Divigel Adverse Reactions

Adverse drug reactions occur most commonly during the 1st months of treatment. They are usually mild and subside with continued treatment.
Adverse drug reactions were recorded eg, in 3 phase III clinical studies (n=611 women at risk) and were included in the table when considered at least possibly related to treatment with estradiol 50 mcg/day or estradiol 100 mcg/day, respectively, following transdermal application.
Adverse drug reactions recorded in clinical studies as well as adverse drug reactions reported post-marketing are listed as follows. The experience of adverse drug reactions is overall expected in 76% of the patients. Adverse drug reactions appearing in >10% of patients in clinical trials were application site reactions and breast pain.
Undesirable effects according to system organ class associated with transdermal estradiol treatment are presented as follows: Common (>1/100, <1/10); uncommon (≥1/1000, <1/100); rare (≥1/10,000, <1/1000); frequency not known (cannot be estimated from the available data).
Benign, Malignant and Unspecified Neoplasms (Including Cysts and Polyps): Uncommon: Benign breast and endometrial neoplasm. Frequency Not Known: Uterine fibroids.
Immune System Disorders: Frequency Not Known: Exacerbation of hereditary angioedema.
Metabolism and Nutrition Disorders: Common: Oedema, increased weight. Uncommon: Increased appetite, hypercholesterolemia¹.
Psychiatric Disorders: Common: Depression, nervousness, lethargy. Uncommon: Anxiety, insomnia, apathy, emotional lability, impaired concentration, changes in mood or libido, euphoria¹, agitation¹.
Nervous System Disorders: Common: Headache, dizziness. Uncommon: Migraine, paraesthesia, tremor¹.
Eye Disorders: Uncommon: Abnormal vision¹, dry eye¹.
Cardiac Disorders: Uncommon: Palpitations.
Vascular Disorders: Common: Hot flushes. Uncommon: Hypertension¹, superficial phlebitis¹, purpura¹. Rare: Venous thromboembolism. Frequency Not Known: Cerebral ischaemic events.
Respiratory, Thoracic and Mediastinal Disorders: Uncommon: Dyspnoea¹, rhinitis¹.
Gastrointestinal Disorders: Common: Nausea, vomiting, stomach cramps, flatulence. Uncommon: Constipation, dyspepsia¹, diarrhoea¹, rectal disorder. Frequency Not Known: Abdominal pain, bloating (abdominal distension).
Hepatobiliary Disorders: Rare: Alterations in liver function and biliary flow. Frequency Not Known: Cholestatic jaundice.
Skin and Subcutaneous Tissue Disorders: Uncommon: Acne, alopecia, dry skin, nail disorder¹, skin nodule¹, hirsutism¹. Rare: Rash. Frequency Not Known: Contact dermatitis, eczema.
Musculoskeletal and Connective Tissue Disorders: Uncommon: Joint disorders, muscle cramps.
Renal and Urinary Disorders: Uncommon: Increased urinary frequency/urgency, urinary incontinence¹, cystitis¹, urine discoloration¹, haematuria¹.
Reproductive System and Breast Disorders: Common: Breast pain/tension, unscheduled vaginal bleeding or spotting, vaginal discharge, disorder of vulva/vagina, menstrual disorder. Uncommon: Breast enlargement and tenderness; endometrial hyperplasia, uterine disorder¹.
General Disorders and Administration Site Conditions: Common: Skin irritation, application site pruritus, pain, increased sweating. Uncommon: Fatigue, abnormal laboratory test¹, asthenia¹, fever¹, flu syndrome¹, malaise¹.
¹Have been reported in single cases in clinical trials. Given the small study population (n=611) it cannot be determined based on these results if the events are uncommon or rare.
Other Adverse Reactions Have Been Reported in Association with Estrogen/Progestagen Treatment: Estrogen-dependent neoplasms benign and malignant eg, endometrial cancer; venous thromboembolism ie, deep leg or pelvic venous thrombosis and pulmonary embolism, is more frequent among HRT users than among non-users (see Contraindications and Precautions); myocardial infarction and stroke; gall bladder disease.
Skin and Subcutaneous Disorders: Chloasma, erythema multiforme, erythema nodosum and vascular purpura.
Probable dementia >65 (see Precautions).
Breast Cancer Risk: An up to 2-fold increased risk of having breast cancer diagnosed is reported in women taking combined estrogen-progestagen therapy for >5 years.
Any increased risk in users of estrogen-only therapy is substantially lower than that seen in users of estrogen-progestagen combinations.
The level of risk is dependent on the duration of use (see Precautions).
Results of the largest randomised placebo-controlled trial (WHI study) and largest epidemiological study (MWS) are presented. (See Tables 1 and 2.)

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Endometrial Cancer Risk: Postmenopausal Women with a Uterus: The endometrial cancer risk is about 5 in every 1000 women with a uterus not using HRT. In women with a uterus, use of estrogen-only HRT is not recommended because it increases the risk of endometrial cancer (see Precautions).
Depending on the duration of estrogen-only use and estrogen dose, the increase in risk of endometrial cancer in epidemiology studies varied from between 5 and 55 extra cases diagnosed in every 1000 women between the ages of 50 and 65.
Adding a progestagen to estrogen-only therapy for at least 12 days per cycle can prevent this increased risk. In the million women study, the use of 5 years of combined (sequential or continuous) HRT did not increase risk of endometrial cancer [RR of 1 (0.8-1.2)].
Ovarian Cancer: Long-term use of estrogen-only and combined estrogen-progestagen HRT has been associated with a slightly increased risk of ovarian cancer. In the million women study 5 years of HRT resulted in 1 extra case per 2500 users.
Risk of Venous Thromboembolism: Hormone replacement therapy (HRT) is associated with a 1.3 to 3-fold increased relative risk of developing venous thromboembolism (VTE) ie, deep vein thrombosis or pulmonary embolism. The occurrence of such an event is more likely in the 1st year of using HRT (see Precautions). Results of the WHI studies are presented (see Table 3).

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Risk of Coronary Artery Disease: The risk of coronary artery disease is slightly increased in users of combined estrogen-progestagen HRT >60 years (see Precautions).
Risk of Ischaemic Stroke: The use of estrogen-only and estrogen+progestagen therapy is associated with an up to 1.5-fold increased relative risk of ischaemic stroke. The risk of haemorrhagic stroke is not increased during use of HRT.
This relative risk is not dependent on age or on duration of use, but as the baseline risk is strongly age-dependent, the overall risk of stroke in women who use HRT will increase with age (see Precautions). (See Table 4.)

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