ZARAH- drospirenone and ethinyl estradiol
Actavis Pharma, Inc.



ZARAH™ (Drospirenone and ethinyl estradiol tablets) provides an oral contraceptive regimen consisting of 21 active tablets each containing 3 mg of drospirenone and 0.030 mg of ethinyl estradiol and 7 inert tablets. The inactive ingredients are lactose monohydrate, corn starch, pregelatinized starch, magnesium stearate, Vitamin E, FD&C Blue #1 Aluminum Lake. The inert tablets contain lactose anhydrous, microcrystalline cellulose, FD&C Yellow #6 Aluminum Lake and magnesium stearate.

Drospirenone (6R,7R,8R,9S,10R,13S,14S,15S,16S,17S)-1,3’,4’,6,6a,7,8,9,10,11,12,13,14,15,15a,16-hexadecahydro-10,13-dimethylspiro-[17H-dicyclopropa-6,7:15,16]cyclopenta[a]phenanthrene-17,2’(5H)-furan]-3,5’(2H)-dione) is a synthetic progestational compound and has a molecular weight of 366.5 and a molecular formula of C24 H30 O3 . Ethinyl estradiol (19-nor-17α-pregna 1,3,5(10)-triene-20-yne-3,17-diol) is a synthetic estrogenic compound and has a molecular weight of 296.4 and a molecular formula of C20 H24 O2 . The structural formulas are as follows:

Drospirenone  and  Ethinyl estradiol Structural Formulas
(click image for full-size original)

Drospirenone Ethinyl estradiol



Combination oral contraceptives (COCs) act by suppression of gonadotropins. Although the primary mechanism of this action is inhibition of ovulation, other alterations include changes in the cervical mucus (which increases the difficulty of sperm entry into the uterus) and the endometrium (which reduces the likelihood of implantation).

Drospirenone is a spironolactone analogue with antimineralocorticoid activity. Preclinical studies in animals and in vitro have shown that drospirenone has no androgenic, estrogenic, glucocorticoid, and antiglucocorticoid activity. Preclinical studies in animals have also shown that drospirenone has antiandrogenic activity.



The absolute bioavailability of drospirenone (DRSP) from a single entity tablet is about 76%. The absolute bioavailability of ethinyl estradiol (EE) is approximately 40% as a result of presystemic conjugation and first-pass metabolism. The absolute bioavailability of a combination tablet of drospirenone and ethinyl estradiol has not been evaluated. Serum concentrations of DRSP and EE reached peak levels within 1 to 3 hours after administration of drospirenone and ethinyl estradiol. After single dose administration of drospirenone and ethinyl estradiol, the relative bioavailability, compared to a suspension, was 107% and 117% for DRSP and EE, respectively.

The pharmacokinetics of DRSP are dose proportional following single doses ranging from 1 to 10 mg. Following daily dosing of drospirenone and ethinyl estradiol, steady-state DRSP concentrations were observed after 10 days. There was about 2 to 3 fold accumulation in serum Cmax and AUC (0 to 24h) values of DRSP following multiple dose administration of drospirenone and ethinyl estradiol (see Table 1).

For EE, steady-state conditions are reported during the second half of a treatment cycle. Following daily administration of drospirenone and ethinyl estradiol serum Cmax and AUC (0 to 24h) values of EE accumulate by a factor of about 1.5 to 2.0.

TABLE 1: Mean Pharmacokinetic Parameters of Drospirenone and Ethinyl Estradiol (3 mg / 0.03 mg)
Drospirenone Mean (%CV) Values
Cycle / Day No. of Subjects C max (ng/mL) T max (h) AUC(0 to 24h) (ng•h/mL) t 1/2 (h)
NA = Not available
1/1 12 36.9 (13) 1.7 (47) 288 (25) NA
1/21 12 87.5 (59) 1.7 (20) 827 (23) 30.9 (44)
6/21 12 84.2 (19) 1.8 (19) 930 (19) 32.5 (38)
9/21 12 81.3 (19) 1.6 (38) 957 (23) 31.4 (39)
13/21 12 78.7 (18) 1.6 (26) 968 (24) 31.1 (36)
Ethinyl Estradiol Mean (%CV) Values
Cycle / Day No. of Subjects C max (pg/mL) T max (h) AUC(0 to 24h) (pg•h/mL) t 1/2 (h)
1/1 11 53.5 (43) 1.9 (45) 280.3 (87) NA
1/21 11 92.1 (35) 1.5 (40) 461.3 (94) NA
6/21 11 99.1 (45) 1.5 (47) 346.4 (74) NA
9/21 11 87.0 (43) 1.5 (42) 485.3 (92) NA
13/21 10 90.5 (45) 1.6 (38) 469.5 (83) NA

Effect of Food

The rate of absorption of DRSP and EE following single administration of two drospirenone and ethinyl estradiol tablets was slower under fed conditions with the serum Cmax being reduced about 40% for both components. The extent of absorption of DRSP, however, remained unchanged. In contrast the extent of absorption of EE was reduced by about 20% under fed conditions.


DRSP and EE serum levels decline in two phases. The apparent volume of distribution of DRSP is approximately 4 L/kg and that of EE is reported to be approximately 4 to 5 L/kg.

DRSP does not bind to sex hormone binding globulin (SHBG) or corticosteroid binding globulin (CBG) but binds about 97% to other serum proteins. Multiple dosing over 3 cycles resulted in no change in the free fraction (as measured at trough levels). EE 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. EE induced effects on SHBG and CBG were not affected by variation of the DRSP dosage in the range of 2 to 3 mg.


The two main metabolites of DRSP found in human plasma were identified to be the acid form of DRSP generated by opening of the lactone ring and the 4,5-dihydrodrospirenone-3-sulfate. These metabolites were shown not to be pharmacologically active. In in vitro studies with human liver microsomes, DRSP was metabolized only to a minor extent mainly by Cytochrome P450 3A4 (CyP3A4)

EE has been reported to be subject to presystemic conjugation in both small bowel mucosa and the liver. Metabolism occurs primarily by aromatic hydroxylation but a wide variety of hydroxylated and methylated metabolites are formed. These are present as free metabolites and as conjugates with glucuronide and sulfate. CYP3A4 in the liver are 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.


DRSP serum levels are characterized by a terminal disposition phase half-life of approximately 30 hours after both single and multiple dose regimens. Excretion of DRSP was nearly complete after ten days and amounts excreted were slightly higher in feces compared to urine. DRSP was extensively metabolized and only trace amounts of unchanged DRSP were excreted in urine and feces. At least 20 different metabolites were observed in urine and feces. About 38 to 47% of the metabolites in urine were glucuronide and sulfate conjugates. In feces, about 17 to 20 % of the metabolites were excreted as glucuronides and sulfates.

For EE the terminal disposition phase half life has been reported to be approximately 24 hours. EE is not excreted unchanged. EE is excreted in the urine and feces as glucuronide and sulfate conjugates and undergoes enterohepatic circulation.

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