Ethinyl Estradiol and Drospirenone
Pronunciation
(ETH in il es tra DYE ole & droh SPYE re none)
U.S. Brand Names
Yasmin®
Synonyms
Drospirenone and Ethinyl Estradiol
Generic Available
No
Use
Prevention of pregnancy
Use - Unlabeled/Investigational
Treatment of hypermenorrhea (menorrhagia); pain associated with endometriosis; dysmenorrhea; dysfunctional uterine bleeding
Pregnancy Risk Factor
X
Pregnancy Implications
In general, the use of oral contraceptives when inadvertently taken early in pregnancy have not been associated with teratogenic effects. Esophageal atresia was reported in one infant with a single-cycle exposure to ethinyl estradiol and drospirenone
in utero (association not known). Pregnancy should be ruled out prior to treatment and discontinued if pregnancy occurs. Due to increased risk of thromboembolism postpartum, do not start oral contraceptives earlier than 4-6 weeks following delivery. Enters breast milk; breast-feeding is not recommended. Hormonal contraceptives may be less effective in obese patients. An increase in oral contraceptive failure was noted in women with a BMI >27.3. Similar findings were noted in patients weighing
90 kg (198 lb) using the contraceptive patch.
Lactation
Enters breast milk/not recommended
Contraindications
Hypersensitivity to ethinyl estradiol, drospirenone, or to any component of the formulation; history of or current thrombophlebitis or venous thromboembolic disorders (including DVT, PE); active or recent (within 1 year) arterial thromboembolic disease (eg, stroke, MI); cerebral vascular disease, coronary artery disease, severe hypertension; diabetes with vascular involvement; headache with focal neurological symptoms; known or suspected breast carcinoma, endometrial cancer, estrogen-dependent neoplasms, undiagnosed abnormal genital bleeding; renal insufficiency, hepatic dysfunction or tumor, adrenal insufficiency, cholestatic jaundice of pregnancy, jaundice with prior oral contraceptive use; heavy smoking (
15 cigarettes/day) in patients >35 years of age; pregnancy
Warnings/Precautions
Oral contraceptives do not protect against HIV infection or other sexually-transmitted diseases. The risk of cardiovascular side effects increases in women who smoke cigarettes, especially those who are >35 years of age; women who use oral contraceptives should be strongly advised not to smoke. Oral contraceptives may lead to increased risk of myocardial infarction, use with caution in patients with risk factors for coronary artery disease. May increase the risk of thromboembolism. Oral contraceptives may have a dose-related risk of vascular disease (decreases HDL), hypertension, and gallbladder disease; a preparation with the lowest effective estrogen/progesterone combination should be used. Women with high blood pressure should be encouraged to use another form of contraception. Oral contraceptives may cause glucose intolerance. Retinal thrombosis has been reported (rarely) with oral contraceptive use. Use with caution in patients with conditions that may be aggravated by fluid retention, depression, or patients with history of migraine. Not for use prior to menarche.
Drospirenone has antimineralocorticoid activity that may lead to hyperkalemia in patients with renal insufficiency, hepatic dysfunction, or adrenal insufficiency. Use caution with medications that may increase serum potassium.
Adverse Reactions
>1%:
Central nervous system: Depression, dizziness, emotional lability, headache, migraine, nervousness
Dermatologic: Acne, pruritus, rash
Endocrine & metabolic: Amenorrhea, dysmenorrhea, intermenstrual bleeding, menstrual irregularities
Gastrointestinal: Abdominal pain, diarrhea, gastroenteritis, nausea, vomiting
Genitourinary: Cystitis, leukorrhea, vaginal moniliasis, vaginitis
Neuromuscular & skeletal: Back pain, weakness
Respiratory: Bronchitis, pharyngitis, sinusitis, upper respiratory infection
Miscellaneous: Allergic reaction, flu-like syndrome, infection
Adverse reactions reported with other oral contraceptives: Appetite changes, antithrombin III decreased, arterial thromboembolism, benign liver tumors, breast changes, Budd-Chiari syndrome, carbohydrate intolerance, cataracts, cerebral hemorrhage, cerebral thrombosis, cervical changes, change in corneal curvature (steepening), cholestatic jaundice, colitis, contact lens intolerance, decreased lactation (postpartum), deep vein thrombosis, diplopia, edema, erythema multiforme, erythema nodosum; factors VII, VIII, IX, X increased; folate serum concentrations decreased, gallbladder disease, glucose intolerance, hemorrhagic eruption, hemolytic uremic syndrome, hepatic adenomas, hirsutism, hypercalcemia, hypertension, hyperglycemia, libido changes, melasma, mesenteric thrombosis, MI, papilledema, platelet aggregability increased, porphyria, premenstrual syndrome, proptosis, prothrombin increased, pulmonary thromboembolism, renal function impairment, retinal thrombosis, sex hormone-binding globulin increased, thrombophlebitis, thyroid-binding globulin increased, total thyroid hormone (T4) increased, triglycerides/phospholipids increased, vaginal candidiasis, weight changes
Overdosage/Toxicology
May cause nausea; withdrawal bleeding may occur in females. Due to antimineralocorticoid properties of drospirenone, monitor potassium and sodium serum concentrations and evidence of metabolic acidosis.
Drug Interactions
Ethinyl estradiol: Substrate of CYP2C8/9 (minor), 3A4 (major), 3A5-7 (minor); Inhibits CYP1A2 (weak), 2B6 (weak), 2C19 (weak), 3A4 (weak)
Drospirenone: Substrate of CYP3A4 (minor); Inhibits CYP1A2 (weak), 2C8/9 (weak), 2C19 (weak), 3A4 (weak)
ACE inhibitors: Potential for hyperkalemia with concomitant use; monitor serum potassium during first cycle
Acetaminophen: May increase plasma concentration of synthetic estrogens, possibly by inhibiting conjugation. Oral contraceptives may also decrease the plasma concentration of acetaminophen.
Aldosterone antagonists: Potential for hyperkalemia with concomitant use; monitor serum potassium during first cycle
Aminoglutethimide: May increase CYP metabolism of progestins.
Angiotensin II receptor antagonists: Potential for hyperkalemia with concomitant use; monitor serum potassium during first cycle
Antibiotics (ampicillin, griseofulvin, tetracycline): Pregnancy has been reported following concomitant use, however, pharmacokinetic studies have not shown consistent effects with these antibiotics on plasma concentrations of synthetic steroids.
Anticoagulants: Oral contraceptives may increase or decrease the effects of coumarin derivatives.
Anticonvulsants (carbamazepine, felbamate, phenobarbital, phenytoin, topiramate): Increase the metabolism of ethinyl estradiol and/or some progestins, leading to possible decrease in contraceptive effectiveness.
Ascorbic acid: May increase plasma concentration of synthetic estrogens, possibly by inhibiting conjugation.
Atorvastatin: Atorvastatin increases the AUC for norethindrone and ethinyl estradiol.
Cyclosporine: Ethinyl estradiol may inhibit the metabolism of cyclosporine, leading to increased plasma concentrations.
CYP3A4 inducers: May decrease the levels/effects of estrogens. Example inducers include aminoglutethimide, carbamazepine, nafcillin, nevirapine, phenobarbital, phenytoin, and rifamycins.
Clofibric acid: Oral contraceptives may increase the clearance of clofibric acid.
Heparin: Potential for hyperkalemia with concomitant use; monitor serum potassium during first cycle
Morphine: Oral contraceptives may increase the clearance of morphine
NSAIDs: Potential for hyperkalemia with concomitant use when taken daily, long term; monitor serum potassium during first cycle
Phenylbutazone: May decrease contraceptive effectiveness and increase menstrual irregularities.
Potassium-sparing diuretics: Potential for hyperkalemia with concomitant use; monitor serum potassium during first cycle
Prednisolone: Ethinyl estradiol may inhibit the metabolism of prednisolone, leading to increased plasma concentrations.
Rifampin: Rifampin increases the metabolism of ethinyl estradiol and some progestins (norethindrone), resulting in decreased contraceptive effectiveness and increased menstrual irregularities.
Ritonavir: May decrease the serum concentration of estrogens, leading to decreased effectiveness.
Salicylic acid: Oral contraceptives may increase the clearance of salicylic acid.
Selegiline: Oral contraceptives may increase the serum concentration of selegiline.
Temazepam: Oral contraceptives may increase the clearance of temazepam.
Theophylline: Ethinyl estradiol may inhibit the metabolism of theophylline, leading to increased plasma concentrations.
Ethanol/Nutrition/Herb Interactions
Food: CNS effects of caffeine may be enhanced if oral contraceptives are used concurrently with caffeine. Grapefruit juice increases ethinyl estradiol concentrations; clinical implications are unclear.
Herb/Nutraceutical: St John's wort may decrease the effectiveness of oral contraceptives by inducing hepatic enzymes; may also result in breakthrough bleeding.
Stability
Store at 25°C (77°F)
Mechanism of Action
Combination oral contraceptives inhibit ovulation via a negative feedback mechanism on the hypothalamus, which alters the normal pattern of gonadotropin secretion of a follicle-stimulating hormone (FSH) and luteinizing hormone by the anterior pituitary. The follicular phase FSH and midcycle surge of gonadotropins are inhibited. In addition, oral contraceptives produce alterations in the genital tract, including changes in the cervical mucus, rendering it unfavorable for sperm penetration even if ovulation occurs. Changes in the endometrium may also occur, producing an unfavorable environment for nidation. Oral contraceptive drugs may alter the tubal transport of the ova through the fallopian tubes. Progestational agents may also alter sperm fertility. Drospirenone is a spironolactone analogue with antimineralocorticoid and antiandrogenic activity.
Pharmacodynamics/Kinetics
Drospirenone:
Distribution: 4 L/kg
Protein binding: Serum proteins (excluding sex hormone-binding globulin and corticosteroid binding globulin): 97%
Metabolism: To inactive metabolites; minor metabolism hepatically via CYP3A4
Bioavailability: 76%
Half-life elimination: 30 hours
Time to peak: 1-3 hours
Excretion: Urine and feces
Dosage
Oral: Adults: Female: Contraception: Dosage is 1 tablet daily for 28 consecutive days. Dose should be taken at the same time each day, either after the evening meal or at bedtime. Dosing may be started on the first day of menstrual period (Day 1 starter) or on the first Sunday after the onset of the menstrual period (Sunday starter).
Day 1 starter: Dose starts on first day of menstrual cycle taking 1 tablet daily.
Sunday starter: Dose begins on first Sunday after onset of menstruation; if the menstrual period starts on Sunday, take first tablet that very same day. With a Sunday start, an additional method of contraception should be used until after the first 7 days of consecutive administration.
If all doses have been taken on schedule and one menstrual period is missed, continue dosing cycle. If two consecutive menstrual periods are missed, pregnancy test is required before new dosing cycle is started.
If doses have been missed during the first 3 weeks and the menstrual period is missed, pregnancy should be ruled out prior to continuing treatment.
Missed doses (monophasic formulations) (refer to package insert for complete information):
One dose missed: Take as soon as remembered or take 2 tablets next day
Two consecutive doses missed in the first 2 weeks: Take 2 tablets as soon as remembered or 2 tablets next 2 days. An additional method of contraception should be used for 7 days after missed dose.
Two consecutive doses missed in week 3 or three consecutive doses missed at any time: An additional method of contraception must be used for 7 days after a missed dose.
Day 1 starter: Current pack should be discarded, and a new pack should be started that same day.
Sunday starter: Continue dose of 1 tablet daily until Sunday, then discard the rest of the pack, and a new pack should be started that same day.
Any number of doses missed in week 4: Continue taking one pill each day until pack is empty; no back-up method of contraception is needed
Dosage adjustment in renal impairment: Contraindicated in patients with renal dysfunction (Clcr 
50 mL/minute)
Dosage adjustment in hepatic impairment: Contraindicated in patients with hepatic dysfunction
Administration
To be taken at the same time each day, either after the evening meal or at bedtime
Monitoring Parameters
Blood pressure, pregnancy, serum potassium in high-risk patients and those on medications with potassium-retaining properties
Patient Education
Take exactly as directed by prescriber (see package insert). An additional form of contraception should be used until after the first 7 consecutive days of administration. You are at risk of becoming pregnant if doses are missed. If you miss a dose, take as soon as possible or double the dose the next day. If two or more consecutive doses are missed, contact prescriber for restarting directions. Detailed and complete information on dosing and missed doses can be found in the package insert. If any number of doses are missed in week 4, continue taking one pill each day until pack is empty; no back-up method of contraception is needed. Be aware that some medications may reduce the effectiveness of oral contraceptives; an alternate form of contraception may be needed (see Drug Interactions). It is important that you check your blood pressure monthly (on same day each month) and report any increased blood pressure to prescriber. Have an annual physical assessment, Pap smear, and vision exam while taking this medication. Avoid smoking while taking this medication; smoking increases risk of adverse effects, including thromboembolic events and heart attacks. You may experience loss of appetite (small, frequent meals will help); or constipation (increased exercise, fluids, fruit, fiber, or stool softeners may help). If you have diabetes, you should use accurate serum glucose testing to identify any changes in glucose tolerance; notify prescriber of significant changes so antidiabetic medication can be adjusted if necessary. Report immediately pain or muscle soreness; warmth, swelling, pain, or redness in calves; shortness of breath; sudden loss of vision; unresolved leg/foot swelling or weight gain (>5 lb); change in menstrual pattern (unusual bleeding, amenorrhea, breakthrough spotting); breast tenderness that does not go away; acute abdominal cramping; signs of vaginal infection (drainage, pain, itching); CNS changes (blurred vision, confusion, acute anxiety, or unresolved depression); or other persistent adverse effects.
Pregnancy/breast-feeding precautions: Inform prescriber if you are pregnant. Breast-feeding is not recommended.
Dental Health: Effects on Dental Treatment
When prescribing antibiotics, patient must be warned to use additional methods of birth control if on oral contraceptives.
Dental Health: Vasoconstrictor/Local Anesthetic Precautions
No information available to require special precautions
Mental Health: Effects on Mental Status
May cause depression, dizziness, nervousness, or emotional lability
Mental Health: Effects on Psychiatric Treatment
May cause flu-like symptoms, take this into consideration if also concerned about SSRI discontinuation syndrome. Carbamazepine and topiramate may increase the metabolism of estradiol, leading to a decrease in serum concentrations. Estrogens may inhibit the metabolism of some benzodiazepines (alprazolam, chlordiazepoxide, diazepam), TCAs, and selegiline. Estrogens may increase the clearance of lorazepam, oxazepam, and temazepam. Associated with an increased risk of developing dementia in postmenopausal women
65 years of age when treated with conjugated etrogen and medroxyprogesterone.
Dosage Forms
Tablet: Ethinyl estradiol 0.03 mg and drospirenone 3 mg [21 yellow active tablets and 7 white inactive tablets] (28s)
References
Burkman R, Schlesselman JJ, and Zieman M, "Safety Concerns and Health Benefits Associated With Oral Contraception,"Am J Obstet Gynecol, 2004, 190(4 Suppl):5-22.
Holt VL, Scholes D, Wicklund KG, et al, "Body Mass Index, Weight, and Oral Contraceptive Failure Risk,"Obstet Gynecol, 2005, 105(1):46-52.