- 1. Name of the medicinal product
- 2. Qualitative and quantitative composition
- 3. Pharmaceutical form
- 4. Clinical particulars
- 4.1 Therapeutic indications
- 4.2 Posology and method of administration
- 4.3 Contraindications
- 4.4 Special warnings and precautions for use
- 4.5 Interaction with other medicinal products and other forms of interaction
- 4.6 Fertility, pregnancy and lactation
- 4.7 Effects on ability to drive and use machines
- 4.8 Undesirable effects
- 4.9 Overdose
- 5. Pharmacological properties
- 5.1 Pharmacodynamic properties
- 5.2 Pharmacokinetic properties
- 5.3 Preclinical safety data
- 6. Pharmaceutical particulars
- 6.1 List of excipients
- 6.2 Incompatibilities
- 6.3 Shelf life
- 6.4 Special precautions for storage
- 6.5 Nature and contents of container
- 6.6 Special precautions for disposal and other handling
- 7. Marketing authorisation holder
- 8. Marketing authorisation number(s)
- 9. Date of first authorisation/renewal of the authorisation
- 10. Date of revision of the text
How to take QlairaTablets 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 patchThe 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 tabletsMissed (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. 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 (see chart below for details), back-up contraceptive measures (e.g. a barrier method such as a condom) have to be used according to the following principles:
|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 missed tablet immediately and the following tablet as usual (even if this means taking two tablets on the same day) - Continue with tablet-taking in the normal way - 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)||- Discard current wallet, and start immediately with the first pill of a new wallet - Continue with tablet-taking in the normal way - Back-up contraception for the next 9 days|
|25 26||Dark red tablets (1.0 mg EV)||- Take missed tablet immediately and the following tablet as usual (even if this means taking two tablets on the same day) - No back-up contraception necessary|
|27-28||White tablets(Placebos)||- Discard missed tablet and continue tablet-taking in the normal way - No back-up contraception necessary|
Paediatric populationNo data available for use in adolescents below 18 years.
Advice in case of gastro-intestinal disturbancesIn 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.
|• diabetes mellitus with vascular symptoms|
|• severe hypertension|
|• severe dyslipoproteinemia|
WarningsIf 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 DisordersEpidemiological 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 other blood vessels, e.g. hepatic, mesenteric, renal, cerebral or retinal veins and arteries, in COC users. There is no consensus as to whether the occurrence of these events is associated with the use of COCs.Symptoms of venous or arterial thrombotic/thromboembolic events or of a cerebrovascular accident can include:• 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 4.6).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.• TumoursAn 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.• Other conditionsWomen 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.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. 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.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, the Lapp lactase deficiency or glucose-galactose malabsorption who are on a lactose-free diet should take this amount into consideration.
Medical examination/consultationA 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). The woman should also be instructed to carefully read the user booklet 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 oral contraceptives do not protect against HIV infections (AIDS) and other sexually transmitted diseases.
Reduced efficacyThe 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 controlWith 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.
PregnancyQlaira 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).
BreastfeedingLactation 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.
FertilityQlaira is indicated for the prevention of pregnancy. For information on return to fertility, see section 5.1.
|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 infection1Vaginal 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 disorder2Insomnia Libido decreased3Mental 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 Hypotension Phlebitis superficialis Vein pain|
|Gastrointestinal disorders||Abdominal pain7Nausea||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 Pruritus10Rash11||Allergic skin reaction12Chloasma 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 discomfort14Dysmenorrhoea Intracyclic bleeding (Metrorrhagia)15||Breast enlargement16Breast 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. spotting17Vaginal 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|
AbsorptionOrally administered dienogest is rapidly and almost completely absorbed. Maximal serum concentrations of 90.5ng/ml are reached at about 1 hour after oral administration of the Qlaira tablet containing 2 mg estradiol valerate + 3 mg dienogest. Bioavailability is about 91 %. The pharmacokinetics of dienogest is dose-proportional within the dose range of 1 8 mg. Concomitant food intake has no clinically relevant effect on the rate and extent of dienogest absorption.
DistributionA relatively high fraction of 10% of circulating dienogest is present in the free form, with approx. 90% being bound non-specifically to albumin. Dienogest does not bind to the specific transport proteins SHBG and CBG. The volume of distribution at steady state (Vd,ss) of dienogest is 46 l after the intravenous administration of 85 µg 3H-dienogest.
MetabolismDienogest 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.
EliminationThe plasma half-life of dienogest is approximately 11 hours. Dienogest is extensively metabolized and only 1% of drug is excreted unchanged. The ratio of urinary to fecal excretion is about 3:1 after oral administration of 0.1 mg/kg. Following oral administration, 42% of the dose is eliminated within the first 24 h and 63% within 6 days by renal excretion. A combined 86% of the dose is excreted by urine and feces after 6 days.
Steady-State ConditionsPharmacokinetics of dienogest are not influenced by SHBG levels. Steady state is reached after 3 days of the same dosage of 3 mg dienogest in combination with 2 mg estradiol valerate. Trough, maximum and average dienogest serum concentrations at steady state are 11.8 ng/ml, 82.9 ng/ml and 33.7 ng/ml, respectively. The mean accumulation ratio for AUC (0-24h) was determined to be 1.24.• Estradiol valerate
AbsorptionAfter oral administration estradiol valerate is completely absorbed. Cleavage to estradiol and valeric acid takes place during absorption by the intestinal mucosa or in the course of the first liver passage. This gives rise to estradiol and its metabolites estrone and estriol. Maximal serum estradiol concentrations of 70.6 pg/ml are reached between 1.5 and 12 hours after single ingestion of the tablet containing 3 mg estradiol valerate on Day 1.
MetabolismThe 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.
DistributionIn serum 38 % of estradiol is bound to SHBG, 60 % to albumin and 2-3 % circulate in free form. Estradiol can slightly induce the serum concentrations of SHBG in a dose-dependent manner. On day 21 of the treatment cycle, SHBG was approximately 148% of the baseline, it decreased to about 141% of the baseline by day 28 (end of placebo phase). An apparent volume of distribution of approximately 1.2 l/kg was determined after iv. administration.
EliminationThe plasma half-life of circulating estradiol is about 90 min. After oral administration, however, the situation differs. Because of the large circulating pool of estrogen sulfates and glucuronides, as well as enterohepatic recirculation, the terminal half-life of estradiol after oral administration represents a composite parameter which is dependent on all of these processes and is in the range of about 13-20 h. Estradiol and its metabolites are mainly excreted in urine, with about 10% being excreted in the stool.
Steady-state conditionsPharmacokinetics of estradiol are influenced by SHBG levels. In young women, the measured estradiol plasma levels are a composite of the endogenous estradiol and the estradiol generated from Qlaira. During the treatment phase of 2 mg estradiol valerate + 3 mg dienogest, maximum and average estradiol serum concentrations at steady state are 66.0 pg/ml and 51.6 pg/ml, respectively. Throughout the 28 day cycle, stable minimum estradiol concentrations were maintained and ranged from 28.7 pg/ml to 64.7 pg/ml.
Special PopulationsPharmacokinetics of Qlaira was not investigated in patients with impaired renal or liver function.
|Active film-coated tablets||Placebo (inactive) film-coated tablet|
|Lactose monohydrate Maize starch Pregelatinized maize starch Povidone K25 (E1201) Magnesium stearate (E572)||Lactose monohydrate Maize starch Povidone K25 (E1201) Magnesium stearate (E572)|
|Hypromellose type 2910 (E464) Macrogol 6000 Talc (E553b) Titanium dioxide (E171) Iron oxide red (E172) and/or Iron oxide yellow (E172)||Hypromellose type 2910 (E464) Talc (E553b) Titanium dioxide (E171)|
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