Prescription Drug Information: Safyral (Page 5 of 9)

8.4 Pediatric Use

Safety and efficacy of Safyral 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

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

8.6 Patients with Renal Impairment

Safyral 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

Safyral 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. Safyral 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.

Levomefolate calcium doses of 17 mg/day (37-fold higher than the levomefolate calcium dose of Safyral) were well tolerated after long-term treatment up to 12 weeks.

11 DESCRIPTION

Safyral (drospirenone/ethinyl estradiol/levomefolate calcium tablets and levomefolate calcium tablets) provides an oral contraceptive regimen consisting of 28 film-coated tablets that contain the active ingredients specified for each tablet below:

21 orange tablets each containing 3 mg DRSP, 0.03 mg EE as betadex clathrate, and 0.451 mg levomefolate calcium
7 light orange tablets each containing 0.451 mg levomefolate calcium

The inactive ingredients in the orange tablets are lactose monohydrate NF, microcrystalline cellulose NF, croscarmellose sodium NF, hydroxypropyl cellulose USP, magnesium stearate NF, hypromellose USP, titanium dioxide USP, talc USP, polyethylene glycol NF, ferric oxide pigment, yellow NF, and ferric oxide pigment, red NF. The light orange film-coated tablets contain 0.451 mg of levomefolate calcium. The inactive ingredients in the light orange tablets are lactose monohydrate NF, microcrystalline cellulose NF, croscarmellose sodium NF, hydroxypropyl cellulose NF, magnesium stearate NF, hypromellose USP, titanium dioxide USP, talc USP, polyethylene glycol NF and ferric oxide pigment, yellow NF, and ferric oxide pigment, red NF.

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 .

Levomefolate calcium (N-[4-[[(2-amino-1,4,5,6,7,8-hexahydro-5-methyl-4-oxo-(6S)-pteridinyl)methyl]amino]benzoyl]-L-glutamic acid, calcium salt) is a synthetic calcium salt of L-5-methyltetrahydrofolate (L-5-methyl-THF), which is a metabolite of vitamin B9 and has a molecular weight of 497.5 and a molecular formula of C20 H23 CaN7 O6.

The structural formulas are as follows:

structural formula
(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.

12.2 Pharmacodynamics

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

Contraception

No specific pharmacodynamic studies were conducted with Safyral.

Folate Supplementation

Two studies evaluated the impact of Safyral on plasma folate and red blood cell (RBC) folate levels. A randomized, double-blind, active-controlled, parallel group study compared plasma folate and RBC folate levels during a 24-week treatment with 3 mg DRSP/0.02 mg EE (YAZ)+0.451 mg levomefolate calcium as compared to YAZ alone in a U.S. population. The pharmacodynamic effect on plasma folate, RBC folate, and the profile of circulating folate metabolites was assessed during 24 weeks of treatment with 0.451 mg levomefolate calcium or with 0.4 mg folic acid (equimolar dose to 0.451 mg levomefolate calcium), both in combination with 3 mg DRSP/0.03 mg EE (Yasmin) followed by 20 weeks of open-label treatment with Yasmin only (elimination phase). [See Clinical Studies, (14.2).]

12.3 Pharmacokinetics

Absorption

Safyral and Yasmin are bioequivalent with respect to DRSP and EE.

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 Safyral, which is a combination tablet of DRSP and EE stabilized by betadex as a clathrate (molecular inclusion complex), has not been evaluated. The bioavailability of EE is similar when dosed via a betadex clathrate formulation compared to when it is dosed as a free steroid. Serum concentrations of DRSP and EE reached peak levels within 1–2 hours after administration of Safyral.

The pharmacokinetics of DRSP are dose proportional following single doses ranging from 1-10 mg. Following daily dosing of Yasmin, 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 Yasmin (see Table 3).

For EE, steady-state conditions are reported during the second half of a treatment cycle. Following daily administration of Yasmin serum Cmax and AUC (0-24h) values of EE accumulate by a factor of about 1.5 to 2 (see Table 3).

Levomefolate calcium is structurally identical to L-5-methyltetrahydrofolate (L-5-methyl-THF), a metabolite of vitamin B9 . Mean baseline concentrations of about 15 nmol/L are reached in populations without folate food fortification under normal nutritional conditions. Orally administered levomefolate calcium is absorbed and is incorporated into the body folate pool. Peak plasma concentrations of about 50 nmol/L above baseline are reached within 0.5–1.5 hours after single oral administration of 0.451 mg levomefolate calcium.

Steady state conditions for total folate in plasma after intake of 0.451 mg levomefolate calcium are reached after about 8–16 weeks depending on the baseline levels. In red blood cells achievement of steady state is delayed due to the long life-span of red blood cells of about 120 days.

Table 3: 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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