drospirenone/ethinyl estradiol/levomefolate (Rx)

>10%

Premenstrual syndrome (13.2%)

Migraine/headache (10.7%)

1-10%

Breast pain/discomfort/tenderness (8.3%)

Menstrual irregularities (4.7%)

Nausea/vomiting (4.5%)

Abdominal pain/discomfort/tenderness (2.3%)

Mood changes, including affect lability, depression, alteration of mood, mood swings, and irritability (2.3%)

Frequency Not Defined

Irregular uterine bleeding

Venous/arterial thromboembolic events, including DVT, PE, stroke, MI, intracardiac thrombosis, sagittal sinus thrombosis, intracranial venous sinus thrombosis, retinal vein thrombosis

Hypertension

Hypersensitivity

Hyperkalemia

Chloasma

Gallbladder disease

Toxic skin eruption

Uterine leiomyoma

Contraindications

Documented hypersensitivity

Active/history of breast cancer or estrogen- or progestin-sensitive caner

Active/history of arterial thromboembolic disease (stroke, MI), thrombophlebitis, DVT/PE, thrombogenic valvular disease

Uncontrolled hypertension

Diabetes mellitus with vascular involvement

History of migraine with aura

Undiagnosed abnormal uterine bleeding

Benign or malignant liver tumors, hepatic impairment or development of jaundice with prior oral contraceptive use

Pregnancy

Renal impairment

Adrenal insufficiency

Receiving hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir

Cautions

Due to increased risk of hyperkalemia, monitor serum potassium during first month if coadministered with potassium-elevating/sparing drugs (eg, spironolactone); consider monitoring serum potassium concentration in high-risk patients who take a strong CYP3A4 inhibitor long-term and concomitantly; strong CYP3A4 inhibitors include azole antifungals (e.g. ketoconazole, itraconazole, voriconazole), HIV/HCV protease inhibitors (e.g., indinavir, boceprevir), and clarithromycin

Family history of breast cancer and or DVT/PE

Current/history of depression, endometriosis, DM, HTN, bone mineral density changes, renal/hepatic impairment, bone metabolic disease, SLE

Conditions exacerbated by fluid retention (eg, migraine, asthma, epilepsy)

Discontinue immediately if any of the following occur: jaundice, visual problems (may cause contact lens intolerance), any signs of VTE, migraine with unusual severity, significant increase in BP, severe depression, increased risk of thromboembolic complications after surgery

Discontinue therapy 4 weeks before major surgery or prolonged immobilization; may resume 2 weeks afterwards

Monitor patients on oral anticoagulants (eg, warfarin); increased anticoagulant dose may be warranted due to thromboembolic risk with oral contraceptives

Some studies have shown a link between the use of oral contraceptive pills (OCPs) and increased risk of breast cancer, whereas other studies have not; risk depends on conditions in which naturally high hormone levels persist for long periods of time, including early onset menstruation before age 12 years, late-onset menopause, age ≥55 years, first child born after age 30 years, nulliparity

Studies have shown an increased risk of cervical cancer with OCP use; however, HPV remains the main risk factor for cervical cancer; evidence suggests long-term use of OCPs (≥5 yr) may be associated with increased risk

Studies have shown a significantly decreased endometrial cancer risk with OCP use; protective effect increases with longer duration of OCP use and may continue to persist years after OCP discontinuation

Risk of ovarian cancer may decrease with increasing duration of OCP use

Discontinue hormonal therapy prior to starting therapy with combination drug regimen ombitasvir/paritaprevir/ritonavir, with or without dasabuvir; may restart approximately 2 weeks following completion of treatment with combination drug regimen

Increased risk of liver cancer with OCP use; risk increases with longer duration of OCP use

Monitor prediabetic and diabetic women with dyslipidemias

Thromboembolic disorders

• Discontinue immediately if thrombotic event occurs
• Risk of VTE is highest during the first year of use; interim data from a large, prospective cohort safety study of various combined oral contraceptives (COCs) suggest that this increased risk, as compared with that in non-COC users, is greatest during the first 6 months of COC use
• Women taking drospirenone-containing contraceptives may have up to a 3-fold increased risk for developing VTE compared with women taking other combined hormonal contraceptives
• To decrease risk of VTE events, CDC guidelines recommend waiting at least 3 weeks following vaginal birth or 6 weeks after cesarean section before initiating use of combined hormonal contraceptives; women with additional risk factors for VTE (besides postpartum) should not use combined hormonal contraceptives

Pregnancy

There is little or no increased risk of birth defects in women who inadvertently use combination oral contraceptives (COCs) during early pregnancy; epidemiologic studies and meta-analyses have not found an increased risk of genital or non-genital birth defects (including cardiac anomalies and limb-reduction defects) following exposure to low dose COCs prior to conception or during early pregnancy.

The administration of COCs to induce withdrawal bleeding should not be used as a test for pregnancy; COCs should not be used during pregnancy to treat threatened or habitual abortion.

Women who do not breastfeed may start COCs no earlier than four weeks postpartum

Lactation

When possible, advise nursing mother to use other forms of contraception until she has weaned her child; estrogen-containing COCs can reduce milk production in breastfeeding mothers; this is less likely to occur once breastfeeding is well-established; however, it can occur at any time in some women; small amounts of oral contraceptive steroids and/or metabolites are present in breast milk

After oral administration of 3 mg DRSP/0.03 mg EE tablets, about 0.02% of the DRSP dose was excreted into the breast milk of postpartum women within 24 hours; this results in a maximal daily dose of about 0.003 mg DRSP in an infant.

Studies to date indicate there is no adverse effect of folate on nursing infants

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

COCs lower the risk of becoming pregnant primarily by suppressing ovulation; other possible mechanisms may include cervical mucus changes that inhibit sperm penetration and endometrial changes that reduce the likelihood of implantation

Absorption

Bioavailability: 76% (drospirenone); 40% (ethinyl estradiol)

Peak plasma time: 1-2 hr

Peak plasma concentration: 88 ng/mL (drospirenone); 99 pg/mL (ethinyl estradiol)

AUC: 830-970 ng.hr/mL (drospirenone); 350-470 pg.hr/mL (ethinyl estradiol)

Distribution

Protein bound

• Ethinyl estradiol: >98% bound to serum albumin
• Drospirenone: 97% bound to serum proteins (not SHBG or corticosteroid-binding globulin)

Metabolism

Hepatic metabolism

Metabolites: Two acid forms of DSRP (inactive)

Elimination

Half-life: 24 hr (ethinyl estradiol); 30 hr (drospirenone)

Excretion: Urine (38-47% as inactive metabolites), feces (17-20% as inactive metabolites)