Source: Health Products Regulatory Authority (ZA) Revision Year: 2022 Publisher: Bayer (Pty) Ltd, Reg. No.: 1968/011192/07, 27 Wrench Road, Isando, 1609
Combined oral contraceptives should not be used in the presence of any of the conditions listed below. Should any of the conditions appear for the first time during combined oral contraceptive use, the product should be stopped immediately.
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.
Epidemiological studies have suggested an association between the use of combined oral contraceptives and an increased risk of venous and arterial thrombotic and thromboembolic diseases such as myocardial infarction, stroke, deep venous thrombosis, and pulmonary embolism.
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 FEMODENE ED, 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 FEMODENE ED, is higher than for non-users of combined oral contraceptives.
VTE may be life-threatening or may have a fatal outcome.
Venous thromboembolism, manifesting as deep venous thrombosis and/or pulmonary embolism, may occur during the use of all combined oral contraceptives, such as FEMODENE ED.
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. FEMODENE ED 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:
The increased risk of thromboembolism in the puerperium must be considered (see section 4.6).
Other medical conditions that have been associated with thrombotic incidents include diabetes mellitus, systemic lupus erythematosus, haemolytic uraemic syndrome, chronic inflammatory bowel disease (Crohn’s disease or ulcerative colitis) and sickle cell disease.
The onset of, or increase in frequency or severity of migraine during combined oral contraceptive use (which may be prodromal of a cerebrovascular event) may be a reason for immediate discontinuation of FEMODENE ED.
Biochemical factors that may be indicative of a hereditary or acquired predisposition for venous or arterial thrombosis include Activated Protein C (APC) 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.
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 FEMODENE ED. The excess risk gradually disappears during the course of the 10 years after cessation of FEMODENE ED use.
Benign liver tumours, and rarely, malignant liver tumours have been reported in users of combined 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 FEMODENE ED.
Malignancies may be life-threatening or may have a fatal outcome.
Women with hypertriglyceridaemia, or a family history thereof, may be at an increased risk of pancreatitis when using FEMODENE ED.
Small increases in blood pressure have been reported in many women taking combined oral contraceptives such as FEMODENE ED; clinically relevant increases may occur. If a sustained clinically significant hypertension develops during the use of FEMODENE ED then it is prudent for the physician to withdraw FEMODENE ED and treat the hypertension. Where considered appropriate, FEMODENE ED use may be resumed if normotensive values can be achieved with antihypertensive therapy.
The following conditions have been reported to occur or deteriorate with combined oral contraceptive use: jaundice and/or pruritus related to cholestasis; gallstone formation; porphyria; systemic lupus erythematosus; haemolytic uraemic syndrome; Sydenham’s chorea; herpes gestationis; otosclerosisrelated hearing loss.
In women with hereditary angioedema exogenous estrogens such as contained in FEMODENE ED may induce or exacerbate symptoms of angioedema.
Acute or chronic disturbances of liver function may necessitate the discontinuation of FEMODENE ED 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 FEMODENE ED.
FEMODENE ED may have an effect on peripheral insulin resistance and glucose tolerance. Hence, diabetic women should be carefully observed while taking FEMODENE ED.
Crohn’s disease and ulcerative colitis have been associated with combined oral contraceptive use such as FEMODENE ED.
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 FEMODENE ED.
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.
Each smaller white coated tablet of this medicine contains 36 mg lactose per tablet, each larger white coated tablet contains 46 mg. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption who are on a lactose-free diet should take this amount into consideration.
A complete medical history and physical examination should be taken prior to the initiation or reinstitution of FEMODENE ED, guided by the contraindications and warnings (see section 4.3 and 4.4) and should be repeated at least annually during the use of FEMODENE ED. 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 a FEMODENE ED. 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 FEMODENE ED does not protect against HIV infections (AIDS) and other sexually transmissible diseases.
The efficacy of FEMODENE ED may be reduced in the event of e.g. missed hormone-containing smaller white tablets, gastrointestinal disturbances during hormone-containing smaller white tablet taking or concomitant medication (see sections 4.2 and 4.5).
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, then 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 larger white tablet phase. If FEMODENE ED has been taken according to the directions described in section 4.2, it is unlikely that the woman is pregnant. However, if FEMODENE ED 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 FEMODENE ED use is continued.
Note: The prescribing information of concomitant medications should be consulted to identify potential interactions.
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/or 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 FEMDOENE ED 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 smaller white tablets in the pack, the hormone-free larger white coated tablets should be omitted and the next pack be started.
Substances increasing the clearance of FEMODENE ED (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 FEMODENE ED, e.g.: When co-administered with FEMODENE ED, 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 FEMODENE ED (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.
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 mechanism-based 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).
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).
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.
FEMODENE ED is contraindicated during pregnancy (see section 4.3). If pregnancy occurs during treatment with FEMODENE ED, 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. Feminisation of the male foetus may occur.
Lactation may be influenced by FEMODENE ED as it may reduce the quantity and change the composition of breast milk. Therefore, the use of FEMODENE ED 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.
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 FEMODENE ED.
The most commonly reported adverse reactions with FEMODENE ED 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.
| System Organ Class (MedDRA) | Common (≥1/100 to <1/10) | Uncommon (≥/1 000 to < 1/100) | Rare (≥1/10 000 to ≤1/1 000) |
|---|---|---|---|
| Eye disorders | contact lens intolerance | ||
| Gastrointestinal disorders | nausea, abdominal pain | vomiting, diarrhoea | |
| Immune system disorders | hypersensitivity | ||
| Investigations | increased weight | decreased weight | |
| Metabolism and nutrition disorders | fluid retention | ||
| Nervous system disorders | headache | migraine | |
| Psychiatric disorders | depressed mood, altered mood | decreased libido | increased libido |
| Reproductive system and breast disorders | breast pain, breast tenderness | breast hypertrophy | vaginal discharge, breast discharge |
| Skin and subcutaneous tissue disorders | rash, urticaria | erythema nodosum, erythema multiforme | |
| Vascular disorders | Venous and arterial thromboembolic events* |
* 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
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):
Breakthrough bleeding and/or contraceptive failure may result from interactions of other medicines (enzyme inducers) with oral contraceptives (see section 4.5).
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.
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