Drospirenone and Estetrol interacts in the following cases:
The clinical relevance of potential interactions with enzyme inhibitors remains unknown. Concomitant administration of strong CYP3A4 inhibitors can increase plasma concentrations of oestrogens or progestogens or both.
Potential interactions with drospirenone:
In a multiple dose study with a drospirenone (3 mg/day)/ethinylestradiol (0.02 mg/day) combination, co-administration of the strong CYP3A4 inhibitor ketoconazole for 10 days increased the area under the curve during a 24-hour period (AUC(0-24h)) of drospirenone (and ethinylestradiol) 2.7-fold (and 1.4-fold, respectively).
Potential interactions with estetrol:
Estetrol is predominantly glucuronised by UDP-glucuronosyltransferase (UGT) 2B7 enzyme. No clinically relevant interaction was observed with estetrol and the strong UGT inhibitor valproic acid.
Drospirenone is an aldosterone antagonist with potassium sparing properties. In most cases, no increase of potassium levels would be expected. In a clinical study with drospirenone, however, in some patients with mild or moderate renal impairment and concomitant use of potassium-sparing medicinal products, serum potassium levels increased slightly, but not significantly, during intake of 3 mg drospirenone for 14 days. Therefore, it is recommended to check serum potassium during the first treatment cycle with drospirenone/estetrol in patients presenting with renal insufficiency and a pretreatment serum potassium in the upper reference range, and particularly during concomitant use of potassium sparing medicinal products.
When co-administered with CHCs, many combinations of HIV protease inhibitors and non-nucleoside reverse transcriptase inhibitors, including combinations with HCV inhibitors can increase or decrease plasma concentrations of oestrogens and progestogens. The effect of these changes may be clinically relevant in some cases.
Therefore, the prescribing information of concomitant HIV/HCV medicinal products should be consulted to identify potential interactions and any related recommendations. In case of any doubt, an additional barrier method of contraception should be used by women on protease inhibitor or nonnucleoside reverse transcriptase inhibitor therapy.
Medicinal products increasing the clearance of CHCs (enzyme-induction), e.g.: barbiturates, bosentan, carbamazepine, phenytoin, primidone, rifampicin and HIV medicinal products (e.g. ritonavir, nevirapine and efavirenz) and possibly also felbamate, griseofulvin, oxcarbazepine, topiramate and products containing the herbal St. John’s wort (Hypericum perforatum).
Worsening of endogenous depression, of epilepsy, of Crohn’s disease and ulcerative colitis has been reported during CHC use.
Women with hypertriglyceridaemia, or a family history thereof, may be at an increased risk of pancreatitis when using CHCs.
Exogenous estrogens may induce or exacerbate symptoms of hereditary and acquired angioedema.
The following conditions have been reported to occur or deteriorate with both pregnancy and CHC use, but the evidence of an association with CHC use is inconclusive: jaundice and/or pruritus related to cholestasis; gallstone formation; porphyria; systemic lupus erythematosus; haemolytic uraemic syndrome; Sydenham’s chorea; herpes gestationis; otosclerosis-related hearing loss.
Although CHCs may have an effect on peripheral insulin resistance and glucose tolerance, there is no evidence for a need to alter the therapeutic regimen in diabetics using low-dose CHCs (containing <50 µg ethinylestradiol). However, diabetic women should be carefully observed, particularly in the early stage of CHC use.
Drospirenone/estetrol combination is not indicated during pregnancy.
If pregnancy occurs while taking drospirenone/estetrol, further intake must be stopped.
There are limited amount of data from the use of drospirenone/estetrol in pregnant women.
Studies in animals have shown reproductive toxicity. Based on animal experience, harmful effects due to hormonal action of the active substances cannot be excluded.
The increased risk of VTE during the postpartum period should be considered when re-starting drospirenone/estetrol.
Small amounts of the contraceptive steroids and/or their metabolites may be excreted with the breast milk and might affect the child.
Breast-feeding may be influenced by CHCs as they may reduce the quantity and change the composition of breast milk. Therefore, the use of CHCs should not be recommended until the breast-feeding mother has completely weaned her child and an alternative method of contraception should be proposed to women wishing to breastfeed.
Drospirenone/estetrol combination is indicated for oral contraception.
Drospirenone/estetrol combination has no or negligible influence on the ability to drive and use machines.
The most commonly reported adverse reactions with drospirenone/estetrol are metrorrhagia (4.3%), headache (3.2%), acne (3.2%), vaginal haemorrhage (2.7%) and dysmenorrhoea (2.4%).
Adverse reactions that have been identified are listed below. Adverse reactions are listed according to the MedDRA system organ class and ranked under frequency groupings using the following convention: common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100) and rare (≥1/10,000 to <1/1,000).
List of adverse reactions:
| System organ class | Common | Uncommon | Rare |
|---|---|---|---|
| Infections and infestations | Fungal infection Vaginal infection Urinary tract infection | Mastitis | |
| Neoplasms benign, malignant and unspecified (including cysts and polyps) | Fibroadenoma of breast | ||
| Immune system disorders | Hypersensitivity | ||
| Metabolism and nutrition disorders | Appetite disorder | Hyperkalaemia Fluid retention | |
| Psychiatric disorders | Mood disorders and disturbances1 Libido disorder | Depression2 Anxiety disorder3 Insomnia Emotional disorder4 Stress | Nervousness |
| Nervous system disorders | Headache | Migraine Dizziness Paraesthesia Somnolence | Amnesia |
| Eye disorders | Visual impairment Vision blurred Dry eye | ||
| Ear and labyrinth disorders | Vertigo | ||
| Vascular disorders | Hot flush | Hypertension Venous thrombosis Thrombophlebitis Hypotension Varicose vein | |
| Gastrointestinal disorders | Abdominal pain Nausea | Abdominal distension Vomiting Diarrhoea | Gastroesophageal reflux disease Colitis Gastrointestinal motility disorder Constipation Dyspepsia Flatulence Dry mouth Lip swelling |
| Skin and subcutaneous tissue disorders | Acne | Alopecia Hyperhidrosis5 Skin disorders6 | Dermatitis7 Pigmentation disorder8 Hirsutism Seborrhoea Pruritus Swelling of face Urticaria Skin discolouration |
| Musculoskeletal and connective tissue disorders | Back pain | Muscle spasms Limb discomfort Joint swelling Pain in extremity | |
| Renal and urinary disorders | Bladder spasm Urine odour abnormal | ||
| Pregnancy, puerperium and perinatal conditions | Ectopic pregnancy | ||
| Reproductive system and breast disorders | Breast pain Metrorrhagia Vaginal haemorrhage Dysmenorrhoea Menorrhagia | Abnormal withdrawal bleeding9 Breast swelling Vulvovaginal disorder10 Vaginal discharge Premenstrual syndrome Breast mass11 Uterine spasm Uterine haemorrhage Menometrorrhagia Dyspareunia | Ovarian cyst Lactation disorders Endometrial disorder Dysfunctional uterine bleeding Pelvic pain Nipple disorder Breast discolouration Coital bleeding |
| General disorders and administration site conditions | Fatigue Oedema Chest pain Feeling abnormal | Malaise12 Pain Hyperthermia | |
| Investigations | Weight fluctuation | Hepatic enzyme increased Lipids abnormal | Blood pressure increased Renal function test abnormal Blood potassium increased Blood glucose increased Haemoglobin decreased Serum ferritin decreased Blood in urine |
1 including affect lability, anger, euphoric mood, irritability, altered mood and mood swings
2 including depressed mood, depressive symptom, tearfulness and depression
3 including agitation, anxiety, generalised anxiety disorder and panic attack
4 including emotional disorder, emotional distress and crying
5 including night sweats, hyperhidrosis and cold sweat
6 including dry skin, rash and skin swelling
7 including dermatitis and eczema
8 including chloasma and skin hyperpigmentation
9 including abnormal withdrawal bleeding, amenorrhoea, menstrual disorder, irregular menstruation, oligomenorrhoea and polymenorrhoe
10 including vaginal odour, vulvovaginal discomfort, vulvovaginal dryness, vulvovaginal pain, vulvovaginal pruritus and vulvovaginal burning sensation
11 including breast mass and fibrocystic breast disease
12 including malaise and decreased performance status
An increased risk of arterial and venous thrombotic and thromboembolic events, including myocardial infarction, stroke, transient ischemic attacks, venous thrombosis and pulmonary embolism has been observed in women using CHCs.
The following serious adverse events have been reported in women using CHCs:
The frequency of diagnosis of breast cancer is very slightly increased among CHC users. As breast cancer is rare in women under 40 years of age the excess number is small in relation to the overall risk of breast cancer. Causation with CHC use is unknown.
Breakthrough bleeding and/or contraceptive failure may result from interactions of other medicinal products (enzyme inducers) with oral contraceptives.
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