Danazol

DANAZOL- danazol capsule
Teva Pharmaceuticals USA, Inc.

DESCRIPTION

Danazol, USP is a synthetic steroid derived from ethisterone. It is a white to pale yellow crystalline powder, practically insoluble or insoluble in water, and sparingly soluble in alcohol. Chemically, danazol, USP is 17α-Pregna-2,4-dien-20-yno [2,3-d ]-isoxazol-17-ol, which has the following structural formula:

C₂₂ H₂₇ NO₂ M.W. 337.46

Danazol capsules, USP for oral administration, contain 50 mg, 100 mg or 200 mg of danazol, USP. In addition, each capsule contains the following inactive ingredients: black iron oxide, D&C yellow no. 10, D&C yellow no. 10 aluminum lake, FD&C blue no. 1 aluminum lake, FD&C blue no. 2 aluminum lake, FD&C red no. 40 aluminum lake, gelatin, lactose monohydrate, magnesium stearate, pharmaceutical glaze, propylene glycol, sodium starch glycolate, stearic acid and titanium dioxide

The 50 mg and 100 mg capsule shells also contain FD&C yellow no. 6.

The 200 mg capsule shell also contains FD&C red no. 40 and D&C red no. 28.

CLINICAL PHARMACOLOGY

Danazol suppresses the pituitary-ovarian axis. This suppression is probably a combination of depressed hypothalamic-pituitary response to lowered estrogen production, the alteration of sex steroid metabolism, and interaction of danazol with sex hormone receptors. The only other demonstrable hormonal effect is weak androgenic activity. Danazol depresses the output of both follicle-stimulating hormone (FSH) and luteinizing hormone (LH).

Recent evidence suggests a direct inhibitory effect at gonadal sites and a binding of danazol to receptors of gonadal steroids at target organs. In addition, danazol has been shown to significantly decrease IgG, IgM and IgA levels, as well as phospholipid and IgG isotope autoantibodies in patients with endometriosis and associated elevations of autoantibodies, suggesting this could be another mechanism by which it facilitates regression of the disease.

In the treatment of endometriosis, danazol alters the normal and ectopic endometrial tissue so that it becomes inactive and atrophic. Complete resolution of endometrial lesions occurs in the majority of cases.

Changes in vaginal cytology and cervical mucus reflect the suppressive effect of danazol on the pituitary-ovarian axis.

Changes in the menstrual pattern may occur.

Generally, the pituitary-suppressive action of danazol is reversible. Ovulation and cyclic bleeding usually return within 60 to 90 days when therapy with danazol is discontinued.

In the treatment of hereditary angioedema, danazol at effective doses prevents attacks of the disease characterized by episodic edema of the abdominal viscera, extremities, face, and airway which may be disabling and, if the airway is involved, fatal. In addition, danazol corrects partially or completely the primary biochemical abnormality of hereditary angioedema by increasing the levels of the deficient C1 esterase inhibitor (C1EI). As a result of this action the serum levels of the C4 component of the complement system are also increased.

Pharmacokinetics

Absorption: After oral administration of a 400 mg dose to healthy male volunteers, peak plasma concentrations of danazol are reached between 2 and 8 hours, with a median T_max value of 4 hours. Steady state conditions are observed following 6 days of twice daily dosing of danazol.

The pharmacokinetic parameters for danazol after administering a 400 mg oral dose to healthy males are summarized in the following table:

Parameters	Mean ± SD (n = 15)
Cmax (ng/mL)	69.6 ± 29.9
Tmax (h)	2.47 ± 1.62
AUC0-∞ (ng*h/mL)	601 ± 181
t1/2 (h)	9.70 ± 3.29
Total Body Clearance (L/h)	727 ± 221

The pharmacokinetic parameters for danazol after oral administration of 100, 200 and 400 mg single doses to healthy female volunteers are summarized in the following table:

Dose (mg)	Mean Cmax ± SD (ng/mL)		Mean Tmax (h)		Mean AUC0-∞ ± SD (ng*h/mL)
	Fasting	Fed	Fasting	Fed	Fasting	Fed
100	45.9 ±23.9	113.8 ± 46	1 to 8	2 to 6	484 ± 263	741 ± 265
200	63.8 ± 27.7	159 ± 57.3	1 to 6	2 to 4	681 ± 363	1252 ± 307
400	60.4 ± 30	253.7 ± 105.5	1 to 6	2 to 4	754 ± 443	1851 ± 605

Dose Proportionality

Bioavailability studies indicate that blood levels do not increase proportionally with increases in the administered dose.

Single dose administration of danazol in healthy female volunteers found that a 4 fold increase in dose produced only a 1.6 and 2.5 fold increase in AUC and a 1.3 and 2.2 fold increase in C_max in the fasted and fed state, respectively. A similar degree of non-dose proportionality was observed at steady state.