Viorele

4.2.1 How to take Viorele

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 Viorele

No preceding hormonal contraceptive use [in the past month]:

It is preferable that tablet intake from the first pack is started on the first day of menstruation in which case no extra contraceptive precautions are necessary.

If menstruation has already begun, (that is 2, 3, or 4 days previously), tablet taking should commence on day 5 of the menstrual period. In this case additional contraceptive precautions must be taken for the first 7 days of tablet taking.

If menstruation began more than 5 days previously then the patient should be advised to wait until her next menstrual period before starting to take Viorele.

Changing from a 21 day pill or another 22 day pill to Viorele:

All tablets in the old pack should be finished. The first Viorele tablet is taken the next day i.e. no gap is left between taking tablets nor does the patient need to wait for her period to begin. Tablets should be taken as instructed in 'How to take Viorele'. Additional contraceptive precautions are not required. The patient will not have a period until the end of the first Viorele pack, but this is not harmful, nor does it matter if she experiences some bleeding on tablet-taking days.

Changing from a combined Every Day Pill (28 day tablets) to Viorele:

Viorele should be started after taking the last active tablet from the 'Every Day Pill' pack (i.e. after taking 21 or 22 tablets). The first Viorele tablet is taken the next day i.e. no gap is left between taking tablets nor does the patient need to wait for her period to begin. One tablet is taken daily at the same time, without interruption for 21 days, followed by a 7 day tablet-free period. Each subsequent pack is started after the 7 day tablet-free period has elapsed. Additional contraceptive precautions are not required. Remaining tablets from the Every Day (ED) pack should be discarded. The patient will not have a period until the end of the first Viorele pack, but this is not harmful, nor does it matter if she experiences some bleeding on tablet-taking days.

Changing from a Progestogen -only Pill (POP or Mini Pill) to Viorele:

The first Viorele tablet should be taken on the first day of the period, even if the patient has already taken a mini pill on that day. One tablet is taken daily at the same time, without interruption for 21 days, followed by a 7 day tablet-free period. Each subsequent pack is started after the 7 day tablet-free period has elapsed. Additional contraceptive precautions are not then required. All the remaining Progestogen-only pills in the mini pill pack should be discarded.

If the patient is taking a (mini) pill, then she may not always have a period, especially when she is breast feeding. The first Viorele tablet should be taken on the day after stopping the mini pill. All remaining pills in the mini pill packet must be discarded. Additional contraceptive precautions must be taken for the first seven days.

Changing from a progestogen-only injection, implant or from a progestogen- releasing intrauterine system [IUS]:

The woman may switch any day from an implant (or the IUS on the day of its removal, from an injectable when the next injection would be due). Additional contraceptive precautions must be taken for the first seven days.

Post-Partum Administration:

Following childbirth hormonal contraceptive administration to non-breast feeding mothers should be started 21 days post-partum in which case no additional contraceptive precautions are required. If intercourse has taken place post-partum, hormonal contraceptive use should be delayed until the first day of the menstrual period.

If post-partum administration of Viorele begins more than 21 days after delivery then additional contraceptive precautions are required for the first 7 days.

N.B. Mothers who are breast feeding should be advised not to use the combined pill since this may reduce the amount of breast-milk, but may be advised instead to use a progestogen-only pill (POP).

After miscarriage or abortion administration should start immediately in which case no additional contraceptive precautions are required.

Additional contraceptive precautions:

When additional contraceptive precautions are required the patient should be advised either not to have sex, or to use a cap plus spermicide, or for her partner to use a condom.

Rhythm methods should not be advised as the pill disrupts the usual cyclical changes associated with the natural menstrual cycle e.g. changes in temperature and cervical mucus.

How to skip a period:

To skip a period, a new pack of Viorele should be started on the day after finishing the current pack (the patient skips the tablet-free days). Tablet-taking should be continued in the usual way. During the use of the second pack she may experience slight spotting or breakthrough bleeding but contraceptive protection will not be diminished provided there are no tablet omissions. The next pack of Viorele is started after the usual 7 tablet-free days, regardless of whether the period has completely finished or not.

4.2.3 Management of missed tablets

Advice in case of missed pills

The reliability of Viorele may be reduced if tablets are forgotten:

If the forgotten tablet is taken within 12 hours, no further precautions are necessary, further tablets should be taken at the usual time.

If one or more tablets are forgotten for more than 12 hours, contraceptive protection will be reduced. The patient should take the last forgotten tablet, even if this means taking two tablets in one day, and then continue to take tablets at the normal time. Additional contraceptive precautions should be taken for the next seven days, and the patient should follow 'the 7-day rule'.

The 7-Day rule

If any one tablet is forgotten for more than 12 hours

If the patient has vomiting or diarrhoea for more than 12 hours

If the patient is taking any of the drugs listed under 'Interactions':

The patient should continue to take her tablets as usual and additional contraceptive precautions must be taken for the next 7 days.

But - if these 7 days run beyond the end of the current pack, the next pack must be started as soon as the current one is finished, i.e. no gap should be left between packs. (This prevents an extended break in tablet taking which may increase the risk of the ovaries releasing an egg and thus reducing contraceptive protection). The patient will not have a period until the end of 2 packs but this is not harmful nor does it matter if she experiences some bleeding on tablet taking days.

Advice in case of Vomiting or severe diarrhea

In case of severe gastro-intestinal disturbance, absorption may not be complete and additional contraceptive measures should be taken. Unless diarrhoea is extremely severe, it does not affect steroidal absorption.

If vomiting occurs within 3-4 hours after tablet taking, or in cases of severe or prolonged diarrhoea, the advice concerning missed tablets, as given in Section 4.2.3, 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.

4.2.4 Paediatric population

The safety and efficacy of desogestrel in adolescents below 18 years has not yet been established. No data are available.

4.2.1 How to take Viorele

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 Viorele

No preceding hormonal contraceptive use [in the past month]:

It is preferable that tablet intake from the first pack is started on the first day of menstruation in which case no extra contraceptive precautions are necessary.

If menstruation has already begun, (that is 2, 3, or 4 days previously), tablet taking should commence on day 5 of the menstrual period. In this case additional contraceptive precautions must be taken for the first 7 days of tablet taking.

If menstruation began more than 5 days previously then the patient should be advised to wait until her next menstrual period before starting to take Viorele.

Changing from a 21 day pill or another 22 day pill to Viorele:

All tablets in the old pack should be finished. The first Viorele tablet is taken the next day i.e. no gap is left between taking tablets nor does the patient need to wait for her period to begin. Tablets should be taken as instructed in 'How to take Viorele'. Additional contraceptive precautions are not required. The patient will not have a period until the end of the first Viorele pack, but this is not harmful, nor does it matter if she experiences some bleeding on tablet-taking days.

Changing from a combined Every Day Pill (28 day tablets) to Viorele:

Viorele should be started after taking the last active tablet from the 'Every Day Pill' pack (i.e. after taking 21 or 22 tablets). The first Viorele tablet is taken the next day i.e. no gap is left between taking tablets nor does the patient need to wait for her period to begin. One tablet is taken daily at the same time, without interruption for 21 days, followed by a 7 day tablet-free period. Each subsequent pack is started after the 7 day tablet-free period has elapsed. Additional contraceptive precautions are not required. Remaining tablets from the Every Day (ED) pack should be discarded. The patient will not have a period until the end of the first Viorele pack, but this is not harmful, nor does it matter if she experiences some bleeding on tablet-taking days.

Changing from a Progestogen -only Pill (POP or Mini Pill) to Viorele:

The first Viorele tablet should be taken on the first day of the period, even if the patient has already taken a mini pill on that day. One tablet is taken daily at the same time, without interruption for 21 days, followed by a 7 day tablet-free period. Each subsequent pack is started after the 7 day tablet-free period has elapsed. Additional contraceptive precautions are not then required. All the remaining Progestogen-only pills in the mini pill pack should be discarded.

If the patient is taking a (mini) pill, then she may not always have a period, especially when she is breast feeding. The first Viorele tablet should be taken on the day after stopping the mini pill. All remaining pills in the mini pill packet must be discarded. Additional contraceptive precautions must be taken for the first seven days.

Changing from a progestogen-only injection, implant or from a progestogen- releasing intrauterine system [IUS]:

The woman may switch any day from an implant (or the IUS on the day of its removal, from an injectable when the next injection would be due). Additional contraceptive precautions must be taken for the first seven days.

Post-Partum Administration:

Following childbirth hormonal contraceptive administration to non-breast feeding mothers should be started 21 days post-partum in which case no additional contraceptive precautions are required. If intercourse has taken place post-partum, hormonal contraceptive use should be delayed until the first day of the menstrual period.

If post-partum administration of Viorele begins more than 21 days after delivery then additional contraceptive precautions are required for the first 7 days.

N.B. Mothers who are breast feeding should be advised not to use the combined pill since this may reduce the amount of breast-milk, but may be advised instead to use a progestogen-only pill (POP).

After miscarriage or abortion administration should start immediately in which case no additional contraceptive precautions are required.

Additional contraceptive precautions:

When additional contraceptive precautions are required the patient should be advised either not to have sex, or to use a cap plus spermicide, or for her partner to use a condom.

Rhythm methods should not be advised as the pill disrupts the usual cyclical changes associated with the natural menstrual cycle e.g. changes in temperature and cervical mucus.

How to skip a period:

To skip a period, a new pack of Viorele should be started on the day after finishing the current pack (the patient skips the tablet-free days). Tablet-taking should be continued in the usual way. During the use of the second pack she may experience slight spotting or breakthrough bleeding but contraceptive protection will not be diminished provided there are no tablet omissions. The next pack of Viorele is started after the usual 7 tablet-free days, regardless of whether the period has completely finished or not.

4.2.3 Management of missed tablets

Advice in case of missed pills

The reliability of Viorele may be reduced if tablets are forgotten:

If the forgotten tablet is taken within 12 hours, no further precautions are necessary, further tablets should be taken at the usual time.

If one or more tablets are forgotten for more than 12 hours, contraceptive protection will be reduced. The patient should take the last forgotten tablet, even if this means taking two tablets in one day, and then continue to take tablets at the normal time. Additional contraceptive precautions should be taken for the next seven days, and the patient should follow 'the 7-day rule'.

The 7-Day rule

If any one tablet is forgotten for more than 12 hours

If the patient has vomiting or diarrhoea for more than 12 hours

If the patient is taking any of the drugs listed under 'Interactions':

The patient should continue to take her tablets as usual and additional contraceptive precautions must be taken for the next 7 days.

But - if these 7 days run beyond the end of the current pack, the next pack must be started as soon as the current one is finished, i.e. no gap should be left between packs. (This prevents an extended break in tablet taking which may increase the risk of the ovaries releasing an egg and thus reducing contraceptive protection). The patient will not have a period until the end of 2 packs but this is not harmful nor does it matter if she experiences some bleeding on tablet taking days.

Advice in case of Vomiting or severe diarrhoea

In case of severe gastro-intestinal disturbance, absorption may not be complete and additional contraceptive measures should be taken. Unless diarrhoea is extremely severe, it does not affect steroidal absorption.

If vomiting occurs within 3-4 hours after tablet taking, or in cases of severe or prolonged diarrhoea, the advice concerning missed tablets, as given in Section 4.2.3, 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.

4.2.4 Paediatric population

The safety and efficacy of desogestrel in adolescents below 18 years has not yet been established. No data are available.

4.4.1 Warnings

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

1. Circulatory Disorders

Risk of venous thromboembolism (VTE)

- The use of any combined hormonal contraceptive (CHC) increases the risk of venous thromboembolism (VTE) compared with no use. Products that contain levonorgestrel, norgestimate or norethisterone are associated with the lowest risk of VTE. Other products such as Viorele may have up to twice this level of risk. The decision to use any product other than one with the lowest VTE risk should be taken only after a discussion with the woman to ensure she understands the risk of VTE with Viorele, how her current risk factors influence this risk, and that her VTE risk is highest in the first ever year of use. There is also some evidence that the risk is increased when a CHC is re-started after a break in use of 4 weeks or more.

- In women who do not use a CHC and are not pregnant about 2 out of 10,000 will develop a VTE over the period of one year. However, in any individual woman the risk may be far higher, depending on her underlying risk factors (see below).

It is estimated¹ that out of 10,000 women who use a CHC containing desogestrel between 9 and 12 women will develop a VTE in one year; this compares with about 6² in women who use a levonorgestrel-containing CHC.

In both cases, the number of VTEs per year is fewer than the number expected during pregnancy or in the postpartum period.

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

Number of VTE events per 10,000 women in one year

Extremely rarely, thrombosis has been reported to occur in CHC users in other blood vessels, e.g. hepatic, mesenteric, renal or retinal veins and arteries.

Risk factors for VTE

The risk for venous thromboembolic complications in CHC users may increase substantially in a woman with additional risk factors, particularly if there are multiple risk factors (see table).

Viorele is contraindicated if a woman has multiple risk factors that put her at high risk of venous thrombosis. 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.

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). Viorele is contraindicated if a woman has one serious or multiple risk factors for ATE that puts her at high risk of arterial thrombosis. 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.

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.

2. Tumours

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

- A meta-analysis from 54 epidemiological studies reported that there is a slightly increased relative risk (RR = 1.24) of having breast cancer diagnosed in women who are currently using combined oral contraceptives (COCs). The observed pattern of increased risk may be due to an earlier diagnosis of breast cancer in COC users, the biological effects of COCs or a combination of both. The additional breast cancers diagnosed in current users of COCs or in women who have used COCs in the last ten years are more likely to be localised to the breast than those in women who never used COCs.

- Breast cancer is rare among women under 40 years of age whether or not they take COCs. Whilst this background risk increases with age, the excess number of breast cancer diagnoses in current and recent COC users is small in relation to the overall risk of breast cancer (see bar chart).

- The most important risk factor for breast cancer in COC users is the age women discontinue the COC; the older the age at stopping, the more breast cancers are diagnosed. Duration of use is less important and the excess risk gradually disappears during the course of the 10 years after stopping COC use such that by 10 years there appears to be no excess.

- The possible increase in risk of breast cancer should be discussed with the user and weighed against the benefits of COCs taking into account the evidence that they offer substantial protection against the risk of developing certain other cancers (e.g. ovarian and endometrial cancer).

- In rare cases, benign liver tumours, and even more rarely, malignant liver tumours have been reported in users of CHCs. In isolated cases, these tumours have led to life-threatening intra-abdominal haemorrhages. A hepatic tumour should be considered in the differential diagnosis when upper abdominal pain, enlarged liver or signs of intra-abdominal haemorrhage occur in women taking CHCs.

3. ALT elevations

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).

4. Other conditions

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

- Although small increases in blood pressure have been reported in many women taking CHCs, clinically relevant increases are rare. A relationship between CHC use and clinical hypertension has not been established. However, if a sustained clinically significant hypertension develops during the use of a CHC then it is prudent for the physician to withdraw the CHC and treat the hypertension. Where considered appropriate, CHC 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 CHC use, but the evidence of an association with CHC use is inconclusive: jaundice and/or pruritus related to cholestasis; gallstone formation; porphyria; systemic lupus erythematosus; haemolytic uraemic syndrome: Sydenham's chorea; herpes gestationis; otosclerosis-related hearing loss; hereditary angioedema.

- Acute or chronic disturbances of liver function may necessitate the discontinuation of CHC use until markers of liver function return to normal. Recurrence of cholestatic jaundice which occurred previously during pregnancy or use of sex steroids necessitates the discontinuation of CHCs.

- Although CHCs 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 CHCs. However, diabetic women should be carefully observed while taking CHCs.

- Crohn's disease and ulcerative colitis have been associated with CHC 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 whilst taking this preparation.

- Viorele contains < 80 mg lactose per tablet. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take medicine.

Relative Contraindications

Severe depression or a history of this condition.

4.4.2 Medical Examination/consultation

Prior to the initiation or reinstitution of Viorele a complete medical history (including family history) should be taken and pregnancy must be ruled out. Blood pressure should be measured and a physical examination should be performed, guided by the contraindications and warnings. It is important to draw a woman's attention to the information on venous and arterial thrombosis, including the risk of Viorele compared with other CHCs, the symptoms of VTE and ATE, the known risk factors and what to do in the event of a suspected thrombosis.

The woman should also be instructed to carefully read the user leaflet and to adhere to the advice given. The frequency and nature of examinations should be based on established practice guidelines and be adapted to the individual woman.

Women should be advised that hormonal contraceptives do not protect against HIV infections (AIDS) and other sexually transmitted diseases. If there is risk of STI/HIV (including during pregnancy or postpartum), the correct and consistent use of condoms is recommended, either alone or with another contraceptive method.

4.4.3 Reduced Efficacy

3), gastrointestinal disturbances (Section 4.2.4) or concomitant medications that decrease the plasma concentration of etonogestrel, the active metabolite of desogestrel (Section 4.5.1).

4.4.4 Reduced Cycle Control/ irregular bleeding

With all CHCs, 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. However, if the CHC 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 CHC use is continued.

¹ These incidences were estimated from the totality of the epidemiological study data, using relative risks for the different products compared with levonorgestrel-containing CHCs.

² Mid-point of range of 5-7 per 10,000 WY, based on a relative risk for CHCs containing levonorgestrel versus non-use of approximately 2.3 to 3.6

4.4.1 Warnings

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

1. Circulatory Disorders

Risk of venous thromboembolism (VTE)

- The use of any combined hormonal contraceptive (CHC) increases the risk of venous thromboembolism (VTE) compared with no use. Products that contain levonorgestrel, norgestimate or norethisterone are associated with the lowest risk of VTE. Other products such as Viorele may have up to twice this level of risk. The decision to use any product other than one with the lowest VTE risk should be taken only after a discussion with the woman to ensure she understands the risk of VTE with Viorele, how her current risk factors influence this risk, and that her VTE risk is highest in the first ever year of use. There is also some evidence that the risk is increased when a CHC is re-started after a break in use of 4 weeks or more.

- In women who do not use a CHC and are not pregnant about 2 out of 10,000 will develop a VTE over the period of one year. However, in any individual woman the risk may be far higher, depending on her underlying risk factors (see below).

It is estimated¹ that out of 10,000 women who use a CHC containing desogestrel between 9 and 12 women will develop a VTE in one year; this compares with about 6² in women who use a levonorgestrel-containing CHC.

In both cases, the number of VTEs per year is fewer than the number expected during pregnancy or in the postpartum period.

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

Number of VTE events per 10,000 women in one year

Extremely rarely, thrombosis has been reported to occur in CHC users in other blood vessels, e.g. hepatic, mesenteric, renal or retinal veins and arteries.

Risk factors for VTE

The risk for venous thromboembolic complications in CHC users may increase substantially in a woman with additional risk factors, particularly if there are multiple risk factors (see table).

Viorele is contraindicated if a woman has multiple risk factors that put her at high risk of venous thrombosis. 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.

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). Viorele is contraindicated if a woman has one serious or multiple risk factors for ATE that puts her at high risk of arterial thrombosis. 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.

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.

2. Tumours

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

- A meta-analysis from 54 epidemiological studies reported that there is a slightly increased relative risk (RR = 1.24) of having breast cancer diagnosed in women who are currently using combined oral contraceptives (COCs). The observed pattern of increased risk may be due to an earlier diagnosis of breast cancer in COC users, the biological effects of COCs or a combination of both. The additional breast cancers diagnosed in current users of COCs or in women who have used COCs in the last ten years are more likely to be localised to the breast than those in women who never used COCs.

- Breast cancer is rare among women under 40 years of age whether or not they take COCs. Whilst this background risk increases with age, the excess number of breast cancer diagnoses in current and recent COC users is small in relation to the overall risk of breast cancer (see bar chart).

- The most important risk factor for breast cancer in COC users is the age women discontinue the COC; the older the age at stopping, the more breast cancers are diagnosed. Duration of use is less important and the excess risk gradually disappears during the course of the 10 years after stopping COC use such that by 10 years there appears to be no excess.

- The possible increase in risk of breast cancer should be discussed with the user and weighed against the benefits of COCs taking into account the evidence that they offer substantial protection against the risk of developing certain other cancers (e.g. ovarian and endometrial cancer).

- In rare cases, benign liver tumours, and even more rarely, malignant liver tumours have been reported in users of CHCs. In isolated cases, these tumours have led to life-threatening intra-abdominal haemorrhages. A hepatic tumour should be considered in the differential diagnosis when upper abdominal pain, enlarged liver or signs of intra-abdominal haemorrhage occur in women taking CHCs.

3. ALT elevations

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).

4 Other conditions

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

- Although small increases in blood pressure have been reported in many women taking CHCs, clinically relevant increases are rare. A relationship between CHC use and clinical hypertension has not been established. However, if a sustained clinically significant hypertension develops during the use of a CHC then it is prudent for the physician to withdraw the CHC and treat the hypertension. Where considered appropriate, CHC 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 CHC use, but the evidence of an association with CHC use is inconclusive: jaundice and/or pruritus related to cholestasis; gallstone formation; porphyria; systemic lupus erythematosus; haemolytic uraemic syndrome: Sydenham's chorea; herpes gestationis; otosclerosis-related hearing loss; hereditary angioedema.

- Acute or chronic disturbances of liver function may necessitate the discontinuation of CHC use until markers of liver function return to normal. Recurrence of cholestatic jaundice which occurred previously during pregnancy or use of sex steroids necessitates the discontinuation of CHCs.

- Although CHCs 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 CHCs. However, diabetic women should be carefully observed while taking CHCs.

- Crohn's disease and ulcerative colitis have been associated with CHC 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 whilst taking this preparation.

- Viorele contains < 80 mg lactose per tablet. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose- galactose malabsorption should not take medicine.

Relative Contraindications

Severe depression or a history of this condition.

4.4.2 Medical Examination/consultation

Prior to the initiation or reinstitution of Viorele a complete medical history (including family history) should be taken and pregnancy must be ruled out. Blood pressure should be measured and a physical examination should be performed, guided by the contraindications and warnings. It is important to draw a woman's attention to the information on venous and arterial thrombosis, including the risk of Viorele compared with other CHCs, the symptoms of VTE and ATE, the known risk factors and what to do in the event of a suspected thrombosis.

The woman should also be instructed to carefully read the user leaflet and to adhere to the advice given. The frequency and nature of examinations should be based on established practice guidelines and be adapted to the individual woman.

Women should be advised that hormonal contraceptives do not protect against HIV infections (AIDS) and other sexually transmitted diseases. If there is risk of STI/HIV (including during pregnancy or postpartum), the correct and consistent use of condoms is recommended, either alone or with another contraceptive method.

4.4.3 Reduced Efficacy

3), gastrointestinal disturbances (Section 4.2.4) or concomitant medications that decrease the plasma concentration of etonogestrel, the active metabolite of desogestrel (Section 4.5.1).

4.4.4 Reduced Cycle Control/ irregular bleeding

With all CHCs, 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. However, if the CHC 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 CHC use is continued.

¹ These incidences were estimated from the totality of the epidemiological study data, using relative risks for the different products compared with levonorgestrel-containing CHCs.

² Mid-point of range of 5-7 per 10,000 WY, based on a relative risk for CHCs containing levonorgestrel versus non-use of approximately 2.3 to 3.6

Pharmacotherapeutic group: progestogens and estrogens, fixed combinations, ATC code: G03AA09

Viorele is an oral contraceptive combination containing 150 micrograms desogestrel and 20 micrograms ethinylestradiol.

Ethinylestradiol is a well-known synthetic estrogen.

Desogestrel is a synthetic progestogen. After oral administration it has a strong ovulation-inhibiting activity, a strong progestational and anti-estrogenic activity, no estrogenic activity, very weak androgenic/anabolic activity.

Paediatric population

No clinical data on efficacy and safety are available in adolescents below 18 years.

Pharmacotherapeutic group: progestogens and estrogens, fixed combinations, ATC code: G03AA09

Viorele is an oral contraceptive combination containing 150 micrograms desogestrel and 30 micrograms ethinylestradiol.

Ethinylestradiol is a well-known synthetic estrogen.

Desogestrel is a synthetic progestogen. After oral administration it has a strong ovulation-inhibiting activity, a strong progestational and anti-estrogenic activity, no estrogenic activity, very weak androgenic/anabolic activity.

Paediatric population

No clinical data on efficacy and safety are available in adolescents below 18 years.