MICROLUT Sugar-coated tablet Ref.[50653] Active ingredients: Levonorgestrel

If any of the conditions/risk factors mentioned below is present, the benefits of using Microlut should be weighed against the possible risks for each individual woman and discussed with the woman before she decides to start using it. In the event of aggravation, exacerbation or first appearance of any of these conditions or risk factors, the woman should contact her physician. The physician should then decide on whether Microlut should be discontinued.

Circulatory Disorders

From epidemiological studies there is little evidence for an association between progestogen-only pills and an increased risk of myocardial infarction and cerebral thromboembolism. The risk of cardiovascular and cerebral events is rather related to increasing age, hypertension and smoking. In women with hypertension the risk of stroke may be slightly enhanced by progestogen-only pills.

Some studies indicated 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 pills. 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 and prolonged immobilisation, major surgery or major trauma. In case of long-term immobilisation, it is advisable to discontinue the use of MICROLUT (in the case of elective surgery at least four weeks in advance) and not to resume until two weeks after complete remobilisation.

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 COCs mainly using oestrogen-progestogen preparations. The excess risk gradually disappears during the course of the 10 years after cessation of 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 COC 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, and even more rarely, malignant liver tumours have been reported in users of oral contraceptives. 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 MICROLUT.

Other conditions

Progestogen-only pills generally do not appear to affect blood pressure in normotensive women. However, if a sustained clinically significant hypertension develops during the use of MICROLUT, it is advisable to withdraw MICROLUT 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 MICROLUT.

An increase in frequency or severity of headaches during MICROLUT use, in particular the onset of migraine which may be prodromal of a cerebrovascular event, may be a reason for immediate discontinuation of MICROLUT.

Although MICROLUT may have a slight effect on peripheral insulin resistance and glucose tolerance, there is generally no need to alter the therapeutic regimen in diabetics using progestogen-only pills. However, diabetic women and those with a history of gestational diabetes mellitus should be carefully observed while taking MICROLUT.

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 MICROLUT.

Pregnancies that occur among users of progestogen-only pills are more likely to be ectopic than are pregnancies among users of COCs. In women with a history of extrauterine pregnancy or an impairment of tube function, the use of MICROLUT should be decided on only after carefully weighing the benefits against the risks. If lower abdominal pain occurs together with an irregular cycle pattern (amenorrhoea or amenorrhoea followed by persistent bleeding), an ectopic pregnancy must be considered.

Persistent ovarian follicles (often referred to as functional ovarian cysts) may occur during the use of MICROLUT. Most of these follicles are asymptomatic, although some may be accompanied by pelvic pain or dyspareunia. In most cases, the enlarged follicles disappear spontaneously during 2-3 months of observation.

Medical examination/consultation

A complete medical history and physical examination should be taken prior to the initiation or reinstitution of MICROLUT, guided by section 4.3 and section 4.4. This should be repeated at least annually during the use of MICROLUT. The frequency and nature of these assessments should be based on established practice quidelines and 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.

Women should be advised that oral contraceptives do not protect against HIV infections (AIDS) and other sexually transmitted diseases.

Reduced efficacy

The efficacy of MICROLUT may be reduced in the event of missed tablets, vomiting and/or diarrhoea, or concomitant medication.

Reduced cycle control

Menstrual bleeding

Menstrual bleeding occurs at normal intervals and is of normal duration and intensity in the majority of cases. However, both shortened and lengthened intervals are observed.

For this reason the possibility of such changes in menstrual rhythm should, as a precaution, be pointed out to the patient before the start of tablet taking. The changes occur mainly during the first few months of use, but with continuing treatment the cycle pattern tends to stabilise, and in most cases an individual pattern is established. The patient should be encouraged to keep a record of bleeding on the calendar contained in each pack.

Procedure in the event of intermenstrual bleeding

Intermenstrual bleeding of varying intensity may occur, particularly during the first few months. It is not a medical reason to stop tablet taking, as long as organic causes for such bleeding can be ruled out by means of adequate diagnostic measures.

It is inadvisable to attempt to influence cycle disturbances by the additional administration of an oestrogen. This would only serve to reverse the changes brought about by MICROLUT in the cervical mucus, thereby considerably jeopardising the contraceptive effect.

Absence of withdrawal bleeding

Amenorrhoea may occur in some women, in most cases only for one or two menstrual periods. In rare cases bleeding may fail to occur at longer intervals.

If no menstrual bleeding has occurred within 6 weeks after the last menstrual bleeding, pregnancy must be excluded before tablet taking is continued.

Use in Children

Microlut is only indicated after menarche.

Use in the Elderly

Microlut is not indicated after menopause.

Patients with Hepatic Impairment

Microlut is contraindicated in women with severe hepatic disease as long as liver function values have not returned to normal (see section 4.3).

Patients with Renal Impairment

Microlut has not been specifically studied in renally impaired patients.

Note: The data sheet of concomitant medications should be consulted to identify potential interactions.

Effects of other medicinal products on Microlut

Interactions can occur with drugs that induce microsomal enzymes, which can result in increased clearance of sex hormones which may lead to changes in the uterine bleeding profile and/or contraceptive failure.

Women on treatment with any of these drugs should temporarily use a barrier method in addition to MICROLUT or choose another method of contraception. The barrier method should be used during the time of concomitant drug administration and for 28 days after their discontinuation.

Substances increasing the clearance of levonorgestrel (diminished efficacy of Microlut by enzyme-induction), e.g.:

Hydantoins, barbiturates, primidone, carbamazepine, rifampicin and possibly also griseofulvin, oxcarbazepine, topiramate, felbamate, rifabutin and products containing St John’s Wort (Hypericum perforatum).

Enzyme induction can already be observed after a few days of treatment. Maximal enzyme induction is generally seen within a few weeks. After the cessation of drug therapy, enzyme induction may be sustained for about 4 weeks.

Substances with variable effects on the clearance of levonorgestrel:

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

These changes may be clinically relevant in some cases.

Substances decreasing the clearance of levonorgestrel (enzyme inhibitors):

Strong and moderate CYP3A4 inhibitors such as azole antifungals (e.g. fluconazole, itraconazole, ketoconazole, voriconazole), verapamil, macrolides (e.g. clarithromycin, erythromycin), diltiazem and grapefruit juice can increase plasma concentrations of the progestin.

Effects of Microlut on other medicinal products

Oral contraceptives may affect the metabolism of certain other drugs. Accordingly, plasma and tissue concentrations may be affected (e.g. cyclosporin).

Other forms of Interaction

Laboratory tests

The use of preparations like MICROLUT 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.

Use in Pregnancy (Category B3)

Microlut is not indicated during pregnancy. If pregnancy occurs during treatment with Microlut, further intake must be stopped. However, extensive extensive epidemiological studies have revealed neither an increased risk of birth defects in children born to women who used OCs prior to pregnancy, nor a teratogenic effect when OCs were taken inadvertently during early pregnancy. See also section 4.3.

Use in Lactation

Hormonal contraceptives are not recommended as the contraceptive method of first choice during lactation, but progestogen-only methods are considered to comprise the next choice category after non-hormonal methods. There appears to be no adverse effect on infant growth or development when using any progestogen-only method after 6 weeks postpartum. Progestogen-only methods do not appear to affect the quantity or quality of breast milk; however, minute amounts of the active substance are excreted with the milk.

There are no observed effects.

Summary of the safety profile

The most commonly reported adverse reactions with progestogen-only pills including Microlut are uterine/vaginal bleeding including spotting, menorrhagia and/ or metrorrhagia and amenorrhea. They occur in ≥1% of users.

Tabulated list of adverse reactions

Serious undesirable effects of MICROLUT have been referred to in section 4.3 and section 4.4.

In addition, the following undesirable effects have been reported in users of progestogen-only pills, although the causal relationships have not been confirmed:

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

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 https://nzphvc.otago.ac.nz/reporting/.

Not applicable.