TriNessa (Norgestimate and Ethinyl Estradiol Tablets): Side Effects, Uses, Dosage, Interactions, Warnings (2024)

Patients should be counseled that this product does not protect against HIV infection (AIDS) and other sexually transmitted diseases.

Description for TriNessa

The following product is a combination oral contraceptive containing the progestational compound norgestimate and the estrogenic compound ethinyl estradiol.

TriNessa® Tablets

Each white tablet contains 0.180 mg of the progestational compound, norgestimate (18,19-Dinor-17- pregn-4-en-20-yn-3-one,17-(acetyloxy)-13-ethyl-,oxime,(17α)-(+)-) and 0.035 mg of the estrogenic compound, ethinyl estradiol (19-nor-17α-pregna,1,3,5(10)-trien-20-yne-3,17-diol). Inactive ingredients include carnauba wax, croscarmellose sodium, hypromellose, lactose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, purified water and titanium dioxide.

Each light blue tablet contains 0.215 mg of the progestational compound norgestimate (18,19-Dinor-17- pregn-4-en-20-yn-3-one,17-(acetyloxy)-13-ethyl-,oxime,(17α)-(+)-) and 0.035 mg of the estrogenic compound, ethinyl estradiol (19-nor-17α-pregna,1,3,5(10)-trien-20-yne-3,17-diol). Inactive ingredients include FD & C Blue No. 2 Aluminum Lake, carnauba wax, croscarmellose sodium, hypromellose, lactose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, purified water and titanium dioxide.

Each blue tablet contains 0.250 mg of the progestational compound norgestimate (18,19-Dinor-17- pregn-4-en-20-yn-3-one,17-(acetyloxy)-13-ethyl-,oxime,(17α)-(+)-) and 0.035 mg of the estrogenic compound, ethinyl estradiol (19-nor-17α-pregna,1,3,5(10)-trien-20-yne-3,17-diol). Inactive ingredients include FD & C Blue No. 2 Aluminum Lake, carnauba wax, croscarmellose sodium, hypromellose, lactose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, purified water and titanium dioxide.

Each dark green tablet contains only inert ingredients, as follows: FD & C Blue No. 2 Aluminum Lake, ferric oxide, lactose, magnesium stearate, polyethylene glycol, pregelatinized corn starch, purified water, polyvinyl alcohol, talc and titanium dioxide.

Uses for TriNessa

TriNessa® is indicated for the prevention of pregnancy inwomen who elect to use oral contraceptives as a method of contraception.

TriNessa® is indicated for the treatment of moderate acnevulgaris in females at least 15 years of age, who have no knowncontraindications to oral contraceptive therapy and have achieved menarche.

TriNessa® should be used for the treatment of acne onlyif the patient desires an oral contraceptive for birth control.

Oral contraceptives are highly effective for pregnancyprevention. Table 2 lists the typical accidental pregnancy rates for users ofcombination oral contraceptives and other methods of contraception. The efficacyof these contraceptive methods, except sterilization, the IUD, and the Norplant®System, depends upon the reliability with which they are used. Correct andconsistent use of methods can result in lower failure rates.

Table 2: Percentage of Women Experiencing anUnintended Pregnancy During the First Year of Typical Use and the First Year ofPerfect Use of Contraception and the Percentage Continuing Use at the End ofthe First Year. United States.

TriNessa® has not been studied for and is notindicated for use in emergency contraception.

In four clinical trials with TriNessa®, a total of 4,756subjects completed 45,244 cycles, and the useefficacy pregnancy rate wasapproximately 1 pregnancy per 100 women-years.

TriNessa® was evaluated for the treatment of acnevulgaris in two randomized, double-blind, placebocontrolled, multicenter, Phase3, six (28 day) cycle studies. 221 patients received TriNessa® and 234 patientsreceived placebo. Mean age at enrollment for both groups was 28 years. At theend of 6 months, the mean total lesion count changes from 55 to 31 (42%reduction) in patients treated with TriNessa® and from 54 to 38 (27% reduction)in patients similarly treated with placebo. Table 3 summarizes the changes inlesion count for each type of lesion in the ITT population. Based on the investigator'sglobal assessment conducted at the final visit, patients treated with TriNessa®showed a statistically significant improvement in total lesions compared tothose treated with placebo.

Table 3: Acne Vulgaris Indication. Combined Results :Two Multicenter, Placebo-Controlled Trials. Observed Means at Six Months (LOCF)and at Baseline. Intent-to-Treat Population.

Dosage for TriNessa

Oral Contraception

To achieve maximum contraceptive effectiveness, TriNessa®must be taken exactly as directed and at intervals not exceeding 24 hours. Thepossibility of ovulation and conception prior to initiation of medicationshould be considered. TriNessa® is available in a blister card with a tabletdispenser which is preset for a Sunday Start. Day 1 Start is also provided.

Sunday Start

When taking TriNessa® the first white tablet should betaken on the first Sunday after menstruation begins. If the period begins onSunday, the first tablet should be taken that day. Take one active tablet dailyfor 21 days followed by one dark green inactive tablet daily for 7 days. After28 tablets have been taken, a new course is started the next day (Sunday). Forthe first cycle of a Sunday Start regimen, another method of contraceptionshould be used until after the first 7 consecutive days of administration. Ifthe patient misses one (1) active tablet in Weeks 1, 2, or 3, the tablet shouldbe taken as soon as she remembers.

If the patient misses two (2) active tablets in Week 1 orWeek 2, the patient should take two (2) tablets the day she remembers and two(2) tablets the next day; and then continue taking one (1) tablet a Â(2)tablets the day she remembers and two (2) tablets the next day; and thencontinue taking one (1) tablet a day until she finishes the pack. The patientshould be instructed to use a back-up method of birth control such as a condomor spermicide if she has sex in the seven (7) days after missing pills. If thepatient misses two (2) active tablets in the third week or misses three (3) ormore active tablets in a row, the patient should continue taking one tabletevery day until Sunday. On Sunday the patient should throw out the rest of thepack and start a new pack that same day. The patient should be instructed touse a back-up method of birth control if she has sex in the seven (7) daysafter missing pills.

Complete instructions to facilitate patient counseling onproper pill usage may be found in the Detailed Patient Labeling (“How toTake the Pill” section).

Day 1 Start

The dosage of TriNessa® for the initial cycle of therapyis one active tablet administered daily from the 1st day through the 21st dayof the menstrual cycle, counting the first day of menstrual flow as “Day 1”followed by one dark green inactive tablet daily for 7 days. Tablets are takenwithout interruption for 28 days. After 28 tablets have been taken, a newcourse is started the next day.

If the patient misses one (1) active tablet in Weeks 1,2, or 3, the tablet should be taken as soon as she remembers. If the patientmisses two (2) active tablets in Week 1 or Week 2, the patient should take two (2)tablets the day she remembers and two (2) tablets the next day; and thencontinue taking one (1) tablet a day until she finishes the pack. The patientshould be instructed to use a back-up method of birth control such as a condomor spermicide if she has sex in the seven (7) days after missing pills. If thepatient misses two (2) active tablets in the third week or misses three (3) ormore active tablets in a row, the patient should throw out the rest of the packand start a new pack that same day. The patient should be instructed to use aback-up method of birth control if she has sex in the seven (7) days aftermissing pills.

Complete instructions to facilitate patient counseling onproper pill usage may be found in the Detailed Patient Labeling (“How toTake the Pill” section).

The use of TriNessa® for contraception may be initiated 4weeks postpartum in women who elect not to breastfeed. When the tablets areadministered during the postpartum period, the increased risk of thromboembolicdisease associated with the postpartum period must be considered. (See CONTRAINDICATIONSand WARNINGS concerning thromboembolic disease. See also PRECAUTIONS:Nursing Mothers.) The possibility of ovulation and conception prior toinitiation of medication should be considered. (See Discussion ofDose-Related Risk of Vascular Disease from Oral Contraceptives.)

Additional Instructions

Breakthrough bleeding, spotting, and amenorrhea arefrequent reasons for patients discontinuing oral contraceptives. Inbreakthrough bleeding, as in all cases of irregular bleeding from the vagin*, nonfunctionalcauses should be borne in mind. In undiagnosed persistent or recurrent abnormalbleeding from the vagin*, adequate diagnostic measures are indicated to ruleout pregnancy or malignancy. If pathology has been excluded, time or a changeto another formulation may solve the problem. Changing to an oral contraceptivewith a higher estrogen content, while potentially useful in minimizingmenstrual irregularity, should be done only if necessary since this mayincrease the risk of thromboembolic disease.

Use of oral contraceptives in the event of a missedmenstrual period:

• If the patient has not adhered to the prescribed schedule, the possibility of pregnancy should be considered at the time of the first missed period and oral contraceptive use should be discontinued if pregnancy is confirmed.
• If the patient has adhered to the prescribed regimen and misses two consecutive periods, pregnancy should be ruled out.

ACNE

The timing of initiation of dosing with TriNessa® foracne should follow the guidelines for use of TriNessa as an oral contraceptive.Consult the DOSAGE AND ADMINISTRATION section for oral contraceptives.The dosage regimen for TriNessa® for treatment of facial acne, as available ina blister card with a tablet dispenser, utilizes a 21-day active and a 7-dayplacebo schedule. Take one active tablet daily for 21 days followed by one darkgreen inactive tablet for 7 days. After 28 tablets have been taken, a newcourse is started the next day.

HOW SUPPLIED

TriNessa® is available in a blister card (NDC52544-248-28) with a tablet dispenser (unfilled). The blister card contains 28tablets as follows: 7 white tablets, 7 light blue tablets, 7 blue tablets, and7 dark green tablets. Each white tablet contains 0.180 mg of the progestationalcompound, norgestimate, together with 0.035 mg of the estrogenic compound,ethinyl estradiol. Each light blue tablet contains 0.215 mg of theprogestational compound, norgestimate, together with 0.035 mg of the estrogeniccompound, ethinyl estradiol. Each blue tablet contains 0.250 mg of theprogestational compound, norgestimate, together with 0.035 mg of the estrogeniccompound, ethinyl estradiol. Each dark green tablet contains inert ingredients.

0.180/0.035 mg tablets - White, round, biconvex, coatedtablet imprinted “WPI” on one side and “524” on the otherside of the tablet.

0.215/0.035 mg tablets - Light blue, round, biconvex,coated tablet imprinted “WPI” on one side and “525” on theother side of the tablet.

0.250/0.035 mg tablets - Blue, round, biconvex, coatedtablet imprinted “WPI” on one side and “526” on the otherside of the tablet.

Each dark green reminder pill is a round, biconvex,coated tablet imprinted “WPI” on one side and “P” on theother side.

Keep out of reach of children.

Store at 25°C (77°F); excursions permitted to 15° - 30°C(59° - 86°F).

Protect from light.

REFERENCES

36. 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 Med1986;315:405-411.

37. Pike MC, Henderson BE, Krailo MD, Duke A, Roy S. Breast cancer in young women and use of oral contraceptives: possible modifyingeffect of formulation and age at use. Lancet 1983;2:926-929.

38. Paul C, Skegg DG, Spears GFS, Kaldor JM. Oralcontraceptives and breast cancer: A national study. Br Med J 1986; 293:723-725.

39. Miller DR, Rosenberg L, Kaufman DW, Schottenfeld D, Stolley PD, Shapiro S. Breast cancer risk in relation to early oralcontraceptive use. Obstet Gynecol 1986;68:863-868.

40. 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.

41. McPherson K, Vessey M, Neil A, Doll R, Jones L, Roberts M. Early contraceptive use and breast cancer: Results of anothercase-control study. Br J Cancer 1987; 56:653-660.

42. Huggins GR, Zucker PF. Oral contraceptives andneoplasia: 1987 update. Fertil Steril 1987; 47:733- 761.

43. McPherson K, Drife JO. The pill and breast cancer:why the uncertainty? Br Med J 1986; 293:709-710.

44. Shapiro S. Oral contraceptives - time to take stock.N Engl J Med 1987; 315:450-451.

45. Ory H, Naib Z, Conger SB, Hatcher RA, Tyler CW. Contraceptive choice and prevalence of cervical dysplasia and carcinoma insitu. Am J Obstet Gynecol 1976; 124:573-577.

46. Vessey MP, Lawless M, McPherson K, Yeates D. Neoplasia of the cervix uteri and contraception: a possible adverse effect ofthe pill. Lancet 1983; 2:930.

47. Brinton LA, Huggins GR, Lehman HF, Malli K, Savitz DA, Trapido E, Rosenthal J, Hoover R. Long term use of oral contraceptives andrisk of invasive cervical cancer. Int J Cancer 1986; 38:339-344.

48. WHO Collaborative Study of Neoplasia and Steroid Contraceptives: Invasive cervical cancer and combined oral contraceptives. BrMed J 1985; 290:961-965.

49. Rooks JB, Ory HW, Ishak KG, Strauss LT, Greenspan JR, Hill AP, Tyler CW. Epidemiology of hepatocellular adenoma: the role of oralcontraceptive use. JAMA 1979; 242:644-648.

50. Bein NN, Goldsmith HS. Recurrent massive hemorrhage from benign hepatic tumors secondary to oral contraceptives. Br J Surg 1977;64:433-435.

51. Klatskin G. Hepatic tumors: possible relationship touse of oral contraceptives. Gastroenterology 1977; 73:386-394.

52. Henderson BE, Preston-Martin S, Edmondson HA, PetersRL, Pike MC. Hepatocellular carcinoma and oral contraceptives. Br J Cancer 1983;48:437-440.

53. Neuberger J, Forman D, Doll R, Williams R. Oralcontraceptives and hepatocellular carcinoma. Br Med J 1986; 292:1355-1357.

54. Forman D, Vincent TJ, Doll R. Cancer of the liver andoral contraceptives. Br Med J 1986; 292:1357-1361.

72. Stockley I. Interactions with oral contraceptives. JPharm 1976;216:140-143.

73. 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.

74. 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; 257:796-800.75. Ory HW. Functional ovarian cysts and oralcontraceptives: negative association confirmed surgically. JAMA 1974;228:68-69.

76. Ory HW, Cole P, MacMahon B, Hoover R. Oral contraceptivesand reduced risk of benign breast disease. N Engl J Med 1976; 294:419-422.

77. Ory HW. The noncontraceptive health benefits fromoral contraceptive use. Fam Plann Perspect 1982; 14:182-184.

78. Ory HW, Forrest JD, Lincoln R. Making choices: Evaluating the health risks and benefits of birth control methods. New York, The AlanGuttmacher Institute, 1983; p.1.

79. Schlesselman J, Stadel BV, Murray P, Lai S. Breast cancer in relation to early use of oral contraceptives. JAMA 1988;259:1828-1833.

80. Hennekens CH, Speizer FE, Lipnick RJ, Rosner B, Bain C, Belanger C, Stampfer MJ, Willett W, Peto R. A case-control study of oralcontraceptive use and breast cancer. JNCI 1984; 72:39-42.

81. 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 casecontrol study.Br J Cancer 1986; 54:311-317.

82. 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.

83. Kay CR, Hannaford PC. Breast cancer and the pill-A further report from the Royal College of General Practitioners' oralcontraception study. Br J Cancer 1988;58:675-680.

84. Stadel BV, Lai S, Schlesselman JJ, Murray P. Oral contraceptives and premenopausal breast cancer in nulliparous women.Contraception 1988; 38:287-299.

85. Miller DR, Rosenberg L, Kaufman DW, Stolley P, Warshauer ME, Shapiro S. Breast cancer before age 45 and oral contraceptiveuse: New Findings. Am J Epidemiol 1989; 129:269-280.

86. The UK National Case-Control Study Group, Oral contraceptive use and breast cancer risk in young women. Lancet 1989;1:973-982.

87. Schlesselman JJ. Cancer of the breast and reproductive tract in relation to use of oral contraceptives. Contraception1989; 40:1-38.

88. Vessey MP, McPherson K, Villard-Mackintosh L, Yeates D. Oral contraceptives and breast cancer: latest findings in a large cohortstudy. Br J Cancer 1989; 59:613-617.

89. Jick SS, Walker AM, Stergachis A, Jick H. Oralcontraceptives and breast cancer. Br J Cancer 1989; 59:618-621.

90. Anderson FD, Selectivity and minimal androgenicity of norgestimate in monophasic and triphasic oral contraceptives. Acta ObstetGynecol Scand 1992; 156 (Supplement):15-21.

91. Chapdelaine A, Desmaris J-L, Derman RJ. Clinical evidence of minimal androgenic activity of norgestimate. Int J Fertil 1989;34(51):347-352.

92. Phillips A, Demarest K, Hahn DW, Wong F, McGuire JL.Progestational and androgenic receptor binding affinities and in vivo activities of norgestimate and other progestins. Contraception 1989; 41(4):399-409.

93. Phillips A, Hahn DW, Klimek S, McGuire JL. A comparison of the potencies and activities of progestogens used incontraceptives. Contraception 1987; 36(2):181-192.

94. Janaud A, Rouffy J, Upmalis D, Dain M-P. A comparison study of lipid and androgen metabolism with triphasic oral contraceptive formulations containing norgestimate or levonorgestrel. Acta Obstet GynecolScand 1992; 156 (Supplement):34-38.

95. 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 withoutbreast cancer from 54 epidemiological studies. Lancet 1996; 347:1713- 1727.

96. Palmer JR, Rosenberg L, Kaufman DW, Warshauer ME, Stolley P, Shapiro S. Oral Contraceptive Use and Liver Cancer. Am J Epidemiol1989;130:878-882.

99. Bork K, Fischer B, DeWald G. Recurrent episodes of skin angioedema and severe attacks of abdominal pain induced by oralcontraceptives or hormone replacement therapy. Am J Med 2003;114:294-298.

100. Van Giersbergen PLM, Halabi A, Dingemanse J. Pharmaco*kinetic interaction between bosentan and the oral contraceptivesnorethisterone and ethinyl estradiol. Int J Clin Pharmacol Ther 2006;44(3):113-118.

101. Christensen J, Petrenaite V, Atterman J, et al. Oral contraceptives induce lamotrigine metabolism: evidence from a double-blind, placebo-controlledtrial. Epilepsia 2007;48(3):484-489.

103. 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 pharmaco*kinetics of pioglitazone, repaglinide, estrogen estradiol, norethindrone, levothyroxine, and glyburide. J Clin Pharmacol 2010;50:554-565.

Mfd.by: JOLLC, Manati, Puerto Rico 00674. Mfd. for: WatsonLaboratories, Inc., A Subsidiary of Watson Pharmaceuticals, Inc., Corona, CA92880 USA. Revised May 2014

Side Effects for TriNessa

An increased risk of the following serious adversereactions 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
• Hypertension
• Gallbladder disease
• Hepatic adenomas or benign liver tumors

There is evidence of an association between the followingconditions and the use of oral contraceptives:

• Mesenteric thrombosis
• Retinal thrombosis

The following adverse reactions have been reported inpatients receiving oral contraceptives and are believed to be drug-related:

• Nausea
• Vomiting
• Gastrointestinal symptoms (such as abdominal cramps and bloating)
• Breakthrough bleeding
• Spotting
• Change in menstrual flow
• Amenorrhea
• Temporary infertility after discontinuation of treatment
• Edema
• 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
• Migraine
• Allergic reaction, including rash, urticaria, angioedema
• Mental depression
• Reduced tolerance to carbohydrates
• vagin*l candidiasis
• Change in corneal curvature (steepening)
• Intolerance to contact lenses

The following adverse reactions have been reported inusers of oral contraceptives and a causal association has been neitherconfirmed nor refuted:

• Pre-menstrual syndrome
• Cataracts
• Changes in appetite
• Cystitis-like syndrome
• Headache
• Nervousness
• Dizziness
• Hirsutism
• Loss of scalp hair
• Erythema multiforme
• Erythema nodosum
• Hemorrhagic eruption
• Vaginitis
• Porphyria
• Impaired renal function
• Hemolytic uremic syndrome
• Acne
• Changes in libido
• Colitis
• Budd-Chiari Syndrome

The following adverse reactions were also reported inclinical trials or during post-marketing experience: Infections andInfestations: vagin*l infection, urinary tract infection; PsychiatricDisorders: mood altered, anxiety, insomnia; Gastrointestinal Disorders:flatulence, pancreatitis, diarrhea, constipation; Reproductive System andBreast Disorders: dysmenorrhea; ovarian cyst, vulvovagin*l dryness; NeoplasmsBenign, Malignant and Unspecified (Including Cysts and Polyps): benignbreast neoplasm, fibroadenoma of breast, breast cyst; Nervous SystemDisorders: syncope, convulsion, paraesthesia; Eye Disorders: visualimpairment, dry eye; Ear and Labyrinth Disorders: vertigo; Cardiac Disorders:tachycardia, palpitations; Vascular Disorders: hot flush; Respiratory,Thoracic and Mediastinal Disorders: dyspnoea; Hepatobiliary Disorders:hepatitis; Skin and Subcutaneous Tissue Disorders: night sweats,hyperhidrosis, photosensitivity reaction, pruritus; Musculoskeletal,Connective Tissue, and Bone Disorders: muscle spasms, pain in extremity,myalgia, back pain; General Disorders and Administration Site Conditions: chestpain, asthenic conditions.

Drug Interactions for TriNessa

Consult the labeling of concurrently-used drugs to obtainfurther information about interactions with hormonal contraceptives or thepotential 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 20-25%. 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 needincreased doses of thyroid hormone because serum concentrations ofthyroid-binding globulin increases with use of COCs.

Interactions With Laboratory Tests

Certain endocrine and liver function tests and bloodcomponents may be affected by oral contraceptives:

1. Increased prothrombin and factors VII, VIII, IX, and X; decreased antithrombin 3; increased norepinephrine-induced platelet aggregability.
2. 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.
3. Other binding proteins may be elevated in serum.
4. Sex hormone binding globulins are increased and result in elevated levels of total circulating sex steroids; however, free or biologically active levels either decrease or remain unchanged.
5. Triglycerides may be increased and levels of various other lipids and lipoproteins may be affected.
6. Glucose tolerance may be decreased.
7. 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.

Warnings for TriNessa

Cigarette smoking increases the risk of seriouscardiovascular events from combination oral contraceptive use. This riskincreases with age, particularly in women over 35 years of age, and with thenumber of cigarettes smoked. For this reason, combination oral contraceptives, includingTriNessa®, should not be used by women who are over 35 years of age andsmoke.

The use of oral contraceptives is associated withincreased risks of several serious conditions including myocardial infarction,thromboembolism, stroke, hepatic neoplasia, and gallbladder disease, althoughthe risk of serious morbidity or mortality is very small in healthy womenwithout underlying risk factors. The risk of morbidity and mortality increasessignificantly in the presence of other underlying risk factors such ashypertension, hyperlipidemias, obesity and diabetes.

Practitioners prescribing oral contraceptives should befamiliar with the following information relating to these risks.

The information contained in this package insert isprincipally based on studies carried out in patients who used oralcontraceptives with higher formulations of estrogens and progestogens thanthose in common use today. The effect of long-term use of the oralcontraceptives with lower formulations of both estrogens and progestogensremains to be determined.

Throughout this labeling, epidemiological studiesreported are of two types: retrospective or case control studies andprospective or cohort studies. Case control studies provide a measure of the relativerisk of a disease, namely, a ratio of the incidence of a disease among oralcontraceptive users to that among nonusers. The relative risk does not provideinformation on the actual clinical occurrence of a disease. Cohort studiesprovide a measure of attributable risk, which is the difference in theincidence of disease between oral contraceptive users and nonusers. Theattributable risk does provide information about the actual occurrence of adisease in the population (adapted from refs. 2 and 3 with the author'spermission). For further information, the reader is referred to a text onepidemiological methods.

Thromboembolic Disorders And Other Vascular Problems

Myocardial Infarction

An increased risk of myocardial infarction has beenattributed to oral contraceptive use. This risk is primarily in smokers orwomen with other underlying risk factors for coronary artery disease such as hypertension,hypercholesterolemia, morbid obesity, and diabetes. The relative risk of heartattack for current oral contraceptive users has been estimated to be two tosix.^4-10 The risk is very low under the age of 30.

Smoking in combination with oral contraceptive use hasbeen shown to contribute substantially to the incidence of myocardial infarctionsin women in their mid-thirties or older with smoking accounting for themajority of excess cases.¹¹ Mortality rates associated withcirculatory disease have been shown to increase substantially in smokers,especially in those 35 years of age and older, and in nonsmokers over the ageof 40 among women who use oral contraceptives. (See Figure 1)

Figure 1: Circulatory Disease Mortality Rates per100,000 Women-Years by Age, Smoking Status and Oral Contraceptive Use

Oral contraceptives may compound the effects ofwell-known risk factors, such as hypertension, diabetes, hyperlipidemias, ageand obesity.¹³ In particular, some progestogens are known todecrease HDL cholesterol and cause glucose intolerance, while estrogens maycreate a state of hyperinsulinism.^14-18 Oral contraceptives havebeen shown to increase blood pressure among users (see Section on Elevated Blood Pressure below).Similar effects on risk factors have been associated with an increased risk ofheart disease. Oral contraceptives must be used with caution in women withcardiovascular disease risk factors.

Norgestimate has minimal androgenic activity (see CLINICALPHARMACOLOGY), and there is some evidence that the risk of myocardialinfarction associated with oral ontraceptives is lower when the progestogenhas minimal androgenic activity than when the activity is greater.⁹⁷

Thromboembolism

An increased risk of thromboembolic and thromboticdisease associated with the use of oral contraceptives is well established.Case control studies have found the relative risk of users compared to nonusersto be 3 for the first episode of superficial venous thrombosis, 4 to 11 fordeep vein thrombosis or pulmonary embolism, and 1.5 to 6 for women withpredisposing conditions for venous thromboembolic disease.^2,319-24Cohort studies have shown the relative risk to be somewhat lower, about 3 fornew cases and about 4.5 for new cases requiring hospitalization.²⁵The risk of thromboembolic disease associated with oral contraceptives is notrelated to length of use and disappears after pill use is stopped.²

A two- to four-fold increase in relative risk ofpost-operative thromboembolic complications has been reported with the use oforal contraceptives.⁹ The relative risk of venous thrombosis inwomen who have predisposing conditions is twice that of women without suchmedical conditions.²⁶ If feasible, oral contraceptives should bediscontinued at least four weeks prior to and for two weeks after elective surgeryof a type associated with an increase in risk of thromboembolism and during andfollowing prolonged immobilization. Since the immediate postpartum period isalso associated with an increased risk of thromboembolism, oral contraceptivesshould be started no earlier than four weeks after delivery in women who electnot to breastfeed.

Cerebrovascular Diseases

Oral contraceptives have been shown to increase both therelative and attributable risks of cerebrovascular events (thrombotic andhemorrhagic strokes), although, in general, the risk is greatest among older( > 35 years), hypertensive women who also smoke. Hypertension was found to bea risk factor for both users and nonusers, for both types of strokes, andsmoking interacted to increase the risk of stroke.^27-29

In a large study, the relative risk of thrombotic strokeshas been shown to range from 3 for normotensive users to 14 for users withsevere hypertension.³⁰ The relative risk of hemorrhagic stroke isreported to be 1.2 for non-smokers who used oral contraceptives, 2.6 forsmokers who did not use oral contraceptives, 7.6 for smokers who used oralcontraceptives, 1.8 for normotensive users and 25.7 for users with severehypertension.³⁰ The attributable risk is also greater in olderwomen.³

Dose-Related Risk Of Vascular Disease From Oral Contraceptives

A positive association has been observed between theamount of estrogen and progestogen in oral contraceptives and the risk ofvascular disease. A decline in serum high density lipoproteins (HDL) has beenreported with many progestational agents. A decline in serum high density lipoproteinshas been associated with an increased incidence of ischemic heart disease.Because estrogens increase HDL cholesterol, the net effect of an oralcontraceptive depends on a balance achieved between doses of estrogen andprogestogen and the activity of the progestogen used in the contraceptives. Theactivity and amount of both hormones should be considered in the choice of anoral contraceptive.

Minimizing exposure to estrogen and progestogen is inkeeping with good principles of therapeutics. For any particularestrogen/progestogen combination, the dosage regimen prescribed should be one whichcontains the least amount of estrogen and progestogen that is compatible with alow failure rate and the needs of the individual patient. New acceptors of oralcontraceptive agents should be started on preparations containing the lowestestrogen content which is judged appropriate for the individual patient.

Persistence Of Risk Of Vascular Disease

There are two studies which have shown persistence ofrisk of vascular disease for ever-users of oral contraceptives. In a study inthe United States, the risk of developing myocardial infarction after discontinuingoral contraceptives persists for at least 9 years for women 40-49 years who hadused oral contraceptives for five or more years, but this increased risk wasnot demonstrated in other age groups.⁸ In another study in GreatBritain, the risk of developing cerebrovascular disease persisted for at least6 years after discontinuation of oral contraceptives, although excess risk wasvery small.³⁴ However, both studies were performed with oralcontraceptive formulations containing 50 micrograms or higher of estrogens.

Estimates Of Mortality From Contraceptive Use

One study gathered data from a variety of sources whichhave estimated the mortality rate associated with different methods ofcontraception at different ages (Table 4). These estimates include the combinedrisk of death associated with contraceptive methods plus the risk attributableto pregnancy in the event of method failure. Each method of contraception hasits specific benefits and risks. The study concluded that with the exception oforal contraceptive users 35 and older who smoke, and 40 and older who do notsmoke, mortality associated with all methods of birth control is low and belowthat associated with childbirth. The observation of an increase in risk ofmortality with age for oral contraceptive users is based on data gathered inthe 1970's. Current clinical recommendation involves the use of lower estrogendose formulations and a careful consideration of risk factors. In 1989, the Fertilityand Maternal Health Drugs Advisory Committee was asked to review the use oforal contraceptives in women 40 years of age and over. The Committee concludedthat although cardiovascular disease risks may be increased with oralcontraceptive use after age 40 in healthy nonsmoking women (even with the newerlow-dose formulations), there are also greater potential health risksassociated with pregnancy in older women and with the alternative surgical andmedical procedures which may be necessary if such women do not have access toeffective and acceptable means of contraception. The Committee recommended thatthe benefits of low-dose oral contraceptive use by healthy non-smoking womenover 40 may outweigh the possible risks.

Of course, older women, as all women, who take oralcontraceptives, should take an oral contraceptive which contains the leastamount of estrogen and progestogen that is compatible with a low failure rate andindividual patient needs.

Table 4: Annual Number of Birth-Related orMethod-Related Deaths Associated with Control of Fertility per 100,000Non-Sterile Women, by Fertility Control Method According to Age

Carcinoma Of The Reproductive Organs And Breasts

Numerous epidemiological studies have been performed onthe incidence of breast, endometrial, ovarian, and cervical cancer in womenusing oral contraceptives. The risk of having breast cancer diagnosed may beslightly increased among current and recent users of combination oralcontraceptives (COCs). However, this excess risk appears to decrease over timeafter COC discontinuation and by 10 years after cessation the increased riskdisappears. Some studies report an increased risk with duration of use whileother studies do not and no consistent relationships have been found with doseor type of steroid. Some studies have found a small increase in risk for womenwho first use COCs before age 20. Most studies show a similar pattern of riskwith COC use regardless of a woman's reproductive history or her family breastcancer history.

Breast cancers diagnosed in current or previous oralcontraceptive users tend to be less clinically advanced than in nonusers. Womenwho currently have or have had breast cancer should not use oral contraceptivesbecause breast cancer is usually a hormonally-sensitive tumor.

Some studies suggest that oral contraceptive use has beenassociated with an increase in the risk of cervical intraepithelial neoplasiain some populations of women. However, there continues to be controversy aboutthe extent to which such findings may be due to differences in sexual behaviorand other factors. In spite of many studies of the relationship between oralcontraceptive use and breast and cervical cancers, a cause-and-effectrelationship has not been established.

Hepatic Neoplasia

Benign hepatic adenomas are associated with oralcontraceptive use, although the incidence of benign tumors is rare in theUnited States. Indirect calculations have estimated the attributable risk to bein the range of 3.3 cases/100,000 for users, a risk that increases after fouror more years of use especially with oral contraceptives of higher dose.Rupture of benign, hepatic adenomas may cause death through intra-abdominalhemorrhage.

Studies from Britain have shown an increased risk ofdeveloping hepatocellular carcinoma in long-term ( > 8 years) oralcontraceptive users. However, these cancers are extremely rare in the U.S. andthe attributable risk (the excess incidence) of liver cancers in oralcontraceptive users approaches less than one per million users.

Ocular Lesions

There have been clinical case reports of retinal thrombosisassociated with the use of oral contraceptives. Oral contraceptives should bediscontinued if there is unexplained partial or complete loss of vision; onsetof proptosis or diplopia; papilledema; or retinal vascular lesions. Appropriatediagnostic and therapeutic measures should be undertaken immediately.

Oral Contraceptive Use Before Or During Early Pregnancy

Extensive epidemiological studies have revealed noincreased risk of birth defects in women who have used oral contraceptivesprior to pregnancy.^56,57 The majority of recent studies also do notindicate a teratogenic effect, particularly in so far as cardiac anomalies andlimb reduction defects are concerned^55,56,58,59, when takeninadvertently during early pregnancy.

The administration of oral contraceptives to inducewithdrawal bleeding should not be used as a test for pregnancy. Oralcontraceptives should not be used during pregnancy to treat threatened orhabitual abortion.

It is recommended that for any patient who has missed twoconsecutive periods, pregnancy should be ruled out. If the patient has notadhered to the prescribed schedule, the possibility of pregnancy should beconsidered at the time of the first missed period. Oral contraceptive useshould be discontinued if pregnancy is confirmed.

Gallbladder Disease

Earlier studies have reported an increased lifetimerelative risk of gallbladder surgery in users of oral contraceptives andestrogens.^60,61 More recent studies, however, have shown that therelative risk of developing gallbladder disease among oral contraceptive usersmay be minimal.^62-64 The recent findings of minimal risk may berelated to the use of oral contraceptive formulations containing lower hormonaldoses of estrogens and progestogens.

Carbohydrate And Lipid Metabolic Effects

Oral contraceptives have been shown to cause a decreasein glucose tolerance in a significant percentage of users.¹⁷ Thiseffect has been shown to be directly related to estrogen dose.⁶⁵ Progestogensincrease insulin secretion and create insulin resistance, this effect varyingwith different progestational agents.^17,66 However, in thenon-diabetic woman, oral contraceptives appear to have no effect on fastingblood glucose.⁶⁷ Because of these demonstrated effects, prediabeticand diabetic women in particular should be carefully monitored while takingoral contraceptives. A small proportion of women will have persistenthypertriglyceridemia while on the pill. As discussed earlier (see Thromboembolic Disorders and Other Vascular Problems), changes in serum triglycerides and lipoprotein levels have been reportedin oral contraceptive users.

In clinical studies with TriNessa® there were noclinically significant changes in fasting blood glucose levels. Minimalstatistically significant changes were noted in glucose levels over 24 cyclesof use. Glucose tolerance tests showed no clinically significant changes frombaseline to cycles 3, 12, and 24.

Elevated Blood Pressure

Women with significant hypertension should not be startedon hormonal contraception.⁹⁸ An increase in blood pressure has beenreported in women taking oral contraceptives⁶⁸ and this increase ismore likely in older oral contraceptive users⁶⁹ and with extendedduration of use.⁶¹ Data from the Royal College of GeneralPractitioners¹² and subsequent randomized trials have shown that theincidence of hypertension increases with increasing progestational activity.

Women with a history of hypertension orhypertension-related diseases, or renal disease⁷⁰ should be encouragedto use another method of contraception. If these women elect to use oralcontraceptives, they should be monitored closely and if a clinicallysignificant persistent elevation of blood pressure (BP) occurs ( ≥ 160 mmHg systolic or ≥ 100 mm Hg diastolic) and cannot be adequatelycontrolled, oral contraceptives should be discontinued. In general, women whodevelop hypertension during hormonal contraceptive therapy should be switchedto a non-hormonal contraceptive. If other contraceptive methods are notsuitable, hormonal contraceptive therapy may continue combined withantihypertensive therapy. Regular monitoring of BP throughout hormonalcontraceptive therapy is recommended.¹⁰² For most women, elevatedblood pressure will return to normal after stopping oral contraceptives, andthere is no difference in the occurrence of hypertension between former andnever users.^68-71

Headache

The onset or exacerbation of migraine or development ofheadache with a new pattern which is recurrent, persistent or severe requiresdiscontinuation of oral contraceptives and evaluation of the cause.

Bleeding Irregularities

Breakthrough bleeding and spotting are sometimesencountered in patients on oral contraceptives, especially during the firstthree months of use. Non-hormonal causes should be considered and adequatediagnostic measures taken to rule out malignancy or pregnancy in the event ofbreakthrough bleeding, as in the case of any abnormal vagin*l bleeding. Ifpathology has been excluded, time or a change to another formulation may solvethe problem. In the event of amenorrhea, pregnancy should be ruled out.

Some women may encounter post-pill amenorrhea oroligomenorrhea, especially when such a condition was preexistent.

Ectopic Pregnancy

Ectopic as well as intrauterine pregnancy may occur incontraceptive failures.

Precautions for TriNessa

General

Patients should be counseled that this product does notprotect against HIV infection (AIDS) and other sexually transmitted diseases.

Physical Examination And Follow-up

It is good medical practice for all women to have annualhistory and physical examinations, including women using oral contraceptives.The physical examination, however, may be deferred until after initiation oforal contraceptives if requested by the woman and judged appropriate by theclinician. The physical examination should include special reference to bloodpressure, breasts, abdomen and pelvic organs, including cervical cytology, andrelevant laboratory tests. In case of undiagnosed, persistent or recurrentabnormal vagin*l bleeding, appropriate measures should be conducted to rule outmalignancy. Women with a strong family history of breast cancer or who havebreast nodules should be monitored with particular care.

Lipid Disorders

Women who are being treated for hyperlipidemias should befollowed closely if they elect to use oral contraceptives. Some progestogensmay elevate LDL levels and may render the control of hyperlipidemias moredifficult.

Liver Function

If jaundice develops in any woman receiving such drugs,the medication should be discontinued. Steroid hormones may be poorlymetabolized in patients with impaired liver function.

Fluid Retention

Oral contraceptives may cause some degree of fluidretention. They should be prescribed with caution, and only with carefulmonitoring, in patients with conditions which might be aggravated by fluid retention.

Emotional Disorders

Women with a history of depression should be carefullyobserved and the drug discontinued if depression recurs to a serious degree.

Contact Lenses

Contact lens wearers who develop visual changes orchanges in lens tolerance should be assessed by an ophthalmologist.

Carcinogenesis

See WARNINGS.

Pregnancy

Pregnancy Category X

See CONTRAINDICATIONS and WARNINGS.

Nursing Mothers

Small amounts of oral contraceptive steroids have beenidentified in the milk of nursing mothers and a few adverse effects on thechild have been reported, including jaundice and breast enlargement. In addition,combination oral contraceptives given in the postpartum period may interferewith lactation by decreasing the quantity and quality of breast milk. Ifpossible, the nursing mother should be advised not to use combination oralcontraceptives but to use other forms of contraception until she has completelyweaned her child.

Pediatric Use

Safety and efficacy of TriNessa® has been established inwomen of reproductive age. Safety and efficacy are expected to be the same forpostpubertal adolescents under the age of 16 and for users 16 years and older.There was no significant difference between TriNessa® Tablets and placebo inmean change in total lumbar spine (L1-L4) and total hip bone mineral densitybetween baseline and Cycle 13 in 123 adolescent females with anorexia nervosain a double-blind, placebo-controlled, multicenter, oneyear treatment durationclinical trial for the Intent To Treat (ITT) population. Use of this productbefore menarche is not indicated.

Geriatric Use

This product has not been studied in women over 65 yearsof age and is not indicated in this population.

Information For The Patient

See Patient Labeling.

REFERENCES

1. 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.

2. Stadel BV, Oral contraceptives and cardiovasculardisease. (Pt.1). N Engl J Med 1981; 305:612- 618.

3. Stadel BV, Oral contraceptives and cardiovasculardisease. (Pt.2). N Engl J Med 1981; 305:672- 677.

4. Adam SA, Thorogood M. Oral contraception and myocardial infarction revisited: the effects of new preparations andprescribing patterns. Br J Obstet Gynaecol 1981; 88:838-845.

5. Mann Jl, Inman WH. Oral contraceptives and death frommyocardial infarction. Br Med J 1975; 2(5965):245-248.

6. Mann Jl, Vessey MP, Thorogood M, Doll R. Myocardial infarction in young women with special reference to oral contraceptivepractice. Br Med J 1975; 2(5956):241-245.

7. Royal College of General Practitioners' Oral Contraception Study: Further analyses of mortality in oral contraceptive users.Lancet 1981; 1:541-546.

8. Slone D, Shapiro S, Kaufman DW, Rosenberg L, Miettinen OS, Stolley PD. Risk of myocardial infarction in relation to current anddiscontinued use of oral contraceptives. N Engl J Med 1981:305:420-424.

9. Vessey MP. Female hormones and vascular disease-anepidemiological overview. Br J Fam Plann 1980; 6(Supplement): 1-12.

10. 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.

11. Goldbaum GM, Kendrick JS, Hogelin GC, Gentry EM. The relative impact of smoking and oral contraceptive use on women in the UnitedStates. JAMA 1987; 258:1339-1342.

12. Layde PM, Beral V. Further analyses of mortality in oral contraceptive users; Royal College of General Practitioners' OralContraception Study. (Table 5) Lancet 1981; 1:541-546.

13. Knopp RH. Arteriosclerosis risk: the roles of oral contraceptives and postmenopausal estrogens. J Reprod Med 1986; 31(9)(Supplement):913-921.

14. 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.

15. Wahl P, Walden C, Knopp R, Hoover J, Wallace R, Heiss G, Rifkind B. Effect of estrogen/progestin potency on lipid/lipoproteincholesterol. N Engl J Med 1983; 308:862-867.

16. Wynn V, Niththyananthan R. The effect of progestin in combined oral contraceptives on serum lipids with special reference to highdensity lipoproteins. Am J Obstet Gynecol 1982;142:766-771.

17. Wynn V, Godsland I. Effects of oral contraceptives oncarbohydrate metabolism. J Reprod Med 1986;31(9)(Supplement):892-897.

18. LaRosa JC. Atherosclerotic risk factors incardiovascular disease. J Reprod Med 1986;31(9)(Supplement):906-912.

19. Inman WH, Vessey MP. Investigation of death from pulmonary, coronary, and cerebral thrombosis and embolism in women ofchild-bearing age. Br Med J 1968;2(5599):193-199.

20. Maguire MG, Tonascia J, Sartwell PE, Stolley PD, Tockman MS. Increased risk of thrombosis due to oral contraceptives: a furtherreport. Am J Epidemiol 1979;110(2):188-195.

21. 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.

22. Vessey MP, Doll R, Investigation of relation between use of oral contraceptives and thromboembolic disease. Br Med J1968;2(5599):199-205.

23. Vessey MP, Doll R. Investigation of relation between use of oral contraceptives and thromboembolic disease. A further report. Br MedJ 1969; 2(5658):651-657.

24. Porter JB, Hunter JR, Danielson DA, Jick H, Stergachis A. Oral contraceptives and non-fatal vascular disease - recentexperience. Obstet Gynecol 1982;59(3):299-302.

25. Vessey M, Doll R, Peto R, Johnson B, Wiggins P. A long-term follow-up study of women using different methods of contraception: aninterim report. J Biosocial Sci 1976;8:375-427.

26. Royal College of General Practitioners: Oral Contraceptives, venous thrombosis, and varicose veins. J Royal Coll Gen Pract1978; 28:393-399.

27. Collaborative Group for the Study of Stroke in Young Women: Oral contraception and increased risk of cerebral ischemia orthrombosis. N Engl J Med 1973;288:871-878.

28. Petitti DB, Wingerd J. Use of oral contraceptives,cigarette smoking, and risk of subarachnoid hemorrhage. Lancet 1978;2:234-236.

29. Inman WH. Oral contraceptives and fatal subarachnoidhemorrhage. Br Med J 1979:2(6203):1468- 1470.

30. 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.

31. Inman WH, Vessey MP, Westerholm B, Engelund A. Thromboembolic disease and the steroidal content of oral contraceptives. Areport to the Committee on Safety of Drugs. Br Med J 1970;2:203- 209.

32. 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 oestrogen preparations. Br Med J1980;280(6224):1157-1161.

33. Kay CR. Progestogens and arterial disease - evidence from the Royal College of General Practitioners' Study. Am J Obstet Gynecol1982;142:762-765.

34. Royal College of General Practitioners: Incidence of arterial disease among oral contraceptive users. J Royal Coll Gen Pract 1983;33:75-82.35. Ory HW. Mortality associated with fertility andfertility control: 1983. Family Planning Perspectives 1983;15:50-56.

55. Harlap S, Eldor J. Births following oralcontraceptive failures. Obstet Gynecol 1980; 55:447-452.

56. Savolainen E, Saksela E, Saxen L. Teratogenic hazards of oral contraceptives analyzed in a national malformation register. Am JObstet Gynecol 1981: 140:521-524.

57. Janerich DT, Piper JM, Glebatis DM. Oralcontraceptives and birth defects. Am J Epidemiol 1980; 112:73-79.

58. Ferencz C, Matanoski GM, Wilson PD, Rubin JD, Neill CA, Gutberlet R. Maternal hormone therapy and congenital heart disease.Teratology 1980; 21:225-239.

59. Rothman KJ, Fyler DC, Goldblatt A, Kreidberg MB. Exogenous hormones and other drug exposures of children with congenital heartdisease. Am J Epidemiol 1979; 109:433-439.

60. Boston Collaborative Drug Surveillance Program: Oral contraceptives and venous thromboembolic disease, surgically confirmedgallbladder disease, and breast tumors. Lancet 1973; 1:1399-1404.

61. Royal College of General Practitioners: Oralcontraceptives and health. New York, Pittman 1974.

62. Layde PM, Vessey MP, Yeates D. Risk of gallbladder disease: a cohort study of young women attending family planning clinics. JEpidemiol Community Health 1982; 36:274-278.

63. Rome Group for Epidemiology and Prevention of Cholelithiasis (GREPCO): Prevalence of gallstone disease in an Italian adultfemale population. Am J Epidemiol 1984; 119:796-805.

64. Storm BL, Tamragouri RT, Morse ML, Lazar EL, West SL, Stolley PD, Jones JK. Oral contraceptives and other risk factors forgallbladder disease. Clin Pharmacol Ther 1986; 39:335- 341.

65. 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.

66. 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.

67. Perlman JA, Roussell-Briefel RG, Ezzati TM, Lieberknecht G. Oral glucose tolerance and the potency of oral contraceptiveprogestogens. J Chronic Dis 1985;38:857-864.

68. Royal College of General Practitioners' Oral Contraception Study: Effect on hypertension and benign breast disease ofprogestogen component in combined oral contraceptives. Lancet 1977; 1:624.

69. Fisch IR, Frank J. Oral contraceptives and bloodpressure. JAMA 1977; 237:2499-2503.

70. Laragh AJ. Oral contraceptive inducedhypertension-nine years later. Am J Obstet Gynecol 1976; 126:141-147.

71. 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 Institutefor Pharmacological Research Milan.)

97. Lewis M, Spitzer WO, Heinemann LAJ, MacRae KD, Bruppacher R, Thorogood M on behalf of Transnational Research Group on Oral Contraceptives and Health of Young Women. Third generation oral contraceptives and risk of myocardial infarction: an international case-control study. Br MedJ, 1996;312:88-90.

98. Improving access to quality care in family planning: Medical eligibility criteria for contraceptive use. Geneva, WHO, Family andReproductive Health, 1996.

102. 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.

Overdose Information for TriNessa

Serious ill effects have not been reported followingacute ingestion of large doses of oral contraceptives by young children.Overdosage may cause nausea and withdrawal bleeding may occur in females.

Non-Contraceptive Health Benefits

The following non-contraceptive health benefits relatedto the use of combination oral contraceptives are supported by epidemiologicalstudies which largely utilized oral contraceptive formulations containingestrogen doses exceeding 0.035 mg of ethinyl estradiol or 0.05 mg mestranol.

Effects on menses:

• increased menstrual cycle regularity
• decreased blood loss and decreased incidence of iron deficiency anemia
• decreased incidence of dysmenorrhea

Effects related to inhibition of ovulation:

• decreased incidence of functional ovarian cysts
• decreased incidence of ectopic pregnancies

Other effects:

• decreased incidence of fibroadenomas and fibrocystic disease of the breast
• decreased incidence of acute pelvic inflammatory disease
• decreased incidence of endometrial cancer
• decreased incidence of ovarian cancer

Contraindications for TriNessa

Oral contraceptives should not be used in women whocurrently have the following conditions:

• Thrombophlebitis or thromboembolic disorders
• A past history of deep vein thrombophlebitis or thromboembolic disorders
• Known thrombophilic conditions
• Cerebral vascular or coronary artery disease (current or past history)
• Valvular heart disease with complications
• Persistent blood pressure values of ≥ 160 mm Hg systolic or ≥ 100 mg Hg diastolic¹⁰²
• Diabetes with vascular involvement
• Headaches with focal neurological symptoms
• Major surgery with prolonged immobilization
• Known or suspected carcinoma of the breast or personal history of breast cancer
• Carcinoma of the endometrium or other known or suspected estrogen-dependent neoplasia
• Undiagnosed abnormal genital bleeding
• Cholestatic jaundice of pregnancy or jaundice with prior pill use
• Acute or chronic hepatocellular disease with abnormal liver function
• Hepatic adenomas or carcinomas
• Known or suspected pregnancy
• Hypersensitivity to any component of this product

REFERENCES

102. 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.

Clinical Pharmacology for TriNessa

Oral Contraception

Combination oral contraceptives act by suppression ofgonadotropins. Although the primary mechanism of this action is inhibition ofovulation, other alterations include changes in the cervical mucus (which increasethe difficulty of sperm entry into the uterus) and the endometrium (whichreduce the likelihood of implantation).

Receptor binding studies, as well as studies in animalsand humans, have shown that norgestimate and 17-deacetyl norgestimate, themajor serum metabolite, combine high progestational activity with minimal intrinsicandrogenicity.^90-93 Norgestimate, in combination with ethinylestradiol, does not counteract

the estrogen-induced increases in sex hormone bindingglobulin (SHBG), resulting in lower serum testosterone.^90,91,94

Acne

Acne is a skin condition with a multifactorial etiology,including androgen stimulation of sebum production. While the combination ofethinyl estradiol and norgestimate increases sex hormone binding globulin(SHBG) and decreases free testosterone, the relationship between these changesand a decrease in the severity of facial acne in otherwise healthy women withthis skin condition has not been established.

Pharmaco*kinetics

Absorption

Norgestimate (NGM) and ethinyl estradiol (EE) are rapidlyabsorbed following oral administration. Norgestimate is rapidly and completelymetabolized by first pass (intestinal and/or hepatic) mechanisms tonorelgestromin (NGMN) and norgestrel (NG), which are the major activemetabolites of norgestimate.

Peak serum concentrations of NGMN and EE are generallyreached by 2 hours after administration of TriNessa®. Accumulation followingmultiple dosing of the 250 mcg NGM / 35 mcg dose is approximately 2-fold forNGMN and EE compared with single dose administration. The pharmaco*kinetics ofNGMN is dose proportional following NGM doses of 180 mcg to 250 mcg. Steady-stateconcentration of EE is achieved by Day 7 of each dosing cycle. Steady-stateconcentrations of NGMN and NG are achieved by Day 21. Non-linear accumulation(approximately 8 fold) of norgestrel is observed as a result of high affinitybinding to SHBG (sex hormone-binding globulin), which limits its biologicalactivity.

Table 1: Summary of norelgestromin, norgestrel andethinyl estradiol pharmaco*kinetic parameters

The effect of food on the pharmaco*kinetics of TriNessahas not been studied.

Distribution

Norelgestromin and norgestrel are highly bound ( > 97%)to serum proteins. Norelgestromin is bound to albumin and not to SHBG, whilenorgestrel is bound primarily to SHBG. Ethinyl estradiol is extensively bound( > 97%) to serum albumin and induces an increase in the serum concentrationsof SHBG.

Metabolism

Norgestimate is extensively metabolized by first-passmechanisms in the gastrointestinal tract and/or liver. Norgestimate's primaryactive metabolite is norelgestromin. Subsequent hepatic metabolism of norelgestrominoccurs and metabolites include norgestrel, which is also active, and various hydroxylatedand conjugated metabolites. Ethinyl estradiol is also metabolized to varioushydroxylated products and their glucuronide and sulfate conjugates.

Excretion

The metabolites of norelgestromin and ethinyl estradiolare eliminated by renal and fecal pathways. Following administration of 14C-norgestimate,47% (45-49%) and 37% (16-49%) of the administered radioactivity was eliminatedin the urine and feces, respectively. Unchanged norgestimate was not detectedin the urine. In addition to 17-deacetyl norgestimate, a number of metabolitesof norgestimate have been identified in human urine following administration ofradiolabeled norgestimate. These include 18,19-Dinor-17-pregn-4-en-20-yn-3-one,17-hydroxy-13-ethyl,(17α)-(-);18,19-Dinor-5β-17-pregnan-20-yn,3α,17β-dihydroxy-13-ethyl,(17α), varioushydroxylated metabolites and conjugates of these metabolites.

Special Populations

The effects of body weight, body surface area or age onthe pharmaco*kinetics of TriNessa® have not been studied.

Hepatic Impairment

The effects of hepatic impairment on the pharmaco*kineticsof TriNessa® have not been studied. However, steroid hormones may be poorlymetabolized in women with impaired liver function (see PRECAUTIONS).

Renal Impairment

The effects of renal impairment on the pharmaco*kineticsof TriNessa® have not been studied.

Drug-Drug Interactions

No formal drug-drug interaction studies were conductedwith TriNessa®. Interactions between contraceptive steroids and other drugshave been reported in the literature (see PRECAUTIONS).

Although norelgestromin and its metabolites inhibit avariety of P450 enzymes in human liver microsomes, under the recommended dosingregimen, the in vivo concentrations of norelgestromin and its metabolites, evenat the peak serum levels, are relatively low compared to the inhibitoryconstant (Ki).

REFERENCES

90. Anderson FD, Selectivity and minimal androgenicity of norgestimate in monophasic and triphasic oral contraceptives. Acta ObstetGynecol Scand 1992; 156 (Supplement):15-21.

91. Chapdelaine A, Desmaris J-L, Derman RJ. Clinical evidence of minimal androgenic activity of norgestimate. Int J Fertil 1989;34(51):347-352.

92. Phillips A, Demarest K, Hahn DW, Wong F, McGuire JL.Progestational and androgenic receptor binding affinities and in vivo activities of norgestimate and other progestins. Contraception 1989; 41(4):399-409.

93. Phillips A, Hahn DW, Klimek S, McGuire JL. A comparison of the potencies and activities of progestogens used incontraceptives. Contraception 1987; 36(2):181-192.

94. Janaud A, Rouffy J, Upmalis D, Dain M-P. A comparison study of lipid and androgen metabolism with triphasic oral contraceptive formulations containing norgestimate or levonorgestrel. Acta Obstet Gynecol Scand 1992; 156 (Supplement):34-38.

Patient Information for TriNessa

Brief Summary Patient Package Insert

This product (like all oral contraceptives) does notprotect against HIV infection (AIDS) and other sexually transmitted diseases.

Oral contraceptives, also known as “birth controlpills” or “the pill,” are taken to prevent pregnancy. When takencorrectly to prevent pregnancy, oral contraceptives have a failure rate ofapproximately 1% per year (1 pregnancy per 100 women per year of use) when usedwithout missing any pills. The typical failure rate is approximately 5% peryear (5 pregnancies per 100 women per year of use) when women who miss pillsare included. For most women oral contraceptives are also free of serious orunpleasant side effects. However, forgetting to take pills considerablyincreases the chances of pregnancy.

TriNessa® may also be taken to treat moderate acne infemales at least 15 years of age, who have started having menstrual periods,are able to take the pill and want to use the pill for birth control.

For the majority of women, oral contraceptives can betaken safely. But there are some women who are at high risk of developingcertain serious diseases that can be fatal or may cause temporary or permanentdisability. The risks associated with taking oral contraceptives increasesignificantly if you:

• smoke
• have high blood pressure, diabetes, high cholesterol
• have or have had clotting disorders, heart attack, stroke, angina pectoris, cancer of the breast or sex organs, jaundice or malignant or benign liver tumors.

Although cardiovascular disease risks may be increasedwith oral contraceptive use after age 40 in healthy, non-smoking women (evenwith the newer low-dose formulations), there are also greater potential healthrisks associated with pregnancy in older women.

You should not take the pill if you suspect you arepregnant or have unexplained vagin*l bleeding.

Do not use TriNessa® if you smoke cigarettesand are over 35 years old. Smoking increases your risk of seriouscardiovascular side effects (heart and blood vessel problems) from combinationoral contraceptives , including death from heart attack, blood clots or stroke.This risk increases with age and the number of cigarettes you smoke.

Most side effects of the pill are not serious. The mostcommon side effects are nausea, vomiting, bleeding between menstrual periods,weight gain, breast tenderness, and difficulty wearing contact lenses. Theseside effects, especially nausea and vomiting, may subside within the firstthree months of use.

The serious side effects of the pill occur veryinfrequently, especially if you are in good health and are young. However, youshould know that the following medical conditions have been associated with or madeworse by the pill:

1. Blood clots in the legs (thrombophlebitis), lungs (pulmonary embolism), stoppage or rupture of a blood vessel in the brain (stroke), blockage of blood vessels in the heart (heart attack or angina pectoris) or other organs of the body. As mentioned above, smoking increases the risk of heart attacks and strokes and subsequent serious medical consequences.
2. In rare cases, oral contraceptives can cause benign but dangerous liver tumors. These benign liver tumors can rupture and cause fatal internal bleeding. In addition, some studies report an increased risk of developing liver cancer. However, liver cancers are rare.
3. High blood pressure, although blood pressure usually returns to normal when the pill is stopped.

The symptoms associated with these serious side effectsare discussed in the detailed leaflet given to you with your supply of pills.Notify your healthcare professional if you notice any unusual physical disturbanceswhile taking the pill. In addition, drugs such as rifampin, bosentan, as wellas some seizure medicines and herbal preparations containing St. John's wort (Hypericumperforatum) may decrease oral contraceptive effectiveness.

Oral contraceptives may interact with lamotrigine(LAMICTAL®), a seizure medicine used for epilepsy. This may increase the riskof seizures so your healthcare professional may need to adjust the dose oflamotrigine.

Various studies give conflicting reports on therelationship between breast cancer and oral contraceptive use. Oralcontraceptive use may slightly increase your chance of having breast cancer diagnosed,particularly after using hormonal contraceptives at a younger age. After youstop using hormonal contraceptives, the chances of having breast cancerdiagnosed begin to go back down. You should have regular breast examinations bya healthcare professional and examine your own breasts monthly. Tell yourhealthcare professional if you have a family history of breast cancer or if youhave had breast nodules or an abnormal mammogram. Women who currently have orhave had breast cancer should not use oral contraceptives because breast canceris usually a hormone-sensitive tumor.

Some studies have found an increase in the incidence ofcancer of the cervix in women who use oral contraceptives. However, thisfinding may be related to factors other than the use of oral contraceptives.There is insufficient evidence to rule out the possibility that the pill maycause such cancers.

Taking the combination pill provides some importantnon-contraceptive benefits. These include less painful menstruation, lessmenstrual blood loss and anemia, fewer pelvic infections, and fewer cancers ofthe ovary and the lining of the uterus.

Be sure to discuss any medical condition you may havewith your healthcare professional. Your healthcare professional will take amedical and family history before prescribing oral contraceptives and willexamine you. The physical examination may be delayed to another time if yourequest it and the healthcare professional believes that it is a good medicalpractice to postpone it. You should be reexamined at least once a year whiletaking oral contraceptives. Your pharmacist should have given you the detailedpatient information labeling which gives you further information which youshould read and discuss with your healthcare professional.

HOW TO TAKE THE PILL

IMPORTANT POINTS TO REMEMBER

BEFORE YOU START TAKING YOUR PILLS:

1. BE SURE TO READ THESE DIRECTIONS:

Before you start taking your pills.

Anytime you are not sure what to do.

2. THE RIGHT WAY TO TAKE THE PILL IS TO TAKE ONE PILLEVERY DAY AT THE SAME TIME.

If you miss pills you could get pregnant. This includesstarting the pack late.

The more pills you miss, the more likely you are to getpregnant.

3. MANY WOMEN HAVE SPOTTING OR LIGHT BLEEDING, OR MAYFEEL SICK TO THEIR STOMACH DURING THE FIRST 1-3 PACKS OF PILLS. If you feelsick to your stomach or have spotting or light bleeding, do not stop taking thepill. The problem will usually go away. If it doesn't go away, check with yourhealthcare professional.

4. MISSING PILLS CAN ALSO CAUSE SPOTTING OR LIGHTBLEEDING, even when you make up these missed pills.

On the days you take 2 pills to make up for missed pills,you could also feel a little sick to your stomach.

5. IF YOU HAVE VOMITING OR DIARRHEA, OR IF YOU TAKE SOMEMEDICINES, your pills may not work as well.

Use a back-up method (such as a condom or spermicide)until you check with your healthcare professional.

6. IF YOU HAVE TROUBLE REMEMBERING TO TAKE THE PILL, talkto your healthcare professional about how to make pill-taking easier or aboutusing another method of birth control.

7. IF YOU HAVE ANY QUESTIONS OR ARE UNSURE ABOUT THEINFORMATION IN THIS LEAFLET, call your healthcare professional.

BEFORE YOU START TAKING YOUR PILLS

1. DECIDE WHAT TIME OF DAY YOU WANT TO TAKE YOUR PILL.

It is important to take it at about the same time everyday.

2. LOOK AT YOUR PILL PACK

The pill pack has 21 “active” pills (withhormones) to take for 3 weeks. This is followed by 1 week of“reminder” dark green pills (without hormones).

There are 7 white “active” pills, 7 light blue“active” pills, 7 blue “active” pills, and 7 dark green “reminder”pills.

3. ALSO FIND:

1) where on the pack to start taking pills,

2) in what order to take the pills.

4. BE SURE YOU HAVE READY AT ALL TIMES:

ANOTHER KIND OF BIRTH CONTROL (such as a condom orspermicide) to use as a back-up method in case you miss pills.

AN EXTRA, FULL PILL PACK.

WHEN TO START THE FIRST PACK OF PILLS

You have a choice of which day to start taking your firstpack of pills. TriNessa is available in a blister card with a tablet dispenserwhich is preset for a Sunday Start. Day 1 Start is also provided. Decide withyour healthcare professional which is the best day for you. Pick a time of daythat will be easy to remember.

Sunday Start:

Take the first white “active” pill of the firstpack on the Sunday after your period starts, even if you are still bleeding. Ifyour period begins on Sunday, start the pack that same day.

Use another method of birth control such as a condom orspermicide as a back-up method if you have sex anytime from the Sunday youstart your first pack until the next Sunday (7 days).

Day 1 Start:

Take the first white “active” pill of the firstpack during the first 24 hours of your period.

You will not need to use a back-up method of birth control,since you are starting the pill at the beginning of your period.

WHAT TO DO DURING THE MONTH

1. TAKE ONE PILL AT THE SAME TIME EVERY DAY UNTIL THEPACK IS EMPTY.

Do not skip pills even if you are spotting or bleedingbetween monthly periods or feel sick to your stomach (nausea).

Do not skip pills even if you do not have sex very often.

2. WHEN YOU FINISH A PACK OR SWITCH YOUR BRAND OFPILLS:

Start the next pack on the day after your last”reminder” pill. Do not wait any days between packs.1.

WHAT TO DO IF YOU MISS PILLS

If you MISS 1 white, light blue, or blue”active” pill:

1. Take it as soon as you remember. Take the next pill atyour regular time. This means you may take 2 pills in 1 day.

2. You do not need to use a back-up birth control methodif you have sex.

If you MISS 2 white or light blue”active” pills in a row in WEEK 1 OR WEEK 2 of your pack:

1. Take 2 pills on the day you remember and 2 pills thenext day.

2. Then take 1 pill a day until you finish the pack.

3. You COULD BECOME PREGNANT if you have sex in the 7days after you miss pills. You MUST use another birth control method (such as acondom or spermicide) as a back-up method for those 7 days.

If you MISS 2 blue ”active” pills in arow in THE 3RD WEEK:

1. If you are a Sunday Starter:

Keep taking 1 pill every day until Sunday. On Sunday,THROW OUT the rest of the pack and start a

new pack of pills that same day.

If you are a Day 1 Starter:

THROW OUT the rest of the pill pack and start a new packthat same day.

2. You may not have your period this month but this isexpected. However, if you miss your period 2 months in a row, call yourhealthcare professional because you might be pregnant.

3. You COULD BECOME PREGNANT if you have sex in the 7days after you miss pills. You MUST use another birth control method (such as acondom or spermicide) as a back-up method for those 7 days.

If you MISS 3 OR MORE white, light blue, or blue”active” pills in a row (during the first 3 weeks):

1. If you are a Sunday Starter:

Keep taking 1 pill every day until Sunday. On Sunday,THROW OUT the rest of the pack and start a new pack of pills that same day.

If you are a Day 1 Starter:

THROW OUT the rest of the pill pack and start a new packthat same day.

2. You may not have your period this month but this isexpected. However, if you miss your period 2 months in a row, call yourhealthcare professional because you might be pregnant.

3. You COULD BECOME PREGNANT if you have sex in the 7days after you miss pills. You MUST use another birth control method (such as acondom or spermicide) as a back-up method for those 7 days.

A REMINDER:

If you forget any of the 7 dark green”reminder” pills in WEEK 4:

THROW AWAY the pills you missed.

Keep taking 1 pill each day until the pack is empty.

You do not need a back-up method.

FINALLY, IF YOU ARE STILL NOT SURE WHAT TO DO ABOUTTHE PILLS YOU HAVE MISSED:

Use a BACK-UP METHOD anytime you have sex.

KEEP TAKING ONE ”ACTIVE” PILL EACH DAY untilyou can reach your healthcare professional.

INSTRUCTIONS FOR USE

1. Open the compact. Place the blister into the compact,with the tablets facing up, so that the V notch in the blister card matches upwith the V-shaped post at the top of the compact. Press down firmly on eachedge of the blister card and make sure that the edge of the card is firmlyseated under each of the nibs inside the compact (see picture). There are 7white ”active” pills, 7 light blue ”active” pills, 7 blue”active” pills and 7 dark green ”reminder” pills.

2. If you are to start pill taking on Sunday, take yourfirst white pill on the first Sunday after your menstrual period begins. Ifyour period begins on Sunday, take your first pill that day. Remove the firstpill at the top of the dispenser (Sunday) by pressing the pill through the holein the bottom of the dispenser.

3. If you are to start pill taking on a day other thanSunday, the enclosed calendar label has been provided and will be placed overthe calendar in the center of the blister card. To put the label in place,identify your correct starting day, locate that day printed in blue on thelabel, and line your blue starting day up with the first white pill which isdirectly under the V notch at the top of the dispenser. Remove the label fromthe backing. Press the center of the label down onto the center of the printedcalendar. Remove that white pill by pressing the pill through the hole in thebottom of the dispenser.

4. Continue taking one pill daily, clockwise, until nopills remain in the outer ring.

5. The next day take the dark green pill from the innerring that corresponds with the day of the week it happens to be. Take a darkgreen pill each day until all seven pills are taken. During this time your periodshould begin.

6. After you have taken all the dark green pills, begin anew blister card (see Step 1 above in ”Instructions for Use”) andtake the first white ”active” pill on the next day, even if yourperiod is not yet over.

DETAILED PATIENT LABELING

PLEASE NOTE: This labeling is revised from time totime as important new medical information becomes available. Therefore, pleas ereview this labeling carefully.

This product (like all oral contraceptives) does notprotect against HIV infection (AIDS) and other sexually trans mitted diseases.

TriNessa® Regimen

Each white tablet contains 0.180 mg norgestimate and0.035 mg ethinyl estradiol. Each light blue tablet contains 0.215 mgnorgestimate and 0.035 mg ethinyl estradiol. Each blue tablet contains 0.250 mgnorgestimate and 0.035 mg ethinyl estradiol. Each dark green tablet containsinert ingredients.

INTRODUCTION

Any woman who considers using oral contraceptives (thebirth control pill or the pill) should understand the benefits and risks ofusing this form of birth control. This patient labeling will give you much ofthe information you will need to make this decision and will also help youdetermine if you are at risk of developing any of the serious side effects ofthe pill. It will tell you how to use the pill properly so that it will be aseffective as possible. However, this labeling is not a replacement for a carefuldiscussion between you and your healthcare professional. You should discuss theinformation provided in this labeling with him or her, both when you firststart taking the pill and during your revisits. You should also follow yourhealthcare professional's advice with regard to regular checkups while you areon the pill.

EFFECTIVENESS OF ORAL CONTRACEPTIVES FOR CONTRACEPTION

Oral contraceptives or ”birth control pills” or”the pill” are used to prevent pregnancy and are more effective thanmost other non-surgical methods of birth control. When they are taken correctlywithout missing any pills, the chance of becoming pregnant is approximately 1%(1 pregnancy per 100 women per year of use). Typical failure rates, includingwomen who do not always take the pill correctly, are approximately 5% per year(5 pregnancies per 100 women per year of use). The chance of becoming pregnantincreases with each missed pill during a menstrual cycle.

In comparison, typical failure rates for other non-surgicalmethods of birth control during the first year of use are as follows:

Implant: < 1%
Male sterilization: < 1%
Injection: < 1%Cervical Cap with spermicides: 20 to 40%
IUD: 1 to 2%
Condom alone (male): 14%
Diaphragm with spermicides: 20%
Condom alone (female): 21%
Spermicides alone: 26%
Periodic abstinence: 25%
vagin*l sponge: 20 to 40%
Withdrawal: 19%
Female sterilization: < 1%
No methods: 85%

TriNessa® may also be taken to treat moderate acneif all of the following are true:

• You have started having menstrual cycles
• You are at least 15 years old
• Your healthcare professional says it is safe for you to use the pill
• You want to use the pill for birth control

WHO SHOULD NOT TAKE ORAL CONTRACEPTIVES

Do not use TriNessa® if you smoke cigarettesand are over 35 years old. Smoking increases your risk of serious cardiovascularside effects (heart and blood vessel problems) from combination oralcontraceptives, including death from heart attack, blood clots or stroke. Thisrisk increases with age and the number of cigarettes you smoke.

Some women should not use the pill. For example, youshould not take the pill if you have any of the following conditions:

• A history of heart attack or stroke
• Blood clots in the legs (thrombophlebitis), lungs (pulmonary embolism), or eyes
• A history of blood clots in the deep veins of your legs
• An inherited problem that makes your blood clot more than normal
• Chest pain (angina pectoris)
• Known or suspected breast cancer or cancer of the lining of the uterus, cervix or vagin*
• Unexplained vagin*l bleeding (until a diagnosis is reached by your healthcare professional)
• Yellowing of the whites of the eyes or of the skin (jaundice) during pregnancy or during previous use of the pill
• Liver tumor (benign or cancerous) or active liver disease
• Known or suspected pregnancy
• Valvular heart disease with complications
• Severe hypertension
• Diabetes with vascular involvement
• Headaches with focal neurological symptoms
• Major surgery with prolonged immobilization
• Hypersensitivity to any component of this product

Tell your healthcare professional if you have had any ofthese conditions. Your healthcare professional can recommend a safer method ofbirth control.

OTHER CONSIDERATIONS BEFORE TAKING ORAL CONTRACEPTIVES

Tell your healthcare professional if you have or havehad:

• Breast nodules, fibrocystic disease of the breast, an abnormal breast x-ray or mammogram
• Diabetes
• Elevated cholesterol or triglycerides
• High blood pressure
• Migraine or other headaches or epilepsy
• Mental depression
• Gallbladder, liver, heart or kidney disease
• History of scanty or irregular menstrual periods

Women with any of these conditions should be checkedoften by their healthcare professional if they choose to use oralcontraceptives.

Also, be sure to inform your healthcare professional if yousmoke or are on any medications.

RISKS OF TAKING ORAL CONTRACEPTIVES

1. Risk of Developing Blood Clots

Blood clots and blockage of blood vessels are one of themost serious side effects of taking oral contraceptives and can cause death orserious disability. In particular, a clot in the legs can cause thrombophlebitisand a clot that travels to the lungs can cause a sudden blocking of the vesselcarrying blood to the lungs. Rarely, clots occur in the blood vessels of theeye and may cause blindness, double vision, or impaired vision.

If you take oral contraceptives and need electivesurgery, need to stay in bed for a prolonged illness or injury or have recentlydelivered a baby, you may be at risk of developing blood clots. You should consultyour healthcare professional about stopping oral contraceptives four weeksbefore surgery and not taking oral contraceptives for two weeks after surgeryor during bed rest. You should also not take oral contraceptives soon afterdelivery of a baby. It is advisable to wait for at least four weeks after deliveryif you are not breastfeeding. If you are breastfeeding, you should wait untilyou have weaned your child before using the pill. (See also the section onBreastfeeding in General Precautions.)

The risk of circulatory disease in oral contraceptiveusers may be higher in users of high-dose pills and may be greater with longerduration of oral contraceptive use. In addition, some of these increased risksmay continue for a number of years after stopping oral contraceptives. The riskof abnormal blood clotting increases with age in both users and nonusers oforal contraceptives, but the increased risk from the oral contraceptive appearsto be present at all ages. For women aged 20 to 44 it is estimated that about 1in 2,000 using oral contraceptives will be hospitalized each year because ofabnormal clotting. Among nonusers in the same age group, about 1 in 20,000would be hospitalized each year. For oral contraceptive users in general, ithas been estimated that in women between the ages of 15 and 34 the risk ofdeath due to a circulatory disorder is about 1 in 12,000 per year, whereas fornonusers the rate is about 1 in 50,000 per year. In the age group 35 to 44, therisk is estimated to be about 1 in 2,500 per year for oral contraceptive usersand about 1 in 10,000 per year for nonusers.

2. Heart Attacks and Strokes

Oral contraceptives may increase the tendency to developstrokes (stoppage or rupture of blood vessels in the brain) and angina pectorisand heart attacks (blockage of blood vessels in the heart). Any of these conditionscan cause death or serious disability.

Smoking greatly increases the possibility of sufferingheart attacks and strokes. Furthermore, smoking and the use of oralcontraceptives greatly increase the chances of developing and dying of heart disease.

3. Gallbladder Disease

Oral contraceptive users probably have a greater riskthan nonusers of having gallbladder disease, although this risk may be relatedto pills containing high doses of estrogens.

4. Liver Tumors

In rare cases, oral contraceptives can cause benign butdangerous liver tumors. These benign liver tumors can rupture and cause fatalinternal bleeding. In addition, some studies report an increased risk of developingliver cancer. However, liver cancers are rare.

5. Cancer of the Reproductive Organs and Breasts

Various studies give conflicting reports on therelationship between breast cancer and oral contraceptive use. Oralcontraceptive use may slightly increase your chance of having breast cancer diagnosed,particularly after using hormonal contraceptives at a younger age. After youstop using hormonal contraceptives, the chances of having breast cancerdiagnosed begin to go back down. You should have regular breast examinations bya healthcare professional and examine your own breasts monthly. Tell yourhealthcare professional if you have a family history of breast cancer or if youhave had breast nodules or an abnormal mammogram. Women who currently have orhave had breast cancer should not use oral contraceptives because breast canceris usually a hormone-sensitive tumor.

Some studies have found an increase in the incidence ofcancer of the cervix in women who use oral contraceptives. However, thisfinding may be related to factors other than the use of oral contraceptives.There is insufficient evidence to rule out the possibility that the pill maycause such cancers.

ESTIMATED RISK OF DEATH FROM A BIRTH CONTROL METHOD ORPREGNANCY

All methods of birth control and pregnancy are associatedwith a risk of developing certain diseases which may lead to disability ordeath. An estimate of the number of deaths associated with different methods ofbirth control and pregnancy has been calculated and is shown in the followingtable.

Annual Number of Birth-Related or Method-RelatedDeaths Associated with Control of Fertility per 100,000 Nonsterile Women, byFertility Control Method According to Age

In the above table, the risk of death from any birthcontrol method is less than the risk of childbirth, except for oralcontraceptive users over the age of 35 who smoke and pill users over the age of40even if they do not smoke. It can be seen in the table that for women aged 15to 39, the risk of death was highest with pregnancy (7 to 26 deaths per 100,000women, depending on age). Among pill users who do not smoke, the risk of deathwas always lower than that associated with pregnancy for any age group lessthan 40. Over the age of 40, the risk increases to 32 deaths per 100,000 women,compared to 28 associated with pregnancy in that age group. However, for pillusers who smoke and are over the age of 35, the estimated number of deathsexceeds those for other methods of birth control. If a woman is over the age of40 and smokes, her estimated risk of death is four times higher (117/100,000women) than the estimated risk associated with pregnancy (28/100,000 women) inthat age group.

The suggestion that women over 40 who do not smoke shouldnot take oral contraceptives is based on information from older, higher-dosepills. An Advisory Committee of the FDA discussed this issue in 1989 andrecommended that the benefits of low-dose oral contraceptive use by healthy,non-smoking women over 40 years of age may outweigh the possible risks. Olderwomen, as all women, who take oral contraceptives, should take an oralcontraceptive which contains the least amount of estrogen and progestogen thatis compatible with the individual patient needs.

WARNING SIGNALS

If any of these adverse effects occur while you aretaking oral contraceptives, call your healthcare professional immediately:

• Sharp chest pain, coughing of blood, or sudden shortness of breath (indicating a possible clot in the lung)
• Pain in the calf (indicating a possible clot in the leg)
• Crushing chest pain, heaviness in the chest, irregular heart beat or palpitations (indicating a possible heart attack)
• Sudden severe headache or vomiting, dizziness or fainting, disturbances of vision or speech, weakness, or numbness in an arm or leg (indicating a possible stroke)
• Sudden partial or complete loss of vision (indicating a possible clot in the eye)
• Breast lumps (indicating possible breast cancer or fibrocystic disease of the breast; ask your healthcare professional to show you how to examine your breasts)
• Severe pain or tenderness in the stomach area (indicating a possibly ruptured liver tumor)
• Difficulty in sleeping, weakness, lack of energy, fatigue, or change in mood (possibly indicating severe depression)
• Jaundice or a yellowing of the skin or eyeballs, accompanied frequently by fever, fatigue, loss of appetite, dark colored urine, or light colored bowel movements (indicating possible liver problems)

Side Effects Of Oral Contraceptives

In addition to the risks and more serious side effectsdiscussed above, the following may also occur:

1. Irregular vagin*l Bleeding

Irregular vagin*l bleeding or spotting may occur whileyou are taking the pills. Irregular bleeding may vary from slight stainingbetween menstrual periods to breakthrough bleeding which is a flow much like aregular period. Irregular bleeding occurs most often during the first fewmonths of oral contraceptive use, but may also occur after you have been takingthe pill for some time. Such bleeding may be temporary and usually does notindicate any serious problems. It is important to continue taking your pills onschedule. If the bleeding occurs in more than one cycle or lasts for more thana few days, talk to your healthcare professional.

2. Contact Lenses

If you wear contact lenses and notice a change in visionor an inability to wear your lenses, contact your healthcare professional.

3. Fluid Retention

Oral contraceptives may cause edema (fluid retention)with swelling of the fingers or ankles and may raise your blood pressure. Ifyou experience fluid retention, contact your healthcare professional.

4. Melasma

A spotty darkening of the skin is possible, particularlyof the face, which may persist.

5. Other Side Effects

Other side effects may include nausea, vomiting, diarrheaand constipation, change in appetite, headache, nervousness, depression,dizziness, muscle cramps, loss of scalp hair, rash, skin sensitivity to the sunor ultraviolet light, vagin*l infections, urinary tract infections, vertigo,pancreatitis and allergic reactions.

If any of these side effects bother you, call yourhealthcare professional.

GENERAL PRECAUTIONS

1. Missed Periods and Use of Oral ContraceptivesBefore or During Early Pregnancy

There may be times when you may not menstruate regularlyafter you have completed taking a cycle of pills. If you have taken your pillsregularly and miss one menstrual period, continue taking your pills for thenext cycle but be sure to inform your healthcare professional. If you have nottaken the pills daily as instructed and missed a menstrual period, or if youmissed two consecutive menstrual periods, you may be pregnant. Check with yourhealthcare professional immediately to determine whether you are pregnant. Stoptaking your pills if you are pregnant.

There is no conclusive evidence that oral contraceptiveuse is associated with an increase in birth defects, when taken inadvertentlyduring early pregnancy. Previously, a few studies had reported that oralcontraceptives might be associated with birth defects, but these findings havenot been seen in more recent studies. Nevertheless, oral contraceptives shouldnot be used during pregnancy. You should check with your healthcareprofessional about risks to your unborn child of any medication taken during pregnancy.

2. While Breastfeeding

If you are breastfeeding, consult your healthcareprofessional before starting oral contraceptives. Some of the drug will bepassed on to the child in the milk. A few adverse effects on the child havebeen reported, including yellowing of the skin (jaundice) and breastenlargement. In addition, combination oral contraceptives may decrease theamount and quality of your milk. If possible, do not use combination oralcontraceptives while breastfeeding. You should use another method ofcontraception since breastfeeding provides only partial protection frombecoming pregnant and this partial protection decreases significantly as youbreastfeed for longer periods of time. You should consider starting combinationoral contraceptives only after you have weaned your child completely.

3. Laboratory Tests

If you are scheduled for any laboratory tests, tell yourhealthcare professional you are taking birth control pills. Certain blood testsmay be affected by birth control pills.

4. Drug Interactions

Tell your healthcare provider about all medicines andherbal products that you take.

Some medicines and herbal products may make hormonalbirth control less effective, including, but not limited to:

• certain seizure medicines (carbamazepine, felbamate, oxcarbazepine, phenytoin, rufinamide, and topiramate)
• aprepitant
• barbiturates
• bosentan
• colesevelam
• griseofulvin
• certain combinations of HIV medicines (nelfinavir, ritonavir, ritonavir-boosted protease inhibitors)
• certain non nucleoside reverse transcriptase inhibitors (nevirapine)
• rifampin and rifabutin
• St. John's wort

Use another birth control method (such as a condom andspermicide or diaphragm and spermicide) when you take medicines that may makeTriNessa® less effective.

Some medicines and grapefruit juice may increase yourlevel of the hormone ethinyl estradiol if used together, including:

• acetaminophen
• ascorbic acid
• medicines that affect how your liver breaks down other medicines (itraconazole, ketoconazole, voriconazole, and fluconazole)
• certain HIV medicines (atazanavir, indinavir)
• atorvastatin
• rosuvastatin
• etravirine

Hormonal birth control methods may interact withlamotrigine, a seizure medicine used for epilepsy. This may increase the riskof seizures, so your healthcare provider may need to adjust the dose of lamotrigine.

Women on thyroid replacement therapy may need increaseddoses of thyroid hormone.

Know the medicines you take. Keep a list of them to showyour doctor and pharmacist when you get a new medicine.

5. Sexually Trans mitted Diseases

TriNessa® (like all oral contraceptives) isintended to prevent pregnancy. Oral contraceptives do not protect againsttransmission of HIV (AIDS) and other sexually transmitted diseases such as chlamydia,genital herpes, genital warts, gonorrhea, hepatitis B, and syphilis.

HOW TO TAKE THE PILL

IMPORTANT POINTS TO REMEMBER

BEFORE YOU START TAKING YOUR PILLS:

1. BE SURE TO READ THESE DIRECTIONS:

Before you start taking your pills.

Anytime you are not sure what to do.

2. THE RIGHT WAY TO TAKE THE PILL IS TO TAKE ONE PILLEVERY DAY AT THE SAME TIME.

If you miss pills you could get pregnant. This includesstarting the pack late.

The more pills you miss, the more likely you are to getpregnant.

3. MANY WOMEN HAVE SPOTTING OR LIGHT BLEEDING, OR MAYFEEL SICK TO THEIR STOMACH DURING THE FIRST 1-3 PACKS OF PILLS. If you feelsick to your stomach or have spotting or light bleeding, do not stop taking thepill. The problem will usually go away. If it doesn't go away, check with yourhealthcare professional.

4. MISSING PILLS CAN ALSO CAUSE SPOTTING OR LIGHTBLEEDING, even when you make up these missed pills.

On the days you take 2 pills to make up for missed pills,you could also feel a little sick to your stomach.

5. IF YOU HAVE VOMITING OR DIARRHEA, OR IF YOU TAKE SOMEMEDICINES, your pills may not work as well.

Use a back-up method (such as a condom or spermicide)until you check with your healthcare professional.

6. IF YOU HAVE TROUBLE REMEMBERING TO TAKE THE PILL, talkto your healthcare professional about how to make pill-taking easier or aboutusing another method of birth control.

7. IF YOU HAVE ANY QUESTIONS OR ARE UNSURE ABOUT THEINFORMATION IN THIS LEAFLET, call your healthcare professional.

BEFORE YOU START TAKING YOUR PILLS

1. DECIDE WHAT TIME OF DAY YOU WANT TO TAKE YOUR PILL.

It is important to take it at about the same time everyday.

2. LOOK AT YOUR PILL PACK:

The pill pack has 21 ”active” pills (withhormones) to take for 3 weeks. There are 7 white ”active” pills, 7light blue ”active” pills, and 7 blue ”active” pills. Thisis followed by 1 week of ”reminder” dark green pills (withouthormones).

3. ALSO FIND:

1) where on the pack to start taking pills,

2) in what order to take the pills.

CHECK PICTURE OF PILL PACK AND ADDITIONAL INSTRUCTIONSFOR USING THIS PACKAGE IN THE BRIEF SUMMARY PATIENT PACKAGE INSERT.

4. BE SURE YOU HAVE READY AT ALL TIMES:

ANOTHER KIND OF BIRTH CONTROL (such as a condom orspermicide) to use as a back-up method in case you miss pills.

AN EXTRA, FULL PILL PACK.

WHEN TO START THE FIRST PACK OF PILLS

You have a choice of which day to start taking your firstpack of pills. TriNessa® is available in a blister card with a tablet dispenserwhich is preset for a Sunday Start. Day 1 Start is also provided. Decide withyour healthcare professional which is the best day for you. Pick a time of daythat will be easy to remember.

Sunday Start:

Take the first white ”active” pill of the firstpack on the Sunday after your period starts, even if you are still bleeding. Ifyour period begins on Sunday, start the pack that same day.

Use another method of birth control such as a condom orspermicide as a back-up method if you have sex anytime from the Sunday youstart your first pack until the next Sunday (7 days).

Day 1 Start:

Take the first white ”active” pill of the firstpack during the first 24 hours of your period.

You will not need to use a back-up method of birthcontrol, since you are starting the pill at the beginning of your period.

WHAT TO DO DURING THE MONTH

1. TAKE ONE PILL AT THE SAME TIME EVERY DAYUNTIL THE PACK IS EMPTY.

Do not skip pills even if you are spotting or bleedingbetween monthly periods or feel sick to your stomach (nausea).

Do not skip pills even if you do not have sex very often.

2. WHEN YOU FINISH A PACK OR SWITCH YOUR BRAND OFPILLS:

Start the next pack on the day after your last”reminder” pill. Do not wait any days between packs.

WHAT TO DO IF YOU MISS PILLS

If you MISS 1 white, light blue, or blue”active” pill:

1. Take it as soon as you remember. Take the next pill atyour regular time. This means you may take 2 pills in 1 day.

2. You do not need to use a back-up birth control methodif you have sex.

If you MISS 2 white or light blue”active” pills in a row in WEEK 1 OR WEEK 2 of your pack:

1. Take 2 pills on the day you remember and 2 pills thenext day.

2. Then take 1 pill a day until you finish the pack.

3. You COULD BECOME PREGNANT if you have sex in the 7days after you miss pills. You MUST use another birth control method (such as acondom or spermicide) as a back-up method for those 7 days.

If you MISS 2 blue ”active” pills in arow in THE 3RD WEEK:

1. If you are a Sunday Starter:

Keep taking 1 pill every day until Sunday. On Sunday,THROW OUT the rest of the pack and start a new pack of pills that same day.

If you are a Day 1 Starter:

THROW OUT the rest of the pill pack and start a new packthat same day.

2. You may not have your period this month but this isexpected. However, if you miss your period 2 months in a row, call yourhealthcare professional because you might be pregnant.

3. You COULD BECOME PREGNANT if you have sex in the 7days after you miss pills. You MUST use another birth control method (such as acondom or spermicide) as a back-up method for those 7 days.

If you MISS 3 OR MORE white, light blue, or blue”active” pills in a row (during the first 3 weeks):

1. If you are a Sunday Starter:

Keep taking 1 pill every day until Sunday. On Sunday,THROW OUT the rest of the pack and start a new pack of pills that same day.

If you are a Day 1 Starter:

THROW OUT the rest of the pill pack and start a new packthat same day.

2. You may not have your period this month but this isexpected. However, if you miss your period 2 months in a row, call yourhealthcare professional because you might be pregnant.

3. You COULD BECOME PREGNANT if you have sex in the 7days after you miss pills. You MUST use another birth control method (such as acondom or spermicide) as a back-up method for those 7 days.

A REMINDER:

If you forget any of the 7 dark green”reminder” pills in WEEK 4:

THROW AWAY the pills you missed.

Keep taking 1 pill each day until the pack is empty.

You do not need a back-up method.

FINALLY, IF YOU ARE STILL NOT SURE WHAT TO DO ABOUTTHE PILLS YOU HAVE MISSED:

Use a BACK-UP METHOD anytime you have sex.

KEEP TAKING ONE ”ACTIVE” PILL EACH DAY untilyou can reach your healthcare professional.

PREGNANCY DUE TO PILL FAILURE

The incidence of pill failure resulting in pregnancy isapproximately 5%, including women who do not always take the pills exactly asdirected. If failure does occur, the risk to the fetus is minimal.

PREGNANCY AFTER STOPPING THE PILL

There may be some delay in becoming pregnant after youstop using oral contraceptives, especially if you had irregular menstrualcycles before you used oral contraceptives. It may be advisable to postpone conceptionuntil you begin menstruating regularly once you have stopped taking the pilland desire pregnancy.

There does not appear to be any increase in birth defectsin newborn babies when pregnancy occurs soon after stopping the pill.

OVERDOSAGE

Serious ill effects have not been reported followingingestion of large doses of oral contraceptives by young children. Overdosagemay cause nausea and withdrawal bleeding in females. In case of overdosage,contact your healthcare professional or pharmacist.

OTHER INFORMATION

Your healthcare professional will take a medical andfamily history before prescribing oral contraceptives and will examine you. Thephysical examination may be delayed to another time if you request it and thehealthcare professional believes that it is a good medical practice to postponeit. You should be reexamined at least once a year. Be sure to inform yourhealthcare professional if there is a family history of any of the conditionslisted previously in this leaflet. Be sure to keep all appointments with yourhealthcare professional, because this is a time to determine if there are earlysigns of side effects of oral contraceptive use.

Do not use the drug for any condition other than the onefor which it was prescribed. This drug has been prescribed specifically foryou; do not give it to others who may want birth control pills.

HEALTH BENEFITS FROM ORAL CONTRACEPTIVES

In addition to preventing pregnancy, use of combinationoral contraceptives may provide certain benefits. They are:

• menstrual cycles may become more regular
• blood flow during menstruation may be lighter and less iron may be lost. Therefore, anemia due to iron deficiency is less likely to occur.
• pain or other symptoms during menstruation may be encountered less frequently
• ectopic (tubal) pregnancy may occur less frequently
• noncancerous cysts or lumps in the breast may occur less frequently
• acute pelvic inflammatory disease may occur less frequently
• oral contraceptive use may provide some protection against developing two forms of cancer: cancer of the ovaries and cancer of the lining of the uterus.

If you want more information about birth control pills,ask your healthcare professional or pharmacist. They have a more technicalleaflet called the Professional Labeling, which you may wish to read.

Keep out of reach of children.

Store at 25°C (77°F); excursions permitted to 15° - 30°C (59°- 86°F).

Protect from light.