Diane 35

Diane^® 35
Bayer Schering Pharma

Important information, please read carefully!

Composition
Each tablet of Diane 35 contains 2 mg Cyproterone acetate and 0.035 mg ethinylestradiol

Properties
The substance cyproterone acetate contained in Diane-35 inhibits the influence of the androgens which are also produced by the female organism. It is thus possible to treat diseases the cause of which is 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 seborrhea 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 (see Warnings, Undesirable effects), 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, there is evidence of reduced risk of endometrial cancer and ovarian cancer. Furthermore, the higher dose COCs (0.05 mg Ethinylestradiol) have been shown to reduce the incidence of ovarian cysts, pelvic inflammatory disease, benign breast disease and ectopic pregnancy. Whether this also applies to lower-dosed COCs remains to be confirmed.

Indications
1. Oral Contraception
2. Acne who accept contraception

Dosage and method of administration
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 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 can lead to inter menstrual bleeding's and could deteriorate the therapeutic and contraceptive reliability.

How to take Diane-35
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 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.

How to start Diane-35

-	No preceding hormonal contraceptive use (in the past month) Table-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,
-	Changing from a combined oral contraceptive (COC); The woman should start with Diane-35 preferably on the day after the last active tablet of her previous CDC, but at the latest on the day following the usual tablet-free or placebo tablet interval of her previous CDC.
-	Changing from a progestogen-only-method (minipill, injection, implant) or from a progestogen releasing intrauterine system (IUS). The woman may switch any day from the mini pill (from an implant or the IUS 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.
-	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; For breast feeding women see Pregnancy and lactation. 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.

Management of missed tablets
If the user is less than 12 hours late in taking any 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 tablet, contraceptive protection may be reduced. The management of missed tablets can be guided by the following two basic rules:

1. Tablet-taking must never be discontinued for longer than 7 days
2. 7 days of uninterrupted tablet-taking are required to attain adequate suppression of the hypothalamic-pituitary-ovarian axis.

Accordingly the following advice can be given in daily practice:

-	Week 1 The user should take the last missed tablet as soon as she remembers, even if this means taking two tablets at the same time. She then continues to take tablets at her usual time. In addition, a barrier method such as a condom should be used for the next 7 days. If intercourse took place in the preceding 7 days, the possibility of a pregnancy should be considered. The more tablets are missed and the closer they are to the regular tablet free interval, the higher the risk of a pregnancy.
-	Week 2 The user should take the last missed tablet as soon as she remembers, even if this means taking two tablets at the same time. She then continues to take tablets at her usual time. Provided that the woman has taken her tablets correctly in the 7 days preceding the first missed tablet, there is no need to use extra contraceptive precautions. However, if this is not the case, or if she missed more than 1 tablet, the woman should be advised to use extra precautions for 7 days.
-	Week 3 The risk of reduced reliability is imminent because of the forthcoming tablet-free interval. However, by adjusting the tablet-intake schedule, reduced contraceptive protection can still be prevented. By adhering to either of the following two options, there is therefore no need to use extra contraceptive precautions, provided that in the 7 days preceding the first missed tablet the woman has taken all tablets correctly. If this is not the case, the woman should be advised to follow the first of these two options and to use extra precautions for the next 7 days as well.

1. The user should take the last missed tablet as soon as she remembers, even if this means taking two tablets at the same time. She then continues to take tablets at her usual time. The next pack must be started as soon as the current pack is finished, i.e., no gap should be left between packs. The user is unlikely to have a withdrawal bleed until the end of the second pack, but she may experience spotting or breakthrough bleeding on tablet-taking days.
2. The woman may also be advised to discontinue tablet-taking from the current pack. She should then have a tablet-free interval of up to 7 days, including the days she missed tablets, and subsequently continue with the next pack.

If the woman missed tablets and subsequently has no withdrawal bleed in the first normal tablet- free interval, the possibility of a pregnancy should be considered.

Advice in case of gastro intestinal disturbances
In case of severe gastro-intestinal disturbances, absorption may not be complete and additional contraceptive measure should be taken.
If vomiting occurs within 3-4 hours after tablet-taking, the advice concerning missed tablets, as given in section management of missed tablets, is applicable. 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.

Length of use
The length of use depends on the severity of the; symptoms of androgenization and their response to treatment. In general, treatment should be carried out over several months. Acne and seborrhea usually respond sooner than hirsutism or alopecia.
It is recommended to take Diane-35 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. In case of recurrence of signs of androgenization after discontinuation of treatment early restart of Diane-35 should be considered.

Overdose
There have been no reports of serious deleterious effects from overdose. Symptoms that may occur in this case are: nausea, vomiting and, in young girls, slight vaginal bleeding. There are no antidotes and further treatment should be symptomatic.

Undesirable effects
The most serious undesirable effects associated with the use of COCs are listed in section Warning. Other side effect that have been reported in users of Diane 35 but for which the association has been neither confirmed nor refuted are:

• Eye disorders: contact lens intolerance
• Gastrointestinal disorders: nausea, vomiting, abdominal pain, diarrhoea
• Immune system disorders: hypersensitivity
• Metabolism and nutrition disorders: fluid retention, weight increased, weight decreased
• Nervous system disorders: Headache, migraine, libido decreased, libido increased, depressed mood, mood altered
• Reproductive system and breast disorders: breast tenderness, breast pain, hypertrophy breast, breast discharge, vaginal discharge
• Skin and subcutaneous Tissue disorders: rash, urticaria, erythema nodusum, erythema multiforme

* The most appropriate MedDRA term to describe a certain adverse reaction is listed. Synonyms or related conditions are not listed, but should be taken into account as well.

Contraindications

• Pregnancy and lactation
• Severe disturbances of liver function, jaundice or persistent itching during a previous pregnancy, Dubin Johnson syndrome, Rotor syndrome, previous or existing liver tumours
• Existing or previous arterial or venous thrombotic or embolic processes, conditions which predispose to them e.g. disorder of the clotting processes, valvular heart disease and atrial fibrillation. 
• Sickle-cell anemia
• Mammary or endometrial carcinoma, or a history of these conditions  
• Severe diabetes mellitus with vascular changes
• Disorders of lipid metabolism
• History of herpes gestationis
• Deterioration of otoschlerosis during pregnancy 
• Undiagnosed abnormal vaginal bleeding
• Hypersensitivity to any of the components of this product

Interaction with other medicaments and other forms of interaction 

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Interactions Interactions between estrogen/progestogen combinations like Diane 35 and other drugs may lead to breakthrough bleeding and/or contraceptive failure. The following interactions have been reported in the literature. Hepatic metabolism: Interactions can occur with drugs that induce microsomal enzymes which can result in increased clearance of sex hormones (e.g. phenytoin, barbiturates, primidone, carbamazepine, rifampicin, and possibly also oxcarbazepine, topiramate, felbamate, ritonavir, griseofulvin, and products containing St. John's wort). Interference with Enterohepatic Circulation: Some clinical reports suggest that enterohepatic circulation of estrogens may decrease when certain antibiotic agents are given, which may reduce ethynilestradiol concentrations (e.g. penicillins, tetracyclines). Women on treatment with any of these drugs should temporarily use a barrier method in addition to Diane-35 or choose another method of contraception. With microsomal enzyme inducing drugs, the barrier method should be used during the time of concomitant drug administration and for 28 days after their discontinuation. Women on treatment with antibiotics (except rifampicin and griseofulvin) should use the barrier method until 7 days after discontinuation. lithe period which the barrier method is used runs beyond the end of the tablets in the Diane 35 pack, the next pack should be started without the usual tablet-free interval. Estrogen/progestogen combinations like Diane-35 may interfere with the metabolism of other drugs. Accordingly, plasma and tissue concentrations maybe affected (e.g. cyclosporin) Note:  The prescribing information of concomitant medications should be consulted to identify potential interactions.

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Laboratory tests The use of preparations like Diane-35 may influence the results of certain laboratory tests, including biochemical parameters of liver, thyroid,. adrenal and renal function, plasma levels of (carrier) proteins, e.g. corticosteroid binding globulin and lipid/lipoprotein fractions, parameters of carbohydrate metabolism and parameters of coagulation and fibrinolysis. Changes generally remain within the normal laboratory range.

Special warnings and special precautions for use
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.

Warnings
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 use of Diane 35 should be discontinued.

-	Circulatory Disorders 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 risk for venous thromboembolism is highest during the first year a woman ever uses a COC. The approximate incidence of VTE in users of low estrogen dose (0.055 109 ethinylestradiol) OCs is up to 4 per 10000 woman years compared to 0.5-3 per 10000 woman years in non-OC users. The incidence of VTE associated with pregnancy is 6 per 10000 pregnant women years. Extremely rarely, thrombosis has been reported to occur in other blood vessels, e.g. hepatic, mesenteric, renal, cerebral 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 arterral thrombotic/thromboembolic or of a cerebrovascular accident 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 venous or arterial thrombotic/thromboembolic events or of a cerebrovascular accident 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); Dyslipoproteinemia; Hypertension; Migraine; Valvular heart disease;  Atrial fibrrilation; 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 remobilization. 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 (for information on Pregnancy and Lactation see Pregnancy and Lactation section). Other medical conditions which have been associated with adverse circulatory events include diabetes mellitus, polycystic ovary syndrome, systemic lupus erythematosus, hemolytic uremic syndrome, chronic inflammatory bowel disease (Crohn's disease or ulcerative colitis) and sickle cell disease. An increase in frequency or seventy 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, hyperhomocysteinemia, antithrombin-III deficiency, protein C deficiency, protein S deficiency, anti phospholipid 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 low dose COC (‹ 0.05 mg ethinylestradiol).
-	Tumors 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 behavior 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. In rare cases, benign liver tumors, and even more rarely, malignant liver tumors have been reported in users of COCs. In isolated cases, these tumors have led to life-threatening intra-abdominal hemorrhages. A hepatic tumor should be considered in the differential diagnosis when severe upper abdominal pain, liver enlargement or signs of Intra-abdominal hemorrhage occur in women taking COCs.
-	Other conditions Women with hypertriglyceridemia, or a family history thereof, may be at an increased risk of pancreatitis when using COCs. Although small increases in blood pressure have been reported in many women taking COCs, clinically relevant Increases are rare. 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. The following conditions have been reported to occur or deteriorate with both pregnancy and COC use, but the evidence of an association with COC use is inconclusive: jaundice and/or pruritus related to cholestasis; gallstone formation; porphyria; systemic lupus erythematosus; hemolytic uremic syndrome; Sydenham's chorea; herpes gestation is; otosclerosis-related hearing loss. Acute or chronic disturbances of liver function may necessitate the discontinuation of COC use until markers of liver function return to normal. Recurrence of cholestatic jaundice which occurred first during pregnancy or previous use of sex steroids necessitates the discontinuation of COCs. Although COCs may have an effect on peripheral insulin resistance and glucose tolerance, there is no evidence for a need to alter the therapeutic regimen in diabetics using COCs (containing ‹ 0.05 mg ethinylestradiol). However, diabetic women should be carefully observed while taking COCs. Crohn's disease and ulcerative colitis have been associated with COC use. Chloasma may occasionally occur, especially in women with a history of chloasma gravidarum. Women with a tendency to chloasma should avoid exposure to the sun or ultraviolet radiation whilst taking COCs. If in women suffering from hirsutism, symptoms have recently developed or increased substantially, the causes (androgen-producing tumor, adrenal enzyme defect) must be clarified by differential diagnosis.

Medical examination/consultation
A complete medical history and physical examination should be taken prior to the initiation or reinstitution Diane-35, guided by the contraindications and warnings, and should be repeated periodically. Periodic medical assessment is also of importance because contraindications (e.g. a transient ischaemic attack, etc.) or risk factors (e.g. a family history of venous or arterial thrombosis) may appear for the first time during the use of Diane-35. The frequency and nature of these assessments should be based on established practice guidelines and be adapted to the individual woman but should generally include special reference to blood pressure, breast, abdomen and pelvic organs, including cervical cytology.
Women should be advised that preparations like Diane-35 do not protect against HIV infections (AIDS) and other sexually transmitted diseases.

Reduced efficacy
The efficacy of Diane-35 may be reduced in the event of e.g. missed, gastro intestinal disturbances or concomitant medication.

Reduced cycle control
With estrogen/progestogen combinations, irregular bleeding (spotting or breakthrough bleeding) may occur, especially during the first months of use. Therefore, the evaluation of any irregular bleeding is only meaningful after an adaptation interval of about three cycles.
If bleeding irregularities persist or occur after previously regular cycles, then non-hormonal causes should be considered and adequate diagnostic measures are indicated to exclude malignancy or pregnancy. These may include curettage.
In some women withdrawal bleeding may not occur during the tablet-free interval. If the COC has been taken according to the directions described in section Dosage and Administration, it is unlikely that the woman is pregnant. However, if the COC has not been taken according to these directions prior to the first missed withdrawal bleed or if two withdrawal bleeds are missed, pregnancy must be ruled out before COC use is continued.

Pregnancy and lactation
The administration of Diane-35 is contraindicated during pregnancy.
If pregnancy occurs during medication with Diane-35, the preparation is to be withdrawn immediately. The administration of Diane-35 is also contraindicated during lactation. Cyproterone acetate is transferred into the milk of lactating women. About 0.2% of the maternal dose will reach the newborn via milk corresponding to a dose of about 1 µg/kg. During established lactation 0.02% of the daily maternal dose of ethinylestradiol could be transferred to the newborn via milk.

Reasons for stopping Diane-35 immediately:

• Occurrence for the first time, or exacerbation, of migrainous headaches or unusually frequent or unusually severe headaches.
• Sudden disturbances of vision or hearing loss or other perceptual disorder.
• First sign of thrombophlebitis or thromboembolic symptoms (e.g. unusual pains in or swelling of the leg(s), stabbing pains on breathing or coughing for no apparent reason). Feeling of pain and tightness in the chest.
• Six week before an elective major operation (e.g. abdominal, orthopedic), any surgery to the legs, medical treatment for varicose veins or prolonged immobilization, e.g. after accidents or surgery. Do not restart until 2 weeks after full ambulation. In case of emergency surgery, thrombotic prophylaxis usually indicated e.g. subcutaneous heparin.
• Onset of jaundice, hepatitis, itching of the whole body.
• Increase in epileptic seizure.
• Significant rise in blood pressure. 
• Onset of severe depression.
• Severe upper abdominal pain or liver enlargement.
• Clear exacerbation of conditions known to be capable of deteriorating during oral contraception or pregnancy.
• Pregnancy is a reason for stopping immediately because it has been suggested by some investigations that oral contraceptives taken in early pregnancy may slightly increase the risk of foetal malformations. Other investigations have failed to support these findings. The possibility therefore cannot be excluded, but it is certain that if a risk exists at all, it is very small.

Precautions:
The following conditions require strict medical supervision during medication With oral contraceptives. Deterioration or first appearance of any of these conditions may indicated that Diane-35 should be discontinued.

• Diabetes mellitus, or a tendency towards diabetes mellitus (e.g. unexplained glycosuria), hypertension, varicose veins, a history of phlebits, otoschlerosis, multiple schlerosis, epilepsy, porphyria, tetany, disturbed liver function, Sydenham's chorea, renal dysfunction, family history of clotting disorder, obesity, family history of breast cancer and patient history of benign breast disease, history of clinical depression, systemic lupus erythematosus, uterine fibroids, an intolerance of contact lenses, migraine, gall-stones, cardiovascular disease, chloasma, asthma, or any disease that is prone to worsen during pregnancy.
• It should be borne in mind that the use of ultraviolet lamps, for the treatment of acne, or prolonged exposure to sunlight, increases the risk of the deterioration of chloasma.
• Some women may experience amenorrhoea or oligomenorrhoea after discontinuation of Diane-35, especially when these conditions existed prior to use. Women should be informed of this possibility

Presentation
Calendar pack containing 21 tablets
Reg. No. DKI0868204416A1

Harus dengan Reser Dokter

Store all drugs properly and keep them out of reach of children.
Do not store above 30°C

PT. BAYER INDONESIA, JAKARTA-INDONESIA

Manufactured by:
Schering GmbH und Co. Produktions KG, Weimar - Germany
For Bayer Schering Pharma AG, Berlin - Germany

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