Source: Health Products Regulatory Authority (ZA) Revision Year: 2022 Publisher: Bayer (Pty) Ltd, Reg. No.: 1968/011192/07, 27 Wrench Road, ISANDO, 1609
Preparations containing estrogen/progestogen combinations should not be used in the presence of any of
the conditions listed below. Should any of these conditions appear for the first time during their use, the
product should be stopped immediately:
DIANE-35 is not for use in men.
DIANE-35 is composed of the progestogen cyproterone acetate and the estrogen ethinylestradiol and is administered for 21 days of a monthly cycle. It has a similar composition to that of a combined oral contraceptive. The clinical and epidemiological experience with estrogen/progestogen combinations like DIANE-35 is predominantly based on combined oral contraceptives. Therefore, the following warnings related to the use of combined oral contraceptives apply also for DIANE-35.
The use of DIANE-35 carries an increased risk of venous thromboembolism (VTE) compared with no use. The excess risk of VTE is highest during the first year a woman starts DIANE-35 or when restarting or switching after a pill-free interval of at least a month. Venous thromboembolism can be fatal in 1-2% of cases.
Epidemiological studies have shown that the incidence of VTE is 1,5 to 2 times higher in users of DIANE35 than in users of levonorgestrel-containing combined oral contraceptives (COCs) 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:
The risk of arterial thromboembolic complications or cerebrovascular accidents rises with:
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. The increased risk of thromboembolism in the puerperium must be considered (see section 4.6).
An increase in frequency or severity of migraine during DIANE-35 use (which may be prodromal of a cerebrovascular event) may be a reason for immediate discontinuation of DIANE-35.
Biochemical factors that may be indicative of hereditary or acquired predisposition for venous or arterial thrombosis include Activated Protein C (APC) resistance, hyperhomocysteinaemia, antithrombin-IIIdeficiency, protein C deficiency, protein S deficiency, antiphospholipid-antibodies (anticardiolipinantibodies, lupus anticoagulant).
Women using DIANE-35 should be specifically pointed out to contact their medical practitioner in case of possible symptoms of thrombosis. In case of suspected or confirmed thrombosis, DIANE-35 use should be discontinued. Adequate contraception should be initiated because of the teratogenicity of anticoagulant therapy.
Arterial thromboembolic events may be life-threatening or may 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 section 4.3).
The most important risk factor for cervical cancer is persistent human papilloma virus infection. Some epidemiological studies have indicated that long-term use of combined oral contraceptives may further contribute to an increased risk of cervical cancer but the extent to which this finding is attributable to confounding effects (e.g. cervical screening and sexual behaviour including use of barrier contraceptives) continues to be discussed.
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 combined oral contraceptives. The excess risk gradually disappears during the course of the 10 years after cessation of combined oral contraceptives use.
Benign liver tumours and malignant liver tumours have been reported in users of combined oral contraceptives possibly leading to life-threatening intra-abdominal haemorrhage. A liver tumour should be considered in the differential diagnosis when severe upper abdominal pain, liver enlargement or signs of intra-abdominal haemorrhage occur in women taking DIANE-35.
Malignancies may be life-threatening or may have a fatal outcome.
Women with hypertriglyceridaemia, or a family history thereof, may be at an increased risk of pancreatitis when using combined oral contraceptives.
Small increases in blood pressure have been reported in many women taking combined oral contraceptives which contains ethinylestradiol. However, clinically relevant increases may also occur. If a sustained clinically significant hypertension develops during the use of DIANE-35, then it is prudent for the medical practitioner to withdraw DIANE-35 and treat the hypertension.
The occurrence or deterioration of the following conditions have been reported to occur or deteriorate with combined oral contraceptive use: 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.
In women with hereditary angioedema exogenous estrogens such as contained in DIANE-35 may induce or exacerbate symptoms of angioedema.
Acute or chronic disturbances of liver function may necessitate the discontinuation of DIANE-35. Recurrence of cholestatic jaundice which first occurred during pregnancy or previous use of sex steroids necessitates the discontinuation of DIANE-35.
DIANE-35 may have an effect on peripheral insulin resistance and glucose tolerance, hence, diabetic women should be carefully monitored while taking DIANE-35.
Crohn’s disease and ulcerative colitis have been associated with combined oral contraceptive use.
Chloasma may 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 DIANE-35.
Depressed mood and depression are well-known undesirable effects oof hormonal contraceptive use (see section 4.8). Depression can be severe and is a well-known risk factor for suicidal behaviour and suicide.
Women should be advised to contact that medical practitioner in case of mood changes and depressive symptoms, including shortly after initiating the treatment.
Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.
A complete medical history and physical examination should be taken prior to the initiation or reinstitution of DIANE-35 use, guided by the Contraindications and Warnings (see section 4.3 and 4.4), 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 a combined oral contraceptive. 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, breasts, abdomen and pelvic organs, including cervical cytology.
Women should be advised that DIANE-35 does not protect against HIV infections (AIDS) and other sexually transmitted diseases (STDs). Women should be advised that additional barrier contraceptive measures are needed to prevent transmission of STDs and HIV.
The contraceptive effect of DIANE-35 may be reduced in the event of missed hormone-containing beige coated tablets, gastro-intestinal disturbances (see section 4.2) during hormone-containing beige coated tablet taking or concomitant medication (see section 4.5).
Irregular bleeding (spotting or breakthrough bleeding) may occur, especially during the first months of use. In some women withdrawal bleeding may not occur during the hormone-free larger white coated tablet phase. If DIANE-35 has been taken according to the directions described in section 4.2, it is unlikely that the woman is pregnant. However, if DIANE-35 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 DIANE-35 use is continued.
Note: The Professional Information on concomitant medications should be consulted to identify potential interactions.
Interactions can occur with medicines that induce microsomal enzymes which can result in increased clearance of sex hormones and which may lead to breakthrough bleeding and/or contraceptive failure.
Enzyme induction can be observed after a few days of treatment. Maximal enzyme induction is generally seen within a few weeks. After the cessation of medicine therapy, enzyme induction may be sustained for about 4 weeks.
Women on treatment with any of these medicines should temporarily use a barrier method in addition to DIANE-35 or choose another method of contraception. The barrier method should be used during the time of concomitant medicine administration and for 28 days after their discontinuation. If the period during which the barrier method is used runs beyond the end of the hormone-containing beige coated tablets in the DIANE-35 pack, the hormone-free larger white coated tablets should be omitted and the next pack started.
Substances increasing the clearance of DIANE-35 (diminished efficacy by enzyme-induction), e.g.:
Phenytoin, barbiturates, primidone, carbamazepine, rifampicin, and possibly also oxcarbazepine, topiramate, felbamate, griseofulvin, and products containing St. John’s wort.
Substances with variable effects on the clearance of DIANE-35, e.g.:
When co-administered with combined oral contraceptives, many HIV/HCV protease inhibitors and nonnucleoside reverse transcriptase inhibitors can increase or decrease plasma concentrations of estrogen or progestin. These changes may be clinically relevant in some cases.
Substances decreasing the clearance of DIANE-35 (enzyme inhibitors):
Strong and moderate CYP3A4 inhibitors such as azole antifungals (e.g. itraconazole, voriconazole, fluconazole), verapamil, macrolides (e.g. clarithromycin, erythromycin), diltiazem and grapefruit juice can increase plasma concentrations of the estrogen or the progestin or both.
Etoricoxib doses of 60 to 120 mg/day have been shown to increase plasma concentrations of ethinylestradiol 1,4 to 1,6-fold, respectively when taken concomitantly with a combined hormonal contraceptive containing 0,035 mg ethinylestradiol
Estrogen/progestogen combinations like DIANE-35 may affect the metabolism of certain other medicines. Accordingly, plasma and tissue concentrations may either increase (e.g. ciclosporin) or decrease (e.g. lamotrigine).
In vitro, ethinylestradiol is a reversible inhibitor of CYP2C19, CYP1A1 and CYP1A2 as well as a mechanism-based inhibitor of CYP3A4/5, CYP2C8, and CYP2J2. In clinical studies, administration of a hormonal contraceptive containing ethinylestradiol did not lead to any increase or only to a weak increase in plasma concentrations of CYP3A4 substrates (e.g. midazolam) while plasma concentrations of CYP1A2 substrates can increase weakly (e.g. theophylline) or moderately (e.g. melatonin and tizanidine).
Co-administration of ethinylestradiol-containing medicines such as DIANE-35 with direct-acting antiviral (DAA) medicines containing ombitasvir, paritaprevir, or dasabuvir, and combinations of these has been shown to be associated with increases in ALT levels to greater than 20 times the upper limit of normal in healthy female subjects and HCV-infected women (see section 4.3).
The use of contraceptive steroids 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.
Use of DIANE-35 is contraindicated in pregnancy (see section 4.3). If pregnancy occurs during treatment with DIANE-35, further intake must be stopped (see section 5.3).
The administration of DIANE-35 is contraindicated during lactation (see section 4.3). Cyproterone acetate is transferred into the milk of lactating women.
None.
The most commonly reported adverse reactions with DIANE-35 are nausea, abdominal pain, increased weight, headache, depressed mood, altered mood, breast pain, breast tenderness. They occur in ≥1% of users.
There is an increased risk of thromboembolism in all women who use DIANE-35 (see section 4.4).
Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. Frequencies are defined as common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100) and rare (≥1/10000 to <1/1000).
| System Organ Class | Common (≥1/100 to <1/10) | Uncommon (≥1/1 000 to <1/100) | Rare (≥1/10 000 to <1/1000) |
|---|---|---|---|
| Eye disorders | Contact lens intolerance | ||
| Gastrointestinal disorders | Nausea, Abdominal pain | Vomiting, Diarrhoea | |
| Immune system disorders | Hypersensitivity | ||
| Investigations | Increased weight | Decreased weight | |
| Metabolism and nutrition disorders | Fluid retention | ||
| Nervous system disorders | Headache | Migraine | |
| Psychiatric disorders | Depressed mood, Altered mood | Decreased libido | Increased libido |
| Reproductive system and breast disorders | Brest pain, Breast tenderness | Breast hypertrophy | Vaginal discharge, Breast discharge |
| Skin and subcutaneous tissue disorders | Rash, Urticaria | Erythema nodosum, Erythema multiforme | |
| Vascular disorders | Thromboembolism |
The most appropriate MedDRA term (version 12,0) to describe a certain adverse reaction is listed. Synonyms or related conditions are not listed, but should be taken into account as well.
Depression can be severe and is a well-known risk factor for suicidal behaviour and suicide. Women should be advised to contact that medical practitioner in case of mood changes and depressive symptoms, including shortly after initiating the treatment.
Adverse reactions with very low frequency or with delayed onset of symptoms which are considered to be related to the group of combined oral contraceptives are listed below (see also sections 4.3 and 4.4).
Breakthrough bleeding and/or contraceptive failure may result from interactions of other medicines (enzyme inducers) with oral contraceptives (see section 4.5).
Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Health care providers are asked to report any suspected adverse reactions to SAHPRA via the “6.04 Adverse Drug reactions Reporting Form”, found online under SAHPRA’s publications: https://www.sahpra.org.za/Publications/Index/8.
Not applicable.
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