Zafrilla^® (Tablets) Instructions for Use

Marketing Authorization Holder

Gedeon Richter, Plc. (Hungary)

Contact Information

GEDEON RICHTER Plc. (Hungary)

ATC Code

G03DB08 (Dienogest)

Active Substance

Dienogest (Rec.INN registered by WHO)

Dosage Form

Zafrilla®

Tablets 2 mg: 28 or 84 pcs.

Dosage Form, Packaging, and Composition

Tablets white or almost white, round in shape, with a flat surface, with a bevel and an engraving on one side “G93”, on the other side “RG”, with a diameter of 7 mm.

Excipients: lactose monohydrate – 62.8 mg, corn starch pregelatinized, microcrystalline cellulose, povidone K-25, crospovidone (type A), talc, magnesium stearate.

14 pcs. – blisters (2) – carton packs.
14 pcs. – blisters (6) – carton packs.

Clinical-Pharmacological Group

Gestagen

Pharmacotherapeutic Group

Sex hormones and modulators of the genital system; progestogens; pregnadiene derivatives

Pharmacological Action

Mechanism of action

Dienogest affects endometriosis by reducing the production of estrogens by the ovaries and their concentration in blood plasma, resulting in the suppression of the trophic effect of estrogens on both eutopic and ectopic endometrium.

With prolonged use, Dienogest causes initial decidualization of endometrial tissue, followed by the development of atrophy of endometriotic lesions.

Pharmacodynamic effects

Dienogest is a derivative of norethisterone with antiandrogenic activity of approximately one-third that of cyproterone acetate. Dienogest binds to progesterone receptors in the human uterus, having only 10% of the relative affinity of progesterone. Despite low affinity for progesterone receptors, Dienogest is characterized by a potent progestogenic effect in vivo. Dienogest does not have significant androgenic, mineralocorticoid, or glucocorticoid activity in vivo.

Clinical efficacy and safety

The benefit of dienogest compared to placebo regarding pelvic pain associated with endometriosis was demonstrated in 198 patients in a clinical study lasting 3 months. Pelvic pain associated with endometriosis was assessed using a visual analog scale (VAS, 0-100 mm). After 3 months of treatment with dienogest, a statistically significant difference from placebo was shown (Δ=12.3 mm; 95% CI: 6.4-18.1; p<0.0001), as well as a clinically significant reduction in pain compared to baseline (mean reduction = 27.4 ± 22.9 mm).

After 3 months of treatment, 37.3% of patients experienced a reduction in the intensity of pelvic pain associated with endometriosis by 50% or more without a corresponding increase in the dose of additional analgesic they were taking (placebo: 19.8%); 18.6% of patients experienced a reduction in the intensity of pelvic pain associated with endometriosis by 75% or more without an increase in the dose of additional analgesic they were taking (placebo: 7.3%).

In the extended open-label phase of this placebo-controlled study, a sustained reduction in pelvic pain associated with endometriosis was observed with treatment duration of up to 15 months.

The results of the placebo-controlled part of the study were supported by results obtained in a study with an active control group (GnRH agonist intake) lasting 6 months in 252 patients with endometriosis.

In three studies, which included a total of 252 patients receiving a daily dose of dienogest 2 mg, a significant reduction in endometriotic lesions was demonstrated after 6 months of treatment.

In a small study (n = 8 in each dose group), it was shown that a daily dose of 1 mg of dienogest caused suppression of ovulation after 1 month of treatment. The contraceptive efficacy of the drug Zafrilla^® has not been studied in larger studies.

The level of endogenous estrogens is moderately suppressed during treatment with dienogest.

Bone mineral density (BMD) was assessed in 21 adult patients before the start of treatment and after 6 months of using the drug; no decrease in the mean BMD value was noted.

In 29 patients receiving leuprorelin acetate (LA), over the same period, a mean decrease of 4.04%±4.84 was observed (Δ between groups = 4.29%; 95% CI: 1.93-6.66; p< 0.0003).

Children

The safety of dienogest regarding BMD was investigated in an uncontrolled clinical study for 12 months in 111 patients (12-18 years old, post-menarche) with clinically suspected or confirmed endometriosis. The mean relative change in the BMD index of the lumbar spine (vertebrae L2 – L4) in 103 patients compared to baseline was -1.2%. In the group of patients who experienced a decrease in BMD, 6 months after the end of treatment within the extended follow-up period, this parameter was measured again, and the analysis showed an increase in BMD level to -0.6%.

During the use of dienogest for up to 15 months, no significant effect of the drug on standard laboratory parameters, including hematology, blood chemistry, liver enzyme levels, lipids, and glycated hemoglobin, was observed.

Long-term use safety data

A long-term observational post-marketing study with active control was conducted to study the incidence of occurrence or worsening of clinically significant depression and the occurrence of anemia. A total of 27,840 women with newly prescribed hormonal therapy for endometriosis were included in the study with follow-up for 7 years.

A total of 3023 women started taking dienogest at a dose of 2 mg, and 3371 patients started taking other approved drugs for the treatment of endometriosis. The overall adjusted risk ratio for new cases of anemia comparing patients receiving Dienogest and patients receiving other approved drugs for the treatment of endometriosis was 1.1 (95% CI: 0.4-2.6). The adjusted risk ratio for the development of depression when comparing dienogest and other approved drugs for the treatment of endometriosis was 1.8 (95% CI: 0.3-9.4). An increased risk of depression in patients taking Dienogest compared to patients taking other approved drugs for the treatment of endometriosis cannot be ruled out.

Pharmacokinetics

Absorption

After oral administration, Dienogest is rapidly and almost completely absorbed. C_max in blood plasma, which is 47 ng/ml, is reached approximately 1.5 hours after a single oral dose. Bioavailability is about 91%. The pharmacokinetics of dienogest in the dose range from 1 to 8 mg is dose-dependent.

Distribution

Dienogest binds to albumin in blood plasma and does not bind to sex hormone-binding globulin (SHBG), or corticosteroid-binding globulin (CBG). 10% of the total plasma concentration of the substance is in the form of free steroid, while about 90% is non-specifically bound to albumin. The apparent V_d of dienogest is 40 L.

Metabolism

Dienogest is almost completely metabolized, predominantly by hydroxylation, forming several practically inactive metabolites. Based on the results of in vitro and in vivo studies, the main enzyme involved in the metabolism of dienogest is CYP3A4. Metabolites are excreted very quickly, so the predominant fraction in blood plasma is unchanged Dienogest.

The metabolic clearance rate from plasma is 64 ml/min.

Excretion

The plasma concentration of dienogest decreases in two phases. T_1/2 in the terminal phase is approximately 9-10 hours. After oral administration of a dose of 0.1 mg/kg, Dienogest is excreted as metabolites by the kidneys and through the intestines in a ratio of approximately 3:1. T_1/2 of metabolites by the kidneys is 14 hours. After oral administration, approximately 86% of the administered dose is excreted within 6 days, with the main part excreted within the first 24 hours, predominantly by the kidneys.

Pharmacokinetic-pharmacodynamic relationship

The pharmacokinetics of dienogest is independent of SHBG levels. The plasma concentration of dienogest after daily administration increases by approximately 1.24 times, reaching C_ss after 4 days of administration. The pharmacokinetics of dienogest after multiple administration of the drug can be predicted based on the pharmacokinetics after a single administration.

Indications

• Treatment of endometriosis in adults and children aged 12 to 18 years after menarche.

ICD codes

Dosage Regimen

Orally.

The drug is taken at 1 tablet per day without interruption, preferably at the same time each day, if necessary with water or another liquid.

Before starting to take the drug Zafrilla^®, it is necessary to stop using any hormonal contraception. If contraception is necessary, then non-hormonal methods of contraception (for example, barrier method) should be used.

Starting to take the drug Zafrilla^® is possible on any day of the menstrual cycle.

Taking the drug Zafrilla^® can be started on any day of the menstrual cycle. Tablets should be taken continuously regardless of vaginal bleeding. After finishing the tablets from one package, start taking the drug Zafrilla^® from the next package, without taking a break in taking the drug.

If tablets are missed and in case of vomiting and/or diarrhea (if this occurs within 3-4 hours after taking the tablet), the effectiveness of the drug Zafrilla^® may decrease. If one or more tablets are missed, the woman should take only one tablet as soon as she remembers, then continue taking the tablets at the usual time the next day. Instead of the tablet that was not absorbed due to vomiting or diarrhea, one tablet should also be taken.

There is no connection between taking the drug and food intake.

Special patient groups

There are no relevant grounds for the use of the drug Zafrilla^® in elderly patients.

The drug Zafrilla^® is contraindicated in severe liver diseases currently or in history (see section “Contraindications”).

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

The safety and efficacy of the drug Zafrilla^® in children aged 0 to 12 years have not been established.

The drug Zafrilla^® can be used in children from 12 years of age after menarche. The dosage regimen for children from 12 to 18 years does not differ from the dosage regimen for adults.

Adverse Reactions

Adverse reactions (ARs) occur more frequently in the first months of taking the drug Zafrilla^® and their number decreases over time. The most common ARs include: vaginal bleeding (including spotting, metrorrhagia, menorrhagia, irregular bleeding), headache, breast discomfort, depressed mood and acne.

Table 1 presents ARs distributed by system organ class. ARs in each frequency group are presented in descending order of frequency. Frequency is defined as “common” (≥1/100 but <1/10) and “uncommon” (≥1/1000 but <1/100).

Reporting of suspected adverse reactions

It is important to report suspected adverse reactions after registration of a medicinal product in order to ensure continuous monitoring of the benefit-risk ratio of the medicinal product. Healthcare professionals are recommended to report any suspected adverse drug reactions through the national adverse reaction reporting systems of the member states of the Eurasian Economic Union.

Contraindications

The use of the drug Zafrilla^® is contraindicated in the presence of any of the conditions/diseases listed below, some of which are common to all drugs containing only a progestogenic component. If any of the conditions listed below develop during the use of the drug Zafrilla^®, treatment with the drug should be stopped immediately.

• Hypersensitivity to dienogest or any of the excipients included in the drug;
• Acute venous thrombophlebitis, venous thromboembolism currently;
• Diseases of the heart and arteries based on atherosclerotic vascular lesions (for example, myocardial infarction, stroke, coronary heart disease and transient ischemic attack) currently or in history;
• Diabetes mellitus with vascular lesions;
• Severe liver diseases currently or in history (in the absence of normalization of liver function tests);
• Liver tumors (benign or malignant) currently or in history;
• Identified or suspected hormone-dependent malignant tumors;
• Vaginal bleeding of unknown origin;
• History of cholestatic jaundice of pregnancy;
• Galactose intolerance, lactase deficiency, glucose-galactose malabsorption;
• Children under 12 years of age (before menarche).

With caution

History of depression, history of ectopic pregnancy, arterial hypertension, chronic heart failure, migraine with aura, diabetes mellitus without vascular complications, hyperlipidemia, history of deep vein thrombophlebitis, history of venous thromboembolism.

Use in Pregnancy and Lactation

Pregnancy

Experience with the use of dienogest in pregnant women is very limited. In animal studies of reproductive toxicity, genotoxicity and carcinogenicity, no such effects were identified with the use of the drug. The drug Zafrilla^® should not be prescribed to pregnant women due to the lack of need for treatment of endometriosis during pregnancy.

Breastfeeding period

Taking the drug Zafrilla^® during breastfeeding is not recommended, because animal studies have shown that Dienogest passes into breast milk. The decision to discontinue breastfeeding or to refuse to take the drug Zafrilla^® should be made taking into account the benefits of breastfeeding for the child and the benefits of treatment for the woman.

Fertility

According to available data, during the use of the drug Zafrilla^®, ovulation is suppressed in most patients. However, Zafrilla^® is not a contraceptive.

Contraceptive efficacy has not been studied for the drug Zafrilla^®, however, as shown in a study, in 20 women a dose of dienogest 2 mg suppressed ovulation after 1 month of treatment.

According to available data, the physiological menstrual cycle is restored within 2 months after discontinuation of the drug Zafrilla^®.

Use in Hepatic Impairment

Contraindications: severe liver diseases currently or in history – until normalization of liver function parameters; liver tumors (benign or malignant) currently or in history.

Use in Renal Impairment

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

Pediatric Use

Use in children and adolescents under the age of 18 years is contraindicated.

Geriatric Use

There are no justified indications for the use of the drug Zafrilla^® in elderly patients (over 65 years of age).

Special Precautions

Before starting the drug, pregnancy must be excluded. During the use of the drug, if contraception is necessary, patients are advised to use non-hormonal contraceptive methods (for example, barrier methods).

The likelihood of ectopic pregnancy is higher in patients taking progestogen-only drugs for contraception compared to patients taking combined oral contraceptives. Therefore, for women with a history of ectopic pregnancy or with fallopian tube obstruction, the benefit-risk ratio should be assessed before using the drug Zafrilla^®. Since Zafrilla^® is a progestogen-only drug, it can be assumed that the special instructions and precautions established for other drugs of this type are also relevant for Zafrilla^®, although not all of these warnings have been confirmed in the clinical studies of Zafrilla^®.

If any of the conditions or risk factors listed below are present or worsening, an individual assessment of the benefit-risk ratio should be performed before starting or continuing the use of Zafrilla^®.

Circulatory disorders

Epidemiological studies have provided insufficient evidence to confirm an association between the use of progestogen-only drugs and an increased risk of myocardial infarction or cerebral thromboembolism. The risk of cardiovascular episodes and cerebrovascular disorders is more likely associated with increasing age, arterial hypertension, and smoking. The risk of stroke in women with arterial hypertension may slightly increase while using progestogen-only drugs.

Some studies indicate the possibility of a statistically non-significant increase in the risk of venous thromboembolism (deep vein thrombosis, pulmonary embolism) associated with the use of progestogen-only drugs. Recognized risk factors for venous thromboembolism (VTE) include a relevant family history (VTE in a sibling or parent at a relatively young age), age, obesity, prolonged immobilization, major surgery, or massive trauma. In case of prolonged immobilization, it is recommended to discontinue Zafrilla^® (for planned surgery, at least 4 weeks before it) and resume taking the drug only 2 weeks after full restoration of mobility.

The increased risk of thromboembolism in the postpartum period should be taken into account.

If symptoms of arterial or venous thrombosis develop or are suspected, the drug should be discontinued immediately.

Tumors

A meta-analysis of 54 epidemiological studies revealed a small increase in the relative risk (RR=1.24) of breast cancer in women who were using oral contraceptives at the time of the study, predominantly estrogen-progestogen drugs. 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 slight increase in such diagnoses in women currently taking or having previously used COCs is small relative to the overall risk rate for breast cancer. The risk of detecting breast cancer in women taking progestogen-only drugs is likely similar in magnitude to the corresponding risk associated with COC use. However, the evidence related to progestogen-only drugs is based on smaller populations of women taking them and is therefore less convincing than the data for COCs. These studies did not provide evidence of a causal relationship. The observed pattern of increased risk may be a consequence of earlier diagnosis of breast cancer in women taking oral contraceptives, the biological effects of oral contraceptives, or a combination of both factors.

In women who have used hormonal contraceptives, breast cancer is diagnosed at earlier clinical stages than in women who have never used them.

In rare cases, the use of hormonal substances similar to the one contained in Zafrilla^® has been associated with benign, and even more rarely, malignant liver tumors. In isolated cases, these tumors have led to life-threatening intra-abdominal bleeding. If women taking Zafrilla^® experience severe pain in the upper abdomen, have an enlarged liver, or show signs of intra-abdominal bleeding, the possibility of a liver tumor should be considered in the differential diagnosis.

Changes in bleeding patterns

In most women, the use of Zafrilla^® affects the nature of menstrual bleeding.

Uterine bleeding may increase during the use of Zafrilla^®, for example, in women with adenomyosis or uterine leiomyoma. Heavy and prolonged bleeding can lead to anemia (in some cases severe). In such cases, discontinuation of Zafrilla^® should be considered.

Changes in bone mineral density (BMD)

The physician should consider the benefit of the drug in relation to the possible risks for each patient, also taking into account the possibility of risk factors for osteoporosis (e.g., dysmetabolic osteopathy, family history of osteoporosis, low body mass index or eating disorders, long-term use of drugs that can reduce bone mass, such as anticonvulsants or glucocorticoids, previous fractures due to minor trauma, alcohol abuse and/or smoking).

It is important for women of all ages to consume calcium and vitamin D, regardless of adherence to a specific diet or use of vitamin supplements.

No decrease in BMD has been observed in adult patients.

Other conditions

Patients with a history of depression require careful monitoring. If depression recurs in a severe form, the drug should be discontinued.

In general, Zafrilla^® does not appear to affect blood pressure in women with normal blood pressure. However, if persistent clinically significant arterial hypertension occurs during the use of Zafrilla^®, it is recommended to discontinue the drug and initiate antihypertensive therapy.

In case of recurrence of cholestatic jaundice and/or cholestatic pruritus, which first occurred during pregnancy or previous use of sex hormones, Zafrilla^® must be discontinued.

Zafrilla^® may have a slight effect on peripheral insulin resistance and glucose tolerance. Women suffering from diabetes mellitus, especially those with a history of gestational diabetes mellitus, require careful monitoring during the use of Zafrilla^®.

In some cases, chloasma may occur, especially in women with a history of chloasma during pregnancy. Women prone to developing chloasma should avoid exposure to sunlight or ultraviolet radiation during the use of Zafrilla^®.

During the use of Zafrilla^®, persistent ovarian follicles (often called functional ovarian cysts) may occur. In most cases, the presence of such follicles is asymptomatic, although some may be accompanied by pelvic pain.

Use in pediatrics

When Zafrilla^® was used in adolescents (12-18 years) over 12 months of treatment, a decrease in lumbar spine BMD by an average of 1.2% was observed. After discontinuation of treatment, BMD in these patients increased again.

The decrease in BMD is of particular concern during adolescence and late adolescence, as this is a particularly important period for bone growth. It is unknown whether the decrease in BMD affects the peak bone mass in this population and increases the risk of fractures in the future.

Medical examination

Before starting or resuming Zafrilla^®, the patient’s medical history should be reviewed in detail and a physical and gynecological examination should be performed. The frequency and nature of such examinations should be based on existing standards of medical practice, taking into account the individual characteristics of each patient (but not less than once every 3-6 months) and should include blood pressure measurement, assessment of the condition of the breasts, abdominal and pelvic organs, including cytological examination of the cervical epithelium.

Excipients

This medicinal product contains lactose.

Patients with rare hereditary galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicine.

Effect on ability to drive and operate machinery

Zafrilla^® does not have a negative effect on the ability to drive vehicles and operate machinery; however, caution should be exercised in patients with impaired concentration during the adaptation period (the first 3 months of using Zafrilla^®).

Overdose

No serious adverse events due to overdose have been reported.

Symptoms may include nausea, vomiting, spotting, or metrorrhagia.

Treatment there is no specific antidote; symptomatic treatment should be provided.

Drug Interactions

Effect of other medicinal products on Zafrilla^®

Progestogens, including Dienogest, are metabolized primarily by cytochrome P450 3A4 (CYP3A4) isoenzymes 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 lead to a decrease in the therapeutic effect of Zafrilla^® and may also cause adverse reactions, such as changes in uterine bleeding patterns.

Decreased clearance of sex hormones due to enzyme inhibition may increase the exposure to dienogest and cause side reactions.

Substances that increase the clearance of sex hormones (reduced efficacy by enzyme induction)

Phenytoin, barbiturates, primidone, carbamazepine, rifampicin, and possibly also oxcarbazepine, topiramate, felbamate, griseofulvin, as well as preparations containing St. John’s wort.

Enzyme induction is generally observed a few days after starting therapy, maximum induction is observed within a few weeks and may then persist for up to 4 weeks after discontinuation of therapy.

The effect of the CYP3A4 inducer rifampicin was studied in healthy postmenopausal women. When rifampicin was used concomitantly with the combination of estradiol valerate + Dienogest, a significant decrease in the steady-state concentration and systemic exposure of dienogest was observed. The systemic exposure of dienogest at steady state, determined by the AUC_{(0-24 h)} value, was reduced by 83%.

Medicinal products with variable effects on the clearance of sex hormones

When used concomitantly with sex hormones, many drugs for the treatment of HIV and hepatitis C and non-nucleoside reverse transcriptase inhibitors may increase or decrease plasma concentrations of progestins. In some cases, such changes may be clinically significant.

Medicinal products that decrease the clearance of sex hormones (enzyme inhibitors)

Dienogest is a substrate of the cytochrome P450 system isoenzyme CYP3A4.

Strong and moderate CYP3A4 inhibitors, such as azole antifungal agents (e.g., itraconazole, voriconazole, fluconazole), verapamil, macrolides (clarithromycin, erythromycin), diltiazem, and grapefruit juice, may increase plasma concentrations of progestogens.

In one study investigating the effect of CYP3A4 inhibitors (ketoconazole, erythromycin), the steady-state plasma concentrations of estradiol valerate and dienogest were increased.

When co-administered with the strong inhibitor ketoconazole, the steady-state AUC_{0-24 h} for dienogest increased by 2.86-fold. When co-administered with the moderate CYP3A4 inhibitor erythromycin, the steady-state AUC_{0-24 h} for dienogest increased by 1.62-fold.

The clinical significance of this interaction is not known.

Effect of dienogest on other medicinal products

Based on in vitro inhibition data, clinically significant interaction of dienogest with other drugs metabolized by cytochrome P450 system isoenzymes is unlikely.

Interaction with food

Food high in fat did not affect the bioavailability of Zafrilla^®.

Other interactions

The use of progestogens may affect the results of some laboratory tests, including biochemical parameters of liver, thyroid, adrenal and kidney function, plasma concentrations of (carrier) proteins, e.g., lipid/lipoprotein fractions, parameters of carbohydrate metabolism, and coagulation parameters.

Storage Conditions

The drug should be stored out of the reach of children in the original packaging (blister in a carton) to protect from light. No special temperature storage conditions are required.

Shelf Life

The shelf life is 5 years. Do not use after the expiration date stated on the packaging.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.