4.1. Therapeutic indications

Oral contraception.

Treatment of heavy menstrual bleeding in women without organic pathology who desire oral contraception.

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

4.2. Posology and method of administration

Method of administration

Oral use

Posology

How to take Qlaira

Tablets must be taken in the order directed on the package every day at about the same time with some liquid as needed. Tablet taking is continuous. One tablet is to be taken daily for 28 consecutive days. Each subsequent pack is started the day after the last tablet of the previous wallet. Withdrawal bleeding usually starts during the intake of the last tablets of a wallet and may not have finished before the next wallet is started. In some women, the bleeding starts after the first tablets of the new wallet are taken.

How to start Qlaira

• 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).

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

The woman should start with Qlaira on the day after the last active tablet (the last tablet containing the active substances) of her previous COC. In case a vaginal ring or transdermal patch has been used, the woman should start using Qlaira on the day of removal.

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

The woman may switch any day from the progestogen-only pill (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 9 days of tablet-taking.

• Following first-trimester abortion

The woman may start immediately. When doing so, she needs not take additional contraceptive measures.

• Following delivery or second-trimester abortion

For breastfeeding women see section 4.6.

Women should be advised to start at day 21 to 28 after delivery or second-trimester abortion. When starting later, the woman should be advised to additionally use a barrier method for the first 9 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

Missed (white) placebo tablets can be disregarded. However, they should be discarded to avoid unintentionally prolonging the interval between active-tablet taking.

The following advice only refers to missed active tablets:

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

If she is more than 12 hours late in taking any tablet, contraceptive protection may be reduced.

Depending on the day of the cycle as indicated in the current wallet on which the tablet has been missed (see table below for details), the following principles on tablet intake and back-up contraceptive measures (e.g. a barrier method such as a condom) apply:

DAY

Color Content of estradiol valerate (EV)/dienogest (DNG)

Principles to follow if missing one tablet for more than 12 hours:

1 – 2

Dark yellow tablets (3.0 mg EV)

- Take the missed tablet immediately

- Take the next tablet at the same time as usual (even if this means taking two tablets at the same day)

- Continue taking one tablet each day at the same time as usual

- Use back-up contraception for the next 9 days

3 - 7

Medium red tablets (2.0 mg EV + 2.0 mg DNG)

8 – 17

Light yellow tablets (2.0 mg EV + 3.0 mg DNG)

18 – 24

Light yellow tablets (2.0 mg EV + 3.0 mg DNG)

- Do not take the missed tablet and discard the current wallet

- Take the first tablet of a new wallet

- Continue taking one tablet each day from the new wallet at the same time as usual

- Use back-up contraception for the next 9 days

25 – 26

Dark red tablets (1.0 mg EV)

- Take the missed tablet immediately

- Take the next tablet at the same time as usual (even if this means taking two tablets at the same day)

- Continue taking one tablet each day at the time as usual

- No back-up contraception necessary

27-28

White tablets (Placebos)

- Discard the missed tablet

- Take the next tablet at the same time as usual

- When the last tablet is missed in the current wallet, continue taking the first tablet from the new wallet at the same time as usual

- No back-up contraception necessary

Not more than two tablets are to be taken on a given day.

If a woman has forgotten to start a new wallet, or if she has missed one or more tablets during days 3 -9 of the wallet, she may already be pregnant (provided she has had intercourse in the 7 days before the oversight). The more tablets (of those with the two combined active ingredients on days 3 – 24) that are missed and the closer they are to the placebo tablet phase, the higher the risk of a pregnancy.

If the woman missed tablets and subsequently has no withdrawal bleed at the end of the wallet /beginning of new wallet, the possibility of a pregnancy should be considered.

Advice in case of gastro-intestinal disturbances

In case of severe gastro-intestinal disturbances (e.g., vomiting or diarrhoea), absorption may not be complete and additional contraceptive measures should be taken.

If vomiting occurs within 3-4 hours after active tablet-taking, the next tablet should be taken as soon as possible. This tablet should be taken within 12 hours of the usual time of tablet-taking, if possible. If more than 12 hours elapse, the advice concerning missed tablets, as given in section 4.2 “Management of missed tablets”, is applicable. If the woman does not want to change her normal tablet-taking schedule, she has to take the corresponding tablet(s) needed from another pack.

Additional information on special populations

Children and adolescents

No data available for use in adolescents below 18 years.

Geriatric patients

Qlaira is not indicated after menopause.

Patients with hepatic impairment

Qlaira is contraindicated in women with severe hepatic diseases. See also section 4.3.

Patients with renal impairment

Qlaira has not been specifically studied in renally impaired patients.

4.3. Contraindications

Combined hormonal contraceptives (CHCs) should not be used in the following conditions. Should any of the conditions appear for the first time during CHC use, the product should be stopped immediately.

• Presence or risk of venous thromboembolism (VTE)

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 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.

• 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 Qlaira 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 Qlaira should be discontinued.

In case of suspected or confirmed VTE or ATE, CHC use should be discontinued. In case anticoagulant therapy is started, adequate alternative contraception should be initiated because of the teratogenicity of anticoagulant therapy (coumarins).

The following warnings and precautions are mainly derived from clinical and epidemiological data of ethinyl estradiol containing COCs.

• 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. Limited data suggests that Qlaira may have a risk of VTE in the same range. The decision to use any other product (such as Qlaira) than one known to have the lowest VTE risk should be taken only after a discussion with the woman to ensure she understands the risk of VTE with CHCs, 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).

Epidemiological studies in women who use low dose (<50 μg ethinylestradiol) combined hormonal contraceptives have found that out of 10,000 women between about 6 and 12 will develop a VTE in one year

It is estimated that out of 10,000 women who use a levonorgestrel-containing CHC about 61 will develop a VTE in one year.

Limited epidemiological evidence suggests that the risk of VTE with the use of Qlaira may be in the same range as the risk with other CHCs, including CHCs containing levonorgestrel.

The number of VTEs per year with low dose CHCs is fewer than the number expected in women during pregnancy or in the postpartum period.

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

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).

Qlaira is contraindicated if a woman has multiple risk factors that put her at high risk of venous thrombosis (see section 4.3). If a woman has more than one risk factor, it is possible that the increase in risk is greater than the sum of the individual factors – in this case her total risk of VTE should be considered. If the balance of benefits and risks is considered to be negative a CHC should not be prescribed (see section 4.3).

Table: Risk factors for VTE

Risk factor

Comment

Obesity (body mass index over 30 kg/m²)

Risk increases substantially as BMI rises.

Particularly important to consider if other risk factors also present.

Prolonged immobilisation, major surgery, any surgery to the legs or pelvis, neurosurgery, or major trauma

Note: temporary immobilisation including air travel >4 hours can also be a risk factor for VTE, particularly in women with other risk factors

In these situations it is advisable to discontinue use of the pill (in the case of elective surgery at least four weeks in advance) and not resume until two weeks after complete remobilisation. Another method of contraception should be used to avoid unintentional pregnancy.

Antithrombotic treatment should be considered if Qlaira has not been discontinued in advance.

Positive family history (venous thromboembolism ever in a sibling or parent especially at a relatively early age e.g. before 50).

If a hereditary predisposition is suspected, the woman should be referred to a specialist for advice before deciding about any CHC use

Other medical conditions associated with VTE

Cancer, systemic lupus erythematosus, haemolytic uraemic syndrome, chronic inflammatory bowel disease (Crohn's disease or ulcerative colitis) and sickle cell disease

Increasing age

Particularly above 35 years

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

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

Symptoms of VTE (deep vein thrombosis and pulmonary embolism)

In the event of symptoms women should be advised to seek urgent medical attention and to inform the healthcare professional that she is taking a CHC.

Symptoms of deep vein thrombosis (DVT) can include:

o unilateral swelling of the leg and/or foot or along a vein in the leg

o pain or tenderness in the leg which may be felt only when standing or walking

o increased warmth in the affected leg; red or discoloured skin on the leg.

Symptoms of pulmonary embolism (PE) can include:

o sudden onset of unexplained shortness of breath or rapid breathing

o sudden coughing which may be associated with haemoptysis

o sharp chest pain

o severe light headedness or dizziness

o 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). Qlaira is contraindicated if a woman has one serious or multiple risk factors for ATE that puts her at high risk of arterial thrombosis (see section 4.3). If a woman has more than one risk factor, it is possible that the increase in risk is greater than the sum of the individual factors - in this case her total risk should be considered. If the balance of benefits and risks is considered to be negative a CHC should not be prescribed (see section 4.3).

Table: Risk factors for ATE

Risk factor

Comment

Increasing age

Particularly above 35 years

Smoking

Women should be advised not to smoke if they wish to use a CHC. Women over 35 who continue to smoke should be strongly advised to use a different method of contraception.

Hypertension

Obesity (body mass index over 30 kg/m2)

Risk increases substantially as BMI increases.

Particularly important in women with additional risk factors

Positive family history (arterial thromboembolism ever in a sibling or parent especially at relatively early age e.g. below 50).

If a hereditary predisposition is suspected, the woman should be referred to a specialist for advice before deciding about any CHC use

Migraine

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

Other medical conditions associated with adverse vascular events

Diabetes mellitus, hyperhomocysteinaemia, valvular heart disease and atrial fibrillation, dyslipoproteinaemia and systemic lupus erythematosus.

Symptoms of ATE

In the event of symptoms women should be advised to seek urgent medical attention and to inform the healthcare professional that she is taking a CHC.

Symptoms of a cerebrovascular accident can include:

o sudden numbness or weakness of the face, arm or leg, especially on one side of the body

o sudden trouble walking, dizziness, loss of balance or coordination

o sudden confusion, trouble speaking or understanding

o sudden trouble seeing in one or both eyes

o sudden, severe or prolonged headache with no known cause

o 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:

o pain, discomfort, pressure, heaviness, sensation of squeezing or fullness in the chest, arm, or below the breastbone

o discomfort radiating to the back, jaw, throat, arm, stomach

o feeling of being full, having indigestion or choking

o sweating, nausea, vomiting or dizziness

o extreme weakness, anxiety, or shortness of breath

o rapid or irregular heartbeats.

• Tumours

An increased risk of cervical cancer in long-term users of COCs (> 5 years) 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 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 COCs. The excess risk gradually disappears during the course of the 10 years after cessation of COC use. Because breast cancer is rare in women under 40 years of age, the excess number of breast cancer diagnoses in current and recent COC users is small in relation to the overall risk of breast cancer. These studies do not provide evidence for causation. The observed pattern of increased risk may be due to an earlier diagnosis of breast cancer in COC users, the biological effects of COCs or a combination of both. The breast cancers diagnosed in ever-users tend to be less advanced clinically than the cancers diagnosed in never-users.

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

Hepatitis C

During clinical trials with the hepatitis C virus (HCV) combination regimen ombitasvir/paritaprevir/ritonavir with and without dasabuvir, ALT elevations greater than 5 times the upper limit of normal (ULN) were significantly more frequent in women using ethinylestradiol-containing medicinal products such as CHCs. Additionally, also in patients treated with glecaprevir/pibrentasvir, ALT elevations were observed in women using ethinylestradiol-containing medications such as CHCs. Women using medicinal products containing oestrogens other than ethinylestradiol, such as estradiol, had a rate of ALT elevation similar to those not receiving any oestrogens; however, due to the limited number of women taking these other oestrogens, caution is warranted for co-administration with the combination drug regimen ombitasvir/paritaprevir/ritonavir with or without dasabuvir and also the regimen glecaprevir/pibrentasvir. See section 4.5.

• Other conditions

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

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

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

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

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

Although COCs may have an effect on peripheral insulin resistance and glucose tolerance, there is no evidence 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, particularly in the early stage of COC use.

Worsening of endogenous depression, of epilepsy, of Crohn's disease and of ulcerative colitis has been reported during COC use.

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.

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 COCs.

Estrogens may cause fluid retention, and therefore patients with cardiac or renal dysfunction should be carefully observed. Patients with terminal renal insufficiency should be closely observed, since the level of circulating estrogens may be increased after administration of Qlaira.

This medicinal product contains not more than 50 mg lactose per tablet. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Medical examination/consultation

Prior to the initiation or reinstitution of Qlaira 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 contra-indications (see section 4.3) and warnings (see section 4.4). It is important to draw a woman's attention to the information on venous and arterial thrombosis, including the risk of Qlaira 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.

Reduced efficacy

The efficacy of COCs may be reduced for example in the following events: missed active tablets (section 4.2), gastro-intestinal disturbances (section 4.2) during active tablet taking or concomitant medication (section 4.5).

Cycle control

With all COCs, irregular bleeding (spotting or breakthrough bleeding) may occur, especially during the first months of use. Therefore, the evaluation of any irregular bleeding is only meaningful after an adaptation interval of about 3 cycles.

Based on patient diaries from a comparative clinical trial, the percentage of women per cycle experiencing intracyclic bleeding was 10 – 18 % for women using Qlaira.

Users of Qlaira may experience amenorrhea although not being pregnant. Based on patient diaries, amenorrhea occurs in approximately 15% of cycles.

If Qlaira has been taken according to the directions described in Section 4.2, it is unlikely that the woman is pregnant. If Qlaira has not been taken according to these directions prior to the first missed withdrawal bleed or if the withdrawal bleeding is missed in two consecutive cycles, pregnancy must be ruled out before Qlaira use is continued.

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.

1 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

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

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

Interaction studies have only been performed in adults.

The following interactions have been reported in the literature for COCs in general or were studied in clinical trials with Qlaira.

• Effects of other medicinal products on Qlaira

Interactions can occur with drugs that induce microsomal enzymes which can result in increased clearance of sex hormones and which may lead to breakthrough bleeding and/or contraceptive failure.

Management

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.

Short-term treatment

Women on treatment with enzyme-inducing drugs should temporarily use a barrier method or another method of contraception in addition to the COC. The barrier method must be used during the whole time of the concomitant drug therapy and for 28 days after its discontinuation. If the drug therapy runs beyond the end of the active tablets in the COC pack, the placebo tablets must be discarded and the next COC pack should be started right away.

Long-term treatment

In women on long-term treatment with hepatic enzyme-inducing active substances, another reliable, non-hormonal, method of contraception is recommended.

Substances increasing the clearance of COCs (diminished efficacy of COCs by enzyme-induction), e.g.:

Barbiturates, carbamazepine, phenytoin, primidone, rifampicin, and HIV medication ritonavir, nevirapine and efavirenz and possibly also felbamate, griseofulvin, oxcarbazepine, topiramate and products containing the herbal remedy St. John's Wort (hypericum perforatum).

In a clinical study the strong cytochrome P450 (CYP 3A4) inducer rifampicin led to significant decreases in steady state concentrations and systemic exposures of dienogest and estradiol. The AUC (0-24h) of dienogest and estradiol at steady state, were decreased by 83% and 44%, respectively.

Substances with variable effects on the clearance of COC:

When co-administered with COCs, many combinations of HIV protease inhibitors and non-nucleoside reverse transcriptase inhibitors, including combinations with HCV inhibitors can increase or decrease plasma concentrations of estrogen or progestins. The net effect of these changes may be clinically relevant in some cases.

Therefore, the prescribing information of concomitant HIV/HCV medications should be consulted to identify potential interactions and any related recommendations. In case of any doubt, an additional barrier contraceptive method should be used by women on protease inhibitor or non-nucleoside reverse transcriptase inhibitor therapy.

Substances decreasing the clearance of COCs (enzyme inhibitors):

Dienogest is a substrate of CYP3A4.

The clinical relevance of potential interactions with enzyme inhibitors remains unknown.

Concomitant administration of strong CYP3A4 inhibitors can increase plasma concentrations of the estrogen or the progestin or both.

Coadministration with the strong CYP3A4 enzyme inhibitor ketoconazole resulted in a 2.9-fold and 1.6-fold increase of AUC (0-24h) at steady state for dienogest and estradiol, respectively. Concomitant administration of the moderate inhibitor erythromycin increased the AUC (0-24h) of dienogest and estradiol at steady state by 1.6-fold and 1.3-fold, respectively.

• Effects of Qlaira on other medicinal products

Oral contraceptives may affect the metabolism of certain other active substances. Accordingly, plasma and tissue concentrations may either increase (e.g. cyclosporin) or decrease (e.g. lamotrigine).

Pharmacokinetics of nifedipine were not affected by concomitant administration of 2 mg dienogest + 0.03 mg ethinyl estradiol thus confirming results of in vitro studies indicating that inhibition of CYP enzymes by Qlaira is unlikely at the therapeutic dose.

• Other interactions

During clinical trials with the HCV combination drug regimen ombitasvir/paritaprevir/ritonavir with and without dasabuvir, ALT elevations greater than 5 times the upper limit of normal (ULN) were significantly more frequent in women using ethinylestradiol-containing medicinal products such as CHCs. Women using medicinal products containing oestrogens other than ethinylestradiol, such as estradiol, had a rate of ALT elevation similar to those not receiving any oestrogens; however, due to the limited number of women taking these other oestrogens, caution is warranted for co-administration with the combination drug regimen ombitasvir/paritaprevir/ritonavir with or without dasabuvir and also the regimen with glecaprevir/pibrentasvir (see section 4.4).

Laboratory tests

The use of contraceptive steroids may influence the results of certain laboratory tests, including biochemical parameters of liver, thyroid, adrenal and renal function, plasma levels of (carrier) proteins, e.g. corticosteroid binding globulin and lipid/lipoprotein fractions, parameters of carbohydrate metabolism and parameters of coagulation and fibrinolysis. Changes generally remain within the normal laboratory range.

4.6. Fertility, pregnancy and lactation

Pregnancy

Qlaira is not indicated during pregnancy.

If pregnancy occurs during use of Qlaira, further intake must be stopped. However, extensive epidemiological studies with ethinylestradiol containing COCs 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 pregnancy. Animal studies do not indicate a risk for reproductive toxicity (see section 5.3).

The increased risk of VTE during the postpartum period should be considered when re-starting Qlaira (see section 4.2 and 4.4).

Breastfeeding

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.

Fertility

Qlaira is indicated for the prevention of pregnancy. For information on return to fertility, see section 5.1.

4.7. Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been performed. No effects on ability to drive and use machines have been observed in users of COCs.

4.8. Undesirable effects

Summary of the safety profile

The most commonly reported adverse reactions with Qlaira when used as an oral contraceptive or in the treatment of heavy menstrual bleeding in women without organic pathology who desire oral contraception are acne, breast discomfort, headache, intracyclic bleeding, nausea and weight increased.

Serious adverse reactions are arterial and venous thromboembolism, which are discussed in section 4.4.

Tabulated list of adverse reactions

The table below reports adverse reactions (ARs) by MedDRA system organ classes (MedDRA SOCs). The most appropriate MedDRA term (version 12.0) to describe a certain adverse reaction is listed. Synonyms or related conditions are not listed, but should be taken into account as well. The frequencies are based on clinical trial data. The adverse reactions were recorded in 5 phase III clinical studies (N=2,266 women at risk for pregnancy, N=264 women suffering from dysfunctional uterine bleeding without organic pathology who desire oral contraception) and considered at least possibly causally related to Qlaira use. All ADRs listed in the category 'rare' occurred in 1 to 2 volunteers resulting in < 0.1%.

N= 2,530women (100.0%)

System Organ Class

Common (≥ 1/100 to <1/10)

Uncommon(≥ 1/1,000 to <1/100)

Rare (≥ 1/10,000 to < 1/1,000)

Infections and infestations

Fungal infection

Vulvovaginal mycotic infection1

Vaginal infection

Candidiasis

Oral herpes

Pelvic inflammatory disease

Presumed ocular histoplasmosis syndrome

Tinea versicolor

Urinary tract infection

Vaginitis bacterial

Metabolism and nutrition disorders

Increased appetite

Fluid retention

Hypertriglyceridaemia

Psychiatric disorders

Depression/depressed mood

Emotional disorder2

Insomnia

Libido decreased3

Mental disorder

Mood change4

Aggression

Anxiety

Dysphoria

Libido increased

Nervousness

Nightmare

Restlessness

Sleep disorder

Stress

Nervous system disorders

Headache5

Dizziness

Migraine6

Disturbance in attention

Paraesthesia

Vertigo

Eye disorders

Contact lens intolerance

Dry eye

Eye swelling

Cardiac disorders

Myocardial infarction

Palpitations

Vascular disorders

Hot flush

Hypertension

Bleeding varicose vein

Venous thromboembolism (VTE)

Arterial thromboembolism (ATE)

Hypotension

Phlebitis superficialis

Vein pain

Gastrointestinal disorders

Abdominal pain7

Nausea

Diarrhoea

Vomiting

Constipation

Dry mouth

Dyspepsia

Gastrooesophageal reflux disease

Hepatobiliary disorders

Liver enzymes increased8

Focal nodular hyperplasia of the liver

Cholecystitis chronic

Skin and subcutaneous tissue disorders

Acne9

Alopecia

Hyperhidrosis

Pruritus10

Rash11

Allergic skin reaction12

Chloasma

Dermatitis

Hirsutism

Hypertrichosis

Neurodermatitis

Pigmentation disorder

Seborrhoea

Skin disorder13

Musculoskeletal and connective tissue disorders

Muscle spasms

Back pain

Pain in jaw

Sensation of heaviness

Renal and urinary disorders

Urinary tract pain

Reproductive system and breast disorders

Amenorrhea

Breast discomfort14

Dysmenorrhoea

Intracyclic bleeding (Metrorrhagia)15

Breast enlargement16

Breast mass

Cervical dysplasia

Dysfunctional uterine bleeding

Dyspareunia

Fibrocystic breast disease

Menorrhagia

Menstrual disorder

Ovarian cyst

Pelvic pain

Premenstrual syndrome

Uterine leiomyoma

Uterine spasm

Uterine/ vaginal bleeding incl. spotting17

Vaginal discharge

Vulvovaginal dryness

Abnormal withdrawal bleeding

Benign breast neoplasm

Breast cancer in situ

Breast cyst

Breast discharge

Cervical polyp

Cervix erythema

Coital bleeding

Galactorrhea

Genital discharge

Hypomenorrhoea

Menstruation delayed

Ovarian cyst ruptured

Vaginal odour

Vulvovaginal burning sensation

Vulvovaginal discomfort

Blood and lymphatic system disorders

Lymphadenopathy

Respiratory, thoracic and mediastinal disorders

Asthma

Dyspnoea

Epistaxis

General disorders and administration site conditions

Fatigue

Irritability

Oedema18

Chest pain

Malaise

Pyrexia

Investigations

Weight increased

Weight decreased

Blood pressure changes19

Smear cervix abnormal

1 including vulvovaginal candidiasis and fungus cervical specimen identified

2 including crying and affect lability

3 including loss of libido

4 including mood altered and mood swings

5 including tension headache and sinus headache

6 including migraine with aura and migraine without aura

7 including abdominal distension, abdominal pain upper and abdominal pain lower

8 including alanine aminotransferase increased, aspartate aminotransferase increased and gamma-glutamyltransferase increased

9 including acne pustular

10 including pruritus generalized and rash pruritic

11 including rash macular

12 including dermatitis allergic and urticaria

13 including skin tightness

14 including breast pain, breast tenderness, nipple disorder and nipple pain

15 including menstruation irregular

16 including breast swelling

17 including vaginal hemorrhage, genital hemorrhage and uterine hemorrhage

18 including oedema peripheral

19 including blood pressure increased and blood pressure decreased

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.

Occurrence of amenorrhea and intracyclic bleeding based on patient diaries is summarized in section 4.4 Cycle control.

The following serious adverse events have been reported in women using COCs, which are discussed in section 4.4 Special warning and precautions for use:

Tumours

- The frequency of diagnosis of breast cancer is very slightly increased among COC 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 4.3 and 4.4;

- Liver tumours;

Other conditions

- Erythema nodosum, Erythema multiforme;

- Breast discharge;

- Hypertension;

- Occurrence or deterioration of conditions for which association with COC use is not conclusive: Crohn's disease, ulcerative colitis, epilepsy, migraine, uterine myoma, porphyria, systemic lupus erythematosus, herpes gestationis, Sydenham's chorea, haemolytic uremic syndrome, cholestatic jaundice;

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

- Acute or chronic disturbances of liver function may necessitate the discontinuation of COC use until markers of liver function return to normal.

- Chloasma;

- Hypersensitivity (including symptoms such as rash, urticaria);

Interactions

Breakthrough bleeding and/or contraceptive failure may result from interactions of other drugs (enzyme inducers) with oral contraceptives (see section 4.5).

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;

United Kingdom

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

Malta

ADR Reporting

Website: www.medicinesauthority.gov.mt/adrportal

4.9. Overdose

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