Vagifem

Vagifem

estradiol

Manufacturer:

Novo Nordisk

Distributor:

Zuellig Pharma
Full Prescribing Info
Contents
Estradiol hemihydrate.
Description
Vagifem also contains the following excipients: Tablet Core: Hypromellose, lactose monohydrate, maize starch, magnesium stearate. Film-coating: Hypromellose, macrogol 6000.
Action
Estrogen (sex hormone) preparation.
Pharmacology: Pharmacodynamics: 17-β oestradiol is the principal and most active of the naturally occurring human oestrogens. It has pharmacological actions in common with all oestrogenic compounds. The action on the vagina is to increase maturation of vaginal epithelial cells and increase cervical secretory activity.
Pharmacokinetics: Oestrogens are well absorbed through skin, mucosa and the GIT. The vaginal delivery circumvents first-pass metabolism. Following a single-dose of Vagifem, low elevations of plasma oestradiol have been observed. After 14 days of treatment, only a marginal absorption of oestradiol could be detected, with mean levels in the postmenopausal range. The levels of oestradiol seen during 12 weeks of Vagifem administration do not show any accumulation. The levels of estrone seen during 12 weeks of Vagifem administration do not show any accumulation of estrone and the observed values are within the postmenopausal range.
Indications/Uses
Treatment of atrophic vaginitis due to estrogen deficiency. The experience of treating women >65 years is limited.
Dosage/Direction for Use
Vagifem is administered intravaginaly using the applicator.
Initial Dose: 1 vaginal tablet/day for 2 weeks. Maintenance Dose: 1 vaginal tablet twice a week. Treatment may start on any convenient day.
If a dose is forgotten, it should be taken as soon as the patient remembers. A double dose should be avoided. For initiation and continuation of symptoms, the lowest effective dose for the shortest duration (see Precautions) 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 but the plasma estradiol levels after the first 2 weeks usually do not exceed postmenopausal levels. The addition of a progestogen is not recommended.
Instruction for Use: Tear off 1 single blister pack and open the end. Insert the applicator carefully into the vagina until some resistance is felt. To release the tablet, gently press the push button until a click is felt. The tablet becomes secure in the wall of the vagina immediately. It will not fall out upon standing or walking. Withdraw and throw away the applicator.
Overdosage
No cases of overdose has been reported. Vagifem is intended for intravaginal use. The dose of estradiol is so low that a considerable number of tablets would have to be ingested to approach the dose normally used for oral systemic treatment. Treatment should be symptomatic.
Vagifem is intended for local treatment intravaginally. The dose of 17β-estradiol (25 mcg) is so low that a considerable number of tablets would have to be ingested to approach the dose normally used for oral systemic treatment. There is no specific antidote and treatment should be symptomatic.
Contraindications
Known or suspected pregnancy; known, past or suspected breast cancer; known or suspected oestrogen-dependent malignant tumours (eg, endometrial cancer); undiagnosed genital bleeding, untreated endometrial hyperplasia; previous idiopathic or current venous thromboembolism (deep venous thrombosis, pulmonary embolism); known hypersensitivity to estradiol or to any of the excipients; porphyria.
Use in pregnancy & lactation: Vagifem is not indicated during pregnancy. If pregnancy occurs during medication with Vagifem, treatment should be withdrawn immediately. The results of most epidemiological studies to date relevant to inadvertent fetal exposure to oestrogens indicate no teratogenic or foetotoxic effects.
Vagifem is not indicated during lactation.
Special Precautions
For the treatment of postmenopausal symptoms, HRT should only be initiated for symptoms that adversely affect quality of life. In all cases, a careful appraisal of the risks and benefits should be undertaken at least annually and HRT should only be continued as long as the benefit outweighs the risk.
Medical Examination/Follow-Up: Before initiating or reinstituting hormone therapy, a complete personal and family medical history should be taken. Physical (including pelvic and breast) examination should be guided by this and by the contraindications. During treatment, periodic check-ups are recommended of a frequency and nature adapted to the individual woman. Women should be advised which changes in their breasts should be reported to the doctor or nurse. Investigations including mammography should be carried out in accordance with currently accepted screening practices, modified to the clinical needs of the individual.
Conditions which Need Supervision: If any of the following conditions are present, have occurred previously and/or have been aggravated during pregnancy or previous hormone treatment, the patient should be closely supervised.
It should be taken into account that these conditions may recur or be aggravated during systemic oestrogen treatment, in particular: Leiomyoma (uterine fibroids) or endometriosis; a history of, or risk factors for, thromboembolic disorders (see as follows); hypertension; liver disorders (eg, liver adenoma), diabetes mellitus with or without vascular involvement; cholelithiasis; migraine or (severe) headache; systemic lupus erythematosus; a history of endometrial hyperplasia (see as follows); epilepsy; asthma; otosclerosis.
Due to the local administration of low dose estradiol in Vagifem, the recurrence or aggravation of the previously mentioned conditions is less likely than with systemic oestrogen treatment.
Reasons For Immediate Withdrawal of Therapy: Therapy should be discontinued in case a contraindication is discovered and in the following situations: Jaundice or deterioration in liver function; significant increase in blood pressure; new onset of migraine-type headache; pregnancy.
Endometrial Hyperplasia: Women with an intact uterus with abnormal bleeding of unknown aetiology or women with an intact uterus, who have previously been treated with unopposed oestrogens, should be examined with special care in order to disclose a possible hyperstimulation/malignancy of the endometrium before initiation of treatment with Vagifem.
The risk of endometrial cancer after treatment with oral unopposed oestrogens is dependent on both duration of treatment and on oestrogen dose. The dose of estradiol in Vagifem is low and treatment is local. A minor degree of systemic absorption may occur in some patients. However, Vagifem has not been associated with an increased risk of endometrial hyperplasia or uterine cancer.
Because there is no systemic effect under the local oestrogen treatment with Vagifem, the addition of a progestagen is not recommended.
As a general rule, oestrogen replacement therapy should not be prescribed for >1 year without another physical examination including gynaecological examination being performed.
Vagifem is a local low-dose estradiol preparation and therefore, the occurrence of the conditions that follows is less likely than with systemic oestrogen treatment.
Breast Cancer: Systemic oestrogen or oestrogen-progestagen treatment may increase the risk of breast cancer. Relative risk of breast cancer with conjugated equine oestrogens (CEE) or estradiol (E2) was greater when a progestagen was added, either sequentially or continuously and regardless of type of progestagen.
Venous Thromboembolism (VTE): Systemic HRT is associated with a higher relative risk of developing VTE ie, deep vein thrombosis or pulmonary embolism. One randomized controlled trial and epidemiological studies found a 2- to 3-fold higher risk for users compared with non-users. For non-users, it is estimated that the number of cases of VTE that will occur over a 5-year period is about 3/1000 women 50-59 years and 8/1000 women 60-69 years. It is estimated that in healthy women who use HRT for 5 years, the number of additional cases of VTE over a 5-year period will be between 2 and 6 (best estimate=4) per 1000 women aged 50-59 and between 5 and 15 (best estimate=9) per 1000 women 60-69 years. The occurrence of such an event is more likely in the 1st year of HRT than later.
Generally recognised risk factors for VTE include a personal history or family history, severe obesity (BMI >30 kg/m2) and systemic lupus erythematosus (SLE). There is no consensus about the possible role of varicose veins in VTE. Patients with a history of VTE or known thrombophilic states have an increased risk of VTE. Hormone replacement therapy may add to this risk. Personal or strong family history of thromboembolism or recurrent spontaneous abortion, should be investigated in order to exclude a thrombophilic predisposition. Until a thorough evaluation of thrombophilic factors has been made or anticoagulant treatment initiated, use of HRT in such patients should be viewed as contraindicated. Those women already on anticoagulant treatment require careful consideration of the benefit-risk of use of HRT.
The risk of VTE may be temporarily increased with prolonged immobilisation, major trauma or major surgery. As in all postoperative patients, scrupulous attention should be given as prophylactic measures to prevent VTE following surgery. Where prolonged immobilisation is liable to follow elective surgery, particularly abdominal or orthopaedic surgery to the lower limbs, consideration should be given to temporarily stopping HRT 4-6 weeks earlier, if possible. Treatment should not be restarted until the woman is completely mobilised.
If VTE develops after initiating therapy, the drug should be discontinued. Patients should be told to contact their doctors immediately when they are aware of a potential thromboembolic symptom (eg, painful swelling of a leg, sudden pain in the chest, dyspnea).
Stroke: One large randomised clinical trial (WHI-trial) found, as a secondary outcome, an increased risk of ischaemic stroke in healthy women during treatment with continuous combined conjugated oestrogens and MPA. For women who do not use HRT, it is estimated that the number of cases of stroke that will occur over a 5-year period is about 3/1000 women 50-59 years and 11/1000 women 60-69 years. It is estimated that for women who use conjugated estrogens and MPA for 5 years, the number of additional cases will be between 0 and 3 (best estimate=1) per 1000 users 50-59 years and between 1 and 9 (best estimate=4) per 1000 users 60-69 years. It is unknown whether the increased risk also extends to other HRT products.
Ovarian Cancer: Long-term (at least 5-10 years) use of oestrogen-only HRT products in hysterectomised women has been associated with an increased risk of ovarian cancer in some epidemiological studies. It is unlikely that long-term use of combined HRT leads to any risk increase for ovarian cancer.
Other Conditions: Oestrogens may cause fluid retention and therefore patients with cardiac or renal dysfunction should be carefully observed during the 1st weeks of treatment.
Patients with terminal renal insufficiency should also be closely observed, since it is expected that the level of circulating active ingredients in Vagifem is increased.
There is no conclusive evidence for improvement of cognitive function.
There is some evidence from the WHI trial of increased risk of probable dementia in women who start using continuous combined CEE and MPA after the age of 65.
It is unknown whether the findings apply to younger postmenopausal women or other HRT products.
Effects on the Ability to Drive or Operate Machinery: No effects known.
Adverse Reactions
More than 640 patients have been treated with Vagifem in clinical trials, including >200 patients treated from 28 weeks and up to 64 weeks. Well-known oestrogen-related adverse events which occurred with a higher frequency in the treated group as compared with the placebo group, are presented as "common (>1/100,<1/10)".
The spontaneous reporting rate on Vagifem corresponds to approximately 1 case per 10,000 patient years. Adverse events for which an increased frequency has not been observed in clinical trials, but which have been spontaneously reported and which on an overall judgement are considered possibly related to Vagifem treatment, are therefore presented as "very rare (<1/10,000)".
Post-marketing experience is subject to under-reporting especially with regard to trivial and well known adverse drug reactions. The presented frequencies should be interpreted in that light.
The most commonly reported adverse drug reactions are: Vaginal discharge and vaginal discomfort.
Oestrogen-related adverse events eg, breast pain, peripheral oedema and postmenopausal bleedings are most likely present at the beginning of Vagifem treatment.
Common (>1/100, <1/10): Infections and Infestations: Genital candidiasis or vaginitis.
Nervous System Disorders: Headache.
Gastrointestinal Disorders: Nausea, abdominal pain, abdominal distension or abdominal discomfort, dyspepsia, vomiting, flatulence.
Reproductive System and Breast Disorders: Vaginal haemorrhage, vaginal discharge or vaginal discomfort, breast oedema, breast enlargement, breast pain or breast tenderness.
General Disorders and Administration Site Conditions: Peripheral oedema.
Very Rare (<1/10,000): Neoplasms Benign and Malignant (including cysts and polyps): Breast cancer, endometrial cancer.
Immune System Disorders: Hypersensitivity, not otherwise specified (NOS).
Metabolism and Nutrition Disorders: Fluid retention.
Psychiatric Disorders: Insomnia, depression.
Nervous System Disorders: Aggravated migraine.
Vascular Disorders: Deep venous thrombosis.
Gastrointestinal Disorders: Diarrhoea.
Skin and Subcutaneous Tissue Disorders: Urticaria, erythematosus rash, rash NOS, pruritic rash, genital pruritus.
Reproductive System and Breast Disorders: Endometrial hyperplasia, vaginal irritation, vaginal pain, vaginismus, vaginal ulceration.
General Disorders and Administration Site Conditions: Ineffective drug.
Investigations: Increased weight, increased blood oestrogen.
The following adverse reactions have been reported in association with other oestrogen treatment: Myocardial infarction, congestive heart disease.
Gall bladder disease.
Skin and Subcutaneous Disorders: Chloasma, erythema multiforme, erythema nodosum, vascular purpura, pruritus.
Vaginal candidiasis.
Risk of developing endometrial cancer, endometrial hyperplasia or increase in size of uterine fibroids*. Insomnia; epilepsy; libido disorder NOS; deterioration of asthma; probable dementia.
* In non-hysterectomised women.
Drug Interactions
Due to a topic administration of the low dose of estradiol in Vagifem, interactions of clinical relevance are not expected.
Storage
Do not store above 25°C. Do not refrigerate. Store in the original package.
ATC Classification
G03CA03 - estradiol ; Belongs to the class of natural and semisynthetic estrogens used in estrogenic hormone preparations.
Presentation/Packing
Film-coated vaginal tab (white, marked "NOVO 279", contained in a single-use applicator) 25 mcg x 15's.
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