Important Safety Information on the discontinuation of Climacteron Injection (estradiol dienanthate, estradiol benzoate and testosterone enanthate benzilic acid hydrazone)- Sandoz Canada Inc. - For Health Professionals

Health Canada Endorsed Important Safety Information on Climacteron^® Injection

November 23^rd, 2005

Subject: Discontinuation of CLIMACTERON^® Injection (estradiol dienanthate / estradiol benzoate and testosterone enanthate benzilic acid hydrazone injection in corn oil)

Sandoz Canada wishes to inform you that CLIMACTERON^® Injection has been discontinued as of October 22, 2005.

• Climacteron^® Injection has been discontinued due to safety concerns.
• Physicians and pharmacists are recommended to contact their patients who are current users of Climacteron^® Injection for re-evaluation.
• Climacteron^® Injection will continue to be sold (at the wholesale level) until stocks are depleted to provide a sufficient transition period for current users to switch to an alternate form of therapy.

According to published literature, testosterone is partially metabolized to estrogen, and should be opposed by a progestin in women with intact uteri in order to prevent the development of endometrial hyperplasia/carcinoma^{Footnote 1}. Currently, there are no recommendations for an appropriate dosage of a progestin for women with intact uteri using a combined testosterone-estrogen Hormone Replacement Therapy (HRT) product, and the pharmacokinetics of the testosterone and estrogen components of Climacteron^® Injection are unknown. Therefore, the appropriate progestin regimen to protect women with intact uteri, who are using Climacteron^® Injection, against endometrial hyperplasia/carcinoma, remains unknown at this time.

The current recommended dose of Climacteron^® Injection (1.0mL by deep intramuscular injection into the gluteus maximus every 4 to 8 weeks) induces a supraphysiological serum testosterone level that is higher than the physiologic testosterone production rate in premenopausal women^{Footnote 2, Footnotee 3, Footnote 4, Footnote 5}, and according to published literature may be associated with problems of hirsutism, virilization, and aggression^{Footnote 1, Footnote 3, Footnote 6}.

Sandoz Canada recommends that physicians and/or pharmacists contact their patients who are currently using Climacteron^® Injection and inform them that Climacteron^® Injection has been discontinued. Patients should be counselled to visit their physicians as soon as possible for re-evaluation and discussion of alternate HRT as necessary. In light of current knowledge and availability of various alternatives, the switching strategy must be individualized for each patient.

Reporting of Adverse Events

Managing marketed health product-related adverse reactions depends on health care professionals and consumers reporting them. Any case of serious or unexpected adverse reactions in patients receiving Climacteron^® Injection, including endometrial hyperplasia and endometrial adenocarcinoma, should be reported to Sandoz Canada or Health Canada at the following addresses:

Medical Information
Sandoz Canada
145 Jules Leger,
Boucherville, Que
Tel: 450-641-4903 extension 4636
medinfo@sandoz.com

Any suspected adverse reaction can also be reported to:
Canadian Adverse Drug Reaction Monitoring Program (CADRMP)
Marketed Health Products Directorate
HEALTH CANADA
Address Locator: 0701C
OTTAWA, Ontario, K1A 0K9
Tel: (613) 957-0337 or Fax: (613) 957-0335
To report an Adverse Reaction, consumers and health professionals may call toll free:
Tel: 866 234-2345
Fax: 866 678-6789
cadrmp@hc-sc.gc.ca

The AR Reporting Form and the AR Guidelines can be found on the Health Canada web site or in The Canadian Compendium of Pharmaceuticals and Specialties.

For other inquiries related to this communication, please contact Health Canada at:
Bureau of Metabolism, Oncology and Reproductive Sciences (BMORS)
E-mail: bmors_enquiries@hc-sc.gc.ca
Tel: (613) 941-3171
Fax: (613) 941-1365

Thank you for your attention to this important safety matter.

original signed by

France Montgrain, M.Sc. Chem.
Vice president Quality Unit
Sandoz Canada In

Len Arsenault
Vice president Scientific Affairs
Sandoz Canada Inc

Notes de bas de page

Footnote 1

Society of Obstetricians and Gynaecologists of Canada (SOGC). The Canadian consensus conference on menopause and osteoporosis. J Soc Obstet Gynaecol Can. 1998;20(13):1243-1272.

Return to footnote 1 referrer

Footnote 2

Sherwin BB, Gelfand MD, Schucher R, Gabor J. Postmenopausal estrogen and androgen replacement and lipoprotein lipid concentration. Am J Obstet Gynecol 1987;156:414-419.

Return to footnote 2 referrer

Footnote 3

Longscope C. Adrenal and gonadal androgen secretion in normal female. J Clin Endocrinol Metab. 1986;15:213-228.

Return to footnote 3 referrer

Footnote 4

Urman B, Pride SM, Yuen BH. Elevated serum testosterone, hirsutism, and virilism associated with combined androgen-estrogen hormone replacement therapy. Obstet Gynecol. 1991;77(4):595-598.

Return to footnote 4 referrer

Footnote 5

Sherwin BB. Use of combined estrogen-androgen preparations in the postmenopause: evidence from clinical studies. Int J Fertil. 1998;43(2):98-103.

Return to footnote 5 referrer

Footnote 6

Sherwin BB, Gelfand MM. Sex steroids and affect in the surgical menopause: a double-blind, cross-over study. Psychoneuroendocrinology. 1985;10(3):325-335.

Return to footnote 6 referrer