MIRELLE Film-coated tablet Ref.[50622] Active ingredients: 17 alpha-Ethinylestradiol Gestodene

If any of the conditions/risk factors mentioned below are present, the benefits of combined oral contraceptive use 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 its use should be discontinued.

Circulatory disorders

Epidemiological studies have suggested an association between the use of combined oral contraceptives and an increased risk of arterial and venous thrombotic and thromboembolic diseases such as myocardial infarction, stroke, deep venous thrombosis, and pulmonary embolism. These events occur rarely.

The risk of venous thromboembolism (VTE) is highest during the first year of use. This increased risk is present after initially starting combined oral contraceptives, such as MIRELLE, or restarting (following a 4 week or greater pill free interval) the same or different combined oral contraceptives. Data from a large, prospective 3-armed cohort study suggest that this increased risk is mainly present during the first 3 months.

Overall the risk for venous thromboembolism (VTE) in users of low estrogen dose (< 50 µg ethinylestradiol) combined oral contraceptives, such as MIRELLE, is higher than for non-users of combined oral contraceptives.

VTE may be life-threatening or may have a fatal outcome (in 1-2 % of the cases).

Venous thromboembolism, manifesting as deep venous thrombosis and/or pulmonary embolism, may occur during the use of all combined oral contraceptives, such as MIRELLE.

Extremely rarely, thrombosis has been reported to occur in other blood vessels, e.g. hepatic, mesenteric, renal or retinal veins and arteries, in combined oral contraceptive users.

Arterial thromboembolic events may be life-threatening or may have a fatal outcome.

The potential for an increased synergistic risk of thrombosis should be considered in women who possess a combination of risk factors or exhibit a greater severity of an individual risk factor. This increased risk may be greater than a simple cumulative risk of the factors. MIRELLE should not be prescribed in case of a negative risk benefit assessment. (see section 4.3).

The risk of venous or arterial thrombotic/thromboembolic events or of a cerebrovascular accident increases with:

• Age.
• Smoking (with heavier smoking and increasing age the risk further increases, especially in women over 35 years of age).
• A positive family history (i.e. venous or arterial thromboembolism ever in a sibling or parent at a relatively early age). If a hereditary predisposition is suspected, the woman should be referred to a specialist for advice before deciding about any combined oral contraceptive use.
• Obesity (body mass index over 30 kg/m²).
• Dyslipoproteinaemia.
• Hypertension.
• Migraine
• Valvular heart disease.
• Atrial fibrillation.
• Prolonged immobilisation, major surgery, any surgery to the legs, or major trauma. In these situations it is advisable to discontinue MIRELLE use (in the case of elective surgery at least four weeks in advance) and not to resume until two weeks after complete remobilisation.

There is no consensus about the possible role of varicose veins and superficial thrombophlebitis in venous thromboembolism.

The increased risk of thromboembolism in the puerperium must be considered.

Other medical conditions which have been associated with adverse circulatory events include diabetes mellitus, systemic lupus erythematosus, haemolytic uraemic syndrome, chronic inflammatory bowel disease (Crohn’s disease or ulcerative colitis) and sickle cell disease.

An increase in frequency or severity of migraine during MIRELLE use (which may be prodromal of a cerebrovascular event) may be a reason for immediate discontinuation of MIRELLE.

Biochemical factors that may be indicative of hereditary or acquired predisposition for venous or arterial thrombosis include Activated Protein C resistance, hyperhomocysteinaemia, antithrombin-III deficiency, protein C deficiency, protein S deficiency, antiphospholipid antibodies (anticardiolipin antibodies, lupus anticoagulant).

When considering risk/benefit, the physician should take into account that adequate treatment of a condition may reduce the associated risk of thrombosis, and that the risk associated with pregnancy is higher than that associated with combined oral contraceptive use.

Tumours

The most important risk factor for cervical cancer is persistent HPV infection. Some epidemiological studies have indicated that long-term use of combined oral contraceptives may further contribute to this increased risk but there continues to be controversy about the extent to which this finding is attributable to confounding effects, e.g., cervical screening and sexual behaviour including use of barrier contraceptives.

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 combined oral contraceptives, such as MIRELLE. The excess risk gradually disappears during the course of the 10 years after cessation of combined oral contraceptive use. Because breast cancer is rare in women under 40 years of age, the excess number of breast cancer diagnoses in current and recent combined oral contraceptive users is small in relation to the overall risk of breast cancer. 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 combined oral contraceptive users, the biological effects of combined oral contraceptives, 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 combined oral contraceptives, such as MIRELLE. 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 combined oral contraceptives.

Malignancies may be life-threatening or may have a fatal outcome.

Other conditions

Women with hypertriglyceridaemia, or a family history thereof, may be at an increased risk of pancreatitis when using MIRELLE.

Although small increases in blood pressure have been reported in many women taking combined oral contraceptives such as MIRELLE, clinically relevant increases are rare. A relationship between combined oral contraceptive use and clinical hypertension has not been established. However, if a sustained clinically significant hypertension develops during the use of MIRELLE then it is prudent for the physician to withdraw MIRELLE and treat the hypertension. Where considered appropriate, MIRELLE use may be resumed if normotensive values can be achieved with antihypertensive therapy.

The following conditions have been reported to occur or deteriorate with both pregnancy and combined oral contraceptive use, but the evidence of an association with combined oral contraceptive use is inconclusive: jaundice and/or pruritus related to cholestasis; gallstone formation; porphyria; systemic lupus erythematosus; haemolytic uraemic syndrome; Sydenham’s chorea; herpes gestationis; otosclerosis-related hearing loss.

Acute or chronic disturbances of liver function may necessitate the discontinuation of MIRELLE use until markers of liver function return to normal. Recurrence of cholestatic jaundice which occurred first during pregnancy or previous use of sex steroids necessitates the discontinuation of MIRELLE.

MIRELLE may have an effect on peripheral insulin resistance and glucose tolerance. Hence, diabetic women should be carefully observed while taking MIRELLE.

Crohn’s disease and ulcerative colitis have been associated with combined oral contraceptive use, such as MIRELLE.

Chloasma may 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 MIRELLE.

Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Depressed mood and depression are well-known undesirable effects of hormonal contraceptive use (see section 4.8). Depression can be serious and is a well-known risk factor for suicidal behaviour and suicide. Women should be advised to contact their physician in case of mood changes and depressive symptoms, including shortly after initiating the treatment.

Medical examination / consultation

A complete medical history and physical examination should be taken prior to the initiation or reinstitution of MIRELLE, guided by the contraindications and warnings (see sections 4.3 and 4.4) and should be repeated at least annually during the use of MIRELLE. Periodic medical assessment is also of importance because contraindications (e.g. a transient ischaemic attack, etc.) or risk factors (e.g. a family history of venous or arterial thrombosis) may appear for the first time during the use of MIRELLE. 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, including cervical cytology, and relevant laboratory tests.

Women should be advised that MIRELLE do not protect against HIV infections (AIDS) and other sexually transmissible diseases.

Reduced efficacy

The efficacy of MIRELLE may be reduced in the event of e.g. missed hormone-containing pale yellow tablets, gastrointestinal disturbances during hormone-containing white tablet taking or concomitant medication (see sections 4.2 and 4.5).

Reduced cycle control

With all combined oral contraceptives, irregular bleeding (spotting or breakthrough bleeding) may occur, especially during the first months of use. Therefore, the evaluation of any irregular bleeding is only meaningful after an adaptation interval of about three cycles.

If bleeding irregularities persist or occur after previously regular cycles, the non-hormonal causes should be considered and adequate diagnostic measures are indicated to exclude malignancy or pregnancy. These may include curettage.

In some women withdrawal bleeding may not occur during the hormone-free white tablet phase. If MIRELLE has been taken according to the directions described, it is unlikely that the woman is pregnant. However, if MIRELLE has not been taken according to these directions prior to the first missed withdrawal bleed or if two withdrawal bleeds are missed, pregnancy must be ruled out before MIRELLE use is continued.

Note: The prescribing information of concomitant medications should be consulted to identify potential interactions.

Effects of other medicines on MIRELLE

Interactions can occur with medicines that induce microsomal enzymes which can result in increased clearance of sex hormones and which may lead to breakthrough bleeding and oral contraceptive failure.

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 medicine therapy enzyme induction may be sustained for about 4 weeks.

Women on treatment with any of these medicines should temporarily use a barrier method in addition to MIRELLE or choose another method of contraception. The barrier method should be used during the time of concomitant medicine administration and for 28 days after their discontinuation. If the period during which the barrier method is used runs beyond the end of the hormone-containing pale yellow tablets in the current pack, the hormone-free white tablets must be discarded and the next pack started right away.

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

Phenytoin, barbiturates, primidone, carbamazepine, rifampicin, and possibly also oxcarbazepine, topiramate, felbamate, griseofulvin and products containing St. John’s wort

Substances with variable effects on the clearance of MIRELLE, e.g.:

When co-administered with MIRELLE, many HIV/HCV protease inhibitors and non-nucleoside reverse transcriptase inhibitors can increase or decrease plasma concentrations of estrogen or progestin. These changes may be clinically relevant in some cases.

Substances decreasing the clearance of MIRELLE (enzyme inhibitors):

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

Etoricoxib doses of 60 to 120 mg/day have been shown to increase plasma concentrations of ethinylestradiol 1,4 to 1,6-fold, respectively when taken concomitantly with a combined hormonal contraceptive containing 0,035 mg ethinylestradiol.

Effects of MIRELLE on other medicines

Oral contraceptives may affect the metabolism of certain other medicine. Accordingly, plasma and tissue concentrations may either increase (e.g. ciclosporin) or decrease (e.g. lamotrigine).

In vitro, ethinylestradiol is a reversible inhibitor of CYP2C19, CYP1A1 and CYP1A2 as well as a mechanismbased inhibitor of CYP3A4/5, CYP2C8, and CYP2J2. In clinical studies, administration of a hormonal contraceptive containing ethinylestradiol did not lead to any increase or only to a weak increase in plasma concentrations of CYP3A4 substrates (e.g. midazolam) while plasma concentrations of CYP1A2 substrates can increase weakly (e.g. theophylline) or moderately (e.g. melatonin and tizanidine).

Pharmacodynamic interactions

Co-administration of ethinylestradiol-containing medicinal products with direct-acting antiviral (DAA) medicinal products containing ombitasvir, paritaprevir, or dasabuvir, and combinations of these has been shown to be associated with increases in ALT levels to greater than 20 times the upper limit of normal in healthy female subjects and HCV infected women (see section 4.3).

Other forms of interactions

Laboratory tests

The use of contraceptive steroids 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.

Pregnancy

MIRELLE is contraindicated during pregnancy (see section 4.3). If pregnancy occurs during treatment with MIRELLE, further intake must be stopped. Extensive epidemiological studies have revealed neither an increased risk of birth defects in children born to women who used combined oral contraceptives prior to pregnancy, nor a teratogenic effect when combined oral contraceptives were taken inadvertently during early pregnancy.

Lactation

Lactation may be influenced by MIRELLE as it may reduce the quantity and change the composition of breast milk, therefore, the use of MIRELLE should generally not be recommended until the nursing mother has completely weaned her child. Small amounts of the contraceptive steroids and/or their metabolites may be excreted with the milk but there is no evidence that this adversely affects infant health.

No studies on the effects on the ability to drive and use machines have been performed. No effects on ability to drive and use machines have been observed in users of MIRELLE.

a) Summary of the safety profile

The most commonly reported adverse reactions with MIRELLE are nausea, abdominal pain, increased weight, headache, depressed mood, altered mood, breast pain, breast tenderness. They occur in ≥1% of users. Serious adverse reactions are arterial and venous thromboembolism.

b) Tabulated list of adverse reactions

^* - Estimated frequency, from epidemiological studies encompassing a group of combined oral contraceptives. - ‘Venous and arterial thromboembolic events’ summarises the following Medical Entities: Peripheral deep venous occlusion, thrombosis and embolism/Pulmonary vascular occlusion, thrombosis, embolism and infarction/Myocardial infarction/Cerebral infarction and stroke not specified as haemorrhagic

c) Description of selected adverse reactions

Adverse reactions with very low frequency or with delayed onset of symptoms which are considered to be related to the group of combined oral contraceptives are listed below (see also sections 4.3 and 4.4):

Tumours

• The frequency of diagnosis of breast cancer is very slightly increased among oral contraceptive users. As breast cancer is rare in women under 40 years of age the excess number is small in relation to the overall risk of breast cancer. Causation with combined oral contraceptive use is unknown.
• Liver tumours (benign and malignant)

Other conditions

− Women with hypertriglyceridemia (increased risk of pancreatitis when using combined oral contraceptives)

• Hypertension
• Occurrence or deterioration of conditions for which association with combined oral contraceptive use is not conclusive: jaundice and/or pruritus related to cholestasis; gallstone formation; porphyria; systemic lupus erythematosus; haemolytic uremic syndrome; Sydenham’s chorea; herpes gestationis; otosclerosisrelated hearing loss.
• In women with hereditary angioedema exogenous estrogens may induce or exacerbate symptoms of angioedema
• Liver function disturbances
• Changes in glucose tolerance or effect on peripheral insulin resistance
• Crohn’s disease, ulcerative colitis.
• Chloasma

Interactions

Breakthrough bleeding and/or contraceptive failure may result from interactions of other medicines (enzyme inducers) with oral contraceptives (see section 4.5).

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. Health care providers are asked to report any suspected adverse reactions to SAHPRA via the “6.04 Adverse Drug Reactions Reporting Form”, found online under SAHPRA’s publications: https://www.sahpra.org.za/Publications/Index/8.

Not applicable.