# Presentation: 749485

## Review of Ovarian Cysts

**Bruce Carr, MD**
**Director, Division of Reproductive Endocrinology**
**The University of Texas****Southwestern Medical Center**

## Safety

**Ovarian cysts: human and animal data**
**Laparotomies in patients due to gynecological and GI indications**

**Notes:**
Note: size definition changes across studies
Conway: n = 1769. Dx by transvaginal ultrasound. Simple ovarian cysts 1.5 - 5 cm, unilocular and anechoic. 1/4 underwent surgery. 17% were lost to follow-up
Borgfeldt: n= 335. Dx by transvaginal ultrasound. At least 2.5 cm 
Porcu: n= 139. Dx by abdominal ultrasound. At least 3 cm
The size of the cyst and the rate of regression are directly correlated: spontaneous regression in 83% of cysts <= 4cm, 63% for cysts 4-6 cm, and 29% for cysts 6-8 cm
Note: Prevalence of polycystic ovaries (Borgfeldt 1999, Koivunen 1999, Polson 1988, Clayton 1992, Farquhar 1994;
Prevalence of PCOsyndrome: Knochenhauer 1998, Solomon 1999)

## Safety

**Ovarian cysts: human and animal data**
**Laparotomies in patients due to gynecological and GI indications**

**Notes:**
Note: size definition changes across studies
Conway: n = 1769. Dx by transvaginal ultrasound. Simple ovarian cysts 1.5 - 5 cm, unilocular and anechoic. 1/4 underwent surgery. 17% were lost to follow-up
Borgfeldt: n= 335. Dx by transvaginal ultrasound. At least 2.5 cm 
Porcu: n= 139. Dx by abdominal ultrasound. At least 3 cm
The size of the cyst and the rate of regression are directly correlated: spontaneous regression in 83% of cysts <= 4cm, 63% for cysts 4-6 cm, and 29% for cysts 6-8 cm
Note: Prevalence of polycystic ovaries (Borgfeldt 1999, Koivunen 1999, Polson 1988, Clayton 1992, Farquhar 1994;
Prevalence of PCOsyndrome: Knochenhauer 1998, Solomon 1999)

## Growth and Development of Ovarian Follicles

**1**

**Corpus luteum**

**Graafian follicle**

**Primary follicles**

**Growth and Development of Ovarian Follicles**

## Slide 5

## Further Analysis of “Ovarian Cysts”

**n = 2**
**on tegaserod**

**n = 1**
**on placebo**

**n = 2:****with history of OCs**

**n = 3:****newly occurring**

**n = 4*:****not confirmed**

**n = 5:****OC confirmed**

**n = 9 "ovarian cysts”**
**(n = 8 tegaserod, n = 1 placebo)**

**Further Analysis of ****“Ovarian Cysts”**

***Revised diagnosis:**
**  ****Cystadenofibroma**
**  ****Peritubal cyst**
**  ****Pelvic adhesions**
**  ****Ruptured ****    ovarian cyst**

**n = 2**
**on tegaserod**

**  ****Adenomyosis/OC**
**  ****Appendicitis****    Recurring/OC**

** ****Cyst/follicle**
**  ****Polycystic ovary**

**  ****Polycystic ovary**

## 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**

**Patients, n (%)**

## 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)**

**11**

## 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)**

## 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)**

**27**

## Preclinical 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**

## Summary

**No evidence of a link between tegaserod and the development of ovarian pathology**
**Clinical studies**
**Preclinical/toxicology studies**

## Safety

**Ovarian cysts: human and animal data**
**Laparotomies in patients due to gynecological and GI indications**

**Notes:**
Note: size definition changes across studies
Conway: n = 1769. Dx by transvaginal ultrasound. Simple ovarian cysts 1.5 - 5 cm, unilocular and anechoic. 1/4 underwent surgery. 17% were lost to follow-up
Borgfeldt: n= 335. Dx by transvaginal ultrasound. At least 2.5 cm 
Porcu: n= 139. Dx by abdominal ultrasound. At least 3 cm
The size of the cyst and the rate of regression are directly correlated: spontaneous regression in 83% of cysts <= 4cm, 63% for cysts 4-6 cm, and 29% for cysts 6-8 cm
Note: Prevalence of polycystic ovaries (Borgfeldt 1999, Koivunen 1999, Polson 1988, Clayton 1992, Farquhar 1994;
Prevalence of PCOsyndrome: Knochenhauer 1998, Solomon 1999)

## 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 = 2**
**on tegaserod**

**n = 1**
**on placebo**

**n = 2:****with history of OCs**

**n = 3:****newly occurring**

**n = 4*:****not confirmed**

**n = 5:****OC confirmed**

**n = 9 "ovarian cysts”**
**(n = 8 tegaserod, n = 1 placebo)**

**n = 2**
**on tegaserod**

## Patients Undergoing Laparotomy for GI Indications

**Dose****	**** Time ****	**** Patient**
**mg/d****	**** (days)****	****(gender/age)****	****Adverse event****	****Comments****	**
**PBO****	****75****	****301/209/13****	****Appendicitis****	****Appendectomy**
**	****	****(34F)****	****	**
**PBO****	****207****	****351/518/19****	****Perforated cecum****	****Perforated cecal ulcer 4**
**	****	**** ****(27F) ****	****	****months after last dose. Partial cecectomy. **
**1****	****18****	****251/42/7****	****Ileus ****	****Incarcerated hernia;**
**	****	**** ****(42F) ****	****	****previous abdominal surgery**
**4****	****36****	****301/112/9****	****Benign 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.****	**

## 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****	**

## 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**