ZAFRILLA Tablet Ref.[50403] Active ingredients: Dienogest

Warnings

As Zafrilla 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 Zafrilla although not all of the warnings and precautions are based on respective findings in the clinical studies with dienogest 2 mg tablet. If any of the conditions/risk factors mentioned below is present or deteriorates, an individual risk-benefit analysis should be done before treatment with Zafrilla can be started or continued.

Serious uterine bleeding

Uterine bleeding, for example in women with adenomyosis uteri or uterine leiomyomata, may be aggravated with the use of Zafrilla. If bleeding is heavy and continuous over time, this may lead to anaemia (severe in some cases). In the event of anaemia, discontinuation of Zafrilla should be considered.

Changes in bleeding pattern

The majority of patients treated with Zafrilla experience changes in their menstrual bleeding pattern (see section 4.8).

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. Rather, the risk of cardiovascular and cerebral events is related to increasing age, hypertension and smoking. In women with hypertension the risk of stroke may be slightly enhanced by progestogen-only preparations.

Although not statistically significant, some studies indicate that there may be a slightly 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 Zafrilla (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 using estrogen-progestogen preparations. The excess risk gradually disappears during the course of the 10 years after cessation of combined OC (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 users of progestogen-only preparations 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 users of OCs tend to be less advanced clinically than the cancers diagnosed in those who have never used OCs.

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 Zafrilla. 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 Zafrilla.

Osteoporosis

Changes in bone mineral density (BMD).

The use of dienogest 2 mg tablet in adolescents (12 to <18 years) over a treatment period of 12 months was associated with a decrease in bone mineral density (BMD) in the lumbar spine (L2-L4). The mean relative change in BMD from baseline to the end of treatment (EOT) was – 1.2% with a range between -6% and 5% (IC 95%: -1.70% and -0.78%, n=103). Repeated measurement at 6 months after the EOT in a subgroup with decreased BMD values showed a trend towards recovery. (Mean relative change from baseline: -2.3% at EOT and -0.6% at 6 months after EOT with a range between -9% and 6% (IC 95%: -1.20% and 0.06% (n=60).

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 sections 4.2 and 5.1).

In patients who are at an increased risk of osteoporosis a careful risk-benefit assessment should be performed before starting Zafrilla because endogenous estrogen levels are moderately decreased during treatment with dienogest 2 mg tablet (see section 5.1).

Adequate intake of calcium and Vitamin D, whether from the diet or from supplements, is important for bone health in women of all ages.

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 Zafrilla, it is advisable to withdraw Zafrilla 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 Zafrilla.

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 Zafrilla.

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 Zafrilla.

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 Zafrilla 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 Zafrilla. Most of these follicles are asymptomatic, although some may be accompanied by pelvic pain.

Lactose

Each Zafrilla tablet contains 62.80 mg of lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Note: The prescribing information of concomitant medication should be consulted to identify potential interactions.

Effects of other medicinal products on {(Invented) name}

Progestogens 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 Zafrilla 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 (Hypericum perforatum). Enzyme induction can already be observed after a few days of treatment. Maximum enzyme induction is generally seen within a few weeks. After cessation of drug therapy enzyme induction may be sustained for about 4 weeks. 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 and estradiol. The systemic exposure of dienogest and estradiol at steady state, measured by AUC_(0-24h), were decreased by 83% and 44%, respectively.

Substances with variable effects on the clearance of sex hormones

When co-administered with sex hormones, many combinations of HIV protease inhibitors and non-nucleoside reverse transcriptase inhibitors, including combinations with HCV inhibitors can increase or decrease plasma concentrations of the progestin. The net effect of 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.

The clinical relevance of potential interactions with enzyme inhibitors remains unknown.

Concomitant administration of strong CYP3A4 inhibitors can increase plasma concentrations of dienogest.

Co-administration with the strong CYP3A4 enzyme inhibitor ketoconazole resulted in a 2.9-fold increase of AUC_(0‑24h) at steady state for dienogest. Concomitant administration of the moderate inhibitor erythromycin increased the AUC_(0‑24h) of dienogest at steady state by 1.6-fold.

Effects of Zafrilla on other medicinal products

Based on in vitro inhibition studies, a clinically relevant interaction of dienogest with the cytochrome P450 enzyme mediated metabolism of other medication is unlikely.

Interaction with food

A standardized high fat meal did not affect the bioavailability of {(Invented) name}.

Laboratory tests

The use of progestogens may influence the results of certain laboratory tests, including biochemical parameters of liver, thyroid, adrenal and renal function, plasma levels of (carrier) proteins (e.g. corticosteroid binding globulin and lipid/lipoprotein fractions), parameters of carbohydrate metabolism and parameters of coagulation and fibrinolysis.

Changes generally remain within the normal laboratory range.

Pregnancy

There is limited data from the use of dienogest in pregnant women.

Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3).

Zafrilla must not be administered to pregnant women because there is no need to treat endometriosis during pregnancy.

Breast-feeding

Treatment with Zafrilla during lactation is not recommended.

It is unknown whether dienogest is excreted in human milk. Data in animals have shown excretion of dienogest in rat milk.

A decision must be made whether to discontinue breast-feeding or to abstain from Zafrilla 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 Zafrilla. However, Zafrilla is not a contraceptive.

If contraception is required a non-hormonal method should be used (see section 4.2).

Based on available data, the menstrual cycle returns to normal within 2 months after cessation of treatment with Zafrilla.

No effects on the ability to drive and use machines have been observed in users of products containing dienogest.

Presentation of undesireable effects is based on MedDRA.

The most appropriate MedDRA term is used to describe a certain reaction and its synonyms and related conditions.

Undesirable effects are more common during the first months after the start of treatment with dienogest 2 mg tablet, and subside with continued treatment. There may be changes in bleeding pattern, such as spotting, irregular bleeding or amenorrhea. The following undesirable effects have been reported in users of dienogest 2 mg tablet. The most frequently reported undesirable effects under treatment with dienogest 2 mg tablet are headache (9.0%), breast discomfort (5.4%), depressed mood (5.1%) and acne (5.1%).

In addition, the majority of patients treated with dienogest 2 mg tablet experience changes in their menstrual bleeding pattern. Menstrual bleeding patterns were assessed systematically using patient diaries and were analysed using the WHO 90 days reference period method. During the first 90 days of treatment with dienogest 2 mg tablet the following bleeding patterns were observed (n=290; 100%): amenorrhea (1.7%), infrequent bleeding (27.2%), frequent bleeding (13.4%), irregular bleeding (35.2%), prolonged bleeding (38.3%), normal bleeding, i.e. none of the previous categories (19.7%). During the fourth reference period the following bleeding patterns were observed (n=149; 100%): amenorrhea (28.2%), infrequent bleeding (24.2%), frequent bleeding (2.7%), irregular bleeding (21.5%), prolonged bleeding (4.0%), normal bleeding, i.e. none of the previous categories (22.8%). Changes in menstrual bleeding patterns were only occasionally reported as adverse event by the patients (see adverse event table).

The frequencies of adverse drug reactions (ADRs) by MedDRA system organ classes (MedDRA SOCs) reported with dienogest 2 mg tablet are summarized in the table below. Within each frequency grouping, undesirable effects are presented in order of decreasing frequency. Frequencies are defined as common (≥1/100 to <1/10) and uncommon (≥1/1,000 to <1/100). The frequencies are based on pooled data of four clinical trials, including 332 patients (100%).

Table 1. Adverse reactions table, phase III clinical trials, N=332:

Decrease of bone mineral density

In an uncontrolled clinical trial with 111 adolescent women (12 to <18 years) who were treated with dienogest 2 mg tablet, 103 had BMD measurements. Approximately 72% of these study participants experienced a decrease in BMD of the lumbar spine (L2-L4) after 12 months of use (see section 4.4).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via HPRA Pharmacovigilance, Earlsfort Terrace, IRL – Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517. Website: www.hpra.ie; E-mail: medsafety@hpra.ie.

Not applicable.