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Estradiol valerate with medroxyprogesterone acetate oral

Updated 2 Feb 2023 | Oestrogens and HRT


Tablets containing estradiol valerate with medroxyprogesterone acetate

Drugs List

  • estradiol valerate 1mg and medroxyprogesterone 2.5mg tablets
  • estradiol valerate 1mg and medroxyprogesterone 5mg tablets
  • estradiol valerate 2mg and medroxyprogesterone 5mg tablets
  • INDIVINA 1mg+2.5mg tablets
  • INDIVINA 1mg+5mg tablets
  • INDIVINA 2mg+5mg tablets
  • Therapeutic Indications


    Replacement therapy for oestrogen deficiency symptoms
    Secondary prophylaxis of postmenopausal osteoporosis where risk of fracture

    Hormone replacement therapy (HRT) for oestrogen deficiency symptoms in postmenopausal women more than three years after the menopause with an intact uterus.

    Prevention of osteoporosis in postmenopausal women at a high risk of fractures and who are intolerant or contraindicated for drugs indicated for the prevention of osteoporosis.

    Use the lowest effective dose for the shortest possible time and review the need to continue treatment at least annually.



    One tablet each day without a tablet-free interval. Tablets should be taken approximately at the same time of the day.

    Treatment should be initiated with the 1 mg/2.5 mg tablet. Depending on the clinical response to treatment, the dosage can then be adjusted to individual needs.

    Medroxyprogesterone acetate 2.5 mg is usually sufficient to prevent breakthrough bleeding. If breakthrough bleeding occurs and persists, the dosage may be increased to 5 mg.

    If 1 mg of estradiol valerate is not sufficient to alleviate oestrogen deficiency symptoms, the dose may be increased to 2 mg.


    One tablet each day without a tablet-free interval. Tablets should be taken approximately at the same time of the day.

    Treatment should be initiated with the 1 mg/2.5 mg tablet. Depending on the clinical response to treatment, the dosage can then be adjusted to individual needs.

    Medroxyprogesterone acetate 2.5 mg is usually sufficient to prevent breakthrough bleeding. If breakthrough bleeding occurs and persists, the dosage may be increased to 5 mg.

    If 1 mg of estradiol valerate is not sufficient to alleviate oestrogen deficiency symptoms, the dose may be increased to 2 mg.

    Additional Dosage Information

    In women with amenorrhoea and not taking hormone replacement therapy (HRT) or women who switch from another continuous combined HRT product, treatment may be started on any day. Women who switch from cyclic HRT regimen should start treatment one week after completion of the cycle.


    Suspected hormone dependent neoplasm
    Abnormal liver function test
    Acute hepatic disorder
    Breast cancer
    Deep vein thrombosis
    Familial conjugated hyperbilirubinaemias
    History of breast cancer
    History of hormone dependent neoplasm
    History of thromboembolic disorder without anticoagulant therapy
    History of venous thromboembolism
    Lupus anticoagulant
    Oestrogen dependent neoplasm
    Protein C deficiency disease
    Protein S deficiency disease
    Pulmonary embolism
    Recent arterial thromboembolic disorder
    Severe cardiac disorder
    Severe renal impairment
    Thromboembolic disorder
    Uncontrolled endometrial hyperplasia
    Undiagnosed gynaecological haemorrhage

    Precautions and Warnings

    Body mass index above 30kg per square metre
    Family history of breast cancer
    Family history of venous thromboembolism
    History of recurrent spontaneous abortion
    Patients over 65 years
    Predisposition to thromboembolic disease
    Prolonged immobilisation
    Recent surgery
    Recent trauma
    Risk factor for oestrogen-dependent neoplasm
    Breast nodules
    Cardiac impairment
    Chronic hepatic disorder
    Diabetes mellitus
    Endometrial hyperplasia
    Epileptic disorder
    Fibrocystic breast disorder
    Glucose-galactose malabsorption syndrome
    Hereditary angioneurotic oedema
    History of angioedema
    History of breast nodules
    History of chloasma
    History of fibrocystic breast disorder
    History of pregnancy-related deterioration in otosclerosis
    History of thromboembolic disorder
    Lactose intolerance
    Malignant melanoma
    Renal impairment
    Systemic lupus erythematosus
    Uterine fibroids

    Assess family medical history prior to commencing treatment
    Contains lactose
    Do breast & pelvic exam. before & during treatment if clinically indicated
    Exclude pregnancy prior to initiation of treatment
    Abnormal and/or irregular bleeding should be investigated
    Advise patients of risks/benefits & review need for treatment regularly
    Discontinue treatment if patient develops seizures
    Monitor for signs of haematological and non-haematological toxicity
    Monitor hepatic function in patients with hepatic impairment
    Advise patient of thromboembolic symptoms and to report them if they occur
    Advise patient that changes in their breasts should be reported to Dr/nurse
    Avoid immobilisation-treatment may cause increased risk of thromboembolism
    Discontinue at the onset of severe depression
    Increased risk of VTE during travel involving >5hr immobilisation
    May affect results of some laboratory tests
    Discontinue 4 - 6 weeks before major surgery
    Advise patient to seek advice at first indications of pregnancy
    Discontinue at first signs of jaundice
    Discontinue at first signs of thrombophlebitis or thromboembolism
    Discontinue if cholestasis develops
    Discontinue if first appearance of migraine or severe or frequent headache
    Discontinue if first occurrence or worsening of visual disturbances
    Discontinue if severe abdominal symptoms develop
    Discontinue if significant rise in blood pressure occurs
    Discontinue if sudden pain in the chest occurs
    Discontinue if symptoms due to endometriosis are exacerbated
    Advise patient not to take St John's wort concurrently
    Female: Not for contraception.Use non-hormonal contraception, if required
    Advise patient of increased risk of breast cancer vs benefits of HRT
    Advise patient to discontinue therapy if any disturbances of vision occur
    Women with a history of chloasma should avoid exposure to sun/UV light

    Hormone replacement therapy should only be initiated in patients with symptoms that adversely affect quality of life. Careful consideration of the risks and benefits should be undertaken at least annually and HRT should only be continued as long as the benefits outweigh the risks. Medical examinations which include appropriate imaging tools, e.g. mammography, should be carried out in accordance with current screening practices and modified to the needs of the individual.

    Women should be examined with special care if they have an intact uterus with undiagnosed abnormal bleeding or women with an intact uterus who have previously been treated with unopposed oestrogens. This is in order to exclude malignancy of the endometrium before treatment initiation.

    The risk of endometrial hyperplasia and carcinoma is increased when oestrogens are administered alone for prolonged periods of time in women with an intact uterus. The increased risk of endometrial cancer, among systemic oestrogen only users, varies from 2 to 12 fold compared with non-users. This is dependant on both duration of treatment and on oestrogen dose. The risk may remain elevated for at least 10 years after withdrawing treatment.

    Evidence suggests there is an increased risk of breast cancer in women taking combined oestrogen-progestogen and possibly oestrogen only HRT. In hysterectomised women using oestrogen only HRT, the WHI trial found no increase in risk of breast cancer. The risk of breast cancer increases with the duration of treatment and, after stopping HRT, the risk will decrease with time. When HRT lasts for more than 5 years, the risk may persist for 10 years or more.

    An association has been made between long-term (at least 5 to 10 years) use of oestrogen only HRT products and a slightly increased risk of ovarian cancer. The long term use of oestrogen-progesterone combined HRT may confer a similar or slightly smaller risk.

    HRT is associated with a 1.3 to 3 fold risk of developing venous thromboembolism (VTE), which is more likely in the first year of HRT than later. In women who have no personal history of VTE, but have a first degree relative with a history of VTE at a young age screening may be offered. The woman should be carefully counselled with regards to the screenings limitations. This should include the information that only a proportion of thrombophilic defects are identified by screening.

    There is a 1.5 fold increase in risk of ischaemic stroke in women taking combined HRT and oestrogen only HRT. It should be noted that the relative risk does not change with age or time since menopause but as the baseline risk of stroke is strongly age dependent, the overall risk of stroke in women who use HRT increase with age.

    Oestrogens increase thyroid binding globulin (TBG), leading to increased circulating total thyroid hormone, T4 levels or T3 levels. 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 and sex hormone binding globulin 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 1 antitrypsin, ceruloplasmin).

    There is some evidence of an increased risk of probable dementia in women who start using continuous combined or oestrogen only HRT after the age of 65.

    Pregnancy and Lactation


    Hormone replacement therapy is contraindicated during pregnancy.

    Should pregnancy occur, treatment should be discontinued immediately.

    Estradiol has been associated with cardiovascular defects, eye and ear abnormalities and hypospadias in the newborn when having been exposed to these in the womb (Briggs, 2011). However, some studies have failed to find a relationship with cardiovascular defects and non-genital malformations. Down's syndrome has also been associated with estrogens as a group, but not for estradiol (Schaefer, 2007).

    Development alterations in the psychosexual performance of boys have been attributed to exposure to estradiol and progestogen in the womb. Males who have been exposed to estradiol and progestogen have demonstrated a trend to have less heterosexual characteristics and fewer masculine interests than males which have not been exposed to these hormones prenatally.

    The use of all medication in pregnancy should be avoided whenever possible; particularly in the first trimester. Non-drug treatments should also be considered. When essential, a medication with the best safety record over time should be chosen, employing the lowest effective dose for the shortest possible time. Polypharmacy should be avoided. Teratogens taken in the pre-embryonic period, often quoted as lasting until 14 to 17 days post-conception, are believed to have an all-or-nothing effect. Where drugs have a short half-life, and when the date of conception is certain, this may allow women to be reassured where drug exposure has occurred within this time frame. Further advice may be available from the UK National Teratology Information Service (NTIS) and through ToxBase, available via password on the internet ( ) or if this is unavailable at the backup site ( ).


    Hormone replacement therapy is contraindicated during breastfeeding.

    Estradiol has been used to suppress postpartum breast engorgement in patients who do not desire to breastfeed (Hale, 2010). Oestrogenic agents demonstrate lower infant weight gain, decreased milk production and decreased composition of nitrogen and protein content of human milk (Briggs, 2011). Even though the extent of these changes is low, the changes in milk production and composition may be of nutritional importance in malnourished mothers. Because of the reasons mentioned above the use of this medication during lactation should be avoided.

    Neonates, infants born prematurely, those with low birth weight, those with an unstable gastrointestinal function or who have serious illnesses may require special consideration. For any infant, if a drug is prescribed to the nursing mother, it should be at the lowest practical dose and for the shortest time. When drug administration is unavoidable and breastfeeding is to continue, minimisation of exposure of the infant to the drug may sometimes be achieved by timing the maternal doses to just after a feeding episode. Infants exposed to drugs via breast milk should be monitored for unusual signs or symptoms. Interactions between the drug received by the infant from the mother's milk and medication prescribed for the infant should also be considered, for example, when the drug given to the infant may prevent metabolism of the drug received via breast milk.
    Specialist advice is available from the UK Drugs in Lactation Advisory Service at


    Encourage patients to participate in the national breast cancer screening programme and the national cervical cancer screening programme as appropriate for their age. Breast awareness should also be encouraged and patients advised to report any changes in their breasts to their doctor or nurse

    Advise patients to contact their doctor if they are aware of a potential thromboembolic symptom (e.g. painful swelling of a leg, sudden pain in the chest, dyspnoea).

    If patient has forgotten to take one tablet, the forgotten tablet is to be discarded. Forgetting a dose may increase the likelihood of breakthrough bleeding and spotting.

    Patients should be advised of the increased risks of diagnosis of breast cancer versus the benefits of HRT.

    Advise patients not to self-medicate with St John's Wort during HRT.

    Stop treatment immediately if pregnancy is suspected.

    Side Effects

    Abdominal pain
    Breast enlargement
    Breast tenderness
    Changes in libido
    Cholestatic jaundice
    Contact lenses may irritate
    Depressed mood
    Erythema multiforme
    Erythema nodosum
    Exacerbation of angioedema
    Gallbladder disease
    Haemorrhagic eruption
    Increase in plasma triglyceride concentration
    Increased risk of oestrogen-dependent neoplasms
    Increased size of uterine fibroids
    Irregular uterine bleeding
    Leg cramps
    Liver function disturbances
    Mood changes
    Myocardial infarction
    Premenstrual-like syndrome
    Sodium/water retention
    Steepening of corneal curvature
    Vaginal candidiasis
    Vascular purpura
    Weight changes

    Effects on Laboratory Tests

    Hormone replacement therapy, especially oestrogen-progestogen combined treatment may increase the density of mammographic images and adversely effect the detection of breast cancer.

    The use of oestrogen may influence the laboratory results of certain endocrine tests and liver enzymes.


    It is strongly recommended that the UK National Poisons Information Service be consulted on cases of suspected or actual overdose where there is doubt over the degree of risk or about appropriate management.

    The following number will direct the caller to the relevant local centre (0844) 892 0111

    Information may be obtained if you have access to ToxBase the primary clinical toxicology database of the National Poisons Information Service. This is available via password on the internet ( ) or if this is unavailable at the backup site ( ).

    Further Information

    Last Full Review Date: July 2014

    Reference Sources

    Drugs During Pregnancy and Lactation: Treatment Options and Risk Assessment, 2nd edition (2007) ed. Schaefer, C., Peters, P. and Miller, R. Elsevier, London.

    Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and Neonatal Risk, 9th edition (2011) ed. Briggs, G., Freeman, R. and Yaffe, S. Lippincott Williams & Wilkins, Philadelphia.

    Medications and Mothers' Milk, 14th Edition (2010) Hale, T. Hale Publishing, Amarillo, Texas.

    Summary of Product Characteristics: Indivina 1 mg/2.5 mg tablets. Orion Pharma (UK) Limited. Revised August 2020.
    Summary of Product Characteristics: Indivina 1 mg/5 mg tablets. Orion Pharma (UK) Limited. Revised August 2020.
    Summary of Product Characteristics: Indivina 2 mg/5 mg tablets. Orion Pharma (UK) Limited. Revised August 2020.

    MHRA Drug Safety Update September 2019
    Available at:
    Last accessed: 07 January 2020

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