DIENOPHAM

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT DİENOFAM (DIENOFAM)

Composition:

Active substance: dienogest;

1 tablet contains 2 mg of dienogest;

Excipients: lactose monohydrate, corn starch, povidone K30, ethanol, magnesium stearate.

Pharmaceutical form. Tablets.

Main physicochemical properties: white, round tablets with a smooth surface.

Pharmacotherapeutic group. Sex gland hormones and drugs used in pathologies of genital organs. Progestogens.

ATC code G03DB08.

Pharmacological Properties

Pharmacodynamics

Dienogest is a derivative of nortestosterone with no androgenic activity and with some antiandrogenic activity, approximately one-third 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 exerts 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, thereby suppressing the trophic effects of estradiol on both eutopic and ectopic endometrial tissue. With continuous administration, dienogest creates a hypoestrogenic, hypergestagenic endocrine environment, leading initially to decidualization of endometrial tissue, followed by atrophy of endometriotic lesions.

Pharmacokinetics

Absorption

After oral administration, dienogest is rapidly and completely absorbed. Maximum serum concentration is reached within 1.5 hours after a single oral dose and amounts to 47 ng/mL. The bioavailability of dienogest is approximately 91%. The pharmacokinetics of dienogest are dose-dependent within the dose range of 1–8 mg.

Distribution

Dienogest binds to serum albumin and does not bind to sex hormone-binding globulin (SHBG) or corticosteroid-binding globulin (CBG). Only 10% of the total dienogest concentration in serum is present as free steroid, while 90% is nonspecifically bound to albumin. The apparent volume of distribution of dienogest is 40 L.

Metabolism

Dienogest is completely metabolized via known steroid metabolic pathways, forming predominantly endocrinologically inactive metabolites. Based on in vitro and in vivo studies, CYP3A4 is the primary enzyme involved in the metabolism of dienogest. These metabolites are rapidly eliminated from plasma such that unchanged dienogest remains the predominant compound in plasma.

The plasma clearance rate is 64 mL/min.

Elimination

Serum dienogest levels decline in a biphasic manner, with an elimination half-life of 9–10 hours. After an oral dose of 0.1 mg/kg, dienogest is excreted in the form of metabolites in urine and feces in a ratio of approximately 3:1. The elimination half-life of metabolites in urine is approximately 14 hours. Within 6 days after oral administration, 86% of the administered dose is excreted from the body, with most of this amount eliminated within the first 24 hours, primarily via urine.

Steady State

The pharmacokinetics of dienogest are independent of SHBG levels. With daily administration, serum concentrations increase by a factor of 1.24, reaching steady state within 4 days of treatment. The pharmacokinetics of dienogest after repeated dosing can be predicted based on data from single-dose pharmacokinetic studies.

Pharmacokinetics in Special Patient Populations

The pharmacokinetics of DIENOPHARM have not been studied in patients with renal impairment.

The pharmacokin游戏副本 of DIENOPHARM have not been studied in patients with hepatic impairment.

Clinical characteristics.

Indications.

Treatment of endometriosis.

Contraindications.

The drug should not be used if any of the conditions or diseases listed below are present. This information is partly based on the use of other drugs containing only progestogens. If any of these conditions or diseases occur for the first time during treatment with DIENOPHARM, the drug should be discontinued immediately.

• Active venous thromboembolism (VTE).
• Arterial or cardiovascular diseases currently present or in medical history (e.g., myocardial infarction, cerebrovascular event, ischemic heart disease).
• Diabetes mellitus with vascular complications.
• Severe liver disease currently present or in medical history until liver function tests return to normal.
• Liver tumors currently present or in medical history (benign or malignant).
• Known or suspected hormone-dependent malignant neoplasms.
• Vaginal bleeding of unknown etiology.
• Hypersensitivity to the active substance or to any of the excipients of the drug.

Interaction with other medicinal products and other forms of interaction.

Note: To identify possible interactions, the instructions for medical use of concomitantly administered medicinal products should be consulted.

Effect of other drugs on DIENOPHARM

Progestogens, including dienogest, are primarily metabolized by the cytochrome P450 3A4 (CYP3A4) system located in the intestinal mucosa and 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 DIENOPHARM and lead to adverse effects, such as changes in the pattern of menstrual bleeding.

Decreased clearance of sex hormones due to enzyme inhibition may reduce the therapeutic effect of DIENOPHARM and lead to the development of adverse reactions.

• Substances that increase the clearance of sex hormones (reduced efficacy via enzyme induction), e.g.: phenytoin, barbiturates, primidone, carbamazepine, rifampicin, and possibly oxcarbazepine, topiramate, felbamate, griseofulvin, and products containing St. John's wort (Hypericum perforatum).

Enzyme induction may be observed after several days of therapy. Maximum enzyme induction is generally reached after several weeks.

Enzyme induction may persist for up to 4 weeks after discontinuation of therapy.

The effect of the CYP3A4 inducer rifampicin was studied in healthy postmenopausal women. Concomitant administration of rifampicin with an oral formulation of estradiol valerate/dienogest resulted in a significant reduction in the steady-state concentration and systemic exposure of dienogest and estradiol. The systemic exposure of dienogest and estradiol at steady state, measured as AUC (0–24 hours), decreased by 83% and 44%, respectively.

• Substances with variable effects on the clearance of sex hormones.

Concomitant use of sex hormones with large combinations of HIV protease inhibitors and non-nucleoside reverse transcriptase inhibitors, in combination with hepatitis C virus inhibitors, may increase or decrease plasma levels of progestin. The combined effect of these changes may be clinically significant in some cases.

• 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 administration with the strong CYP3A4 enzyme inhibitor ketoconazole led to a 2.9-fold increase in the steady-state AUC (0–24 hours) of dienogest. Concomitant administration with the moderate inhibitor erythromycin led to a 1.6-fold increase in the steady-state AUC (0–24 hours) of dienogest.

Effect of dienogest on other medicinal products

Based on in vitro inhibition studies, clinically relevant interactions between dienogest and other drugs whose metabolism is mediated by cytochrome P450 enzymes are unlikely.

Interaction with food

Consumption of a high-fat meal does not affect the bioavailability of DIENOPHARM.

Laboratory tests

The use of progestogens may affect the results of certain laboratory tests, including liver, thyroid, kidney, and adrenal gland function tests, plasma protein levels (carriers) (e.g., SHBG and lipid/lipoprotein fractions), carbohydrate metabolism parameters, and coagulation and fibrinolysis parameters. Changes are usually within the normal laboratory range.

Special precautions.

Warnings

Since DIENOFAM is a progestogen-only preparation, it is considered that special warnings and safety measures regarding the use of progestin-containing preparations also apply to DIENOFAM, although not all warnings and precautions are based on appropriate clinical trial results specifically for this drug.

If any of the conditions/factors listed below worsen or occur for the first time, an individual risk/benefit assessment must be performed before initiating or continuing treatment with DIENOFAM.

Severe uterine bleeding

Uterine bleeding, for example in women with adenomyosis or uterine leiomyoma, may increase during treatment with DIENOFAM. If bleeding is heavy and persistent over a prolonged period, it may lead to anemia (in some cases, severe). In such cases, discontinuation of the drug should be considered.

Changes in bleeding pattern

Treatment with DIENOFAM affects the nature of menstrual bleeding in most women (see section "Adverse reactions").

Circulatory disorders

Epidemiological studies have provided limited data on a possible association between the use of progestogen-only preparations and an increased risk of myocardial infarction or cerebral thromboembolism. Cardiovascular and cerebrovascular events are more likely related to age, hypertension, and smoking. In women with arterial hypertension, the risk of stroke may slightly increase with the use of progestogen-only preparations.

Some studies suggest a certain, although not statistically significant, increased risk of venous thromboembolism (VTE) (deep vein thrombosis, pulmonary embolism) associated with progestogen-only preparations. Well-established factors increasing 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 cases of prolonged immobilization, use of DIENOFAM should be discontinued (in case of planned surgery – at least 4 weeks prior to the procedure) and should not be restarted until at least 2 weeks after full recovery.

An increased risk of thromboembolism should be considered during the postpartum period.

If symptoms of venous or arterial thrombotic disorders occur or are suspected, treatment should be discontinued immediately.

Tumors

A meta-analysis of 54 epidemiological studies indicates a slight increase in relative risk (RR = 1.24) of breast cancer in women using oral contraceptives (OCs), particularly combined estrogen-progestogen contraceptives. This increased risk gradually disappears within 10 years after discontinuation of combined oral contraceptives (COCs). Since breast cancer is rare in women under 40 years of age, the increase in diagnosed cases among women currently or recently using COCs is small relative to the overall risk of breast cancer. The risk of detecting breast cancer is similar in women using progestogen-only preparations or COCs. However, data on progestogen-only preparations are based on a much smaller number of users and are therefore less conclusive than data on COCs. These study results do not provide evidence of a causal relationship. The increased risk may be due to earlier diagnosis of breast cancer in OC users, a biological effect of these drugs, or a combination of both factors. A trend has been observed that breast cancer diagnosed in women who have ever used OCs tends to be less advanced clinically than in those who have never used oral contraceptives.

In rare cases, benign and even more rarely malignant liver tumors have been observed in women using hormonal substances similar to the one contained in DIENOFAM, which in some instances led to life-threatening intra-abdominal bleeding. In case of complaints of severe epigastric pain, hepatomegaly, or signs of intra-abdominal bleeding, the possibility of a liver tumor should be considered in the differential diagnosis of women taking DIENOFAM.

Osteoporosis

Changes in bone mineral density (BMD).

Use of DIENOFAM in adolescents (12–18 years) over a 12-month treatment period was associated with a mean decrease in 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% to –0.78%, n=103). Repeat measurements 6 months after treatment in a subgroup with reduced BMD values showed a trend toward recovery (mean relative change from baseline: –2.3% at end of treatment and –0.6% at 6 months post-treatment, range between –9% and 6%; 95% CI: –1.20% to 0.06%, n=60).

Changes in BMD are of particular importance during adolescence and early puberty, which are critical periods for bone growth. It is unknown whether reduced BMD in adolescents of this group will reduce peak bone mass and increase the risk of fractures in later life (see section "Pharmacological properties" and "Children").

Before initiating treatment, physicians should weigh the benefits of using DIENOFAM against potential risks for each individual adolescent, also considering the presence of significant risk factors for osteoporosis.

Adequate intake of calcium and vitamin D through diet or dietary supplements is important for maintaining healthy bone in women of all ages.

No decrease in BMD was observed in adult women (see section "Pharmacological properties").

In patients at increased risk of osteoporosis, a careful risk/benefit assessment should be performed before starting treatment with DIENOFAM, as endogenous estrogen levels are moderately reduced during treatment (see section "Pharmacodynamics").

Other conditions

Patients with a history of depression should be closely monitored, and treatment should be discontinued if severe depressive symptoms develop.

Dienogest generally does not affect blood pressure in normotensive women. However, if prolonged clinically evident arterial hypertension develops during treatment, DIENOFAM should be discontinued and hypertension treated.

If cholestatic jaundice and/or pruritus, which occurred during pregnancy or previous use of sex hormones, recurs, treatment with DIENOFAM should be discontinued.

Dienogest may have a minor effect on peripheral insulin resistance and glucose tolerance. Women with diabetes mellitus, particularly those with a history of gestational diabetes, should be closely monitored during treatment with DIENOFAM.

Melasma may occasionally develop, especially in women with a history of melasma of pregnancy. Women prone to melasma should avoid direct sunlight or ultraviolet radiation during treatment with DIENOFAM.

The likelihood of ectopic pregnancy in women using progestogen-only contraceptives is higher than in women using COCs. Therefore, for women with a history of ectopic pregnancy or impaired tubal function, the decision to use DIENOFAM should be made only after careful benefit/risk assessment.

During treatment with DIENOFAM, follicular persistence (often referred to as functional ovarian cysts) may occur. Most of these follicles are asymptomatic, although some may be associated with pelvic pain.

Not used in geriatric practice.

Lactose

One tablet of DIENOFAM contains 62.8 mg of lactose monohydrate. Patients with rare hereditary disorders of galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption who are on a lactose-free diet should take into account the amount of this substance in DIENOFAM tablets.

Use during pregnancy or breastfeeding.

Pregnancy

Limited data are available on the use of dienogest in pregnant women. Animal studies do not indicate direct or indirect risks of reproductive toxicity (see section "Pharmacological properties").

DIENOFAM is not recommended for use in pregnant women, as there is no need to treat endometriosis during pregnancy.

Breastfeeding period

Use of DIENOFAM during breastfeeding is not recommended. It is unknown whether dienogest passes into human breast milk. Animal studies indicate that dienogest is excreted in breast milk. A decision should be made whether to discontinue breastfeeding or discontinue therapy with DIENOFAM, taking into account the benefits of breastfeeding for the child and the necessity of therapy for the mother.

Fertility

Based on available data, ovulation is inhibited in most patients during treatment with DIENOFAM. However, DIENOFAM is not a contraceptive.

If contraception is needed, a non-hormonal method of contraception should be used additionally (see section "Dosage and administration").

Based on available data, the menstrual cycle returns to normal within 2 months after discontinuation of DIENOFAM treatment.

Ability to influence reaction speed when driving or operating machinery.

No effect on the ability to drive or operate machinery has been observed in patients taking dienogest-containing preparations.

Method of Administration and Dosage

Method of Administration

For oral use.

Dosage

Take 1 tablet daily without interruption in the use of the drug, approximately at the same time each day, with a small amount of liquid. The tablets may be taken regardless of food intake.

The tablets should be taken regularly, regardless of menstrual bleeding. As soon as the tablets from one pack are finished, start taking tablets from the next pack without any break in the use of the medication.

There is no experience with treatment of endometriosis in patients using DİENOFAM for longer than 15 months.

The drug may be started on any day of the menstrual cycle.

Any hormonal contraceptives should be discontinued before starting therapy with DİENOFAM. If contraception is needed, a non-hormonal method of contraception (e.g., a barrier method) should be used additionally.

Missed Dose

If a tablet is missed, or if vomiting and/or diarrhea occur within 3–4 hours after taking the tablet, the effectiveness of DİENOFAM may be reduced. If one or more tablets are missed, one tablet should be taken as soon as the patient remembers, and the next tablet should be taken at the usual time. Similarly, a tablet that was not absorbed due to vomiting or diarrhea should be replaced with another tablet.

Additional Information on Use in Special Patient Groups

Elderly Patients

There are no relevant indications for use of the drug in this patient group.

Hepatic Impairment

The drug is contraindicated in patients with severe liver disease, either currently or in the medical history (see section "Contraindications").

Renal Impairment

There are no data indicating the need for dose adjustment in patients with renal impairment.

Children

DİENOFAM is not indicated for use in children before menarche.

The safety and efficacy of the drug were evaluated in an uncontrolled 12-month study involving 111 adolescent patients (12 – <18 years) with clinically suspected or confirmed endometriosis (see sections "Pharmacological Properties" and "Special Warnings and Precautions for Use").

The efficacy of DİENOFAM in treating endometriosis-associated pelvic pain has been demonstrated in adolescents (12–18 years) with an overall favorable safety and tolerability profile.

Use of the drug in adolescents over a 12-month treatment period was associated with a 1.2% decrease in the mean lumbar spine BMD (bone mineral density). After discontinuation of treatment, BMD increased again in these patients.

Alterations in BMD are of particular importance during adolescence and early stages of sexual maturation, which are critical periods for bone growth. It is unknown whether the reduction in BMD in this patient group may reduce peak bone mass and increase the risk of fractures in later life.

Therefore, physicians should carefully weigh the benefits of using DİENOFAM against the potential risks for each individual adolescent (see sections "Pharmacological Properties" and "Special Warnings and Precautions for Use").

Overdose

Acute toxicity studies conducted with dienogest did not indicate a risk of acute adverse reactions following accidental ingestion of several daily therapeutic doses. No specific antidotes are available. Administration of 20–30 mg of dienogest per day (10–15 times higher than the dose in DİENOFAM tablets) for more than 24 weeks was very well tolerated.

Adverse reactions

Adverse reactions are listed according to MedDRA.

Adverse reactions most commonly occur during the first months of treatment with DIENOPHARM and usually subside during continued use. Changes in bleeding patterns may occur, such as spotting, irregular bleeding, or amenorrhea.

The following adverse reactions have been reported during treatment with DIENOPHARM. The most frequently reported adverse reactions during treatment with DIENOPHARM include headache (9.0%), breast discomfort (5.4%), depressed mood (5.1%), and acne (5.1%).

Table 1 lists the adverse reactions according to MedDRA system organ classes (MedDRA SOCs) reported during treatment with DIENOPHARM and their frequency.

The following adverse reactions were also observed: follicular persistence, increased appetite, hypersensitivity reactions.

Other serious adverse reactions observed during the use of steroidal sex hormones and progestogens (see section "Special Warnings and Precautions for Use") include: venous and arterial thromboembolic events, arterial 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.

Shelf life.

3 years.

Storage conditions.

Store in the original packaging to protect from light. Keep the medicinal product out of reach of children.

Packaging.

28 tablets in a blister pack, one blister pack in a cardboard box.

Prescription category.

Prescription only.

Manufacturer.

Laboratorios Leon Farma, S.A.

Manufacturer's address and place of business.

C/ La Vallina s/n, Polígono Industrial Navatejera, Villacilambre, 24008 León, Spain