Drugs List

Therapeutic Indications

Uses

HRT for treatment of oestrogen deficiency in women with intact uterus

Contraindications

Major surgery with prolonged post-operative immobilisation
Abnormal liver function test
Angina
Breast cancer
Breastfeeding
Deep vein thrombosis
Galactosaemia
Hereditary fructose intolerance
History of breast cancer
History of thromboembolic disorder
Myocardial infarction
Oestrogen dependent neoplasm
Porphyria
Pregnancy
Pulmonary embolism
Thromboembolic disorder
Thrombophilia
Uncontrolled endometrial hyperplasia
Undiagnosed gynaecological haemorrhage

Precautions and Warnings

Body mass index above 30kg per square metre
History of recurrent spontaneous abortion
Predisposition to thromboembolic disease
Risk factor for oestrogen-dependent neoplasm
Severe trauma
Asthma
Cardiac impairment
Cholelithiasis
Diabetes mellitus
Endometriosis
Epileptic disorder
Glucose-galactose malabsorption syndrome
Hepatic adenoma
History of endometrial hyperplasia
Hypertension
Hypertriglyceridaemia
Hypocalcaemia
Hypophyseal neoplasm
Hypothyroidism
Lactose intolerance
Migraine
Otosclerosis
Renal impairment
Systemic lupus erythematosus
Uterine fibroids

Patients on thyroid replacement therapy may require increased doses
Assess family medical history prior to commencing treatment
Exclude breast cancer before treatment
Exclude oestrogen dependent neoplasm before treatment
Contains lactose
Preparation contains sucrose
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
Monitor blood glucose closely in patients with diabetes mellitus
Women with hypertriglyceridaemia need special surveillance
Advise patient that changes in their breasts should be reported to Dr/nurse
Advise patient to contact a doctor if symptoms of thromboembolism develop
Avoid immobilisation-treatment may cause increased risk of thromboembolism
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 thrombophlebitis or thromboembolism
Discontinue if cholestasis develops
Discontinue if first occurrence or worsening of migraine/severe headache
Discontinue if jaundice or other evidence of hepatic impairment occurs
Discontinue if significant rise in blood pressure occurs
Advise patient not to take St John's wort concurrently
Advise patient grapefruit products may increase plasma level
Female: Not for contraception.Use non-hormonal contraception, if required

For the treatment of menopausal symptoms the benefits of short-term HRT are considered to outweigh the risks in the majority of women.
In all cases, it is good practice to use the lowest effective dose for the shortest possible time and to review the need to continue treatment at least annually.
For postmenopausal women over 50 years who are at an increased risk of bone fracture, HRT should be used to prevent osteoporosis only in those who are intolerant of, or contraindicated for, other osteoporosis therapies.

Physical examination should be guided by this and a knowledge of the contraindications, precautions and warnings for use of the product. Investigations including mammography should be carried out in accordance with currently accepted screening practices and modified according to the clinical needs of the individual.

There is an increased risk of breast cancer in women currently or recently using Hormone Replacement Therapy (HRT). The risk of breast cancer increases with the duration of treatment and returns to normal after 5 years of stopping treatment.

Ovarian cancer is much rarer than breast cancer. Evidence suggests a slight increased risk in women taking oestrogen-only or combined oestrogen and progestogen HRT, which becomes apparent within 5 years of use and diminishes over time after stopping.

Examinations to rule out endometrial abnormalities should be undertaken at regular intervals. Prolonged monotherapy with oestrogens increases the risk of endometrial hyperplasia and carcinoma in postmenopausal women unless supplemented by administration of a progestogen to protect the endometrium. Unless there is a previous diagnosis of endometriosis it is not recommended to add a progestogen in hysterectomised women.

Pregnancy and Lactation

Pregnancy

Conjugated oestrogens with medroxyprogesterone acetate are contraindicated in pregnancy.

Should pregnancy occur, treatment should be discontinued immediately.

Oestrogens have been associated with cardiovascular defects, eye and ear abnormalities and hypospadias in the newborn when having been exposed to these in the womb. However, some studies have failed to find a relationship with cardiovascular defects and non-genital malformations. Down's syndrome has also been associated with oestrogens as a group.

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

Medroxyprogesterone has been found to exhibit dose-related teratogenicity and toxicity in animals. If medroxyprogesterone is administered within 4 weeks of conception then foetal growth retardation may be a low risk complication, but more research needs to be done to confirm these findings.

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 ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).

Lactation

Conjugated oestrogens with medroxyprogesterone acetate are contraindicated in breastfeeding.

Oestrogens have been used to suppress postpartum breast engorgement in patients who do not desire to breast feed. Oestrogenic agents demonstrate lower infant weight gain, decreased milk production and decreased composition of nitrogen and protein content of human milk. 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 https://www.midlandsmedicines.nhs.uk/content.asp?section=6&subsection=17&pageIdx=1

Side Effects

"Spotting" bleeding
Abdominal pain
Acne
Aggravation of porphyria
Alopecia
Altered glucose tolerance
Anaphylactic reaction
Anaphylactoid reaction
Angioedema
Anxiety
Arthralgia
Bloating
Breakthrough bleeding
Breast enlargement
Breast pain
Breast secretion
Breast tenderness
Change in amount of cervical secretion
Change in menstrual flow
Changes in libido
Cholestatic jaundice
Chorea
Deep vein thrombosis (DVT)
Dementia
Depression
Dizziness
Dysmenorrhoea
Endometrial hyperplasia
Enlargement of hepatic haemangiomas
Erythema multiforme
Erythema nodosum
Exacerbation of epilepsy
Exacerbation of hypocalcaemia
Exacerbation of otosclerosis
Exacerbation of pre-existing asthma
Fibrocystic breast changes
Fluid retention
Galactorrhoea
Gallbladder disease
Headache
Hirsutism
Hypertension
Increase in plasma triglyceride concentration
Increased risk of breast cancer
Increased risk of endometrial cancer
Increased size of uterine fibroids
Intolerance to contact lenses
Irritability
Leg cramps
Melasma
Migraine
Mood changes
Myocardial infarction
Nausea
Oedema
Ovarian cancer
Pancreatitis
Premenstrual-like syndrome
Pruritus
Pulmonary embolism
Rash
Retinal vascular thrombosis
Sodium retention
Stroke
Superficial vein thrombophlebitis
Thromboembolism
Urticaria
Vaginal candidiasis
Vaginitis
Vascular purpura
Venous thrombosis
Vomiting
Weight changes

Presentation

Tablets containing conjugated oestrogens and medroxyprogesterone acetate

Drugs List

Therapeutic Indications

Uses

HRT for treatment of oestrogen deficiency in women with intact uterus

Dosage

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

Patients should be re-evaluated periodically to determine if treatment is still necessary.

Adults

Elderly

Additional Dosage Information

Contraindications

Major surgery with prolonged post-operative immobilisation
Abnormal liver function test
Angina
Breast cancer
Breastfeeding
Deep vein thrombosis
Galactosaemia
Hereditary fructose intolerance
History of breast cancer
History of thromboembolic disorder
Myocardial infarction
Oestrogen dependent neoplasm
Porphyria
Pregnancy
Pulmonary embolism
Thromboembolic disorder
Thrombophilia
Uncontrolled endometrial hyperplasia
Undiagnosed gynaecological haemorrhage

Precautions and Warnings

Body mass index above 30kg per square metre
History of recurrent spontaneous abortion
Predisposition to thromboembolic disease
Risk factor for oestrogen-dependent neoplasm
Severe trauma
Asthma
Cardiac impairment
Cholelithiasis
Diabetes mellitus
Endometriosis
Epileptic disorder
Glucose-galactose malabsorption syndrome
Hepatic adenoma
History of endometrial hyperplasia
Hypertension
Hypertriglyceridaemia
Hypocalcaemia
Hypophyseal neoplasm
Hypothyroidism
Lactose intolerance
Migraine
Otosclerosis
Renal impairment
Systemic lupus erythematosus
Uterine fibroids

Patients on thyroid replacement therapy may require increased doses
Assess family medical history prior to commencing treatment
Exclude breast cancer before treatment
Exclude oestrogen dependent neoplasm before treatment
Contains lactose
Preparation contains sucrose
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
Monitor blood glucose closely in patients with diabetes mellitus
Women with hypertriglyceridaemia need special surveillance
Advise patient that changes in their breasts should be reported to Dr/nurse
Advise patient to contact a doctor if symptoms of thromboembolism develop
Avoid immobilisation-treatment may cause increased risk of thromboembolism
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 thrombophlebitis or thromboembolism
Discontinue if cholestasis develops
Discontinue if first occurrence or worsening of migraine/severe headache
Discontinue if jaundice or other evidence of hepatic impairment occurs
Discontinue if significant rise in blood pressure occurs
Advise patient not to take St John's wort concurrently
Advise patient grapefruit products may increase plasma level
Female: Not for contraception.Use non-hormonal contraception, if required

For the treatment of menopausal symptoms the benefits of short-term HRT are considered to outweigh the risks in the majority of women.
In all cases, it is good practice to use the lowest effective dose for the shortest possible time and to review the need to continue treatment at least annually.
For postmenopausal women over 50 years who are at an increased risk of bone fracture, HRT should be used to prevent osteoporosis only in those who are intolerant of, or contraindicated for, other osteoporosis therapies.

Physical examination should be guided by this and a knowledge of the contraindications, precautions and warnings for use of the product. Investigations including mammography should be carried out in accordance with currently accepted screening practices and modified according to the clinical needs of the individual.

There is an increased risk of breast cancer in women currently or recently using Hormone Replacement Therapy (HRT). The risk of breast cancer increases with the duration of treatment and returns to normal after 5 years of stopping treatment.

Ovarian cancer is much rarer than breast cancer. Evidence suggests a slight increased risk in women taking oestrogen-only or combined oestrogen and progestogen HRT, which becomes apparent within 5 years of use and diminishes over time after stopping.

Examinations to rule out endometrial abnormalities should be undertaken at regular intervals. Prolonged monotherapy with oestrogens increases the risk of endometrial hyperplasia and carcinoma in postmenopausal women unless supplemented by administration of a progestogen to protect the endometrium. Unless there is a previous diagnosis of endometriosis it is not recommended to add a progestogen in hysterectomised women.

Pregnancy and Lactation

Pregnancy

Conjugated oestrogens with medroxyprogesterone acetate are contraindicated in pregnancy.

Should pregnancy occur, treatment should be discontinued immediately.

Oestrogens have been associated with cardiovascular defects, eye and ear abnormalities and hypospadias in the newborn when having been exposed to these in the womb. However, some studies have failed to find a relationship with cardiovascular defects and non-genital malformations. Down's syndrome has also been associated with oestrogens as a group.

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

Medroxyprogesterone has been found to exhibit dose-related teratogenicity and toxicity in animals. If medroxyprogesterone is administered within 4 weeks of conception then foetal growth retardation may be a low risk complication, but more research needs to be done to confirm these findings.

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 ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).

Lactation

Conjugated oestrogens with medroxyprogesterone acetate are contraindicated in breastfeeding.

Oestrogens have been used to suppress postpartum breast engorgement in patients who do not desire to breast feed. Oestrogenic agents demonstrate lower infant weight gain, decreased milk production and decreased composition of nitrogen and protein content of human milk. 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 https://www.midlandsmedicines.nhs.uk/content.asp?section=6&subsection=17&pageIdx=1

Counselling

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).

Patients should be advised not to take St John's Wort concurrently with this medication.

Advise patient to seek advice at the first indications of pregnancy.

Advise patient grapefruit products may increase the plasma level of the drug.

Side Effects

"Spotting" bleeding
Abdominal pain
Acne
Aggravation of porphyria
Alopecia
Altered glucose tolerance
Anaphylactic reaction
Anaphylactoid reaction
Angioedema
Anxiety
Arthralgia
Bloating
Breakthrough bleeding
Breast enlargement
Breast pain
Breast secretion
Breast tenderness
Change in amount of cervical secretion
Change in menstrual flow
Changes in libido
Cholestatic jaundice
Chorea
Deep vein thrombosis (DVT)
Dementia
Depression
Dizziness
Dysmenorrhoea
Endometrial hyperplasia
Enlargement of hepatic haemangiomas
Erythema multiforme
Erythema nodosum
Exacerbation of epilepsy
Exacerbation of hypocalcaemia
Exacerbation of otosclerosis
Exacerbation of pre-existing asthma
Fibrocystic breast changes
Fluid retention
Galactorrhoea
Gallbladder disease
Headache
Hirsutism
Hypertension
Increase in plasma triglyceride concentration
Increased risk of breast cancer
Increased risk of endometrial cancer
Increased size of uterine fibroids
Intolerance to contact lenses
Irritability
Leg cramps
Melasma
Migraine
Mood changes
Myocardial infarction
Nausea
Oedema
Ovarian cancer
Pancreatitis
Premenstrual-like syndrome
Pruritus
Pulmonary embolism
Rash
Retinal vascular thrombosis
Sodium retention
Stroke
Superficial vein thrombophlebitis
Thromboembolism
Urticaria
Vaginal candidiasis
Vaginitis
Vascular purpura
Venous thrombosis
Vomiting
Weight changes

Effects on Laboratory Tests

Some laboratory tests may be influenced by oestrogens, for example tests for glucose tolerance, liver function or thyroid function.

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

Overdosage

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 ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).

Further Information

Last Full Review Date: April 2016

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.

Joint Formulary Committee. British National Formulary. 71st ed. London: BMJ Group and Pharmaceutical Press; 2016.

Summary of Product Characteristics: Premique Low Dose 0.3mg/1.5mg Modified Release Tablets. Pfizer Limited. Revised April 2016.