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E. Drug/Drug Interactions

No drug-drug interaction studies have been conducted with norethindrone acetate and ethinyl estradiol.

In vitro and in vivo studies have shown that estrogens are metabolized partially by cytochrome P450 3A4 (CYP3A4). Therefore, inducers or inhibitors of CYP3A4 may affect estrogen drug metabolism. Inducers of CYP3A4 such as St. John’s Wort preparations (Hypericum perforatum), Phenobarbital, carbamazepine, and rifampin may reduce plasma concentrations of estrogens, possibly resulting in a decrease in therapeutic effects and/or changes in the uterine bleeding profile. Inhibitors of CYP3A4 such as erythromycin, clarithromycin, ketoconazole, intraconazole, ritonavir and grapefruit juice may increase plasma concentrations of estrogens and may result in side effects.

The following section contains information on drug interactions with ethinyl estradiol-containing products (specifically, oral contraceptives) that have been reported in the public literature. It is unknown whether such interactions occur with norethindrone acetate and ethinyl estradiol or drug products containing other types of estrogens.

The Effect of Ethinyl Estradiol on Other Drugs

Drug products containing ethinyl estradiol may inhibit the metabolism of other compounds. Increased plasma concentrations of cyclosporin, prednisolone, and theophylline have been reported with concomitant administration of certain drugs containing ethinyl estradiol (e.g., oral contraceptives containing ethinyl estradiol). In addition, drugs containing ethinyl estradiol may induce the conjugation of other compounds.

Decreased plasma concentrations of acetaminophen and increased clearance of temazapam, salicylic acid, morphine, and clofibric acid have been noted when these drugs were administered with certain ethinyl-estradiol containing drug products (e.g., oral contraceptives containing ethinyl estradiol).

F. Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term continuous administration of estrogen, with and without progestin, in women with and without a uterus, has shown an increased risk of endometrial cancer, breast cancer, and ovarian cancer. (See BOXED WARNING, WARNINGS and PRECAUTIONS.)

Long-term continuous administration of natural and synthetic estrogens in certain animal species increases the frequency of carcinomas of the breast, uterus, cervix, vagina, testis, and liver.

G. Pregnancy

Norethindrone acetate and ethinyl estradiol should not be used during pregnancy. (See CONTRAINDICATIONS.)

H. Nursing Mothers

Estrogen administration to nursing mothers has been shown to decrease the quantity and quality of the milk. Detectable amounts of drug have been identified in the milk of mothers receiving these drugs. Caution should be exercised when norethindrone acetate and ethinyl estradiol is administered to nursing mothers.

I. Pediatric Use

Norethindrone acetate and ethinyl estradiol is not indicated in children.

J. Geriatric Use

There have not been sufficient numbers of geriatric patients involved in clinical trials utilizing norethindrone acetate and ethinyl estradiol to determine whether those over 65 years of age differ from younger subjects in their response to norethindrone acetate and ethinyl estradiol.

In the Women’s Health Initiative Memory Study, including 4,532 women 65 years of age and older, followed for an average of 4 years, 82% (n = 3,729) were 65 to 74 while 18% (n = 803) were 75 and over. Most women (80%) had no prior hormone therapy use. Women treated with conjugated estrogens plus medroxyprogesterone acetate were reported to have a two-fold increase in the risk of developing probable dementia. Alzheimer’s disease was the most common classification of probable dementia in both the conjugated estrogens plus medroxyprogesterone acetate group and the placebo group. Ninety percent of the cases of probable dementia occurred in the 54% of women that were older than 70. (See WARNINGS, Dementia.)

ADVERSE REACTIONS

See BOXED WARNING , WARNINGS , and PRECAUTIONS.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The adverse reaction information from clinical trials does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates.

Adverse events reported in controlled clinical studies of norethindrone acetate and ethinyl estradiol are shown in Table 6 below.

Table 6: All Treatment-Emergent Adverse Events Reported at a Frequency of ≥5% of Patients with Norethindrone Acetate and Ethinyl Estradiol
Percent of Patients (%)

BODY SYSTEM/

Adverse Event

Placebo

N = 247

Norethindrone Acetate

and Ethinyl

Estradiol,

0.5/2.5

N = 244

Norethindrone Acetate

and Ethinyl

Estradiol,

1/5

N = 258
BODY AS A WHOLE 40.1 38.5 39.5
Headache 14.6 15.2 18.2
Back Pain 5.3 5.3 4.7
Viral Infection 7.7 8.6 7.0
DIGESTIVE SYSTEM 24.4 30.5 33.0
Nausea and/or Vomiting 5.3 5.3 7.4
Abdominal Pain 4.5 10.2 8.1
Dyspepsia 2.0 5.3 3.1
Diarrhea 3.6 5.7 3.9

MUSCULOSKELETAL

SYSTEM
21.7 20.3 20.4
Arthralgia 6.9 2.9 5.8
Myalgia 8.5 8.6 7.8

PSYCHOBIOLOGIC

FUNCTION
8.3 7.9 14.1
Nervousness 1.6 1.6 5.4
Depression 3.6 3.7 5.8
RESPIRATORY SYSTEM 37.2 33.9 35.6
Rhinitis 15.4 12.7 15.1
Sinusitis 9.7 9.4 8.1
UROGENITAL SYSTEM 25.0 31.6 40.8
Breast Pain 5.3 9.0 8.1
Urinary Tract Infection 3.2 3.7 6.2
Vaginitis 4.9 4.5 5.4

The following additional adverse reactions have been reported with estrogen and/or progestin therapy.

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