Dienoval (Estradiol Valerate/Dienogest)

What Is Dienoval and What Is It Used For?

Dienoval belongs to the group of combined oral contraceptives (COCs), commonly known as "the pill." It contains two active hormones: estradiol valerate, a natural estrogen, and dienogest, a progestogen. Together, these hormones work to prevent pregnancy through multiple mechanisms: they suppress ovulation (the release of an egg from the ovary), alter the cervical mucus to make it more difficult for sperm to reach the egg, and modify the uterine lining to reduce the likelihood of implantation.

What sets Dienoval apart from most other combined oral contraceptives is its use of estradiol valerate rather than synthetic ethinylestradiol (EE). Estradiol valerate is a prodrug that is rapidly converted in the body to 17-beta-estradiol, the same form of estrogen naturally produced by the ovaries. This natural estrogen component is thought to have a more favorable metabolic profile, potentially resulting in fewer estrogen-related side effects such as headaches, breast tenderness, and nausea, although individual responses vary.

Dienoval is a generic version of Qlaira (known as Natazia in some markets), the original brand-name product developed by Bayer. It was approved through a decentralized regulatory procedure in the European Union after bioequivalence studies confirmed that Dienoval produces the same blood levels of active hormones as the reference product. It is manufactured by Laboratorios Leon Farma S.A. in Spain.

Approved Indications

Dienoval is officially approved for two indications:

1. Oral contraception: Prevention of pregnancy in women of childbearing age.
2. Treatment of heavy menstrual bleeding (menorrhagia): Specifically in women without organic pathology (such as fibroids or endometriosis) who desire oral contraception. Clinical studies showed that after 6 months of treatment, median menstrual blood loss decreased by approximately 88%, from 142 mL to 17 mL per cycle.

How the Quadriphasic Regimen Works

Unlike monophasic pills that deliver the same dose of hormones every day, Dienoval follows a quadriphasic (four-phase) dosing regimen. This means the amount of estradiol valerate and dienogest changes across the 28-day cycle, designed to more closely mimic the natural rise and fall of hormones during a menstrual cycle. The pack contains 26 active tablets of varying strengths and 2 inactive (placebo) tablets:

One tablet should be taken at approximately the same time every day, regardless of meals. Each pack is taken continuously, with the next pack started immediately after finishing the previous one, without any tablet-free break. A withdrawal bleed (similar to a period) typically occurs during the placebo tablet days or the early days of the next pack.

What Should You Know Before Taking Dienoval?

Before starting Dienoval, your healthcare provider will assess your medical history, family history, and current health status to determine whether this contraceptive is appropriate for you. Combined oral contraceptives are not suitable for everyone, and certain conditions significantly increase the risk of serious adverse events, particularly blood clots (venous thromboembolism) and cardiovascular complications.

Contraindications

You should not take Dienoval if you have any of the following conditions:

• Current or history of venous thromboembolism (VTE): Deep vein thrombosis (DVT) or pulmonary embolism (PE), whether currently present or in the past.
• Current or history of arterial thromboembolism: Myocardial infarction (heart attack), stroke, or transient ischemic attack (TIA).
• Known hereditary or acquired thrombophilia: Including Factor V Leiden mutation, prothrombin mutation, protein C deficiency, protein S deficiency, or antithrombin III deficiency.
• Migraine with aura: Current or past history of migraine accompanied by focal neurological symptoms.
• Diabetes mellitus with vascular complications: Including diabetic retinopathy, nephropathy, or neuropathy.
• Severe or multiple cardiovascular risk factors: Such as severe hypertension (systolic ≥160 mmHg or diastolic ≥100 mmHg) or severe dyslipoproteinemia.
• Severe hepatic disease: Current or history of severe liver disease, as long as liver function values have not returned to normal. This includes liver tumors (benign or malignant).
• Known or suspected sex-steroid-influenced malignancies: Such as breast cancer or genital cancer.
• Undiagnosed vaginal bleeding.
• History of cholestatic jaundice during pregnancy or prior hormonal contraceptive use.
• Hypersensitivity to estradiol valerate, dienogest, or any excipients.
• Concomitant use with certain hepatitis C antiviral combinations (ombitasvir/paritaprevir/ritonavir or glecaprevir/pibrentasvir).

Warnings and Precautions

The risk of blood clots is increased by several factors, and you should discuss these with your doctor before starting Dienoval:

• Smoking: Strongly increases the risk of serious cardiovascular side effects. Women who smoke and are over 35 years old should not use combined oral contraceptives.
• Obesity: Body mass index (BMI) above 30 kg/m² increases VTE risk.
• Prolonged immobility: Extended bed rest, long-distance travel, or major surgery may require temporary discontinuation.
• Age: The risk of VTE increases with age, particularly after 35 years.
• Family history: A close relative who has had a blood clot before age 50 may indicate hereditary thrombophilia.
• Postpartum period: The risk of VTE is elevated for several weeks after delivery.

Additional precautions apply if you have a history of depression, inflammatory bowel disease (Crohn's disease or ulcerative colitis), systemic lupus erythematosus (SLE), hemolytic uremic syndrome, sickle cell disease, epilepsy, or hereditary angioedema. Your doctor may recommend more frequent monitoring or an alternative contraceptive method in these cases.

Pregnancy and Breastfeeding

Dienoval is not indicated during pregnancy. If pregnancy occurs while taking Dienoval, the medication should be discontinued immediately. However, epidemiological studies have not shown an increased risk of birth defects in children born to women who used combined oral contraceptives inadvertently during early pregnancy.

Dienoval is not recommended during breastfeeding. Combined oral contraceptives may reduce the quantity and alter the composition of breast milk. Small amounts of the active substances or their metabolites may be excreted in breast milk. Women who are breastfeeding are generally advised to use progestogen-only methods of contraception instead.

How Does Dienoval Interact with Other Drugs?

Drug interactions with Dienoval can either reduce its contraceptive effectiveness (leading to breakthrough bleeding or unintended pregnancy) or increase the blood levels of its hormonal components (potentially increasing side effects). Understanding these interactions is critical for maintaining both safety and efficacy.

Major Interactions — Reduced Contraceptive Effectiveness

Substances that induce hepatic enzymes (particularly CYP3A4) can increase the metabolism and clearance of Dienoval's hormones, significantly reducing their blood levels and contraceptive protection. Rifampicin, one of the most potent enzyme inducers, has been shown to decrease dienogest blood levels by 83% and estradiol levels by 44%.

Minor Interactions — Increased Hormone Levels

Substances that inhibit CYP3A4 may increase blood levels of Dienoval's hormonal components. While this does not reduce contraceptive effectiveness, it may increase the likelihood of side effects.

• Ketoconazole (strong CYP3A4 inhibitor): Increased dienogest AUC by 2.9-fold and estradiol by 1.6-fold.
• Erythromycin (moderate CYP3A4 inhibitor): Increased dienogest AUC by 1.6-fold.
• Grapefruit juice: May modestly increase estrogen levels through intestinal CYP3A4 inhibition.

Effects of Dienoval on Other Medications

Dienoval may also affect the metabolism of other drugs you are taking:

• Cyclosporine: Dienoval may increase cyclosporine plasma levels, requiring monitoring of drug levels and possible dose adjustment.
• Lamotrigine: Combined oral contraceptives may decrease lamotrigine levels by up to 50%, potentially reducing seizure control. Lamotrigine dose adjustments may be necessary when starting or stopping Dienoval.

What Is the Correct Dosage of Dienoval?

Dienoval uses a unique quadriphasic dosing schedule that requires careful attention to the order of tablets. Each blister pack is clearly marked with the day of the cycle, and tablets must be taken in the correct sequence. Swallow each tablet whole with a small amount of water, with or without food, at approximately the same time each day.

Adults

Children and Adolescents

Dienoval is intended for women of childbearing age. It is not indicated before menarche (the onset of menstruation). For adolescents who have reached menarche, no dose adjustment is required. Clinical data in adolescents under 18 years are limited, and the safety and efficacy profile is expected to be comparable to that in adult women.

Elderly

Dienoval is not indicated after menopause. Combined oral contraceptives are intended for women of reproductive age only.

Missed Dose

Overdose

There are no reports of serious harmful effects from an overdose of combined oral contraceptives. Symptoms that may occur include nausea, vomiting, and, in young girls, slight vaginal bleeding. No specific antidote exists; treatment is symptomatic and supportive. If an overdose is suspected, contact a healthcare provider or poison control center.

What Are the Side Effects of Dienoval?

Like all medications, Dienoval can cause side effects, although not everyone experiences them. Most side effects are mild and tend to decrease over the first few months of use as the body adjusts to the hormonal changes. However, some side effects can be serious and require immediate medical attention.

The following side effect frequencies are based on clinical trial data and post-marketing surveillance. The frequency categories follow the standard medical classification system:

The risk of venous thromboembolism is highest during the first year of use or when restarting combined oral contraceptives after a break of four weeks or more. While all COCs carry this risk, Dienoval's use of natural estradiol valerate rather than synthetic ethinylestradiol may be associated with a somewhat lower VTE risk, although definitive comparative data are limited.

Long-term use of combined oral contraceptives has been associated with a slightly increased risk of cervical cancer and breast cancer, though the absolute risk increase is small and must be weighed against the protective effects, including a reduced risk of ovarian and endometrial cancer. Discuss the benefit-risk balance with your healthcare provider.

How Should You Store Dienoval?

Proper storage of Dienoval is important to ensure the tablets retain their full potency and effectiveness throughout their shelf life. Combined oral contraceptive tablets are sensitive to environmental conditions, and degradation of the active ingredients could reduce contraceptive protection.

• Temperature: Store below 25°C (77°F). Do not refrigerate or freeze.
• Light protection: Keep the tablets in the original blister packaging to protect from light exposure.
• Moisture: Store in a dry place. Do not remove tablets from the blister until you are ready to take them.
• Children: Keep out of the reach and sight of children.
• Expiry date: Do not use Dienoval after the expiry date stated on the packaging (EXP). The expiry date refers to the last day of that month.
• Disposal: Do not dispose of medications via wastewater or household waste. Return unused medications to your pharmacy for safe disposal, in accordance with local environmental regulations.

If you travel to hot climates, keep the medication in a cool bag or at room temperature. Avoid leaving it in direct sunlight, in a car, or near heat sources. If you suspect the tablets have been exposed to extreme temperatures for a prolonged period, consult your pharmacist about whether they are still safe to use.

What Does Dienoval Contain?

Active Ingredients

The active substances vary by tablet phase, as described in the dosing schedule above:

• Estradiol valerate: 1 mg, 2 mg, or 3 mg depending on the tablet phase. Estradiol valerate is a prodrug of 17-beta-estradiol, the primary natural estrogen produced by the ovaries. It has a bioavailability of approximately 3% due to extensive first-pass hepatic metabolism, with a terminal half-life of 13–20 hours (including enterohepatic recirculation).
• Dienogest: 2 mg or 3 mg depending on the tablet phase (absent in Phase 1, Phase 4, and placebo tablets). Dienogest is a 19-nortestosterone-derived progestogen with potent progestogenic activity and approximately one-third the antiandrogenic activity of cyproterone acetate. It has a bioavailability of approximately 91% and a half-life of about 11 hours, metabolized primarily by CYP3A4.

Inactive Ingredients (Excipients)

The tablet cores and film coatings contain the following inactive ingredients, which serve as binders, fillers, lubricants, and coloring agents:

• Lactose monohydrate
• Maize starch
• Pregelatinized maize starch
• Povidone K25
• Magnesium stearate
• Hypromellose (coating agent)
• Macrogol 6000
• Talc
• Titanium dioxide (E171)
• Iron oxide yellow (E172) — in dark yellow and light yellow tablets
• Iron oxide red (E172) — in medium red and dark red tablets