Jadenu Special Precautions

See Warnings.
General: The decision to remove accumulated iron should be individualized based on anticipated clinical benefits and risks of chelation therapy (see Dosage & Administration).
The safety of JADENU when administered with other iron chelation therapy has not been established.
No studies on the effects of deferasirox on the ability to drive or use machines have been performed. Patients experiencing dizziness should exercise caution when driving or operating machinery.
Carcinogenesis and Mutagenesis: See Pharmacology: Toxicology: Non-Clinical Toxicology: Mutagenicity and Carcinogenicity under Actions.
Cardiovascular: Deferasirox has not been studied in patients with acute cardiac failure due to iron overload. Therefore, the use of JADENU is not recommended in these patients.
Ear/Nose/Throat: Auditory disturbances (high-frequency hearing loss, decreased hearing) have been reported with deferasirox therapy (see Adverse Reactions). Auditory testing is recommended before the start of JADENU treatment and thereafter at regular intervals.
The frequency of auditory adverse events irrespective of causality was increased among pediatric patients, who received deferasirox dispersible tablets doses greater than 25 mg/kg/day equivalent to 17.5 mg/kg/day JADENU when serum ferritin was less than 1,000 mcg/L (patients received high doses despite body iron burden being in the target range or consistently below the target range which is not recommended; see Dosage & Administration).
Gastrointestinal: Gastrointestinal irritation may occur during JADENU treatment. Upper gastrointestinal (GI) ulceration and haemorrhage and upper and lower GI perforations have been reported uncommonly in patients, including children and adolescents, receiving deferasirox. There have been rare reports of fatal GI haemorrhages and perforations. Fatal haemorrhages have been reported more frequently in elderly patients who had advanced hematologic malignancies and/or low platelet counts. Multiple ulcers have been observed in some patients and there have been reports of ulcers complicated with gastrointestinal perforation (see Adverse Reactions). Physicians and patients should remain alert for signs and symptoms of GI ulceration, perforation and haemorrhage during JADENU therapy and promptly initiate additional evaluation and treatment if a serious GI adverse event is suspected.
Caution should be exercised in patients who are taking JADENU in combination with drugs that have known ulcerogenic potential, such as NSAIDs, corticosteroids, or oral bisphosphonates, and in patients receiving anticoagulants (see Interactions).
Hematologic: There have been post-marketing reports (both spontaneous and from clinical trials) of cytopenias in patients treated with deferasirox. Most of these patients had preexisting hematologic disorders that are frequently associated with bone marrow failure (see Post-Market Adverse Reactions under Adverse Reactions). The relationship of these episodes to treatment with deferasirox is unknown. In line with the standard clinical management of such hematological disorders, complete blood count (CBC) should be available at baseline and blood counts should be monitored regularly during therapy. Dose interruption of treatment with JADENU should be considered in patients who develop unexplained cytopenia. Reintroduction of therapy with JADENU may be considered, once the cause of the cytopenia has been elucidated.
Hepatic/Biliary/Pancreatic: JADENU is not recommended in patients with severe hepatic impairment (Child-Pugh C) (see Dosing Considerations under Dosage & Administration and Pharmacology: Pharmacokinetics: Special Populations and Conditions under Actions). Elevations of serum transaminase levels (greater than 5 times the upper limit of normal) have been observed in 40 patients (6.1%; 40/652) receiving deferasirox in the context of 4 registration studies. In these patients, the transaminase levels were already >5*ULN at baseline in 6 of the 40 patients. In 25 of the 40 patients, the transaminase levels at baseline were above the upper limit of normal but less than 5*ULN.
Although uncommon (0.3%), elevations of transaminases greater than 10 times the upper limit of the normal range, suggestive of hepatitis, have been observed in clinical trials.
In a 5 year pediatric observational study, single events of elevations in ALT and AST suspected to be related to deferasirox were reported in 21.1% and 11.9%, respectively. Approximately 12% of patients on study required a dose reduction or interruption of deferasirox to manage the increase in transaminases and 2.7% of patients discontinued treatment.
There have been post-marketing reports of hepatic failure in patients treated with deferasirox. There are a total of 24 international reports of hepatic failure - 21 post-marketing reports and 3 reports from clinical studies. Two of the 24 cases were reported in Canada. Most reports of hepatic failure involved patients with significant comorbidities including liver cirrhosis and multi-organ failure; fatal outcomes were reported in some of these patients. As of the cut-off date previously mentioned, no patient with normal baseline liver function or without additional life-threatening complications of their underlying disease has developed hepatic failure.
It is recommended that serum transaminases, bilirubin and alkaline phosphatase be monitored before the initiation of treatment, every 2 weeks during the first month and monthly thereafter. If there is an unexplained, persistent and progressive increase in serum transaminase levels, JADENU treatment should be interrupted.
Acute liver injury and failure, including fatal outcomes, have occurred in pediatric deferasirox- treated patients. Liver failure occurred in association with acute kidney injury in pediatric patients at risk for over chelation during a volume depleting event. Interrupt JADENU 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 JADENU in the 14-28 mg/kg/day range and when iron burden is approaching normal. Use the minimum effective dose to achieve and maintain a low iron burden (see Dosage & Administration).
In the clinical trial and post-marketing settings, cases of serious acute pancreatitis were observed with and without documented underlying biliary conditions. A causal association to deferasirox could not be ruled out.
Immune: Rare cases of serious hypersensitivity reactions (such as anaphylaxis and angioedema) have been reported in patients receiving deferasirox, with the onset of the reaction occurring in the majority of cases within the first month of treatment (see Post-Market Adverse Reactions under Adverse Reactions). If hypersensitivity reactions occur, JADENU should be discontinued and appropriate medical intervention instituted. JADENU should not be reintroduced in patients who have experienced previous hypersensitivity reactions on deferasirox due to the risk of anaphylactic shock.
Monitoring and Laboratory Tests: Monitor renal function more frequently in patients with pre-existing renal disease or decreased renal function. Monitor liver and renal function more frequently during volume depletion and in patients receiving JADENU in the 14-28 mg/kg/day range when iron burden is approaching the normal range (see Dosage & Administration).
Serum Ferritin: Serum ferritin should be measured monthly to assess response to therapy and to evaluate for the possibility of overchelation of iron, although the correlation coefficient between serum ferritin and liver iron content (LIC) was 0.63, and changes in serum ferritin levels may not always reliably reflect changes in LIC. If the serum ferritin falls consistently below 500 mcg/L, temporary interruption of JADENU therapy should be considered (see Dosage & Administration). Closer monitoring of serum ferritin levels, as well as renal and hepatic function is recommended during periods of treatment with high doses and when serum ferritin levels are close to the target range. Dose reduction may be considered to avoid overchelation.
As with other iron chelator treatment, the risk of toxicity of JADENU may be increased when inappropriately given to patients with a low iron burden or with serum ferritin levels that are only slightly elevated (see Dosage & Administration).
Renal: Evaluate renal glomerular and tubular function before initiating therapy or increasing the dose and during therapy. It is recommended that serum creatinine and creatinine clearance be assessed twice before initiating therapy. Weekly monitoring of serum creatinine and creatinine clearance is recommended in the first month after initiation or modification of therapy, and monthly thereafter. Tests for proteinuria should be performed monthly (see Renal as follows).
Hepatic: It is recommended that serum transaminases, bilirubin and alkaline phosphatase be monitored before the initiation of treatment, every 2 weeks during the first month and monthly thereafter (see Hepatic/Biliary/Pancreatic as previously mentioned).
Hematologic: In line with the standard clinical management of such hematological disorders, complete blood count (CBC) should be available at baseline and blood counts should be monitored regularly during therapy. Dose interruption of treatment with JADENU should be considered in patients who develop unexplained cytopenia. Reintroduction of therapy with JADENU may be considered, once the cause of the cytopenia has been elucidated (see Hematologic as previously mentioned).
Auditory: Auditory disturbances (high-frequency hearing loss, decreased hearing) have been reported with JADENU therapy (see Adverse Reactions).
Auditory testing is recommended before the start of JADENU treatment and thereafter at regular intervals.
Ophthalmologic: Ocular disturbances (lens opacities, early cataracts, maculopathies) have been reported with JADENU therapy (see Adverse Reactions). Ophthalmic testing (including fundoscopy) is recommended before the start of JADENU treatment and thereafter at regular intervals.
Ophthalmologic: Ocular disturbances (lens opacities, early cataracts, maculopathies) have been reported with deferasirox therapy (see Adverse Reactions). Ophthalmic testing (including fundoscopy) is recommended before the start of JADENU treatment and thereafter at regular intervals.
Renal: Deferasirox has not been studied in patients with renal impairment. Deferasirox treatment has been initiated only in patients with serum creatinine within the age-appropriate normal range and therefore must be used with caution in patients with elevated serum creatinine levels (see Contraindications).
Deferasirox-treated patients experienced dose-dependent increases in serum creatinine. Increases in creatinine that were >33% at ≥2 consecutive post baseline visits occurred at a greater frequency in deferasirox-treated patients compared to deferoxamine-treated patients (38% vs. 14%, respectively) in study 0107. In these beta-thalassemia patients, 94% of the creatinine elevations remained within the normal range. Under the dose adjustment instructions, dose reduction was required in one third of patients showing serum creatinine increase. In most patients undergoing dose reductions serum creatinine levels did not return to baseline; in 60% of patients undergoing dose reduction, serum creatinine remained elevated at >33% without progression (see Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data under Adverse Reactions).
JADENU can cause acute kidney injury. Pre-existing renal disease and concomitant use of other nephrotoxic drugs may increase the risk of acute kidney injury in adult and pediatric patients. An analysis of pediatric patients treated with deferasirox dispersible tablets in pooled clinical trials (n=158) found a higher rate of renal adverse events among patients receiving doses greater than 25 mg/kg/day, equivalent to 17.5 mg/kg/day JADENU, while their serum ferritin values were less than 1,000 mcg/L (patients received high doses despite body iron burden being in the target range or consistently below the target range which is not recommended; (see Dosage & Administration). The risk of toxicity of JADENU may be increased when inappropriately high doses are given in patients with a low iron burden or with serum ferritin levels that are only slightly elevated. Use the minimum dose to establish and maintain a low iron burden (see Dosage & Administration). 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 estimated glomerular filtration rate (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.
Cases of acute renal failure (some with fatal outcome) have been reported following the post-marketing use of deferasirox. There have been rare cases of acute renal failure requiring dialysis. For the fatal cases, it is impossible to completely exclude a contributory role of deferasirox to the renal impairment, although the fatalities in these critically ill patients could be attributable to other underlying diseases. The fact that there was an improvement after stopping the treatment in most of the cases with non-fatal acute renal failure is suggestive of a contributory role of deferasirox to these cases (see Post-Market Adverse Reactions under Adverse Reactions).
Evaluate renal glomerular and tubular function before initiating therapy or increasing the dose and during therapy. It is recommended that serum creatinine and creatinine clearance be assessed twice before initiating therapy. Weekly monitoring of serum creatinine and creatinine clearance is recommended in the first month after initiation or modification of therapy, and monthly thereafter. Patients with pre-existing renal conditions or patients who are receiving medicinal products that may depress renal function may be more at risk of complications. Care should be taken to maintain adequate hydration in patients (see Dosing Considerations under Dosage & Administration). In pediatric patients, interrupt JADENU 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. Dose reduction, interruption, or discontinuations should be considered for elevations in serum creatinine (see Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data under Adverse Reactions).
Renal tubulopathy has been reported in patients treated with deferasirox. The majority of these patients were children and adolescents with beta-thalassemia and serum ferritin levels <1,500 mcg/L.
Tests for proteinuria should be performed monthly. As needed, additional markers of renal tubular function (e.g. glycosuria in non-diabetics and low levels of serum potassium, phosphate, magnesium or urate, phosphaturia, aminoaciduria) may also be monitored. Dose reduction or interruption may be considered if there are abnormalities in levels of tubular markers and/or if clinically indicated.
If there is a progressive increase in serum creatinine beyond the upper limit of normal, JADENU should be interrupted (see Dosage & Administration).
Skin: Serious skin reactions: Severe cutaneous adverse reactions (SCARs), including cases of Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and hypersensitivity vasculitis, as well as drug reaction with eosinophilia and systemic symptoms (DRESS) which could be life-threatening or fatal, and rare cases of erythema multiforme, have occurred during treatment with deferasirox. Patients should be advised of the signs and symptoms of severe skin reactions and be closely monitored. Upon suspicion of any SCAR, JADENU should be discontinued immediately and should not be reintroduced.
Skin rashes: skin rashes may also appear during JADENU treatment. For rashes of mild to moderate severity, JADENU may be continued without dose adjustment, since the rash often resolves spontaneously. For more severe rash, where interruption of treatment may be necessary, JADENU may be re-introduced after resolution of the rash, at a lower dose followed by gradual dose escalation.
Use in Children (2 to 16 years of age): There are limited data on the safety and effectiveness of deferasirox in pediatric patients aged 2 to 5 (see Pharmacology: Pharmacodynamics: Clinical Trials under Actions). Deferasirox has not been associated with growth retardation in children followed for up to 5 years in clinical studies. However, as a precautionary measure, body weight and longitudinal growth in pediatric patients should be monitored at regular intervals (every 12 months), see Pediatrics under Indications/Uses.
In a 5-year observational study in which 267 children aged 2 to <6 years (at enrollment) with transfusional hemosiderosis received deferasirox, there were no unexpected safety findings observed regarding adverse events or laboratory abnormalities with the exception of an increase in single events of elevated transaminases suspected to be related to deferasirox: 21.1% and 11.9% of pediatric patients had elevated alanine aminotransferase (ALT) and aspartate aminotransferase, respectively. Within the range of the known safety profile, increases in serum creatinine of >33% and above the upper limit of normal (ULN) on ≥2 consecutive occasions were observed in 3.1% of children and elevation of ALT greater than 5 times the ULN on ≥2 consecutive occasions was reported in 4.3% of children.
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).
An analysis of pediatric patients treated with deferasirox dispersible tablets in pooled clinical trials (n=158) found a higher rate of renal adverse events among patients receiving doses greater than 25 mg/kg/day, equivalent to 17.5 mg/kg/day JADENU, while their serum ferritin values were less than 1,000 mcg/L (patients received high doses despite body iron burden being in the target range or consistently below the target range which is not recommended; see Dosage & Administration).
JADENU 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 dispersible tablets doses in the 20-40 mg/kg/day range, equivalent to 14-28 mg/kg/day JADENU, when body iron burden was approaching or in the normal range (patients received high doses despite body iron burden being in the target range or consistently below the target range which is not recommended; see Dosage & Administration).
Monitor renal and liver function more frequently in pediatric patients in the presence of renal toxicity risk factors, including episodes of dehydration, fever and acute illness that may result in volume depletion or decreased renal perfusion. Use the minimum effective dose.
Interrupt JADENU in pediatric patients with transfusional iron overload and consider dose interruption in pediatric patients with non-transfusion-dependent iron overload, 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.
Evaluate the risk benefit profile of continued JADENU use in the setting of decreased renal function. Avoid use of other nephrotoxic drugs.
Use in the Elderly (≥65 years of age): Four hundred and thirty-one (431) patients ≥65 years of age have been studied in clinical trials of deferasirox. The majority of these patients had myelodysplastic syndrome (MDS, n=393; β-thalassemia, n=2; other anemias, n=36). In general, caution should be used in elderly patients due to the greater frequency of decreased hepatic, renal, or cardiac function, concomitant disease or other drug therapy. In clinical trials, elderly patients experienced a higher frequency of adverse reactions than younger patients and should be monitored closely for adverse reactions that may require a dose adjustment, see Geriatrics under Indications/Uses.