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

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

Breast cancer

• Epidemiology studies have not found a consistent association between use of combined oral contraceptives (COCs) and breast cancer risk; studies do not show an association between ever (current or past) use of COCs and risk of breast cancer
• Some studies report a small increase in risk of breast cancer among current or recent users(<6 months since last use) and current users with longer duration of COC use
• A woman's risk depends on conditions where naturally high hormone levels persist for long periods of time including early-onset

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 no use for contraception in pregnancy; this medication should be discontinued during 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 CHCs before conception or during early pregnancy

Lactation

The drug is present in human milk; after a single oral administration of 3 mg DRSP/0.03 mg EE tablets, DRSP concentration in breast milk over the 24-h period ranged from 1.4 to 7.0 ng/mL, with a mean ± standard deviation value of 3.7 ± 1.9 ng/mL; estimated mean infant dose was 0.003 mg/day, which is about 0.1% of maternal dose; there is limited information on effects of this drug on breast-fed infant

CHCs can reduce milk production in breastfeeding females; this reduction can occur at any time but is less likely to occur once breastfeeding is well-established; when possible, advise nursing female to use other methods of contraception until she discontinues breast-feeding

Developmental and health benefits of breastfeeding should be considered along with mother’s clinical need for therapy and any potential adverse effects on breastfed child from therapy or from underlying maternal condition

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)