Medical knowledge | Dermatology » Cyproterone Acetate, Ethinylestradiol

EURMP Diane®-35 05/2017 Version 2.0 196 of 976 DIANE®-35 (Cyproterone acetate + ethinylestradiol) EU Risk Management Plan Part VI – Summary of activities in the risk management plan by product Safety concern Routine risk minimisation measures Additional risk minimisation measures the differential diagnosis in case of occurrence of corresponding signs or symptoms. Insulin resistance SmPC provides information in section “Special warnings and precautions for use” that treatment may have an effect on peripheral insulin resistance and glucose tolerance, that there is no evidence for a need to alter the therapeutic regimen in diabetics using low-dose COCs, such as Diane®-35, and that diabetic women should be carefully observed while taking COCs. No activities currently planned. Crohn’s Disease and ulcerative colitis SmPC provides information in section “Special warnings and precautions for use” that ulcerative colitis and Crohn’s disease have been associated with

COC use. No activities currently planned. Pancreatitis (hypertriglyceridemiaassociated) SmPC section “Special warnings and precautions for use” provides information that women with hypertriglyceridemia, or a family history thereof, may be at an increased risk of pancreatitis. No activities currently planned. Increase in onset or deterioration of depression SmPC section “Undesirable effects” provides information that depressed mood and mood changes are reported in COC users No activities currently planned. 2. 2.1 2.11 Elements for a Public Summary Overview of disease epidemiology Acne Acne vulgaris affects the great majority of adolescents and adults at some time in their lives. The prevalence in adolescents ranges from 70% to 87%. Mild acne declines or disappears in a large proportion of teenage acne patients with the increasing age. The prevalence of acne in 1.82 196 EURMP Diane®-35 05/2017 Version 2.0 197 of 976 DIANE®-35 (Cyproterone acetate +

ethinylestradiol) EU Risk Management Plan Part VI – Summary of activities in the risk management plan by product adults is reported to be 13.6% to 54% Adult women are affected more often than men Several studies show that the prevalence of moderate to severe acne in adult women is between 12% and 13%. While hereditary factors appear to influence occurrence of acne, other risk factors, e.g smoking, stress, dietary factors and body mass index are discussed controversily in the literature. 2.12 Hirsutism Hirsutism is a clinical sign and not a separate disease and is often caused by an excess of circulating androgens. Hirsutism is not a life threatening condition However, its presence often has an impact on women’s wellbeing. There is a wide range in the prevalence of hirsutism in the different ethnia varying in Europe from 5.4% to 71% In the Middle East the prevalence in women is higher (8.3% to 108%) The lowest prevalence is found in women of Thai and Chinese ethnicity and is only

2.0% Risk factors for hirsutism are tobacco smoking, drug exposure, obesity, insulin resistance and a family history of hirsutism and an excess of male hormons. 2.2 Summary of treatment benefits Diane®-35 is used to treat skin conditions such as acne, very oily skin and excessive hair growth in women of reproductive age. The composition and properties of the active ingredients of Diane®-35 make it possible to treat diseases the cause of which is either an increased production of male sexual hormones or a particular sensitivity to these hormones. Diane®-35 should only be taken if the patient’s skin condition has not improved after use of other anti-acne treatments, including topical treatments and antibiotics. Treatment with Diane®-35 leads usually after 3 to 4 months of therapy to the healing of existing acne efflorescences. The excessive greasiness of the hair and skin generally disappears earlier However, in women experiencing mild forms of excessive hair growth and, in

particular, slightly increased facial hair, results do not become apparent until after several months of use. Diane®-35 also works as an oral contraceptive. The patient and her doctor will have to consider all the factors that would normally apply to the safe use of oral hormonal contraceptives. If Diane®-35 is taken correctly (without missing tablets), the chance of becoming pregnant is very low. The simultaneous use of other hormonal contraceptives is, therefore, contraindicated. Previously used hormonal contraception should be discontinued It is used for female patients after menarche and before menopause. The main clinical study with Diane®-35 involved 425 patients with mild to moderately severe acne, very oily skin or a mild form of excessive hair growth between 18 and 50 years of age who were randomised to 1 of 2 different treatments: 1.82  Diane®-35 (35 µg ethinylestradiol [EE]/ 2 mg cyproterone acetate CPA])  Diane®-50 (50 µg EE/ 2 mg CPA) 197 EURMP

Diane®-35 05/2017 Version 2.0 198 of 976 DIANE®-35 (Cyproterone acetate + ethinylestradiol) EU Risk Management Plan Part VI – Summary of activities in the risk management plan by product Diane®-50 reached the market a few years before Diane®-35. Diane®-35 was developed in order to lower the estrogen dosis of the drug, as the estrogen is responsible for some of the side effects. All patients were treated for 9 months. Facial acne, greasy skin and greasy hair were improved or even cured in about 50% of the participating women receiving Diane®-35 after 3 months of treatment, and in approximately 85% after 9 months. Mild facial excessive hair growth disappeared completely by the 3rd treatment cycle in about 10% of women, and in approximately 48% after 9 months of treatment. A supporting study involved 1161 patients between 18 and 50 years of age also suffering from mild to severe forms of acne, very oily skin or excessive hair growth who were treated with Diane®-35 for up to 3

years. The cure/improvement rates of mild to severe facial acne were approximately 42% at cycle 3, 73% at the 6th and 90% at the 12th cycle. Similar treatment success was achieved for greasy skin. With excessive hair growth, the influence of Diane®-35 became apparent only somewhat later. The therapy led to the complete disappearance of excessive hair growth in 20% of the cases with facial hair by the 6th cycle, and in 35% by the 12th cycle. In this study with a large number of particpants on long-term treatment it was also demonstrated that Diane®-35 also ensures a good bleeding pattern and reliably protects from becoming pregnant. There are no post-authorisation data which impact on efficacy. Diane®-35 and other hormonal combinations of estrogens and progestins are often considered for treatment in women between menarche and menopause to treat their moderate to severe skin conditions, the cause of which is either an increased production of androgens or a particular sensitivity to

these hormones, if topical treatments are not sufficiently effective, or if antibiotics cannot or should not be taken any longer. There are alternative treatments available. The choice of the most suitable treatment depends on the severity of acne or excessive hair growth. Local treatments are suitable for the treatment of mild forms. Treatment options for (more serious) acne include antibiotics (topical or systemic), keratolytics and retinoids (oral). The oral form of isotretinoin is reserved for severe acne with the risk of scarring or with scarring. For excessive hair growth, in addition to non-pharmacological treatment options (e.g laser treatment), pharmacological intervention can be indicated. There is one licensed alternative therapy available, i.e monotherapy with CPA (the progestin, contained in Diane®-35, however, in a much higher dose compared to that in Diane®-35). However, CPA monotherapy should be combined with adequate contraception because the high dose may harm an

unborn child. Additionally, hormonal contraceptives with a progestin that is also able to decrease the blood level of male sexual hormones are used. However, they are not licensed for this indication. 1.82 198 EURMP Diane®-35 05/2017 Version 2.0 199 of 976 DIANE®-35 (Cyproterone acetate + ethinylestradiol) EU Risk Management Plan Part VI – Summary of activities in the risk management plan by product 2.3 Unknowns relating to treatment benefits Diane®-35 has been available for the treatment of acne and excessive hair growth for more than 28 years. It was tested in clinical trials in more than 2400 patients of all relevant age groups and for all forms of severity of the underlying skin conditions. In the main and supporting studies nearly all patients were white Caucasians. It is assumed that the results in white Caucasians will not be any different in non-white patients in providing an effective cure for acne, very oily skin and excessive hair growth, and in providing

prevention from pregnancy. The safety of Diane®-35 was carefully observed during this time. There is no evidence that there are any undetected patient groups suffering from acne, very oily skin and excessive hair growth, who would not benefit from Diane®-35 as expected from the considerable scientific knowledge about this product after 28 years of real-life use. 2.4 Summary of safety concerns Important identified risks 1.82 Risk What is known Preventability Blood clots (thromboembolic events [TEE]) A thrombosis is the formation of a blood clot which may block a blood vessel. A thrombosis sometimes occurs in the deep veins of the legs (deep venous thrombosis). Venous thromboembolism (VTE) can develop whether or not you are taking the pill. It can also happen if you become pregnant. If a blood clot breaks away from the vein where it has formed, it may reach and block the arteries of the lungs, causing a so-called “pulmonary embolism”. Blood clots can also occur very rarely

in the blood vessels of the heart (causing a heart attack). Blood clots or a ruptured blood vessel in the brain may cause a stroke. Taking Diane®-35 may slightly increase the risk of having a blood clot (called a thrombosis). The chances of having a blood clot are only increased slightly by taking Diane®-35 compared with women who do not take Diane®-35 or any contraceptive pill. A full recovery is not always made and in 1-2% of cases, it can be fatal. Control for higher risk of a thrombosis due to a combination of risk factors or perhaps one very strong risk factor. In the case of a combination of factors the risk may be higher than simply adding two individual risks. If the risk is too high, Diane®-35 should not be prescribed. Liver and bile ducts disorders Asymptomatic elevations of transaminases are the common manifestations of liver function disturbances. Liver and bile duct disorders are considered a class effect of preparations which combine two different female hormones,

socalled estrogens and progestogens, such as Diane®-35 or any contraceptive pill. Severe Patients who have (or have had) liver disease (symptoms of which may be yellowing of the skin or itching over the whole body) and whose liver is still not working normally 199 EURMP Diane®-35 05/2017 Version 2.0 200 of 976 DIANE®-35 (Cyproterone acetate + ethinylestradiol) EU Risk Management Plan Part VI – Summary of activities in the risk management plan by product Risk What is known Preventability liver damage remains rare. Studies showed that the risk of acute liver damage associated with Diane®-35 use is not substantially higher than for any contraceptive pill. should not use Diane®35. Increased blood pressure Blood pressure increase is common and may have numerous causes. Preparations which combine two different female hormones, socalled estrogens and progestogens, such as Diane®-35 or any contraceptive pill, have been associated with the risk of an increase in blood

pressure. Patient with very high blood pressure should not be prescribed Diane®-35. If a high blood pressure develops during use of Diane®-35 then it is prudent for the physician to withdraw Diane®-35 and treat the high blood pressure. Effect on hereditary angioedema Some people inherit a tendency to develop episodes of angioedema, but it is uncommon. Women are affected more often than men. Preparations which combine two different female hormones, so-called estrogens and progestogens, such as Diane®-35 or any contraceptive pill, have been associated with an effect on hereditary angioedema. It is not known how estrogens influence the occurrence of angioedema. In patients with hereditary angioedema, the exacerbation of hereditary angioedema is potentially life-threatening. Patient with family history or known diagnosis of hereditary angioedema should be prescribed Diane®-35 with special care and close observation should be kept. If onset or exacerbation of hereditary angioedema

develops during use of Diane®-35 then it is prudent for the physician to withdraw Diane®-35 and treat patient accordingly. Important potential risks 1.82 Risk What is known (including reason why it is considered a potential risk) Breast cancer Breast cancer is considered a class effect of preparations which combine two different female hormones, so-called estrogens and progestogens, such as Diane®-35 or any contraceptive pill. Breast cancer has been observed slightly more often in women using combined pills, but it is not known whether this is caused by the treatment itself. For example, it may be that more tumors are detected in women on combined pills because they are examined by their doctor more often. The risk of breast tumors becomes gradually less after stopping the combined hormonal contraceptive.Breast cancer may be life-threatening or may have a fatal outcome As the risk attributable to Diane®-35 has not been completely established this is seen as a potential risk.

200 EURMP Diane®-35 05/2017 Version 2.0 201 of 976 DIANE®-35 (Cyproterone acetate + ethinylestradiol) EU Risk Management Plan Part VI – Summary of activities in the risk management plan by product 1.82 Risk What is known (including reason why it is considered a potential risk) Cervical cancer Cervical cancer is considered a class effect of preparations which combine two different female hormones, so-called estrogens and progestogens, such as Diane®-35 or any contraceptive pill. The most important risk factor for cervical cancer is persistent Human Papilloma Virus (HPV) infection. Some studies suggest that long-term use of the pill increases a womans risk of developing cervical cancer. However, it is not clear to what extent sexual behavior or other factors, such as HPV, increase this risk. Cervical cancer may be life-threatening or may have a fatal outcome As the risk attributable to Diane®-35 has not been completely established this is seen as a potential risk.

Benign and malignant liver tumors Benign and malignant liver tumors are considered a class effect of preparations which combine two different female hormones, so-called estrogens and progestogens, such as Diane®-35 or any contraceptive pill.In rare cases, benign liver tumors, and in even fewer cases malignant liver tumors have been reported in contraceptive pill users. In isolated cases, these tumors have led to life-threatening internal bleeding. As the risk attributable to Diane®-35 has not been completely established this is seen as a potential risk. Insulin resistance/decreased glucose tolerance Among other potential causes, the preparations which combine two different female hormones, so-called estrogens and progestogens, such as Diane®35 or any contraceptive pill, have been implicated as possible factors in triggering insulin resistance, also known as "pre-diabetes", and blood sugar tolerance disorder. As the risk attributable to Diane®-35 has not been

completely established this is seen as a potential risk. Routine patient monitoring is considered a suitable and sufficient method to detect clinically relevant high blood sugar during the treatment with Diane®-35. Diabetic women should be carefully observed while taking Diane®-35. Crohn’s disease and ulcerative colitis Crohns disease is a condition that causes inflammation of the wall of the gut. Any part of the gut can be affected Ulcerative colitis is a disease where inflammation develops in the colon and the rectum (the large intestine). The cause for these conditions is not known and they could affect anyone. Among other potential causes, the preparations which combine two different female hormones, so-called estrogens and progestogens, such as Diane®35 or any contraceptive pill, have been implicated as possible factors in triggering the disease to start. To date, no evidence has showen that Crohn’s disease and ulcerative colitis are independent adverse reactions of

Diane®-35. Pancreatitis (in patients with high levels of lipids in blood) In women on the preparations which combine two different female hormones, so-called estrogens and progestogens, such as Diane®-35 or any contraceptive pill, severe hypertriglyceridemia (high levels of lipids in blood) is a known rare risk factor for developing acute pancreatitis. Avoiding the prescription of Diane®-35 to women with pre-existing severe high levels of lipids in blood and close monitoring of women with moderately increased blood lipids levels can be assumed to be adequate strategies to prevent the occurrence of hypertriglyceridemia-associated pancreatitis. 201 EURMP Diane®-35 05/2017 Version 2.0 202 of 976 DIANE®-35 (Cyproterone acetate + ethinylestradiol) EU Risk Management Plan Part VI – Summary of activities in the risk management plan by product Risk What is known (including reason why it is considered a potential risk) Increase in onset and deterioration of depression

Lifetime prevalence of major depressive disorder in women is almost twice than in men. The hyperandrogenic patients (eg acne and polycystic ovary syndrome (PCOS) patients further constitute a high risk group for common affective and anxiety disorder as well as depression and suicidality. Depressive symptoms and mood changes are labelled side effects for many COCs as for Diane®-35. Nonetheless, there is no conclusive evidence available that COCs or Diane®-35 cause major depression or lead to clinically significant deterioration of preexisting depression. Furthermore, there are published data available which suggest mood improvement in women using COCs and that COCs containing less androgenic progestogens, such as desogestrel, drospirenone or CPA appear to be more favorable in terms of mood symptoms than progestogens with a more androgenic profile. Important missing information Risk What is known None Not applicable 2.5 Summary of risk minimisation measures by safety concern

These additional risk minimisation measures are for the following risks: Blood clots (thromboembolic events [TEE]) Risk minimisation measure(s): Healthcare Professionals and patients education Objective and rationale: HCPs and patients to understand the risk of blood clots and the appropriate management of this risk to minimise its occurrence and its severity. Main additional risk minimisation measures: Educational material 1.82  Prescribers checklist  Patient information card for handout by HCP  Digital re-distribution of educational materials in agreement with the national competent authority (NCA) to be provided to HCP and subsequently to patients with a focus on thromboembolism and its risks factors, signs, and symptoms and contraindications relevant to TEEs as well as on the indication 202 EURMP Diane®-35 05/2017 Version 2.0 203 of 976 DIANE®-35 (Cyproterone acetate + ethinylestradiol) EU Risk Management Plan Part VI – Summary of activities in the risk

management plan by product 2.6 Planned post authorisation development plan List of studies in post authorisation development plan Study/activity (including study number) Objectives Safety concerns/efficacy issue addressed Status Planned date for submission of (interim and) final results DUS (database) Amendment to Study 17660 To characterize the proportion of Diane®35 users with concomitant periods of other hormonal contraceptives prescriptions. Potential for concomitant prescribing of other hormonal contraceptives Planned Final study report Q1/2019 2.7 Summary of changes to the Risk Management Plan over time Part I: none Part II SI: minor updates reflecting recent literature Part II SII: minor updates reflecting recent understanding of scientific evidence Part II SIII: no substantial changes Part II S IV: no substantial changes Part II SV: Section Action taken by regulatory authorities and/or marketing authorisation holders (MAHs) for safety reasons update

to reflect regulatory activities Section Non-study post-authorisation exposure updated Section Post-authorisation off-label use updated to include information on newly completed drug utilisation studies (survey and database study) Section Epidemiological study exposure updated to include newly completed studies Part II SVI: no substantial changes Part II SVII: updates reflecting recent understanding of scientific evidence of safety concerns, drug-drug interactions Part II SVIII: no substantial changes Part III: 1.82 Section 1 Safety concerns and overview of planned pharmacovigilance actions updated to reflect list of safety concerns and include concomitant use of hormonal contraception as an area requiring confirmation or further investigation to identified important risk VTE/ATE, 203 EURMP Diane®-35 05/2017 Version 2.0 204 of 976 DIANE®-35 (Cyproterone acetate + ethinylestradiol) EU Risk Management Plan Part VI – Summary of activities in the risk management plan by

product Section 2. Additional pharmacovigilance activities to assess effectivness of risk minimisation measures updated Section 3. Updated to include information on completed studies (DUS survey, DUS database, physician knowledge survey post-authorisation safety study [PASS]), also in table 5.2 Section 4, updated to include information on planned study to assess concomitant use of hormonal contraception (amendment to database DUS, study 17660) Corrected classification of educational material as additional riskminimisation material Part IV: none Part V: Section 1 updated to include information from conducted studies Harmonized list of safety concerns with part II 1.82 Part VI: Updated to include changes made Part VII: Updated to include pertinent annexes 204