Estrofem Side Effects

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Answer the side-effect intent for estrofem without diagnosing; distinguish common from serious reactions and give safe next-step/reporting guidance.

What is Estrofem?

Estrofem contains the active ingredient Estradiol.

• Active ingredient — Estradiol
• Registration number — 34/21.8.1/0159; J/21.8.1/214
• Registration holder — Novo Nordisk (Pty) Ltd

It is approved for:

• To relieve unpleasant symptoms like hot flushes, night sweats, vaginal dryness which occur when the estrogen levels decline and the periods stop (menopause)
• For the prevention of osteoporosis (thinning of the bones), if you are at high risk of future fracture and if you are unable to take other medicines for this purpose. Estrofem® is prescribed for women who have had their womb removed (have had a hysterectomy). There is only limited experience of treating women older than 65 years with Estrofem®

Common side effects of Estrofem

Not everyone gets side effects. The effects below are those listed in the South African approved leaflet, grouped using the leaflet’s own frequency wording.

Reported side effects

• Swelling of your hands, feet, ankles, face, lips, tongue, mouth or throat, which may cause difficulty in swallowing or breathing; low blood pressure (paleness and coldness of skin, rapid heartbeat), feeling dizzy, sweating
• Rash, hives or itching
• Fainting
• These are all very serious side effects. If you have them, you may have had a serious allergic reaction to Estrofem®. You may need urgent medical attention or hospitalisation. Tell your doctor immediately or go to the casualty department at your nearest hospital if you notice any of the following: Less frequent side effects:
• Blood clots in the veins (venous embolism). Side effects with unknown frequencies:
• Migraine, worse than before
• Stroke
• These are all serious side effects. You may need urgent medical attention. Tell your doctor if you notice any of the following: Frequent side effects:
• Depression
• Headache
• Abdominal (stomach) pain
• Feeling sick (nausea)
• Leg cramps
• Breast pain, breast tenderness or breast enlargement
• Oedema (retention of fluid)
• Weight increase. Less frequent side effects:
• Abnormal vision
• Heartburn (dyspepsia)
• Vomiting
• Flatulence or bloating
• Gallstones
• Itching or hives (urticaria). Side effects with unknown frequencies:
• Irregular vaginal bleeding*
• Insomnia (being unable to sleep)
• Epilepsy
• Changes in libido
• Vaginal infection caused by a fungus
• Deterioration of asthma
• Dizziness
• Diarrhoea
• Hair loss (alopecia)
• Increased blood pressure
• If prescribed for women with a uterus. Other side effects of Estrofem®: The below mentioned side effects have been reported after taking estrogen and estrogen/ progestagen products. For further information consult section Warnings and precautions above
• Heart disease
• Stroke
• Blot clots
• Breast cancer
• Endometrial cancer
• Ovarian cancer
• Suicidal thoughts/behaviour and suicide. Dementia Estrofem® will not prevent memory loss. In one study of women who started using combined HRT after the age of 65, a small increase in the risk of dementia was observed. It is not known whether these results also applies to women younger than 65 years when starting the treatment or to women taking other HRT preparations. Gall bladder disease Gall bladder disease has been reported after treatment with estrogen/progestagen. Effects on the skin Brown pigmented patches in the face (chloasma), skin rashes including red inflammation on the hands or the legs (erythema multiforme), formation of tender, red nodules on the front of the legs/knees (erythema nodosum) or a bruise-like rash (vascular purpura) and itching (pruritus)

Serious side effects and warning signs

The leaflet lists these as serious side effects needing immediate attention.

Less frequent

• Abnormal vision
• Heartburn (dyspepsia)
• Vomiting
• Flatulence or bloating
• Gallstones
• Itching or hives (urticaria). Side effects with unknown frequencies:
• Irregular vaginal bleeding*
• Insomnia (being unable to sleep)
• Epilepsy
• Changes in libido
• Vaginal infection caused by a fungus
• Deterioration of asthma
• Dizziness
• Diarrhoea
• Hair loss (alopecia)
• Increased blood pressure
• If prescribed for women with a uterus

Frequent

• Depression
• Headache
• Abdominal (stomach) pain
• Feeling sick (nausea)
• Leg cramps
• Breast pain, breast tenderness or breast enlargement
• Oedema (retention of fluid)
• Weight increase

General warning signs that apply to any medicine

How long can side effects last?

How long a side effect lasts depends on the effect, the product, how long it has been used, and the person. Some effects ease within days as the body adjusts. Others continue for as long as the product is used. A few can persist after stopping, and some need review rather than waiting.

• Settling effects — mild effects that ease over the first days or weeks of use
• Ongoing effects — effects that continue while the product is being used and improve after stopping
• Persistent effects — effects that continue after stopping and need medical review
• Delayed effects — effects that appear after weeks or months rather than immediately

Which of these applies to a particular effect is a clinical question. If a side effect is not settling, is getting worse, or is affecting your daily life, that is worth a conversation with a pharmacist or doctor regardless of how long it has been going on.

Factors that may affect side effects

The approved leaflet identifies the following cautions and factors.

Do not use it at all if

• If you are allergic (hypersensitive) to estradiol or any other ingredients in Estrofem®
• If you have, have had or suspect you have breast cancer
• If you have a family history of breast cancer
• If you have or suspect you have or have had a hormone dependent tumour (e.g. cancer of the lining of the womb)
• If you have any vaginal bleeding, which has not been diagnosed by your doctor
• If you have endometrial hyperplasia (excessive growth of the womb lining) that is not being treated
• If you have a blood clot (like deep vein thrombosis (DVT) or lung embolism) or previously have had a blood clot without obvious cause e.g. in connection with surgery or pregnancy
• Have a blood clotting disorder (such as protein C, protein S or antithrombin deficiency)
• Have or previously have had a disease caused by blood clots in the arteries, such as a heart attack or angina
• If you have high blood pressure
• If you have or have had a liver disorder and your liver tests have not returned to normal
• If you have porphyria (a liver enzyme disease)
• If you are pregnant
• If you are known to have inherited genetic changes called BRCA1 and/or BRCA2 genes
• If you started your menstrual periods early (before the age of 12 years)
• If you have a history of non-cancerous breast diseases such as atypical hyperplasia or lobular carcinoma in situ
• If you had any previous treatment using radiation therapy to the chest or breast
• If you have been treated or exposed while in your mother’s womb to a medicine called diethylstilbestrol (DES)

Use with care, and tell your doctor, if

• If you have any condition affecting the womb lining, such as a leiomyoma (benign tissue tumour), endometriosis (presence of womb lining tissue outside the womb) or have had endometrial hyperplasia (excessive growth of the womb lining)
• If you have a history of blood clots (thrombosis) or have risk factors for blood clots (these risk factors and symptoms for a blood clot are listed in section “Blood clots”)
• If any of your immediate family has had cancers related to estrogen (endometrial cancer)
• If you have a liver disorder such as liver adenoma (a benign tumour)
• If you have a kidney or heart disorder
• If you have diabetes or gallstones
• If you have epilepsy (fits) or asthma
• If you have migraine or severe headache
• If you have systemic lupus erythematosus (SLE, autoimmune collagen disease, which may affect many organ systems)
• If you have high levels of fat in your blood (hypertriglyceridemia)
• If you have otosclerosis (hearing loss sometimes linked to pregnancy)
• You are on treatment for depression
• You have had depression with previous use of estrogen and/or progesterone/progestogen- containing medicines
• You have a substance abuse problem
• You have an underlying psychiatric disorder such as post-traumatic stress disorder or bipolar disorder
• You have a family history of mental disorders
• You have a history of physical or sexual abuse. Estrogen containing medicines, including Estrofem®, may cause mood changes and depression, which may be severe. Severe depression is associated with a higher risk of suicidal thoughts/behaviour (e.g. talking about suicide, withdrawing from social contact, having mood swings, being preoccupied with death or violence, feeling hopeless about a situation, increasing use of alcohol/drugs, doing self-destructive things, personality changes) and suicide. Contact your doctor in case of mood changes and depressive symptoms, including shortly after beginning treatment of Estrofem®. If you need a blood test, tell your doctor that you are taking Estrofem®, since estrogen can affect the results of certain laboratory tests. If you are going to have surgery, talk to your doctor
• You may need to stop taking these tablets 4 to 6 weeks before the operation, to reduce the risk of a blood clot. Your doctor will tell you when you can start treatment again. Stop taking Estrofem® If you are experiencing any of the following conditions below, stop taking Estrofem®, and contact your doctor immediately:
• If you get a migraine-type headache for the first time
• If you develop yellow skin or eyes (jaundice) or other liver problems
• If you have symptoms of significant increase in blood pressure (e.g. headache)
• If you become pregnant
• If any of the conditions listed contraindications “Do not take Estrofem®” occur. Medical check-ups Before you start taking Estrofem®, your doctor should ask about your own and your family’s medical history. Your doctor may decide to examine your breasts and/or your abdomen, and may do an internal examination – but only if these examinations are necessary for you, or if you have any special concerns. Once you have started on Estrofem®, you should see your doctor for regular check-ups (at least once a year). At these check-ups, your doctor may discuss with you the benefits and risks of continuing to take Estrofem®. Be sure to:
• Go for regular breast screening and cervical smear tests
• Regularly check your breasts for any changes such as dimpling of the skin, changes in the nipple, or any lumps you can see or feel. Additionally, you are advised to join mammography screening programs when offered to you. For mammogram screening, it is important that you inform the nurse/health care provider who is actually taking the x-ray that you use Estrofem®, as this medicine may increase the density of your breasts which may affect the outcome of the mammogram. Where the density of the breast is increased, mammography may not detect all lumps. Safety of HRT As well as benefits, Estrofem® has some risks which you need to consider when you’re deciding whether to take it or whether to carry on taking it. Effects on your heart or circulation Heart disease Estrofem® is not recommended for women who have heart disease or have had heart disease recently. If you have ever had heart disease, talk to your doctor to see if you should be taking Estrofem®. Estrofem® will not help to prevent heart disease. Studies with one type of HRT (containing conjugated estrogen plus the progestagen, medroxyprogesterone acetate (MPA) have shown that women may be more likely to get heart disease during the first year of taking the medicine. Stroke Recent research suggests that HRT such as Estrofem® increases the risk of having a stroke. If you have had a stroke in the past, talk to your doctor. If you get unexplained migraine-type headaches, with or without disturbed vision, see a doctor as soon as possible and do not take any more Estrofem® until your doctor says you can. These headaches may be an early warning sign of a stroke. Blood clots Estrofem® may increase the risk of blood clots in the veins (also called deep vein thrombosis, or DVT), especially during the first year of taking it. If a blood clot travels to the lungs, it can cause chest pain, breathlessness, collapse or death. This condition is called pulmonary embolism, or PE. Effects on your risk of developing cancer Estrofem® and breast cancer Women who have breast cancer, or have had breast cancer in the past, should not take Estrofem®. Evidence shows that taking combined estrogen-progestagen or estrogen-only hormone replacement therapy (HRT) increases the risk of breast cancer. The extra risk depends on how long you use HRT. The additional risk becomes clear within 3 years of use. After stopping HRT the extra risk will decrease with time, but the risk may persist for 10 years or more if you have used HRT for more than 5 years. Compare Women aged 50 to 79 who are not taking HRT, on average, 9 to 17 in 1 000 will be diagnosed with breast cancer over a 5-year period. For women aged 50 to 79 who are taking estrogen- progestagen HRT over 5 years, there will be 13 to 23 cases in 1 000 users (i.e. an extra 4 to 6 cases). Breast cancer has been diagnosed slightly more often in women who use HRT than in women of the same age who do not use HRT. This slight increase in the number of breast cancer diagnoses gradually disappears during the course of the 10 years after stopping use of HRT. When you are using Estrofem®, you must perform monthly breast self-examinations. Your doctor will advise you on when to report for breast examinations and any appropriate investigations. Your risk of breast cancer is also higher:
• If you have a close relative (mother, sister or grandmother) who has had breast cancer
• If you are seriously overweight. If you notice any changes in your breast, such as:
• Dimpling of the skin
• Changes in the nipple
• Any lumps you can see or feel, make an appointment to see your doctor as soon as possible. Endometrial cancer (cancer of the lining of the womb) Taking Estrofem® for a long time can increase the risk of cancer of the lining of the womb (the endometrium). Taking a progestagen as well as the estrogen helps to lower the extra risk. If you get breakthrough bleeding or spotting, it’s usually nothing to worry about, especially during the first few months of taking Estrofem®. But if the bleeding or spotting:
• Carries on for more than the first few months
• Starts after you’ve been on Estrofem® for a while
• Carries on even after you have stopped taking Estrofem®, make an appointment to see your doctor. Ovarian cancer Some studies have indicated that taking estrogen-only HRT such as Estrofem® for more than 5 years may increase the risk of ovarian cancer

Pregnancy and breastfeeding

• If you are pregnant or breastfeeding, think you may be pregnant or are planning to have a baby, please consult your doctor, pharmacist or other health care provider for advice before taking Estrofem®
• Do not take Estrofem® if you suspect being pregnant, are pregnant or breastfeeding

Interactions and medicines to check

The approved leaflet names these interactions.

• Medicines used for epilepsy (such as phenobarbital, phenytoin and carbamazepine)
• Medicines used for tuberculosis (such as rifampicin, rifabutin)
• Medicines used for HIV infections (such as nevirapine, efavirenz, ritonavir and nelfinavir)
• Herbal products with St John’s wort (Hypericum perforatum). Estrofem® 1 mg/2 mg may reduce the effect of lamotrigine (used for the treatment of seizures) which may reduce seizure control. Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines including medicines obtained without a prescription, herbal medicines or other natural products. Estrofem® with food, drink and alcohol

What to do if you experience side effects

If you think you are having a side effect, the response depends on how severe it is. Use the warning signs above first — if any of those apply, treat it as urgent.

If the symptom is severe or frightening

Get medical help immediately. Call 10177 for an ambulance, or 112 from a mobile phone, or go to the nearest emergency department. Take the product and its packaging with you if you can.

If the symptom is mild but bothering you

• Write down what the symptom is, when it started, and how it relates to when you take the product
• Check the leaflet that came with the product to see whether the symptom is listed
• Speak to your pharmacist — for many questions this is the fastest route to a useful answer
• Contact the prescriber if the symptom is affecting your daily life or is not settling

You can also report a suspected side effect in South Africa. Reporting does not replace getting medical advice, and you do not need to be certain the product was the cause.

When to seek urgent medical help

Some symptoms need medical attention straight away rather than an appointment in a few days. Do not wait to see whether they settle.

Get same-day medical advice if you have

• A high fever, or a rash together with feeling generally unwell
• Yellowing of the eyes or skin, or unusually dark urine
• Unusual bruising or bleeding that you cannot explain
• Severe or persistent vomiting or diarrhoea, especially if you cannot keep fluids down
• A sudden change in mood, or thoughts of harming yourself
• Any symptom that is rapidly getting worse

How to report a suspected side effect in South Africa

South Africa has an official system for reporting suspected side effects, run by the South African Health Products Regulatory Authority (SAHPRA). Reports from the public and from healthcare professionals are how safety signals get detected after a product is already in use.

Who can report

Anyone can report — you do not have to be a healthcare professional, and you do not need to prove that the product caused the problem. A suspicion is enough. Patients, caregivers and family members can all submit a report.

What to have ready

• The name of the product, its strength and form, and the batch number if you have it
• Why it was being used, and when it was started and stopped
• What the suspected reaction was, when it began, and how long it lasted
• Any other medicines, supplements or remedies being used at the same time
• Basic details about the person affected — age and sex are usually enough

How to report

SAHPRA accepts adverse reaction reports through its e-Services reporting system and through the Med Safety mobile app. Healthcare professionals can also report through the same routes. Current forms and access points are published on the SAHPRA site.

• SAHPRA Health Products Vigilance — the main vigilance and reporting hub
• SAHPRA e-Services — current adverse reaction reporting access

For a fuller walkthrough see how to report an adverse drug reaction.

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