VI.2. ELEMENTS FOR A PUBLIC SUMMARY

VI.2. ELEMENTS FOR A PUBLIC SUMMARY VI.2.1 Overview of Disease Epidemiology COCs (Combined Oral Contraceptives) containing DRSP-EE (Drospirenone- Ethinylestradiol) are indicated for the prevention of pregnancy in women who elect to use oral contraceptives as a method of contraception. Target population is comprised of women in fertile age. There are 60 million women of reproductive age in the US, approximately 64% of whom use some method of contraception. COCs are the most popular reversible method of contraception due to their high efficacy, ease of use, minimal side effects and good cycle control (Bachmann and Kopacz, 2009). VI.2.2 Summary of Treatment Benefits (lay language). Combined Oral Contraceptives are not intended to treat any disease. Hormonal contraception suppresses menstruation and its use is intended to prevent undesired pregnancies. Hormonal contraception has the characteristic of being both user-controlled and highly effective, with negligible failure rates. The efficacy of ethinylestradiol/ drospirenone combination has been well documented over many years of widespread clinical use. 516 healthy females aged 18-35 (excluding smokers above 30 years of age) with a need for contraception were included in a study conducted at 33 centres in Germany and Switzerland. After 2 years of treatment with ethinylestradiol/ drospirenone 0.02 mg/ 3 mg, only two pregnancies happened, which reflected a 99.56% contraceptive protection over two years. Approximately 87% of the women were satisfied or very satisfied with study treatment. Additionally, a total of 73% indicated they would continue with the study medication if given the choice. These results suggest that the medicine was generally well accepted A second study was conducted at 25 centers in 4 European countries to compare the efficacy of ethinylestradiol/ drospirenone (EE/drospirenone) 0.02 mg/ 3 mg with ethinylestradiol/ desogestrel (EE/desogestrel) 0.03 mg/ 0.15 mg combination. A total of 445 women received the contraceptive treatment randomly assigned in the study. Slightly more women on EE/drospirenone group were very satisfied (59.5%) with the treatment compared to EE/desogestrel (55.7%). At the end of the study, around 2% more would choose the option of continuing the treatment on EE/drospirenone vs EE/desogestrel treatment. 75 186

VI.2.3. Unknowns Relating to Treatment Benefits The safety profile of COCs containing DRSP-EE is well known and similar to that of other COCs. These COCs are well tolerated and a good number of clinical trials have been performed in target population (women in reproductive age). DRSP-EE COCs are contraindicated in women with severe hepatic or renal diseases. Related to age, COCs are only indicated before menarche and after menopause. Concerning ethnic groups, no clinically relevant differences in the pharmacokinetics of DRSP-EE COCs between Japanese and Caucasian women have been found therefore differences in efficacy are not expected. 76 186

VI.2.4 Summary of Safety Concerns Important Identified Risks Important Identified Risk What is known Preventability Blood clots in a vein (referred to as venous thrombosis, venous thromboembolism or VTE) Using a combined hormonal contraceptive such as 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 (referred to as a venous thrombosis, venous thromboembolism or VTE) in the arteries (referred to as an arterial thrombosis, arterial thromboembolism or ATE). Recovery from blood clots is not always complete. Rarely, there may be serious lasting effects or, very rarely, they may be fatal 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 a blood clot in the leg or lung (DVT or PE) with <invented name> is small. - Out of 10,000 women who are not using any combined hormonal contraceptive and are not pregnant, about 2 will develop a blood clot in predisposing factors monitoring Women should be advised to seek urgent medical attention in case of: o Symptoms of deep vein thrombosis: unilateral swelling of the leg and/or foot 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 discoloured skin on the leg o Symptoms of pulmonary embolism: sudden onset of unexplained shortness of breath or rapid breathing 77 186

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. - Out of 10,000 women who are using a combined hormonal contraceptive that contains drospirenone such as <invented name>, between about 9 and 12 women will develop a blood clot in a year. - The risk of having a blood clot will vary according to your personal medical history (see Factors that increase your risk of a blood clot below) sudden coughing which may be associated with haemoptysis sharp chest pain severe light headedness or dizziness rapid or irregular heartbeat. o Symptoms of retinal vein thrombosis (blood clot in the eye): blurring of vision which can progress to loss of vision In case of suspected or confirmed VTE, COC use should be Blood clots in an artery (Artery thrombosis) Epidemiological studies have associated the use of CHCs with an increased risk for arterial thromboembolism (myocardial infarction) or for cerebrovascular accident (e.g. transient ischaemic attack, stroke). Arterial thromboembolic events may be fatal. Combined hormonal contraceptives should not be used in presence or risk of arterial thromboembolism (ATE): - Current ATE, history (e.g. myocardial infarction) - Current or history of cerebrovascular disease - History of migraine with focal neurological symptoms - High risk due to multiple risk factors or predisposing factors. monitoring. Women should be advised to seek urgent medical attention in case of: o Symptoms of a cerebrovascular accident: Sudden numbness or weakness of the face, arm or leg, especially on one side of the body 78 186

one serious risk factor such as: diabetes mellitus with vascular symptoms, severe hypertension, severe dyslipoproteinaemia. Risk factors for ATE include: increasing age (>35 years), smoking, hypertension, obesity, positive family history (arterial thromboembolism ever in a sibling or parent especially at relatively early age e.g. below 50), migraine, and other medical conditions associated with adverse vascular events. sudden trouble walking, dizziness, loss of balance or coordination sudden confusion, trouble speaking or understanding sudden trouble seeing in one or both eyes sudden, severe or prolonged headache with no known cause loss of consciousness or fainting with or without seizure o Symptoms of myocardial infarction (MI): 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 feeling of being full, having indigestion or choking sweating, vomiting dizziness nausea, or extreme weakness, anxiety, or shortness of breath rapid or irregular 79 186

heartbeats Breast cancer Benign and malignant liver tumours Disturbances of liver Function (Hepatic disease) The excess risk gradually disappears during the course of the 10 years after cessation of COC use. Because breast cancer is a 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 tends to be less advanced clinically than the cancers diagnosed in never-users. In rare cases, benign liver tumours, and in even fewer cases malignant liver tumours have been reported in pill users. In women using COCs have been reported cholestasis jaundice that resulting from abnormality of bile flow in the liver, biliary pain, etc. Acute or chronic disturbances of liver function may necessitate the discontinuation of COC use until markers of liver function return to normal. In case of suspected or confirmed ATE, COC use should be predisposing factors monitoring COC may be discontinued if necessary. Do not take the pill if you have (or have ever had) a tumour in the liver. Contact your doctor if you have unusually severe abdominal pain. predisposing factors. monitoring. CHC may be discontinued if necessary. Pancreatitis (inflammation Women with high levels of triglycerides increase risk of pancreatitis when using 80 186

of the pancreas) COCs. Combined oral contraceptives (COCs) should not be used in the presence of any of the conditions listed below. Should any of the conditions appear for the first time during COC use, the product should be immediately stopped: -Pancreatitis or a history there of if associated with severe hypertriglyceridemia predisposing factors. monitoring. CHC may be discontinued if necessary. Increased blood pressure Rare inherited disorder characterized by recurrent episodes of the accumulation of fluids outside of the blood (Induction or exacerbation of the symptoms of hereditary angioedema) Although small increases in blood pressure have been reported in many women taking COCs, clinically relevant increases are rare. A systematic relationship between COC use and clinical hypertension has not been established. 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. In women with hereditary angioedema, exogenous estrogens may induce or exacerbate symptoms of angioedema. (Hereditary) angioedema have been reported to occur or deteriorate with both pregnancy and COC use, but the evidence of an association with COC use is inconclusive. predisposing factors. monitoring. CHC may be discontinued if neccesary. predisposing factors. monitoring. CHC may be discontinued if necessary. Important Potential Risks 81 186

RISK WHAT IS KNOWN PREVENTABILITY - Cervical cancer An increased risk of cervical cancer in women taking COCs (> 5 years) has been reported in some studies, but there continues to be controversy about the extent to which this finding is attributable to other effects or factors such as infection by human papilloma virus. The relative risk has not been established. Do not take the pill if you have (or have ever had) a cervical cancer. -Worsening of depression -Worsening of Crohn s disease and ulcerative colitis -Insulin resistance This potential increase in risk is especially important in patients with known or suspected sex-steroid influenced malignancies of the genital organs or the breasts. Depression or emotional swings may be developed or worsened while you are using pill. Crohn s disease and ulcerative colitis may be developed or worsened while you are using pill Diabetes may be developed or worsened while you are using pill Consult your doctor if you suffer from worsening. If you have Crohn s disease and ulcerative colitis, consult your doctor If you have diabetes, consult your doctor. - Hyperkalemia Concomitant use of COCs containing DRSP and potassium-sparing medicinal products may be a potential risk for hyperkalemia, mainly in patient with mild or moderate renal impairment. Contact your doctor if potassium levels increased. High serum potassium levels may lead to severe or fatal cardiac events. Important Missing Information None. 82 186

VI.2.5 Summary of Additional Risk Minimization Measures by Safety Concern All medicines have a Summary of Product Characteristics (SmPC) which provides physicians, pharmacists and other health care professionals with details on how to use the medicine, the risks and recommendations for minimising them. An abbreviated version of this in lay language is provided in the form of the package leaflet (PL). The measures in these documents are known as routine risk minimisation measures. The Summary of Product Characteristics and the Package leaflet for Drospirenone/ Ethinyl estradiol can be found on the web pages of the national competent authorities in the EU. This medicine has special conditions and restrictions for its safe and effective use (additional risk minimisation measures). Full details on these conditions and the key elements of any educational material can be found in Annex II of the product information which is published in EPAR page; how they are implemented in each country however will depend upon agreement between the marketing authorisation holder and the national authorities. These additional risk minimisation measures are for the following risks: Venous thromboembolism Risk Minimisation Measure(s) Direct Healthcare Professional Communication (DHPC), the Checklist, user card and information sheet Objective and rationale: The objective is to minimise the risk of thromboembolism based on class label. Summary description of main additional risk minimisation measure to inform about the completed referral procedure and its impact on combined hormonal contraceptives (CHCs) to inform about the class label associated with the CHCs to inform about the strengthened recommendations for use of CHCs Arterial thromboembolism 83 186

Risk Minimisation Measure(s) Direct Healthcare Professional Communication (DHPC), the Checklist, user card and information sheet Objective and rationale: The objective is to minimise the risk of thromboembolism based on class label. Summary description of main additional risk minimisation measure to inform about the completed referral procedure and its impact on combined hormonal contraceptives (CHCs) to inform about the class label associated with the CHCs to inform about the strengthened recommendations for use of CHCs VI.2.6 Planned Post-authorisation Development Plan Not applicable. VI.2.7 Summary of Changes to the Risk Management Plan over Time Not applicable. 84 186