Source: Health Products Regulatory Authority (ZA) Revision Year: 2022 Publisher: Bayer (Pty) Ltd, Reg. No.: 1968/011192/07, 27 Wrench Road, ISANDO, 1609
MELODENE 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 MELODENE use, MELODENE should be stopped immediately.
If any of the conditions/risk factors mentioned below are present, the benefits of MELODENE 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 medical practitioner. The medical practitioner should then decide on whether its use should be discontinued.
Epidemiological studies have suggested an association between the use of combined oral contraceptives, such as MELODENE, and an increased risk of arterial and venous 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 MELODENE, 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 MELODENE, 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 combined oral contraceptives, such as MELODENE.
Thrombosis has been reported to occur in other blood vessels, e.g. hepatic, mesenteric, renal, cerebral or retinal veins and arteries, in combined oral contraceptive users, such as MELODENE.
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. MELODENE 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 MELODENE use (which may be prodromal of a cerebrovascular event) may be a reason for immediate discontinuation of MELODENE.
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 medical practitioner 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 low-dose oral contraceptive use, such as MELODENE, (<0,05 mg ethinylestradiol).
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 MELODENE. The excess risk gradually disappears during the course of the 10 years after cessation of MELODENE 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 MELODENE.
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 MELODENE.
Small increases in blood pressure have been reported in many women taking combined oral contraceptives, such as MELODENE; clinically relevant increases may occur. If a sustained clinically significant hypertension develops during the use of MELODENE, then it is prudent for the medical practitioner to withdraw MELODENE and treat the hypertension. Where considered appropriate, MELODENE 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 may induce or exacerbate symptoms of angioedema.
Acute or chronic disturbances of liver function may necessitate the discontinuation of MELODENE use until markers of liver function return to normal. The recurrence of cholestatic jaundice that occurred first during pregnancy or previous use of sex steroids necessitates the discontinuation of MELODENE.
Although MELODENE may have an effect on peripheral insulin resistance and glucose tolerance, there is no evidence for a need to alter the therapeutic regimen in diabetics using MELODENE. However, diabetic women should be carefully observed while taking MELODENE.
Crohn’s disease and ulcerative colitis have been associated with combined oral contraceptives.
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 MELODENE.
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.
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.
A complete medical history and physical examination should be taken prior to the initiation or reinstitution of MELODENE use, guided by the contraindications and warnings (see sections 4.3 and 4.4), and should be repeated periodically. 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 MELODENE. 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 MELODENE does not protect against HIV infections (AIDS) and other sexually transmitted diseases.
The efficacy of MELODENE may be reduced in the event of e.g. missed hormone-containing white tablets taking (see section 4.2), gastrointestinal disturbances during hormone-containing white tablettaking (see section 4.2), or concomitant medication (see section 4.5).
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 pink tablet phase. If MELODENE has been taken according to the directions described in section 4.2, it is unlikely that the woman is pregnant. However, if MELODENE 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 MELODENE 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 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 MELODENE, 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 white tablets in the MELODENE pack, the hormone-free pink tablets should be omitted and the next MELODENE pack should be started.
Substances increasing the clearance of MELODENE (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 MELODENE, e.g.:
When co-administered with MELODENE, 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 MELODENE (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.
MELODENE may interfere with the metabolism of other medicines. Accordingly, plasma and tissue concentrations may either increase (e.g. ciclosporin and benzodiazepines) 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 CYP2J. 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 medicines with direct-acting antiviral (DAA) medicines 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 MELODENE 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.
MELODENE is contraindicated in pregnancy. If pregnancy occurs during treatment with MELODENE, further intake should be stopped.
Lactation may be influenced by MELODENE as it may reduce the quantity and change the composition of breast milk. Therefore, the use of MELODENE should generally not be recommended until the breast-feeding mother has completely weaned her child. Small amounts of the active ingredients of MELODENE and/or their metabolites may be excreted with the milk.
No observed effects.
The most commonly reported adverse reactions with MELODENE 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 (≥1/1000 to <1/100) | Rare (≥1/10,000 to ≤1/1000) |
|---|---|---|---|
| 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):
Tumours:
Other conditions:
Interactions:
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.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.
