- Cyonanz mg
- Cyonanz tablet
- Cyonanz action
- Cyonanz drug
- Cyonanz dosage
- Cyonanz effects of
- Cyonanz adverse effects
- Cyonanz the effects of
- Cyonanz side effects
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Combined oral contraceptives
The following product is a combined oral contraceptive containing the progestational compound norethindrone and the estrogenic compound ethinyl estradiol.
Each white to off-white tablet contains 0.5 mg of norethindrone USP and 0.035 mg of ethinyl estradiol USP. Inactive ingredients include anhydrous lactose, lactose monohydrate, magnesium stearate and pregelatinized starch (maize). Each green tablet contains only inert ingredients, as follows: anhydrous lactose, croscarmellose sodium, FD&C Blue No. 2 aluminum lake, ferric oxide yellow, magnesium stearate, microcrystalline cellulose, and povidone.
The chemical name for norethindrone is 17-Hydroxy-19-nor-17α-pregn-4-en-20-yn-3-one, and for ethinyl estradiol is 19-Nor-17α-pregna-1,3,5(10)-trien-20-yne-3,17-diol. Their structural formulas are as follows:
Cyonanz - Clinical Pharmacology
Combined Oral Contraceptives
Combined oral contraceptives act by suppression of gonadotropins. Although the primary mechanism of this action is inhibition of ovulation, other alterations include changes in the cervical mucus (which increase the difficulty of sperm entry into the uterus) and the endometrium (which reduce the likelihood of implantation).
Indications and Usage for Cyonanz
CyonanzTM tablets are indicated for the prevention of pregnancy in women who elect to use this product as a method of contraception.
Oral contraceptives are highly effective. Table 1 lists the typical accidental pregnancy rates for users of combined oral contraceptives and other methods of contraception. The efficacy of these contraceptive methods, except sterilization, the IUD, and the NORPLANT® System depends upon the reliability with which they are used. Correct and consistent use of methods can result in lower failure rates.
|Adapted from Hatcher et al, 1998, Ref. #1. |
Emergency Contraceptive Pills: Treatment initiated within 72 hours after unprotected intercourse reduces the risk of pregnancy by at least 75%.§
Lactational Amenorrhea Method: LAM is a highly effective, temporary method of contraception. ¶
Source: Trussell J. Contraceptive efficacy. In Hatcher RA, Trussell J, Stewart F, Cates W, Stewart GK, Kowal D, Guest F. Contraceptive Technology: Seventeenth Revised Edition. New York, NY: Irvington Publishers, 1998.
* Among couples attempting to avoid pregnancy, the percentage who continue to use a method for one year.
† Among typical couples who initiate use of a method (not necessarily for the first time), the percentage who experience an accidental pregnancy during the first year if they do not stop use for any other reason.
‡ Among couples who initiate use of a method (not necessarily for the first time) and who use it perfectly (both consistently and correctly), the percentage who experience an accidental pregnancy during the first year if they do not stop use for any other reason.
§ The treatment schedule is one dose within 72 hours after unprotected intercourse, and a second dose 12 hours after the first dose. The Food and Drug Administration has declared the following brands of oral contraceptives to be safe and effective for emergency contraception: Ovral® (1 dose is 2 white pills), Alesse® (1 dose is 5 pink pills), Nordette® or Levlen® (1 dose is 2 light-orange pills), Lo/Ovral®(1 dose is 4 white pills), Triphasil® or Tri-Levlen® (1 dose is 4 yellow pills).
¶ However, to maintain effective protection against pregnancy, another method of contraception must be used as soon as menstruation resumes, the frequency or duration of breastfeeds is reduced, bottle feeds are introduced, or the baby reaches six months of age.
# The percents becoming pregnant in columns (2) and (3) are based on data from populations where contraception is not used and from women who cease using contraception in order to become pregnant. Among such populations, about 89% become pregnant within one year. This estimate was lowered slightly (to 85%) to represent the percent who would become pregnant within one year among women now relying on reversible methods of contraception if they abandoned contraception altogether.
Þ Foams, creams, gels, vaginal suppositories, and vaginal film.
ß Cervical mucus (ovulation) method supplemented by calendar in the pre-ovulatory and basal body temperature in the post-ovulatory phases.
à With spermicidal cream or jelly.
è Without spermicides.
|% of Women Experiencing an |
within the First Year of Use
|% of Women Continuing Use at One Year* |
|Typical Use† |
|Perfect Use‡ |
|Chance# ||85 ||85 |
|SpermicidesÞ ||26 ||6 ||40 |
|Periodic abstinence ||25 ||63 |
| Calendar ||9 |
| Ovulation Method ||3 |
| Sympto-Thermalß ||2 |
| Post-Ovulation ||1 |
| Parous Women ||40 ||26 ||42 |
| Nulliparous Women ||20 ||9 ||56 |
| Parous Women ||40 ||20 ||42 |
| Nulliparous Women ||20 ||9 ||56 |
|Diaphragmà ||20 ||6 ||56 |
|Withdrawal ||19 ||4 |
|Female (Reality®) ||21 ||5 ||56 |
|Male ||14 ||3 ||61 |
|Pill ||5 ||71 |
| Progestin Only ||0.5 |
| Combined ||0.1 |
| Progesterone T ||2 ||1.5 ||81 |
| Copper T380A ||0.8 ||0.6 ||78 |
| LNg 20 ||0.1 ||0.1 ||81 |
|Depo-Provera® ||0.3 ||0.3 ||70 |
|Norplant® and Norplant-2® ||0.05 ||0.05 ||88 |
|Female Sterilization ||0.5 ||0.5 ||100 |
|Male Sterilization ||0.15 ||0.1 ||100 |
CyonanzTM has not been studied for and are not indicated for use in emergency contraception.
Patients should be counseled that this product does not protect against HIV infection (AIDS) and other sexually transmitted diseases.
2. Physical Examination and Follow-Up
It is good medical practice for all women to have annual history and physical examinations, including women using oral contraceptives. The physical examination, however, may be deferred until after initiation of oral contraceptives if requested by the woman and judged appropriate by the clinician. The physical examination should include special reference to blood pressure, breasts, abdomen and pelvic organs, including cervical cytology, and relevant laboratory tests. In case of undiagnosed, persistent or recurrent abnormal vaginal bleeding, appropriate measures should be conducted to rule out malignancy. Women with a strong family history of breast cancer or who have breast nodules should be monitored with particular care.
3. Lipid Disorders
Women who are being treated for hyperlipidemias should be followed closely if they elect to use oral contraceptives. Some progestogens may elevate LDL levels and may render the control of hyperlipidemias more difficult.
4. Liver Function
If jaundice develops in any woman receiving such drugs, the medication should be discontinued. Steroid hormones may be poorly metabolized in patients with impaired liver function.
5. Fluid Retention
Oral contraceptives may cause some degree of fluid retention. They should be prescribed with caution, and only with careful monitoring, in patients with conditions which might be aggravated by fluid retention.
6. Emotional Disorders
Women with a history of depression should be carefully observed and the drug discontinued if depression recurs to a serious degree.
7. Contact Lenses
Contact lens wearers who develop visual changes or changes in lens tolerance should be assessed by an ophthalmologist.
8. Drug Interactions
Consult the labeling of concurrently-used drugs to obtain further information about interactions with hormonal contraceptives or the potential for enzyme alterations.
Effects of Other Drugs on Combined Hormonal Contraceptives
Substances decreasing the plasma concentrations of COCs and potentially diminishing the efficacy of COCs
Drugs or herbal products that induce certain enzymes, including cytochrome P450 3A4 (CYP3A4), may decrease the plasma concentrations of COCs and potentially diminish the effectiveness of CHCs or increase breakthrough bleeding. Some drugs or herbal products that may decrease the effectiveness of hormonal contraceptives include phenytoin, barbiturates, carbamazepine, bosentan, felbamate, griseofulvin, oxcarbazepine, rifampicin, topiramate, rifabutin, rufinamide, aprepitant, and products containing St. John’s wort. Interactions between hormonal contraceptives and other drugs may lead to breakthrough bleeding and/or contraceptive failure. Counsel women to use an alternative method of contraception or a back-up method when enzyme inducers are used with CHCs, and to continue back-up contraception for 28 days after discontinuing the enzyme inducer to ensure contraceptive reliability.
Substances increasing the plasma concentrations of COCs
Co-administration of atorvastatin or rosuvastatin and certain COCs containing EE increase AUC values for EE by approximately 20 to 25%. Ascorbic acid and acetaminophen may increase plasma EE concentrations, possibly by inhibition of conjugation. CYP3A4 inhibitors such as itraconazole, voriconazole, fluconazole, grapefruit juice, or ketoconazole may increase plasma hormone concentrations.
Human immunodeficiency virus (HIV)/Hepatitis C virus (HCV) protease inhibitors and non-nucleoside reverse transcriptase inhibitors
Significant changes (increase or decrease) in the plasma concentrations of estrogen and/or progestin have been noted in some cases of co-administration with HIV protease inhibitors (decrease [e.g., nelfinavir, ritonavir, darunavir/ritonavir, (fos)amprenavir/ritonavir, lopinavir/ritonavir, and tipranavir/ritonavir] or increase [e.g., indinavir and atazanavir/ritonavir]) /HCV protease inhibitors (decrease [e.g., boceprevir and telaprevir]) or with non-nucleoside reverse transcriptase inhibitors (decrease [e.g., nevirapine] or increase [e.g., etravirine]).
Colesevelam: Colesevelam, a bile acid sequestrant, given together with a combination oral hormonal contraceptive, has been shown to significantly decrease the AUC of EE. A drug interaction between the contraceptive and colesevelam was decreased when the two drug products were given 4 hours apart.
Effects of Combined Hormonal Contraceptives on Other Drugs
COCs containing EE may inhibit the metabolism of other compounds (e.g., cyclosporine, prednisolone, theophylline, tizanidine, and voriconazole) and increase their plasma concentrations. COCs have been shown to decrease plasma concentrations of acetaminophen, clofibric acid, morphine, salicylic acid, temazepam and lamotrigine. Significant decrease in plasma concentration of lamotrigine has been shown, likely due to induction of lamotrigine glucuronidation. This may reduce seizure control; therefore, dosage adjustments of lamotrigine may be necessary.
Women on thyroid hormone replacement therapy may need increased doses of thyroid hormone because serum concentrations of thyroid-binding globulin increases with use of COCs.
9. Interactions with Laboratory Tests
Certain endocrine and liver function tests and blood components may be affected by oral contraceptives:
a. Increased prothrombin and factors VII, VIII, IX, and X; decreased antithrombin 3; increased norepinephrine-induced platelet aggregability.
b. Increased thyroid binding globulin (TBG) leading to increased circulating total thyroid hormone, as measured by protein-bound iodine (PBI), T4 by column or by radioimmunoassay. Free T3 resin uptake is decreased, reflecting the elevated TBG, free T4 concentration is unaltered.
c. Other binding proteins may be elevated in serum.
d. Sex-binding globulins are increased and result in elevated levels of total circulating sex steroids and corticoids; however, free or biologically active levels remain unchanged.
e. Triglycerides may be increased and levels of various other lipids and lipoproteins may be affected.
f. Glucose tolerance may be decreased.
g. Serum folate levels may be depressed by oral contraceptive therapy. This may be of clinical significance if a woman becomes pregnant shortly after discontinuing oral contraceptives.
Pregnancy Category X. See CONTRAINDICATIONS and WARNINGS.
12. Nursing Mothers
Small amounts of oral contraceptive steroids have been identified in the milk of nursing mothers and a few adverse effects on the child have been reported, including jaundice and breast enlargement. In addition, combined oral contraceptives given in the postpartum period may interfere with lactation by decreasing the quantity and quality of breast milk. If possible, the nursing mother should be advised not to use combined oral contraceptives but to use other forms of contraception until she has completely weaned her child.
13. Pediatric Use
Safety and efficacy of CyonanzTM Tablets have been established in women of reproductive age. Safety and efficacy are expected to be the same for postpubertal adolescents under the age of 16 and for users 16 years and older. Use of this product before menarche is not indicated.
14. Geriatric Use
This product has not been studied in women over 65 years of age and is not indicated in this population.
INFORMATION FOR THE PATIENT
See Patient Labeling printed below.
An increased risk of the following serious adverse reactions has been associated with the use of oral contraceptives (See WARNINGS).
- Thrombophlebitis and venous thrombosis with or without embolism
- Arterial thromboembolism
- Pulmonary embolism
- Myocardial infarction
- Cerebral hemorrhage
- Cerebral thrombosis
- Gallbladder disease
- Hepatic adenomas or benign liver tumors
There is evidence of an association between the following conditions and the use of oral contraceptives:
- Mesenteric thrombosis
- Retinal thrombosis
The following adverse reactions have been reported in patients receiving oral contraceptives and are believed to be drug-related:
- Gastrointestinal symptoms (such as abdominal cramps and bloating)
- Breakthrough bleeding
- Change in menstrual flow
- Temporary infertility after discontinuation of treatment
- Melasma which may persist
- Breast changes: tenderness, enlargement, secretion
- Change in weight (increase or decrease)
- Change in cervical erosion and secretion
- Diminution in lactation when given immediately postpartum
- Cholestatic jaundice
- Allergic reaction, including rash, urticaria, angioedema
- Mental depression
- Reduced tolerance to carbohydrates
- Vaginal candidiasis
- Change in corneal curvature (steepening)
- Intolerance to contact lenses
The following adverse reactions have been reported in users of oral contraceptives and a causal association has been neither confirmed nor refuted:
- Pre-menstrual syndrome
- Changes in appetite
- Cystitis-like syndrome
- Loss of scalp hair
- Erythema multiforme
- Erythema nodosum
- Hemorrhagic eruption
- Impaired renal function
- Hemolytic uremic syndrome
- Changes in libido
- Budd-Chiari Syndrome
The following adverse reactions were also reported in clinical trials or during post-marketing experience: Gastrointestinal Disorders: diarrhea, pancreatitis; Musculoskeletal and Connective Tissue Disorders: muscle spasms, back pain; Reproductive System and Breast Disorders: vulvovaginal pruritus, pelvic pain, dysmenorrhea, vulvovaginal dryness; Psychiatric Disorders: anxiety, mood swings, mood altered; Skin and Subcutaneous Tissue Disorders: pruritus, photosensitivity reaction; General Disorders and Administration Site Conditions: edema peripheral, fatigue, irritability, asthenia, malaise; Neoplasms Benign, Malignant, and Unspecified (Including Cysts and Polyps): breast cancer, breast mass, breast neoplasm, cervix carcinoma; Immune System Disorders: anaphylactic/anaphylactoid reaction; Hepatobiliary Disorders: hepatitis, cholelithiasis.
How is Cyonanz Supplied
CyonanzTM (Norethindrone and Ethinyl Estradiol Tablets, USP) 0.5 mg/0.035 mg are available in a blister pack containing 28 tablets, as follows: 21 white to off-white, round, flat-faced beveled edged tablets, debossed with ‘S’ on one side and ‘31’ on other side of the tablet (0.5 mg norethindrone USP and 0.035 mg ethinyl estradiol USP) and 7 green, round, mottled, flat-faced, beveled-edge uncoated tablets, debossed with “S” on one side and “37” on other side containing inert ingredients.
The blister packs are available in the following package:
- The Blister Packs are packed in Pouches (NDC 65862-899-28) and the pouches are packaged in cartons
Carton of 6 Pouches NDC 65862-899-92
Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].
- Trussell J. Contraceptive efficacy. In Hatcher RA, Trussell J, Stewart F, Cates W, Stewart GK, Kowal D, Guest F, Contraceptive Technology: Seventeenth Revised Edition. New York, NY: Irvington Publishers, 1998.
- Stadel BV, Oral contraceptives and cardiovascular disease. (Pt. 1). N Engl J Med 1981; 305:612-618.
- Stadel BV, Oral contraceptives and cardiovascular disease. (Pt. 2). N Engl J Med 1981; 305:672-677.
- Adam SA, Thorogood M. Oral contraception and myocardial infarction revisited: the effects of new preparations and prescribing patterns. Br J Obstet Gynecol 1981; 88:838-845.
- Mann JI, Inman WH. Oral contraceptives and death from myocardial infarction. Br Med J 1975; 2(5965):245-248.
- Mann JI, Vessey MP, Thorogood M, Doll R. Myocardial infarction in young women with special reference to oral contraceptive practice. Br Med J 1975; 2(5956):241-245.
- Royal College of General Practitioners’ Oral Contraception Study: further analyses of mortality in oral contraceptive users. Lancet 1981; 1:541-546.
- Slone D, Shapiro S, Kaufman DW, Rosenberg L, Miettinen OS, Stolley PD. Risk of myocardial infarction in relation to current and discontinued use of oral contraceptives. N Engl J Med 1981; 305:420-424.
- Vessey MP. Female hormones and vascular disease – an epidemiological overview. Br J Fam Plann 1980; 6 (Supplement): 1-12.
- Russell-Briefel RG, Ezzati TM, Fulwood R, Perlman JA, Murphy RS. Cardiovascular risk status and oral contraceptive use, United States, 1976-80. Prevent Med 1986; 15:352-362.
- Goldbaum GM, Kendrick JS, Hogelin GC, Gentry EM. The relative impact of smoking and oral contraceptive use on women in the United States. JAMA 1987; 258:1339-1342.
- Layde PM, Beral V. Further analyses of mortality in oral contraceptive users; Royal College of General Practitioners’ Oral Contraception Study. (Table 5) Lancet 1981; 1:541-546.
- Knopp RH. Arteriosclerosis risk: the roles of oral contraceptives and postmenopausal estrogens. J Reprod Med 1986; 31(9) (Supplement): 913-921.
- Krauss RM, Roy S, Mishell DR, Casagrande J, Pike MC. Effects of two low-dose oral contraceptives on serum lipids and lipoproteins: Differential changes in high-density lipoproteins subclasses. Am J Obstet 1983; 145:446-452.
- Wahl P, Walden C, Knopp R, Hoover J, Wallace R, Heiss G, Rifkind B. Effect of estrogen/progestin potency on lipid/lipoprotein cholesterol. N Engl J Med 1983; 308:862-867.
- Wynn V, Niththyananthan R. The effect of progestin in combined oral contraceptives on serum lipids with special reference to high density lipoproteins. Am J Obstet Gynecol 1982; 142:766-771.
- Wynn V, Godsland I. Effects of oral contraceptives on carbohydrate metabolism. J Reprod Med 1986; 31(9)(Supplement):892-897.
- LaRosa JC. Atherosclerotic risk factors in cardiovascular disease. J Reprod Med 1986; 31(9)(Supplement):906-912.
- Inman WH, Vessey MP. Investigation of death from pulmonary, coronary, and cerebral thrombosis and embolism in women of child-bearing age. Br Med J 1968; 2(5599):193-199.
- Maguire MG, Tonascia J, Sartwell PE, Stolley PD, Tockman MS. Increased risk of thrombosis due to oral contraceptives: a further report. Am J Epidemiol 1979; 110(2):188-195.
- Petitti DB, Wingerd J, Pellegrin F, Ramacharan S. Risk of vascular disease in women: smoking, oral contraceptives, noncontraceptive estrogens, and other factors. JAMA 1979; 242:1150-1154.
- Vessey MP, Doll R. Investigation of relation between use of oral contraceptives and thromboembolic disease. Br Med J 1968; 2(5599):199-205.
- Vessey MP, Doll R. Investigation of relation between use of oral contraceptives and thromboembolic disease. A further report. Br Med J 1969; 2(5658):651-657.
- Porter JB, Hunter JR, Danielson DA, Jick H, Stergachis A. Oral contraceptives and non-fatal vascular disease – recent experience. Obstet Gynecol 1982; 59(3):299-302.
- Vessey M, Doll R, Peto R, Johnson B, Wiggins P. A long-term follow-up study of women using different methods of contraception: an interim report. J Biosocial Sci 1976; 8:375-427.
- Royal College of General Practitioners: Oral Contraceptives, venous thrombosis, and varicose veins. J Royal Coll Gen Pract 1978; 28:393-399.
- Collaborative Group for the Study of Stroke in Young Women: Oral contraception and increased risk of cerebral ischemia or thrombosis. N Engl J Med 1973; 288:871-878.
- Petitti DB, Wingerd J. Use of oral contraceptives, cigarette smoking, and risk of subarachnoid hemorrhage. Lancet 1978; 2:234-236.
- Inman WH. Oral contraceptives and fatal subarachnoid hemorrhage. Br Med J 1979; 2(6203):1468-1470.
- Collaborative Group for the Study of Stroke in Young Women: Oral Contraceptives and stroke in young women: associated risk factors. JAMA 1975; 231:718-722.
- Inman WH, Vessey MP, Westerholm B, Engelund A. Thromboembolic disease and the steroidal content of oral contraceptives. A report to the Committee on Safety of Drugs. Br Med J 1970; 2:203-209.
- Meade TW, Greenberg G, Thompson SG. Progestogens and cardiovascular reactions associated with oral contraceptives and a comparison of the safety of 50- and 35-mcg estrogen preparations. Br Med J 1980; 280(6224):1157-1161.
- Kay CR. Progestogens and arterial disease – evidence from the Royal College of General Practitioners’ Study. Am J Obstet Gynecol 1982; 142:762-765.
- Royal College of General Practitioners: Incidence of arterial disease among oral contraceptive users. J Royal Coll Gen Pract 1983; 33:75-82.
- Ory HW. Mortality associated with fertility and fertility control: 1983. Family Planning Perspectives 1983; 15:50-56.
- The Cancer and Steroid Hormone Study of the Centers for Disease Control and the National Institute of Child Health and Human Development: Oral contraceptive use and the risk of breast cancer. N Engl J Med 1986; 315:405-411.
- Pike MC, Henderson BE, Krailo MD, Duke A, Roy S. Breast cancer in young women and use of oral contraceptives: possible modifying effect of formulation and age at use. Lancet 1983; 2:926-929.
- Paul C, Skegg DG, Spears GFS, Kaldor JM. Oral contraceptives and breast cancer: A national study. Br Med J 1986; 293:723-725.
- Miller DR, Rosenberg L, Kaufman DW, Schottenfeld D, Stolley PD, Shapiro S. Breast cancer risk in relation to early oral contraceptive use. Obstet Gynecol 1986; 68:863-868.
- Olsson H, Olsson ML, Moller TR, Ranstam J, Holm P. Oral contraceptive use and breast cancer in young women in Sweden (letter). Lancet 1985; 1(8431):748-749.
- McPherson K, Vessey M, Neil A, Doll R, Jones L, Roberts M. Early contraceptive use and breast cancer: Results of another case-control study. Br J Cancer 1987; 56:653-660.
- Huggins GR, Zucker PF. Oral contraceptives and neoplasia: 1987 update. Fertil Steril 1987; 47:733-761.
- McPherson K, Drife JO. The pill and breast cancer: why the uncertainty? Br Med J 1986; 293:709-710.
- Shapiro S. Oral contraceptives – time to take stock. N Engl J Med 1987; 315:450-451.
- Ory H, Naib Z, Conger SB, Hatcher RA, Tyler CW. Contraceptive choice and prevalence of cervical dysplasia and carcinoma in situ. Am J Obstet Gynecol 1976; 124:573-577.
- Vessey MP, Lawless M, McPherson K, Yeates D. Neoplasia of the cervix uteri and contraception: a possible adverse effect of the pill. Lancet 1983; 2:930.
- Brinton LA, Huggins GR, Lehman HF, Malli K, Savitz DA, Trapido E, Rosenthal J, Hoover R. Long term use of oral contraceptives and risk of invasive cervical cancer. Int J Cancer 1986; 38:339-344.
- WHO Collaborative Study of Neoplasia and Steroid Contraceptives: Invasive cervical cancer and combined oral contraceptives. Br Med J 1985; 290:961-965.
- Rooks JB, Ory HW, Ishak KG, Strauss LT, Greenspan JR, Hill AP, Tyler CW. Epidemiology of hepatocellular adenoma: the role of oral contraceptive use. JAMA 1979; 242:644-648.
- Bein NN, Goldsmith HS. Recurrent massive hemorrhage from benign hepatic tumors secondary to oral contraceptives. Br J Surg 1977; 64:433-435.
- Klatskin G. Hepatic tumors: possible relationship to use of oral contraceptives. Gastroenterology 1977; 73:386-394.
- Henderson BE, Preston-Martin S, Edmondson HA, Peters RL, Pike MC. Hepatocellular carcinoma and oral contraceptives. Br J Cancer 1983; 48:437-440.
- Neuberger J, Forman D, Doll R, Williams R. Oral contraceptives and hepatocellular carcinoma. Br Med J 1986; 292:1355-1357.
- Forman D, Vincent TJ, Doll R. Cancer of the liver and oral contraceptives. Br Med J 1986; 292:1357-1361.
- Harlap S, Eldor J. Births following oral contraceptive failures. Obstet Gynecol 1980; 55:447-452.
- Savolainen E, Saksela E, Saxen L. Teratogenic hazards of oral contraceptives analyzed in a national malformation register. Am J Obstet Gynecol 1981; 140:521-524.
- Janerich DT, Piper JM, Glebatis DM. Oral contraceptives and birth defects. Am J Epidemiol 1980; 112:73-79.
- Ferencz C, Matanoski GM, Wilson PD, Rubin JD, Neill CA, Gutberlet R. Maternal hormone therapy and congenital heart disease. Teratology 1980; 21:225-239.
- Rothman KJ, Fyler DC, Goldblatt A, Kreidberg MB. Exogenous hormones and other drug exposures of children with congenital heart disease. Am J Epidemiol 1979; 109:433-439.
- Boston Collaborative Drug Surveillance Program: Oral contraceptives and venous thromboembolic disease, surgically confirmed gallbladder disease, and breast tumors. Lancet 1973; 1:1399-1404.
- Royal College of General Practitioners: Oral contraceptives and health. New York, Pittman 1974.
- Layde PM, Vessey MP, Yeates D. Risk of gallbladder disease: a cohort study of young women attending family planning clinics. J Epidemiol Community Health 1982; 36:274-278.
- Rome Group for Epidemiology and Prevention of Cholelithiasis (GREPCO): Prevalence of gallstone disease in an Italian adult female population. Am J Epidemiol 1984; 119:796-805.
- Storm BL, Tamragouri RT, Morse ML, Lazar EL, West SL, Stolley PD, Jones JK. Oral contraceptives and other risk factors for gallbladder disease. Clin Pharmacol Ther 1986; 39:335-341.
- Wynn V, Adams PW, Godsland IF, Melrose J, Niththyananthan R, Oakley NW, Seedj A. Comparison of effects of different combined oral contraceptive formulations on carbohydrate and lipid metabolism. Lancet 1979; 1:1045-1049.
- Wynn V. Effect of progesterone and progestins on carbohydrate metabolism. In: Progesterone and Progestin. Bardin CW, Milgrom E, Mauvis-Jarvis P. eds. New York, Raven Press, 1983; pp. 395-410.
- Perlman JA, Roussell-Briefel RG, Ezzati TM, Lieberknecht G. Oral glucose tolerance and the potency of oral contraceptive progestogens. J Chronic Dis 1985; 38:857-864.
- Royal College of General Practitioners’ Oral Contraception Study: Effect on hypertension and benign breast disease of progestogen component in combined oral contraceptives. Lancet 1977; 1:624.
- Fisch IR, Frank J. Oral contraceptives and blood pressure. JAMA 1977; 237:2499-2503.
- Laragh AJ. Oral contraceptive induced hypertension – nine years later. Am J Obstet Gynecol 1976; 126:141-147.
- Ramcharan S, Peritz E, Pellegrin FA, Williams WT. Incidence of hypertension in the Walnut Creek Contraceptive Drug Study cohort: In: Pharmacology of steroid contraceptive drugs. Garattini S, Berendes HW. Eds. New York, Raven Press, 1977; pp. 277-288, (Monographs of the Mario Negri Institute for Pharmacological Research Milan.)
- Stockley I. Interactions with oral contraceptives. J Pharm 1976; 216:140-143.
- The Cancer and Steroid Hormone Study of the Centers for Disease Control and the National Institute of Child Health and Human Development: Oral contraceptive use and the risk of ovarian cancer. JAMA 1983; 249:1596-1599.
- The Cancer and Steroid Hormone Study of the Centers for Disease Control and the National Institute of Child Health and Human Development: Combination oral contraceptive use and the risk of endometrial cancer. JAMA 1987; 257:796-800.
- Ory HW. Functional ovarian cysts and oral contraceptives: negative association confirmed surgically. JAMA 1974; 228:68-69.
- Ory HW, Cole P, MacMahon B, Hoover R. Oral contraceptives and reduced risk of benign breast disease. N Engl J Med 1976; 294:419-422.
- Ory HW. The noncontraceptive health benefits from oral contraceptive use. Fam Plann Perspect 1982; 14:182-184.
- Ory HW, Forrest JD, Lincoln R. Making choices: Evaluating the health risks and benefits of birth control methods. New York, The Alan Guttmacher Institute, 1983; p. 1.
- Schlesselman J, Stadel BV, Murray P, Lai S. Breast cancer in relation to early use of oral contraceptives. JAMA 1988; 259:1828-1833.
- Hennekens CH, Speizer FE, Lipnick RJ, Rosner B, Bain C, Belanger C, Stampfer MJ, Willett W, Peto R. A case-control study of oral contraceptive use and breast cancer. JNCI 1984; 72:39-42.
- LaVecchia C, Decarli A, Fasoli M, Franceschi S, Gentile A, Negri E, Parazzini F, Tognoni G. Oral contraceptives and cancers of the breast and of the female genital tract. Interim results from a case-control study. Br J Cancer 1986; 54:311-317.
- Meirik O, Lund E, Adami H, Bergstrom R, Christoffersen T, Bergsjo P. Oral contraceptive use and breast cancer in young women. A Joint National Case-control study in Sweden and Norway. Lancet 1986; 11:650-654.
- Kay CR, Hannaford PC. Breast cancer and the pill – A further report from the Royal College of General Practitioners’ oral contraception study. Br J Cancer 1988; 58:675-680.
- Stadel BV, Lai S, Schlesselman JJ, Murray P. Oral contraceptives and premenopausal breast cancer in nulliparous women. Contraception 1988; 38:287-299.
- Miller DR, Rosenberg L, Kaufman DW, Stolley P, Warshauer ME, Shapiro S. Breast cancer before age 45 and oral contraceptive use: New Findings. Am J Epidemiol 1989; 129:269-280.
- The UK National Case-Control Study Group, Oral contraceptive use and breast cancer risk in young women. Lancet 1989; 1:973-982.
- Schlesselman JJ. Cancer of the breast and reproductive tract in relation to use of oral contraceptives. Contraception 1989; 40:1-38.
- Vessey MP, McPherson K, Villard-Mackintosh L, Yeates D. Oral contraceptives and breast cancer: latest findings in a large cohort study. Br J Cancer 1989; 59:613-617.
- Jick SS, Walker AM, Stergachis A, Jick H. Oral contraceptives and breast cancer. Br J Cancer 1989; 59:618-621.
- Collaborative Group on Hormonal Factors in Breast Cancer. Breast cancer and hormonal contraceptives: collaborative reanalysis of individual data on 53,297 women with breast cancer and 100,239 women without breast cancer from 54 epidemiological studies. Lancet 1996; 347:1713-1727.
- Palmer JR, Rosenberg L, Kaufman DW, Warshauer ME, Stolley P, Shapiro S. Oral Contraceptive Use and Liver Cancer. Am J Epidemiol 1989; 130:878-882.
- Improving access to quality care in family planning: Medical eligibility criteria for contraceptive use. Geneva, WHO, Family and Reproductive Health, 1996.
- Bork K, Fischer B, DeWald G. Recurrent episodes of skin angioedema and severe attacks of abdominal pain induced by oral contraceptives or hormone replacement therapy. Am J Med 2003;114:294-298.
- Van Giersbergen PLM, Halabi A, Dingemanse J. Pharmacokinetic interaction between bosentan and the oral contraceptives norethisterone and ethinyl estradiol. Int J Clin Pharmacol Ther 2006;44(3):113-118.
- Christensen J, Petrenaite V, Atterman J, et al. Oral contraceptives induce lamotrigine metabolism: evidence from a double-blind, placebo-controlled trial. Epilepsia 2007;48(3):484-489.
- Chobanian et al. Seventh report of the joint national committee on prevention, detection, evaluation, and treatment of high blood pressure. Hypertension 2003;42;1206–1252.
- Brown KS, Armstrong IC, Wang A, Walker JR, Noveck RJ, Swearingen D, Allison M, Kissling JC, Kisicki J, Salazar D. Effect of the bile acid sequestrant colesevelam on the pharmacokinetics of pioglitazone, repaglinide, estrogen estradiol, norethindrone, levothyroxine, and glyburide. J Clin Pharmacol 2010;50:554–565.
For Healthcare Professionals
Applies to ethinyl estradiol / norethindrone: oral capsule, oral tablet, oral tablet chewable
A number of studies have suggested that use of oral contraceptives decreases the risk of ovarian cancer. Specifically, the risk of epithelial ovarian cancers is decreased by 40%. The protection against ovarian cancer may last for 10 to 15 years after discontinuation of oral contraceptives. After long term use (12 years), the risk of ovarian cancer is decreased by as much as 80%.
The risk of endometrial cancer is decreased by approximately 50%. Protection may last for 15 years after discontinuation and may be greatest for nulliparous women who may be at higher risk for endometrial carcinoma than other women.
The incidence of hospitalization for pelvic inflammatory disease is approximately 50% lower in women taking oral contraceptives. The reason for the decrease in the frequency (or severity) of pelvic inflammatory disease in women taking oral contraceptives has not been fully elucidated.
Some recent studies have suggested that the decrease in frequency of functional ovarian cysts reported with some older formulations may not occur in women taking newer low dose formulations.
One recent study (The Nurses' Health Study) has suggested that long term use of oral contraceptives is safe and does not adversely affect long term risk for mortality.[Ref]
Women taking oral contraceptive combinations may have experienced several non-contraceptive health benefits. These benefits include protection against two malignant neoplasms (endometrial carcinoma and ovarian cancer). In addition, use of oral contraceptive combinations has reportedly decreased the frequency of benign breast tumors, decreased the risk of ovarian cysts, decreased the risk of ectopic pregnancy, increased menstrual regularity, decreased the incidence of iron deficiency anemia, decreased the incidence of dysmenorrhea, and decreased the incidence of pelvic inflammatory disease.[Ref]
Gastrointestinal side effects have included nausea, which occurred in approximately 10% of treated women and was more frequent during the first cycles of therapy. Some early reports suggested an association between oral contraceptive use and gallbladder disease.[Ref]
Cases of oral contraceptive-induced esophageal ulceration and geographic tongue have been reported rarely.
More recent studies have suggested that the risk of gallbladder disease is minimal.[Ref]
Oncologic side effects have included reports of increased risk of invasive breast cancer. A large study (n = 16,608 postmenopausal women) of conjugated equine estrogens and medroxyprogesterone was terminated in 2002 due to the increased risk of coronary heart disease, stroke, and pulmonary embolism. A number of studies have examined a possible relationship between the use of oral contraceptives and the development of breast cancer. Many of the studies have reported conflicting results. A committee of the World Health Organization evaluated these studies and the risks of breast cancer and concluded that: "Numerous studies have found no overall association between oral contraceptive use and risk of breast cancer." In addition, the same committee also examined a possible relationship between oral contraceptive use and neoplasms of the uterine cervix and concluded that: "There are insufficient data to draw any firm conclusions regarding the effects of combined oral contraceptives on the risk of cervical adenocarcinoma."[Ref]
The World Health Organization committee also noted that some studies "have found a weak association between long-term use of oral contraceptives and breast cancer diagnosed before the age of 36, and perhaps up to the age 45....It is unclear whether this observed association is attributable to bias, the development of new cases of cancer, or accelerated growth of existing cancers."
The World Health Organization committee further concluded that there is no increased risk of breast cancer in women over the age of 45 who have previously taken oral contraceptives. In addition, studies suggest that use of oral contraceptives does not place specific groups of women (like those with a family history of breast cancer) at higher or lower risk, and variations in the hormonal content of oral contraceptives do not influence the risk of breast cancer.
In general, studies evaluating the potential risk of cervical cancer in patients taking oral contraceptives have been complicated by the large number of confounding factors which make investigations into the epidemiology of this neoplasm difficult. Some studies have suggested that women taking oral contraceptives are at increased risk of dysplasia, epidermoid carcinoma, and adenocarcinoma of the cervix. However, other studies have not found such an association.[Ref]
Detailed information concerning the effects of oral contraceptive therapy on lipid metabolism is available in the Endocrine paragraph of this side effect monograph.
Some early investigations of women taking high dose estrogen combinations (50 mcg or more of ethinyl estradiol or equivalent daily) suggested that such women may be at increased risk of cardiovascular complications (myocardial infarction, stroke, and vascular thrombosis, including venous thromboembolism). However, more recent large investigations of women taking low dose estrogen combinations have suggested that oral contraceptive use is not associated with an increased risk of serious cardiovascular complications in healthy non smoking women up to the age of 45. (For women aged 35 to 44 who smoke or who have preexisting systemic diseases that may affect the cardiovascular system, use of oral contraceptives is not recommended.)
However, some investigators have suggested that even the new low dose products may result in adverse effects on lipid metabolism and should prompt careful review of a woman's cardiovascular risk factors before a decision to use oral contraceptive combinations is made.
The frequency of both subarachnoid hemorrhage and thrombotic stroke has been reported by some investigators to be higher in women taking oral contraceptive hormones. However, other investigators have suggested that the risk of these effects for women using newer low dose formulations are very small for young women without underlying cardiovascular disease or other risk factors.[Ref]
Cardiovascular side effects have included reports of increased risk of coronary heart disease, stroke, and pulmonary embolism. A large study (n = 16,608 postmenopausal women) of conjugated equine estrogens and medroxyprogesterone was terminated in 2002 due to the increased risk of coronary heart disease, stroke, and pulmonary embolism. Earlier studies had suggested that unopposed estrogen therapy may decrease the risk of coronary heart disease by as much as 35% and that combination therapy with a progestin may also decrease coronary risk. Cardiovascular side effects of the estrogen component of this combination have also included reports of hypertension. However, significant blood pressure increases generally occur only in women receiving high-dose estrogen products (50 mcg or more of ethinyl estradiol or equivalent daily). Estrogens have also been associated with edema. In addition, exogenous estrogens may exert cardioprotective effects by causing favorable changes in lipid profiles. These beneficial effects, however, may be partially or completely offset by alterations in lipid profiles induced by exogenous progestins.[Ref]
Endocrine side effects have included reports of complex alterations in plasma lipid profiles and carbohydrate metabolism. In addition, oral contraceptive use has been reported to cause conception delay.[Ref]
All the progestins which occur in commercially available oral contraceptive combinations have adverse effects on lipid profiles. Specifically, these progestins exert antiestrogen and androgen effects and decrease HDL (and HDL2) cholesterol levels and increase LDL cholesterol levels. However, the estrogens in oral contraceptive combinations exert opposing effects. Consequently, alterations in lipid profiles are related to the relative amount and potency of the specific estrogen and progestin in a given product. (Norethindrone exerts a moderate androgen effect and weak progestin and antiestrogen effects.)
A number of investigations have suggested that oral contraceptive combinations may decrease glucose tolerance. However, some recent studies with low dose preparations have suggested that decreases in glucose tolerance due to oral contraceptive combinations are generally minimal.
Despite the potentially adverse effects of oral contraceptives on lipid levels and glucose tolerance, some investigators have suggested that young diabetic women without existing vascular disease or severe lipidemias may be candidates for low dose oral contraceptive combinations provided that they receive close monitoring for adverse metabolic effects.[Ref]
Hepatic side effects have included focal nodular hyperplasia, intrahepatic cholestasis, liver cell adenomas, hepatic granulomas, hepatic hemangiomas and well-differentiated hepatocellular carcinomas, which have been reported rarely in association with estrogen therapy and therapy with oral contraceptive combinations.[Ref]
The rate of death due to hepatocellular carcinoma in the United States has not changed during the last 25 years (a time during which use of oral contraceptive hormones has increased dramatically).
A committee of the World Health Organization has reported that in developing countries where hepatitis B virus infection and hepatocellular carcinoma are common, "short term use of oral contraceptives does not appear to be associated with an increased risk. Data on the effects of long term use are scarce."
A recent Italian case-control study of women with hepatocellular carcinoma has suggested that the relative risk of hepatocellular carcinoma is 2.2 for oral contraceptive users compared to women who never used oral contraceptives.
A similar American case-control study from 1989 also reported a strong association between oral contraceptive use and hepatocellular carcinoma but concluded that: "If this observed association is causal, the actual number of cases of liver cancer in the United States attributable to oral contraceptive use is small. Therefore, these findings do not have public health importance in the United States and other Western nations."[Ref]
Cases of venous thrombosis, pulmonary embolism (sometimes fatal), and arterial thrombosis have been reported rarely.
Previous thrombotic disease is considered a contraindication to use of oral contraceptive combinations.[Ref]
Hematologic side effects have included the risk of thromboembolism that is associated with the use of exogenous estrogens. However, because the dose of exogenous estrogens is low in most commercially available preparations, the risk of thromboembolism is minimal for most women (except women who are over age 35 and smoke and women with a history of previous thrombotic diseases).[Ref]
Genitourinary side effects have commonly included breakthrough bleeding and spotting, especially during the first several cycles of oral contraceptive use. Non-hormonal causes of such bleeding should be excluded. Additional side effects reported with estrogen and/or progestin therapy include changes in vaginal bleeding pattern and abnormal withdrawal bleeding or flow, increase in size of uterine leiomyomata, vaginal candidiasis, change in amount of cervical secretion, change in cervical ectropion, ovarian cancer, endometrial hyperplasia, endometrial cancer and vaginitis.[Ref]
Some women experience oligomenorrhea and amenorrhea following termination or oral contraceptive use.[Ref]
Psychiatric side effects have included depression and precipitation of panic disorder.[Ref]
Immunologic side effects have included rare cases of oral contraceptive-induced systemic lupus erythematosus.[Ref]
Nervous system side effects have included chorea, which has been reported once in association with oral contraceptives.[Ref]
Ocular side effects have included rare cases of retinal thrombosis. In addition, the manufacturers of oral contraceptive products report that some patients develop changes in contact lens tolerance.[Ref]
Respiratory side effects have included reports of increased risk of pulmonary embolism. A large study (n = 16,608 postmenopausal women) of conjugated equine estrogens and medroxyprogesterone was terminated in 2002 due to the increased risk of coronary heart disease, stroke, and pulmonary embolism.[Ref]
A case of fatal pulmonary venooclusive disease has been associated with oral contraceptive therapy.[Ref]
Some side effects of Cyonanz may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.