Safyral (Page 5 of 10)

7.3 Concomitant Use with HCV Combination Therapy – Liver Enzyme Elevation

Do not co-administer Safyral with HCV drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, due to potential for ALT elevations [see Warnings and Precautions (5.5)].

7.4 Effects of Folates on Other Drugs

Folates may modify the pharmacokinetics or pharmacodynamics of certain antifolate drugs, e.g., antiepileptics (such as phenytoin), methotrexate or pyrimethamine, and may result in a decreased pharmacological effect of the antifolate drug.

7.5 Effects of Other Drugs on Folates

Several drugs have been reported to reduce folate concentrations by inhibition of the dihydrofolate reductase enzyme (e.g., methotrexate and sulfasalazine) or by reducing folate absorption (e.g., cholestyramine), or via unknown mechanisms (e.g., antiepileptics such as carbamazepine, phenytoin, phenobarbital, primidone and valproic acid).

7.6 Interference with Laboratory Tests

The use of contraceptive steroids may influence the results of certain laboratory tests, such as coagulation factors, lipids, glucose tolerance, and binding proteins. DRSP causes an increase in plasma renin activity and plasma aldosterone induced by its mild anti-mineralocorticoid activity. Folates may mask vitamin B12 deficiency. [See Warnings and Precautions (5.13) and Drug Interactions (7.2).]

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

There is little or no increased risk of birth defects in women who inadvertently use COCs during early pregnancy. Epidemiologic studies and meta-analyses have not found an increased risk of genital or non-genital birth defects (including cardiac anomalies and limb-reduction defects) following exposure to low dose COCs prior to conception or during early pregnancy.

The administration of COCs to induce withdrawal bleeding should not be used as a test for pregnancy. COCs should not be used during pregnancy to treat threatened or habitual abortion.

Women who do not breastfeed may start COCs no earlier than four weeks postpartum.

8.3 Nursing Mothers

When possible, advise the nursing mother to use other forms of contraception until she has weaned her child. Estrogen-containing COCs can reduce milk production in breastfeeding mothers. This is less likely to occur once breastfeeding is well-established; however, it can occur at any time in some women. Small amounts of oral contraceptive steroids and/or metabolites are present in breast milk.

After oral administration of 3 mg DRSP/0.03 mg EE tablets (Yasmin), about 0.02% of the DRSP dose was excreted into the breast milk of postpartum women within 24 hours. This results in a maximal daily dose of about 0.003 mg DRSP in an infant.

Studies to date indicate there is no adverse effect of folate on nursing infants.

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)

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