drospirenone/ethinyl estradiol/levomefolate (monophasic OCP)

Adult Dosing

Contraception with folate supplementation

drospirenone 3 mg/ethinyl estradiol 0.02 mg/levomefolate 0.451 mg (24 tabs); 0.451 mg levomefolate (4 tabs)

1 tab PO qd
Start first tablet on day 1 of menstrual cycle or 1st Sunday after onset of menses x 24 days, followed by one levomefolate tablet x 4 days
After taking 28 tabs, start a new course the day after taking last levomefolate tablet

drospirenone 3 mg/ethinyl estradiol 0.03 mg/levomefolate 0.451 mg (21 tabs); 0.451 mg levomefolate (7 tabs)

1 tab PO qd
Start first tablet on day 1 of menstrual cycle or 1st Sunday after onset of menses x 21 days, followed by one levomefolate tablet x 7 days
After taking 28 tabs, start a new course the day after taking last levomefolate tablet

Premenstrual dysphoric disorder (PMDD)

drospirenone 3 mg/ethinyl estradiol 0.02 mg/levomefolate 0.451 mg (24 tabs); 0.451 mg levomefolate (4 tabs)

1 tab PO qd
Start first tablet on day 1 of menstrual cycle or 1st Sunday after onset of menses x 24 days, followed by one levomefolate tablet x 4 days
After taking 28 tabs, start a new course the day after taking last levomefolate tablet

Moderate acne vulgaris

drospirenone 3 mg/ethinyl estradiol 0.02 mg/levomefolate 0.451 mg (24 tabs); 0.451 mg levomefolate (4 tabs)

1 tab PO qd
Start first tablet on day 1 of menstrual cycle or 1st Sunday after onset of menses x24 days, followed by one levomefolate tablet x 4 days
After taking 28 tabs, start a new course the day after taking last levomefolate tablet

Notes:

Tablets should be taken at the same time each day. Tablets must be taken as recommended and at intervals not exceeding 24 hrs
For the first cycle of the regimen, use another non-hormonal back-up method of contraception until after the first 7 consecutive days of starting the tablet
May be started 4 wks postpartum in women who elect not to breastfeed or >6 wks postpartum if breastfeeding

Pediatric Dosing

Contraception with folate supplementation (postpubertal adolescents)

drospirenone 3 mg/ethinyl estradiol 0.02 mg/levomefolate 0.451 mg (24 tabs); 0.451 mg levomefolate (4 tabs)

1 tab PO qd
Start first tablet on day 1 of menstrual cycle or 1st Sunday after onset of menses x 24 days, followed by one levomefolate tablet x 4 days
After taking 28 tabs, start a new course the day after taking last levomefolate tablet

drospirenone 3 mg/ethinyl estradiol 0.03 mg/levomefolate 0.451 mg (21 tabs); 0.451 mg levomefolate (7 tabs)

1 tab PO qd
Start first tablet on day 1 of menstrual cycle or 1st Sunday after onset of menses x 21 days, followed by one levomefolate tablet x 7 days
After taking 28 tabs, start a new course the day after taking last levomefolate tablet

Premenstrual dysphoric disorder (postpubertal adolescents)

drospirenone 3 mg/ethinyl estradiol 0.02 mg/levomefolate 0.451 mg (24 tabs); 0.451 mg levomefolate (4 tabs)

1 tab PO qd
Start first tablet on day 1 of menstrual cycle or 1st Sunday after onset of menses x 24 days, followed by one levomefolate tablet x 4 days
After taking 28 tabs, start a new course the day after taking last levomefolate tablet

Moderate acne vulgaris (postpubertal females)

drospirenone 3 mg/ethinyl estradiol 0.02 mg/levomefolate 0.451 mg (24 tabs); 0.451 mg levomefolate (4 tabs)

1 tab PO qd
Start first tablet on day 1 of menstrual cycle or 1st Sunday after onset of menses x24 days, followed by one levomefolate tablet x 4 days
After taking 28 tabs, start a new course the day after taking last levomefolate tablet

Notes:

Tablets should be taken at the same time each day. Tablets must be taken as recommended and at intervals not exceeding 24 hrs
For the first cycle of the regimen, use another non-hormonal back-up method of contraception until after the first 7 consecutive days of starting the tablet
May be started 4 wks postpartum in women who elect not to breastfeed or >6 wks postpartum if breastfeeding

[Outline]

Adult Dosing
Pediatric Dosing

Indications ⬆ ⬇

Indicated for use by women to:

Prevent pregnancy
Raise folate levels, in women who choose to use an oral contraceptive for contraception, in order to reduce the risk of a neural tube defect in a pregnancy conceived while taking the product or soon after its discontinuation
Treat symptoms of premenstrual dysphoric disorder (Beyaz only)
Treat moderate acne vulgaris in women at least 14 yrs of age who have achieved menarche (Beyaz only)

Contraindications ⬆ ⬇

Hypersensitivity to any of the ingredients of the product
Renal impairment
Adrenal insufficiency
Known or suspected pregnancy
Carcinoma of the endometrium or other known or suspected estrogen- or progestin-dependent neoplasia
Known or suspected carcinoma of the breast
Endometrial CA
Hepatic adenomas or carcinomas
Cholestatic jaundice of pregnancy or jaundice with prior pill use
Acute or chronic hepatocellular disease with abnormal liver function
Thrombophlebitis or thromboembolic disorders
History of deep vein thrombophlebitis or thromboembolic disorders
Major surgery with prolonged immobilization
Smokers >35 yrs or heavy smokers
Valvular heart disease with complications
Thrombogenic rhythm heart disorders
Current or past history of cerebral vascular or coronary artery disease
Acquired or hereditary thrombophilias
Uncontrolled hypertension
Hypertension with vascular disease
Diabetes mellitus with vascular involvement
Headaches with focal neurological symptoms
Hyperkalemia
Undiagnosed abnormal genital bleeding
Antibody positive or unknown SLE
Within 21 days postpartum or 6 wks postpartum if breastfeeding

Black Box Warnings ⬆ ⬇

Women using oral contraceptives should be strongly advised not to smoke, as cigarette smoking increases the risk of serious cardiovascular side effects in these women. The risk further increases with age and with heavy smoking (15 cigarettes/day) and is quite marked in women over 35 years of age

Dosing Adjustment ⬆ ⬇

Renal Dose Adjustment

Renal impairment: Contraindicated

Hepatic Dose Adjustment

Hepatic impairment: Contraindicated

Warnings/Precautions ⬆ ⬇

See Supplemental Patient Information

Cigarette smokers are more prone to the risk of serious cardiovascular side effects from oral contraceptive use. Advise women who use contraceptives to avoid smoking [US Black Box Warning]
Increased risk of several serious conditions such as MI, thromboembolism, stroke, hepatic neoplasia, and gallbladder disease has been associated with the therapy. Risk of morbidity and mortality markedly increases in the presence of underlying risk factors such as hypertension, hyperlipidemias, obesity, and diabetes
Increased risk of thromboembolic and thrombotic disease has been reported with the use of COCs; risk of post-operative thromboembolic complications has been reported with the use of COCs. Discontinue use at least 4 weeks prior to and for 2 weeks after elective surgery of a type associated with an increase in risk of thromboembolism and during and following prolonged immobilization
Start therapy no earlier than 4 weeks after delivery in women who are not breastfeeding as the risk of postpartum thromboembolism decreases after the third postpartum week, whereas the risk of ovulation increases after the third postpartum week
Oral contraceptives may increase the risk of cerebrovascular events such as thrombotic and hemorrhagic strokes; this risk is greatest among older (>35 yrs) and hypertensive women who also smoke. Use therapy cautiously in women with cardiovascular disease risk factors
Oral contraceptives may cause retinal thrombosis leading to partial or complete loss of vision. Discontinue the drug if there is unexplained partial or complete loss of vision; onset of proptosis or diplopia; papilledema; or retinal vascular lesions and initiate appropriate diagnostic and therapeutic measures
Avoid this therapy in patients with conditions that predispose to hyperkalemia such as renal or hepatic impairment and adrenal insufficiency. Examine serum potassium level during the first treatment cycle in women receiving long-term treatment for chronic conditions with medications that may increase serum potassium levels
COCs may increase the risk of breast and cervical cancer; discontinuation of therapy decreases this risk
Discontinue therapy if jaundice occurs; discontinue COC use if acute or chronic disturbances of liver function occurs until markers of liver function return to normal
Rarely, fatal benign hepatic adenomas have been reported with COC use. Rupture of these benign, hepatic adenomas may cause intra-abdominal hemorrhage leading to death
Hypertension may occur during therapy. Closely monitor hypertensive women electing to use oral contraceptives; discontinue use in women with significant elevation of blood pressure. Avoid this therapy in women with uncontrolled hypertension or hypertension with vascular disease
Combination oral contraceptives may worsen existing gallbladder disease and may accelerate the development of this disease in previously asymptomatic women
COCs may decrease glucose intolerance in a dose-related manner; closely monitor prediabetic and diabetic women taking this therapy. Consider alternative contraception for women with uncontrolled dyslipidemia. Increased risk of pancreatitis may occur in women with family history of hypertriglyceridemia
Discontinue therapy on onset or exacerbation of migraine, development of headache with a new pattern that is recurrent, persistent or severe
Bleeding irregularities such as breakthrough bleeding and spotting may occur, especially during the first 3 months of combined oral contraceptive use. Consider non-hormonal causes and initiate adequate diagnostic measures to rule out malignancy/pregnancy in the event of breakthrough bleeding or any abnormal vaginal bleeding
Discontinue therapy if pregnancy is confirmed and initiate a prenatal vitamin containing folate supplementation
Closely monitor women with a history of depression; discontinue use if depression recurs to a serious degree
Exogenous estrogens may induce or exacerbate symptoms of angioedema in women with hereditary angioedema
Chloasma may rarely occur, particularly in women with a history of chloasma gravidarum; such individuals should avoid exposure to the sun or ultraviolet radiation while taking COCs
Therapy may change the results of certain lab tests including coagulation factors, lipids, glucose tolerance, and binding proteins
Increased doses of thyroid hormone may be needed in women on thyroid hormone replacement therapy as serum concentrations of thyroid-binding globulin increase with use of COCs. Therapy may cause an increase in plasma renin activity and plasma aldosterone induced by its mild antimineralocorticoid activity
Do not use COCs during pregnancy to treat threatened or habitual abortion
Counsel the patients that this product does not protect against HIV infection (AIDS) and other sexually transmitted diseases
Consider physical examination and follow up in relevance to blood pressure, breasts, abdomen and pelvic organs, including cervical cytology, and perform relevant laboratory tests in all the women taking COCs

Cautions: Use cautiously in

Cardiovascular disease
History of depression
Fluid retention
Vomiting or diarrhea
Breastfeeding 6 wks-6 months postpartum
Hereditary angioedema
Inflammatory bowel disease

Supplemental Patient Information

Inform patients that this product does not protect against HIV infection (AIDS) and other sexually transmitted diseases
Instruct patients to take pill exactly as directed and at intervals not exceeding 24 hrs
Advise women to use an additional method of protection until after the first 7 days of administration in the initial cycle
Instruct patients that amenorrhea may occur during therapy; advise them to rule out pregnancy in the event of amenorrhea in two or more consecutive cycles
Advise patients to maintain folate supplementation if they discontinue therapy due to pregnancy

Pregnancy/Breast Feeding ⬆ ⬇

Pregnancy Category:X

Breastfeeding: Combination oral contraceptives probably do not affect the composition of milk substantially in healthy, well-nourished mothers and do not adversely affect long-term infant growth and development, but can transiently affect growth negatively during the first month after introduction. Rarely, reversible breast enlargement has been reported with higher doses of estrogen. Ethinyl estradiol in doses of 30 mcg daily or greater can suppress lactation leading to earlier discontinuation of breastfeeding than nonhormonal or progestin-only contraception. The magnitude of the effect on lactation likely depends on the dose and the time of introduction postpartum. As per US expert opinion, the risks of combination contraceptive products usually outweigh the benefits before 4 weeks postpartum. Between 4 weeks and 6 months postpartum, the advantages of using the method generally outweigh the theoretical or proven risks. After 6 months postpartum, combination contraceptives can be used, but progestin-only methods are preferred if breastfeeding will be continued. This information is based upon LactMed database (available at http://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?LACT last accessed 17 August 2011). Manufacturer advises the nursing mother to avoid using combination oral contraceptives and to use other forms of contraception until she has completely weaned her child.

Adverse Reactions ⬆ ⬇

CNS: Migraine headache, headache, stroke, cerebral hemorrhage, chorea exacerbation
PSYCHIATRY: Depression, emotional lability
CV: Thromboembolism, thrombosis, MI, hypertension, edema, thrombophlebitis, arterial thromboembolism
RESP: Pulmonary embolism
GI: Intra-abdominal hemorrhage, nausea, gallbladder disease, pancreatitis, vomiting, abdominal cramps, bloating
HEPA: Liver dysfunction, hepatic adenomas, hepatocellular carcinoma, cholestatic jaundice
REPRODUCTIVE: Changes in libido, breakthrough bleeding, bleeding irregularities, breast tenderness, vulvovaginal candidiasis
GU: Irregular uterine bleeding, uterine leiomyoma, cervical dysplasia, cervix carcinoma, fluid retention
METABOLIC: Weight changes, hyperkalemia, glucose intolerance, increased cholesterol
EENT: Contact lens intolerance, ocular lesions
DERM: Erythema multiforme, toxic skin eruption, acne, chloasma
IMMU: Porphyria exacerbation, SLE exacerbation
HYPERSENSITIVITY: Anaphylaxis/anaphylactoid reactions
MUSC: Fatigue

Clinical Pharmacology ⬆ ⬇

Drospirenone

Progestin; diffuses freely into the target cells in female reproductive tract, mammary gland, hypothalamus, and pituitary; binds to the progesterone receptor and slows frequency of release of gonadotropin releasing hormone from the hypothalamus and blunts pre-ovulatory LH surge
Metabolized by liver; CYP450: 3A4 (minor) substrate
Excreted in feces and urine
Half-life: 30 hrs

Ethinyl estradiol

Estrogens; increase the hepatic synthesis of sex hormone binding globulin, thyroid-binding globulin, and other serum proteins and suppress follicle-stimulating hormone (FSH) from the anterior pituitary. The combination of an estrogen with a progestin suppresses the hypothalamic-pituitary system, thereby reducing the secretion of gonadotropin-releasing hormone (GnRH). Also, inhibits ovulation and alters cervical mucus and endometrium, which prevents penetration of sperm into the uterus and implantation of the egg
Metabolized in the liver and GI tract; CYP450: 3A4 substrate
Excreted in urine and feces
Half-life: 24 hrs

Levomefolate

Synthetic alternative for folic acid; participates in DNA synthesis and erythropoiesis and normalizes high homocysteine levels
Metabolism: Unknown; CYP450: Unknown
Excretion: Urine and feces
Half-life: Unknown

Brands and Availability ⬆ ⬇