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Review of Ovarian CystsReview of Ovarian Cysts
Bruce Carr, MD
Director, Division of Reproductive Endocrinology
The University of TexasSouthwestern Medical Center
Bruce Carr, MD
Director, Division of Reproductive Endocrinology
The University of TexasSouthwestern Medical Center
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SafetySafety
Ovarian cysts: human and animal data
Laparotomies in patients due to gynecological and GI indications
Ovarian cysts: human and animal data
Laparotomies in patients due to gynecological and GI indications
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SafetySafety
Ovarian cysts: human and animal data
Laparotomies in patients due to gynecological and GI indications
Ovarian cysts: human and animal data
Laparotomies in patients due to gynecological and GI indications
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Corpus luteumCorpus luteum
Graafian follicle
Graafian follicle
Primary folliclesPrimary follicles
Growth and Development of Ovarian Follicles
Growth and Development of Ovarian Follicles
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n = 2n = 2on tegaserodon tegaserod
n = 1n = 1on placeboon placebo
n = 2:n = 2:with history of OCswith history of OCs
n = 3:n = 3:newly occurringnewly occurring
n = 4*:n = 4*:not confirmednot confirmed
n = 5:n = 5:OC confirmedOC confirmed
n = 9 "ovarian cysts”n = 9 "ovarian cysts”(n = 8 tegaserod, n = 1 placebo)(n = 8 tegaserod, n = 1 placebo)
Further Analysis of “Ovarian Cysts”
Further Analysis of “Ovarian Cysts”
*Revised diagnosis:
– Cystadenofibroma
– Peritubal cyst
– Pelvic adhesions
– Ruptured ovarian cyst
n = 2n = 2on tegaserodon tegaserod
– Adenomyosis/OC
– Appendicitis Recurring/OC
– Cyst/follicle– Polycystic ovary
– Polycystic ovary
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Female Patients With Ovarian Cysts
Female Patients With Ovarian Cysts
Placebo Tegaserod
Controlled studies
Phase III 1/707 (0.14) 1/1,419 (0.07)
Phase II 0/140 (0.0) 2/456 (0.44)
Phase II/III 1/847 (0.12) 3/1,875 (0.16)
Uncontrolled, long-term – 1/611 (0.16) studies
Placebo Tegaserod
Controlled studies
Phase III 1/707 (0.14) 1/1,419 (0.07)
Phase II 0/140 (0.0) 2/456 (0.44)
Phase II/III 1/847 (0.12) 3/1,875 (0.16)
Uncontrolled, long-term – 1/611 (0.16) studies
Patients, n (%)Patients, n (%)
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OC 8OC 8Estimated Ovarian Cyst Frequency in
Women Aged < 50 Years(Pooled Phase II/III and Long-term Studies)
Estimated Ovarian Cyst Frequency in Women Aged < 50 Years
(Pooled Phase II/III and Long-term Studies) Estimated
Exposure frequency per (women- No. of 1,000 women-
Total N days) cysts years (95% CI)
Tegaserod 1,649 203,323 4 7.2 (2.1 - 18.4)
Placebo 607 49,734 1 7.3 (0 - 40.6)
Estimated Exposure frequency per (women- No. of 1,000 women-
Total N days) cysts years (95% CI)
Tegaserod 1,649 203,323 4 7.2 (2.1 - 18.4)
Placebo 607 49,734 1 7.3 (0 - 40.6)
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Patients With History of Ovarian Diseases or Ovarian Surgery at Baseline
Patients With History of Ovarian Diseases or Ovarian Surgery at Baseline
Patients, n (%)
Phase II/III Long-term
Placebo Tegaserod Tegaserod History (n = 847) (n = 1,875) (n = 611)
Ovarian surgery 4 (0.5) 23 (1.2) 3 (0.5)
Ovarian cysts 41 (4.8) 85 (4.5) 36 (5.9)
Patients, n (%)
Phase II/III Long-term
Placebo Tegaserod Tegaserod History (n = 847) (n = 1,875) (n = 611)
Ovarian surgery 4 (0.5) 23 (1.2) 3 (0.5)
Ovarian cysts 41 (4.8) 85 (4.5) 36 (5.9)
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OC 10OC 10Prevalence of Simple Cysts and Polycystic Ovaries Detected by Ultrasound in Asymptomatic/healthy Populations
Prevalence of Simple Cysts and Polycystic Ovaries Detected by Ultrasound in Asymptomatic/healthy Populations
Postmenopausal: 6.6% – 23% resolved spontaneously by 2 years
(Conway, 1998)
Women 25-40 years: 6.6%– 82% disappeared after 3 months
(Borgfeldt, 1999)
Adolescent girls: 12%– 65% disappeared after 3 months
(Porcu, 1994)
Postmenopausal: 6.6% – 23% resolved spontaneously by 2 years
(Conway, 1998)
Women 25-40 years: 6.6%– 82% disappeared after 3 months
(Borgfeldt, 1999)
Adolescent girls: 12%– 65% disappeared after 3 months
(Porcu, 1994)
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Preclinical Studies With TegaserodPreclinical Studies With Tegaserod
No treatment-related ovarian cysts in
– Rat toxicity studies up to 6 months
– Dog toxicity studies up to 12 months
– Mouse carcinogenicity study or after reevaluation in the rat carcinogenicity study
No histopathological evidence of hormonal perturbation in any studies
No treatment-related ovarian cysts in
– Rat toxicity studies up to 6 months
– Dog toxicity studies up to 12 months
– Mouse carcinogenicity study or after reevaluation in the rat carcinogenicity study
No histopathological evidence of hormonal perturbation in any studies
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SummarySummary
No evidence of a link between tegaserod and the development of ovarian pathology
– Clinical studies
– Preclinical/toxicology studies
No evidence of a link between tegaserod and the development of ovarian pathology
– Clinical studies
– Preclinical/toxicology studies
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SafetySafety
Ovarian cysts: human and animal data
Laparotomies in patients due to gynecological and GI indications
Ovarian cysts: human and animal data
Laparotomies in patients due to gynecological and GI indications
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Gynecology Surgery for “Ovarian Cysts”
Gynecology Surgery for “Ovarian Cysts”
*Revised diagnosis:
– Cystadenofibroma
– Peritubal cyst
– Pelvic adhesions
– Ruptured ovarian cyst
– Adenomyosis/OC
– Appendicitis Recurring/OC
– Cyst/follicle– Polycystic ovary
– Polycystic ovary
n = 2n = 2on tegaserodon tegaserod
n = 1n = 1on placeboon placebo
n = 2:n = 2:with history of OCswith history of OCs
n = 3:n = 3:newly occurringnewly occurring
n = 4*:n = 4*:not confirmednot confirmed
n = 5:n = 5:OC confirmedOC confirmed
n = 9 "ovarian cysts”n = 9 "ovarian cysts”(n = 8 tegaserod, n = 1 placebo)(n = 8 tegaserod, n = 1 placebo)
n = 2n = 2on tegaserodon tegaserod
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Patients Undergoing Laparotomy for GI Indications
Patients Undergoing Laparotomy for GI Indications
Dose Time Patientmg/d (days)(gender/age)Adverse event
Comments
PBO 75 301/209/13Appendicitis Appendectomy(34F)
PBO 207 351/518/19Perforated cecumPerforated cecal ulcer 4 (27F) months after last dose. Partial cecectomy.
1 18 251/42/7 Ileus Incarcerated hernia; (42F) previous abdominal surgery
4 36 301/112/9Benign pancreatic Exploratory laparotomy and (71F) cyst cystectomy
12 183 209/28/6 Small bowel History of small bowel(58F)obstruction obstruction after hysterectomy. Adhesiolysis and reduction of internal hernia.
Dose Time Patientmg/d (days)(gender/age)Adverse event
Comments
PBO 75 301/209/13Appendicitis Appendectomy(34F)
PBO 207 351/518/19Perforated cecumPerforated cecal ulcer 4 (27F) months after last dose. Partial cecectomy.
1 18 251/42/7 Ileus Incarcerated hernia; (42F) previous abdominal surgery
4 36 301/112/9Benign pancreatic Exploratory laparotomy and (71F) cyst cystectomy
12 183 209/28/6 Small bowel History of small bowel(58F)obstruction obstruction after hysterectomy. Adhesiolysis and reduction of internal hernia.
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Frequency of Laparotomies by Year in NDA Database
Frequency of Laparotomies by Year in NDA Database
Placebo Tegaserod
Frequency per Frequency per n/N patient year n/N patient year
Phase II/III 2/988 0.0091 4/2198 0.0083
Long-term - - 4/675 0.0097
Placebo Tegaserod
Frequency per Frequency per n/N patient year n/N patient year
Phase II/III 2/988 0.0091 4/2198 0.0083
Long-term - - 4/675 0.0097
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Summary: Tegaserod and Laparotomies
Summary: Tegaserod and Laparotomies
In the study population a variety of different gynecological and GI disorders led to laparotomies
Frequency of laparotomies by exposure duration similar for tegaserod and placebo
No obvious causal relationship or signal that tegaserod affects the frequency of laparotomies
In the study population a variety of different gynecological and GI disorders led to laparotomies
Frequency of laparotomies by exposure duration similar for tegaserod and placebo
No obvious causal relationship or signal that tegaserod affects the frequency of laparotomies