OCELLA: Package Insert and Label Information

OCELLA — drospirenone and ethinyl estradiol
Physicians Total Care, Inc.

PHYSICIAN LABELIN G

Rx only

PATIENTS SHOULD BE COUNSELED THAT THIS PRODUCT DOES NOT PROTECT AGAINST HIV INFECTION (AIDS) AND OTHER SEXUALLY TRANSMITTED DISEASES.

Description

OCELLA provides an oral contraceptive regimen consisting of 21 active film coated tablets each containing 3 mg of drospirenone and 0.03 mg of ethinyl estradiol and 7 inert film coated tablets. The inactive ingredients are lactose monohydrate NF, corn starch NF, modified starch NF, povidone 25000 USP, magnesium stearate NF, hydroxylpropylmethyl cellulose USP, macrogol 6000 NF, talc USP, titanium dioxide USP, ferric oxide pigment, yellow NF. The inert film coated tablets contain lactose monohydrate NF, corn starch NF, povidone 25000 USP, magnesium stearate NF, hydroxylpropylmethyl cellulose USP, talc USP, titanium dioxide USP.

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:

CLINICAL PHARMACOLOGY

PHARMACODYNAMICS

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.

PHARMACOKINETICS

Absorption

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 OCELLA which is a combination tablet of drospirenone and ethinyl estradiol has not been evaluated. Serum concentrations of DRSP and EE reached peak levels within 1–3 hours after administration of OCELLA. After single dose administration of OCELLA , 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 1–10 mg. Following daily dosing of OCELLA , steady state DRSP concentrations were observed after 10 days. There was about 2 to 3 fold accumulation in serum C_max and AUC (0–24h) values of DRSP following multiple dose administration of OCELLA (see TABLE I).

For EE, steady-state conditions are reported during the second half of a treatment cycle. Following daily administration of OCELLA serum C_max and AUC(0–24h) values of EE accumulate by a factor of about 1.5 to 2.

TABLE I TABLE OF MEAN PHARMACOKINETIC PARAMETERS OF OCELLA (Drospirenone 3 mg and Ethinyl Estradiol 0.03 mg )

* NA = Not available
Drospirenone Mean (%CV) Values
Cycle / Day	No. of Subjects	Cmax (ng/mL)	T max (h)	AUC(0–24h) (ng•h/mL)	t1/2 (h)
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	Cmax (pg/mL)	Tmax (h)	AUC(0–24h) (pg•h/mL)	t1/2 (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 (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 OCELLA tablets was slower under fed conditions with the serum C_max 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.

Distribution

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 4–5 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.

Metabolism

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.

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 38–47% of the metabolites in urine were glucuronide and sulfate conjugates. In feces, about 17–20% 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.

Special Populations

Race

The effect of race on the disposition of OCELLA has not been evaluated.

Hepatic Dysfunction

OCELLA is contraindicated in patients with hepatic dysfunction (also see BOLDED WARNINGS). The mean exposure to DRSP in women with moderate liver impairment is approximately three times the exposure in women with normal liver function.

Renal Insufficiency

OCELLA is contraindicated in patients with renal insufficiency (also see WARNINGS).

The effect of renal insufficiency on the pharmacokinetics of DRSP (3 mg daily for 14 days) and the effect of DRSP on serum potassium levels were investigated in female subjects (n=28, age 30–65) with normal renal function and mild and moderate renal impairment. All subjects were on a low potassium diet. During the study 7 subjects continued the use of potassium sparing drugs for the treatment of the underlying illness. On the 14th day (steady-state) of DRSP treatment, the serum DRSP levels in the group with mild renal impairment (creatinine clearance CLcr, 50–80 mL/min) were comparable to those in the group with normal renal function (CLcr, >80 mL/min). The serum DRSP levels were on average 37% higher in the group with moderate renal impairment (CLcr, 30–50 mL/min) compared to those in the group with normal renal function. DRSP treatment was well tolerated by all groups. DRSP treatment did not show any clinically significant effect on serum potassium concentration. Although hyperkalemia was not observed in the study, in five of the seven subjects who continued use of potassium sparing drugs during the study, mean serum potassium levels increased by up to 0.33 mEq/L. Therefore, potential exists for hyperkalemia to occur in subjects with renal impairment whose serum potassium is in the upper reference range, and who are concomitantly using potassium sparing drugs.

INDICATIONS AND USAGE

OCELLA is indicated for the prevention of pregnancy in women who elect to use an oral contraceptive.

Oral contraceptives are highly effective. TABLE II lists the typical accidental pregnancy rates for users of combination oral contraceptives and other methods of contraception. The efficacy of these contraceptive methods, except sterilization, depends upon the reliability with which they are used. Correct and consistent use of methods can result in lower failure rates.

TABLE II Percentage of women experiencing an unintended pregnancy during the first year of typical use and first year of perfect use of contraception and the percentage continuing use at the end of the first year: United States.

Source: Trussell J, Contraceptive efficacy. In Hatcher RA, Trussell J, Stewart F, Cates W, Stewart GK, Kowal D, Guest F, Contraceptive Technology: Seventeenth Revised Edition. New York NY: Irvington Publishers, 1998.
* With spermicidal cream or jelly.
	% of Women Experiencing an Accidental Pregnancy		% of Women Continuing Use At One Year
Method	Typical Use	Perfect Use	(4)
Chance	85	85
Spermicides	26	6	40
Periodic abstinence	25		63
Calendar		9
Ovulation method		3
Sympto-thermal		2
Post-ovulation		1
Withdrawal	19	4
Cap *
Parous women	40	26	42
Nulliparous women	20	9	56
Sponge
Parous women	40	20	42
Nulliparous women	20	9	56
Diaphragm *	20	6	56
Condom
Female (Reality)	21	5	56
Male	14	3	61
Pill	5		71
progestin only		0.5
combined		0.1
IUD
Progesterone T:	2	1.5	81
Copper T 380A	0.8	0.6	78
Lng 20	0.1	0.1	81
Depo Provera	0.3	0.3	70
Norplant and Norplant-2	0.05	0.05	88
Female Sterilization	0.5	0.5	100
Male Sterilization	0.15	0.1	100
Emergency Contraceptive Pills: Treatment initiated within 72 hours after unprotected intercourse reduces the risk of pregnancy by at least 75%
Lactational Amenorrhea Method: LAM is highly effective, temporary method of contraception

In clinical efficacy studies of OCELLA of up to 2 years duration, 2,629 subjects completed 33,160 cycles of use without any other contraception. The mean age of the subjects was 25.5 ± 4.7 years. The age range was 16 to 37 years. The racial demographic was: 83% Caucasian, 1% Hispanic, 1% Black, <1% Asian, <1% other, <1% missing data, 14% not inquired and <1% unspecified. Pregnancy rates in the clinical trials were less than one per 100 woman-years of use.