Consumer medicine information

Premarin

Conjugated estrogens

BRAND INFORMATION

Brand name

Premarin Tablets

Active ingredient

Conjugated estrogens

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Premarin.

What is in this leaflet

This leaflet answers some of the common questions about PREMARIN Tablets. It does not contain all of the available information. It does not take the place of talking to your doctor or pharmacist. All medicines have risks and benefits. Your doctor has weighed the risks of you taking PREMARIN against the benefits this medicine is expected to have for you.

If you have any concerns about this medicine, ask your doctor or pharmacist.

Keep this leaflet with the medicine. You may need to read it again.

What PREMARIN is used for

PREMARIN is a type of treatment called hormone replacement therapy (HRT) and contains the hormone estrogen in the form known as conjugated estrogens.

PREMARIN helps to relieve the discomfort many women feel during and after menopause, including symptoms such as "hot flushes", sweating and vaginal dryness. It helps to prevent thinning of the bones (osteoporosis), which can cause fractures.

PREMARIN is also used to treat women where either the ovary does not function properly or has been removed.

If your doctor thinks you will need to take estrogens for a long time, including for the prevention of osteoporosis, he or she will have considered the benefits and risks of other treatments before prescribing PREMARIN for you.

How it works

Menopause occurs naturally in women, typically between the ages of 45 and 55. During menopause, your body produces less estrogen than it did beforehand. This can cause symptoms such as "hot flushes". Some women also have problems with dryness of the vagina causing discomfort during or after sexual intercourse. Some women develop osteoporosis during or after menopause. This is a thinning of the bones making them weaker and more likely to break, especially the bones of the spine, hip and wrist.

Conjugated estrogens are like the hormones produced by the ovaries before menopause. When given during or after menopause, they can help control the symptoms.

Estrogen is used treat women who have had their uterus or "womb" removed. If you have not had your uterus or "womb" removed, you will need to take an estrogen with a progestogen.

Ask your doctor if you have any questions why PREMARIN has been prescribed for you. Your doctor may have prescribed PREMARIN for another use.

This medicine is available only with a doctor's prescription.

PREMARIN is not habit-forming.

PREMARIN is not suitable for birth control and it will not restore fertility.

This medicine is not expected to affect your ability to drive a car or operate machinery.

Before you take PREMARIN

When you must not take PREMARIN

HRT should only be used if you have been fully informed of the risks. The decision to use HRT should be based on your particular needs and health, and made after a careful medical evaluation.

Talk regularly with your doctor about whether you still need treatment with PREMARIN.

Treatment with estrogens, with or without progestogens should be used at the lowest effective dose and for the shortest period of time.

Clinical trials have reported a slight increase in risk of ovarian cancer in women aged between 50-54 years old when PREMARIN alone or in combination with a progestogen is taken over 5 years.

Do not take PREMARIN either alone or with a progestogen to prevent heart attacks, stroke or dementia.

Do not take PREMARIN if you have an allergy, or think you have an allergy, to:

  • any medicine containing conjugated estrogens, the active ingredient in PREMARIN
  • any of the ingredients listed at the end of this leaflet
  • any other similar medicines, such as other HRT medicines or oral contraceptives ("birth control pill").

Some of the symptoms of an allergic reaction may include:

  • shortness of breath
  • wheezing or difficulty breathing
  • swelling of the face, lips, tongue or other parts of the body
  • rash, itching or hives on the skin.

Do not take PREMARIN if you have or have had any of the following medical conditions:

  • breast cancer
  • endometrial or cervical cancer
  • abnormal genital bleeding, which your doctor has not investigated.
  • a problem with blood clots forming in your blood vessels, such as painful inflammation of the veins (thrombophlebitis) or the blockage of a blood vessel in the legs (deep vein thrombosis or DVT), or lungs (pulmonary embolism)
  • heart disease or stroke
  • very high blood pressure that is not properly controlled
  • problems with your breasts that your doctor has not investigated
  • liver disease
  • blood clotting problems.

If you are not certain whether these may apply to you, or you are worried about anything in this list tell your doctor.

Do not take this medicine if you are pregnant or think you are pregnant. Pregnancy must be excluded before you take PREMARIN.

Do not give PREMARIN to a child. This medicine is not suitable for use in children.

Do not take PREMARIN if you are breast feeding. Estrogens have been found in breast milk, and may reduce the production of breast milk.

Do not take this medicine after the expiry date (EXP) printed on the pack or if the packaging is torn or shows signs of tampering. If it is expired or damaged, return it to your pharmacist for disposal.

If you are not sure whether you should start taking this medicine, talk to your doctor.

Before you start to take PREMARIN

You must have a thorough medical check-up before starting PREMARIN for the first time or if you are taking it again after a break.

Tell your doctor if you are allergic to any foods, dyes preservatives or any other medicines.

Tell your doctor if you have:

  • a family history of breast cancer
  • nodules, lumps or cysts in your breasts or any other benign breast condition (not cancer)
  • fibroids or other benign tumours of the uterus (not cancer)
  • unusual or irregular genital bleeding or spotting
  • endometriosis (material similar to the lining of the uterus growing outside the uterus, causing pain or bleeding)
  • high blood pressure
  • liver problems
  • a condition called porphyria
  • hearing difficulties
  • yellowing of the whites of the eyes or skin (jaundice) during pregnancy or when taking estrogen (e.g. birth control pill or HRT)
  • fluid retention
  • kidney problems
  • heart problems
  • diabetes
  • migraine
  • asthma
  • epilepsy
  • lupus (systemic lupus erythematosus)
  • hereditary angioedema (swelling of the face, lips, tongue or throat that may cause difficulty swallowing or breathing)
  • gall bladder disease
  • a high level of blood fats
  • high or low levels of calcium in the blood
  • underactive thyroid gland
  • obesity.

Tell your doctor if anyone in your immediate family has had blood clots in the deep veins of the legs or blood vessels of lungs, a stroke or heart attack.

Taking Other Medicines

Tell your doctor if you are taking birth control pills. PREMARIN is not a contraceptive. Since pregnancy may be possible early in the menopause, while you are still having menstrual periods, you should ask your doctor about another (non-hormonal) method of birth control.

Tell your doctor or pharmacist if you are taking any other medicines including:

  • all prescription medicines
  • all medicines, vitamins, herbal supplements or natural therapies you buy without a prescription from a pharmacy, supermarket, naturopath or health food shop.

Some medicines may be affected by PREMARIN or may affect how well it works. You may need different amounts of your medicines, or you may need to take different medicines. Your doctor will advise you.

Tell your doctor or pharmacist if you are taking any of the following:

  • herbal medicines containing St John's Wort
  • some medicines for epilepsy such as phenytoin, phenobarbitone and carbamazepine
  • some antibiotics and anti-infectives such as rifampicin, erythromycin and clarithromycin
  • anti-fungal agents such as ketoconazole and itraconazole
  • thyroid replacement therapy
  • corticosteroids, such as dexamethasone
  • ritonavir for the treatment of HIV infection
  • cyclosporin used to prevent organ rejection.

Grapefruit juice may also affect how well PREMARIN works.

If you have not told your doctor about any of the above, tell them before you start taking PREMARIN.

Your doctor and pharmacist have more information on medicines to be careful with or avoid while you are taking this medicine.

How to take PREMARIN

Follow all directions given to you by your doctor or pharmacist carefully. They may differ from the information contained in this leaflet.

If you do not understand the instructions on the box, ask your doctor or pharmacist for help.

How to take it

Swallow tablets whole with a full glass of water. Do not divide, crushed, chew, or dissolve the tablet in your mouth.

When to take PREMARIN

If you are not already using any type of HRT you can start PREMARIN on any convenient day. However, it is recommended you start PREMARIN after your last period. If you do not have predictable periods, then start PREMARIN on a Monday as this matches the directions on the calendar pack.

If you are already using a different type of HRT, your doctor can advise you when to start PREMARIN.

It does not matter if you take PREMARIN before or after food.

How much to take

For symptoms of menopause and prevention of osteoporosis, take one tablet daily.

For women with a uterus, your doctor will also prescribe a progestogen tablet to be taken with your PREMARIN. For some women with a history of endometriosis, who have had a hysterectomy, a progestogen may also be needed. Your doctor will advise you.

For women without fully-functioning ovaries, your doctor will prescribe PREMARIN according to your needs. The dose may be higher or lower than that prescribed for the treatment of menopause symptoms.

Take all tablets in a blister pack before starting a new pack.

How long to take it

Continue to take your medicine for as long as your doctor tells you. Your doctor can discuss the risks and benefits of long-term treatment with HRT in your particular case.

If you forget to take your tablets

If less than 12 hours has passed from the time you normally take PREMARIN, take the missed tablet. Take the next tablet at the usual time.

If more than 12 hours has passed, discard the missed tablet and take the next tablet when you normally would.

Do not take a double dose to make up for the one you missed.

If you have trouble remembering when to take your medicine, ask your pharmacist for some hints.

If you take too much (Overdose)

Immediately telephone your doctor or the Poisons Information Centre on 13 11 26 or go to Accident and Emergency at the nearest hospital if you think you or anybody else has taken too much PREMARIN.

Do this even if there are no signs of discomfort or poisoning.

You may need urgent medical attention.

Symptoms of an overdose may include:

  • feeling sick or vomiting
  • dizziness
  • feeling sleepy or tired
  • breast tenderness
  • stomach pain
  • women may also experience menstrual bleeding.

While you are taking PREMARIN

Things you must do

Tell any doctors, dentists and pharmacists who are treating you that you are taking PREMARIN.

If you are about to take any new medicines, tell your doctor or pharmacist that you are taking PREMARIN.

If you become pregnant while taking PREMARIN, see your doctor immediately. PREMARIN should not be taken while you are pregnant.

See your doctor at least every six months for a check up. Some women may need to go more often.

Your doctor will at regular intervals:

  • check your breasts
  • send you to have a mammogram
  • check your uterus and cervix
  • do a Pap smear
  • check your blood pressure.

Your doctor may also take blood to check your blood fats, sugar levels and liver function.

This helps to monitor for any unwanted effects of HRT.

If you have used PREMARIN as HRT for 5 or more years, there may be a slight increase in risk of you developing ovarian cancer.

See your doctor if you experience symptoms such as pressure, discomfort or pain in your stomach or pelvis; swollen or bloated stomach; appetite loss; changes in toilet habits (e.g., constipation, diarrhoea, passing urine more frequently, increased flatulence); heartburn and nausea; tiredness; unexplained weight loss or weight gain especially if these symptoms are new for you or continue for a few weeks. Having these symptoms does not necessarily mean you have ovarian cancer, but it is best to have a check-up. Your doctor will physically check your pelvic organs and conduct blood tests, to rule out the ovarian cancer.

If you need to have blood tests tell the doctor that you are taking PREMARIN. PREMARIN can affect the results of some tests. These include hormone and liver function tests.

Check your breasts regularly. Your doctor or nurse can show you how to check your breasts properly. If you notice any changes to your breasts, see your doctor.

Include foods that are good sources of calcium and vitamin D in your daily diet, and exercise regularly. Calcium, vitamin D and exercise may help prevent thinning of the bones. Your doctor can advise you on which foods and types of exercise are best for you.

Tell your doctor well in advance (at least 4 to 6 weeks) of any expected hospitalisation or surgery.

If you go to hospital unexpectedly, tell the doctor who admits you that you are taking PREMARIN. The risk of developing blood clots in your blood vessels may be temporarily increased as a result of an operation, serious injury or having to stay in bed for a prolonged period.

Tell your doctor if you have any breakthrough bleeding or spotting, which persists after 2 to 3 months of treatment with PREMARIN. Breakthrough bleeding or spotting may occur during the first few months of treatment and then stop. However, if the bleeding continues, your doctor may wish to check why it is happening.

Things you must not do

Do not take PREMARIN to treat any other complaints unless your doctor tells you to.

Do not give your medicine to anyone else even if they have the same condition as you.

Do not stop taking PREMARIN, or change the dosage without checking with your doctor.

Side Effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking PREMARIN.

All medicines have side effects. Sometimes they are serious, most of the time they are not. You may need medical attention if you get some side effects.

It can be difficult to tell whether side effects are the result of taking PREMARIN or are side effects of another medicine you are taking.

Do not be alarmed by the list of side effects. You may not experience any of them.

Ask your doctor or pharmacist to answer any questions you may have.

Tell your doctor if you notice any of the following and they worry you:

  • abnormal genital bleeding or spotting (if bleeding is heavy check with your doctor as soon as possible)
  • tender, painful or swollen breasts, or secretions from the breasts
  • period-like pain or pelvic pain
  • vaginal discharge or change in secretions
  • vaginal thrush
  • stomach pain
  • stomach swelling or passing wind
  • nausea or vomiting
  • headache or migraine
  • loss of hearing
  • loss of memory
  • irregular, rapid jerky movements
  • dizziness
  • depression or anxiety
  • problems sleeping or sleepiness
  • moodiness or irritability
  • changes in sex drive
  • swelling of the lower legs, ankles or fingers
  • swelling and redness along a vein which is extremely tender to touch
  • weight changes
  • acne, itchy skin, or skin discolouration
  • skin rash
  • hair loss or extra hair growth
  • intolerance to contact lenses
  • worsening of porphyria.

Tell your doctor immediately or go to Accident and Emergency at your nearest hospital if you notice any of the following:

  • signs of allergy such as rash, itching or hives on the skin; swelling of the face, lips, tongue or other part of the body; shortness of breath, wheezing or troubled breathing
  • signs that clots may have formed, such as sudden severe headache, sudden loss of coordination, blurred vision, slurred speech, numbness or tingling in an arm or leg, painful swelling in the calves or thighs, chest pain, difficulty breathing, coughing blood
  • sudden partial or complete loss of vision or other problems with your eyesight
  • pain or tenderness in the stomach, which may be accompanied by fever, loss of appetite, nausea and vomiting
  • a yellow colour to the skin or eyes, itching, dark coloured urine or light coloured bowel motions
  • bloody diarrhoea, abdominal pain or tenderness, fever, nausea or vomiting.

Whilst these side effects are rare, they are serious. You may need urgent medical attention or hospitalisation.

Other side effects not listed above may also occur in some patients. Tell your doctor if you notice anything else that is making you feel unwell, even if it is not on this list.

After taking PREMARIN

Storage

Keep your tablets in the blister pack until it is time to take them. If you take them out of the blister, they may not keep well.

Keep your tablets in a cool dry place where the temperature stays below 25°C.

Do not store PREMARIN, or any medicine, in a bathroom or near a sink. Do not leave PREMARIN in the car or on windowsills. Heat and dampness can destroy some medicines.

Keep it where children cannot reach it. A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Disposal

If your doctor tells you to stop taking PREMARIN, or the expiry date has passed, ask your pharmacist what to do with any medicine that is left over.

Product Description

What it looks like

PREMARIN tablets are available in two different strengths:

  • PREMARIN 0.3 mg tablets
  • PREMARIN 0.625 mg tablets

Each strength comes in a pack of 28 tablets. PREMARIN 0.3 mg tablets are also available in packs of 7 tablets.

Ingredients

The active ingredient is conjugated estrogens.

Each dark green PREMARIN 0.3 mg tablet contains conjugated estrogens 0.3 mg and is marked "0.3".

Each maroon PREMARIN 0.625 mg tablet contains conjugated estrogens 0.625 mg and is marked "0.625".

The following inactive ingredients are also found in all strengths of PREMARIN:

  • Lactose monohydrate
  • hypromellose
  • microcrystalline cellulose
  • powdered cellulose
  • calcium phosphate
  • sucrose
  • hyprolose
  • magnesium stearate
  • macrogol 400
  • carnauba wax
  • white ink.

The colouring agent found in PREMARIN 0.3 mg tablet is opadry green.

The colouring agent found in PREMARIN 0.625 mg tablets is opadry maroon.

Manufacturer

PREMARIN tablets are supplied by:

Pfizer Australia Pty Ltd
Sydney NSW
Toll Free Number: 1800 675 229
www.pfizer.com.au

Australian Registration Numbers:

PREMARIN 0.3 mg tablets AUST R 177673.

PREMARIN 0.625 mg tablets AUST R 177674.

This leaflet was prepared in February 2020.

® Registered Trade Mark

Published by MIMS May 2020

BRAND INFORMATION

Brand name

Premarin Tablets

Active ingredient

Conjugated estrogens

Schedule

S4

 

1 Name of Medicine

Conjugated estrogens.

6.7 Physicochemical Properties

Chemical structure.

Conjugated estrogens (CE) is a mixture of natural estrogens (of equine origin) composed principally of the sodium salts of water soluble sulfate esters of estrone, equilin and 17α-dihydroequilin, together with smaller amounts of 17α-estradiol, equilenin, and 17α-dihydroequilenin, 17β-dihydroequilin, 17β-dihydroequilenin, 17β-estradiol and δ8,9-dihydroestrone.

CAS number.

12126-59-9.

2 Qualitative and Quantitative Composition

Premarin 0.3 mg tablets contain 0.3 mg conjugated estrogens as the active ingredient.
Premarin 0.625 mg tablets contain 0.625 mg conjugated estrogens as the active ingredient.

Excipient(s) with known effect.

Premarin tablets contain sugars (lactose monohydrate, sucrose).
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Film coated tablet.
The 0.3 mg tablets are dark green and marked "0.3".
The 0.625 mg tablets are maroon and marked "0.625".

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Estrogen production occurs primarily in the ovarian follicles in women from the menarche to the menopause and is important in the development and maintenance of the female urogenital system and secondary sex characteristics.
During the menopause the ovarian estrogen production decreases and in postmenopausal women, when the ovaries have ceased to function, only a small amount of estrogen is still produced.
This decrease and eventual cessation of estrogen production in perimenopausal and postmenopausal women, respectively, may result in vasomotor symptoms (sweating, hot flushes) and atrophic vaginitis. In addition to relieving or eliminating these disorders, estrogen replacement therapy has also been demonstrated to retard or halt the postmenopausal bone mass loss (osteoporosis).
The pharmacological effects of CE are similar to those of endogenous estrogens.

Clinical trials.

Women's Health Initiative studies.

The Women's Health Initiative (WHI) enrolled approximately 27,000 predominantly healthy postmenopausal women in two substudies to assess the risks and benefits of oral CE (CE 0.625 mg) alone or in combination with MPA (CE 0.625 mg/MPA 2.5 mg) compared to placebo. The primary endpoint was the incidence of coronary heart disease (CHD) (nonfatal myocardial infarction (MI), silent MI and CHD death). The primary safety endpoint was the incidence of invasive breast cancer.
A global index included the earliest occurrence of CHD, invasive breast cancer, stroke, pulmonary embolism (PE), endometrial cancer (only in CE/MPA), colorectal cancer, hip fracture and death due to other causes. The study did not evaluate the effects of CE alone or CE/MPA on menopausal symptoms.

Estrogen alone substudy.

The estrogen alone substudy included 10,739 women (average age of 63 years, range 50 to 79; 75.3% White, 15.1% Black, 6.1% Hispanic, 3.6% Other), who were followed up on average for 7.1 years.
The estrogen alone substudy was stopped early because an increased risk of stroke was observed and it was deemed that no further information would be obtained regarding the risks and benefits of estrogen alone in predetermined primary endpoints. Results of the substudy are presented in Table 1. The confidence intervals are unadjusted for multiple looks and multiple comparisons.
For those outcomes included in the WHI global index that reached statistical significance, the absolute excess risk per 10,000 women-years in the group treated with CE alone were 12 more strokes while the absolute risk reduction per 10,000 women-years was seven fewer hip fractures. The absolute excess risk of events included in the global index was a nonsignificant two events per 10,000 woman years. There was no difference between the groups in terms of all cause mortality (see Boxed Warnings; see Section 4.4 Special Warnings and Precautions for Use).
Final centrally adjudicated results for CHD events and centrally adjudicated results for invasive breast cancer, after an average follow-up of 7.1 years, reported no overall difference for primary CHD events (nonfatal MI, silent MI and CHD death) and invasive breast cancer incidence in women receiving CE alone compared with placebo (see Table 1).
Centrally adjudicated results for stroke events, after an average follow-up of 7.1 years, reported no significant difference in distribution of stroke subtype or severity, including fatal strokes, in women receiving CE alone compared to placebo. Estrogen alone increased the risk of ischaemic stroke, and this excess was present in all subgroups of women examined (see Table 1).

Estrogen-progestogen substudy.

The estrogen plus progestogen substudy, which included 16,608 women (average age of 63 years, range 50 to 79; 83.9% White, 6.8% Black, 5.4% Hispanic, 3.9% Other), was also stopped early. According to the predefined stopping rule, after an average follow-up of 5.2 years of treatment, the increased risk of breast cancer and cardiovascular events exceeded the specified benefits included in the global index. The absolute excess risk of events included in the global index was 19 per 10,000 women-years (RR 1.15, 95% nCI 1.03-1.28).
For those outcomes included in the WHI global index that reached statistical significance after 5.6 years of follow-up, the absolute excess risks per 10,000 women-years in the group treated with CE/MPA were six more CHD events, seven more strokes, ten more PEs and eight more invasive breast cancers, while the absolute risk reductions per 10,000 women-years were seven fewer colorectal cancers and five fewer hip fractures (see Boxed Warnings; see Section 4.4 Special Warnings and Precautions for Use).
Results of the estrogen plus progestogen substudy are presented in Table 2. These results reflect centrally adjudicated data after an average follow-up of 5.6 years.

Women's Health Initiative Memory study.

The estrogen alone Women's Health Initiative Memory study (WHIMS), a substudy of WHI, enrolled 2,947 predominantly healthy postmenopausal women 65 years of age and older (45% were age 65 to 69 years, 36% were 70 to 74 years and 19% were 75 years of age and older) to evaluate the effects of CE 0.625 mg daily on the incidence of probable dementia (primary outcome) compared with placebo.
After an average follow-up of 5.2 years, 28 women in the estrogen alone group (37 per 10,000 woman years) and 19 in the placebo group (25 per 10,000 woman years) were diagnosed with probable dementia. The relative risk of probable dementia in the estrogen alone group was 1.49 (95% CI: 0.83 to 2.66) compared to placebo. The most common classification of probable dementia in the treatment group and placebo group was Alzheimer's disease. Since the substudy was conducted in women aged 65 to 79 years, it is unknown whether these findings apply to younger postmenopausal women (see Boxed Warnings; see Section 4.4 Special Warnings and Precautions for Use, Dementia, Use in the elderly).
The estrogen plus progestogen WHIMS substudy enrolled 4,532 predominantly healthy postmenopausal women 65 years of age and older (47%, age 65 to 69 years; 35%, 70 to 74 years; 18%, 75 years of age and older) to evaluate the effects of CE 0.625 mg/MPA 2.5 mg) on the incidence of probable dementia (primary outcome) compared with placebo.
After an average follow-up of four years, 40 women in the estrogen plus progestogen group (45 per 10,000 woman years) and 21 in the placebo group (22 per 10,000 woman years) were diagnosed with probable dementia. The relative risk of probable dementia in the estrogen plus progestogen group was 2.05 (95% CI: 1.21 to 3.48) compared to placebo.
When the data from the two populations were pooled as planned in the WHIMS protocol, the reported overall relative risk for probable dementia was 1.76 (95% CI: 1.19 to 2.60). Differences between groups became apparent in the first year of treatment. It is unknown whether these findings apply to younger postmenopausal women (see Boxed Warnings; see Section 4.4 Special Warnings and Precautions for Use, Dementia, Use in the elderly).

5.2 Pharmacokinetic Properties

Absorption.

CE are water soluble and are well absorbed from the gastrointestinal tract after release from the drug formulation. The Premarin tablet releases CE slowly over several hours. Table 3 summarises the mean pharmacokinetic parameters for CE following the administration of a single dose of 0.625 mg tablet to healthy postmenopausal women.

Metabolism.

Metabolism and inactivation occur primarily in the liver.

Excretion.

Some estrogens are excreted into the bile; however, they are reabsorbed from the intestine and returned to the liver through the portal venous system. Water soluble estrogen conjugates are strongly acidic and are ionised in body fluids, which favours excretion through the kidneys since tubular reabsorption is minimal.

5.3 Preclinical Safety Data

Genotoxicity.

No data available.

Carcinogenicity.

Studies suggest that combination estrogen and progestogen increases the risk of breast cancer, ovarian cancer and endometrial cancer in women in a time dependant manner (see Section 4.4 Special Warnings and Precautions for Use).
Long-term, continuous administration of natural and synthetic estrogens in certain animal species increases the frequency of carcinomas of the breast, cervix, vagina and liver.

4 Clinical Particulars

4.1 Therapeutic Indications

Estrogens with or without progestogens should be prescribed at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman.
Premarin is indicated as replacement therapy for estrogen deficiency states associated with climacteric manifested by:
Moderate to severe vasomotor symptoms associated with the estrogen deficiency in natural and surgical menopause (sweating, hot flushes).
Periodic re-evaluation with a view to short-term treatment is recommended.
Atrophic vaginitis.
When prescribing solely for the treatment of symptoms of vaginal atrophy, topical vaginal products should be considered.
There is no evidence that estrogens are effective for anxiety or depression without associated vasomotor symptoms, and they should not be used to treat such conditions.
Premarin is indicated for the prevention of postmenopausal osteoporosis in select patients.
When prescribed solely for the prevention of postmenopausal osteoporosis, therapy should only be prescribed for women who are at high risk of osteoporosis and future fracture and who are intolerant of, or contraindicated for, nonestrogen products approved for prevention of osteoporosis. Life style modifications and the risk benefit profile of Premarin should be taken into careful consideration and discussed with the patient, to allow the patient to make an informed decision prior to prescribing (see Section 4.4 Special Warnings and Precautions for Use; Section 4.2 Dose and Method of Administration).
Hypoestrogenic states, e.g. female hypogonadism, primary ovarian failure or female castration.
See Boxed Warnings, particularly when considering Premarin for long-term usage.

4.3 Contraindications

Premarin is contraindicated in patients with:
Known or suspected pregnancy.
Known, suspected or history of breast cancer.
Known or suspected estrogen dependent neoplasia (e.g. endometrial cancer, endometrial hyperplasia).
Undiagnosed abnormal genital bleeding.
Active or history of confirmed venous thromboembolism (such as deep venous thrombosis, pulmonary embolism).
Active or history of arterial thromboembolic disease (e.g. stroke, myocardial infarction).
Severe uncontrolled hypertension.
Other undiagnosed breast pathology.
Active or chronic liver dysfunction or disease.
Known thrombophilic disorders (e.g. protein C, protein S or antithrombin deficiency).
Known or suspected hypersensitivity to CE or any excipients in the tablet.

4.4 Special Warnings and Precautions for Use

The benefits and risks of estrogen therapy must always be carefully weighed, including consideration of the emergence of risks as therapy continues. Estrogen therapy or hormone therapy should not be initiated or continued to prevent cardiovascular disease or dementia.

Physical examination.

A complete medical and family history should be obtained prior to initiating or reinstating any estrogen therapy. Pretreatment and subsequent physical examinations should include special reference to blood pressure, breasts, abdomen and pelvic organs including histological endometrial assessment, when indicated and papanicolaou smear. Before starting treatment pregnancy should be excluded. Periodic checkups and careful benefit/ risk evaluations should be undertaken in women treated with estrogen therapy.

Combined estrogen and progestogen therapy.

There are additional and/or increased risks that may be associated with the use of combination estrogen progestogen therapy compared with using estrogen alone regimens. These include an increased risk of myocardial infarction, pulmonary embolism, invasive breast cancer and ovarian cancer (see Section 5.1 Pharmacodynamic Properties, Clinical trials).

Cardiovascular risk.

An increased risk of stroke and deep vein thrombosis has been reported with estrogen alone therapy.
An increased risk of stroke, deep vein thrombosis, pulmonary embolism, and myocardial infarction has been reported with estrogen progestogen therapy.
The physician should be aware of the possibility of thrombotic disorders (including thrombophlebitis, retinal thrombosis, cerebral embolism and pulmonary embolism) during estrogen therapy and alert to their earliest manifestations.
Should any of these events occur or be suspected, estrogens with or without progestogens should be discontinued immediately.
Patients who have risk factors for thrombotic disorders should be kept under careful observation.
Risk factors for arterial vascular disease (e.g. hypertension, diabetes mellitus, tobacco use, hypercholesterolaemia and obesity) and/or venous thromboembolism (e.g. personal history or family history of venous thromboembolism, obesity and systemic lupus erythematosus) should be managed appropriately.

Stroke.

In the estrogen alone substudy of the WHI, a statistically significant increased risk of stroke was observed in women receiving CE 0.625 mg daily compared to women receiving placebo (45 vs. 33 per 10,000 woman years). The increase in risk was observed in year 1 and persisted. Should a stroke occur or be suspected, estrogens should be discontinued immediately (see Section 5.1 Pharmacodynamic Properties, Clinical trials).
In the estrogen plus progestogen substudy of the WHI, a statistically significant increased risk of stroke was reported in women receiving CE 0.625 mg/MPA 2.5 mg daily compared to women receiving placebo (31 vs. 24 per 10,000 woman years). The increase in risk was demonstrated after the first year and persisted (see Section 5.1 Pharmacodynamic Properties, Clinical trials).
Patients who are at risk of developing migraines with aura may be at risk of ischemic stroke and should be kept under careful observation.

Coronary heart disease.

In the estrogen alone substudy of the WHI, no overall effect on coronary heart disease events (defined as nonfatal myocardial infarction, silent myocardial infarction, or death due to coronary heart disease) was reported in women receiving estrogen alone compared to placebo (see Section 5.1 Pharmacodynamic Properties, Clinical trials).
In the estrogen plus progestogen substudy of the WHI, no statistically significant increase of coronary heart disease events was reported in women receiving CE/MPA compared to women receiving placebo (39 vs. 33 per 10,000 woman years). An increase in the relative risk was demonstrated in year 1, and a trend towards decreasing relative risk was reported in years two through five.

Venous thromboembolism (VTE).

In the estrogen alone substudy of the WHI study, the risk of VTE (deep vein thrombosis and pulmonary embolism) was reported to be increased for women taking CE (30 vs. 22 per 10,000 woman years), although only the increased risk of deep vein thrombosis reached statistical significance (23 vs. 15 per 10,000 woman years). The increase in VTE risk was demonstrated during the first two years. Should a VTE occur or be suspected, estrogens should be discontinued immediately (see Section 5.1 Pharmacodynamic Properties, Clinical trials).
In the estrogen plus progestogen substudy of WHI, a statistically significant 2-fold greater rate of VTE was reported in women receiving CE/MPA compared to women receiving placebo (35 vs. 17 per 10,000 woman years). Statistically significant increases in risk for both DVT (26 vs. 13 per 10,000 woman years) and PE (18 vs. 8 per 10,000 woman years) were also demonstrated. The increase in VTE risk was demonstrated during the first year and persisted.
If feasible, estrogens should be discontinued at least four to six weeks before surgery of the type associated with increased risk of thromboembolism or during periods of prolonged immobilisation.

Malignant neoplasms.

Breast cancer.

Studies involving the use of estrogens by postmenopausal women have reported inconsistent results on the risk of breast cancer. The most important randomised clinical trial providing information about this issue is the WHI. In the estrogen alone substudy of WHI, after an average of 7.1 years of follow-up, CE 0.625 mg daily was not associated with an increased risk of invasive breast cancer (RR 0.80, 95% nCI 0.62-1.04) (see Section 5.1 Pharmacodynamic Properties, Clinical trials).
In the estrogen plus progestogen substudy, after a mean follow-up of 5.6 years, the WHI substudy reported an increased risk of breast cancer. In this substudy, prior use of estrogen alone or estrogen plus progestogen combination hormone therapy was reported by 26% of the women. The relative risk of invasive breast cancer was 1.24 (95% nCI 1.01-1.54) and the absolute risk was 41 vs. 33 cases per 10,000 woman years for estrogen plus progestogen compared with placebo, respectively. Among women who reported prior use of hormone therapy, the relative risk of invasive breast cancer was 1.86 and the absolute risk was 46 vs. 25 cases per 10,000 woman years for estrogen plus progestogen compared with placebo. Among women who reported no prior use of hormone therapy, the relative risk of invasive breast cancer was 1.09 and the absolute risk was 40 vs. 36 cases per 10,000 woman years for estrogen plus progestogen compared with placebo.
In the same substudy, invasive breast cancers were larger and diagnosed at a more advanced stage in the estrogen plus progestogen group compared with the placebo group. Metastatic disease was rare with no apparent difference between the two groups. Other prognostic factors such as histological subtype, grade and hormone receptor status did not differ between the groups (see Section 5.1 Pharmacodynamic Properties, Clinical trials).
Some observational studies have reported an increased risk of breast cancer for estrogen alone therapy after several years of use. The risk increased with duration of use, and appeared to return to baseline within approximately five years after stopping treatment (only the observational studies have substantial data on risk after stopping).
The observational Million Women Study in Europe reported an increased risk of mortality due to breast cancer among current users of estrogens alone or estrogens plus progestogens compared to never users, while the estrogen plus progestogen substudy of WHI showed no effect on breast cancer mortality with a mean follow-up of 5.6 years.
The use of estrogen alone and estrogen plus progestogen has been reported to result in an increase in abnormal mammograms requiring further evaluation.
All women should receive yearly breast examinations by a healthcare provider, and perform monthly breast self examinations. In addition, mammography examinations should be scheduled 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 (see Exacerbation of other conditions).
The reported endometrial cancer risk among unopposed estrogen users is about 2 to 12-fold greater than in nonusers and appears dependent on duration of treatment and on estrogen dose. The greatest risk appears associated with prolonged use, with increased risks of 15 to 24-fold for five to ten years or more, and this risk has been shown to persist for at least 8 to 15 years after estrogen therapy is discontinued.
Clinical surveillance of all women taking estrogen or estrogen plus progestogen 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 vaginal 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. Adding a progestogen to postmenopausal estrogen therapy has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer.

Addition of a progestogen when a woman has not had a hysterectomy.

Studies of the addition of a progestogen for 10 or more days of a cycle of estrogen administration or daily with estrogen in a continuous regimen, have reported a lower incidence of endometrial hyperplasia than would be induced by estrogen treatment alone.
There are, however, possible risks that may be associated with the use of progestogens with estrogens compared to estrogen alone regimens. These include a possible increased risk of breast cancer, adverse effects on lipoprotein metabolism (e.g. lowering HDL, raising LDL) and impairment of glucose tolerance (see Section 5.1 Pharmacodynamic Properties, Clinical trials; Section 4.4 Special Warnings and Precautions for Use, Combined estrogen and progestogen therapy).

Ovarian cancer.

Ovarian cancer is much rarer than breast cancer.
Epidemiological evidence from a large meta-analysis suggests a slightly increased risk in women taking estrogen-only or combined estrogen-progestogen HRT, which becomes apparent within 5 years of use and diminishes over time after stopping.
Some other studies, including the WHI trial, suggest that the long-term use of combined HRTs may be associated with a similar or slightly smaller risk.

Dementia.

In the estrogen alone Women's Health Initiative Memory Study (WHIMS), a substudy of WHI, a population of 2,947 hysterectomised women aged 65 to 79 years was randomised to CE 0.625 mg daily or placebo. In the estrogen plus progestogen WHIMS substudy, a population of 4,532 postmenopausal women aged 65 to 79 years was randomised to CE 0.625 mg/MPA 2.5 mg daily or placebo.
In the estrogen alone substudy, after an average follow-up of 5.2 years, 28 women in the estrogen alone group and 19 women in the placebo group were diagnosed with probable dementia. The relative risk of probable dementia for CE alone vs. placebo was 1.49 (95% CI 0.83-2.66). The absolute risk of probable dementia for CE alone vs. placebo was 37 vs. 25 cases per 10,000 woman years (see Section 5.1 Pharmacodynamic Properties, Clinical trials).
In the estrogen plus progestogen substudy, after an average follow-up of four years, 40 women in the estrogen plus progestogen group and 21 women in the placebo group were diagnosed with probable dementia. The relative risk of probable dementia for estrogen plus progestogen vs. placebo was 2.05 (95% CI 1.21-3.48). The absolute risk of probable dementia for CE/MPA vs. placebo was 45 vs. 22 cases per 10,000 woman years (see Section 5.1 Pharmacodynamic Properties, Clinical trials).
When data from the two populations were pooled as planned in the WHIMS protocol, the reported overall relative risk for probable dementia was 1.76 (95% CI 1.19-2.60). Since both substudies were conducted in women aged 65 to 79 years, it is unknown whether these findings apply to younger postmenopausal women (see Boxed Warnings; Section 4.4 Special Warnings and Precautions for Use, Use in the elderly).

Gall bladder disease.

A 2 to 4-fold increase in the risk of gall bladder disease requiring surgery in postmenopausal women receiving estrogens has been reported.

Uterine bleeding.

Certain patients may develop abnormal uterine bleeding (see Endometrial cancer).

Fluid retention.

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

Exacerbation of other conditions.

Estrogen therapy may cause an exacerbation of asthma, epilepsy, migraine with or without aura, diabetes mellitus, otosclerosis, porphyria, systemic lupus erythematosus and hepatic haemangioma and should be used with caution in women with these conditions.
Endometriosis may be exacerbated with administration of estrogen therapy. Malignant transformation of residual endometrial implants have been reported in women treated posthysterectomy with estrogen alone therapy. For patients known to have residual endometriosis posthysterectomy, the addition of progestogen should be considered.

Elevated blood pressure.

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

Use in hepatic impairment.

Estrogens may be poorly metabolised in patients with impaired liver function (see Section 4.3 Contraindications).

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, medication should be discontinued.

Angioedema.

Exogenous estrogens may induce or exacerbate symptoms of angioedema, particularly in women with hereditary angioedema.

Hypercalcaemia.

Estrogen administration may lead to severe hypercalcaemia in patients with breast cancer and bone metastases. If hypercalcaemia occurs, use of the medication should be stopped and appropriate measures taken to reduce the serum calcium level.

Hypocalcaemia.

Estrogens should be used with caution in patients with severe hypocalcaemia.

Hypothyroidism.

Estrogen administration leads to increased thyroid binding globulin (TBG) levels. Patients with normal thyroid function can compensate for the increased TBG by making more thyroid hormone, thus maintaining free T4 and T3 serum concentrations in the normal range. Patients dependent on thyroid hormone replacement therapy who are receiving estrogens may require increased doses of their thyroid hormone replacement therapy. These patients should have their thyroid function monitored in order to maintain their free thyroid hormone levels in an acceptable range.

Visual abnormalities.

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

Hypertriglyceridaemia.

In patients with pre-existing hypertriglyceridaemia, estrogen therapy may be associated with elevations of plasma triglycerides leading to pancreatitis and other complications. Consider discontinuation of treatment if pancreatitis occurs.
In the HOPE study, the mean percent increase from baseline in serum triglycerides after one year of treatment with Premarin 0.625 mg, 0.45 mg and 0.3 mg compared with placebo were 34.3, 30.2, 25.1 and 10.7, respectively. After two years of treatment, the mean percent changes were 47.6, 32.5, 19.0 and 5.5, respectively.

Laboratory monitoring.

Estrogen administration should be guided by clinical response instead of by hormone levels, e.g. oestradiol, follicle stimulating hormone (FSH) (see Effects on laboratory tests).

Other.

Premarin is not an oral contraceptive, nor will it restore fertility. If it is administered, with or without a progestogen, to a woman of childbearing potential she should be advised to use nonhormonal methods of contraception.

Use in the elderly.

The estrogen alone substudy of the WHI reported an increased risk of stroke compared with placebo in postmenopausal women 70 years of age or older. Of the total number of subjects in the estrogen alone substudy of the Women's Health Initiative study, 46% (n = 4,943) were 65 years and over, while 7.1% (n = 767) were 75 years and over. There was a higher relative risk (CE versus placebo) of stroke in women less than 75 years of age compared to women 75 years and over (see Section 4.4 Special Warnings and Precautions for Use, Cardiovascular risk).
In the estrogen plus progestogen substudy of the WHI, there was a higher relative risk (CE/MPA versus placebo) of nonfatal stroke and invasive breast cancer in women 75 and over compared to women less than 75 years of age. In women greater than 75, the increased risk of nonfatal stroke and invasive breast cancer observed in the estrogen plus progestogen combination group compared to the placebo group was 75 versus 24 per 10,000 wome- years and 52 versus 12 per 10,000 women-years, respectively (see Section 4.4 Special Warnings and Precautions for Use, Cardiovascular risk).
The estrogen alone substudy of the WHIMS conducted in women aged 65-79, reported an increased risk of developing probable dementia for CE alone compared to placebo (see Section 5.1 Pharmacodynamic Properties, Clinical trials; Section 4.4 Special Warnings and Precautions for Use, Dementia).
Seventy nine percent of the cases of probable dementia occurred in women that were older than 70 for the CE group and 82 percent of the cases of probable dementia occurred in women who were older than 70 in the CE/MPA group. The most common classification of probable dementia in both treatment groups and placebo groups was Alzheimer's disease.
When data from the two populations were pooled as planned in the WHIMS protocol, the reported overall relative risk for probable dementia was 1.76 (95% CI: 1.19 to 2.60). Since both substudies were conducted in women aged 65 to 79 years, it is unknown whether these findings apply to younger postmenopausal women (see Boxed Warnings; see Section 4.4 Special Warnings and Precautions for Use, Dementia).
With respect to efficacy in the approved indications, there have not been sufficient numbers of elderly patients involved in studies utilising Premarin to determine whether those over 65 years of age differ from younger subjects in their response to Premarin.

Paediatric use.

Premarin is not indicated for use in paediatrics. Safety and effectiveness in paediatric use have not been established. Estrogen treatment of prepubertal girls induces premature breast development and vaginal cornification, and may induce uterine bleeding.
Since large and repeated doses of estrogen over an extended time period have been shown to accelerate epiphyseal closure, hormonal therapy should not be started before epiphyseal closure has occurred in order not to compromise final height.

Effects on laboratory tests.

Pathologists should be advised that a patient is receiving estrogen therapy when relevant specimens are submitted.
Certain endocrine and liver function tests may be affected by administration of estrogens.
Accelerated prothrombin time, partial thromboplastin time and platelet aggregation time; increased platelet count; increased factors II, VII antigen, VIII coagulant activity, IX, X, XII, VII-X complex, II-VII-X complex and β-thromboglobulin; decreased levels of anti-factor Xa and antithrombin III activity; increased levels of fibrinogen and fibrinogen activity; increased plasminogen antigen and activity.
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 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 or biologically active hormone concentrations may be decreased. Other plasma proteins may be increased (angiotensinogen/ renin substrate, α-1-trypsin, ceruloplasmin).
Impaired glucose tolerance.
The response to metyrapone test may be reduced.
Increased plasma HDL and HDL2 cholesterol subfraction concentrations, reduced LDL cholesterol concentration, increased triglyceride levels.
The results of these tests should not be regarded as reliable until estrogen use has been discontinued for one to two months. Abnormal tests results should be repeated.
Gonadotrophin levels.
Plasma cortisol levels.
Increased plasma estrogen levels.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Data from a drug-drug interaction study involving CE and MPA indicate that the pharmacokinetic disposition of both medicines is not altered when the medicines are coadministered. Other clinical drug-drug interaction studies have not been conducted with CE.
In vitro and in vivo studies have shown that estrogens are metabolised partially by cytochrome P450 3A4 (CYP3A4). Therefore, CYP3A4 inducers or inhibitors may affect drug metabolism. Inducers of CYP3A4, such as St John's wort (Hypericum perforatum) preparations, phenobarbitone, phenytoin, carbamazepine, rifampicin and dexamethasone may reduce plasma concentrations of estrogens. This may lead to a decreased effect and/or changes in the uterine bleeding profile. CYP3A4 inhibitors such as cimetidine, erythromycin, clarithromycin, cyclosporin, grapefruit juice, ketoconazole, itraconazole and ritonavir, may increase plasma concentrations of estrogens and may result in side effects.
Hot flushes and vaginal bleeding have been reported in patients taking estrogens and St John's wort (Hypericum perforatum).
Alteration of the effectiveness of antihypertensive agents, theophyllines, phenothiazines, corticosteroids, tricyclic antidepressants, diazepam and caffeine, by either potentiating/ enhancing their pharmacological effect or by decreasing their clearance may occur during estrogen use.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

No data available.
(Category D)
Premarin should not be used during pregnancy (see Section 4.3 Contraindications).
Estrogens are ineffective in the prevention or treatment of threatened or habitual abortion when given in the first trimester of pregnancy.
If a woman becomes pregnant while using Premarin, it should be discontinued immediately.
Estrogen administration to nursing mothers has been shown to decrease the quantity and quality of breast milk. Detectable amounts of estrogens have been identified in the milk of mothers receiving the drug. Lactating mothers should not use estrogens.

4.8 Adverse Effects (Undesirable Effects)

The most serious adverse reactions associated with the use of estrogens are indicated, see Section 4.4 Special Warnings and Precautions for Use. The following adverse reactions have been reported and are listed in CIOMS frequency categories as follows: very common: > 10%; common: > 1% and < 10%; uncommon: > 0.1% and < 1%; rare: > 0.01% and < 0.1%; very rare: < 0.01%.

Adverse reactions by body system.

Immune system disorders.

Uncommon: hypersensitivity.
Rare: anaphylactic/ anaphylactoid reactions, urticaria, angioedema.

Reproductive system and breast disorders.

Common: abnormal uterine bleeding, breast pain, tenderness, enlargement, discharge, leucorrhoea.
Uncommon: change in menstrual flow, change in cervical ectropion and secretion.
Rare: galactorrhoea, dysmenorrhoea/ pelvic pain, increased size of uterine leiomyomata.
Very rare: endometrial hyperplasia.

Gastrointestinal disorders.

Uncommon: nausea, bloating, abdominal pain.
Rare: vomiting, pancreatitis, ischaemic colitis.

Hepatobiliary disorders.

Rare: gall bladder disease.
Very rare: cholestatic jaundice.

Infections and infestations.

Uncommon: vaginitis including vaginal candidiasis.

Neoplasms benign and malignant (including cysts and polyps).

Rare: breast cancer, ovarian cancer, fibrocystic breast changes, growth potentiation of benign meningioma.
Very rare: endometrial cancer, enlargement of hepatic haemangiomas.

Musculoskeletal, connective tissue and bone disorders.

Common: arthralgias, leg cramp.

Psychiatric disorders.

Uncommon: changes in libido, depression, mood disturbances, dementia.
Rare: irritability.

Skin and subcutaneous tissue disorders.

Common: alopecia.
Uncommon: chloasma/ melasma, hirsutism, rash, pruritus.
Very rare: erythema multiforme, erythema nodosum.

Cardiac disorders.

Rare: myocardial infarction.

Vascular disorders.

Uncommon: venous thrombosis, pulmonary embolism.
Rare: superficial thrombophlebitis.

Respiratory, thoracic and mediastinal disorders.

Rare: exacerbation of asthma.

General disorders and administration site conditions.

Uncommon: oedema.

Metabolism and nutrition disorders.

Rare: glucose intolerance.
Very rare: exacerbation of porphyria, hypocalcaemia (in patients with disease that can predispose to severe hypocalcaemia).

Eye disorders.

Uncommon: steepening of corneal curvature, intolerance to contact lenses.
Very rare: retinal vascular thrombosis.

Nervous system disorders.

Uncommon: nervousness, dizziness, headache, migraine.
Rare: exacerbation of epilepsy, stroke.
Very rare: exacerbation of chorea.

Investigations.

Common: changes in weight (increase or decrease), increased triglycerides.
Very rare: increase in blood pressure.

Ovarian cancer.

Use of estrogen-only or combined estrogen-progestogen HRT has been associated with a slightly increased risk of having ovarian cancer diagnosed.
A meta-analysis from 52 epidemiological studies reported an increased risk of ovarian cancer in women currently using HRT compared to women who have never used HRT (RR 1.43, 95% CI 1.31-1.56). For women aged 50 to 54 years taking 5 years of HRT, this results in about 1 extra case per 2000 users. In women aged 50 to 54 who are not taking HRT, about 2 women in 2000 will be diagnosed with ovarian cancer over a 5-year period.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.

4.2 Dose and Method of Administration

Continuous daily administration of Premarin is generally recommended.
Physicians should advise their patients that the tablets should be swallowed whole. The tablets should not be divided, crushed, chewed, or dissolved in the mouth.
Patients should be re-evaluated periodically to determine if treatment for symptoms is still necessary. See Boxed Warnings, particularly when considering Premarin for long-term usage.
For women with an intact uterus, when indicated for climacteric symptoms or prevention of postmenopausal osteoporosis, it is recommended that a progestogen is administered (see Section 4.4 Special Warnings and Precautions for Use, Malignant neoplasms). For continuous Premarin administration, a progestogen should be added for at least 10 to 14 consecutive days each month. In some cases, hysterectomised women with a history of endometriosis may need a progestogen (see Section 4.4 Special Warnings and Precautions for Use, Exacerbation of other conditions). If Premarin is administered cyclically (i.e. 21 days out of 28 days), it is recommended that the progestogen is added for the last 10-14 days of the estrogen course.

Climacteric symptoms.

For treatment of moderate to severe vasomotor symptoms and atrophic vaginitis associated with the menopause, the lowest dose that will control symptoms should be chosen.
Vasomotor symptoms: 0.3 mg to 1.25 mg daily.
Atrophic vaginitis: 0.3 mg to 1.25 mg daily, depending upon the tissue responses of the individual patient.

Prevention of postmenopausal osteoporosis.

0.3 mg-0.625 mg daily.
The mainstays for decreasing the risk of postmenopausal osteoporosis are weight bearing exercise, adequate calcium and vitamin D intake and, when indicated, pharmacological therapy. Postmenopausal women require an adequate daily intake of elemental calcium. Therefore when not contraindicated, calcium supplementation may be helpful for women with suboptimal dietary intake. Vitamin D supplementation may also be required to ensure adequate daily intake in postmenopausal women.

Hypoestrogenism.

Female hypogonadism.

2.5 to 7.5 mg daily, in divided doses for 20 days, followed by a rest period of 10 days duration. If bleeding does not occur by the end of this period, the same dosage schedule is repeated. The number of courses of estrogen therapy necessary to produce bleeding may vary depending on the responsiveness of the endometrium.
If bleeding occurs before the end of the 10 day period, begin a 20 day estrogen/ progestogen cyclic regimen with Premarin 2.5 to 7.5 mg daily in divided doses. During the last five days of estrogen therapy, give an oral progestogen. If bleeding occurs before this regimen is concluded, therapy is discontinued and may be resumed on the fifth day of bleeding.

Female castration and primary ovarian failure.

0.3 to 1.25 mg daily. Adjust dosage according to severity of symptoms and response of the patient.

4.7 Effects on Ability to Drive and Use Machines

The effects of this medicine on a person's ability to drive and use machines were not assessed as part of its registration.

4.9 Overdose

Symptoms of overdosage of estrogen containing products 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.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

7 Medicine Schedule (Poisons Standard)

S4.

6 Pharmaceutical Particulars

6.1 List of Excipients

Each tablet contains lactose monohydrate, hypromellose, magnesium stearate, macrogol 400, sucrose, microcrystalline cellulose, powdered cellulose, hyprolose, calcium phosphate, carnauba wax and Opacode monogramming ink NS-white.
The colouring agent in Premarin 0.3 mg tablet is Opadry 152B21511 Green. The colouring agent in Premarin 0.625 mg tablet is Opadry 03B16083 Maroon.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 25°C.

6.5 Nature and Contents of Container

Premarin 0.3 mg and Premarin 0.625 mg tablets are available in blister packs PVC/Aclar/PVC and a hard tempered aluminium foil lid of 28, 56, 84 and 132 tablets.
Premarin 0.3 mg tablets are also available in blister packs of 7 tablets.
Not all pack sizes may be marketed.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

Summary Table of Changes