Drospirenone, Ethinyl Estradiol and Levomefolate

The following serious adverse reactions with the use of COCs are discussed elsewhere in the labeling:

Adverse reactions commonly reported by COC users are:

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared to rates in other clinical trials and may not reflect the rates observed in practice.

Contraception and Folate Supplementation Clinical Trials

The data provided reflect the experience with the use of Yasmin (3 mg DRSP/0.03 mg EE) in the adequate and well-controlled studies for contraception (N=2,837) and folate supplementation (N=172). For contraception, the US pivotal clinical study (N=326) for the oral contraception indication for Yasmin was a multicenter, open-label trial in healthy women aged 18 -35 who were treated with Yasmin for up to 13 cycles. The second contraceptive pivotal study (N=442) was a multicenter, randomized, open-label comparative European study of Yasmin vs. 0.150 mg desogestrel/0.03 mg EE conducted in healthy women aged 17-40 who were treated for up to 26 cycles. The primary efficacy study using Drospirenone/Ethinyl Estradiol/Levomefolate Calcium and Levomefolate Calcium for folate supplementation was a randomized, single-center European trial in 172 healthy, female subjects aged 18-40 years comparing the pharmacodynamic effects of Yasmin + 0.451 mg levomefolate calcium to Yasmin co-administered with folic acid during 24 weeks of treatment followed by 20 weeks of open-label Yasmin.

The adverse reactions seen across the 2 indications overlapped and are reported using the frequencies from the pooled dataset. The most common adverse reactions (≥ 2% of users) were: premenstrual syndrome (12.4%), headache/migraine (10.3%), breast pain/tenderness/discomfort (8.1%), nausea/vomiting (4.4%), mood changes (depression, depressed mood, irritability, mood swings, mood altered and affect lability (2.3%), and abdominal pain/discomfort/tenderness (2.2%).

Adverse Reactions (≥ 1%) Leading to Study Discontinuation

Contraception Clinical Trials

Of 2,837 women, 6.7% discontinued from the clinical trials due to an adverse reaction; the most frequent adverse reaction leading to discontinuation was headache/migraine (1.5%).

Folate Clinical Trial

There were no subjects who discontinued due to an adverse reaction.

Serious Adverse Reactions:

Contraception Clinical Trials: depression, pulmonary embolism, toxic skin eruption, and uterine leiomyoma.

Folate Supplementation Clinical Trial: none reported in the clinical trial

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of Yasmin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Adverse reactions, including fatalities, are grouped into System Organ Classes and ordered by frequency.

Vascular disorders: Venous and arterial thromboembolic events (including pulmonary emboli, deep vein thrombosis, intracardiac thrombosis, intracranial venous sinus thrombosis, sagittal sinus thrombosis, retinal vein occlusion, myocardial infarction and stroke), hypertension

Hepatobiliary disorders: Gallbladder disease

Immune system disorders: Hypersensitivity

Metabolism and nutrition disorders: Hyperkalemia

Skin and subcutaneous tissue disorders: Chloasma

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 antimineralocorticoid 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 Drospirenone/Ethinyl Estradiol/Levomefolate Calcium and Levomefolate Calcium) were well tolerated after long-term treatment up to 12 weeks.

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.

Pharmacodynamics

Drospirenone is a spironolactone analogue with antimineralocorticoid activity. The estrogen in Drospirenone/Ethinyl Estradiol/Levomefolate Calcium is ethinyl estradiol (EE).

Contraception

No specific pharmacodynamic studies were conducted with Drospirenone/Ethinyl Estradiol/Levomefolate Calcium and Levomefolate Calcium.

Folate Supplementation

Two studies evaluated the impact of Drospirenone/Ethinyl Estradiol/Levomefolate Calcium and Levomefolate Calcium 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).]

Pharmacokinetics

Absorption

Drospirenone/Ethinyl Estradiol/Levomefolate Calcium and Levomefolate Calcium 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 Drospirenone/Ethinyl Estradiol/Levomefolate Calcium and Levomefolate Calcium, 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 Drospirenone/Ethinyl Estradiol/Levomefolate Calcium and Levomefolate Calcium.

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 2).

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 2).

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.

NA – Not available

Food Effect

The rate of absorption of DRSP and EE following single administration of a formulation similar to Drospirenone/Ethinyl Estradiol/Levomefolate Calcium and Levomefolate Calcium was slower under fed (high fat meal) 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.

The effect of food on absorption of levomefolate calcium following administration of Drospirenone/Ethinyl Estradiol/Levomefolate Calcium and Levomefolate Calcium has not been evaluated.

Distribution

DRSP and EE serum concentrations 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 concentrations). 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.

Biphasic kinetics is reported for folates with a fast- and a slow-turnover pool. The fast-turnover pool, probably reflecting newly absorbed folate, is consistent with the terminal half-life of approximately 4-5 hours after single oral administration of 0.451 mg levomefolate calcium. The slow-turnover pool reflecting turnover of folate polyglutamate has a mean residence time of greater than or equal to 100 days.

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 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 is 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.

L-5-methyl-THF is the predominant folate transport form in blood under physiological conditions and during folic acid and levomefolate calcium administration.

Excretion

DRSP serum concentrations 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.

L-5-methyl-THF is eliminated from the body by urinary excretion of intact folates and catabolic products as well as fecal excretion through a biphasic kinetics process.

Use in Specific Populations

Pediatric Use: Safety and efficacy of Drospirenone/Ethinyl Estradiol/Levomefolate Calcium and Levomefolate Calcium 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.

Geriatric Use: Drospirenone/Ethinyl Estradiol/Levomefolate Calcium and Levomefolate Calcium has not been studied in postmenopausal women and is not indicated in this population.

Race: No clinically significant difference was observed between the pharmacokinetics of DRSP or EE in Japanese versus Caucasian women (age 25-35) when 3 mg DRSP/0.02 mg EE was administered daily for 21 days. Other ethnic groups have not been specifically studied.

Renal Impairment: Drospirenone/Ethinyl Estradiol/Levomefolate Calcium and Levomefolate Calcium is contraindicated in patients with renal impairment.

The effect of renal impairment on the pharmacokinetics of DRSP (3 mg daily for 14 days) and the effect of DRSP on serum potassium concentrations were investigated in three separate groups of female subjects (n=28, age 30-65). All subjects were on a low potassium diet. During the study, 7 subjects continued the use of potassium-sparing drugs for the treatment of their underlying illness. On the 14th day (steady-state) of DRSP treatment, the serum DRSP concentrations in the group with CLcr of 50–79 mL/min were comparable to those in the control group with CLcr ≥ 80 mL/min. The serum DRSP concentrations were on average 37% higher in the group with CLcr of 30–49 mL/min compared to those in the control group. 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 concentrations increased by up to 0.33 mEq/L. [See Contraindications (4) and Warnings and Precautions (5.2).]

Hepatic Impairment: Drospirenone/Ethinyl Estradiol/Levomefolate Calcium and Levomefolate Calcium is contraindicated in patients with hepatic disease.

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. Drospirenone/Ethinyl Estradiol/Levomefolate Calcium and Levomefolate Calcium has not been studied in women with severe hepatic impairment. [See Contraindications (4) and Warnings and Precautions (5.4).]

Drug Interactions

Consult the labeling of all concurrently used drugs to obtain further information about interactions with oral contraceptives or the potential for enzyme alterations.

Effects of Other Drugs on Combined Oral Contraceptives

Substances diminishing the efficacy of COCs: Drugs or herbal products that induce certain enzymes, including CYP3A4, may decrease the effectiveness of COCs or increase breakthrough bleeding.

Substances increasing the plasma concentrations of COCs:Co-administration of atorvastatin with certain COCs containing ethinyl estradiol increase AUC values for ethinyl estradiol by approximately 20%. Ascorbic acid and acetaminophen may increase plasma ethinyl estradiol concentrations, possibly by inhibition of conjugation. CYP3A4 inhibitors such as itraconazole or ketoconazole may increase plasma hormone concentrations.

HIV/HCV protease inhibitors and non-nucleoside reverse transcriptase inhibitors:Significant changes (increase or decrease) in the plasma concentrations of estrogen and progestin have been noted in some cases of co-administration with HIV/HCV protease inhibitors or with non-nucleoside reverse transcriptase inhibitors.

Antibiotics: There have been reports of pregnancy while taking hormonal contraceptives and antibiotics, but clinical pharmacokinetic studies have not shown consistent effects of antibiotics on plasma concentrations of synthetic steroids.

Effects of Combined Oral Contraceptives on Other Drugs

COCs containing ethinyl estradiol may inhibit the metabolism of other compounds. COCs have been shown to significantly decrease plasma concentrations of lamotrigine, likely due to induction of lamotrigine glucuronidation. This may reduce seizure control; therefore, dosage adjustments of lamotrigine may be necessary. Consult the labeling of the concurrently-used drug to obtain further information about interactions with COCs or the potential for enzyme alterations.

Metabolism of DRSP and potential effects of DRSP on hepatic CYP enzymes have been investigated in in vitro and in vivo studies. In in vitro studies DRSP did not affect turnover of model substrates of CYP1A2 and CYP2D6, but had an inhibitory influence on the turnover of model substrates of CYP1A1, CYP2C9, CYP2C19, and CYP3A4, with CYP2C19 being the most sensitive enzyme. The potential effect of DRSP on CYP2C19 activity was investigated in a clinical pharmacokinetic study using omeprazole as a marker substrate. In the study with 24 postmenopausal women [including 12 women with homozygous (wild type) CYP2C19 genotype and 12 women with heterozygous CYP2C19 genotype] the daily oral administration of 3 mg DRSP for 14 days did not affect the oral clearance of omeprazole (40 mg, single oral dose) and the CYP2C19 product 5-hydroxy omeprazole. Furthermore, no significant effect of DRSP on the systemic clearance of the CYP3A4 product omeprazole sulfone was found. These results demonstrate that DRSP did not inhibit CYP2C19 and CYP3A4 in vivo.

Two additional clinical drug-drug interaction studies using simvastatin and midazolam as marker substrates for CYP3A4 were each performed in 24 healthy postmenopausal women. The results of these studies demonstrated that pharmacokinetics of the CYP3A4 substrates were not influenced by steady state DRSP concentrations achieved after administration of 3 mg DRSP/day.

Women on thyroid hormone replacement therapy may need increased doses of thyroid hormone because serum concentration of thyroid-binding globulin increases with use of COCs.

Interactions With Drugs That Have the Potential to Increase Serum Potassium Concentration: There is a potential for an increase in serum potassium concentration in women taking Drospirenone/Ethinyl Estradiol/Levomefolate Calcium and Levomefolate Calcium with other drugs that may increase serum potassium concentration [see Warnings and Precautions (5.2)].

A drug-drug interaction study of DRSP 3 mg/estradiol (E2) 1 mg versus placebo was performed in 24 mildly hypertensive postmenopausal women taking enalapril maleate 10 mg twice daily. Potassium concentrations were obtained every other day for a total of 2 weeks in all subjects. Mean serum potassium concentrations in the DRSP/E2 treatment group relative to baseline were 0.22 mEq/L higher than those in the placebo group. Serum potassium concentrations also were measured at multiple time points over 24 hours at baseline and on Day 14. On Day 14, the ratios for serum potassium Cmax and AUC in the DRSP/E2 group to those in the placebo group were 0.955 (90% CI: 0.914, 0.999) and 1.010 (90% CI: 0.944, 1.08), respectively. No patient in either treatment group developed hyperkalemia (serum potassium concentrations >5.5 mEq/L).

Effects of Folates on Other Drugs

There is a potential that folates such as folic acid and levomefolate calcium may modify the pharmacokinetics or pharmacodynamics of certain antifolate drugs (e.g., antiepileptics, methotrexate).

Effects of other Drugs on Folate

Several drugs (e.g., methotrexate, sulfasalazine, cholestyramine, antiepileptics) have been reported to reduce folate concentrations.

Carcinogenesis, Mutagenesis, Impairment of Fertility

In a 24 month oral carcinogenicity study in mice dosed with 10 mg/kg/day DRSP alone or 1 + 0.01, 3 + 0.03 and 10 + 0.1 mg/kg/day of DRSP and EE, 0.1 to 2 times the exposure (AUC of DRSP) of women taking a contraceptive dose, there was an increase in carcinomas of the harderian gland in the group that received the high dose of DRSP alone. In a similar study in rats given 10 mg/kg/day DRSP alone or 0.3 + 0.003, 3 + 0.03 and 10 + 0.1 mg/kg/day DRSP and EE, 0.8 to
10 times the exposure of women taking a contraceptive dose, there was an increased incidence of benign and total (benign and malignant) adrenal gland pheochromocytomas in the group receiving the high dose of DRSP. Mutagenesis studies for DRSP were conducted in vivo and in vitro and no evidence of mutagenic activity was observed.

Long-term animal studies have not been conducted to evaluate the carcinogenic potential of levomefolate. Mutagenesis studies for levomefolate were conducted in vitro and in vivo and no evidence of mutagenic activity was observed.

Follow all directions on your prescription label. Do not take this medicine in larger or smaller amounts or for longer than recommended. You will take your first pill on the first day of your period or on the first Sunday after your period begins. You may need to use back-up birth control (such as condoms and spermicides) when you first start using this medicine. Follow your doctor's instructions.

Take one pill every day, no more than 24 hours apart. When the pills run out, start a new pack the following day. You could get pregnant if you do not take one pill daily. Get your prescription refilled before you run out of pills completely.

You must take the pills in the right order for this medicine to be effective in preventing pregnancy. Follow the arrows shown on each row of pills in your blister pack. The last few pills you will take contain only levomefolate and not the contraceptive (birth control) medicines.

You may have breakthrough bleeding, especially during the first 3 months. Tell your doctor if this bleeding continues or is very heavy.

Use back-up birth control if you are sick with severe vomiting or diarrhea.

If you need surgery or medical tests or if you will be on bed rest, you may need to stop using this medicine for a short time. Any doctor or surgeon who treats you should know that you take birth control pills.

Store at room temperature away from moisture and heat.

Do not smoke while taking birth control pills, especially if you are older than 35 years of age.

Birth control pills will not protect you from sexually transmitted diseases, including HIV and AIDS. Using a condom is the only way to protect yourself from these diseases.

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For drospirenone, ethinyl estradiol, and levomefolate, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to drospirenone, ethinyl estradiol, and levomefolate or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Appropriate studies on the relationship of age to the effects of drospirenone, ethinyl estradiol, and levomefolate combination have not been performed in the pediatric population. However, pediatric-specific problems that would limit the usefulness of this medication in teenagers are not expected. drospirenone, ethinyl estradiol, and levomefolate may be used for birth control in teenage females but should not be used before the start of menstruation.

Geriatric

Appropriate studies on the relationship of age to the effects of drospirenone, ethinyl estradiol, and levomefolate combination have not been performed in the geriatric population. drospirenone, ethinyl estradiol, and levomefolate should not be used in elderly women.

Breast Feeding

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking drospirenone, ethinyl estradiol, and levomefolate, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using drospirenone, ethinyl estradiol, and levomefolate with any of the following medicines is not recommended. Your doctor may decide not to treat you with this medication or change some of the other medicines you take.

• Boceprevir
• Dasabuvir
• Ombitasvir
• Paritaprevir
• Ritonavir
• Tranexamic Acid

Using drospirenone, ethinyl estradiol, and levomefolate with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Anagrelide
• Aprepitant
• Boceprevir
• Bosentan
• Bupropion
• Carbamazepine
• Ceritinib
• Dabrafenib
• Darunavir
• Dexamethasone
• Donepezil
• Eliglustat
• Enzalutamide
• Fosphenytoin
• Griseofulvin
• Idelalisib
• Isotretinoin
• Lesinurad
• Lixisenatide
• Lumacaftor
• Mitotane
• Modafinil
• Oxcarbazepine
• Paclitaxel
• Paclitaxel Protein-Bound
• Phenytoin
• Piperaquine
• Pitolisant
• Prednisone
• Rifabutin
• Rifampin
• St John's Wort
• Sugammadex
• Theophylline
• Tizanidine
• Topiramate
• Ulipristal
• Valproic Acid

Using drospirenone, ethinyl estradiol, and levomefolate with any of the following medicines may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Alprazolam
• Amprenavir
• Atazanavir
• Bacampicillin
• Betamethasone
• Bexarotene
• Clarithromycin
• Colesevelam
• Cyclosporine
• Delavirdine
• Efavirenz
• Eslicarbazepine Acetate
• Etoricoxib
• Fosamprenavir
• Fosaprepitant
• Ginseng
• Lamotrigine
• Licorice
• Mycophenolate Mofetil
• Mycophenolic Acid
• Nelfinavir
• Parecoxib
• Prednisolone
• Rifapentine
• Ritonavir
• Roflumilast
• Rosuvastatin
• Rufinamide
• Selegiline
• Telaprevir
• Tipranavir
• Troglitazone
• Troleandomycin
• Valdecoxib
• Voriconazole
• Warfarin

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using drospirenone, ethinyl estradiol, and levomefolate with any of the following may cause an increased risk of certain side effects but may be unavoidable in some cases. If used together, your doctor may change the dose or how often you use drospirenone, ethinyl estradiol, and levomefolate, or give you special instructions about the use of food, alcohol, or tobacco.

• Caffeine
• Grapefruit Juice

Other Medical Problems

The presence of other medical problems may affect the use of drospirenone, ethinyl estradiol, and levomefolate. Make sure you tell your doctor if you have any other medical problems, especially:

• Abnormal or unusual vaginal bleeding or
• Adrenal disease or
• Blood disorders (e.g., hypercoagulopathy) or
• Breast cancer, active or history of or
• Diabetes with kidney, eye, nerve, or blood vessel damage or
• Heart attack, history of or
• Heart or blood vessel disease (e.g., coronary artery disease) or
• Heart rhythm problems or
• Hypertension (high blood pressure), uncontrolled or
• Kidney disease or
• Liver disease, including tumors or cancer or
• Migraine headache, new or worse or a new kind of headache or
• Problems with circulation or blood clots, now or in the past or
• Problems with heart valves or
• Stroke, history of—Should not be used in patients with these conditions.

• Angioedema (swelling of the face, tongue, or throat), inherited or
• Chloasma gravidarum (skin disorder during pregnancy), history of or
• Cholestasis (bile problem) during pregnancy, history of or
• Depression, history of or
• Diabetes or
• Dyslipidemia (high cholesterol or fats in the blood), uncontrolled or
• Gallbladder disease or
• Hyperkalemia (high potassium in the blood) or
• Hypertension (high blood pressure), controlled—Use with caution. May make these conditions worse.

Applies to drospirenone / ethinyl estradiol / levomefolate calcium: oral tablet

Cardiovascular

Cardiovascular side effects have included hypertension, arterial or deep venous thrombotic events, strokes, and myocardial infarctions.[Ref]

Genitourinary

Genitourinary side effects have included breast tenderness, decreased libido, unscheduled (breakthrough or intracyclic) bleeding and spotting.

Gastrointestinal

Gastrointestinal side effects have included nausea, vomiting, and inflammatory bowel disease.[Ref]

Hepatic

Hepatic side effects have included jaundice, cholestasis and hepatic adenomas.[Ref]

Metabolic

Metabolic side effects have included gallbladder disease, liver function disturbances, liver tumors, hyperkalemia, hypertriglyceridemia, changes in glucose tolerance, and effect on peripheral insulin resistance (including diabetes mellitus).[Ref]

Nervous system

Nervous system side effects have included an increase in frequency or severity of migraine headaches.[Ref]

Ocular

Ocular side effects have included loss of vision, proptosis, diplopia, papilledema, or retinal vascular lesions.[Ref]

Psychiatric

Psychiatric side effects have included irritability, depression and affect lability.[Ref]

Oncologic

Oncologic side effects have included carcinoma of the breasts and reproductive organs.[Ref]

Musculoskeletal

Musculoskeletal side effects have included systemic lupus erythematosus.[Ref]

Dermatologic

Dermatologic side effects have included chloasma, angioedema, erythema nodosum, and erythema multiforme.[Ref]

Hypersensitivity

Hypersensitivity side effects have included anaphylactic reaction.[Ref]

Some side effects of drospirenone / ethinyl estradiol / levomefolate calcium may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

1 tablet orally each day. A patient should begin taking either on the first day of the menstrual period (Day 1 Start) or on the first Sunday after the onset of the menstrual period (Sunday Start). The patient should begin the next and all subsequent 28-day regimens on the same day of the week as she began the first regimen, following the same schedule.

Data not available