1. Name Of The Medicinal Product
Premarin* Vaginal Cream.
2. Qualitative And Quantitative Composition
Each 1gram of the cream contains 0.625mg conjugated estrogens USP.
3. Pharmaceutical Form
Cream for intravaginal or topical administration.
4. Clinical Particulars
4.1 Therapeutic Indications
Short-term treatment of atrophic vaginitis and post-menopausal atrophic urethritis, kraurosis vulvae.
4.2 Posology And Method Of Administration
Adults: The usual recommended dose is 1 to 2g daily administered intravaginally or topically to the vaginal area, depending on the severity of the condition.
The applicator has dosage markings showing how much of the cream is equivalent to 1g or 2g to help you with applying the correct amount of cream.
The following 'Instruction for Use' should be given to the patient and are included in the Patient Information Leaflet:
To apply the cream into the vagina, the applicator should be used as follows:
1. Remove the cap from the aluminium tube of cream and screw the nozzle end of the applicator onto the tube.
2. Gently squeeze the tube to force the cream into the barrel of the applicator. Depending on the dose your doctor advised you to use, fill the applicator with cream up to the appropriate dosage marking.
3. Unscrew the filled applicator from the tube of cream and replace the cap on the tube.
4. To apply the cream, gently insert the applicator into your vagina and then press the plunger back to its original position.
5. After use, remove the empty applicator.
To clean the applicator after use, pull the plunger out from the barrel and wash both parts with mild soap and warm water. Do not boil or use hot water.
Administration should be cyclic (e.g. three weeks on and one week off). It should start on the fifth day of bleeding in the patient who is menstruating and arbitrarily if not.
For initiation and continuation of treatment of postmenopausal symptoms, the lowest effective dose for the shortest duration (see also Section 4.4 Special warnings and special precautions for use) should be used.
The addition of a progestogen is not needed during treatment with Premarin Vaginal Cream (see Section 4.4 Special warnings and special precautions for use)
Missed dose: If the patient forgets to apply a dose, it should be applied as soon as possible. The patient should not use doubled their usual dose to make up for missed applications.
Elderly: There are no special dosage requirements for elderly patients, but as with all medicines, the lowest effective dose should be used.
Children: Not recommended.
4.3 Contraindications
1. Known past or suspected cancer of the breast.
2. Known or suspected estrogen-dependent malignant tumours (e.g. endometrial cancer)
3. Undiagnosed abnormal genital bleeding.
4. Untreated endometrial hyperplasia
5. Active or past history of venous thromboembolism (e.g. deep vein thrombosis, pulmonary embolism)
6. Active or recent arterial thromboembolic disease (e.g. angina, myocardial infarction)
7. Acute liver disease or history of liver disease where the liver function tests have failed to return to normal.
8. Known hypersensitivity to the active substance or to any of the excipients of Premarin Vaginal Cream.
9. Porphyria
4.4 Special Warnings And Precautions For Use
Due to estrogen absorption following the application of Premarin Vaginal Cream, prolonged administration might result in systemic effects. Therefore, the following warnings and precautions should be considered.
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.
1. Medical Examination/Follow up
Before initiating or reinstituting HRT, a complete personal and family medical history should be taken. Physical (including pelvic and breast) examination should be guided by the contraindications and warnings for use. During treatment, periodic check-ups are recommended of a frequency and nature adapted to the individual women. Women should be advised what changes in their breasts should be reported to their doctor or nurse (see 'Breast Cancer' below). Investigations, including mammography, should be carried out in accordance with currently accepted screening practices, modified to the clinical needs of the individual.
2. Conditions that 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 treatment with Premarin Vaginal Cream, in particular:
− Leiomyoma (uterine fibroids) or endometriosis
− A family history of, or other risk factors for, thromboembolic disorders (see below)
− Risk factors for estrogen dependent tumours (e.g. first degree heredity for breast cancer)
− Hypertension
− Liver disorders (e.g. liver adenoma)
− Diabetes mellitus with or without vascular involvement
− Cholelithiasis
− Migraine or (severe) headaches
− Systemic lupus erythematosus (SLE)
− A history of endometrial hyperplasia (see below)
− Epilepsy
− Asthma
− Otosclerosis
3. Reasons for immediate withdrawal of therapy
Therapy should be discontinued if a contra-indication 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
4. Endometrial Hyperplasia
The risk of endometrial hyperplasia and carcinoma is increased when systemic estrogens are administered alone for prolonged periods of time. The endometrial safety of long-term or repeated use of topical vaginal estrogens is uncertain. Therefore, if repeated, treatment should be reviewed at least annually, with special consideration given to any symptoms of endometrial hyperplasia or carcinoma.
Unopposed Estrogen stimulation may lead to premalignant or malignant transformation in the residual foci of endometriosis. Therefore, caution is advised when using this product in women who have undergone hysterectomy because of endometriosis, especially if they are known to have residual endometriosis.
If break-through bleeding or spotting appears at any time on therapy, the reason should be investigated, which may include endometrial biopsy to exclude endometrial malignancy.
5. Breast Cancer
A randomised placebo-controlled trial, the Women's Health Initiative study (WHI), and epidemiological studies, including the Million Women Study (MWS), have reported an increased risk of breast cancer in women taking estrogens, estrogen-progestogen combinations or tibolone for HRT for several years (see Section 4.8 Undesirable effects). For all HRT, an excess risk becomes apparent within a few years of use and increases with the duration of intake but returns to baseline within a few (at most five) years after stopping treatment.
In the MWS, the relative risk of breast cancer with conjugated equine estrogens (CEE) or estradiol (E2) was greater when a progestogen was added, either sequentially or continuously, and regardless of type of progestogen. There was no evidence of a difference in risk between the different routes of administration.
In the WHI study, the continuous combined conjugated equine estrogen and medroxyprogesterone acetate (CEE + MPA) product used was associated with breast cancers that were slightly larger in size and more frequently had local lymph node metastases compared to placebo.
HRT, especially estrogen-progestogen combined treatment, increases the density of mammographic images which may adversely affect the radiological detection of breast cancer.
6. Venous Thromboembolism
Hormone replacement therapy (HRT) is associated with a higher relative risk of developing venous thromboembolism (VTE) i.e. deep vein thrombosis or pulmonary embolism. One randomised controlled trial and epidemiological studies found a two to threefold 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 per 1000 women aged 50-59 years and 8 per 1000 women aged between 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 years and between 5 and 15 (best estimate = 9) per 1000 women aged 60-69 years. The occurrence of such an event is more likely in the first year of HRT than later.
Generally recognised risk factors for VTE include a personal or family history and severe obesity (Body Mass Index>30kg/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. HRT 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 to 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 weeks earlier, if this is possible. Treatment should not be restarted until the woman is completely mobilised.
If venous thromboembolism develops after initiating therapy the drug should be discontinued. Patients should be told to contact their doctors immediately when they are aware of potential thromboembolic symptoms (e.g. painful swelling of leg, sudden pain in the chest, dyspnoea)
7. Coronary Artery Disease (CAD)
There is no evidence from randomised controlled trials of cardiovascular benefit with continuous combined conjugated estrogens and MPA. Two large clinical trials (WHI and HERS i.e. Heart and Estrogen/progestin Replacement Study) showed a possible increased risk of cardiovascular morbidity in the first year of use and no overall benefit. For other HRT products, there are only limited data from randomised controlled trials examining effects in cardiovascular morbidity or mortality. Therefore, it is uncertain whether these findings also extend to other HRT products.
8. 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 estrogens 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 per 1000 women aged 50-59 years and 11 per 1000 women aged 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 aged 50-59 years and between 1 and 9 (best estimate = 4) per 1000 users aged 60-69 years. It is unknown whether the increased risk also extends to other HRT products.
9. Ovarian Cancer
Long term (at least 5 –10 years) use of estrogen-only HRT products in hysterectomised women has been associated with an increased risk of ovarian cancer in some epidemiological studies. It is uncertain whether long-term use of combined HRT confers different risk than estrogen-only products.
Other Conditions
10. Estrogens may cause fluid retention and therefore patients with cardiac or renal dysfunction should be carefully observed. Patients with terminal renal insufficiency should be closely observed, since it is expected that the level of circulating active ingredients in Premarin is increased.
11. Women with an intact uterus of child-bearing potential should be advised to adhere to non-hormonal contraceptive methods.
Premarin Vaginal Cream has been shown to weaken latex condoms. The potential for Premarin Vaginal Cream to weaken and contribute to the failure of condoms, diaphragms or cervical caps made of latex or rubber should be considered. If there is still a possibility that a patient could become pregnant, they should be advised to use an alternative form of non-hormonal contraceptive.
12. The use of estrogen may influence the laboratory results of certain endocrine tests and liver enzymes.
Estrogens increase thyroid binding globulin (TBG), leading to increased circulating total thyroid hormone, as measured by protein-bound iodine (PBI), T4 levels (by column or by radio-immunoassay) or T3 levels (by radio-immunoassay). T3 resin uptake is decreased, reflecting the elevated TBG. Free T4 and free T3 concentrations are unaltered.
Other binding proteins may be elevated in serum, i.e. corticoid binding globulin (CBG), sex-hormone-binding globulin (SHBG) leading to increased circulating corticosteroids and sex steroids, respectively. Free or biologically active hormone concentrations are unchanged. Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha-I-antitrypsin, ceruloplasmin).
Some patients dependent on thyroid hormone replacement therapy may require increased doses in order to maintain their free thyroid hormone levels in an acceptable range. Therefore, patients should have their thyroid function monitored more frequently when commencing concurrent treatment in order to maintain their free thyroid hormone levels in an acceptable range.
13. There is an increase in the risk of gallbladder disease in women receiving HRT (see conditions that need supervision)
14. A worsening of glucose tolerance may occur in patients taking estrogens and therefore diabetic patients should be carefully observed while receiving hormone replacement therapy.
15. Women with pre-existing hypertriglyceridemia should be followed closely during estrogen replacement or hormone replacement therapy, since rare cases of large increases of plasma triglycerides leading to pancreatitis have been reported with estrogen therapy in this condition.
16. Estrogens should be used with caution in individuals with severe hypocalcaemia
17. 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 post-menopausal women or other HRT products.
18. Exogenous estrogens may induce or exacerbate symptoms of angioedema, particularly in women with hereditary angioedema.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
The metabolism of estrogens may be increased by concomitant use of substances known to induce drug-metabolising enzymes, specifically cytochrome P450 enzymes, such as anticonvulsants (e.g. phenobarbital, phenytoin, carbamazepine) and anti-infectives (e.g. rifampicin, rifabutin, nevirapine, efavirenz).
Ritonavir and nelfinavir, although known as strong inhibitors, by contrast exhibit inducing properties when used concomitantly with steroid hormones.
Herbal preparations containing St John's wort (Hypericum perforatum) may induce the metabolism of estrogens.
Clinically, an increased metabolism of estrogens and progestogens may lead to decreased effect and changes in the uterine bleeding profile.
The response to metyrapone may be reduced.
4.6 Pregnancy And Lactation
Premarin is not indicated during pregnancy.
For women with a uterus:
If pregnancy occurs during medication with Premarin, treatment should be withdrawn immediately. The results of most epidemiological studies to date relevant to inadvertent foetal exposure to estrogens indicate no teratogenic or foetotoxic effects.
Lactation:
Premarin is not indicated during lactation.
4.7 Effects On Ability To Drive And Use Machines
Not applicable.
4.8 Undesirable Effects
See also 4.4 Special warnings and special precautions for use.
Adverse drug reactions (ADRs)
The following adverse reactions have been reported with Premarin Vaginal Cream or are undesirable effects associated with estrogens.
System Organ Class
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Adverse Reaction
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Reproductive system
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Breakthrough bleeding/spotting
Application site reactions of vulvovaginal discomfort including burning, irritation, and genital pruritus
Vaginal discharge
Increased size of uterine leiomyomata
Endometrial hyperplasia
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Breast disorders
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Breast pain, tenderness, enlargement, discharge
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Gastrointestinal disorders
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Nausea, vomiting bloating, abdominal pain
Pancreatitis
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Nervous system disorders
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Dizziness, headache, migraine, nervousness, stroke
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Musculoskeletal, connective tissue and bone disorders
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Arthralgias, leg cramps
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Psychiatric disorders
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Changes in libido, mood disturbances, irritability, depression
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Vascular disorders
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Pulmonary embolism.
Venous thromboembolism
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Cardiac disorders
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Myocardial Infarction
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General disorders and administration site conditions
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Oedema
Exacerbation of otosclerosis
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Skin and subcutaneous tissue disorders
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Alopecia
Chloasma, hirsutism, pruritus, rash
Erythema multiforme, erythema nodosum
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Hepatobiliary disorder
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Gallbladder disease
Cholestatic jaundice
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Infections and Infestations
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Vaginitis, including vaginal candidiasis
Cystitis
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Neoplasms benign and malignant (including cysts and polyps)
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Breast cancer*, Fibrocystic breast changes
Endometrial cancer, Enlargement of hepatic haemangiomas
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Immune system disorders
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Urticaria, Angioedema, Anaphylactic/anaphylactoid reactions, Hypersensitivity
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Metabolism and nutrition disorders
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Glucose intolerance
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Eye Disorders
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Intolerance to contact lenses
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Investigations
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Changes in weight (increase or decrease)
Increased triglycerides
Increases in blood pressure
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Breast Cancer
According to evidence from a large number of epidemiological studies and one randomised placebo-controlled trial, the Women's Health Initiative (WHI), the overall risk of breast cancer increases with increasing duration of HRT use in current or recent HRT users.
For estrogen-only HRT, estimates of relative risk (RR) from a reanalysis of original data from 51 epidemiological studies (in which>80% of HRT use was estrogen-only HRT) and from the epidemiological Million Women Study (MWS) are similar at 1.35 (95%CI 1.21 – 1.49) and 1.30 (95%CI 1.21 – 1.40), respectively.
For estrogen plus progestogen combined HRT, several epidemiological studies have reported an overall higher risk for breast cancer than with estrogens alone.
The MWS reported that, compared to never users, the use of various types of estrogen-progestogen combined HRT was associated with a higher risk of breast cancer (RR = 2.00, 95%CI: 1.88 – 2.12) than use of estrogens alone (RR = 1.30, 95%CI: 1.21 – 1.40) or use of tibolone (RR=1.45; 95%CI 1.25-1.68).
The WHI trial reported a risk estimate of 1.24 (95%CI 1.01 – 1.54) after 5.6 years of use of estrogen-progestogen combined HRT (CEE + MPA) in all users compared with placebo.
The absolute risks calculated from the MWS and the WHI trial are presented below:
The MWS has estimated, from the known average incidence of breast cancer in developed countries, that:
• For women not using HRT, about 32 in every 1000 are expected to have breast cancer diagnosed between the ages of 50 and 64 years.
• For 1000 current or recent users of HRT, the number of additional cases during the corresponding period will be
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• For users of estrogen-only replacement therapy
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|
|
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• between 0 and 3 (best estimate = 1.5) for 5 years' use
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|
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• between 3 and 7 (best estimate = 5) for 10 years' use.
|
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• For users of estrogen plus progestogen combined HRT
|
|
|
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• between 5 and 7 (best estimate = 6) for 5 years' use
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|
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• between 18 and 20 (best estimate = 19) for 10 years' use.
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The WHI trial estimated that after 5.6 years of follow-up of women between the ages of 50 and 79 years, an additional 8 cases of invasive breast cancer would be due to estrogen-progestogen combined HRT (CEE + MPA) per 10,000 women years.
According to calculations from the trial data, it is estimated that:
• For 1000 women in the placebo group.
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• About 16 cases of invasive breast cancer would be diagnosed in 5 years.
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• For 1000 women who used estrogen plus progestogen combined HRT (CEE + MPA), the number of additional cases would be
|
• Between 0 and 9 (best estimate = 4) for 5 years' use.
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The number of additional cases of breast cancer in women who use HRT is broadly similar for women who start HRT irrespective of age at start of use (between the ages of 45-65) (see section 4.4 Special warnings and special precautions for use).
Other adverse reactions reported in association with estrogen/progestogen treatment including Premarin Vaginal Cream:
• Estrogen-dependent neoplasms benign and malignant, e.g. endometrial hyperplasia, endometrial cancer
• Venous thromboembolism, i.e. deep leg or pelvic venous thrombosis and pulmonary embolism, is more frequent among hormone replacement therapy users than among non-users. For further information, see section 4.3 Contraindications and 4.4 Special warnings and special precautions for use.
• Retinal vascular thrombosis
• Myocardial infarction
• Increases in blood pressure
• Cholestatic jaundice
• Enlargement of hepatic haemangiomas
• Skin and subcutaneous disorders: erythema multiforme, erythema nodosum, vascular purpura
• Probable dementia (see section 4.4 Special warnings and special precautions for use)
• Exacerbation of chorea
• Exacerbation of porphyria,
• Exacerbation of hypocalcaemia
• Exacerbation of otosclerosis
4.9 Overdose
Numerous reports of ingestion of large doses of estrogen-containing oral contraceptives by young children indicate that acute serious ill effects do not occur. Overdosage of estrogen may cause nausea and vomiting, and withdrawal bleeding may occur in females. There is no specific antidote and further treatment should be symptomatic.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
ATC Code: G03C A57
Conjugated Estrogens
Conjugated estrogen cream has identical pharmacological actions to endogenous estrogens. The active ingredients are primarily the sulphate esters of estrone, equilin sulphates, 17α-estradiol and 17β-estradiol. These substitute for the loss of estrogen production in menopausal women, and alleviate menopausal symptoms.
5.2 Pharmacokinetic Properties
Absorption
The estrogens in Premarin Vaginal Cream are absorbed systemically.
Distribution
The distribution of exogenous estrogen is similar to that of endogenous estrogens. Estrogens are widely distributed in the body and are generally found in higher concentrations in the sex hormone target organs. Estrogens circulate in the blood largely bound to sex hormone binding globulin (SHBG) and albumin.
Metabolism
Exogenous estrogens are metabolised in the same manner as endogenous estrogens. Circulating estrogens exist in dynamic equilibrium of metabolic interconversions. These transformations take place mainly in the liver. Estradiol is converted reversibly to estrone, and both can be converted to estriol, which is the major urinary metabolite. Estrogens also undergo enterohepatic recirculation via sulphate and glucuronide conjugation in the liver, biliary secretion of conjugates into the intestine, and hydrolysis in the gut following reabsorption. In post-menopausal women a significant proportion of the circulating estrogens exists as sulphate conjugates, especially estrone sulphate, which serves as a circulating reservoir for the formation of more active estrogens.
Excretion
Estriol, estrone and estradiol are excreted in the urine along with glucuronide and sulphate conjugates.
5.3 Preclinical Safety Data
There are no preclinical data of relevance to the prescriber which are additional to that already included in other sections of the SPC.
6. Pharmaceutical Particulars
6.1 List Of Excipients
Liquid paraffin, glyceryl monostearate, cetyl alcohol, cetyl esters wax, white wax, methyl stearate, sodium lauryl sulphate, phenylethyl alcohol, glycerin, propylene glycol monostearate, purified water.
6.2 Incompatibilities
Not applicable.
6.3 Shelf Life
2 years.
6.4 Special Precautions For Storage
Do not store above 25°C.
6.5 Nature And Contents Of Container
Primary container: Aluminium tube with a white screw-on cap, containing 42.5g of cream.
Secondary container: Cardboard carton.
6.6 Special Precautions For Disposal And Other Handling
Not applicable.
7. Marketing Authorisation Holder
John Wyeth and Brother Limited
Trading as Wyeth Pharmaceuticals
Huntercombe Lane South
Taplow, Maidenhead
Berkshire, SL6 0PH
8. Marketing Authorisation Number(S)
PL 0011/0163.
9. Date Of First Authorisation/Renewal Of The Authorisation
22 November 1990 / 12 December 1995
10. Date Of Revision Of The Text
05 July 2010
* Trade marks
