BP22036, REC30610

Note:

Text in blue = added text

Text in red with strikethrough = deleted text

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

[…]

This leaflet was last revised in April September 2022

BP22036, REC30610

Note:

Text in blue = added text

Text in red with strikethrough = deleted text

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

 April September2022

Correct of typographical error to including missing word. The added word is shown below as bold underlined text.

There are no further changes or impact to any other sections of the PIL.

(...)

·        if you have hereditary or acquired angioedema. Stop taking Qlaira and consult your doctor immediately if you experience symptoms such as swollen face, tongue and/or throat and/or difficulty swallowing or hives, together with difficulty breathing which are suggestive of an angioedema. Products containing oestrogens may induce or worsen symptoms of angioedema

(...)

Following a CMDh Request (estradiol-containing products) “Angioedema & Drug-drug interaction HCV”, the following sections of the PIL have been updated (green = new text added; red striked throught text = deleted text): :

Section 2

Warnings and precautions

(...)

•          if you have hereditary or and acquired angioedema. Stop taking Qlaira and cConsult your doctor immediately if you experience symptoms of angioedema such as swollen face, tongue and/or throat and/or difficulty swallowing or hives, together with difficulty breathing which are suggestive of an angioedema. Products containing oestrogens may induce or worsen symptoms of angioedema

(…)

Other medicines and Qlaira

Some medicines

•          can have an influence on the blood levels of Qlaira

•          can make it less effective in preventing pregnancy

•          can cause unexpected bleeding.

These include:

• medicines used for the treatment of:
• epilepsy (e.g. primidone, phenytoin, barbiturates, carbamazepine, oxcarbazepine,

topiramate, felbamate)

• tuberculosis (e.g. rifampicin)
• HIV and Hepatitis C Virus infections (so-called protease inhibitors and non-nucleoside reverse transcriptase inhibitors such as ritonavir, nevirapine, efavirenz)
• Medicines for Hepatitis C virus (HCV) (such as combination regimen ombitasvir/paritaprevir/ritonavir with or without dasabuvir as well as regimen glecaprevir/pibrentasvir) may cause increases in liver function blood test results (increase in ALT liver enzyme) in women using CHCs containing ethinylestradiol. Qlaira contains estradiol instead of ethinylestradiol. It is not known whether an increase in ALT liver enzyme can occur when using Qlaira with this HCV combination regimen. Your doctor will advise you.
• fungal infections (e.g. griseofulvin, ketoconazole)
• the herbal remedy St. John's wort

(…)

Section 4

4.        Possible side effects

(…)

Reporting of side effects

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly (see details below). via HPRA Pharmacovigilance, Earlsfort Terrace, IRL – Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517. Website: www.hpra.ie; E-mail: medsafety@hpra.ie. By reporting side effects you can help provide more information on the safety of this medicine.

Ireland

HPRA Pharmacovigilance

Website: www.hpra.ie

Malta

ADR Reporting Website: www.medicinesauthority.gov.mt/adrportal

Section 6

6.          Contents of the pack and other information

(…)

This leaflet was last revised in April 2022July 2021.

Following a CMDh Request (estradiol-containing products) “Angioedema & Drug-drug interaction HCV”, the following sections of the SmPC were updated (green = new text added; red striked throught text = deleted text):

Section 4.4

4.4       Special warnings and precautions for use

Warnings

(…)

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

(…)

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

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

(…)

This medicinal product contains not more than 50 mg lactose per tablet. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency, the Lapp lactase deficiency or glucose-galactose malabsorption who are on a lactose-free diet should not take this medicineamount into consideration.

Section 4.5

4.5      Interaction with other medicinal products and other forms of interaction

• Other forms of 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).

Section 4.8

4.8      Undesirable effects

(…)

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via HPRA Pharmacovigilance, Earlsfort Terrace, IRL – Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517. wWebsite: www.hpra.ie; E-mail: medsafety@hpra.ie.

Section 10

10.      DATE OF REVISION OF THE TEXT

April 2022December 2018

Editorial update. In section 8, the space between "PA" and "1410/058/001"  was deleted, to read as "PA1410/058/001".

"Ireland" add to the Marketing Authorisation holder address in section 6.

The date of revision was updated to July 2021. 

In section 3 Pharmaceutical form, the following changes have been made:

Dark yellow film-coated tablet, round with biconvex faces, one side is markedembossed with the letters “DD” in a regular hexagon

Medium red film-coated tablet, round with biconvex faces, one side is markedembossed with the letters “DJ” in a regular hexagon

Light yellow film-coated tablet, round with biconvex faces, one side is markedembossed with the letters “DH” in a regular hexagon

Dark red film-coated tablet, round with biconvex faces, one side is markedembossed with the letters “DN” in a regular hexagon

White film-coated tablet, round with biconvex faces, one side is markedembossed with the letters “DT” in a regular hexagon

In section 4.2 posology and method of administration, the following has been deleted:

Paediatric population

No data available for use in adolescents below 18 years.

·      Pancreatitis or a history thereof if associated with severe hypertriglyceridemia.

In the same section, the following has been added:

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.

In section 4.5, the following section has been altered:

Substances decreasing the clearance of COCs interfering with the metabolism of combined hormonal contraceptives (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.

Known CYP3A4 enzyme inhibitors like azole antifungals, cimetidine, verapamil, macrolides, diltiazem, antidepressants and grapefruit juice may increase plasma levels of dienogest.

In a clinical study investigating the effect of CYP3A4 inhibitors (ketoconazole, erythromycin), steady state dienogest and estradiol plasma levels were increased. Co-administration with the strong CYP3A4 enzyme inhibitor ketoconazole resulted in a 186% and 57% 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 62% and 33%, respectively. The clinical relevance of these interactions is unknown.

In section 4.6, the following changes have been made:

If pregnancy occurs during use of Qlaira, further intake mustshould be stopped.

In section 4.7, the following section has been altered:

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.Qlaira has no influence on the ability to drive or use machines.

In section 4.8, the following section has been added:

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 following has been altered in the same section:

Venous thromboembolic disorders;

Arterial thromboembolic disorders;

Tumours

-             Hypertension;

-             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;

-             Chloasma;

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

-             Chloasma;

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

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

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.

In addition to the above mentioned adverse reactions, erythema nodosum, erythema multiforme, breast discharge and hypersensitivity have occurred under treatment with ethinylestradiol containing COCs. Although these symptoms were not reported during the clinical studies performed with Qlaira, the possibility that they also occur under treatment cannot be ruled out.

2.                QUALITATIVE AND QUANTITATIVE COMPOSITION

Each wallet (28 film-coated tablets) contains in the following order:
2 dark yellow tablets each containing 3 mg estradiol valerate
5 medium red tablets each containing 2 mg estradiol valerate and 2 mg dienogest
17 light yellow tablets each containing 2 mg estradiol valerate and 3 mg dienogest
2 dark red tablets each containing 1 mg estradiol valerate
2 white tablets do not contain active substances

Excipient with known effect: lactose (not more than 50 mg per tablet)

For the full list of excipients, see section 6.1.

4.                CLINICAL PARTICULARS

4.2             Posology and method of administration

Method of administration

Oral use

Posology

How to take Qlaira

…

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.

·        Interactions 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 between oral contraceptives and other drugs may lead to breakthrough bleeding and/or contraceptive failure. The following interactions have been reported in the literature for COCs in general or were studied in clinical trials with Qlaira.

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.

Dienogest is a substrate of cytochrome P450 (CYP) 3A4.

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).

Interactions can occur with phenytoin, barbiturates, primidone, carbamazepine, rifampicin, and possibly oxcarbazepine, topiramate, felbamate, HIV-medications (e.g. ritonavir and/or nevirapine), griseofulvin and the herbal remedy St. John’s wort (hypericum perforatum). The mechanism of this interaction appears to be based on the hepatic enzyme-inducing properties (e.g. CYP 3A4 enzymes) of these drugs which can result in increased clearance of sex hormones.

Maximal enzyme induction is generally not seen for 2-3 weeks but may then be sustained for at least 4 weeks after the cessation of drug therapy.

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.

Women on short-term treatment (up to one week) with any of the above-mentioned classes of medicinal products or individual active substances besides rifampicin should temporarily use a barrier method in addition to the COC, i.e. during the time of concomitant medicinal product administration and for 14 days after their discontinuation.

For women on rifampicin a barrier method should be used in addition to the COC during the time of rifampicin administration and for 28 days after its discontinuation.

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

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 interfering with the metabolism of combined hormonal contraceptives (enzyme inhibitors):

Dienogest is a substrate of CYP3A4.

Known CYP3A4 enzyme inhibitors like azole antifungals, cimetidine, verapamil, macrolides, diltiazem, antidepressants and grapefruit juice may increase plasma levels of dienogest.

In a clinical study investigating the effect of CYP3A4 inhibitors (ketoconazole, erythromycin), steady state dienogest and estradiol plasma levels were increased. Co-administration with the strong CYP3A4 enzyme inhibitor ketoconazole resulted in a 186% and 57% 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 62% and 33%, respectively. The clinical relevance of these interactions is unknown.

Contraceptive failures have also been reported with antibiotics, such as penicillins and tetracyclines. The mechanism of this effect has not been elucidated.

·        Interactions 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 forms of interactionsLaboratory tests

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.

4.8             Undesirable effects

Description of selected adverse reactions

…

Interactions

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

…

5.                PHARMACOLOGICAL PROPERTIES

5.2             Pharmacokinetic properties

·        Dienogest

…

BiotransformationMetabolism

Dienogest is nearly completely metabolized by the known pathways of steroid metabolism (hydroxylation, conjugation), mainly by CYP3A4. The pharmacologically inactive metabolites are excreted rapidly resulting in dienogest as the major fraction in plasma accounting for approximately 50% of circulating dienogest derived compounds. The total clearance following the intravenous administration of ³H-dienogest was calculated as 5.1 l/h.

…

·        Estradiol valerate

…

BiotransformationMetabolism

The valeric acid undergoes very fast metabolism. After oral administration approximately 3% of the dose is directly bioavailable as estradiol. Estradiol undergoes an extensive first-pass effect and a considerable part of the dose administered is already metabolized in the gastrointestinal mucosa. Together with the presystemic metabolism in the liver, about 95 % of the orally administered dose becomes metabolized before entering the systemic circulation. The main metabolites are estrone, estrone sulfate and estrone glucuronide.

10.             DATE OF REVISION OF THE TEXT

September 2014January 2015

4.      CLINICAL PARTICULARS

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).

4.3   Contraindications

Combined hormonaloral contraceptives (CHOCs) should not be used in the presence of any of the following conditions listed below. Should any of the conditions appear for the first time during CHOC 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

·      Venous thrombosis present or history (deep venous thrombosis, pulmonary embolism)

·      Arterial thrombosis present or in history (e.g. myocardial infarction) or prodromal conditions (e.g. angina pectoris und transient ischaemic attack)

·      Cerebrovascular accident present or in history

·      Presence of severe or multiple risk factor(s) for venous (see 4.4) or arterial thrombosis such as:

·      diabetes mellitus with vascular symptoms

·      severe hypertension

·      severe dyslipoproteinemia

·      Hereditary or acquired predisposition for venous or arterial thrombosis, such as APC-resistance, antithrombin-III-deficiency, protein C deficiency, protein S deficiency, hyperhomocysteinemia and antiphospholipid-antibodies (anticardiolipin-antibodies, lupus anticoagulant).

·      Pancreatitis or a history thereof if associated with severe hypertriglyceridemia.

·      Presence or history of severe hepatic disease as long as liver function values have not returned to normal.

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

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

·      Undiagnosed vaginal bleeding.

·      History of migraine with focal neurological symptoms.

·      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 anti-coagulant therapy is started, adequate alternative contraception should be initiated because of the teratogenicity of anticoagulant therapy (coumarins).

If any of the conditions/risk factors mentioned below are 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 taking 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 whether COC use should be discontinued.

No epidemiological studies on the effects of estradiol/ estradiol valerate containing COC’s exist. All the following warnings and precautions are derived from clinical and epidemiological data of ethinyl estradiol containing COCs. Whether these warning and precautions apply to Qlaira is unknown.

·         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. It is not yet known how the risk with Qlaira compares with these lower risk products. The decision to use any product other 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 6[1] will develop a VTE in one year.

It is not yet known how the risk of VTE with CHCs that contain dienogest in combination with estradiol compares with the risk with low dose levonorgestrel-containing CHCs.

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.

·        Circulatory Disorders

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 woman-years, but this risk estimate varies according to the progestogen. This compares with 5 to 10 cases per 100,000 woman-years for non-users.

The use of any combined oral contraceptive (COC; including Qlaira) 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.

The incidence of VTE associated with pregnancy is estimated as 60 cases per 100,000 pregnancies. VTE is fatal in 1-2% of cases.

The risk of VTE during use of Qlaira is currently unknown.

Epidemiological studies have also associated the use of ethinylestradiol containing COCs with an increased risk for arterial (myocardial infarction, transient ischaemic attack) thromboembolism.

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

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

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

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.

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

unilateral leg pain and/ or swelling;

sudden severe pain in the chest, whether or not it radiates to the left arm;

sudden breathlessness;

sudden onset of coughing;

any unusual, severe, prolonged headache;

sudden partial or complete loss of vision;

diplopia;

slurred speech or aphasia;

vertigo;

collapse with or without focal seizure;

weakness or very marked numbness suddenly affecting one side or one part of the body; motor disturbances;

”acute” abdomen.

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

increasing age

a positive family history (venous thromboembolism ever in a sibling or parent at 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 resume until two weeks after complete remobilisation. Antithrombotic treatment should be considered if the pills have not been discontinued in advance.

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 events or of a cerebrovascular accident increases with:

-        increasing age;

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

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

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

-        dyslipoproteinaemia;

-        hypertension;

-        migraine;

-        valvular heart disease;

-        atrial fibrillation;

The presence of one serious risk factor or multiple risk factors for venous or arterial disease, respectively, can also constitute a contra-indication. The possibility of anticoagulant therapy should also be taken into account. COC users should be specifically pointed out to contact their physician in case of possible symptoms of thrombosis. In case of suspected or confirmed thrombosis, COC use should be discontinued. Adequate alternative contraception should be initiated because of the teratogenicity of anticoagulant therapy (coumarins).

The increased risk of venous thromboembolism in the puerperium must be considered (for information on “Pregnancy and Lactation” see section ).

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

An increase in 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.

…

Medical examination/consultation

Prior to the initiation or reinstitution of Qlaira a A complete medical history (including family history) and physical examination should be taken prior to the initiation or reinstitution of COC use 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 bookletleaflet 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 oralhormonal contraceptives do not protect against HIV infections (AIDS) and other sexually transmitted diseases.

4.6   Fertility, pregnancy and lactation

Pregnancy

Qlaira should not be used during pregnancy.

If pregnancy occurs during use of Qlaira, further intake should 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.

4.8   Undesirable effects

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.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via HPRA Pharmacovigilance, Earlsfort Terrace, IRL – Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517. Website: www.hpra.ie; E-mail: medsafety@hpra.ie.  

10    DATE OF REVISION OF THE TEXT

September 2014

For a the full list of excipients, see section 6.1.

1.1              Fertility, Ppregnancy and lactation

Pregnancy

Qlaira should not be used during pregnancy.

If pregnancy occurs during use of Qlaira, further intake should 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).

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.

In the adverse effects table in section 4.8 (Undesirable effects) venous thromboembolism has been added as a rare side effect.


In section 5.1 (Pharmacodynamic effects) the ATC code has been changed from G03Ab to G03AB08

The following text has also been added:

In a 3-cycle ovulation inhibition study treatment with Qlaira lead to suppression of follicular development in the majority of women. Ovarian activity returned to pre-treatment levels during the post-treatment cycle.

The date of revision has been changed to October 2013

In Section 4.4 - Warnings - Circulatory Disorders the following highlighted changes were made:


The use of any combined oral contraceptive (COC; including Qlaira) 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.  

Sections  Updated:

Section 4.1: Therapeutic indications

New Indication:

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

Section 5.1 :Pharmacodynamic properties

Additional Information:

Qlaira is dosed using an estrogen step-down and a progestin step-up regimen that can be used to treat heavy menstrual bleeding in the absence of an organic pathology, symptoms sometimes referred to as dysfunctional uterine bleeding (DUB).

Two multicenter, double blind randomised studies of similar design were performed to evaluate the efficacy and safety of Qlaira in women with symptoms of DUB who desired oral contraception. In total, 269 women were randomised on Qlaira and 152 patients on placebo.

After 6 months of treatment the median menstrual blood loss (MBL) was decreased by
88% from 142 mL to 17 mL in the Qlaira group compared to 24% from 154 mL to
117 mL in the placebo group.

After 6 months of treatment, the proportion of women who were completely cured from any DUB symptom was 29% in the Qlaira group compared to 2% in the placebo group.

10.0  DATE OF REVISION OF THE TEXT

Updated:

October 2010

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