Riliz Special Precautions

General: Before initiating treatment with dienogest, pregnancy must be excluded. Dienogest is not a contraceptive. If contraception is desired during treatment, hormonal methods of contraception should not be used in combination with dienogest.
As dienogest is a progestogen-only therapy, it can be assumed that special warnings and special precautions for use of other progestogen-only therapies are valid for the use of dienogest although not all of the warnings and precautions are based on respective findings in the clinical studies with dienogest.
If any of the conditions/risk factors mentioned as follows is present or deteriorates, an individual risk-benefit analysis should be done before treatment with dienogest can be started or continued.
Cigarette smoking increases the risk of serious adverse effects on the heart and blood vessels. Smoking may also increase the risk of bone mineral density decline. Women should be advised not to smoke.
Serious Uterine Bleeding: Uterine bleeding, for example in women with adenomyosis uteri or uterine leiomyomata, may be aggravated with the use of dienogest. If bleeding is heavy and continuous over time, this may lead to anemia (severe in some cases). In the event of anemia, discontinuation of dienogest should be considered.
Changes in Bleeding Pattern: The majority of women treated with dienogest experience changes in their menstrual bleeding pattern (see Adverse Reactions).
Dienogest is expected to exhibit typical progestogenic effects on the endometrium by reducing estrogen levels which are the main growth stimulus for endometrial tissue. This may result in reduced endometrial thickness and an atrophic endometrium during treatment.
The menstrual cycle returns to pretreatment characteristics within 2 months after cessation of treatment with dienogest.
Abnormal vaginal bleeding (e.g., prolonged and/or heavy) should be thoroughly investigated by pelvic ultrasound, endometrial biopsy or hysteroscopy.
Thrombotic and Vascular Events: From epidemiological studies there is little evidence for an association between progestogen-only preparations and an increased risk of myocardial infarction or cerebral thromboembolism. 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 dienogest (in the case of elective surgery at least four weeks in advance) and not to resume treatment until 2 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.
Breast Cancer: A meta-analysis from 54 epidemiological studies reported that there is a slightly increased relative risk (RR of 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.
Regular breast exams should be done in patients using dienogest. Any irregularity or anomaly of the breast should be adequately investigated (e.g., by mammography or ultrasound).
Liver Tumor: In rare cases, benign liver tumors, and even more rarely, malignant liver tumors have been reported in users of hormonal substances such as the one contained in dienogest. In isolated cases, these tumors have led to life-threatening intra-abdominal hemorrhages. A hepatic tumor should be considered in the differential diagnosis when severe upper abdominal pain, liver enlargement or signs of intra-abdominal hemorrhage occur in women taking dienogest.
Osteoporosis and Changes in Bone Mineral Density: In patients who are at an increased risk of osteoporosis a careful risk-benefit assessment should be performed before starting dienogest because endogenous estrogen levels are moderately decreased during treatment with dienogest. There are no long-term data available on bone mineral density (BMD) and risk of fractures in patients taking dienogest.
In adult patients, BMD was assessed before and after 6 months of treatment with dienogest and there was no reduction of mean BMD. In adolescents (12 to <18 years of age), the use of dienogest over a treatment period of 12 months was associated with a mean decrease in BMD in the lumbar spine of 1.2%. After cessation of treatment, BMD increased towards pretreatment levels over a period of 6 months.
Plateauing or 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.
Adequate intake of calcium and vitamin D, whether from the diet or from supplements, is important for bone health in women of all ages.
Chloasma: 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 while taking dienogest.
Diabetes: Dienogest may have a slight effect on peripheral insulin resistance and glucose tolerance. Women with diabetes, especially those with a history of gestational diabetes mellitus, should be carefully observed while taking dienogest.
Depression: Patients who have a history of depression should be carefully observed. Dienogest should be discontinued if clinically relevant depression occurs or if pre-existing depression is aggravated during treatment.
Ectopic Pregnancy: 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 dienogest should be decided only after carefully weighing the benefits against the risks.
Other Conditions: Dienogest generally does not appear to affect blood pressure in normotensive women. However, if a sustained clinically significant hypertension develops during the use of dienogest, it is advisable to withdraw dienogest 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 dienogest.
Persistent ovarian follicles (often referred to as functional ovarian cysts) may occur during the use of dienogest. Most of these follicles are asymptomatic, although some may be accompanied by pelvic pain.
Medical Examination: A complete medical history and physical and gynecological examination should be taken prior to the initiation or reinstitution of dienogest, guided by the contraindications (see Contraindications), and should be repeated at least annually during the use of dienogest. The frequency and nature of these assessments should be adapted to the individual woman but should generally include special reference to blood pressure, breasts, abdomen and pelvic organs and should also include cervical cytology.
Effects on Ability to Drive and Use Machines: Dienogest has no or negligible influence on the ability to drive and use machines.
Use in Children: Dienogest is not indicated for use in pediatric patients prior to menarche. The safety and efficacy of dienogest in adolescents (menarche to 18 years of age) have not been established.
Use in the Elderly: Dienogest is not indicated for use in geriatric (> 65 years of age) patients.