warning

Renal Failure, Hepatic Failure and Gastrointestinal Hemorrhage

See full prescribing information for complete boxed warning

DEFERASIROX may cause:

acute kidney injury, including acute renal failure requiring dialysis and renal tubular toxicity including Fanconi syndrome
hepatic toxicity, including failure
gastrointestinal hemorrhage

DEFERASIROX therapy requires close patient monitoring, including laboratory tests

of renal and hepatic function

Qualitative and Quantitative Composition

DESIROX-500

Each uncoated dispersible tablet contains deferasirox 500 mg

DESIROX-250

Each uncoated dispersible tablet contains deferasirox 250 mg

Dosage Form And Strength

Uncoated dispersible tablet, 250 mg and 500 mg

Clinical Particulars

Therapeutic Indications

Treatment of Chronic Iron Overload Due to Blood Transfusions (Transfusional Iron Overload)

Deferasirox is indicated for the treatment of chronic iron overload due to blood transfusions (transfusional hemosiderosis) in patients 2 years of age and above.

Limitation of Use

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

Posology and Method of Administration

Transfusional Iron Overload

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 or increasing dose, evaluate:

Serum ferritin level
Baseline renal function:

Obtain serum creatinine in duplicate (due to variations in measurements) to establish accurate baseline
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

Serum transaminases and bilirubin
Baseline auditory and ophthalmic examinations

Initiating Therapy

The recommended initial dose of deferasirox for patients 2 years of age and older with eGFR greater than 60 mL/min/1.73 m²is 20 mg per kg body weight orally, once daily. Calculate doses (mg per kg per day) to the nearest whole tablet.

During Therapy

Monitor serum ferritin monthly and adjust the dose of deferasirox, if necessary, every 3-6 months based on serum ferritin trends.
Use the minimum effective dose to achieve a trend of decreasing ferritin.
Make dose adjustments in steps of 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 2,500 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
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 dose is greater than 25 mg/kg/day
If the serum ferritin falls below 500 mcg/L, interrupt deferasirox 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

Monitor blood counts, liver function, renal function and ferritin monthly.
Interrupt deferasirox 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

DEFERASIROX Administration

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 than1 g in 3.5 ounces of liquid and doses of 1 g or greater in 7.0 ounces of liquid. After swallowing the suspension, resuspend any residue in a small volume of liquid and swallow. Do not take with aluminum-containing antacid products.

Use in Patient 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 hepatic impairment (Child-Pugh C): Avoid deferasirox

Patients with Baseline Renal Impairment

Do not use deferasirox in adult or pediatric patients with eGFR less than 40 mL/min/1.73 m²
For patients with renal impairment (ClCr 40–60 mL/min), reduce the starting dose by 50%.
Exercise caution in pediatric patients with eGFR between 40 and 60 mL/min/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 Deferasirox

Deferasirox is contraindicated in patients with eGFR less than 40 mL/min/1.73 m². For decreases in renal function while receiving Deferasirox 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 serum creatinine within one week, and if still elevated by 33% or more, reduce the dose by 10 mg per kg.

Pediatric Patients (Ages 2 years–17 years)

Reduce the dose by 10 mg/ kg/day if eGFR decreases by greater than 33% below the average baseline measurement and repeat the eGFR within 1 week.
Interrupt Deferasirox for 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.
Avoid use of other nephrotoxic drugs In the setting of decreased renal function, evaluate the risk benefit profile of continued Deferasirox use. Use the minimum effective Deferasirox 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 Deferasirox to prevent severe and irreversible renal injury

All Patients (Regardless of age)

Discontinue therapy for for eGFR less than 40 mL/min/1.73 m²

Dose Modifications Based on Concomitant Medications

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 one 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 one of these agents, consider increasing the initial dose of Deferasirox by 50%, and monitor serum ferritin levels and clinical responses for further dose modification

Contraindications

DEFERASIROX is contraindicated in patients with:

Estimated GFR less than 40 mL/min/1.73 m²
Poor performance status;
High-risk myelodysplastic syndromes; (this patient population was not studied and is not expected to benefit from chelation therapy)
Advanced malignancies
Platelet counts <50 x 10⁹/L;
Known hypersensitivity to deferasirox or any component of deferasirox

Special Warnings and Precautions for Use

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

Deferasirox is contraindicated in patients with eGFR less than 40 mL/min/1.73 m2. 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. For patients with renal impairment (eGFR 40–60 mL/min/1.73 m2), reduce the starting dose by 50%

Deferasirox 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 comorbidities and who were in advanced stages of their hematological disorders. In the clinical trials, adult and pediatric Deferasirox -treated patients with no preexisting renal disease experienced dose-dependent mild, non-progressive increases in serum creatinine and proteinuria. Preexisting 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 exposure, particularly in younger patients with body surface area typical of patients less than age 7 years. This can lead to a cycle of worsening renal function and further 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 pediatric patients with beta-thalassemia and serum ferritin levels less than 1,500 mcg/L

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

Monitor all patients for changes in eGFR and for renal tubular toxicity weekly during the first month after initiation or modification of therapy and at least monthly thereafter. Monitor serum ferritin monthly to evaluate for overchelation. 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 Deferasirox 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 fluid deficits to prevent renal injury. Resume therapy as appropriate, based on assessments of renal function, when oral intake and volume status are normal

Hepatic Toxicity and Failure

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. Liver failure occurred in association with acute kidney injury in pediatric patients at risk for overchelation during a volume depleting event. Interrupt Deferasirox 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 Deferasirox in the 20-40 mg/kg/day range and when iron burden is approaching normal. Use the minimum effective dose to achieve and maintain a low iron burden

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.

Gastrointestinal (GI) Ulceration, Hemorrhage, and Perforation

GI hemorrhage, including deaths, has been reported in deferasirox treated patients, especially in elderly patients who had advanced hematologic malignancies and/or low platelet counts. Non-fatal 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 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 non-steroidal anti-inflammatory drugs (NSAIDs), corticosteroids, oral bisphosphonates, or anticoagulants. There have been reports of ulcers complicated with gastrointestinal perforation (including fatal outcome).

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 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.

Age-Related Risk of Toxicity

Elderly Patients

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

Pediatric Patients

Deferasirox has been associated with serious and fatal adverse reactions in pediatric patients in the postmarketing setting. These events were frequently associated with volume depletion or with continued deferasirox doses in the 20-40 mg/kg/day range when body iron burden was approaching or in the normal range. Interrupt deferasirox in patients with volume depletion, and resume deferasirox when renal function and fluid volume have normalized. Monitor liver and renal function more frequently during volume depletion and in patients receiving deferasirox in the 20-40 mg/kg/day range when iron burden is approaching the normal range. Use the minimum effective dose to achieve and maintain a low iron burden

Overchelation

For patients with transfusional iron overload, Measure serum ferritin monthly to assess for possible overchelation of iron. An analysis of pediatric patients treated with deferasirox in pooled clinical trials (n = 158) found a higher rate of renal adverse events among patients receiving doses greater than 25 mg/kg/day while their serum ferritin values were less than 1,000 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

If the serum ferritin falls below 1000 mcg/L at 2 consecutive visits, consider dose reduction, especially if the dose is greater than 25 mg/kg/day If the serum ferritin falls below 500mcg/L, consider temporarily interrupting therapy with deferasirox and continue monthly monitoring since this result may increase deferasirox toxicity. 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 in the 20-40 mg/kg/day range when the body iron burden is approaching or within the normal range has resulted in life-threatening adverse events

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

Hypersensitivity

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. If reactions are severe, discontinue deferasirox and institute appropriate medical intervention. Deferasirox is contraindicated in patients with known hypersensitivity to deferasirox products and 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 epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS) which could be life threatening or fatal have been reported during deferasirox therapy. 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 immediately and do not reintroduce deferasirox therapy.

Skin Rash

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 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 doses greater than 25 mg/kg/day when serum ferritin was less than 1,000 mcg/L

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 closely. Consider dose reduction or interruption.

Drug Interactions

Aluminum Containing Antacid Preparations

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.

Agents Metabolized by CYP3A4

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).

Agents Metabolized by CYP2C8

Deferasirox inhibits CYP2C8 resulting in an increase in CYP2C8 substrate (e.g., repaglinide and paclitaxel) concentration when these drugs are co-administered. 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 co-administered with other CYP2C8 substrates.

Agents Metabolized by CYP1A2

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 co-administer theophylline with deferasirox. Closely monitor patients for signs of exposure related toxicity when deferasirox is coadministered with other drugs metabolized by CYP1A2.

Agents Inducing UDP-glucuronosyltransferase (UGT) Metabolism

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 co-administer these agents together.

Bile Acid Sequestrants

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 co-administer these agents together, consider increasing the initial dose of deferasirox.

Busulfan

Increased exposure of busulfan was observed with concomitant use with deferasirox. Monitor plasma concentrations of busulfan when coadministered with deferasirox to allow dose adjustment of busulfan as needed.

Use in Special Population

Pregnancy

Risk Summary

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.

The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. However, the background risk in the U.S. general population of major birth defects is 2% to 4% and of miscarriage is 15% to 20% of clinically recognized pregnancies.

Data

Animal Data

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 MRHD (Maximum Recommended Human Dose) 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.

Lactation

Risk Summary

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.

Pediatric Use

Transfusional Iron Overload

The safety and effectiveness of deferasirox have been established in pediatric patients 2 years of age and older for the treatment of transfusional iron overload

Safety and effectiveness have not been established in pediatric patients less than 2 years of age for the treatment of transfusional iron overload.

Pediatric approval for treatment of transfusional iron overload was based on clinical studies of 292 pediatric patients 2 years to less than 16 years of age with various congenital and acquired anemias. Seventy percent of these patients had beta-thalassemia. In those clinical studies, 173 children (ages 2 to < 12 years) and 119 adolescents (ages 12 to < 17 years) were exposed to deferasirox.

A trial conducted in treatment naïve pediatric patients, 2 to < 18 years of age with transfusional iron overload (NCT02435212) did not provide additional relevant information about the safety or effectiveness of the deferasirox granules dosage form (Jadenu Sprinkle) compared to the deferasirox oral tablets for suspension dosage form.

Juvenile Animal Toxicity Data

Renal toxicity was observed in adult mice, rats, and marmoset monkeys administered deferasirox at therapeutic doses. In a neonatal and juvenile toxicity study in rats, deferasirox was administered orally from postpartum Day 7 through 70, which equates to a human age range of term neonate through adolescence. Increased renal toxicity was identified in juvenile rats compared to adult rats at a dose based on mg/m²approximately 0.4 times the recommended dose of 20 mg/kg/day. A higher frequency of renal abnormalities was noted when deferasirox was administered to non-iron overloaded animals compared to iron overloaded animals.

Geriatric Use

Four hundred and thirty-one (431) patients ≥65 years of age were studied in clinical trials of deferasirox in the transfusional iron overload. 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.

Renal Impairment

Deferasirox is contraindicated in patients with eGFR less than 40 ml/min/1.73 m^2.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 with enhanced monitoring of glomerular and renal tubular function. Individualize dose titration based on improvement in renal injury.

Deferasirox can cause glomerular dysfunction, renal tubular toxicity, or both, and can result in acute renal failure. Monitor all patients closely for changes in eGFR and renal tubular dysfunction during Deferasirox treatment. If either develops, consider dose reduction, interruption or discontinuation of Deferasirox until glomerular or renal tubular function returns to baseline.

Hepatic Impairment

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.

Effects on ability to drive and use machines

Caution patients experiencing dizziness to avoid driving or operating machinery

Undesirable Effects

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

Acute Kidney Injury, Including Acute Renal Failure Requiring Dialysis, and Renal Tubular Toxicity Including Fanconi Syndrome
Hepatic Toxicity and Failure Gastrointestinal Hemorrhage
Gastrointestinal (GI) Hemorrhage
Bone Marrow Suppression
Hypersensitivity
Severe Skin Reactions
Skin rash ‘
Auditory and Ocular Abnormalities

Clinical Trials Experience

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 for 48 weeks in premarketing studies. These included 469 patients with ß-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 ß-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 greater than 5% of deferasirox-treated β-thalassemia patients (Study 1) and 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.

Table 1. Adverse reactions* occurring in greater 5% of deferasirox-treated patients in study 1 and study 3 and MDS pool

	Study 1 (ß-Thalassemia)		Study 3 (Sickle Cell Disease)		MDS Pool
Adverse Reactions	Deferasirox N=296 n (%)	Deferoxamine N=290 n (%)	Deferasirox N=132 n (%)	Deferoxamine N=63 n (%)	Deferasirox N=627 n (%)
Abdominal Pain Pain Pain Pain**	63 (21)	41 (14)	37 (28)	9 (14)	145 (23)
Diarrhea	35 (12)	21 (7)	26 (20)	3 (5)	297 (47)
Creatinine Increased***	33 (11)	0 (0)	9 (7)	0	89 (14)
Nausea	31 (11)	14 (5)	30 (23)	7 (11)	161(26)
Vomiting	30 (10)	28 (10)	28 (21)	10 (16)	83 (13)
Rash	25(8)	9(3)	14(11)	3(5)	83 (13)

*Adverse reaction frequencies are based on adverse events reported regardless of relationship to study drug.

** Includes ‘abdominal pain’, ‘abdominal pain lower’, and ‘abdominal pain upper’ which were reported as adverse events.

*** Includes ‘blood creatinine increased’ and ‘blood creatinine abnormal’ which were reported as adverse events. Also SEE Table 2.

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 greater than5 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 greater than 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.

Table 2. Number (%) of patients with increases in serum creatinine or SGPT/ALT in study 1 and study 3 and MDS pool

	Study 1 (ß-Thalassemia)			Study 3 (Sickle Cell Disease)				MDS Pool
Laboratory Parameter	Deferasirox N=296 n (%) N=296	Deferoxamine N=290 n (%)		Deferasirox N=132 n (%)		Deferoxamine n=63 n (%)		Deferasirox N=627 n (%)
Serum Creatinine
Creatinine increase >33% and<ULN at 2 consecutive potsbaseline visits	113 (38)	41 ( 14)		48 (36)		14 (22)		229 (37)
Creatinine increase >33% and > ULN at 2 consecutive postbaseline visits	7 (2)	1 (0)		3 (2)		2 (3)		126 (20)
SGPT/ALT
SGPT/ALT >5 x ULN at 2postbaseline visits	25 (8)		7 (2)		2 (2)		0	9 (1)
SGPT/ALT >5 x ULN at 2 consecutive postbaseline visits	17 (6)		5 (2)		5 (4)		0	5 (1)

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 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, and drug reaction with eosinophilia and systemic symptoms (DRESS). 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.

Pooled Analysis of Pediatric Clinical Trial Data

A nested case control analysis was conducted within a deferasirox pediatric pooled clinical trial dataset to evaluate the effects of dose and serum ferritin level, separately and combined, on kidney function. Among 1213 children (aged 2 to 15 years) with transfusion-dependent thalassemia, 162 cases of acute kidney injury (eGFR < 90 mL/min/1.73 m²) and 621 matched-controls with normal kidney function (eGFR > 120 mL/min/1.73 m²) were identified. The primary findings were:

A 26% increased risk of acute kidney injury was observed with each 5 mg/kg increase in daily Deferasirox dosage starting at 20 mg/kg/day (95% CI: 1.08-1.48).
A 25% increased risk for acute kidney injury was observed with each 250 mcg/L decrease in serum ferritin starting at 1250 mcg/L (95% CI: 1.01-1.56).
Among pediatric patients with a serum ferritin < 1000 mcg/L, those who received Deferasirox dosage > 30 mg/kg/day, compared to those who received lower dosages, had a higher risk for acute kidney injury (OR = 4.47, 95% CI: 1.25-15.95), consistent with overchelation.

In addition, a cohort based analysis of adverse events was conducted in the deferasirox pediatric pooled clinical trial data. Pediatric patients who received Deferasiroxdose > 25 mg/kg/day when their serum ferritin was < 1000 mcg/L (n = 158) had a 6-fold greater rate of renal adverse events (IRR = 6.00, 95% CI: 1.75-21.36) and a 2-fold greater rate of dose interruptions (IRR = 2.06, 95% CI: 1.33-3.17) compared to the time-period prior to meeting these simultaneous criteria. Adverse events of special interest (cytopenia, renal, hearing, and gastrointestinal disorders) occurred 1.9-fold more frequently when these simultaneous criteria were met, compared to preceding time-periods (IRR = 1.91, 95% CI: 1.05-3.48)

Postmarketing Experience

The following adverse reactions have been spontaneously reported during post-approval use of deferasirox. 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), hypersensitivity leukocytoclastic vasculitis, urticaria, alopecia toxic epidermal necrolysis (TEN)

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 perforation

Blood and Lymphatic system disorders: Worsening anemia

5-Year Pediatric Registry

In a 5-year observational study, 267 pediatric patients 2 to < 6 years of age (at enrollment) with transfusional hemosiderosis received deferasirox. Of the 242 patients who had pre- and post-baseline eGFR measurements, 116 (48%) patients had a decrease in eGFR of ≥ 33% observed at least once. Twenty-one (18%) of these 116 patients with decreased eGFR had a dose interruption, and 15 (13%) of these 116 patients had a dose decrease within 30 days. Adverse events leading to permanent discontinuation from the study included liver injury (n = 11), renal tubular disorder (n = 1), proteinuria (n = 1), hematuria (n = 1), upper gastrointestinal hemorrhage (n = 1), vomiting (n = 2), abdominal pain (n = 1), and hypokalemia (n = 1).

If you experience any side effects, talk to your doctor or pharmacist or write to drugsafety@cipla.com. You can also report side effects directly via the national pharmacovigilance program of India by calling on 1800 180 3024 or you can report to Cipla Ltd. on 18002677779.

By reporting side effects, you can help provide more information on the safety of this product.

Overdose

Cases of overdose (2-3 times the prescribed dose for several weeks) have been reported. In one case, this resulted in hepatitis which resolved without long-term consequences after a dose interruption. In one pediatric case, a dose of 2-3 times the prescribed dose for six days, resulted in acute renal failure requiring hemofiltration and acute liver injury/failure, which were reversible with intensive care support. Single doses up to 80 mg per kg per day in iron overloaded β-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.

Pharmacological Properties

Mechanism of Action

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.

Pharmacodynamics

Pharmacodynamic effects tested in an iron balance metabolic study showed that deferasirox (10, 20 and 40 mg/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/kg per day). Iron excretion was predominantly fecal.

An analysis of pooled pediatric clinical trial data found a statistically significant relationship between exposure and the probability of renal toxicity (increase in serum creatinine and urinary protein), resulting in a decrease in renal function. Decreases in renal function resulted in an increase in deferasirox exposure, which may increase the probability of renal toxicity.

Cardiac Electrophysiology

At the maximum approved recommended dose, deferasirox does not prolong the QT interval to any clinically relevant extent.

Pharmacokinetics

Absorption

Deferasirox is absorbed following oral administration with median times to maximum plasma concentration (t_max) of about 1.5 to 4 hours. The C_max 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 to 2.3 after multiple doses. The absolute bioavailability (AUC) of deferasirox tablets 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 (t_1/2) ranged from 8 to 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).

Busulfan: Concomitant administration of deferasirox and busulfan resulted in an increase of busulfan exposure (AUC).

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 geriatric 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.

Hepatic Impairment

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.

Nonclinical Properties

Carcinogenesis, Mutagenesis, Impairment of Fertility

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 an mg/m²basis). 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 an mg/m²basis) in males and 300 mg per kg per day (1.21 times the MRHD on a mg/m²basis) 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 an mg/m²basis) was found to have no adverse effect on fertility and reproductive performance of male and female rats.

Description

DEFERASIROX is an iron chelating agent. DEFERASIROX tablets 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-1yl]-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 g/mol.

Pharmaceutical Particulars

Incompatibilities

Not Applicable

Shelf-life

As on the pack

Packaging Information

DESIROX – 250 mg …………Bottles of 30 tablets

DESIROX– 500 mg …………Bottles of 30 tablets

Storage and Handling Instructions

Store in a cool dry place away from moisture

Patient Counseling Information

Dosing Instructions

Advise patients to take DESIROX 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.

Blood Testing

Advise patients that blood tests will be performed frequently to check for damage to kidneys, liver, or blood cells

Gastrointestinal Ulceration and Hemorrhage

Caution patients about the potential for the development of GI ulcers or bleeding when taking DESIROX in combination with drugs that have ulcerogenic or hemorrhagic potential, such as NSAIDs, corticosteroids, oral bisphosphonates, or anticoagulants. Advise patients to contact their health care provider for signs and symptoms of gastrointestinal ulceration and hemorrhage

Allergic Reactions

Serious allergic reactions (which include swelling of the throat) have been reported in patients taking DESIROX, usually within the first month of treatment. If reactions are severe, advise patients to stop taking DESIROX and contact their doctor immediately

Skin Rash

Skin rashes may occur during DESIROX treatment and if severe, interrupt treatment and seek medical attention

Pediatric Patients with Acute Illness

Instruct pediatric patients and their caregivers to contact their healthcare provider during episodes of acute illness, especially if the patient has not been drinking fluids or the patient has volume depletion due to fever, vomiting, or diarrhea

Auditory and Ocular Testing

Because auditory and ocular disturbances have been reported with DESIROX, conduct auditory testing and ophthalmic testing before starting DESIROX treatment and thereafter at regular intervals Advise patients to contact their healthcare provider if they develop visual or auditory changes during treatment

Drug Interactions

Caution patients not to take aluminum-containing antacids and DESIROX simultaneously
Caution patients about potential loss of effectiveness of drugs metabolized by CYP3A4 (e.g., cyclosporine, simvastatin, hormonal contraceptive agents) when DESIROX administered with these drugs
Caution patients about potential loss of effectiveness of DESIROX 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 DESIROX when concomitantly used with potent UGT inducers
Caution patients about potential loss of effectiveness of DESIROX 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 DESIROX when concomitantly used with bile acid sequestrants

Caution patients with diabetes to monitor their glucose levels more frequently when repaglinide is used concomitantly with DESIROX

Medication Guide

What is the most important information I should know about DESIROX?

DESIROX can cause serious side effects, including:

Kidney problems

DESIROX can cause sudden (acute) kidney problems, including kidney failure that may require treatment with dialysis, and may cause death. Deaths have happened mostly in people who also have other health problems and had a blood disorder that was in an advanced stage. Adults and children who already have kidney problems and are taking certain medicines with DESIROX, may also have an increased risk of sudden kidney problems.

Be sure to tell your healthcare provider about all the medicines you take during treatment with DESIROX.

Your healthcare provider should do blood and urine tests to check your or your child’s kidney function before and during treatment with DESIROX. Call your or your child’s healthcare provider right away if:

your child becomes sick with fever, vomiting, or diarrhea and cannot drink fluids normally during treatment with DESIROX. Your child may be dehydrated. Your child’s healthcare provider may need to temporarily stop treatment with DESIROX and treat your child for dehydration to help prevent kidney problems. Your child’s healthcare provider may monitor your child’s kidney function more closely.
you notice that you or your child are passing less urine than usual during treatment with DESIROX.

Liver problems

DESIROX can cause liver problems, including liver failure that can sometimes cause death. Liver problems with DESIROX may be more common in people who are over 55 years of age but can also happen in children.

Liver failure has happened more often in people with cirrhosis of the liver and failure of other organs. Liver failure has also happened along with kidney problems in certain children who become dehydrated.

Your healthcare provider should do blood tests to check your liver function before you start and regularly during treatment with DESIROX, Call your healthcare provider right away, if you develop any of the following signs and symptoms:

drowsiness
upper right stomach-area (abdomen) pain
yellowing or increased yellowing of your skin or eyes,
dark urine

Bleeding, ulcers, and tears of the stomach or intestine

Severe stomach and intestine bleeding (hemorrhage) that have caused death have happened in some people treated with DESIROX, especially in elderly people who have advanced blood cancers or low platelet counts. Some people have also had ulcers of the stomach or intestine, sometimes with tears (perforation) that have caused death. In some people who have taken DESIROX, including children and adolescents, irritation of the upper gastrointestinal tract, ulcers, and bleeding have happened, but did not cause death.

Your risk of severe bleeding (hemorrhage) may be increased if you take DESIROX along with other medicines that can cause ulcers or bleeding, such as:

nonsteroidal anti-inflammatory drugs (NSAIDs)
corticosteroids
certain osteoporosis medicines called oral bisphosphonates
blood thinner medicines

Before you start taking DESIROX, tell your healthcare provider if you are taking one of these medicines. Ask your healthcare provider if you are not sure. If you develop an ulcer of the stomach or intestine, or severe bleeding, your healthcare provider may stop DESIROX.

Elderly people may be at a higher risk of developing serious side effects and death due to serious side effects with DESIROX. Your healthcare provider may need to monitor you more closely during treatment with DESIROX.

Tell your healthcare provider if you get heartburn during treatment with DESIROX.
Get emergency medical help right away if you vomit blood or pass black or bloody stools, or if you have severe stomach-area (abdomen) pain during treatment with DESIROX.

What is DESIROX?

DESIROX is a prescription medicine that is used to treat:

people 2 years of age and older who have an increased amount of iron in their blood for a long period of time (chronic), caused by repeated blood transfusions.

It is not known if DESIROX is safe and effective when used with other medicines to treat an increased amount of iron in the blood.

It is not known if DESIROX is safe and effective for treating children under 2 years of age who have an increased amount of iron in their blood for a long period of time (chronic) caused by repeated blood transfusions.

Do not take DESIROX if you:

have certain kidney problems
have high-risk myelodysplastic syndrome (MDS)
have advanced cancer
have a low platelet count
are allergic to DESIROX or any of the ingredients in DESIROX.

Ask your healthcare provider if you are not sure if you have any of the medical conditions listed above.

Before taking DESIROX, tell your healthcare provider about all of your medical conditions, including if you:

have kidney problems
have liver problems
have advanced cancer.
have a blood disorder that may increase your risk for bleeding
are pregnant or plan to become pregnant. It is not known if DESIROX can harm your unborn baby. Hormonal forms of birth control may not be as effective if used during treatment with DESIROX. You could become pregnant. Talk to your healthcare provider about other birth control options that you can use during this time. Tell your healthcare provider right away if you become pregnant during treatment with DESIROX.
are breastfeeding or plan to breastfeed. It is not known if DESIROX passes into your breast milk and can harm your baby. You and your healthcare provider should decide if you will take DESIROX or breastfeed. You should not do both.

Tell your healthcare provider about all the medicines you take, including prescription medicines, over-the-counter medicines, vitamins, and herbal supplements. Some medicines may affect how DESIROX works, and DESIROX may affect how other medicines work. Also, your risk of sudden kidney problems or severe bleeding may be increased if you take DESIROX with certain medicines

Avoid taking the following medicines during treatment with DESIROX:

antacid products (medicines used to treat heartburn) that contain aluminium
theophylline
certain medicines to lower your cholesterol, called bile acid sequestrants.

How should I take DESIROX?

Take DESIROX exactly as your healthcare provider tells you to.
Do not change your dose of DESIROX or stop taking it unless your healthcare provider tells you to.
Take DESIROX 1 time every day, preferably at the same time every day.
Take DESIROX on an empty stomach at least 30 minutes before eating food.
Do not to chew DESIROX tablets or swallow them whole.
Place the prescribed number of DESIROX tablets in a cup with water, orange juice, or apple juice. Stir to disperse the tablets in the liquid.

If your prescribed dose of DESIROX is less than 1 gram, use 3.5 ounces of liquid to disperse the tablets.
If your prescribed dose of DESIROX is 1 gram or more, use 7 ounces of liquid to disperse the tablets.

Completely disperse the tablets until it becomes a fine suspension, then drink the suspension right away.
Do not disperse DESIROX tablets in carbonated drinks or milk.
After drinking the suspension, add a small amount of water, orange juice, or apple juice to the cup to disperse any remaining medicine, and then drink it.
Do not take DESIROX with aluminum-containing antacid products.
Tell your healthcare provider if you or your child gain or lose any weight. Your or your child’s dose of DESIROX may need to be adjusted.
If you take the diabetes medicine repaglinide during treatment with DESIROX, you may need to test your blood sugar (glucose) levels more often. Follow your healthcare provider’s instructions about how often to test your blood sugar during this time.
Your healthcare provider should do blood and urine tests before, and during treatment to check how you respond to DESIROX, and to monitor you for side effects. Your healthcare provider may change your dose, temporarily or permanently stop DESIROX if you have certain side effects.
In people who have thalassemia, your healthcare provider will check the amount of iron in your liver before and during treatment with DESIROX.
If you or your child take too much DESIROX, call your healthcare provider right away or go to the nearest hospital emergency room.

What should I avoid while taking DESIROX?

DESIROX may cause dizziness. Avoid driving or operating machinery until you know how DESIROXaffects you. Do not drive or operate machinery if DESIROX makes you dizzy.

What are the possible side effects of DESIROX?

DESIROX can affect your bone marrow and cause you to have low white blood cell count which can be serious, decreased platelets, or worsening of your anemia, and may lead to death. Your risk for effects on your bone marrow may be increased if you already have other blood disorders. Your healthcare provider will do blood tests to monitor your blood cell counts for these problems.

Serious allergic reactions DESIROX may cause serious allergic reactions, which usually start within the first month of treatment. Get medical help right away if you develop any of the following symptoms of a serious allergic reaction including:

difficulty in breathing or swallowing
chest pain
rapid heartbeat
feeling faint
swelling of the face, lips, mouth, tongue or throat
severe itching of the skin with a red rash or raised bumps
hives

Skin rash and severe skin reactions Skin rashes are common with DESIROX. If you get a more severe rash, your healthcare provider may temporarily stop DESIROX

Severe skin reactions can also happen with DESIROX and can be life-threatening or lead to death. Get medical help right away if you develop any one or more of the following signs and symptoms of a severe skin reaction, including:

rash or red skin
blisters on your lips, or around your mouth or eyes
mouth sores
skin peeling
high fever or flu-like symptoms
enlarged lymph nodes

Hearing and vision problems

DESIROXcan cause decreased hearing and changes in your vision including cataracts, increased pressure in your eye, and problems with your retinas. Your healthcare provider should do hearing and vision tests before you start and then regularly during treatment. Your healthcare provider may decrease your dose or stop DESIROX if you develop hearing or vision problems.

Tell your healthcare provider if you develop any changes in your vision or hearing during treatment with DESIROX.

The most common side effects in anyone who takes DESIROX include: diarrhea and nausea.

Other common side effects in people with too much iron in their blood due to repeated blood transfusions include: