Qlaira^® (Tablet kit) Instructions for Use

Marketing Authorization Holder

Bayer, AG (Germany)

Manufactured By

Bayer Weimar, GmbH & Co. KG (Germany)

ATC Code

G03AB08 (Dienogest and estradiol)

Active Substances

Estradiol valerate (Rec.INN registered by WHO)

Dienogest (Rec.INN registered by WHO)

Dosage Form

Qlaira®

Kit of film-coated tablets: 28 or 84 pcs, incl.: dark yellow 3 mg tablets: 2 pcs, pink 2 mg+2 mg tablets: 5 pcs, pale yellow 2 mg+3 mg tablets: 17 pcs, red 1 mg tablets: 2 pcs, white (placebo) tablets: 2 pcs.

Dosage Form, Packaging, and Composition

Kit of film-coated tablets , of five types.

Dark yellow film-coated tablets, round, biconvex, with the engraving “DD” in a regular hexagon on one side; (2 pcs. in a blister).

Excipients : lactose monohydrate – 48.36 mg, corn starch – 14.4 mg, pregelatinized corn starch – 9.6 mg, povidone 25 – 4 mg, magnesium stearate – 0.64 mg.

Shell composition hypromellose – 1.5168 mg, macrogol 6000 – 0.3036 mg, talc – 0.3036 mg, titanium dioxide – 0.584 mg, iron oxide yellow dye – 0.292 mg.

Pink film-coated tablets, round, biconvex, with the engraving “DJ” in a regular hexagon on one side; (5 pcs. in a blister).

Excipients : lactose monohydrate – 47.36 mg, corn starch – 14.4 mg, pregelatinized corn starch – 9.6 mg, povidone 25 – 4 mg, magnesium stearate – 0.64 mg.

Shell composition hypromellose – 1.5168 mg, macrogol 6000 – 0.3036 mg, talc – 0.3036 mg, titanium dioxide – 0.83694 mg, iron oxide red dye – 0.03906 mg.

Pale yellow film-coated tablets, round, biconvex, with the engraving “DH” in a regular hexagon on one side; (17 pcs. in a blister).

Excipients : lactose monohydrate – 46.36 mg, corn starch – 14.4 mg, pregelatinized corn starch – 9.6 mg, povidone 25 – 4 mg, magnesium stearate – 0.64 mg.

Shell composition hypromellose – 1.5168 mg, macrogol 6000 – 0.3036 mg, talc – 0.3036 mg, titanium dioxide – 0.83694 mg, iron oxide yellow dye – 0.03906 mg.

Red film-coated tablets, round, biconvex, with the engraving “DN” in a regular hexagon on one side; (2 pcs. in a blister).

Excipients : lactose monohydrate – 50.36 mg, corn starch – 14.4 mg, pregelatinized corn starch – 9.6 mg, povidone 25 – 4 mg, magnesium stearate – 0.64 mg.

Shell composition hypromellose – 1.5168 mg, macrogol 6000 – 0.3036 mg, talc – 0.3036 mg, titanium dioxide – 0.5109 mg, iron oxide red dye – 0.3651 mg.

White film-coated tablets (placebo), round, biconvex, with the engraving “DT” in a regular hexagon on one side; (2 pcs. in a blister).

Excipients (per 1 tab. (placebo)) lactose monohydrate – 52.1455 mg, corn starch – 24 mg, povidone 25 – 3.0545 mg, magnesium stearate – 0.8 mg.

Shell composition (per 1 tab. (placebo)) hypromellose – 1.0112 mg, talc – 0.2024 mg, titanium dioxide – 0.7864 mg.

28 pcs. – blisters (1) – blister books (1) with a self-adhesive intake calendar – film^×.
28 pcs. – blisters (1) – blister books (3) with a self-adhesive intake calendar – film^×.

^× A packaging sticker is applied to the transparent film.

Clinical-Pharmacological Group

Contraceptive combined drug (estrogen + progestogen)

Pharmacotherapeutic Group

Combined contraceptive agent (estrogen + gestagen)

Pharmacological Action

A combined (estrogen + progestogen) oral contraceptive (COC). The contraceptive effect of COCs is carried out through complementary mechanisms, the most important of which are suppression of ovulation; increased viscosity of cervical secretion, preventing the penetration of sperm into the uterine cavity, and changes in the endometrium that prevent the implantation of a fertilized egg. In women taking COCs, the pain and intensity of menstrual-like bleeding are reduced, thereby reducing the risk of iron deficiency anemia.

The combination of dienogest and estradiol valerate has a beneficial effect on the endometrium, which may be applicable for the treatment of heavy and/or prolonged menstrual bleeding without organic pathology. Studies have demonstrated a clinically and statistically significant reduction in menstrual blood loss. This was accompanied by a statistically significant improvement in iron metabolism parameters (hemoglobin, hematocrit, and ferritin).

In combination with dienogest, estradiol valerate demonstrates an increase in HDL, while the concentration of LDL cholesterol decreases somewhat.

Dienogest is a derivative of norethisterone, does not have androgenic, but exhibits antiandrogenic activity, which is approximately 1/3 of the activity of cyproterone acetate. Despite low affinity for progesterone receptors (dienogest binds to progesterone receptors in the uterus with a relative affinity of only 10%), dienogest has a strong progestogenic effect in vivo. Dienogest does not have significant androgenic, mineralocorticoid or glucocorticoid activity in vivo.

Estradiol valerate is a precursor of natural human 17β-estradiol (1 mg of estradiol valerate corresponds to 0.76 mg of 17β-estradiol).

When used correctly, the Pearl index (an indicator reflecting the frequency of pregnancy in 100 women during one year of contraceptive use) is less than 1. If a dose is missed or used incorrectly, the Pearl index may increase.

Pharmacokinetics

Dienogest

After oral administration, dienogest is rapidly and almost completely absorbed. C_max in plasma is 90.5 ng/ml and is reached approximately 1 hour after oral administration of the combination of 2 mg estradiol valerate + 3 mg dienogest. Bioavailability is about 91%. The pharmacokinetics of dienogest in the dose range from 1 to 8 mg is dose-dependent. Simultaneous food intake does not have a clinically significant effect on the rate and extent of absorption of dienogest. A relatively large (10%) portion of circulating dienogest is in the unbound form, while about 90% is non-specifically bound to albumin. Dienogest does not bind to SHBG and corticosteroid-binding globulin (CBG). For this reason, there is no possibility of displacing testosterone from its binding to SHBG or cortisol from its binding to CBG. Any influence on the physiological processes of transport of endogenous steroids is therefore unlikely. The V_d of dienogest at equilibrium concentration is 46 L after intravenous administration of 85 μg of tritium-labeled dienogest. The pharmacokinetics of dienogest is independent of SHBG concentration. C_ss is reached after 3 days of administration of the same dose of 3 mg dienogest in combination with 2 mg estradiol valerate. C_min, C_max and the average plasma concentrations of dienogest at steady state are 11.8, 82.9 and 33.7 ng/ml, respectively. The mean accumulation ratio for AUC_{0-24 h} is 1.24. Dienogest is almost completely metabolized, passing through known pathways of sex hormone metabolism (hydroxylation, conjugation), forming predominantly pharmacologically inactive metabolites. Metabolites are excreted very quickly, so the predominant fraction in plasma is unchanged dienogest. Total clearance after intravenous administration of tritium-labeled dienogest is 5.1 L/h. T_1/2 of dienogest from plasma is approximately 11 hours. After oral administration at a dose of 0.1 mg/kg, dienogest is excreted in the form of metabolites, which are excreted by the kidneys and through the intestines in a ratio of approximately 3:1. After oral administration, 42% of the dose is excreted within the first 24 hours, and 63% within 6 days by renal excretion. After 6 days, a total of 86% of the dose is excreted by the kidneys and through the intestines.

Estradiol valerate

After oral administration, estradiol valerate is rapidly and completely absorbed. Cleavage into estradiol and valeric acid occurs during absorption in the gastrointestinal mucosa or during the “first pass” through the liver, resulting in the formation of estradiol and its metabolites – estrone and estriol. C_max of estradiol in plasma, equal to 70.6 pg/ml, is reached between 1.5 and 12 hours after a single oral administration of the combination of 3 mg estradiol valerate, on the 1st day of the course. Simultaneous food intake does not have a clinically significant effect on the rate and extent of absorption of estradiol valerate. In plasma, 38% of estradiol is bound to SHBG, 60% to albumin, and 2-3% circulates in unbound form. Estradiol may slightly increase the concentration of SHBG in plasma; this effect is dose-dependent. On the 21st day of the intake cycle, the SHBG concentration was approximately 148% of the baseline, and by the 28th day (end of hormone-free tablet intake) it decreased to approximately 141% of the baseline. The apparent V_d after intravenous administration is 1.2 L/kg. The pharmacokinetics of estradiol is influenced by SHBG concentration. In women, the measured plasma concentration of estradiol represents the sum of endogenous estradiol and estradiol supplied by the intake of this combination. During the phase of taking the drug containing 2 mg estradiol valerate + 3 mg dienogest, C_max and the average plasma concentration of estradiol at steady state are 66.0 and 51.6 pg/ml, respectively. Throughout the entire 28-day cycle, stable C_min of estradiol were maintained in the range from 28.7 to 64.7 pg/ml. Valeric acid is metabolized very quickly. After oral administration, approximately 3% of the dose becomes directly bioavailable as estradiol. Estradiol undergoes an intensive “first pass” effect through the liver, and a significant part of the administered dose is metabolized already in the gastrointestinal mucosa. Together with presystemic metabolism in the liver, about 95% of the orally administered dose is metabolized before entering the systemic circulation. The main metabolites are estrone, estrone sulfate and estrone glucuronide. Due to the large circulating pool of estrogen sulfates and glucuronides, as well as enterohepatic recirculation, the T_1/2 of estradiol in the terminal phase after oral administration is a complex parameter that depends on all these processes and is in the range of about 13-20 hours. Estradiol and its metabolites are excreted mainly by the kidneys, with about 10% excreted through the intestines.

Indications

Oral contraception; therapy of heavy and/or prolonged menstrual bleeding without organic causes in women wishing to use oral contraceptives.

ICD codes

Dosage Regimen

Take one tablet orally once daily at approximately the same time each day.

Follow the sequential order indicated on the blister pack: start with the two dark yellow tablets, then the five pink tablets, followed by the seventeen pale yellow tablets, the two red tablets, and finish with the two white placebo tablets.

Begin a new 28-day blister pack immediately after finishing the previous one, without a tablet-free interval. Withdrawal bleeding typically occurs during the days of placebo tablet intake.

For first-time users or those restarting after a cycle break, begin on the first day of the menstrual cycle.

If switching from another combined hormonal contraceptive, start Qlaira^® the day after the last active tablet of the previous product; no additional contraceptive protection is required.

After a first-trimester abortion, start immediately; no additional contraceptive protection is needed.

Following a delivery or second-trimester abortion, start no earlier than day 21-28 postpartum or post-abortion; if started later, use a barrier method for the first seven days of tablet intake.

If a vomiting or severe diarrhea episode occurs within 3-4 hours of taking an active tablet, treat it as a missed tablet and follow the respective instructions.

If a hormone-containing tablet is missed and the delay is less than 12 hours, take the missed tablet immediately and continue the pack as usual; contraceptive protection is not reduced.

If the delay is more than 12 hours, contraceptive protection may be reduced. Take the most recently missed tablet immediately, even if it means taking two tablets in one day, and discard any other overdue tablets. Continue taking the remaining tablets at the usual time. Use a barrier method for the next seven days. If these seven days run beyond the active tablets in the current pack, omit the placebo tablets from the current pack and start the next pack immediately.

Manage breakthrough bleeding by continuing the pack; if it persists for several cycles or starts after previous regular cycles, consult a physician to rule out other causes.

Adverse Reactions

Infections and infestations: uncommon – fungal infection, unspecified vaginal infection, candidal vulvovaginitis; rare – candidiasis, labial herpes, ocular histoplasmosis syndrome, herpes zoster, urinary tract infection, bacterial vaginitis, pelvic inflammatory disease.

Metabolism and nutrition disorders: uncommon – increased appetite; rare – fluid retention, hypertriglyceridemia.

Nervous system disorders: common – headache (including tension headache), sinus pain; uncommon – dizziness, migraine with aura, migraine without aura; rare – attention disturbance, paresthesia, vertigo.

Psychiatric disorders: uncommon – depression/depressed mood, decreased libido, mental disorder, mood swings, affective lability, insomnia; rare – aggressiveness, anxiety, dysphoria, increased libido, nervousness, restlessness, sleep disorder, stress.

Eye disorders rare – contact lens intolerance, dry eye mucosa, eyelid edema.

Cardiac and vascular disorders: uncommon – increased blood pressure, “hot flashes”; rare – bleeding from varicose veins, decreased blood pressure, pain along the veins, venous thromboembolism, arterial thromboembolism, superficial phlebitis, thrombophlebitis, myocardial infarction, palpitations.

Gastrointestinal disorders: common – abdominal pain, abdominal distension, nausea; uncommon – diarrhea, vomiting; rare – constipation, dyspepsia, gastroesophageal reflux, dry mouth.

Hepatobiliary disorders: uncommon – increased activity of liver enzymes (ALT, AST, GGT); rare – focal nodular hyperplasia of the liver, chronic cholecystitis.

Skin and subcutaneous tissue disorders: common – acne; uncommon – alopecia, pruritus (including generalized pruritus and pruritic rash), rash (including maculopapular rash), hyperhidrosis; rare – allergic skin reaction, including allergic dermatitis and urticaria, chloasma, dermatitis, hirsutism, hypertrichosis, neurodermatitis, pigmentation disorder, seborrhea, skin lesion, including impaired skin turgor.

Musculoskeletal and connective tissue disorders: uncommon – muscle spasms; rare – back pain, feeling of heaviness, jaw pain.

Renal and urinary disorders rare – pain in the urinary tract area.

Reproductive system and breast disorders: common – absence of menstrual-like bleeding, breast discomfort, breast pain, nipple tenderness, nipple pain, painful menstrual-like bleeding, irregular menstrual-like bleeding (metrorrhagia); uncommon – breast enlargement, diffuse breast thickening, cervical epithelial dysplasia, dysfunctional uterine bleeding, dyspareunia, fibrocystic mastopathy, heavy menstrual-like bleeding, ovarian cyst, pelvic pain, premenstrual-like syndrome, uterine leiomyoma, uterine muscle spasm, vaginal discharge, dryness of the vulvar and vaginal mucosa, vaginal spotting/bleeding, including spotting; rare – benign neoplasm in the breast, including breast cyst, breast cancer in situ, cervical polyp, bleeding during sexual intercourse, galactorrhea, scanty bloody menstrual-like discharge, delayed menstrual-like bleeding, ovarian cyst rupture, burning sensation in the vagina, vaginal odor, vulvovaginal discomfort.

Blood and lymphatic system disorders rare – lymphadenopathy.

Respiratory, thoracic and mediastinal disorders: rare – bronchial asthma, dyspnea, epistaxis.

General disorders and administration site conditions: common – weight increased; uncommon – irritability, peripheral edema, weight decreased, fatigue; rare – chest pain, malaise, pyrexia.

Adverse reactions with very low frequency or delayed onset of symptoms associated with COC use

Neoplasms: in women using COCs, the frequency of detection of breast cancer (BC) is slightly increased. Since BC is rare in women under 40 years of age, the excess frequency is insignificant in relation to the overall risk of BC. A causal relationship between the occurrence of BC and the use of COCs has not been established. Liver tumors (benign and malignant).

Other conditions: arterial and venous thrombosis and thromboembolic complications; erythema nodosum, erythema multiforme; breast discharge; hypertriglyceridemia (increased risk of pancreatitis when using COCs); increased blood pressure; onset or worsening of conditions for which the association with COC use is not indisputable: jaundice and/or pruritus associated with cholestasis; gallstone formation; porphyria; systemic lupus erythematosus; hemolytic-uremic syndrome; Sydenham’s chorea; herpes of pregnancy; hearing loss associated with otosclerosis; epilepsy; in women with hereditary angioedema, exogenous estrogens may cause or worsen symptoms of angioedema; liver function disorders; impaired glucose tolerance or effect on peripheral insulin resistance; Crohn’s disease, ulcerative colitis; chloasma; hypersensitivity (including symptoms such as rash, urticaria).

Contraindications

Venous thrombosis or thromboembolism (VTE), including deep vein thrombosis (DVT), pulmonary embolism (PE), currently or in history; arterial thrombosis or thromboembolism (ATE), including myocardial infarction, stroke; prodromal conditions, including transient ischemic attack, angina pectoris; identified hereditary or acquired predisposition to VTE or ATE, including resistance to activated protein C, hyperhomocysteinemia, antithrombin III deficiency, protein C deficiency, protein S deficiency, antiphospholipid antibodies (anticardiolipin antibodies, lupus anticoagulant); presence of a high risk of developing VTE and ATE due to the presence of multiple risk factors or the presence of one serious risk factor, such as diabetes mellitus with diabetic angiopathy, uncontrolled arterial hypertension, severe dyslipoproteinemia; major surgical interventions with prolonged immobilization or extensive trauma; migraine with focal neurological symptoms currently or in history; severe liver diseases (until liver function tests normalize) currently or in history; liver tumors (benign and malignant) currently or in history; hormone-dependent malignant neoplasms of the genital organs or mammary glands (including suspected ones); vaginal bleeding of unknown etiology; pregnancy (including suspected), breastfeeding period; hypersensitivity to dienogest and/or estradiol valerate.

Use with caution

Risk factors for thrombosis and thromboembolism (smoking, obesity, dyslipoproteinemia, controlled arterial hypertension, migraine without focal symptoms, uncomplicated heart valve diseases, cardiac arrhythmia, major surgical interventions without prolonged immobilization); other diseases in which peripheral circulation disorders may be noted (diabetes mellitus, systemic lupus erythematosus, hemolytic-uremic syndrome, Crohn’s disease and ulcerative colitis, sickle cell anemia); hereditary angioedema; hypertriglyceridemia; diseases that first appeared or worsened during pregnancy or against the background of previous use of sex hormones (for example, cholestatic jaundice, cholestatic pruritus, cholelithiasis, otosclerosis with hearing impairment, porphyria, herpes gestations, Sydenham’s chorea); postpartum period.

Use in Pregnancy and Lactation

Contraindicated for use during pregnancy and breastfeeding.

Use in Hepatic Impairment

Contraindicated for use in severe liver diseases (until liver function tests normalize) currently or in history; liver tumors (benign and malignant) currently or in history.

Use in Renal Impairment

No specific studies of this combination in patients with renal impairment have been conducted. Available data do not suggest a dosage regimen adjustment in such patients.

Pediatric Use

Data on efficacy and safety in girls under 18 years of age are absent.

Geriatric Use

Not applicable. Use is not indicated after menopause.

Special Precautions

Results of epidemiological studies indicate a relationship between the use of combined oral contraceptives (COCs) and an increased incidence of venous and arterial thrombosis and thromboembolism (such as deep vein thrombosis (DVT), pulmonary embolism (PE), myocardial infarction, and cerebrovascular disorders). These diseases are rare.

An increased risk is present after initial use of COCs or resumption of use after a break of 4 weeks or more. The highest risk of developing venous thromboembolism (VTE) is observed in the first year of COC use, mainly during the first 3 months.

The use of any COC increases the risk of VTE compared with non-use. Drugs containing levonorgestrel, norgestimate, or norethisterone are associated with the lowest risk of VTE. Limited data suggest that the drug containing this combination may have a VTE risk in the same range. The decision to use this combination rather than one of the components with the lowest VTE risk should be made only after discussion with the woman, ensuring that she fully understands the risk of VTE associated with COC use; the influence of her existing risk factors on the VTE risk; and that the risk of developing VTE is highest in the first year of COC use.

VTE can be life-threatening or fatal (in 1-2% of cases).

Very rarely, thrombosis of other blood vessels occurs with COC use, for example, hepatic, mesenteric, renal, cerebral veins and arteries, or retinal vessels.

A small increase (by a factor of 1.24) in the risk of developing breast cancer (BC) has been identified in women taking COCs. The increased risk gradually disappears within 10 years after stopping COCs. Since BC is rare in women under 40 years of age, the increase in the number of BC diagnoses in women currently taking or recently taking COCs is small relative to the overall risk of developing this disease. Its connection with COC use has not been proven. The observed increase in the risk of BC may be due not only to earlier diagnosis of BC but also to the biological effect of sex hormones or a combination of these two factors. In women who have ever used COCs, earlier clinical stages of BC are detected compared to women who have never used them.

In rare cases, the development of benign, and in extremely rare cases, malignant liver tumors has been observed during the use of COCs, which in some cases led to life-threatening intra-abdominal bleeding. In case of severe abdominal pain, liver enlargement, or signs of intra-abdominal bleeding, this should be considered during differential diagnosis.

In women with hypertriglyceridemia (or a family history of this condition), the risk of developing pancreatitis may increase while taking COCs.

Although a slight increase in blood pressure (BP) has been observed in many women taking COCs, clinically significant increases have been rare. However, if a persistent, clinically significant increase in BP develops during COC use, COCs should be discontinued and treatment for arterial hypertension initiated. Use may be resumed if normal BP values are achieved with antihypertensive therapy.

The following conditions have been reported to develop or worsen both during pregnancy and during COC use, but their connection with COC use has not been proven: jaundice and/or pruritus associated with cholestasis; gallstone formation; porphyria; systemic lupus erythematosus; hemolytic-uremic syndrome; Sydenham’s chorea; herpes gestations; hearing loss associated with otosclerosis.

Cases of worsening of endogenous depression, epilepsy, Crohn’s disease, and ulcerative colitis during COC use have also been described.

In women with hereditary forms of angioedema, exogenous estrogens may cause or worsen symptoms of angioedema.

Acute or chronic liver function disorders may require discontinuation of the contraceptive until liver function tests normalize. Recurrence of cholestatic jaundice that first developed during a previous pregnancy or previous use of sex hormones requires discontinuation of COCs.

Although COCs can affect insulin resistance and glucose tolerance, there is generally no need to adjust the dose of hypoglycemic drugs in patients with diabetes using low-dose COCs (<0.05 mg ethinyl estradiol). Nevertheless, women with diabetes should be closely monitored while taking COCs.

Since estrogens can cause fluid retention, women with chronic heart or renal failure should also be under close medical supervision.

Chloasma may sometimes develop, especially in women with a history of chloasma during pregnancy. Women prone to chloasma while taking this drug should avoid prolonged sun exposure and ultraviolet radiation.

Use of this combination may affect the results of some laboratory tests, including biochemical parameters of liver, thyroid, adrenal, and kidney function, the concentration of transport proteins in plasma, e.g., corticosteroid-binding globulin (CBG) and lipid/lipoprotein fractions, parameters of carbohydrate metabolism and hemostasis. These changes usually remain within laboratory normal ranges.

The effectiveness of the contraceptive may be reduced in the following cases: when missing a dose containing hormones, gastrointestinal disorders at the time of intake, or as a result of drug interactions.

During the use of this combination, especially in the first months of use, irregular menstrual-like bleeding (“spotting” or “breakthrough” uterine bleeding) may occur. Therefore, evaluation of any irregular menstrual-like bleeding should be performed only after an adaptation period, which is approximately 3 menstrual-like cycles.

If irregular menstrual-like bleeding recurs or occurs for the first time after previous regular cycles, the possibility of non-hormonal causes should be considered and a thorough examination should be performed to rule out malignant neoplasms or pregnancy. Such measures may include diagnostic curettage.

Drug Interactions

Interaction with drugs that induce hepatic microsomal enzymes is possible, which may increase the clearance of sex hormones, which in turn can lead to breakthrough uterine bleeding and/or reduced contraceptive effect.

Induction of hepatic microsomal enzymes can be observed within a few days of concomitant use of inducing drugs and this combination and persist for up to 4 weeks after its cessation.

Women receiving treatment with drugs that induce hepatic microsomal enzymes should temporarily use a barrier method of contraception or choose another non-hormonal method of contraception in addition to taking this combination.

Women receiving long-term treatment with drugs that induce hepatic microsomal enzymes are recommended to consider another effective non-hormonal method of contraception.

Substances that increase the clearance of COCs (reducing effectiveness by inducing enzymes): phenytoin, barbiturates, bosentan, primidone, carbamazepine, rifampicin, and possibly also oxcarbazepine, topiramate, felbamate, griseofulvin, as well as preparations containing St. John’s wort (Hypericum perforatum).

Concomitant administration of rifampicin with this combination containing estradiol valerate and dienogest led to a significant decrease in the steady-state concentration and systemic exposure of dienogest and estradiol. The systemic exposure of dienogest and estradiol at steady-state, measured as AUC_{0-24 h}, decreased by 83% and 44%, respectively.

Substances with variable effects on the clearance of COCs when used concomitantly with COCs, many HIV or hepatitis C virus protease inhibitors and non-nucleoside reverse transcriptase inhibitors can either increase or decrease the plasma concentrations of estrogens or progestins. In some cases, this effect may be clinically significant.

Substances that decrease the clearance of COCs (enzyme inhibitors). Dienogest is a substrate of cytochrome CYP3A4. Strong and moderate CYP3A4 inhibitors, such as azole antifungals (e.g., itraconazole, voriconazole, fluconazole), verapamil, macrolide antibiotics (e.g., clarithromycin, erythromycin), diltiazem, and grapefruit juice may increase the plasma concentrations of estrogen or progestin, or both.

When co-administered with the strong inhibitor ketoconazole, the steady-state AUC_{0-24 h} for dienogest increased by 2.86-fold, and for estradiol by 1.57-fold. When co-administered with the moderate inhibitor erythromycin, the steady-state AUC_{0-24 h} for dienogest and estradiol increased by 1.62-fold and 1.33-fold, respectively.

COCs can affect the metabolism of other drugs, leading to an increase (e.g., cyclosporine) or decrease (e.g., lamotrigine) in their plasma and tissue concentrations.

However, based on in vitro data, inhibition of CYP enzymes when using this combination at the therapeutic dose is unlikely.

Storage Conditions

Store at 2°C (36°F) to 30°C (86°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.