Delsia Mechanism of Action

Pharmacology: Pharmacodynamics: Drospirenone is a spironolactone analogue with anti-mineralocorticoid activity. The estrogen in DELSIA is ethinyl estradiol.
No specific pharmacodynamic studies were reported with drospirenone 3 mg and ethinyl estradiol 0.03 mg tablets.
Mechanism of action: Combined oral contraceptives (COCs) lower the risk of becoming pregnant primarily by suppressing ovulation. Other possible mechanisms may include cervical mucus changes that inhibit sperm penetration and endometrial changes that reduce the likelihood of implantation.
Pharmacokinetics: Absorption: The absolute bioavailability of drospirenone from a single entity tablet is about 76%. The absolute bioavailability of ethinyl estradiol is approximately 40% as a result of presystemic conjugation and first-pass metabolism. The absolute bioavailability of combination tablet of drospirenone and ethinyl estradiol has not been reported. Serum concentrations of drospirenone and ethinyl estradiol have been reported to reach peak levels within 1-2 hours after administration of drospirenone 3 mg and ethinyl estradiol 0.03 mg combination.
The pharmacokinetics of drospirenone are dose proportional following single doses ranging from 1-10 mg. Following daily dosing of drospirenone 3 mg and ethinyl estradiol 0.03 mg combination, steady state drospirenone concentrations were reported after 8 days. There was about 2 to 3 fold accumulation in serum C_max and AUC_(0-24h) values of drospirenone following multiple dose administration of drospirenone 3 mg and ethinyl estradiol 0.03 mg combination (see table as follows).
For ethinyl estradiol, steady-state conditions are reported during the second half of a treatment cycle. Following daily administration of drospirenone 3 mg and ethinyl estradiol 0.03 mg combination serum C_max and AUC_(0-24h) values of ethinyl estradiol accumulate by a factor of about 1.5 to 2 (see table as follows).

Click on icon to see table/diagram/image

Food Effect: The rate of absorption of drospirenone and ethinyl estradiol following single administration of a formulation similar to drospirenone 3 mg and ethinyl estradiol 0.03 mg combination was reported to be slower under fed (high fat meal) conditions with the serum C_max being reduced about 40% for both components. The extent of absorption of drospirenone, however, remained unchanged. In contrast, the extent of absorption of ethinyl estradiol was reported to be reduced by about 20% under fed conditions.
Distribution: Drospirenone and ethinyl estradiol serum concentrations decline in two phases. The reported apparent volume of distribution of drospirenone is approximately 4 L/kg and that of ethinyl estradiol is approximately 4-5 L/kg.
Drospirenone does not bind to sex hormone binding globulin (SHBG) or corticosteroid binding globulin (CBG) but binds about 97% to other serum proteins. It has been reported that multiple dosing over 3 cycles resulted in no change in the free fraction (as measured at trough concentrations). Ethinyl estradiol is reported to be highly but non-specifically bound to serum albumin (approximately 98.5%) and induces an increase in the serum concentrations of both SHBG and CBG. Ethinyl estradiol induced effects on SHBG and CBG were not reported to be affected by variation of the drospirenone dosage in the range of 2 to 3 mg.
Metabolism: The two main metabolites of drospirenone found in human plasma were reported to be the acid form of drospirenone generated by opening of the lactone ring and the 4,5-dihydrodrospirenone-3-sulfate, formed by reduction and subsequent sulfation. These metabolites were reported not to be pharmacologically active. Drospirenone is also subject to oxidative metabolism catalyzed by CYP3A4.
Ethinyl estradiol has been reported to be subject to significant gut and hepatic first-pass metabolism. Metabolism of ethinyl estradiol and its oxidative metabolites occur primarily by conjugation with glucuronide or sulfate. CYP3A4 in the liver is responsible for the 2-hydroxylation which is the major oxidative reaction. The 2-hydroxy metabolite is further transformed by methylation and glucuronidation prior to urinary and fecal excretion.
Excretion: Drospirenone serum concentrations are characterized by a terminal disposition phase half-life of approximately 30 hours after both single and multiple dose regimens. Excretion of drospirenone was reported to be nearly complete after ten days and amounts excreted were slightly higher in feces compared to urine. Drospirenone was extensively metabolized and only trace amounts of unchanged drospirenone were excreted in urine and feces. At least 20 different metabolites were reported in urine and feces. About 38-47% of the metabolites in urine were reported to be glucuronide and sulfate conjugates. In feces, about 17-20% of the metabolites were reported to be excreted as glucuronides and sulfates.
For ethinyl estradiol the terminal disposition phase half-life has been reported to be approximately 24 hours. Ethinyl estradiol is not excreted unchanged. Ethinyl estradiol is excreted in the urine and feces as glucuronide and sulfate conjugates and undergoes enterohepatic circulation.
Use in Specific Populations: Pediatric Use: Safety and efficacy of drospirenone 3 mg and ethinyl estradiol 0.03 mg combination has been reported in women of reproductive age. Efficacy is expected to be the same for postpubertal adolescents under the age of 18 and for users 18 years and older. Use of this product before menarche is not indicated.
Geriatric Use: The effect of drospirenone 3 mg and ethinyl estradiol 0.03 mg combination has not been reported in postmenopausal women and is not indicated in this population.
Race: No clinically significant difference was reported between the pharmacokinetics of drospirenone or ethinyl estradiol in Japanese versus Caucasian women (age 25-35) when 3 mg drospirenone/0.02 mg ethinyl estradiol was administered daily for 21 days. The effect in other ethnic groups has not been specifically reported.
Renal Impairment: Drospirenone 3 mg and ethinyl estradiol 0.03 mg combination is contraindicated in patients with renal impairment.
The effect of renal impairment on the pharmacokinetics of drospirenone (3 mg daily for 14 days) and the effect of drospirenone on serum potassium concentrations has been reported in females aged 30-65 years. All females were on a low potassium diet. During the reported study, the subjects continued the use of potassium-sparing drugs for the treatment of their underlying illness. On the 14th day (steady-state) of drospirenone treatment, the serum drospirenone concentrations in the group with CL_cr of 50-79 mL/min were reported to be comparable to those in the control group with CL_cr ≥ 80 mL/min. The serum drospirenone concentrations were reported to be on average 37% higher in the group with CL_cr of 30-49 mL/min compared to those in the control group. Drospirenone treatment did not reportedly show any clinically significant effect on serum potassium concentration. Although hyperkalemia was not reported, mean serum potassium concentrations were reported to increase by up to 0.33 mEq/L in subjects who continued use of potassium sparing drugs (see CONTRAINDICATIONS and PRECAUTIONS).
Hepatic Impairment: Drospirenone 3 mg and ethinyl estradiol 0.03 mg combination is contraindicated in patients with hepatic disease.
The mean exposure to drospirenone in women with moderate liver impairment is reported to be approximately three times higher than the exposure in women with normal liver function. The effect of drospirenone 3 mg and ethinyl estradiol 0.03 mg combination has not been reported in women with severe hepatic impairment (see CONTRAINDICATIONS and PRECAUTIONS).