Zelmac safety database

11,000 healthy volunteers or patients exposed to Zelmac*

– maximum daily dose up to 200 mg in healthy volunteers

*Prior to marketing approval Novartis, data on file

2,690 patients treated for at least 85 days*

302 IBS patients treated for at least 335 days*

No clinically relevant abnormalities in clinical chemistry, hematology or biochemistry

Adverse events (≥0.5%) leading to discontinuation in phase III studies

Patients (%)

EventsPlacebo(n=1,589)

Zelmac all doses(n=2,446)

Total 5.2 7.0

Diarrhea 0.3 1.6

Abdominal pain 1.3 1.6

Nausea 0.8 0.4

Flatulence 0.6 0.8

Headache 0.8 1.0

Dizziness 0.6 0.7

Reproductive disorders 0.6 0.7

Other 0.2 0.2

Pooled data Studies 1, 2 and 3 Novartis, data on file

Cardiac safety assessment

>10,000 ECG tracings made in Zelmac clinical studies1

1Novartis, data on file2Morganroth et al. 2002

QTc interval and other ECG changes similar in Zelmac and placebo groups2

Data confirm pre-clinical findings that at therapeutic doses, Zelmac is devoid of ECG effects2

FDA has found out that Zelmac causes Ischemic Colitis and severe diarrhea

Doctor received the medscape update on the 24th of April 2004

FDA asked for a revision in the label of Zelnorm (US) for the following

1. Addition of a new warning:– "Serious consequences of diarrhea, including

hypovolemia, hypotension and syncope have been reported in the clinical studies and during marketed use of Zelmac.

– In some cases, these complications have required hospitalization for rehydration

– Zelmac should not be initiated in patients who are currently experiencing or frequently experience diarrhea

– (this is what we are clearly stating on our promotion)

ON IC…

Zelmac should be discontinued immediately in patients who develop symptoms of ischemic colitis:

such as :• rectal bleeding• bloody diarrhea • new or worsening abdominal pain

Patients developing these symptoms should be evaluated promptly and have appropriate diagnostic testing performed.

ON IC…

Zelmac should be discontinued immediately in patients who develop symptoms of ischemic colitis:

such as :• rectal bleeding• bloody diarrhea • new or worsening abdominal pain

Patients developing these symptoms should be evaluated promptly and have appropriate diagnostic testing performed.