Delsia

Drospirenone, ethinylestradiol.

Each film-coated tablet contains Drospirenone 3 mg, Ethinyl estradiol 0.03 mg.
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 g/mol and a molecular formula of C₂₄H₃₀O₃.
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 g/mol and a molecular formula of C₂₀H₂₄O₂.

Pharmacology: Pharmacodynamics: Drospirenone is a spironolactone analogue with anti-mineralocorticoid activity. The estrogen in DELSIA is ethinyl estradiol.
No specific pharmacodynamic studies were reported with drospirenone 3 mg and ethinyl estradiol 0.03 mg tablets.
Mechanism of action: Combined oral contraceptives (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.
Pharmacokinetics: Absorption: The absolute bioavailability of drospirenone from a single entity tablet is about 76%. The absolute bioavailability of ethinyl estradiol is approximately 40% as a result of presystemic conjugation and first-pass metabolism. The absolute bioavailability of combination tablet of drospirenone and ethinyl estradiol has not been reported. Serum concentrations of drospirenone and ethinyl estradiol have been reported to reach peak levels within 1-2 hours after administration of drospirenone 3 mg and ethinyl estradiol 0.03 mg combination.
The pharmacokinetics of drospirenone are dose proportional following single doses ranging from 1-10 mg. Following daily dosing of drospirenone 3 mg and ethinyl estradiol 0.03 mg combination, steady state drospirenone concentrations were reported after 8 days. There was about 2 to 3 fold accumulation in serum C_max and AUC_(0-24h) values of drospirenone following multiple dose administration of drospirenone 3 mg and ethinyl estradiol 0.03 mg combination (see table as follows).
For ethinyl estradiol, steady-state conditions are reported during the second half of a treatment cycle. Following daily administration of drospirenone 3 mg and ethinyl estradiol 0.03 mg combination serum C_max and AUC_(0-24h) values of ethinyl estradiol accumulate by a factor of about 1.5 to 2 (see table as follows).

Click on icon to see table/diagram/image

Food Effect: The rate of absorption of drospirenone and ethinyl estradiol following single administration of a formulation similar to drospirenone 3 mg and ethinyl estradiol 0.03 mg combination was reported to be slower under fed (high fat meal) conditions with the serum C_max being reduced about 40% for both components. The extent of absorption of drospirenone, however, remained unchanged. In contrast, the extent of absorption of ethinyl estradiol was reported to be reduced by about 20% under fed conditions.
Distribution: Drospirenone and ethinyl estradiol serum concentrations decline in two phases. The reported apparent volume of distribution of drospirenone is approximately 4 L/kg and that of ethinyl estradiol is approximately 4-5 L/kg.
Drospirenone does not bind to sex hormone binding globulin (SHBG) or corticosteroid binding globulin (CBG) but binds about 97% to other serum proteins. It has been reported that multiple dosing over 3 cycles resulted in no change in the free fraction (as measured at trough concentrations). Ethinyl estradiol 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. Ethinyl estradiol induced effects on SHBG and CBG were not reported to be affected by variation of the drospirenone dosage in the range of 2 to 3 mg.
Metabolism: The two main metabolites of drospirenone found in human plasma were reported to be the acid form of drospirenone generated by opening of the lactone ring and the 4,5-dihydrodrospirenone-3-sulfate, formed by reduction and subsequent sulfation. These metabolites were reported not to be pharmacologically active. Drospirenone is also subject to oxidative metabolism catalyzed by CYP3A4.
Ethinyl estradiol has been reported to be subject to significant gut and hepatic first-pass metabolism. Metabolism of ethinyl estradiol and its oxidative metabolites occur primarily by conjugation with glucuronide or 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.
Excretion: Drospirenone serum concentrations are characterized by a terminal disposition phase half-life of approximately 30 hours after both single and multiple dose regimens. Excretion of drospirenone was reported to be nearly complete after ten days and amounts excreted were slightly higher in feces compared to urine. Drospirenone was extensively metabolized and only trace amounts of unchanged drospirenone were excreted in urine and feces. At least 20 different metabolites were reported in urine and feces. About 38-47% of the metabolites in urine were reported to be glucuronide and sulfate conjugates. In feces, about 17-20% of the metabolites were reported to be excreted as glucuronides and sulfates.
For ethinyl estradiol the terminal disposition phase half-life has been reported to be approximately 24 hours. Ethinyl estradiol is not excreted unchanged. Ethinyl estradiol is excreted in the urine and feces as glucuronide and sulfate conjugates and undergoes enterohepatic circulation.
Use in Specific Populations: Pediatric Use: Safety and efficacy of drospirenone 3 mg and ethinyl estradiol 0.03 mg combination has been reported 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: The effect of drospirenone 3 mg and ethinyl estradiol 0.03 mg combination has not been reported in postmenopausal women and is not indicated in this population.
Race: No clinically significant difference was reported between the pharmacokinetics of drospirenone or ethinyl estradiol in Japanese versus Caucasian women (age 25-35) when 3 mg drospirenone/0.02 mg ethinyl estradiol was administered daily for 21 days. The effect in other ethnic groups has not been specifically reported.
Renal Impairment: Drospirenone 3 mg and ethinyl estradiol 0.03 mg combination is contraindicated in patients with renal impairment.
The effect of renal impairment on the pharmacokinetics of drospirenone (3 mg daily for 14 days) and the effect of drospirenone on serum potassium concentrations has been reported in females aged 30-65 years. All females were on a low potassium diet. During the reported study, the subjects continued the use of potassium-sparing drugs for the treatment of their underlying illness. On the 14th day (steady-state) of drospirenone treatment, the serum drospirenone concentrations in the group with CL_cr of 50-79 mL/min were reported to be comparable to those in the control group with CL_cr ≥ 80 mL/min. The serum drospirenone concentrations were reported to be on average 37% higher in the group with CL_cr of 30-49 mL/min compared to those in the control group. Drospirenone treatment did not reportedly show any clinically significant effect on serum potassium concentration. Although hyperkalemia was not reported, mean serum potassium concentrations were reported to increase by up to 0.33 mEq/L in subjects who continued use of potassium sparing drugs (see CONTRAINDICATIONS and PRECAUTIONS).
Hepatic Impairment: Drospirenone 3 mg and ethinyl estradiol 0.03 mg combination is contraindicated in patients with hepatic disease.
The mean exposure to drospirenone in women with moderate liver impairment is reported to be approximately three times higher than the exposure in women with normal liver function. The effect of drospirenone 3 mg and ethinyl estradiol 0.03 mg combination has not been reported in women with severe hepatic impairment (see CONTRAINDICATIONS and PRECAUTIONS).

DELSIA is indicated for use by women to prevent pregnancy.

RECOMMENDED DOSE: How to Start DELSIA: Instruct the patient to begin taking DELSIA either on the first day of her menstrual period (Day 1 Start) or on the first Sunday after the onset of her menstrual period (Sunday Start).
Day 1 Start: During the first cycle of DELSIA use, instruct the patient to take one yellow DELSIA daily, beginning on Day 1 of her menstrual cycle (the first day of menstruation is Day 1). She should take one yellow DELSIA daily for 21 consecutive days, followed by a 7-day tablet-free interval. DELSIA should be taken in the order directed on the package at the same time each day, preferably after the evening meal or at bedtime with some liquid, as needed. DELSIA can be taken without regard to meals. If DELSIA is first taken later than the first day of the menstrual cycle, it should not be considered effective as a contraceptive until after the first 7 consecutive days of product administration. Instruct the patient to use a non-hormonal contraceptive as back-up during the first 7 days. The possibility of ovulation and conception prior to initiation of medication should be considered.
Sunday Start: During the first cycle of DELSIA use, instruct the patient to take one yellow DELSIA daily, beginning on the first Sunday after the onset of her menstrual period. She should take one yellow DELSIA daily for 21 consecutive days, followed by 7-day-free interval. DELSIA should be taken in the order directed on the package at the same time each day, preferably after the evening meal or at bedtime with some liquid, as needed. DELSIA can be taken without regard to meals. DELSIA should not be considered effective as a contraceptive until after the first 7 consecutive days of product administration. Instruct the patient to use a non-hormonal contraceptive as back-up during the first 7 days. The possibility of ovulation and conception prior to initiation of medication should be considered.
The patient should begin her next and all subsequent 21-day regimens of DELSIA on the same day of the week that she began her first regimen, following the same schedule. She should begin taking her yellow tablets on the next day after 7-day tablet-free interval, regardless of whether or not a menstrual period has occurred or is still in progress. Anytime a subsequent cycle of DELSIA is started later than the day following a 7-day tablet-free interval, the patient should use another method of contraception until she has taken a yellow DELSIA daily for seven consecutive days.
When switching from a different birth control pill: When switching from another birth control pill, DELSIA should be started on the same day that a new pack of the previous oral contraceptive would have been started.
When switching from a method other than a birth control pill: When switching from a transdermal patch or vaginal ring, DELSIA should be started when the next application would have been due. When switching from an injection, DELSIA should be started when the next dose would have been due. When switching from an intrauterine contraceptive or an implant, DELSIA should be started on the day of removal.
Withdrawal bleeding usually occurs within 3 days following the last yellow tablet. If spotting or breakthrough bleeding occurs while taking DELSIA, instruct the patient to continue taking DELSIA by the regimen described as previously mentioned. Counsel her that this type of bleeding is usually transient and without significance; however, advise her that if the bleeding is persistent or prolonged, she should consult her healthcare provider.
Although the occurrence of pregnancy is low if DELSIA is taken according to directions, if withdrawal bleeding does not occur, consider the possibility of pregnancy. If the patient has not adhered to the prescribed dosing schedule (missed one or more active yellow tablets or started taking them on a day later than she should have), consider the possibility of pregnancy at the time of the first missed period and take appropriate diagnostic measures. If the patient has adhered to the prescribed regimen and misses two consecutive periods, rule out pregnancy. Discontinue DELSIA if pregnancy is confirmed.
The risk of pregnancy increases with each active yellow tablet missed. If breakthrough bleeding occurs following missed tablets, it will usually be transient and of no consequence.
For postpartum women who do not breastfeed or after a second trimester abortion, start DELSIA no earlier than 4 weeks postpartum due to the increased risk of thromboembolism. If the patient starts DELSIA postpartum and has not yet had a period, evaluate for possible pregnancy, and instruct her to use an additional method of contraception until she has taken DELSIA for 7 consecutive days.
Advice in Case of Gastrointestinal Disturbances: In case of severe vomiting or diarrhea, absorption may not be complete and additional contraceptive measures should be taken. If vomiting occurs within 3-4 hours after tablet-taking, this can be regarded as a missed tablet.
MODE OF ADMINISTRATION: How to Take DELSIA: Take one tablet by mouth at the same time every day. The failure rate may increase when pills are missed or taken incorrectly.
To achieve maximum contraceptive effectiveness, DELSIA must be taken as directed, in the order directed on the blister pack. Single missed pills should be taken as soon as remembered.

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

Do not prescribe DELSIA to women who are known to have the following: Renal impairment; Adrenal insufficiency; A high risk of arterial or venous thrombotic diseases. Examples include women who are known to: Smoke, if over age 35 years (see PRECAUTIONS); Have deep vein thrombosis or pulmonary embolism, now or in the past (see PRECAUTIONS); Have cerebrovascular disease (see PRECAUTIONS); Have coronary artery disease (see PRECAUTIONS); Have thrombogenic valvular or thrombogenic rhythm diseases of the heart (for example, subacute bacterial endocarditis with valvular disease, or atrial fibrillation) (see PRECAUTIONS); Have inherited or acquired hypercoagulopathies (see PRECAUTIONS); Have uncontrolled hypertension (see PRECAUTIONS); Have diabetes mellitus with vascular disease (see PRECAUTIONS); Have headaches with focal neurological symptoms or have migraine headaches with or without aura if over age 35 years (see PRECAUTIONS).
Undiagnosed abnormal uterine bleeding (see PRECAUTIONS); Breast cancer or other estrogen- or progestin-sensitive cancer, now or in the past (see PRECAUTIONS); Liver tumor (benign or malignant) or liver disease (see PRECAUTIONS); Pregnancy, because there is no reason to use COCs during pregnancy (see PRECAUTIONS and USE IN PREGNANCY & LACTATION); Use of Hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir due to the potential for ALT elevations (see PRECAUTIONS and INTERACTIONS).

CIGARETTE SMOKING AND SERIOUS CARDIOVASCULAR EVENTS: Cigarette smoking increases the risk of serious cardiovascular events from combination oral contraceptives (COCs) use. This risk increases with age, particularly in women over 35 years of age, and with the number of cigarettes smoked. For this reason, COCs should not be used by women who are over 35 years of age and smoke (see CONTRAINDICATIONS).

Thromboembolic Disorders and Other Vascular Problems: Stop drospirenone 3 mg and ethinyl estradiol 0.03 mg combination if an arterial or venous thrombotic event occurs. Drospirenone-containing COCs may be associated with a higher risk of venous thromboembolism (VTE) than COCs containing the progestin levonorgestrel or some other progestins. The risk of VTE has been reported to range from no increase to a three-fold increase. Before initiating use of drospirenone 3 mg and ethinyl estradiol 0.03 mg combination in a new COCs user or a woman who is switching from a contraceptive that does not contain drospirenone, consider the risks and benefits of a drospirenone-containing COCs in light of her risk of a VTE. Known risk factors for VTE include smoking, obesity, and family history of VTE, in addition to other factors that contraindicate use of COCs (see CONTRAINDICATIONS).
A number of reported studies have compared the risk of VTE for users of drospirenone 3 mg and ethinyl estradiol 0.03 mg combination to the risk for users of other COCs, including COCs containing levonorgestrel.
Although the absolute VTE rates are increased for users of hormonal contraceptives compared to non-users, the rates during pregnancy are even greater, especially during the post-partum period. The risk of VTE in women using COCs has been estimated to be 3 to 9 per 10,000 woman-years. The risk of VTE is reported to be highest during the first year of use. This increased risk, as compared to that in non-COCs users, is reported to be greatest during the first 6 months of COCs use. The greatest risk of VTE is reported to be present after initially starting a COCs or restarting (following a 4 week or greater pill-free interval) the same or a different COCs.
The risk of thromboembolic disease due to oral contraceptives gradually disappears after COCs use is discontinued.
If feasible, stop drospirenone 3 mg and ethinyl estradiol 0.03 mg combination at least 4 weeks before and through 2 weeks after major surgery or other surgeries known to have an elevated risk of thromboembolism.
Start drospirenone 3 mg and ethinyl estradiol 0.03 mg combination no earlier than 4 weeks after delivery, in women who are not breastfeeding. The risk of postpartum thromboembolism decreases after the third postpartum week, whereas the risk of ovulation increases after the third postpartum week.
Use of COCs also increases the risk of arterial thromboses such as strokes and myocardial infarctions, especially in women with other risk factors for these events.
COCs have been reported to increase both the relative and attributable risks of cerebrovascular events (thrombotic and hemorrhagic strokes), although, in general, the risk is greatest among older (>35 years of age), hypertensive women who also smoke. COCs also increase the risk for stroke in women with other underlying risk factors.
Oral contraceptives must be used with caution in women with cardiovascular disease risk factors.
Stop drospirenone 3 mg and ethinyl estradiol 0.03 mg combination if there is unexplained loss of vision, proptosis, diplopia, papilledema, or retinal vascular lesions. Evaluate for retinal vein thrombosis immediately (see ADVERSE REACTIONS).
Hyperkalemia: Drospirenone 3 mg and ethinyl estradiol 0.03 mg combination contains 3 mg of the progestin drospirenone, which has anti-mineralocorticoid activity, including the potential for hyperkalemia in high-risk patients, comparable to a 25 mg dose of spironolactone. Drospirenone 3 mg and ethinyl estradiol 0.03 mg combination is contraindicated in patients with conditions that predispose to hyperkalemia (that is, renal impairment, hepatic impairment, and adrenal insufficiency). Women receiving daily, long-term treatment for chronic conditions or diseases with medications that may increase serum potassium concentration should have their serum potassium concentration checked during the first treatment cycle. Medications that may increase serum potassium concentration include ACE inhibitors, angiotensin-II receptor antagonists, potassium-sparing diuretics, potassium supplementation, heparin, aldosterone antagonists, and NSAIDs. Consider monitoring serum potassium concentration in high-risk patients who take a strong CYP3A4 inhibitor long-term and concomitantly. Strong CYP3A4 inhibitors include azole antifungals (e.g. ketoconazole, itraconazole, voriconazole), HIV/HCV protease inhibitors (e.g., indinavir, boceprevir), and clarithromycin (see INTERACTIONS).
Carcinoma of the Breasts and Reproductive Organs: Women who currently have or have had breast cancer should not use drospirenone 3 mg and ethinyl estradiol 0.03 mg combination because breast cancer is a hormonally-sensitive tumor. There is substantial reported evidence that COCs do not increase the incidence of breast cancer. Although some past studies have reported that COCs might increase the incidence of breast cancer, more recent studies have not confirmed such findings.
COCs are reported to be associated with an increase in the risk of cervical cancer or intraepithelial neoplasia. However, there is controversy about the extent to which these findings may be due to differences in sexual behavior and other factors.
Liver Disease: Discontinue drospirenone 3 mg and ethinyl estradiol 0.03 mg combination if jaundice develops. Steroid hormones may be poorly metabolized in patients with impaired liver function. Acute or chronic disturbances of liver function may necessitate the discontinuation of COCs use until markers of liver function return to normal and COCs causation has been excluded.
Hepatic adenomas are reported to be associated with COCs use. Rupture of hepatic adenomas may cause death through intra-abdominal hemorrhage.
An increased risk of developing hepatocellular carcinoma has been reported in long-term (> 8 years) COCs users. However, the attributable risk of liver cancers in COCs users is reported to be less than one case per million users.
Oral contraceptive-related cholestasis may occur in women with a history of pregnancy-related cholestasis. Women with a history of COCs-related cholestasis may have the condition recur with subsequent COCs use.
Risk of Liver Enzyme Elevations with Concomitant Hepatitis C Treatment: During reported clinical studies with the Hepatitis C combination drug regimen that contains ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, ALT elevations greater than 5 times the upper limit of normal (ULN), including some cases greater than 20 times the ULN, were significantly more frequent in women using ethinyl estradiol-containing medications, such as COCs. Discontinue drospirenone 3 mg and ethinyl estradiol 0.03 mg combination prior to starting therapy with the combination drug regimen ombitasvir/paritaprevir/ritonavir, with or without dasabuvir (see CONTRAINDICATIONS). Drospirenone 3 mg and ethinyl estradiol 0.03 mg combination can be restarted approximately 2 weeks following completion of treatment with the Hepatitis C combination drug regimen.
High Blood Pressure: For women with well-controlled hypertension, monitor blood pressure and stop drospirenone 3 mg and ethinyl estradiol 0.03 mg combination if blood pressure rises significantly. Women with uncontrolled hypertension or hypertension with vascular disease should not use COCs.
An increase in blood pressure has been reported in women taking COCs, and this increase is more likely in older women and with extended duration of use. The incidence of hypertension increases with increasing concentration of progestin.
Gallbladder Disease: A small increased relative risk of developing gallbladder disease has been reported among COCs users.
Carbohydrate and Lipid Metabolic Effects: Carefully monitor prediabetic and diabetic women who are taking drospirenone 3 mg and ethinyl estradiol 0.03 mg combination. COCs may decrease glucose tolerance in a dose-related fashion.
Consider alternative contraception for women with uncontrolled dyslipidemia. A small proportion of women will have adverse lipid changes while on COCs.
Women with hypertriglyceridemia, or a family history thereof, may be at an increased risk of pancreatitis when using COCs.
Headache: If a woman taking drospirenone 3 mg and ethinyl estradiol 0.03 mg combination develops new headaches that are recurrent, persistent, or severe, evaluate the cause and discontinue drospirenone 3 mg and ethinyl estradiol 0.03 mg combination if indicated.
An increase in frequency or severity of migraine during COCs use (which may be prodromal of a cerebrovascular event) may be a reason for immediate discontinuation of the COCs.
Bleeding Irregularities: Unscheduled (breakthrough or intracyclic) bleeding and spotting sometimes occur in patients on COCs, especially during the first three months of use. If bleeding persists or occurs after previously regular cycles, check for causes such as pregnancy or malignancy. If pathology and pregnancy are excluded, bleeding irregularities may resolve over time or with a change to a different COCs.
The percent of women who took drospirenone 3 mg and ethinyl estradiol 0.03 mg combination and experienced unscheduled bleeding has been reported to decrease over time from 12% at cycle 2 to 6% at cycle 13. <1% of the patients have been reported to discontinue due to bleeding complaints. These are described as metrorrhagia, vaginal hemorrhage, menorrhagia, abnormal withdrawal bleeding, and menometrorrhagia.
The average duration of scheduled bleeding episodes in the majority of subjects (86%-88%) was reported to be 4-7 days. Women who use drospirenone 3 mg and ethinyl estradiol 0.03 mg combination may experience absence of withdrawal bleeding, even if they are not pregnant. During cycles 2-13, 1-11% of women per cycle have been reported to experience no withdrawal bleeding. Some women may encounter post-pill amenorrhea or oligomenorrhea, especially when such a condition was pre-existent.
If withdrawal bleeding does not occur, consider the possibility of pregnancy. If the patient has not adhered to the prescribed dosing schedule (missed one or more active tablets or started taking them on a day later than she should have), consider the possibility of pregnancy at the time of the first missed period and take appropriate diagnostic measures. If the patient has adhered to the prescribed regimen and misses two consecutive periods, rule out pregnancy.
Depression: Women with a history of depression should be carefully observed and drospirenone 3 mg and ethinyl estradiol 0.03 mg combination discontinued if depression recurs to a serious degree.
Interference with Laboratory Tests: The use of COCs may change the results of some laboratory tests, such as coagulation factors, lipids, glucose tolerance, and binding proteins. Women on thyroid hormone replacement therapy may need increased doses of thyroid hormone because serum concentrations of thyroid-binding globulin increase with use of COCs (see INTERACTIONS).
Drospirenone has been reported to cause an increase in plasma renin activity and plasma aldosterone induced by its mild anti-mineralocorticoid activity.
Monitoring: A woman who is taking COCs should have a yearly visit with her healthcare provider for a blood pressure check and for other indicated healthcare.
Other Conditions: In women with hereditary angioedema, exogenous estrogens may induce or exacerbate symptoms of angioedema. Chloasma may occasionally occur, especially in women with a history of chloasma gravidarum. Women with a tendency to chloasma should avoid exposure to the sun or ultraviolet radiation while taking COCs.
Excipients: DELSIA contains lactose. If patient has been told by the doctor that she has an intolerance to some sugars, contact the doctor before taking this medicinal product.
Use in Pregnancy: COCs Use Before or During Early Pregnancy: No increased risk of birth defects has been reported in women who have used oral contraceptives prior to pregnancy. No teratogenic effect has been reported when COCs are taken inadvertently during early pregnancy, particularly in so far as cardiac anomalies and limb-reduction defects are concerned.
The administration of oral contraceptives to induce withdrawal bleeding should not be used as a test for pregnancy (see USE IN PREGNANCY & LACTATION).

Pregnancy: There is little or no increased risk of birth defects in women who inadvertently use COCs during early pregnancy. No increased risk of genital or non-genital birth defects (including cardiac anomalies and limb-reduction defects) has been reported 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.
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 reported to be present in breast milk.
After oral administration of drospirenone 3 mg and ethinyl estradiol 0.03 mg combination, about 0.02% of the drospirenone dose was reported to be excreted into the breast milk of postpartum women within 24 hours. This results in a maximal daily dose of about 0.003 mg drospirenone in an infant.

The following serious adverse reactions have been reported with the use of COCs: Serious cardiovascular events and stroke (see PRECAUTIONS); Vascular events (see PRECAUTIONS); Liver disease (see PRECAUTIONS).
Adverse reactions commonly reported by COC users are: Irregular uterine bleeding; Nausea; Breast tenderness; Headache.
Clinical Trials Experience: The most common adverse reactions (≥ 2% of users) reported were: premenstrual syndrome (13.2%), headache/migraine (10.7%), breast pain/tenderness/discomfort (8.3%), nausea/vomiting (4.5%), abdominal pain/discomfort/tenderness (2.3%) and mood changes (depression, depressed mood, irritability, mood swings, mood altered and affect lability) (2.3%).
Adverse Reactions (≥ 1%) Leading to Study Discontinuation: 6.7% discontinued from the reported clinical studies due to an adverse reaction; the most frequent adverse reaction leading to discontinuation was reported to be headache/migraine (1.5%).
Serious Adverse Reactions: Depression, pulmonary embolism, toxic skin eruption, and uterine leiomyoma.
Post-marketing Experience: The following adverse reactions have been reported during post-approval use of drospirenone 3 mg and ethinyl estradiol 0.03 mg combination. 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.

Effects of Other Drugs on Combined Oral Contraceptives: Substances diminishing the efficacy of COCs: Drugs or herbal products that induce certain enzymes, including cytochrome P450 3A4 (CYP3A4), may decrease the effectiveness of COCs or increase breakthrough bleeding. Some drugs or herbal products that may decrease the effectiveness of hormonal contraceptives include phenytoin, barbiturates, carbamazepine, bosentan, felbamate, griseofulvin, oxcarbazepine, rifampin, topiramate and products containing St. John's wort. Interactions between oral contraceptives and other drugs may lead to breakthrough bleeding and/or contraceptive failure. Counsel women to use an alternative method of contraception or a back-up method when enzyme inducers are used with COCs, and to continue back-up contraception for 28 days after discontinuing the enzyme inducer to ensure contraceptive reliability.
Substances increasing the plasma concentrations of COCs: Co-administration of atorvastatin and certain COCs containing ethinyl estradiol has been reported to increase AUC values for ethinyl estradiol by approximately 20%. Ascorbic acid and acetaminophen may increase plasma ethinyl estradiol concentrations, possibly by inhibition of conjugation.
Concomitant administration of moderate or strong CYP3A4 inhibitors such as azole antifungals (e.g., ketoconazole, itraconazole, voriconazole, fluconazole), verapamil, macrolides (e.g., clarithromycin, erythromycin), diltiazem, and grapefruit juice can increase the plasma concentrations of the estrogen or the progestin or both. It has been reported that once daily co-administration of drospirenone 3 mg and ethinyl estradiol 0.02 mg containing tablets with strong CYP3A4 inhibitor, ketoconazole 200 mg twice daily for 10 days to a premenopausal women resulted in a moderate increase of drospirenone systemic exposure. The exposure of ethinyl estradiol was reported to increase mildly (see PRECAUTIONS).
Human immunodeficiency virus (HIV)/Hepatitis C virus (HCV) protease inhibitors and non-nucleoside reverse transcriptase inhibitors: Significant changes (increase or decrease) in the plasma concentrations of estrogen and progestin have been reported 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 consistent effects of antibiotics on plasma concentrations of synthetic steroids has not been reported.
Effects of Combined Oral Contraceptives on Other Drugs: COCs containing ethinyl estradiol may inhibit the metabolism of other compounds. COCs have been reported 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.
COCs Increasing the Plasma Concentrations of CYP450 Enzymes: It has been reported that administration of a hormonal contraceptive containing ethinyl estradiol did not lead to any increase or only to a weak increase in plasma concentrations of CYP3A4 substrates (e.g., midazolam) while plasma concentrations of CYP2C19 substrates (e.g., omeprazole and voriconazole) and CYP1A2 substrates (e.g., theophylline and tizanidine) can have a weak or moderate increase.
Clinical studies did not report an inhibitory potential of drospirenone towards human CYP enzymes at clinically relevant concentrations.
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.
Potential to Increase Serum Potassium Concentration: There is a potential for an increase in serum potassium concentration in women taking drospirenone 3 mg and ethinyl estradiol 0.03 mg combination with other drugs that may increase serum potassium concentration (see PRECAUTIONS and PHARMACOLOGY under Actions).
A drug-drug interaction study of drospirenone 3 mg/estradiol 1 mg versus placebo was reported in 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 drospirenone/estradiol treatment group relative to baseline were reported to be 0.22 mEq/L higher than those in the placebo group. Serum potassium concentrations also were reported to be measured at multiple time points over 24 hours at baseline and on Day 14. On Day 14, the ratios for serum potassium C_max and AUC in the drospirenone/estradiol group to those in the placebo group were reported to be 0.955 (90% CI: 0.914, 0.999) and 1.010 (90% CI: 0.944, 1.08), respectively. No patient in either treatment group was reported to develop hyperkalemia (serum potassium concentrations > 5.5 mEq/L).
Concomitant Use with HCV Combination Therapy - Liver Enzyme Elevation: Do not co-administer drospirenone 3 mg and ethinyl estradiol 0.03 mg combination with HCV drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, due to potential for ALT elevations (see PRECAUTIONS). Significant changes (increase or decrease) in the plasma concentrations of estrogen and progestin have been reported in some cases of co-administration with HIV/HCV protease inhibitors or with non-nucleoside reverse transcriptase inhibitors.
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. Drospirenone causes an increase in plasma renin activity and plasma aldosterone induced by its mild anti-mineralocorticoid activity (see PRECAUTIONS and previous text).

Do not store above 30°C, protected from light.

Oral Contraceptives

G03AA12 - drospirenone and ethinylestradiol ; Belongs to the class of progestogens and estrogens in fixed combinations. Used as systemic contraceptives.

D