Beyaz (Ethinyl estradiol, drospirenone, and levomefolate) is a combined oral contraceptive pill used for contraception. It is also used to treat moderate to severe acne in adolescents older than 14 years of age.

Beyaz (Ethinyl estradiol, drospirenone, and levomefolate) Uses:

• Acne vulgaris (Beyaz, Rajani):

  • Used for the treatment of moderate acne vulgaris in women 14 years and older who have achieved menarche and who desire an oral contraceptive for birth control.

• Contraception:

  • Used for the prevention of pregnancy.
  • Folate supplementation: To increase folate concentrations in women choosing an oral contraceptive for birth control, in order to reduce the risk of neural tube defects in pregnancies conceived during therapy or soon after treatment is discontinued.

• Premenstrual dysphoric disorder (Beyaz, Rajani):

  • Used for the treatment of symptoms of the premenstrual dysphoric disorder (PMDD) in women who choose to use an oral contraceptive for contraception.
  • Limitations of use: The effectiveness of use for more than 3 menstrual cycles has not been evaluated. Has not been evaluated for the treatment of premenstrual syndrome (PMS).

• Off Label Use of Ethinyl estradiol, drospirenone, and levomefolate in Adults:

  • Abnormal uterine bleeding
  • Menstrual bleeding (menorrhagia)
  • Pain associated with endometriosis
  • Polycystic ovary syndrome (PCOS) in women with menstrual irregularities and hirsutism/acne
  • Dysmenorrhea
  • Hirsutism

Beyaz (Ethinyl estradiol, drospirenone, and levomefolate) Dose in Adults

Beyaz (Ethinyl estradiol, drospirenone, and levomefolate) Dose in the treatment of Acne, PMDD:

• Oral: Females: (Beyaz, Rajani):
  • Refer to dosing for contraception

Beyaz (Ethinyl estradiol, drospirenone, and levomefolate) Dose in the treatment of Contraception, Folate supplementation:

• Oral: Females: (Beyaz, Rajani, Safyral):
  • One tablet once in a day.

• Day 1 starter:

  • Dose starts on the first day of the menstrual cycle taking 1 tablet daily.
  • If the first dose is taken later than the first day of the menstrual cycle, an additional method of contraception should be used until after the first week of consecutive administration.

• Sunday starter:

  • Dose begins on the first Sunday after the onset of menstruation; if the menstrual period starts on Sunday, take the first tablet that very same day.
  • With a Sunday start, an additional method of contraception should be used until after the first weak of consecutive administration.

• Missed or late doses:

  • If one dose is late (less than 24 hours since the dose should have been taken) or if one dose is missed (24 to <48 hours since the dose should have been taken):
    • Take dose as soon as possible.
    • Continue remaining doses at the usual time (even if that means 2 doses on the same day).
  • If 2 or more than 2  consecutive doses are missed (≥48 hours since dose should have been taken):
    • Take the most recently missed dose as soon as possible, discard any other missed doses.
    • Continue remaining doses at the usual time (even if that means taking 2 doses on the same day); use back-up contraception until hormonal pills have been taken for 7 consecutive days.
    • If doses were missed during the last week of hormonal (active) tablets (eg, days 15 to 21 of a 28-day pack), omit the hormone-free interval by finishing the current pack and starting a new pack.
    • If unable to start a new pack immediately, back up contraception is needed until hormonal pills from a new pack have been taken for 7 consecutive days.
    • Consider the use of emergency contraception in some situations (refer to guidelines for details).
  • Also, refer to prescribing information for product specific information.

• Switching from a different contraceptive:

  • Oral contraceptive:
    • Start on the same day that a new pack of the previous oral contraceptive would have been taken
  • Transdermal patch, vaginal ring, injection:
    • Start on the day the next dose would have been due
  • IUD or implant:
    • Start on the day of removal
• Use after childbirth (in women who are not breast-feeding) or after second-trimester abortion:
  • Therapy may be initiated ≥4 weeks postpartum.
  • Pregnancy should be ruled out prior to treatment if menstrual periods have not restarted and an additional method of contraception (nonhormonal) should be used until after the first weak of consecutive administration.

Beyaz (Ethinyl estradiol, drospirenone, and levomefolate) Dose in Childrens

Beyaz (Ethinyl estradiol, drospirenone, and levomefolate) Dose in the treatment of Acne:

• Females:

  • Adolescents ≥14 years: Oral: Refer to adult dosing.

Beyaz (Ethinyl estradiol, drospirenone, and levomefolate) use for Contraception, Folate supplementation, PMDD:

• Females

  • Oral: Refer to adult dosing; not to be used prior to menarche.

Beyaz (Ethinyl estradiol, drospirenone, and levomefolate) Pregnancy Risk Category: X

• It is contraindicated in pregnant women.
• To prevent pregnancy, combination hormonal contraceptives can be used. If pregnancy does occur, treatment should be stopped.
• Combination hormonal contraceptives are generally not associated with any adverse effects on the fetus or mother if used inadvertently early in pregnancy.
• This product contains levomefolate to reduce the chance of developing a neural tube defect if pregnancy occurs while on therapy or soon after.
• According to the manufacturer, combination hormonal contraceptives should be stopped 4 weeks or more after birth in women who have chosen not to breastfeed or 4 weeks after miscarriage or second-trimester abortion.
• Combination hormonal contraceptives should be stopped for less than 21 days after delivery due to increased risk of venous embolism (VTE).
• Postpartum day 42 sees a decrease in the risk to baseline.
• Combination hormonal contraceptives should be used in women 21 to 42 days after delivery.
• Women must consider their individual risk factors for VTE (eg., age 35 and over, immobility and preeclampsia), BMI >=30kg/m2, postpartum bleeding, smoking, and peripartum cardiomyopathy.

Use of ethinyl estradiol, Drospirenone and levomefolate during breastfeeding

• Breast milk may contain contraceptive steroids.
• Breastfeeding women should not start combination hormonal contraceptives less than 21 days after delivery due to increased risk of venous embolism (VTE).
• Postpartum day 42 sees a decrease in the risk to baseline.
• Breast milk contains 0.02% of drospirenone, which results in an infant receiving a maximum daily intake of 3 mg of drospirenone.
• Breastfeeding mothers who use combination hormonal contraceptives have not reported any adverse health effects or persistent effects on infant growth and illness.
• The manufacturer suggests that contraceptives containing estrogen be used until the child is at least two years old.
• Combination hormonal contraceptives should be used in women 21 to 42 days after delivery. Women must consider their risk factors for VTE, such as age, gender, and previous VTE.
• When starting treatment for breastfeeding women, it is important to consider the risks and benefits of combination hormonal contraception.

Beyaz (Ethinyl estradiol, drospirenone, and levomefolate) Dose in Kidney Disease:

Contraindicated in patients with renal dysfunction.

Beyaz (Ethinyl estradiol, drospirenone, and levomefolate) Dose in Liver disease:

Contraindicated in patients with liver dysfunction.

Side effects of Beyaz (Ethinyl estradiol, drospirenone, and levomefolate):

Percentages reported with Beyaz. For additional adverse events and postmarketing reports, refer to the Ethinyl Estradiol and Drospirenone (Yasmin, Yaz) monograph.

• Central Nervous System:

  • Fatigue
  • Irritability
  • Emotional Lability
  • Headache
  • Migraine

• Endocrine & Metabolic:

  • Decreased Libido
  • Weight Gain
  • Menstrual Disease

• Gastrointestinal:

  • Nausea
  • Vomiting

• Genitourinary:

  • Cervical Carcinoma
  • Cervical Dysplasia
  • Breast Tenderness
  • Mastalgia

Contraindications to Beyaz (Ethinyl estradiol, drospirenone, and levomefolate):

• Insufficiency of the adrenals
• Breast cancer or other estrogen- and progestin dependent neoplasms (currently or in the past).
• Hepatic tumors (benign and malignant) or hepatic diseases.
• pregnancy,
• Renal impairment
• Undiagnosed abnormal uterine bleeding
• use of hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir with or without dasabuvir.

Women at high risk for arterial or venous complications such as:

• Cerebrovascular Disease
• Coronary artery disease
• Diabetes mellitus and vascular disease
• DVT or PE (current and/or historical of),
• Hypercoagulopathies (inherited and acquired)
• Headaches with focal neurological symptoms
• hypertension (uncontrolled),
• Migraine headaches are possible if you're older than 35 years.
• Thrombogenic valvular and rhythm diseases of heart (eg subacute bacteria endocarditis or atrial fibrillation)
• Women over 35 years old who smoke.

Canadian labeling: Additional contraindications not in US labeling

• Hypersensitivity to ethinylestradiol or drospirenone, levofolate, and any other component of the formulation
• Myocardial Infarction (current and/or history of);
• Persistent blood pressure >=160mm Hg Systolic or >=100mm Hg Diastolic
• Steroid-dependent jaundice
• Symptoms of cholestatic jaundice or history of jaundice during pregnancy
• Any ocular lession that results from ophthalmic vessels disease (such as vision loss or visual field defect)
• Prodromi ofthrombosis (eg transient ischemic attacks, angina pectoris; history or current of)
• Major surgery is associated with a higher risk of postoperative bleeding.
• Long-term immobilization
• Pancreatitis in association with severe hypertriglyceridemia (current and/or history of);
• severe dyslipoproteinemia;
• Women with an acquired or hereditary predisposition to arterial or vein thrombosis may be:
  • Factor V Leiden mutation,
  • activated protein C (APC-) resistance,
  • Antithrombin-III-deficiency
  • protein C deficiency,
  • protein S deficiency,
  • Hyperhomocysteinemia (eg due to M.THFR C677T and A1298 mutations)
  • Prothrombin mutation G20210A and antiphospholipid antibody (anticardiolipin anticoagulant, lupus-anticoagulant);
  • coadministration with paritaprevir, ritonavir, ombitasvir (with or without dasabuvir).

Warnings and precautions

• Breast cancer

  • Women with breast cancer history or who have had it are advised to not use this product.
  • Combination hormonal contraceptives have not been proven to reduce breast cancer risk in women who are at high risk due to their family history or susceptibility genes (BRCA1, BRCA2)
  • Breast cancer is a hormone sensitive tumor. Women with a history of breast cancer or a recent diagnosis may have a worse prognosis if they use combination hormonal contraceptives.

• Cervical cancer:

  • Theoretically, it may influence the prognosis for existing diseases.
  • Combination hormonal contraceptives may be used by women who are awaiting treatment for cervical carcinoma.
  • Combination hormonal contraceptives have been linked to a slight increase in cervical cancer risk. However, the evidence is inconsistent and could be due to other risk factors.

• Chloasma

  • Treatment should be avoided for women who are susceptible to chloasma and other risk factors.
  • Combination hormonal contraceptives as well as sun exposure, pregnancy and sun exposure are all triggers for chloasma.

• Cholestasis:

  • Cholesteasis risk may increase if there has been a history of cholestatic jaundice during pregnancy, or with prior use of oral contraceptives.

• Hyperkalemia:

  • Drospirenone has an anti-mineralocorticoid activity that may lead to hyperkalemia.
  • Patients with hyperkalemia-predisposing conditions (eg, hepatic dysfunction or adrenal insufficiency) should not use this medication.

• The Lipid Effects

  • Combination hormonal contraceptives can adversely affect lipid levels, especially serum triglycerides.
  • Combination hormonal contraceptives can increase the risk of pancreatitis in women with hypertriglyceridemia and a family history.
  • Women with uncontrolled dyslipidemia should consider alternative contraception.

• Retinal vascular embolism:

  • If you experience an undiagnosed loss of vision, proptosis or diplopia, or retinal vessels lesions, discontinue use immediately and get checked for retinal vein embolism.

• Thromboembolic disorders

  • If you experience an arterial or vein thrombotic event, discontinue using combination hormonal contraceptives.
  • The risk of venous embolism may increase if oral contraceptives are used (risk is highest in the first year and lower than that associated with pregnancy); some studies have suggested that the risk is higher if preparations contain third- or fourth-generation progestins, and/or high doses of ethinylestradiol.
  • Women who have inherited thrombophilias, such as protein C or S deficiency and factor V Leiden mutation, antithrombin deficiencies, and prothrombin mutation, may be at greater risk for venous thromboembolism.
  • Women who use combined hormonal contraceptives for longer periods of time, such as 35 and older, are more likely to experience thrombotic events.
  • Combining hormonal contraceptives can increase the risk for arterial thrombosis (eg MI, stroke), and should be avoided in women who have had strokes or ischemic heart diseases.
  • Combination hormonal contraceptives are not recommended for women at high risk of venous or arterial thrombotic diseases.

• Vaginal bleeding

  • There may be occasional missed periods.
  • In the initial 3 months of therapy, it is possible to experience intra-cyclic bleeding or breakthrough.
  • Unresolved vaginal bleeding is a sign of malignancy and pregnancy.
  • Combination hormonal contraceptives may cause amenorrhea and oligomenorrhea, particularly if the condition was not present previously.

• Cardiovascular disease

  • Patients at high risk for cardiovascular disease should be cautious (eg. hypertension, low HDL and high LDL, older age or diabetes, women who smoke, high triglycerides) and combination hormonal contraceptives can increase the likelihood of developing it.
  • Women at high risk for arterial or vein thrombotic disease may find it contraindicated to use combination hormonal contraceptives.

• Depression

  • Patients with severe depression should be cautious; discontinue use if you experience severe depression.

• Diabetes:

  • Combination oral contraceptives have a limited effect on insulin requirements and do not have long-term effects on diabetes control for women who are not suffering from non-vascular diseases.
  • This may impair glucose tolerance. Women with diabetes and prediabetes should be cautious.
  • Contraceptive use should not be used in women who have concomitant neuropathy, nephropathy, retinopathy or other vascular conditions.
  • Women with diabetes mellitus or vascular disease should not use this medication.

• Endometrial and ovarian cancers:

  • Women with BRCA1 or BRCA2 mutations may have to use oral contraceptives to lower their risk of developing ovarian cancer.
  • Combination hormonal contraceptives may be used by women awaiting treatment for ovarian or endometrial cancer.
  • Combination hormonal contraceptives reduce the risk of ovarian or endometrial cancer.

• Gallbladder disease

  • Combining hormonal contraceptives can increase the risk of gallbladder diseases or worsen existing gallbladder diseases.

• Hepatic adenomas and carcinomas

  • A higher risk of developing hepatocellular carcinoma in the long term (rare).
  • Women with hepatic cancer should not use this product.
  • Combination hormonal contraceptives can cause hepatic tumors (rare). A rupture could lead to fatal intra-abdominal bleeding.

• Hepatic impairment

  • Women with impaired liver function may not be able to process hormonal contraceptives in combination.
  • If jaundice occurs during treatment or if the liver function is abnormal, discontinue use.

• Hepatitis

  • Combination hormonal contraceptives are not recommended for women suffering from acute viral hepatitis, flares, or other severe conditions.
  • It has been proven that continued use of a drug by women who are carriers does not cause liver disease or severe hepatic dysfunction.
  • Women with chronic hepatitis have not been shown to experience an increase in the severity or rate of cirrhotic fibrisis.

• Hereditary angioedema:

  • Women with hereditary angioedema may be affected by estrogens.

• Hypertension:

  • Hypertension risk may increase with age, dosage, and length of use.
  • Women with hypertension or vascular disease or persistent blood pressure levels >=160mm Hg Systolic or >=100mm Hg Diastolic should not use combination hormonal contraceptives.
  • The manufacturer warns against use in women with uncontrolled hypertension. They recommend monitoring women with well-controlled hypertension. Stop taking the medication if your blood pressure increases significantly.
  • Women with mild hypertension (140-159 mmHg systolic, 90-99 mmHg diastolic) and women with moderate hypertension (140-159 mmHg systolic; or hypertension controlled to an acceptable level) may not be at risk.
  • When prescribing contraceptives, it is important to consider other risk factors such as older age, smoking, and diabetes.

• Migraine

  • Assess new, persistent, severe or recurring headaches.
  • Women with migraines without aura, including menstrual migraines, may consider using combination hormonal contraceptives.
  • Assess new, persistent, severe or recurring headaches.
  • If you are over 35 years old, it is not recommended to be used in women suffering from migraine headaches or focal neurological symptoms.

• Transplantation of solid-organs:

  • Although the data is not complete, serious medical complications were reported by women who have had to undergo complicated organ transplants (eg., rejection, cardiac allograft vasculopathy and graft failure).
  • Combination hormonal contraceptives are not recommended for women who have had multiple organ transplants.

• Systemic lupus, erythematosus

  • Systemic lupus-erythematosus (SLE), a condition that causes women to have a higher risk of stroke, heart disease, or VTE, is known as systemic lupus.
  • Women with SLE should not use combination hormonal contraceptives if they have antiphospholipid antibodies. This is because there is a greater risk of arterial or venous embolism.

Monitoring parameters:

• Assessment of pregnancy status (prior to therapy);
• blood pressure (prior to therapy and yearly);
• weight (optional;
• BMI at baseline may be helpful to monitor changes during therapy);
• asses s potential health status changes at routine visits.
• In patients with conditions requiring chronic therapy with medications that may increase potassium, monitor serum potassium during the first treatment cycle.
• Consider monitoring serum potassium in high-risk patients taking strong CYP3A4 inhibitors.

If all doses have not been taken on schedule and 1 menstrual period is missed, the possibility of pregnancy should be considered. If 2 consecutive menstrual periods are missed, assess pregnancy status before a new dosing cycle is started.

• Monitor patient for vision changes;
• blood pressure;
• signs and symptoms of thromboembolic disorders;
• signs or symptoms of depression;
• glycemic control in patients with diabetes;
• lipid profiles in patients being treated for hyperlipidemias.
• Adequate diagnostic measures, including endometrial sampling, if indicated, should be performed to rule out malignancy in all cases of undiagnosed abnormal vaginal bleeding.

How to administer Beyaz (Ethinyl estradiol, drospirenone, and levomefolate)?

• The dose should be taken at the same time each day, either after the evening meal or at bedtime.
• May be administered with or without food. Combined hormonal contraceptives may be initiated at any time during the menstrual cycle if it is reasonably sure the woman is not pregnant.
• Back-up contraception should be used for a weak unless contraception is initiated within the first 5 days of menstrual bleeding or the woman abstains from sexual intercourse.
• Combined hormonal contraceptives may be started immediately following or within the weak  of a first or second-trimester abortion; backup contraception is needed for a weak unless contraception is started at the time of surgical abortion.
• According to the manufacturer, if severe vomiting or diarrhea occurs, additional contraception (nonhormonal) should be used.
• If vomiting occurs within 3 to 4 hours of dosing, consider the dose to be missed. Additional guidelines are available

Mechanism of action of Beyaz (Ethinyl estradiol, drospirenone, and levomefolate):

• Combination oral contraceptives can inhibit ovulation through a negative feedback mechanism on hypothalamus.
• This alters the normal pattern gonadotropin production of a follicle stimulating hormone (FSH), and luteinizing hormone from the anterior pituitary. Inhibition of the follicular phase FSH, and the midcycle surge in gonadotropins is possible.
• Oral contraceptives can also cause alterations in the genital system, including cervical mucus changes, which makes it difficult for sperm penetration, even if there is ovulation.
• Alterations in the endometrium can also cause unfavorable conditions for nidation.
• Oral contraceptives drugs can alter tubal transport of the eggs through the fallopian tubes. Also, progestational agents can alter sperm fertility. 
• Drospirenone is a spironolactone analog with anti-mineralocorticoid and antiandrogenic activity.

Protein binding:

• Drospirenone: Serum proteins (excluding sex hormone-binding globulin and corticosteroid-binding globulin): ~97%;
• Ethinyl estradiol: ~99%

Metabolism:

• Drospirenone: To inactive metabolites, minor metabolism hepatically via CYP3A4;
• Ethinyl estradiol: Hepatic via CYP3A4; forms metabolites; undergoes first-pass metabolism and enterohepatic circulation

Bioavailability:

• Drospirenone: ~76%;
• Ethinyl estradiol: ~40%

Terminal Half-life elimination:

• Drospirenone:
  • ~31 hours;
• Ethinyl estradiol:
  • ~24 hours;
• levomefolate calcium:
  • ~4-5 hours

Time to peak:

• Drospirenone, Ethinylestradiol: 1-2 hours; Levomefolate calcium: 0.5-1.5 hours

Excretion:

• Drospirenone, ethinylestradiol, levomefolate calcium: Urine and feces

International Brand Names of Ethinyl estradiol, drospirenone, and levomefolate:

• Beyaz
• Rajani
• Kala Folic
• Yaz Metafolin
• Safyral
• Tydemy
• YAZ Plus

Ethinyl estradiol, drospirenone, and levomefolate Brand Names in Pakistan:

There is no brand available in Pakistan.