mestranol/norethindrone (Discontinued)

Frequency Not Defined

Common

• Emotional lability
• Headache
• Breast symptoms
• Menstrual cramps
• Abdominal pains
• Nausea

Serious

• Arterial/venous thromboembolism
• Hypertension
• MI
• Cerebral hemorrhage
• Gallbladder disease
• Hepatic adenoma

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

Precautions

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 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 w/ 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.

Mechanism of Action

Mestranol: Estrogen; reduces LHRH release from hypothalamus, reduces gonadotropin release from pituitary; increases synthesis of DNA, RNA, and various proteins in target tissues

Norethindrone: Progestin; inhibits secretion of gonadotropins from pituitary; prevents follicular maturation and ovulation, stimulates growth of mammary tissues

Absorption

Bioavailability: 60% (norethindrone)

Peak plasma time: 8 hr (ethinyl estradiol [active metabolite]); 1-2 hr (norethindrone)

Distribution

Protein bound: 80% (ethinyl estradiol [active metabolite]); 61% (norethindrone)

Metabolism

Mestranol: Metabolized to ethinyl estradiol via demethylation

Norethindrone: Liver

Metabolites

• Mestranol metabolized to ethinyl estradiol; ethinyl estradiol further metabolized to estriol, estrone by liver CYP3A4
• Norethindrone: Sulfate and glucuronide metabolites (inactive)

Elimination

Half-life: 4-13 hr (norethindrone)

Excretion

• Ethinyl estradiol (active metabolite): in urine as conjugates, most estrogens are also excreted in the bile and undergo enterohepatic recycling
• Norethindrone: 33-81% urine; 35-43% feces