Estradiol valerate, dienogest.
26 hormone-containing film-coated tablets 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 hormone-free white film-coated tablets.
Excipients/Inactive Ingredients: Yellow ferric oxide pigment (E172, C.I. 77 492), red ferric oxide pigment (E172, C.I. 77 491), hypromellose, lactose monohydrate, macrogol 6000, magnesium stearate, maize starch, pregelatinized maize starch, povidone 25, talc, titanium dioxide (E171, C.I. 77891).
ATC Code: G03A.
Pharmacology: Pharmacodynamics: The contraceptive effect of COCs is based on the interaction of various factors, the most important of which are seen as the inhibition of ovulation and the changes in the cervical secretion.
Pharmacokinetics: Dienogest: Absorption: Orally administered dienogest is rapidly and almost completely absorbed. Maximal serum concentrations of 90.5 ng/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 are dose-proportional within the dose range of 1-8 mg.
Distribution: A 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 sex hormone-binding globulin (SHBG) and corticosteroid-binding globulin (CBG). There is therefore no possibility of testosterone being displaced from its SHBG-binding or cortisol from its CBG-binding. Any influence on physiological transport processes for endogenous steroids is consequently unlikely. The volume of distribution at steady state (Vd,ss) of dienogest is 46 l after the intravenous administration of 85 μg 3H-dienogest.
Metabolism: Dienogest is nearly completely metabolized by the known pathways of steroid metabolism (hydroxylation, conjugation) with the formation of endocrinologically mostly inactive metabolites. The metabolites are excreted very quickly so that in plasma unchanged dienogest is the dominating fraction.
The total clearance following the intravenous administration of 3H-dienogest was calculated as 5.1 l/h.
Elimination: The plasma half-life of dienogest is approximately 11 hours. Dienogest is excreted in the form of metabolites which are excreted at a urinary to fecal ratio of 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 Conditions: Pharmacokinetics 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: Absorption: After 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.
Metabolism: 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.
Distribution: In 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, and 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.
Elimination: The 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 conditions: Pharmacokinetics 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.
Toxicology: Preclinical safety data: Preclinical data reveal no special risks for humans based on conventional studies of repeated dose toxicity, genotoxicity, carcinogenic potential and toxicity to reproduction. However, it should be borne in mind that sex steroids can promote the growth of certain hormone-dependent tissues and tumors.
Oral contraception.
Treatment of heavy and/or prolonged menstrual bleeding in women without organic pathology who elect to use oral contraception.
Method of administration: Oral use.
Dosage regimen: How to take Qlaira: 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.
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 calendar pack.
How to start Qlaira: Tablet-taking has to start on day 1 of the woman's natural cycle (i.e. the first day of her menstrual bleeding).
Management of missed tablets: Missed hormone-free white film-coated tablets can be disregarded. However, they should be discarded to avoid unintentionally prolonging the hormone-free white tablet phase.
The following advice only refers to missed hormone-containing tablets: If the user is less than 12 hours late in taking any active 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 active tablet, contraceptive protection may be reduced. The user 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 as follows for details), back-up contraceptive measures (e.g. a barrier method such as a condom) have to be used according to the following principles: See Table 1.
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Not more than two tablets are to be taken on a given day.
If a woman has forgotten to start a new calendar pack, or if she has missed one or more tablets during days 3-9 of the calendar pack, she may already be pregnant (provided she has had intercourse in the 7 days before the oversight). The more tablets (especially those with the two combined hormones on days 3-24) are missed and the closer they are to the hormone-free 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 calendar pack/beginning of new calendar pack, the possibility of a pregnancy should be considered.
Advice in case of gastro-intestinal disturbances: In case of severe gastro-intestinal disturbances, absorption may not be complete and additional contraceptive measures should be taken.
If vomiting occurs within 3-4 hours after taking a hormone-containing tablet, the advice concerning missed tablets, as given in 'Management of missed tablets' as previously mentioned, is applicable.
Additional information on special populations: Children and adolescents: Qlaira is only indicated after menarche.
Geriatric patients: Not applicable. Qlaira is not indicated after menopause.
Patients with hepatic impairment: Qlaira is contraindicated in women with severe hepatic diseases. See also 'Contraindications'.
Patients with renal impairment: Qlaira has not been specifically studied in renally impaired patients. Available data do not suggest a change in treatment in this patient population.
There have been no reports of serious deleterious effects from overdose. Symptoms that may occur in case of taking an overdose of hormone-containing film-coated tablets are: nausea, vomiting and, in young girls, slight vaginal bleeding. There are no antidotes and further treatment should be symptomatic.
Combined oral contraceptives (COCs) should not be used in the presence of any of the conditions listed as follows. Should any of the conditions appear for the first time during COC 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 prodromi of a thrombosis (e.g. transient ischaemic attack, angina pectoris); A high risk of venous or arterial thrombosis (see 'Precautions'); History of migraine with focal neurological symptoms; Diabetes mellitus with vascular involvement; Severe hepatic disease as long as liver function values have not returned to normal; Presence or history of liver tumors (benign or malignant); Known or suspected sex-steroid influenced malignancies (e.g. of the genital organs or the breasts); Undiagnosed vaginal bleeding; Known or suspected pregnancy; Hypersensitivity to the active substances or to any of the excipients.
Warnings: The following warnings and precautions are derived from clinical and epidemiological data of ethinylestradiol containing COCs.
Circulatory disorders: Epidemiological studies have suggested an association between the use of EE-containing COCs and an increased risk of arterial and venous thrombotic and thromboembolic diseases such as myocardial infarction, deep venous thrombosis, pulmonary embolism and of cerebrovascular accidents. These events occur rarely.
The risk of VTE is highest during the first year of use. This increased risk is present after initially starting a COC or restarting (following a 4 week or greater pill free interval) the same or a different COC. Data from a large, prospective 3-armed cohort study suggest that this increased risk is mainly present during the first 3 months.
Overall the risk for venous thromboembolism (VTE) in users of low estrogen dose (<50 μg ethinylestradiol) COCs is two to threefold higher than for non-users of COCs who are not pregnant and remains lower than the risk associated with pregnancy and delivery.
VTE may be life-threatening, or may have a fatal outcome (in 1-2% of the cases).
Venous thromboembolism (VTE), manifesting as deep venous thrombosis and/or pulmonary embolism, may occur during the use of all COCs.
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.
Symptoms of deep venous thrombosis (DVT) can include: unilateral swelling of the leg or along a vein in the leg; pain or tenderness in the leg which may be felt only when standing or walking, increased warmth in the affected leg; red or discolored skin on the leg.
Symptoms of pulmonary embolism (PE) can include: sudden onset of unexplained shortness of breath or rapid breathing; sudden coughing which may bring up blood; sharp chest pain which may increase with deep breathing; sense of anxiety; severe light headedness or dizziness; rapid or irregular heartbeat. Some of these symptoms (e.g. "shortness of breath", "coughing') are non-specific and might be misinterpreted as more common or less severe events (e.g. respiratory tract infections).
An arterial thromboembolic event can include cerebrovascular accident, vascular occlusion or myocardial infarction (MI). Symptoms of a cerebrovascular accident can include: sudden numbness or weakness of the face, arm or leg, especially on one side of the body; sudden confusion, trouble speaking or understanding; sudden trouble seeing in one or both eyes; sudden trouble walking, dizziness, loss of balance or coordination; sudden, severe or prolonged headache with no known cause; loss of consciousness or fainting with or without seizure. Other signs of vascular occlusion can include: sudden pain, swelling and slight blue discoloration of an extremity; acute abdomen.
Symptoms of MI can include: pain, discomfort, pressure, heaviness, sensation of squeezing or fullness in the chest, arm, or below the breastbone; discomfort radiating to the back, jaw, throat, arm, stomach; fullness, indigestion or choking feeling; sweating, nausea, vomiting or dizziness; extreme weakness, anxiety, or shortness of breath; rapid or irregular heartbeats.
Arterial thromboembolic events may be life-threatening or may have a fatal outcome.
The potential for an increased synergistic risk of thrombosis should be considered in women who possess a combination of risk factors or exhibit a greater severity of an individual risk factor. This increased risk may be greater than a simple cumulative risk of the factors. A COC should not be prescribed in case of a negative risk benefit assessment (see 'Contraindications').
The risk of venous or arterial thrombotic/thromboembolic events or of a cerebrovascular accident increases with: age; obesity (body mass index over 30 kg/m2); 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 known or suspected, the woman should be referred to a specialist for advice before deciding about any COC use; prolonged immobilization, major surgery, any surgery to the legs, or major trauma. In these situations it is advisable to discontinue COC use (in the case of elective surgery at least four weeks in advance) and not to resume until two weeks after complete remobilization; smoking (with heavier smoking and increasing age the risk further increases, especially in women over 35 years of age); dyslipoproteinemia; hypertension; migraine; valvular heart disease; atrial fibrillation.
There is no consensus about the possible role of varicose veins and superficial thrombophlebitis in venous thromboembolism.
The increased risk of thromboembolism in the puerperium must be considered (for information on pregnancy and lactation see 'Use in Pregnancy & Lactation').
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.
Biochemical factors that may be indicative of hereditary or acquired predisposition for venous or arterial thrombosis include Activated Protein C (APC) resistance, hyperhomocysteinemia, antithrombin-III deficiency, protein C deficiency, protein S deficiency, antiphospholipid antibodies (anticardiolipin antibodies, lupus anticoagulant).
When considering risk/benefit, the physician 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).
Tumors: 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 but there continues to be controversy about the extent to which this finding is attributable to confounding effects, e.g., cervical screening and sexual behaviour including use of barrier contraceptives.
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 tumors, and even more rarely, malignant liver tumors have been reported in users of COCs. In isolated cases, these tumors have led to life-threatening intra-abdominal hemorrhages. A liver tumor 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.
Malignancies may be life-threatening or may have a fatal outcome.
Other conditions: Women with hypertriglyceridemia, 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.
Crohn's disease and ulcerative colitis have been associated with 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.
Medical examination/consultation: Women should be advised that oral contraceptives do not protect against HIV infections (AIDS) and other sexually transmitted diseases.
Reduced efficacy: The efficacy of COCs may be reduced in the event of e.g. missed hormone-containing film-coated tablets (see 'Management of missed tablets' under Dosage & Administration), gastro-intestinal disturbances (see 'Advice in case of gastro-intestinal disturbances' under Dosage & Administration) during hormone-containing film-coated tablet taking or concomitant medication (see 'Interactions').
Cycle control: With all COCs, irregular bleeding (spotting or breakthrough bleeding) may occur, especially during the first months of use.
In some women withdrawal bleeding may not occur during the hormone-free white film-coated tablet phase. If the COC has been taken according to the directions described in 'Dosage & Administration' it is unlikely that the woman is pregnant. However, if the COC has not been taken according to these directions prior to the first missed withdrawal bleed or if two withdrawal bleeds are missed, pregnancy must be ruled out before COC use is continued.
Effects on ability to drive or 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.
Pregnancy: Qlaira is not indicated during pregnancy. If pregnancy occurs during use of Qlaira, further intake must be stopped. However, extensive epidemiological studies with EE-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 early pregnancy.
Lactation: 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.
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 and/or prolonged menstrual bleeding in women without organic pathology who elect to use oral contraception are nausea, breast pain, and unscheduled uterine bleeding. They occur in >2% of users.
Serious adverse reactions are arterial and venous thromboembolism.
Tabulated list of adverse reactions: The frequencies of adverse drug reactions (ADRs) reported in clinical Phase 2 and 3 studies with Qlaira as an oral contraceptive (N=2423) and in the treatment of heavy and/or prolonged menstrual bleeding in women without organic pathology who elect to use oral contraception (N=264) are summarized in the table as follows by MedDRA system organ classes (MedDRA SOCs). Within each frequency grouping, undesirable effects are presented in order of decreasing frequency. Frequencies are defined as common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), and rare (≥1/10,000 to <1/1,000). (See Table 2.)
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Description of selected adverse reactions: Adverse reactions with very low frequency or with delayed onset of symptoms which are considered to be related to the group of combined oral contraceptives are listed as follows (see also "Contraindications" and "Precautions"):
Tumors: The frequency of diagnosis of breast cancer is very slightly increased among OC 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.
Liver tumors (benign and malignant).
Other conditions: Erythema nodosum, Erythema multiforme; Breast discharge; Women with hypertriglyceridemia (increased risk of pancreatitis when using COCs); Hypertension; Occurrence or deterioration of conditions for which association with COC use is not conclusive: 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; Liver function disturbances; Changes in glucose tolerance or effect on peripheral insulin resistance; Crohn's disease, ulcerative colitis; 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 "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 may lead to breakthrough bleeding and/or contraceptive failure.
Women on treatment with any of these drugs should temporarily use a barrier method in addition to the COC or choose another method of contraception. The barrier method should be used during the time of concomitant drug administration and for 28 days after their discontinuation.
Substances increasing the clearance of COCs (diminished efficacy of COCs by enzyme-induction), e.g.: Phenytoin, barbiturates, primidone, carbamazepine, rifampicin, and possibly also oxcarbazepine, topiramate, felbamate, griseofulvin and products containing St. John's wort.
Substances with variable effects on the clearance of COCs, e.g.: When co-administered with COCs, many HIV/HCV protease inhibitors and non-nucleoside reverse transcriptase inhibitors can increase or decrease plasma concentrations of estrogen or progestin. These changes may be clinically relevant in some cases.
Substances decreasing the clearance of COCs (enzyme inhibitors): Dienogest is a substrate of cytochrome P450 (CYP) 3A4.
Strong and moderate CYP3A4 inhibitors such as azole antifungals (e.g. itraconazole, voriconazole, fluconazole), verapamil, macrolides (e.g. clarithromycin, erythromycin), diltiazem and grapefruit juice can increase plasma concentrations of the estrogen or the progestin or both.
Effects of Qlaira on other medicinal products: Oral contraceptives may affect the metabolism of certain other drugs. Accordingly, plasma and tissue concentrations may either increase or decrease (e.g. lamotrigine).
Other forms of interactions: Laboratory tests: The use of contraceptive steroids may influence the results of certain laboratory tests.
Incompatibilities: None.
Instructions for use/handling: Store all drugs properly.
G03CA53 - estradiol, combinations ; Belongs to the class of natural and semisynthetic estrogens used in estrogenic hormone preparations.
Qlaira FC tab
(with 2 hormone free FC tab) 26's
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