24 hormone-containing light pink film-coated tablets: Each film-coated tablet contains 0.020 mg ethinylestradiol (as betadex clathrate), 3 mg drospirenone.
Excipients/Inactive Ingredients: 24 hormone-containing light pink film-coated tab: Lactose monohydrate, maize starch, magnesium stearate (E470b), hypromellose (E464), talc (E553b), titanium dioxide (E171), ferric oxide red (E172).
4 hormone-free white film-coated tab: Lactose monohydrate, magnesium stearate (E470b), cellulose microcrystalline, hypromellose (E464), talc (E553b), titanium dioxide (E171).
Pharmacotherapeutic group: Progestogens and estrogens, fixed combinations. ATC Code: G03AA12.
Pharmacology: Pharmacodynamics: The contraceptive effect of COCs 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.
In a 3-cycle ovulation inhibition study comparing Yaz with a COC containing drospirenone 3 mg/ethinylestradiol 0.020 mg in a conventional 21-day-regimen, the 24-day-regimen of Yaz was associated with greater suppression of follicular development. After intentionally introduced dosing errors during the third cycle of treatment, a greater proportion of women in the 21-day-regimen showed ovarian activity including escape ovulations compared to the women taking Yaz.
A large prospective, comparative, non-interventional US cohort study in COC users identified a typical use Pearl Index for Yaz that was statistically significantly lower compared to the Pearl Index of all other COCs in this study. These results indicate that Yaz has higher contraceptive effectiveness under routine medical conditions compared to other COCs.
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 of VTE associated with COC use in 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 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 Yaz.
As well as protection against pregnancy, COCs have several positive properties which, next to the negative properties (see Precautions and Adverse Reactions), can be useful in deciding on the method of birth control. The cycle is more regular and the menstruation is often less painful and bleeding is lighter. The latter may result in a decrease in the occurrence of iron deficiency.
Drospirenone has beneficial properties in addition to contraception. Drospirenone has antimineralocorticoid activity that can prevent weight gain and other symptoms caused by fluid retention. It counteracts the estrogen-related sodium retention, providing for a very good tolerance and has positive effects on the premenstrual syndrome (PMS). Yaz with a shortened hormone free interval, was studied in PMDD. PMDD is a severe form of PMS. In two placebo controlled phase 3 studies including over 500 subjects, Yaz showed clinical superiority in relief of symptoms of PMDD. In combination with ethinylestradiol, drospirenone displays a favorable lipid profile with an increase in HDL. Drospirenone exerts antiandrogenic activity leading to a positive effect on the skin and to a reduction in acne lesions and sebum production. In addition, drospirenone does not counteract the ethinylestradiol-related SHBG increase which is useful for binding and inactivating the endogenous androgens.
In two multicenter, double blind, randomized, placebo controlled studies on the efficacy and safety of Yaz as an acne therapy in women with moderate acne vulgaris, Yaz produced clinically and statistically significant anti-acne effects on all the primary efficacy variables (inflammatory lesion, non-inflammatory lesion, total lesion counts, and the number and percentage of subjects with a "clear" or "almost clear" rating on the Investigator's Stated Global Assessment (ISGA) scale) and on the majority of secondary efficacy variables.
In two Japanese multicenter studies, the efficacy and safety of Yaz [drospirenone 3 mg/ethinylestradiol 20 μg (as β-cyclodextrin clathrate)] was demonstrated in women suffering from dysmenorrhea: In a double-blind, randomized, placebo-controlled comparative study, Yaz was demonstrated to have the optimal dose as compared with preparations containing drospirenone 2 mg/ethinylestradiol 20 μg (as β-cyclodextrin clathrate), drospirenone 1 mg/ethinylestradiol 20 μg (as β-cyclodextrin clathrate) and placebo.
A single-blind, randomized study, investigated the efficacy of ethinylestradiol for intracyclic bleeding profile during 24 weeks (6 cycles) with Yaz and a preparation containing drospirenone 3 mg/ ethinylestradiol 30 μg in patients with dysmenorrhea. This study also investigated the long term safety of Yaz administered for 52 weeks (13 cycles).
Drospirenone is devoid of any androgenic, estrogenic, glucocorticoid, and antiglucocorticoid activity. This, in combination with the antimineralocorticoid and antiandrogenic properties, gives drospirenone a biochemical and pharmacological profile closely resembling the natural hormone progesterone. Apart from this, there is evidence of a reduced risk of endometrial cancer and ovarian cancer. Furthermore, the higher dosed COCs (0.05 mg ethinylestradiol) have been shown to reduce the incidence of ovarian cysts, pelvic inflammatory disease, benign breast disease and ectopic pregnancy. Whether this also applies to lower-dosed COCs remains to be confirmed.
Pharmacokinetics: Drospirenone: Absorption: Orally administered drospirenone is rapidly and almost completely absorbed. Maximum concentrations of the drug in serum of about 35 ng/ml are reached at about 1-2 h after single ingestion. Bioavailability is between 76 and 85%. The intake of food had no influence on the bioavailability of drospirenone as compared to drug intake on an empty stomach.
Distribution: After oral administration, serum drospirenone levels decrease in two phases which are characterized by half-lives of 1.6 ± 0.7 h and 27.0 ± 7.5 h, respectively. 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 drug concentrations 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 ± 1.2 l/kg.
Metabolism: 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, formed by reduction and subsequent sulfatation. Drospirenone is also subject to oxidative metabolism catalyzed by CYP3A4.
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 60 ng/ml are reached between day 7 and day 14 of treatment. Serum drospirenone levels accumulated by a factor of about 2 to 3 as a consequence of the ratio of terminal half-life and dosing interval. Further accumulation of drospirenone levels beyond treatment cycles was observed between cycles 1 and 6 but thereafter, no further accumulation was observed.
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 (CLcr, >80 mL/min). 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 well tolerated by all groups. Drospirenone treatment did not show any clinically significant effect on serum potassium concentration.
Effect of hepatic impairment: In women with moderate hepatic function, (Child-Pugh B) mean serum drospirenone concentration-time profiles were comparable to those of women with normal hepatic function during the absorption/distribution phases with similar Cmax values. The mean terminal half-life of drospirenone for volunteers with moderate hepatic impairment was 1.8 times greater than for volunteers with normal hepatic function.
An about 50 % decrease in apparent oral clearance (CL/f) was seen in volunteers with moderate hepatic impairment as compared to those with normal liver function. The observed decline in drospirenone clearance in volunteers with moderate hepatic impairment compared to normal volunteers did not translate into any apparent difference in terms of serum potassium concentrations between the two groups of volunteers. Even in the presence of diabetes and concomitant treatment with spironolactone (two factors that can predispose a patient to hyperkalemia) an increase in serum potassium concentrations above the upper limit of the normal range was not observed. It can be concluded that drospirenone is well tolerated in patients with mild or moderate hepatic impairment (Child-Pugh B).
Ethnic groups: The impact of ethnic factors on the pharmacokinetics of drospirenone and ethinylestradiol was studied after single and repeated daily oral administration to young, healthy Caucasian and Japanese women. The results showed that ethnic differences between Japanese and Caucasian women had no clinically relevant influence on the pharmacokinetics of drospirenone and ethinylestradiol.
Ethinylestradiol: Absorption: Orally administered ethinylestradiol is absorbed rapidly and completely. Peak serum concentrations of about 33 pg/ml are reached within 1 - 2 hours after single oral administration. Absolute bioavailability as a result of presystemic conjugation and first-pass metabolism is approximately 60 % . 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: Serum ethinylestradiol levels decrease in two phases, the terminal disposition phase is characterized by a half-life of approximately 24 hours. Ethinylestradiol is highly but non-specifically bound to serum albumin (approximately 98.5 %), and induces an increase in the serum concentrations of SHBG. An apparent volume of distribution of about 5 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 of ethinylestradiol is about 5 ml/min/kg.
Elimination: Ethinylestradiol is not excreted in unchanged form to any significant extent. The metabolites of ethinylestradiol 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 and serum levels of ethinylestradiol accumulate by a factor of about 1.4 to 2.1.
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. However, it should be borne in mind that sex steroids can promote the growth of certain hormone-dependent tissues and tumors.
Treatment of hormone related moderate acne vulgaris in women who elect to use oral contraception.
Treatment of symptoms of PMDD (Premenstrual Dysphoric Disorder) in women who elect to use oral contraception.
Method of administration: Oral use.
Dosage regimen: How to take Yaz: Combined oral contraceptives, when taken correctly, have a failure rate of approximately 1% per year. The failure rate may increase when pills are missed or taken incorrectly.
Tablets must be taken in the order directed on the package every day at about the same time with some liquid as needed. Tablet taking is continuous. One tablet is to be taken daily for 28 consecutive days. Each subsequent pack is started the day after the last tablet of the previous pack.
How to start Yaz: Tablet-taking has to start on day 1 of the woman's natural cycle (i.e. the first day of her menstrual bleeding).
Management of missed tablets: Missed hormone-free white film-coated tablets can be disregarded. However, they should be discarded to avoid unintentionally prolonging the hormone-free white tablet phase. The following advice only refers to missed hormone-containing light pink film-coated tablets: If the user is less than 24 hours late in taking any hormone-containing 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 24 hours late in taking any hormone-containing tablet, contraceptive protection may be reduced. The management of missed tablets can be guided by the following two basic rules: 1. tablet-taking must never be discontinued for longer than 7 days (please note the recommended hormone-free tablet interval is 4 days).
2. 7 days of uninterrupted hormone-containing 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 1-7: 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 should be considered. The more tablets are missed and the closer they are to the hormone-free white film-coated tablet phase, the higher the risk of a pregnancy.
Day 8-14: 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 15-24: The risk of reduced reliability is imminent because of the forthcoming hormone-free white film-coated tablet phase. 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, the woman should be advised to follow the first of these two options and to 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 light pink film-coated tablets are used up. The 4 white hormone-free film-coated 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 hormone-containing light pink film-coated tablets section of the second pack, but she may experience spotting or breakthrough bleeding.
2. The woman may also be advised to discontinue taking the light pink film-coated tablets 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.
If the woman missed tablets and subsequently has no withdrawal bleed in the hormone-free white film-coated tablet phase, the possibility of a pregnancy should be considered.
Advice in case of gastro-intestinal disturbances: In case of severe gastro-intestinal disturbances, absorption may not be complete and additional contraceptive measures should be taken.
If vomiting occurs within 3-4 hours after taking a light pink hormone-containing film-coated tablet, the advice concerning missed tablets as given in 'Management of missed tablets' is applicable.
Additional information on special populations: Pediatric patients: Yaz is only indicated after menarche. There are no data suggesting the need for a dosage adjustment.
Geriatric patients: Not applicable. Yaz is not indicated after menopause.
Patients with hepatic impairment: Yaz is contraindicated in women with severe hepatic diseases. See also Pharmacology: Pharmacokinetics under Actions and Contraindications.
Patients with renal impairment: Yaz is contraindicated in women with severe renal insufficiency or acute renal failure. See also Pharmacology: Pharmacokinetics under Actions and Contraindications.
There has not yet been any clinical experience of overdose with Yaz hormone-containing light pink film-coated tablets. On the basis of general experience with combined oral contraceptives, symptoms that may occur in case of taking an overdose of hormone-containing tablets are: nausea, vomiting and, withdrawal bleeding. The last may even occur in girls before their menarche, if they have accidentally taken the medicinal product. 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 below. Should any of the conditions appear for the first time during COC use, the product should be stopped immediately.
Presence or a history of venous or arterial thrombotic/thromboembolic events (e.g. deep venous thrombosis, pulmonary embolism, myocardial infarction) or of a cerebrovascular accident.
Presence or history of prodromi of a thrombosis (e.g. transient ischaemic attack, angina pectoris).
A high risk of venous or arterial thrombosis (see Precautions).
History of migraine with focal neurological symptoms.
Diabetes mellitus with vascular involvement.
Severe hepatic disease as long as liver function values have not returned to normal.
Use of direct-acting antiviral (DAA) medicinal products containing ombitasvir, paritaprevir, or dasabuvir, and combinations of these (see Interactions).
Severe renal insufficiency or acute renal failure.
Presence or history of liver tumors (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.
Hypersensitivity to the active substances or to any of the excipients.
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 the first 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.
VTE may be life-threatening or may have a fatal outcome (in 1-2 % of the cases).
Venous thromboembolism (VTE), manifesting as deep venous thrombosis and/or pulmonary embolism, may occur during the use of all COCs.
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.
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.)
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 a relatively early age). If a hereditary predisposition is known or 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.
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, hemolytic uremic syndrome, 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).
Tumors: 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.
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 tumors, and even more rarely, malignant liver tumors have been reported in users of COCs. In isolated cases, these tumors have led to life-threatening intra-abdominal hemorrhages. A liver tumor should be considered in the differential diagnosis when severe upper abdominal pain, liver enlargement or signs of intra-abdominal hemorrhage occur in women taking COCs.
Malignancies may be life-threatening or may have a fatal outcome.
Other conditions: A theoretical risk for hyperkalemia can be assumed only for patients with renal impairment whose pretreatment serum potassium is in the upper reference range, and who are additionally using potassium sparing drugs.
Women with hypertriglyceridemia, 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. However, if a sustained clinically significant hypertension develops during the use of a COC then it is prudent for the physician to withdraw the COC and treat the hypertension. 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; 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.
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 which occurred first during pregnancy or 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 while taking COCs.
Crohn's disease and ulcerative colitis have been associated with 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.
Each light pink active tablet contains 48.180 mg of lactose and each white placebo tablet contains 23.205 mg of lactose. Patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption who are on a lactose-free diet should take this amount into consideration.
Medical examination/consultation: 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 hormone-containing light pink film-coated tablets, gastro-intestinal disturbances (see Advice in case of gastro-intestinal disturbances as follows) during hormone-containing light pink film-coated tablet taking or concomitant medication (Interactions).
Reduced cycle control: With all COCs, irregular bleeding (spotting or breakthrough bleeding) may occur, especially during the first months of use.
In some women, withdrawal bleeding may not occur during the hormone-free white film-coated tablet phase. 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 or 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: Yaz is not indicated during pregnancy. If pregnancy occurs during treatment with Yaz, further intake must be stopped. However, 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 early pregnancy.
The available data regarding the use of Yaz during pregnancy are too limited to permit conclusions concerning negative effects of Yaz on pregnancy, health of the fetus or neonate. No relevant epidemiological data are available yet.
Lactation: 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 nursing mother has completely weaned her child. Small amounts of the contraceptive steroids and/or their metabolites may be excreted with the milk .
Adverse drug reactions which have been associated with the use of YAZ as an oral contraceptive or in the treatment of moderate acne vulgaris. (See table.)
Click on icon to see table/diagram/image
In addition, the following undesirable effects have been reported in users of COCs and the association has been neither confirmed nor refuted: Common: breast tenderness.
Uncommon: breast hypertrophy, fluid retention.
Rare: vaginal discharge, breast discharge, contact lens intolerance.
In women with hereditary angioedema, exogenous oestrogens may induce or exacerbate symptoms of angioedema.
Erythema multiforme has been reported in post marketing surveillance. The frequency cannot be estimated from the available data and is therefore unknown.
Note: The prescribing information of concomitant medications should be consulted to identify potential interactions.
Effects of other medicinal products on Yaz: Interactions can occur with drugs that induce microsomal enzymes which can result in increased clearance of sex hormones and which may lead to breakthrough bleeding and/or contraceptive failure.
Enzyme induction can 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 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 the hormone-containing light pink film-coated tablets in the COC pack, the hormone-free white film-coated tablets should be omitted and the next COC pack be started.
Substances increasing the clearance of COCs (diminished efficacy of COCs by enzyme-induction), e.g.: Phenytoin, barbiturates, primidone, carbamazepine, rifampicin, and possibly also oxcarbazepine, topiramate, felbamate, griseofulvin and products containing St. John's wort).
Substances with variable effects on the clearance of COCs, e.g.: When co-administered with COCs, many HIV/HCV protease inhibitors and non-nucleoside reverse transcriptase inhibitors can increase or decrease plasma concentrations of estrogen or progestin. These changes may be clinically relevant in some cases.
Substances decreasing the clearance of COCs (enzyme inhibitors): Strong and moderate CYP3A4 inhibitors such as azole antifungals (e.g. itraconazole, voriconazole, fluconazole), verapamil, macrolides (e.g. clarithromycin, erythromycin), diltiazem and grapefruit juice can increase plasma concentrations of the estrogen or the progestin or both.
In a multiple dose study with a drospirenone (3 mg/day) / ethinylestradiol (0.02 mg/day) combination, co-administration of the strong CYP3A4 inhibitor ketoconazole for 10 days increased the AUC(0-24h) of drospirenone and ethinylestradiol 2.68-fold (90% confidence interval (CI): 2.44, 2.95) and 1.40-fold (90%CI: 1.31, 1.49), respectively.
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 COCs on other medicinal products: COCs may affect the metabolism of certain other drugs. Accordingly, plasma and tissue concentrations may either increase (e.g. cyclosporin) or decrease (e.g. lamotrigine).
In vitro, drospirenone is capable to inhibit weakly to moderately the cytochrome P450 enzymes CYP1A1, CYP2C9, CYP2C19 and CYP3A4.
Based on in vivo interaction studies in female volunteers using omeprazole, simvastatin and midazolam as marker substrates, a clinically relevant interaction of drospirenone at doses of 3 mg with the cytochrome P450 mediated metabolism of other drugs is unlikely.
In vitro, ethinylestradiol is a reversible inhibitor of CYP2C19, CYP1A1 and CYP1A2 as well as a mechanism based inhibitor of CYP3A4/5, CYP2C8, and CYP2J2. In clinical studies, administration of a hormonal contraceptive containing ethinylestradiol did not lead to any increase or only to a weak increase in plasma concentrations of CYP3A4 substrates (e.g. midazolam) while plasma concentrations of CYP1A2 substrates can increase weakly (e.g. theophylline) or moderately (e.g. melatonin and tizanidine).
Pharmacodynamic interactions: Co-administration of ethinylestradiol-containing medicinal products with direct-acting antiviral (DAA) medicinal products containing ombitasvir, paritaprevir, or dasabuvir, and combinations of these has been shown to be associated with increases in ALT levels to greater than 20 times the upper limit of normal in healthy female subjects and HCV infected women (see Contraindications).
Other forms of interactions: Serum potassium: There is a theoretical potential for an increase in serum potassium in women taking Yaz hormone-containing light pink film-coated tablets with other drugs that may increase serum potassium levels.
Laboratory test: The use of contraceptive steroids may influence the results of certain laboratory tests. Drospirenone causes an increase in plasma renin activity and plasma aldosterone induced by its mild antimineralocorticoid activity.
Instruction for use/handling: None.
Store below 30°C.
Shelf-life: 36 months from the date of manufacture.
G03AA12 - drospirenone and ethinylestradiol ; Belongs to the class of progestogens and estrogens in fixed combinations. Used as systemic contraceptives.
FC tab 28's [hormone-containing tablet (light pink, round with convex faces, one side marked with the letters "DS" in a regular hexagon) x 24's + hormone-free tablet (white, round with convex faces, one side marked with the letters "DP" in a regular hexagon) x 4's] 28's.