Norethindrone (NET) and Norethindrone acetate (NETA) are synthetic progestin hormones used as contraceptives and abnormal uterine bleeding secondary to deranged hormonal profile.

Norethindrone Uses:

• Abnormal uterine bleeding (norethindrone acetate):

  • Used for treatment of abnormal uterine bleeding due to hormonal imbalance in the absence of organic pathologies, such as submucous fibroids or uterine cancer.

• Secondary Amenorrhea (norethindrone acetate):

  • Treatment of secondary amenorrhea

• Contraception (norethindrone):

  • Prevention of pregnancy

• Endometriosis (norethindrone acetate):

  • Treatment of endometriosis

• Limitations of use:

  • Norethindrone is not indicated for emergency contraception.
  • Norethindrone acetate is not indicated for use with estrogen therapy in postmenopausal women for endometrial protection.

Norethindrone dose in Adults

Norethindrone dose in the treatment of abnormal uterine bleeding and amenorrhea:

• Oral: Norethindrone acetate:
  • 2.5 to 10 mg/day for 5 to 10 days.
• Secretory transformation of the endometrium will occur when adequately primed with endogenous or exogenous estrogen.
• Withdrawal bleeding may be expected within 3 to 7 days after discontinuing norethindrone acetate.

Norethindrone dose in the treatment of contraception:

• Oral: Norethindrone:

  • 0.35 mg every day (no missed days)

• Initial dose:

  • Start on the first day of the menstrual period or the day after a miscarriage or abortion. If switching from a combined oral contraceptive, begin the day after finishing the last active combined tablet.

• Missed dose:

  • Take as soon as you remembered. A backup method of contraception should be used for 48 hours if the dose is taken ≥3 hours late.

• Additional contraception dosing considerations:

  • Initiation of therapy: May be started at any time in the menstrual cycle once it is determined that the woman is not pregnant.
  • Back-up contraception is not needed if started within 5 days of onset of menstruation.
  • If started >5 days after the onset of menstruation or at any time in a woman experiencing amenorrhea (not postpartum), back up contraception should be used for 2 days.

• Switching from a different contraceptive to a progestin-only contraceptive:

  • If it is determined that the woman is not pregnant it may be started at any time
  • Unless the woman abstains from sexual intercourse, a backup method of contraception is needed if it has been >5 days since menstrual bleeding has begun.
  • When an additional method of contraception is needed, consider continuing the woman’s previous method for 2 days after starting the progestin-only contraceptive.

• Switching from an IUD to a progestin-only contraceptive:

  • Continue the IUD for at least 2 days after the progestin-only contraceptive is started or advise the woman to abstain from sexual intercourse or use a barrier contraceptive for 7 days before removing the IUD.
  • Alternately, an emergency contraceptive may be used at the time of IUD removal.

Norethindrone Dose in the treatment of Endometriosis:

Females:

• Oral: Norethindrone acetate: 5 mg/day for 14 days.
• Increase at increments of 2.5 mg/day every 2 weeks to reach 15 mg/day.
• Continue for 6 to 9 months or until breakthrough bleeding demands temporary termination.

Norethindrone dose in Childrens

Norethindrone Dose in the treatment of abnormal uterine bleeding and Secondary amenorrhea:

• Postmenarche females:

  • Norethindrone acetate: Oral:
    • 2.5 to 10 mg once a day for 5 to 12 days each month.
  • Most pediatric experts suggest 5 mg once a day for 12 days per month.
  • Secretory transformation of the endometrium will occur when adequately primed with endogenous or exogenous estrogen.
  • Withdrawal bleeding may be expected within 3 to 7 days after discontinuing norethindrone acetate.

Norethindrone Dose in the treatment of Contraception:

• Postmenarche adolescent females:

  • Norethindrone:
    • Oral: 0.35 mg once a day every day (no missed days)
  • Initial dose:
    • Start on the first day of the menstrual period or the day after a miscarriage or abortion. If switching from a combined oral contraceptive, begin the day after finishing the last active combined tablet.
  • Missed dose:
    • Take as soon as you remembered. A back-up method of contraception should be used for 48 hours if the dose is taken ≥3 hours late.

  • Additional contraception dosing considerations:

    • Initiation of therapy:
      • May be started at any time in the menstrual cycle once it is determined that the female is not pregnant.
      • Back-up contraception is not needed if started within 5 days of onset of menstruation.
      • If started >5 days after the onset of menstruation or at any time in a female experiencing amenorrhea (not postpartum), back up contraception should be used for 2 days.

    • Switching from a different contraceptive to a progestin-only contraceptive:

      • May be started at any time if it is determined that the female is not pregnant.
      • Unless the female abstains from sexual intercourse, a back-up method of contraception is needed if it has been >5 days since menstrual bleeding has begun.
      • When an additional method of contraception is needed, consider continuing the woman’s previous method for 2 days after starting the progestin-only contraceptive.

    • Switching from an IUD to a progestin-only contraceptive:

      • Continue the IUD for at least 2 days after the progestin-only contraceptive is started or advise the female to abstain from sexual intercourse or use a barrier contraceptive for 7 days before removing the IUD.
      • Alternately, an emergency contraceptive may be used at the time of IUD removal.

Norethindrone Dose in the treatment of Endometriosis:

• Postmenarche females ≥10 years:

• Norethindrone acetate:

• Oral: 5 mg once a day for 14 days.
• Increase at increments of 2.5 mg/day every 2 weeks to reach target maintenance of 15 mg/day; continue for 6 to 9 months or until breakthrough bleeding demands temporary termination.

Norethindrone pregnancy risk category: X

• Pregnancy is a contraindication to the use of this product.
• Progestins can cause genital abnormalities in the first trimester, including hypospadias for male infants and mild female virilization.
• Female infants who were exposed to norethindrone have experienced changes in their external genitalia.
• Limited studies have not shown any significant adverse effects on growth or development following contraceptive doses of oral progestins.
• Norethindrone
  • You can start progestin-only contraceptives immediately after birth.
  • When progestin-only contraceptives stop being used, there is a rapid return to fertility.
• Norethindrone acetateIt is unknown what the contraceptive dose of norethindrone-acetate is. 
• To prevent unintended pregnancies (eg when treating endometriosis), it is recommended that you use barrier contraception.

Use of Norethindrone while breastfeeding

• Breast milk contains norethindrone.
• When norethindrone was calculated from the highest breastmilk concentration and compared with a maternal dose of 0.35mg per day, the relative infant dose (RID), of norethindrone was 4.1%.
• When the RID of medication falls below 10%, breastfeeding is generally acceptable.
• The RID of norethindrone was calculated with a milk concentration 1,364 pg/mL. This gives an estimated daily infant dose via breastmilk of 0.205 mg/kg/day.
• This was achieved after maternal administration of oral norendrone 0.35 mg to five mothers within one month of birth.
• The maternal milk concentrations were measured for 24 hours following the initial treatment. Peak milk concentrations occurred two hours later.
• Actual milk concentrations differed widely among women, and were only about one-tenth the levels in maternal plasma.
• Studies that used higher doses of norethindrone in combination with estrogen and norethindrone via different routes showed milk concentrations that varied.
• There have been isolated reports of reduced milk production and rare cases of jaundice among breastfeeding infants.
• There have been no reports of adverse events relating to infant development and growth.
• Norethindrone-acetate manufacturer recommends caution when administered to breastfeeding women.
• Norethindrone can be used to contraceptive purposes in nursing women at any stage after birth.

Norethindrone Dose in Kidney Disease:

• In the manufacturer’s labeling there are no dosage adjustments provided

Norethindrone Dose in Liver Disease:

• There are no dosage adjustments provided in the manufacturer’s labeling.
• However, use is contraindicated in patients with hepatic tumors or impairment.

Side effects of Norethindrone:

• Cardiovascular:

  • Cerebral Embolism
  • Cerebral Thrombosis
  • Deep Vein Thrombosis
  • Edema
  • Pulmonary Embolism
  • Retinal Thrombosis

• Central Nervous System:

  • Depression
  • Dizziness
  • Fatigue
  • Headache
  • Insomnia
  • Migraine
  • Emotional Lability
  • Nervousness

• Dermatologic:

  • Acne Vulgaris
  • Alopecia
  • Chloasma
  • Pruritus
  • Skin Rash
  • Urticaria

• Endocrine & Metabolic:

  • Amenorrhea
  • Hirsutism
  • Hypermenorrhea
  • Menstrual Disease
  • Weight Gain

• Gastrointestinal:

  • Abdominal Pain
  • Nausea
  • Vomiting

• Genitourinary:

  • Breakthrough Bleeding
  • Breast Hypertrophy
  • Breast Tenderness
  • Cervical Erosion
  • Change In Cervical Secretions
  • Decreased Lactation
  • Genital Discharge
  • Mastalgia
  • Spotting
  • Vaginal Hemorrhage

• Hypersensitivity:

  • Anaphylaxis
  • Hypersensitivity

• Hepatic:

  • Cholestatic Jaundice
  • Hepatitis
  • Abnormal Hepatic Function Tests

• Neuromuscular & Skeletal:

  • Arm Pain
  • Leg Pain

• Ophthalmic:

  • Optic Neuritis (With Or Without Vision Loss)

Contraindications to Norethindrone:

• Hypersensitivity to norethindrone and any component of the formula
• Hepatic impairment and disease
• Breast cancer (known, suspected or history).
• Atypical genital bleeding that is not diagnosed.
• Pregnancy

Norethindrone: Other contraindications

• Liver tumors can be benign or malignant.

Norethindrone acetate

Additional contraindications

• DVT or PE (currently or in the past); Active or recent history arterial thromboembolic diseases (eg stroke, MI); as a diagnostic test to determine pregnancy.

Additional contraindications to Canadian labeling

• Progestin dependent or estrogen dependent malignant tumor
• Ophthalmic vascular disease can cause vision loss, partial or complete.
• Missed abortion

Warnings and precautions

• Bleeding

  • Progestin-only contraceptives can cause irregular menstrual patterns.
  • It is important to rule out other causes of abnormal bleeding.

• Breast cancer

  • Combination hormonal contraceptives have been shown to be associated with an increase in breast cancer incidence, but studies are inconsistent.
  • It is not possible to determine whether progestin-only contraceptives increase this risk.
  • Breast cancer patients should not take norethindrone or norethindrone-acetate.

• Delayed follicular Atresia/ Ovarian Cysts

  • Follicular development can occur after contraception. Follicles may grow beyond what is normal.
  • This could be either asymptomatic, or it can be associated with mild abdominal discomfort.
  • Rarely is surgery required.

• Ectopic pregnancy

  • Patients with lower abdominal pain should be aware of the possibility of an ectopic pregnancy after using a progestin only contraceptive.

• The Lipid Effects

  • Could have negative effects on lipid metabolism
  • Women with hyperlipidemia should be cautious.

• Visual abnormalities

  • Norethindrone acetateIf you experience migraine, vision loss, dizziness, headaches, proptosis, diplopia or any other visual disturbances, discontinue use immediately.

• Cardiovascular disease

  • Norethindrone acetate Risk factors for cardiovascular disorders include diabetes mellitus, hypercholesterolemia, hypertension, SLE, obesity, tobacco use, and/or history of venous thromboembolism (VTE). It is important to manage risk factors.

• Depression

  • Norethindrone acetatePatients with depression should be cautious. Women with depression may use progestin-only contraceptive pills.

• Diabetes:

  • Could have negative effects on glucose tolerance
  • Women with diabetes should be cautious.
  • Women with diabetes may use progestin-only contraceptive pills.

• Fluid retention can lead to more severe diseases

  • Norethindrone acetatePatients with fluid retention or other conditions, such as asthma, epilepsy, cardiac or renal dysfunction, should be cautious.

• Hepatic adenomas

  • In association with long-term combination oral contraceptive use, extremely rare cases of hepatic hyperplasia and focal nodular hyperplasia leading to fatal intra-abdominal bleeding have been reported.
  • It is not possible to determine whether progestin-only contraceptives increase this risk.
  • Women with hepatic cancer should not use contraceptives.

• Migraine

  • Patients with migraine history should be cautious.
  • Women with migraines or headaches may need to use progestin-only contraceptives tablets.
  • It is important to evaluate any new headaches or changes in your headaches.

Monitoring Parameters:

Norethindrone:

• Contraception: Assessment of pregnancy status (prior to therapy).
• Weight (optional; BMI at baseline may be helpful to monitor changes during therapy).
• Assess potential health status changes at routine visits.

Norethindrone acetate:

• Monitor patients for vision changes.
• Signs or symptoms of depression.
• Glycemic control in patients with diabetes.
• Lipid profiles in patients being treated for hyperlipidemias.
• Regardless of indication, adequate diagnostic measures, including endometrial sampling, if indicated, should be performed to rule out malignancy in all cases of undiagnosed abnormal vaginal bleeding.
• Pathologists should be informed of therapy when submitting endometrial tissue for histologic evaluation.

How to administer Norethindrone?

• Administer at the same time each day for oral administration.
• When used for the prevention of pregnancy, a backup method of contraception should be used for 48 hours if the dose is missed or taken ≥3 hours late.
• If vomiting or severe diarrhea occurs within 3 hours of taking a dose, take another dose as soon as possible, then continue taking one dose a day and use a backup method of contraception (or avoid sexual intercourse) until 2 days after vomiting or diarrhea have resolved.
• Emergency contraception should be considered in the event of unprotected intercourse.

Mechanism of action of Norethindrone:

• Once absorbed, norethindrone is still in the body.
• The preparations of progestin-only contraception are made with NET.
• NET reduces ovulation and thickens cervical mucus (which hinders sperm penetration), alters FSH and LH concentrations, slows down the movement of the egg through the fallopian tubes and alters the endometrium.
• Progestogens such as NETA, in doses used to treat abnormal uterine bleeding and amenorrhea, or endometriosis, can cause tissue atrophy.
• They can also inhibit new growth and implantation.
• Endometriosis pain is lessened.
• When treating endometriosis, NETA may be used in combination with gonadotropin-releasing hormone agonists to decrease side effects from hypoestrogenism.

Absorption:

• Oral: Rapidly absorbed

Protein binding:

• 61% to albumin; 36% to sex hormone-binding globulin (SHBG); SHBG capacity affected by plasma ethinyl estradiol levels.

Metabolism:

• Oral: Norethindrone acetate is deacetylated to norethindrone.
• Norethindrone undergoes hepatic reduction and conjugation; orally administered norethindrone is subject to the first-pass effect (Orme 1983).
• In addition to forming glucuronide and sulfide conjugates, norethindrone is also metabolized to ethinyl estradiol.

Bioavailability:

• 64% (Orme 1983)

Half-life elimination:

• ~8 to 9 hours

Time to peak:

• ~2 hours (varies by dose and use of concomitant estrogen (Orme 1983)

Excretion:

• Urine (>50% as metabolites); feces (20% to 40% as metabolites)

International Brands of Norethindrone:

• Aygestin
• Camila
• Deblitane
• Errin
• Heather
• Incassia
• Jencycla
• Jolivette
• Lyza
• Nor-QD
• Nora-BE
• Norlyda
• Norlyroc
• Ortho Micronor
• Sharobel
• Tulana
• Jencycla
• Micronor
• Movisse
• Norlutate
• Aminor
• Ethinor
• Menogia
• Menoral-S
• Micro-Novom
• Micronor
• Micronovum
• Mini-PE
• Norcolut
• Norcutin
• Norestin
• Noretone
• Norgest
• Noriday
• Noriday 28
• Norlut-N
• Norluten
• Ortho-Novum
• Primolut
• Primolut N
• Primolut Nor
• Primolut-N
• Primolut-Nor
• Primolutin
• Regamen
• Renorcyl
• Rontril
• Shiton
• Steron
• Styptin 5
• Sunolut
• Utovlan

Norethindrone Brand Names in Pakistan:

• No Brands Available in Pakistan.