DIANE-35: The memo-pack holds 21 beige tablets, diameter 5.7mm, containing 2mg cyproterone acetate and 0.035mg ethinylestradiol.

DIANE-35 ED: The memo-pack holds 21 beige tablets, diameter 5.7mm, containing 2mg cyproterone acetate and 0.035mg ethinylestradiol and in addition, 7 larger white placebo tablets diameter 6.8 mm.

All tablets have a lustrous sugar coating.

The substance cyproterone acetate contained in DIANE-35 inhibits the influence of androgens produced by the female system. It is thus possible to treat diseases caused by either an increased production of androgens or a particular sensitivity to these hormones.

While DIANE-35 is being taken, the increased sebaceous gland function, which plays an important role in the development of acne and seborrhea, is reduced. This 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. The loss of hair which frequently accompanies seborrhoea likewise diminishes.

Treatment with DIANE-35 is indicated in women of child-bearing age who exhibit mild forms of hirsutism, and in particular in slightly increased facial hair; results do not, however, become apparent until after several months of use.

Apart from the described antiandrogen effect, cyproterone acetate has also a pronounced progestational action. The sole administration of cyproterone acetate would thus lead to cycle disturbances which are avoided by its combination with ethinylestradiol in DIANE-35. This holds true as long as the preparation is taken cyclically according to the instructions.

The contraceptive effect of DIANE-35 is based on the interaction of various factors, the most important of which are seen as the inhibition of ovulation and the changes in the cervical secretion. As well as protection against pregnancy, estrogen/progestogen combinations have several positive properties which, next to the negative properties, can be useful in deciding on the method of birth control. The cycle is more regular and the menstruation is often less painful and bleeding is lighter. The latter may result in a decrease in the occurrence of iron deficiency.

Apart from this, with the higher-dosed combined oral contraceptives (COCs) containing 50 mcg ethinylestradiol, there is evidence of a reduced risk of fibrocystic tumors of the breasts, ovarian cysts, pelvic inflammatory disease, ectopic pregnancy and endometrial and ovarian cancer. This may also apply to lower-dosed COCs.

Cyproterone acetate

Following oral administration cyproterone acetate is completely absorbed in a wide dose range. The ingestion of DIANE-35 effects a maximum serum level of 15 ng cyproterone acetate/ml at 1.6 hours. Thereafter, drug serum levels decrease in two disposition phases characterized by half-lives of 0.8 hours and 2.3 days. The total clearance of cyproterone acetate from serum was determined to 3.6 ml/min/kg. Cyproterone acetate is metabolized by various pathways including hydroxylations and conjugations. The main metabolite in human plasma is the 15ß-hydroxy derivative.

Some dose parts are excreted unchanged with bile fluid. Most of the dose is excreted in form of metabolites at a urinary to biliary ratio of 3:7. The renal and biliary excretion was determined to proceed with a half-life of 1.9 days. Metabolites from plasma were eliminated at a similar rate (half-life of 1.7 days).

Cyproterone acetate is almost exclusively bound to plasma albumins. About 3.5 - 4.0 % of total drug levels are present unbound. Because protein binding is non-specific, changes in SHBG (sex hormone binding globulin) levels do not affect the pharmacokinetics of cyproterone acetate.

Due to the long half-life of the terminal disposition phase from plasma (serum) and the daily intake, cyproterone acetate accumulates during one treatment cycle. Mean maximum drug serum levels increased from 15 ng/ml (day 1) to 21 ng/ml and 24 ng/ml, at the end of treatment cycles 1 and 3, respectively. The area under the concentration versus time profile increased 2.2 fold (end of cycle 1) and 2.4 fold (end of cycle 3). Steady-state conditions were reached after about 10 days. During long-term treatment cyproterone acetate accumulates over treatment cycles by a factor of 2.

The absolute bioavailability of cyproterone acetate is almost complete (88 % of dose). The relative bioavailability of cyproterone acetate from DIANE-35 was 109 % when compared to an aqueous microcrystalline suspension.

Ethinylestradiol

Orally administered ethinylestradiol is rapidly and completely absorbed. Following ingestion of DIANE-35, maximum drug serum levels of about 80 pg/ml are reached at 1.7 hours. Thereafter, ethinylestradiol plasma levels decrease in two phases characterized by half-lives of 1 - 2 hours and about 20 hours. For analytical reasons these parameters can only be calculated for higher dosages.

For ethinylestradiol an apparent volume of distribution of about 5 l/kg and a metabolic clearance rate from plasma of about 5 ml/min/kg were determined.

Ethinylestradiol is highly but non-specifically bound to serum albumin. 2% of drug levels are at present unbound. During absorption and first-liver passage ethinylestradiol is metabolized resulting in a reduced absolute and variable oral bioavailability. Unchanged drug is not excreted. Ethinylestradiol metabolites are excreted at a urinary to biliary ratio of 4:6 with a half-life of about one day.

Due to the half-life of the terminal disposition phase from plasma and the daily ingestion, steady-state plasma levels are reached after 3 - 4 days and are higher by 30 - 40 % as compared to a single dose. The relative bioavailability (reference: aqueous microcrystalline suspension) of ethinylestradiol from DIANE-35 was almost complete.

The systemic availability of ethinylestradiol might be influenced in both directions by other drugs. There is, however, no interaction with high doses of vitamin C. Ethinylestradiol induces the hepatic synthesis of SHBG (sex hormone binding globulin) and CBG (corticoid binding globulin) during continuous use. The extent of SHBG induction, however, is dependent upon the chemical structure and dose of the coadministered progestin. During treatment with DIANE-35 SHBG concentrations in serum increased from about 100 nmol/l to 300 nmol/l and the serum concentrations of CBG increased from about 50 mcg/ml to 95 mcg/ml.

For the treatment of androgen-dependent diseases in women, such as acne, especially pronounced forms and those which are accompanied by seborrhea or by inflammation or formation of nodes (acne papulopustulosa, acne nodulocystica), androgenetic alopecia and mild forms of hirsutism. DIANE-35 is also indicated for oral contraception in women with androgen-dependent diseases and for the treatment of polycystic ovary syndrome.

DIANE-35 is to be taken regularly in order to achieve the therapeutic efficacy and the required contraceptive protection. The dose regimen of DIANE-35 and DIANE-35 ED is similar to the usual regimen of most of the combined oral contraceptives. Thus, the same administration rules must be considered.

The irregular intake of DIANE-35 or DIANE-35 ED can lead to intermenstrual bleedings and could deteriorate the therapeutic and contraceptive reliability.

Tablets must be taken in the order directed on the package every day at about the same time with some liquid as needed. One active tablet is to be taken daily for 21 consecutive days. Each subsequent pack is started after a 7-day tablet-free interval or 7 day period of placebo tablets, during which time a withdrawal bleed usually occurs. This usually starts on day 2-3 after the last tablet and may not have finished before the next pack is started.

No preceding hormonal contraceptive use (in the past month)

Tablet-taking has to start on day 1 of the woman's natural cycle (i.e. the first day of her menstrual bleeding). Starting on days 2-5 is allowed, but during the first cycle a barrier method is recommended in addition for the first 7 days of tablet-taking.

The woman should start with DIANE-35 preferably on the day after the last active tablet of her previous COC, but at the latest on the day following the usual tablet-free or placebo tablet interval of her previous COC.

Changing from a progestogen-only-method (minipill, injection, implant)

The woman may switch any day from the minipill (from an implant on the day of its removal, from an injectable when the next injection would be due), but should in all of these cases be advised to additionally use a barrier method for the first 7 days of tablet-taking.

The woman may start immediately. When doing so, she need not take additional contraceptive measures.

Following delivery or second-trimester abortion

Women should be advised to start at day 21 to 28 after delivery or second-trimester abortion.

When starting later, the woman should be advised to additionally use a barrier method for the first 7 days of tablet-taking. However, if intercourse has already occurred, pregnancy should be excluded before the actual start of DIANE-35 use or the woman has to wait for her first menstrual period.

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. Each subsequent pack is started immediately following the previous pack. While taking the 7 placebo tablets a withdrawal bleed usually occurs.

No preceding hormonal contraceptive use (in the past month)

Tablet-taking has to start on day 1 of the woman's natural cycle (i.e. the first day of her menstrual bleeding). The first tablet should be selected from the red starting section of the pack. An additional method of contraception such as condoms or a diaphragm must be used for the first 14 days of tablet taking.

Changing from another combined oral contraceptive (COC)

The woman should start DIANE-35 ED in the red section on the day after the last active tablet of her previous COC.

Changing from a progestogen-only-method (minipill, injection, implant)

The woman may switch any day from the minipill (from an implant on the day of its removal, from an injectable when the next injection would be due), but should in all of these cases be advised to additionally use a barrier method for the first 14 days of tablet-taking.

Following first-trimester abortion

The woman may start immediately. When doing so, she need not take additional contraceptive measures.

Following delivery or second-trimester abortion

Women should be advised to start at day 21 to 28 after delivery or second-trimester abortion.

When starting later, the woman should be advised to additionally use a barrier method for the first 14 days of tablet taking. However, if intercourse has already occurred, pregnancy should be excluded before the actual start of DIANE-35ED use or the woman has to wait for her first menstrual period.

Management of missed tablets

Errors in taking the non-hormonal tablets contained in DIANE-35ED can be ignored.

If the user is less than 12 hours late in taking any hormonal tablet, contraceptive protection is not reduced. The woman should take the tablet as soon as she remembers and should take further tablets at the usual time.

If she is more than 12 hours late in taking any hormonal tablet, contraceptive protection may be reduced.

There is a particularly high risk of pregnancy if tablets are missed at the beginning or end of the pack. If tablets are missed in the first week of taking hormonal tablets and intercourse took place in the preceding 7 days the possibility of pregnancy should be considered.

1. Tablet taking must never be discontinued for longer than 7 days

7 days of uninterrupted tablet taking are required to attain adequate suppression of the hypothalamic-pituitary-ovarian axis.

These rules form the basis of the instructions to patients provided in the package insert.

Extra Contraceptive precautions

When you need extra contraceptive precautions, either:

- don't have sex;

- or use a cap plus spermicide; or

- use a condom

Do not use the rhythm or temperature methods as extra contraceptive precautions. This is because oral contraceptives alter the usual menstrual cycle changes such as changes in temperature and cervical mucus.

Continue taking your pills

You will not be protected from pregnancy until you have taken your daily small hormone pill for the next 7 days in a row.

Use another method of contraception (extra contraceptive precautions) such as condoms or do not have sexual intercourse for the next 7 days while taking the next 7 small hormone pills.

If there are fewer than 7 small hormone pills left in the pack, finish the small hormone pills and go straight on to the small hormone pills of the next pack. This means that you do not leave a gap between the small hormone pills and you miss out the large non-hormonal pills if you have the 28-day pack. You may not have a period until the end of the next pack. This is not harmful.

If vomiting occurs within 3-4 hours after tablet taking, absorption may not be complete. If the woman does not want to change her normal tablet-taking schedule, she has to take the extra tablet(s) needed from another pack.

How to shift periods or how to delay a period

To delay a period the woman should continue with hormonal tablets from another pack of DIANE-35 or DIANE-35 ED without a tablet-free interval or the non-hormonal tablets. The extension can be carried on for as long as desired until the end of the second pack. During the extension the woman may experience breakthrough bleeding or spotting.

To shift her periods to another day of the week than the woman is used to with her current scheme, she can be advised to shorten her forthcoming tablet-free interval or omit the non-hormonal tablets in DIANE-35ED by as many days as she likes. The shorter the interval, the higher the risk that she does not have a withdrawal bleed and will experience breakthrough-bleeding and spotting during the second pack (just as when delaying a period).

The length of use depends on the severity of the clinical picture; in general, treatment should be carried out over several months.

It is recommended to take DIANE-35 or DIANE-35ED for at least another 3 to 4 cycles after the signs have subsided. Should there be a recurrence weeks or months after discontinuation of tablet-taking, treatment with DIANE-35 may be resumed. A longer period of treatment may be recommended for the polycystic ovary syndrome.

Preparations containing oestrogen/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.

Thrombosis (venous or arterial) present or in history (e.g. deep venous thrombosis, pulmonary embolism, myocardial infarction, cerebrovascular accident)

Presence or history of prodromi of a thrombosis (e.g. transient ischaemic attack, angina pectoris)

Diabetes mellitus with vascular involvement

The presence of a severe or multiple risk factor(s) for venous or arterial thrombosis may also constitute a contraindication

Presence or history of severe hepatic disease as long as liver function values have not returned to normal

Presence or history of liver tumours (benign or malignant)

Known or suspected malignant conditions of the genital organs or the breasts, if sex steroid-influenced

Undiagnosed vaginal bleeding

Known or suspected pregnancy

Lactation

Hypersensitivity to any of the components of DIANE-35

DIANE-35 is not for use in men.

Warnings and Precautions

The clinical and epidemiological experience with estrogen/progestogen combinations like DIANE-35 is predominantly based on combined oral contraceptives (COC). Therefore, the following warnings related to the use of COC apply also for DIANE-35.

If any of the conditions/risk factors mentioned below is present, the benefits of the use of DIANE-35 should be weighed against the possible risks for each individual woman and discussed with the woman before she decides to start using it. In the event of aggravation, exacerbation or first appearance of any of these conditions or risk factors, the woman should contact her physician. The physician should then decide on whether its use should be discontinued.

Epidemiological studies have suggested an association between the use of COCs and an increased risk of arterial and venous thrombotic and thromboembolic diseases such as myocardial infarction, stroke, deep venous thrombosis, and pulmonary embolism. These events occur rarely.

Venous thromboembolism (VTE), manifesting as deep venous thrombosis and/or pulmonary embolism, may occur during the use of all COCs. The approximate incidence of VTE in users of low estrogen dose (< 50 mcg EE) OCs is up to 4 per 10 000 woman years compared to 0.5-3 per 10 000 woman years in non-OC users. However, the incidence of VTE occurring during COC use is substantially less than the incidence associated with pregnancy (i.e. 6 per 10 000 pregnant woman years).

Extremely rarely, thrombosis has been reported to occur in other blood vessels, e.g. hepatic, mesenteric, renal or retinal veins and arteries, in COC users. There is no consensus as to whether the occurrence of these events is associated with the use of COCs.

Symptoms of venous or arterial thrombosis can include: unilateral leg pain and/ or swelling; sudden severe pain in the chest, whether or not it radiates to the left arm; sudden breathlessness; sudden onset of coughing; any unusual, severe, prolonged headache; sudden partial or complete loss of vision; diplopia; slurred speech or aphasia; vertigo; collapse with or without focal seizure; weakness or very marked numbness suddenly affecting one side or one part of the body; motor disturbances; "acute" abdomen.

The risk of thromboembolism (venous and/or arterial) increases with:

- age

- smoking (with heavier smoking and increasing age the risk further increases, especially in women over 35 years of age)

- a positive family history (i.e. venous or arterial thromboembolism ever in a sibling or parent at a relatively early age). If a hereditary predisposition is suspected, the woman should be referred to a specialist for advice before deciding about any COC use.

- obesity (body mass index over 30 kg/ m2)

- dyslipoproteinaemia

- hypertension

- valvular heart disease

- atrial fibrillation

- prolonged immobilization, major surgery, any surgery to the legs, or major trauma. In these situations it is advisable to discontinue COC use (in the case of elective surgery at least four weeks in advance) and not to resume until two weeks after complete demobilization.

There is no consensus about the possible role of varicose veins and superficial thrombophlebitis in venous thromboembolism.

The increased risk of thromboembolism in the puerperium must be considered.

Other medical conditions which have been associated with adverse circulatory events include diabetes mellitus, systemic lupus erythematosus, haemolytic uraemic syndrome, chronic inflammatory bowel disease (Crohn's disease or ulcerative colitis) and sickle cell disease.

An increase in frequency or severity of migraine during COC use (which may be prodromal of a cerebrovascular event) may be a reason for immediate discontinuation of the COC.

Biochemical factors that may be indicative of hereditary or acquired predisposition for venous or arterial thrombosis include Activated Protein C (APC) resistance, hyperhomocysteinaemia, antithrombin-III deficiency, protein C deficiency, protein S deficiency, antiphospholipid antibodies (anticardiolipin antibodies, lupus anticoagulant).

When considering risk/benefit, the physician should take into account that adequate treatment of a condition may reduce the associated risk of thrombosis and that the risk associated with pregnancy is higher than that associated with COC use.

An increased risk of cervical cancer in long-term users of COCs has been reported in some epidemiological studies, but there continues to be controversy about the extent to which this finding is attributable to the confounding effects of sexual behaviour and other factors such as human papilloma virus (HPV).

A meta-analysis from 54 epidemiological studies reported that there is a slightly increased relative risk (RR = 1.24) of having breast cancer diagnosed in women who are currently using COCs. The excess risk gradually disappears during the course of the 10 years after cessation of COC use. Because breast cancer is rare in women under 40 years of age, the excess number of breast cancer diagnoses in current and recent COC users is small in relation to the overall risk of breast cancer. These studies do not provide evidence for causation. The observed pattern of increased risk may be due to an earlier diagnosis of breast cancer in COC users, the biological effects of COCs or a combination of both. The breast cancers diagnosed in ever-users tend to be less advanced clinically than the cancers diagnosed in never-users.< /FONT >