Pharmacokinetic and Pharmacodynamic Study of Cyclofem

Concept Foundation, an international nonprofit organization based in Bangkok, Thailand, was given the commercial rights to Cyclofem® by the World Health Organization (WHO) for use internationally. The brand names that the Concept Foundation has registered internationally include Cyclofem®, and Novafem® (Pharmacia Pharmaceuticals, Peapack NJ, formerly (Pharmacia and Upjohn of Kalamazoo, Michigan). The company launched its product under license from Concept Foundation with their own brand name, Lunelle™ in the US market. Lunelle™ was approved by the Food and Drug Administration (FDA) in October, 2000 following which approximately 350,000 women had used the product. However, following the acquisition of Pharmacia and Upjohn by Pfizer and due to several production problems, Pfizer withdrew Lunelle™ from the United States (US) market. Concept Foundation has licensed Sun Pharmaceutical Industries Ltd, Mumbai, India to manufacture and market Cyclofem® in India and other developing countries. United States Food and Drug Administration (US FDA) approval of Cyclofem® is pivotal to the ultimate acceptance of such products in many countries because of the rigorous standards applied by the Food and Drug Administration (FDA) for drug safety and efficacy. This initial pharmacokinetic (PK) study is the first step on the road to Food and Drug Administration (FDA) approval with the ultimate goal to expand the access and range of methods available to women in the public sector. Approval of Cyclofem® by the United States Food and Drug Administration (US FDA) would also allow the reintroduction of CICs to the United States (US) market.

Inclusion criteria

• Between 18 and 45 years of age, inclusive;
• In good health, as evidenced by history and procedures at screening/enrollment visit
• Without any clinically significant systemic disease;
• Not at risk for pregnancy, having undergone surgical sterilization
• Have had regular menstrual cycles (every 21-35 days) for the past two cycles;
• Planning to reside in the area for at least 7 months after enrolling in the study; and
• Willing and able to comply with study procedures
• Have a body mass index (BMI) between 18 and 30 inclusive.

Exclusion criteria

• Contraindications to the use of Cyclofem® include:

• Smoking any number of cigarettes per day in a woman > 35 years old (or in a woman 34 years-old who will turn 35 years-old during the study),
• Symptoms of chest pain or shortness of breath,
• Screening visit blood pressure >140/90, (subjects on hypertensive medications, in good blood pressure control will be admitted).
• Past or current thrombophlebitis or thromboembolic disorders,
• Past or current cerebral vascular or coronary artery disease
• History of stroke, myocardial infarction or ischemic heart disease or complicated valvular heart disease
• Diabetes
• Past or current carcinoma of the endometrium cervix or vagina; breast or other known or suspected estrogen-depended neoplasia,
• Headaches with focal neurological symptoms,
• Unexplained abnormal vaginal bleeding,
• Liver dysfunction or disease, such as a history of hepatic adenoma or carcinoma; history of cholestatic jaundice of pregnancy or jaundice with prior hormonal contraceptive use including severe pruritus of pregnancy, severe cirrhosis, or active hepatitis (defined as aspartate aminotransferase [AST or SGOT ≥ 120 IU/L] or alanine aminotransferase [ALT or SGPT ≥ 135 IU/L]) or clinically significant laboratory abnormalities as judged by the physician evaluating the individual subject).
• Known hypersensitivity to any component of Cyclofem®
• Have an abnormal Pap smear in the past 12 months defined as:

• Atypical squamous cells of undetermined significance (ASC-US) without a normal repeat Pap smear at least 6 months later;
• Atypical squamous cells of undetermined significance (ASC-US) with positive reflex high-risk human papillomavirus (HPV) testing (Atypical squamous cells of undetermined significance [ASC-US]/human papillomavirus [HPV]+) or low-grade squamous intraepithelial lesion (LSIL) except when a colposcopy was performed (with or without biopsy) and found no evidence of high-grade disease (cervical intraepithelial neoplasia [CIN II] or worse) unless treatment is indicated per local standard of care;
• ASC-H, atypical glandular cells, or high grade squamous intraepithelial lesion (HSIL) unless treatment was received and follow-up at least 6 months after the treatment showed no evidence of disease; malignant cells;
• Current use of rifampin, griseofulvin, phenytoin, carbamazepine, barbiturates, or primidone;
• Other conditions that, in the opinion of the investigator, would constitute contraindications to participation in the study or would compromise ability to comply with the study protocol, such as any major chronic illness including cancer, serious autoimmune disease or a major psychiatric disorder (e.g. schizophrenia);
• Current participation in any other drug or device study, or any study which, in the opinion of the investigator, would jeopardize interpretation of results of this study;
• Active thyroid disease as measured by thyroid-stimulating hormone [TSH] levels ≤0.3 mU/L or ≥ 5 mU/L. Subjects with thyroid disease in good control with thyroid medication will be admitted.