Vagifem

No Drug-Herb Interactions with Vagifem have been reported.

Physicians and other health care providers should be made aware of other non-prescription products concomitantly used by the patient, including herbal and natural products.

No Drug-Food Interactions with Vagifem have been reported.

No Drug-Drug Interactions with Vagifem have been reported.

See Warnings and Precautions regarding potential induction of malignant neoplasms and adverse effects similar to those of oral contraceptives.

There are no studies investigating Drug-Laboratory interactions with Vagifem.

The pathologist should be informed that the patient is receiving hormone therapy (HT) when relevant specimens are submitted.

Vagifem is a topical vaginal estrogen therapy product. The following drug-interactions are based on the experience of systematic estrogen treatment.

Enzyme inducers, (e.g. barbiturates, hydantoins, carbamazepine, meprobamates, or rifampicin) can enhance estrogen metabolism, resulting in breakthrough bleeding or vaginal spotting.

Estrogens may diminish the effectiveness of anticoagulant, antidiabetic and antihypertensive agents.

For initiation and continuation of treatment of postmenopausal symptoms, the lowest effective dose for the shortest duration should be used.

Vagifem may be used in women with or without an intact uterus.

During treatment, especially during the first 2 weeks, minimal absorption may be seen however, as plasma estradiol levels after the first 2 weeks usually do not exceed postmenopausal levels; the addition of a progestin is not recommended.

Treatment may be started on any convenient day.

Accidental injury during administration of Vagifem may occur if the applicator is introduced too high into the vagina. Women should be shown how to administer Vagifem correctly. No incidences of applicator injury were reported in the clinical trials of Vagifem.

Vagifem (estradiol vaginal tablet) 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 Information for the Patient.

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.

goiter.

acne, dermatitis contact, nail disorder, pruritus, pruritus genital, rash, skin disorder, skin ulceration, urticaria.

breast cancer, endometrial cancer.

haematoma, purpura.

herpes simplex, infection, fungal infection, candidiasis genital, lymphadenopathy.

migraine aggravated.

allergic reaction, allergy, aesthenia, back pain, carpal tunnel syndrome, fatigue, fever, headache, hot flushes, influenza-like symptoms, leg pain, neck rigidity, oedema peripheral, pain.

cerebrovascular disorder, thrombophlebitis leg superficial.

urticaria, rash erythematous, rash pruritic.

basal cell carcinoma, breast fibroadenomosis, renal carcinoma, uterine fibroid, vaginal neoplasm benign.

spinal malformation.

deep venous thrombosis.

blepharitis, conjunctivitis.

ear disorder NOS, earache.

weight increase, blood estrogen increase.

diarrhea.

insomnia, depression.

endometrial hyperplasia, vaginal irritation, vaginal pain, vaginismus, vaginal ulceration.

abdominal pain, constipation, diarrhea, diverticulitis, dyspepsia, flatulence, gastroesophageal reflux, nausea, tooth disorder, vomiting.

The following events have been spontaneously reported during Vagifem use in clinical practice. Because these reactions were reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

fluid retention.

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.

drug ineffective.

gama-GT increased, hepatitis, AST and ALT increased.

The following adverse events were reported at an incidence of <5% for Vagifem regardless of drug relationship.

abdominal pain, breast disorder (not otherwise specified), breast pain, endometrial hyperplasia, leukorrhea, perineal pain, postmenopausal bleeding, vaginitis, vaginitis ulcerative, vulva discomfort.

arthralgia, arthritis, arthritis aggravated, arthrosis, bone disorder, myalgia.

bronchitis, bronchospasm, coughing, pharyngitis, rhinitis, sinusitis.

dizziness, hypertonia, hypoaesthesia, migraine, involuntary muscle contractions, paraesthesia.

dysuria, haematuria, micturition frequency, urethral disorder, urinary incontinence, urinary tract infection.

LHD increased, oedema legs, phosphatase alkaline increased.

hypersensitivity.

hearth murmur, hypertension, palpitation.

Vagifem is not indicated for use in the pediatric population.

Clinical studies of Vagifem did not include sufficient number of subjects aged 65 and over to determine if they responded differently from younger subjects.

Available epidemiological data indicate that use of oral estrogen with or without progestin by postmenopausal women is associated with an increased risk of developing venous thromboembolism (VTE).

The benefits and risks of hormone therapy should be carefully weighed when prescribing Vagifem to women with a risk factor for thrombotic disorders. The physician should be alert to the earliest manifestations of thrombotic disorders. If these occur or are suspected, estrogen therapy should be discontinued immediately. Women with a positive family history and women with a history of thromboembolic disorders during pregnancy or in association with estrogen use should be kept under special observation.

Generally recognized risk factors for VTE include a personal history, a family history (the occurrence of VTE in a direct relative at a relatively early age may indicate genetic predisposition), severe obesity (body mass index >30 kg/m²) and systemic lupus erythematosus. The risk of VTE also increases with age and smoking.

The risk of VTE may be temporarily increased with prolonged immobilization, major surgery or trauma. In women on HT, attention should be given to prophylactic measures to prevent VTE following surgery. Also, patients with varicose veins should be closely supervised. The physician should be alert to the earliest manifestations of thrombotic disorders (thrombophlebitis, retinal thrombosis, cerebral embolism and pulmonary embolism). If these occur or are suspected, hormone therapy should be discontinued immediately, given the risks of long-term disability or fatality.

If feasible, estrogens should be discontinued at least 4 weeks before major surgery which may be associated with an increased risk of thromboembolism, or during periods of prolonged immobilization.

Patients who develop visual disturbances, classical migraine, transient aphasia, paralysis or loss of consciousness should discontinue medication.

Patients with a previous history of classical migraine and who develop a recurrence or worsening of migraine symptoms should be reevaluated.

Women using hormone therapy sometimes experience increased blood pressure. Blood pressure should be monitored with HT use. Elevation of blood pressure in previously normotensive or hypertensive patients should be investigated and HT may have to be discontinued.

HT may cause an exacerbation of epilepsy.

Estrogen should not be used in pregnancy. Any possibility of pregnancy must be ruled out before prescribing Vagifem. If pregnancy occurs during Vagifem treatment, the medication should be discontinued immediately.

Clinical studies of Vagifem did not include sufficient number of subjects aged 65 and over to determine if they responded differently from younger subjects.

Due to the local administration of low dose estradiol in Vagifem, the recurrence or aggravation of some conditions is less likely than with systemic estrogen treatment, such as:

• Leiomyomata (uterine fibroids) or endometriosis

  
  

• A history of, or risk factors for, thromboembolic disorders (see below)

  
  

• Hypertension

  
  

• Liver disorders (e.g. liver adenoma)

  
  

• Diabetes mellitus with or without vascular involvement

  
  

• Cholelithiasis

  
  

• Migraine or (severe) headache

  
  

• Systemic lupus erythematosus

  
  

• A history of endometrial hyperplasia (see below)

  
  

• Epilepsy

  
  

• Asthma

  
  

• Otosclerosis.

  
  

Therapy should be discontinued if any of the following situations is discovered:

• Jaundice or deterioration in liver function

  
  

• Significant increase in blood pressure

  
  

• New onset of migraine-type headache

  
  

• Pregnancy

Risks and benefits of treatment with Vagifem should be re-assessed at least annually. Vagifem should only be continued as long as the benefits outweigh the risks.

Vagifem is a topical, low-dose vaginal estrogen therapy product (see Action and Clinical Pharmacology, 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.

Trauma induced by the Vagifem applicator may occur, especially in patients with severely atrophic vaginal mucosa. After gynecological surgery, any vaginal applicator should be used with caution and only if clearly indicated.

Vaginal infection is generally more common in postmenopausal women due to the lack of the normal flora seen in fertile women, especially lactobacillus, and the subsequent higher pH. Vaginal infections should be treated with appropriate antimicrobial therapy before initiation of Vagifem. If a vaginal infection develops during the maintenance phase of the treatment, appropriate therapy should be instituted. The next dose of Vagifem should be inserted once the therapy is completed.

Although no effect of low dose vaginal estradiol supplementation has been seen on glucose tolerance, fluid retention, elevation of blood pressure or other liver or endocrine functions, women with predisposition to or signs indicating an effect on those variables could indicate caution.

Hyperlipidemia has been reported in women on other types of estrogen replacement therapy, but it has not been observed in women using Vagifem.

Pre-existing uterine leiomyomata may increase in size during estrogen use. Growth, pain or tenderness of uterine leiomyomata requires discontinuation of medication and appropriate investigation.

Vagifem is not indicated for use in the pediatric population.

A 2- to 4-fold increase in the risk of gallbladder disease requiring surgery in women receiving postmenopausal estrogens has been reported.

Abnormal vaginal bleeding, due to its prolongation, irregularity or heaviness, occurring during therapy should prompt appropriate diagnostic measures to rule out the possibility of uterine malignancy and the treatment should be re-evaluated.

Women should be advised to inform their physician if irritation, pain, discharge, unusual or unexpected bleeding occur during treatment.

Women with signs of ulceration or severe inflammation due to unresponsive atrophic vaginitis, withdrawal from treatment should be considered and appropriate investigations should be conducted.

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 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.

It is recommended that women undergo mammography prior to the start of HT treatment and at regular intervals during treatment, as deemed appropriate by the treating physician and according to the perceived risks for each patient.

The overall benefits and possible risks of hormone therapy should be fully considered and discussed with patients.

Instructions for regular self-examination of the breasts should be included in this counseling.

Available epidemiological data indicate that the use of combined oral estrogen plus progestin in women age 65 and over may increase the risk of developing probable dementia.

Symptoms and physical findings associated with a previous diagnosis of endometriosis may reappear or become aggravated with estrogen use.

Recent epidemiologic studies have found the use of hormone therapy (estrogen-alone and estrogen plus progestin therapies), in particular for five or more years, has been associated with an increased risk of ovarian cancer.

Before Vagifem is administered, the patient should have a complete physical examination including a blood pressure determination. Breasts and pelvic organs should be appropriately examined and a Papanicolaou smear should be performed. Endometrial biopsy should be done only when indicated. Baseline tests should include mammography, measurements of blood glucose, calcium, triglycerides and cholesterol, and liver function tests.

The first follow-up examination should be done within 3-6 months after initiation of treatment to assess response to treatment. Thereafter, examinations should be made at intervals at least once a year. Appropriate investigations should be arranged at regular intervals as determined by the physician.

The importance of regular self-examination of the breasts should be discussed with the patient.

Women treated with Vagifem should be advised to keep their regular medical checkups to assess the need for continuing therapy.

Estrogens may cause fluid retention.

Therefore, particular caution is indicated in cardiac or renal dysfunction, epilepsy or asthma. If, in any of the above-mentioned conditions, a worsening of the underlying disease is diagnosed or suspected during treatment, the benefits and risks of treatment should be reassessed based on the individual case.

Estrogens should not be used during lactation. Vagifem should not be prescribed for nursing mothers.

The results of the Heart and Estrogen/progestin Replacement Studies (HERS and HERS II) and the Women's Health Initiative (WHI) trial indicate that the use of continuous combined oral conjugated estrogens (CEE) and medroxyprogesterone acetate (MPA) is associated with an increased risk of coronary heart disease (CHD) in postmenopausal women. The results of the WHI trial indicate that the use of oral estrogen-alone and oral estrogen plus progestin is associated with an increased risk of stroke in postmenopausal women.

Circulating, unbound estrogens are known to modulate pharmacological response. Estrogens circulate in the blood bound to sex-hormone binding globulin (SHBG) and albumin.

Estrogens are well absorbed through skin, mucous membranes, and the gastrointestinal (GI) tract. The vaginal route of estrogen delivery avoids firs-pass metabolism. After administration of Vagifem, 17 β-estradiol is absorbed form the vaginal mucosa.

A single-centre, randomized, double-blind, comparison study was conducted in U.S. to investigate the effects of Vagifem treatment on serum hormone concentrations. Subjects were treated with Vagifem daily for 2 weeks followed by twice weekly administration for 10 weeks. Serum estradiol (E₂) and estrone (E₁) levels were measured after the first dose at 1, 2, 4, 5, 6, 7, 8, 10, 12 and 24 hours after administration at each study visit. E₁S (estrone sulfate) and FSH levels were determined after the first dose at 6, 12 and 24 hours after administration at each study visit. Study visits were scheduled on the first day of dosing after 1, 2, 4, 8, and 12 weeks of treatment. A total of 28 healthy women with atrophic vaginitis received Vagifem of which 22 completed the study.

Figure 2 illustrates the serum E₂ levels following the first dose after 2 and 12 weeks of treatment. This study showed that the vaginal application of Vagifem over a 12-week period did not result in accumulation of estradiol as measured by the AUC_0-24 (see Table 5). C_max of serum estradiol was constant from the first day of treatment (week 0) to the end of treatment (week 12). There was a small statistically significant increase in mean E₁S (estrone sulfate) concentrations during the 12 weeks of therapy. The mean concentrations over the 24-hour period after dosing at weeks 0, 2 and 12 ranged from 360-469 pg/mL, 572-673 pg/mL, and 470-556 pg/mL, respectively, for women treated with Vagifem. Mean FSH (averaged over the 24-hour sampling period) decreased significantly, with a median change of −9.0 IU/L at week 2 and −4.4 IU/L at week 12.

Vagifem (estradiol vaginal tablet) is a hydrophilic, cellulose-derived matrix tablet which hydrates upon contact with moisture, releasing 17β-estradiol (see Figure 1). The estradiol in Vagifem is chemically and biologically identical to the endogenous human estradiol and is therefore classified as a human estrogen. 17β-estradiol is the primary estrogen and the most active of the ovarian hormones.

Estrogen metabolites are primarily excreted in the urine as glucuronides and sulfates.

Exogenously-derived or enogenously-derived estrogens are primarily metabolized in the liver to estrone and estradiol, which are also found in the systemic circulation. Vagifem intravaginal administration avoids first-pass metabolism that occurs with oral estrogens.

In vivo estrogens diffuse through cell membranes, distribute throughout the cell, bind to and activate the estrogen receptors, thereby eliciting their biological effects. Estrogen receptors have been identified in the tissue of the reproductive tract, breast, pituitary, hypothalamus, liver and bone of women. Estrogens regulate growth, differentiation and function of many different tissues within and outside of the reproductive system. Estrogens are intricately involved with other hormones, especially progesterone, and during the ovulatory phase of the menstrual cycle cause proliferation of the endometrium.

Endogenous 17β-estradiol induces and maintains the primary and secondary female sexual characteristics. Most of the activities of 17β-estradiol appear to be exerted via binding to specific estrogen receptors in target cells of tissue. The steroid-receptor complex is bound to the cell’s DNA and induces synthesis of specific proteins.

The hormone deficient state associated with menopause leads to atrophic changes in the urogenital epithelial and subepithelial tissues. Vaginal blood flow is reduced, causing decreased lubrification during sexual arousal rendering the tissue more susceptible to trauma. Thinning of the vaginal mucosa occurs, cellular and glycogen production declines, decreasing the colonization of lactobacilli and thus lactic acid production. The usual acidity of the vagina, which serves as a potent defence mechanism, is lost. Symptoms associated with the atrophic changes are vaginal dryness, genital itching and burning and dyspareunia. The goal of local estrogen therapy is to provide sufficient estrogen to reverse atrophic changes in the local tissues and relieve associated symptoms.

Maturation of the vaginal epithelium is dependent on estrogen. Estrogen increases the number of superficial and intermediate cells as compared to basal cells.

Estrogen keeps pH in the vagina down to around 4.5 which enhances normal bacterial flora, Lactobacillus Döderlein predominating.