Diane-35 Special Precautions

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 as follows 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); dyslipoproteinaemia; obesity (body mass index over 30 kg/m²); hypertension; migraine; valvular heart disease; atrial fibrillation; 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.
Arterial thromboembolic events can be life-threatening or have a fatal outcome.
It should be noted that the risk of thrombosis may be higher due to synergistic effects of individual risk factors, when a combination of these risk factors is present, or if any marked risk factor occurs in the user.
Diane-35 should not be prescribed in the event of a negative benefit/risk assessment (see Contraindications).
Tumours: The most important risk factor for cervical cancer is persistent infection with the human papillomavirus (HPV). Some epidemiological studies have indicated that long-term use of oestrogen-progestogen combination might further increase risk this risk.
However, there is some controversy about the extent to which these findings are attributable to confounding factors, such as cervical screening and sexual behaviour, including the use of barrier methods.
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 oestrogen-progestogen combinations. The excess risk gradually disappears during the course of the 10 years after cessation of oestrogen-progestogen combinations. Because breast cancer is rare in women under 40 years of age, the excess number of breast cancer diagnoses in current and recent users of oestrogen progestogen combinations 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 users, the biological effects of these medicines 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.
Malignant tumours can be life-threatening or have a fatal outcome.
Meningioma: The occurrence of meningiomas (single and multiple) has been reported in association with the use of cyproterone acetate, in particular at high doses of 25 mg a day and above as well as in the event of prolonged use (see Pharmacology: Pharmacodynamics under Actions). If a patient is diagnosed with meningioma, treatment with all cyproterone-containing products, including Diane-35, must be stopped as a precaution.
Other disorders: Women with hypertriglyceridaemia, or a positive family history thereof, may be at increased risk of developing pancreatitis if they take oestrogen-progestogen combinations.
Although a slight increase in blood pressure has been reported in many women taking oestrogen-progestogen combinations (such as, for example, COCs or Diane-35), clinically significant increases in blood pressure are rare. However, if persistent, clinically relevant hypertension develops during use of Diane-35, the woman should stop taking Diane-35 and the hypertension should be treated. If it seems appropriate, the woman can resume taking Diane-35 as soon as blood pressure values have normalised with antihypertensive therapy.
The following disorders are reported to occur or deteriorate during both pregnancy and the use of oestrogen-progestogen combinations. However, no connection with oestrogen-progestogen combinations use could be demonstrated: cholestatic jaundice and/or pruritus; gallstones; porphyria; systemic lupus erythematosus; haemolytic-uraemic syndrome; Sydenham's chorea; herpes gestationis; otosclerosis-related hearing loss, epilepsy.
Exogenously administered oestrogens may precipitate or exacerbate symptoms of hereditary and acquired angioedema.
Acute or chronic liver dysfunction may necessitate discontinuation of Diane-35 use until liver function values have normalised. Recurrence of cholestatic jaundice and/or cholestasis-related pruritus that occurred during a previous pregnancy or during previous use of steroid sex hormones also requires discontinuation of Diane-35.
Although oestrogen-progestogen combinations can have an effect on peripheral insulin resistance and glucose tolerance, there is no evidence of any need to change the therapeutic regimen in diabetics using low-dose oestrogen-progestogen combinations (with < 0.05 mg ethinylestradiol). However, diabetics must be carefully monitored whilst they are taking Diane-35.
Crohn's disease and ulcerative colitis have been associated with the use of oestrogen-progestogen combinations.
Depressed mood and depression are well-known undesirable effects of hormonal contraceptive use (see Adverse Reactions). Depression can be serious and is a well-known risk factor for suicidal behaviour and suicide. Women should be advised to contact their doctor in the event of mood changes or depressive symptoms, including shortly after initiating treatment.
Chloasma can occur uncommonly, especially in women with a history of chloasma gravidarum. Women with this predisposition should not directly expose themselves to the sun or ultraviolet light whilst taking Diane-35.
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).
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).
Irregular bleeding: With all preparations containing an oestrogen/progestogen combination, irregular bleeding (spotting or breakthrough bleeding) may occur, especially during the first few months of use.
It is possible that withdrawal bleeding may fail to occur in some users during the tablet-free interval (7-day break between tablet-taking). Pregnancy is unlikely if Diane-35 has been taken as described in Dosage & Administration. However, if Diane-35 has not been taken as prescribed prior to the first absence of withdrawal bleeding or if breakthrough bleeding has failed to occur for a second time, pregnancy must be excluded before Diane-35 use is continued.
Diane-35 contains 31 mg lactose monohydrate and 19 mg sucrose per tablet. Patients with rare hereditary problems of galactose or fructose intolerance, lactase deficiency, glucose-galactose malabsorption or sucrase-isomaltase deficiency should not take Diane-35.
Effects on ability to drive or use machines: No effects on the ability to drive and use machines have been observed.