OCELLA (Page 5 of 7)

8.4 Pediatric Use

Safety and efficacy of OCELLA has been established 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.

8.5 Geriatric Use

OCELLA has not been studied in postmenopausal women and is not indicated in this population.

8.6 Patients with Renal Impairment

OCELLA is contraindicated in patients with renal impairment [see Contraindications (4) and Warnings and Precautions (5.2)].

In subjects with creatinine clearance (CLcr) of 50–79 mL/min, serum DRSP concentrations were comparable to those in a control group with CLcr ≥ 80 mL/min. In subjects with CLcr of 30–49 mL/min, serum DRSP concentrations were on average 37% higher than those in the control group. In addition, there is a potential to develop hyperkalemia in subjects with renal impairment whose serum potassium is in the upper reference range, and who are concomitantly using potassium sparing drugs [see Clinical Pharmacology (12.3)].

8.7 Patients with Hepatic Impairment

OCELLA is contraindicated in patients with hepatic disease [see Contraindications (4) and Warnings and Precautions (5.4)]. The mean exposure to DRSP in women with moderate liver impairment is approximately three times higher than the exposure in women with normal liver function. OCELLA has not been studied in women with severe hepatic impairment.

8.8 Race

No clinically significant difference was observed between the pharmacokinetics of DRSP or EE in Japanese versus Caucasian women [see Clinical Pharmacology (12.3)].

10 OVERDOSAGE

There have been no reports of serious ill effects from overdose, including ingestion by children. Overdosage may cause withdrawal bleeding in females and nausea.

DRSP is a spironolactone analogue which has anti-mineralocorticoid properties. Serum concentration of potassium and sodium, and evidence of metabolic acidosis, should be monitored in cases of overdose.

11 DESCRIPTION

OCELLA (drospirenone/ethinyl estradiol) tablets provide an oral contraceptive regimen consisting of 28 film-coated tablets that contain the ingredients specified for each tablet below:

21 yellow tablets each containing 3 mg DRSP and 0.03 mg EE
7 inert white tablets

The inactive ingredients in the yellow tablets are lactose monohydrate NF, corn starch NF, pregelatinized starch NF, povidone 25000 NF, magnesium stearate NF, hypromellose USP, macrogol 6000 NF, titanium dioxide USP, talc USP, and ferric oxide pigment, yellow NF. The white inert film-coated tablets contain lactose monohydrate NF, microcrystalline cellulose NF, magnesium stearate NF, hypromellose USP, talc USP, and 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:

Structural Formulas
(click image for full-size original)

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

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.

12.2 Pharmacodynamics

Drospirenone is a spironolactone analogue with anti-mineralocorticoid activity. The estrogen in OCELLA is ethinyl estradiol (EE).

No specific pharmacodynamic studies were conducted with OCELLA.

12.3 Pharmacokinetics

Absorption

The absolute bioavailability of DRSP from a single entity tablet is about 76%. The absolute bioavailability of 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 DRSP and EE, has not been evaluated. Serum concentrations of DRSP and EE reached peak levels within 1-2 hours after administration of OCELLA.

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 8 days. There was about 2 to 3 fold accumulation in serum Cmax and AUC (0-24h) values of DRSP following multiple dose administration of OCELLA (see Table 2).

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

Table 2 Mean Pharmacokinetic Parameters of Yasmin (DRSP 3 mg and EE 0.03 mg)
*
NA-Not available

DRSP Mean (%CV) Values

Cycle / Day

No. of Subjects

Cmax (ng/mL)

Tmax (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)

EE 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 (87)

NA *

1/21

11

92.1 (35)

1.5 (40)

461 (94)

NA *

6/21

11

99.1 (45)

1.5 (47)

346 (74)

NA *

9/21

11

87 (43)

1.5 (42)

485 (92)

NA *

13/21

10

90.5 (45)

1.6 (38)

469 (83)

NA *

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