Angeliq®: composition and dosage form
One film-coated tablet contains 1 mg of estradiol as the hemihydrate and 2 mg of drospirenone. Each blister is intended for 28 days of treatment — exactly a month of continuous dosing, with no break before the next pack.
The tablet is swallowed whole with liquid, independently of meals, and preferably at the same time every day.
How Angeliq® works
The first active substance is synthetic 17β-estradiol, chemically and biologically identical to endogenous human estradiol. The second substance, drospirenone, is a synthetic progestogen, and its presence is explained by the risks of the first. Oestrogens stimulate the growth of the lining of the body of the uterus, so using oestrogens alone raises the risk of endometrial hyperplasia and cancer; adding a progestogen reduces that risk, though it does not remove it entirely in women who still have a uterus.
Drospirenone has a property the progestogens in other HRT products lack: it acts as an aldosterone antagonist. During treatment, therefore, an increase in the excretion of sodium and water and a decrease in the excretion of potassium may be observed. It is precisely from this anti-aldosterone action that two practical consequences grow, ones the product information returns to twice: monitoring potassium and a possible fall in blood pressure.
Indications
There are two indications. The first is hormone replacement therapy for treating the symptoms of oestrogen deficiency in women more than a year past the menopause. The second is the prevention of osteoporosis in postmenopausal women at high risk of future fractures who are intolerant of, or have contraindications to, other medicines used in preventing osteoporosis. Experience in treating women over 65 is, however, limited.
To the indications the product information adds conditions that in effect narrow them. Replacement therapy is used only for those symptoms that adversely affect quality of life. At least once a year the benefit-to-risk ratio is carefully assessed, and therapy continues for as long as the benefit outweighs the risk.
Method of administration and dosage
The schedule is simple: one tablet a day. Treatment is continuous, meaning no break is taken before starting the next pack. The difficulties begin not with the dose but with the changeover — with which day to start on if you are already receiving hormone therapy.
- women who have not used hormone replacement therapy so far, and women who were on a continuous regimen, may start treatment at any time;
- women who were on a sequential regimen start on the day after the previous cycle ends;
- a forgotten tablet is taken as soon as possible;
- if more than 24 hours have passed, the forgotten tablet no longer needs to be taken;
- if several tablets are missed, bleeding from the genital tract may occur.
Bleeding deserves a separate word, because in the first months of treatment it and spotting are common. The irregularity usually passes as therapy continues, and over time the frequency of bleeding falls.
Contraindications
The list opens with a situation that cannot be left unexamined: bleeding from the genital tract whose cause has not been established. Then comes the oncological group — breast cancer in the history, diagnosed or suspected; known or suspected malignant oestrogen-dependent tumours, for example cancer of the uterine lining; untreated hyperplasia of the uterine lining.
The second half of the list concerns the vessels, the liver and the kidneys. It is past or present venous thromboembolic disease — deep vein thrombosis, pulmonary embolism; active or recent arterial thromboembolic disorders, for example angina pectoris or a heart attack; a known tendency to thrombosis, say a deficiency of protein C, protein S or antithrombin. Here too belongs acute liver disease or liver disease in the history — until the results of liver function tests return to normal. Severe or acute renal failure stands apart: this contraindication is tied specifically to drospirenone and is far from present in every HRT product. The list closes with hypersensitivity to the active substances or excipients, and porphyria.
Special warnings and precautions
Before starting or restarting therapy a full medical history is taken, including the family history, and the medical examination — of the pelvic organs and the breasts as well — is directed by that history, by the contraindications and by the warnings. During treatment periodic check-ups are carried out, their frequency and character set for each patient individually; mammography and other investigations are ordered according to accepted screening rules. Treatment is stopped in case of jaundice or worsening liver function, a significant rise in blood pressure, a new attack of migraine-type headache, and pregnancy.
| Risk | How much higher | What is known about it |
| Endometrial cancer on oestrogen alone | 2–12 times | depends on the duration of treatment and the dose; adding a progestogen for at least 12 days of the cycle prevents that increase |
| Breast cancer on combined therapy | doubled with use longer than 5 years | becomes visible after about 3 years and disappears within a few years, at most 5, after stopping; the therapy increases mammographic density |
| Venous thromboembolism | 1.3–3 times | more likely in the first year of therapy; the background risk is age, extensive surgery, obesity, pregnancy and the postpartum period, lupus and cancer |
| Ischaemic stroke | up to 1.5 times | the relative risk does not depend on age or on time since the menopause, but the overall risk rises with age; the risk of haemorrhagic stroke is not increased |
| Ovarian cancer | 1 extra case per 2000 women aged 50–54 over 5 years | without therapy, over those same 5 years ovarian cancer is diagnosed in 2 women out of 2000 |
A separate group of warnings is tied to drospirenone. It spares potassium weakly, and in most cases no rise in its concentration is expected, but in a clinical study a small increase was recorded in some patients with mild to moderate renal impairment and in those simultaneously taking other potassium-sparing medicines — ACE inhibitors, angiotensin II receptor antagonists, NSAIDs. Potassium is therefore checked during the first month of treatment in women with renal failure and a baseline potassium at the upper limit of normal. In women with raised blood pressure it may fall on the medicine, but the medicine must not be used to treat hypertension.
Interaction with other medicines
The main interaction here is not an enhancement but a weakening. The metabolism of oestrogens and progestogens may accelerate when substances that stimulate cytochrome P-450 enzymes are taken at the same time, and clinically this leads to a weaker effect of the medicine and to changes in the pattern of uterine bleeding. Enzyme induction is noticeable within a few days, reaches its maximum over a few weeks and persists for about 4 weeks after such therapy ends.
- metabolism is accelerated by anticonvulsants — barbiturates, phenytoin, primidone, carbamazepine — and by anti-infectives: rifampicin, rifabutin, nevirapine, efavirenz; probably also felbamate, griseofulvin, oxcarbazepine, topiramate and preparations containing St John's wort;
- the concentrations of the progestogen, the oestrogen or both may be raised by strong and moderate CYP3A4 inhibitors: azole antifungals, verapamil, macrolides, diltiazem and grapefruit juice;
- in a study, ketoconazole over 10 days increased the AUC of drospirenone 2.30-fold; there was no effect on estradiol, while the AUC of estrone, a weaker metabolite, rose 1.39-fold;
- in women with hypertension taking antihypertensive drugs an additional fall in blood pressure is possible.
In the other direction drospirenone barely acts: in vitro it weakly or moderately inhibits CYP1A1, CYP2C9, CYP2C19 and CYP3A4, but studies in volunteers with omeprazole, simvastatin and midazolam found no clinically significant interactions at the 3 mg dose. Sex steroids, on the other hand, alter test results — liver, thyroid, adrenal and kidney biochemistry, the concentrations of carrier proteins, lipid fractions, and the parameters of carbohydrate metabolism, coagulation and fibrinolysis — though the changes usually stay within laboratory reference ranges. Drospirenone itself raises plasma renin activity and the aldosterone concentration.
Pregnancy and breastfeeding
The wording here is unusual: the medicine is not indicated in pregnancy — not "contraindicated" but precisely not indicated. The rule, however, applies unconditionally: if during use the patient turns out to be pregnant, the product is stopped at once, and pregnancy appears in the list of situations that require treatment to be discontinued.
What is known about the substances themselves. There are no sufficient clinical data on the use of drospirenone in pregnant women, and animal studies showed reproductive toxicity, while the potential risk to humans is not known. During lactation the product is likewise not indicated.
Adverse effects
Two reactions occur more often than all the rest, and both concern the very thing the medicine is taken for: breast pain in more than 10% of women and bleeding with spotting during the first few cycles of treatment, also in more than 10%. Commonly — that is, less often but still not rarely — depression, emotional lability and nervousness are recorded; headache; abdominal pain, nausea and abdominal enlargement; on the reproductive side, benign breast tumours, breast enlargement, growth of uterine fibroids, benign tumours of the cervix, menstrual disorders and discharge; as well as weakness and local oedema.
The uncommon reactions form a long list: weight change, anorexia, increased appetite, hyperlipidaemia; sleep disturbances, anxiety, decreased libido; embolism, venous thrombosis, hypertension, migraine, thrombophlebitis, varicose veins; stomach and intestinal disorders, diarrhoea, constipation, vomiting, dry mouth, bloating, taste disturbances; abnormal liver function tests; skin disorders, acne, alopecia, itching, rash, hirsutism; pain in the limbs, back and joints, muscle cramps; breast cancer, endometrial hyperplasia and a number of other gynaecological disorders; generalised or local oedema, chest pain, malaise, increased sweating. In women with hypertension two clinical studies described hyperkalaemia, heart failure, atrial flutter, QT prolongation, cardiomegaly and a rise in blood aldosterone, while hormone therapy in general is associated with erythema nodosum and erythema multiforme, melasma and haemorrhagic inflammation of the skin.
Overdose
This section rests on someone else's experience, and it shows. In clinical studies in male volunteers doses of up to 100 mg of drospirenone were well tolerated. And the picture of the symptoms is drawn from general experience with combined oral contraceptives: nausea and vomiting are possible and, in young girls and some women, bleeding from the genital tract.
There is no specific antidote, so treatment should be symptomatic.
How to get a prescription for Angeliq® online
Angeliq® carries a contraindication that most replacement therapy products do not: severe or acute renal failure. The reason is drospirenone — a progestogen that works as an aldosterone antagonist and weakly spares potassium. That is why the conversation about prescribing begins not with hot flushes but with the kidneys. On e-zdrowie.com you fill in a medical questionnaire, the doctor reviews the answers and, if the medicine is suitable, issues an electronic prescription: the code arrives by message, and any Polish pharmacy will dispense the tablets against it.
Begin the questionnaire with kidneys and potassium: give your creatinine or estimated filtration rate, your latest potassium level, whether you have diabetes and whether you take ACE inhibitors, angiotensin II receptor antagonists, potassium-sparing diuretics or regular NSAIDs. Then gynaecology: whether you still have a uterus, when your last period was and whether a year has passed since the menopause, whether you have bleeding from the genital tract of unexplained cause, whether there are fibroids, endometriosis or endometrial hyperplasia in your history. Be sure to report the oncological history: breast cancer in yourself and in close female relatives, any oestrogen-dependent tumours. Name separately any past deep vein thrombosis, pulmonary embolism, angina and heart attack, a known tendency to thrombosis and any planned surgery with long immobilisation, as well as liver disease, migraine, epilepsy, asthma and your blood pressure. And list your medicines: anticonvulsants, rifampicin, HIV drugs and St John's wort weaken the effect, while azole antifungals, macrolides and verapamil strengthen it.
