drospirenone/ethinylestradiol (Yasmin, Yaz, Gianvi, Beyaz, Loryna, Ocella, Syeda, Safyral, Vestura, Zarah, Rajani)

Dosing and uses of Yasmin, Yaz (drospirenone-ethinyl-estradiol)

• Adult
• Pediatric

 

Adult dosage forms and strengths

tablet

• 3mg/0.02mg (Yaz, Gianvi, Loryna, Vestura)
• 3mg/0.02mg plus 0.451mg levomefolate (Beyaz, Rajani)
• 3mg/0.03mg (Yasmin, Syeda, Zarah)
• 3mg/0.03mg plus 0.451mg levomefolate (Safyral)

 

Contraception

Yasmin, Ocella, Zarah, Safyral, Syeda

• 1 active tablet (3 mg drospirenone/0.03 mg EE) PO qDay for 21 days, THEN 1 inert tablet PO qDay for 7 days

Yaz, Beyaz, Gianvi, Loryna, Rajani, Vestura

• 1 active tablet (3 mg drospirenone/0.02 mg EE) PO qDay for 24 days, THEN 1 inert tablet PO qDay for 4 days

Dosing considerations

• Women should be advised to use additional nonhormonal contraception during the first 7 days of therapy
• Administer tablets in the order directed on the blister pack calendar at the same time each day
• Increased risk for venous thromboembolism (VTE) with combined hormonal contraceptives following delivery; risk declines rapidly after 21 days but does not return to normal until 42 days after delivery
• CDC guidelines recommend waiting 21-42 days to initiate therapy in postpartum women without additional VTE risks (MMWR July 7, 2011)
• Postpartum women who do not breastfeed or after a second trimester abortion: Wait ≥4 weeks to initiate therapy
• Postpartum women who have had a caesarean section birth: Wait ≥6 weeks to initiate therapy
• Women with other risk factors for VTE in addition to postpartum: Do not use combined hormonal contraceptives

 

Moderate Acne Vulgaris

Yaz, Gianvi, Beyaz, Loryna, Rajani

• Indicated for moderate acne in women, but only if oral contraceptive is chosen as method of birth control
• 1 active tablet (3 mg drospirenone/0.02 mg EE) PO qDay for 24 days, THEN 1 inert tablet PO qDay for 4 days

 

Premenstrual Dysphoric Disorder

Yaz, Beyaz, Gianvi, Rajani

• Indicated for symptoms of premenstrual dysphoric disorder (PMDD), but only if oral contraceptive is chosen as method of birth control
• 1 active tablet (3 mg drospirenone/0.02 mg EE) PO qDay for 24 days, THEN 1 inert tablet PO qDay for 4 days

 

Dosage modifications

Renal impairment: Contraindicated

Hepatic impairment: Contraindicated

 

Dosing considerations

Women should be advised to use additional nonhormonal contraception during the first 7 days of therapy

Administer tablets in the order directed on the blister pack calendar at the same time each day

Increased risk for venous thromboembolism (VTE) with combined hormonal contraceptives following delivery; risk declines rapidly after 21 days but does not return to normal until 42 days after delivery

CDC guidelines recommend waiting 21-42 days to initiate therapy in postpartum women without additional VTE risks (MMWR July 7, 2011)

Postpartum women who do not breastfeed or after a second trimester abortion: Wait ≥4 weeks to initiate therapy

Postpartum women who have had a caesarean section birth: Wait ≥6 weeks to initiate therapy

Women with other risk factors for VTE in addition to postpartum: Do not use combined hormonal contraceptives

 

Pediatric dosage forms and strengths

tablet

• 3mg/0.02mg (Yaz, Gianvi, Loryna, Vestura)
• 3mg/0.02mg plus 0.451mg levomefolate (Beyaz, Rajani)
• 3mg/0.03mg (Yasmin, Syeda, Zarah)
• 3mg/0.03mg plus 0.451mg levomefolate (Safyral)

 

Contraception

<14 years: Safety and efficacy not established

≥14 years: Same as adult dosing

 

Moderate Acne Vulgaris

Moderate acne in females ≥14 years, but only if oral contraceptive is chosen as method of birth controL

Same as adult dosing

 

Yasmin, Yaz (drospirenone-ethinyl-estradiol) adverse (side) effects

>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

 

Warnings

Black box warnings

Cigarette smoking and risk of cardiovascular disease

• Women >35 years who smoke should not use oral contraceptives
• Cigarette smoking increases risk of serious cardiovascular adverse effects from combination oral contraceptive use
• This risk increases with age (>35 yr) and with heavy smoking (15 or more cigarettes/day)
• Advise women taking oral contraceptives not to smoke

 

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

 

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

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 and lactation

Pregnancy category: X

Lactation: Small amounts of steroids are excreted in breast milk; estrogens may reduce quality/quantity of milk; may be prudent to use other forms of birth control until full weaning (AAP Committee states compatible with nursing)

 

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.

 

Pharmacology of Yasmin, Yaz (drospirenone-ethinyl-estradiol)

Mechanism of action

Ethinyl estradiol: Reduces LHRH release from hypothalamus, reduces gonadotropin release from pituitary; increases synthesis of DNA, RNA, and various proteins in target tissues; other possible mechanisms include changes in cervical mucus that cause inhibition of sperm penetration and endometrial changes that reduce likelihood of implantation

Drospirenone: Progestin; spironolactone analogue with anti-mineralocorticoid and anti-androgenic activity

 

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 metabolization

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)