Endovelle

Dienogest.

Each tablet contains 2 mg dienogest.
Excipients/Inactive Ingredients: Lactose Monohydrate, Maize Starch, Povidone K 30, Ethanol, Magnesium Stearate.

Pharmacotherapeutic group: Progestogens. ATC code: G03DB08.
Pharmacology: Pharmacodynamics: Pharmacodynamic effects: Dienogest is a nortestosterone derivative with no androgenic but rather an antiandrogenic activity of approximately one third 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.
Mechanism of action: Dienogest acts on endometriosis by reducing the endogenous production of estradiol and thereby suppresses 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.
Pharmacokinetics: Methodology: This is an open-label, single-dose, randomized, two-period, two-sequence, two-treatment, crossover study, designed to evaluate the comparative bioavailability of two formulations of dienogest 2 mg tablets administered to healthy female subjects under fasting conditions.
Subjects were randomly assigned to one of the two dosing sequence AB or BA under fasting conditions.
Concentrations of dienogest were measured from the samples collected over a 60-hour interval after dosing in each period.
Summary-Conclusion: Pharmacokinetic Results: Analyte: Dienogest (N=27). (See Table 1.)


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Safety Results: No serious AEs were reported during the conduct of this study.
None of the AEs had a significant impact on the safety of the subjects or on the integrity of the study results.

Treatment of endometriosis.

Method of Administration: For oral use.
Dosage Regimen: Tablet-taking can be started on any day of the menstrual cycle.
The dosage of ENDOVELLE is one tablet daily without any break, taken preferably at the same time each day with some liquid as needed. Tablets must be taken throughout 28 days without regard to bleeding. When a pack is finished the next one should be started without interruption.
The efficacy of ENDOVELLE may be reduced in the event of missed tablets, vomiting and/or diarrhea (if occurring within 3-4 hours after tablet taking). In the event of missed tablet(s), the woman should take one 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 one tablet.
If a short acting, e.g. oral, hormonal treatment was prescribed before starting treatment with dienogest, treatment may be started on the first day of menstrual bleeding after cessation of treatment.
If a long-acting, i.e. injectable, hormonal treatment was administered before starting treatment with dienogest then dienogest may be started.
There is no experience with ENDOVELLE treatment for more than 15 months in patients with endometriosis.
Additional information on special populations: Children and adolescents: ENDOVELLE is not indicated in children prior to menarche. The safety and efficacy of ENDOVELLE in adolescent (menarche to 18 years) has not yet been established.
Geriatric population: There is no relevant indication for the use of ENDOVELLE in the geriatric population.
Patients with hepatic impairment: ENDOVELLE is contraindicated in patients with present or past severe hepatic disease (see Contraindications).
Patients with renal impairment: There are no data suggesting the need for a dosage adjustment in patients with renal impairment.

Acute toxicity studies performed with ENDOVELLE 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 20-30 mg dienogest per day (10 to 15 times higher dose than in ENDOVELLE) over 24 weeks of use was very well tolerated.

ENDOVELLE should not be used in the presence of any of the conditions listed as follows, which are partially derived from information on other progesterone-only preparations. Should any of the conditions appear during the use of ENDOVELLE, treatment must be discontinued immediately: active venous thromboembolic disorder; arterial and cardiovascular disease, present or history (e.g. 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 tumours (benign or malignant); known or suspected sex hormone-dependent malignancies; undiagnosed vaginal bleeding; hypersensitivity to the active substance or to any of the excipients listed in Description; known or suspected pregnancy; lactation.

Before starting ENDOVELLE treatment, pregnancy must be excluded (see Use in Pregnancy & Lactation). During treatment, patient are advised to use non-hormonal method of contraception (e.g. barrier method) if contraception is required.
Pregnancies that occur among users of progesterone-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 ENDOVELLE should be decided on only after carefully weighing the benefits against the risk.
As ENDOVELLE is a progesterone-only preparation, it can be assumed that special warnings and special precautions for use of other progesterone-only preparations are also valid for the use of ENDOVELLE although not all of the warnings and precautions are based on respective findings in the clinical studies with ENDOVELLE.
If any of the conditions/risk factors mentioned as follows is present or deteriorates, and individual risk-benefit analysis should be done before ENDOVELLE is started or continued.
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 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 ENDOVELLE (in the case of elective surgery at least four weeks in advance) and not to resume treatment until two 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.
Tumours: There is a slightly increased relative risk 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 contraceptive (COC) use. Because breast cancer is rare in women under 40 years of age, 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 tumours, and even more rarely, malignant liver tumours have been reported in users of hormonal substances such as the one contained in ENDOVELLE. In isolated cases, these tumours have led to life-threatening intra-abdominal haemorrhages.
A hepatic tumour should be considered in the differential diagnosis when severe upper abdominal pain, liver enlargement or signs of intra-abdominal haemorrhage occur in women taking ENDOVELLE.
Long-term studies in rats and mice with dienogest showed increased incidences of pituitary adenomas, fibroepithelial mammary tumours, stromal polyps of the uterus and malignant lymphoma, at doses corresponding to exposure levels about 10 times that anticipated at the maximum recommended clinical dose, based on area under the plasma concentration time curve (AUC). Similar tumours have been shown to develop with other oestrogenic/progestogenic compounds. The tumuors are thought to result from marked species differences in the optimal oestrogen: progestogen ratio for reproductive function. Dienogest showed no tumuor promotion activity in the rat liver foci assay at the exposure levels corresponding to >100 times the estimated human exposure at the clinical dose, based on AUC.
Changes in bleeding pattern: ENDOVELLE treatment affects the menstrual bleeding pattern in majority of women (see Adverse Reactions).
Uterine bleeding for example in women with adenomyosis uteri or uterine leiomyomata, may be aggravated with the use of ENDOVELLE. If bleeding is heavy and continuous over time, this may lead to anemia (severe in some cases). Discontinuation of ENDOVELLE 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.
Dienogest generally does not appear to affect blood pressure in normotensive women. However, if a sustained clinically significant hypertension develops during the use of ENDOVELLE, it is advisable to withdraw ENDOVELLE and treat the hypertension.
Dienogest 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 ENDOVELLE.
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 ENDOVELLE.
Persistent ovarian follicles (often referred to as functional ovarian cysts) may occur during the use of ENDOVELLE. Most of these follicles are asymptomatic, although some may be accompanied by pelvic pain.
Each ENDOVELLE tablet contains lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption who are on a lactose free diet should consider the amount contained in ENDOVELLE.
Genotoxicity: Dienogest did not exhibit any evidence of genotoxic potential in assays for gene mutations in bacterial or mammalian cells, in vitro and in vivo.
Medical Examination: A complete medical history and physical and gynaecological examination should be taken prior to the initiation or reinstitution of ENDOVELLE, guided by the contraindications (see Contraindications) and warnings, and these should be repeated regularly during the use of ENDOVELLE. The frequency and nature of these assessments should be adapted to the individual woman but should generally induce special reference to blood pressure, breasts, abdomen and pelvic organs and should also include cervical cytology.
Osteoporosis: Currently, long-term data of bone mineral density (BMD) and risk of fractures in users of ENDOVELLE are not available.
In patients who are at an increased risk of osteoporosis a careful risk-benefit assessment should be performed before starting ENDOVELLE because endogenous oestrogen levels are moderately decreased during treatment with ENDOVELLE.

Pregnancy: There is 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: Preclinical safety data under Actions). However, ENDOVELLE should not be administered to pregnant women because there is no need to treat endometriosis during pregnancy.
Lactation: ENDOVELLE should not be used during lactation. Physiochemical properties and animal data indicate excretion of dienogest in breast milk. A decision must be made whether to discontinue breast-feeding or to abstain from ENDOVELLE therapy taking into account the benefit of breast-feeding for the child and benefit of therapy for the woman.
Fertility: Based on the available data, ovulation is inhibited in the majority of patients during treatment with ENDOVELLE. However, ENDOVELLE is not a contraceptive.
If contraception is required a non-hormonal method should be used (See Precautions).
Based on available data, the menstrual cycle returns to normal within 2 months after cessation of treatment with ENDOVELLE.

Summary of the safety profile: Undesirable effects are more common during the first months after the start of intake of ENDOVELLE, and subside with duration of treatment. The following undesirable effects have been reported in users of ENDOVELLE. The most frequently reported undesirable effects during treatment that were considered at least possibly related to ENDOVELLE were headache, breast discomfort, depressed mood and acne.
Table 2, the frequencies of adverse drug reactions (ADRs) by MedDRA system organ classes (MedDRA SOCs) reported with ENDOVELLE are summarized in the table 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 (≥1/1,000 to <1/100). (See Table 2.)


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Description of selected adverse reaction: Uterine bleeding irregularities: The following bleeding patterns were observed: Amenorrhea, infrequent bleeding, frequent bleeding, irregular bleeding, prolonged bleeding, normal bleeding.

Note: The prescribing information of concomitant medication should be consulted to identify potential interactions.
Effects of other medication on ENDOVELLE: Progestins 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 ENDOVELLE and may result in undesirable effects e.g. 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 increasing the clearance of sex hormones (diminished efficacy by enzyme-induction), e.g.: Phenytoin, barbiturates, primidone, carbamazepine, rifampicin, and possibly also oxcarbazepine, topiramate, felbamate, griseofulvin, and products containing St. John's wort. Enzyme induction can already be observed after a few days of treatment. Maximum enzyme induction is generally seen within a few weeks. After cessation of drug therapy enzyme induction may be sustained for about 4 weeks.
Substances with variable effects on the clearance of sex hormones, e.g.: When co-administered with sex hormones, many HIV/HCV protease inhibitors and non-nucleoside reverse transcriptase inhibitors can increase or decrease plasma concentrations of the progestin. These changes may be clinically relevant in some cases.
Substances decreasing the clearance of sex hormones (enzyme inhibitors): Dienogest is a substrate of cytochrome P450 (CYP) 3A4. Strong and moderate CYP3A4 inhibitors such as azole antifungals (e.g. itraconazole, voriconazole, fluconazole), verapamil, macrolides (e.g. clarithromycin, erythromycin), diltiazem and grapefruit juice can increase plasma concentrations of the progestin.
Effects of ENDOVELLE on other medicinal products: Based on in vitro inhibition studies, a clinically relevant interaction of ENDOVELLE with the cytochrome P450 enzyme mediated metabolism of other medication is unlikely.
Drug-food interactions: A standardized high fat meal did not affect the bioavailability of ENDOVELLE.
Other forms of interactions: The use of progestins may influence the results of certain laboratory tests.
Effects of Laboratory tests: The use of progestogens may influence the results of certain laboratory tests, including biochemical parameters of liver, thyroid, adrenal and renal function, plasma levels of (carrier) proteins e.g. lipid/lipoprotein fractions, parameters of carbohydrate metabolism and parameters of coagulation and fibrinolysis. Changes generally remain within the normal laboratory range.

Store below 30°C.
Store in the outer carton to protect from light.

Oestrogens, Progesterones & Related Synthetic Drugs

G03DB08 - dienogest ; Belongs to the class of pregnadien derivative progestogens used in progestogenic hormone preparations.