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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 (%)

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)

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