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General: Discontinue Medication at the Earliest Manifestation of: A. Thromboembolic and cardiovascular disorders such as thrombophlebitis, pulmonary embolism, cerebrovascular disorders, myocardial ischemia, mesenteric thrombosis, and retinal thrombosis.
B. Conditions that predispose to venous stasis and to vascular thrombosis (eg, immobilization after accidents or confinement to bed during long-term illness). Other nonhormonal methods of contraception should be used until regular activities are resumed. For use of oral contraceptives when surgery is contemplated, see Peri-operative Considerations as follows.
C. Visual defects: partial or complete.
D. Papilledema, or ophthalmic vascular lesions.
E. Severe headache of unknown etiology or worsening of preexisting migraine headache.
F. Increase in epileptic seizures.
The following information is provided from studies of combination oral contraceptives (COCs).
The use of combination hormonal contraceptives is associated with increased risks of several serious conditions including myocardial infarction, thromboembolism, stroke, hepatic neoplasia, and gallbladder disease, although the risk of serious morbidity and mortality is small in healthy women without underlying risk factors. The risk of morbidity and mortality increases significantly if associated with the presence of other risk factors such as hypertension, hyperlipidemias, obesity, and diabetes. Other medical conditions which have been associated with adverse circulatory events include systemic lupus erythematosus, hemolytic uremic syndrome, chronic inflammatory bowel disease (Crohn's disease or ulcerative colitis), sickle cell disease, valvular heart disease and atrial fibrillation.
The following conditions have been reported to occur or deteriorate with both pregnancy and COC use, although a direct association with COCs has not been firmly established: porphyria, systemic lupus erythematosus, hemolytic uremic syndrome, Sydenham's chorea, herpes gestationis, and otosclerosis-related hearing loss.
The information contained in this section is principally from studies carried out in women who used combination oral contraceptives with higher formulations of estrogens and progestogens than those in common use today. The effect of long-term use of combination hormonal contraceptives with lower doses of both estrogen and progestogen administered orally remains to be determined.
YASMIN contains 3 mg of the progestogen drospirenone (DRSP) that has antimineralocorticoid activity, including the potential for hyperkalemia in high-risk patients, comparable to a 25 mg dose of spironolactone. YASMIN should not be used in patients with conditions that predispose to hyperkalemia (ie, renal insufficiency, hepatic dysfunction, and adrenal insufficiency). Women receiving daily, long-term treatment for chronic conditions or diseases with medications that may increase serum potassium should have their serum potassium level checked during the first treatment cycle. Drugs that may increase serum potassium include ACE inhibitors, angiotensin-II receptor antagonists, potassium-sparing diuretics, heparin, aldosterone antagonists, and NSAIDs.
Carcinogenesis and Mutagenesis: Malignancies may be life-threatening or may have a fatal outcome.
Breast Cancer: 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 relationship to the overall risk of breast cancer. Causation with COC use is unknown.
Increasing age and a strong family history are the most significant risk factors for the development of breast cancer. Other established risk factors include obesity, nulliparity, and late age for first full-term pregnancy. The identified groups of women that may be at increased risk of developing breast cancer before menopause are long-term users of oral contraceptives (more than eight years) and starters at early age. In a few women, the use of oral contraceptives may accelerate the growth of an existing but undiagnosed breast cancer. Since any potential increased risk related to oral contraceptive use is small, there is no reason to change prescribing habits at present.
Women receiving oral contraceptives should be instructed in self-examination of their breasts. Their physicians should be notified whenever any masses are detected. A yearly clinical breast examination is also recommended, because, if a breast cancer should develop, drugs that contain estrogen may cause a rapid progression.
Cervical Cancer: The most important risk factor for cervical cancer is persistent human papillomavirus infection (HPV). 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 behaviour including use of barrier contraceptives.
Hepatocellular Carcinoma: Hepatocellular carcinoma may be associated with oral contraceptives. The risk appears to increase with duration of hormonal contraceptive use. However, the attributable risk (the excess incidence) of liver cancers in oral contraceptive users is extremely small. 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.
See Pharmacology: Toxicology under Actions for discussion of animal data.
Cardiovascular: Predisposing Factors for Coronary Artery Disease: Cigarette smoking increases the risk of serious cardiovascular side effects and mortality. Birth control pills increase this risk, particularly in women over 35 years of age, and with the number of cigarettes smoked. Convincing data are available to support an upper age limit of 35 years for oral contraceptive use by women who smoke. For this reason, combination oral contraceptives, including YASMIN, should not be used by women who are over 35 years of age and smoke.
Other women who are independently at high risk for cardiovascular disease include those with diabetes, hypertension, abnormal lipid profile, or a family history of these. Whether oral contraceptives accentuate this risk is unclear.
In low-risk, nonsmoking women of any age, the benefits of oral contraceptive use outweigh the possible cardiovascular risks associated with low-dose formulations. Consequently, oral contraceptives may be prescribed for these women up to the age of menopause.
Hypertension: Patients with essential hypertension, whose blood pressure is well-controlled, may be given hormonal contraceptives, but only under close supervision. If a significant elevation of blood pressure in previously normotensive or hypertensive subjects occurs at any time during the administration of the drug, cessation of medication is necessary. An increase in blood pressure has been reported in women taking COCs, and this increase is more likely in older women and with extended duration of use.
Endocrine and Metabolism: Diabetes: Current low-dose oral contraceptives exert minimal impact on glucose metabolism. Diabetic patients, or those with a family history of diabetes, should be observed closely to detect any worsening of carbohydrate metabolism. Patients predisposed to diabetes who can be kept under close supervision may be given oral contraceptives. Young diabetic patients whose disease is of recent origin, well-controlled, and not associated with hypertension or other signs of vascular disease such as ocular fundal changes should be monitored more frequently while using oral contraceptives.
Lipid and Other Metabolic Effects: A small proportion of women will have adverse lipid changes while on oral contraceptives. Alternative contraception should be used in women with uncontrolled dyslipidemia (see also Contraindications). Elevations of plasma triglycerides may lead to pancreatitis and other complications.
Gastrointestinal: Published epidemiological studies indicate a possible association of COC use and the development of Crohn's disease and ulcerative colitis, although this has not been firmly established.
Genitourinary: Vaginal Bleeding: Persistent irregular vaginal bleeding requires assessment to exclude underlying pathology.
Fibroids: Patients with fibroids (leiomyomata) should be carefully observed. Sudden enlargement, pain, or tenderness requires discontinuation of the use of oral contraceptives.
Hematologic: 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 use of any combined oral contraceptive carries an increased risk of venous thromboembolism (VTE) compared with no use. The excess risk of VTE is highest during the first year a woman ever uses a combined oral contraceptive or restarts (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. VTE is life-threatening and is fatal in 1% to 2% of cases.
A large, prospective 3-armed cohort study has shown that the frequency of VTE diagnosis ranges from about 8 to 10 per 10,000 woman-years in users of oral contraceptives with low estrogen content (<50 μg ethinyl estradiol). The most recent data suggest that the frequency of VTE diagnosis is approximately 4.4 per 10,000 woman-years in nonpregnant, non-COC users and ranges from 20 to 30 per 10,000 woman-years in pregnant women or postpartum.
Overall the risk for VTE in users of oral contraceptives with low estrogen content (<50 μg ethinyl estradiol) is two- to three-fold higher than for nonusers of COCs who are not pregnant and remains lower than the risk associated with pregnancy and delivery.
The risk of VTE for combined oral contraceptives that contain drospirenone is higher than the risk for levonorgestrel-containing second generation COCs, and may be similar to the risk for desogestrel-containing or gestoden-containing third generation COCs.
Several epidemiological studies have examined the risk of VTE with drospirenone-containing COCs versus other COCs. Two prospective cohort studies showed that the risk of VTE with drospirenone-containing COCs is comparable to that of other COCs, including levonorgestrel-containing COCs. One case-control and three retrospective cohort studies suggested that the risk of VTE with drospirenone-containing COCs is higher compared to users of levonorgestrel-containing COCs. Two additional nested case-control studies have reported a two-fold and three-fold increased risk of idiopathic VTE in users of drospirenone-containing COCs as compared with levonorgestrel-containing COCs. These retrospective studies suggest a potential 1.5-3 times risk of VTE in users of drospirenone-containing COCs. Epidemiological studies have inherent methodological issues making the interpretation of their results complex. However, prescribers should consider the benefits and risks for specific patients with respect to VTE risk given the current retrospective epidemiological studies suggesting a higher risk of VTE with drospirenone-containing COCs compared to levonorgestrel-containing COCs.
VTE, manifesting as deep venous thrombosis (DVT) and/or pulmonary embolism (PE), 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.
Symptoms of 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 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 (eg, "shortness of breath", "coughing") are nonspecific and might be misinterpreted as more common or less severe events (eg, respiratory tract infections).
The risk for arterial thromboembolism (ATE) in users of oral contraceptives with low estrogen content (<50 μg ethinyl estradiol) ranges from about 1 to 3 cases per 10,000 woman-years. An arterial thromboembolic event (ATE) 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 are life-threatening and may have a fatal outcome.
Other Risk Factors for Venous or Arterial Thromboembolism or of a Cerebrovascular Accident: Other generalized risk factors for venous or arterial thromboembolism include but are not limited to age, severe obesity (body mass index >30 kg/m2), a personal history, a positive family history (the occurrence of VTE/ATE in a direct relative at a relatively early age may indicate genetic predisposition) and systemic lupus erythematosus. If a hereditary or acquired predisposition for venous or arterial thromboembolism is suspected, the woman should be referred to a specialist for advice before deciding on any COC use. The risk of VTE/ATE may be temporarily increased with prolonged immobilization, major surgery, or 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 COC use until two weeks after complete remobilization. Also, patients with varicose veins and leg cast should be closely supervised. Other risk factors may include 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, and atrial fibrillation.
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 ethinyl estradiol).
Hepatic/Biliary/Pancreatic: In some cases of elevated liver enzymes reported during clinical trials with YASMIN, a contributory role of YASMIN could not be ruled out. YASMIN is contraindicated in patients with active liver disease (see Contraindications; Drug-Laboratory Test Interactions under Interactions).
Acute or chronic disturbances of liver function may necessitate the discontinuation of COC use until markers of liver function return to normal.
Jaundice: Patients who have had jaundice should be given oral contraceptives with great care and under close observation. Oral contraceptive-related cholestasis has been described in women with a history of pregnancy-related cholestasis. Women with a history of cholestasis may have the condition recur with subsequent hormonal contraceptive use.
The development of severe generalized pruritus or icterus requires that the medication be withdrawn until the problem is resolved.
If a patient develops jaundice that proves to be cholestatic in type, the use of oral contraceptives should not be resumed. In patients taking hormonal contraceptives, changes in the composition of the bile may occur, and an increased incidence of gallstones has been reported.
Gallbladder Disease: Patients taking oral contraceptives have a greater risk of developing gallbladder disease requiring surgery with the first year of use. The risk may double after 4 or 5 years.
Hepatic Nodules: Hepatic nodules (adenoma and focal nodular hyperplasia) have been reported, particularly in long-term users of oral contraceptives. Although these lesions are extremely rare, they have caused fatal intra-abdominal hemorrhage and should be considered in women presenting with an abdominal mass, acute abdominal pain, or evidence of intra-abdominal bleeding.
Immune: Angioedema: Exogenous estrogens may induce or exacerbate symptoms of angioedema, in particular, in women with hereditary angioedema.
Neurologic: Migraine and Headache: The onset or exacerbation of migraine or the development of headache with a new pattern that is recurrent, persistent, or severe requires discontinuation of hormonal contraceptives and evaluation of the cause. Women with migraine headaches who take oral contraceptives may be at increased risk of stroke (see Contraindications).
Ophthalmologic: Ocular Disease: Patients who are pregnant or are taking oral contraceptives may experience corneal edema that may cause visual disturbances and changes in tolerance to contact lenses, especially of the rigid type. Soft contact lenses usually do not cause disturbances. If visual changes or alterations in tolerance to contact lenses occur, temporary or permanent cessation of wear may be advised.
Ocular Lesions: There have been clinical case reports of retinal thrombosis associated with the use of oral contraceptives. Oral contraceptives should be discontinued if there is unexplained partial or complete loss of vision, onset of proptosis or diplopia, papilledema, or retinal vascular lesions. Appropriate diagnostic and therapeutic measures should be undertaken immediately.
Peri-operative Considerations: There is an increased risk of thromboembolic complications in oral contraceptive users after major surgery. If feasible, oral contraceptives should be discontinued and an alternative method substituted at least one month prior to MAJOR elective surgery. Oral contraceptive use should not be resumed until the first menstrual period after hospital discharge following surgery.
Psychiatric: Patients with a history of emotional disturbances, especially the depressive type, may be more prone to have a recurrence of depression while taking oral contraceptives. In cases of a serious recurrence, a trial of an alternate method of contraception should be made, which may help to clarify the possible relationship. Women with premenstrual syndrome (PMS) may have a varied response to oral contraceptives, ranging from symptomatic improvement to worsening of the condition.
Renal: Fluid Retention: Hormonal contraceptives may cause some degree of fluid retention. They should be prescribed with caution and only with careful monitoring in patients with conditions which might be aggravated by fluid retention.
Sexual Function/Reproduction: Return to Fertility: After discontinuing oral contraceptive therapy, the patient should delay pregnancy until at least one normal spontaneous menstrual cycle has occurred in order to date the pregnancy. An alternate contraceptive method should be used during this time.
Amenorrhea: In some women, withdrawal bleeding may not occur during the tablet-free interval. If the COC has been taken according to directions, it is unlikely that the woman is pregnant. However, if the COC has not been taken according to 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.
Women having a history of oligomenorrhea, secondary amenorrhea, or irregular cycles may remain anovulatory or become amenorrheic following discontinuation of estrogen-progestin combination therapy.
Amenorrhea, especially if associated with breast secretion that continues for six months or more after withdrawal, warrants a careful assessment of hypothalamic-pituitary function.
Reduced Efficacy: The efficacy of COCs may be reduced in the event of missed tablets, gastro-intestinal disturbances, or concomitant medication (see Dosage & Administration and Interactions).
Skin: Chloasma may occasionally occur with use of COCs, 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.
Monitoring and Laboratory Tests: Physical Examination and Follow-up: Before oral contraceptives are used, a thorough history and physical examination should be performed, including a blood pressure determination and the family case history carefully noted. In addition, disturbances of the clotting system must be ruled out if any members of the family have suffered from thromboembolic diseases (eg, deep vein thrombosis, stroke, myocardial infarction) at a young age. Breasts, liver, extremities, and pelvic organs should be examined, and a Papanicolaou (PAP) smear should be taken if the patient has been sexually active.
The first follow-up visit should be done three months after oral contraceptives are prescribed. Thereafter, examinations should be performed at least once a year, or more frequently if indicated. At each annual visit, examination should include those procedures that were done at the initial visit as outlined previously.
Use in Pregnancy: Oral contraceptives should not be taken by pregnant women. If pregnancy occurs during treatment with YASMIN, further intake must be stopped. However, if conception accidentally occurs while taking the pill, there is no conclusive evidence that the estrogen and progestin contained in the oral contraceptive will damage the developing child. One infant was born with esophageal atresia. A causal association with YASMIN is unknown.
Use in Lactation: In breast-feeding women, the use of oral contraceptives results in the hormonal components being excreted in breast milk and may reduce its quantity and quality. If the use of oral contraceptives is initiated after the establishment of lactation, there does not appear to be any effect on the quantity and quality of the milk. There is no evidence that low-dose oral contraceptives are harmful to the nursing infant.
If possible, the nursing mother should be advised not to use oral contraceptives, but to use other forms of contraception, until she has completely weaned her child.
After oral administration of YASMIN, about 0.02% of the drospirenone dose was excreted into the breast milk of postpartum women within 24 hours. This results in a maximal daily dose of about 3 μg drospirenone in an infant.
Use in Children: The safety and efficacy of YASMIN has not been established in women under the age of 16 years. Use of this product before menarche is not indicated.
Use in the Elderly: YASMIN is not indicated for use in postmenopausal women.
