GINETTE 35 Tablets (Cyproterone acetate + Ethinylestradiol)

Table of Content

Composition

GINETTE 35

Each film-coated tablet contains:

Cyproterone acetate …............ 2 mg

Ethinylestradiol ………. 0.035 mg

Dosage Form

Tablets for oral use.

Description

GINETTE 35 is an oral contraceptive indicated for the treatment of androgen-dependent disease in women. Each pack consists of 21 tablets and each tablet contains 2 mg of cyproterone acetate (CPA) and 0.035 mg of ethinylestradiol (EE).

Pharmacology

Pharmacodynamics

GINETTE 35 (CPA+EE) blocks androgen receptors. It also reduces androgen synthesis both by negative feedback effect on the hypothalamo-pituitary-ovarian systems and by the inhibition of androgen-synthesizing enzymes.

Although GINETTE 35 also acts as an oral contraceptive, it is not recommended in women solely for contraception, but should be reserved for those women requiring treatment for the androgen-dependent conditions described.

Pharmacokinetics

Cyproterone Acetate

Following oral administration, CPA is completely absorbed in a wide dose range. The ingestion of CPA+EE attains a maximum serum level of 15 ng CPA /ml at 1.6 hours. Thereafter, drug serum levels decrease in two disposition phases characterized by half-lives of 0.8 hours and 2.3 days. The total clearance of CPA from serum was determined to be 3.6 ml/min/kg. CPA is metabolized by various pathways, including hydroxylations and conjugations. The main metabolite in human plasma is the 15 beta-hydroxy derivative.

Some dose parts are excreted unchanged with the bile fluid. Most of the dose is excreted in the form of metabolites at a urinary to biliary ratio of 3:7. The renal and biliary excretion was determined to proceed with a half-life of 1.9 days. Metabolites from plasma were eliminated at a similar rate (half-life of 1.7 days). CPA is almost exclusively bound to plasma albumin. About 3.5–4.0% of total drug levels are present unbound. Because protein binding is non-specific, changes in sex hormone-binding globulin (SHBG) levels do not affect CPA pharmacokinetics.

According to the long half-life of the terminal disposition phase from plasma (serum) and the daily intake, CPA accumulates during one treatment cycle. Mean maximum drug serum levels increased from 15 ng/ml (day 1) to 21 ng/ml and 24 ng/ml at the end of the treatment cycles 1 and 3, respectively. The area under the concentration versus time profile increased 2.2-fold (end of cycle 1) and 2.4-fold (end of cycle 3). Steady-state conditions were reached after about 16 days. During long-term treatment, CPA accumulates over treatment cycles by a factor of 2.

The absolute bioavailability of CPA is almost complete (88% of dose). The relative bioavailability of CPA from CPA+EE was 109% when compared to an aqueous microcrystalline suspension.

Ethinylestradiol

Orally administered EE is rapidly and completely absorbed. Following ingestion of CPA+EE, maximum drug serum levels of about 80 pg/ml are reached at 1.7 hours. Thereafter, EE plasma levels decrease in two phases characterized by half-lives of 1–2 hours and about 20 hours. For analytical reasons, these parameters can only be calculated for higher dosages.

For EE, an apparent volume of distribution of about 5 l/kg and a metabolic clearance rate from plasma of about 5 ml/min/kg were determined.

EE is highly but non-specifically bound to serum albumin. 2% of the drug levels are present unbound. During absorption and first liver passage, EE is metabolized resulting in a reduced absolute and variable oral bioavailability. Unchanged drug is not excreted. EE metabolites are excreted at a urinary to biliary ratio of 4:6, with a half-life of about 1 day.

According to the half-life of the terminal disposition phase from plasma and the daily ingestion, steady-state plasma levels are reached after 3–4 days and are higher by 30–40% as compared to a single dose. The relative bioavailability (reference: aqueous microcrystalline suspension) of EE was almost complete.

The systemic bioavailability of EE might be influenced in both directions by other drugs. There is, however, no interaction with high doses of vitamin C.

EE induces the hepatic synthesis of SHBG and corticosteroid-binding globulin (CBG) during continuous use. The extent of SHBG induction, however, is dependent upon the chemical structure and dose of the co-administered progestin. During treatment with CPA+EE, SHBG concentrations in serum increased from about 100–300 nmol/l and the serum concentrations of CBG were increased from about 50–95 mcg/ml.

In vitro, ethinyl estradiol is a reversible inhibitor of CYP2C19, CYP1A1 and CYP1A2 as well as a mechanism based inhibitor of CYP3A4/5, CYP2C8 and CYP2J2.

Indication

GINETTE 35 is indicated for the treatment of androgen-dependent disease in women such as acne, alopecia and mild form of hirsutism.

Dosage and Administration

GINETTE 35 inhibits ovulation and, thereby, prevents conception. Patients who are using GINETTE 35 should not, therefore, use an additional hormonal contraceptive, as this will expose the patient to an excessive dose of hormones and is not necessary for effective contraception.

First Treatment Course

One tablet daily for 21 days following the arrows, starting on the first day of the menstrual cycle (the first day of menstruation counting as day 1).

Subsequent Courses

Each subsequent course is started after 7 tablet-free days have followed the preceding course.

When the contraceptive action of GINETTE 35 is also to be employed, it is essential that the above instructions be rigidly adhered to. Should bleeding fail to occur during the tablet-free interval, the possibility of pregnancy must be excluded before the next pack is started.

When changing from an oral contraceptive and relying on the contraceptive action of GINETTE 35, follow the instructions given below:

Changing from 21-Day Combined Oral Contraceptives (COCs)

The first tablet of GINETTE 35 should be taken on the first day immediately after the end of the previous COC course. Additional contraceptive precautions are not required.

Changing from a Combined Every Day Pill (28 day tablets)

GINETTE 35 should be started after taking the last hormone containing tablet from the Every Day Pill pack. The first tablet of GINETTE 35 is taken the next day. Additional contraceptive precautions are not then required.

Changing from a Progestogen-only Pill (POP)

The first tablet of GINETTE 35 should be taken on the first day of bleeding, even if a POP has already been taken on that day. Additional contraceptive precautions are not then required. The remaining POPs should be discarded.

Postpartum and Post-abortum Use

After pregnancy, GINETTE 35 can be started 21 days after a vaginal delivery, provided that the patient is fully ambulant and there are no puerperal complications. Additional contraceptive precautions will be required for the first 7 days of tablet taking. Since the first postpartum ovulation may precede the first bleeding, another method of contraception should be used in the interval between childbirth and the first course of tablets. Lactation is contraindicated with GINETTE 35. After a first trimester abortion, GINETTE 35 may be started immediately, in which case no additional contraceptive precautions are required.

Duration of Use

Time to relief of symptoms is at least three months. The need to continue treatment should be evaluated periodically by the treating physician.

Special Circumstances Requiring Additional Contraception

Incorrect Administration

A single delayed tablet should be taken as soon as possible, and if this can be done within 12 hours of the correct time, contraceptive protection is maintained. With longer delays, additional contraception is needed. Only the most recently delayed tablet should be taken, earlier missed tablets being omitted, and additional non-hormonal methods of contraception (except the rhythm or temperature methods) should be used for the next 7 days, while the next 7 tablets are being taken. Additionally, therefore, if tablet(s) have been missed during the last 7 days of a pack, there should be no break before the next pack is started. In this situation, a withdrawal bleed should not be expected until the end of the second pack. Some breakthrough bleeding may occur on the days a tablet is taken, but this is not clinically significant. If the patient does not have a withdrawal bleed during the tablet-free interval following the end of the second pack, the possibility of pregnancy must be ruled out before starting the next pack.

Gastrointestinal Upset

Vomiting or diarrhoea may reduce the efficacy of oral contraceptives by preventing full absorption. Tablets from the current pack should be continued. Additional non-hormonal methods of contraception (except the rhythm or temperature methods) should be used during the gastrointestinal upset and for 7 days following the upset. If these 7 days overrun the end of a pack, the next pack should be started without a break. In this situation, a withdrawal bleed should not be expected until the end of the second pack. If the patient does not have a withdrawal bleed during the tablet-free interval following the end of the second pack, the possibility of pregnancy must be ruled out before starting the next pack. Other methods of contraception should be considered if the gastrointestinal disorder is likely to be prolonged.

Contraindications

Preparations containing oestrogen/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.

  • Concomitant use with another hormonal contraceptive.
  • Venous thrombosis present or in history (e.g. deep venous thrombosis, pulmonary embolism)
  • Arterial thrombosis present or in history (e.g. myocardial infarction) or prodromal conditions (e.g. angina pectoris and transient ischaemic attack)
  • Presence or history of cerebrovascular accident
  • The presence of a severe or multiple risk factor(s) for venous or arterial thrombosis such as:
    • diabetes mellitus with vascular symptoms
    • severe hypertension
    • severe dyslipoproteinaemia
  • Hereditary or acquired predisposition for venous or arterial thrombosis, such as activated protein C (APC) resistance, antithrombin-III-deficiency, protein C deficiency, protein S deficiency, hyperhomocysteinaemia and antiphospholipid-antibodies (anticardiolipin-antibodies, lupus anticoagulant).
  • History of migraine with focal neurological symptoms
  • Presence or history of severe hepatic disease e.g. active viral hepatitis and severe cirrhosis, as long as liver function values have not returned to normal.
  • Presence or history of liver tumours (benign or malignant)
  • Current or history of breast cancer
  • Known or suspected pregnancy
  • Breastfeeding
  • Hypersensitivity to the active substances or to any of the excipients

CPA+EE is contraindicated for concomitant use with the medicinal products containing ombitasvir / paritaprevir / ritonavir or dasabuvir.

CPA+EE is not for use in men.

Warnings and Precautions

General

This product is composed of the progestogen CPA and the oestrogen EE and is administered for 21 days of a monthly cycle. It has a similar composition to that of a COC.

Duration of Use

Time to relief of symptoms is at least 3 months. The need to continue treatment should be evaluated periodically by the treating physician.

Women should be advised that CPA+EE does not protect against HIV infection (AIDS) and other sexually transmitted diseases.

Medical Examination

Assessment of women prior to starting oral contraceptives (and at regular intervals thereafter) should include a personal and family medical history of each woman. Physical examination should be guided by this and by the contraindications and warnings for this product. The frequency and nature of these assessments should be based upon relevant guidelines and should be adapted to the individual woman, but should include measurement of blood pressure and, if judged appropriate by the clinician, breast, abdominal and pelvic examination including cervical cytology.

Exclude the likelihood of pregnancy before starting treatment.

Undiagnosed vaginal bleeding that is suspicious for underlying conditions should be investigated.

Conditions That Require Strict Medical Supervision

If any of the conditions/risk factors mentioned below is present, the benefits of the use of CPA+EE should be weighed against the possible risks for each individual woman and discussed with the woman before she decides to start using CPA+EE. 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 the use of CPA+EE should be discontinued.

  • Diabetes mellitus, with mild vascular disease or mild nephropathy, retinopathy or neuropathy
  • Hypertension that is adequately controlled, i.e. systolic > 140–159 mmHg or diastolic > 90–94 mmHg
  • Porphyria
  • Clinical depression
  • Obesity
  • Migraine
  • Cardiovascular diseases
  • Chloasma

Patients with a history of depression or any condition mentioned above should be monitored during treatment with CPA+EE.

Reasons for Stopping CPA+EE Immediately

When stopping oral contraception, non-hormonal contraception should be used to ensure contraceptive protection is maintained, if needed.

  • Occurrence for the first time, or exacerbation, of migrainous headaches or unusually frequent or unusually severe headaches.
  • Sudden disturbances of vision or hearing or other perceptual disorders.
  • First signs of thrombosis or blood clots (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 weeks before an elective major operation (e.g. abdominal, orthopaedic), 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 is usually indicated e.g. subcutaneous heparin.
  • Onset of jaundice, hepatitis, itching of the whole body.
  • Significant rise in blood pressure.
  • Onset of severe depression.
  • Severe upper abdominal pain or liver enlargement.
  • Clear worsening of conditions known to deteriorate during use of hormonal contraception or during pregnancy.
  • Pregnancy.

Circulatory Disorders

  • The use of CPA+EE 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 CPA+EE or when restarting or switching after a pill-free interval of at least a month. VTE is fatal in 1–2% of cases.
  • Epidemiological studies have shown that the incidence of VTE is 1.5–2 times higher in users of CPA+EE than in users of levonorgestrel-containing COCs and may be similar to the risk for desogestrel/gestodene/drospirenone-containing COCs.
  • The user group of CPA+EE is likely to include patients that may have an inherently increased cardiovascular risk such as that associated with polycystic ovarian syndrome (PCOS).
  • Epidemiological studies have also associated the use of hormonal contraceptive with an increased risk for arterial (myocardial infarction, transient ischaemic attack) thromboembolism.
  • Extremely rarely, thrombosis has been reported to occur in other blood vessels, e.g. hepatic, mesenteric, renal, cerebral or retinal veins and arteries, in hormonal contraceptive users.
  • Symptoms of venous or arterial thrombosis or of a cerebrovascular accident can include: unusual 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 thromboembolic events increases with the following:
    • Increasing age
    • Smoking (with heavier smoking and increasing age the risk further increases, 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 CPA+EE);
    • A positive family history (i.e. venous thromboembolism ever in a sibling or parent at a relatively early age). If a hereditary is suspected, the woman should be referred to a specialist for advice before deciding about any hormonal contraceptive use.
    • Prolonged immobilization, major surgery, any surgery to the legs, or major trauma. In these situations, it is advisable to discontinue use (in the case of elective surgery at least 4 weeks in advance) and not to resume until 2 weeks after complete remobilization. Antithrombotic treatment should be considered if the use of CPA+EE has not been discontinued in advance.
    • Obesity (body mass index > 30 kg/m2)

There is no consensus about the possible role of varicose veins and superficial thrombophlebitis in VTE.

  • The risk of arterial thromboembolic complications or of a cerebrovascular accident increases with the following:
    • Increasing age
    • Smoking (with heavier smoking and increasing age the risk further increases, 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 CPA+EE)
    • A positive family history (arterial thrombosis 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 hormonal contraceptive use.
    • Obesity (body mass index > 30 kg/m2)
    • Dyslipoproteinaemia
    • Hypertension
    • Valvular heart disease
    • Atrial fibrillation
    • Migraine

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.

An increase in frequency or severity of migraine during use of CPA+EE (which may be prodromal of a cerebrovascular event) may be a reason for immediate discontinuation of CPA+EE.

Women using CPA+EE should be specifically pointed out to contact their physician in case of possible symptoms of thrombosis. In case of suspected or confirmed thrombosis, CPA+EE use should be discontinued. Adequate contraception should be initiated because of the teratogenicity of anti-coagulant therapy (coumarins).

Other Factors Affecting Circulatory Events

The user group of CPA+EE as a treatment for acne or moderately severe hirsutism is likely to include patients that may have an inherently increased cardiovascular risk such as that associated with PCOS.

Biochemical factors that may be indicative of hereditary or acquired predisposition for venous or arterial thrombosis include 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 or CPA+EE use.

Tumours

Like many other steroids, CPA+EE when given in very high doses and for the majority of the animal's life-span, has been found to cause an increase in the incidence of tumours, including carcinoma, in the liver of rats. The relevance of this finding to humans is unknown.

Numerous epidemiological studies have been reported on the risks of ovarian, endometrial, cervical and breast cancer in women using COCs. The evidence is clear that high dose COCs offer substantial protection against both ovarian and endometrial cancer. However, it is not clear whether low dose COCs or CPA+EE confer protective effects to the same level.

Breast Cancer

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 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 additional breast cancers diagnosed in current users of COCs or in women who have used COCs in the last ten years are more likely to be localized to the breast than those in women who never used COCs.

Breast cancer is rare among women under 40 years of age whether or not they take COCs. Whilst this background risk increases with 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.

The most important risk factor for breast cancer in COC users is the age women discontinue the COC; the older the age at stopping, the more breast cancers are diagnosed. Duration of use is less important and the excess risk gradually disappears during the course of the 10 years after stopping COC use such that by 10 years there appears to be no excess.

The possible increase in risk of breast cancer should be discussed with the user and weighed against the benefits of COCs taking into account the evidence that they offer substantial protection against the risk of developing certain other cancers (e.g. ovarian and endometrial cancer).

Cervical Cancer

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.

Liver Cancer

In rare cases benign, and in even rarer cases malignant liver tumours leading in isolated cases to life-threatening intra-abdominal haemorrhage have been observed after the use of hormonal substances such as CPA+EE. If severe upper abdominal complaints, liver enlargement or signs of intra-abdominal haemorrhage occur, a liver tumour should be included in the differential diagnosis.

Other Conditions

The possibility cannot be ruled out that certain chronic diseases may occasionally deteriorate during the use of CPA+EE.

Known Hyperlipidaemias

Women with hypertriglyceridaemia, or a family history thereof, may be at an increased risk of pancreatitis when using COCs or CPA+EE.

Women with hyperlipidaemias are at an increased risk of arterial disease. However routine screening of women on COCs or CPA+EE is not appropriate.

Blood Pressure

Hypertension is a risk factor for stroke and myocardial infarction. Although small increases in blood pressure have been reported in many women taking COCs or oestrogen/progestogen combinations like CPA+EE, clinically relevant increases are rare. However, if sustained hypertension develops during the use of CPA+EE, antihypertensive treatment should normally be instigated at a level of 160/100 mm Hg in uncomplicated patients or at 140/90 mm Hg in those with target organ damage, established cardiovascular disease, diabetes or with increased cardiovascular risk factors. Decisions about the continued use of CPA+EE should be made at lower BP levels, and alternative contraception may be advised.

Conditions That Deteriorate with Pregnancy or During Previous COC or CPA+EE Use

The following conditions have been reported to occur or deteriorate with both pregnancy and use of a COC or oestrogen/progestogen combinations like CPA+EE. Consideration should be given to stopping CPA+EE if any of the following occur during use:

  • Jaundice and/or pruritus related to cholestasis
  • COCs or CPA+EE may increase the risk of gallstone formation and may worsen existing disease
  • Systemic lupus erythematosus
  • Herpes gestationis
  • Otosclerosis-related hearing loss
  • Sickle cell anaemia
  • Renal dysfunction
  • Hereditary angio-oedema
  • Epilepsy
  • Any other condition an individual woman has experienced worsening of during pregnancy or previous use of COCs or CPA+EE.

Disturbances of Liver Function

Acute or chronic disturbances of liver function may necessitate the discontinuation of COC or CPA+EE use until markers of liver function return to normal.

Diabetes (Without Vascular Involvement)

Insulin-dependent diabetics without vascular disease can use CPA+EE. However, it should be remembered that all diabetics are at an increased risk of arterial disease and this should be considered when prescribing COCs or CPA+EE. Diabetics with existing vascular disease are contraindicated from using CPA+EE.

Although COCs or oestrogen/progestogen combinations like CPA+EE 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 low-dose COCs (containing <0.05 mg EE). However, diabetic women should be carefully observed while taking COCs or CPA+EE.

Chloasma

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 CPA+EE.

Menstrual Changes

Reduction of menstrual flow

This is not abnormal and it is to be expected in some patients. Indeed, it may be beneficial where heavy periods were previously experienced.

Missed Menstruation

Occasionally, withdrawal bleeding may not occur at all. If the tablets have been taken correctly, pregnancy is unlikely. Should bleeding fail to occur during the tablet-free interval the possibility of pregnancy must be excluded before the next pack is started.

Intermenstrual Bleeding

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. This may include curettage.

Some women may experience amenorrhoea or oligomenorrhoea after discontinuation of CPA+EE, especially when these conditions existed prior to use. Women should be informed of this possibility.

ALT elevations

During clinical trials with patients treated for hepatitis C virus infections (HCV) with the medicinal products 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 frequently in women using EE-containing medications such as combined hormonal contraceptives (CHC).

Drug Interactions

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

Enzyme Inducers

Interactions can occur with drugs that induce microsomal enzymes (especially cytochrome P4503A4) which can result in increased clearance of sex hormones and which may lead to breakthrough bleeding and/or contraceptive failure.

Enzyme induction can already be observed after a few days of treatment. Maximal enzyme induction is generally seen within a few weeks. After the cessation of drug therapy enzyme induction may be sustained for about 4 weeks.

Women on short term treatment with any of these drugs should temporarily use a barrier method in addition to the COC or choose another method of contraception. The barrier method should be used during the time of concomitant drug administration and for 28 days after their discontinuation. If the period during which the barrier method is used runs beyond the end of a pack, the next pack should be started without a break. In this situation, a withdrawal bleed should not be expected until the end of the second pack. If the patient does not have a withdrawal bleed during the tablet free interval following the end of the second pack, the possibility of pregnancy must be ruled out before resuming with the next pack.

For women receiving long-term therapy with enzyme inducers, another method of contraception should be used.

The following have been shown to have clinically important interactions with CPA+EE:

  • Antiretroviral Agents: ritonavir, nelfinavir, nevirapine
  • Anticonvulsants: barbiturates (including phenobarbitone), primidone, phenytoin, carbamazepine, oxcarbazepine, topiramate
  • Antibiotics/Antifungals: griseofulvin, rifampicin
  • Herbal Remedies: St John's wort (Hypericum perforatum)

Note: There are other antiretroviral agents that may increase plasma concentration of sex hormones.

Substances decreasing the Clearance of CHC (Enzyme Inhibitors)

The clinical relevance of potential interactions with enzyme inhibitors remains unknown.

Concomitant administration of strong CYP3A4 inhibitors can increase plasma concentrations of the oestrogen 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.

Effects of Oestrogen/Progestogen Combinations on Other Drugs

Oral contraceptives and oestrogen/progestogen combinations like CPA+EE may affect the metabolism of certain other drugs. Accordingly, plasma and tissue concentrations may either increase (e.g. cyclosporin) or decrease (e.g. lamotrigine).

Pharmacodynamic interactions

Concomitant use with the medicinal products containing ombitasvir/paritaprevir/ritonavir and dasabuvir, with or without ribavirin may increase the risk of ALT elevations.

Therefore, CPA+EE-users must switch to an alternative method of contraception (e.g., progestagen-only contraception or non-hormonal methods) prior to starting therapy with this combination drug regimen. CPA+EE can be restarted 2 weeks following completion of treatment with this combination drug regimen.

Clinical data suggest 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.

Laboratory Tests

The use of oral contraceptives may influence the results of certain laboratory tests including biochemical parameters of liver, thyroid, adrenal and renal function, plasma levels of carrier proteins and lipid/lipoprotein fractions, parameters of carbohydrate metabolism and parameters of coagulation and fibrinolysis. Laboratory staff should, therefore, be informed about oral contraceptive use when laboratory tests are requested.

Renal Impairment

CPA+EE has not been specifically studied in renally impaired patients. Available data do not suggest a change in treatment in this patient population.

Hepatic Impairment

CPA+EE is contraindicated in women with severe hepatic disease as long as liver function values have not returned to normal.

Pregnancy 

CPA+EE is not indicated during pregnancy. If pregnancy occurs during treatment with CPA+EE, further intake must be stopped.

Animal studies have revealed that feminization of male foetuses may occur if CPA is administered during the phase of embryogenesis at which differentiation of the external genitalia occurs. Although the results of these tests are not necessarily relevant to humans, the possibility must be considered that administration of CPA+EE to women after the 45th day of pregnancy could cause feminization of male foetuses. It follows from this that pregnancy is an absolute contraindication for treatment with CPA+EE, and must be excluded before such treatment is begun.

Lactation

The use of CPA+EE during lactation may lead to a reduction in the volume of milk produced and to a change in its composition. Minute amounts of the active substances are excreted with the milk. These amounts may affect the child particularly in the first 6 weeks postpartum. Mothers who are breastfeeding should be advised not to take CPA+EE until the nursing mother has weaned her child off breast milk.

Paediatric use

CPA+EE is only indicated after menarche.

Geriatric use

CPA+EE is not indicated after menopause.

Undesirable Effects

The most commonly reported adverse reactions with CPA+EE 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 for all women who use CPA+EE.

Tabulated list of adverse events:

System Organ Class

Adverse Events Reported in Clinical Trials

Adverse Events Reported Post-Marketing

Common

(GREATER-THAN OR EQUAL TO (8805) 1/100 to <1/10)

Uncommon

(GREATER-THAN OR EQUAL TO (8805) 1/1000, <1/100)

Rare

(>1/10,000 to < 1/1000)

Eye Disorders

   

contact lens intolerance

 

Gastrointestinal Disorders

nausea, abdominal pain

vomiting, diarrhoea

 

Crohn's disease, ulcerative colitis

Immune System Disorders

   

hypersensitivity

exacerbation of hereditary angio-oedema

Investigations

weight increased

 

weight decreased

 

Metabolism and Nutrition Disorders

 

fluid retention

 

hypertriglyceridaemia

Nervous System Disorders

headache

migraine

 

exacerbation of chorea

Hepatobiliary Disorders

     

liver function disturbances

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

reduced menstrual flow, spotting, breakthrough bleeding and missed withdrawal bleeding, post-pill amenorrhoea

Skin and Subcutaneous Tissue Disorders

 

rash, urticaria

erythema nodosum, erythema multiforme

chloasma

Vascular disorders

 

 

thromboembolism

increase in blood pressure

Post-marketing reports of severe depression (including very rare reports of suicidal ideation or behaviour) in patients using CPA+EE have been received. However, a causal relationship between clinical depression and CPA+EE has not been established.

An increased risk of arterial and venous thrombotic and thrombo-embolic events, including myocardial infarction, stroke, transient ischemic attacks, venous thrombosis and pulmonary embolism has been observed in women using CHCs.

The following serious adverse events have been reported in women using CHCs.  Special warnings and precautions for use:

  • Venous thromboembolic disorders
  • Arterial thromboembolic disorders
  • Hypertension
  • Liver tumours
  • Occurrence or deterioration of conditions for which association with COC 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 COC 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 COC users. 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 COC or CPA+EE use is unknown.

Interactions

Breakthrough bleeding and/or contraceptive failure may result from interactions of other drugs (enzyme inducers) with oral contraceptives.

Overdosage

Overdose may cause nausea, vomiting and withdrawal bleeding. Withdrawal bleeding may even occur in girls before their menarche, if they accidentally take the medicinal product. There are no specific antidotes and further treatment should be symptomatic.

Storage and Handling Instructions

Store in a cool, dry place. Protect from moisture.

Packaging Information

GINETTE 35 is available in a blister pack of 21 tablets.

Patient Information

  1. What is GINETTE 35?

GINETTE 35 is a hormonal tablet containing two hormones – cyproterone acetate (2 mg) and ethinylestradiol (0.035 mg).

  1. How should I take GINETTE 35?

GINETTE 35 should be taken at the same time each day, preferably after the evening meal or at bedtime.

You should begin GINETTE 35 on the first day (day 1) of your menstrual period or on the day instructed by your doctor and continue taking the tablets, following the arrows, for 21 consecutive days. Following the 21 days, no tablets have to be taken for the next 7 days (tablet-free days).  Withdrawal bleeding (menses) could occur during these 7 tablet-free days.

  1. When do I start the next pack of GINETTE 35?

A new pack of GINETTE 35 is started by taking the tablets on the day after 7 tablet-free days. To remember to start the next pack of GINETTE 35, mark the day you have to start the next pack on the calendar or set an alarm on your mobile.

  1. Do I have to take GINETTE 35 everyday?

Yes. For GINETTE 35 to be effective, it has to be taken daily at a time convenient to you. It does not matter at what time of the day the tablet is taken, but once selected, the tablet should be taken as near as possible at the same time each day.

Tips to remember to take GINETTE 35 regularly:

  • Carry GINETTE 35 in your purse/handbag.
  • Keep a spare pack of GINETTE 35.
  • Keep GINETTE 35 at a place where you can see it, e.g., next to your toothbrush.
  • Link the time of taking GINETTE 35 to a daily activity, e.g., before going to bed at night, or after dinner.
  1. What should I do if I have missed a dose?

A single delayed tablet should be taken as soon as possible, and if this can be done within 12 hours of the correct time, contraceptive protection is maintained.

With longer delays, only the most recently delayed tablet should be taken, earlier missed tablets being omitted, and additional non-hormonal methods of contraception (except the rhythm or temperature methods) should be used for the next 7 days, while the next 7 tablets are being taken.

Additionally, therefore, if tablet(s) have been missed during the last 7 days of a pack, there should be no break before the next pack is started. If you have missed more than one tablet in this strip, contact your doctor.

Last updated: September 2018

Last reviewed: September 2018