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) Use:

• Contraception:

  • Used in the Prevention of pregnancy.

• Emergency contraception:

  • Postcoital emergency contraception.
  • Limitations of use:
    • When other techniques are unavailable, the combination of Ethinyl estradiol and levonorgestrel is effective and advised as a backup option for managing emergency contraception.
    • Due to the increased adverse effects and decreased efficacy seen with this combination, it is preferable to employ alternate techniques.

• 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: Once a day, one pill. General dosage recommendations; consult the prescription instructions for information relevant to the product

• Schedule 1 (Sunday starter):

  • The first Sunday following the start of menstruation is when the dose is started; if the period occurs on a Sunday, take the first pill on that day.
  • A second method of birth control should be used with a Sunday start until after the first weak of each subsequent dose.

• Schedule 2 (Day 1 starter):

  • Take 1 pill once daily beginning on the first day of the menstrual cycle to begin the dose.

• Missed or late doses:

  • If one dose is missed (more than 48 hours after the dose was supposed to be taken) or is taken late (less than 24 hours after the dose should have been taken):
    • As soon as you can, take your dose.
      Take the remaining doses as usual (even if that means 2 doses on the same day).
  • If two or more doses are missed in a row (within 48 hours of the scheduled dose):
    • Discard any more missed pills and take the most recent missed dose as soon as you remember.
    • Use backup contraception until hormonal tablets have been taken for 7 days straight; continue remaining doses at the regular time (even if it means taking 2 doses on the same day).
    • When starting a new pack, finish the previous pack if doses were missed during the final week of hormonal (active) pills (e.g., days 15 to 21 of a 28-day pack).
    • Back-up contraception must be used until hormone tablets from a new pack have been taken for 7 days straight if a new pack cannot be started right away.
    • In such circumstances, take into account using emergency contraception (refer to guidelines for details).

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

• Oral (off-label dosing):
  • 12 hours after the first treatment, a second dose is administered.
  • Levonorgestrel 0.5 mg and ethinylestradiol 100 mcg should be the absolute lowest amounts in each dose.
  • Even though there isn't a dedicated dosage form available anymore, you can still get this dose by using a combined oral contraceptive pill.
  • Emergency contraception should start as soon as feasible, although if used within five days of unprotected or insufficiently protected intercourse, treatment is still only moderately effective.
  • Antiemetics should not be used routinely, although, for some women, pretreatment may be an option.

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 weeks after delivery before starting the combination.
• Combination hormonal contraceptives should be stopped in women 21 days after delivery due to the increased risk of venous embolism (VTE).
• To prevent pregnancy, combination of 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, and smoking.
• If emergency contraception is required, it is advisable to immediately use a barrier contraceptive.
• After combined estrogen/progestin emergency 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 labelling 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):

The reactions listed may not have been explicitly recorded for Ethinyl estradiol/levonorgestrel; rather, they are based on reports for other oral contraceptives in the same pharmacologic class.

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 another 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),
• 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 the heart (eg subacute bacteria endocarditis or atrial fibrillation)
• Women over 35 who smoke

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

• Intolerance to ethinylestradiol, levonorgestrel, or any other formulation ingredient
• Ocular diseases brought on by ophthalmic vascular disease, include partial or complete blindness and visual field defects.
  severely dyslipidemic;
• continuous blood pressure greater than or equal to 160 mmHg Systolic, greater than or equal to 100 mmHg Diastolic Myocardial Infarction, either present or past;
• Prodromi of thrombosis (such as transient ischemic episodes, angina pectoris, or a history or current case of); Postoperative bleeding is more likely after major surgery.
• permanent immobility
• history of cholestatic jaundice, steroid-dependent jaundice, and jaundice during pregnancy
• Pancreatitis may develop in the presence or history of severe hypertriglyceridemia.
• 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 tumour. Women with a history of breast cancer or a recent diagnosis may have a worse prognosis if they use combination hormonal contraceptives.
  • Women with a 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 tumour. Women with a history of breast cancer or a recent diagnosis may have a worse prognosis if they use combination hormonal contraceptives.
  • Women with a 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 family history.
  • Women with uncontrolled dyslipidemia should consider alternative contraception
  • Combination hormonal contraceptives can adversely affect lipid levels, especially serum triglycerides.

• Retinal vascular embolism:

  • Women who are at high risk for arterial or venous thrombosis may not use combination hormonal contraceptives.

• 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 of 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 a breakthrough.
  • There may be occasional missed periods.

• Cardiovascular disease

  • Patients at high risk for coronary artery diseases 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.
  • Women who are at high risk for arterial or venous thrombosis may not use combination hormonal contraceptives.

• 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:

  • Oral contraceptives may be necessary for women who have BRCA1 or BRCA2 mutations in order to reduce their chance of getting 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 tumours (rare); rupture could lead to fatal intra-abdominal bleeding.

• Hepatic impairment

  • Stop using if jaundice develops while receiving medication or if the liver function is off.
  • Hepatic conditions that have already existed are not advised.
  • Women with mild (compensated), but not severe (decompensated), cirrhosis can take combination of hormonal contraceptives.
  • Combining hormonal contraceptives may not be processed by women with reduced liver function.

• Hepatitis

  • Women with chronic hepatitis have not been shown to experience an increase in the severity or rate of cirrhotic fibrosis.
  • 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:

  • Despite a lack of data, women who had to endure difficult organ transplants reported severe medical consequences (eg rejection, graft failure and cardiac allograft vasculopathy).
  • Women who have undergone numerous organ transplants shouldn't use combination hormonal contraceptives.

• 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:

•  pregnancy 
• blood pressure
• weight 
• BMI 

The potential of pregnancy should be taken into account if all medicines have not been taken as directed and one menstrual period has been missed. Before beginning a new dosage cycle, determine whether the pregnancy is present if two consecutive menstrual cycles are missed. observe the patient for:

• vision changes
• blood pressure
• thromboembolic disorders
• glycemic control 
• depression
• lipid profiles 

Emergency contraception:

• If your period is delayed for a week or longer after using emergency contraception, or if you experience lower abdominal pain or chronic irregular bleeding, you should be evaluated for pregnancy, spontaneous abortion, or ectopic pregnancy.

How to administer Ethinyl estradiol and levonorgestrel (Famila)?

Contraception:

• Administer every day at the same time. If it is generally certain the woman is not pregnant, combined hormonal contraceptives may be started at any point throughout the menstrual cycle.
• Unless contraception is started within the first five days of menstrual bleeding or the woman abstains from sexual activity, backup contraception should be taken for seven days.
• Following a first or second-trimester abortion, combined hormonal contraceptives may be started; backup contraception is required during a week unless contraception is started at the time of the surgical procedure.

Emergency contraception:

• A second dose should be given as soon as possible if vomiting starts within three hours; you might also want to use an antiemetic.

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

• Combination hormonal contraceptives can inhibit ovulation through a negative feedback mechanism on the hypothalamus.
• This alters the normal pattern of 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 unfavourable conditions for nidation.
• Combination hormonal contraceptives drugs can alter the tubal transport of eggs through the fallopian tubes. 
• The fertility of sperm may also be affected by progestational drugs.

Absorption:

• Rapid

Protein binding:

• 95–97% of ethinyl estradiol is bound to albumin.
• Levonorgestrel binds mostly to sex hormone-binding globulin (SHBG) and to a lesser extent to albumin (97–99%).

Metabolism:

• Ethinyl estradiol: First-pass metabolism occurs in the liver via CYP3A4 and results in metabolites.
• Forms conjugated in unconjugated metabolites of levonorgestrel.

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: