MINESSE Film-coated tablet Ref.[50575] Active ingredients: 17 alpha-Ethinylestradiol Gestodene

Cigarette smoking increases the risk of serious cardiovascular adverse reactions from oral contraceptive use. This risk increases with age and the extent of smoking (15 or more cigarettes per day was associated with a significantly increased risk) and is quite marked in women over 35 years of age. Women who use MINESSE should be strongly advised not to smoke.

Medical examinations

Prior to the initiation or reinstitution of MINESSE a complete medical history (including family history) should be taken and pregnancy must be ruled out. Blood pressure should be measured and a physical examination should be performed, guided by the contraindications (see section 4.3) and warnings (see section 4.4). A Papanicolaou (Pap) smear should be performed if the patient has been sexually active or if it is otherwise indicated.

Venous and arterial thrombosis and thromboembolism

Use of MINESSE is associated with an increased risk of venous and arterial thrombotic and thromboembolic events.

Minimising exposure to estrogens and progestins is in keeping with good principles of therapeutics. For any particular estrogen/progestin combination, the dosage regimen prescribed should be one that contains the least amount of estrogen and progestin that is compatible with a low failure rate and the needs of the individual patient.

New acceptors of MINESSE should be started on preparations containing less than 50 µg of estrogen.

Venous thrombosis and thromboembolism

Use of MINESSE increases the risk of venous thrombotic and thromboembolic events. Reported events include deep venous thrombosis and pulmonary embolism. For information on retinal vascular thrombosis see Ocular lesions below.

The use of MINESSE carries an increased risk of venous thrombotic and thromboembolic events compared with no use. The excess risk is highest during the first year a woman ever uses a combined oral contraceptive. Venous thromboembolism is fatal in 1 – 2 % of cases.

For combination oral contraceptives containing gestodene with 15 µg of EE (such as MINESSE) there are no data on the comparative risk of venous thrombotic and thromboembolic events.

The risk of venous thrombotic or thromboembolic events is further increased in women with conditions predisposing for venous thrombosis and thromboembolism. Caution must be exercised when prescribing MINESSE for such women.

Examples of predisposing conditions for venous thrombosis and thromboembolism are:

• obesity
• surgery or trauma with increased risk of thrombosis
• recent delivery or second-trimester abortion
• prolonged immobilisation
• increasing age

Further risk factors, which represent contraindications for the use of MINESSE, are listed under section 4.3.

The relative risk of postoperative thromboembolic complications has been reported to be increased two- to four-fold with the use of combination oral contraceptives, such as MINESSE. The relative risk of venous thrombosis in women with predisposing conditions is twice that of women without such conditions. If feasible, MINESSE should be discontinued for four weeks prior to and for two weeks after elective surgery with increased risk of thrombosis, and during prolonged immobilisation.

Since the immediate post-partum period is associated with an increased risk of thromboembolism, MINESSE should be started no earlier than day 28 after delivery or second-trimester abortion.

Arterial thrombosis and thromboembolism

The use of MINESSE increases the risk of arterial thrombotic and thromboembolic events.

Reported events include myocardial infarction and cerebrovascular events (ischaemic and haemorrhagic stroke, transient ischaemic attack). For information on retinal vascular thrombosis see Ocular lesions below.

The risk of arterial thrombotic and thromboembolic events is further increased in women with underlying risk factors.

Caution must be exercised when prescribing MINESSE for women with risk factors for arterial thrombotic and thromboembolic events.

Examples of risk factors for arterial thrombotic and thromboembolic events are:

• smoking
• hypertension
• hyperlipidaemias
• obesity
• increasing age

Further risk factors, which represent contraindications for the use of MINESSE, are listed under section 4.3.

Ocular lesions

With use of MINESSE, there have been reports of retinal vascular thrombosis, which may lead to partial or complete loss of vision. If there are signs or symptoms such as visual changes, onset of proptosis or diplopia, papilledema, or retinal vascular lesions, MINESSE should be discontinued and the cause immediately evaluated.

Blood pressure

Increases in blood pressure have been reported in women taking MINESSE.

In women with hypertension, a history of hypertension or hypertension related diseases (including certain renal diseases); another method of contraception may be preferable. If MINESSE is used in such cases, close monitoring is recommended and, if a significant increase in blood pressure occurs, MINESSE should be discontinued.

Elevated blood pressure associated with MINESSE use will generally return to baseline after stopping MINESSE and there appears to be no difference in the occurrence of hypertension among ever- and never-users.

MINESSE use is contraindicated in women with uncontrolled hypertension (see section 4.3).

Angioedema

Exogenous estrogens may induce or exacerbate symptoms of angioedema, particularly in women with hereditary angioedema.

Carcinoma of the reproductive organs

Cervical cancer

Combination oral contraceptive use, such as MINESSE use may be associated with an increase in the risk of cervical intraepithelial neoplasia or invasive cervical cancer in some populations of women.

In cases of undiagnosed abnormal genital bleeding, adequate diagnostic measures are indicated.

Breast cancer

There is evidence of an increased risk of having breast cancer diagnosed in women who are using combination oral contraceptives compared to never-users.

Established risk factors for the development of breast cancer include increasing age, family history, obesity, nulliparity, and late age for first full-term pregnancy.

Hepatic neoplasia/liver disease/hepatitis C

Hepatic adenomas, and hepatocellular carcinoma may be associated with combination oral contraceptive use, such as MINESSE. The risk appears to increase with duration of oral contraceptive use. Rupture of hepatic adenomas may cause death through intra-abdominal haemorrhage. Women with a history of oral contraceptive related cholestasis or women with cholestasis during pregnancy are more likely to have this condition with MINESSE use.

If these patients receive MINESSE they should be carefully monitored and, if the condition recurs, MINESSE should be discontinued.

Hepatocellular injury has been reported with MINESSE use. Early identification of medicinerelated hepatocellular injury can decrease the severity of hepatotoxicity when MINESSE is discontinued. If hepatocellular injury is diagnosed, patients should stop MINESSE, use a nonhormonal form of contraception, and consult their medical practitioner.

Acute or chronic disturbances of liver function require the discontinuation of MINESSE until liver function has returned to normal (see section 4.3).

Hepatitis C

Patients treated for HCV infections with the medicines containing ombitasvir/paritaprevir/ritonavir and dasabuvir with or without ribavirin, transaminase (ALT) elevations higher than 5 times the upper limit of normal (ULN) occurred significantly more frequently in women using EE-containing medicines such as MINESSE (see sections 4.3 and 4.5).

Migraine/headache

The onset or exacerbation of migraine or development of headache with a new pattern that is recurrent, persistent or severe requires discontinuation of MINESSE and evaluation of the cause.

Women with migraine (particularly migraine with aura) who take MINESSE may be at increased risk of stroke (see section 4.3).

Carbohydrate and lipid effects

Glucose intolerance has been reported in MINESSE users. Women with impaired glucose tolerance or diabetes mellitus who use MINESSE should be carefully monitored.

Adverse lipid changes may occur in women taking MINESSE. Nonhormonal contraception should be considered in women with uncontrolled dyslipidaemias.

Persistent hypertriglyceridaemia may occur in a small proportion of MINESSE users. Elevations of plasma triglycerides may lead to pancreatitis and other complications.

Estrogens increase serum high-density lipoproteins (HDL cholesterol), whereas a decline in serum HDL cholesterol has been reported with many progestational medicines. Some progestins may elevate low-density lipoprotein (LDL) levels and may render the control of hyperlipidaemias more difficult. The net effect of a combination oral contraceptive depends on the balance achieved between doses of estrogen and progestin and the nature and absolute amount of progestins used in the contraceptive. The amount of both hormones should be considered in the choice of MINESSE.

Women who are being treated for hyperlipidaemias should be followed closely if they elect to use MINESSE.

Genital bleeding

In some women withdrawal bleeding may not occur during the inactive-tablet interval. If MINESSE has not been taken according to directions prior to the first missed withdrawal bleed, or if two consecutive withdrawal bleeds are missed, tablet-taking should be discontinued and a nonhormonal back-up method of contraception should be used until the possibility of pregnancy is excluded.

Breakthrough bleeding/spotting may occur in women taking MINESSE, especially during the first three months of use. The type and dose of progestin may be important. If this bleeding persists or recurs, nonhormonal causes should be considered and adequate diagnostic measures may be indicated to rule out pregnancy, infection, malignancy or other conditions. If pathology has been excluded, continued use of MINESSE or a change to another formulation may solve the problem.

Some women may encounter post-pill amenorrhoea (possibly with anovulation) or oligomenorrhoea, especially when such a condition was pre-existent.

Depression

Depressed mood and depression are well-known undesirable effects of hormonal contraceptive use and preparations containing estrogen and/or progesterone/progestogen (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 medical practitioner in case of mood changes and depressive symptoms, including shortly after initiating the treatment.

Women with a history of depression who use MINESSE should be carefully observed and the medicine discontinued if depression recurs to a serious degree. Patients becoming significantly depressed while taking MINESSE should stop the medicine and use an alternate method of contraception in an attempt to determine whether the symptom is medicine related.

Other

Patients should be counselled that MINESSE does not protect against HIV infections (AIDS) and other sexually transmitted diseases.

Diarrhoea and/or vomiting may reduce hormone absorption resulting in decreased serum concentrations (see section 4.2).

Excipients with known effect

This medicine contains 39,84 mg and 39,900 mg lactose monohydrate per active and inactive (placebo) tablet respectively. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

The prescribing information of concomitant medicines should be consulted to identify potential interactions.

Interactions between EE and other medicines may lead to decreased or increased serum EE concentrations, respectively.

Concomitant use with the medicines containing ombitasvir/paritaprevir/ ritonavir and dasabuvir, with or without ribavirin may increase the risk of ALT elevations (see section 4.3 and section 4.4 – Hepatic neoplasia/liver disease/hepatitis C). Therefore, MINESSE users must switch to an alternative method of contraception (e.g., progestogen-only contraception or nonhormonal methods) prior to starting therapy with anti-viral HCV medicines such as ombitasvir, paritaprevir, ritonavir, dasabuvir. MINESSE can be restarted 2 weeks following completion of treatment with an anti-viral HCV medicine.

Medicines that may decrease EE concentrations

Decreased EE serum concentrations may cause an increased incidence of breakthrough bleeding and menstrual irregularities and may possibly reduce efficacy of MINESSE.

During concomitant use of MINESSE and medicines that may lead to decreased EE serum concentrations, it is recommended that a nonhormonal back-up method of contraception (such as condoms and spermicide) be used in addition to the regular intake of MINESSE. In the case of prolonged use of such medicines, MINESSE should not be considered the primary contraceptive.

After discontinuation of medicines that may lead to decreased EE serum concentrations, use of a nonhormonal back-up method is recommended for at least 7 days. Longer use of a back-up method is advisable after discontinuation of medicines that have led to induction of hepatic microsomal enzymes, resulting in decreased EE serum concentrations. It may sometimes take several weeks until enzyme induction has completely subsided, depending on dosage, duration of use and rate of elimination of the inducing medicine.

Examples of medicines that may decrease serum EE concentrations include:

• any medicine that reduces gastrointestinal transit time and, therefore, EE absorption
• medicines that induce hepatic microsomal enzymes, such as rifampicin, rifabutin, barbiturates, primidone, phenytoin, dexamethasone, griseofulvin, topiramate, some protease inhibitors, modafinil
• Hypericum perforatum, also known as St. John’s wort, and ritonavir* (possibly by induction of hepatic microsomal enzymes)
• certain antibiotics (e.g. ampicillin and other penicillins, tetracyclines), by a decrease of enterohepatic circulation of estrogens

^* Although ritonavir is an inhibitor of cytochrome P450 3A4, treatment with ritonavir has been shown to decrease EE serum concentrations.

Medicines that may increase EE concentrations

Examples of medicines that may increase serum EE concentrations include:

• atorvastatin
• competitive inhibitors for sulphation in the gastrointestinal wall, such as ascorbic acid (vitamin C) and paracetamol
• medicines that inhibit cytochrome P450 3A4 isoenzyme such as indinavir, fluconazole and troleandomycin*

^* Troleandomycin may increase the risk of intrahepatic cholestasis during co-administration with MINESSE.

Effect of EE on the metabolism of other medicines

EE may interfere with the metabolism of other medicines by inhibiting hepatic microsomal enzymes, or by inducing hepatic medicine conjugation, particularly glucuronidation.

Accordingly, plasma and tissue concentrations may either be increased (e.g., ciclosporin, theophylline, corticosteroids) or decreased (e.g., lamotrigine).

In patients treated with flunarizine, use of MINESSE may increase the risk of galactorrhoea.

Interference with laboratory and other diagnostic tests

Effects on laboratory parameters

The use of MINESSE may cause certain physiologic changes, which may be reflected in the results of certain laboratory tests, including:

• biochemical parameters of liver function (including a decrease in bilirubin and alkaline phosphatase), thyroid function (increased total T3 and T4 due to increased TBG, decreased free T3 resin uptake), adrenal function (increased plasma cortisol, increased cortisol binding globulin, decreased dehydroepiandrosterone sulfate (DHEAS), and renal function (increased plasma creatinine and creatinine clearance)
• plasma levels of (carrier) proteins, such as corticosteroid-binding globulin and lipid/lipoprotein fractions
• parameters of carbohydrate metabolism
• parameters of coagulation and fibrinolysis
• decreased serum folate levels

Pregnancy

MINESSE is not indicated in pregnancy. If pregnancy occurs during use of MINESSEE, it must be withdrawn immediately.

There is no increased risk of birth defects in children born to women who used combination oral contraceptives prior to pregnancy.

Foetal abnormalities, including heart defects have been reported in the infants of women who have taken oral contraceptives early in pregnancy.

The increased risk of VTE during the postpartum period should be considered when re-starting MINESSE (see section 4.2 and 4.4).

Breastfeeding

Small amounts of contraceptive steroids and/or metabolites have been identified in the milk of nursing mothers and a few adverse effects on the child have been reported, including jaundice and breast enlargement. Lactation may be influenced by MINESSE as it may reduce the quantity and change the composition of breast milk.

The use of MINESSE is not recommended until the breastfeeding mother has completely weaned her child (see section 4.4 regarding postpartum use).

MINESSE may influence your ability to drive and use machines. Dizziness, nervousness, headaches, migraines and mood changes have been reported.

Summary of the safety profile

Use of combination oral contraceptives such as MINESSE has been associated with an increased risk of:

• arterial and venous thrombotic and thromboembolic events, including myocardial infarction, stroke, transient ischaemic attack, venous thrombosis and pulmonary embolism
• cervical intraepithelial neoplasia and cervical cancer
• breast cancer diagnosis
• benign hepatic tumours (e.g. focal nodular hyperplasia, hepatic adenomas)

Tabulated summary of adverse reactions

Adverse reactions are listed per CIOMS frequency categories: Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1 000 to <1/100); rare (≥1/10 000 to <1/1 000); very rare (<1/10 000), not known (cannot be estimated from the available data).

^* Optic neuritis may lead to partial or complete loss of vision.
^** Combination oral contraceptives may worsen existing gallbladder disease and may accelerate the development of this disease in previously asymptomatic women.
^*** Serum folate levels may be depressed by combination oral contraceptive therapy. This may be of clinical significance if the woman becomes pregnant shortly after discontinuing combination oral contraceptives.

Post-marketing reported side effects

The following side effects have been reported with the post-marketing use of hormonal contraceptives:

Severe depression with a higher risk of suicidal thoughts/behaviour and suicide.

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/healthproducts-vigilance/.

Not applicable.