Instructions for use Dienogest Zentiva tablets 2 mg No. 84
Composition
active ingredient: dienogest;
1 film-coated tablet contains dienogest 2 mg;
excipients: lactose monohydrate, corn starch, povidone (K-30), sodium starch glycolate (type A), magnesium stearate;
film coating: Aqua Polish white 014.17MS, containing hypromellose (E 464), hydroxypropylcellulose (E 463), talc (E 553b), hydrogenated cottonseed oil, titanium dioxide (E 171).
Dosage form: Film-coated tablets.
Main physicochemical properties: white, round, biconvex, film-coated tablets, embossed with "2" on one side.
Pharmacotherapeutic group
Hormones of the sex glands and drugs used in pathologies of the genital organs. Progestogens. ATX code G03D B08.
Pharmacological properties
Pharmacodynamics
Dienogest is a nortestosterone derivative without androgenic and with some antiandrogenic activity, which is approximately one third of the activity of cyproterone acetate. Dienogest binds to progesterone receptors in the uterus with only 10% relative affinity. Despite its low affinity for progesterone receptors, dienogest exhibits a strong progestogenic effect in vivo. Dienogest does not exhibit significant androgenic, mineralocorticoid, or glucocorticoid activity in vivo.
Dienogest affects endometriosis by reducing endogenous estradiol production and thus inhibiting the trophic effects of estradiol on eutopic and ectopic endometrium. With continuous use, dienogest leads to the creation of a hypoestrogenic, hypergestagenic endocrine environment, which causes initial decidualization of endometrial tissue with subsequent atrophy of endometrioid foci.
Performance data
The superiority of dienogest over placebo was demonstrated in a three-month study in 198 patients with endometriosis. Pelvic pain associated with endometriosis was measured using a visual analogue scale (0-100 mm). After 3 months of dienogest therapy, a statistically significant difference was found compared to placebo (D = 12.3 mm; 95% CI: 6.4–18.1; p
After 3 months of treatment, a reduction in the number of pelvic pain manifestations by 50% or more in the absence of an increase in the dose of analgesics was observed in 37.3% of patients taking dienogest (placebo: 19.8%); a reduction in the number of pelvic pain manifestations by 75% or more in the absence of an increase in the dose of analgesics was observed in 18.6% of patients taking dienogest (placebo: 7.3%).
An extension of this study showed continued reduction in endometriosis-related pelvic pain with treatment for up to 15 months.
Data from three studies involving patients receiving dienogest 2 mg daily indicate a significant reduction in endometrioid lesions after 6 months of treatment.
A small study of dienogest at a dose of 1 mg per day showed no ovulation after 1 month of therapy. Dienogest has not been studied for contraceptive efficacy in larger studies.
Safety data
During the use of dienogest, the level of endogenous estrogen decreased moderately.
To date, there are no long-term data on bone mineral density (BMD) and fracture risk in patients taking dienogest. BMD was assessed in 21 adult patients before and after 6 months of dienogest treatment, and the mean value did not decrease. In 29 patients taking leupropelin acetate (LA), the mean decrease was 4.04% ± 4.84 over the same period (∆ between groups = 4.29%; 95%CI: 1.93–6.66; p,0003).
No significant differences in standard laboratory parameters (hematological blood test, biochemical blood test, liver enzymes, fats and glycohemoglobin) were recorded during dienogest administration for a period of up to 15 months (n=168).
Safety data for teenagers
The safety and efficacy of dienogest on BMD were investigated in an uncontrolled clinical trial of 12 months duration in 111 girls (12-18 years) with clinically confirmed endometriosis (see sections 4.4 and 5.1). The mean change in lumbar spine (L2-L4) BMD from baseline was 1.2% in 103 patients. The subgroup of patients with decreased BMD was re-examined 6 months after the end of treatment, and an increase of 0.6% in BMD was observed.
Preclinical safety data
Non-clinical data reveal no special hazard for humans based on conventional studies of repeated dose toxicity, genotoxicity, carcinogenic potential, and toxicity to reproduction. However, it should be noted that sex steroids may induce the growth of certain hormone-dependent tissues and tumors.
Pharmacokinetics
Absorption
Orally administered dienogest is rapidly and completely absorbed. Peak serum concentrations of 47 ng/ml are reached approximately 1.5 hours after a single oral dose. Bioavailability is approximately 91%. The pharmacokinetics of dienogest are directly proportional to its dose over the range of 1-8 mg.
Dienogest binds to serum albumin and does not bind to sex hormone-binding globulin or corticoid-binding globulin. 10% of the total blood concentration of the drug is present as free steroids, 90% is nonspecifically bound to albumin.
The theoretical volume of distribution of dienogest (Vd/F) is 40 liters.
Biotransformation
Dienogest is metabolized via the known steroid metabolism pathway to form endocrine-inactive metabolites. Based on in vitro inhibition studies and in vivo studies, CYP3A4 is the major enzyme involved in the metabolism of dienogest. The metabolites are eliminated very rapidly, so the majority of the drug concentration in plasma is unchanged dienogest.
The metabolic clearance rate in serum Cl/F is 64 ml/min.
Breeding
The serum concentration of dienogest decreases in two phases. In the terminal distribution phase, the half-life is approximately 9-10 hours. Dienogest is excreted in the form of metabolites in the urine, the ratio to the feces is 3:1 at an oral dose of 0.1 mg/kg. The half-life of the metabolites is almost 14 hours.
When administered orally, about 86% of the dose is excreted within 6 days, with a significant portion excreted within 24 hours, mainly in the urine.
Balanced state
The pharmacokinetics of dienogest are not affected by the level of sex hormone-binding globulin. With daily administration, the concentration of the drug in the blood serum increases by 1.24 times and reaches a steady state after 4 days of treatment. The pharmacokinetics of dienogest during repeated administration can be predicted based on data on the pharmacokinetics of a single dose of the drug.
Pharmacokinetic properties of the drug among special population groups
No specific studies have been conducted on the use of dienogest in the treatment of patients with renal impairment.
The use of dienogest in the treatment of patients with hepatic insufficiency has not been studied.
Clinical characteristics
Indication
Treatment of endometriosis.
Contraindication
Dienogest Zentiva should not be used if any of the following conditions or diseases are present. This information is partly based on the use of other progestogen-only products. If any of these conditions or diseases occur for the first time while using Dienogest Zentiva, the drug should be discontinued immediately.
Venous thromboembolism in active form.
Current or history of arterial or cardiovascular disease (e.g., myocardial infarction, cerebrovascular accident, ischemic heart disease).
Diabetes mellitus with vascular damage.
Current or history of severe liver disease, until liver function tests return to normal.
Current or history of liver tumors (benign or malignant).
Known or suspected sex hormone-dependent malignant tumors.
Vaginal bleeding of unknown etiology.
Hypersensitivity to the active substance or to any of the components of the drug.
Interaction with other medicinal products and other types of interactions
Note: To identify possible interactions, consult the instructions for medical use of concomitantly used medications.
Effects of other drugs on dienogest
Progestogens, including dienogest, are metabolized mainly by the cytochrome P450 3A4 (CYP3A4) system, which is located in the intestinal mucosa and in the liver. Therefore, inducers or inhibitors of CYP3A4 may affect the metabolism of progestogens. Increased clearance of sex hormones due to enzyme induction may reduce the therapeutic effect of Dienogest Zentiva and lead to undesirable effects, such as changes in the pattern of menstrual bleeding.
Reduced clearance of sex hormones due to enzyme inhibition may reduce the therapeutic effect of Dienogest Zentiva and lead to the development of adverse reactions.
- Substances that increase the clearance of sex hormones (reduced efficacy by enzyme induction), such as phenytoin, barbiturates, primidone, carbamazepine, rifampicin, and possibly oxcarbazepine, topiramate, felbamate, griseofulvin and products containing St. John's wort (Hypericum perforatum).
Enzyme induction may occur after a few days of therapy. Maximum enzyme induction is generally seen after a few weeks.
Enzyme induction may persist for up to 4 weeks after discontinuation of therapy.
The effect of the CYP 3A4 inducer rifampicin was studied in healthy postmenopausal women. Co-administration of rifampicin with estradiol valerate/dienogest tablets resulted in a significant decrease in the steady-state concentration and systemic exposure of dienogest and estradiol. The steady-state systemic exposure of dienogest and estradiol, as measured by AUC (0–24 hours), was reduced by 83% and 44%, respectively.
- Substances with different effects on the clearance of sex hormones.
- Substances that reduce the clearance of sex hormones (enzyme inhibitors).
Dienogest is a substrate of cytochrome P450 (CYP) 3A4.
The clinical significance of potential interactions with enzyme inhibitors remains unknown.
Concomitant use of strong CYP3A4 inhibitors may increase plasma concentrations of dienogest.
Concomitant use with the strong CYP3A4 inhibitor ketoconazole resulted in a 2.9-fold increase in the steady-state AUC (0-24 hours) of dienogest. Concomitant use with the moderate inhibitor erythromycin resulted in a 1.6-fold increase in the steady-state AUC (0-24 hours).
Effect of dienogest on other medicinal products
Based on the results of in vitro inhibition studies, clinically significant interactions of dienogest with other drugs metabolized by cytochrome P450 enzymes are unlikely.
Interaction with food products
Consuming a high-fat meal did not affect the bioavailability of Dienogest Zentiva.
Laboratory tests
The use of progestogens may affect the results of some laboratory tests, including biochemical parameters of the liver, thyroid gland, renal and adrenal function, levels of proteins (carriers) in the blood plasma (e.g. GSK and lipid/lipoprotein fractions), parameters of carbohydrate metabolism and indicators of coagulation and fibrinolysis. Changes usually remain within the laboratory norm.
Application features
Reservation.
Since Dienogest Zentiva is a progestogen-only preparation, it is considered that the special warnings and precautions for the use of progestin-containing preparations also apply to Dienogest Zentiva, although not all warnings and precautions are based on the relevant results of clinical studies with this particular preparation.
If any of the following conditions/risk factors worsen or appear for the first time, an individual risk/benefit analysis should be performed before initiating or continuing the use of Dienogest Zentiva.
Heavy uterine bleeding
Uterine bleeding, for example in women with uterine adenomyosis or uterine leiomyoma, may increase with the use of Dienogest Zentiva. If the bleeding is severe and does not stop for a long time, it may lead to anemia (in some cases severe). In this case, it is necessary to consider stopping the drug.
Change in bleeding pattern
Treatment with Dienogest Zentiva affects the pattern of menstrual bleeding in most women (see section "Adverse reactions").
Circulatory disorders
There is limited evidence from epidemiological studies of an association between the use of progestogen-only contraceptives and an increased risk of myocardial infarction or cerebral thromboembolism. The risk of cardiovascular and cerebral events is more likely to be related to age, hypertension and smoking. In women with hypertension, the risk of stroke may be slightly increased with the use of progestogen-only contraceptives.
Some studies suggest a slight, but not statistically significant, increased risk of venous thromboembolism (VTE) (deep vein thrombosis, pulmonary embolism) associated with the use of progestogen-only products. Generally accepted factors that increase the risk of VTE include: personal or family history (e.g., VTE in siblings or parents at a relatively young age); age; obesity, prolonged immobilization, major surgery or trauma. In the event of prolonged immobilization, it is recommended to discontinue Dienogest Zentiva (at least 4 weeks before elective surgery) and not to restart it until 2 weeks after full recovery.
The increased risk of thromboembolism in the postpartum period should be taken into account.
If symptoms of venous and arterial thrombotic diseases occur or are suspected, treatment should be discontinued.
A meta-analysis of 54 epidemiological studies suggests a small increased relative risk (RR=1.24) of breast cancer in women using oral contraceptives (OCs), mainly those containing estrogen-progestogen. 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 increase in breast cancer diagnoses in women who use or have recently used COCs is small in relation to the overall risk of breast cancer. There is a similar risk of breast cancer in women who have used progestogen-only pills or COCs. However, the information on progestogen-only pills is based on a much smaller number of women using them and is therefore less conclusive than the data on COCs. The results of these studies do not provide evidence of a causal relationship. The increased risk may be due to earlier diagnosis of breast cancer in women who use OCs, or to the biological action of these drugs, or a combination of both. There is a tendency for breast cancer detected in women who have ever used OCs to be clinically less severe than in those who have never used OCs.
In isolated cases, benign and, even more rarely, malignant liver tumors have been observed in women taking hormonal agents similar to those contained in Dienogest Zentiva, which in some cases have led to life-threatening intra-abdominal bleeding. In the event of complaints of severe epigastric pain, liver enlargement or signs of intra-abdominal bleeding, the possibility of a liver tumor should be considered in the differential diagnosis in women taking Dienogest Zentiva.
Osteoporosis
Changes in BMD.
The use of dienogest in adolescents (12–18 years) during a treatment period of 12 months was associated with a decrease in mean BMD at the lumbar spine (L2–L4) of 1.2%. After discontinuation of treatment, BMD increased again in these patients.
The mean relative change in BMD from baseline to end of treatment was 1.2% with a range between -6% and 5% (95% CI: -1.70% and -0.78%, n=103). Repeat measurement 6 months after end of treatment in the subgroup with reduced BMD values showed a trend towards recovery (mean relative change from baseline: -2.3% at end of treatment and -0.6% 6 months after end of treatment with a range between -9% and 6% (95% CI: -1.20% and 0.06% (n=60)).
BMD loss is of particular importance during adolescence and early puberty, a critical period of bone growth. It is unknown whether BMD reduction in this population will reduce peak bone mass and increase the risk of bone fracture in old age (see sections 5.1 and 5.2).
Before starting treatment, the doctor should weigh the benefits of using Dienogest Zentiva and the possible risks of use for each individual adolescent, also taking into account the presence of significant risk factors for osteoporosis.
Adequate intake of calcium and vitamin D through diet or supplementation is important for bone health in women of all ages.
No decrease in BMD was observed in adults (see section "Pharmacological properties").
In patients at increased risk of osteoporosis, a careful benefit/risk assessment should be performed before initiating treatment with Dienogest Zentiva, as endogenous estrogen levels are moderately reduced during treatment with Dienogest Zentiva (see section 5.1).
Other states
Patients with a history of depression should be carefully monitored and the drug should be discontinued if severe depression develops.
Dienogest usually does not affect blood pressure in normotensive women. However, if prolonged clinically significant hypertension occurs during use of the drug, it is recommended to discontinue Dienogest Zentiva and treat the hypertension.
If cholestatic jaundice and/or pruritus that occurred during pregnancy or previous use of sex hormones recur, the drug should be discontinued.
Dienogest may have a minor effect on peripheral insulin resistance and glucose tolerance. Women with diabetes mellitus, especially those with a history of gestational diabetes mellitus, should be carefully monitored during the use of Dienogest Zentiva.
Chloasma may occasionally develop, especially in women with a history of chloasma during pregnancy. Women prone to chloasma should avoid exposure to direct sunlight or ultraviolet radiation while taking Dienogest Zentiva.
Persistent follicles (often referred to as functional ovarian cysts) may occur during the use of Dienogest Zentiva. Most of these follicles are asymptomatic, although some may be accompanied by pelvic pain.
Not used in geriatric practice.
Lactose
One Dienogest Zentiva tablet contains 57.20 mg of lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption who are on a lactose-free diet should take into account the amount of this substance in a Dienogest Zentiva tablet.
Use during pregnancy or breastfeeding
Pregnancy
There are limited data from the use of dienogest in pregnant women. Animal studies do not indicate direct or indirect reproductive toxicity (see section 5.1).
Dienogest Zentiva is not recommended for use in pregnant women, as there is no need to treat endometriosis during pregnancy.
Breastfeeding period
Treatment with Dienogest Zentiva during breastfeeding is not recommended. It is not known whether dienogest is excreted in human milk. Animal data indicate that dienogest is excreted in human milk. A decision must be made whether to discontinue breast-feeding or to discontinue Dienogest Zentiva therapy taking into account the benefit of breast-feeding for the child and the need for therapy for the woman.
Fertility
Based on the available data, it can be stated that ovulation is inhibited in most patients during treatment with Dienogest Zentiva. However, Dienogest Zentiva is not a contraceptive.
If contraception is required, a non-hormonal method of contraception should be used in addition (see section “Method of administration and dosage”).
Based on the available data, it can be stated that the menstrual cycle returns to normal within 2 months after discontinuation of treatment with Dienogest Zentiva.
Ability to influence reaction speed when driving vehicles or other mechanisms
No effects on the ability to drive and use machines were observed in patients taking drugs containing dienogest.
Method of administration and doses
Method of application
For oral use.
Dosage
Take 1 tablet daily without a break in taking the drug at about the same time, with a small amount of liquid. The tablets can be taken regardless of food intake.
The tablets should be taken regularly, regardless of menstrual bleeding. As soon as the tablets from one package are finished, start taking the tablets from the next package without taking a break in taking the medicine.
There is no experience of treatment with Dienogest Zentiva in patients with endometriosis for longer than 15 months.
You can start taking the drug on any day of the menstrual cycle.
The use of any hormonal contraceptives should be discontinued before starting therapy with Dienogest Zentiva. If contraception is necessary, a non-hormonal method of contraception (e.g., a barrier method) should be used in addition.
Skipping a medication
In case of missed tablets, vomiting and/or diarrhoea (occurring within 3-4 hours after taking the tablet), the effectiveness of Dienogest Zentiva may be reduced. If one or more tablets are missed, one tablet should be taken as soon as the woman remembers and the next tablet should be taken at the usual time. Similarly, a tablet not absorbed due to vomiting or diarrhoea should be replaced by another tablet.
Additional information regarding use in special patient groups
Elderly patients
There are no relevant indications for the use of Dienogest Zentiva in patients in this group.
Liver failure
The drug is contraindicated in patients with current or history of severe liver disease (see section "Contraindications").
Kidney failure
There is no evidence to suggest the need for dose adjustment in patients with renal impairment.
Children.
Dienogest Zentiva is contraindicated in children before their first menstruation.
The safety and efficacy of dienogest were studied in uncontrolled clinical trials for 12 months in 111 girls (12-18 years) with clinically confirmed endometriosis (see sections “Pharmacological properties”, “Special instructions for use”).
The use of Dienogest Zentiva in adolescents during a treatment period of 12 months was associated with a decrease in mean lumbar spine BMD of 1.2%. After discontinuation of treatment, BMD increased again in these patients.
BMD loss is particularly important during adolescence and early puberty, a critical period for bone growth. It is not known whether decreased BMD in this population will reduce peak bone mass and increase the risk of bone fracture in old age.
Therefore, the doctor should weigh the benefits of using Dienogest Zentiva and the possible risks of use for each individual adolescent (see sections “Pharmacological properties”, “Peculiarities of use”).
Overdose
Acute toxicity studies conducted with dienogest did not indicate a risk of acute adverse reactions in case of unintentional administration of several daily therapeutic doses. No specific antidotes exist. The use of 20-30 mg of dienogest per day (which is 10-15 times higher than the dose in a Dienogest Zentiva tablet) for more than 24 weeks was very well tolerated.
Adverse reactions
Adverse reactions are described according to MedDRA.
Adverse reactions most often develop during the first months of dienogest use and disappear during treatment. Changes in bleeding patterns, such as spotting, irregular bleeding or amenorrhea, may occur.
The following adverse reactions have been reported during treatment with dienogest. The most frequently reported adverse reactions during treatment with dienogest include headache (9.0%), breast discomfort (5.4%), depressed mood (5.1%) and acne (5.1%).
In addition, dienogest treatment affects the menstrual bleeding pattern in most women. The menstrual bleeding pattern was assessed systematically using patient diaries and analyzed using the WHO method during a 90-day reporting period. During the first 90 days of treatment, the following bleeding patterns were observed: amenorrhea (1.7%), infrequent bleeding (27.2%), frequent bleeding (13.4%), irregular bleeding (35.2%), prolonged bleeding (38.3%), normal menstrual bleeding, i.e. none of the previous categories (19.7%). During the fourth reporting period, the following bleeding patterns were observed: amenorrhea (28.2%), infrequent bleeding (24.2%), frequent bleeding (2.7%), irregular bleeding (21.5%), prolonged bleeding (4.0%), normal menstrual bleeding, i.e. none of the previous categories (22.8%). Changes in menstrual bleeding patterns have only occasionally been reported as adverse reactions in female patients (see table of adverse reactions).
Table 1 lists the adverse reactions according to the MedDRA classification (MedDRA SOCs) reported during treatment with dienogest and their frequency.
Within each group, adverse reactions are listed in order of decreasing frequency: common (≥ 1/100 to pooled data from four clinical studies.
Table 1
Organ systems (MedDRA)
Often
Infrequently
Blood and lymphatic system disorders
anemia
Metabolism and metabolic disorders
weight gain
weight loss, increased appetite
Mental disorders
depressed mood, sleep disturbances, nervousness, decreased libido, mood swings
anxiety, depression, mood lability
From the nervous system
headache, migraine
impaired autonomic regulation, impaired attention
From the organs of vision
dry eyes
From the side of the organs of hearing and vestibular apparatus
tingle
From the heart
nonspecific circulatory disorders, increased heartbeat
From the vascular side
arterial hypotension
Respiratory, thoracic and mediastinal disorders
dyspnea
Gastrointestinal tract
nausea, abdominal pain, flatulence, bloating, vomiting
diarrhea, constipation, abdominal discomfort, gastrointestinal inflammation, gingivitis
Skin and subcutaneous tissue disorders
acne, alopecia
dry skin, hyperhidrosis, itching, hirsutism, onychoclasia, dandruff, dermatitis, hair growth disorders, photosensitivity reactions, pigmentation changes
Musculoskeletal and connective tissue disorders
back pain
bone pain, muscle cramps, pain in limbs, feeling of heaviness in limbs
Renal and urinary disorders
urinary tract infection
Reproductive system and breast disorders
breast discomfort, ovarian cyst, hot flashes, uterine/vaginal bleeding,
including blood smear
vaginal candidiasis, vulvar and vaginal dryness, genital discharge, pelvic pain, atrophic vulvovaginitis, breast enlargement, cystic fibrosis of the breasts, breast engorgement
General disorders and local reactions
asthenic conditions, irritability
edema
The following adverse reactions were also observed: follicle persistence, increased appetite, hypersensitivity reactions.
Other serious adverse reactions have been observed with the use of steroid sex hormones and progestogens (see section "Special warnings and precautions for use"): venous and arterial thromboembolic disorders, hypertension, myocardial infarction, stroke, breast neoplasms, liver tumors, back discomfort, chloasma, cholestatic jaundice, osteoporosis (see below), changes in glucose tolerance or effects on peripheral insulin resistance.
Decreased BMD
The use of dienogest in adolescents (12-18 years) during a treatment period of 12 months was associated with a decrease in mean BMD at the lumbar spine (L2-L4) of 1.2%. After discontinuation of treatment, BMD increased again in these patients.
Reporting possible adverse reactions
In case of undesirable manifestations, adverse reactions or in case of lack of therapeutic effect, it is necessary to report to the address "Zentiva Ukraine" LLC, 02660, Kyiv, Brovarskyi Avenue, 5 "I", tel./fax +38 044 517-75-00, e-mail address PV-Ukraine@zentiva.com
Expiration date
2 years.
Storage conditions
Does not require special storage conditions.
Keep out of reach of children.
Packaging
14 tablets in a blister. 2 or 6 blisters in a cardboard pack.
Vacation category
According to the recipe.
Producer
Haupt Pharma Münster GmbH.
Location of the manufacturer and address of its place of business.
Schleebrüggenkamp 15, 48159 Münster, Germany.
