Lydisilka: Uses, Dosage & Side Effects

What Is Lydisilka and What Is It Used For?

Lydisilka is a combined hormonal contraceptive (CHC) designed for oral use, taken once daily to prevent pregnancy. Each blister pack contains 28 tablets: 24 active pink film-coated tablets, each containing 3 mg of drospirenone and 14.2 mg of estetrol (as estetrol monohydrate), followed by 4 inactive white placebo tablets. This 24/4 dosing regimen was chosen to optimize contraceptive efficacy and cycle control while minimizing hormone-free days.

What sets Lydisilka apart from other combined oral contraceptives is its estrogenic component. While the vast majority of combined pills on the market contain ethinylestradiol (EE) — a potent synthetic estrogen that has been the standard estrogenic component since the 1960s — Lydisilka contains estetrol (E4). Estetrol is a natural estrogen that is produced by the human fetal liver during pregnancy and enters the maternal circulation via the placenta. It was first identified in 1965 by Egon Diczfalusy at the Karolinska Institute, but its therapeutic potential was not fully explored until recent decades, when advances in chemical synthesis made it possible to produce pharmaceutical-grade estetrol for clinical use.

Estetrol has a unique pharmacological profile that distinguishes it from both ethinylestradiol and estradiol. It acts as an estrogen receptor agonist but demonstrates what researchers have termed a native estrogen with selective action in tissues (NEST) profile. This means that estetrol activates estrogen receptors in a tissue-selective manner: it has potent estrogenic effects on the hypothalamic-pituitary-ovarian (HPO) axis (necessary for ovulation suppression) and on the endometrium (supporting cycle control), but it has significantly less impact on liver protein synthesis compared to ethinylestradiol. This reduced hepatic impact is clinically relevant because many of the cardiovascular risks associated with combined oral contraceptives — including changes in coagulation factors, lipoproteins, and sex hormone-binding globulin (SHBG) — are driven by the first-pass hepatic effects of ethinylestradiol.

Drospirenone, the progestogenic component of Lydisilka, is a fourth-generation progestogen derived from spironolactone. It has a pharmacological profile that closely resembles natural progesterone, including anti-mineralocorticoid activity (which can counteract estrogen-related sodium and water retention) and anti-androgenic properties (which can benefit conditions influenced by androgens, such as acne and hirsutism). Drospirenone does not possess any estrogenic, androgenic, glucocorticoid, or anti-glucocorticoid activity. These properties make it a well-suited progestogenic partner for estetrol in a combined contraceptive formulation.

The contraceptive effect of Lydisilka is achieved primarily through suppression of ovulation. The combination of estetrol and drospirenone acts on the hypothalamic-pituitary-ovarian axis to inhibit the mid-cycle surge of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), thereby preventing the release of an egg from the ovary. Additionally, drospirenone induces changes in the cervical mucus (making it thicker and less permeable to sperm) and in the endometrium (making it less receptive to implantation), providing secondary contraceptive mechanisms.

Lydisilka was first authorized in the European Union in May 2021 following a positive opinion from the European Medicines Agency (EMA). It has subsequently been approved in multiple countries worldwide. The U.S. equivalent product, marketed under the brand name Nextstellis, was approved by the FDA in April 2021. Both products contain the same active substances in the same doses and use the same 24/4 regimen.

What Should You Know Before Taking Lydisilka?

Contraindications

Lydisilka must not be used in any of the following circumstances. If any of these conditions apply to you, inform your prescribing healthcare provider before starting Lydisilka, and discuss alternative contraceptive methods:

• Venous thromboembolism (VTE): Current or past history of deep vein thrombosis (DVT) or pulmonary embolism (PE), whether treated with anticoagulants or not.
• Arterial thromboembolism (ATE): Current or past history of myocardial infarction (heart attack), stroke, transient ischemic attack (TIA), or angina pectoris.
• Known thrombophilia: Hereditary or acquired predisposition to venous or arterial thrombosis, including Factor V Leiden mutation, prothrombin G20210A mutation, protein C deficiency, protein S deficiency, antithrombin deficiency, or antiphospholipid antibodies.
• Multiple risk factors for VTE or ATE: Such as severe obesity (BMI >35 kg/m²), prolonged immobilization, major surgery with extended immobilization, smoking in women over 35 years, severe hypertension, severe dyslipoproteinemia, or diabetes mellitus with vascular complications.
• Migraine with aura: Current or past history of migraine accompanied by focal neurological symptoms (aura), at any age.
• Pancreatitis: Current or past pancreatitis associated with severe hypertriglyceridemia.
• Severe hepatic disease: Severe liver disease where liver function tests have not returned to normal, including liver tumors (benign or malignant).
• Sex steroid-sensitive malignancies: Known or suspected malignancies influenced by sex hormones, such as certain breast cancers or endometrial cancers.
• Undiagnosed vaginal bleeding: Any unexplained vaginal bleeding that has not been medically evaluated.
• Hypersensitivity: Known allergy to estetrol, drospirenone, or any of the excipients in Lydisilka.

Warnings and Precautions

Before prescribing Lydisilka, your healthcare provider should conduct a thorough assessment of your individual risk factors for venous and arterial thromboembolism. While clinical data suggest that estetrol-containing contraceptives may have a more favorable hemostatic profile compared to those containing ethinylestradiol, Lydisilka is still a combined hormonal contraceptive and carries the inherent risks associated with this class of medication. Key risk factors for VTE include increasing age, obesity (BMI >30 kg/m²), positive family history of VTE before age 45, prolonged immobilization (including long-haul travel), recent surgery, and the postpartum period.

Risk factors for arterial thromboembolism include smoking (especially in women over 35 — Lydisilka is strongly contraindicated in women over 35 who smoke), hypertension, hyperlipidemia, diabetes mellitus, obesity, migraine (especially with aura), and valvular heart disease. The combination of multiple risk factors may create a synergistic increase in overall thrombotic risk that exceeds the sum of the individual risks.

You should be vigilant for signs and symptoms of thromboembolism while using Lydisilka. Symptoms of deep vein thrombosis (DVT) include unilateral leg swelling, pain, or tenderness, especially in the calf, and warmth or discoloration of the affected leg. Symptoms of pulmonary embolism (PE) include sudden onset of unexplained shortness of breath, chest pain (which may worsen with deep breathing), cough (which may produce blood-tinged sputum), and rapid heartbeat. If you experience any of these symptoms, seek emergency medical care immediately and inform the medical team that you are using a combined hormonal contraceptive.

Lydisilka should be discontinued at least 4 weeks before elective surgery associated with an increased risk of thromboembolism and during prolonged immobilization. Use should not be resumed until at least 2 weeks after complete mobilization.

Cancer Risk

Epidemiological studies have shown a slightly increased risk of breast cancer in women using combined hormonal contraceptives. This increased risk appears to decline gradually over the 10 years after discontinuation. It is important to note that breast cancer is rare in women under 40, and the additional risk of breast cancer attributable to CHC use is small relative to the overall lifetime risk. Combined oral contraceptives also appear to reduce the risk of ovarian cancer and endometrial cancer, with the protective effect persisting for many years after discontinuation.

In rare cases, benign liver tumors and, even more rarely, malignant liver tumors have been reported in users of combined hormonal contraceptives. These tumors may lead to life-threatening intra-abdominal hemorrhage. A liver tumor should be considered in the differential diagnosis when severe upper abdominal pain, liver enlargement, or signs of intra-abdominal hemorrhage occur in women using Lydisilka.

Pregnancy and Breastfeeding

Lydisilka is not indicated during pregnancy. If pregnancy occurs while using Lydisilka, the medication should be discontinued immediately. Epidemiological studies with combined oral contraceptives containing ethinylestradiol have not shown an increased risk of birth defects in children born to women who used COCs before pregnancy, nor teratogenic effects when COCs were inadvertently taken during early pregnancy. The limited clinical data available for estetrol in pregnancy are insufficient to draw firm conclusions about potential risks.

Lydisilka is not recommended during breastfeeding. Combined hormonal contraceptives may reduce the quantity and alter the composition of breast milk. Small amounts of hormonal steroids and their metabolites may be excreted in breast milk, with potential effects on the nursing infant. The World Health Organization (WHO) recommends that breastfeeding women avoid combined hormonal contraceptives during the first 6 months postpartum and consider progestogen-only methods (such as the progestogen-only pill, implant, or hormonal IUD) or non-hormonal contraception as alternatives.

Other Precautions

Additional conditions that require careful consideration and monitoring during Lydisilka use include: depression or history of depression (hormonal contraceptives may influence mood), hypertriglyceridemia (drospirenone does not counteract estrogen-induced triglyceride increases), inflammatory bowel disease (Crohn’s disease, ulcerative colitis), systemic lupus erythematosus (SLE), hemolytic uremic syndrome, sickle cell disease, hereditary angioedema, chloasma (especially in women with a history of chloasma gravidarum), and conditions that may be aggravated by fluid retention. Drospirenone has mild anti-mineralocorticoid activity. In women with renal impairment, monitor serum potassium levels during the first treatment cycle, as drospirenone may increase potassium levels.

How Does Lydisilka Interact with Other Drugs?

Drug interactions with Lydisilka can occur through several mechanisms, the most clinically significant being the induction of hepatic enzymes (particularly CYP3A4 and UGT enzymes) that metabolize the hormonal components. Unlike monoclonal antibodies, which have minimal drug interaction potential, combined oral contraceptives like Lydisilka are small molecules that are subject to hepatic metabolism, and their efficacy can be significantly affected by concomitant medications.

The most important interactions are those that can reduce the plasma concentrations of estetrol and drospirenone, potentially compromising contraceptive efficacy. Women taking Lydisilka concurrently with enzyme-inducing drugs should use additional barrier contraception (such as condoms) during co-treatment and for a defined period after discontinuation, or consider switching to a non-hormonal contraceptive method.

The effect of enzyme inducers on estetrol pharmacokinetics is particularly important because estetrol undergoes limited hepatic metabolism compared to ethinylestradiol. Nevertheless, strong CYP3A4 inducers like rifampicin can still significantly reduce estetrol plasma concentrations. In a pharmacokinetic study, co-administration of rifampicin with estetrol/drospirenone reduced the area under the curve (AUC) of estetrol by approximately 55% and drospirenone by approximately 85%, making the contraceptive unreliable during co-treatment.

Hormonal contraceptives may also affect the metabolism of other drugs. Of particular clinical importance is the interaction with lamotrigine, an anti-epileptic medication commonly prescribed to women of childbearing age. Combined oral contraceptives can reduce lamotrigine plasma levels by inducing its glucuronidation via UGT1A4 enzymes, potentially leading to breakthrough seizures. Conversely, when the CHC is stopped or during the pill-free interval, lamotrigine levels may rise, increasing the risk of side effects. Women taking lamotrigine and Lydisilka require careful monitoring of lamotrigine serum levels and may need dose adjustments.

What Is the Correct Dosage of Lydisilka?

Lydisilka follows a 24/4 dosing regimen. This means each blister pack contains 28 tablets arranged in a specific order: 24 active pink film-coated tablets (each containing 3 mg drospirenone and 14.2 mg estetrol) followed by 4 inactive white placebo tablets. The tablets should be taken in the order indicated on the blister pack, one tablet per day, at approximately the same time each day, with or without food. Swallow the tablet whole with a small amount of water.

Starting Treatment

A withdrawal bleed usually occurs during the 4-day placebo tablet period. It typically starts 2–3 days after taking the last active tablet and may not have finished before the next pack is started. This is normal and expected.

Missed Tablets

The advice for missed tablets depends on which tablets were missed. Missing placebo (white) tablets is inconsequential — simply discard the missed placebo tablet(s) and continue as usual. However, missing active (pink) tablets can compromise contraceptive protection:

Vomiting or Severe Diarrhea

If vomiting or severe diarrhea occurs within 3–4 hours after taking an active tablet, absorption may not be complete. In this case, the same advice as for missed tablets applies. Take a replacement tablet from a spare blister pack as soon as possible. If vomiting or diarrhea persists for more than 24 hours, consult the instructions for missed tablets or contact your healthcare provider. Use additional barrier contraception if needed.

Overdose

There is limited experience with overdose of Lydisilka. Based on the general experience with combined oral contraceptives, symptoms of overdose may include nausea, vomiting, and, in young girls, slight vaginal bleeding. There is no specific antidote. Treatment is supportive and symptomatic. Drospirenone has anti-mineralocorticoid properties; serum electrolytes (particularly potassium and sodium) and signs of metabolic acidosis should be monitored in cases of overdose.

What Are the Side Effects of Lydisilka?

Like all medicines, Lydisilka can cause side effects, although not everybody gets them. The side effects observed in clinical trials and post-marketing surveillance are consistent with the known class effects of combined hormonal contraceptives, although the estetrol component may confer a somewhat different side effect profile compared to ethinylestradiol-containing pills. The following side effects have been reported, organized by frequency according to the European Medicines Agency (EMA) convention:

Irregular menstrual bleeding, including breakthrough bleeding and spotting, is the most commonly reported side effect and is particularly frequent during the first 1–3 months of use. In clinical trials with Lydisilka, approximately 15–20% of women experienced unscheduled bleeding during the first cycle, but this decreased substantially by cycle 3 and continued to improve with continued use. Absent withdrawal bleeding (no period during the placebo tablet phase) occurred in approximately 10–15% of cycles and is not harmful — it does not indicate pregnancy if the tablets have been taken correctly.

Mood changes, including depressed mood and mood swings, have been reported with all combined hormonal contraceptives. Depression is listed as a possible side effect, and women with a history of depression should be carefully monitored during Lydisilka use. If serious depression develops, the medication should be discontinued and an alternative contraceptive method should be recommended. However, establishing a clear causal relationship between CHC use and depression has been challenging in clinical studies, as many confounding factors influence mood.

Weight changes during Lydisilka use tend to be modest. In clinical trials, the mean weight change from baseline was approximately +0.5 kg over 13 cycles. The anti-mineralocorticoid properties of drospirenone may help counteract estrogen-related water retention, which is a common complaint with other CHCs. Some women may experience a slight weight gain, while others may notice no change or even a slight decrease in weight.

How Should You Store Lydisilka?

Lydisilka should be stored at room temperature, not exceeding 30°C (86°F). The tablets should be kept in the original blister packaging to protect them from light and moisture. Do not remove tablets from the blister until you are ready to take them. Do not store Lydisilka in the bathroom or other areas with high humidity, and do not refrigerate or freeze the tablets.

Keep this medicine out of the sight and reach of children. Do not use Lydisilka after the expiration date stated on the carton and blister. The expiration date refers to the last day of that month. Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.

If you notice that a tablet has changed color or appears damaged, do not take that tablet. Discard it safely and take the next tablet in the blister at your usual time, treating the damaged tablet as a missed tablet if it was an active tablet.

What Does Lydisilka Contain?

Active Tablets (Pink Film-Coated Tablets)

Each active pink film-coated tablet contains:

• Active substances: 3 mg drospirenone and estetrol monohydrate equivalent to 14.2 mg estetrol.
• Tablet core excipients: Lactose monohydrate, sodium starch glycolate (Type A), corn starch, povidone K30, magnesium stearate (E470b), adipic acid.
• Film coating: Hypromellose (E464), hydroxypropylcellulose (E463), talc (E553b), cottonseed oil (hydrogenated), titanium dioxide (E171), iron oxide red (E172).

Placebo Tablets (White Film-Coated Tablets)

Each placebo white film-coated tablet contains no active substances. The excipients are:

• Tablet core: Lactose monohydrate, corn starch, magnesium stearate (E470b).
• Film coating: Hypromellose (E464), hydroxypropylcellulose (E463), talc (E553b), cottonseed oil (hydrogenated), titanium dioxide (E171).

Lydisilka contains lactose monohydrate in both active and placebo tablets. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption should not take this medicine. The sodium content per tablet is less than 1 mmol (23 mg), making Lydisilka essentially sodium-free.

Medical Editorial Team

This article was written and reviewed by the iMedic Medical Editorial Team, a group of licensed specialist physicians with expertise in gynecology, reproductive medicine, and clinical pharmacology. All content follows the GRADE evidence framework and is reviewed according to international medical standards.