Endovelle Special Precautions

Before starting ENDOVELLE treatment, pregnancy must be excluded (see Use in Pregnancy & Lactation). During treatment, patient are advised to use non-hormonal method of contraception (e.g. barrier method) if contraception is required.
Pregnancies that occur among users of progesterone-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 ENDOVELLE should be decided on only after carefully weighing the benefits against the risk.
As ENDOVELLE is a progesterone-only preparation, it can be assumed that special warnings and special precautions for use of other progesterone-only preparations are also valid for the use of ENDOVELLE although not all of the warnings and precautions are based on respective findings in the clinical studies with ENDOVELLE.
If any of the conditions/risk factors mentioned as follows is present or deteriorates, and individual risk-benefit analysis should be done before ENDOVELLE is started or continued.
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. 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.
Some studies indicate that there may be a slightly, but not statistically significant 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 ENDOVELLE (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 slightly increased relative risk of having breast cancer diagnosed in women who are currently using oral contraceptives (OCs), mainly estrogen-progestogen preparations. The excess risk gradually disappears during the course of the 10 years after cessation of combined oral contraceptive (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 progestogen-only pill users 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 ever-users tend to be less advanced clinically than the cancers diagnosed in never-users.
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 ENDOVELLE. 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 ENDOVELLE.
Long-term studies in rats and mice with dienogest showed increased incidences of pituitary adenomas, fibroepithelial mammary tumours, stromal polyps of the uterus and malignant lymphoma, at doses corresponding to exposure levels about 10 times that anticipated at the maximum recommended clinical dose, based on area under the plasma concentration time curve (AUC). Similar tumours have been shown to develop with other oestrogenic/progestogenic compounds. The tumuors are thought to result from marked species differences in the optimal oestrogen: progestogen ratio for reproductive function. Dienogest showed no tumuor promotion activity in the rat liver foci assay at the exposure levels corresponding to >100 times the estimated human exposure at the clinical dose, based on AUC.
Changes in bleeding pattern: ENDOVELLE treatment affects the menstrual bleeding pattern in majority of women (see Adverse Reactions).
Uterine bleeding for example in women with adenomyosis uteri or uterine leiomyomata, may be aggravated with the use of ENDOVELLE. If bleeding is heavy and continuous over time, this may lead to anemia (severe in some cases). Discontinuation of ENDOVELLE should be considered in such cases.
Other conditions: Patients who have a history of depression should be carefully observed and the drug 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 ENDOVELLE, it is advisable to withdraw ENDOVELLE and treat the hypertension.
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 ENDOVELLE.
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 ENDOVELLE.
Persistent ovarian follicles (often referred to as functional ovarian cysts) may occur during the use of ENDOVELLE. Most of these follicles are asymptomatic, although some may be accompanied by pelvic pain.
Each ENDOVELLE tablet contains lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption who are on a lactose free diet should consider the amount contained in ENDOVELLE.
Genotoxicity: Dienogest did not exhibit any evidence of genotoxic potential in assays for gene mutations in bacterial or mammalian cells, in vitro and in vivo.
Medical Examination: A complete medical history and physical and gynaecological examination should be taken prior to the initiation or reinstitution of ENDOVELLE, guided by the contraindications (see Contraindications) and warnings, and these should be repeated regularly during the use of ENDOVELLE. The frequency and nature of these assessments should be adapted to the individual woman but should generally induce special reference to blood pressure, breasts, abdomen and pelvic organs and should also include cervical cytology.
Osteoporosis: Currently, long-term data of bone mineral density (BMD) and risk of fractures in users of ENDOVELLE are not available.
In patients who are at an increased risk of osteoporosis a careful risk-benefit assessment should be performed before starting ENDOVELLE because endogenous oestrogen levels are moderately decreased during treatment with ENDOVELLE.