Ethinyl estradiol, cyproterone acetate.
Each coated tablet contains 0.035 mg of ethinyl estradiol and 2 mg of cyproterone acetate.
Excipients/Inactive Ingredients: Core: lactose monohydrate; maize starch; polyvidone 25 000; talc; magnesium stearate.
Coating: sucrose; polyvidone 700 000; macrogol 6000; calcium carbonate (E 170); talc; glycerol 85 % (E 422); titanium dioxide (E 171); iron(lll) hydroxide/oxide x H20 (E 172); montanglycol wax, Wax E.
Pharmacotherapeutic group: antiandrogens and estrogens. ATC code: G03HB.
Pharmacology: Pharmacodynamics: Hair follicles and sebaceous glands are androgen sensitive. Acne and seborrhea are due, in part, to a sebaceous gland dysfunction, caused by increased peripheral sensitivity or raised androgen plasma levels. Both active ingredients in Diane-35 have a positive therapeutic effect. Cyproterone acetate competitively displaces androgens in the effector organ, thus cancelling the androgenic effect. The plasma androgen concentration is then reduced by an antigonadotropic effect. Ethinyl estradiol intensifies this effect, which leads to an up-regulation of sex-hormone binding globulin (SHBG). Plasma free androgen levels are reduced. Acne efflorescences generally heal after 3 to 4 months when treated with Diane-35. Oiliness of the skin and hair disappears first. Androgen-dependent hair loss is also reduced. It has to be pointed out that the effect is slow when treating female hirsutism. It may take several months to show effects.
Cyproterone acetate is also a potent progestogen, which possesses a contraceptive effect when used in combination with ethinyl estradiol. It rests on the interaction of central and peripheral mechanisms, of which ovulation inhibition and changes to cervical secretion have to be considered the most important. Moreover, the morphological and enzymatic changes in the endometrium provide extremely unfavorable conditions for nidation.
Contraceptive protection begins with the first day of use.
Pharmacokinetics: Cyproterone acetate (CPA): Absorption: Following oral administration CPA is completely absorbed in a wide dose range. The ingestion of Diane-35 effects a maximum serum level of 15 ng of CPA/mL at 1.6 hours. The absolute bioavailability of CPA is 88 % of dose. The relative bioavailability of CPA from Diane-35 was 109%, when compared to an aqueous microcrystal suspension.
Distribution: CPA is present in serum almost exclusively in protein-bound form. About 3.5 - 4.0% of total CPA levels are present unbound and the remainder is bound to albumin. Since CPA binding to sex hormone binding globulin (SHBG) is non-specific, changes in SHBG levels caused by ethinyl estradiol do not affect the pharmacokinetics of CPA.
Metabolism: CPA is metabolized by various pathways, including hydroxylations and conjugations. The main metabolite in human plasma is the 15β-hydroxy derivative.
Elimination: Drug serum levels decrease in two disposition phases characterised by half-lives of 0.8 hours and 2.3 days. The total clearance of CPA from serum is 3.6 mL/min-1/kg-1.
Some CPA dose parts are excreted unchanged with the bile fluid. Most of the dose is excreted in form of metabolites at a urinary to biliary ratio of 3:7 with a half-life of 1.9 days. Metabolites from plasma are eliminated at a similar rate (half-life of 1.7 days).
Steady-state conditions: That CPA accumulates during one treatment cycle is to be expected by virtue of the long half-life of the terminal disposition phase of CPA from serum and the daily intake. Mean maximum drug serum levels increase from 15 ng/mL (day 1) to 21 ng/mL and 24 ng/mL at the end of the treatment cycles 1 and 3 respectively. Steady-state conditions are reached after approximately 10 days. During long-term treatment, CPA accumulates over treatment cycles by about a factor of 2 to 2.5.
Smoking does not affect the pharmacokinetics of CPA.
Ethinyl estradiol (EE2): Absorption: Orally administered EE2 is absorbed rapidly and completely. After a single ingestion of Diane-35, maximum EE2 serum levels of about 80 pg/mL are reached at 1.7 hours.
The relative bioavailability of EE2 from Diane-35, with reference to an aqueous microcrystal suspension, was almost complete.
Distribution: An apparent distribution volume of approximately 5 L/kg was determined for EE2.
EE2 is highly but non-specifically bound to serum albumin. 2 % of the EE2 levels are present unbound.
The bioavailability of EE2 can be changed in both directions by other active substances. There is, however, no interaction with high doses of vitamin C. EE2 induces the hepatic synthesis of SHBG and corticosteroid-binding globulin (CBG) during continuous use. The extent of SHBG induction is dependent, however, on the chemical structure and dose of the co-administered progestogen. During treatment with Diane-35, an increase was observed in the SHBG serum levels from approximately 100 nmol/L to 300 nmol/L and in the CBG serum levels from about 50 ug/mL to 95 pg/mL.
Metabolism: EE2 is metabolized during absorption and the first liver passage resulting in a reduced absolute and variable oral bioavailability.
For EE2, the metabolic clearance rate from plasma was determined to be about 5 mL/min/kg.
Elimination: The EE2 plasma levels decrease in two phases characterised by half-lives of 1 - 2 hours and about 20 hours. For analytical reasons, these parameters can only be calculated for higher dosages.
Unchanged EE2 is not eliminated. The metabolites of EE2 are eliminated at a urinary to biliary ratio of 4:6 with a half-life of about 1 day.
Steady-state conditions: According to the half-life of the terminal disposition phase of EE2 from serum and the daily ingestion, steady state levels are reached after 3 - 4 days and are higher by 30 - 40 % as compared to a single dose.
Toxicology: Preclinical safety data: Ethinyl estradiol: The toxicity profile of ethinyl estradiol is well known. There are no preclinical safety data, which reveal relevant risks for humans and are not already included in other sections of the summary of product characteristics.
Cyproterone acetate: Systemic toxicity: Preclinical data reveal no specific risk for humans using Diane-35 based on conventional studies of repeated dose toxicity.
Reproductive toxicity, teratogenicity: The administration of cyproterone acetate during the hormone-sensitive differentiation phase of the genital organs causes signs of feminization in male fetuses after high doses. Observation of male neonates who had been exposed in utero to cyproterone acetate did not show any signs of feminization. Nevertheless, pregnancy is a contraindication for the use of Diane-35. Investigations into embryo-fetal development toxicity using the combination of both active ingredients showed no potential indicative of a teratogenic effect following treatment during organogenesis (end of treatment preceded the completed differentiation of the external genitalia) that exceeded the known effects on the differentiation of the male genital tract.
Genotoxicity, carcinogenicity: Recognized first-line tests of genotoxicity gave no indication of a mutagenic effect when conducted with cyproterone acetate. In further investigations, cyproterone acetate, however, was capable of producing adducts with DNA (and an increase in DNA repair activity) in liver cells from rats, monkeys and humans.
This DNA-adduct formation occurred at systemic exposures that might be expected to occur in the recommended dose regimens for cyproterone acetate. In-vivo consequences of cyproterone acetate treatment were the increased incidence of focal, possibly pre-neoplastic, liver lesions in which cellular enzymes were altered in female rats.
The clinical significance of these findings is currently uncertain. Clinical experience to date would not support an increased incidence of hepatic tumors in man.
Investigations into the tumorigenicity of cyproterone acetate in rodents did not reveal any results that fundamentally differed from those obtained with other steroid hormones. However, it must be borne in mind that sex steroids can promote the growth of certain hormone-dependent tissue and tumors.
On the whole, the available findings do not raise any objection to the use of Diane-35 in humans if used in accordance with the directions for the given indication and at the recommended doses.
Treatment of moderate to severe acne due to androgen sensitivity (with or without seborrhoea) and/or hirsutism in women of childbearing age.
Diane-35 should be used only after the failure of topical therapy or systemic antibiotic treatments for acne therapy.
As Diane-35 is also a hormonal contraceptive, it must not be used in combination with other hormonal contraceptives (see Contraindications).
Although this product also acts as an oral contraceptive, it should not be used in women solely for contraception, but should be reserved for those women requiring treatment for androgen-dependent conditions only, i.e. moderately severe hirsutism and severe acne.
Diane-35 inhibits ovulation and thereby has a contraceptive effect. Patients who are using Diane-35 should, therefore, not use an additional hormonal contraceptive, since this leads to an overdose of hormones and is not necessary for effective contraceptive protection. For the same reason, women who desire to become pregnant should not use Diane-35. Diane-35 must be taken regularly in order to develop an adequate therapeutic efficacy and effective contraceptive protection.
Method of administration: Oral use.
Use: Tablets must be taken in the order directed on the package every day at about the same time with some liquid as needed. One tablet is to be taken daily for 21 consecutive days. Each subsequent pack is started after a 7-day tablet-free interval, during which withdrawal bleeding usually occurs, which often starts on the 2nd-3rd day after taking the last tablet and can continue until the next pack is started.
Contraceptive protection starts on the first day the tablets are taken and also continues during the 7 tablet-free days. The simultaneous use of hormonal contraceptives must therefore stop.
Medical examination/consultation: Before using, it is advisable to perform a thorough general medical examination (including body weight, blood pressure, heart, legs and skin, urine test for diabetes, and liver diagnostic tests when necessary) as well as gynecological examinations (including the breasts and a cytological smear taken from the vaginal portion of the cervix and the cervix) and to compile a thorough family medical history in order to be able to detect diseases requiring treatment and risks. Pregnancy must be ruled out. It is advisable to have checkups every six months during use.
Coagulation system disorders should be ruled out if thromboembolic events (e.g. deep venous thrombosis, stroke, heart attack) have occurred in blood relatives at an early age.
It should also be pointed out that taking oral contraceptives does not protect against HIV infections (AIDS) and other sexually transmitted diseases.
Starting treatment: No previous hormonal contraception (during the past month): Tablet taking of one tablet daily has to start on day 1 of the woman's natural cycle (the first day of her menstrual bleeding). If the course is started between days 2 and 5, an additional contraceptive precaution (barrier contraceptive) is recommended during the first 7 days of tablet taking.
Only amenorrheic women start treatment immediately as prescribed by their physician; in the case of which, the first day of tablet taking is equivalent to the first day of the menstrual cycle and counting is continued according to the following recommendations.
Having previously taken combined oral contraceptives or having used a vaginal ring or a transdermal patch: Diane-35 should preferably be started on the day after having taken the last hormone-containing tablet of the previous combination product (or after the removal of the ring or of the patch), but at the latest on the day after the usual hormone-free interval, or on the day after having taken the last placebo from the previous combination product. If a ring or patch has previously been used, Diane-35 should preferably be started on the day of its removal, but at the latest on the day when re-administration of the previous contraceptive would be necessary.
Changing from a progestagen-only product (minipill, injection, implant) or from an intrauterine system (IUS): If the minipill has been taken previously, Diane-35 can be started on any day (the change from an implant or intrauterine system must take place on the day of removal, and at the time the next injection would be due, when changing from an injectable contraceptive). However, in all cases, additional contraceptive precautions are required during the first 7 days of tablet use.
After a first-trimester abortion: The tablets can be started immediately. In this case, no additional contraceptive precautions are required.
After delivery or a second-trimester abortion: The tablets should be started on days 21 to 28 after delivery or after an abortion in the second trimester. If they are started later, an additional barrier contraceptive must be used during the first 7 days of tablet taking. If, however, sexual intercourse has already taken place, pregnancy must be ruled out or the first menstrual period must have occurred before starting use.
Duration of administration: The time to symptomatic relief is at least three months. The treating physician should regularly check whether there is still a need for treatment.
The length of use depends on the severity of the symptoms of androgenisation and their response to treatment. Acne and seborrhea usually respond sooner than hirsutism. It is recommended to take Diane 35 for at least another 3 to 4 cycles after the signs have subsided.
If there has been a lack of response or only insufficient response in treating severe acne or seborrhea for at least six months or hirsutism for at least 12 months achieved, combined use of Diane-35 and Androcur 10 mg tablets or Androcur 50 mg tablets has to be considered or rather the treatment approach has to be reconsidered. As soon as the androgenisation signs have subsided but contraception is still desired, maybe a switch should be made to a low-dose oral contraceptive. Should there be a recurrence of androgenic symptoms, treatment with Diane-35 can be resumed. When resuming treatment with Diane-35 (after a tablet-free interval of at least 4 weeks), the increased risk of venous thromboembolism should be considered (see Precautions).
How to proceed when a tablet has been missed: If a user of Diane-35 forgot to take a tablet at the usual time, it has to be taken within 12 hours. All subsequent tablets should then be taken again at the usual time. Contraceptive protection is not impaired. If it has been more than 12 hours, contraception is no longer reliable. When tablets have been forgotten, there are basically two things to bear in mind: 1. Tablet taking must never be interrupted for longer than 7 days.
2. In order to build up adequate contraceptive protection, i.e. to achieve suppression of the hypothalamic-pituitary-ovarian system, it is necessary to take the tablets for 7 days.
Accordingly, the following recommendations can be made for routine practice.
Week 1: The missed tablet should be taken as soon as possible, even if this means taking two tablets at the same time. The remaining tablets are then taken at the usual time. During the next 7 days, however, an additional barrier contraceptive, such as a condom, should be used. If sexual intercourse has taken place in the past 7 days, the possibility of pregnancy should be taken into consideration. The risk of pregnancy is all the higher, the more tablets have been forgotten and the closer this is to the regular tablet-free interval.
Week 2: The missed tablet should be taken as soon as possible, even if this means taking two tablets at the same time. The remaining tablets are then taken at the usual time.
Provided that the tablets have been taken correctly on the 7 days before the first missed tablet, there is no need to use additional protective measures. If this was not the case or if more than 1 tablet was forgotten, the use of additional protective measures for 7 days should be recommended.
Week 3: On account of the approaching 7 tablet-free days, complete contraceptive protection can no longer be guaranteed. On the other hand, reduction of the contraceptive effect can be prevented by adjusting the tablet-taking schedule. By adhering to either of the two following procedures, there is no need for additional contraceptive measures, provided that the tablets were taken correctly on the 7 days preceding the first missed tablet. If this is not the case, the woman should proceed as described in item 1 and also use additional protective measures during the next 7 days.
1. The user should make up for the last missed tablet as soon as possible, even if this means taking two tablets at the same time. The remaining tablets are then taken at the usual time. The next blister pack is started directly after completion of the current blister pack, i.e. there should be no tablet-free interval between the two packs. It is unlikely that the user will have withdrawal bleeding before completing the second pack, however spotting or breakthrough bleeding can occur during use.
2. It can also be recommended to stop taking tablets from the current blister pack, followed by a tablet-free interval of up to 7 days, including the days on which tablets were omitted. The next pack should then be started.
In the event of missed tablets and missed withdrawal bleeding during the next regular tablet-free interval, the possibility of pregnancy should be considered.
Absence of withdrawal bleeding: In the absence of withdrawal bleeding, use should be discontinued until pregnancy has been excluded with certainty.
How to proceed in the case of intermenstrual bleeding: It is imperative to continue taking Diane-35 in the event of intermenstrual bleeding. Spotting usually ceases spontaneously or can be resolved within 4 to 5 days - as can intermenstrual bleeding of menstrual intensity (breakthrough bleeding) - by the additional administration of 25 - 50 μg of ethinyl estradiol (but not extending beyond the last tablet in a pack of Diane-35).
If breakthrough bleeding does not cease or if it recurs, a thorough examination to exclude an organic cause is indicated, including curettage.
This also applies to spotting, which occurs at irregular intervals in several consecutive cycles or which occurs for the first time after long use of Diane-35. In these cases, the bleeding is usually caused by organic changes and not by the product.
How to proceed in the case of vomiting or severe diarrhea: Vomiting or severe diarrhea may lead to incomplete absorption of the active ingredients. Additional non-hormonal methods of contraception (except the rhythm or temperature methods) should be used. If vomiting or severe diarrhea occur within 3 to 4 hours after tablet taking, the procedure quoted with regard to missed tablets as previously mentioned should be followed. If the user concerned does not want to depart from her normal tablet-taking rhythm, she must take the replacement tablet(s) from another blister pack.
Liver: After recovering from viral hepatitis (when the liver parameters have returned to normal), approximately six months should elapse before using a product, such as Diane-35.
Additional information on certain patient groups: Children and adolescents: Diane-35 may only be used after the menarche.
Geriatric patients: Not applicable. Diane-35 is not indicated after the menopause.
Patients with hepatic dysfunction: Diane-35 is contraindicated in women with severe hepatic disease, as long as liver function values have not returned to normal. See also Contraindications.
Patients with renal dysfunction: Diane-35 has not been specifically studied in patients with impaired renal function. The available data do not indicate the need for any treatment adjustment in this patient group.
There are no data available on overdose in humans. Based on the general data gathered with combined oral contraceptives, symptoms that can possibly occur are: nausea, vomiting and slight vaginal bleeding in young girls. There are no antidotes, and further treatment should be symptomatic.
Preparations containing estrogen/progestogen combinations 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 their use, the product should be stopped immediately.
Concomitant use of another hormonal contraceptive (see Indications/Uses).
Existing or previous venous thrombosis (e.g. deep vein thrombosis, pulmonary embolism).
Personal or family medical history of known, idiopathic venous thromboembolism (VTE) (where the family medical history relates to VTE in a sibling or parent at a relatively early age).
Existing or previous arterial thrombosis (e.g. myocardial infarction) or previous disorders (e.g. angina pectoris and transient ischemic attack).
Existing or previous cerebrovascular accident.
Presence of severe or multiple risk factors for venous or arterial thrombosis (see Precautions), e.g.: diabetes mellitus with vascular symptoms; severe hypertension; severe dyslipoproteinaemia.
Inherited or acquired predisposition for venous or arterial thrombosis, e.g. resistance to activated protein C (APC resistance), antithrombin III deficiency, protein C deficiency, protein S deficiency, hyperhomocysteinaemia and antiphospholipid antibodies (anticardiolipin antibodies, lupus anticoagulant).
Sickle cell anemia.
Pancreatitis or a history thereof if associated with severe hypertriglyceridaemia and/or other disturbances in lipid metabolism.
Severe hepatic disorders (also disorders of the excretory system such as Dubin-Johnson and Rotor syndrome) as long as the liver function values have not returned to normal.
Presence or a history of liver tumors (benign or malignant).
Undiagnosed vaginal bleeding.
History of migraine with focal neurological symptoms.
Smokers (see Precautions).
Known or suspected sex-steroid influenced malignancies (e.g. of the genital organs or the breasts).
History of idiopathic jaundice of pregnancy, severe pruritus of pregnancy or herpes gestationis, otosclerosis worsening with each pregnancy.
Presence of a desire for pregnancy, pregnancy, breast-feeding.
Hypersensitivity to the active substances or to any of the excipients.
Diane-35 is not for use in men.
This product is contraindicated in women with thrombophlebitis, thromboembolic disorders, or a history of these conditions.
Diane-35 consists of the progestogen cyproterone acetate and the oestrogen ethinylestradiol and is administered for 21 days of a monthly cycle. It has a composition similar to a combined oral contraceptive (COC).
Duration of administration: The time to symptomatic relief is at least three months. The treating physician should regularly check whether there is still a need for treatment (see Dosage & Administration).
If any of the disorders/risk factors mentioned below are present, the benefit of using Diane-35 should be weighed against the possible risks for the woman and discussed with her before she decides to use Diane-35. In the event of aggravation/exacerbation or first appearance of any of these disorders or risk factors, the woman should contact her physician. The physician should then decide whether the use of Diane-35 should be terminated.
Circulatory diseases: The use of Diane-35 carries an increased risk of venous thromboembolism (VTE) compared with non-use. The additional VTE risk is greatest during the first year of initial Diane-35 use by a woman or upon resumed use or a switch after a pill-free interval of at least one month. A venous thromboembolism can be fatal in 1-2% of cases.
Epidemiological studies have shown that the incidence of VTE in users of Diane-35 is 1.5 to 2 times higher than in users of combined oral contraceptives (COCs) containing levonorgestrel and may be similar to the risk for COCs containing desogestrel/gestodene/drospirenone.
The Diane-35 user group is likely to include patients who have a congenital increased cardiovascular risk, e.g. due to polycystic ovary syndrome.
Furthermore, epidemiological studies have associated the use of hormonal contraceptives with an increased risk for arterial (myocardial infarction, transient ischemic attack) thromboembolism.
In very rare cases, thrombosis has been reported to occur in other blood vessels among users of hormonal contraceptives, e.g. arteries and veins of the liver, mesentery, kidney, brain or retina.
The following may occur as symptoms of venous or arterial thrombosis or a cerebrovascular accident: unusual unilateral leg pain and/or swelling; sudden severe chest pain, regardless of whether it radiates to the left arm; sudden dyspnoea; sudden onset of cough; any unusual, severe, persistent headache; sudden partial or complete loss of vision; diplopia; slurred speech or aphasia; vertigo; collapse with or without a focal seizure; weakness or very significant numbness suddenly affecting one side or one part of the body; motor disorders; "acute" abdomen.
The risk of venous thromboembolic events rises with: Increasing age.
Smoking (the risk increases further with increasing tobacco consumption and age, especially in women over 35 years of age. Women over 35 years of age should be strongly advised not to smoke if they wish to use Diane-35).
A positive family history (i.e. venous thromboembolism in a sibling or parent at a relatively young age). If a hereditary predisposition is suspected, the woman should be referred to a specialist for advice before making a decision regarding the use of a hormonal contraceptive.
Prolonged bed confinement, major surgery, leg surgery or severe trauma. In these situations, it is recommended that use be terminated (in case of elective surgery, at least four weeks in advance) and not resumed until two weeks after full mobility has been regained. If the use of Diane-35 has not been terminated in advance, therapy with an antithrombotic agent should be considered.
Obesity (body mass index over 30 kg/m2).
The risk of arterial thromboembolic complications or cerebrovascular accident rises with: Increasing age.
Smoking (the risk rises further with increasing tobacco consumption and age, especially in women over 35 years of age. Women over 35 years of age should be strongly advised not to smoke if they wish to use Diane-35).
Obesity (body mass index over 30 kg/m2).
Valvular heart disease.
A positive family history (arterial thrombosis in a sibling or parent at a relatively young age). If a hereditary predisposition is suspected, the woman should be referred to a specialist for advice before making a decision regarding the use of a hormonal contraceptive.
Other diseases that have been associated with adverse circulatory events, including diabetes mellitus, systemic lupus erythematosus, haemolytic-uraemic syndrome, chronic inflammatory bowel disease (e.g. Crohn's disease or ulcerative colitis) and sickle cell anaemia.
The increased risk of thromboembolism in the puerperium must be considered (for information on Pregnancy and lactation, see Use in Pregnancy & Lactation).
An increase in the frequency or severity of migraine whilst using Diane-35 (which may be prodromal for a cerebrovascular event) can be a reason for immediate discontinuation of Diane-35.
Women using Diane-35 should be specifically instructed to contact their physician if possible symptoms of thrombosis occur. Diane-35 must be discontinued if thrombosis is suspected or confirmed. Due to the teratogenicity of anticoagulants (coumarins), appropriate methods of contraception should be used.
Tumors: Some epidemiological studies have indicated that long-term use of combined oral contraceptives may contribute to an increased risk of cervical cancer. There continues to be controversy about the extent to which this is attributable to sexual behaviour and other factors, such as infection with human papillomavirus (HPV).
A meta-analysis from 54 epidemiological studies reported that there is a slightly increased relative risk (RR = 1.24) of having breast cancer in women who are currently using combined oral contraceptives. The excess risk gradually disappears during the course of the 10 years after cessation of COC use. Because breast cancer is rare in women under 40 years of age, the excess number of breast cancer diagnoses in current and recent COC users is small in relation to the overall risk of breast cancer. These studies do not provide evidence for causation. The observed pattern of increased risk may be due to an earlier diagnosis of breast cancer in COC users, the biological effects of COCs or a combination of both. The breast cancers diagnosed in ever-users tend to be less advanced clinically than the cancers diagnosed in never-users.
In rare cases, benign liver tumors, and even more rarely, malignant liver tumors have been reported, possibly leading to life-threatening intra-abdominal hemorrhages, after the use of hormonal substances, such as those contained in Diane-35. If non-specific upper abdominal complaints, liver enlargement or signs of intra-abdominal hemorrhage occur, a liver tumor should be included in the differential diagnosis.
Reduced efficacy: The contraceptive efficacy of Diane-35 may be reduced in the event of e.g. missed tablets (Dosage & Administration), gastrointestinal disturbances (Dosage & Administration) or certain concomitant medication (Interactions).
Diane-35 contains 31 mg lactose per tablet. Patients with rare genetic galactose or fructose intolerance, lactase deficiency, glucose-galactose malabsorption or sucrase-isomaltase deficiency should not take Diane-35.
There is some epidemiological evidence that the incidence of venous thromboembolism is higher in users of this product when compared to users of combined oral contraceptives with low oestrogen content (<50 mcg ethinylestradiol).
Effects on ability to drive or use machines: No observed effects.
Pregnancy must be excluded. The administration of Diane-35 is contraindicated during pregnancy and lactation. If pregnancy occurs during medication with Diane-35, the preparation is to be withdrawn immediately. Previous use of Diane-35, however, is not a reason for a termination of pregnancy.
Cyproterone acetate is transferred into the milk of lactating women. Approximately 0.2 % of the maternal dose can be transferred to the breast-fed infant, which corresponds to a dose of approximately 1 μg/kg.
During lactation, approximately 0.02 % of the daily maternal dose of ethinyl estradiol can be absorbed by the neonate via breast milk.
There is an increased risk of thromboembolism in all women who use Diane-35 (see Precautions).
This risk can be aggravated by added factors (smoking, hypertension, clotting disorders or disturbances in lipid metabolism, obesity, varicose veins, previous phlebitis and thrombosis), see Precautions.
For further serious side effects, such as liver tumors, cervical and breast cancer, see Precautions.
Side effects that have been reported in users of Diane-35, but for which the association has been neither confirmed nor refuted, are: See table.
Click on icon to see table/diagram/image
The following serious adverse reactions have been reported by women who have used Diane-35 and are described in Precautions: Venous thromboembolic disorders; Arterial thromboembolic disorders; Cerebrovascular accidents; Hypertension; Hypertriglyceridaemia; Changes in glucose tolerance or effects on peripheral insulin resistance; Hepatic tumours (benign or malignant); Hepatic dysfunction; Chloasma; Onset or exacerbation of disorders associated with taking COCs, but whose cause has not been clearly established: cholestatic jaundice and/or pruritus, cholelithiasis, porphyria, systemic lupus erythematosus, haemolytic-uraemic syndrome, Sydenham's chorea (chorea minor), herpes gestationis, otosclerosis-related hearing loss, Crohn's disease, ulcerative colitis, cervical cancer; In women with hereditary angioedema, exogenously administered oestrogens can trigger or worsen symptoms of angioedema.
The incidence of breast cancer diagnoses is slightly increased in users of oral contraceptives. As breast cancer rarely occurs in women below 40 years of age, the number of additional breast cancer diagnoses is small in relation to the overall risk of developing breast cancer. For more information, see Contraindications and Precautions.
Effect on breast tissue: Sex hormones affect breast tissue by possibly increasing its susceptibility to other carcinogenic factors. Sex hormones do indeed represent only one among various other possible risk factors unrelated to taking hormonal contraceptives. Epidemiological studies that investigated the possible link between hormonal contraceptives and breast cancer failed to resolve the issue of whether this disease actually does afflict women more frequently prior to middle age who are early, long-term users of oral contraceptives.
Worsening of endogenous depression and epilepsy has also been reported during the use of combined oral contraceptives.
If symptoms have significantly worsened recently in women who suffer from hirsutism, the causes of this (androgen-producing tumor, enzyme defect in the adrenal cortex) must be clarified by differential diagnosis.
Effect on clinical chemistry normal values:
The erythrocyte sedimentation rate can increase without a disease being present. There have also been reports of increased serum copper and serum iron levels, as well as alkaline leukocyte phosphatase activity.
Other metabolic functions:
Infrequent disturbances in folic acid and tryptophan metabolism may occur.
Taken regularly, Diane-35 has a contraceptive effect due to its composition. The irregular intake of Diane-35 can lead to irregular menstrual cycles. The regular intake of Diane-35 is very important in preventing both cycle irregularities and pregnancy (because of a possible effect of cyproterone acetate on a developing child).
Interactions between estrogen/progestagen combinations like Diane-35 and other drugs may lead to breakthrough bleeding and/or contraceptive failure.
Various substances, such as barbiturates, rifampicin and antiepileptic drugs (such as barbexaclone, carbamazepine, phenytoin, primidone) and possibly also oxcarbazepine, topiramate, felbamate, griseofulvin and products containing St. John's wort (Hypericum), accelerate the metabolisation of sex hormones (possible loss of contraceptive effect).
Also HIV protease inhibitors (e.g. ritonavir) and non-nucleoside reverse transcriptase inhibitors (e.g. nevirapine), and combinations of them, have been reported to potentially affect hepatic metabolism.
Diane-35 may affect the metabolism of certain other drugs. Accordingly, plasma and tissue concentrations may either increase (e.g. cyclosporin) or decrease (e.g. lamotrigine).
Women who are being treated with a medication of the substance classes mentioned above should use additional barrier contraceptives alongside the combination oral contraceptive, i.e. while taking the concomitant medication and for 28 days afterward.
Reduced levels of the active ingredients have been observed due to alteration of the intestinal flora when some antibiotics (e.g. penicillins and tetracyclines) are taken at the same time. Increased rates of intermenstrual bleeding as well as isolated pregnancies have been recorded. Women receiving antibiotic treatment should use additional barrier contraceptives during this time of concomitant medication and for 7 days afterward. If the use of an additional barrier contraceptive overruns the end of the pack, the next Diane-35 pack should be started without a 7-day break.
The requirement for antidiabetics can change as a result of the effect on glucose tolerance.
Note: Diane-35 may not be used with an additional hormonal contraceptive; such medicinal products have to be discontinued prior to starting treatment with Diane-35 (for this, see also Dosage & Administration).
G03HB01 - cyproterone and estrogen ; Belongs to the class of antiandrogen preparations in combination with estrogens. Used to counter androgenic activities.