Visanne (Tablets) Instructions for Use

Marketing Authorization Holder

Bayer, AG (Germany)

Manufactured By

Bayer Weimar, GmbH & Co. KG (Germany)

Contact Information

BAYER AG (Germany)

ATC Code

G03DB08 (Dienogest)

Active Substance

Dienogest (Rec.INN registered by WHO)

Dosage Form

Visanne

Tablets 2 mg: 28 or 84 pcs.

Dosage Form, Packaging, and Composition

Tablets white or almost white, round, with a flat surface and beveled edges, engraved with “B” on one side.

Excipients: lactose monohydrate – 62.8 mg, potato starch – 36 mg, microcrystalline cellulose – 18 mg, povidone K25 – 8.1 mg, talc – 4.05 mg, crospovidone – 2.7 mg, magnesium stearate – 1.35 mg.

14 pcs. – blisters (2) – cardboard boxes with first opening control.
14 pcs. – blisters (6) – cardboard boxes with first opening control.

Clinical-Pharmacological Group

Gestagen

Pharmacotherapeutic Group

Sex hormones and modulators of the genital system; progestogens; pregnadiene derivatives

Pharmacological Action

Pharmacodynamics

Dienogest is a derivative of norethisterone and is characterized by antiandrogenic activity, which is approximately one-third that of cyproterone acetate. Dienogest binds to progesterone receptors in the human uterus, having only 10% of the relative affinity of progesterone. Despite its low affinity for progesterone receptors, Dienogest is characterized by a potent progestogenic effect in vivo. Dienogest does not have significant androgenic, mineralocorticoid, or glucocorticoid activity in vivo.

Dienogest acts on endometriosis by suppressing the trophic effects of estrogens on the eutopic and ectopic endometrium, due to a reduction in estrogen production in the ovaries and a decrease in their plasma concentration.

With prolonged use, it causes initial decidualization of endometrial tissue followed by atrophy of endometriotic lesions.

Efficacy data

The advantage of Visanne over placebo in relation to pelvic pain associated with endometriosis was demonstrated in a clinical trial that included 198 patients, lasting 3 months. Pelvic pain associated with endometriosis was assessed using a visual analog scale (VAS, 0-100 mm). After 3 months of treatment with Visanne, a statistically significant difference compared to placebo was shown (Δ=12.3 mm; 95% CI: 6.4-18.1; p<0.0001), as well as a clinically significant reduction in pain compared to baseline (mean = 27.4 mm ± 22.9).

After 3 months of treatment, 37.3% of patients experienced a reduction in the intensity of pelvic pain associated with endometriosis by 50% or more without increasing the dose of additional analgesic they were taking (placebo: 19.8%); 18.6% of patients experienced a reduction in the intensity of pelvic pain associated with endometriosis by 75% or more without increasing the dose of additional analgesic they were taking (placebo: 7.3%).

In the extended open-label phase of this placebo-controlled study, a sustained reduction in pelvic pain associated with endometriosis was observed with treatment duration of up to 15 months.

The results of the placebo-controlled study were confirmed by data obtained during a 6-month study compared with a GnRH agonist, which included 252 patients with endometriosis.

In 3 studies involving a total of 252 patients receiving a daily dose of dienogest 2 mg, a significant reduction in endometriotic lesions was demonstrated after 6 months of treatment.

A small study (n=8 per dose group) showed that a daily dose of 1 mg dienogest causes suppression of ovulation after 1 month of treatment. The contraceptive efficacy of Visanne has not been studied in larger trials.

Safety data

The level of endogenous estrogens is moderately suppressed during treatment with Visanne.

Bone mineral density (BMD) was assessed in 21 adult patients before the start of treatment and after 6 months of using the drug; no decrease in the mean BMD value was noted.

In 29 patients receiving leuprorelin acetate (LA), a mean decrease of 4.04% ± 4.84 was noted over the same period (Δ between groups = 4.29%; 95% CI: 1.93-6.66; p<0.0003).

Safety data in adolescents

The safety of Visanne regarding BMD was investigated in an uncontrolled clinical trial over 12 months in 111 female adolescents (12-18 years, post-menarche) with clinically suspected or confirmed endometriosis (see sections “Special Precautions”, “Pharmacological Action”). The mean relative change in lumbar spine BMD (L2-L4 vertebrae) from baseline in 103 patients was -1.2%. In the group of patients who experienced a decrease in BMD, this parameter was measured again 6 months after the end of treatment during the extended follow-up period, and the analysis showed an increase in BMD level to -0.6%.

During the use of Visanne for up to 15 months, no significant effect of the drug on standard laboratory parameters, including hematology, blood chemistry, liver enzyme levels, lipids, and glycosylated hemoglobin, was observed.

Long-term use safety data

A long-term observational post-marketing study with active control was conducted to study the incidence or worsening of clinically significant depression and the occurrence of anemia. A total of 27,840 women with newly initiated hormonal therapy for endometriosis were included in the study and followed for 7 years.

A total of 3,023 women started taking dienogest 2 mg, and 3,371 patients started taking other approved drugs for the treatment of endometriosis. The overall adjusted hazard ratio for new cases of anemia comparing patients receiving Dienogest and patients receiving other approved drugs for the treatment of endometriosis was 1.1 (95% CI: 0.4-2.6).

The adjusted hazard ratio for the development of depression comparing dienogest and other approved drugs for the treatment of endometriosis was 1.8 (95% CI: 0.3-9.4). An increased risk of depression in patients taking Dienogest compared to patients taking other approved drugs for the treatment of endometriosis cannot be ruled out.

Pharmacokinetics

Absorption

After oral administration, Dienogest is rapidly and almost completely absorbed. The C_max in plasma, which is 47 ng/ml, is reached approximately 1.5 hours after a single oral dose. Bioavailability is about 91%. The pharmacokinetics of dienogest in the dose range from 1 to 8 mg is dose-dependent.

Distribution

Dienogest binds to albumin in plasma and does not bind to sex hormone-binding globulin (SHBG) or corticosteroid-binding globulin (CBG). 10% of the total plasma concentration is in the form of free steroid, while about 90% is non-specifically bound to albumin.

The apparent volume of distribution of dienogest (V_d/F) is 40 L.

Steady-state concentration. The pharmacokinetics of dienogest is independent of SHBG levels. The plasma concentration of dienogest after daily administration increases by approximately 1.24 times, reaching C_ss after 4 days of administration. The pharmacokinetics of dienogest after repeated administration of Visanne can be predicted based on the pharmacokinetics after a single dose.

Metabolism

Dienogest is almost completely metabolized, predominantly by hydroxylation, forming several virtually inactive metabolites. Based on the results of in vitro and in vivo studies, the main enzyme involved in the metabolism of dienogest is CYP3A4. Metabolites are excreted very rapidly, so the predominant fraction in plasma is unchanged Dienogest.

The metabolic clearance rate (Cl/F) from plasma is 64 ml/min.

Excretion

The plasma concentration of dienogest decreases in two phases. The T_1/2 in the terminal phase is approximately 9-10 hours. After oral administration of a dose of 0.1 mg/kg, Dienogest is excreted as metabolites by the kidneys and through the intestines in a ratio of approximately 3:1. The T_1/2 of metabolites upon renal excretion is 14 hours. After oral administration, approximately 86% of the administered dose is excreted within 6 days, with the majority excreted within the first 24 hours, predominantly by the kidneys.

Indications

• Treatment of endometriosis.

ICD codes

Dosage Regimen

For oral administration.

Before starting Visanne, the use of hormonal contraception must be discontinued. If contraception is necessary, non-hormonal contraceptive methods (e.g., barrier method) should be used.

Visanne can be started on any day of the menstrual cycle. The drug is taken 1 tablet/day without interruption, preferably at the same time each day, if necessary with water or another liquid. Tablets should be taken continuously regardless of vaginal bleeding. After finishing the tablets from one package, start taking tablets from the next package without a break in taking the drug.

If tablets are missed and in case of vomiting and/or diarrhea (if this occurs within 3-4 hours after taking the tablet), the effectiveness of Visanne may decrease. If one or more tablets are missed, the woman should take 1 tablet as soon as she remembers, and then continue taking the tablets at the usual time the next day. One tablet should also be taken instead of the tablet that was not absorbed due to vomiting or diarrhea.

There is no relationship between drug intake and food intake.

Additional information for special patient groups

Pediatric patients

Visanne is not indicated for use in children before menarche.

The safety and efficacy of Visanne were demonstrated in an uncontrolled clinical trial over 12 months involving 111 female adolescents (12-18 years) with clinically suspected or confirmed endometriosis (see sections “Special Precautions”, “Pharmacological Action”).

Elderly patients

There is no relevant basis for the use of Visanne in elderly patients.

Patients with impaired liver function

Visanne is contraindicated in severe liver diseases currently or in history (see section “Contraindications”).

Patients with impaired renal function

There are no data indicating a need for dose adjustment in patients with impaired renal function.

Adverse Reactions

Adverse effects occur more frequently in the first months of taking Visanne, and their number decreases over time. The most common adverse effects include: vaginal bleeding (including spotting, metrorrhagia, menorrhagia, irregular bleeding), headache, breast discomfort, depressed mood, and acne.

Table 1 lists adverse drug reactions (ADRs), categorized by system organ class. Adverse effects in each frequency group are presented in descending order of frequency. Frequency is defined as common (from ≥1/100 to <1/10) and uncommon (from ≥1/1000 to <1/100).

Table 1. Categorized relative frequency rates of women with ADRs

Contraindications

The use of Visanne is contraindicated in the presence of any of the conditions listed below, some of which are common to all drugs containing only a progestogenic component. If any of these conditions develop during the use of Visanne, treatment with the drug should be discontinued immediately

• Acute thrombophlebitis, current venous thromboembolism;
• Heart and arterial diseases based on atherosclerotic vascular lesions (including coronary artery disease, myocardial infarction, stroke and transient ischemic attack) currently or in history;
• Diabetes mellitus with vascular complications;
• Severe liver diseases currently or in history (in the absence of normalization of liver function tests);
• Liver tumors (benign and malignant) currently or in history;
• Identified or suspected hormone-dependent malignant tumors, including breast cancer;
• Vaginal bleeding of unknown origin;
• History of cholestatic jaundice of pregnancy;
• Galactose intolerance, lactase deficiency, glucose-galactose malabsorption;
• Children under 12 years of age (before menarche);
• Pregnancy;
• Breastfeeding period;
• Hypersensitivity to the active substances or to any of the excipients.

With caution

History of depression, history of ectopic pregnancy, arterial hypertension, chronic heart failure, migraine with aura, diabetes mellitus without vascular complications, hyperlipidemia, history of deep vein thrombophlebitis, history of venous thromboembolism (see section “Special Precautions”).

Use in Pregnancy and Lactation

Pregnancy

Experience with the use of dienogest in pregnant women is very limited. Studies in animals have not revealed reproductive toxicity, genotoxicity, or carcinogenicity with the use of the drug. Visanne should not be prescribed to pregnant women, as there is no need for endometriosis treatment during pregnancy.

Breastfeeding period

The use of Visanne during breastfeeding is not recommended, as animal studies indicate the excretion of dienogest in breast milk. The decision to discontinue breastfeeding or to discontinue Visanne is made based on an assessment of the benefits of breastfeeding for the child and the benefits of treatment for the woman.

Use in Hepatic Impairment

Visanne is contraindicated in severe liver diseases currently or in history, liver tumors (benign and malignant) currently or in history.

Use in Renal Impairment

There are no data indicating the need for dose adjustment in patients with kidney disease.

Pediatric Use

Contraindicated in children under 12 years of age (before menarche).

Geriatric Use

There is no relevant basis for the use of Visanne in elderly patients.

Special Precautions

Before starting Visanne, pregnancy must be excluded. During the use of Visanne, if contraception is necessary, patients are recommended to use non-hormonal contraceptive methods (e.g., barrier method).

Fertility

According to available data, ovulation is suppressed in most patients during Visanne use. However, Visanne is not a contraceptive.

The contraceptive efficacy of Visanne has not been studied; however, a study showed that in 20 women, a dose of dienogest 2 mg suppressed ovulation after 1 month of treatment.

According to available data, the physiological menstrual cycle is restored within 2 months after discontinuation of Visanne.

The likelihood of ectopic pregnancy is higher in patients using progestogen-only preparations for contraception compared to patients using combined oral contraceptives. Therefore, for women with a history of ectopic pregnancy or with fallopian tube obstruction, the benefit-risk ratio should be assessed before using Visanne.

Since Visanne is a progestogen-only preparation, it can be assumed that the special instructions and precautions for use of other preparations of this type are also valid for Visanne, although not all of them have been confirmed in the course of clinical studies of Visanne.

If any of the conditions or risk factors listed below are present or worsening, an individual benefit-risk assessment should be performed before starting or continuing Visanne.

Circulatory disorders

Epidemiological studies have provided insufficient evidence to confirm an association between the use of progestogen-only preparations and an increased risk of myocardial infarction or cerebral thromboembolism. The risk of cardiovascular episodes and cerebrovascular disorders is more likely associated with increasing age, arterial hypertension, and smoking. The risk of stroke in women with arterial hypertension may slightly increase while taking progestogen-only preparations.

Some studies indicate the possibility of a statistically insignificant increase in the risk of venous thromboembolism (deep vein thrombosis, pulmonary embolism) associated with the use of progestogen-only preparations. Recognized risk factors for venous thromboembolism (VTE) include a relevant family history (VTE in a sibling or parent at a relatively young age), age, obesity, prolonged immobilization, major surgery, or serious trauma. In case of prolonged immobilization, it is recommended to discontinue Visanne (for planned surgery, at least 4 weeks before) and resume use only 2 weeks after full mobility is restored.

The increased risk of thromboembolism in the postpartum period should be considered.

If arterial or venous thrombosis develops or is suspected, the drug should be discontinued immediately.

Tumors

A meta-analysis of 54 epidemiological studies revealed a small increase in the relative risk (RR=1.24) of breast cancer in women who were using oral contraceptives at the time of the study, predominantly estrogen-progestogen preparations. This increased risk gradually disappears within 10 years after stopping combined oral contraceptives (COCs). Since breast cancer is rare in women under 40 years of age, the slight increase in such diagnoses in women currently taking or previously using COCs is small relative to the overall risk of breast cancer. The risk of detecting breast cancer in women using progestogen-only hormonal contraceptives may be similar in magnitude to the corresponding risk associated with COC use. However, data related to progestogen-only preparations are based on much smaller populations of women taking them and are therefore less convincing than data for COCs. Establishing a causal relationship based on these studies is not possible. The observed pattern of increasing risk may be due to earlier diagnosis of breast cancer in women taking oral contraceptives, the biological effects of oral contraceptives, or a combination of both factors. Women who have used hormonal contraceptives are diagnosed with earlier clinical stages of breast cancer than women who have never used them.

In rare cases, the use of hormonal substances similar to that contained in Visanne has been associated with benign, and even more rarely, malignant liver tumors. In some cases, these tumors have led to life-threatening intra-abdominal bleeding. If a woman taking Visanne experiences severe pain in the upper abdomen, has an enlarged liver, or shows signs of intra-abdominal bleeding, the possibility of a liver tumor should be considered in the differential diagnosis.

Changes in bleeding patterns

In most women, taking Visanne affects the nature of menstrual bleeding.

Uterine bleeding may increase during the use of Visanne, for example, in women with adenomyosis or uterine leiomyoma. Heavy and prolonged bleeding can lead to anemia (in some cases severe). In such cases, discontinuation of Visanne should be considered.

Changes in bone mineral density (BMD)

When Visanne was used in adolescents (12-18 years) for 12 months of treatment, a decrease in lumbar spine BMD was observed by an average of 1.2%. After discontinuation of treatment, BMD in these patients increased again.

The decrease in BMD is of particular concern during adolescence and late adolescence, as this is a particularly important period for bone growth. It is unknown whether the decrease in BMD affects peak bone mass in this population and increases the risk of fractures later in life.

Therefore, the physician should weigh the benefit of the drug against the potential risks for each patient, also taking into account the possible occurrence of risk factors for osteoporosis (e.g., dysmetabolic osteopathy, family history of osteoporosis, low BMI or eating disorders, long-term use of medications that can reduce bone mass, such as anticonvulsants or glucocorticoids, previous fractures due to minor trauma, alcohol abuse and/or smoking).

It is important for women of all ages to consume calcium and vitamin D, regardless of following a specific diet or using vitamin supplements.

No decrease in BMD was observed in adult patients.

Other conditions

Patients with a history of depression require careful observation. If depression recurs in a severe form, the drug should be discontinued.

In general, Visanne does not appear to affect blood pressure in women with normal blood pressure. However, if persistent clinically significant arterial hypertension occurs during Visanne use, it is recommended to discontinue the drug and initiate antihypertensive treatment.

If cholestatic jaundice and/or cholestatic pruritus recur, which first occurred during pregnancy or previous use of sex steroids, Visanne must be discontinued.

Visanne may have a slight effect on peripheral insulin resistance and glucose tolerance. Women suffering from diabetes mellitus, especially those with a history of gestational diabetes, require careful monitoring during Visanne use.

In some cases, chloasma may occur, especially in women with a history of chloasma of pregnancy. Women prone to developing chloasma should avoid sun exposure or ultraviolet radiation during Visanne use.

During the use of Visanne, persistent ovarian follicles (often called functional ovarian cysts) may occur. Most of these follicles are asymptomatic, although some may be accompanied by pelvic pain.

Lactose

One tablet of Visanne contains 63 mg of lactose monohydrate. Patients on a lactose-free diet with rare hereditary disorders such as galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption should take into account the lactose content in Visanne.

Medical examination

Before starting or resuming Visanne, the patient’s medical history should be reviewed in detail and a physical and gynecological examination should be performed. The frequency and nature of such examinations should be based on existing standards of medical practice, taking into account the individual characteristics of each patient (but not less than once every 3-6 months) and should include blood pressure measurement, assessment of the condition of the breasts, abdomen, and pelvic organs, including cytological examination of the cervical epithelium.

Effect on ability to drive vehicles and machinery

No negative effect of Visanne on the ability to drive vehicles and machinery has been noted; however, patients who experience impaired concentration during the adaptation period (the first 3 months of drug use) should exercise caution.

Overdose

No serious adverse events due to overdose have been reported.

Symptoms that may occur with overdose: nausea, vomiting, spotting, or metrorrhagia.

Treatment There is no specific antidote; symptomatic treatment should be provided.

Drug Interactions

Effect of other medicinal products on Visanne

Progestogens, including dienogest, are metabolized primarily by the cytochrome P450 3A4 (CYP3A4) system, located in both the intestinal mucosa and the liver. Therefore, inducers or inhibitors of CYP3A4 may affect the metabolism of progestogenic drugs.

Increased clearance of sex hormones due to enzyme induction may lead to a decrease in the therapeutic effect of Visanne and may also cause adverse effects, such as changes in uterine bleeding patterns.

Decreased clearance of sex hormones due to enzyme inhibition may increase exposure to dienogest and cause adverse reactions.

Substances that increase the clearance of sex hormones (reduced efficacy by enzyme induction) phenytoin, barbiturates, primidone, carbamazepine, rifampicin, and possibly oxcarbazepine, topiramate, felbamate, griseofulvin, and preparations containing St. John’s wort.

Enzyme induction is generally observed a few days after starting therapy, reaches its maximum within a few weeks, and may then persist for up to 4 weeks after discontinuation of therapy.

The effect of the CYP3A4 inducer rifampicin was studied in healthy postmenopausal women. When rifampicin was taken concomitantly with tablets containing estradiol valerate/dienogest, a significant decrease in C_ss and systemic exposure to dienogest was observed. The systemic exposure to dienogest at C_ss, determined by the AUC_{0-24 h} value, was reduced by 83%.

Substances with variable effects on the clearance of sex hormones. When used concomitantly with sex hormones, many drugs for the treatment of HIV and hepatitis C and non-nucleoside reverse transcriptase inhibitors may increase or decrease plasma concentrations of progestins. In some cases, such changes may be clinically significant.

Substances that decrease the clearance of sex hormones (enzyme inhibitors). Dienogest is a substrate of CYP3A4. Potent inhibitors and moderate inhibitors of CYP3A4, such as azole antifungals (itraconazole, voriconazole, fluconazole), verapamil, macrolides (clarithromycin, erythromycin), diltiazem, and grapefruit juice may lead to an increase in plasma concentrations of the progestogen.

In one study investigating the effect of CYP3A4 inhibitors (ketoconazole, erythromycin), plasma concentrations of estradiol valerate and dienogest at C_ss were increased. When co-administered with the potent inhibitor ketoconazole, the AUC_{0-24 h} at C_ss for dienogest increased by 2.86-fold. When co-administered with the moderate CYP3A4 inhibitor erythromycin, the AUC_{0-24 h} for dienogest at C_ss increased by 1.62-fold. The clinical significance of these interactions is unknown.

Effect of dienogest on other medicinal products

Based on data from in vitro inhibition studies, a clinically significant interaction of Visanne with other medicinal products metabolized by cytochrome P450 isoenzymes is unlikely.

Interaction with food

Food high in fat did not affect the bioavailability of Visanne.

Other interactions

The use of progestogens may affect the results of some laboratory tests, including biochemical parameters of liver, thyroid, adrenal, and kidney function, plasma concentrations of (carrier) proteins, e.g., lipid/lipoprotein fractions, parameters of carbohydrate metabolism, and coagulation parameters.

Storage Conditions

The drug should be stored out of the reach of children at a temperature not exceeding 30°C (86°F).

Shelf Life

The shelf life is 5 years. Do not use after the expiration date.

Dispensing Status

The drug is dispensed by prescription.

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.