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Data Sheet

DIANE® 35 ED

Cyproterone Acetate/Ethinylestradiol Tablets

Presentation

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

All tablets have a lustrous sugar coating.

Uses

Actions

The pilosebaceous unit, comprises the sebaceous gland and the hair follicle and is an androgen-sensitive skin component. Acne, seborrhea, hirsutism and androgenic alopecia are clinical conditions which result from aberrations of this target organ. The clinical conditions may be caused by either an increased sensitivity to or by higher plasma levels of androgen. Both the substances contained in DIANE-35 ED beneficially influence the hyperandrogenic state. Cyproterone acetate is a competitive antagonist on the androgen receptor, has inhibitory effects on the androgen-synthesis in target cells and produces a decrease on the androgen blood concentration through an anti-gonadotropic effect. This anti-gonadotropic effect is amplified by ethinylestradiol which also up-regulates the synthesis of Sex-Hormone-Binding-Globulin (SHBG) in plasma. By this mechanism, it reduces free, biologically available androgen in the circulation.

Treatment with DIANE-35 ED 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. In women experiencing mild forms of hirsutism and in particular, slightly increased facial hair, results do not, however become apparent until after several months of use.

The contraceptive effect of DIANE-35 ED 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.

Pharmacokinetics

Cyproterone acetate

Absorption

Orally administered cyproterone acetate is rapidly and completely absorbed. Peak serum concentrations of 15 ng/mL are reached at about 1.6 hours after single ingestion. Bioavailability is about 88%.

Distribution

Cyproterone acetate is almost exclusively bound to serum albumin. Only 3.5 - 4.0% of the total serum drug concentrations are present as free steroid. The ethinylestradiol-induced increase in SHBG does not influence the serum protein binding of cyproterone acetate. The apparent volume of distribution of cyproterone acetate is about 986 + 437 L.

Metabolism

Cyproterone acetate is almost completely metabolized. The main metabolite in plasma was identified as 15beta-OH-CPA which is formed via the cytochrome P450 enzyme CYP3A4. The clearance rate from serum is about 3.6mL/min/kg.

Elimination

Cyproterone acetate serum levels decrease in two phases which are characterized by half-lives of about 0.8 h and about 2.3 - 3.3 days. Cyproterone acetate is partly excreted in unchanged form. Its metabolites are excreted at a urinary to biliary ratio of about 1:2. The half-life of metabolite excretion is about 1.8 days.

Steady-state conditions

Cyproterone acetate pharmacokinetics are not influenced by SHBG levels. Following daily ingestion drug serum levels increase about 2.5-fold reaching steady-state conditions during the second half of a treatment cycle.

Ethinylestradiol

Absorption

Orally administered ethinylestradiol is rapidly and completely absorbed. Peak serum concentrations of about 71 pg/mL are reached at 1.6 hours. During absorption and first-liver passage, ethinylestradiol is metabolized extensively, resulting in a mean oral bioavailability of about 45% with a large interindividual variation of about 20-65%.

Distribution

Ethinylestradiol is highly but non-specifically bound to serum albumin (approximately 98%) and induces an increase in the serum concentrations of SHBG. An apparent volume of distribution of about 2.8 - 8.6 L/kg was determined.

Metabolism

Ethinylestradiol is subject to pre-systemic conjugation in both small bowel mucosa and the liver. Ethinylestradiol is primarily metabolized by aromatic hydroxylation but a wide variety of hydroxylated and methylated metabolites are formed, and these are present as free metabolites and as conjugates with glucuronides and sulfate. The clearance rate was reported to be about 2.3-7 mL/min/kg.

Elimination

Ethinylestradiol serum levels decrease in two disposition phases characterized by half-lives of about 1 h and 10-20 h, respectively. Unchanged drug is not excreted. Ethinylestradiol metabolites are excreted at a urinary to biliary ratio of 4:6. The half-life of metabolite excretion is about 1 day.

Steady-state conditions

Steady-state conditions are reached during the second half of a treatment cycle when serum drug levels are higher by 60% as compared to single dose.

Indications

For the treatment of androgen-dependent diseases in women, such as acne (where oral antibiotic or local treatment alone has not been successful), especially pronounced forms and those which are accompanied by seborrhea or by inflammation or formation of nodes (acne papulopustulosa, acne nodulocystica), androgenic alopecia and mild forms of hirsutism. DIANE-35 ED is also indicated for oral contraception in women requiring treatment for these androgen-dependent diseases; it is not recommended in women solely for contraception. DIANE-35 ED is also indicated for the treatment of polycystic ovary syndrome.

Dosage and Administration

DIANE-35 ED is to be taken regularly in order to achieve the therapeutic efficacy and the required contraceptive protection. Previously used hormonal contraception should be discontinued. The dose regimen of 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 ED can lead to intermenstrual bleeding and could deteriorate the therapeutic and contraceptive reliability.

How to Take DIANE-35 ED

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 inactive tablets a withdrawal bleed usually occurs.

How to Start DIANE-35 ED

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 inactive tablets contained in DIANE-35ED can be ignored.

If the user is less than 12 hours late in taking any active 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 active 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 week of inactive tablets. If tablets are missed in the first week of taking active tablets and intercourse took place in the preceding 7 days the possibility of pregnancy should be considered.

The management of missed active 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.

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:

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.


The 7 Day Rule

Advice in Case of Gastrointestinal Disturbances

In case of severe gastrointestinal disturbances, absorption may not be complete and additional contraceptive measures should be taken. The advice concerning missed tablets should be followed.

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 active 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 active tablets from another pack of DIANE-35 ED without taking the inactive 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 inactive 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).

Length of Use

The length of use depends on the severity of the clinical picture; in general, treatment should be carried out over several months. Acne and seborrhea usually respond sooner than hirsutism or alopecia. A longer period of treatment may be recommended for polycystic ovary syndrome.

It is recommended to take DIANE-35 ED 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 ED may be resumed.

Contraindications

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.

DIANE-35 ED is not for use in men.

Warnings and Precautions

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

If any of the conditions/risk factors mentioned below is present, the benefits of the use of DIANE-35 ED 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.

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 (< 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 thrombotic/thromboembolic events 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 thromboembolism (venous and/or arterial) increases with:

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, 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 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.

Tumours

The most important risk factor for cervical cancer is persistent HPV infection. Some epidemiological studies have indicated that long-term use of COCs may further contribute to this increased risk but there continues to be controversy about the extent to which this finding is attributable to confounding effects, e.g. cervical screening and sexual behaviour including use of barrier contraceptives.

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; haemolytic uraemic syndrome; Sydenham's chorea; herpes gestationis; 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. 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 ED, guided by the contraindications and warnings. This should be repeated periodically during the use of DIANE-35 ED. Periodic medical assessment is also of importance because contraindications (e.g. a transient ischemic 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 ED. The frequency and nature of these assessments should be adapted to the individual woman but should generally include special reference to blood pressure, breasts, abdomen and pelvic organs, including cervical cytology, and relevant laboratory tests.

Women should be advised that preparations like DIANE-35 ED do not protect against HIV infections (AIDS) and other sexually transmissible diseases.

Reduced Efficacy

The efficacy of DIANE-35 ED may be reduced in the event of missed tablets, vomiting 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 suggested directions, 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

Use in Pregnancy

The administration of DIANE-35 ED is contraindicated during pregnancy.

If pregnancy occurs during medication with DIANE-35 ED, the preparation is to be withdrawn immediately.

Use in Lactation

The administration of DIANE-35 ED 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 mcg/kg. During established lactation 0.02 % of the daily maternal dose of ethinylestradiol could be transferred to the newborn via milk.

Effects on Ability to Drive and Use Machines

No observed effects.

Preclinical Safety Data

Ethinyl estradiol

The toxicity profile of ethinyl estradiol is well known. There are no preclinical data of relevance to the prescriber that provide additional safety information to those already included in other sections of the product information.

Cyproterone acetate

Preclinical data reveal no specific risk for humans based on conventional studies of repeated dose toxicity.

No animal-experimental studies into a possible sensitizing effect of ethinylestradiol and cyproterone acetate have been carried out.

Embryotoxicity/Teratogenicity

Investigations into embryotoxic or teratogenic effects, using the combination of the two active ingredients, showed no effects indicative of a general teratogenic effect following treatment during organogenesis before development of the external genital organs. Administration of cyproterone acetate during the hormone-sensitive differentiation phase of the genital organs (after approx. day 45 of pregnancy) could lead to signs of feminization in male fetuses following higher doses. Observation of male newborn children who had been exposed in utero to cyproterone acetate did not show any signs of feminization. However, pregnancy is a contraindication for the use of DIANE-35 ED.

Genotoxicity and Carcinogenicity

Recognized first-line tests of genotoxicity gave negative results when conducted with cyproterone acetate. However, further tests showed that cyproterone acetate was capable of producing adducts with DNA (and an increase in DNA repair activity) in liver cells from rats and monkeys and also in freshly isolated human hepatocytes, whereas the DNA-adduct level in dog liver cells was extremely low.

This DNA-adduct formation occurred at 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 and an increase of mutation frequency in transgenic rats carrying a bacterial gene as target for mutations.

Clinical experience and well conducted epidemiological trials to-date would not support an increased incidence of hepatic tumors in man. Nor did investigations into the tumorigenicity of cyproterone acetate in rodents reveal any indication of a specific tumorigenic potential. However, it must be borne in mind that sex steroids can promote the growth of certain hormone-dependent tissues and tumors.

On the whole, the available findings do not raise any objection to the use of DIANE-35 ED in humans if used in accordance with the directions for the given indication and at the recommended dose.

Adverse Effects

The most serious undesirable effects associated with the use of COCs such as DIANE-35 ED have been referred to in the Warnings and Precautions section.

Other side effects that have been reported in users of DIANE-35 ED but for which the association has been neither confirmed nor refuted are:

System Organ Class Common
(≥ 1/100)
Uncommon
(≥ 1/1,000 and < 1/100)
Rare
(<1/1,000)
Eye disorders     contact lens intolerance
Gastrointestinal disorders nausea, abdominal pain vomiting, diarrhea  
Immune system disorders     hypersensitivity
Investigations weight increased   weight decreased
Metabolism and nutrition disorders   fluid retention  
Nervous system disorders Headache migraine  
Psychiatric disorders depressed mood, mood altered libido decreased libido increased
Reproductive system and breast disorders breast pain, breast tenderness breast hypertrophy vaginal discharge, breast discharge
Skin and subcutaneous tissue disorders   rash, urticaria erythema nodosum, erythema multiforme

Interactions

Interactions between estrogen/progestogen combinations like DIANE-35 ED 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 such as phenytoin, barbiturates, primidone, carbamazepine, rifabutin, 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 entero hepatic circulation of estrogens may decrease when certain antibiotic agents are given, which may reduce ethinylestradiol concentrations (e.g. penicillins, tetracyclines).

Women on treatment with any of these drugs should temporarily use a barrier method in addition to DIANE-35 ED 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. If the period during which the barrier method is used includes the inactive tablets, they should not be taken and the next pack started without delay.

Estrogen/progestogen combinations like DIANE-35 ED may interfere with the metabolism of other drugs. Accordingly, plasma and tissue concentrations may be affected (e.g. cyclosporin).

Note: The prescribing information of concomitant medications should be consulted to identify potential interactions.

Laboratory Tests

The use of preparations like DIANE-35 ED 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.

Overdosage

There have been no reports of serious deleterious effects from overdose.

Symptoms

Symptoms that may occur in this case are nausea, vomiting and, in young girls, slight vaginal bleeding.

Treatment

There are no antidotes and further treatment should be symptomatic.

Pharmaceutical Precautions

Shelf Life: 5 years

Special Precautions for Storage: Store below 30°C

Medicine Classification

Prescription Medicine

Package Quantities

3 calendar-packs containing 28 tablets.

DIANE-35 ED tablets are contained in blister packs consisting of deep-drawn strips made of polyvinyl chloride film with counter sealing foil made of aluminum with heat sealable coating.

Further Information

List of Excipients

Lactose monohydrate, maize starch, povidone 25 000, magnesium stearate, sucrose, povidone 700 000, macrogol 6000, calcium carbonate, talc, glycerol 85%, titanium dioxide, ferric oxide pigment (yellow), montanglycol wax

Instructions for Use/Handling

Store all drugs properly and keep them out of reach of children.

Name and Address

Schering NZ Ltd.,
5 William Pickering Drive, Albany
PO Box 101-691, North Shore Mail Centre, Auckland.

Telephone: (09) 415-2850

Facsimile: (09) 415-6497

Toll free 0800-80-45-45

Date of Preparation

9 December 2005