Drospirenone Ethinyl Estradiol is a combination of two medicines. These drugs are primarily used as oral contraceptives.

Drospirenone Ethinyl estradiol Uses:

• Acne vulgaris (Gianvi, Loryna, Nikki, Vestura, Yaz):

  • It is used for the treatment of moderate acne vulgaris in women 14 years and older only if the patient is willing for  oral contraceptive for birth control,

• Contraception:

  • It is highly recommended for the prevention of pregnancy

• Premenstrual dysphoric disorder (Gianvi, Yaz):

  • In different conditions such as  premenstrual dysphoric disorder (PMDD), it is suitable for women who opt to use an oral contraceptive for contraception

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

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

Drospirenone Ethinyl estradiol Dose in Adults

The treatment dose of drospirenone Ethinyl estradiol for Acne vulgaris:

• Oral therapy for females:

  • Refer to dosing for contraception.

Drospirenone Ethinylestradiol Dose in the treatment of Premenstrual Dysphoric Disorder:

• Oral dose for females:

  • Refer to dosing for contraception.

Drospirenone Ethinyl estradiol Dosage for Contraception:

• Female:

  • One tablet per oral once every 24 hours

• Schedule 1 (Sunday starter):

  • Dose begins on the first Sunday after the onset of the menstrual cycle.
  • 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 week of consecutive administration.

• Schedule 2 (Day 1 starter):

  • The dose is initiated on the first day of menstrual cycle taking 1 tablet every 24 hours

• 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 was to be administered

  • Intra-uterine device or implant:

    • Start on the day of removal of the device

  • Use after childbirth (in women who are not breast-feeding) or after second-trimester abortion:

    • Therapy should be initiated ≥4 weeks postpartum.
    • Pregnancy should be ruled out before starting treatment if menstrual periods have not restarted and an additional method of contraception (non-hormonal, such as barrier methods) should be used until after the first week of consecutive administration.

• Missed or late doses:

  • If a dose is taken lately (<24 hours since dose should have been taken) or if one dose is missed (one to two since dose should have been taken):

    • Take the dose as soon as possible. Continue remaining doses according to the same schedule (even if that means 2 doses on the same day).

  • If ≥2 consecutive doses are missed (≥48 hours since dose should have been taken):

    • the most recently missed dose should be taken as soon as possible, any other missed doses should be discarded.
  • Further doses should be administered at the scheduled time (even if that means taking 2 doses on the same day);
  • use another form of contraception until hormonal pills have been taken for 7 consecutive days.
  • If doses were missed during the last 7 days of hormonal (active) tablets (eg, days 15 to 21 of a 28-day pack), skip the hormone-free interval by completing the current pack and starting a new pack.
  • If a new pack cannot be started immediately, back up contraception method is required 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).

Dose in Childrens

Refer to adult dosing.

Pregnancy Risk Factor: X

• It is not recommended for pregnant women.
• Combination oral contraceptives can be helpful in preventing pregnancy
• If pregnancy is confirmed, the treatment should be stopped.
• If given early in pregnancy, combined hormonal contraceptives are not associated with any adverse effects on the fetus or mother.
• According to the manufacturer, combined oral contraceptive medications should not be taken until one month after birth if women aren't willing to breastfeed or after a second-trimester miscarriage or abortion.
• Because of the higher incidence of postpartum vein thromboembolism, combination hormonal contraceptives shouldn't be used for at least 21 days after delivery.
• Postpartum day 42 has a lower risk of venous embolism than the baseline.
• Women should not take combination hormonal contraceptives for more than 21 days after delivery. This is dependent on their individual risk factors for Venous embolism.

Breastfeeding: Ethinyl estradiol or drospirenone

• Breast milk contains Drospirenone.
• Concentration is less than 0.02% of the maternal dose. This results in newborns receiving a maximum of 3 mg/day of drospirenone.
• The newborn has not been shown to experience side effects from hormonal contraceptives combined with breastfeeding mothers.
• Contraceptives in estrogen can cause a decrease in milk production. The manufacturer recommends that contraception be used until the child is weaned.
• Breastfeeding women should not take combination hormonal contraceptives within 21 days of delivery. This is because there is a higher risk of venous embolism (VTE), postpartum.
• Postpartum day 42 reduces the risk to baseline.
• Women can use combination hormonal contraceptives between 21 and 42 days after childbirth depending on their individual risk factors (eg, age >=35, previous VTEs, thrombophilia or immobility), peripartum cardiomyopathy (BMI >=30kg/m2, postpartum hemorhage, smoking, and peripartum cardiomyopathy).
• When starting treatment for breastfeeding women, it is important to consider the risks and benefits of combined hormonal oral contraceptives (Curtis 2016,b).

Renal disease dose adjustment of drospirenone Ethinyl estradiol:

Contraindicated in patients with renal dysfunction.

Liver disease dose adjustment of drospirenone ethinyl estradiol:

Contraindicated in patients with renal dysfunction.

Adverse effects of drospirenone ethinyl estradiol:

Complications listed are based on reports for other agents in this same pharmacologic class (oral contraceptives) and may not be specifically associated with  drospirenone/ethinyl estradiol.

Adverse reactions of drospirenone Ethinyl estradiol:

• Cardiovascular:

  • Arterial Thromboembolism
  • Cerebral Thrombosis
  • Hypertension
  • Local Thrombophlebitis
  • Mesenteric Thrombosis
  • Myocardial Infarction
  • Pulmonary Embolism
  • Retinal Thrombosis

• Central Nervous System:

  • Cerebral Hemorrhage

• Gastrointestinal:

  • Gallbladder Disease

• Hepatic:

  • Hepatic Adenoma
  • Hepatic Neoplasm (Benign)

Side effects of drospirenone Ethinyl estradiol (Less common):

• Cardiovascular:

  • Edema
  • Worsening Of Varicose Veins

• Central Nervous System:

  • Depression
  • Exacerbation Of Tics
  • Migraine

• Dermatologic:

  • Allergic Skin Rash
  • Chloasma

• Endocrine & Metabolic:

  • Amenorrhea
  • Breast Changes (Breast Hypertrophy, Breast Secretion, Breast Tenderness, Mastalgia)
  • Decreased Serum Folate Level
  • Exacerbation Of Porphyria
  • Menstrual Disease (Menstrual Flow Changes), Weight Changes

• Gastrointestinal:

  • Abdominal Cramps
  • Bloating
  • Carbohydrate Intolerance
  • Nausea
  • Vomiting

• Genitourinary:

  • Breakthrough Bleeding
  • Cervical Ectropion
  • Cervical Erosion
  • Change In Cervical Secretions
  • Decreased Lactation (With Use Immediately Postpartum)
  • Infertility (Temporary)
  • Spotting
  • Vulvovaginal Candidiasis

• Hepatic:

  • Cholestatic Jaundice

• Hypersensitivity:

  • Anaphylaxis/ Anaphylactoid Reaction (Including Angioedema, Circulatory Shock, Respiratory Collapse, and Urticaria)

• Neuromuscular & Skeletal:

  • Exacerbation Of Systemic Lupus Erythematosus

• Ophthalmic:

  • Change In Corneal Curvature (Steepening)
  • Contact Lens Intolerance

Side effects of Drospirenone Ethinyl estradiol in which the association is not confirmed:

• Cardiovascular:

  • Budd-Chiari Syndrome

• Central Nervous System:

  • Dizziness
  • Headache
  • Nervousness

• Dermatologic:

  • Acne Vulgaris
  • Erythema Multiforme
  • Erythema Nodosum
  • Loss Of Scalp Hair

• Endocrine & Metabolic:

  • Change In Libido
  • Hirsutism
  • Porphyria
  • Premenstrual Syndrome

• Gastrointestinal:

  • Change In Appetite
  • Colitis
  • Pancreatitis

• Genitourinary:

  • Cystitis-Like Syndrome
  • Dysmenorrhea
  • Vaginitis

• Hematologic & Oncologic:

  • Hemolytic-Uremic Syndrome
  • Hemorrhagic Eruption

• Ophthalmic:

  • Cataract
  • Optic Neuritis (With Or Without Partial Or Complete Loss Of Vision)

• Renal:

  • Renal Insufficiency

Contraindication to Drospirenone Ethinyl estradiol:

These include:

• Insufficiency of the adrenals
• Breast cancer and other estrogen- or progestin-sensitive forms of cancer
• Liver disease or tumors (benign and malignant)
• pregnancy
• Renal impairment
• Undiagnosed abnormal uterine bleeding
• concurrent use of hepatitis C drug combinations containing ombitasvir/ paritaprevir/ ritonavir with or without dasabuvir

It is also not recommended for women who are at high risk of venous or arterial thrombotic disease such as:

• Cerebrovascular Disease
• Coronary artery disease
• Diabetes mellitus and vascular disease
• Deep vein thrombosis, or pulmonary embolism.
• Hypercoagulopathies (familial and acquired)
• Hypertension uncontrolled
• If you are older than 35 years old, headaches with focal neurological symptoms (or migraine headaches) may occur.
• Thrombogenic valvular diseases and arrhythmias (eg subacute bacteria endocarditis or atrial fibrillation).
• Women and smokers >35 years

It is contraindicated according to the Canadian Guidelines.

• Patients who are hypersensitive to Ethinyl estradiol or drospirenone, or any other component of this formulation
• Myocardial Infarction (current and/or history of);
• Persistent hypertension >=160mm Hg Systolic or >=100mm Hg Diastolic
• Prodromal of an thrombotic event, such as transient Ischemic Attack, Angina Pectoris (current or historical)
• Major surgery is associated with a higher incidence of postoperative hemoglobinemia
• Long-term immobilization
• severe dyslipoproteinemia
• Pancreatitis is associated with higher triglyceride levels
• Steroid-induced jaundice/cholestatic jaundice/antenatal transaminitis
• Ocular lesions caused by ophthalmic vessels disease (partial or complete vision loss, visual field defects)
• women with a hereditary or acquired predisposition for venous or arterial thrombosis, for example: Factor V Leiden mutation and activated protein C (APC-) resistance, antithrombin-III-deficiency, protein C deficiency, protein S deficiency, hyperhomocysteinemia, and antiphospholipid syndrome.
• combination therapy with ombitasvir, paritaprevir, ritonavir (with or without dasabuvir)

Warnings and precautions

• Breast cancer
  • Combination hormonal contraceptives have not been shown to reduce breast cancer risk in women with strong family histories or susceptibility genes (BRCA1, BRCA2).
  • Women with a history or breast cancer are at risk for poor prognosis if they use combined oral contraceptives, as breast cancer can be hormone-sensitive.
  • Women with a history or breast cancer are not advised to use oral contraception.

• Cervical cancer:

  • Combination hormonal contraceptives have been shown to slightly increase the risk of developing cervical cancer. However, there is limited evidence and it could be associated with other risk factors.
  • Oral contraception can adversely affect the prognosis for cervical cancer.
  • Women who have not started treatment for cervical carcinoma can receive combination hormonal contraceptives.

• Chloasma

  • The triggers for chloasma are pregnancy, sun exposure and combination hormonal contraceptives.
  • Treatment should be avoided for women who are susceptible to chloasma, or have additional risk factors.

• Cholestasis:

  • Cholestatic jaundice during pregnancy, or previous oral contraceptive use, increases the likelihood of cholestasis.

• Hyperkalemia:

  • Drospirenone can result in hyperkalemia due to anti-mineralocorticoid activity
  • Patients with hyperkalemia-predisposing conditions (such as liver dysfunction, renal insufficiency, or adrenal insufficiency) are advised not to use it.
  • Take caution when taking medications that can increase serum potassium levels.

• The Lipid Effects

  • Combination hormonal contraceptives can cause hypertriglyceridemia.
  • Patients with hypertriglyceridemia and a family history are at greater risk for pancreatitis when they use combination hormonal contraceptives.
  • Women with uncontrolled dyslipidemia should consider alternative contraception options.

• Retinal vascular embolism:

  • If there is an unexplained loss of vision, proptosis or papilledema or retinal vascular lesion, it should be discontinued immediately. A retinal vein thrombosis evaluation should be performed as soon as possible.

• Thromboembolic disorders

  • In the event of arterial or venous embolism, discontinue using combination hormonal contraceptives.
  • The increased risk of venous embolism from oral contraceptives is a result of the fact that they are more likely to be used in the first year.
  • Some studies have shown that this risk increases when using third- or fourth-generation progestins, and/or high dose Ethinylestradiol.
  • The risk of venous embolism increases when there are inherited thrombophilias, such as protein C or S deficiencies, factor V Leiden mutations, prothrombin mutations, and antithrombin deficiencies.
  • Women who smoke, are more likely to have thrombotic events than those who are older than 35, or have hypertension.
  • Women with a history or stroke should avoid using hormonal contraceptives in combination.
  • Oral hormonal contraception is not recommended for women at high risk for venous or arterial thrombotic diseases.

• Vaginal bleeding

  • Unscheduled bleeding (breakthrough, intra-cyclic) or spotting can occur, especially in the initial 3 months of therapy.
  • It can lead to amenorrhoea.
  • If there is any unresolved or irregular vaginal bleeding, further evaluation and endometrial sampling are required to rule out pregnancy or malignancy.
  • Amenorrhea/oligomenorrhea can be seen after discontinuing combination hormonal contraceptives, especially when the patient had previous events.

• Cardiovascular disease

  • Use with caution in patients with risk factors for cardiovascular disease (eg, hypertension, low concentration of high-density lipoproteins, high concentration of low-density lipoprotein, hypertriglyceridemia, elderly, diabetes, smoker, use of combination hormonal contraceptives may increase the risk of cardiovascular disease.
  • Women at high risk for arterial or vein thrombosis should not use combination hormonal contraceptives.

• Depression

  • Patients with depression should be cautious. You should stop using it if you are suffering from severe depression.

• Diabetes:

  • It can lead to impaired glucose tolerance. Be cautious with DM and prediabetes.
  • There have been limited effects on insulin requirements daily and no long-term effects on diabetes control if there is no history of vascular disease.
  • Patients with concomitant neuropathy, retinopathy or nephropathy may need to use contraceptives depending on their severity.
  • It is not recommended for patients with diabetes mellitus or vascular disease.

• Endometrial and ovarian cancers:

  • Combination hormonal contraceptives reduce the chance of ovarian or endometrial cancer in women.
  • Oral contraceptives have been shown to decrease the risk of ovarian cancer in women with BRCA1 or BRCA2 mutations.
  • Women undergoing treatment for ovarian or endometrial cancer can use combination hormonal contraceptives.

• Gallbladder disease

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

• Hepatic adenomas

  • Combination hormonal contraceptives may result in hepatic tumors, which can rupture and cause intra-abdominal hemorhage.
  • If it is used for a prolonged period (rare), it can also be associated with hepatocellular cancer.
  • Patients with hepatic cancers should not take it.

• Hepatic impairment

  • Poor metabolism can occur in the liver.
  • The drug should be discontinued if there is jaundice or other abnormalities in the liver.
  • Preexisting liver disease is not recommended.
  • Combination hormonal contraceptives may be used in mild (compensated), but not severe (decompensated), cirrhosis.

• Hepatitis

  • Women with severe viral hepatitis, flares or women who are pregnant by combination hormonal contraceptives should not use them.
  • Women with chronic hepatitis have not experienced an increase in the severity of cirrhotic fibris or hepatocellular malignancy if they continue to use it.
  • It has not been proven that the drug can be continued in carriers without causing liver damage or severe hepatic dysfunction.

• Hereditary angioedema:

  • Hereditary angioedema can be exacerbated by estrogens.

• Hypertension:

  • Hypertension can be caused by factors such as age, dosage, and length of use.
  • In hypertension, vascular disease, persistent blood pressure >=160 mmHg systolic and >=100mmHg diastolic, hormonal contraceptives in combination with other hormones are best avoided.
  • 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 smoking, age, and diabetes.
  • The manufacturer warns against the use of this drug in women who have uncontrolled hypertension.

• Migraine

  • Combination hormonal contraceptives may be used in migraines that do not have aura (including menstrual migraines).
  • If you are over 35 years old, it is not recommended for women suffering from headaches that have focal neurological symptoms or migraine headaches without or with aura.

• Transplantation of solid-organs

  • Combinations of hormonal contraceptives are not recommended for women who have had complicated organ transplants. This is because of potential complications like graft rejection/ graft failure/ cardiac allograft vasculopathy.

• Systemic lupus erythematosus (SLE):

  • SLE affects women at greater risk for heart disease, stroke, and vein thrombosis.
  • Women with SLE who have antiphospholipid antibodies (positive or unknown) are advised to avoid using hormonal contraceptives. This is because of the increased risk of arterial/venous embolism.

Monitoring parameters:

• Assessment of pregnancy status (prior to therapy)
• Blood pressure (prior to therapy and once a year)
• Weight (optional- Body mass index at baseline may be helpful in monitoring changes during therapy)
• Assess potential health status changes at routine visits.
• In patients with conditions requiring chronic therapy with medications that may result in hyperkalemia, serum potassium levels should be checked during the first treatment cycle.
• Serum potassium levels should be monitored in high-risk patients taking strong CYP3A4 inhibitors.
• If all doses have been taken on schedule and 1 menstrual period is missed, continue the dosing cycle.
• If 2 consecutive menstrual periods are missed, rule out pregnancy prior to a new dosing cycle.
• Monitor patients for vision changes, blood pressure, signs and symptoms of thromboembolic disorders, depression,  blood glucose level in patients with diabetes, lipid profiles in patients being treated for hyperlipidemias.
• Adequate diagnostic measures, including endometrial sampling, if required should be performed to rule out malignancy in all cases of undiagnosed abnormal vaginal bleeding

Administration of drospirenone ethinyl estradiol:

• The dose should be taken at the same time every day, preferably either after the evening meal or at bedtime.
• Combined hormonal contraceptives may be started at any time during the menstrual cycle after ruling out pregnancy.
• Back-up contraception should be used for one week unless contraception is started within the first 5 days of menstrual bleeding or the woman abstains from coitus.
• Combined hormonal contraceptives may be started immediately following or within one week of a first or second-trimester abortion.
• Backup contraception is needed for 7 days unless contraception is started at the time of the surgical abortion.
• Back-up contraceptive measures may be required according to the manufacturer if severe diarrhea or vomiting occurs within 3 to 4 hours after taking a pill.

Mechanism of action of Drospirenone Ethinyl estradiol:

• Combining oral drospirenone Ethinyl esteradiol with oral drospirenone Ethinyl cause a negative feedback mechanism in the hypothalamus, leading to inhibition of the ovulation.
• This alters the normal pattern gonadotropin production of a follicle stimulating hormone (FSH), and luteinizinghormone by the anterior pituitary.
• It is possible to inhibit the follicular phase FSH, and the midcycle surge gonadotropins.
• Oral contraceptives can also cause genital tract changes, such as changes in cervical mucus.
• This makes it difficult for sperm penetration, even if ovulation happens. Endometrium changes can lead to unfavorable conditions for nidation. 
• Alteration in the tubal transport of ova through fallopian tubes can be caused by oral contraceptives. 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: ~98% to serum albumin

Metabolism:

• Drospirenone; To inactive metabolites minor metabolism hepatically via CYP3A4:
• Ethinyl estradiol; Hepatic via CYP3A4: Forms metabolites; goes through first-pass metabolism, enterohepatic circulation

Bioavailability:

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

Half-life elimination: Terminal:

• Drospirenone: ~30 hours;
• Ethinyl estradiol: ~24 hours

Time to peak:

• 1 to 2 hours

Excretion:

• Drospirenone, Ethinyl estradiol: Urine and feces

International Brands of Ethinyl estradiol and drospirenone:

• Gianvi
• Jasmiel
• Loryna
• Nikki
• Ocella
• Syeda
• Vestura
• Yasmin 28
• YAZ
• Zarah
• MYA
• Yasmin 21
• Yasmin 28
• YAZ
• Zamine 21
• Zamine 28
• Zarah 21
• Zarah 28
• Acondro
• Cleosensa
• Convuline
• Dalyne
• Damsel
• Dileva
• Dretine
• Drosiane
• Drospera
• Drosperin
• Drospifem
• Eloine
• Elvina
• Elvinette
• Femelle
• Gveza
• Isabelle
• Jasmine
• Jasminelle
• Jastinda
• Jazz
• Jazz Plus
• Justima
• Ladonna
• Liara
• Liz
• Liza
• Lizelle
• Lucette
• Melodia
• Midiana
• Mozanglic
• Novelon
• Novelon Lite
• Palandra
• Radiance
• Rosen 28
• Rosen Gold
• Synfonia
• Taz
• Yacella
• Yadine
• Yana
• Yarina
• Yaryna
• Yasmin
• Yasmin IQ
• Yasminelle
• Yax
• Yax Femicare
• Yaz
• YAZ
• YazFlex
• Zahra

Drospirenone ethinyl estradiol Brand Names in Pakistan:

No Brands Available in Pakistan.