Active ingredients: Estradiol (Estradiol valerate), Dienogest
KLAIRA film-coated tablets
Why is Qlaira used? What is it for?
- Qlaira is a contraceptive pill and is used to prevent pregnancy.
- Qlaira is used to treat heavy periods (not caused by uterine diseases) in women who wish to use oral contraception.
- Each colored active tablet contains a small amount of female hormones, estradiol valerate or estradiol valerate combined with dienogest.
- The 2 white tablets do not contain any active ingredients and are called inactive tablets.
- Contraceptive pills that contain two hormones are also called "combination pills".
Contraindications When Qlaira should not be used
When you should not take Qlaira Do not use Qlaira if you have any of the conditions listed below. If you have any of the conditions listed below, please contact your doctor. Your doctor will discuss with you other birth control methods that may be more suitable for you.
Do not take Qlaira:
- if you have (or have ever had) a blood clot in a blood vessel of the leg (deep vein thrombosis, DVT), lung (pulmonary embolism, PE) or other organs;
- if you know you have a disorder that affects blood clotting, such as protein C deficiency, protein S deficiency, antithrombin-III deficiency, factor V Leiden or antiphospholipid antibodies;
- if you are due to have an "operation or if you are going to lie down for a long time (see section" Blood clots ");
- if you have ever had a heart attack or stroke;
- if you have (or have ever had) angina pectoris (a condition that causes severe chest pain and may be a first sign of a heart attack) or transient ischemic attack (TIA - temporary stroke symptoms);
- if you have any of the following diseases, which could increase your risk of blood clots in the arteries: - severe diabetes with damage to the blood vessels - very high blood pressure - very high level of fat (cholesterol or triglycerides) in the blood - a disease known as hyperhomocysteinemia
- if you have (or have ever had) a type of migraine called 'migraine with aura';
- if you have (or have ever had) an inflammation of the pancreas (pancreatitis)
- if you have (or have ever had) liver disease and your liver function is still abnormal
- if you have (or have ever had) liver cancer
- if you have (or have ever had) cancer or if you suspect that you have cancer of the breast or of the genitals
- if you have unexplained vaginal bleeding
- if you are allergic (hypersensitive) to estradiol valerate or dienogest or any of the other ingredients of this medicine (listed in section 6). This may cause itching, rash or swelling.
Precautions for use What you need to know before taking Qlaira
General notes
Before you start using Qlaira you should read the information on blood clots in section 2. It is especially important that you read the symptoms of a blood clot (see section 2 "Blood clots").
Before taking Qlaira, your doctor will ask you a few questions about your personal health history and that of your family members. The doctor will also measure your blood pressure and, depending on your personal situation, may also carry out other tests.
This leaflet describes various situations where the use of Qlaira should be discontinued or where the reliability of Qlaira may be decreased.In such situations it is necessary to refrain from sexual intercourse or to take additional non-hormonal contraceptive measures, such as condoms or other barrier methods. Do not use the rhythm method or the basal temperature method. In fact, these methods may be insufficient, as Klaira alters the monthly changes in body temperature and cervical mucus.
Klaira, like all hormonal contraceptives, offers no protection against HIV infection (AIDS) or other sexually transmitted diseases.
Warnings and Precautions
When should you see a doctor?
Contact a doctor urgently
- if you notice possible signs of a blood clot which may indicate that you are suffering from a blood clot in the leg (deep vein thrombosis), a blood clot in the lung (pulmonary embolism), a heart attack or a stroke (see section below " Blood clot ").
For a description of the symptoms of these serious side effects go to the section "How to recognize a blood clot".
Tell your doctor if any of the following apply to you.
In some situations you need to be especially careful when using Qlaira or any other combined oral contraceptive, and your doctor may need to see you regularly. If this condition appears or worsens while you are using Qlaira you should tell your doctor:
- if a close relative has or has ever had breast cancer
- if you have liver or gallbladder disease
- if you have jaundice
- if you have diabetes
- if you suffer from depression
- if you have Crohn's disease or ulcerative colitis (chronic inflammatory bowel disease);
- if you have systemic lupus erythematosus (SLE, a disease that affects the natural defense system);
- if you have haemolytic uremic syndrome (HUS, a blood clotting disorder causing kidney failure);
- if you have sickle cell anemia (an inherited disease of the red blood cells);
- if you have high levels of fat in the blood (hypertriglyceridaemia) or a "family history of this condition." Hypertriglyceridaemia has been associated with an increased risk of developing pancreatitis (inflammation of the pancreas);
- if you are due to have an "operation or if you will be lying down for a long time (see section 2" Blood clots ");
- if you have just given birth, your risk of developing blood clots is higher. Ask your doctor how long after having a baby you can start taking Qlaira;
- if you have "inflammation of the veins under the skin (superficial thrombophlebitis);
- if you have varicose veins.
- if you have epilepsy (see section "Other medicines and Qlaira")
- if you have a disease that first appeared during pregnancy or during previous use of sex hormones, for example hearing loss, porphyria (a blood disorder), herpes gestationis (rash with blisters during pregnancy), Sydenham's chorea (a nerve disease in which sudden body movements occur)
- if you have (or have ever had) patchy yellow-brown pigmentation, known as 'pregnancy mask', especially on the face (chloasma). In this case, avoid direct exposure to sunlight or ultraviolet rays
- if you suffer from hereditary angioedema. If you notice symptoms of angioedema such as swelling of the face, tongue and / or pharynx and / or difficulty swallowing or hives with difficulty in breathing, consult your doctor immediately. Medicines containing estrogen may induce or aggravate the symptoms of angioedema.
- if you have heart or kidney failure.
Consult your doctor before taking Qlaira.
BLOOD CLOTS
Using a combined hormonal contraceptive such as Qlaira increases your risk of developing a blood clot compared with not using one. In rare cases, a blood clot can block blood vessels and cause serious problems.
Blood clots can develop
- in veins (called "venous thrombosis", "venous thromboembolism" or VTE)
- in the arteries (referred to as 'arterial thrombosis', 'arterial thromboembolism' or ATE).
Recovery from blood clots is not always complete. Rarely, long-lasting severe effects can occur or, very rarely, they can be fatal.
It is important to remember that the overall risk of a harmful blood clot associated with Qlaira is low.
HOW TO RECOGNIZE A BLOOD CLOT
See a doctor immediately if you notice any of the following signs or symptoms.
- swelling of one leg or along a vein in the leg or foot, especially when accompanied by:
- pain or tenderness in the leg which may only be felt when standing or walking
- increased sensation of heat in the affected leg
- change in color of the skin on the leg, such as turning pale, red or blue
- shortness of breath or sudden, unexplained rapid breathing;
- sudden cough with no obvious cause, possibly causing blood to be emitted;
- sharp chest pain which may increase with deep breathing;
- severe light headedness or dizziness;
- rapid or irregular heartbeat;
- severe pain in the stomach
- immediate loss of vision or
- painless blurring of vision which can progress to loss of vision
- chest pain, discomfort, feeling of pressure or heaviness
- sensation of squeezing or fullness in the chest, arm or below the breastbone;
- feeling of fullness, indigestion or choking;
- upper body discomfort radiating to the back, jaw, throat, arms and stomach;
- sweating, nausea, vomiting or dizziness;
- extreme weakness, anxiety, or shortness of breath;
- rapid or irregular heartbeats
- sudden numbness or weakness of the face, arm or leg, especially on one side of the body;
- sudden confusion, difficulty speaking or understanding;
- sudden difficulty seeing in one or both eyes;
- sudden difficulty walking, dizziness, loss of balance or coordination;
- sudden, severe or prolonged migraine with no known cause;
- loss of consciousness or fainting with or without seizures.
- swelling and pale blue discoloration of one extremity;
- severe stomach pain (acute abdomen)
BLOOD CLOTS IN A VEIN
What can happen if a blood clot forms in a vein?
- The use of combined hormonal contraceptives has been linked to an increased risk of blood clots forming in the veins (venous thrombosis). However, these side effects are rare. In most cases they occur in the first year of using a combined hormonal contraceptive.
- If a blood clot forms in a vein in the leg or foot, it can cause a deep vein thrombosis (DVT).
- If a blood clot travels from the leg and lodges in the lung, it can cause a "pulmonary embolism."
- Very rarely, a clot can form in another organ such as the eye (retinal vein thrombosis).
When is the risk of developing a blood clot in a vein highest?
The risk of developing a blood clot in a vein is highest during the first year of taking a combined hormonal contraceptive for the first time. The risk may be even higher if you restart taking a combined hormonal contraceptive (the same drug or a different drug) after a break of 4 or more weeks.
After the first year, the risk is reduced but is always slightly higher than if you were not using a combined hormonal contraceptive.
When you stop taking Qlaira your risk of developing a blood clot returns to normal within a few weeks.
What is the risk of developing a blood clot?
The risk depends on your natural risk of VTE and the type of combined hormonal contraceptive you are taking.
The overall risk of developing a blood clot in the leg or lung (DVT or PE) with Qlaira is low.
- Out of 10,000 women who are not using any combined hormonal contraceptive and who are not pregnant, about 2 will develop a blood clot in a year.
- Out of 10,000 women who are using a combined hormonal contraceptive that contains levonorgestrel, norethisterone or norgestimate, about 5-7 will develop a blood clot in a year.
- It is not yet known how the risk of developing a blood clot with Qlaira compares with the risk associated with a combined hormonal contraceptive containing levonorgestrel.
- The risk of a blood clot forming depends on your medical history (see under "Factors that increase the risk of a blood clot forming").
Factors that increase the risk of developing a blood clot in a vein
The risk of developing a blood clot with Qlaira is low but some conditions increase the risk. Its risk is greater:
- if you are severely overweight (body mass index or BMI above 30 kg / m2);
- if a member of your immediate family has had a blood clot in the leg, lung or other organ at a young age (less than about 50 years). In this case you could have an inherited blood clotting disorder;
- if you are going to have an operation or if you have to lie down for a long time because of an injury or illness or if you have a leg in a cast. You may need to stop taking Qlaira a few weeks before the surgery or during the period where you are less mobile. If you have to stop taking Qlaira, ask your doctor when you can start taking it again;
- as you get older (especially over the age of 35);
- if you gave birth less than a few weeks ago.
The risk of developing a blood clot increases the more conditions you have of this type.
Air travel (lasting> 4 hours) may temporarily increase the risk of a blood clot, especially if you have some of the other risk factors listed.
It is important that you tell your doctor if any of these apply to you, even if you are not sure. Your doctor may decide that Qlaira needs to be stopped.
If any of the above conditions change while you are using Qlaira, for example if a close relative has a thrombosis for no known reason or if you gain a lot of weight, contact your doctor.
BLOOD CLOTS IN AN ARTERY
What can happen if a blood clot forms in an "artery?"
Like blood clots in a vein, clots in an artery can cause serious problems, for example, they can cause a heart attack or stroke.
Factors that increase the risk of developing a blood clot in an artery
It is important to note that the risk of heart attack or stroke associated with the use of Qlaira is very low but can increase:
- with increasing age (over 35 years);
- if you smoke. When using a combined hormonal contraceptive like Qlaira you are advised to stop smoking. If you are unable to stop smoking and are over the age of 35, your doctor may advise you to use a different type of contraceptive;
- if you are overweight;
- if you have high blood pressure;
- if a member of your immediate family has had a heart attack or stroke at a young age (less than about 50 years). In this case, you may also be at high risk of having a heart attack or stroke;
- if you or a close relative have a high level of fat in the blood (cholesterol or triglycerides);
- if you suffer from migraines, especially migraines with aura;
- if you have any heart problems (valve defect, a heart rhythm disorder called atrial fibrillation);
- if you have diabetes.
If you have more than one of these conditions or if any of them are particularly severe, the risk of developing a blood clot may be even higher.
If any of the above conditions change while you are using Qlaira, for example if you start smoking, if a close relative has a thrombosis for no known reason, or if you gain a lot of weight, contact your doctor.
Klaira and cancer
Breast cancer has been observed slightly more often in women using the combined pill, but it is not known whether this is due to the treatment. For example, more cancers may be discovered in women using the combined pill because they are seen more often. The risk of breast cancer gradually decreases after stopping combined hormonal contraception. It is important that you check your breasts regularly and you should contact your doctor if you feel any lump.
Benign liver tumors have been observed in rare cases in women using the pill, and even more rarely malignant liver tumors. In isolated cases, these tumors have led to life-threatening internal bleeding. Contact your doctor if you experience particularly severe abdominal pain.
Some studies suggest that long-term use of the pill increases the risk of developing cervical cancer. However, it is unclear to what extent sexual behavior or other factors such as human papilloma virus (HPV) increase this risk.
Intermenstrual bleeding
During the first few months of taking Qlaira, unexpected bleeding may occur. Bleeding usually starts on day 26, the day you take your second dark red tablet, or on the following days. Information provided by diaries kept by women during a clinical study with Qlaira shows that it is not unusual to have unexpected bleeding in a given cycle (10-18% of users). If unexpected bleeding occurs for more than 3 consecutive months, or if these appear after a few months, the doctor must investigate the cause.
What to do if menstruation does not appear on day 26 or the following days
The information provided by the diaries kept by women during a clinical study with Qlaira shows that it is not uncommon for no menstruation to occur on day 26 (observed in about 15% of cycles).
If you have taken all the tablets correctly, have not had vomiting or severe diarrhea and have not taken any other medicines, it is highly unlikely that you are pregnant.
If your period does not appear twice in a row or if you have not taken the tablets correctly, you may be pregnant. Contact your doctor immediately. Do not start the next pack until you are sure that you have ruled out pregnancy.
Interactions Which drugs or foods can change the effect of Qlaira
Always tell your doctor or pharmacist if you are taking or have recently taken any other medicines or herbal remedies, including those obtained without a prescription. Also tell any other doctor or dentist who prescribes other medicines (or the pharmacist) that you are taking Qlaira. They can tell you if you need to take additional contraceptive measures (e.g. condoms) and if so, for how long.
Some medicines affect the blood levels of Qlaira and can make it less effective in preventing pregnancy or can cause unexpected bleeding. These include:
o medicines used to treat:
- epilepsy (ex: primidone, phenytoin, barbiturates, carbamazepine, oxcarbazepine, topiramate, felbamate),
- tuberculosis (ex: rifampicin),
- HIV and Hepatitis C virus infection (ritonavir, nevirapine, efavirenz known as protease inhibitors and non-nucleoside reverse transcriptase inhibitors), other infections (griseofulvin).
or preparations based on St. John's wort (Hypericum Perforatum)
Some medicines can increase the levels of the active substances of Qlaira in the blood. Tell your doctor if you are using:
- antifungal medicines containing ketoconazole,
- antibiotics containing erythromycin.
Qlaira may influence the effect of other medicines, for example:
- medicines containing cyclosporine,
- the antiepileptic lamotrigine (this can cause an increase in the frequency of seizures).
Ask your doctor or pharmacist for advice before taking any medicine. Your doctor or pharmacist can tell you if you need to take additional protective measures while taking Qlaira together with other medicines.
Klaira with food and drink
Qlaira can be taken with or without food, if needed with a small amount of water.
Laboratory analysis
If you need a blood test or other laboratory tests, tell your doctor or laboratory staff that you are taking the pill, as oral contraceptives can affect the results of some tests.
Warnings It is important to know that:
Pregnancy and breastfeeding
During pregnancy, you should not use Qlaira. If you become pregnant while taking Qlaira, you must stop treatment immediately and contact your doctor. If you want to become pregnant, you can stop taking Qlaira at any time (see also "If you stop taking Qlaira ").
The use of Qlaira is generally not recommended while breastfeeding.If you want to take the pill while breastfeeding, you will need to contact your doctor.
Ask your doctor or pharmacist for advice before taking any medicine during pregnancy or breastfeeding.
Driving and using machines
There is no reason to believe that Qlaira affects the ability to drive or use machines.
Qlaira contains lactose
If you have been told by your doctor that you have "intolerance to some sugars, contact your doctor before taking this medicinal product.
Dose, Method and Time of Administration How to use Qlaira: Posology
Each pack contains 26 colored active tablets and 2 white inactive tablets.
Take one Qlaira tablet every day, with a small amount of liquid as needed. You can take the tablets with or without food, but you must take them around the same time each day.
Preparation of the package
To help you follow the correct sequence, each pack of Klaira contains 7 self-adhesive labels with the 7 days of the week.
Choose the sticker of the week that starts with the day you start taking your tablets. For example, if it starts on a Wednesday, use the sticker that starts with "WED".
Attach the week sticker to the entire length of the top of the Qlaira pack where it reads "Put sticker here", so that the first day is on top of the tablet marked "1".
This way there is a day indicated above each tablet and you can check if you have taken the pill on a given day. Follow the direction of the arrow on the pack until all 28 tablets have been taken.
Your period, also called withdrawal bleeding, usually starts when you are taking the second dark red tablet or the white tablets, and it may not have finished before the next pack starts. Some women still have their period even after taking the first tablets of the new pack.
You start the next pack without a break, ie the day after you finish the current pack, even if your period is not over yet. This means that you must start the next pack on the same day of the week and your period should occur on the same days each month. .
If you use Qlaira in this way, contraception is guaranteed even during the 2 days you are taking the inactive tablets.
When can you start the first pack
- If you have not used a hormonal contraceptive in the previous month, start taking Qlaira on the first day of your period (the first day of your period).
- Changing from another combined oral contraceptive pill, or vaginal ring, or patch, combined contraceptive. Start taking Qlaira the day after the last active tablet (the last tablet containing the active ingredients) of the previous pill. from a vaginal contraceptive ring or patch, start using Qlaira on the day of removal or follow your doctor's advice.
- Changing from a progestogen-only method (progestogen-only pill, injection, implant or progestogen-releasing IUS) You can switch to Qlaira on any day from the progestogen-only pill (from an implant or the IUS on the day of its removal, from the injectable when the next injection would be scheduled), but in all these cases you must take additional contraceptive measures (eg condoms) for the first 9 days you use Qlaira.
- After a miscarriage Follow your doctor's advice.
- After having a baby. You can start taking Qlaira between the 21st and 28th days after having a baby. If you start taking Qlaira later than the 28th day, use a barrier method (for example a condom) during the first few days. 9 days of taking Qlaira. If, after having a baby, you have had intercourse before starting Qlaira, you must rule out pregnancy or wait until your next period. If you want to start Qlaira after becoming pregnant and breastfeeding, read the section "Pregnancy and breastfeeding".
Ask your doctor for advice if you are not sure when to start.
Overdose What to do if you have taken too much Qlaira
If you take more KLAIRA than you should
There have been no reports of serious harmful effects if you take multiple Qlaira tablets.
If you take several tablets at once, you may feel sick or vomit. The
Young girls may have vaginal bleeding. If you have taken too many KLAIRA tablets, or if you find that some tablets have been taken by a child, contact your doctor or pharmacist immediately.
If you forget to take QLAIRA
Inactive tablets: if you forget a white tablet (the two tablets at the end of the pack), you do not need to take them later as they do not contain any active ingredients. However, it is important that you discard the forgotten white tablet so that you are sure that the number of days of taking the inactive tablets has not increased; this would increase the risk of pregnancy. Continue with the next tablet at the usual time.
Active tablets: Depending on the day of the cycle on which an active tablet has been forgotten, she must take additional contraceptive measures, for example a barrier method such as a condom. Take the tablets following the directions below. For details, see also the diagram below:
- If you are less than 12 hours late in taking a tablet, contraceptive protection is not reduced. Take the tablet as soon as you remember and then take the next tablets as planned.
- If the delay in taking a tablet is more than 12 hours, contraceptive protection may be reduced. Depending on the day of the cycle on which the forgetfulness occurred, additional contraceptive measures, such as a barrier method such as a condom, should be used. See also the diagram below.
- More than one tablet forgotten in a pack Contact your doctor.
You must not take more than two active tablets in one day.
If you have forgotten to start a new pack, or if you have forgotten one or more tablets during days 3-9 of the pack, there is a risk that you are pregnant (if you have had sex in the 7 days before forgetting the tablet) In this case, please contact your doctor The greater the number of missed tablets (especially those on days 3-24) and the closer this is to the inactive tablet phase, the greater the risk of reduced contraceptive protection. details, see also the diagram below.
If you have forgotten any of the active tablets in a pack and have not had your period at the end of the pack you may be pregnant. Talk to your doctor before starting the next pack.
Use in children
No data are available in adolescents under 18 years.
What to do in case of vomiting or severe diarrhea
If you vomit within 3-4 hours of taking an active tablet, or if you have severe diarrhea, it is possible that the active ingredients of the pill are not completely absorbed by your body. forget to take a tablet.
After vomiting or severe diarrhea, you will need to take the next tablet as soon as possible. If possible within 12 hours of the usual time of taking the pill. If this is not possible, or if it has already been 12 hours, you should follow the instructions under "If you forget to take Qlaira". take the corresponding tablet from another pack.
If you stop taking Qlaira
You can stop taking Qlaira at any time. If you still want to avoid becoming pregnant, ask your doctor for advice on other safe methods of contraception. If you want to become pregnant, stop taking Qlaira and wait for a period before trying. to seek pregnancy. This will allow you to more accurately calculate the expected date of delivery.
If you have any further questions on the use of Qlaira, ask your doctor or pharmacist.
Side Effects What are the side effects of Qlaira
Like all medicines, Qlaira can cause side effects, although not everybody gets them. If you get any side effects, especially if they are severe or persistent, or if there is any change in your health that you think might be due to Qlaira, please tell your doctor.
An increased risk of developing blood clots in the veins (venous thromboembolism (VTE)) or blood clots in the arteries (arterial thromboembolism (ATE)) is present in all women taking combined hormonal contraceptives. For more detailed information on the different risks from "taking combined hormonal contraceptives, see section 2" What you need to know before you use Qlaira ".
Serious side effects
Serious reactions associated with "pill use, as well as related symptoms, are described in the following sections:" Blood clots "and" Klaira and cancer. "Read these sections carefully and consult your doctor immediately if necessary.
Other possible side effects
The following side effects have been associated with the use of Qlaira:
Common side effects (between 1 and 10 users in 100)
- headache
- abdominal pain, nausea
- acne
- absence of menstruation, discomfort in the breasts, painful menstruation, irregular periods (with abundant irregular bleeding)
- weight gain.
Uncommon side effects (between 1 and 10 users in 1,000)
- fungal infection, fungal infection of the vulva and vagina, vaginal infection
- increased appetite
- depression, depressed mood, emotional disorder, difficulty sleeping, decreased sexual desire, mental disorder, mood swings
- dizziness, migraine
- hot flashes, high blood pressure
- diarrhea, vomiting
- increased liver enzymes
- hair loss, excessive sweating (hyperhidrosis), itching, rash
- muscle cramps
- breast enlargement, breast lumps, abnormal cell growth in the cervix (cervical dysplasia), genital dysfunctional bleeding, pain during intercourse, fibrocystic mastopathy, heavy menstruation, menstrual disorders, ovarian cyst, pelvic pain, premenstrual syndrome, benign tumor of the uterus, contractions of the uterus, uterine / vaginal bleeding including spotting, vaginal discharge, vulvovaginal dryness
- fatigue, irritability, swelling of some parts of the body, for example the ankles (edema)
- weight loss, blood pressure changes.
Rare side effects (between 1 and 10 users in 10,000)
- candida infection, oral herpes, pelvic inflammatory disease, a vascular disease of the eye that resembles a fungal infection (presumed ocular histoplasmosis syndrome), a fungal skin infection (tinea versicolor), urinary tract infection, bacterial inflammation of the vagina
- water retention, increase in certain blood fats (triglycerides)
- aggression, anxiety, feeling unhappy, increased sexual desire, nervousness, nightmares, restlessness, sleep disturbances, stress
- reduced attention, "pins and needles" sensation, dizziness
- contact lens intolerance, dry eyes, swollen eyes
- heart attack (myocardial infarction), palpitations
- bleeding from a varicose vein, low blood pressure, inflammation of superficial veins, pain in the veins
- harmful blood clots in a vein or artery, for example: in a leg or foot (DVT), lung (PE), heart attack, stroke, mini-stroke or temporary stroke-like symptoms , known as transient ischemic attack (TIA), blood clots in the liver, stomach / intestines, kidneys or eye.
The chance of developing a blood clot may be higher if you have any other conditions that increase this risk (see section 2 for more information on conditions that increase the risk of blood clots and the symptoms of a blood clot).
- constipation, dry mouth, indigestion, heartburn
- hepatic nodules (focal nodular hyperplasia), chronic inflammation of the gallbladder
- allergic skin reactions, yellow-brown spots (chloasma) and other pigmentation disorders, hirsutism, excessive hair growth, skin disorders such as: dermatitis and neurodermatitis, dandruff and oily skin (seborrhea) and other skin conditions
- back pain, jaw pain, feeling of heaviness
- pain in the urinary tract
- abnormal withdrawal bleeding, benign breast lumps, early stage breast cancer, breast cyst, breast discharge, cervical polyp, cervical redness, bleeding during intercourse, spontaneous breast milk discharge, genital discharge, low menstruation, menstrual delay, ruptured ovarian cyst, foul-smelling vaginal discharge, burning sensation in the vulva and vagina, vulvovaginal discomfort
- enlarged lymph glands,
- asthma, difficulty in breathing, nosebleeds
- chest pain, tiredness and general feeling of being unwell, fever
- Pap smear (smear) of the cervix abnormal
Further information (taken from the diaries kept by women during a clinical study with Qlaira) about possible side effects "irregular menstruation (with heavy irregular bleeding)" and "no menstruation" can be found in the sections "Intermenstrual bleeding" and "What to do if not menstruation occurs on day 26 or the following days ".
In addition to the side effects listed above, erythema nodosum, erythema multiforme, breast discharge and hypersensitivity have occurred in users of combination pills containing ethinylestradiol. Although these symptoms have not been reported during clinical trials with Qlaira, the possibility that they occur during treatment cannot be excluded.
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 via the national reporting system at https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse. By reporting side effects you can help provide more information on safety. of this medicine.
Expiry and Retention
Keep this medicine out of the sight and reach of children.
This medicinal product does not require any special storage conditions.
Do not use this medicine after the expiry date which is stated on the package after "EXP". The expiry date refers to the last day of the month.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.
Composition and pharmaceutical form
What KLAIRA contains
The active ingredients are estradiol valerate, or estradiol valerate combined with dienogest.
One pack (28 film-coated tablets) of Qlaira contains 26 active tablets of 4 different colors, in the 1st, 2nd, 3rd and 4th row and 2 white inactive tablets in the 4th row.
Composition of colored tablets containing one or two active ingredients:
- 2 dark yellow tablets each containing 3 mg estradiol valerate,
- 5 red tablets each containing 2 mg of estradiol valerate and 2 mg of dienogest,
- 17 light yellow tablets each containing 2 mg of estradiol valerate and 3 mg of dienogest,
- 2 dark red tablets each containing 1 mg estradiol valerate.
Composition of the inactive white tablets:
These tablets do not contain any active ingredients.
The excipients of the colored tablets containing the active ingredients are:
Tablet core: lactose monohydrate, maize starch, pregelatinised maize starch, povidone K25 (E1201), magnesium stearate (E572).
Tablet coating: hypromellose type 2910 (E464), macrogol 6000, talc (E553b), titanium dioxide (E 171), red iron oxide (E172) and / or yellow iron oxide (E172).
The other ingredients of the white inactive tablets are:
Tablet core: lactose monohydrate, corn starch, povidone K25 (E1201), magnesium stearate (E572).
Tablet coating: hypromellose type 2910 (E464), talc (E553b), titanium dioxide (E171).
What KLAIRA looks like and contents of the pack
Qlaira tablets are film-coated tablets; the tablet core is covered with a coating.
One pack (28 film-coated tablets) of Qlaira contains 2 dark yellow tablets in the 1st row, 5 red tablets in the 1st row, 17 light yellow tablets in the 2nd, 3rd and 4th row, 2 dark red tablets in the 4th row. 1st row and 2 inactive white tablets in the 4th row.
The dark yellow tablet is round, with biconvex faces, on one of which the letters "DD" are imprinted in a regular hexagon.
The red tablet is round, with biconvex faces, on one of which the letters "DJ" are imprinted in a regular hexagon.
The light yellow tablet is round, with biconvex faces, on one of which the letters "DH" are imprinted in a regular hexagon.
The dark red tablet is round, with biconvex faces, on one of which the letters "DN" are imprinted in a regular hexagon.
The white (inactive) tablet is round, with biconvex faces, on one of which the letters "DT" are imprinted in a regular hexagon.
Qlaira is available in packs of 1, 3 and 6 blisters, each with 28 tablets. Not all pack sizes may be marketed.
Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.
01.0 NAME OF THE MEDICINAL PRODUCT
KLAIRA TABLETS COATED WITH FILM
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each calendar pack (28 film-coated tablets) contains in the following order:
2 dark yellow tablets, each containing 3 mg estradiol valerate,
5 red tablets, each containing 2 mg of estradiol valerate and 2 mg of dienogest,
17 light yellow tablets, each containing 2 mg of estradiol valerate and 3 mg of dienogest,
2 dark red tablets, each containing 1 mg estradiol valerate,
2 white tablets that do not contain active ingredients.
Excipient with known effect: lactose (not more than 50 mg per tablet).
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM
Film-coated tablet (tablet).
Round, dark yellow, film-coated tablet with biconvex faces, one of which is embossed with the letters "DD" in a regular hexagon.
Round, red, film-coated tablet with biconvex faces, one of which is embossed with the letters "DJ" in a regular hexagon.
Round, light yellow, film-coated tablet with biconvex faces, one of which is embossed with the letters "DH" in a regular hexagon.
Round, dark red, film-coated tablet with biconvex faces, one of which is embossed with the letters "DN" in a regular hexagon.
Round, white, film-coated tablet with biconvex faces, one of which is embossed with the letters "DT" in a regular hexagon.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
Oral contraception.
Treatment of heavy menstrual flows, in the absence of organic pathology, in women who wish to resort to oral contraception.
The decision to prescribe Qlaira must take into account the individual woman's current risk factors, particularly those related to venous thromboembolism (VTE) and the comparison between the risk of VTE associated with Qlaira and that associated with other combined hormonal contraceptives (COCs). (see sections 4.3 and 4.4).
04.2 Posology and method of administration
Method of administration
Oral use
Dosage
How to take KLAIRA
The tablets should be taken at about the same time each day with a small amount of liquid if needed, and in the order they come in the blister pack. Tablet-taking is continuous. It is necessary to take one tablet a day for 28 consecutive days. The next pack is started the day after the last tablet from the previous pack. Withdrawal bleeding usually occurs while taking the last tablets of a calendar pack and may not have finished before the new calendar pack is started. In some women, bleeding starts after they take the first tablets of the new calendar pack.
How to start treatment with KLAIRA
• No previous use of hormonal contraceptives (in the previous month).
The first tablet should be taken on the first day of the natural cycle (i.e. the first day of menstruation).
• Changing from a combined hormonal contraceptive (combined oral contraceptive), vaginal ring, or transdermal patch.
You should start taking Qlaira the day after the last active tablet (the last tablet containing the active substances) of your previous combined oral contraceptive. In case of a vaginal ring or transdermal patch, Qlaira should be started on the day of removal.
• Changing from a progestogen-only method (progestogen-only pill, injection, implant) or from a progestogen-releasing intrauterine system (IUS).
You can switch to Klaira at any time if you are using the progestogen-only pill (if you change from an implant or IUS from the day of its removal; from a product for injectable use from the time of injection later), however in all these cases an additional barrier method of contraception must be used for the first 9 days of taking Qlaira.
• After an abortion in the first trimester of pregnancy.
You can start immediately. In this case, no additional contraceptive method is required.
• After childbirth or after an abortion in the second trimester of pregnancy.
For breastfeeding women see section 4.6.
It is advisable to start between the 21st and 28th day after giving birth or after an abortion in the second trimester of pregnancy. In case of a later onset, an additional barrier method of contraception should be used for the first 9 days of taking Qlaira. However, if you have had sexual intercourse, pregnancy must be ruled out before you start using the combination oral contraceptive, or you must wait for your first menstruation.
If you miss a tablet
Any missed placebo (white) tablets should be discarded, so as not to prolong the interval between the active tablet-taking periods.
The following tips refer only to forgetting active tablets:
If you are less than 12 hours late in taking a tablet, contraceptive protection is not reduced. You should take the tablet as soon as you remember and then take the following tablets at the usual time.
If you are more than 12 hours late in taking a tablet, contraceptive protection may be reduced. You should take the forgotten tablet as soon as you remember, even if that means taking two tablets together. Then you should continue taking the tablets. at the usual time.
Depending on the day of the cycle on which the tablet was forgotten (see chart below for details), additional contraceptive methods (for example, a barrier method such as condoms) should be used according to the following criteria:
No more than two tablets should be taken on the same day.
If a woman has forgotten to start a new calendar pack, or has forgotten to take one or more tablets during days 3-9 of the calendar pack, she may have already become pregnant ). The more tablets that are forgotten (of those with the two associated active substances on days 3-24) and the closer you are to the placebo tablet days, the higher the risk of pregnancy.
If the woman has forgotten tablets and subsequently does not experience withdrawal bleeding at the end of the calendar pack or at the beginning of the new pack, the possibility of pregnancy should be considered.
Pediatric population
No data are available for use in adolescents below 18 years.
Warnings in the case of gastrointestinal disorders
In the case of severe gastrointestinal disturbances (eg vomiting or diarrhea), absorption may be impaired and additional contraceptive methods must be used.
If vomiting occurs within 3-4 hours of taking an active tablet, the next tablet should be taken as soon as possible. This tablet should be taken within 12 hours of the usual tablet-taking time. If the delay is greater than 12 hours the instructions given in paragraph 4.2 apply "If you miss a tablet".
If the woman does not wish to change her normal tablet-taking schedule, she will need to take the required tablet (s) from another pack.
04.3 Contraindications
Combined hormonal contraceptives (COCs) should not be used in the following conditions. Should any of these conditions appear for the first time during COC use, treatment should be stopped immediately.
• Presence or risk of venous thromboembolism (VTE)
- Venous thromboembolism - VTE (with anticoagulants) or a history of VTE (eg deep vein thrombosis [DVT] or pulmonary embolism [PE])
- Known hereditary or acquired predisposition to venous thromboembolism, such as resistance to activated protein C (including factor V Leiden), antithrombin III deficiency, protein C deficiency, protein S deficiency
- Major surgery with prolonged immobilization (see section 4.4)
- High risk of venous thromboembolism due to the presence of multiple risk factors (see section 4.4)
• Presence or risk of arterial thromboembolism (ATE)
- Arterial thromboembolism - current or previous arterial thromboembolism (e.g. myocardial infarction) or prodromal conditions (e.g. angina pectoris)
- Cerebrovascular disease - current or previous stroke or prodromal conditions (e.g. transient ischaemic attack (TIA))
- Known hereditary or acquired predisposition to arterial thromboembolism, such as hyperhomocysteinaemia and antiphospholipid antibodies (anticardiolipin antibodies, lupus anticoagulant)
- History of migraine with focal neurological symptoms
- High risk of arterial thromboembolism due to the presence of multiple risk factors (see section 4.4) or the presence of a serious risk factor such as:
• diabetes mellitus with vascular symptoms
• severe hypertension
• severe dyslipoproteinemia
• pancreatitis or its history if associated with severe hypertriglyceridaemia;
• existing or previous severe liver diseases, until liver function values return to normal;
• current or previous liver tumors (benign or malignant);
• Known or suspected sex steroid-dependent malignancies (eg of the genital organs or breast);
• vaginal bleeding of an unknown nature;
• hypersensitivity to the active substances or to any of the excipients listed in section 6.1.
04.4 Special warnings and appropriate precautions for use
Warnings
If any of the conditions or risk factors mentioned below are present, the suitability of Klaira should be discussed with the woman.
In the event of worsening or first appearance of any of these risk factors or conditions, the woman should contact her doctor to determine whether the use of Qlaira should be discontinued.
In the case of suspected or confirmed VTE or ATE, the use of COCs should be discontinued. In the event that anticoagulation therapy is initiated, a suitable method of contraception should be used because of the teratogenicity associated with anticoagulant therapy (coumarins).
There are no epidemiological studies on the effects of combined oral contraceptives containing estradiol / estradiol valerate. All of the following warnings and precautions are derived from clinical and epidemiological data of combined oral contraceptives containing ethinylestradiol. It is not known whether these warnings and precautions apply to Qlaira.
• Circulatory disorders
Risk of venous thromboembolism (VTE)
The use of any combined hormonal contraceptive (COC) results in an increased risk of venous thromboembolism (VTE) compared with no use. Products containing levonorgestrel, norgestimate or norethisterone are associated with a lower risk of VTE. It is not yet known in how the risk associated with Qlaira compares with these lower risk products. The decision to use a product other than those associated with a lower risk of VTE should only be made after discussions with the woman to ensure that she understands the risk of VTE associated with CHCs, how its current risk factors affect that risk, and the fact that the risk of developing a VTE is highest in the first year of use. There is also some evidence that the risk increases when taking of a COC is resumed after a break of 4 or more weeks.
About 2 out of 10,000 women who do not use a CHC and who are not pregnant will develop a VTE over a period of one year. In a single woman, however, the risk can be much higher, depending on her underlying risk factors (see below).
Epidemiological studies in women using low-dose combined oral contraceptives (
It is estimated that out of 10,000 women who use a levonorgestrel-containing CHC, about 6 will develop a VTE in a year.
It is not yet known whether the risk of VTE associated with COCs containing dienogest in combination with estradiol is comparable to the risk associated with COCs containing levonorgestrel.
The number of VTEs per year with low-dose CHCs is lower than the number expected in pregnant or postpartum women.
VTE can be fatal in 1-2% of cases.
Very rarely, thrombosis has been reported in CHC users in other blood vessels, e.g. hepatic, mesenteric, renal or retinal veins and arteries.
Risk factors for VTE
The risk of venous thromboembolic complications in CHC users may increase substantially if additional risk factors are present, especially if there are more than one risk factors (see table).
Qlaira is contraindicated if a woman has several risk factors that increase her risk of venous thrombosis (see section 4.3). If a woman has more than one risk factor, it is possible that the increased risk is greater than the sum of the individual factors; in this case her total risk of VTE should be considered. If the benefit-risk ratio is considered to be negative, a COC should not be prescribed (see section 4.3).
There is no agreement on the possible role of varicose veins and superficial thrombophlebitis in the onset and progression of venous thrombosis.
The increased risk of thromboembolism in pregnancy, 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)
If symptoms of this type occur, women should seek immediate medical attention and inform them that they are taking a CHC.
Symptoms of deep vein thrombosis (DVT) can include:
- unilateral swelling of the leg and / or foot or along a vein in the leg;
- pain or tenderness in the leg which may only be felt when standing or walking;
- increased sensation of heat in the affected leg; skin on the leg that is red or discolored.
Symptoms of pulmonary embolism (PE) can include:
- sudden and unexplained onset of shortness of breath and rapid breathing;
- sudden cough which may be associated with hemoptysis;
- sharp pain in the chest;
- severe light headedness or dizziness;
- rapid or irregular heartbeat.
Some of these symptoms (such as "shortness of breath" and "cough") are non-specific and may be misinterpreted as more common or less serious events (eg respiratory tract infections).
Other signs of vascular occlusion may include: sudden pain, swelling or a pale blue discoloration of one "extremity.
If the occlusion takes place in the eye, symptoms can range from painless blurring of vision to loss of vision. Sometimes vision loss occurs almost immediately.
Risk of arterial thromboembolism (ATE)
Epidemiological studies have associated the use of CHCs with an increased risk of arterial thromboembolism (myocardial infarction) or of cerebrovascular accidents (eg transient ischemic attack, stroke). Arterial thromboembolic events can be fatal.
Risk factors of ATE
The risk of arterial thromboembolic complications or a cerebrovascular accident in CHC users increases in the presence of risk factors (see table). Qlaira is contraindicated if a woman has one serious risk factor or multiple risk factors for ATE that increase her 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 benefit-risk balance is believed to be negative, a CHC should not be prescribed (see section 4.3).
Symptoms of ATE
If symptoms of this type occur, women should contact a healthcare professional immediately and inform them that they are taking a CHC.
Symptoms of cerebrovascular accident can include:
• sudden numbness or weakness of the face, arm or leg, especially on one side of the body;
• sudden difficulty walking, dizziness, loss of balance or coordination;
• sudden confusion, difficulty speaking or understanding;
• sudden difficulty seeing in one or both eyes;
• sudden, severe or prolonged migraine with no known cause;
- loss of consciousness or fainting with or without convulsions.
Temporary symptoms suggest it is a transient ischemic attack (TIA).
Symptoms of myocardial infarction (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, arms, stomach;
• feeling of fullness, indigestion or choking;
• sweating, nausea, vomiting or dizziness;
• extreme weakness, anxiety or shortness of breath;
• rapid or irregular heartbeats.
• Tumors
An increased risk of cervical cancer has been reported in some epidemiological studies in COC users for long periods (> 5 years), but it is still controversial to what extent these findings are attributable to the confounding effects of sexual and other behavior. factors such as the human papilloma virus (HPV).
A meta-analysis of 54 epidemiological studies reported a slightly higher relative risk (RR = 1.24) of breast cancer diagnosis in women using COCs. This increased risk gradually disappears over 10 years after stopping the use of COCs. Because breast cancer is rare in women under the age of 40, the extra number of diagnosed cases of breast cancer in women using or who have recently used COCs is small in relation to the overall risk of breast cancer. These studies do not provide evidence of a causal relationship. The observed 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 factors. Breast cancers diagnosed in COC users tend to be fewer. clinically advanced forms diagnosed in women who have never used them.
Benign liver tumors and, even more rarely, malignant liver tumors have been reported rarely in women taking COCs. In isolated cases, these tumors have resulted in life-threatening intra-abdominal haemorrhages. If a woman taking a combined oral contraceptive experiences severe upper abdominal pain, liver enlargement, or signs suggestive of intra-abdominal haemorrhage, the presence of a liver tumor should be considered in the differential diagnosis.
• Other conditions
Women with hypertriglyceridaemia, or with a positive family history of the condition, may have 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 rarely occur. However, if clinically significant hypertension develops during the use of a COC and blood pressure levels remain elevated, it is prudent for the physician to stop the COC and treat the hypertension. If deemed appropriate, COC use can be resumed if antihypertensive therapy achieves normal blood pressure values.
The following conditions have been reported to occur or worsen with both pregnancy and COC use, but evidence of an association with COC use is inconclusive: jaundice and / or pruritus from cholestasis; gallbladder stones; porphyria; systemic lupus erythematosus; hemolytic-uremic syndrome; Sydenham's chorea, herpes gestationis, hearing loss from otosclerosis.
In women with hereditary angioedema, exogenous estrogens can induce or exacerbate the symptoms of angioedema.
Acute or chronic disturbances of liver function may require discontinuation of COC treatment until markers of liver function have returned to normal. The return of cholestatic jaundice already occurring in pregnancy or during previous sex steroid treatment requires treatment. "discontinuation of the combined oral contraceptive.
Although COCs may have an effect on peripheral insulin resistance and glucose tolerance, there is no evidence for the need to change the treatment regimen in diabetic women using low-dose combined oral contraceptives (containing
Worsening of endogenous depression, epilepsy, Crohn's disease and 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 rays during treatment with COCs.
Estrogen can cause water retention and therefore women with kidney or heart dysfunction should be followed closely. Women with end-stage renal insufficiency should be carefully observed, as the level of circulating estrogens may increase after administration of Qlaira.
This medicinal product contains no more than 50 mg of lactose per tablet. Patients with rare hereditary problems of galactose intolerance, lactase deficiency or glucose-galactose malabsorption who are on a lactose-free diet should take this amount into account.
Medical examinations / visits
Before initiating or resuming use of Qlaira, a complete medical history (including family history) should be taken and pregnancy should be ruled out. Blood pressure should be measured and a clinical examination, guided by contraindications, should be performed (see section 4.3 ) and warnings (see section 4.4). It is important to draw a woman's attention to information relating to venous or arterial thrombosis, including the risk associated with Qlaira compared to other CHCs, symptoms of VTE and ATE, known risk factors and what to do in case of suspected thrombosis.
The woman should also be advised of the need to read the package leaflet carefully and to follow its advice. The frequency and type of examinations should be based on established guidelines and should be adapted to the individual woman.
Women should be advised that hormonal contraceptives do not protect against HIV infections (AIDS) and other sexually transmitted diseases.
Reduced effectiveness
The efficacy of COCs may be reduced in the following cases: forgetting to take active tablets (see section 4.2), gastro-intestinal disturbances during the period of taking active tablets (see section 4.2) or concomitant drug therapies (see section 4.5 ).
Control of the cycle
With all COCs, irregular bleeding (spotting or breakthrough bleeding) may occur, especially in the first months of use. Thus, the assessment of any irregular bleeding becomes meaningful after an adjustment period of approximately three treatment courses.
Based on patient diaries from a comparative clinical study, the percentage of women per cycle who had intermenstrual bleeding was 10-18% for users of Qlaira.
Amenorrhea may occur even in the absence of pregnancy while using Qlaira. Based on patient diaries, amenorrhea occurs in approximately 15% of courses.
If Qlaira has been taken according to the directions given in section 4.2, it is unlikely that the woman is pregnant. two consecutive cycles, pregnancy must be ruled out before continuing to use Qlaira.
If irregular blood loss persists or occurs after previously regular cycles, non-hormonal causes should be considered and appropriate diagnostic measures should be taken to rule out malignancy or pregnancy. Such measures may include scraping.
04.5 Interactions with other medicinal products and other forms of interaction
Note: The summary of product characteristics of the concomitant drug 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 have been studied in clinical trials with Qlaira.
• Effects of other medicines on Qlaira
Interactions may occur with drugs that induce microsomal enzymes resulting in increased clearance of sex hormones and which can lead to breakthrough bleeding and / or contraceptive failure.
Management
Enzyme induction can already be observed after a few days of treatment. Maximal enzyme induction is generally observed within a few weeks. After discontinuation of therapy, enzyme induction may persist for approximately 4 weeks.
Short-term treatment
Women undergoing treatment with enzyme inducers should temporarily use a barrier method or another method of contraception in addition to the combined oral contraceptive. The barrier method should be used for the entire period of concomitant drug intake and for 28 days following discontinuation of therapy. If therapy continues after the end of the active tablets of the COC pack, the placebo tablets should be discarded and the next COC pack started.
Long-term treatment
For women undergoing long-term treatment with hepatic enzyme inducers, another reliable, non-hormonal method of contraception is recommended.
Substances that increase the clearance of COCs (decreased efficacy of COCs by enzyme inducers) e.g.:
Barbiturates, carbamazepine, phenytoin, primidone, rifampicin, the HIV drug ritonavir, nevirapine and efavirenz and possibly also felbamate, griseofulvin, oxycarbazepine, topiramate and products containing "St. John's wort" (Hypericum perforatum).
In a clinical study, rifampicin, a potent inducer of cytochrome P450 (CYP) 3A4, resulted in a significant decrease in steady-state concentrations and systemic exposure to dienogest and estradiol. The steady-state AUC (0-24 hours) of dienogest and estradiol decreased by 83% and 44%, respectively.
Substances with variable effect on the clearance of COCs:
When co-administered with COCs, combinations of HIV protease inhibitors and non-nucleoside reverse transcriptase inhibitors, including combinations with HCV inhibitors, may increase or decrease plasma concentrations of estrogen or progestogen. The net effect of these changes in some cases may be clinically relevant.
Consequently, prescribing information regarding HIV / HCV concomitant medications should be consulted to identify potential interactions and any related recommendations. If in doubt, the woman undergoing therapy with protease inhibitors or non-nucleoside reverse transcriptase inhibitors should use a barrier method of contraception.
Substances that interfere with the metabolism of combined hormonal contraceptives (enzyme inhibitors):
Dienogest is a substrate of CYP3A4
Known inhibitors of CYP3A4, such as azole antifungals, cimetidine, verapamil, macrolides, diltiazem, antidepressants and grapefruit juice, may increase the plasma levels of dienogest.
In a clinical study evaluating the effect of CYP3A4 inhibitors (ketoconazole, erythromycin), steady-state plasma levels of dienogest and estradiol were increased. Co-administration with the strong CYP3A4 inhibitor ketoconazole resulted in a 186% and 57% increase in steady-state AUC (0-24 hours) of dienogest and estradiol, respectively. Concomitant administration of the moderate inhibitor erythromycin increased the steady-state AUC (0-24 hours) of dienogest and estradiol by 62% and 33%, respectively. The clinical relevance of these interactions is unknown.
• Effects of Qlaira on other medicines
Oral contraceptives can affect the metabolism of some other active ingredients. Consequently, plasma and tissue concentrations may either increase (e.g. cyclosporine) or decrease (e.g. lamotrigine).
The pharmacokinetics of nifedipine were not affected by the concomitant administration of 2 mg dienogest + 0.03 mg ethinylestradiol, thus confirming the results of in vitro studies indicating that inhibition of CYP enzymes by Klaira is unlikely to occur. therapeutic dose.
• Other forms of interaction
Laboratory tests
The use of contraceptive steroids can influence the results of some laboratory tests, including biochemical parameters relating to liver, thyroid, adrenal and renal function, plasma levels of proteins (transporters), such as eg.corticosteroid-binding globulin and lipid / lipoprotein fractions, parameters of carbohydrate metabolism and parameters of coagulation and fibrinolysis. Variations generally remain within the laboratory norm.
04.6 Pregnancy and lactation
Pregnancy
Qlaira should not be used during pregnancy.
If pregnancy occurs while using Qlaira, further intake should be stopped immediately. However, large epidemiological studies with combined oral contraceptives containing ethinylestradiol have not revealed an increased risk of malformations in children born to women who used combined oral contraceptives prior to pregnancy, nor teratogenic effects in case of accidental use of combined oral contraceptives during pregnancy. the pregnancy. Animal studies do not indicate a risk of reproductive toxicity (see section 5.3).
The increased risk of thromboembolism in the postpartum period should be considered when Qlaira is restarted (see sections 4.2. And 4.4).
Feeding time
Lactation may be affected by COCs, as they can decrease the amount and alter the composition of breast milk. Therefore, the use of COCs should not be recommended until weaning has been completed. Small amounts of the contraceptive steroids and / or their metabolites may be excreted in breast milk and may affect the newborn.
Fertility
Qlaira is indicated for preventing pregnancy. For information regarding return to fertility, see section 5.1.
04.7 Effects on ability to drive and use machines
Qlaira does not affect the ability to drive or use machines.
04.8 Undesirable effects
The table below lists adverse reactions (ARs) classified by MedDRA system organ (MedDRA SOC). The list contains the MedDRA term (version 12.0) that is most appropriate to describe a particular adverse reaction. Related symptoms or conditions are not listed, but should still be considered.
Frequencies are based on data from clinical studies. Adverse reactions were recorded in 5 phase III clinical trials (n = 2266 women at risk for pregnancy, n = 264 women with dysfunctional uterine bleeding, in the absence of organic pathology, who wished to use oral contraception) and were believed to have at least one possible causal link with the use of Klaira. All ADRs listed in the "rare" category occurred in 1-2 volunteers, with a frequency
N = 2530 women (100.0%)
1 including vulvovaginal candidiasis and cervical fungus identified in a specimen
2 including crying and emotional lability
3 including loss of libido
4 including altered mood and mood swings
5 including tension headache and sinus headache
6 including migraine with aura and migraine without aura
7 including abdominal distension, upper abdominal pain, lower abdominal pain
8 including increased alanine aminotransferase, increased aspartate aminotransferase, increased gammaglutamyltransferase
9 including acne pustules
10 including generalized itching and itchy rash
11 including macular rash
12 including allergic dermatitis and urticaria
13 including skin tension
14 including breast pain, breast tenderness, nipple discomfort and pain
15 including irregular menstruation
16 including breast swelling
17 including vaginal haemorrhage, genital haemorrhage and uterine haemorrhage
18 including peripheral edema
19 included increase in blood pressure, and decrease in blood pressure
Description of some adverse reactions
An increased risk of arterial and venous thrombotic and thromboembolic events, including myocardial infarction, stroke, transient ischemic attacks, venous thrombosis and pulmonary embolism has been observed in CHC users, and this risk is discussed in more detail in section 4.4.
The occurrence of amenorrhea and intra-menstrual bleeding, based on patient diaries, is summarized in section 4.4 "Control of the cycle'.
The following serious adverse events, discussed in section 4.4, have been reported in women using COCs "Special warnings and precautions for use":
• venous thromboembolic disorders;
• arterial thromboembolic disorders;
• hypertension;
• liver tumors;
• onset or worsening of conditions for which the association with COCs is inconclusive: Crohn's disease, ulcerative colitis, epilepsy, migraine, uterine myoma, porphyria, systemic lupus erythematosus, herpes gestationis, Sydenham's chorea, haemolytic syndrome- uremic, cholestatic jaundice;
• chloasma;
• Chronic or acute disturbances of liver function may require discontinuation of COC administration until markers of liver function have returned to normal limits;
• in women with hereditary angioedema, exogenous estrogens can induce or exacerbate the symptoms of angioedema.
The frequency of breast cancer diagnoses among COC users increased very slightly. Since breast cancer is rare in women under the age of 40, the number of extra cases is small in relation to the overall risk of breast cancer. It is not known whether there is a causal link with the use of COCs. For further information see sections 4.3 and 4.4.
In addition to the adverse reactions mentioned above, cases of erythema nodosum, erythema multiforme, breast discharge and hypersensitivity have occurred during treatment with combined oral contraceptives containing ethinylestradiol. Although these symptoms were not reported during clinical studies with Qlaira, the possibility that they also occur during treatment with this medicine cannot be excluded.
Interactions
Interaction between oral contraceptives and other drugs (enzyme inducers) may cause breakthrough bleeding and / or contraception failure (see section 4.5).
Reporting of suspected adverse reactions
Reporting of suspected adverse reactions occurring after authorization of the medicinal product is important as it allows continuous monitoring of the benefit / risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system. "address https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse.
04.9 Overdose
No serious harmful effects from overdose have been reported. Symptoms that can occur when taking an overdose of active tablets are: nausea, vomiting and, in young girls, mild blood loss. There are no antidotes and treatment should be symptomatic.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: estrogen-progestogen sequential preparations.
ATC code: G03AB08.
In the clinical studies performed with Klaira in the European Union and in the USA / Canada the following Pearl indices were calculated:
Pearl Index (18-50 years old)
Method failure: 0.42 (upper limit 95% CI 0.77)
User error + method failure: 0.79 (upper limit 95% CI 1.23)
Pearl Index (18-35 years)
Method failure: 0.51 (upper limit 95% CI 0.97)
User error + method failure: 1.01 (upper limit 95% CI 1.59)
The contraceptive effect of COCs is based on the interaction of several factors, the main ones being the inhibition of ovulation, changes in the cervical mucus and changes in the endometrium.
In a 3-cycle ovulation inhibition study, treatment with Qlaira resulted in suppression of follicular development in the majority of women. During the post-treatment cycle, ovarian activity returned to pre-treatment levels.
Qlaira is formulated with a decreasing estrogen dosage and an increasing progestogen dosage. This regimen can be used to treat heavy menstrual flows in the absence of organic pathology, a disorder sometimes referred to as dysfunctional uterine bleeding (DUB).
To evaluate the safety and efficacy of Qlaira in women with symptoms of DUB who wished to use oral contraception, two multicenter, randomized, double-blind, similarly designed studies were conducted. Overall, 269 women were randomized to treatment with Klaira and 152 with placebo.
After 6 months of treatment, there was a decrease in median relative menstrual blood loss (MBL) of 88%, from 142 mL to 17 mL, in the Klaira group, versus 24%, from 154 mL to 117 mL, of the placebo group.
After 6 months of treatment, the percentage of women who were completely cured of DUB symptoms was 29% in the Klaira group, versus 2% in the placebo group.
The estrogen present in Klaira is estradiol valerate, an ester of natural human 17β-estradiol (1 mg of estradiol valerate corresponds to 0.76 mg of 17β-estradiol). This estrogen differs from the estrogens normally used in combined oral contraceptives, which are ethinyl estradiol or its pro-drug mestranol, by the lack of an ethinyl group in the 17α position.
Dienogest is a derivative of nortestosterone devoid of androgenic activity, but with an antiandrogenic activity equal to about one third of that of cyproterone acetate. Dienogest binds to the progesterone receptor of the human uterus with only 10% of the "Relative affinity of progesterone. Despite its low affinity for the progesterone receptor, dienogest has a potent progestogen effect in vivo. Dienogest does not have significant androgenic, mineralocorticoid or glucocorticoid activity in vivo.
The histology of the endometrium was studied in a subgroup of women (n = 218) in a clinical study, after 20 courses of treatment. No anomalies were found.
05.2 Pharmacokinetic properties
• Dienogest
Absorption
After oral administration, dienogest is rapidly and almost completely absorbed. After oral administration of a Qlaira tablet containing 2 mg of estradiol valerate and 3 mg of dienogest, maximum serum levels of 90.5 ng / ml are achieved in approximately 1 hour. Bioavailability is approximately 91%. The pharmacokinetics of dienogest are dose proportional over the range of 1-8 mg.
Concomitant food intake has no clinically relevant effect on the rate or extent of absorption.
Distribution
A relatively high fraction, equal to 10%, is present in plasma in free form, while about 90% is nonspecifically bound to albumin. Dienogest does not bind to specific transport proteins SHBG and CBG. The volume of distribution at steady state (Vd, SS) of dienogest is 46 l after intravenous administration of 85 mcg 3H-dienogest.
Biotransformation
Dienogest is almost completely metabolised via the metabolic pathways already known for steroids (hydroxylation, conjugation), mainly by CYP3A4. Pharmacologically inactive metabolites are rapidly excreted, so that dienogest is the largest fraction present in plasma, accounting for about 50% of the circulating dienogest-derived compounds.
Total clearance after intravenous administration of 3H-dienogest was equal to 5.1 l / h.
Elimination
The plasma half-life of dienogest is approximately 11 hours. Dienogest is extensively metabolised and only 1% of the drug is excreted unchanged. The urinary / faecal excretion ratio is approximately 3: 1 after oral administration of 0.1 mg / kg. Following oral administration, 42% of the dose is eliminated within the first 24 hours and 63% within 6 days by renal excretion. Overall, 86% of the dose is excreted in the urine and faeces after 6 days.
Steady state conditions
The pharmacokinetics of dienogest are not affected by SHBG levels. Steady state is reached after 3 days with constant dosage of 3 mg of dienogest in combination with 2 mg of estradiol valerate. The minimum, maximum and mean steady-state serum dienogesT concentrations are 11.8 ng / mL, 82.9 ng / mL, and 33.7 ng / mL, respectively. The mean accumulation ratio for AUC (0-24 hours) was 1.24.
• Estradiol valerate
Absorption
After oral administration, estradiol valerate is completely absorbed. Cleavage to estradiol and valeric acid occurs during absorption from the intestinal mucosa or during the first hepatic passage. This results in an increase in estradiol and its metabolites estrone and estriol. A maximum serum concentration of estradiol of 70.6 pg / ml is reached between 1.5 and 12 hours after a single ingestion of the tablet containing 3 mg of estradiol. valued on day 1.
Biotransformation
Valeric acid is metabolised very rapidly. After oral administration about 3% of the dose is directly bioavailable as estradiol. Estradiol is subject to a marked first pass effect and a considerable part of the administered dose is already metabolised in the gastrointestinal mucosa. Along with presystemic metabolism in the liver, approximately 95% of the orally administered dose is metabolized before reaching 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% circulates in free form. Estradiol has a moderate dose-dependent induction activity on serum SHBG concentrations. At day 21 of the treatment cycle, SHBG is approximately 148% from baseline, and decreases to approximately 141% of baseline at day 28 (end of placebo phase) After intravenous administration, an apparent volume of distribution of approximately 1.2 L / kg was determined.
Elimination
The plasma half-life of circulating estradiol is approximately 90 min. After oral administration, the situation is completely different. Due to the large circulating pool of estrogen sulfates and glucuronides and the enteropathic circulation, the terminal half-life of estradiol represents a composite parameter, which depends on all these processes and is in the range of about 13-20 hours.
Estradiol and its metabolites are mainly excreted in the urine. Approximately 10% is excreted in the faeces.
Steady state conditions
The pharmacokinetics of estradiol are influenced by SHBG levels.In young women, the measured estradiol levels in plasma are the result of endogenous estradiol and that generated by Qlaira. During the treatment phase of 2 mg estradiol valerate and 3 mg dienogest, the maximum and mean serum concentrations of estradiol at steady state are 66.0 pg / mL and 51.6 pg / mL, respectively. Over the 28-day cycle, stable trough concentrations of estradiol are maintained, ranging between 28.7 pg / mL and 64.7 pg / ml.
Special populations
The pharmacokinetics of Qlaira have not been studied in patients with renal or hepatic insufficiency.
05.3 Preclinical safety data
Non-clinical data reveal no special hazard for humans based on conventional studies of repeated dose toxicity, genotoxicity, reproductive toxicity.
A carcinogenicity study with dienogest in mice and a more limited study in rats did not show an increase in tumors.
However, it should still be borne in mind that, due to their hormonal action, sex steroids can promote the growth of certain hormone-dependent tissues and tumors.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
06.2 Incompatibility
Not relevant.
06.3 Period of validity
5 years.
06.4 Special precautions for storage
This medicinal product does not require any special storage conditions.
06.5 Nature of the immediate packaging and contents of the package
Transparent PVC / aluminum blister in a cardboard calendar package.
Packs of:
1x28 tablets.
3x28 tablets.
6x28 tablets.
Each calendar pack (28 film-coated tablets) contains in the following order: 2 dark yellow tablets, 5 red tablets, 17 light yellow tablets, 2 dark red tablets and 2 white tablets.
Not all pack sizes may be marketed.
06.6 Instructions for use and handling
Unused medicine and wastes derived from this medicine must be disposed of in accordance with local regulations.
07.0 MARKETING AUTHORIZATION HOLDER
Bayer S.p.A. - Viale Certosa, 130 - 20156 Milan (MI)
08.0 MARKETING AUTHORIZATION NUMBER
1x28 film-coated tablets AIC n. 038900015
3x28 film-coated tablets AIC n. 038900027
6x28 film-coated tablets AIC n. 038900039
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
15 May 2009/03 November 2013
10.0 DATE OF REVISION OF THE TEXT
05/2015
