YASMIN Drospirenone / Ethinylestradiol 3mg / 30mcg Tablet 21's

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

 

 

If any of the following conditions/risk factors 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 1st 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 eg, myocardial infarction, deep venous thrombosis and pulmonary embolism. These events occur rarely.
The risk of VTE is highest during the 1st year of use. This increased risk is present after initially starting a COC or restarting (following a ≥4 week 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 VTE in users of low estrogen dose (<50 mcg ethinylestradiol) COCs is 2- to 3-fold higher than for nonusers of COCs who are not pregnant and remains lower than the risk associated with pregnancy and delivery.
Venous thromboembolism may be life-threatening or may have a fatal outcome (in 1-2% of the cases).
Venous thromboembolism, 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 eg, hepatic, mesenteric, renal, cerebral or retinal veins and arteries, in COC users. There is no consensus as to whether the occurrence of these events is associated with the use of COCs.
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 lightheadedness or dizziness; rapid or irregular heartbeat. Some of these symptoms (eg, shortness of breath, coughing) are nonspecific and might be misinterpreted as more common or less severe events (eg, 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 1 side of the body; sudden confusion, trouble speaking or understanding; sudden trouble seeing in 1 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 risk of venous or arterial thrombotic/thromboembolic events or of a cerebrovascular accident increases with: Age; obesity (body mass index >30 kg/m²); a positive family history (ie, venous or arterial thromboembolism 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 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 4 weeks in advance) and not to resume until 2 weeks after complete remobilization; smoking (with heavier smoking and increasing age, the risk further increases, especially in women >35 years); 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 (see Use in pregnancy & lactation under Precautions).
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 eg, cervical screening and sexual behavior 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 <40 years, 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: Potassium excretion capacity may be limited in patients with renal insufficiency. In a clinical study, drospirenone intake did not show an effect on the serum potassium concentration in patients with mild or moderate renal impairment. 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. The antimineralocorticoid effect of drospirenone may counteract ethinylestradiol-induced increases in blood pressure observed in normotensive women using other combined oral contraceptives. 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 1st 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 while taking COCs.
Each film-coated tablet of Yasmin contains 46 mg lactose. 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.

 

Yasmin is not indicated during pregnancy. If pregnancy occurs during treatment with Yasmin, further intake should 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 Yasmin during pregnancy are too limited to permit conclusions concerning negative effects of Yasmin on pregnancy, health of the fetus or neonate. No relevant epidemiological data are available yet.
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.

 

 

Store below 25°C.

 

Pharmacology: Pharmacodynamics: The contraceptive effect of combined oral contraceptives (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.
A large, prospective 3-armed cohort study has shown that the frequency of venous thromboembolism (VTE) diagnosis ranges between 8 to 10/10,000 woman years in low estrogen dose (<50 mcg ethinylestradiol) COC users. The most recent data suggest that the frequency of VTE diagnosis is approximately 4.4/10,000 woman years in nonpregnant non-COC users, and ranges between 20-30/10,000 pregnant women or postpartum. The incidence of VTE in women with or without other risk factors for VTE who used ethinylestradiol/drospirenone 0.03 mg/3 mg is in the same range as that for users of levonorgestrel-containing COCs and other COCs (various other COC brands). This has also been confirmed in a prospective controlled database study comparing users of ethinylestradiol 0.03 mg/drospirenone 3 mg to other COC users showing similar incidence of VTE among the cohorts.
As well as protection against pregnancy, COCs have several positive properties which, next to the negative properties (see Warnings and Side Effects), 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. It 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 premenstrual syndrome. 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.
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 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. Peak serum concentrations of approximately 37 ng/mL are reached at about 1-2 hrs after single ingestion. Bioavailability is about 76-85%. Concomitant ingestion of food has no influence on bioavailability.
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 drug concentrations are present as free steroid, 95-97% are nonspecifically bound to albumin. The ethinylestradiol-induced increase in SHBG influences the serum protein-binding of drospirenone. The apparent volume of distribution of drospirenone is about 3.7-4.2 L/kg.
Metabolism: Drospirenone is completely metabolized. 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 P-450 system. It is metabolized to a minor extent by cytochrome P-450 3A4 based on in vitro data. The clearance rate from serum is about 1.2-1.5 mL/min/kg. When drospirenone was acutely co-administered with ethinylestradiol, no direct interaction was found.
Elimination: Drospirenone serum levels decrease in 2 phases. The terminal disposition phase is characterized by a t_½ of 31 hrs. Drospirenone is not excreted in unchanged form. Its metabolites are excreted at a biliary-to-urinary ratio of about 1.2:1.4. The t_½ of metabolite excretion with the urine and feces is about 1.7 days.
Steady-State Conditions: Drospirenone pharmacokinetics is not influenced by SHBG levels. Following daily ingestion, drug serum levels increase about 2- to 3-fold reaching steady-state conditions during the 2nd half of a treatment cycle.
Effect of Renal Impairment: Steady-state serum drospirenone levels in women with mild renal impairment (creatinine clearance [CrCl], 50-80 mL/min) were comparable to those of women with normal renal function (CrCl >80 mL/min). The serum drospirenone levels were on average 37% higher in women with moderate renal impairment (CrCl, 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 C_max values. The mean terminal t_½ of drospirenone for volunteers with moderate hepatic impairment was >1.8 times than for volunteers with normal hepatic function. 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 2 groups of volunteers. Even in the presence of diabetes and concomitant treatment with spironolactone (2 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 rapidly and completely absorbed. Peak serum concentrations of about 54-100 pg/mL are reached within 1-2 hrs. 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 nonspecifically 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 presystemic conjugation in both small bowel mucosa and the liver. It is primarily metabolized by aromatic hydroxylation, but a wide variety of hydroxylated and methylated metabolites are formed, and these are present as free metabolites and as conjugates with glucuronides and sulfate. The clearance rate was reported to be 2.3-7 mL/min/kg.
Elimination: Ethinylestradiol serum levels decrease in 2 disposition phases characterized by half-lives of about 1 hr and 10-20 hrs, respectively. Unchanged drug is not excreted; ethinylestradiol metabolites are excreted at a urinary-to-biliary ratio of 4:6. The t_½ of metabolite excretion is about 1 day.
Steady-State Conditions: Steady-state conditions are reached during the 2nd half of a treatment cycle when serum drug levels are higher by 40-110% as compared to a 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. However, it should be borne in mind that sex steroids can promote the growth of certain hormone-dependent tissues and tumors.