Contrez 0,02 mg, 3,0 mg Tablet

• Oral contraceptive.
• Treatment of moderate acne vulgaris in women seeking oral contraception.
• Treatment of symptoms of premenstrual dysphoric disorder (PMDD) in women who have chosen oral contraception as their method of birth control. CONTREZ has not been evaluated for treatment of premenstrual syndrome (PMS).

Tablets must be taken in the order directed on the package, at about the same time every day, with some liquid if needed. One tablet is taken daily for 28 days. Each subsequent pack is started the day after the last intake of the previous pack. A withdrawal bleed usually starts on day 2 to 3 after starting placebo tablets (white tablets in the last row) and may not be finished before the next pack is started.

How to start CONTREZ:

a) No preceding hormonal contraceptive use (in the past month): The first tablet must be taken on day 1 of the womanu2019s natural cycle (i.e. the first day of her menstrual bleeding). Starting on day 2 to 5 is allowed, but during the first cycle a barrier method is recommended in addition for the first 7 days of tablet-taking.

b) Changing from a combined hormonal contraceptive (combined oral contraceptive), vaginal ring or transdermal patch): Start with CONTREZ preferably on the day after the last active tablet of her previous combined oral contraceptive, but at the latest on the day following the usual tablet-free or inactive tablet interval of her previous combined oral contraceptive. In the event a vaginal ring or transdermal patch has been used, start using CONTREZ preferably on the day of removal, but at the latest when the next application would have been due.

c) Changing from a progestogen-only method (minipill, injection, implant) or from a progestogen-releasing intrauterine system: The patient may switch any day from the minipill, from an implant or the intrauterine system on the day of its removal and 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.

d) Following first-trimester abortion: The patient may start immediately. When doing so, she need not take additional contraceptive measures.

e) 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 CONTREZ use or the woman must wait for her first menstrual period.

Management of missed tablets: Placebo tablets from the last (4th) row of the blister can be disregarded. However, they should be discarded to avoid unintentionally prolonging the placebo tablet phase. The following advice only refers to missed active tablets: 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. The management of missed tablets can be guided by the following two basic rules:

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

Accordingly, the following advice can be given in daily practice:

Day 1 to 7: 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 cannot be excluded. The more tablets that are missed and the closer they are to the inactive tablet phase, the higher the risk of a pregnancy.

Day 8 to 14: 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.

Day 15 to 24: The risk of reduced reliability is imminent because of the forthcoming inactive tablet phase. However, by adjusting the tablet-intake schedule, reduced contraceptive protection can still be prevented. If either of the following two options is adhered to, there is 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 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 until the active tablets are used up. The 4 inactive tablets must be discarded. The next pack must be started right away. The user is unlikely to have a withdrawal bleed until the end of the active tablets section of the second pack, but she may experience spotting or breakthrough bleeding on active tablets-taking days.
2. The woman may also be advised to discontinue active tablet-taking from the current pack. She should then have a tablet-free interval of up to 4 days, including the days she missed tablets, and subsequently continue with the next pack, starting in the silver section with the tablets for the appropriate day of the week. If the woman missed active tablets and subsequently has no withdrawal bleed in the inactive tablet phase, the possibility of a pregnancy should be considered.

Advice in case of gastrointestinal disturbances: In case of gastrointestinal disturbances, absorption may not be complete and additional contraceptive measure should be taken. If vomiting occurs within 3 to 4 hours after active tablet-taking, the advice concerning missed tablets is applicable. If the woman does not want to change her normal tablet-taking schedule, she must take the extra tablet(s) needed from another pack.

How to delay a period: To delay a period the woman should continue with another pack of CONTREZ without taking the inactive tablets from her current pack. The extension can be carried on for as long as wished until the end of the active tablets in the second pack. During the extension the woman may experience breakthrough bleeding or spotting. Regular intake of CONTREZ is then resumed after the inactive tablet phase.

Special populations:

Elderly: CONTREZ is not indicated after menopause.

Patients with hepatic impairment: CONTREZ is contraindicated in women with severe hepatic diseases. See also sections 4.3 and 5.2.

Patients with renal impairment: CONTREZ is contraindicated in women with severe renal insufficiency or acute renal failure. See also sections 4.3 and 5.2.

Paediatric population: CONTREZ is only indicated after menarche.

Method of administration: For oral use.

Hypersensitivity to the active substances or to any of the excipients listed in section 6.1. Combined oral contraceptives such as CONTREZ 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 treatment with CONTREZ, the product should be stopped immediately.

• Presence or risk of venous thromboembolism (VTE)
• Venous thromboembolism u2013 current VTE (on anticoagulants) or history of (e.g. deep venous thrombosis [DVT] or pulmonary embolism [PE])
• Known hereditary or acquired predisposition for venous thromboembolism, such as APC-resistance, (including Factor V Leiden), antithrombin-III- deficiency, protein C deficiency, protein S deficiency
• Major surgery with prolonged immobilisation (see section 4.4)
• A high risk of venous thromboembolism due to the presence of multiple risk factors (see section 4.4)
• Presence or risk of arterial thromboembolism (ATE)
• Arterial thromboembolism u2013 current arterial thromboembolism, history of arterial thromboembolism (e.g. myocardial infarction) or prodromal condition (e.g. angina pectoris)
• Cerebrovascular disease u2013 current stroke, history of stroke or prodromal condition (e.g. transient ischaemic attack, TIA)
• Known hereditary or acquired predisposition for arterial thromboembolism, such as hyperhomocysteinaemia and antiphospholipid-antibodies (anticardiolipin-antibodies, lupus anticoagulant)
• History of migraine with focal neurological symptoms
• The presence of a severe or multiple risk factor(s) for arterial thromboembolism (see section 4.4) such as:
• diabetes mellitus with vascular symptoms
• severe hypertension
• severe dyslipoproteinaemia
• Severe hepatic disease as long as liver function values have not returned to normal.
• Severe renal insufficiency or acute renal failure with a creatine clearance of < 30 mL/min.
• Presence or history of liver tumours (benign or malignant).
• Known or suspected sex-steroid influenced malignancies (e.g. of the genital organs or the breasts).
• Undiagnosed vaginal bleeding.
• Known or suspected pregnancy.
• CONTREZ is contraindicated for concomitant use with the medicine containing ombitasvir/paritaprevir/ritonavir and dasabuvir, (see sections 4.4 and 4.5).

Warnings: If any of the conditions or risk factors mentioned below is present, the suitability of CONTREZ should be discussed with the woman. In the event of aggravation, or first appearance of any of these conditions or risk factors, the woman should be advised to contact her healthcare provider to determine whether the use of CONTREZ should be discontinued.

In case of suspected or confirmed VTE or ATE, CONTREZ use should be discontinued. In case anticoagulant therapy is started, adequate alternative contraception should be initiated because of the teratogenicity of anticoagulant therapy (coumarins).

Circulatory disorders: The risk of VTE is highest during the first year of use. This increased risk is present after initially starting CONTREZ or restarting (following a 4 week or greater pill free interval) the same or a different combined oral contraceptive. This increased risk is mainly present during the first 3 months. The overall risk for venous thromboembolism (VTE) in patients of low oestrogen dose combined oral contraceptives is two to threefold higher than for non-patients of combined oral contraceptives who are not pregnant.

Risk factors for VTE and ATE: The risk for venous and arterial thromboembolic complications in CONTREZ patients may increase substantially in a woman with additional risk factors, particularly if there are multiple risk factors (see table). CONTREZ is contraindicated if a woman has multiple risk factors that put her at high risk of venous and arterial thrombosis (see section 4.3). If a woman has more than one risk factor, it is possible that the increase in risk is greater than the sum of the individual factors u2013 in this case her total risk of VTE/ATE should be considered. If the balance of benefits and risks is negative a combined hormonal contraceptive (CHC) should not be prescribed (see section 4.3).

Risk factors for VTE and ATE include:

• Obesity (body mass index over 30 kg/m2)
  • Risk increases substantially as BMI rises. It is particularly important to consider if other risk factors also present
• Prolonged immobilisation
  • major surgery, any surgery to the legs or pelvis, neurosurgery, or major trauma. In these situations, it is advisable to discontinue use of the pill (in the case of elective surgery at least four weeks in advance) and not resume until two weeks after complete remobilisation. Another method of contraception should be used to avoid unintentional pregnancy.
  • Antithrombotic treatment should be considered if CONTREZ has not been discontinued in advance.
  • Note: temporary immobilisation including air travel > 4 hours can also be a risk factor for VTE, particularly in women with other risk factors
• Family history
  • Positive family history (venous thromboembolism ever in a sibling or parent especially at a relatively early age e.g. before 50)
  • If a hereditary predisposition is suspected, the woman should be referred to a medical practitioner for advice before deciding about any CONTREZ use.
• Other medical conditions associated with VTE
  • Cancer, systemic lupus erythematosus, haemolytic uraemic syndrome, chronic inflammatory bowel disease (Crohn's disease or ulcerative colitis) and sickle cell disease
  • Diabetes mellitus, hyperhomocysteinaemia, valvular heart disease and atrial fibrillation, dyslipoproteinaemia and systemic lupus erythematosus.
• Increasing age
  • Particularly above 35 years
• Hypertension
• Smoking
  • Women should be advised not to smoke if they wish to use CONTREZ. Women over 35 who continue to smoke should be strongly advised to use a different method of contraception
• Migraine
  • An increase in frequency or severity of migraine during CONTREZ use (which may be prodromal of a cerebrovascular event) may be a reason for immediate discontinuation

The increased risk of thromboembolism in pregnancy, and particularly the 6-week period of the puerperium, must be considered (for information see section 4.6)

Symptoms of VTE (deep vein thrombosis and pulmonary embolism): In the event of symptoms women should be advised to seek urgent medical attention and to inform the healthcare professional that she is taking a CONTREZ. Symptoms of deep vein thrombosis (DVT) can include:

• unilateral swelling of the leg and/or foot or along a vein in the leg.
• pain or tenderness in the leg which may be felt only when standing or walking,
• increased warmth in the affected leg; red or discoloured skin on the leg.

Symptoms of pulmonary embolism (PE) can include:

• sudden onset of unexplained shortness of breath or rapid breathing.
• sudden coughing which may be associated with haemoptysis.
• sharp chest pain.
• severe light headedness or dizziness.
• rapid or irregular heartbeat.

Some of these symptoms (e.g. u201cshortness of breathu201d, u201ccoughingu201d) are non-specific and might be misinterpreted as more common or less severe events (e.g. respiratory tract infections). Other signs of vascular occlusion can include sudden pain, swelling and slight blue discolouration of an extremity. If the occlusion occurs in the eye symptoms can range from painless blurring of vision which can progress to loss of vision. Sometimes loss of vision can occur almost immediately.

Symptoms of ATE: In the event of symptoms women should be advised to seek urgent medical attention and to inform the healthcare professional that she is taking a CONTREZ. Symptoms of a cerebrovascular accident can include:

• sudden numbness or weakness of the face, arm, or leg, especially on one side of the body.
• sudden trouble walking, dizziness, loss of balance or coordination.
• sudden confusion, trouble speaking or understanding.
• sudden trouble seeing in one or both eyes.
• sudden, severe, or prolonged headache with no known cause.
• loss of consciousness or fainting with or without seizure.

Temporary symptoms suggest the event is a transient ischaemic attack (TIA). Symptoms of myocardial infarction (MI) can include:

• pain, discomfort, pressure, heaviness, sensation of squeezing or fullness in the chest, arm, or below the breastbone.
• discomfort radiating to the back, jaw, throat, arm, stomach.
• feeling of being full, having indigestion or choking.
• sweating, nausea, vomiting or dizziness.
• extreme weakness, anxiety, or shortness of breath.
• rapid or irregular heartbeats.

Tumours: The most important risk factor for cervical cancer is persistent human papilloma virus infection. Long-term use of combined oral contraceptives (COCs) may further contribute to an increased risk of cervical cancer.

There is a slightly increased relative risk (RR = 1,24) of having breast cancer diagnosed in women who are currently using CONTREZ. The excess risk gradually disappears during the course of the 10 years after cessation of CONTREZ use. Benign liver tumours and, even more rarely, malignant liver tumours have been reported in patients of CONTREZ. In isolated cases, these tumours have led to life-threatening intra-abdominal haemorrhages. A hepatic 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 CONTREZ.

Other conditions: Women with hypertriglyceridaemia, or a family history thereof, may be at an increased risk of pancreatitis when using COCs such as CONTREZ. Small increases in blood pressure have been reported in many women taking COCs and clinically relevant increases may occur. If a sustained clinically significant hypertension develops during the use of CONTREZ, then it is prudent for the medical practitioner to withdraw CONTREZ and treat the hypertension. The occurrence or deterioration of the following conditions have been reported with COCs use jaundice and/or pruritus related to cholestasis, gallstone formation, porphyria; systemic lupus erythematosus, haemolytic uraemic syndrome; Sydenhamu2019s chorea; herpes gestationis; otosclerosis-related hearing loss.

In women with hereditary angioedema, exogenous oestrogens included in CONTREZ may induce or exacerbate symptoms of angioedema. Acute or chronic disturbances of liver function may necessitate the discontinuation of CONTREZ. Recurrence of cholestatic jaundice which first occurred during pregnancy or previous use of sex steroids necessitates the discontinuation of CONTREZ. CONTREZ may influence peripheral insulin resistance and glucose tolerance. Hence diabetic women should be carefully observed while taking CONTREZ. Crohnu2019s disease and ulcerative colitis have been associated with combined oral contraceptives such as CONTREZ. 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 CONTREZ. Depressed mood and depression are well-known undesirable effects of hormonal contraceptive use (see section 4.8). Depression can be serious and is a well-known risk factor for suicidal behaviour and suicide. Women should be advised to contact their medical practitioner in case of mood changes and depressive symptoms, including shortly after initiating treatment.

Worsening of epilepsy, of Crohn's disease and of ulcerative colitis has been reported during COCs use. ALT elevations during clinical trials with patients treated for hepatitis C virus infections (HCV) with the medicines containing ombitasvir/paritaprevir/ritonavir and dasabuvir with or without ribavirin, transaminase (ALT) elevations higher than 5 times the upper limit of normal (ULN) occurred significantly more frequent in women using ethinylestradiol-containing medicines such as CONTREZ (see sections 4.3 and 4.5).

Medical examination/consultation: A complete medical history and physical examination should be taken prior to the initiation or reinstitution of CONTREZ use, guided by u201csection 4.3u201d and u201csection 4.4u201d, and should be repeated periodically. Periodic medical assessment is also of importance because contraindications (e.g. a transient ischaemic heart attack, etc) or risk factors (e.g. family history of venous or arterial thrombosis) may appear for the first time during the use of CONTREZ. 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 and relevant laboratory tests.

Women should be advised that CONTREZ 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 transmissions of STDs and HIV infection.

Reduced efficacy: The efficacy of CONTREZ may be reduced in the event of e.g. missed active tablets, gastro-intestinal disturbances during active tablet taking (see u201csection 4.2u201d) or concomitant medication (see u201csection 4.5u201d).

Reduced cycle control: Irregular bleeding (spotting or breakthrough bleeding) may occur, especially during the first months of use. 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. This may include curettage. In some women withdrawal bleeding may not occur during the inactive tablet phase. If CONTREZ has been taken according to the directions described under u201csection 4.2u201d, it is unlikely that the woman is pregnant. However, if CONTREZ 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 CONTREZ is continued.

Excipients: CONTREZ tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take CONTREZ.

Interactions between CONTREZ and other medicines may lead to breakthrough bleeding and/or contraceptive failure. The following interactions have been reported in the literature.

Hepatic metabolism: Interactions can occur with medicines 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, griseofulvin and products containing St Johnu2019s Wort). HIV protease (e.g. ritonavir) and non-nucleoside reverse transcriptase inhibitors (e.g. nevirapine), and combinations of them, have been reported to potentially affect hepatic metabolism.

Enzyme inhibitors: Concomitant administration of strong CYP3A4 inhibitors can increase plasma concentrations of the oestrogen or the progestin or both. (e.g. ketoconazole, etoricoxib)

Other medicines: CONTREZ may affect the metabolism of certain other medicines. Accordingly, plasma and tissue concentrations either increase (e.g. cyclosporine) or decrease (e.g. lamotrigine).

Based on in vivo interaction studies in female patients using omeprazole, simvastatin or midazolam as marker substrate, an interaction of drospirenone at doses of 3 mg with the cytochrome P450 mediated metabolism of other medicines is unlikely.

Clinical data suggests that ethinylestradiol is inhibiting the clearance of CYP1A2 substrates leading to a weak (e.g. theophylline) or moderate (e.g. tizanidine) increase in their plasma concentration.

Interference with enterohepatic circulation: Enterohepatic circulation of oestrogens may decrease when certain antibiotic medicines are given, which may reduce ethinylestradiol concentrations (e.g. penicillins, tetracyclines). Women on treatment with any of these medicines should temporarily use a barrier method in addition to CONTREZ or choose another method of contraception. With microsomal enzyme-inducing medicines, the barrier method should be used during the time of concomitant medicine 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 runs beyond the end of the active tablets in the CONTREZ pack, the inactive tablets should be omitted and the next pack of CONTREZ should be started with the active tablets (i.e. without the usual inactive tablet interval).

Other interactions: Concomitant use with the medicines containing ombitasvir/paritaprevir/ritonavir and dasabuvir, with or without ribavirin may increase the risk of ALT elevations (see sections 4.3 and 4.4). Therefore, CONTREZ-patients must switch to an alternative method of contraception (e.g., progestogen-only contraception or non-hormonal methods) prior to starting therapy with this combination drug regimen. CONTREZ can be restarted 2 weeks following completion of treatment with this combination drug regimen. In patients without renal insufficiency, the concomitant use of drospirenone and ACE-inhibitors or NSAIDs did not show a significant effect on serum potassium. Nevertheless, concomitant use of CONTREZ with aldosterone antagonists or potassium-sparing diuretics has not been studied. In this case, serum potassium should be tested during the first treatment cycle.

See also section 4.4.

Women of Childbearing Potential: CONTREZ is indicated for use by women of childbearing potential. Refer to sections 4.1, 4.2, 4.3 and 4.4.

Pregnancy: CONTREZ is not indicated during pregnancy. If pregnancy occurs during treatment with CONTREZ, further intake should be stopped.

Breastfeeding: The use of CONTREZ is not recommended during breastfeeding. Small amounts of the contraceptive steroids and/or their metabolites may be excreted with the milk.

Fertility: CONTREZ is a contraceptive. It is indicated for the prevention of pregnancy.

CONTREZ can cause dizziness (see section 4.8) which may affect the ability to execute sound coordination and therefore influence the ability to drive and use machinery.

System Organ Class

• Frequent
• Less frequent
• Frequency unknown

Infections and infestations: Candidiasis

Blood and lymphatic system disorders: Anaemia, thrombocythemia

Immune system disorders: Allergic reaction, Hypersensitivity

Endocrine disorders: Endocrine disorder

Metabolism and nutrition disorders: Increased appetite, anorexia, hyperkalaemia, hyponatremia

Psychiatric disorders: Emotional lability, Depression, nervousness, somnolence, anorgasmia, insomnia

Nervous system disorders: Headache, Dizziness, paraesthesia, vertigo, tremor

Eye disorders: Conjunctivitis, dry eye, eye disorder

Ear and labyrinth disorders: Hypacusia

Cardiac disorders: Tachycardia

Vascular disorders: Migraine, varicose vein, hypertension, hypotension, phlebitis, vascular disorder, epistaxis, syncope, venous thromboembolism (VTE), arterial thromboembolism (ATE)

Respiratory, thoracic and mediastinal disorders: Asthma

Gastrointestinal disorders: Nausea, Abdominal pain, vomiting, dyspepsia, flatulence, gastritis, diarrhoea, abdomen enlarged, gastrointestinal disorder, gastrointestinal fullness, hiatus hernia, oral candidiasis, constipation, dry mouth

Hepatobiliary disorders: Biliary pain, cholecystitis

Skin and subcutaneous tissue disorders: Acne, pruritus, rash, chloasma, eczema, alopecia, dermatitis acneiform, dry skin, erythema nodosum, hypertrichosis, skin disorder, skin striae, contact dermatitis, photosensitive dermatitis, skin nodule, Erythema multiforme

Musculoskeletal and connective tissue disorders: Back pain, pain in extremity, muscle cramps

Reproductive system and breast disorders: Breast pain, Metrorrhagia, amenorrhea, leukorrhoea, vaginal moniliasis, Intermenstrual bleeding, Vaginal candidiasis, pelvic pain, breast enlargement, fibrocystic breast, uterine / vaginal bleeding, genital discharge, hot flushes, vaginitis, menstrual disorder, dysmenorrhea, hypomenorrhea, menorrhagia, vaginal dryness, papanicolaou smear suspicious, libido decreased, dyspareunia, vulvovaginitis, postcoital bleeding, withdrawal bleeding, breast cyst, breast hyperplasia, breast neoplasm, cervical polyp, endometrial atrophy, ovarian cyst, uterine enlargement

General disorders and administration site conditions: Asthenia, sweating increased, oedema (generalized oedema, peripheral oedema, face oedema), malaise

Investigations: weight increase, weight decrease

The following serious side effects have been reported in women using COCs, which are discussed under section 4.4 Special warning and precautions for use:

• Venous thromboembolic disorders.
• Arterial thromboembolic disorders.
• Hypertension.
• Liver tumours.
• Occurrence or deterioration of conditions for which association with CONTREZ use is not conclusive: Crohn's disease, ulcerative colitis, epilepsy, uterine myoma, porphyria, systemic lupus erythematosus, herpes gestationis, Sydenham's chorea, haemolytic uremic syndrome, cholestatic jaundice.
• Chloasma.
• Acute or chronic disturbances of liver function may necessitate the discontinuation of CONTREZ use until markers of liver function return to normal.
• In women with hereditary angioedema exogenous oestrogens may induce or exacerbate symptoms of angioedema.

The frequency of diagnosis of breast cancer is very slightly increased among CONTREZ patients. As breast cancer is rare in women under 40 years of age the excess number is small in relation to the overall risk of breast cancer. Causation with CONTREZ use is unknown. For further information, see sections 4.3 and 4.4.

Interactions: Breakthrough bleeding and/or contraceptive failure may result from interactions of other medicines (enzyme inducers) with oral contraceptives (see section 4.5).

On the basis of general experience with combined oral contraceptives, symptoms that may occur in case of taking an overdose of active tablets are nausea, vomiting, and, in young girls, slight vaginal bleeding. Treatment is symptomatic and supportive.