Premarin Cream 0,625 mg Vaginal cream

PREMARIN cream is indicated for the treatment of:

• postmenopausal and senile vulvovaginitis
• atrophic vaginitis
• pruritus vulvae caused by atrophic changes in the vulval epithelium
• dyspareunia associated with an atrophic vaginal epithelium
• and for use prior to plastic pelvic surgery in menopausal cases

Posology

Administration should be cyclic (e.g., three weeks on and one week off) and for short term use only.

For treatment of atrophic vaginitis

The lowest dose that will control symptoms should be chosen and PREMARIN should be discontinued as promptly as possible. Attempts to discontinue or taper PREMARIN should be made at three- to six-month intervals.

Usual dosage

0,5 to 2 gram(s) daily, intravaginally, depending on the severity of the condition.

Special populations

Elderly use

The oestrogen-alone sub study of the Womenu2019s Health Initiative (WHI) reported an increased risk of stroke compared with placebo in postmenopausal women 65 years of age or older (see section 5.1). A sub study of the Womenu2019s Health Initiative Memory Study (WHIMS), an ancillary study of WHI conducted in women aged 65 to 79, reported an increased risk of developing probable dementia when compared with placebo (see section 5.1).

Paediatric population

Clinical studies have not been conducted in the paediatric population. Safety and effectiveness in paediatric patients have not been established. PREMARIN cream treatment of prepubertal girls may induce premature breast development and vaginal cornification and may induce uterine bleeding. Large and repeated doses of PREMARIN cream over an extended time period have been shown to accelerate epiphyseal closure and should therefore not be started before epiphyseal closure has occurred in order not to compromise final growth. PREMARIN cream is not indicated in children.

Method of administration

For intravaginal use.

PREMARIN cream is contraindicated in patients with:

• known or suspected hypersensitivity to conjugated estrogens or to any of the excipients of PREMARIN (listed in section 6.1)
• known or suspected pregnancy (see section 4.6)
• undiagnosed abnormal genital bleeding
• personal and family history of known or suspected breast cancer
• history of non-cancerous breast diseases (atypical hyperplasia or lobular carcinoma in situ)
• previous treatment using radiation therapy to the chest or breast
• known or suspected estrogen-dependent neoplasia (e.g., endometrial cancer, endometrial hyperplasia)
• active or history of arterial thromboembolic disease (e.g., stroke, myocardial infarction)
• previous proven deep-vein thrombosis (DVT)
• previous pulmonary embolism
• inherited thrombophilia
• known protein C, protein S or antithrombin deficiency or other known thrombophilic disorders
• active or chronic liver dysfunction or disease
• known inherited genetic mutations: BRCA1 and BRCA2 genes
• early menstrual periods (before the age of 12 years)
• previous exposure to diethylstilbestrol (DES)

General

Systemic absorption may occur with the use of PREMARIN cream. Warnings and precautions associated with oral PREMARIN treatment should be taken into account.

Cardiovascular risk

Estrogen Replacement Therapy (ERT) has been reported to increase the risk of stroke and deep venous thrombosis (DVT). Patients who have risk factors for thrombotic disorders should be kept under careful observation.

Stroke

In the estrogen-alone sub study of the Womenu2019s Health Initiative (WHI), (see section 5.1), a statistically significant increased risk of stroke was reported in women receiving estrogen alone compared to women receiving placebo (45 vs. 33 per 10 000 person-years). The increase in risk was observed during year one and persisted. Should a stroke occur or be suspected, PREMARIN cream should be discontinued immediately.

Coronary heart disease

In the estrogen alone sub study of WHI, no overall effect on coronary heart disease (CHD) events (defined as non-fatal MI, silent MI, or death due to CHD) was reported in women receiving estrogen alone compared to placebo.

Venous thromboembolism (VTE)

In the estrogen-alone sub study of the WHI, the increased risk of deep vein thrombosis (DVT), was reported to be statistically significant (23 vs. 15 per 10 000 person-years). The risk of pulmonary embolism (PE) was reported to be increased although it did not reach statistical significance. The increase in VTE (DVT and PE) risk was demonstrated during the first two years (30 vs. 22 per 10 000 person-years). Should a VTE occur or be suspected, PREMARIN cream should be discontinued immediately (see section 5.1). If feasible, PREMARIN cream should be discontinued at least 4 to 6 weeks before surgery of the type associated with an increased risk of thromboembolism, or during periods of prolonged immobilisation.

Malignant neoplasms

Breast cancer PREMARIN cream contains estrogen which, on prolonged use, may increase the risk of developing breast cancer. A meta-analysis of prospective epidemiological studies from 1992 to 2018 reported a significant increase in the risk of developing breast cancer in 55 575 women 40 u2013 59 years of age who used menopausal hormone therapy (MHT). The risk increased steadily with duration of use and was slightly greater for estrogen plus progestogen than estrogen only preparations, and the risk persisted for more than 10 years after stopping the treatment. The relative risk (RR) to develop breast cancer for estrogen plus progestogen preparations was 1,60 at 1 u2013 4 years and RR=2,08 at 5 u2013 14 years, while that for estrogen only preparations were 1,17 at 1 u2013 4 years and 1,33 at 5 u2013 14 years. There was no risk to develop breast cancer in women who started MHT at 60 years of age.

All women on PREMARIN cream should receive yearly breast examinations by a health care provider and perform monthly breast self-examinations. Mammography evaluations should be done based on patient age, risk factors, and prior mammogram results.

Endometrial cancer

The use of unopposed estrogens in women with an intact uterus has been associated with an increased risk of endometrial cancer. The reported endometrial cancer risk among unopposed estrogen users is about 2- to 12-fold greater than in non-users and appears dependent on duration of treatment and on estrogen dose. Most studies show no significant increased risk associated with the use of estrogens for less than 1 year. The greatest risk appears associated with prolonged use, with increased risks of 15- to 24-fold for 5 to 10 years or more, and this risk has been shown to persist for at least 8 to 15 years after ERT is discontinued. Adding a progestin to postmenopausal estrogen therapy has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer. Clinical surveillance of all women taking estrogen or estrogen plus progestin combinations is important. Adequate diagnostic measures, including endometrial sampling when indicated, should be undertaken to rule out malignancy in all cases of undiagnosed persistent or recurring abnormal uterine bleeding. There is no evidence that the use of natural estrogens results in a different endometrial risk profile than synthetic estrogens of equivalent estrogen dose.

Ovarian cancer

In some epidemiologic studies, the use of estrogen-only medicines has been associated with an increased risk of ovarian cancer over multiple years of use. Other epidemiologic studies have not found these associations.

Dementia

A sub study of the Womenu2019s Health Initiative Memory Study (WHIMS), an ancillary study of WHI conducted in women aged 65 - 79, reported an increased risk of developing probable dementia when compared with placebo. Since this study was conducted in women aged 65 u2013 79 years, it is unknown whether these findings apply to younger postmenopausal women.

Gallbladder disease

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

Visual abnormalities

Retinal vascular thrombosis has been reported in patients receiving estrogens. Discontinue PREMARIN cream pending examination if there is sudden partial or complete loss of vision, or a sudden onset of proptosis, diplopia, or migraine. If examination reveals papilledema or retinal vascular lesions, PREMARIN cream should be withdrawn.

Hypercalcaemia

Administration of estrogens may lead to severe hypercalcaemia in patients with breast cancer and bone metastases. If this occurs, PREMARIN cream should be stopped and appropriate measures be taken to reduce the serum calcium level.

The following special precautions are relevant to PREMARIN cream and/or treatment with estrogens:

Angioedema

Exogenous estrogens may exacerbate symptoms of angioedema in women with hereditary angioedema.

Fluid retention

Because estrogens may cause some degree of fluid retention, patients with conditions which might be influenced by this factor, such as cardiac or renal dysfunction, warrant careful observation when PREMARIN cream is prescribed.

Hypertriglyceridaemia

Caution should be exercised in patients with pre-existing hypertriglyceridaemia since rare cases of large increases of plasma triglycerides leading to pancreatitis have been reported with estrogen therapy in this population. Women with pre-existing hypertriglyceridaemia should be followed closely during ERT.

Hepatic impairment

Estrogens may be poorly metabolised in patients with impaired liver function.

Past history of cholestatic jaundice

For patients with a history of cholestatic jaundice associated with past estrogen use or with pregnancy, caution should be exercised and in the case of recurrence, PREMARIN cream should be discontinued.

Addition of a progestin when a woman has not had a hysterectomy

Studies of the addition of a progestin for 10 or more days of a cycle of estrogen administration or daily with estrogen in a continuous regimen, have reported a lowered incidence of endometrial hyperplasia than would be induced by estrogen treatment alone. Endometrial hyperplasia may be a precursor to endometrial cancer. There are, however, possible risks that may be associated with the use of progestins in ERT regimens compared to estrogen-alone regimens. These include an increased risk of breast cancer; adverse effects on lipoprotein metabolism, (e.g., lowering HDL, raising LDL); and impairment of glucose tolerance (see section 4.5).

Elevated blood pressure

In a small number of case reports, substantial increases in blood pressure during ERT have been attributed to idiosyncratic reactions to estrogens. In a large, randomised placebo-controlled clinical trial a generalised effect of ERT on blood pressure was not seen. Blood pressure should be monitored at regular intervals with estrogen use.

Exacerbation of other conditions

ERT may cause an exacerbation of asthma, epilepsy, migraine, diabetes mellitus, porphyria, systemic lupus erythematosus and hepatic haemangiomas, and should be used with caution in women with these conditions.

Depression

Depressed mood and depression are well-known undesirable effects of hormonal contraceptive use and preparations containing estrogen and/or progesterone/progestogen (see section 4.8). Depression can be serious and is a well-known risk factor for suicidal behaviour and suicide. Women should be advised to contact their medical practitioner in case of mood changes and depressive symptoms, including shortly after initiating the treatment.

Exacerbation of endometriosis

Endometriosis may be exacerbated with administration of ERT. Addition of a progestin should be considered in women who have undergone hysterectomy, but are known to have residual endometriosis, since malignant transformation after ERT has been reported.

Hypocalcaemia

PREMARIN cream should be used with caution in individuals with disease that can predispose to severe hypocalcaemia.

Hypothyroidism

Estrogen administration leads to increased thyroid-binding globulin (TBG) levels. Patients dependent on thyroid hormone replacement therapy may require increased doses of their thyroid replacement therapy. These women should have their thyroid function monitored in order to maintain their free thyroid hormone levels in an acceptable range (see section 4.5).

Laboratory monitoring

PREMARIN cream administration should be guided by clinical response rather than by hormone levels (e.g., estradiol, FSH).

Uterine bleeding

Certain patients may develop abnormal uterine bleeding.

Latex condoms

PREMARIN cream has been shown to weaken latex condoms. The potential for PREMARIN cream to weaken and contribute to the failure of condoms, diaphragms, or cervical caps made of latex or rubber should be considered.

Data from a drug-drug interaction study involving conjugated estrogens and medroxyprogesterone acetate indicate that the pharmacokinetic disposition of both medicines are not altered when the medicines are co-administered. Other clinical drug-drug interaction studies have not been conducted with conjugated estrogens. In vitro and in vivo studies have shown that estrogens are metabolised partially by cytochrome P450 3A4 (CYP3A4). Therefore, inducers or inhibitors of CYP3A4 may affect estrogen medicine metabolism. Inducers of CYP3A4, such as St. Johnu2019s Wort preparations (Hypericum perforatum), phenobarbital, phenytoin, carbamazepine, rifampicin and dexamethasone may reduce plasma concentrations of estrogens, possibly resulting in a decrease in the therapeutic effects and/or changes in the uterine bleeding profile. Inhibitors of CYP3A4, such as cimetidine, erythromycin, clarithromycin, ketoconazole, itraconazole, ritonavir and grapefruit juice, may increase plasma concentrations of estrogens and may result in side effects.

Laboratory test interactions

• Increased platelet count, decreased levels of antithrombin III, and increased plasminogen antigen and activity.
• Increased thyroid-binding globulin (TBG) leading to increased circulating total thyroid hormone, as measured by protein-bound iodine (PBI), T4 levels (by column, or by radioimmunoassay) or T3 levels (by radioimmunoassay). 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. corticosteroid binding globulin (CBG), sex-hormone binding globulin (SHBG), leading to increased circulating corticosteroid and sex steroids respectively. Free hormone concentrations may be decreased. Other plasma proteins may be increased (angiotensin/renin substrate, alpha-1-antitrypsin, ceruloplasmin).
• Increased plasma high-density lipoprotein (HDL) and HDL2 cholesterol subfraction concentrations, reduced low-density lipoprotein (LDL) cholesterol concentrations, increased triglyceride levels (see section 4.4).
• Impaired glucose tolerance.
• The response to metyrapone may be reduced.

Pregnancy

PREMARIN cream should not be used during pregnancy (see section 4.3).

Breastfeeding

PREMARIN cream should not be used during lactation. Estrogen administration to nursing women have been shown to decrease the quantity and quality of the breast milk. Detectable amounts of estrogens have been identified in the breast milk of mothers receiving estrogen-alone therapy. Caution should be exercised when PREMARIN cream is administered to a nursing woman.

No studies on the effect of ability to drive or use machines have been performed. However, the adverse effects of PREMARIN cream include dizziness, which could affect the ability to drive or use machines (see section 4.8).

Summary of the safety profile

Systemic absorption may occur with the use of PREMARIN cream. Adverse reactions associated with oral PREMARIN treatment should be taken into account.

Tabulated summary of adverse reactions

The following adverse reactions have been either reported with PREMARIN cream or are undesirable effects associated with estrogens. It is not possible to calculate frequencies for these events based on prescription data for patient exposure because the dose of PREMARIN cream varies from patient to patient and the medicine is available worldwide in various sized units.

Post-marketing reported side effects

Severe depression with a higher risk of suicidal thoughts/behaviour and suicide.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Health care providers are asked to report any suspected adverse reactions to SAHPRA via the u201c6.04 Adverse Drug Reactions Reporting Formu201d, found online under SAHPRAu2019s publications: https://www.sahpra.org.za/Publications/Index/8

Symptoms of overdosage of estrogen-containing medicines in adults and children may include nausea, vomiting, breast tenderness, dizziness, abdominal pain, drowsiness/fatigue; withdrawal bleeding may occur in females. There is no specific antidote and further treatment if necessary, should be symptomatic (see section 4.8). Treatment is symptomatic and supportive.