Qlaira 3 mg FC tablets

Oral contraception.

Combined oral contraceptives, when taken correctly, have a failure rate of approximately 1 % per year. The failure rate may increase when pills are missed or taken incorrectly.

How to start QLAIRA:

• No preceding hormonal contraceptive use (in the past month)
  Tablet-taking has to start on day 1 of the womanu2019s natural cycle (i.e. the first day of her menstrual bleeding).
• When changing over from another 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. If 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 (minipill, injection, implant) or from a progestogen-releasing intrauterine system (IUS)
  The woman may switch any day from the minipill (from an implant or the IUS on the day of its removal, from an injectable when the next injection would be due), but should in all of these cases be advised to additionally use a barrier method for the first 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 u201cPregnancy and lactationu201d. 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 QLAIRA 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 intervals. If she is more than 12 hours late in taking any tablet, contraceptive protection may be reduced. The woman should take the last missed tablet as soon as she remembers, even if this means taking two tablets at the same time. She then continues to take tablets at her usual time. Depending on the day of the cycle on which the tablet has been missed, back-up contraceptive measures (e.g. a barrier method such as a condom) have to be used according to the following principles. Not more than two tablets are to be taken on a given day.

QLAIRA should not be used in the presence of any of the conditions listed below. Should any of the conditions appear for the first time during QLAIRA use, the product should be stopped immediately.

• Presence or a history of venous or arterial thrombotic/thromboembolic events (e.g. deep venous thrombosis, pulmonary embolism, myocardial infarction) or of a cerebrovascular accident.
• Presence or history of prodromal signs of thrombosis (e.g. transient ischaemic attack, angina pectoris).
• History of migraine with focal neurological symptoms.
• Diabetes mellitus with vascular involvement.
• Presence of severe or multiple risk factor(s) for venous or arterial thrombosis.
• Pancreatitis or a history thereof if associated with severe hypertriglyceridaemia.
• Presence or history of 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) or a family history thereof.
• Undiagnosed vaginal bleeding.
• Known or suspected pregnancy.
• Hypersensitivity to the active substances or to any of the excipients.

If any of the conditions/risk factors mentioned below are present, the benefits of QLAIRA use should be weighed against the possible risks for each individual woman and discussed with her 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 doctor. The doctor should then decide whether QLAIRA use should be discontinued.

No epidemiological studies on the effects of oestradiol/oestradiol valerate containing COCs exist. All the following warnings and precautions are derived from clinical and epidemiological data of ethinylestradiol. Whether these warnings and precautions apply to QLAIRA is unknown.

Circulatory disorders:
Epidemiological studies have suggested an association between the use of ethinylestradiol containing COCs and an increased risk of arterial and venous thrombotic and thromboembolic diseases such as myocardial infarction, stroke, deep venous thrombosis, and pulmonary embolism. Venous thromboembolism (VTE), manifesting as deep venous thrombosis and/or pulmonary embolism, may occur during the use of QLAIRA. The risk for venous thromboembolism is highest during the first year a woman ever uses QLAIRA. The approximate incidence of VTE in users of low oestrogen dose (< 0.05 mg ethinylestradiol) OCs is up to 4 per 10 000 woman years compared to 0.5 to 3 per 10 000 woman years in non-OC users. The incidence of VTE associated with pregnancy is 6 per 10 000 pregnant woman years. Thrombosis has been reported to occur in other blood vessels, e.g. hepatic, mesenteric, renal, cerebral or retinal veins and arteries, in COC users. There is no consensus as to whether the occurrence of these events is associated with the use of QLAIRA.

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; u201cacuteu201d abdomen.

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

• age;
• smoking (with heavier smoking and increasing age the risk further increases, especially in women over 35 years of age);
• a positive family history (i.e. venous or 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 QLAIRA use;
• obesity (body mass index over 30 kg/m2);
• dyslipoproteinaemia;
• hypertension;
• migraine;
• valvular heart disease;
• atrial fibrillation;
• prolonged immobilisation, major surgery, any surgery to the legs, or major trauma.

In these situations it is advisable to discontinue QLAIRA use (in the case of elective surgery at least four weeks in advance) and not to resume until two weeks after complete remobilisation. There is no consensus about the possible role of varicose veins and superficial thrombophlebitis in venous thromboembolism. An increased risk of thromboembolism in the puerperium must be considered (see u201cPregnancy and lactationu201d). Other medical conditions which have been associated with adverse circulatory events include diabetes mellitus, systemic lupus erythematosus, haemolytic uraemic syndrome, chronic inflammatory bowel disease (Crohn's disease or ulcerative colitis) and sickle cell disease. An increase in frequency or severity of migraine during QLAIRA use (which may be prodromal of a cerebrovascular event) may be a reason for immediate discontinuation of QLAIRA. Biochemical factors that may be indicative of hereditary or acquired predisposition for venous or arterial thrombosis include Activated Protein C (APC) resistance, hyperhomocysteinaemia, antithrombin-III deficiency, protein C deficiency, protein S deficiency, antiphospholipid antibodies (anticardiolipin antibodies, lupus anticoagulant). When considering risk/benefit, the doctor should take into account that adequate treatment of a condition may reduce the associated risk of thrombosis and that the risk associated with pregnancy is higher than that associated with low-dose COCs (< 0.05 mg ethinylestradiol).

Tumours:
The most important risk factor for cervical cancer is persistent HPV infection. Some epidemiological studies have indicated that long-term use of COCs may further contribute to this increased risk. A meta-analysis from 54 epidemiological studies reported that there is a slightly increased relative risk (RR=1.24) of having breast cancer diagnosed in women who are currently using COCs. The excess risk gradually disappears during the course of the 10 years after cessation of COC use. Because breast cancer is rare in women under 40 years of age, the excess number of breast cancer diagnoses in current and recent COC users is small in relation to the overall risk of breast cancer. These studies do not provide evidence for causation. The observed pattern of increased risk may be due to an earlier diagnosis of breast cancer in COC users, the biological effects of COCs or a combination of both. The breast cancers diagnosed in ever-users tend to be less advanced clinically than the cancers diagnosed in never-users. In rare cases, benign liver tumours, and even more rarely, malignant liver tumours have been reported in users of COCs. In isolated cases, these tumours have led to life-threatening intra-abdominal haemorrhages. A hepatic tumour should be considered in the differential diagnosis when severe upper abdominal pain, liver enlargement or signs of intra-abdominal haemorrhage occur in women taking QLAIRA.

Other conditions:
Women with hypertriglyceridaemia, or a family history thereof, may be at an increased risk of pancreatitis when using QLAIRA. Increases in blood pressure have been reported in many women taking COCs. If a sustained clinically significant hypertension develops during the use of QLAIRA then it is prudent for the doctor to withdraw QLAIRA and treat the hypertension. Where considered appropriate, QLAIRA 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: jaundice and/or pruritus related to cholestasis; gallstone formation; porphyria; systemic lupus erythematosus; haemolytic uraemic syndrome; Sydenhamu2019s chorea; gestational herpes; otosclerosis-related hearing loss. In women with hereditary angioedema exogenous oestrogens may induce or exacerbate symptoms of angioedema. Acute or chronic disturbances of liver function may necessitate the discontinuation of QLAIRA 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 QLAIRA. 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 QLAIRA. Crohnu2019s disease and ulcerative colitis have been associated with QLAIRA 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 QLAIRA.

Medical examination/consultation:
A complete medical history and physical examination should be taken prior to the initiation or reinstitution of QLAIRA use, guided by the u201cContra-indicationsu201d and u201cWarningsu201d and it should be repeated periodically. Periodic medical assessment is also of importance because contra-indications (e.g. a transient ischaemic attack) or risk factors (e.g. a family history of venous or arterial thrombosis) may appear for the first time during the use of QLAIRA. The frequency and nature of these assessments should be based on established practice guidelines and be adapted to the individual woman but should generally include special reference to blood pressure, breasts, abdomen and pelvic organs, including cervical cytology. Women should be advised that oral contraceptives do not protect against HIV infections (AIDS) and other sexually transmitted diseases.

Interaction studies have only been performed in adults. Interactions of other medicinal products with QLAIRA: Interactions between oral contraceptives and other medicines 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.

Hepatic metabolism:
Interactions can occur with medicines (e.g. phenytoin, barbiturates, primidone, carbamazepine, rifampicin, and possibly oxcarbazepine, topiramate, felbamate, griseofulvin and products containing St. Johnu2019s wort) that induce microsomal enzymes (e.g. cytochrome P450 enzymes) which can result in increased clearance of sex hormones. HIV protease (e.g. ritonavir) and non-nucleoside reverse transcriptase inhibitors (e.g. nevirapine), and combinations of them, have also been reported to potentially affect hepatic metabolism. Dienogest in QLAIRA, is a substrate of cytochrome P450 (CYP) 3A4. The effect of the CYP3A4 inducer rifampicin was studied in healthy postmenopausal women. Co-administration of rifampicin with QLAIRA led to significant decreases in steady-state concentrations and systemic exposures of dienogest and oestradiol. The systemic exposure of dienogest and oestradiol at steady-state, measured by AUC (0-24 hours), were decreased by 83 % and 44 %, respectively. Known CYP3A4 inhibitors e.g. azole antifungals, cimetidine, verapamil, macrolides, diltiazem, antidepressants and grapefruit juice may increase plasma levels of dienogest. In a study investigating the effect of CYP3A4 inhibitors (ketoconazole, erythromycin), steady-state dienogest and oestradiol plasma levels were increased. Co-administration with the strong inhibitor ketoconazole resulted in a 186 % increase of AUC (0-24 hours) at steady-state for dienogest and a 57 % increase for oestradiol. When co-administered with the moderate inhibitor erythromycin, the AUC (0-24 hours) of dienogest and oestradiol at steady-state were increased by 62 % and 33 %, respectively.

Interference with enterohepatic circulation:
Enterohepatic circulation of oestrogens may decrease when certain antibiotic agents are given which may reduce oestradiol concentrations (e.g. penicillins, tetracyclines). Women on treatment with microsomal enzyme-inducing medicines or with antibiotics should temporarily use a barrier method in addition to QLAIRA or choose another method of contraception. The barrier method should be used during the time of concomitant medicine administration and for 28 days after its discontinuation.

Interactions of QLAIRA with other medicinal products:
Oral contraceptives may affect the metabolism of certain other medicines (e.g. lamotrigine) and may result in either increased or decreased plasma and tissue concentrations. However, based on the in vitro data, inhibition of CYP enzymes by QLAIRA is unlikely at the therapeutic dose.

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.

QLAIRA is contra-indicated in pregnancy. If pregnancy occurs during use of QLAIRA, further intake should be stopped. Lactation may be influenced by QLAIRA as it may reduce the quantity and change the composition of breast milk. The use of QLAIRA should 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.

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

The table below reports adverse reactions (ARs) by MedDRA system organ classes (MedDRA SOCs). The frequencies are based on clinical trial data. The adverse reactions were recorded in 2 phase III clinical studies (N=1776 women at risk for pregnancy) and considered at least possibly causally related to QLAIRA use.

System organ class

• Common ( u2265 1/100 to 1/10)
  • Infections and infestations: Vaginal candidiasis (0.2 %)
• Uncommon ( u2265 1/1000 to < 1/100)
  • Neoplasms benign, malignant and unspecified (incl. cysts and polyps): Uterine leiomyoma (0.3 %)
• Rare ( u2265 1/10 000 to < 1/1 000)
  • Metabolism and nutrition disorders: Increased appetite

Psychiatric disorders: Depression/depressed mood (0.8 %), Mood changes (0.3 %), Decreased libido (0.6 %), Mental disorder (0.2 %), Sleep disorder (0.1 %), Aggression, Increased libido, Nervousness, Restlessness

Nervous system disorders: Headache (1.9 %), Migraine (0.5 %), Disturbance in attention, Migraine with aura, Tension headache

Eye disorders: Contact lens intolerance

Vascular disorders: Hypertension (0.3 %), Hot flush, Hypotension, Vein pain

Gastrointestinal disorders: Abdominal pain (0.5 %), Nausea (0.5 %), Abdominal distension, Diarrhoea, Vomiting

Hepato-biliary disorders: Increased alanine aminotransferase (0.1 %)

Skin and subcutaneous tissue disorders: Acne (2.3 %), Alopecia (0.8 %), Chloasma, Allergic dermatitis, Hirsutism, Neurodermatitis, Pigmentation disorder (pigmented spots on face), Generalised pruritus, Pruritic rash, Seborrhoea, Skin disorder including skin tightness, Urticaria

Musculoskeletal, connective tissue and bone disorders: Muscle spasms, Sensation of heaviness

Reproductive system and breast disorders: Breast pain (3.5 %), Breast discomfort (1.2 %), Metrorrhagia (1.5 %), Breast enlargement (0.3 %), Fibrocystic breast disease (0.3 %), Vaginal discharge (0.1 %), Amenorrhoea (0.1 %), Dysmenorrhoea (0.8 %), Menstrual disorder (0.2 %), Menorrhagia (0.2 %), Premenstrual syndrome (0.2 %), Cervical dysplasia (0.3 %), Ovarian cyst (0.3 %), Breast cyst, Genital haemorrhage, Hypomenorrhoea, Irregular menstruation, Pelvic pain, Vulvovaginal dryness

General disorders and administrative site conditions: Irritability (0.2 %), Malaise (0.1 %), Oedema (0.2 %)

Investigations: Weight increased (1.3 %), Weight decreased (0.2 %)

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

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.