VAGIFEM

1 Dosing Considerations For initiation and continuation of treatment of postmenopausal symptoms, the lowest effective dose for the shortest duration should be used. Vagifem® 10 may be used in women with or without an intact uterus. During treatment, especially during the first 2 weeks, minimal absorption may be seen but as average plasma estradiol levels usually do not exceed postmenopausal levels; the addition of a progestin is not needed.

2 Recommended Dose and Dosage Adjustment Treatment may be started on any convenient day. 4 Administration Accidental injury during administration of Vagifem® 10 may occur if the applicator is introduced too high into the vagina. Women should be shown how to administer Vagifem® 10 correctly.

No incidences of applicator injury were reported in the clinical trials of Vagifem® 10. Vagifem® 10 (estradiol vaginal insert USP) is gently inserted into the vagina as far as it can comfortably go without force, using the supplied applicator.

Detailed instructions for use are provided in PATIENT MEDICATION INFORMATION. 5 Missed Dose If a patient misses a dose, it should be administered as soon as possible. If it is close to the patient’s next scheduled dose, the missed dose should be skipped, and the patient should continue with her normal schedule.

The patient should not take two doses at the same time.

1 Adverse Reaction Overview See 7 WARNINGS AND PRECAUTIONS regarding potential induction of malignant neoplasms and adverse effects similar to those of oral contraceptives. The following adverse reactions have been reported with estrogen/progestin combination in general: Reproductive system and breast disorders Breakthrough bleeding; spotting; change in menstrual flow; dysmenorrhea; vaginal itching/discharge; dyspareunia; endometrial hyperplasia; pre-menstrual-like syndrome; reactivation of endometriosis; changes in cervical erosion and amount of cervical secretion; breast swelling and tenderness.

2 Clinical Trial Adverse Reactions Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug.

Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates. S. and Canada, in which 308 patients were randomized to receive either placebo (N=103) or Vagifem® 10 inserts (N=205).

Patients inserted one insert intra-vaginally each day for the first two weeks, followed by administration of one insert intra-vaginally twice weekly administration for the remaining 50 weeks. All patients were assessed for vaginal symptoms.

Overall, Vagifem® 10 was generally well tolerated; 41 (20%) patients discontinued treatment in the Vagifem® 10 group and 34 (33%) in the placebo group. Adverse events with an incidence of ≥ 1% in the Vagifem® 10 group and greater than those seen in placebo are reported in Table 1 for this placebo-controlled, multicenter trial.

3 Less Common Clinical Trial Adverse Reactions Gastrointestinal: Abdominal distension; Nausea. 5 Post-Market Adverse Reactions In addition to the above-mentioned adverse drug reactions, those presented below have been spontaneously reported for patients treated with Vagifem® 10 and are considered possibly related to treatment.

Vagifem® 10 is a locally administered vaginal treatment containing 10 mcg of estradiol and therefore the occurrence of the conditions mentioned in the box above, is less likely than with estrogen products used for systemic treatment.

However, since Vagifem® 10 is a hormone therapy product these risks should be considered. General Risks and benefits of treatment with Vagifem® 10 should be re-assessed at least annually. Vagifem® 10 should only be continued as long as the benefits outweigh the risks.

3 Vagifem® 10 (estradiol vaginal insert USP) Page 7 of 34 Pharmacokinetics - Absorption). The following warnings and precautions associated with oral estrogen therapy should be considered in the absence of comparable data with other dosage forms of estrogens.

3 Pharmacokinetics section). g. g. 1st degree heredity for breast cancer Therapy should be discontinued if any of the following situations is discovered: • Jaundice or deterioration of liver function • Significant increase in blood pressure • New onset of migraine-type headache • Pregnancy Vagifem® 10 is a locally acting low dose estradiol preparation and therefore the occurrence of conditions mentioned above is less likely than with systemic estrogen treatment.

Carcinogenesis and Mutagenesis Breast cancer:

There is a need for caution in prescribing estrogens of any kind to women with a strong family history (first degree relative) of breast cancer or women who have nodules, fibro cystic disease or abnormal mammograms and/or atypical hyperplasia at breast biopsy.

In the oral estrogen-alone arm of the WHI trial, there was no statistically significant difference in the rate of invasive breast cancer in hysterectomized women treated with conjugated equine estrogens versus women treated with placebo.

It is recommended that estrogens not be given to women with existing breast cancer or those with a previous history of the disease (see 2 CONTRAINDICATIONS). Other known risk factors for the development of breast cancer such as nulliparity, obesity, early menarche, late age at first full term pregnancy and at menopause should also be evaluated.

Vagifem® 10 (estradiol vaginal insert USP) is contraindicated in women with: • Hypersensitivity to this drug or to any ingredient in the formulation or component of the container. g. g. stroke, myocardial infarction, coronary heart disease) • Partial or complete loss of vision due to ophthalmic vascular disease • Breastfeeding • Porphyria Vagifem® 10 (estradiol vaginal insert USP) Page 5 of 34