Microlite 100/20 microgram Tablets

Superceded text

Updated text

4.1 Therapeutic indications

4.1 Therapeutic indications

Hormonal contraception.

Oral contraception

4.2 Posology and method of administration

4.2 Posology and method of administration

4.2.1 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 tablet and may not have finished before the next pack is started.

4.2.2 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 active tablet (the last tablet containing the active substances) of her previous COC, but at the latest on the day following the usual tablet-free or placebo 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 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 need not take 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. 

4.2.3 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.

If the woman forgets to take an active Microlite tablet then it must be taken within 12 hours of the usual time for taking it. If a missed tablet is not taken within 12 hours then it should be taken when remembered and the remaining tablets taken as usual with extra non-hormonal contraceptive measures (except rhythm or temperature method) used for the next 7 days. If these seven days extend beyond the end of the pack then the next pack of tablets should be commenced at once with no tablet-free interval. 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 excluded before resuming with the next pack.

4.2.4 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 occurs within 3-4 hours after tablet-taking, the advice concerning missed tablets, as given in Section 4.2.3, is applicable. 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 resuming with the next pack. Other methods of contraception should be considered if the gastro-intestinal disorder is likely to be prolonged.

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.

4.2.5 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). 

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 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 need not take 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:

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

4.       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 occurs within 3-4 hours after tablet-taking, the advice concerning missed tablets, as given in ‘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
Miranova is only indicated after menarche.

Geriatric patients
Not applicable. Miranova is not indicated after menopause.

Patients with hepatic impairment
Miranova is contraindicated in women with severe hepatic diseases. See also section ‘Contraindications’.

Patients with renal impairment
Miranova has not been specifically studied in renally impaired patients. Available data do not suggest a change in treatment in this patient population.

4.3 Contraindications

4.3 Contraindications

Combined oral contraceptives (COCs) should not be used in the presence of any of the conditions listed below.  Should any of the conditions appear for the first time during COC use, the product should be stopped immediately.

• Presence or history of venous or arterial thrombotic/thromboembolic events (e.g. deep venous thrombosis, pulmonary embolism, myocardial infarction) or of a cerebrovascular accident.
• Presence or history of prodromi of a thrombosis (e.g. transient ischaemic attack, angina pectoris).
• History of migraine with focal neurological symptoms.
• Diabetes mellitus with vascular involvement.
• The presence of a severe or multiple risk factor(s) for venous or arterial thrombosis may also constitute a contraindication (see under “Special warnings and precautions for use”).
• Pancreatitis or a history thereof if associated with severe hypertriglyceridemia.
• Presence or history of 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.

Combined oral contraceptives (COCs) should not be used in the presence of any of the conditions listed below.  Should any of the conditions appear for the first time during COC use, the product should be stopped immediately.

• Presence or history of venous or arterial thrombotic/thromboembolic events (e.g. deep venous thrombosis, pulmonary embolism, myocardial infarction) or of a cerebrovascular accident.
• Presence or history of prodromi of a thrombosis (e.g. transient ischaemic attack, angina pectoris).
• The presence of a severe or multiple risk factor(s) for venous or arterial thrombosis may also constitute a contraindication (see “Special warnings and precautions for use”).
• History of migraine with focal neurological symptoms.
• Diabetes mellitus with vascular involvement.
• 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.

4.4 Special warnings and precautions for use

4.4 Special warnings and precautions for use

4.4.1 Warnings

If any of the conditions/risk factors mentioned below is present, the benefits of COC use should be weighed against the possible risks for each individual woman and discussed with the woman before she decides to start using it. In the event of aggravation, exacerbation or first appearance of any of these conditions or risk factors, the woman should contact her physician. The physician should then decide on whether COC use should be discontinued.

·                Circulatory Disorders

 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, stroke, deep venous thrombosis and pulmonary embolism. These events occur rarely.

Venous thromboembolism (VTE), manifesting as deep venous thrombosis and/or pulmonary embolism, may occur during the use of all COCs. The risk for venous thromboembolism is highest during the first year a woman ever uses a COC. The approximate incidence of VTE in users of low oestrogen dose (< 0.05 mg ethinylestradiol) OCs is up to 4 per 10 000 woman years compared to 0.5 – 3 per 10 000 woman years in non-OC users. The incidence of VTE associated with pregnancy is 6 per 10 000 pregnant woman years.

 Extremely rarely, thrombosis has been reported to occur in other blood vessels e.g. hepatic, mesenteric, renal, cerebral or retinal veins and arteries, in COC users. There is no consensus as to whether the occurrence of these events is associated with the use of COCs.

Symptoms of venous or arterial thrombotic/thromboembolic events or of a cerebrovascular accident can include: unilateral leg pain and / or swelling: sudden severe pain in the chest, whether or not it radiates to the left arm; sudden breathlessness, sudden onset of coughing; any unusual, severe, prolonged headache; sudden partial or complete loss of vision; diplopia; slurred speech or aphasia; vertigo; collapse with or without focal seizure; weakness or very marked numbness suddenly affecting one side or one part of the body; motor disturbances; “acute” abdomen.

The risk of venous or arterial thrombotic/thromboembolic events or of a cerebrovascular accident increases with:

-          Age;

-          Smoking (with heavier smoking and increasing age the risk further increases, especially in women over 35 years of age);

- A positive family history (i.e. venous thromboembolism ever in a sibling or parent    at a relatively early age).  If a hereditary predisposition is suspected the woman should be referred to a specialist for advice before deciding about any COC use;

-          Obesity (body mass index over 30 kg/m²);

-          Dyslipoproteinaemia

-          Hypertension

-          Migraine

-          Valvular heart disease

-          Atrial fibrillation

-          Prolonged immobilization, major surgery, any surgery to the legs or major trauma. In these situations it is advisable to discontinue COC use (in the case of elective surgery at least four weeks in advance) and not to resume until two weeks after complete remobilization;

-          There is no consensus about the possible role of varicose veins and superficial thrombophlebitis in venous thromboembolism.

-          The increased risk of venous thromboembolism in the puerperium must be considered (for information on “Pregnancy and lactation” see Section 4.6);

Other medical conditions which have been associated with adverse circulatory events include diabetes mellitus, systemic lupus erythematosus, haemolytic uraemic syndrome, chronic inflammatory bowel disease (Crohn’s disease or ulcerative colitis) and sickle cell disease.

An increase in the frequency or severity of migraine during COC use (which may be prodromal of a cerebrovascular event) may be a reason for immediate discontinuation of the COC.

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

Some epidemiological studies indicate that the long-term use of oral contraceptives (> 5 years) displays a risk factor for the development of cervical cancer in women infected with human papillomavirus (HPV).  However, there continues to be controversy about the extent to which this finding is influenced by other factors (e.g. differences in number of sexual partners or in use of barrier contraceptives).

A meta-analysis from 54 epidemiological studies reported that there is a slightly increased relative risk (RR = 1.24) of having breast cancer diagnosed in women who are currently using 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 hepatic tumour should be considered in the differential diagnosis when severe upper abdominal pain, liver enlargement or signs of intra-abdominal haemorrhage occur in women taking COCs. 

·                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 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 observed while taking COCs.

Crohn’s disease and ulcerative colitis have been associated with 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. 

This product contains lactose and sucrose. Patients with rare hereditary problems of galactose intolerance, fructose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.

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 4.5 Interactions).

4.4.2 Medical examination/consultation

A complete medical history and physical examination should be taken prior to the initiation or reinstitution of COC use, guided by the contraindications (Section 4.3) and warnings (Section 4.4.1) and should be repeated periodically.  Periodic medical assessment is also of importance because contraindications (e.g. a transient ischaemic attack, etc.) or risk factors (e.g. a family history of venous or arterial thrombosis) may appear for the first time during the use of 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. 

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

  4.4.3 Reduced efficacy

The efficacy of COCs may be reduced in the event of e.g. missed tablets (Section 4.2.3), gastro-intestinal disturbances (Section 4.2.4) or concomitant medication (Section 4.5). 

4.4.4 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.

Warnings

If any of the conditions/risk factors mentioned below is present, the benefits of COC use should be weighed against the possible risks for each individual woman and discussed with the woman before she decides to start using it. In the event of aggravation, exacerbation or first appearance of any of these conditions or risk factors, the woman should contact her physician. The physician should then decide on whether COC use should be discontinued.

Circulatory Disorders

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 risk of VTE is highest during the first year of use. This increased risk is present after initially starting a COC or restarting (following a 4 week or greater pill free interval) the same or a different COC. Data from a large, prospective 3-armed cohort study suggest that this increased risk is mainly present during the first 3 months.

Overall the risk for venous thromboembolism (VTE) in users of low estrogen dose (< 50 µg  ethinylestradiol) COCs is two to threefold higher than for non-users of COCs who are not pregnant and remains lower than the risk associated with pregnancy and delivery.

VTE may be fatal (in 1-2 % of the cases).

Venous thromboembolism (VTE), manifesting as deep venous thrombosis and/or pulmonary embolism, may occur during the use of all COCs.

Extremely rarely, thrombosis has been reported to occur in other blood vessels e.g. hepatic, mesenteric, renal, cerebral or retinal veins and arteries, in COC users. There is no consensus as to whether the occurrence of these events is associated with the use of COCs.

Symptoms of deep venous thrombosis (DVT) can include: unilateral swelling of the leg 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 bring up blood; sharp chest pain which may increase with deep breathing; sense of anxiety; 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).

An arterial thromboembolic event can include cerebrovascular accident, vascular occlusion or myocardial infarction (MI).  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 confusion, trouble speaking or understanding; sudden trouble seeing in one or both eyes; sudden trouble walking, dizziness, loss of balance or coordination; sudden, severe or prolonged headache with no known cause; loss of consciousness or fainting with or without seizure. Other signs of vascular occlusion can include: sudden pain, swelling and slight blue discoloration of an extremity; acute abdomen.

Symptoms of 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; fullness, indigestion or choking feeling; sweating, nausea, vomiting or dizziness; extreme weakness, anxiety, or shortness of breath; rapid or irregular heartbeats.

Arterial thromboembolic events may be fatal.

The risk of venous or arterial thrombotic/thromboembolic events or of a cerebrovascular accident increases with:

-          Age;

-          Obesity (body mass index over 30 kg/m²);

-          A positive family history (i.e. venous thromboembolism ever in a sibling or parent    at a relatively early age).  If a hereditary predisposition is suspected the woman should be referred to a specialist for advice before deciding about any COC use;

-          Prolonged immobilization, major surgery, any surgery to the legs or major trauma. In these situations it is advisable to discontinue COC use (in the case of elective surgery at least four weeks in advance) and not to resume until two weeks after complete remobilization;

-          Smoking (with heavier smoking and increasing age the risk further increases, especially in women over 35 years of age);

-          Dyslipoproteinaemia

-          Hypertension

-          Migraine

-          Valvular heart disease

-          Atrial fibrillation

There is no consensus about the possible role of varicose veins and superficial thrombophlebitis in venous thromboembolism.

The increased risk of thromboembolism in the puerperium must be considered (for information on “Pregnancy and lactation” see Section 4.6);

Other medical conditions which have been associated with adverse circulatory events include diabetes mellitus, systemic lupus erythematosus, haemolytic uraemic syndrome, chronic inflammatory bowel disease (Crohn’s disease or ulcerative colitis) and sickle cell disease.

An increase in the frequency or severity of migraine during COC use (which may be prodromal of a cerebrovascular event) may be a reason for immediate discontinuation of the COC.

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

The 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.

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. 

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 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 observed while taking COCs.

Crohn’s disease and ulcerative colitis have been associated with 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 4.5 Interactions).

Medical examination/consultation

A complete medical history and physical examination should be taken prior to the initiation or reinstitution of COC use, guided by the contraindications (Section 4.3) and warnings (section ‘Warnings‘), and should be repeated periodically.  Periodic medical assessment is also of importance because contraindications (e.g. a transient ischaemic attack, etc.) or risk factors (e.g. a family history of venous or arterial thrombosis) may appear for the first time during the use of 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. 

Women should be advised that oral 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’), gastro-intestinal disturbances (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.

4.5 Interaction with other medicinal products and other forms of interaction

4.5 Interaction with other medicinal products and other forms of interaction

• Interactions

Interactions between oral contraceptives and other drugs may lead to breakthrough bleeding and/or contraceptive failure. The following interactions have been reported in the literature.

Hepatic metabolism: Interactions can occur with drugs that induce microsomal enzymes which can result in increased clearance of sex hormones (e.g. phenytoin,   barbiturates, primidone, carbamazepine, rifampicin and possibly also oxcarbazepine, topiramate, felbamate,  griseofulvin and products containing St. John’s Wort.

Also HIV protease (e.g. ritonavir) and non-nucleoside reverse transcriptase inhibitors (e.g. nevirapine) and combinations of them, have been reported to potentially affect hepatic metabolism.

Interference with Enterohepatic Circulation:  Some clinical reports suggest that enterohepatic circulation of oestrogens may decrease when certain antibiotic agents are given, which may reduce ethinylestradiol concentrations (e.g. penicillins, tetracyclines).

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.  With microsomal enzyme-inducing drugs, the barrier method should be used during the time of concomitant drug administration and for 28 days after their discontinuation.  Women on treatment with antibiotics (except rifampicin and griseofulvin) should use the barrier method until 7 days after discontinuation.  If the period during which the barrier method is used runs beyond the end of the tablets in a COC pack, the next COC pack should be started without the usual tablet-free interval. 

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). 

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

Effects of other medicaments on Microlite

Interactions of other drugs (enzyme inducers, some antibiotics) with oral contraceptives 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.  With microsomal enzyme-inducing drugs, the barrier method should be used during the time of concomitant drug administration and for 28 days after their discontinuation. 

Women on treatment with antibiotics (except rifampicin and griseofulvin) should use the barrier method until 7 days after 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 diminishing the efficacy of COCs (enzyme-inducers and  antibiotics)

·         Enzyme induction (increase of hepatic metabolism): Interactions can occur with drugs that induce microsomal enzymes which can result in increased clearance of sex hormones (e.g. phenytoin, barbiturates, primidone, carbamazepine, rifampicin, and possibly also oxcarbazepine, topiramate, felbamate, griseofulvin and products containing St. John’s wort).

Also HIV protease (e.g. ritonavir) and non-nucleoside reverse transcriptase inhibitors (e.g. nevirapine), and combinations of them, have been reported to potentially increase hepatic metabolism.

·         Antibiotics (interference with enterohepatic circulation): Some clinical reports suggest that enterohepatic circulation of estrogens may decrease when certain antibiotic agents are given, which may reduce ethinylestradiol concentrations (e.g. penicillins, tetracyclines).

Effects of COCs on other medicaments

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).

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. 

4.6 Pregnancy and lactation

4.6 Pregnancy and lactation

Microlite is not indicated during pregnancy. If pregnancy occurs during medication with Microlite, further intake should 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. 

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 but there is no evidence that this adversely affects infant health. 

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. 

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. 

4.7 Effects on ability to drive and use machines

4.7 Effects on ability to drive and use machines

No observed effects.

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.

4.8 Undesirable effects

4.8 Undesirable effects

The most serious undesirable effects associated with the use of COCs are listed in section 4.4.1.

Other side effects that have been reported in users of COCs are*:

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

Note: no change to table

Note: no change to table

* The most appropriate MedDRA term (version 7.0) to describe a certain adverse reaction is listed. Synonyms or related conditions are not listed but should be taken into account as well.

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

* 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.

The following serious adverse events have been reported in women using COCs, which are discussed in section ‘Special warnings and precautions for use’:

·         Venous thromboembolic disorders

·         Arterial thromboembolic disorders

·         Cerebrovascular accidents

·         Hypertension

·         Hypertriglyceridemia

·         Changes in glucose tolerance or effect on peripheral insulin resistance

·         Liver tumours (benign and malignant)

·         Liver function disturbances

·         Chloasma

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

·         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, Crohn’s disease, ulcerative colitis, cervical cancer

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. For further information, see sections ‘Contraindications’ and ‘Special warnings and precautions for use’. 

5.1 Pharmacodynamic properties

5.1 Pharmacodynamic properties

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. 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.

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.

A large, prospective 3-armed cohort study has shown that the frequency of VTE diagnosis ranges between 8 to 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 4.4 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.

5.2 Pharmacokinetic properties

5.2 Pharmacokinetic properties

Only changes to the following sentence in this section:

Levonorgestrel is bound to serum albumin and to serum hormone binding globulin (SHBG).

Only changes to the following sentence in this section:

Levonorgestrel is bound to serum albumin and to sex hormone binding globulin (SHBG).

10. Date of Revision of the Text

June 2008

10. Date of Revision of the Text

November 2010