Ethinyl estradiol and levonorgestrel (Famila 28) is a combined estrogen and progestin containing oral contraceptive pill used to prevent pregnancy.

Ethinyl estradiol and levonorgestrel (Famila) Uses:

• Contraception:

  • Used in the Prevention of pregnancy.

• Emergency contraception:

  • Postcoital emergency contraception.
  • Limitations of use:
    • Ethinyl estradiol in combination with levonorgestrel is effective and recommended as an alternative method for the management of emergency contraception when other methods are not present.
    • The use of other methods is preferred due to increased side effects and decreased efficacy observed with this combination.

• Off Label Use of Ethinyl estradiol and levonorgestrel (Famila) in Adults:

  • Used for dysmenorrhea
  • Used for hirsutism
  • Used for menstrual bleeding (menorrhagia)
  • Used for pain associated with endometriosis
  • Used for polycystic ovary syndrome (PCOS) in women with menstrual irregularities and hirsutism/acne
  • Used for abnormal uterine bleeding

Ethinyl estradiol and levonorgestrel (Famila) Dose in Adult females:

Ethinyl estradiol and levonorgestrel (Famila) Dose for Contraception:

• Oral: One tablet once in a day. General dosing guidelines; refer to prescribing information for product specific information:

• Schedule 1 (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.

• Schedule 2 (Day 1 starter):

  • Dose starts on the first day of the menstrual cycle taking 1 tablet once a day.

• 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).

Ethinyl estradiol and levonorgestrel (Famila) Dose for Emergency Contraception:

• Oral (off label dosing):
  • One dose followed by a second dose 12 hours later.
  • Each dose should contain a minimum of Ethinylestradiol 100 mcg and levonorgestrel 0.5 mg.
  • Although no longer available in a dedicated dosage form, available combination oral contraceptive pills can be used to achieve this dose.
  • Treatment for emergency contraception should begin as soon as possible; however, treatment is still moderately effective if used within 5 days after unprotected or inadequately protected intercourse.
  • Although routine use of antiemetics is not recommended, pretreatment may be considered for specific women.

Females: Contraception or emergency contraception:

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

Pregnancy Risk Factor X

• Pregnant women should not use this product.
• Manufacturers recommend that you wait at least 4 to 6 week after delivery before starting the combination.
• Combination hormonal contraceptives should be stopped in women 21 days after delivery due to increased risk of venous embolism (VTE).
• 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.
• 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 risk factors for VTE (eg., age 35 and older, immobility, transfusion at birth, cesarean delivery), peripartum cardiomyopathy and BMI >=30kg/m2, postpartum bleeding, smoking.
• If emergency contraception is required, it is advisable to immediately use a barrier contraceptive.
• After combined estrogen/progestin emergencies contraception, any regular (non-emergency contraceptive method) can be initiated immediately.
• However, for seven days, a barrier method or abstinence from all sexual activity is required.

Use of ethinyl estradiol or levonorgestrel during breastfeeding

• Breast milk may contain contraceptive steroids.
• Some manufacturers recommend that contraceptives containing estrogen be used until the child is old enough to produce milk.
• Breastfeeding mothers who use combination hormonal contraceptives have not reported any adverse health effects or persistent effects on infant growth and illness.
• Breastfeeding women should not start combination hormonal contraceptives less than 21 days after delivery due to an 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 birth. Women who use combination hormonal contraceptives must take into account the risk factors for VTE.
• When starting treatment for breastfeeding women, it is important to consider the risks and benefits of combination hormonal contraception.

Ethinyl estradiol and levonorgestrel (Famila) Dose in Kidney Disease:

The manufacturer's labeling doesn't provide any dosage adjustments (has not been studied); use with caution and monitor blood pressure closely.

Ethinyl estradiol and levonorgestrel (Famila) Dose in Liver disease:

Use is contraindicated in patients with hepatic impairment.

Side effects of Ethinyl estradiol and levonorgestrel (Famila):

Reactions listed are based on reports for other agents in this same pharmacologic class (oral contraceptives) and may not be specifically reported for ethinyl estradiol/levonorgestrel.

Increased Risk Or Evidence Of Association With Use:

• Cardiovascular:

  • Local Thrombophlebitis
  • Mesenteric Thrombosis
  • Myocardial Infarction
  • Pulmonary Embolism
  • Retinal Thrombosis
  • Arterial Thromboembolism
  • Cerebral Thrombosis
  • Hypertension
  • Venous Thrombosis (With Or Without Embolism)

• Central Nervous System:

  • Cerebral Hemorrhage

• Gastrointestinal:

  • Gallbladder Disease

• Hepatic:

  • Hepatic Neoplasm (Benign)
  • Hepatic Adenoma

Adverse Reactions Considered Drug Related:

• Cardiovascular:

  • Worsening Of Varicose Veins
  • Edema

• Central Nervous System:

  • Exacerbation Of Tics
  • Migraine
  • Mood Changes
  • Depression

• Dermatologic:

  • Allergic Skin Rash
  • Chloasma

• Endocrine & Metabolic:

  • Amenorrhea
  • Breast Changes
    • Breast Hypertrophy
    • Mastalgia
    • Breast Secretion
    • Breast Tenderness
  • Carbohydrate Intolerance
  • Menstrual Disease (Menstrual Flow Changes)
  • Weight Changes
  • Decreased Lactation (With Use Immediately Postpartum)
  • Decreased Serum Folate Level
  • Exacerbation Of Porphyria
  • Fluid Retention

• Gastrointestinal:

  • Abdominal Cramps
  • Bloating
  • Change In Appetite
  • Nausea
  • Vomiting
  • Abdominal Pain

• Genitourinary:

  • Breakthrough Bleeding
  • Change In Cervical Secretions
  • Endocervical Hyperplasia
  • Infertility (Temporary)
  • Spotting
  • Vulvovaginal Candidiasis
  • Vaginitis
  • Cervical Ectropion
  • Cervical Erosion

• Hematologic & Oncologic:

  • Uterine Fibroid Enlargement

• Hepatic:

  • Cholestatic Jaundice
  • Hepatic Focal Nodular Hyperplasia

• Hypersensitivity:

  • Anaphylaxis/Anaphylactoid Reaction Including
    • Circulatory Shock
    • Respiratory Collapse
    • Urticaria
    • Angioedema

• Neuromuscular & Skeletal:

  • Exacerbation Of Systemic Lupus Erythematosus

• Ophthalmic:

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

• Respiratory:

  • Rhinitis

Adverse Reactions In Which Association Is Not Confirmed Or Denied:

• Cardiovascular:

  • Budd-Chiari Syndrome

• Central Nervous System:

  • Headache
  • Nervousness
  • Dizziness

• Dermatologic:

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

• Endocrine & Metabolic:

  • Premenstrual Syndrome
  • Change In Libido
  • Hirsutism

• Gastrointestinal:

  • Colitis
  • Pancreatitis

• Genitourinary:

  • Abnormal Pap Smear
  • Cystitis-Like Syndrome
  • Dysmenorrhea

• Hematologic & Oncologic:

  • Hemolytic-Uremic Syndrome
  • Hemorrhagic Eruption

• Ophthalmic:

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

• Otic:

  • Auditory Disturbance

• Renal:

  • Renal Insufficiency

Contraindications to Ethinyl estradiol and levonorgestrel (Famila):

• Breast cancer and other estrogen-, progestin-dependent Neoplasms (currently or in the past).
• Hepatic cancers and disease
• pregnancy;
• 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 can occur if you are older than 35.
• Thrombogenic valvular and rhythm diseases of heart (eg subacute bacteria endocarditis or atrial fibrillation)
• Women over 35 who smoke

Canadian labeling: Additional contraindications (not in the US labeling).

• Hypersensitivity to Ethinylestradiol or levonorgestrel or any other component of the formulation
• Ocular lesions caused by ophthalmic vessels disease, including partial or total loss of vision and defect in the visual fields.
• severe dyslipoproteinemia;
• Persistent blood pressure 160 mmHg or more that 160mm Hg Systolic, 100 mmHg or more about 100 mmHg Diastolic
• Myocardial Infarction (current and/or history of);
• 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
• History of jaundice during pregnancy, cholestatic jaundice and steroid-dependent jaundice
• If severe hypertriglyceridemia is present or history, pancreatitis may occur.
• 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 MTHFR C677T and A1298 mutations),
  • Prothrombin mutation G20210A
  • antiphospholipid-antibodies (anticardiolipin antibodies, lupus anticoagulant);
• coadministration with ombitasvir, paritaprevir, ritonavir (with or without dasabuvir or ribavirin);
• Hereditary or acquired thrombophilias
• Tests for abnormal liver function
• Undiagnosed abnormal vaginal bleeding

Warnings and precautions

• Breast cancer

  • 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.
  • 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)

• Cervical cancer:

  • 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.
  • 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.
  • Women with breast cancer history or who have had it are advised to not use this product.

• Chloasma

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

• Cholestasis:

  • Cholestasis risk may increase if there has been a history of cholestatic jaundice during pregnancy, or if an oral contraceptive was used.

• The Lipid Effects

  • 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
  • Combination hormonal contraceptives can adversely affect lipid levels, especially serum triglycerides.

• 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

  • The risk of venous embolism may be increased by oral contraceptives (risk is highest in the first year and lowest during pregnancy); some studies have suggested that the risk may be greater for preparations containing third- or fourth-generation progestins, and/or high dose Ethinylestradiol.
  • Women who have inherited thrombophilias, such as protein C or S deficiency and factor V Leiden mutation, antithrombin deficiencies, and prothrombin mutations, may be at greater risk for venous thromboembolism.
  • If you experience an arterial or vein thrombotic event, discontinue using combination hormonal contraceptives.
  • Women who use combined hormonal contraceptives are more likely to have thrombotic events if they are older than 35.
  • Combination hormonal contraceptives are not recommended for women at high risk of venous or arterial thrombotic diseases.
  • Combination hormonal contraceptives can also increase the risk for arterial thrombosis (eg MI, stroke). Women with a history or ischemic heart disease should not use them.

• Vaginal bleeding

  • 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.
  • In the initial 3 months of therapy, it is possible to experience intra-cyclic bleeding or breakthrough.
  • There may be occasional missed periods.

• Cardiovascular disease

  • Patients at high risk for coronary artery disease such as hypertension, low HDL and high LDL, older people, diabetes, smokers, or those with high blood pressure should be cautious.
  • Combination hormonal contraceptives can increase your risk of developing cardiovascular disease.
  • Combination hormonal contraceptives might be contraindicated for women with high risk of venous or arterial thrombotic disease.

• Depression

  • Patients at high risk for depression should be cautious.
  • Discontinue if serious depression recurs.

• Diabetes:

  • This may cause impaired glucose tolerance.
  • Contraceptive use should not be used in women who have concomitant neuropathy, nephropathy, retinopathy or other vascular conditions.
  • Combination oral contraceptives have a limited effect on insulin requirements and do not have long-term effects on diabetes control for women with non-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 rare form of hepatocellular carcinoma is the risk associated with long-term, prolonged use.
  • Preexisting hepatic cancers are not recommended.
  • Combination hormonal contraceptives can cause hepatic tumors (rare); rupture could lead to fatal intra-abdominal bleeding.

• Hepatic impairment

  • If jaundice occurs during treatment or if the liver function is abnormal, discontinue use.
  • Preexisting hepatic diseases are contraindicated.
  • Combination hormonal contraceptives can be used for women with mild (compensated), but not severe (decompensated), cirrhosis.
  • Women with impaired liver function may not be able to process hormonal contraceptives in combination.

• Hepatitis

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

• Hereditary angioedema:

  • Women with hereditary angioedema may be affected by estrogens.

• Hypertension:

  • Hypertension can be caused by increased doses, prolonged use, and age.
  • Women with hypertension or vascular disease should not use combination hormonal contraceptives.
  • Women with mild hypertension (140-159 mmHg systolic, 90-99 mmHg diastolic) and women with well controlled hypertension may not be at greater risk.
  • When prescribing contraceptives, it is important to consider other risk factors such as diabetes, older age and smoking.
  • 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.

• Migraine

  • 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:

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

• Systemic lupus erythematosus (SLE):

  • 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.
  • SLE women are more at risk for heart disease, stroke and VTE.

Ethinyl estradiol and levonorgestrel: Drug Interaction

Monitoring parameters:

Contraception:

• Assessment of pregnancy status (prior to therapy);
• blood pressure (prior to therapy and yearly);
• weight (optional;
• BMI at baseline may be helpful to mo nitor changes during therapy); assess potential health status ch anges at routine visits.

If all doses have not been taken on schedule and one menstrual period is missed, the possibility of pregnancy should be considered. If two 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;
• glycemic control in patients with diabetes;
• signs or symptoms of depression;
• 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.

Emergency contraception:

• Evaluate for pregnancy, spontaneous abortion, or ectopic pregnancy if menses is delayed for 1 week or more than 1 weak following emergency contraception, or if lower abdominal pain or persistent irregular bleeding develops.

How to administer Ethinyl estradiol and levonorgestrel (Famila)?

Contraception:

• Administer at the same time each day. 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 7 days 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 within a weak unless contraception is started at the time of the surgical abortion.

Emergency contraception:

• If vomiting occurs within 3 hours, a second dose should be taken as soon as possible; consider the use of an antiemetic.

Mechanism of action of Ethinyl estradiol and levonorgestrel (Famila):

• Combination hormonal 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 mid-cycle surge gonadotropins is observed.
• Combination hormonal 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.
• Combination hormonal contraceptives drugs can alter tubal transport of the eggs through the fallopian tubes. 
• The fertility of sperm may also be affected by progestational drugs.

Absorption:

• Rapid

Protein binding:

• Ethinyl estradiol: 95 percent  to 97 percent to albumin
• Levonorgestrel: 97percent  to 99 percent primarily to sex hormone-binding globulin (SHBG), lesser amounts to albumin

Metabolism:

• Ethinyl estradiol: Hepatic via CYP3A4; undergoes first-pass metabolism; forms metabolites
• Levonorgestrel: Forms conjugated in unconjugated metabolites

Bioavailability:

• Ethinyl estradiol: 38 percent  to 48 percent;
• Levonorgestrel: 100 Percent

Half-life elimination:

• Ethinyl estradiol: 12-23 hours;
• Levonorgestrel: 22-49 hours

Excretion:

• Ethinyl estradiol: Urine and feces
• Levonorgestrel:
  • Urine (40 Percent to 68 Percent, parent drug, and metabolites);
  • feces (16 percent  to 48 percent as metabolites)

International Brand Names of Ethinyl estradiol and levonorgestrel:

• Altavera
• Amethia
• Amethia Lo
• Chateal
• Chateal EQ
• Daysee
• Delyla
• Enpresse-28
• FaLessa
• Falmina
• Fayosim
• Introvale
• Amethyst
• Ashlyna
• Aubra
• Aubra EQ
• Aviane
• Balcoltra
• Camrese
• Camrese Lo
• Jolessa
• Kurvelo
• Larissia
• Lessina
• Levonest
• Levora 0.15/30 (28)
• Lillow
• LoSeasonique
• Quasense
• Rivelsa
• Seasonique
• Setlakin
• Sronyx
• Trivora (28)
• Vienva
• Alesse 21
• Alesse 28
• Alysena 21
• Alysena 28
• Aviane
• ESME 21
• ESME 28
• Lutera
• Marlissa
• Myzilra
• Orsythia
• Portia-28
• Quartette
• Indayo
• Lutera 21
• Lutera 28
• Min Ovral 21
• Min Ovral 28
• Ovima 21
• Ovima 28
• Portia 21
• Portia 28
• Seasonale
• Seasonique
• Almina 28
• Anna
• Anulette
• Anulit
• Biphasil
• Ciclo 21
• Cleo
• Cyclogynon
• Daily Ge
• E-Gen-C
• Elevin
• Erlibelle
• Evelea MD
• Gynatrol
• Logynon
• Logynon ED
• Ludeal Ge
• Maexeni
• Microcept
• Microdette
• Microfemin
• Microfemin CD
• Microgyhnon 21
• Microgyn
• Microgynon
• Microgynon 20 ED
• Microgynon 21
• Microgynon 28
• Microgynon 30
• Microgynon 30 ED
• Microgynon CD
• Microlenyn 30 ED
• Microlite
• Mileva
• Minidril
• Minipil
• Minisiston
• Minivlar
• Mirabella
• Missee
• Klimonorm
• Lady
• Levest
• Levlen ED
• Lindella
• Lindella CD
• Loette
• Loette 21
• Monofeme
• Neogynon 21
• Nordet
• Nordette
• Nordette 21
• Nordette 28
• Norvetal
• Novastep
• Oralcon
• Ovoplex 30-150
• Ovranette
• Protec
• Rigevidon
• Rigevidon 21+7
• Safe Pill
• Seif
• Selina Mite
• Stediril 30
• Sydnaginon
• Tri-Regol
• Triciclor
• Trifeme
• Trigoa
• Trigynon
• Trinordiol
• Trinordiol 21
• Triphasil
• Triquilar
• Triquilar ED
• TriRegol
• Trolit
• Winstop 30
• Winstop T/28
• Zarine

Ethinyl estradiol and levonorgestrel Brand Names in Pakistan: