- 1. Name of the medicinal product
- 2. Qualitative and quantitative composition
- 3. Pharmaceutical form
- 4. Clinical particulars
- 4.1 Therapeutic indications
- 4.2 Posology and method of administration
- 4.3 Contraindications
- 4.4 Special warnings and precautions for use
- 4.5 Interaction with other medicinal products and other forms of interaction
- 4.6 Pregnancy and lactation
- 4.7 Effects on ability to drive and use machines
- 4.8 Undesirable effects
- 4.9 Overdose
- 5. Pharmacological properties
- 5.1 Pharmacodynamic properties
- 5.2 Pharmacokinetic properties
- 5.3 Preclinical safety data
- 6. Pharmaceutical particulars
- 6.1 List of excipients
- 6.2 Incompatibilities
- 6.3 Shelf life
- 6.4 Special precautions for storage
- 6.5 Nature and contents of container
- 6.6 Special precautions for disposal and other handling
- 7. Marketing authorisation holder
- 8. Marketing authorisation number(s)
- 9. Date of first authorisation/renewal of the authorisation
- 10. Date of revision of the text
Changing from a combined Every Day pill (28 day tablets):Femodette should be started after taking the last active tablet from the Every Day Pill pack. The first Femodette tablet is taken the next day. Additional contraceptive precautions are not then required.
Changing from a progestogen-only pill (POP):The first tablet of Femodette should be taken on the first day of bleeding, even if a POP has already been taken on that day. Additional contraceptive precautions are not then required. The remaining progestogen-only pills should be discarded.Post-partum and post-abortum use: After pregnancy, oral contraception can be started 21 days after a vaginal delivery, provided that the patient is fully ambulant and there are no puerperal complications. Additional contraceptive precautions will be required for the first 7 days of pill taking. Since the first post-partum ovulation may precede the first bleeding, another method of contraception should be used in the interval between childbirth and the first course of tablets. After a first-trimester abortion, oral contraception may be started immediately in which case no additional contraceptive precautions are required.
Special circumstances requiring additional contraceptionIncorrect administration: A single delayed tablet should be taken as soon as possible, and if this can be done within 12 hours of the correct time, contraceptive protection is maintained. With longer delays, additional contraception is needed. Only the most recently delayed tablet should be taken, earlier missed tablets being omitted, and additional non-hormonal methods of contraception (except the rhythm and temperature methods) should be used for the next 7 days, while the next 7 tablets are being taken. Additionally, therefore, if tablet(s) have been missed during the last 7 days of a pack, there should be no break before the next pack is started. In this situation, a withdrawal bleed should not be expected until the end of the second pack. Some breakthrough bleeding may occur on pill taking days but this is not clinically significant. If the patient does not have a withdrawal bleed during the tablet-free interval following the end of the second pack, the possibility of pregnancy must be ruled out before starting the next pack.Gastro-intestinal upset: Vomiting or diarrhoea may reduce the efficacy of oral contraceptives by preventing full absorption. If vomiting or diarrhoea occurs within 4 hours of taking Femodette tablet-taking from the current pack should be continued. Additional non-hormonal methods of contraception (except the rhythm or temperature methods) should be used during the gastro-intestinal upset and for 7 days following the upset. If these 7 days overrun the end of a pack, the next pack should be started without a break. In this situation, a withdrawal bleed should not be expected until the end of the second pack. If the patient does not have a withdrawal bleed during the tablet-free interval following the end of the second pack, the possibility of pregnancy must be ruled out before starting the next pack. Other methods of contraception should be considered if the gastro-intestinal disorder is likely to be prolonged.Children: Not applicable.Elderly: Not applicable.
|• diabetes mellitus with vascular symptoms|
|• severe hypertension|
|• severe dyslipoproteinaemia|
Warnings• If any of the conditions or risk factors mentioned below is present, the suitability of Femodette should be discussed with the woman.• In the event of aggravation, or first appearance of any of these conditions or risk factors, the woman should be advised to contact her doctor to determine whether the use of Femodette should be discontinued.
Risk of venous thromboembolism (VTE)The use of any combined hormonal contraceptive (CHC) increases the risk of venous thromboembolism (VTE) compared with no use. Products that contain levonorgestrel, norgestimate or norethisterone are associated with the lowest risk of VTE. Other products such as Femodette may have up to twice this level of risk. The decision to use any product other than one with the lowest VTE risk should be taken only after a discussion with the woman to ensure she understands the risk of VTE with Femodette, how her current risk factors influence this risk, and that her VTE risk is highest in the first ever year of use. There is also some evidence that the risk is increased when a CHC is re-started after a break in use of 4 weeks or more.In women who do not use a CHC and are not pregnant, about 2 out of 10,000 will develop a VTE over the period of one year. However, in any individual woman the risk may be far higher, depending on her underlying risk factors (see below).It is estimated1 that out of 10,000 women who use a CHC containing gestodene between 9 and 12 women will develop a VTE in one year; this compares with about 62 in women who use a levonorgestrel-containing CHC.In both cases, the number of VTEs per year is fewer than the number expected during pregnancy or in the postpartum period.VTE may be fatal in 1-2% of cases.
Number of VTE events per 10,000 women in one yearExtremely rarely, thrombosis has been reported to occur in CHC users in other blood vessels, e.g. hepatic, mesenteric, renal, cerebral or retinal veins and arteries.
Risk factors for VTEThe risk for venous thromboembolic complications in CHC users may increase substantially in a woman with additional risk factors, particularly if there are multiple risk factors (see table).Femodette is contraindicated if a woman has multiple risk factors that put her at high risk of venous thrombosis (see section 4.3). If a woman has more than one risk factor, it is possible that the increase in risk is greater than the sum of the individual factors in this case her total risk of VTE should be considered. If the balance of benefits and risks is considered to be negative a CHC should not be prescribed (see section 4.3).
Table: Risk factors for VTE
|Obesity (body mass index over 30 kg/m2)||Risk increases substantially as BMI rises. Particularly important to consider if other risk factors also present.|
|Prolonged immobilisation, major surgery, any surgery to the legs or pelvis, neurosurgery, or major trauma Note: temporary immobilisation including air travel >4 hours can also be a risk factor for VTE, particularly in women with other risk factors||In these situations it is advisable to discontinue use of the pill (in the case of elective surgery at least four weeks in advance) and not resume until two weeks after complete remobilisation. Another method of contraception should be used to avoid unintentional pregnancy. Antithrombotic treatment should be considered if Femodette has not been discontinued in advance.|
|Positive family history (venous thromboembolism ever in a sibling or parent especially at a relatively early age e.g. before 50).||If a hereditary predisposition is suspected, the woman should be referred to a specialist for advice before deciding about any CHC use.|
|Other medical conditions associated with VTE||Cancer, systemic lupus erythematosus, haemolytic uraemic syndrome, chronic inflammatory bowel disease (Crohn's disease or ulcerative colitis) and sickle cell disease.|
|Increasing age||Particularly above 35 years.|
Symptoms of VTE (deep vein thrombosis and pulmonary embolism)In the event of symptoms women should be advised to seek urgent medical attention and to inform the healthcare professional that she is taking a CHC.Symptoms of deep vein thrombosis (DVT) can include:- unilateral swelling of the leg and/or foot or along a vein in the leg;- pain or tenderness in the leg which may be felt only when standing or walking,- increased warmth in the affected leg; red or discoloured skin on the leg. Symptoms of pulmonary embolism (PE) can include:- sudden onset of unexplained shortness of breath or rapid breathing;- sudden coughing which may be associated with haemoptysis;- sharp chest pain;- severe light headedness or dizziness;- rapid or irregular heartbeat.Some of these symptoms (e.g. shortness of breath, coughing) are non-specific and might be misinterpreted as more common or less severe events (e.g. respiratory tract infections).Other signs of vascular occlusion can include: sudden pain, swelling and slight blue discoloration of an extremity. If the occlusion occurs in the eye symptoms can range from painless blurring of vision which can progress to loss of vision. Sometimes loss of vision can occur almost immediately.
Risk of arterial thromboembolism (ATE)Epidemiological studies have associated the use of CHCs with an increased risk for arterial thromboembolism (myocardial infarction) or for cerebrovascular accident (e.g. transient ischaemic attack, stroke). Arterial thromboembolic events may be fatal.
Risk factors for ATEThe risk of arterial thromboembolic complications or of a cerebrovascular accident in CHC users increases in women with risk factors (see table). Femodette is contraindicated if a woman has one serious or multiple risk factors for ATE that puts her at high risk of arterial thrombosis (see section 4.3). If a woman has more than one risk factor, it is possible that the increase in risk is greater than the sum of the individual factors - in this case her total risk should be considered. If the balance of benefits and risks is considered to be negative a CHC should not be prescribed (see section 4.3).
Table: Risk factors for ATE
|Increasing age||Particularly above 35 years|
|Smoking||Women should be advised not to smoke if they wish to use a CHC. Women over 35 who continue to smoke should be strongly advised to use a different method of contraception.|
|Obesity (body mass index over 30 kg/m2)||Risk increases substantially as BMI increases. Particularly important in women with additional risk factors|
|Positive family history (arterial thromboembolism ever in a sibling or parent especially at relatively early age e.g. below 50).||If a hereditary predisposition is suspected, the woman should be referred to a specialist for advice before deciding about any CHC use|
|Migraine||An increase in frequency or severity of migraine during CHC use (which may be prodromal of a cerebrovascular event) may be a reason for immediate discontinuation|
|Other medical conditions associated with adverse vascular events||Diabetes mellitus, hyperhomocysteinaemia, valvular heart disease and atrial fibrillation, dyslipoproteinaemia and systemic lupus erythematosus.|
Symptoms of ATEIn the event of symptoms women should be advised to seek urgent medical attention and to inform the healthcare professional that she is taking a CHC.Symptoms of a cerebrovascular accident can include:- sudden numbness or weakness of the face, arm or leg, especially on one side of the body;- sudden trouble walking, dizziness, loss of balance or coordination;- sudden confusion, trouble speaking or understanding;- sudden trouble seeing in one or both eyes;- sudden, severe or prolonged headache with no known cause;- loss of consciousness or fainting with or without seizure.Temporary symptoms suggest the event is a transient ischaemic attack (TIA).Symptoms of myocardial infarction (MI) can include:- pain, discomfort, pressure, heaviness, sensation of squeezing or fullness in the chest, arm, or below the breastbone;- discomfort radiating to the back, jaw, throat, arm, stomach;- feeling of being full, having indigestion or choking;- sweating, nausea, vomiting or dizziness;- extreme weakness, anxiety, or shortness of breath; - rapid or irregular heartbeats.
Medical Examination/ConsultationPrior to the initiation or reinstitution of Femodette 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 contra-indications (see section 4.3) and warnings (see section 4.4). It is important to draw a woman's attention to the information on venous and arterial thrombosis, including the risk of Femodette compared with other CHCs, the symptoms of VTE and ATE, the known risk factors and what to do in the event of a suspected thrombosis.The woman should also be instructed to carefully read the user leaflet and to adhere to the advice given. The frequency and nature of examinations should be based on established practice guidelines and be adapted to the individual woman.Women should be advised that hormonal contraceptives do not protect against HIV infections (AIDS) and other sexually transmitted diseases.Undiagnosed vaginal bleeding that is suspicious for underlying conditions should be investigated.
Conditions which require strict medical supervisionThe decision to prescribe the COC must be made using clinical judgement and in consultation with the woman. Exacerbation or first appearance of any of these conditions may indicate that use of the oral contraceptive should be discontinued: • Diabetes mellitus with mild vascular disease or mild nephropathy, retinopathy or neuropathy• Hypertension that is adequately controlled, i.e. systolic >140 to159 mm Hg or diastolic > 90 to 94mmHg (see also Section 4.4 'Reasons for stopping oral contraception immediately') • porphyria• obesity• migraine• cardiovascular diseases
Reasons for stopping oral contraception immediately:When stopping oral contraception non-hormonal contraception should be used to ensure contraceptive protection is maintained.1. Occurrence for the first time, or exacerbation, of migrainous headaches or unusually frequent or unusually severe headaches2. Sudden disturbances of vision, of hearing or other perceptual disorders3. First signs of thrombosis or blood clots (e.g. unusual pains in or swelling of the leg(s), stabbing pains on breathing or coughing for no apparent reason). Feeling of pain and tightness in the chest4. Six weeks before an elective major operation (e.g. abdominal, orthopaedic), any surgery to the legs, medical treatment for varicose veins or prolonged immobilisation, e.g. after accidents or surgery. Do not restart until 2 weeks after full ambulation. In case of emergency surgery, thrombotic prophylaxis is usually indicated e.g. subcutaneous heparin5. Onset of jaundice, hepatitis, itching of the whole body6. Significant rise in blood pressure 7. Severe upper abdominal pain or liver enlargement8. Clear exacerbation of conditions known to be capable of deteriorating during oral contraception or pregnancy (see section 4.4 'Conditions which deteriorate in pregnancy or during previous COC use' under 'Other conditions')TumoursNumerous epidemiological studies have been reported on the risks of ovarian, endometrial, cervical and breast cancer in women using combined oral contraceptives. The evidence is clear that high dose combined oral contraceptives offer substantial protection against both ovarian and endometrial cancer. However, it is not clear whether low dose COCs confer protective effects to the same level.• Breast cancerA 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 (COCs). The observed pattern of increased risk may be due to an earlier diagnosis of breast cancer in COC users, the biological effects of COCs or a combination of both. The additional breast cancers diagnosed in current users of COCs or in women who have used COCs in the last ten years are more likely to be localised to the breast than those in women who never used COCs.Breast cancer is rare among women under 40 years of age whether or not they take COCs. Whilst this background risk increases with 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 (see bar chart).The most important risk factor for breast cancer in COC users is the age women discontinue the COC; the older the age at stopping, the more breast cancers are diagnosed. Duration of use is less important and the excess risk gradually disappears during the course of the 10 years after stopping COC use such that by 10 years there appears to be no excess.The possible increase in risk of breast cancer should be discussed with the user and weighed against the benefits of COCs taking into account the evidence that they offer substantial protection against the risk of developing certain other cancers (e.g. ovarian and endometrial cancer).Estimated cumulative numbers of breast cancers per 10,000 women diagnosed in 5 years of use and up to 10 years after stopping COCs, compared with numbers of breast cancers diagnosed in 10,000 women who had never used COCs• Cervical CancerThe most important risk factor for cervical cancer is persistent HPV infection. Some epidemiological studies have indicated that long-term use of COCs 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.• Liver CancerIn rare cases benign and, in even rarer cases, malignant liver tumours leading in isolated cases to life-threatening intraabdominal haemorrhage have been observed after the use of hormonal substances such as those contained in Femodette. If severe upper abdominal complaints, liver enlargement or signs of intra-abdominal haemorrhage occur, the possibility of a liver tumour should be included in the differential diagnosis.
Other conditionsThe possibility cannot be ruled out that certain chronic diseases may occasionally deteriorate during the use of combined oral contraceptives • Known hyperlipidaemiasWomen with hypertriglyceridemia, or a family history thereof, may be at an increased risk of pancreatitis when using COCs.Women with hyperlipidaemias are at an increased risk of arterial disease (see section 4.4 'Circulatory disorders'). However routine screening of women on COCs is not appropriate.• Blood pressureHypertension is a risk factor for stroke and myocardial infarction (see section 4.4 'Arterial thromboembolic-related conditions'). Although small increases in blood pressure have been reported in many women taking COCs, clinically relevant increases are rare. However, if sustained hypertension develops during the use of a COC, antihypertensive treatment should normally be instigated at a level of 160/100 mm Hg in uncomplicated patients or at 140/90 mm Hg in those with target organ damage, established cardiovascular disease, diabetes or with increased cardiovascular risk factors. Decisions about the continued use of the COC should be made at lower BP levels, and alternative contraception may be advised.• Conditions which deteriorate in pregnancy or during previous COC useThe following conditions have been reported to occur or deteriorate with both pregnancy and COC use. Consideration should be given to stopping Femodette if any of the following occur during use: • jaundice and/or pruritus related to cholestasis • COCs may increase the risk of gallstone formation and may worsen existing disease • systemic lupus erythematosus • herpes gestationis • otosclerosis-related hearing loss • sickle cell anaemia • renal dysfunction • hereditary angioedema • any other condition an individual woman has experienced worsening of during pregnancy or previous use of COCs. • Disturbances of liver functionAcute or chronic disturbances of liver function may necessitate the discontinuation of COC use until markers of liver function return to normal.• Diabetes (without vascular involvement)Insulin-dependent diabetics without vascular disease can use COCs. However it should be remembered that all diabetics are at an increased risk of arterial disease and this should be considered when prescribing COCs. Diabetics with existing vascular disease are contraindicated from using COCs (see section 4.3 Contraindications).Although COCs 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 low-dose COCs (containing < 0.05 mg ethinylestradiol). However, diabetic women should be carefully observed while taking COCs.• ChloasmaChloasma 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 COCs.• Menstrual ChangesReduction of menstrual flow: This is not abnormal and it is to be expected in some patients. Indeed, it may be beneficial where heavy periods were previously experienced.Missed menstruation: Occasionally, withdrawal bleeding may not occur at all. If the tablets have been taken correctly, pregnancy is very unlikely. If withdrawal bleeding fails to occur at the end of a second pack, the possibility of pregnancy must be ruled out before resuming with the next pack.Intermenstrual bleeding: 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. This may include curettage.Some women may experience amenorrhoea or oligomenorrhoea after discontinuation of oral contraceptives, especially when these conditions existed prior to use. Women should be informed of this possibility.• Lactose and Sucrose IntoleranceEach tablet of this medicinal product contains 37.155 mg lactose and 19.660 mg sucrose per tablet. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, fructose intolerance or glucose-galactose malabsorption or sucrase-isomaltase should not take this medicine.1 These incidences were estimated from the totality of the epidemiological study data, using relative risks for the different products compared with levonorgestrel-containing CHCs. 2 Mid-point of range of 5-7 per 10,000 WY, based on a relative risk for CHCs containing levonorgestrel versus non-use of approximately 2.3 to 3.6.
Enzyme inducersInteractions can occur with drugs that induce microsomal enzymes (especially cytochrome P450 3A4) which can result in increased clearance of sex hormones and which may lead to breakthrough bleeding and/or contraceptive failure.Women on short term treatment with any of these drugs should temporarily use a barrier method in addition to the COC 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. If the period during which the barrier method is used runs beyond the end of a pack, the next pack should be started without a break. In this situation, a withdrawal bleed should not be expected until the end of the second pack. If the patient does not have a withdrawal bleed during the tablet-free interval following the end of the second pack, the possibility of pregnancy must be ruled out before resuming with the next pack.For women receiving long-term therapy with enzyme inducers, another method of contraception should be used.The following have been shown to have clinically important interactions with COCs: Anticonvulsants: barbiturates (including phenobarbitone), primidone, phenytoin, carbamazepine, oxcarbazepine, topiramate. Antibiotics/antifungals: griseofulvin, rifampacin. Herbal remedies: St John's wort (Hypericum perforatum) Antiretroviral agents: ritonavir, nelfinavir, nevirapine. Note: There are other antiretroviral agents that may increase plasma concentration of sex hormones.
Substances decreasing the clearance of COCs (enzyme inhibitors)Strong and moderate CYP3A4 inhibitors such as azole antifungals (e.g. itraconazole, voriconazole, fluconazole) and macrolides (e.g. erythromycin) 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 on other drugsOral contraceptives may affect the metabolism of certain other drugs. Accordingly, plasma and tissue concentrations may either increase (e.g. cyclosporin, tizanidine, theophylline) or decrease (e.g. lamotrigine).• Laboratory testsThe use of oral contraceptives may influence the results of certain laboratory tests including biochemical parameters of liver, thyroid, adrenal and renal function, plasma levels of carrier proteins and lipid/lipoprotein fractions, parameters of carbohydrate metabolism and parameters of coagulation and fibrinolysis. Laboratory staff should therefore be informed about oral contraceptive use when laboratory tests are requested.
|System Organ Class||Adverse events reported in clinical trials||Adverse events reported post marketing|
|Common (≥ 1/100)||Uncommon (≥ 1/1000, <1/100)||Rare (< 1/1000)|
|Eye disorders||contact lens intolerance|
|Gastrointestinal disorders||nausea, abdominal pain||vomiting, diarrhea|
|Immune system disorders||hypersensitivity||exacerbation of hereditary angioedema|
|Investigations||weight increased||weight decreased|
|Metabolism and nutrition disorders||fluid retention||Hypertriglyceridemia, changes in glucose tolerance or effect on peripheral insulin resistance|
|Nervous system disorders||headache||migraine|
|Vascular system||Venous thromboembolism (VTE), Arterial thromboembolism (ATE)|
|Hepatobiliary disorders||liver function disturbances|
|Psychiatric disorders||depressed mood, mood altered||libido decreased||libido increased|
|Reproductive system and breast disorders||breast pain, breast tenderness||breast hypertrophy||vaginal discharge, breast discharge||reduced menstrual flow, spotting, breakthrough bleeding and missed withdrawal bleeding, post pill amenorrhoea|
|Skin and subcutaneous tissue disorders||rash, urticaria||erythema nodosum, erythema multiforme||chloasma|
Description of selected adverse reactionsAn increased risk of arterial and venous thrombotic and thrombo-embolic events, including myocardial infarction, stroke, transient ischemic attacks, venous thrombosis and pulmonary embolism has been observed in women using CHCs, which are discussed in more detail in section 4.4.The following serious adverse events have been reported in women using COCs, which are discussed in section 4.4 'Special warnings and precautions for use': • Venous thromboembolic disorders • Arterial thromboembolic disorders • Strokes (e.g. transient ischemic attack, ischemic stroke, haemorrhagic stroke) • Hypertension • Liver tumours (benign and malignant) The frequency of diagnosis of breast cancer is very slightly increased among COC 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 COC use is unknown. For further information, see sections 4.3 'Contraindications' and 4.4 'Special warnings and precautions for use'.
Conditions reported to deteriorate with pregnancy or previous COC use• Jaundice and/or pruritus related to cholestasis; gallstone formation; systemic lupus erythematosus; exacerbation of chorea, herpes gestationis; otosclerosis-related hearing loss; Crohn's disease, ulcerative colitis, sickle cell anaemia; renal dysfunction; hereditary angioedema; porphyria; cervical cancer.
Reporting of suspected adverse reactionsReporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.
Primary containers:The blister packs consist of hard tempered aluminium foil of thickness 20µm and transparent PVC film of thickness 250µm.Presentation:Blister calendar pack contaiing 21 tablets.
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