Norgestimate/ethinyl estradiol

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Norgestimate/ethinyl estradiol quick reference

Image:Norgestimate/Ethinyl Estradiol Chemical Structure.png
Norgestimate/ethinyl estradiol general drug information
 Pronunciation nor-JESS-tim-eht/ETH-in-il ess-tra-DIE-ohl (.wav file)
 Trade Name(s) Ortho Tri-Cyclen® Lo, Ortho Tri-Cyclen®
 How Supplied Norgestimate: Tablets: 0.18 mg, 0.215mg, 0.25mg
Ethinyl Estradiol: Tablets: 0.025mg
 Generic Availability Sprintec-28, Tri-Previfem, Tri-Sprintec, Trinessa
No generics are currently available for Ortho Tri-Cyclen® Lo
 Patent Expiry Date June 9, 2019
 Classification Combination oral contraceptive
 Schedule Rx
 Pregnancy Category X
 Breast-feeding Estrogens and progestins can enter the breast milk (albeit, in small amounts) and affect lactation. A barrier or other non-hormonal form of contraception is recommended until the infant is no longer breast-feeding.
Norgestimate/ethinyl estradiol chemical information
 IUPAC Name Ethinyl estradiol: (19-nor-17a-pregna,1,3,5(10)-trien-20-yne-3,17-diol)
Norgestimate: (+)-13-Ethyl-17-hydroxy-18, 19-dinor-17a-pregn-4-en-20-yn-3-one oxime acetate (ester)
 Empirical Formula Ethinyl Estradiol: C20H24O2
Norgestimate: C23H31NO3
 Molecular Weight 296.403 g/mol
pharmacokinetic information  |  pharmacogenomic information
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Description

Norgestimate and Ethinyl estradiol (EE) are used in combination primarily for hormonal contraceptive purposes. EE is one of two synthetic estrogens used in combination oral contraceptives (COCs). The other, mestranol, is converted to EE in the body. Mestranol itself is not pharmacologically active. Norgestimate-containing COCs are considered third-generation. They are thought to have no estrogenic effects and limited androgenic effects compared to other, older COCs. Most progestins have very little effect on carbohydrate metabolism. Low dose COCs generally do not produce a large or significant bleeding problem. In general, lipid metabolism can be adversely affected by progestins leading to a decrease in high density lipids (HDLs) and an increase in low density lipids (LDLs). In most low dose COCs, the effects are minimal.[1][2]

Benefits other than contraception include less risk for ovarian and endometrial cancers, less risk of pelvic inflammatory disease, increased regularity of menstrual cycle, decreased blood loss, decreased risk of iron deficiency anemia, less dysmenorrhea, less risk of functional ovarian cysts, less risk of ectopic pregnancies, and less risk of fibroadenomas and fibrocystic disease of the breast.[2]

Norgestimate has not been studied for emergency contraception.[2]

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Mechanism of Action

Oral contraceptives act primarily by inhibition of ovulation via gonadotropin suppression. Combination oral contraceptives use estrogen (in this case ethinyl estradiol)to suppress the luteinizing hormone, and a progestin (norgestimate) to inhibit the follicle-stimulating hormone. The resulting effects help block pregnancy: 1) Thickening of the cervical mucus prevents entry of the sperm; 2) Thinning of the endometrium (the lining of the uterus) prevents implantation of a fertilized egg. Estrogen also increases the production of sex hormone binding globulin.[2]

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Time Required for Therapeutic Response

  • Initial: type initial response time
  • Maximum: type maximum response time
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Pharmacokinetics

Absorption
After oral administration, norgestimate and ethinyl estradiol undergo rapid absorption.[2]

Distribution
Norelgestromin and its metabolite, norgestrel, are 97% bound to serum proteins. Norelgestromin binds to albumin, while norgestrel binds primarily to the sex hormone binding globulin. Ethinyl estradiol is 97% bound to serum albumin.[2]

Metabolism
Norgestimate undergoes extensive hepatic and/or intestinal first-pass metabolism to norelgestromin, its main metabolite with pharmacological activity. Norelgestromin undergoes further metabolism (via hydroxylation and conjugation) to other metabolites including an active one, norelgestrel. Ethinyl estradiol is hydroxylated, followed by glucuronidation and sulfate conjugation.[2]

Excretion
The following excretion information occurs after 3 cycles (84 days) of continuous use of Ortho Tri-Cyclen Lo: Elimination half-life at steady-state: (in terms of mean +/- SD)
Norelgestromin: 28.1 (+/- 10.6) hours
Norgestrel: 36.4 (+/- 10.2) hours
Ethinyl estradiol: 17.7 (+/- 4.4) hours
The metabolites of norelgestromin and ethinyl estradiol are excreted renally and fecally.[2]

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Special Population Pharmacokinetics

  • Renal insufficiency: No studies conducted on Ortho Tri-Cyclen Lo.[2]
  • Hepatic insufficiency: The use of oral contraceptives are contraindicated in hepatic impairment[2]
  • Geriatric: Not indicated for use in the eldery.[2]
  • Pediatric: Not indicated for use in pre-pubescent females or females who have not reached menarche.[2]
  • Gender: Males should not use norgestimate/ethinyl estradiol[2]
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Indications and Dosages

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FDA Approved Indications

Oral Contraception[2]

  • Sunday Start:
    • The first white tablet should be taken the Sunday after the first day of menstruation.
    • Continue taking one white tablet daily until finished. Continue this regimen with the light blue and dark blue tablets. The green tablets are inactive and are there to remind the patient to take the medication at the same time everyday. For maximum efficacy, each tablet should be taken at exactly the same time everyday.
    • After one 28-day course, menstruation will begin on a Sunday (which will be the following day).
    • A barrier or other method of contraception should be employed for the first 7 days of the first cycle.
  • Day 1 Start:
    • The first white tablet should be taken the first day of menstruation.
    • Continue taking one white tablet daily until finished. Continue this regimen with the light blue and dark blue tablets. The green tablets are inactive and are there to remind the patient to take the medication at the same time everyday. For maximum efficacy, each tablet should be taken at exactly the same time everyday.
    • After one 28-day course, menstruation will begin the following day.
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Non-FDA Approved Indications

  • amenorrhea[2]
  • dysfunctional uterine bleeding[2]
  • endometriosis[2]
  • hirsutism[2]
  • polycystic ovary syndrome[2]
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Dosage Adjustment

  • Renal insufficiency: No dosage adjustment is necessary.[2]
  • Hepatic insufficiency: the use of hormonal contraception is contraindicated in hepatic disease or dysfunction.[2]
  • Geriatric: Oral contraceptives are not indicated for the eldery.[2]
  • Pediatric: Oral contraceptives are not indicated for pre-pubescent females or those that have not reached menarche.[2]
  • Gender: Norgestimate/ethinyl estradiol is contraindicated in males.[2]
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Dosage Limits

  • Adults: enter adult dosing limit
  • Elderly: enter elderly dosing limit
  • Adolescents and children: enter adolescent/children dosing limit (may be different, especially for small children and neonates...use extra bullet points for these special populations if necessary


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Missed Dose

A back-up contraceptive measure must be employed for 7 days from the first missed dose.

  • Sunday Start:[2]
    • Missed one active tablet:
      • The dose should be taken as soon as possible. This may mean taking two tablets in one day.
    • Missed two tablets:
      • White or light blue: If these tablets are missed in Weeks 1 or 2, take 2 tablets as soon as remembered. The next day, 2 active tablets must also be taken. The remainder of the pack can be completed with one tablet daily.
      • Dark blue:If these tablets are missed in Week 3, take one tablet daily until Sunday. On Sunday, the remainder of the pack should be discarded, and a new pack should be started.
    • Missed 3 or more consecutive active tablets (white, light blue, dark blue):
      • Take one tablet daily until Sunday. On Sunday, the remainder of the pack should be discarded, and a new pack should be started.


  • Day 1 Start:[2]
    • Missed one active tablet:
      • The dose should be taken as soon as possible. This may mean taking two tablets in one day.
    • Missed two tablets:
      • White or light blue: If these tablets are missed in Weeks 1 or 2, take 2 tablets as soon as remembered. The next day, 2 active tablets must also be taken. The remainder of the pack can be completed with one tablet daily.
      • Dark blue:If these tablets are missed in Week 3, take one tablet daily until Sunday. On Sunday, the remainder of the pack should be discarded, and a new pack should be started.
    • Missed 3 or more consecutive active tablets (white, light blue, dark blue):
      • The remainder of the pack should be discarded, and a new pack should be started that same day.
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Administration

  • Route: oral
  • Method:
    • Take one tablet daily with a full glass of water.
    • It is important to take this medication at the same time everyday[2]
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Monitoring Parameters

If any of these symptoms occur, contact your health care practitioner immediately[2]

  • Chest pain (sharp, crushing, or feelings of heaviness)
  • Calf pain
  • Shortness of breath
  • Coughing of blood
  • Headache
  • Vomiting
  • Dizziness
  • Visual disturbances
  • Weakness or numbness in any limb
  • Speech disturbances
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Contraindications/Precautions

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Contraindications

  • Thrombophlebitis or thromboembolic disorders[2]
  • A past history of deep vein thrombophlebitis or thromboembolic disorders[2]
  • Cerebral vascular or coronary artery disease (current or history)[2]
  • Valvular heart disease with complications[2]
  • Severe hypertension[2]
  • Diabetes with vascular involvement[2]
  • Headaches with focal neurological symptoms[2]
  • Major surgery with prolonged immobilization[2]
  • Known or suspected carcinoma of the breast or personal history of breast cancer[2]
  • Carcinoma of the endometrium or other known or suspected estrogen-dependent neoplasia[2]
  • Undiagnosed abnormal genital bleeding[2]
  • Cholestatic jaundice of pregnancy or jaundice with prior pill use[2]
  • Hepatic adenomas or carcinomas[2]
  • Known or suspected pregnancy[2]
  • Hypersensitivity to any component of this product[2]
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Precautions

  • General

This product does not protect against HIV infection (AIDS) and other sexually transmitted diseases.[2]

  • Physical Examination and Follow-Up

It is recommended that women have a physical examination prior to taking oral contraceptives. The woman may request to obtain a physical examination after the oral contraception has been started, if the health care practitioner deems it appropriate. A complete physical examination should include blood pressure, breasts, abdomen and pelvic organs, including cervical cytology, and laboratory tests. For women with frequent abnormal vaginal bleeding, an examination for a malignancy should be performed. Of particular concern for complications/adverse events are women with a family history of breast cancer or those with breast nodules.[2]

  • Lipid Disorders

Women with hyperlipidemia should use caution, as oral contraceptives may increase LDL levels.[2]

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Pregnancy indications

Category X

This medication is absolutely contraindicated in any stage of pregnancy. If the patient becomes pregnant, she should stop taking the oral contraceptives immediately.[2]

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Breast-feeding indications

Norgestimate and ethinyl estradiol have been known to enter the breast milk in small amounts. Few adverse reactions have been reported in infants ingesting this milk such as jaundice and breast enlargement. Production and quality of breast milk has also decreased. It is recommended that women do not use oral contraceptives until the child has stopped nursing.[2]

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Drug-Drug, -Food, -Herb Interactions

Click the link above to go to the drug interactions page.

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Adverse Reactions/Side Effects

Ortho Tri-Cyclen Lo Adverse Reactions Chart
Incidence Body System Adverse Reactions
>10% All AE's > 10% Here
1-10% CNS TYPE CNS ADVERSE EFFECTS OCCURRING AT 1-10%
Cardiovascular TYPE CARDIOVASCULAR ADVERSE EFFECTS OCCURRING AT 1-10%
Dermatologic TYPE DERMATOLOGIC ADVERSE EFFECTS OCCURRING AT 1-10%
GI TYPE GI ADVERSE EFFECTS OCCURRING AT 1-10%
Genitourinary TYPE GENITOURINARY ADVERSE EFFECTS OCCURRING AT 1-10%
Neuromuscular/skeletal TYPE NEUROMUSCULAR/SKELETAL ADVERSE EFFECTS OCCURRING AT 1-10%
Respiratory TYPE RESPIRATORY ADVERSE EFFECTS OCCURRING AT 1-10%
Miscellaneous TYPE MISCELLANEOUS ADVERSE EFFECTS OCCURRING AT 1-10%
<1% All ENTER ALL ADVERSE REACTIONS WITH AN INCIDENCE OF <1% HERE (just a list is sufficient)
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Overdosage Measures

In young children, no serious adverse effects have been reported after a large dose of norgestimate/ethinyl estradiol. In women, an overdose may lead to nausea and withdrawal bleeding.[2]

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Product Information and Distribution

Note: appearance only available for brand-name product
Ortho Tri-Cyclen Lo[2]
Dose/form Drug color(s) Drug shape Markings or odor/flavor
Ethinyl Estradiol 0.025mg/Norgestimate 0.18 mg tablet white round O-M/180
Ethinyl Estradiol 0.025mg/Norgestimate 0.215 mg tablet light blue round O-M/215
Ethinyl Estradiol 0.025mg/Norgestimate 0.25 mg tablet dark blue round O-M/250
Placebo reminder tablet dark green round O-M/P
  • Inactive ingredients for tablets:[2]
    • White tablets: lactose, magnesium stearate, croscarmellose sodium, microcrystalline cellulose, carnauba wax, hypromellose, polyethylene glycol, titanium dioxide, purified water.
    • Light Blue tablets: FD & C Blue No. 2 Aluminum Lake, lactose, magnesium stearate, croscarmellose sodium, microcrystalline cellulose, carnauba wax, hypromellose, polyethylene glycol, titanium dioxide, purified water.
    • Dark Blue tablets: FD & C Blue No. 2 Aluminum Lake, lactose, magnesium stearate, croscarmellose sodium, microcrystalline cellulose, carnauba wax, hypromellose, polysorbate 80, titanium dioxide, purified water.
    • Dark Green tablets: FD & C Blue No. 2 Aluminum Lake, lactose, magnesium stearate, pregelatinized starch, ferric oxide, hypromellose, polyethylene glycol, titanium dioxide, talc, purified water.
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Patient Information

  • Type patient information using bullet points.
  • Use as many bullet points as you need.
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References

  1. ↑ Bucci KK, Carson DS, (1999). Contraception. Eds: DiPiro JT., et al. Pharmacotherapy: A Pathophysiologic Approach. pgs: 1327-41. New York, McGraw-Hill.
  2. ↑ 2.00 2.01 2.02 2.03 2.04 2.05 2.06 2.07 2.08 2.09 2.10 2.11 2.12 2.13 2.14 2.15 2.16 2.17 2.18 2.19 2.20 2.21 2.22 2.23 2.24 2.25 2.26 2.27 2.28 2.29 2.30 2.31 2.32 2.33 2.34 2.35 2.36 2.37 2.38 2.39 2.40 2.41 2.42 2.43 2.44 2.45 2.46 2.47 2.48 2.49 2.50 Ortho Tri-Cyclen Lo® (Norgestimate/ethinyl estradiol) package insert. Raritan, NJ; Ortho-McNeil; 2004 Nov.
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PUBMED References

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Efficacy Trial Articles

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Therapeutic Class Comparison Articles

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Pharmacokinetics Articles

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Drug Interaction Articles

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Adverse Effects Articles

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Compliance Articles

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Pharmacoeconomic Articles

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External Links

Clinical treatment guidelines

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Patient information pages

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Other resources

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