Dienterna 2 2 mg Tablet

DIENTERNA is indicated for the treatment of endometriosis. Safety and efficacy beyond 24 months have not been established.

Posology

Tablet- taking from the very first pack should start on day 1 of the womanu2019s natural cycle (i.e. the first day of her menstrual bleeding). The dosage of DIENTERNA is one tablet daily without any break, taken preferably at the same time each day with some liquid as needed. Tablets must be taken throughout 28 days without regard for bleeding. When a pack is finished the next one should be started without interruption. The efficacy of DIENTERNA may be reduced in the event of missed tablets, vomiting, and/ or diarrhoea (if occurring within 3 to 4 hours after tablet taking). In the event of missed tablet(s), the woman should take one tablet only, as soon as she remembers, and should then continue next day to take tablet at her usual time. A tablet not absorbed due to vomiting or diarrhoea should likewise be replaced by one tablet.

Method of administration

For oral use.

DIENTERNA should not be used in the presence of any condition listed below. Should any of the conditions appear during the use of DIENTERNA, the use of DIENTERNA must be discontinued immediately:

• Hypersensitivity to dienogest or to any of the excipients listed in section 6.1.
• Known or suspected pregnancy (see section 4.6).
• Breastfeeding (see section 4.6).
• History of or active venous thromboembolic disorder.
• Arterial and cardiovascular diseases, past or present (e.g. myocardial infarction, cerebrovascular events, ischaemic 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.

Serious uterine bleeding

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

Changes in menstrual bleeding pattern

The majority of patients treated with DIENTERNA 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 as in DIENTERNA 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 DIENTERNA. 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 DIENTERNA (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

There is a risk of having breast cancer diagnosed in patients using DIENTERNA. 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 DIENTERNA. 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 DIENTERNA.

Osteoporosis

Changes in bone mineral density (BMD). The use of dienogest 2 mg (as in DIENTERNA) was monitored in adolescents (12 to <18 years) over a treatment period of 12 months. The use of dienogest 2 mg was associated with a decrease in bone mineral density (BMD) in the lumbar spine (L2-L4). 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. In patients who are at an increased risk of osteoporosis a careful risk-benefit assessment should be performed before starting DIENTERNA because endogenous estrogen levels are moderately decreased during treatment with DIENTERNA.

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 medicine 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 DIENTERNA, it is advisable to withdraw therapy 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 DIENTERNA.
• 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 DIENTERNA.
• 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 DIENTERNA.
• 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 DIENTERNA should be decided on only after carefully weighing the benefits against the risks.
• Patients are advised to use non-hormonal methods of contraception (barrier contraception, e.g. condom) to prevent unwanted pregnancies.
• Persistent ovarian follicles (often referred to as functional ovarian cysts) may occur during the use of DIENTERNA. Most of these follicles are asymptomatic, although some may be accompanied by pelvic pain.

Lactose

DIENTERNA contains lactose (as lactose monohydrate): Patients with the rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take DIENTERNA.

Effects of other medicines on DIENTERNA

Individual enzyme-inducers or inhibitors (CYP3A4): Progestogens, including DIENTERNA, are metabolised mainly by the cytochrome P450 system (CYP3A4) located both in the intestinal mucosa and in the liver. Therefore, inducers or inhibitors of CYP3A4 may affect the metabolism of DIENTERNA.

An increased clearance of sex hormones due to enzyme induction may reduce the therapeutic effect of DIENTERNA and may result in undesirable effects e.g. change in bleeding profile. A reduced clearance of sex hormones due to enzyme inhibition may increase the therapeutic effects of DIENTERNA and may result in undesirable effects.

Substances with enzyme-inducing properties: Interaction can occur with medicines (e.g. phenytoin, barbiturates, primidone, carbamazepine, rifampicin and possibly oxcarbazepine, topiramate, felbamate, griseofulvin, nevirapine and products containing St. Johnu2019s wort) that induces microsomal enzymes (e.g. cytochrome P450 enzymes) which can result in increased clearance of sex hormones and diminished efficacy of dienogest. Maximum enzyme induction is generally not seen for 2 to 3 weeks but may then be sustained for at least 4 weeks after cessation of therapy.

Substances with enzyme-inhibiting properties: Known CYP3A4 inhibitors like azole antifungals (e.g. ketoconazole, itraconazole, fluconazole), cimetidine, verapamil, macrolides (e.g. erythromycin, clarithromycin and roxithromycin), diltiazem, protease inhibitors (e.g. ritonavir, saquinavir, indinavir, nelfinavir), antidepressants (e.g. nefazodone, fluvoxamine, fluoxetine) may increase plasma levels of progestogens and result in undesirable effects.

Effects of DIENTERNA on other medicines

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

Other forms of interactions

The use DIENTERNA 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.

Interaction with food. A standardized high fat meal did not affect the bioavailability of 2 mg dienogest tablets.

Pregnancy

There is limited data from the use of dienogest in pregnant women. The administration of DIENTERNA during pregnancy is contraindicated (see section 4.3). If pregnancy occurs during the use of DIENTERNA, further intake should be stopped.

Breastfeeding

DIENTERNA should not be used by breastfeeding women (see section 4.3).

Fertility

Based on the available data, ovulation is inhibited in the majority of patients during treatment with DIENTERNA. However, DIENTERNA is not a contraceptive. If contraception is required a non-hormonal method should be used (see section 4.4). Based on available data, the menstrual cycle returns to normal within 2 months after cessation of treatment with DIENTERNA.

DIENTERNA has no influence on the ability to drive and use machines. No effects on the ability to drive or use machines have been observed in users of medicines containing dienogest.

a. Summary of the safety profile

Undesirable effects are more common during the first months after the start of treatment with DIENTERNA 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 (as in DIENTERNA). The most frequently reported undesirable effects are headache, breast discomfort, depressed mood and acne. Furthermore, the majority of patients treated experience changes in their menstrual bleeding pattern.

b. Tabulated summary of adverse reactions

c. Description of selected adverse reactions

Uterine bleeding irregularities: The following bleeding patterns were observed: amenorrhea, infrequent bleeding, frequent bleeding, irregular bleeding, prolonged bleeding, and normal bleeding.

Decrease of bone mineral density: In an uncontrolled study with 111 adolescent women (12 to <18 years) who were treated with dienogest 2 mg, 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 medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Healthcare professionals are asked to report any suspected adverse reactions to SAHPRA via the u201c6.04 Adverse Drug Reaction Reporting Formu201d, found online under SAHPRAu2019s publications: https://www.sahpra.org.za/Publications/Index/8

Symptoms

Acute toxicity studies performed with dienogest (as in DIENTERNA) did not indicate a risk of acute adverse effects in case of inadvertent intake of a multiple of the daily therapeutic dose. A daily intake of 20 to 30 mg dienogest (10 to 15 times higher dose than in DIENTERNA) over 24 weeks of use was very well tolerated. However, overdosage may potentiate the adverse effects reported under section 4.4 (u201cSpecial warnings and precautions for useu201d) and section 4.8 (u201cUndesirable effectsu201d).

Treatment

There is no specific antidote, treatment is symptomatic and supportive.