Review of Ovarian Cysts

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Review of Ovarian Cysts

• Bruce Carr, MD
• Director, Division of Reproductive Endocrinology
• The University of TexasSouthwestern Medical
  Center

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Safety

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

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Safety

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

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Growth and Development of Ovarian Follicles
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Graafian follicle
Primary follicles
Corpus luteum
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(No Transcript)
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Further Analysis of Ovarian Cysts
n 9 "ovarian cysts (n 8 tegaserod, n 1
placebo)
n 5OC confirmed
n 4not confirmed
n 2with history of OCs
n 3newly occurring

• Revised diagnosis
• Cystadenofibroma
• Peritubal cyst
• Pelvic adhesions
• Ruptured ovarian cyst

n 2 on tegaserod
n 1 on placebo
n 2 on tegaserod

• Adenomyosis/OC
• Appendicitis Recurring/OC

• Cyst/follicle
• Polycystic ovary

• Polycystic ovary

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Female Patients With Ovarian Cysts
Patients, n ()

• 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

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Estimated Ovarian Cyst Frequency in Women Aged lt
50 Years(Pooled Phase II/III and Long-term
Studies)
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• 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, 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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Prevalence of Simple Cysts and Polycystic Ovaries
Detected by Ultrasound in Asymptomatic/healthy
Populations
27

• 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 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

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Summary

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

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Safety

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

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Gynecology Surgery for Ovarian Cysts
n 9 "ovarian cysts (n 8 tegaserod, n 1
placebo)
n 5OC confirmed
n 4not confirmed
n 2with history of OCs
n 3newly occurring

• Revised diagnosis
• Cystadenofibroma
• Peritubal cyst
• Pelvic adhesions
• Ruptured ovarian cyst

n 2 on tegaserod
n 1 on placebo
n 2 on tegaserod

• Adenomyosis/OC
• Appendicitis Recurring/OC

• Cyst/follicle
• Polycystic ovary

• Polycystic ovary

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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.

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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

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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