norethindrone acetate/ethinylestradiol (Femhrt, Gildess 1/20, Gildess 1.5/30, Jinteli, Loestrin 1.5/30, Loestrin 1/20, Microgestin 1.5/30, Microgestin 1/20, Junel 1.5/30, Junel 1/20)

Dosing and uses of Loestrin (norethindrone acetate/ethinyl estradiol)

• Adult
• Pediatric

 

Adult dosage forms and strengths

norethindrone acetate/ethinyl estradioL

tablet, hormone replacement (Femhrt, Jinteli)

• 0.5mg/2.5mcg
• 1mg/5mcg

tablet, monophasic

• 0.4mg/35mcg
• 0.5mg/35 cg
• 1mg/20mcg
• 1mg/35mcg
• 1mg/50mcg
• 1.5mg/30mcg
• 1.5mg/35mcg

tablet, biphasic

• 0.5mg/35mcg; 1mg/35mcg

tablet, triphasic

• 0.5mg/35mcg; 1mg/35mcg; 0.5mg/35mcg
• 0.5mg/35mcg; 0.7 mg/35mcg; 1mg/35mcg

 

Contraception

Follow Manufacturer's color-coding for sequence

Monophasic formulation

• Take 1 tablet PO qDay for days 1-21, then take 1 inert tablet qDay (or no tablets) for days 22-28, and then restart new pill pack

Biphasic formulation

• Take 1 tablet PO qDay for days 1-10, then take another tablet qDay with a different hormone combination ratio for days 11-21; then take 1 inert tablet qDay for days 22-28

Triphasic formulation

• Take 1 tablet PO qDay for days 1-7; then take another tablet qDay with a different hormone combination ratio for days 8-16; then take 1 tablet of the original formulation ratio qDay for days 17-21; then take 1 inert tablet qDay for days 22-28

Initiating after pregnancy

• Increased risk for venous thromboembolism (VTE) following delivery with combined hormonal contraceptives; risk declines rapidly after 21 days, but does not return to normal until 42 days after delivery
• CDC guidelines recommend waiting 3-6 weeks in postpartum women without additional VTE risks (MMWR July 7, 2011)
• Initiating after vaginal birth: Wait at least 3 weeks
• Initiating after caesarean section birth: Wait at least 6 weeks
• Women with other risk factors for VTE in addition to postpartum: Do not use combined hormonal contraceptives

 

Hormone Replacement Therapy

Treatment of moderate to severe vasomotor symptoms in menopause with an intact uterus, prevention of osteoporosis in postmenopausal women with an intact uterus

1 tablet (Femhrt 0.5 mg norethindrone/2.5 mcg ethinyl estradiol) PO qDay

Initiate with lowest possible dose and increase only if needed to 1 mg/5 mcg

 

Pediatric dosage forms and strengths

Not recommended premenarche

 

Loestrin (norethindrone acetate/ethinyl estradiol) adverse (side) effects

>10%

Edema

Weakness

Anorexia

Amenorrhea

Breakthrough bleeding

Change in menstrual flow

Spotting

 

Frequency not defined

Deep vein thrombosis

Thrombophlebitis

Depression

Dizziness

Headache

Nervousness

Somnolence

Breast tenderness

Galactorrhea

Abdominal pain

Nausea

Vomiting

Weight change

Cholestatic jaundice

 

Warnings

Black box warnings

Cardiovascular Risks

• Estrogens with and without progestins should not be used to prevent cardiovascular disease
• Estrogens plus progestins: Women’s Health Initiative (WHI) Estrogen Plus Progestin substudy reported increased risks of myocardial infarction, stroke, invasive breast cancer, pulmonary emboli, and deep vein thrombosis (DVT) in postmenopausal women (aged 50-79 yr) during 5.6 yr of treatment with daily PO conjugated estrogens (CE 0.625 mg) combined with medroxyprogesterone acetate (MPA 2.5 mg) compared with placebo
• Estrogens alone: The estrogen alone substudy of the WHI Study reported increased risks of stroke & DVT in postmenopausal women (aged 50-79 yr) during 6.8 yr of treatment with oral conjugated estrogens (0.625 mg/day) alone compared with placebo

Dementia Risks

• Estrogens with or without progestins should not be used to prevent dementia
• Women's Health Initiative Memory Study (WHIMS), a substudy of the WHI study, reported increased risk of developing probable dementia in postmenopausal women aged 65 yr or older during 4 yr of treatment w/ daily CE 0.625 mg combined with MPA 2.5 mg, compared with placebo
• Estrogens alone: A substudy of the WHIMS reported an increased risk of developing probable dementia in postmenopausal women aged 65 yr or older during 5.2 yr of treatment with conjugated estrogens 0.625 mg alone compared with placebo
• Unknown whether these findings apply to younger postmenopausal women

Dose & Duration

• In the absence of comparable data, these risks should be assumed to be similar for other doses of CE and MPA and other combinations and dosage forms of estrogens and progestins
• Because of these risks, estrogens w/ or without progestins should be prescribed at lowest effective dose and for shortest duration consistent w/ treatment goals and individual risks

Cigarette smoking & risk of cardiovascular disease

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

 

Contraindications

Documented hypersensitivity

Active or history of breast cancer

Arterial thromboembolic disease (stroke, MI), thrombophlebitis, DVT/PE, thrombogenic valvular disease

Estrogen-dependent neoplasia

Liver disease, liver tumors

Undiagnosed abnormal vaginal bleeding

Uncontrolled hypertension

Diabetes mellitus with vascular involvement

Jaundice with prior oral contraceptive use

 

Cautions

Acitretin inhibits contraceptive efficacy of norethindrone preparations

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 if the following develop jaundice, visual problems (may cause contact lens intolerance), any signs of VTE, migraine with unusual severity, significang blood pressure increase, severe depression, increased risk of thromboembolic complications after surgery

Discontinue 4 week before major surgery or prolonged immobilization

Patients on warfarin, oral anticoagulants (increase in anticoagulant dose may be warranted)

Some studies link OCP use with increased risk of breast cancer, whereas other studies have not shown a change in risk; woman's risk depends on conditions where naturally high hormone levels persist for long periods of time including early onset menstruation before age 12, late onset menopause, after age 55, first child after age 30, nulliparity

Increased risk of cervical cancer with OCP use, however HPV remains as main risk factor for this cancer; evidence suggests long-term use of OCPs, 5 or more years, may be associated with increased risk

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

CDC guidelines recommend waiting at least 3 weeks following vaginal birth or 6 weeks after cesarean section to decrease risk for venous thromboembolism before initiating combined hormonal contraceptives; women with additional risk factors for VTE (besides postpartum) should not use combined hormonal contraceptives (MMWR July 7, 2011)

 

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 Loestrin (norethindrone acetate/ethinyl estradiol)

Mechanism of action

Ethinyl Estradiol (EE): Reduces LHRH release from hypothalamus, reduces gonadotropin release from pituitary; increases synthesis of DNA, RNA, and various proteins in target tissues

Norethindrone acetate: progestin; inhibits gonadotropin secretion of gonadotropins from pituitary; prevents follicular maturation & ovulation, stimulates growth of mammary tissues

 

Absorption

Peak Plasma Time: 8 hr (EE); 1-2 hr (norethindrone)

 

Distribution

Ethinyl Estradiol: Vd: 2-4 L/Kg

Protein binding: Ethinyl estradiol 80%; norethindrone 61%

 

Metabolism

Both components are metabolized in the liver; estradiol undergoes extensive first-pass metabolism

Ethinyl estradiol metabolites: Estriol, estrone

Norethindrone metabolites: Sulfate and glucuronide metabolites (inactive)

 

Elimination

Half-Life: Ethinyl Estradiol: PO:19-24 hr

Excretion

• Ethinyl estradiol: Urine as conjugates, most estrogens are also excreted in bile and undergo enterohepatic recycling
• Norethindrone: Urine: 33-81%; feces 35-43%