The Labeling for Exjade (deferasirox) has Been Changed to Include Information about Postmarketing Reports of Hepatic Failure, Some with a Fatal Outcome

Exjade (deferasirox) Tablets For Oral Suspension

Audience: Oncologists, Hematology-Oncologists, Pediatric Hematologists, Specialty Pharmacists

[UPDATE 12/13/2007]

ROCKVILLE, Md., Dec. 13, 2007--Novartis informed healthcare professionals of changes made to the WARNINGS, ADVERSE REACTIONS, and DOSAGE and ADMINISTRATION sections of prescribing information for Exjade Tablets for Oral Suspension. The WARNINGS and ADVERSE REACTIONS sections of the labeling were revised to include information about postmarketing reports of hepatic failure, some with a fatal outcome, in patients treated with Exjade. Most of these events occurred in patients greater than 55 years of age. Most reports of hepatic failure involved patients with significant comorbidities, including liver cirrhosis and multi-organ failure.

[Posted 05/22/2007] Novartis and FDA notified healthcare professionals of changes to the WARNINGS and ADVERSE REACTIONS sections of the product labeling for Exjade, a drug used to treat chronic iron overload due to blood transfusions (transfusional hemosiderosis) in patients 2 years of age and older. Cases of acute renal failure, some with a fatal outcome, have been reported following the post marketing use of Exjade. Most of the fatalities occurred in patients with multiple co-morbidities and who were in advanced stages of their hematological disorders. Additionally, there were post marketing reports of cytopenias, including agranulocytosis, neutropenia and thrombocytopenia in patients treated with Exjade where some of the patients died. The relationship of these episodes to treatment with Exjade is uncertain. Most of these patients had preexisting hematologic disorders that are frequently associated with bone marrow failure. Further, cases of leukocytoclastic vasculitis, urticaria, and hypersensitivity reactions (including anaphylaxis and angioedema) were reported.

Healthcare professionals should monitor serum creatinine in patients who are at increased risk of complications, having preexisting renal conditions, are elderly, have co-morbid conditions, or are receiving medicinal products that depress renal function. Blood counts should also be monitored regularly and treatment should be interrupted in patients who develop unexplained cytopenia.

Important Information about Exjade® (deferasirox)

Tablets for Oral Suspension

IMPORTANT DRUG WARNING

DATE: December 12, 2007

Dear Healthcare Provider (or Doctor):

Novartis would like to inform you of changes made to the WARNINGS, ADVERSE REACTIONS, and DOSAGE AND ADMINISTRATION sections of the Exjade® (deferasirox) Tablets for Oral Suspension prescribing information.

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

Further studies are being performed to determine the long-term benefits and risks of Exjade.

As Novartis is committed to providing you with up-to-date information regarding Exjade, this letter provides additional context to information that you may have received via the mailed prescribing information update card, at meetings, in discussions with your Exjade sales specialist or the FDA Drug Safety Newsletter (Volume 1, Issue 1, Fall 2007). This letter reiterates changes to the prescribing information.

In the U.S. Package Insert for Exjade, the WARNINGS: “Hepatic” section heading has been changed to “Hepatic Dysfunction and Failure.” The following information has been added to this section to provide greater clarification and context to the label update from April 2007 regarding postmarketing reports of hepatic dysfunction. This information has also been added to the

ADVERSE REACTIONS: Postmarketing Experience section.

There have been postmarketing reports of hepatic failure, some with a fatal outcome, in patients treated with Exjade. Most of these events occurred in patients greater than 55 years of age. Most reports of hepatic failure involved patients with significant comorbidities, including liver cirrhosis and multi-organ failure.

In addition, the WARNINGS: Hepatic Dysfunction and Failure section has been updated to consider dose interruption for severe or persistent elevations in liver function tests.

The following information has been added to the DOSAGE AND ADMINISTRATION section:

The decision to remove accumulated iron should be individualized based on anticipated clinical benefit and risks of Exjade therapy.

Novartis hopes these updates will be beneficial for appropriate treatment and management of patients with Exjade.

Important safety information

EXJADE is contraindicated in patients with hypersensitivity to deferasirox or to any other component of EXJADE.

Cases of acute renal failure, some with a fatal outcome, have been reported following the postmarketing use of EXJADE. Most of the fatalities occurred in patients with multiple comorbidities and who were in advanced stages of their hematologic disorders. Particular attention should be given to monitoring serum creatinine in patients who are at increased risk of complications, have pre-existing renal conditions, are elderly, have comorbid conditions, or are receiving medicinal products that depress renal function.

Serum creatinine should be assessed in duplicate before initiating therapy to establish a reliable pretreatment baseline, due to variations in measurements. Serum creatinine should be monitored monthly thereafter. Patients with additional renal risk factors (those who are at increased risk of complications, have pre-existing renal conditions, are elderly, have comorbid conditions, or are receiving medicinal products that depress renal function) should be monitored weekly during the first month after initiation or modification of therapy, and monthly thereafter. Nonprogressive increases in serum creatinine have been noted in 38% of EXJADE-treated patients, compared to 14% of deferoxamine-treated patients, and appear to be dose related. These increases were within the normal range in 94% of patients. EXJADE dosages were adjusted when serum creatinine elevations were detected during the study.

Dose reduction, interruption, or discontinuation should be considered for elevations in serum creatinine. If there is a progressive increase in serum creatinine beyond the age-appropriate upper limit of normal, EXJADE should be interrupted. Once the creatinine has returned to within the normal range, therapy with EXJADE may be reinitiated at a lower dose followed by gradual dose escalation, if the clinical benefit is expected to outweigh potential risks.

Intermittent proteinuria (urine protein/creatinine ratio >0.6 mg/mg) occurred in 18.6% of EXJADE-treated patients, compared to 7.2% of deferoxamine-treated patients in Study 1, and monthly monitoring is recommended.

There have been postmarketing reports of cytopenias (including agranulocytosis, neutropenia and thrombocytopenia) in patients treated with EXJADE. Some of these patients died. The relationship of these episodes to treatment with EXJADE is uncertain. Most of these patients had pre-existing hematologic disorders that are frequently associated with bone marrow failure. In line with standard clinical management, blood counts should be monitored regularly and dose interruption considered in patients who develop unexplained cytopenia. Reintroduction of therapy with EXJADE may be considered once the cause of the cytopenia has been elucidated.

There have been postmarketing reports of hepatic failure, some with a fatal outcome, in patients treated with Exjade. Most of these events occurred in patients greater than 55 years of age. Most reports of hepatic failure involved patients with significant comorbidities, including liver cirrhosis and multi-organ failure. Liver function should be monitored monthly, and if there is an unexplained, persistent, or progressive increase in serum transaminase levels, treatment with EXJADE should be modified or interrupted. In Study 1, seventeen (5.7%) patients treated with EXJADE developed elevations in SGPT/ALT levels >5 times the upper limit of normal at 2 consecutive visits versus five (1.7%) patients treated with deferoxamine.

Serious hypersensitivity reactions (such as anaphylaxis and angioedema) have been reported in patients receiving EXJADE, with the onset of the reaction occurring in the majority of cases within the first month of treatment. If reactions are severe, EXJADE should be discontinued and appropriate medical intervention instituted.

Leukocytoclastic vasculitis and urticaria have been spontaneously reported during the post-approval use of EXJADE.

Auditory (high-frequency hearing loss, decreased hearing) and ocular (lens opacities, cataracts, elevations in intraocular pressure, and retinal disorders) disturbances have been reported with EXJADE therapy in less than 1% of patients in clinical trials. Auditory and ophthalmic testing (including slit lamp examinations and dilated fundoscopy) are recommended before the start of EXJADE treatment and thereafter at regular intervals (every 12 months). If disturbances are noted, dose reduction or interruption should be considered. Skin rashes may occur during treatment with EXJADE. For rashes of mild to moderate severity, EXJADE may be continued without dose adjustment, since the rash often resolves spontaneously.

For more severe rashes where interruption of treatment may be necessary, EXJADE may be reintroduced at a lower dose and gradually escalated after resolution of the rash. Reintroduction of EXJADE at a lower dose with escalation may be considered in combination with a short period of oral steroid administration.

The most frequently occurring adverse events with EXJADE included diarrhea, vomiting, nausea, headache, abdominal pain, pyrexia, cough, and increases in serum creatinine. Maintenance of adequate hydration for patients experiencing diarrhea or vomiting is recommended. Gastrointestinal symptoms, increases in serum creatinine, and skin rash were dose related. These commonly reported adverse events were predominantly mild to moderate in severity with serious adverse events reported in 9.1% of patients in the EXJADE arm and 8.6% of patients in the deferoxamine arm.

Healthcare professionals should report all serious adverse events suspected to be associated with the use of Exjade® to Novartis Pharmaceuticals Corporation, One Health Plaza, East Hanover NJ 07936 or by phone (888-NOW NOVARTIS or 888 669 6682) or the internet at http://www.novartis.com

The Medical Community can further our understanding of adverse events by reporting all cases to the Agency via the MedWatch program by phone at 1-800- FDA-1088, by fax at 1-800-FDA- 0178, via the MedWatch website at www.fda.gov/medwatch or by mail:

MEDWATCH
Food and Drug Administration
5600 Fishers Lane
Rockville
MD 20852-9787

Please see the enclosed revised Package Insert for the complete prescribing information for Exjade® (deferasirox) Tablets for Oral Suspension.

Please contact Novartis Oncology Medical Information, Communication and Education at 1-888-669-6682 if you have further questions.

Sincerely,

John A. Hohneker, MD
Senior Vice President, US Clinical Development and Medical Affairs- Oncology
One Health Plaza
East Hanover, NJ 07936

Posted: December 2007


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