Special Warning : אזהרת שימוש

4.4       Special warnings and precautions for use

Warnings
As Visabelle 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 Visabelle although not all of the warnings and precautions are based on respective findings in the clinical studies with Visabelle.
If any of the conditions/risk factors mentioned below is present or deteriorates, an individual risk- benefit analysis should be done before treatment with Visabelle 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 Visabelle. If bleeding is heavy and continuous over time, this may lead to anemia (severe in some cases). In the event of anemia, discontinuation of Visabelle should be considered.


•     Changes in bleeding pattern

The majority of patients treated with Visabelle 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 Visabelle (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 Visabelle. 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 Visabelle.


• Osteoporosis
Changes in bone mineral density (BMD)
The use of Visabelle 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 Visabelle because endogenous estrogen levels are moderately decreased during treatment with Visabelle (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 Visabelle, it is advisable to withdraw Visabelle 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 Visabelle.

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 Visabelle.

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 Visabelle.

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

•     Lactose

Each Visabelle tablet contains 62.8 mg of lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption who are on a lactose-free diet should consider the amount contained in Visabelle.

Effects on Driving

4.7     Effects on ability to drive and use machines

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