Danazol

DANAZOL- danazol capsule
Carilion Materials Management

DESCRIPTION

Danazol 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 is 17α-Pregna-2, 4-dien-20-yno [2, 3- ]-isoxazol-17-ol. The molecular formula is C H NO . It has a molecular weight of 337.46 and the following structural formula: d 22 27 2

Danazol Molecular Structure
(click image for full-size original)

Danazol capsules for oral administration contain 50 mg, 100 mg, or 200 mg danazol.

anhydrous lactose, lactose monohydrate, magnesium stearate, pregelatinized starch, sodium lauryl sulfate, talc. Capsule shells for 200 mg danazol contain D&C Yellow #10, FD&C Red #40, D&C Red #28, gelatin, and titanium dioxide. Capsule shells for 50 mg and 100 mg danazol contain D&C Yellow # 10, FD&C Red # 40, gelatin, and titanium dioxide. The capsule imprinting ink contains: shellac glaze in ethanol, iron oxide black, n-butyl alcohol, propylene glycol, ethanol, methanol, FD&C Blue No. 2 Aluminum Lake, FD&C Red No. 40 Aluminum Lake, FD&C Blue No. 1 Aluminum Lake, and D&C Yellow No. 10 Aluminum Lake. Inactive Ingredients:

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.

In the treatment of fibrocystic breast disease, danazol usually produces partial to complete disappearance of nodularity and complete relief of pain and tenderness. 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 (C1El). 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 value of 4 hours. Steady state conditions are observed following 6 days of twice daily dosing of danazol. max

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)
C (ng/mL) max 69.6 ± 29.9
T (h) max 2.47 ± 1.62
AUC (ng*h/mL) 0-∞ 601 ± 181
t (h) 1/2 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 C ± ( max SD
ng/mL)

Mean T (h) max

Mean AUC ± SD ( 0-∞
ng*h/mL)

Fasting Fed Fasting Fed Fasting Fed
100 45.9 ±23.9 113.8 ± 46.0 1-8 2-6 484 ± 263 741 ± 265
200 63.8 ± 27.7 159 ± 57.3 1-6 2-4 681 ± 363 1252 ± 307
400 60.4 ± 30.0 253.7 ± 105.5 1-6 2-4 754 ± 443 1851 ± 605

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

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 in the fasted and fed state, respectively. A similar degree of non-dose proportionality was observed at steady state. max

Single dose administration of 100 mg and 200 mg capsules of danazol to female volunteers showed that both the extent of availability and the maximum plasma concentration increased by 3 to 4 fold, respectively, following a meal (> 30 grams of fat), when compared to the fasted state. Further, food also delayed mean time to peak concentration of danazol by about 30 minutes. Even after multiple dosing under less extreme food/fasting conditions, there remained approximately a 2 to 2.5 fold difference in bioavailability between the fed and fasted states. Food Effect:

Distribution: Danazol is lipophilic and can partition into cell membranes, indicating the likelihood of distribution into deep tissue compartments.

Metabolism and Excretion: Danazol appears to be metabolized and the metabolites are eliminated by renal and fecal pathways. The two primary metabolites excreted in the urine are 2-hydroxymethyl danazol and ethisterone. At least ten different products were identified in feces.

The reported elimination half-life of danazol is variable across studies. The mean half-life of danazol in healthy males is 9.7 h. After 6 months of 200 mg three times a day dosing in endometriosis patients, the half-life of danazol was reported as 23.7 hours.

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