Bayer HealthCare Pharma


Full Prescribing Info
Each tablet also contains the following excipients: Lactose monohydrate, potato starch, microcrystalline cellulose, povidone K 25, talc, crospovidone and magnesium stearate.
Pharmacology: Pharmacodynamics: Dienogest is a nortestosterone derivative with no androgenic but rather an antiandrogenic activity of approximately ⅓ of that of cyproterone acetate. Dienogest binds to the progesterone receptor of the human uterus with only 10% of the relative affinity of progesterone. Despite its low affinity to the progesterone receptor, dienogest has a strong progestogenic effect in vivo. Dienogest has no significant androgenic, mineralocorticoid or glucocorticoid activity in vivo.
Dienogest acts on endometriosis by reducing the endogenous production of estradiol and thereby suppressing the trophic effects of estradiol on both the eutopic and ectopic endometrium. When given continuously, dienogest leads to a hypoestrogenic, hypergestagenic endocrine environment causing initial decidualization of endometrial tissue followed by atrophy of endometriotic lesions. Additional properties, like immunologic and antiangiogenic effects, seem to contribute to the inhibitory action of dienogest on cell proliferation.
Data on Efficacy: Superiority of Visanne over placebo with regard to reduction of endometriosis-associated pelvic pain (EAPP) and clinically meaningful reduction of pain compared to baseline were demonstrated in a 3-month study including 102 patients on Visanne.
The open-label extension to this placebo-controlled study showed a continued improvement of endometriosis-associated pelvic pain for a treatment duration of up to 15 months.
In addition, efficacy on endometriosis-associated pelvic pain was shown in a 6-month comparative trial of Visanne versus the gonadotropin-releasing hormone (GnRH) analogue leuprorelin acetate (LA) including 120 patients on Visanne. A clinically meaningful reduction of pain compared to baseline was observed in both treatment groups. Non-inferiority versus LA based on a predefined non-inferiority margin of 15 mm was demonstrated (p<0.0001).
Three (3) studies including a total of 252 patients who received a daily dose of dienogest 2 mg demonstrated a substantial reduction of endometriotic lesions after 6 months of treatment.
Data on Safety: Endogenous estrogen levels are only moderately suppressed during treatment with Visanne. Bone mineral density (BMD) was assessed in 21 patients before and after 6 months of treatment and there was no reduction in mean BMD.
No significant impact on standard laboratory parameters, including hematology, blood chemistry, liver enzymes, lipids, and lipids and hemoglobin A1C (HbA1C) was observed during treatment with Visanne for up to 15 months (n=168).
Pharmacokinetics: Absorption: Orally administered dienogest is rapidly and almost completely absorbed. Peak serum concentrations of 47 ng/mL are reached at about 1.5 hrs after single ingestion. Bioavailability is about 91%. The pharmacokinetics of dienogest are dose-proportional within the dose range of 1-8 mg.
Distribution: Dienogest is bound to serum albumin and does not bind to sex hormone binding globulin (SHBG) or corticoid binding globulin (CBG). Ten percent (10%) of the total serum drug concentrations are present as free steroid, 90% are nonspecifically bound to albumin.
The apparent volume of distribution (Vd/F) of dienogest is 40 L.
Metabolism: Dienogest is completely metabolized by the known pathways of steroid metabolism, with the formation of endocrinologically mostly inactive metabolites. Based on in vitro and in vivo studies, CYP3A4 is the major enzyme involved in the metabolism of dienogest. The metabolites are excreted very quickly so that in plasma unchanged dienogest is the dominating fraction.
The metabolic clearance rate from serum (Cl/F) is 64 mL/min.
Elimination: Dienogest serum levels decrease in 2 phases. The terminal disposition phase is characterized by a half-life (t½) of approximately 9-10 hrs. Dienogest is excreted in form of metabolites which are excreted at a urinary to fecal ratio of about 3:1 after oral administration of 0.1 mg/kg. The t½ of urinary metabolites excretion is 14 hrs. Following oral administration approximately 86% of the dose administered is eliminated within 6 days, the bulk of this amount excreted within the first 24 hrs, mostly with the urine.
Steady-State Conditions: Pharmacokinetics of dienogest are not influenced by SHBG levels. Following daily ingestion, drug serum levels increase about 1.24-fold reaching steady-state conditions after 4 days of treatment. The pharmacokinetics of dienogest after repeated administration of Visanne can be predicted from single dose pharmacokinetics.
Toxicology: Preclinical Safety Data: Preclinical data reveal no special risks for humans based on conventional studies of safety pharmacology, repeated-dose toxicity, genotoxicity, carcinogenic potential and toxicity to reproduction. However, it should be borne in mind that sex steroids can promote the growth of certain hormone-dependent tissues and tumors.
Treatment of endometriosis.
Dosage/Direction for Use
Tablet-taking can be started on any day of the menstrual cycle.
The dosage of Visanne is 1 tablet daily without any break, taken preferably at the same time each day with some liquid as needed. Tablets must be taken continuously without regard to vaginal bleeding. When a pack is finished, the next one should be started without interruption.
The efficacy of Visanne may be reduced in the event of missed tablets, vomiting and/or diarrhea (if occurring within 3-4 hrs after tablet taking). In the event of missed tablet(s), the woman should take 1 tablet only, as soon as she remembers, and should then continue the next day to take the tablet at her usual time. A tablet not absorbed due to vomiting or diarrhea should likewise be replaced by 1 tablet.
Renal Impairment: There are no data suggesting the need for a dosage adjustment in patients with renal impairment.
Acute toxicity studies performed with Visanne did not indicate a risk of acute adverse effects in case of inadvertent intake of a multiple of the daily therapeutic dose. There is no specific antidote. Dienogest 20-30 mg/day (10-15 times higher dose than in Visanne) over 24 weeks of use were very well tolerated.
Hypersensitivity to dienogest or to any of the excipients of Visanne. Visanne should not be used in the presence of any of the conditions listed as follows, which are partially derived from information on other progestogen-only preparations. Should any of the conditions appear during the use of Visanne, treatment must be discontinued immediately: Active venous thromboembolic disorder; arterial and cardiovascular disease, present or in history (eg, myocardial infarction, cerebrovascular accident, ischemic heart disease); diabetes mellitus with vascular involvement; presence or history of severe hepatic disease as long as liver function values have not returned to normal; presence or history of liver tumors (benign or malignant); known or suspected sex hormone-dependent malignancies and undiagnosed vaginal bleeding.
Special Precautions
Before starting Visanne treatment, pregnancy must be excluded (see Use in pregnancy & lactation as follows). During treatment, patients are advised to use nonhormonal methods of contraception (eg, barrier method) if contraception is required.
Pregnancies that occur among users of progestogen-only preparations used for contraception are more likely to be ectopic than are pregnancies among users of combined oral contraceptives.
Therefore, in women with a history of extrauterine pregnancy or an impairment of tube function, the use of Visanne should be decided on only after carefully weighing the benefits against the risks.
As Visanne is a progestogen-only preparation, it can be assumed that special warnings and special precautions for use of other progestogen-only preparations are also valid for the use of Visanne although not all of the warnings and precautions are based on respective findings in the clinical studies with Visanne.
Circulatory Disorders: From epidemiological studies, there is little evidence for an association between progestogen-only preparations and an increased risk of myocardial infarction or cerebral thromboembolism. The risk of cardiovascular and cerebral events is rather related to increasing age, hypertension and smoking. In women with hypertension, the risk of stroke may be slightly enhanced by progestogen-only preparations.
Some studies indicate that there may be a slightly, but not statistically significant increased risk of venous thromboembolism (deep venous thrombosis, pulmonary embolism) associated with the use of progestogen-only preparations. Generally recognized risk factors for venous thromboembolism (VTE) include a positive personal or family history (VTE in a sibling or a parent at a relatively early age), age, obesity, prolonged immobilization, major surgery or major trauma. In case of long-term immobilization, it is advisable to discontinue the use of Visanne (in the case of elective surgery at least 4 weeks in advance) and not to resume treatment until 2 weeks after complete remobilization.
The increased risk of thromboembolism in the puerperium must be considered.
Treatment should be stopped at once if there are symptoms of an arterial or venous thrombotic event or suspicion thereof.
Tumors: A meta-analysis from 54 epidemiological studies reported that there is a slightly increased relative risk (RR=1.24) of having breast cancer diagnosed in women who are currently using oral contraceptives (OCs), mainly estrogen-progestogen preparations. The excess risk gradually disappears during the course of the 10 years after cessation of combined oral contraceptives (COC) use. Because breast cancer is rare in women <40 years, the excess number of breast cancer diagnoses in current and recent COC users is small in relation to the overall risk of breast cancer. The risk of having breast cancer diagnosed in progestogen-only pill users is possibly of similar magnitude to that associated with COC. However, for progestogen-only preparations, the evidence is based on much smaller populations of users and so is less conclusive than that for COCs. These studies do not provide evidence for causation. The observed pattern of increased risk may be due to an earlier diagnosis of breast cancer in OC users, the biological effects of OCs or a combination of both. The breast cancers diagnosed in ever-users tend to be less advanced clinically than the cancers diagnosed in never-users.
In rare cases, benign liver tumors, and even more rarely, malignant liver tumors have been reported in users of hormonal substances eg, the 1 contained in Visanne. In isolated cases, these tumors have led to life-threatening intra-abdominal hemorrhages.
Changes in Bleeding Pattern: Visanne treatment affects the menstrual bleeding pattern in the majority of women (see Adverse Reactions).
Uterine bleeding eg, in women with adenomyosis uteri or uterine leiomyomata, may be aggravated with the use of Visanne. If bleeding is heavy and continuous over time, this may lead to anemia (severe in some cases). Discontinuation of Visanne should be considered in such cases.
Other Conditions: Patients who have a history of depression should be carefully observed and the drug discontinued if the depression recurs to a serious degree.
Visanne generally does not appear to affect blood pressure in normotensive women. However, if a sustained clinically significant hypertension develops during the use of Visanne, it is advisable to withdraw Visanne and treat the hypertension.
Recurrence of cholestatic jaundice and/or pruritus which occurred 1st during pregnancy or previous use of sex steroids necessitates the discontinuation of Visanne.
Visanne may have a slight effect on peripheral insulin resistance and glucose tolerance. Diabetic women, especially those with a history of gestational diabetes mellitus, should be carefully observed while taking Visanne.
Chloasma may occasionally occur, especially in women with a history of chloasma gravidarum. Women with a tendency to chloasma should avoid exposure to the sun or ultraviolet radiation whilst taking Visanne.
Persistent ovarian follicles (often referred to as functional ovarian cysts) may occur during the use of Visanne. Most of these follicles are asymptomatic, although some may be accompanied by pelvic pain.
Special Populations: Hepatic Impairment: Visanne is contraindicated in patients with present or past severe hepatic disease (see Contraindications).
Effects on the Ability to Drive or Operate Machinery: Not known.
Impairment of Fertility: Based on available data, ovulation is inhibited in the majority of patients during treatment with Visanne. However, Visanne is not a contraceptive.
If contraception is required, a nonhormonal method should be used.
Based on available data, the menstrual cycle returns to normal within 2 months after cessation of treatment with Visanne.
Use in Pregnancy: There are limited data from the use of dienogest in pregnant women. Animal studies and data from women exposed to dienogest during pregnancy reveal no special risks on pregnancy, embryonic/fetal development, birth or development after birth for humans (see Pharmacology: Toxicology under Actions). However, Visanne should not be administered to pregnant women because there is no need to treat endometriosis during pregnancy.
Use in Lactation: Treatment with Visanne during lactation is not recommended. Physiochemical properties and animal data indicate excretion of dienogest in breast milk. A decision must be made whether to discontinue breastfeeding or to abstain from Visanne therapy taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman.
Use in Children: Visanne is not indicated in children prior to menarche. The safety and efficacy of Visanne in adolescents (menarche to 18 years) has not yet been established.
Use in the Elderly: There is no relevant indication for the use of Visanne in the geriatric population.
Use In Pregnancy & Lactation
Use in Pregnancy: There are limited data from the use of dienogest in pregnant women. Animal studies and data from women exposed to dienogest during pregnancy reveal no special risks on pregnancy, embryonic/fetal development, birth or development after birth for humans (see Pharmacology: Toxicology under Actions). However, Visanne should not be administered to pregnant women because there is no need to treat endometriosis during pregnancy.
Use in Lactation: Treatment with Visanne during lactation is not recommended. Physiochemical properties and animal data indicate excretion of dienogest in breast milk. A decision must be made whether to discontinue breastfeeding or to abstain from Visanne therapy taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman.
Adverse Reactions
Summary of the Safety Profile: Undesirable effects are more common during the 1st months after start of intake of Visanne, and subside with duration of treatment. The following undesirable effects have been reported in users of Visanne.
The most frequently reported undesirable effects during treatment that were considered at least possibly related to Visanne were headache (9%), breast discomfort (5.4%), depressed mood (5.1%) and acne (5.1%).
The frequencies of adverse drug reactions (ADRs) by MedDRA system organ classes (MedDRA SOCs) reported with Visanne are summarized as follows. Within each frequency grouping, undesirable effects are presented in order of decreasing frequency. Frequencies are defined as common (≥1/100 to <1/10) and uncommon (≥1/1000 to <1/100). The frequencies are based on pooled data of 4 clinical trials including 332 patients (100%).
Categorized relative frequency of women with ADRs, by MedDRA SOC, Dienogest 2 mg group based on pooled data of 4 clinical trials including 332 patients: Blood and Lymphatic System Disorders: Uncommon: Anemia.
Metabolism and Nutrition Disorders: Common: Increased weight. Uncommon: Decreased weight, increased appetite.
Psychiatric Disorders: Common: Depressed mood, sleep disorder, nervousness, loss of libido, altered mood. Uncommon: Anxiety, depression, mood swings.
Nervous System Disorders: Common: Headache, migraine. Uncommon: Autonomic nervous system imbalance, attention disturbance.
Eye Disorders: Uncommon: Dry eye.
Ear and Labyrinth Disorders: Uncommon: Tinnitus.
Cardiac Disorders: Uncommon: Unspecified circulatory system disorder, palpitations.
Vascular Disorders: Uncommon: Hypotension.
Respiratory, Thoracic and Mediastinal Disorders: Uncommon: Dyspnoea.
Gastrointestinal Disorders: Common: Nausea, abdominal pain, flatulence, abdominal distension, vomiting. Uncommon: Diarrhoea, constipation, abdominal discomfort, gastrointestinal inflammation, gingivitis.
Skin and Subcutaneous Tissue Disorders: Common: Acne, alopecia. Uncommon: Dry skin, hyperhidrosis, pruritus, hirsutism, onychoclasis, dandruff, dermatitis, abnormal hair growth, photosensitivity reaction, pigmentation disorder.
Musculoskeletal and Connective Tissue Disorders: Common: Back pain. Uncommon: Bone pain, muscle spasms, pain and heaviness in extremities.
Renal and Urinary Disorders: Uncommon: Urinary tract infection.
Reproductive System and Breast Disorders: Common: Breast discomfort, ovarian cyst, hot flush, uterine/vaginal bleeding including spotting. Uncommon: Vaginal candidiasis, vulvovaginal dryness, genital discharge, pelvic pain, atrophic vulvovaginitis, breast mass, fibrocystic breast disease, breast induration.
General Disorders and Administration Site Conditions: Common: Asthenic conditions, irritability. Uncommon: Oedema.
Description of Selected Adverse Reactions: Uterine Bleeding Irregularities: The following bleeding patterns were observed: Amenorrhea, bleeding (infrequent, frequent, irregular, prolonged and normal).
Drug Interactions
Effects of Other Medicaments on Visanne: Individual Enzyme-Inducers or Inhibitors (CYP3A4): Progestogens including dienogest are metabolized mainly by the cytochrome P450 3A4 system (CYP3A4) located both in the intestinal mucosa and in the liver. Therefore, inducers or inhibitors of CYP3A4 may affect the progestogen drug metabolism.
An increased clearance of sex hormones due to enzyme induction may reduce the therapeutic effect of Visanne and may result in undesirable effects eg, changes in the uterine bleeding profile.
A reduced clearance of sex hormones due to enzyme inhibition may increase the exposure to dienogest and may result in undesirable effects.
Substances with Enzyme-Inducing Properties: Interactions can occur with drugs (eg, phenytoin, barbiturates, primidone, carbamazepine, rifampicin and possibly also oxcarbazepine, topiramate, felbamate, griseofulvin, nevirapine and products containing St. John's wort) that induce microsomal enzymes (eg, cytochrome P450 enzymes) which can result in increased clearance of sex hormones.
Maximum enzyme induction is generally not seen for 2-3 weeks but may then be sustained for at least 4 weeks after the cessation of therapy.
Substances with Enzyme-Inhibiting Properties: Known CYP3A4 inhibitors like azole antifungals (eg, ketoconazole, itraconazole, fluconazole), cimetidine, verapamil, macrolides (eg, erythromycin, clarithromycin and roxithromycin), diltiazem, protease inhibitors (eg, ritonavir, saquinavir, indinavir, nelfinavir), antidepressants (eg, nefazodone, fluvoxamine, fluoxetine) may increase plasma levels of progestogens and result in adverse reactions.
Effects of Dienogest on Other Medicaments: Based on in vitro inhibition studies, a clinically relevant interaction of Visanne with the cytochrome P450 enzyme mediated metabolism of other medicaments is unlikely.
Drug-Food Interactions: A standardized high fat meal did not affect the bioavailability of Visanne.
Other Forms of Interactions: The use of progestogens may influence the results of certain laboratory tests.
Incompatibilities: None known.
Do not store above 30°C.
ATC Classification
G03DB08 - dienogest ; Belongs to the class of pregnadien derivative progestogens used in progestogenic hormone preparations.
Tab 2 mg (white to off-white, round, flat-faced, bevelled-edge with an embossed "B" on one side and a diameter of 7 mm) x 2 x 14's.
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