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Each tablets contains 0.15 mg of Levonogestrel BP/Ph. Eur and 0.03 mg of Ethynylestradiol BP/Ph. Eur
Pharmacotherapeutic group: Sex hormones and modulators of the genital system, Progestogens and oestrogens, fixed combinations. ATC Code: G03AA07.
Levorest® is an oestrogen-progestogen combination which acts by inhibiting ovulation by suppression of the mid-cycle surge of luteinising hormone, the inspissation of cervical mucus producing a barrier to sperm, and the rendering of the endometrium unreceptive to implantation.
Therapeutic indications
Oral contraception and the recognized gynecological indications for such oestrogen-progestogen combinations.
The decision to prescribe Levorest® should take into consideration the individual woman’s current risk factors, particularly those for venous thromboembolism (VTE), and how the risk of VTE with Levorest® compares with other combined hormonal contraceptives (CHCs).
Posology and method of administration
Tablets must be taken orally in the order directed on the blister package at about the same time every day, with some liquid if necessary.
First treatment cycle: 1 tablet daily for 21 days, starting on the first day of the menstrual cycle.
Contraceptive protection begins immediately.
Subsequent cycles: Tablet-taking from the next pack of Levorest® is continued after a 7-day tabletfree interval, beginning on the same day of the week as the first pack. A withdrawal bleed usually occurs during the tablet-free interval.
Changing from 21-day combined oral contraceptives: The first tablet of Levorest® should be taken on the first day immediately after the end of theprevious oral contraceptive course. Additional contraceptive precautions are not required.
Changing from a combined Every Day pill (28 -day tablets): Levorest® should be started after taking the last active tablet from the Every Day Pill pack. Thefirst Levorest® tablet is taken the next day. Additional contraceptive precautions are not thenrequired.
Changing from a progestogen-only pill (POP): The first tablet of Levorest® should be taken on the first day of bleeding, even if a POP hasalready been taken on that day. Additional contraceptive precautions are not then required. Theremaining 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 thatthe patient is fully ambulant and there are no puerperal complications. Additional contraceptiveprecautions will be required for the first 7 days of tablet taking. Since the first post-partumovulation may precede the first bleeding, another method of contraception should be used in theinterval between childbirth and the first course of tablets. After a first-trimester abortion, oralcontraception may be started immediately in which case no additional contraceptive precautionsare required.
Special circumstances requiring additional contraception
Incorrect administration: A single delayed tablet should be taken as soon as possible, and if this can be done within 12hours of the correct time, contraceptive protection is maintained. With longer delays, additionalcontraception is needed. Only the most recently delayed tablet should be taken, earlier missedtablets being omitted, and additional non-hormonal methods of contraception (except therhythm or temperature methods) should be used for the next 7 days, while the next 7 tablets arebeing taken. Additionally, therefore, if tablet(s) have been missed during the last 7 days of apack, there should be no break before the next pack is started. In this situation, a withdrawalbleed should not be expected until the end of the second pack. Some breakthrough bleeding mayoccur on tablet taking days but this is not clinically significant. If the patient does not have awithdrawal bleed during the tablet-free interval following the end of the second pack, thepossibility 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 fullabsorption. If vomiting or diarrhoea occurs within 4 hours of taking Microgynon tablet-takingfrom 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 upsetand for 7 days following the upset. If these 7 days overrun the end of a pack, the next packshould be started without a break. In this situation, a withdrawal bleed should not be expecteduntil the end of the second pack. If the patient does not have a withdrawal bleed during thetablet-free interval following the end of the second pack, the possibility of pregnancy must beruled out before starting the next pack. Other methods of contraception should be considered ifthe gastro-intestinal disorder is likely to be prolonged.
Children: Not applicable.
Elderly: Not applicable.
Contraindications
Combined hormonal contraceptives (CHCs) should not be used in the following conditions.
Should any of the conditions appear for the first time during CHC use, the product should be stopped immediately.
- Presence or risk of venous thromboembolism (VTE)
- Venous thromboembolism – current VTE (on anticoagulants) or history of (e.g. deep venous thrombosis [DVT] or pulmonary embolism [PE])
- Known hereditary or acquired predisposition for venous thromboembolism, such as APC-resistance, (including Factor V Leiden), antithrombin-III-deficiency, protein C deficiency, protein S deficiency
- Major surgery with prolonged immobilization.
- A high risk of venous thromboembolism due to the presence of multiple risk factors
- Presence or risk of arterial thromboembolism (ATE)
- Arterial thromboembolism – current arterial thromboembolism, history of arterial thromboembolism (e.g. myocardial infarction) or prodromal condition (e.g. angina pectoris).
- Cerebrovascular disease – current stroke, history of stroke or prodromal condition (e.g. transient ischaemic attack, TIA).
- Known hereditary or acquired predisposition for arterial thromboembolism, such as hyperhomocysteinaemia and anti-phospholipid antibodies (anticardiolipinantibodies, lupus anticoagulant).
- History of migraine with focal neurological symptoms.
- A high risk of arterial thromboembolism due to multiple risk factors or to the presence of one serious risk factor such as: diabetes mellitus with vascular symptoms, severe hypertension, severe dyslipoproteinaemia
- Presence or history of severe hepatic disease, e.g. active viral hepatitis and severe cirrhosis, as long as liver function values have not returned to normal.
- Presence or history of liver tumours (benign or malignant).
- Current or history of breast cancer.
- Hypersensitivity to the active substance(s) or to any of the excipients.
Levorest® is contraindicated for concomitant use with medicinal products containing ombitasvir/paritaprevir/ritonavir, dasabuvir, glecaprevir/pibrentasvir and ofosbuvir/velpatasvir/voxilaprevir.
Special warnings and precautions for use
Warnings
- If any of the conditions or risk factors mentioned below is present, the suitability of Levorest® 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 Levorest® 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, such as Levorest® , norgestimate or norethisterone are associated with the lowest risk of VTE. The decision to use Levorest® should be taken after a discussion with the woman to ensure she understands the risk of VTE with Levorest® , 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.
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 discolored 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.
Reasons for stopping oral contraception immediately:
When stopping oral contraception non-hormonal contraception should be used to ensure contraceptive protection is maintained.
- Occurrence for the first time, or exacerbation, of migrainous headaches or unusually frequent or unusually severe headaches
- Sudden disturbances of vision, of hearing or other perceptual disorders
- First signs of thrombosis or blood clots (e.g. unusual pains in or swelling of the leg(s), stabbingnpains on breathing or coughing for no apparent reason). Feeling of pain and tightness in the chest
- At least four 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 heparin.
- Onset of jaundice, hepatitis, itching of the whole body
- Significant rise in blood pressure
- Severe upper abdominal pain or liver enlargement
- Clear exacerbation of conditions known to be capable of deteriorating during oral contraception or pregnancy
Tumours: Numerous 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 cancer: 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 (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.
Cervical Cancer: The most important risk factor for cervical cancer is persistent HPV infection. Someepidemiological studies have indicated that long-term use of COCs may further contribute tothis increased risk but there continues to be controversy about the extent to which this finding isattributable to confounding effects, e.g., cervical screening and sexual behaviour including use ofbarrier contraceptives.
Liver Cancer: In rare cases benign and, in even rarer cases, malignant liver tumours leading in isolated cases tolife-threatening intra-abdominal haemorrhage have been observed after the use of hormonalsubstances such as those contained in Levorest® . If severe upper abdominal complaints, liverenlargement or signs of intra-abdominal haemorrhage occur, the possibility of a liver tumourshould be included in the differential diagnosis.
Known hyperlipidaemias: Women with hypertriglyceridemia, or a family history thereof, may be at an increased risk ofpancreatitis when using COCs.
Women with hyperlipidaemias are at an increased risk of arterial disease (see section 4.4 ‘Risk of arterial thromboembolism (ATE)’). However routine screening of women on COCs is not appropriate.
Blood pressure: Hypertension is a risk factor for stroke and myocardial infarction. 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 use
The following conditions have been reported to occur or deteriorate with both pregnancy and COC use. Consideration should be given to stopping Levorest® 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.
Angioedema: Exogenous oestrogens may induce or exacerbate symptoms of hereditary and acquiredangioedema.
Disturbances of liver function: Acute or chronic disturbances of liver function may necessitate the discontinuation of COC useuntil markers of liver function return to normal. Recurrence of cholestatic jaundice and/orcholestasis-related pruritus which occurred during pregnancy or previous use of sex steroidsnecessitates the discontinuation of COCs.
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.
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.
Psychiatric disorders: Depressed mood and depression are well-known undesirable effects of hormonal contraceptiveuse. Depression can be serious and is a well-known risk factor for suicidalbehaviour and suicide. Women should be advised to contact their physician in case of moodchanges and depressive symptoms, including shortly after initiating the treatment.
Chloasma: 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 radiationwhilst taking COCs.
Menstrual Changes
Reduction 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.
Lactose and Sucrose Intolerance: Each tablet of this medicinal product contains 32.82 mg lactose and 19.371 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.
Reduced efficacy: The efficacy of COCs may be reduced, in the event of missed tablets, vomiting or diarhhoea, orconcomitant medication.
Interaction with other medicinal products and other forms of interaction
Note: The prescribing information of concomitant medications should be consulted to identify potential interactions.
Enzyme inducers: Interactions 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.
Pregnancy and lactation
Levorest® is not indicated during pregnancy. If pregnancy occurs during treatment with Levorest®, further intake must be stopped. However, extensive epidemiological studies have revealed neither an increased risk of birth defects in children born to women who used COCs prior to pregnancy, nor a teratogenic effect when COCs were taken inadvertently during early pregnancy.
The increased risk of VTE during the postpartum period should be considered when re-starting Levorest®.
The use of Levorest® during lactation may lead to a reduction in the volume of milk produced and to a change in its composition. Minute amounts of the active substances are excreted with the milk. These amounts may affect the child particularly in the first 6 weeks post-partum.
Mothers who are breast-feeding may be advised instead to use another method of contraception.
Effects on ability to drive and use machines
Ethinylestradiol / levonorgestrel has no effects or negligible influence on the ability to drive and use machines.
Undesirable effects
The most commonly reported adverse reactions with Levorest® are nausea, abdominal pain, increased weight, headache, depressed mood, altered mood, breast pain, breast tenderness. They occur in ≥1% of users.
Overdose
There have been no reports of serious effects from overdose. Overdosage may cause nausea, vomiting and, in females, withdrawal bleeding. Withdrawal bleeding may even occur in girls before their menarche, if they accidentally take the medicinal product.
There are no specific antidotes and treatment should be symptomatic.
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