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Bayer Limited

The Atrium, Blackthorn Road, Dublin 18,
Telephone: +353 1 2999 313
Fax: +353 1 2061 456


Summary of Product Characteristics last updated on medicines.ie: 30/07/2015
SPC Microlite 100/20 microgram Tablets



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1. NAME OF THE MEDICINAL PRODUCT

Microlite 100/20 microgram Tablets


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2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 100 micrograms Levonorgestrel and 20 micrograms Ethinylestradiol.

Excipients: also includes lactose monohydrate 35.19 mg and sucrose 19.374 mg per tablet.

For a full list of excipients, see section 6.1.


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3. PHARMACEUTICAL FORM

Coated tablet (Tablet)

Pink coated tablets.


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4. CLINICAL PARTICULARS

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4.1 Therapeutic indications

Oral contraception.

The decision to prescribe Microlite should take into consideration the individual woman's current risk factors, particularly those for venous thromboembolism (VTE), and how the risk of VTE with Microlite compares with other combined hormonal contraceptives (CHCs) (see sections 4.3 and 4.4).


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4.2 Posology and method of administration

Method of administration

Oral use

Dosage regimen

How to take Microlite

Combined oral contraceptives, when taken correctly, have a failure rate of approximately 1% per year. The failure rate may increase when pills are missed or taken incorrectly.

Tablets must be taken in the order directed on the package every day at about the same time with some liquid as needed. One tablet is to be taken daily for 21 consecutive days. Each subsequent pack is started after a 7-day tablet-free interval, during which time a withdrawal bleed usually occurs. This usually starts on day 2-3 after the last coated tablet and may not have finished before the next pack is started.

How to start Microlite

No preceding hormonal contraceptive use (in the past month)

Tablet-taking has to start on day 1 of the woman's natural cycle (i.e. the first day of her menstrual bleeding). Starting on days 2-5 is allowed but during the first cycle a barrier method is recommended in addition for the first 7 days of tablet-taking.

Changing from a combined hormonal contraceptive (combined oral contraceptive/COC), vaginal ring or transdermal patch.

The woman should start with Microlite preferably on the day after the last hormone-containing tablet of her previous COC, but at the latest on the day following the usual tablet-free or hormone-free tablet interval of her previous COC. In case a vaginal ring or transdermal patch has been used, the woman should start using Microlite preferably on the day of removal of the last ring or patch of a cycle pack, but at the latest when the next application would have been due.

Changing from a progestogen-only-method (minipill, injection, implant) or from a progestogen-releasing intrauterine system (IUS)

The woman may switch any day from the minipill (from an implant or the IUS on the day of its removal, from an injectable when the next injection would be due) but should in all of these cases be advised to additionally use a barrier method for the first 7 days of tablet-taking.

Following first-trimester abortion

The woman may start immediately. When doing so, she does not need additional contraceptive measures.

Following delivery or second-trimester abortion

For breastfeeding women see Section 4.6

Women should be advised to start at day 21 to 28 after delivery or second-trimester abortion. When starting later, the woman should be advised to additionally use a barrier method for the first 7 days of tablet-taking. However, if intercourse has already occurred, pregnancy should be excluded before the actual start of COC use or the woman has to wait for her first menstrual period.

Management of missed tablets

If the user is less than 12 hours late in taking any tablet, contraceptive protection is not reduced. The woman should take the tablet as soon as she remembers and should take further tablets at the usual time.

If she is more than 12 hours late in taking any tablet, contraceptive protection may be reduced. The management of missed tablets can be guided by the following two basic rules:

1. tablet-taking must never be discontinued for longer than 7 days.

2. 7 days of uninterrupted tablet-taking are required to attain adequate suppression of the hypothalamic-pituitary-ovarian- axis.

Accordingly the following advice can be given in daily practice.

Week 1

The user should take the last missed tablet as soon as she remembers, even if this means taking two tablets at the same time. She then continues to take tablets at her usual time. In addition, a barrier method such as a condom should be used for the next 7 days. If intercourse took place in the preceding 7 days, the possibility of a pregnancy should be considered. The more tablets are missed and the closer they are to the regular tablet-free interval, the higher the risk of a pregnancy.

Week 2

The user should take the last missed tablet as soon as she remembers, even if this means taking two tablets at the same time. She then continues to take tablets at her usual time. Provided that the woman has taken her tablets correctly in the 7 days preceding the first missed tablet, there is no need to use extra contraceptive precautions. However, if this is not the case, or if she missed more than 1 tablet, the woman should be advised to use extra precautions for 7 days.

Week 3

The risk of reduced reliability is imminent because of the forthcoming tablet-free interval. However, by adjusting the tablet-intake schedule, reduced contraceptive protection can still be prevented. By adhering to either of the following two options, there is therefore no need to use extra contraceptive precautions, provided that in the 7 days preceding the first missed tablet the woman has taken all tablets correctly. If this is not the case, the woman should be advised to follow the first of these two options and to use extra precautions for the next 7 days as well.

1. The user should take the last missed tablet as soon as she remembers, even if this means taking two tablets at the same time. She then continues to take tablets at her usual time. The next pack must be started as soon as the current pack is finished, i.e., no gap should be left between packs. The user is unlikely to have a withdrawal bleed until the end of the second pack, but she may experience spotting or breakthrough bleeding on tablet-taking days.

2. The woman may also be advised to discontinue tablet-taking from the current pack. She should then have a tablet-free interval of up to 7 days, including the days she missed tablets, and subsequently continue with the next pack.

If the woman missed tablets and subsequently has no withdrawal bleed in the first normal tablet-free interval, the possibility of a pregnancy should be considered.

Advice in case of gastro-intestinal disturbances

In case of severe gastro-intestinal disturbance, absorption may not be complete and additional contraceptive measures should be taken.

If vomiting or severe diarrhoea occurs within 3-4 hours after tablet-taking, the advice concerning missed tablets, as given in section 'Management of missed tablets', is applicable. If the woman does not want to change her normal tablet-taking schedule, she has to take the extra tablet(s) needed from another pack.

In case of persisting or recurrent gastrointestinal disturbances, additional contraceptive measures should be taken and the physician should be informed.

How to shift periods or how to delay a period

To delay a period the woman should continue with another pack of Microlite without a tablet-free interval. The extension can be carried on for as long as wished until the end of the second pack. During the extension the woman may experience breakthrough-bleeding or spotting. Regular intake of Microlite is then resumed after the usual 7-day tablet-free interval.

To shift her periods to another day of the week than the woman is used to with her current scheme, she can be advised to shorten her forthcoming tablet-free interval by as many days as she likes. The shorter the interval, the higher the risk that she does not have a withdrawal bleed and will experience breakthrough-bleeding and spotting during the second pack (just as when delaying a period).

Additional information on special populations

Children and adolescents

Microlite is only indicated after menarche.

Geriatric patients

Not applicable. Microlite is not indicated after menopause.

Patients with hepatic impairment

Microlite is contraindicated in women with severe hepatic diseases. See also section 'Contraindications'.

Patients with renal impairment

Microlite has not been specifically studied in renally impaired patients. Available data do not suggest a change in treatment in this patient population.


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4.3 Contraindications

Combined hormonal contraceptives (CHCs) should not be used in the presence of any of 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)

o Venous thromboembolism – current VTE (on anticoagulants) or history of (e.g. deep venous thrombosis [DVT] or pulmonary embolism [PE])

o 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

o Major surgery with prolonged immobilisation (see section 4.4)

o A high risk of venous thromboembolism due to the presence of multiple risk factors (see section 4.4)

• Presence or risk of arterial thromboembolism (ATE)

o Arterial thromboembolism – current arterial thromboembolism, history of arterial thromboembolism (e.g. myocardial infarction) or prodromal condition (e.g. angina pectoris)

o Cerebrovascular disease – current stroke, history of stroke or prodromal condition (e.g. transient ischaemic attack, TIA)

o Known hereditary or acquired predisposition for arterial thromboembolism, such as hyperhomocysteinaemia and antiphospholipid-antibodies (anticardiolipin-antibodies, lupus anticoagulant)

o History of migraine with focal neurological symptoms

o A high risk of arterial thromboembolism due to multiple risk factors (see section 4.4) or to the presence of one serious risk factor such as:

 

• diabetes mellitus with vascular symptoms

• severe hypertension

• severe dyslipoproteinaemia

• Severe hepatic disease as long as liver function values have not returned to normal.

• Presence or history of liver tumours (benign or malignant).

• Known or suspected sex-steroid influenced malignancies (e.g. of the genital organs or the breasts).

• Undiagnosed vaginal bleeding.

• Known or suspected pregnancy.

• Hypersensitivity to the active substances or to any of the excipients listed in section 6.1.


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4.4 Special warnings and precautions for use

Warnings

If any of the conditions or risk factors mentioned below is present, the suitability of Microlite 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 Microlite should be discontinued.

Risk of venous thromboembolism (VTE)

Epidemiological studies have suggested an association between the use of COCs and an increased risk of arterial and venous thrombotic and thromboembolic diseases such as myocardial infarction, deep venous thrombosis, pulmonary embolism and of cerebrovascular accidents. These events occur rarely.

The use of any combined hormonal contraceptive (CHC) increases the risk of venous thromboembolism (VTE) compared with no use. The decision to use Microlite should be taken after a discussion with the woman to ensure she understands the risk of VTE with Microlite, 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.

Extremely 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 VTE

The 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).

Microlite 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

Risk factor

Comment

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 Microlite 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

There is no consensus about the possible role of varicose veins and superficial thrombophlebitis in the onset or progression of venous thrombosis.

The increased risk of thromboembolism in pregnancy, and particularly the 6 week period of the puerperium, must be considered (for information on “Pregnancy and lactation” see section 4.6).

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 ATE

The risk of arterial thromboembolic complications or of a cerebrovascular accident in CHC users increases in women with risk factors (see table). Microlite 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

Risk factor

Comment

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.

Hypertension

 

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 ATE

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 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.

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. A COC should not be prescribed in case of a negative risk benefit assessment (see section 4.3)

Biochemical factors that may be indicative of 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 low-dose COCs (< 0.05 mg ethinylestradiol).

Tumours

An increased risk of cervical cancer in long-term users of COCs has been reported in some epidemiological studies, but there continues to be controversy about the extent to which this finding is attributable to the confounding effects of sexual behavior and other factors such as human papilloma virus (HPV).

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 COCs. The excess risk gradually disappears during the course of the 10 years after cessation of COC use. Because breast cancer is rare in women under 40 years of 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. These studies do not provide evidence for causation. 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 breast cancers diagnosed in ever-users tend to be less advanced clinically than the cancers diagnosed in never-users.

In rare cases, benign liver tumours and even more rarely, malignant liver tumours have been reported in users of COCs. In isolated cases, these tumours have led to life-threatening intra-abdominal haemorrhages. A liver 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 COCs.

Malignancies may be life-threatening or may have a fatal outcome.

Other conditions

Women with hypertriglyceridemia, or a family history thereof, may be at an increased risk of pancreatitis when using COCs.

Although small increases in blood pressure have been reported in many women taking COCs, clinically relevant increases are rare. However, if a sustained clinically significant hypertension develops during the use of a COC then it is prudent for the physician to withdraw the COC and treat the hypertension. Where considered appropriate, COC use may be resumed if normotensive values can be achieved with antihypertensive therapy.

The following conditions have been reported to occur or deteriorate with both pregnancy and COC use, but the evidence of an association with COC use is inconclusive: jaundice and/or pruritus related to cholestasis; gallstone formation; porphyria; systemic lupus erythematosus; haemolytic uremic syndrome; Sydenham's chorea; herpes gestationis; otosclerosis-related hearing loss, depression.

In women with hereditary angioedema, exogenous oestrogens may induce or exacerbate symptoms of angioedema.

Acute or chronic disturbances of liver function may necessitate the discontinuation of COC use until markers of liver function return to normal. Recurrence of cholestatic jaundice and/or cholestasis related pruritus which occurred first during pregnancy or previous use of sex steroids necessitates the discontinuation of COCs.

Although COCs may have an effect on peripheral insulin resistance and glucose tolerance, there is no evidence of a need to alter the therapeutic regimen in diabetics using low dose COCs (containing < 0.05 mg ethinylestradiol). However, diabetic women should be carefully monitored, particularly in the early stage of COC use.

Worsening of crohn's disease and of ulcerative colitis has been reported during COC use.

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 while taking COCs.

Each coated tablet of this medicinal product contains 33 mg lactose per tablet. 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.

Herbal preparations containing St. John's Wort (Hypericum perforatum) should not be used while taking Microlite due to the risk of decreased plasma concentrations and reduced clinical effects of Microlite (see section 4.5 Interactions).

Medical examination/consultation

Prior to the initiation or reinstitution of COC use, a complete medical history and physical examination should be taken guided by the contraindications (Section 4.3) and warnings (section 'Warnings') and should be repeated periodically and pregnancy must be ruled out. 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 COC. The frequency and nature of these assessments should be based on established practice guidelines and be adapted to the individual woman but should generally include special reference to blood pressure, breasts, abdomen and pelvic organs, including cervical cytology.

It is important to draw a woman's attention to the information on venous and arterial thrombosis, including the risk of Microlite 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.

Women should be advised that hormonal contraceptives do not protect against HIV infections (AIDS) and other sexually transmitted diseases.

Reduced efficacy

The efficacy of COCs may be reduced in the event of e.g. missed tablets (section 'Management of missed tablets'), vomiting or diarrhoea (section 'Advice in case of gastro-intestinal disturbances') during tablet taking or concomitant medication (Section 4.5).

Reduced cycle control

With all COCs, 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 tablet-free interval. If the COC has been taken according to the directions described in Section 4.2, it is unlikely that the woman is pregnant. However, if the COC 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 COC use is continued.


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4.5 Interaction with other medicinal products and other forms of interaction

Effects of other medicinal products on Microlite

Interactions can occur with drugs that induce microsomal enzymes which can result in increased clearance of sex hormones and which may lead to breakthrough bleeding and/or contraceptive failure. Women on 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 the tablets in the COC pack, the next COC pack should be started without the usual tablet-free interval.

Substances increasing the clearance of COCs (dimished efficacy of COCs 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 COCs, e.g.:

When co-administered with COCs, 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 COCs (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.

Troleandomycin may increase the risk of intrahepatic cholestasis during coadministration with COCs.

Effects of COCs on other medicinal products

Oral contraceptives may affect the metabolism of certain other drugs. Accordingly, plasma and tissue concentrations may either increase (e.g. cyclosporin) 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).

Other forms of interactions

Laboratory tests

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.

Note: The prescribing information of concomitant medications should be consulted to identify potential interactions.


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4.6 Pregnancy and lactation

Pregnancy

Microlite is not indicated during pregnancy. If pregnancy occurs during treatment with Microlite, 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 Microlite (see section 4.2 and 4.4).

Lactation

Lactation may be influenced by COCs as they may reduce the quantity and change the composition of breast milk. Therefore the use of COCs 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. These amounts may affect the child.


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4.7 Effects on ability to drive and use machines

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 COCs.


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4.8 Undesirable effects

Summary of the safety profile

The most commonly reported adverse reactions with Microlite 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.

Tabulated list of adverse reactions

Side effects that have been reported in users of COCs but for which the association has been neither confirmed nor refuted are *:

System Organ Class

(MedDRA)

Common

Uncommon

Rare

Eye disorders

  

Contact lens intolerance

Gastrointestinal disorders

Nausea,

Abdominal pain

Vomiting,

Diarrhoea

 

Immune system disorders

  

Hypersensitivity

Investigations

Weight increased

 

Weight decreased

Metabolism and nutrition disorders

 

Fluid retention

 

Nervous system disorders

Headache

Migraine

 

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

Skin and subcutaneous tissue disorders

 

Rash,

Urticaria

Erythema nodosum,

Erythema multiforme

Vascular system disorders

  

Arterial thromboembolism (ATE),

Venous thromboembolism (VTE)**

* The most appropriate MedDRA term (version 12.0) to describe a certain adverse reaction is listed. Synonyms or related conditions are not listed but should be taken into account as well.

** - Estimated frequency, from epidemiological studies encompassing a group of combined oral contraceptives.

- 'Venous and arterial thromboembolic events' summarizes 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 hemorrhagic

Description of selected adverse reactions

An 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.

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 ”Contraindications”, “Special warnings and precautions for use”):

Tumors

• The frequency of diagnosis of breast cancer is very slightly increased among OC 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.

• Liver tumors (benign and malignant)

Other conditions

• Women with hypertriglyceridemia (increased risk of pancreatitis when using COCs)

• Hypertension

• Occurrence or deterioration of conditions for which association with COC use is not conclusive: jaundice and/or pruritus related to cholestasis; gallstone formation; porphyria; systemic lupus erythematosus; hemolytic uremic syndrome; Sydenham's chorea; herpes gestationis; otosclerosis-related hearing loss

• In women with hereditary angioedema exogenous estrogens may induce or exacerbate symptoms of angioedema

• Liver function disturbances

• Changes in glucose tolerance or effect on peripheral insulin resistance

• Crohn's disease, ulcerative colitis.

• Chloasma

Interactions

Breakthrough bleeding and/or contraceptive failure may result from interactions of other drugs (enzyme inducers) with oral contraceptives (see section 'Interaction with other medicinal products and other forms of interaction').

Reporting of suspected adverse reactions

Reporting 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 HPRA Pharmacovigilance, Earlsfort Terrace, IRL – Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517. Website: www.hpra.ie; E-mail: medsafety@hpra.ie.


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4.9 Overdose

There have been no reports of serious deleterious effects from overdose. Symptoms that may occur in this case are: nausea, vomiting and, in young girls, slight vaginal bleeding. There are no antidotes and further treatment should be symptomatic.


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5. PHARMACOLOGICAL PROPERTIES

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5.1 Pharmacodynamic properties

Pharmacotherapeutic group (ATC): Progestogens and estrogens, fixed combinations

ATC Code: G03AA

The contraceptive effect of COCs is based on the interaction of various factors, the most important of which are seen as the inhibition of ovulation and the changes in the cervical secretion.

Post Authorization Safety Studies (PASS) have shown that the frequency of VTE diagnosis ranges between 7-10 per 10,000 woman years in low estrogen dose (< 50 µg ethinylestradiol) COC users. The most recent data suggest that the frequency of VTE diagnosis is approximately 4 per 10,000 woman years in non-pregnant non-COC users, and ranges between 20 to 30 per 10,000 pregnant women or post partum.

As well as protection against pregnancy, COCs have several positive properties which, next to the negative properties (see Warnings, Undesirable effects), can be useful in deciding on the method of birth control. The cycle is more regular and the menstruation is often less painful and the bleeding is lighter.

The latter may result in a decrease in the occurrence of iron deficiency. Apart from this, there is evidence of a reduced risk of endometrial cancer and ovarian cancer. Furthermore, the higher dosed COCs (0.05 mg ethinylestradiol) have been shown to reduce the incidence of ovarian cysts, pelvic inflammatory disease, benign breast disease and ectopic pregnancy. Whether this also applies to lower-dosed COCs remains to be confirmed.


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5.2 Pharmacokinetic properties

Levonorgestrel

Absorption

Orally administered levonorgestrel is rapidly and completely absorbed. Peak serum concentrations of 2.3 ng/ml are reached at about 1.3 hours after single ingestion. Levonorgestrel is almost completely bioavailable after oral administration.

Distribution

Levonorgestrel is bound to serum albumin and to sex hormone binding globulin (SHBG). Only 1.1% of the total serum drug concentrations are present as free steroid, approximately 65% are specifically bound to SHBG and about 34% are non-specifically bound to albumin. The ethinylestradiol-induced increase in SHBG influences the proportion of levonorgestrel bound to the serum proteins, causing an increase of the SHBG-bound fraction and a decrease of the albumin-bound fraction. The apparent volume of distribution of levonorgestrel is 129l.

Metabolism

Levonorgestrel is extensively metabolized. The major metabolites in plasma are the unconjugated and conjugated forms of 3α, 5β-tetrahydrolevonorgestrel. Based on in vitro and in vivo studies, CYP3A4 is the main enzyme involved in the metabolism of levonorgestrel. The clearance rate from serum is approximately 1.0 ml/min/kg.

Elimination

Levonorgestrel serum levels decrease in two phases. The terminal disposition phase is characterized by a half-life of approximately 25 hours.

Levonorgestrel is not excreted in unchanged form. Its metabolites are excreted at a urinary to biliary ratio of about 1:1. The half-life of metabolite excretion is about 1 day.

Steady-state conditions

Following daily ingestion drug serum levels increase about threefold reaching steady-state conditions during the second half of a treatment cycle. Levonorgestrel pharmacokinetics are influenced by SHBG levels, which are increased 1.5 – 1.6 fold when co-administered with ethinylestradiol. At steady-state, clearance rate and volume of distribution are slightly reduced to 0.7 ml/min/kg and about 100 l, respectively.

Ethinylestradiol

Absorption

Orally administered ethinylestradiol is rapidly and completely absorbed. Peak serum concentrations of about 50 pg/ml are reached within 1 – 2 hours. During absorption and first-liver passage, ethinylestradiol is metabolised extensively, resulting in a mean oral bioavailability of about 45% with a large interindividual variation of about 20-65%.

Distribution

Ethinylestradiol is highly but non-specifically bound to serum albumin (approximately 98%) and induces an increase in the serum concentrations of SHBG. An apparent volume of distribution of about 2.8 – 8.6 l/kg was reported.

Metabolism

Ethinylestradiol is subject to presystemic conjugation in both small bowel mucosa and the liver. Ethinylestradiol is primarily metabolised by aromatic hydroxylation but a wide variety of hydroxylated and methylated metabolites are formed and these are present as free metabolites and as conjugates with glucuronides and sulphate. The metabolic clearance rate was reported to be 2.3 – 7 ml/min/kg.

Elimination

Ethinylestradiol serum levels decrease in two disposition phases characterized by half-lives of about 1 hour and 10 –20 hours, respectively. Unchanged drug is not excreted; ethinylestradiol metabolites are excreted at a urinary to biliary ratio of 4:6. The half-life of metabolite excretion is about 1 day.

Steady-state conditions

Ethinylestradiol serum concentrations increase about twofold after daily oral administration of Microlite. According to the variable half-life of the terminal disposition phase from serum and the daily ingestion, steady-state serum levels of ethinylestradiol will be reached after about one week.


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5.3 Preclinical safety data

Preclinical data reveal no special risks for humans based on conventional studies of repeated dose toxicity, genotoxicity, carcinogenic potential and toxicity to reproduction. However, it should be borne in mind that sex steroids can promote the growth of certain hormone-dependent tissues and tumours.


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6. PHARMACEUTICAL PARTICULARS

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6.1 List of excipient(s)

Lactose monohydrate

Maize starch

Pregelatinised starch

Povidone

Magnesium stearate (E572)

Sucrose

Povidone

Macrogols

Calcium carbonate (E170)

Talc

Glycerol 85% (E422)

Ferric oxide pigment, red (E172)

Ferric oxide pigment, yellow (E172)

Titanium dioxide (E171)

Montanglycol wax


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6.2 Incompatibilities

Not applicable.


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6.3 Shelf life

3 years.


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6.4 Special precautions for storage

Store below 25°C.


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6.5 Nature and contents of container

Primary container:

Blister pack of PVC with counter sealing foil made of 20 µm aluminium.

Presentation;

Carton containing memo packs of either 1 x 21 tablets, 3 x 21 tablets or 50 x 21 tablets.

Not all pack sizes may be marketed.


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6.6 Special precautions for disposal and other handling

No special requirements.


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7. MARKETING AUTHORISATION HOLDER

Bayer Limited

The Atrium

Blackthorn Road

Dublin 18


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8. MARKETING AUTHORISATION NUMBER(S)

PA 1410/7/1


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9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorization:3rd April 1998

Date of last renewal: 3rd April 2008


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10. DATE OF REVISION OF THE TEXT

July 2015



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Active Ingredients

 
   Ethinyloestradiol
   Levonorgestrel