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Zelnorm ® (tegaserod) Division of Gastrointestinal and Coagulation Drug Products Division of Drug Risk Evaluation Gary Della’Zanna, D.O., M.Sc., F.A.C.O.S.

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Presentation on theme: "Zelnorm ® (tegaserod) Division of Gastrointestinal and Coagulation Drug Products Division of Drug Risk Evaluation Gary Della’Zanna, D.O., M.Sc., F.A.C.O.S."— Presentation transcript:

1 Zelnorm ® (tegaserod) Division of Gastrointestinal and Coagulation Drug Products Division of Drug Risk Evaluation Gary Della’Zanna, D.O., M.Sc., F.A.C.O.S Ann Corken Mackey, Ann Corken Mackey, R.Ph., M.P.H. Allen Brinker, M.D., M.S. July 14, 2004 Division of Gastrointestinal and Coagulation Drug Products Division of Drug Risk Evaluation Gary Della’Zanna, D.O., M.Sc., F.A.C.O.S Ann Corken Mackey, Ann Corken Mackey, R.Ph., M.P.H. Allen Brinker, M.D., M.S. July 14, 2004 Center for Drug Evaluation and Research

2 Gastrointestinal Drugs Advisory Committee Meeting July 14, 2004 2OverviewOverview Current Safety Issues Serious Consequences of Diarrhea hypotension syncope Abdominal and Pelvic Surgery Ischemic Colitis / Intestinal Ischemia Current Safety Issues Serious Consequences of Diarrhea hypotension syncope Abdominal and Pelvic Surgery Ischemic Colitis / Intestinal Ischemia

3 Gastrointestinal Drugs Advisory Committee Meeting July 14, 2004 3 Zelnorm ® (tegaserod) 5-HT 4 partial agonist Moderate 5-HT 1 receptor affinity Approved C-IBS dose: 6 mg BID Chronic Constipation dose: 6 mg BID 5-HT 4 partial agonist Moderate 5-HT 1 receptor affinity Approved C-IBS dose: 6 mg BID Chronic Constipation dose: 6 mg BID

4 Gastrointestinal Drugs Advisory Committee Meeting July 14, 2004 4 Post Marketing Experience April 27, 2004 Label Revision & Dear Doctor Letter WARNINGS Section: Serious Consequences of Diarrhea hypovolemia hypotension syncope PRECAUTIONS Section: Ischemic Colitis / Intestinal Ischemia Label Revision & Dear Doctor Letter WARNINGS Section: Serious Consequences of Diarrhea hypovolemia hypotension syncope PRECAUTIONS Section: Ischemic Colitis / Intestinal Ischemia

5 Gastrointestinal Drugs Advisory Committee Meeting July 14, 2004 5 Chronic Constipation Trials Similar AE Profile to C-IBS Trials

6 Gastrointestinal Drugs Advisory Committee Meeting July 14, 2004 6 Chronic Constipation Trials

7 Gastrointestinal Drugs Advisory Committee Meeting July 14, 2004 7 Zelnorm ® Safety Profile Post Marketing –MedWatch Program Clinical Trials –Chronic Constipation Trials –C-IBS Trials –Other GI Studies Post Marketing –MedWatch Program Clinical Trials –Chronic Constipation Trials –C-IBS Trials –Other GI Studies

8 Gastrointestinal Drugs Advisory Committee Meeting July 14, 2004 8 Post Marketing Serious Consequences of Diarrhea (n=22) Females (n=20) Males (n=2) –Range: 24 to 82 years –Mean Age: 56 years –Time to onset: 1 to 210 days –Hospitalized (n=15) –Described as Life Threatening (n=3) Dehydration (n=12) Abdominal pain (n=8) Hypotension(n=3) Electrolyte disorder(n=3) Shock(n=2) (Adverse Events not mutually exclusive) Females (n=20) Males (n=2) –Range: 24 to 82 years –Mean Age: 56 years –Time to onset: 1 to 210 days –Hospitalized (n=15) –Described as Life Threatening (n=3) Dehydration (n=12) Abdominal pain (n=8) Hypotension(n=3) Electrolyte disorder(n=3) Shock(n=2) (Adverse Events not mutually exclusive)

9 Gastrointestinal Drugs Advisory Committee Meeting July 14, 2004 9 Chronic Constipation Trials Diarrhea

10 Gastrointestinal Drugs Advisory Committee Meeting July 14, 2004 10 Chronic Constipation Trials Diarrhea

11 Gastrointestinal Drugs Advisory Committee Meeting July 14, 2004 11 Chronic Constipation Trials Diarrhea

12 Gastrointestinal Drugs Advisory Committee Meeting July 14, 2004 12 Post Marketing Hypotension 15 cases: Multiple confounding factors Case: PHEH2003US08259 45 y/o female No PMH of hyper/hypotension, BP:138/80 prior to Zelnorm BP:75/60 after Zelnorm (2 weeks) 15 cases: Multiple confounding factors Case: PHEH2003US08259 45 y/o female No PMH of hyper/hypotension, BP:138/80 prior to Zelnorm BP:75/60 after Zelnorm (2 weeks)

13 Gastrointestinal Drugs Advisory Committee Meeting July 14, 2004 13 Chronic Constipation Trials Hypotension Orthostatic Hypotension –Zelnorm 6mg BID11% –Zelnorm 2mg BID15% –Placebo12% Severe Diarrhea  Hypotension Orthostatic Hypotension –Zelnorm 6mg BID11% –Zelnorm 2mg BID15% –Placebo12% Severe Diarrhea  Hypotension

14 Gastrointestinal Drugs Advisory Committee Meeting July 14, 2004 14 SyncopeSyncope Post Marketing: 8 cases Multiple confounding factors Chronic Constipation Trials: 4 cases Zelnorm 6 mg BID (n=2) Placebo(n=2) Post Marketing: 8 cases Multiple confounding factors Chronic Constipation Trials: 4 cases Zelnorm 6 mg BID (n=2) Placebo(n=2)

15 Gastrointestinal Drugs Advisory Committee Meeting July 14, 2004 15 Selected Abdominal and Pelvic Adverse Events (Original Approval)

16 Gastrointestinal Drugs Advisory Committee Meeting July 14, 2004 16 Selected Abdominal and Pelvic Adverse Events Post Marketing: AERS Not designed to track common surgeries Post Marketing: AERS Not designed to track common surgeries

17 Gastrointestinal Drugs Advisory Committee Meeting July 14, 2004 17 Cholecystectomy Completed Clinical Trials

18 Gastrointestinal Drugs Advisory Committee Meeting July 14, 2004 18 Post Marketing GI Ischemic Events  2 million Rx * –April 15, 2004 Cutoff : 24 cases –Ischemic Colitis (n=20) –Other Intestinal Ischemia (n=4) –April 16 thru June 1, 2004: 9 cases –Ischemic Colitis (n=7) –Other Intestinal Ischemia (n=2) * IMS Projected Data through April 30, 2004  2 million Rx * –April 15, 2004 Cutoff : 24 cases –Ischemic Colitis (n=20) –Other Intestinal Ischemia (n=4) –April 16 thru June 1, 2004: 9 cases –Ischemic Colitis (n=7) –Other Intestinal Ischemia (n=2) * IMS Projected Data through April 30, 2004

19 Gastrointestinal Drugs Advisory Committee Meeting July 14, 2004 19 Post Marketing Ischemic Colitis (n=20) Females (n=19) Males (n=1) –Range: 26 to 82 years –Mean Age: 55 years –Time to onset: 1 to 398 days Treatment: IBS (n=16) Constipation (n=2) Postoperative Ileus (n=1) Unknown (n=1) Females (n=19) Males (n=1) –Range: 26 to 82 years –Mean Age: 55 years –Time to onset: 1 to 398 days Treatment: IBS (n=16) Constipation (n=2) Postoperative Ileus (n=1) Unknown (n=1)

20 Gastrointestinal Drugs Advisory Committee Meeting July 14, 2004 20 Post Marketing Ischemic Colitis (n=20) Outcomes –Hospitalization (n=13) –Surgery (n=1) –Death (n=1) –Outpatient treatment (n=7) Outcomes –Hospitalization (n=13) –Surgery (n=1) –Death (n=1) –Outpatient treatment (n=7)

21 Gastrointestinal Drugs Advisory Committee Meeting July 14, 2004 21 Post Marketing No Documented Risk Factors

22 Gastrointestinal Drugs Advisory Committee Meeting July 14, 2004 22 Post Marketing Other Intestinal Ischemia (n=4) Females (n=4) Males (n=0) –Ages: 41, 61, 66, 67 years –Mean Age: 59 years –Time to onset: 6 to 105 days –Hospitalized (n=4) –Surgery (n=3) –Death (n=3) Confounding medical conditions (n=4) Females (n=4) Males (n=0) –Ages: 41, 61, 66, 67 years –Mean Age: 59 years –Time to onset: 6 to 105 days –Hospitalized (n=4) –Surgery (n=3) –Death (n=3) Confounding medical conditions (n=4)

23 Gastrointestinal Drugs Advisory Committee Meeting July 14, 2004 23 Clinical Trials GI Ischemic Events  12,000 patients –Study Indications –Chronic Constipation –C-IBS –Other GI Studies Suspicious for GI Ischemia (n=0)  7000 patients exposed  3 months –Incidence no more than 1:2000 * *Based on Poisson Distribution  12,000 patients –Study Indications –Chronic Constipation –C-IBS –Other GI Studies Suspicious for GI Ischemia (n=0)  7000 patients exposed  3 months –Incidence no more than 1:2000 * *Based on Poisson Distribution

24 Gastrointestinal Drugs Advisory Committee Meeting July 14, 2004 24 ConclusionsConclusions Ischemic Colitis / Intestinal Ischemia: (n=24) < 49 years of age: (n=7) < 30 years of age: (n=2) No documented risk factors (n=5) Occurred on 1st Day of Therapy (n=3) Additional Cases since Labeling Change Ischemic Colitis / Intestinal Ischemia: (n=24) < 49 years of age: (n=7) < 30 years of age: (n=2) No documented risk factors (n=5) Occurred on 1st Day of Therapy (n=3) Additional Cases since Labeling Change

25 Gastrointestinal Drugs Advisory Committee Meeting July 14, 2004 25 ConclusionsConclusions Ischemic Colitis Background Incidence Novartis Higher background incidence in IBS patients FDA No increased background incidence in IBS ICD9 Code 564.1: sensitive, not specific Ischemic Colitis Background Incidence Novartis Higher background incidence in IBS patients FDA No increased background incidence in IBS ICD9 Code 564.1: sensitive, not specific

26 Gastrointestinal Drugs Advisory Committee Meeting July 14, 2004 26 ConclusionsConclusions Cross reactivity? Mechanism of action ? –Raynaud's phenomenon –5HT 1 mediated arterial spasm Mechanistic studies pending Cross reactivity? Mechanism of action ? –Raynaud's phenomenon –5HT 1 mediated arterial spasm Mechanistic studies pending

27 Gastrointestinal Drugs Advisory Committee Meeting July 14, 2004 27 ConclusionsConclusions Chronic Constipation Trials: No new Safety Issues Limited data in males Limited data in Patients  65 years Questionable risk/benefit  65 years Complications of Diarrhea Possible increased risk in elderly Appropriately labeled ? Chronic Constipation Trials: No new Safety Issues Limited data in males Limited data in Patients  65 years Questionable risk/benefit  65 years Complications of Diarrhea Possible increased risk in elderly Appropriately labeled ?

28 Gastrointestinal Drugs Advisory Committee Meeting July 14, 2004 28 ConclusionsConclusions Abdominal / Pelvic Surgery Phase IV studies pending Still unknown Ischemic Colitis Higher background incidence? Appropriately labeled ? Abdominal / Pelvic Surgery Phase IV studies pending Still unknown Ischemic Colitis Higher background incidence? Appropriately labeled ?

29 Gastrointestinal Drugs Advisory Committee Meeting July 14, 2004 29 QuestionsQuestions

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