Consumer medicine information

Climara

Estradiol

BRAND INFORMATION

Brand name

Climara

Active ingredient

Estradiol

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Climara.

WHAT IS IN THIS LEAFLET

This leaflet answers some common questions about Climara. It does not contain all 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 using Climara against the benefits they expect it will have for you.

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

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

WHAT CLIMARA IS USED FOR

Climara is used for the treatment of menopausal symptoms due to estrogen deficiency during menopause or after a surgical procedure, where estrogen production is decreased. Climara is only intended for short term use.

Climara is an adhesive patch, which delivers estradiol through the skin and into the blood stream. Climara releases estradiol in a continuous and controlled way just as your ovaries were doing before. Because the medicine does not have to pass through your stomach and liver, it allows you to take a much lower dose of estrogen than would be needed in a tablet. The estradiol in Climara can replace the estrogen in the body.

During menopause, the estradiol production of the ovaries declines. Although menopause is natural, it often causes distressing symptoms, which are connected with the gradual loss of the hormones produced by the ovaries.

Climara provides estrogen, which the body is no longer making, to prevent or relieve menopausal symptoms such as hot flushes (night sweats), sleep disturbances, vaginal dryness, depression, nervousness, irritability, headache, dizziness.

Climara can also be used to prevent bone mineral density loss (where the bones become weaker, more brittle and likely to break) during menopause.

Calcium, vitamin D and regular exercise are some other factors that may help to prevent thinning of the bones. You should include foods that are good sources of calcium and vitamin D in your daily diet and exercise regularly. Your doctor can advise you on which foods and types of exercise are best for you.

Climara is not a contraceptive. It will not prevent you from falling pregnant.

Ask your doctor if you have any questions about why this medicine has been prescribed for you. Your doctor may have prescribed it for another reason.

BEFORE YOU USE CLIMARA

When you must not use it

Do not use Climara if you have an allergy to:

  • estradiol, the active ingredient in Climara
  • any of the ingredients listed at the end of this leaflet.

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 use Climara if you have:

  • severe uncontrolled high blood pressure
  • severe liver disease such as jaundice (signs of liver problems such as yellowing of skin and/or eyes) or persistent itching during a previous pregnancy
  • a history of or existing liver tumours
  • suspected or existing tumours in the uterus, ovaries or breast
  • known or suspected tumours influenced by sex hormones
  • endometriosis (the presence of tissue of the lining of the womb in places in the body where it is not usually found)
  • a history of or existing blood clot in the blood vessels (such as blood clots in the legs)
  • if you recently had a heart attack and/or stroke
  • if you have a high risk of venous or arterial thrombosis (blood clot)
  • severe diabetes
  • sickle-cell anaemia (inherited disorder which causes the red blood cells to change shape)
  • disturbances of fat metabolism
  • a history of herpes during pregnancy
  • hearing loss (otosclerosis) that worsens during pregnancy
  • undiagnosed abnormal vaginal bleeding

If you have not had your uterus (womb) removed (hysterectomy), do not use Climara unless your doctor has prescribed another hormone progestogen to take with Climara.

The use of estrogens alone and over a prolonged period can lead to excessive development of the lining of the womb and this can increase the incidence of cancer of the womb. This risk can be avoided by the additional administration of a progestogen. The general result of this is regular shedding of the lining of the womb and, therefore, menstruation-like bleeding. If you have not had a hysterectomy (your uterus/womb removed) your doctor should prescribe a progestogen for you to take and you should discuss this with your doctor before using Climara.

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

Do not use this medicine if you are pregnant. It may affect your developing baby if you use it during pregnancy.

Do not breast-feed if you are using this medicine. The active ingredient in Climara passes into breast milk and there is a possibility that your baby may be affected.

Do not use this medicine after the expiry date printed on the pack and pouch. The expiry date is printed on the carton and on each pouch after “EXP” (e.g. 11 18 refers to November 2018). The expiry date refers to the last day of that month. If it has expired return it to your pharmacist for disposal.

Do not use this medicine if the packaging is torn or shows signs of tampering. If the packaging is damaged, return it to your pharmacist for disposal.

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

Before you start to use it

Tell your doctor if you have allergies to any other medicines, foods, preservatives or dyes.

Tell your doctor if:

  • you are overweight
  • you smoke
  • you or anyone in your immediate family has had blood clots (thrombosis)
  • systemic lupus erythematosus (SLE, a chronic inflammatory disease)
  • you have any planned hospitalisation, surgery or prolonged immobilisation

Studies have suggested that HRT may be associated with an increased risk of developing blood clots. You have an increased risk of a blood clot if you have any of the above risk factors. In addition to these, there may be other risk factors. In the case of a combination of factors, the risk may be higher than simply adding two individual risks.

Talk to your doctor if you have any concerns.

Using Climara may also increase your risk of coronary heart disease. Tell your doctor if you experience chest pain or discomfort.

Using Climara may increase your risk of gall bladder disease. This is because estrogen stimulates the liver to remove more cholesterol from blood and divert it to the gallbladder.

Before being prescribed Climara, your doctor should perform a thorough medical and gynaecological examination (including the breasts and a pap smear). Your doctor will also note your family medical history and exclude pregnancy.

Tell your doctor if you have or have had any of the following medical conditions:

  • diabetes
  • high blood pressure
  • varicose veins
  • otosclerosis (a type of hearing loss)
  • endometriosis (the presence of tissue of the lining of the womb in places in the body where it is not normally found)
  • multiple sclerosis
  • epilepsy
  • porphyria (inherited or acquired disorder of certain enzymes)
  • tetany (mineral imbalance in the body that results in severe muscle spasms)
  • chorea minor (disorder characterised by irregular and involuntary muscles)
  • kidney or heart disease
  • tumours in the pituitary gland
  • yellowing of the skin and/or eyes (cholestatic jaundice) with previous estrogen use or during pregnancy
  • migraine
  • a high level of triglycerides (fats) in the blood
  • high or low calcium levels in the blood
  • an underactive thyroid gland (hypothyroidism)
  • an abnormal build-up of blood vessels in the liver (hepatic haemangioma)
  • chloasma (yellowish brown pigmentation patches on the skin, particularly of the face); if so, avoid too much exposure to the sun or ultraviolet radiation
  • asthma
  • systemic lupus erythematosus (SLE; a disease affecting the skin all over the body)
  • tumours in the womb or liver
  • hereditary angioedema, an inherited disorder where repeated episodes of severe swelling occur

Tell your doctor if you are 65 years or older when HRT is initiated. The reason is that there is limited evidence from clinical studies that hormonal treatment may increase the risk of significant loss of intellectual abilities such as memory capacity (dementia).

If Climara is used in the presence of any of the conditions listed above you will need to be kept under close observation. Your doctor can explain this to you. Therefore, if any of these apply to you, tell your doctor before starting to use Climara.

HRT and cancer

Endometrial cancer

The risk of cancer of the lining of the womb (endometrial cancer) increases when estrogens are used alone for prolonged periods. Taking a progestogen in addition to the estrogen lowers this risk.

Please inform your doctor if you frequently have bleeding irregularities or persistent bleeding during the treatment with Climara.

Breast cancer

Tell your doctor if you have suffered from fibrocystic disease of the breasts (lumps in the breast) or if you have first degree relatives (mother, sisters, daughters) who have had breast cancer.

Breast cancer has been diagnosed slightly more often in women who use hormone replacement therapy (HRT) than in women of the same age who do not use HRT. If you are concerned about this information you should discuss this with your doctor. It is recommended that yearly breast examinations are conducted and regular breast self examination (monthly) should be carried out.

HRT has been reported to result in an increased number of abnormal mammograms requiring further evaluation.

Ovarian cancer

Some observational studies show a slightly increased overall risk of developing ovarian cancer in women who have used HRT compared to women who have never used HRT. In women currently using HRT, this risk was further increased. These associations have not been shown in all studies. There is no consistent evidence that the risk of developing ovarian cancer is related to the duration of use of HRT. However, the risk may be more relevant with long-term use (for several years).

Liver tumour

During or after the use of hormones such as those that are contained in Climara, benign liver tumours have rarely occurred, and malignant liver tumours even more rarely. In isolated cases, bleeding has occurred from such tumours into the abdominal cavity. Although such events are rare, you should inform your doctor about any pain in your upper abdomen that does not disappear within a short time.

Taking other medicines

Tell your doctor or pharmacist if you are taking any other medicines, including any that you get without a prescription from your pharmacy, supermarket or health food shop.

Some medicines and Climara may interfere with each other. These include:

  • medicines to treat high blood pressure, chest pain and/or irregular heart beat such as ACE inhibitors, verapamil, diltiazem
  • macrolide antibiotics (e.g. clarithromycin, erythromycin)
  • medication used to treat epilepsy, such as hydantoins, barbituates, primidone, carbamazepine
  • rifampicin for the treatment of tuberculosis
  • herbal medicines containing St John’s Wort
  • medicines used to treat HIV such as ritonavir or nevirapine
  • some medicines used to treat Hepatitis C Virus (HCV) such as boceprevir, telaprevir
  • medicines used to treat fungal infections such as ketoconazole, itraconazole, voriconazole, fluconazole
  • grapefruit juice
  • medicines used to treat diabetes, such as insulin or anti-diabetic medications

These medicines may be affected by Climara 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 and pharmacist have more information on medicines to be careful with or avoid while using this medicine.

HOW TO USE CLIMARA

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 printed on the pharmacist label, ask your doctor or pharmacist for help.

How much to use

The amount of estrogen you need will depend upon your body's requirements. Your doctor may adjust this amount by changing the size of the patch you use.

How to use it

The best place to apply Climara patches is on your lower abdomen or buttocks. NEVER put Climara patches on your breasts. Do not put the patch on your waistline where tight clothes may rub it. Avoid putting the patch on areas where the skin is hairy or folded.

Before applying a Climara patch, make sure your skin is clean and dry. Do not apply the patch to oily, broken or irritated skin.

  1. Remove Climara from the pouch
The Climara patch is packed in a protective pouch. Tear open the pouch at the notched corner and remove the patch. Do not use scissors as you may accidentally cut the patch. Do not peel the square silver sticker inside the pouch as this contains the desiccant. This is not the Climara patch. Dispose of the pouch once the Climara patch has been applied.
  1. Take the backing off the patch
A clear plastic protective backing which is slightly larger than the patch itself covers the sticky side of the patch. The backing must be removed before you apply the patch to your skin.
Remove the backing by holding the edge of the patch in one hand and peeling the backing off with the other hand from the crease line. Half of the backing will come off, exposing part of the patch. As you apply the patch to your skin, peel off the rest of the backing. Do not touch the sticky side of the patch. Apply the patch immediately after opening the pouch and removing the backing. Throw away the backing.
  1. Apply the patch to your skin
Place the sticky side of the patch on a clean, dry area of skin. Press the patch firmly in place for about 10 seconds. Make sure the patch sticks well, especially around the edges.
  1. Changing Climara patches
Change the patch once every week (every 7 days). Remove the old patch and discard it, out of the way of children. Apply your new patch to a different area of clean, dry skin. Do not put the patch on the same area of skin each week.
  1. What to do if your patch comes off
Climara patches are unlikely to fall off. But if the patch does fall off put a new patch on for the rest of the seven days.

When to use it

Climara patches are usually worn continuously, and replaced every 7 days. You should only wear one patch at a time, unless your doctor tells you otherwise.

Your doctor will explain when to start using the patch and if you should use it any other way (for example, for 3 weeks out of 4).

How long to use it

Your doctor will advise you on how long to use Climara. Your doctor should discuss with you the risks and benefits with extended use of this product and your treatment with hormone therapy should also be re-evaluated at regular intervals.

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

You may have an increased risk of developing breast cancer, heart disease, stroke, blood clots on the lungs and dementia. On the other hand, the risk of hip fractures and bowel cancer may be reduced. Your doctor can discuss these risks and benefits with you, taking into account your particular circumstances.

If you forget to use it

If you forget to change the Climara patch, change it as soon as you remember. One patch only works for 7 days.

If you lose a patch or forget to replace it for several days, irregular bleeding may occur.

If you use too much (overdose)

Estrogen overdose is unlikely with this type of application. In the event of accidental overdose, remove the patch.

If you are worried, telephone your doctor or the Poisons Information Centre (Australia: 13 11 26 or New Zealand: 0800 POISON or 0800 764 766) for advice, or go to Accident and Emergency at the nearest hospital, if you think that you or anyone else may have used too much Climara.

Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

Symptoms of an overdose may include nausea, vomiting, breast discomfort, breakthrough bleeding, fluid retention and bloating.

WHILE YOU ARE USING CLIMARA

Things you must do

If you are about to be started on any new medicine, remind your doctor and pharmacist that you are using Climara.

Tell any other doctors, dentists, and pharmacists who treat you that you are using this medicine.

Tell your doctor immediately if you become pregnant while using Climara. The use of Climara should be stopped immediately.

If you are still able to fall pregnant, barrier methods of contraception should be practised (such as condoms or a diaphragm). If there is a chance that pregnancy has occurred, stop using the patch until it has been ruled out.

If you are going to have surgery, tell the surgeon or anaesthetist well in advance that you are using this medicine. Climara should not be used at least four to six weeks before surgery.

If irregular menstrual bleeding occurs repeatedly during the use of Climara or if the bleeding in the treatment-free weeks is unusually heavy, tell your doctor.

See your doctor at least once a year for a check-up. Some women will need to go more often. Your doctor will check your breasts and order a mammogram at regular intervals, check your uterus and cervix and do a pap smear at regular intervals, and monitor your blood pressure

Check your breasts each month and report any changes promptly to your doctor. Your doctor or nurse can show you how to check your breasts properly.

Stop using it immediately if

You should stop treatment at once and consult your doctor if you have any of the following conditions:

  • your very first attack of migraine (typically a throbbing headache and nausea preceded by visual disturbances)
  • worsening of pre-existing migraine, any unusually frequent or unusually severe headaches
  • sudden disturbances of vision or hearing
  • swollen veins (thrombophlebitis),
  • itching of the whole body
  • unusual upper abdominal pains that do not disappear within a short period of time
  • planned operations/surgery or immobilisation
  • seizures
  • increase in blood pressure

If you get a blood clot while you are using Climara or there is a suspicion of this you should stop using it immediately and contact your doctor. Warning signs to look out for are:

  • coughing blood
  • unusual pains or swelling of your arms or legs
  • sudden shortness of breath, pain or tightness in the chest
  • fainting

Climara must also be stopped at once if you develop jaundice (yellowing of the skin and/or eyes). Tell your doctor immediately if either occurs.

Things you must not do

Do not use Climara 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 using your medicine or lower the dosage without checking with your doctor. If you stop using it suddenly, your condition may worsen or you may have unwanted side effects.

What to be careful of

Excess intake of alcohol during use of HRT has an influence on the treatment. Your doctor will advise you.

Other things to know

  • You can bathe, shower or swim when wearing a Climara patch. The patch might, however, become detached from the skin in very hot water or in the sauna.
  • You can still drive safely when you are using Climara patches.
  • If there are, repeatedly, persistent skin irritations (e.g. persistent reddening or itching at the application site) even if the application site is changed according to the directions given, you should consider stopping treatment.

SIDE EFFECTS

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

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

Do not be alarmed by the following 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 or pharmacist if you notice any of the following and they worry you:

  • redness, rash, itching, stinging and blisters on the skin after the patch has been removed
  • tender or painful breasts, breast enlargement
  • irregular menstrual bleeding
  • fluid retention (bloating or swelling in the arms, ankles or feet)
  • rash or itching
  • nausea
  • headache
  • nervousness or depressive moods
  • dizziness
  • unusual tiredness
  • changes in body weight
  • pain (including back and pelvic pain)
  • increased sweating
  • leg cramps
  • stomach pain, cramps or wind
  • acne
  • vaginal itching, burning or discharge

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 parts of the body, shortness of breath, wheezing, or trouble breathing
  • yellowing of the skin and/or eyes (cholestatic jaundice)
  • coughing blood, unusual pains or swelling of your arms or legs, sudden shortness of breath, fainting

If you have these side effects, you may need urgent medical attention.

Skin disorders have been reported in women receiving HRT. Tell your doctor if you notice itchy, reddish, painful lumps (erythema nodosum, erythema multiforme, haemorrhagic dermatitis) or yellowish brown pigmentation on the skin (chloasma).

Tell your doctor or pharmacist if you notice anything that is making you feel unwell.

Other side effects not listed above may also occur in some people.

Also tell your doctor if you have any of the symptoms listed under “While you are taking Climara - stop taking it immediately”.

AFTER USING CLIMARA

Storage

Keep your patches in the pack until it is time to use them.

Do not remove the patch from the protective pouch until you are ready to apply it.

Keep your patches in a cool dry place below 30°C.

Do not store it or any other medicine in the bathroom, near a sink, or on a window-sill.

Do not leave it in the car. 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 using this medicine or the expiry date has passed, ask your pharmacist what to do with any medicine that is left over.

When disposing of patches, make sure children cannot reach them.

Return any unused medicine to your pharmacist.

PRODUCT DESCRIPTION

What it looks like

A Climara patch is a clear oval thin film with an adhesive side (sticky side) attached to a clear plastic protective backing. Each pack of Climara contains 4 pouches each containing a patch.

Climara is available in 4 strengths:

  • Climara 25
  • Climara 50
  • Climara 75
  • Climara 100

The suffixes '25”, “50”,”75” and “100” refer to the daily amount of estradiol transferred via the skin to your body from the respective Climara patch.

Not all strengths may be marketed.

Ingredients

Active ingredient per patch:

  • Climara 25 - 2 mg of estradiol
  • Climara 50 - 3.8 mg of estradiol
  • Climara 75 - 5.7 mg of estradiol
  • Climara 100 - 7.6 mg of estradiol

Inactive ingredients:

  • polymer 55236
  • ethyl oleate
  • polyethylene backing
  • acrylate copolymer adhesive
  • glycerol laurate
  • isopropyl myristate

Supplier

Made in USA for:

Bayer Australia Ltd
ABN 22 000 138 714
875 Pacific Highway
Pymble NSW 2073
Australia

Bayer New Zealand Limited
3 Argus Place
Hillcrest, North Shore
Auckland 0627
New Zealand

Australian Registration Number

Climara 25 - AUST R 73962

Climara 50 - AUST R 56197

Climara 75 - AUST R 73963

Climara 100 - AUST R 56198

Date of preparation

February 2020

See TGA website (www.ebs.tga.gov.au) for latest Australian Consumer Medicine Information.

See MEDSAFE website (www.medsafe.govt.nz) for latest New Zealand Consumer Medicine Information.

® Registered trademark of the Bayer group, Germany

© Bayer Australia Ltd

All rights reserved.

Published by MIMS May 2020

BRAND INFORMATION

Brand name

Climara

Active ingredient

Estradiol

Schedule

S4

 

1 Name of Medicine

Estradiol.

2 Qualitative and Quantitative Composition

The Climara transdermal delivery system is a transparent oval patch containing estradiol in an adhesive matrix. Four strengths of Climara are available: 25, 50, 75 and 100. See Table 1.
When applied to intact skin, the transdermal delivery from Climara patches is maintained over 7 days. Transdermal delivery of estradiol overcomes the problems of its short half-life, seen when estradiol is given orally, due to extensive first-pass metabolism.
The excipients of the Climara transdermal delivery system include acrylate copolymer adhesive, fatty acid esters and polyethylene backing. Climara patches do not contain alcohol.

3 Pharmaceutical Form

The Climara transdermal delivery system is comprised of two layers.
1. A backing layer of translucent polyethylene film;
2. Estradiol in an adhesive matrix.
A protective liner is attached to the adhesive surface. This must be removed prior to applying the patch to the skin.

4 Clinical Particulars

4.1 Therapeutic Indications

For short-term treatment of signs and symptoms of estrogen deficiency due to the menopause, whether natural or surgically induced.
For the prevention of postmenopausal bone mineral density loss. When prescribed solely for the prevention of postmenopausal bone mineral density loss, 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. Lifestyle modifications and the risk benefit profile of Climara 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 4.2 Dose and Method of Administration; Section 4.4 Special Warnings and Precautions for Use).
In women with an intact uterus, estrogen should always be opposed by a progestogen in an adequate dosage regimen to ensure secretory transformation of the endometrium at regular intervals.

4.2 Dose and Method of Administration

Hormone therapy should only be continued as long as the benefit in alleviation of severe symptoms outweighs the risk.
A complete medical history should be taken and a physical examination should be conducted prior to the initiation or reinstitution of HT, guided by the contraindications and precautions for use and should be repeated periodically (see Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use). The frequency and nature of these examinations should be based on established practice guidelines, 6 monthly reviews are generally considered appropriate, and be adapted to the individual woman, but should generally include pelvic organs, including routine cervical cytology, abdomen, breasts and blood pressure. The need for continued therapy should be reconsidered at each review.
Continuous therapy is recommended. Climara should be applied once weekly.
Treatment is usually initiated with Climara 50, applied to the skin on the lower trunk or buttocks once weekly. Thereafter the dosage should be adapted to the needs of the individual. Breast discomfort, breakthrough bleeding, water retention or bloating (if persisting for more than six weeks) are generally signs that the dose is too high and needs to be lowered. If, however, the dose selected fails to eliminate the signs and symptoms of estrogen deficiency, a higher dose should be given. Doses of Climara, Estraderm and Premarin (conjugated estrogens) which have been shown to produce the same effect are:
Climara 50 : Estraderm 50 : Premarin 0.625 mg;
Climara 100 : Estraderm 100 : Premarin 1.25 mg.
Based on the pharmacokinetic parameters obtained in different studies, doses of Climara 25, Estraderm 25 and Premarin 0.3 mg are likely to have similar clinical effects. Studies with Climara 25 in the treatment of menopausal signs and symptoms are not available. Climara 25 should be used after titration down from Climara 50.
In women who are not currently taking oral estrogens, treatment with Climara can be initiated at once. In women who are currently taking oral estrogen, treatment with Climara can be initiated on reappearance of symptoms following discontinuation of oral therapy (generally within 5 to 7 days).

Prevention of postmenopausal bone mineral density loss.

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.
Climara can prevent the accelerated loss of bone density due to estrogen deficiency and may be used for prevention of postmenopausal bone mineral density loss in the appropriate patient group (see Section 4.1 Therapeutic Indications). The effect is seen only while estrogen replacement therapy continues and discontinuation may re-establish the natural rate of bone loss. The optimal duration of use to prevent fractures has not yet been determined (see Section 4.1 Therapeutic Indications). In patients with established osteoporosis and evidence of fractures, therapy should be initiated with Climara 100.
Usually, Climara is applied continuously. In women with an intact uterus, a progestogen should be administered sequentially for the first 10-14 (preferably 12) days of each calendar month to avoid overstimulation of the endometrium. The addition of sufficient progestogen to induce secretory transformation of the endometrium is strongly recommended. Consideration should be given to a minimum progestogen dose of medroxyprogesterone acetate 10 mg, for at least 10 days of the month as a means of achieving endometrial transformation. Specific studies in the adequacy of an appropriate progestogen regimen when used with Climara have not been evaluated.
If required, Climara can be applied in a cyclic manner. In such cases, the progestogen should be taken on the last 12 days of each 3-week period of estradiol administration, so that the 4th week of each cycle remains without any treatment.
In either case, a withdrawal bleed usually occurs following the progestogen administration.
In hysterectomised women, Climara can be applied continuously without the coadministration of a progestogen.

Method of application.

Following removal of the protective liner, the adhesive side of the Climara patch should be placed on a clean, dry area of the skin of the lower trunk and buttocks. Climara must not be applied to the breasts. The sites of application should be rotated, with an interval of at least one week between applications to a particular site. The patches should not be applied twice in succession to the same site. The area selected should not be oily, damaged, or irritated. The waistline should be avoided since tight clothing may rub the patch off. Climara should be applied to skin sites that will be covered by clothes. The patch should be applied immediately after opening the pouch and removing the protective liner. The patch should be pressed firmly in place with the palm of the hand for about 10 seconds, making sure there is good contact, especially around the edges. If the patch lifts, pressure should be applied to maintain adhesion.
The patch should be changed once weekly. Only one system should be worn at any time during the 7-day dosing interval.
If the patch is applied correctly, the patient can bath or shower as usual. Application to areas where sitting would dislodge the patch should be avoided.
In the event that a patch falls off before 7 days are up, it may be reapplied. If necessary, a new patch should be applied for the remainder of the 7 day dosing interval. If the patient forgets to replace a patch, this should be done as soon as possible after she notices this. The next patch has to be used after the normal 7 day interval.

4.3 Contraindications

Known allergy to estradiol or any of the components of the transdermal delivery system;
severe uncontrolled hypertension;
pregnancy;
lactation;
suspected or existing tumour of the uterus, breast or ovaries;
endometriosis; severe disturbances of liver function;
previous or existing liver tumours;
acute arterial thromboembolism (e.g. myocardial infarction, stroke);
active deep venous thrombosis, thromboembolic disorders, or a documented history of these conditions;
a high risk of venous or arterial thrombosis;
severe diabetes with vascular changes;
sickle cell anaemia;
disturbances of lipometabolism;
a history of herpes of pregnancy;
otosclerosis with deterioration during pregnancy;
jaundice or persistent itching during a previous pregnancy;
undiagnosed abnormal vaginal bleeding;
nonhysterectomised women unless on concomitant progestogen therapy.

4.4 Special Warnings and Precautions for Use

The benefits and risks of hormone replacement therapy (HRT) must be carefully weighed, including consideration of the emergence of risks as therapy continues. Estrogens with or without progestogens should be prescribed at the lowest effective doses and for the shortest duration consistent with the treatment goal and risks for the individual women.
Before starting therapy with Climara, a thorough general medical and gynaecological examination (including the breasts and a Pap-smear) should be carried out and pregnancy excluded. As a precaution, control examinations should be conducted at intervals of about 12 months during treatment.
Where applicable, contraception should be practised with nonhormonal methods (with the exception of the rhythm and temperature methods).

Cardiovascular disorders.

Estrogen and estrogen/ progestogen therapy have been associated with an increased risk of cardiovascular events such as myocardial infarction and stroke, as well as venous thrombosis and pulmonary embolism (venous thromboembolism or VTE). Should any of these occur or be suspected, estrogens should be discontinued immediately.
Risk factors for arterial vascular disease (e.g. hypertension, diabetes mellitus, tobacco use, hypercholesterolemia and obesity) and/or venous thromboembolism (e.g. personal history or family history of VTE, obesity and systemic lupus erythematosus) should be managed appropriately.

Coronary heart disease and stroke.

In the estrogen alone substudy of the Women's Health Initiative (WHI) study, an increased risk of stroke was observed in women receiving 0.625 mg conjugated estrogens per day compared to women receiving placebo (44 vs 32 per 10,000 women-years). The increase in risk was observed in year one and persisted (see Section 5.1 Pharmacodynamic Properties, Clinical trials).
In the estrogen plus progestogen substudy of WHI, an increased risk of coronary heart disease (CHD) events (defined as nonfatal myocardial infarction and CHD death) was observed in women receiving 0.625 mg conjugated estrogens plus 2.5 mg medroxyprogesterone acetate (CE/MPA) per day compared to women receiving placebo (37 vs 30 per 10,000 women-years). The increase in risk was observed in year one and persisted.
In the same estrogen plus progestogen substudy of WHI, an increased risk of stroke was observed in women receiving CE/MPA compared to women receiving placebo (29 vs 21 per 10,000 women-years). The increase in risk was observed after the first year and persisted.
In postmenopausal women with documented heart disease (n = 2,763, average age 66.7 years) a controlled clinical trial of secondary prevention of cardiovascular disease (Heart and Estrogen/ progestin Replacement Study; HERS) treatment with 0.625 mg conjugated estrogens plus 2.5 mg medroxyprogesterone acetate per day demonstrated no cardiovascular benefit. During an average follow-up of 4.1 years, treatment with 0.625 mg conjugated estrogens plus 2.5 mg medroxyprogesterone acetate did not reduce the overall rate of CHD events in postmenopausal women with established coronary heart disease. There were more CHD events in the 0.625 mg conjugated estrogens plus 2.5 mg medroxyprogesterone acetate treated group than in the placebo group in year 1, but not during the subsequent years. Two thousand three hundred and twenty one women from the original HERS trial agreed to participate in an open label extension of HERS, HERS II. Average follow-up in HERS II was an additional 2.7 years, for a total of 6.8 years overall. Rates of CHD events were comparable among women in the 0.625 mg conjugated estrogens plus 2.5 mg medroxyprogesterone acetate group and the placebo group in HERS, HERS II and overall.

Venous thromboembolism (VTE).

In the estrogen alone substudy of the Women's Health Initiative (WHI) study, an increased risk of deep vein thrombosis was observed in women receiving 0.625 mg conjugated estrogens compared to placebo (21 vs 15 per 10,000 women-years). The increase in VTE risk was observed during the first year (see Section 5.1 Pharmacodynamic Properties, Clinical trials).
In the estrogen plus progestogen substudy of WHI, a 2-fold greater rate of VTE, including deep venous thrombosis and pulmonary embolism, was observed in women receiving with 0.625 mg conjugated estrogens plus 2.5 mg medroxyprogesterone acetate compared to women receiving placebo. The rate of VTE was 34 per 10,000 women-years in the 0.625 mg conjugated estrogens plus 2.5 mg medroxyprogesterone acetate group compared to 16 per 10,000 women-years in the placebo group. The increase in VTE risk was observed during the first year and persisted.
Generally recognised risk factors for VTE include a personal history, a family history (the occurrence of VTE in a direct relative at a relatively early age may indicate genetic disposition), and severe obesity. The risk of VTE also increases with age. There is no consensus about the possible role of varicose veins in VTE.
The risk of VTE may be temporarily increased with prolonged immobilisation, major elective or post-traumatic surgery, or major trauma.
If feasible, estrogens should be discontinued at least 4 to 6 weeks before surgery of the type associated with an increased risk of thromboembolism, or during periods of prolonged immobilisation.
Treatment should be stopped at once if there are symptoms of a thrombotic event or suspicion thereof.
The potential for an increased synergistic risk of thrombosis should be considered in women who possess a combination of risk factors or exhibit a greater severity of an individual risk factor. This increased risk may be greater than a simple cumulative risk of the factors. HRT should not be prescribed in case of a negative risk/ benefit assessment.

Malignant neoplasms.

Endometrial cancer.

The use of unopposed estrogens in women with intact uteri has been associated with an increased risk of endometrial cancer. The reported endometrial cancer risk among unopposed estrogen users with an intact uterus is about 2 to 12-fold greater than in nonusers, and appears dependent on duration of treatment and on estrogen dose. Most studies show no significant increased risk associated with the use of estrogens for less than one year. 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/ 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 lowered incidence of endometrial hyperplasia than would be induced by estrogen treatment alone. Endometrial hyperplasia may be a precursor to endometrial cancer.
There are, however, possible risks that may be associated with the use of 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.

Breast cancer.

In some studies, the use of estrogens and progestogens by postmenopausal women has been reported to increase the risk of breast cancer. The most important randomized clinical trial providing information about this issue is the Women's Health Initiative (WHI) trial of estrogen plus progestogen (see Section 5.1 Pharmacodynamic Properties, Clinical trials). The results from observational studies are generally consistent with those of the WHI clinical trial.
After a mean follow-up of 5.6 years, the WHI trial reported an increased risk of breast cancer in women who took estrogen plus progestogen. Observational studies have also reported an increased risk for estrogen/ progestogen combination therapy and a smaller increased risk for estrogen alone therapy, after several years of use. For both findings, the excess risk increased with duration of use and decreases with time after stopping HRT (only the observational studies have substantial data on risk after stopping). In these studies, the risk of breast cancer was greater, and became apparent earlier, with estrogen/ progestogen combination therapy as compared to estrogen alone therapy. However, these studies have not found significant variation in the risk of breast cancer among different estrogens or among different estrogen/ progestogen combinations, doses, or routes of administration.
In the WHI trial of estrogen plus progestogen, 26% of the women reported prior use of estrogen alone and/or estrogen/ progestogen combination hormone therapy. After a mean follow-up of 5.6 years during the clinical trial, the overall relative risk of invasive breast cancer was 1.24 (95% confidence interval 1.01-1.54), and the overall absolute risk was 41 vs 33 cases per 10,000 women-years, for estrogen plus progestogen compared with placebo. 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 women-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 women-years for estrogen plus progestogen compared with placebo. In the WHI trial, 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 histologic subtype, grade and hormone receptor status did not differ between the groups.
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 plus progestogen has been reported to result in an increase in abnormal mammograms requiring further evaluation. All women should undertake yearly breast examinations and perform monthly breast self-examinations. In addition, mammography examinations should be scheduled based on patient age, risk factors, and prior mammogram results.

Liver tumour.

In rare cases benign and, in even rarer cases, malignant liver tumours leading in isolated cases to life threatening intra-abdominal haemorrhage have been observed after the use of hormonal substances such as the one contained in Climara. If severe upper abdominal complaints, liver enlargement or signs of intra-abdominal haemorrhage occur, a liver tumour should be included in the differential diagnostic considerations.

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 0.625 mg conjugated estrogens or placebo. In the estrogen plus progestogen WHIMS substudy, a population of 4,532 postmenopausal women aged 65 to 79 years was randomised to 0.625 mg conjugated estrogens plus 2.5 mg medroxyprogesterone acetate 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 0.625 mg conjugated estrogens alone versus placebo was 1.49 (95% CI 0.83 to 2.66). The absolute risk of probable dementia for 0.625 mg conjugated estrogens alone versus placebo was 37 versus 25 cases per 10,000 women-years.
In the estrogen plus progestogen substudy, after an average follow-up of 4 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 versus placebo was 2.05 (95% CI 1.21-3.48). The absolute risk of probable dementia for 0.625 mg conjugated estrogens plus 2.5 mg medroxyprogesterone acetate versus placebo was 45 versus 22 cases per 10,000 women-years.
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, 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.

Hypercalcaemia.

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

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.

General precautions.

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. However, if in individual cases sustained, clinically significant hypertension develops during the use of HRT, then withdrawing the HRT may be considered. Blood pressure should be monitored at regular intervals during estrogen use.

Hypertriglyceridemia.

In patients with pre-existing hypertriglyceridemia, estrogen therapy may be associated with elevations of plasma triglycerides leading to pancreatitis and other complications.

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 also receiving estrogens may require increased doses of their thyroid replacement therapy. These patients should have their thyroid function monitored in order to maintain their free thyroid hormone levels in an acceptable range.

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.

Hypocalcemia.

Estrogens should be used with caution in individuals with severe hypocalcemia.

Ovarian cancer.

Ovarian cancer is less prevalent than breast cancer. A meta-analysis from 52 epidemiological studies reported that the overall risk of being diagnosed with ovarian cancer is slightly increased for users of estrogen only and combined HRT compared to women who have never used HRT (prospective studies: RR 1.20, 95% CI 1.15-1.26; all studies combined: RR 1.14, 95% CI 1.10-1.19). In women currently using HRT the risk of ovarian cancer was further increased (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.
These associations were not shown in the WHI.
Furthermore, an effect of duration of exposure has not been consistently shown, but the risk may be more relevant with long-term use (several years).

Exacerbation of endometriosis.

Endometriosis may be exacerbated with administration of estrogen therapy. Should this occur, discontinuation of therapy is recommended.

Exacerbation of other conditions.

Estrogen therapy may cause an exacerbation of asthma, diabetes mellitus, epilepsy, migraine, porphyria, systemic lupus erythematosus and hepatic hemangiomas and should be used with caution in patients with these conditions. Uterine myomas may increase in size under the influence of estrogens. If this is observed, treatment should be discontinued.
In women with hereditary angioedema, exogenous estrogens may induce or exacerbate symptoms of angioedema.

Other conditions and product specific precautions.

Should there be a suspicion of a prolactinoma, this should be ruled out before starting treatment.
If irregular bleeding occurs repeatedly during the use of Climara, or if the bleeding in the treatment free weeks is unusually profuse, thorough differential diagnostic clarification is essential.
Chloasma may occasionally occur, especially in women with a history of chloasma gravidarum. Women with a tendency to chloasma should avoid exposure to the sun or ultraviolet radiation while taking HT.
If there are, repeatedly, persistent skin irritations (e.g. persistent erythema or pruritus at the application site) even if the application site has been regularly changed as instructed in the directions, one should consider cessation of transdermal treatment.
Contact sensitisation is known to occur with all topical drug applications. Although contact sensitisation to any components of the patch is extremely rare, patients who develop it should be warned that a severe hypersensitivity reaction may occur with subsequent exposure to the causative agent.
Close medical supervision is necessary in patients with varicose veins, otosclerosis, multiple sclerosis, tetany, chorea minor, heart failure, disturbances of kidney or liver function. Patients with fibrocystic disease of the breasts and patients with first degree relatives who have had breast cancer also require close supervision and should be instructed in breast self examination. The same applies to patients with benign tumours of the uterine smooth muscles, since the size of such tumours can increase under estrogen therapy. It is recommended in long-term use the benefits should be weighed against the risks for each woman.

Reasons for immediate discontinuation.

Occurrence for the first time of migrainous headaches or more frequent occurrence of unusually severe headaches, sudden perceptual disorders (e.g. disturbances of vision or hearing), first signs of thrombophlebitis or thromboembolic symptoms (for example unusual pains in or swelling of the legs, stabbing pains on breathing or coughing for no apparent reason), acute arterial thromboembolism (e.g. myocardial infarction, stroke), a feeling of pain and tightness in the chest, pending operations (six weeks beforehand), immobilisation (for instance, following accidents), onset of jaundice, onset of hepatitis, itching of the whole body, increase in epileptic seizures, significant rise in blood pressure, pregnancy.

Use in hepatic impairment.

Climara has not been specifically studied in patients with hepatic impairment. Climara is contraindicated in women with presence or history of liver tumours (see Section 4.3 Contraindications).
Estrogens may be poorly metabolised in patients with impaired liver function. 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.

Use in the elderly.

Of the total number of subjects in the estrogen alone substudy of the Women's Health Initiative (WHI) 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 (conjugated estrogens (CE) vs placebo) of stroke in women less than 75 years of age compared to women 75 years and over.
In the estrogen alone substudy of the Women's Health Initiative Memory Study (WHIMS), a substudy of WHI, a population of 2,947 hysterectomized women, aged 65 to 79 years, was randomised to CE (0.625 mg) or placebo. In the estrogen alone group, after an average follow-up of 5.2 years, the relative risk (CE versus placebo) of probable dementia was 1.49 (95% CI 0.83-2.66).
Of the total number of subjects in the estrogen plus progestogen substudy of the Women's Health Initiative study, 44% (n = 7,320) were 65 years and over, while 6.6% (n = 1,095) were 75 years and over. There was a higher relative risk (CE/MPA vs placebo) of stroke and invasive breast cancer in women 75 and over compared to women less than 75 years of age.
In the estrogen plus progestogen substudy of WHIMS, a population of 4,532 postmenopausal women, aged 65 to 79 years, was randomised to CE/MPA (0.625 mg/2.5 mg) or placebo. In the estrogen plus progestogen group, after an average follow-up of 4 years, the relative risk (CE/MPA versus placebo) of probable dementia was 2.05 (95% CI 1.21-3.48).
Pooling the events in women receiving CE or CE/MPA in comparison to those in women on placebo, the 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; 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 estrogens to determine whether those over 65 years of age differ from younger subjects in their response to estrogens.

Paediatric use.

No data available.

Effects on laboratory tests.

The use of sex steroids may influence the results of certain laboratory tests, including biochemical parameters of liver, thyroid, adrenal and renal function, plasma levels of (carrier) proteins, e.g. corticosteroid binding globulin and lipid/ lipoprotein fractions, parameters of carbohydrate metabolism and parameters of coagulation and fibrinolysis. Changes generally remain within the normal laboratory range.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Drug interaction studies have not been performed with the Climara patches nor with other estradiol transdermal systems. The product information of concomitant medicines should be consulted to identify potential interactions.
The requirement for oral antidiabetics or insulin can change.

Effects of other medicines on Climara.

It may be anticipated, as for other steroid hormones, that drugs, which induce or inhibit microsomal liver enzymes could affect the systemic bioavailability of transdermal estradiol. However, it is probable that the systemic bioavailability of transdermally applied estradiol is less affected by such an interaction than that of orally applied estrogens.
Interactions can occur with medicines that induce microsomal enzymes which can result in increased clearance of sex hormones and which may lead to changes in the uterine bleeding profile and/or reduction of the therapeutic effect.

Substances increasing the clearance of sex hormones (diminished efficacy by enzyme induction), e.g.:

Phenytoin, barbiturates, primidone, carbamazepine, rifampicin and possibly also oxcarbazepine, topiramate, felbamate, griseofulvin and products containing St. John's wort (Hypericum perforatum).
Enzyme induction can already be observed after a few days of treatment. Maximal enzyme induction is generally seen within a few weeks. After cessation of drug therapy, enzyme induction may be sustained for about four weeks.

Substances with variable effects on the clearance of sex hormones.

When co-administered with sex hormones, many HIV/HCV protease inhibitors and non-nucleoside reverse transcriptase inhibitors can increase or decrease plasma concentrations of the estrogen. These changes may be clinically relevant in some cases.

Substances decreasing the clearance of sex hormones (enzyme inhibitors).

Strong and moderate CYP3A4 inhibitors such as azole antifungals (e.g. fluconazole, itraconazole, ketoconazole, voriconazole), verapamil, macrolides (e.g. clarithromycin, erythromycin), diltiazem and grapefruit juice can increase plasma concentrations of the estrogen.

Interaction with alcohol.

Acute alcohol ingestion during use of HRT may lead to elevations in circulating estradiol levels.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

No data available.
(Category B1)
Estrogens must not be used during pregnancy (see Section 4.3 Contraindications).
Estrogens must not be used during lactation (see Section 4.3 Contraindications).

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.

4.8 Adverse Effects (Undesirable Effects)

In clinical trials adverse reactions were reported at the frequencies reported below. Very common: ≥ 1/10; common: ≥ 1/100 and < 1/10; uncommon ≥ 1/1,000 and < 1/100.

Application site.

Very common: application site reaction, tape site reaction.
Application site reactions were the most commonly reported adverse experiences in all trials. Symptoms are generally mild and include erythema, itching, stinging and vesicle formation.

Autonomic nervous system.

Common: increased sweating.

Body as a whole.

Very common: headache, oedema; common: back pain, fatigue, pain.

Cardiovascular.

Uncommon: tachycardia.

Central and peripheral nervous system.

Common: dizziness, cramp legs.

Gastrointestinal system.

Common: abdominal pain, flatulence, nausea.

Metabolic and nutritional.

Common: alteration in bodyweight.

Psychiatric.

Common: depressive moods, nervousness.

Reproductive.

Very common: breast pain, menstrual disorders; common: breast engorgement, endometrial hyperplasia, leukorrhoea, pelvic pain, uterine disorder, uterine spasm, vaginal disorder, vaginal moniliasis.

Skin and appendages.

Common: acne, pruritus, rash.
In addition to the above adverse reactions, the following adverse reactions are also known to be estrogen related and therefore may be associated with Climara therapy.

Central nervous system.

Migraine.

Gastrointestinal system.

Vomiting, cholestatic jaundice, increased incidence of gall bladder disease, abdominal cramps, bloating.

Cardiovascular system.

Rise in blood pressure in susceptible individuals.

Haematological.

Thromboembolism and thrombotic disorders (see Section 4.4 Special Warnings and Precautions for Use).

Genitourinary system.

Increase in size of uterine leiomyomata, alterations in the amount of cervical secretion, change in cervical erosion, reactivation of endometriosis, cystitis-like syndrome.

Skin.

Chloasma or melasma which may persist after the drug is discontinued, allergic contact dermatitis, haemorrhagic eruptions, erythema nodosum, erythema multiforme, postinflammatory pruritus, rash.

Miscellaneous.

Worsening of porphyria, changes in libido, premenstrual-like syndrome.

Ocular.

Steepening of corneal curvature, intolerance of contact lenses.
In women with hereditary angioedema, exogenous estrogens may induce or exacerbate symptoms of angioedema (see Section 4.4 Special Warnings and Precautions for Use).
Estrogen only and combined estrogen progestogen HRT has been associated with a slightly increased risk of ovarian cancer in epidemiological studies. The risk may be more relevant with long-term use (several years) (see Section 4.4 Special Warnings and Precautions for Use).
The most serious adverse reactions associated with the use of Climara are described under Special Warnings and Precautions for Use.

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.

4.9 Overdose

Estrogen overdosage is unlikely with this type of application. Overdosage may cause nausea and vomiting and withdrawal bleeding may occur in some women. There is no specific antidote. Signs of overdosage may be one or more of the following: breast discomfort, breakthrough bleeding, fluid retention and bloating (see Section 4.2 Dose and Method of Administration). Toxicity is unlikely following acute single exposure; ingestion may cause nausea and vomiting. Treatment should be symptomatic and the patch(es) should be removed.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Climara provides systemic estrogen replacement therapy by releasing estradiol. Estradiol is the major estrogenic hormone secreted by the human ovary from the menarche to the menopause and is the most potent of the endogenous estrogens.
Estrogens are important in the development and maintenance of the female reproductive system and secondary sexual characteristics. They also contribute to the shaping of the skeleton, maintenance of tone and elasticity of urogenital structures and changes in the epiphyses of the long bones that allow for the pubertal growth spurt and its termination. Estrogens play an important role in various metabolic processes, including the modulation of bone resorption.
Estrogens exert their metabolic effects by binding to specific receptors in target cells. Estrogen receptors have been identified in all known estrogen target organs including the uterus, hypothalamus, pituitary, vagina, urethra, breast, liver and osteoblasts. There are several forms of naturally occurring estrogen. Estradiol is the principal intracellular human estrogen and is substantially more potent than the others, estrone or estriol. The ovarian follicle secretes 70 to 500 microgram of estradiol daily, varying with the phase of the menstrual cycle. This is converted primarily to estrone, and to small amounts of estriol in the liver. The estradiol/ estrone ratio during fertile life is greater than 1. However, in postmenopausal women, estrone is the most abundant circulating estrogen. After menopause, when the ovaries have ceased to function, estrone is produced from the aromatisation of androstenedione and only small amounts of estradiol are produced from metabolic conversion of testosterone and estrone.
The estrogen deficiency around and after the menopause produces symptoms such as severe hot flushes, night sweats, insomnia, dyspareunia and progressive atrophy of the urogenital system in many women. These disorders can be largely eliminated by means of estrogen replacement therapy. There is also an increased risk of bone fractures and osteoporosis, particularly of the vertebral column, hip and wrist, due to the increased loss of bone substance caused by low levels of estrogen, and cardiovascular disease. Short-term treatment with estrogen replacement therapy perimenopausally has been shown to prevent loss of bone density. There is currently no evidence of the minimum duration of estrogen replacement therapy, which will be effective for younger postmenopausal women in reducing fracture when they reach 75 years of age (the age of greatest fracture risk).
Known risk factors for postmenopausal osteoporosis include early menopause or surgical oophorectomy, prolonged secondary amenorrhoea, prolonged systemic steroid use and a family history of osteoporosis. Women especially at risk are those who are Caucasian, small boned, smokers and live a sedentary lifestyle. The mainstays for decreasing the risk of postmenopausal osteoporosis are weightbearing exercise, adequate calcium and vitamin D intake and when indicated, pharmacologic therapy. When Climara is used for the short-term relief of menopausal symptoms, it will provide a concomitant effect in reducing the loss of bone mineral density. Estrogen replacement therapy has been shown to alleviate or prevent the consequences of ovarian failure.
Transdermal administration of estrogen offers many advantages over conventional oral delivery. It avoids the hepatic first-pass effects resulting in a constant serum level which reflects the premenopausal physiological serum profile and ratio of estradiol to estrone. In plasma, the concentration ratio of estradiol (E2) to estrone (E1) undergoes a shift from between 1:5 and 1:2 to approximately 1:1, i.e. to values which are recorded before the menopause in women with normally functioning ovaries. Gastrointestinal side effects are avoided also. The skin metabolises estradiol to a small extent only, thus transdermal administration provides therapeutic serum levels of estradiol using smaller total doses than oral therapy. Constant delivery of the therapeutic dose is maintained with Climara patches over the 7 day application period. However, therapy is easily discontinued by removal of the patch.
Following the application of transdermal estradiol for 28 days, no effect has been observed on the concentrations or activity of the blood coagulation factors fibrinopeptide A, high molecular weight fibrinogen and antithrombin III. After this period of 28 days, transdermally administered estradiol did not induce any change in the concentrations either of circulating renin substrate or of the sex hormone binding, thyroxine binding or cortisol binding globulins. It has been found, however, that after only three weeks' administration, transdermally administered estradiol elicits a dose dependent reduction in urinary excretion of calcium and hydroxyproline.
Independent of the route of administration, estrogen doses which are necessary for improvement of menopausal complaints exert a dose dependent stimulating effect on mitosis and proliferation of the endometrium. Estrogen monotherapy increases the frequency of endometrial hyperplasia and thus the risk of endometrial cancer. In order to avoid endometrial hyperplasia the sequential administration of a progestogen for 10 to 12 days is recommended in nonhysterectomised postmenopausal women.

Clinical trials.

A two year clinical trial was conducted in 175 healthy hysterectomised, postmenopausal, nonosteoporotic (lumbar spine density > 0.9 g/cm2) women to evaluate the safety and efficacy of Climara 25, Climara 50 and Climara 100 compared to placebo in the prevention of osteoporosis. Efficacy in the prevention of postmenopausal bone loss at two sites was demonstrated for all active doses of transdermal estradiol. Results of the change in BMD at the lumbar spine and total hip showed a statistically significant overall treatment effect at each timepoint. Mean percent change in BMD was positive (bone preservation) for all active treatment groups at all timepoints at the lumbar spine and the total hip while it was negative (bone loss) for placebo at all timepoints at these areas. Mean percent changes in BMD at the lumbar spine and total hip were statistically significantly different from placebo for all active treatment groups at all timepoints. The mean percentage difference in BMD at the lumbar spine, relative to placebo, varied from 1.94% to 3.92% at 6 months and 4.86% to 7.19% at 24 months and 1.54% to 1.92% and 2.30% to 5.09% at the hip at 6 and 24 months, respectively. The results of measurements of BMD of the femoral neck were generally indicative of a treatment effect relative to placebo for Climara 50 and Climara 100, but there were no statistically significant differences between the results for Climara 25 and placebo. At the midshaft of the radius, only Climara 100 showed a statistically significant trend to efficacy in maintaining bone mineral density.
The results of the measurements of biochemical markers supported the finding of efficacy for all doses of transdermal estradiol. This study was conducted before the results of the WHI and Million Women study were available (see Women's Health Initiative studies (WHI) below and see Section 4.4 Special Warnings and Precautions for Use).

Women's Health Initiative studies (WHI).

The Women's Health Initiative (WHI) enrolled a total of 27,000 predominantly healthy postmenopausal women to assess the risks and benefits of either the use of 0.625 mg conjugated estrogens (CE) per day alone or the use of 0.625 mg conjugated estrogens plus 2.5 mg medroxyprogesterone acetate (MPA) per day compared to placebo in the prevention of certain chronic diseases. The primary endpoint was the incidence of coronary heart disease (CHD) (nonfatal myocardial infarction and CHD death), with invasive breast cancer as the primary adverse outcome studied. A global index included the earliest occurrence of CHD, invasive breast cancer, stroke, pulmonary embolism (PE), endometrial cancer, colorectal cancer, hip fracture or death due to other cause. The study did not evaluate the effects of CE or CE/MPA on menopausal symptoms.
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 estrogen alone substudy, which included 10,739 women (average age of 63 years, range 50 to 79; 75.3% white, 15% black, 6.1% Hispanic), after an average follow-up of 6.8 years are presented in Table 2.
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 6 fewer hip fractures. The absolute excess risk of events included in the "global index" was a nonsignificant 2 events per 10,000 women-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).
The estrogen plus progestogen substudy was also stopped early because, according to the predefined stopping rule, the increased risk of breast cancer and cardiovascular events exceeded the specified benefits included in the "global index". Results of the estrogen plus progestogen substudy, which included 16,608 women (average age of 63 years, range 50 to 79; 83.9% white, 6.5% black, 5.5% Hispanic), after an average follow-up of 5.2 years are presented in Table 3.
For those outcomes included in the WHI "global index", the absolute excess risks per 10,000 women-years in the group treated with CE/MPA were 7 more CHD events, 8 more strokes, 8 more PEs and 8 more invasive breast cancers, while the absolute risk reductions per 10,000 women-years were 6 fewer colorectal cancers and 5 fewer hip fractures. The absolute excess risk of events included in the "global index" was 19 per 10,000 women-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).

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 0.625 mg conjugated estrogens 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 women-years) and 19 in the placebo group (25 per 10,000 women-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. 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 and Use in the elderly).
The estrogen plus progestogen WHIMS substudy enrolled 4,532 predominantly healthy postmenopausal women 65 years of age and older (47% were age 65 to 69 years, 35% were 70 to 74 years and 18% were 75 years of age and older) to evaluate the effects of 0.625 mg conjugated estrogens plus 2.5 mg medroxyprogesterone acetate on the incidence of probable dementia (primary outcome) compared with placebo.
After an average follow-up of 4 years, 40 women in the estrogen/ progestogen group (45 per 10,000 women-years) and 21 in the placebo group (22 per 10,000 women-years) were diagnosed with probable dementia. The relative risk of probable dementia in the hormone therapy group was 2.05 (95% CI, 1.21 to 3.48) compared to placebo. 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 and Use in the elderly).

5.2 Pharmacokinetic Properties

Transdermal estradiol administration aims at achieving smooth, stable, plateau-like estradiol serum levels similar to those during the early/ midfollicular phase of the reproductive life span. Estradiol serum levels in the range between 30-100 picogram/mL are necessary for an efficacious transdermal estrogen replacement therapy. In pharmacokinetic studies, mean steady-state estradiol levels of 35 picogram/mL were obtained after application of the 12.5 cm2 patch and 70 picogram/mL after application of the 25 cm2 patch. Nominal average in vivo absorption rates for Climara 25, Climara 50, Climara 75 and Climara 100 are 25 microgram/day, 50 microgram/day, 75 microgram/day and 100 microgram/day, respectively. No accumulation of either estradiol or estrone occurred after multiple one week applications, with serum levels returning to baseline within 6 hours of patch removal.
Linear dose proportionality has been demonstrated for the Climara transdermal delivery system. In a 1-week application study in 54 postmenopausal women, Climara 100 produced estradiol serum level profiles and pharmacokinetic parameters that were twice as high as Climara 50. Statistical analyses confirmed that 2:1 dose proportionality. Similarly, a 2-week crossover study with one week washout period between in 24 postmenopausal women demonstrated dose proportionality between Climara 50 and Climara 25, with a Cave of 38 picogram/mL and 22 picogram/mL for Climara 50 and Climara 25, respectively.
Two transdermal absorption studies were conducted comparing serum estradiol level profiles and pharmacokinetic parameters following once a week application of Climara patches and twice a week applications of Estraderm patches. Both patch sizes were examined. In the first study, Climara 50 (12.5 cm2) was compared with Estraderm 50 (10 cm2) and in the second study, Climara 100 (25 cm2) was compared with Estraderm 100 (20 cm2). With both patch sizes, Climara once a week treatments maintained smoother and more stable estradiol serum level profiles than did the Estraderm twice a week patches. Cmax, AUC and MSS were all significantly higher for the Estraderm patch application, but towards the end of the one week application interval, both Climara patches maintained similar (144 hours) or higher (168 hours) mean trough serum levels than did the Estraderm patches. The mean peak to end of application interval trough level fluctuations were smaller with Climara than Estraderm.
The biotransformation and excretion of transdermally administered estradiol is the same as that of the endogenous hormone. The plasma elimination half-life of estradiol is approximately one hour. Estradiol is eliminated from the body with a total serum clearance of approximately 15-30 mL/min/kg by biotransformation mainly in the liver but also extrahepatically. Its most important metabolites are estriol and estrone and their conjugates (glucuronides, sulphates); these are far less pharmacologically active than estradiol. The bulk of the conjugates are excreted in the urine. Estrogen metabolites are also subject to enterohepatic circulation.

5.3 Preclinical Safety Data

In primary dermal irritation studies in rabbits, application of Climara resulted in mild irritation related to mechanical trauma at removal. In sensitisation studies in guinea pigs, Climara had no dermal sensitising potential.
The components of the adhesive matrix of Climara (monomer and polymer) have been studied extensively and, at many multiples of the projected human exposure, present a low risk. Additional excipients used in the adhesive matrix are either generally regarded as safe for use in food components or considered acceptable as an inactive ingredient for prescription and topical transdermal products.
The adhesive backing and release liner of Climara were tested in biological test methods and were considered to be compatible with biological systems.

Genotoxicity.

No data available.

Carcinogenicity.

No data available.

6 Pharmaceutical Particulars

6.1 List of Excipients

See Section 2 Qualitative and Quantitative Composition.

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 30°C.
Do not store unpouched. Apply immediately upon removal from the protective pouch. Keep out of reach of children.

6.5 Nature and Contents of Container

Packs containing 1 patch, 2 patches, 4 patches, 8 patches, 12 patches individually wrapped in a protective pouch. The pouch contains a desiccant.

6.6 Special Precautions for Disposal

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

6.7 Physicochemical Properties

Chemical structure.

Climara is a transdermal delivery system containing estradiol as the active ingredient. Estradiol is estra-1,3,5(10)-triene-3,17β-diol, the major estrogenic hormone produced by the human ovary.

CAS number.

The CAS Registry number for estradiol is 50-28-2.

7 Medicine Schedule (Poisons Standard)

S4 - Prescription Only Medicine.

Summary Table of Changes