Femhrt Side Effects, and Drug Interactions - Norethindrone acetate and ethinyl estradiol

Femhrt Side Effects, and Drug Interactions - Norethindrone acetate and ethinyl estradiol

SIDE EFFECTS

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 femhrt 1/5 are shown in Table 5 below.

The following adverse events have been reported with estrogen and/or progestin therapy:

Cardiovascular: changes in blood pressure, cerebrovascular accidents, deep venous thrombosis, and pulmonary embolism.

Genitourinary system: changes in vaginal bleeding pattern and abnormal withdrawal bleeding or flow, breakthrough bleeding, spotting, increase in size of uterine leiomyomata, vaginal candidiasis, changes in amount of cervical secretion, pre-menstrual-like syndrome, cystitis-like syndrome.

Breasts: tenderness, enlargement, fibrocystic disease of the breast.

Gastrointestinal: cholestatic jaundice, pancreatitis, flatulence, bloating, abdominal cramps.

Skin: chloasma or melasma that may persist when drug is discontinued, erythema multiforme, erythema nodosum, hemorrhagic eruption, loss of scalp hair, hirsutism, itching, skin rash and pruritus.

CNS: headache, migraine, dizziness, chorea, insomnia.

Eyes: intolerance to contact lenses, sudden partial or complete loss of vision, proptosis, diplopia, otosclerosis.

Miscellaneous: increase or decrease in weight, reduced carbohydrate tolerance, aggravation of porphyria, changes in libido, fatigue, allergic or anaphylactoid reactions, leiomyoma, fibromyoma of the uterus, endometriosis.

The following drug/laboratory interactions have been observed with estrogen therapy, and/or femhrt 1/5:

1. In a 12-week study, femhrt 1/5 decreased Factor VII and plasminogen activator inhibitor-1 from baseline in a dose-related manner, but remained within the laboratory reference range for postmenopausal women. Mean levels of fibrinogen and partial thromboplastin time did not change from baseline for femhrt 1/5.

2. Estrogen therapy may increase thyroxine-binding globulin (TBG), leading to increased circulating total thyroid hormone (T4) as measured by protein-bound iodine (PBI), T4 levels (by column or radioimmunoassay), or T3 levels by radioimmunoassay. T3 resin uptake is decreased, reflecting the elevated TBG. Free T4 and free T3 concentrations are unaltered.

3. Estrogen therapy may elevate other binding proteins in serum, ie, corticosteroid binding globulin (CBG), sex hormone-binding globulin (SHBG), leading to increased circulating corticosteroids and sex steroids, respectively. Free or biologically active hormone concentrations are unchanged. Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha-1-antitrypsin, ceruloplasmin). femhrt 1/5 was associated with a SHBG increase of 22%.

4. Estrogen therapy increases plasma HDL and HDL-2 subfraction concentrations, reduces LDL cholesterol concentration and increases triglyceride levels.

5. Estrogen therapy is associated with impaired glucose tolerance.

6. Estrogen therapy reduces response to metyrapone test.

No drug-drug interaction studies have been conducted with femhrt 1/5.

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 femhrt 1/5 or drug products containing other types of estrogens.

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 (eg, 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 (eg, oral contraceptives containing ethinyl estradiol).