Gveza

Drospirenone, ethinylestradiol.

Each film-coated tablet contains 3 mg drospirenone and 0.030 mg ethinylestradiol.
Excipient with known effect: Each tablet contains 62.00 mg lactose monohydrate.
Excipients/Inactive Ingredients: Tablet core: Lactose monohydrate, Maize starch, Pregelatinized starch (maize), Crospovidone (Plasdone XL-10), Crospovidone (Plasdone XL), Povidone K-30, Polysorbate 80 (Tween 80), Magnesium stearate.
Film-coating: Polyvinyl alcohol-partial hydrolyzed, Titanium dioxide (E171), Macrogol 3350, Talc, Yellow iron oxide (E172).

Pharmacotherapeutic group: Progestogens and estrogens, fixed combinations. ATC code: G03AA12.
Pharmacology: Pharmacodynamics: Pearl Index for method failure: 0.09 (upper two-sided 95% confidence limit: 0.32).
Overall Pearl Index (method failure + patient failure): 0.57 (upper two-sided 95% confidence limit: 0.90).
The contraceptive effect of GVEZA is based on the interaction of various factors, the most important of which are seen as the inhibition of ovulation and the changes in the cervical secretion.
GVEZA is a combined oral contraceptive with ethinylestradiol and the progestogen drospirenone. In a therapeutic dosage, drospirenone also possesses antiandrogenic and mild antimineralocorticoid properties. It has no estrogenic, glucocorticoid and antiglucocorticoid activity. This gives drospirenone a pharmacological profile closely resembling the natural hormone progesterone.
There are indications from clinical studies that the mild antimineralocorticoid properties of drospirenone/ethinylestradiol result in a mild antimineralocorticoid effect.
Pharmacokinetics: Drospirenone: Absorption: Orally administered drospirenone is rapidly and almost completely absorbed. Maximum concentrations of the active substance in serum of about 37 ng/ml are reached at about 1-2 h after single ingestion. Bioavailability is between 76 and 85%. Concomitant ingestion of food has no influence on the bioavailability of drospirenone.
Distribution: Drospirenone is bound to serum albumin and does not bind to sex hormone binding globulin (SHBG) or corticoid binding globulin (CBG). Only 3-5% of the total serum concentrations of the active substance are present as free steroid. The ethinylestradiol-induced increase in SHBG does not influence the serum protein binding of drospirenone. The mean apparent volume of distribution of drospirenone is 3.7-4.2 l/kg.
Biotransformation: Drospirenone is extensively metabolized after oral administration. The major metabolites in the plasma are the acid form of drospirenone, generated by opening of the lactone ring, and the 4,5-dihydro-drospirenone-3-sulfate, both of which are formed without involvement of the P450 system. Drospirenone is metabolized to a minor extent by cytochrome P450 3A4 and has demonstrated a capacity to inhibit this enzyme and cytochrome P450 1A1, cytochrome P450 2C9 and cytochrome P450 2C19 in vitro.
Elimination: The metabolic clearance rate of drospirenone in serum is 1.5 ± 0.2 ml/min/kg. Drospirenone is excreted only in trace amounts in unchanged form. The metabolites of drospirenone are excreted with the feces and urine at an excretion ratio of about 1.2 to 1.4. The half-life of metabolite excretion with the urine and feces is about 40 h.
Steady-state conditions: During a treatment cycle, maximum steady-state concentrations of drospirenone in serum of about 70 ng/ml are reached after about 8 days of treatment. Serum drospirenone levels accumulated by a factor of about 3 as a consequence of the ratio of terminal half-life and dosing interval.
Special populations: Effect of renal impairment: Steady-state serum drospirenone levels in women with mild renal impairment (creatinine clearance CLcr, 50-80 ml/min) were comparable to those of women with normal renal function. The serum drospirenone levels were on average 37% higher in women with moderate renal impairment (CLcr, 30-50 ml/min) compared to those in women with normal renal function. Drospirenone treatment was also well tolerated by women with mild and moderate renal impairment. Drospirenone treatment did not show any clinically significant effect on serum potassium concentration.
Effect of hepatic impairment: GVEZA is contraindicated in patients with hepatic dysfunction (see Contraindications). The mean exposure to drospirenone in women with moderate liver impairment is approximately three times the exposure in women with normal liver function. GVEZA has not been studied in women with severe hepatic impairment.
Ethnic groups: No clinically relevant differences in the pharmacokinetics of drospirenone or ethinylestradiol between Japanese and Caucasian women have been observed.
Ethinylestradiol: Absorption: Orally administered ethinylestradiol is rapidly and completely absorbed. Peak serum concentrations of about 54-100 pg/ml are reached within 1-2 hours. During absorption and first-liver passage, ethinylestradiol is metabolized extensively, resulting in a mean oral bioavailability of about 45% with a large interindividual variation of about 20-65%. Concomitant intake of food reduced the bioavailability of ethinylestradiol in about 25% of the investigated subjects while no change was observed in the others.
Distribution: Ethinylestradiol is highly but non-specifically bound to serum albumin (approximately 98%), and induces an increase in the serum concentrations of SHBG. An apparent volume of distribution of about 2.8-8.6 l/kg was determined.
Metabolism: Ethinylestradiol is subject to significant gut and hepatic first-pass metabolism. Ethinylestradiol and its oxidative metabolites are primarily conjugated with glucuronides or sulfate. The metabolic clearance rate was reported to be about 2.3-7 ml/min/kg.
Elimination: Ethinylestradiol serum levels decrease in two disposition phases characterized by half-lives of about 1 hour and 10-20 hours, respectively. Unchanged drug is not excreted, ethinylestradiol metabolites are excreted at a urinary to biliary ratio of 4:6. The half-life of metabolite excretion is about 1 day.
Steady-state conditions: Steady-state conditions are reached during the second half of a treatment cycle when serum drug levels are higher by 40-110% as compared to single dose.
Toxicology: Preclinical safety data: Preclinical data reveal no special risks for humans based on conventional studies of repeated dose toxicity, genotoxicity, carcinogenic potential and toxicity to reproduction. In laboratory animals, the effects of drospirenone and ethinylestradiol were confined to those associated with the recognized pharmacological action. In particular, reproduction toxicity studies revealed embryotoxic and foetotoxic effects in animals which are considered as species specific. Ethinylestradiol-induced tumours in rodents have previously been seen with other ethinylestradiol-containing products, and are considered attributable to species-specific effects of estrogens on prolactin secretion in rodents. Although long-term animal studies did not definitely indicate a tumourigenic potential for the clinical use of either drospirenone or ethinylestradiol, it should be borne in mind that sex steroids can promote the growth of certain hormone-dependent tissues and tumours.

Oral contraception.

Posology: How to take GVEZA: The tablets must be taken every day at about the same time, if necessary with a little liquid, in the order shown on the blister pack. One tablet is to be taken daily for 21 consecutive days. Each subsequent pack is started after a 7-day tablet-free interval, during which time a withdrawal bleed usually occurs. This usually starts on day 2-3 after the last tablet and may not have finished before the next pack is started.
How to start GVEZA: No preceding hormonal contraceptive use (in the past month).
Tablet-taking has to start on day 1 of the woman's natural cycle (i.e. the first day of her menstrual bleeding). Starting on days 2-5 is allowed, but during the first cycle a barrier method is recommended in addition for the first 7 days of tablet-taking.
Changing from a combined hormonal contraceptive (combined oral contraceptive (COC), vaginal ring, or transdermal patch): The woman should start with GVEZA preferably on the day after the last active tablet (the last tablet containing the active substances) of her previous COC, but at the latest on the day following the usual tablet-free or placebo tablet interval of her previous COC. In case a vaginal ring or transdermal patch has been used, the woman should start using GVEZA preferably on the day of removal, but at the latest when the next application would have been due.
Changing from a progestogen-only-method (progestogen-only pill, injection, implant) or from a progestogen-releasing intrauterine system (IUS): The woman may switch any day from the progestogen-only pill (from an implant or the IUS on the day of its removal, from an injectable when the next injection would be due) but should in all of these cases be advised to additionally use a barrier method for the first 7 days of tablet taking.
Following first-trimester abortion: The woman may start immediately. When doing so, she need not take additional contraceptive measures.
Following delivery or second-trimester abortion: Women should be advised to start at day 21 to 28 after delivery or second-trimester abortion. When starting later, the woman should be advised to additionally use a barrier method for the first 7 days. However, if intercourse has already occurred, pregnancy should be excluded before the actual start of COC use or the woman has to wait for her first menstrual period.
For breastfeeding women, see Use in Pregnancy & Lactation.
Management of missed tablets: If the user is less than 12 hours late in taking any 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 tablet, contraceptive protection may be reduced. The management of missed tablets can be guided by the following two basic rules: Tablet-taking must never be discontinued for longer than 7 days.
7 days of uninterrupted tablet-taking are required to attain adequate suppression of the hypothalamic-pituitary-ovarian-axis.
Accordingly the following advice can be given in daily practice: Week 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. 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 should be considered. The more tablets are missed and the closer they are to the regular tablet-free interval, the higher the risk of a pregnancy.
Week 2: 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 has missed more than 1 tablet, the woman should be advised to use extra precautions for 7 days.
Week 3: The risk of reduced reliability is imminent because of the forthcoming 7 day tablet-free interval. However, by adjusting the tablet-intake schedule, reduced contraceptive protection can still be prevented. By adhering to either of the following two options, there is therefore 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, she should follow the first of these two options and use extra precautions for the next 7 days as well.
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. The next blister pack must be started as soon as the current blister pack is finished, i.e., no gap should be left between packs. The user is unlikely to have a withdrawal bleed until the end of the second pack, but she may experience spotting or breakthrough bleeding on tablet-taking days.
The woman may also be advised to discontinue tablet-taking from the current blister pack. She should then have a tablet-free interval of up to 7 days, including the days she missed tablets, and subsequently continue with the next blister pack.
If the woman missed tablets and subsequently has no withdrawal bleed in the first normal tablet-free interval, the possibility of a pregnancy should be considered.
Advice in case of gastro-intestinal disturbances: In case of severe gastro-intestinal disturbances (e.g. vomiting or diarrhoea), absorption may not be complete and additional contraceptive measures should be taken.
If vomiting occurs within 3-4 hours after tablet taking, a new (replacement) tablet should be taken as soon as possible. The new tablet should be taken within 12 hours of the usual time of tablet-taking if possible. If more than 12 hours elapse, the advice concerning missed tablets, as given in "Management of missed tablets" as previously mentioned, is applicable. If the woman does not want to change her normal tablet-taking schedule, she has to take the extra tablet(s) from another blister pack.
How to postpone a withdrawal bleed: To delay a period the woman should continue with another blister pack of GVEZA without a tablet-free interval. The extension can be carried on for as long as wished until the end of the second pack. During the extension the woman may experience breakthrough-bleeding or spotting. Regular intake of GVEZA is then resumed after the usual 7-day tablet-free interval.
To shift her periods to another day of the week than the woman is used to with her current scheme, she can be advised to shorten her forthcoming tablet-free interval by as many days as she likes. The shorter the interval, the higher the risk that she does not have a withdrawal bleed and will experience breakthrough-bleeding and spotting during the subsequent pack (just as when delaying a period).
Additional information on special populations: Children and adolescents: GVEZA is only indicated after menarche. There are no data suggesting the need for a dosage adjustment.
Geriatric patients: Not applicable. GVEZA is not indicated after menopause.
Patients with hepatic impairment: GVEZA is contraindicated in women with severe hepatic diseases. See also Contraindications and Pharmacology: Pharmacokinetics under Actions.
Patients with renal impairment: GVEZA is contraindicated in women with severe renal insufficiency or acute renal failure. See also Contraindications and Pharmacology: Pharmacokinetics under Actions.
Method of administration: Oral use.

There has not yet been any experience of overdose with drospirenone/ethinylestradiol. On the basis of general experience with combined oral contraceptives, symptoms that may possibly occur in this case are: nausea, vomiting and, in young girls, slight vaginal bleeding. There are no antidotes and further treatment should be symptomatic.

Combined oral contraceptives (COCs) should not be used in the presence of any of the conditions listed as follows. Should any of the conditions appear for the first time during COC use, the product should be stopped immediately.
Presence or risk of venous thromboembolism (VTE): Venous thromboembolism - current VTE (on anticoagulants) or history of 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 immobilization (see Precautions).
A high risk of venous thromboembolism due to the presence of multiple risk factors.
Presence or risk of arterial thromboembolism (ATE): Arterial thromboembolism - current arterial thromboembolism, history of arterial thromboembolism (e.g. myocardial infarction) or prodromal condition (e.g. angina pectoris).
Cerebrovascular disease - 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.
A high risk of arterial thromboembolism due to multiple risk factors (see Precautions) or to the presence of one serious risk factor such as: Diabetes mellitus with vascular symptoms; Severe hypertension; Severe dyslipoproteinaemia.
Pancreatitis, or a history thereof, if associated with severe hypertriglyceridaemia.
Presence or history of severe hepatic disease as long as liver function values have not returned to normal.
Renal Impairment.
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.
Cholestatic jaundice or pregnancy or jaundice with prior pill use.
Hypersensitivity to the active substances or to any of the excipients listed in Description.

Warnings: If any of the conditions/risk factors mentioned as follows is present, the benefits of COC use should be weighed against the possible risks for each individual woman and discussed with the woman before she decides to start using it. In the event of aggravation, exacerbation or first appearance of any of these conditions or risk factors, the woman should contact her physician. The physician should then decide on whether COC use should be discontinued.
Circulatory disorders: Epidemiological studies have suggested an association between the use of COCs and an increased risk of arterial and venous thrombotic and thromboembolic diseases such as myocardial infarction, deep venous thrombosis, pulmonary embolism and of cerebrovascular accidents. These events occur rarely.
The risk of VTE is highest during the first year of use. This increased risk is present after initially starting a COC or restarting (following a 4 week or greater pill free interval) the same or a different COC. Data from a large, prospective 3-armed cohort study suggest that this increased risk is mainly present during first the 3 months.
Overall the risk for venous thromboembolism (VTE) in users of low estrogen dose(< 50 μg ethinylestradiol) COCs is two to threefold higher than for non-users of COCs who are not pregnant and remains lower than the risk associated with pregnancy and delivery.
Post Authorization Safety Studies (PASS) have shown that the frequency of VTE diagnosis ranges between 7-10 per 10,000 woman years in low estrogen dose (< 50 μg ethinylestradiol) COC users. The most recent data suggest that the frequency of VTE diagnosis is approximately 4 per 10,000 woman years in non-pregnant non-COC users, and ranges between 20 to 30 per 10,000 pregnant women or post-partum.
The increased risk associated with COC use is attributed to the estrogen component. There remains a scientific debate regarding any modulating effect on the risk of VTE by the progestin component of COCs. Epidemiological studies that compared the risk of VTE associated with use of COCs containing ethinylestradiol/drospirenone to the risk with use of COCs containing levonorgestrel reported differing results ranging from no difference in risk to a three-fold increase in risk. The majority of studies investigated ethinylestradiol/drospirenone 0.03 mg/3 mg.
Two post approval commitment studies have been completed specifically for ethinylestradiol/drospirenone 0.03 mg/3 mg. In one, prospective active surveillance study, the incidence of VTE in women with or without other risk factors for VTE who used ethinylestradiol/drospirenone 0.03 mg/3mg was found to be in the same range as that for users of levonorgestrel-containing COCs and other COCs (various other COC brands). The other, a prospective, controlled, database study comparing users of ethinylestradiol/drospirenone 0.03 mg/ 3mg to other COC users also confirmed a similar incidence of VTE among all of the cohorts.
VTE may be life-threatening or may have a fatal outcome (in 1-2% of cases).
Venous thromboembolism (VTE), manifesting as deep venous thrombosis and/or pulmonary embolism, may occur during the use of all COCs.
The use of any combined oral contraceptive (COC) increases the risk of venous thromboembolism (VTE) compared with no use. Products that contain levonorgestrel, norgestimate, or norethisterone are associated with the lowest risk of VTE. Other products such as GVEZA may have up to twice this level of risk. The decision to use any product other than one with the lowest VTE risk should be taken only after a discussion with the woman to ensure she understands the risk of VTE with GVEZA, how her current risk factors influence this risk, and that her VTE risk is highest in the first ever year of use. There is also some evidence that the risk is increased when a COC is re-started after a break in use of 4 weeks or more.
In women who do not use a COC and are not pregnant, about 2 out of 10,000 will develop a VTE over the period of one year. However, in any individual woman, the risk may be far higher, depending on her underlying risk factors (see as follows).
It is estimated that out of 10,000 women who use a COC-containing drospirenone, between 9 to 12 women will develop a VTE in one year; this compares with about 6 in women who use a levonorgestrel-containing COC.
Extremely rarely, thrombosis has been reported to occur in other blood vessels, e.g. hepatic, mesenteric, renal, cerebral or retinal veins and arteries, in COC users.
Symptoms of deep venous thrombosis (DVT) can include: unilateral swelling of the leg 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 discolored 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 bring up blood; sharp chest pain which may increase with deep breathing; sense of anxiety; severe light headedness or dizziness; rapid or irregular heartbeat. Some of these symptoms (e.g. ''shortness of breath'', ''coughing'') are non-specific and might be misinterpreted as more common or less severe events (e.g. respiratory tract infections).
An arterial thromboembolic event can include cerebrovascular accident, vascular occlusion or myocardial infarction (MI). 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 confusion, trouble speaking or understanding; sudden trouble seeing in one or both eyes; sudden trouble walking, dizziness, loss of balance or coordination; sudden, severe or prolonged headache with no known cause; loss of consciousness or fainting with or without seizure. Other signs of vascular occlusion can include: sudden pain, swelling and slight blue discoloration of an extremity; acute abdomen.
Symptoms of 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; fullness, indigestion or choking feeling; sweating, nausea, vomiting or dizziness; extreme weakness, anxiety, or shortness of breath; rapid or irregular heartbeats.
Arterial thromboembolic events may be life-threatening or may have a fatal outcome.
A potential for an increased synergistic risk of thrombosis should be considered in women who possess a combination of risk factors or exhibit a greater severity of an individual risk factor. This increased risk may be greater than a simple cumulative risk of the factors. A COC should not be prescribed in case of a negative risk benefit assessment (see Contraindications).
The risk of venous or arterial thrombotic/thromboembolic events or of a cerebrovascular accident increases with: age; obesity (body mass index over 30 kg/m²); a positive family history (i.e. venous or arterial thromboembolism ever in a sibling or parent at relatively early age). If a hereditary or acquired predisposition is suspected, the woman should be referred to a specialist for advice before deciding about any COC use; prolonged immobilization, major surgery, any surgery to the legs, or major trauma. In these situations it is advisable to discontinue COC use (in the case of elective surgery at least four weeks in advance) and not to resume until two weeks after complete remobilization; smoking (with heavier smoking and increasing age the risk further increases, especially in women over 35 years of age); dyslipoproteinemia; hypertension; migraine; valvular heart disease; atrial fibrillation.
The presence of one serious risk factor or multiple risk factors for venous or arterial disease, respectively, can also constitute a contra-indication. The possibility of anticoagulant therapy should also be taken into account. COC users should be specifically pointed out to contact their physician in case of possible symptoms of thrombosis. In case of suspected or confirmed thrombosis, COC use should be discontinued. Adequate alternative contraception should be initiated because of the teratogenicity of anticoagulant therapy (coumarins).
The potential for an increased synergistic risk of thrombosis should be considered in women who possess a combination of risk factors or exhibit a greater severity of an individual risk factor. This increased risk may be greater than a simple cumulative risk of the factors. A COC should not be prescribed in case of a negative risk benefit assessment (see Contraindications).
There is no consensus about the possible role of varicose veins and superficial thrombophlebitis in venous thromboembolism.
The increased risk of thromboembolism in the puerperium must be considered (for information on pregnancy and lactation, see Use in Pregnancy & Lactation).
Other medical conditions which have been associated with adverse circulatory events include diabetes mellitus, systemic lupus erythematosus, haemolytic uraemic syndrome and chronic inflammatory bowel disease (Crohn's disease or ulcerative colitis) and sickle cell disease.
An increase in frequency or severity of migraine during COC use (which may be prodromal of a cerebrovascular event) may be a reason for immediate discontinuation of the COC.
Biochemical factors that may be indicative of hereditary or acquired predisposition for venous or arterial thrombosis include Activated Protein C (APC) resistance, hyperhomocysteinemia, 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 low-dose COCs (<0.05 mg ethinylestradiol).
Tumours: The most important risk factor for cervical cancer is persistent HPV infection. Some epidemiological studies have indicated that long-term use of COCs may further contribute to this increased risk but there continues to be controversy about the extent to which this finding is an attributable to confounding effects, e.g., cervical screening and sexual behaviour including use of barrier contraceptives.
A meta-analysis from 54 epidemiological studies reported that there is a slightly increased relative risk (RR = 1.24) of having breast cancer diagnosed in women who are currently using COCs. The excess risk gradually disappears during the course of the 10 years after cessation of COC use. Because breast cancer is rare in women under 40 years of age, the excess number of breast cancer diagnoses in current and recent COC users is small in relation to the overall risk of breast cancer. These studies do not provide evidence for causation. The observed pattern of increased risk may be due to an earlier diagnosis of breast cancer in COC users, the biological effects of COCs or a combination of both. The breast cancers diagnosed in ever-users tend to be less advanced clinically than the cancers diagnosed in never-users.
In rare cases, benign liver tumours, and even more rarely, malignant liver tumours have been reported in users of COCs. 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 COCs.
Other conditions: The progestogen component in GVEZA is an aldosterone antagonist with potassium sparing properties. In most cases, no increase of potassium levels is to be expected. In a clinical study, however, in some patients with mild or moderate renal impairment and concomitant use of potassium-sparing medicinal products, serum potassium levels slightly, but not significantly, increased during drospirenone intake. Potassium excretion capacity may be limited in patients with renal insufficiency. GVEZA is contraindicated in renal impairment (see Contraindications).
Women with hypertriglyceridaemia, or a family history thereof, may be at an increased risk of pancreatitis when using COCs.
Although small increases in blood pressure have been reported in many women taking COCs, clinically relevant increases are rare. Only in these rare cases an immediate discontinuation of COC use is justified. If, during the use of a COC in pre-existing hypertension, constantly elevated blood pressure values or a significant increase in blood pressure do not respond adequately to antihypertensive treatment, the COC must be withdrawn. Where considered appropriate, COC use may be resumed if normotensive values can be achieved with antihypertensive therapy.
The following conditions have been reported to occur or deteriorate with both pregnancy and COC use, but the evidence of an association with COC use is inconclusive: jaundice and/or pruritus related to cholestasis; gallstones; porphyria; systemic lupus erythematosus; haemolytic uraemic syndrome; Sydenham's chorea; herpes gestationis; otosclerosis-related hearing loss.
In women with hereditary angioedema exogenous oestrogens may induce or exacerbate symptoms of angioedema.
Acute or chronic disturbances of liver function may necessitate the discontinuation of COC use until markers of liver function return to normal. Recurrence of cholestatic jaundice and/or cholestasis-related pruritus which previously occurred during pregnancy or during previous use of sex steroids necessitates the discontinuation of COCs.
Although COCs may have an effect on peripheral insulin resistance and glucose tolerance, there is no evidence for a need to alter the therapeutic regimen in diabetics using low-dose COCs (containing < 0.05 mg ethinylestradiol). However, diabetic women should be carefully observed, particularly in the early stage of COC use.
Worsening of endogenous depression, of epilepsy, of Crohn's disease and of ulcerative colitis has been reported during COC use.
Chloasma may occasionally occur, especially in women with a history of chloasma gravidarum. Women with a tendency to chloasma should avoid exposure to the sun or ultraviolet radiation whilst taking COCs.
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 physician in case of mood changes and depressive symptoms, including shortly after initiating the treatment.
Excipients: This medicinal product contains 62 mg lactose per tablet. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption who are on a lactose-free diet should take this amount into consideration.
Medical examination/consultation: A complete medical history and physical examination should be taken prior to the initiation or reinstitution of COC use, guided by the contraindications and warnings, 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 COC. 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 oral contraceptives do not protect against HIV infections (AIDS) and other sexually transmitted diseases.
Reduced efficacy: The efficacy of COCs may be reduced in the event of e.g. missed tablets (see Dosage & Administration), gastrointestinal disturbances (see Dosage & Administration) or concomitant medication (see Interactions).
Reduced cycle control: With all COCs, irregular bleeding (spotting or breakthrough bleeding) may occur, especially during the first months of use. Therefore, the evaluation of any irregular bleeding is only meaningful after an adaptation interval of about three cycles.
If bleeding irregularities persist or occur after previously regular cycles, then non-hormonal causes should be considered and adequate diagnostic measures are indicated to exclude malignancy or pregnancy. These may include curettage.
In some women withdrawal bleeding may not occur during the tablet-free interval. If the COC has been taken according to the directions described in Dosage & Administration, it is unlikely that the woman is pregnant. However, if the COC has not been taken according to these directions prior to the first missed withdrawal bleed or if two withdrawal bleeds are missed, pregnancy must be ruled out before COC use is continued.
Effects on ability to drive and use machines: No studies on the effects on the ability to drive and use machines have been performed. No effects on ability to drive and use machines have been observed in users of COCs.

Pregnancy: GVEZA is not indicated during pregnancy.
If pregnancy occurs during use of GVEZA, the preparation should be withdrawn immediately. Extensive epidemiological studies have revealed neither an increased risk of birth defects in children born to women who used COCs prior to pregnancy, nor a teratogenic effect when COCs were taken inadvertently during pregnancy.
Animal studies have shown undesirable effects during pregnancy and lactation (see Pharmacology: Toxicology: Preclinical safety data under Actions). Based on these animal data, undesirable effects due to hormonal action of the active compounds cannot be excluded. However, general experience with COCs during pregnancy did not provide evidence for an actual undesirable effect in humans.
The available data regarding the use of drospirenone/ethinylestradiol during pregnancy are too limited to permit conclusions concerning negative effects of drospirenone/ethinylestradiol on pregnancy, health of the foetus or neonate. To date, no relevant epidemiological data are available.
The increased risk of VTE during the postpartum period should be considered when re-starting GVEZA.
Breastfeeding: Lactation may be influenced by COCs as they may reduce the quantity and change the composition of breast milk. Therefore, the use of COCs should generally not be recommended until the breast-feeding mother has completely weaned her child. Small amounts of the contraceptive steroids and/or their metabolites may be excreted with the milk during COC use. These amounts may affect the child.

Summary of safety profile: The most commonly reported adverse reactions with GVEZA are nausea and breast pain. They occur in > 6% of users.
Serious adverse reactions are arterial and venous thromboembolism.
Tabulated list of adverse reactions: The frequencies of ADRs reported in clinical trials with ethinylestradiol/drospirenone 0.03 mg/3 mg (N=4897) are summarised in the table as follows. Within each frequency grouping, ADRs are presented in order of decreasing seriousness. Additional ADRs identified only during post-marketing surveillance, and for which a frequency could not be estimated, are listed under 'not known'. (See Table 1.)

Click on icon to see table/diagram/image

For venous and arterial thromboembolic events and migraine see also Contraindications, Precautions.
Adverse reactions reported in women using COCs: 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 as follows (see also Contraindications, Precautions): Tumours: The frequency of diagnosis of breast cancer is very slightly increased among OC 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 use is unknown; Liver tumours (benign and malignant).
Other conditions: Erythema nodosum; Women with hypertriglyceridemia (increased risk of pancreatitis when using COCs); Hypertension; Occurrence or deterioration of conditions for which association with COC use is not conclusive: jaundice and/or pruritus related to cholestasis; gallstone formation; porphyria; systemic lupus erythematosus; hemolytic uremic syndrome; Sydenham's chorea; herpes gestationis; otosclerosis-related hearing loss; In women with hereditary angioedema exogenous estrogens may induce or exacerbate symptoms of angioedema; Liver function disturbances; Changes in glucose tolerance or effect on peripheral insulin resistance; Crohn's disease, ulcerative colitis; Chloasma; Hypersensitivity (including symptoms such as rash, urticaria).
Other side effects that had been reported with the use of COCs that have neither been confirmed nor refuted are: (See Table 2.)

Click on icon to see table/diagram/image

Interactions: Breakthrough bleeding and/or contraceptive failure may result from interactions of other drugs (enzyme inducers) with oral contraceptives (see lnteraction with other medicinal products and other forms of interaction under Interactions).

Note: The prescribing information of concomitant medications should be consulted to identify potential interactions.
Influence of other medicinal products on GVEZA: Interactions between oral contraceptives and other medicinal products may lead to breakthrough bleeding and/or contraceptive failure. The following interactions have been reported in the literature.
Hepatic metabolism: Interactions can occur with drugs that induce hepatic enzymes which can result in increased clearance of sex hormones (e.g. phenytoin, barbiturates, primidone, carbamazepine, rifampicin, bosentan and HIV-medication (e.g. ritonavir, nevirapine) and possibly also oxcarbazepine, topiramate, felbamate, griseofulvin and products containing the herbal remedy St. John's Wort (hypericum perforatum). Maximal enzyme induction is generally seen in about 10 days but may then be sustained for at least 4 weeks after the cessation of drug therapy.
Interference with enterohepatic circulation: Contraceptive failures have also been reported with antibiotics, such as penicillins and tetracyclines. The mechanism of this effect has not been elucidated.
Management: Women on short-term treatment with any of the above-mentioned classes of medicinal products or individual active substances (hepatic enzyme-inducing medicine) should temporarily use a barrier method in addition to the COC, i.e. during the time of concomitant medicinal product administration and for 28 days after their discontinuation.
If the period during which the barrier method is used runs beyond the end of the tablets in the COC pack, the next COC pack should be started without the usual tablet-free interval.
In women on long-term treatment with hepatic enzyme-inducing active substances, another reliable, non-hormonal, method of contraception is recommended.
The main metabolites of drospirenone in human plasma are generated without involvement of the cytochrome P450 system. Inhibitors of this enzyme system are therefore unlikely to influence the metabolism of drospirenone.
Influence of COCs on other medicinal products: Oral contraceptives may affect the metabolism of certain other active substances. Accordingly, plasma and tissue concentrations may either increase(e.g. ciclosporin) or decrease (e.g. lamotrigine).
Based on in vitro inhibition studies and in vivo interaction studies in female volunteers using omeprazole, simvastatin and midazolam as marker substrate, an interaction of drospirenone at doses of 3 mg with the metabolism of other active substances is unlikely.
Other interactions: There is a theoretical potential for an increase in serum potassium in women taking GVEZA with other drugs that may increase serum potassium levels. Such drugs include angiotensin-II-receptor antagonists, potassium-sparing diuretics, and aldosterone antagonists. However, in studies evaluating the interaction of drospirenone (combined with estradiol) with an ACE inhibitor or indomethacin, no clinically or statistically significant differences in serum potassium concentrations were observed.
Laboratory tests: 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.
Drospirenone causes an increase in plasma renin activity and plasma aldosterone induced by its mild antimineralocorticoid activity.

Incompatibilities: Not applicable.
Special precautions for disposal: No special requirements.

Special precautions for storage: This medicinal product does not require any special storage conditions.

Oral Contraceptives

G03AA12 - drospirenone and ethinylestradiol ; Belongs to the class of progestogens and estrogens in fixed combinations. Used as systemic contraceptives.

POM