Estradiol hemihydrate, drospirenone.
Each tablet contains estradiol hemihydrate 1 mg and drospirenone 2 mg.
Pharmacokinetics: Estradiol: Based on data obtained with estradiol/drospirenone combination tablets containing estradiol 1 mg and drospirenone 1 or 4 mg, maximum serum estradiol concentrations of about 22 pg/mL are expected 6-8 hrs after administering a single oral dose. Estradiol undergoes extensive hepatic first-pass metabolism, reducing the oral bioavailability of the estrogen to about 5%. Following repeated oral administration of estradiol/drospirenone combination tablets, serum estradiol levels show little variation over 24-hr dosing interval. Because of the large circulating pool of estrogen sulfates and glucuronides and the enterohepatic recirculation, the terminal half-life of estradiol is a composite parameter, and is in the range of about 13-20 hrs for oral administration. Within the circulation, estradiol is bound nonspecifically to serum albumin and specifically to sex hormone-binding globulin (SHBG; 38%); only about 2-3% of circulating estradiol is present as free steroid. Orally administered Angeliq induces SHBG formation, and the ~20% increase in SHBG influences the distribution of estradiol with respect to the plasma proteins. The apparent volume of distribution of estradiol after a single IV dose is about 1 L/kg. Estradiol is rapidly metabolized, and besides estrone and estrone sulfate, a large number of other metabolites and conjugates are formed. Estrone and estriol are pharmacologically active; however, only estrone occurs at relevant concentrations in plasma. Estrone reaches about 6-fold higher serum levels than estradiol. The serum level of the estrone conjugates are about 26-fold higher than the corresponding levels of free estrone. The metabolite clearance of estradiol is 10-30 mL/min/kg. The metabolites are excreted via the urine and bile with a half-life of about 1 day. Following once-daily oral administration of estradiol/drospirenone combination tablets, estradiol and estrone concentrations reach steady state after 5 days. Serum estradiol levels accumulate approximately 2-fold between the 1st dose and steady state.
Drospirenone: The absorption of drospirenone is rapid and almost complete after oral administration. Maximum serum concentrations occur about 1 hr after oral administration of Angeliq. The absolute bioavailability of drospirenone is 76-85%, and is not influenced by food. After oral administration, serum drospirenone levels decrease with a mean terminal half-life of about 35-39 hrs. Drospirenone does not bind to SHBG or corticoid-binding globulin, but binds to other plasma proteins. The free fraction of drospirenone in the plasma is approximately 3-5%. Drospirenone is extensively metabolized after oral or IV administration. At least 20 different metabolites have been observed in the urine and feces, but only trace amounts are excreted unchanged. The renally excreted drospirenone metabolites do not exhibit pharmacological activity. The total clearance of drospirenone is 1.2-1.5 mL/min/kg. Excretion is nearly complete 10 days after a single dose, and the feces to urine excretion ratio is 1.2-1.4. The excretion half-life in urine and feces is ~40 hrs, which is similar to the terminal half-life of the drug in plasma. In patients with impaired renal function, serum drospirenone concentrations increase slightly as creatinine clearance decreases. This is not expected to be of clinical relevance because of the excellent tolerability of drospirenone. Following repeated once-daily oral administration of estradiol/drospirenone combination tablets, serum drospirenone concentrations increase within the 1st 10 days of treatment and then reach steady state. The mean accumulation factor for drospirenone between the 1st dose and steady state is 2.4-2.9, which is to be expected from the daily dosing interval and the terminal half-life of the drug. The pharmacokinetics of drospirenone were clearly dose-proportional after repeated daily administration of drospirenone 1-4 mg in combination with estradiol 1 mg to postmenopausal women.
Hormone replacement therapy (HRT) for estrogen deficiency symptoms in postmenopausal women >1 year post menopause. Prevention of postmenopausal osteoporosis in women with an increased risk of future osteoporosis fractures that are intolerant of, or contraindicated for, other medicinal products approved for the prevention of osteoporosis.
1 tab daily with some liquid. Each blister pack is for 28 days of treatment. Treatment is continuous, which means that the estrogen and the progestogen are given everyday without interruption.
Undiagnosed genital bleeding, known, past or suspected cancer of the breast, known or suspected estrogen-dependent malignant tumours (eg, endometrial cancer), untreated endometrial hyperplasia, previous idiopathic or current venous thromboembolism (deep venous thrombosis, pulmonary embolism), active or recent arterial thromboembolic disease (eg, angina, myocardial infarction), acute liver disease, or a history of liver disease as long as liver function tests have failed to return to normal, porphyria, severe renal insufficiency or acute renal failure, known hypersensitivity to the active substances or to any of the excipients of Angeliq.
Before initiating or reinstituting HRT, a complete personal and family medical history should be taken. Physical (including pelvic and breast) examination should be guided by this and by the contraindications and warnings for use. During treatment, periodic check-ups are recommended of a frequency and nature adapted to the individual woman. Women should be advised what changes in their breasts should be reported to their doctor or nurse. Investigations, including mammography should be carried out in accordance with currently accepted screening practices, modified to the clinical needs of the individual. A careful appraisal of the risks and benefits should be undertaken over time in women treated with HRT.
If any of the following conditions are present, have occurred previously, and/or have been aggravated during pregnancy or previous hormone treatment, the patient should be closely supervised. It should be taken into account that these conditions may recur or be aggravated during treatment with Angeliq, in particular: Leiomyoma (uterine fibroids) or endometriosis, a history of, or risk factor for, thromboembolic disorders, risk factors for estrogen-dependent tumours eg, 1st degree heredity for breast cancer, hypertension, liver disorders (eg, liver adenoma), diabetes mellitus with or without vascular involvement, cholelithiasis, migraine or (severe) headache, systemic lupus erythematosus, history of endometrial hyperplasia, epilepsy, asthma, otosclerosis.
Therapy should be discontinued in case a contraindication is discovered and in the following situations: Jaundice or deterioration in liver function, significant increase in blood pressure, new onset of migraine-type headache, pregnancy.
Drospirenone displays aldosterone antagonistic activity. Therefore, increases in sodium and water excretion may be observed. Patients who are concomitantly using potassium-sparing drugs must be closely monitored, and may need to be adjusted accordingly.
Therapy should be discontinued in case of pregnancy.
Abdominal pain or bloating, asthenia, pain in extremity, nausea, headache, mood swings, hot flashes, nervousness, benign breast neoplasms, breast enlargement, enlarged uterine fibroids, cervix neoplasm, leukorrhea, breakthrough bleeding, pain in back or pelvis, chills, malaise, migraine, hypertension, chest pain, palpitations, varicose veins, venous thrombosis, superficial thrombophlebitis, vasodilatation, gastrointestinal disorder, increased appetite, abnormal liver function test, generalized or localized edema, weight gain, hyperlipidemia, muscle cramps, arthralgia, insomnia, dizziness, decreased libido, impaired concentration, paresthesia, increased sweating, anxiety, dry mouth, vertigo, dyspnea, alopecia, skin or hair disorder, hirsutism, breast carcinoma, breast enlargement, taste disturbance, vulvovaginitis, endometrial or cervical disorder, dysmenorrhea, ovarian cyst.
Some medicinal products may affect the effectiveness of HRT and eventually cause irregular bleeding. These include antiepileptics (eg, hydantoins, barbiturates, primidone, carbamazepine) and antituberculosis (eg, rifampicin); and antibiotics (eg, penicillins and tetracyclines) for some other infectious diseases.
Angeliq has the potential to lower blood pressure. The dose of concurrent antihypertensive agent may need to be adjusted accordingly.
G03FA17 - drospirenone and estrogen ; Belongs to the class of progestogens and estrogens in fixed combinations.