Vinca

White, round and plain, with a diameter of 5 mm.
Each tablet contains: Dienogest 2 mg.

Pharmacology: Pharmacodynamics: 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.
Dienogest acts on endometriasis by reducing the endogenous production of oestradiol 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.
Pharmacokinetics: Absorption: Orally administered dienogest is rapidly and almost completely absorbed. Peak serum concentrations of 47 ng/ml are reached at about 1.5 hours 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). 10% of the total serum drug concentration is present as free steroid, 90% is non-specifically bound to albumin. The apparent volume of distribution (Vd/F) of dienogest is 40 L.
Metabolism/Biotransformation: 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/Excretion: Dienogest serum levels decrease in two phases. The terminal disposition phase is characterized by a half-life of approximately 9-10 hours. 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 half-life of urinary metabolites excretion is 14 hours. Following oral administration approximately 86% of the dose administered is eliminated within 6 days, the bulk of this amount excreted within the first 24h, 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 Dienogest (Vinca) can be predicted from single dose pharmacokinetics.
Pharmacokinetics in Special Population: Dienogest (Vinca) has not been studied specifically in renally impaired and with hepatic impairment subjects.
Toxicology: Preclinical Safety Data: Preclinical data reveal no special risks for humans based on conventional studies of 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 tumours.

For the 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 Dienogest (Vinca) is one 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.
Management of missed tablets: The efficacy of Dienogest (Vinca) 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 tablets, the woman should take one tablet only, as soon as she remembers, and should then continue the next day at her usual time. A tablet not absorbed due to vomiting or diarrhea should likewise be replaced by one tablet.
Additional information on special populations: Paediatric population: Dienogest (Vinca) is not indicated in children prior to menarche.
The efficacy of Dienogest (Vinca) in adolescents over a treatment period of 12 month was associated with a mean decrease in Bone Mineral Density (BMD) in the lumbar spine of 1.2%. After cessation of treatment, BMD increased again in these patients.
Loss of BMD is of particular concern during adolescence and early adulthood, a critical period of bone accretion. It is unknown if BMD decrease in this population will reduce peak bone mass and increase the risk for fracture in later life. Therefore, the treating physician should weigh the benefits of Dienogest (Vinca) against the possible risks of use in each individual adolescent patient (see Precautions and Pharmacology: Pharmacodynamics under Actions).
Geriatric Population: There is no relevant indication for use of Dienogest (Vinca) in the geriatric population.
Patients with hepatic impairment: Dienogest (Vinca) 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 Dienogest 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 Dienogest (Vinca) over 24 weeks of use was very well tolerated.

Dienogest (Vinca) 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 Dienogest (Vinca), treatment must be discontinued immediately: active venous thromboembolic disorder; arterial and cardiovascular disease, present or in 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.

Before starting Dienogest (Vinca) treatment, pregnancy must be excluded (see Use in Pregnancy & Lactation). During treatment, patients are advised to use non-hormonal methods of contraception (e.g. barrier method) if contraception is required.
Pregnancies that occur among users of progestogen-only preparations used for contraception (e.g. minipill) 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 Dienogest (Vinca) should be decided on only after carefully weighing the benefits against the risks.
As Dienogest (Vinca) is a progestogen-only preparation. It can be assumed that the special warnings and precautions for use of progestogen-only preparations are also valid for the use of Dienogest (Vinca) although not all of the warnings and precautions are based on respective findings in the clinical studies with Dienogest (Vinca).
If any of the conditions/risk factors mentioned as follows is present or deteriorates, an individual risk-benefit analysis should be done before treatment with Dienogest (Vinca) can be 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 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 Dienogest (Vinca) (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: 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 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 Dienogest (Vinca). 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 Dienogest (Vinca).
Changes in bleeding pattern: Dienogest (Vinca) treatment affects the menstrual bleeding pattern in the 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 Dienogest (Vinca). If bleeding is heavy and continuous over time, this may lead to anemia (severe in some cases). Discontinuation of Dienogest (Vinca) should be considered in such cases.
Changes in Bone Mineral Density (BMD): The use of Dienogest (Vinca) in adolescents (12 to 18 years) over a treatment period of 12 months was associated with a mean decrease in bone mineral density (BMD) in the lumbar spine of 1.2%. After cessation of treatment, BD increased again in these patients.
Loss of BMD is of particular concern during adolescence and early adulthood, a critical period of bone accretion. It is unknown if BMD decrease in this population will reduce peak bone mass and increase the risk for fracture in later life. (See Pediatric population under Dosage & Administration and Pharmacology: Pharmacodynamics under Actions).
Therefore, the treating physician should weigh the benefits of Dienogest (Vinca) against the possible risks of use in each individual adolescent patient also taking into account the presence of significant risk factors for osteoporosis (e.g. metabolic bone disease, family history of osteoporosis, low body mass index or eating disorders, such as anorexia nervosa or bulimia, chronic use of drugs that can reduce bone mass, e.g. anticonvulsants or corticosteroids, previous low trauma fracture, alcohol abuse and/or smoking).
Adequate intake of calcium and Vitamin D, whether from the diet or from supplements, is important for bone heath in women of all ages.
No BMD decrease was observed in adults (see Pharmacology: Pharmacodynamics under Actions).
Other conditions: Patients who have a history of depression should be carefully observed and the drug should be 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 Dienogest (Vinca), it is advisable to withdraw Dienogest (Vinca) and treat the hypertension. Recurrence of cholestatic jaundice and/or pruritus which occurred first during pregnancy or previous use of sex steroids necessitates the discontinuation of Dienogest (Vinca).
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 Dienogest (Vinca).
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 Dienogest (Vinca).
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 Dienogest (Vinca) should be decided on only after carefully weighing the benefits against the risks.
Persistent ovarian follicles (often referred to as functional ovarian cysts) may occur during the use of Dienogest (Vinca). Most of these follicles are asymptomatic, although some may be accompanied by pelvic pain.
Lactose: Patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption who are on a lactose-free diet should consider the amount contained in Dienogest (Vinca).
Effects on Ability to Drive and Use Machines: No effects on the ability to drive and use machines have been observed in users of products containing Dienogest.

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 also Pharmacology: Toxicology: Preclinical safety data under Actions). However, Dienogest (Vinca) should not be administered to pregnant women because there is no need to treat endometriosis during pregnancy.
Lactation: Treatment with Dienogest (Vinca) during lactation is not recommended. Physicochemical 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 Dienogest (Vinca) therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.
Fertility: Based on the available data, ovulation is inhibited in the majority of patients during treatment with Dienogest (Vinca). However, Dienogest (Vinca) is not a contraceptive.
Dienogest (Vinca) was not studied for contraceptive efficacy, but DNG 2 mg has been shown in a study involving 20 women to inhibit ovulation after 1 month of treatment.
If contraception is required a non-hormonal method should be used (See Dosage & Administration).
Based on available data, the menstrual cycle returns to normal within 2 months after cessation of treatment with Dienogest (Vinca).

Undesirable effects are more common during the first months after the start of intake of Dienogest (Vinca), and subside with duration of treatment. The following undesirable effects have been reported in users of Dienogest (Vinca).
The most frequently reported undesirable effects during treatment that were considered at least possible related to Dienogest (Vinca) were headache (9.0%), 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 Dienogest (Vinca) are summarized in the following table. Within each frequency grouping, undesirable effects are presented in order of decreasing frequency. Frequencies are defined as common. (See table.)

Click on icon to see table/diagram/image

Effects of other medication on Dienogest (Vinca): 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 Dienogest (Vinca) 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 the cessation of drug therapy enzyme induction may be sustained for about 4 weeks.
The effect of the CYP 3A4 inducer rifampicin was studied in healthy postmenopausal women. Co-administration of rifampicin with estradiol valerate/dienogest tablets led to significant decreases in steady state concentrations and systemic exposures of dienogest. The systemic exposure of dienogest at steady state, measured by AUC(0-24h), were decreased by 83%.
Substance with variable effects in 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 may increase plasma levels of the progestin.
In a study investigating the effect of CYP3A4 inhibitors (ketoconazole, erythromycin) on the combination of estradiol valerate/dienogest, steady state dienogest plasma levels were increased. Co-administration with the strong inhibitor ketoconazole resulted in a 186% increase of AUC(0-24h) at steady state for dienogest. When co-administered with the moderate inhibitor erythromycin, the AUC (0-24h) of dienogest at steady state were increased by 62%.
The clinical relevance of these interactions is unknown.
Effects of Dienogest (Vinca) on other medication: Based on in vitro inhibition studies, a clinically relevant interaction of Dienogest with the cytochrome P450 enzyme mediated metabolism of other medicaments is unlikely.
Note: The prescribing information of concomitant medication should be consulted to identify potential interactions.
Drug-food interaction: A standardized high fat meal did not affect the bioavailability of Dienogest (Vinca).
Other forms of interactions: 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.

Incompatibilities: There is no known incompatibility.

Keep the blister in the outer carton in order to protect from the light. Store at temperatures not exceeding 30°C.

Oestrogens, Progesterones & Related Synthetic Drugs

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

Rx