Logynon Tablets

BP22046, REC30885 : Article 61.3 notification

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6. Contents of the pack and other information

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Manufacturer

The manufacturer can be identified by the batch number printed on the carton and on each blister:

·        If the first and second characters are KT, the manufacturer is:

Bayer AG

Müllerstraße 178

13353 Berlin

Germany

·        If the first and second characters are WE, the manufacturer is:

Bayer Weimar GmbH und Co. KG

Doebereinerstr. 20

99427 Weimar

Germany                                       

This leaflet was last revised in February 2023 October 2022

BP22055, REC30965

Implementation of the outcome of PSUSA on chlormadinone acetate/ethinylestradiol: In the framework of the PSUSA on chlormadinone acetate / ethinylestradiol (PSUSA/00000679/202111) PRAC considered that the risk of elevated liver enzymes would also be relevant to be included in products containing ethinylestradiol as a single agent or in fixed dose combinations as the risk of elevated liver enzymes is associated with concomitant use of ethinylestradiol and sofosbuvir/velpatasvir/voxilaprevir.

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Package Leaflet

2. What you need to know before you take Logynon

Do not take Logynon if you have hepatitis C and are taking medicinal products containing ombitasvir/paritaprevir/ritonavir, dasabuvir, glecaprevir/pibrentasvir and or sofosbuvir/velpatasvir/voxilaprevir (see also in section “Other medicines and Logynon”).

[...]

Other medicines and Logynon

Do not take Logynon if you have hepatitis C and are taking medicinal products containing ombitasvir/paritaprevir/ritonavir dasabuvir, glecaprevir/pibrentasvir and or sofosbuvir/velpatasvir/voxilaprevir, as these products may cause increases in liver function blood test results (increase in ALT liver enzyme). Your doctor will prescribe another type of contraceptive prior to start of the treatment with these medicinal products. Logynon can be restarted approximately 2 weeks after completion of this treatment. See section "Do not take Logynon".

 [...]

BP22055, REC30965

Implementation of the outcome of PSUSA on chlormadinone acetate/ethinylestradiol: In the framework of the PSUSA on chlormadinone acetate / ethinylestradiol (PSUSA/00000679/202111) PRAC considered that the risk of elevated liver enzymes would also be relevant to be included in products containing ethinylestradiol as a single agent or in fixed dose combinations as the risk of elevated liver enzymes is associated with concomitant use of ethinylestradiol and sofosbuvir/velpatasvir/voxilaprevir.

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Summary of Product Characteristics

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4.3 Contraindications

Logynon is contraindicated for concomitant use with the medicinal products containing ombitasvir/paritaprevir/ritonavir and dasabuvir or medicinal products containing glecaprevir/pibrentasvir or sofosbuvir/velpatasvir/voxilaprevir (see sections 4.4 and 4.5).

4.4 Special warnings and precautions for use

Other conditions

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ALT elevations

During clinical trials with patients treated for hepatitis C virus infections (HCV) with the medicinal products containing ombitasvir/paritaprevir/ritonavir and dasabuvir with or without ribavirin, transaminase (ALT) elevations higher than 5 times the upper limit of normal (ULN) occurred significantly more frequent in women using ethinylestradiol-containing medications such as combined hormonal contraceptives (CHCs). Additionally, also in patients treated with glecaprevir/pibrentasvir, ALT elevations were observed in women using ethinylestradiol-containing medications such as CHCs (see sections 4.3 and 4.5).

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Section 4.5 Interaction with other medicinal products and other forms of interaction

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Pharmacodynamic interactions

During clinical trials with patients treated for hepatitis C virus infections (HCV) with medicinal products containing ombitasvir/paritaprevir/ritonavir and dasabuvir with or without ribavirin, transaminase (ALT) elevations higher than 5 times the upper limit of normal (ULN) occurred significantly more frequently in women using ethinylestradiol-containing medications such as combined hormonal contraceptives (CHCs). Additionally, also in patients treated with glecaprevir/pibrentasvir or sofosbuvir/velpatasvir/voxilaprevir, ALT elevations were observed in women using ethinylestradiol-containing medications such as CHCs (see section 4.3).Concomitant use with the medicinal products containing ombitasvir/paritaprevir/ritonavir and dasabuvir, with or without ribavirin, or glecaprevir/pibrentasvir may increase the risk of ALT elevations (see sections 4.3 and 4.4).

Therefore, Logynon-users must switch to an alternative method of contraception (e.g., progestagen-only contraception or non-hormonal methods) prior to starting therapy with these combination drug regimens. Dianette can be restarted 2 weeks following completion of treatment with these combination drug regimens.

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BP22034, BEC20788

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4. Possible side effects

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Description of selected adverse reactions

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Other conditions

•          In women with hereditary angioedema (symptoms include sudden swelling of e.g. the eyes, mouth, throat etc.) products containing estrogens may induce or worsen symptoms of angioedema

6. Contents of the pack and other information

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This leaflet was last revised in OctoberSeptember 2022

BP22034, BEC20788

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Section 4.8 Undesirable effects

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 Description of selected adverse reactions

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Other conditions

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•          Exogenous estrogens may induce or exacerbate symptoms of hereditary and acquired angioedema.

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10. Date of Revision of the Text

 OctoberSeptember2022

BP22036, REC30610

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6. Contents of the pack and other information

[…]

Marketing Authorisation Holder:

Bayer Limited, 1st Floor, The Grange Offices, The Grange, Brewery Road, Stillorgan, Co. Dublin, A94 H2K7, The Atrium, Blackthorn road, Dublin 18, Ireland

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This leaflet was last revised in September 2022December 2020

BP22036, REC30610

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7. MARKETING AUTHORISATION HOLDER

Bayer Limited

1^st Floor

The Grange Offices

The Grange

Brewery Road

Stillorgan

Co. Dublin

A94 H2K7

The Atrium

Blackthorn Road

Dublin 18

Ireland

10. DATE OF REVISION OF THE TEXT

 September2022February2021

SPC updated in line with new PRAC update regarding depression

Section 4.4

Depressed mood and depression

Depressed mood and depression are well-known undesirable effects of hormonal

contraceptive use (see section 4.8). Depression can be serious and is a well-known

risk factor for suicidal behaviour and suicide.

Women should be advised to contact their physician in case of mood changes and

depressive symptoms, including shortly after initiating the treatment.

SPC updated in line with new PRAC update regarding depression

The text below in red has been added.

4.3 Contraindications

[…]

Logynon is contraindicated for concomitant use with the medicinal products containing ombitasvir/paritaprevir/ritonavir and dasabuvir (see sections 4.4 and 4.5).

4.4 Special warnings and precautions for use

[…]

ALT elevations

During clinical trials with patients treated for hepatitis C virus infections (HCV) with the medicinal products containing ombitasvir/paritaprevir/ritonavir and dasabuvir with or without ribavirin, transaminase (ALT) elevations higher than 5 times the upper limit of normal (ULN) occurred significantly more frequent in women using ethinylestradiol-containing medications such as combined hormonal contraceptives (CHCs) (see sections 4.3 and 4.5).

4.5 Interaction with other medicinal products and other forms of interaction

[…]

Enzyme induction can already be observed after a few days of treatment. Maximal enzyme induction is generally seen within a few weeks. After the cessation of drug therapy enzyme induction may be sustained for about 4 weeks.

[…]

Pharmacodynamic interactions

Concomitant use with the medicinal products containing ombitasvir/paritaprevir/ritonavir and dasabuvir, with or without ribavirin may increase the risk of ALT elevations (see sections 4.3 and 4.4).

Therefore, Logynon users must switch to an alternative method of contraception (e.g., progestagen-only contraception or non-hormonal methods) prior to starting therapy with this combination drug regimen. Logynon can be restarted 2 weeks following completion of treatment with this combination drug regimen.

4.9 Overdose

There have been no reports of serious deleterious effect from overdose. Symptoms that may occur in this case are: nausea, vomiting and, in young girls, slight vaginal bleeding, withdrawal bleeding. Withdrawal bleeding may even occur in girls before their menarche, if they accidentally take the medicinal product. There are no antidotes and further treatment should be symptomatic.

Logynon – 1410/5/1
BP14035 & BP14066
www.medicines.ie

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4.1          Therapeutic indications

Oral contraception

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

4.2          Posology and method of administration

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Dosage regimen

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How to start Logynon

·         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 Logynon 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 Logynon 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 need not take does not need to 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.

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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.

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4.3          Contraindications

Combined oralhormonal contraceptives (COCsCHCs) should not be used in the presence of any of the following conditionslisted below. Should any of the conditions appear for the first time during COCCHC 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

·         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 listed in section 6.1.

4.4          Special warnings and precautions for use

Warnings

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

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.

Risk of venous thromboembolism (VTE)

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 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 Logynon should be taken after a discussion with the woman to ensure she understands the risk of VTE with Logynon, 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.

Epidemiological studies have shown that the incidence of VTE in users of oral contraceptives with low oestrogen content (<50 µg ethinylestradiol) ranges from about 20 to 40 cases per 100,000 women-years, but this risk estimate varies according to the progestogen. This compares with 5 to 10 cases per 100,000 women-years for non-users. The use of any combined oral contraceptive (COC) carries an increased risk of venous thromboembolism (VTE) compared with no use.

The excess risk of VTE is highest during the first year a woman initially starts using a COC or when she restarts COC use after a pill-free interval of at least a month. This increased risk is less than the risk of VTE associated with pregnancy, which is estimated as 60 cases per 100,000 pregnancies.

VTE is fatal in 1-2 % of the cases.

The overall absolute risk (incidence) of VTE for levonorgestrel containing combined oral contraceptives with 30 µg ethinylestradiol is approximately 20 cases per 100,000 women-years of use. Epidemiological studies have also associated the use of combined COCs with an increased risk for myocardial infarction, transient ischaemic attack and for stroke.

Extremely rarely, thrombosis has been reported to occur in CHC users in 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..

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).

Logynon 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

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). Logynon 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

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.

Symptoms of venous or arterial thrombotic/thromboembolic events or of a cerebrovascular accident can include:

·         unusual 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

·         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.

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 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)

The risk for venous thromboembolic complications in COCs users increases with:

·         increasing age

·         a positive family history (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 immobilisation, major surgery, any surgery to the legs, or major trauma. In these situations it is advisable to discontinue the pill (in the case of elective surgery at least four weeks in advance) and not to resume until two weeks after complete remobilisation.

·         obesity (body mass index over 30 kg/m²).

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

The risk of arterial thromboembolic complications or of a cerebrovascular accident in COC users increases with:

·           increasing age

·           smoking (women over 35 years should be strongly advised not to smoke if they wish to use an COC)

·           dyslipoproteinemia

·           hypertension

·           migraine

·           valvular heart disease

·         atrial fibrillation

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.

...

Tumours

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.

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

Other conditions

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

Medical examination/consultation

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It is important to draw a woman’s attention to the information on venous and arterial thrombosis, including the risk of Logynon 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 oral hormonal contraceptives do not protect against HIV infections (AIDS) and other sexually transmitted diseases.

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4.5          Interaction with other medicinal products and other forms of interaction

Effects of other medicaments medicinal products  on Logynon

Interactions of other drugs (enzyme inducers, some antibiotics) with oral contraceptivesInteractions can occur with drugs that induce microsomal enzymes which can result in increased clearance of sex hormones and which may impair the contraceptive efficacy and/or 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 liver enzyme-inducing drugs, tThe 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 during the use of the antibiotics and 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) Substances increasing the clearance of COCs (dimished efficacy of COCs by enzyme induction), e.g.:

Enzyme induction (increase of hepatic metabolism): Interactions can occur with drugs that induce hepatic microsomal enzymes which can result in increased clearance of sex hormones (e.g. pPhenytoin, 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.:

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.When co-administered with COCs, many HIV/HCV protease inhibitors and non-neucleoside reverse transcriptase inhibitors can increase or decrease plasma concentrations of estrogen or progestin, These changes may be clinically relevant in some cases.

·         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).

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 medicamentsmedicinal 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).

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4.6          Pregnancy and lactation

Pregnancy

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

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4.8          Undesirable effects

Summary of the safety profile

The most commonly reported adverse reactions with Logynon 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*:

* 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’).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’.

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 HPRAPharmacovigilance, 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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5              Pharmacological properties

5.1          Pharmacodynamic properties

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Post Authorization Safety Studies (PASS) have A large, prospective 3-armed cohort study has shown that the frequency of VTE diagnosis ranges between 8 to 107-10  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.

5.2          Pharmacokinetic properties

Levonorgestrel

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Metabolism

Levonorgestrel is extensively metabolized. The major metabolites in plasma are the unconjugated and conjugated forms of 3a, 5b-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 1.3 – 1.6 ml/min/kg. Levonorgestrel is completely metabolized by the known pathways of steroid metabolism. The clearance rate from serum is approximately 1.0 ml/min/kg after single oral administration of the highest levonorgestrel dose of Logynon.

10           Date of revision of the text

March 2013July 2015

(Inserted text; Deleted text)

4.2. Posology and method of administration

 Advice in case of gastro-intestinal disturbances

… If vomiting or severe diarrhoea occurs within 3-4 hours

4.3 Contraindications

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

4.4 Special warnings and precautions for use

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 and of cerebrovascular accidents. These events occur rarely.

Epidemiological studies have shown that the incidence of VTE in users of oral contraceptives with low oestrogen content (<50 µg ethinylestradiol) ranges from about 20 to 40 cases per 100,000 women-years, but this risk estimate varies according to the progestogen. This compares with 5 to 10 cases per 100,000 women-years for non-users. The use of any combined oral contraceptive (COC) carries an increased risk of venous thromboembolism (VTE) compared with no use.

The excess risk of VTE is highest during the first year a woman initially starts using a COC or when she restarts COC use after a pill-free interval of at least a month. This increased risk is less than the risk of VTE associated with pregnancy, which is estimated as 60 cases per 100,000 pregnancies.

VTE is fatal in 1-2 % of the cases.

The overall absolute risk (incidence) of VTE for levonorgestrel containing combined oral contraceptives with 30 µg ethinylestradiol is approximately 20 cases per 100,000 women-years of use. Epidemiological studies have also associated the use of combined COCs with an increased risk for myocardial infarction, transient ischaemic attack and for stroke.

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. Date 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 (<50µg 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 venous or arterial thrombotic/thromboembolic events or of a cerebrovascular accident can include:

·         unusual 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

·         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.

…

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 for venous thromboembolic complications in COCs users increases with:

·         increasing age

·         a positive family history (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 immobilisation, major surgery, any surgery to the legs, or major trauma. In these situations it is advisable to discontinue the pill (in the case of elective surgery at least four weeks in advance) and not to resume until two weeks after complete remobilisation.

·         obesity (body mass index over 30 kg/m²).

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

The risk of arterial thromboembolic complications or of a cerebrovascular accident in COC users increases with:

·         increasing age

·         smoking (women over 35 years should be strongly advised not to smoke if they wish to use an COC)

·         dyslipoproteinemia

·         hypertension

·         migraine

·         valvular heart disease

·         atrial fibrillation

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 or arterial thromboembolism ever in a sibling or parent at a relatively early age). If a hereditary predisposition is known or 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);

•     dyslipoproteinemia;

•     hypertension;

•     migraine;

•     valvular heart disease;

•     atrial fibrillation;

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

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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).

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.

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Other conditions

...

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 for a need to alter the therapeutic regimen in diabetics using low-dose COCs (containing < 0.05 mg ethinylestradiol). However, diabetic women should be carefully observed while taking COCs monitored, particularly in the early stage of COC use.

Crohn’s Worsening of crohn’s disease and of ulcerative colitis have has been associated with reported during COC use.

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Medical examination/consultation

Prior to the initiation or reinstitution of COC use, a .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 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.

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Reduced efficacy

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

4.5 Interaction with other medicinal products and other forms of interaction

Effects of other medicaments on Logynon

Interactions of other drugs (enzyme inducers, some antibiotics) with oral contraceptives may impair the contraceptive efficacy and/or 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 liver 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 during the use of the antibiotics and 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 hepatic microsomal enzymes which can result…

…

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

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4.6 Pregnancy and lactation

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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10. Date of Revision of the Text

January 2011 March 2013

6.4 Special precautions for storage

Changed from "No special precautions for storage" to "Do not store above 30ºC."

10. Date of Revision of the Text

Changed to "January 2011"

Main changes to the SPC include:

Section 1. Name of the Medicinal Product

Inclusion of the pharmaceutical form in the name of the medicinal product.

Section 2. Qualitative and Quantitative Composition

Addition of reference to the excipients lactose and sucrose.

Section 4.4. Special Warnings and Precautions for Use

Updated information regarding the role of long-term contraceptive use on the risk of development of cervical cancer.

Section 4.8. Undesirable Effects

Undesirable effects have been tabulated according to the System Organ Class affected and the frequency of occurrence.

In addition, the following possible undesirable effects have been included: breast hypertrophy, vaginal discharge, breast discharge, hypersensitivity,

Section 6.5 Nature and Contents of Container

Inclusion of the standard phrase, ‘Not all pack sizes may be marketed’.

Section 6.6 Instructions for Use and Handling

Use of the standard phrase, ‘No special requirements’.