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Trivora-28

Generic Name: levonorgestrel and ethinyl estradiol
Dosage Form: tablet
Trivora official prescribing information for healthcare professionals. Includes: indications, dosage, adverse reactions, pharmacology and more.
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Drug Information:
Each Trivora cycle of 28 tablets consists of three different drug phases as follows: Phase 1 comprised of 6 blue tablets, each containing 0.050 mg of Levonorgestrel (d (-)-13 beta-ethyl-17-alpha-ethinyl-17-beta-hydroxygon-4-en-3-one), a totally synthetic progestogen, and 0.030 mg of ethinyl Estradiol (19-nor-17α-pregna-1,3,5(10)-trien-20-yne-3, 17-diol); phase 2 comprised of 5 white tablets, each containing 0.075 mg Levonorgestrel and 0.040 mg ethinyl Estradiol; and phase 3 comprised of 10 pink tablets, each containing 0.125 mg Levonorgestrel and 0.030 mg ethinyl Estradiol; then followed by 7 peach inert tablets. The iNactive ingredients present in the blue, white and pink tablets are lActose monohydrate, Magnesium stearate, Povidone and starch (corn). Each blue tablet also contains FD&C Blue #1. Each pink tablet also contains FD&C Red #40. Each iNactive peach tablet contains the following iNactive ingredients: anhydrous lActose, FD&C Yellow #6, lActose monohydrate, Magnesium stearate and microcrystAlline cellulose. Learn more

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Contraindications

Combination oral contraceptives should not be used in women with any of the following conditions:

  •  Thrombophlebitis or thromboembolic disorders.
  •  A past history of deep-vein thrombophlebitis or thromboembolic disorders.
  •  Cerebral-vascular or coronary-artery disease.
  •  Thrombogenic valvulopathies.
  •  Thrombogenic rhythm disorders.
  •  Diabetes with vascular involvement.
  •  Uncontrolled hypertension.
  •  Known or suspected carcinoma of the breast.
  •  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.
  •  Hepatic adenomas or carcinomas, or active liver disease, as long as liver function has not returned to normal.
  •  Known or suspected pregnancy.
  •  Hypersensitivity to any of the components of Trivora (levonorgestrel and ethinyl estradiol tablets–triphasic regimen).
  •  Are receiving Hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, due to the potential for ALT elevations (see Warnings, RISK OF LIVER ENZYME ELEVATIONS WITH CONCOMITANT HEPATITIS C TREATMENT)

Warnings

Cigarette smoking increases the risk of serious cardiovascular side effects from oral-contraceptive use. This risk increases with age and with the extent of smoking (in epidemiologic studies, 15 or more cigarettes per day was associated with a significantly increased risk) and is quite marked in women over 35 years of age. Women who use oral contraceptives should be strongly advised not to smoke.

The use of oral contraceptives is associated with increased risks of several serious conditions including venous and arterial thrombotic and thromboembolic events (such as myocardial infarction, thromboembolism, and stroke), hepatic neoplasia, gallbladder disease, and hypertension, although the risk of serious morbidity or mortality is very small in healthy women without underlying risk factors. The risk of morbidity and mortality increases significantly in the presence of other underlying risk factors such as certain inherited or acquired thrombophilias, hypertension, hyperlipidemias, obesity, and diabetes.

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

The information contained in this package insert is based principally on studies carried out in patients who used oral contraceptives with higher formulations of estrogens and progestogens than those in common use today.

The effect of long-term use of the oral contraceptives with lower formulations of both estrogens and progestogens remains to be determined.

Throughout this labeling, epidemiological studies reported are of two types: retrospective or case control studies and prospective or cohort studies. Case control studies provide a measure of the relative risk of disease, namely, a ratio of the incidence of a disease among oral-contraceptive users to that among nonusers. The relative risk does not provide information on the actual clinical occurrence of a disease. Cohort studies provide a measure of attributable risk, which is the difference in the incidence of disease between oral-contraceptive users and nonusers. The attributable risk does provide information about the actual occurrence of a disease in the population. For further information, the reader is referred to a text on epidemiological methods.

1. Thromboembolic Disorders And Other Vascular Problems

a. Myocardial infarction

An increased risk of myocardial infarction has been attributed to oral-contraceptive use. This risk is primarily in smokers or women with other underlying risk factors for coronary-artery disease such as hypertension, hypercholesterolemia, morbid obesity, and diabetes. The relative risk of heart attack for current oral-contraceptive users has been estimated to be two to six. The risk is very low under the age of 30.

Smoking in combination with oral-contraceptive use has been shown to contribute substantially to the incidence of myocardial infarctions in women in their mid-thirties or older with smoking accounting for the majority of excess cases. Mortality rates associated with circulatory disease have been shown to increase substantially in smokers over the age of 35 and nonsmokers over the age of 40 (Table III) among women who use oral contraceptives.

CIRCULATORY DISEASE MORTALITY RATES PER 100,000 WOMAN YEARS BY AGE, SMOKING STATUS AND ORAL-CONTRACEPTIVE USE

TABLE III. (Adapted from P.M. Layde and V. Beral, Lancet, 1:541-546, 1981.)

Oral contraceptives may compound the effects of well-known risk factors, such as hypertension, diabetes, hyperlipidemias, age, and obesity. In particular, some progestogens are known to decrease HDL cholesterol and cause glucose intolerance, while estrogens may create a state of hyperinsulinism. Oral contraceptives have been shown to increase blood pressure among users (see section 10 in "WARNINGS"). Similar effects on risk factors have been associated with an increased risk of heart disease. Oral contraceptives must be used with caution in women with cardiovascular disease risk factors.

b. Thromboembolism

An increased risk of venous thromboembolic and thrombotic disease associated with the use of oral contraceptives is well established. Case control studies have found the relative risk of users compared to nonusers to be 3 for the first episode of superficial venous thrombosis, 4 to 11 for deep-vein thrombosis or pulmonary embolism, and 1.5 to 6 for women with predisposing conditions for venous thromboembolic disease. Cohort studies have shown the relative risk to be somewhat lower, about 3 for new cases and about 4.5 for new cases requiring hospitalization. The approximate incidence of deep-vein thrombosis and pulmonary embolism in users of low dose (<50 μg ethinyl estradiol) combination oral contraceptives is up to 4 per 10,000 woman-years compared to 0.5-3 per 10,000 woman-years for non-users. However, the incidence is substantially less than that associated with pregnancy (6 per 10,000 woman-years). The risk of thromboembolic disease due to oral contraceptives is not related to length of use and disappears after pill use is stopped.

A two- to four-fold increase in relative risk of postoperative thromboembolic complications has been reported with the use of oral contraceptives. The relative risk of venous thrombosis in women who have predisposing conditions is twice that of women without such medical conditions. If feasible, oral contraceptives should be discontinued at least four weeks prior to and for two weeks after elective surgery of a type associated with an increase in risk of thromboembolism and during and following prolonged immobilization. Since the immediate postpartum period is also associated with an increased risk of thromboembolism, oral contraceptives should be started no earlier than four to six weeks after delivery in women who elect not to breast-feed, or a midtrimester pregnancy termination.

c. Cerebrovascular diseases

Oral contraceptives have been shown to increase both the relative and attributable risks of cerebrovascular events (thrombotic and hemorrhagic strokes), although, in general, the risk is greatest among older (>35 years), hypertensive women who also smoke. Hypertension was found to be a risk factor for both users and nonusers, for both types of strokes, while smoking interacted to increase the risk for hemorrhagic strokes.

In a large study, the relative risk of thrombotic strokes has been shown to range from 3 for normotensive users to 14 for users with severe hypertension. The relative risk of hemorrhagic stroke is reported to be 1.2 for nonsmokers who used oral contraceptives, 2.6 for smokers who did not use oral contraceptives, 7.6 for smokers who used oral contraceptives, 1.8 for normotensive users, and 25.7 for users with severe hypertension. The attributable risk is also greater in older women. Oral contraceptives also increase the risk for stroke in women with other underlying risk factors such as certain inherited or acquired thrombophilias, hyperlipidemias, and obesity.

Women with migraine (particularly migraine with aura) who take combination oral contraceptives may be at an increased risk of stroke.

d. Dose-related risk of vascular disease from oral contraceptives

A positive association has been observed between the amount of estrogen and progestogen in oral contraceptives and the risk of vascular disease. A decline in serum high-density lipoproteins (HDL) has been reported with many progestational agents. A decline in serum high-density lipoproteins has been associated with an increased incidence of ischemic heart disease. Because estrogens increase HDL cholesterol, the net effect of an oral contraceptive depends on a balance achieved between doses of estrogen and progestogen and the nature and absolute amount of progestogen used in the contraceptive. The amount of both hormones should be considered in the choice of an oral contraceptive.

Minimizing exposure to estrogen and progestogen is in keeping with good principles of therapeutics. For any particular estrogen/progestogen combination, the dosage regimen prescribed should be one which contains the least amount of estrogen and progestogen that is compatible with a low failure rate and the needs of the individual patient. New acceptors of oral-contraceptive agents should be started on preparations containing less than 50 mcg of estrogen.

e. Persistence of risk of vascular disease

There are two studies which have shown persistence of risk of vascular disease for ever-users of oral contraceptives. In a study in the United States, the risk of developing myocardial infarction after discontinuing oral contraceptives persists for at least 9 years for women 40 to 49 years who had used oral contraceptives for five or more years, but this increased risk was not demonstrated in other age groups. In another study in Great Britain, the risk of developing cerebrovascular disease persisted for at least 6 years after discontinuation of oral contraceptives, although excess risk was very small. However, both studies were performed with oral-contraceptive formulations containing 50 micrograms or higher of estrogens.

2. Estimates Of Mortality From Contraceptive Use

One study gathered data from a variety of sources which have estimated the mortality rate associated with different methods of contraception at different ages (Table IV). These estimates include the combined risk of death associated with contraceptive methods plus the risk attributable to pregnancy in the event of method failure. Each method of contraception has its specific benefits and risks. The study concluded that with the exception of oral-contraceptive users 35 and older who smoke and 40 and older who do not smoke, mortality associated with all methods of birth control is less than that associated with childbirth. The observation of a possible increase in risk of mortality with age for oral-contraceptive users is based on data gathered in the 1970's — but not reported until 1983. However, current clinical practice involves the use of lower estrogen dose formulations combined with careful restriction of oral-contraceptive use to women who do not have the various risk factors listed in this labeling.

Because of these changes in practice and, also, because of some limited new data which suggest that the risk of cardiovascular disease with the use of oral contraceptives may now be less than previously observed, the Fertility and Maternal Health Drugs Advisory Committee was asked to review the topic in 1989. The Committee concluded that although cardiovascular-disease risks may be increased with oral-contraceptive use after age 40 in healthy nonsmoking women (even with the newer low-dose formulations), there are greater potential health risks associated with pregnancy in older women and with the alternative surgical and medical procedures which may be necessary if such women do not have access to effective and acceptable means of contraception.

Therefore, the Committee recommended that the benefits of oral-contraceptive use by healthy nonsmoking women over 40 may outweigh the possible risks. Of course, older women, as all women who take oral contraceptives, should take the lowest possible dose formulation that is effective.

TABLE IV—ANNUAL NUMBER OF BIRTH-RELATED OR METHOD-RELATED DEATHS ASSOCIATED WITH CONTROL OF FERTILITY PER 100,000 NONSTERILE WOMEN, BY FERTILITY-CONTROL METHOD ACCORDING TO AGE Method of control and outcome 15-19 20-24 25-29 30-34 35-39 40-44  Adapted from H.W. Ory, Family Planning Perspectives, 15:57-63, 1983.
*
Deaths are birth related
Deaths are method related
 No fertility-control methods*  7.0  7.4  9.1  14.8  25.7  28.2  Oral contraceptives  0.3  0.5  0.9  1.9  13.8  31.6    nonsmoker†  Oral contraceptives  2.2  3.4  6.6  13.5  51.1  117.2    smoker†  IUD†  0.8  0.8  1.0  1.0  1.4  1.4  Condom*  1.1  1.6  0.7  0.2  0.3  0.4  Diaphragm/spermicide*  1.9  1.2  1.2  1.3  2.2  2.8  Periodic abstinence*  2.5  1.6  1.6  1.7  2.9  3.6

3. Carcinoma Of The Reproductive Organs

A meta-analysis from 54 epidemiological studies reported that there is a slightly increased relative risk (RR=1.24) of having breast cancer diagnosed in women who are currently using combination oral contraceptives compared to never-users. The increased risk gradually disappears during the course of the 10 years after cessation of combination oral-contraceptive use. These studies do not provide evidence for causation. The observed pattern of increased risk of breast cancer diagnosis may be due to earlier detection of breast cancer in combination oral contraceptive users, the biological effects of combination oral contraceptives, or a combination of both. Because breast cancer is rare in women under 40 years of age, the excess number of breast cancer diagnoses in current and recent combination oral contraceptive users is small in relation to the lifetime risk of breast cancer. Breast cancers diagnosed in ever-users tend to be less advanced clinically than the cancers diagnosed in never-users.

Some studies suggest that oral-contraceptive use has been associated with an increase in the risk of cervical intraepithelial neoplasia or invasive cervical cancer in some populations of women. However, there continues to be controversy about the extent to which such findings may be due to differences in sexual behavior and other factors.

In spite of many studies of the relationship between oral-contraceptive use and breast and cervical cancers, a cause-and-effect relationship has not been established.

4. Hepatic Neoplasia

Benign hepatic adenomas are associated with oral-contraceptive use, although the incidence of benign tumors is rare in the United States. Indirect calculations have estimated the attributable risk to be in the range of 3.3 cases/100,000 for users, a risk that increases after four or more years of use. Rupture of rare, benign, hepatic adenomas may cause death through intra-abdominal hemorrhage.

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

5. RISK OF LIVER ENZYME ELEVATIONS WITH CONCOMITANT HEPATITIS C TREATMENT

During clinical trials with the Hepatitis C combination drug regimen that contains ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, ALT elevations greater than 5 times the upper limit of normal (ULN), including some cases greater than 20 times the ULN, were significantly more frequent in women using ethinyl estradiol-containing medications such as COCs. Discontinue Trivora prior to starting therapy with the combination drug regimen ombitasvir/paritaprevir/ritonavir, with or without dasabuvir [see Contraindications]. Trivora can be restarted approximately 2 weeks following completion of treatment with the combination drug regimen.

6. Ocular Lesions

There have been clinical case reports of retinal thrombosis associated with the use of oral contraceptives that may lead to partial or complete loss of vision. Oral contraceptives should be discontinued if there is unexplained partial or complete loss of vision; onset of proptosis or diplopia; papilledema; or retinal vascular lesions. Appropriate diagnostic and therapeutic measures should be undertaken immediately.

7. Oral-Contraceptive Use Before Or During Early Pregnancy

Extensive epidemiological studies have revealed no increased risk of birth defects in women who have used oral contraceptives prior to pregnancy. Studies also do not suggest a teratogenic effect, particularly insofar as cardiac anomalies and limb-reduction defects are concerned, when taken inadvertently during early pregnancy. (See "CONTRAINDICATIONS" section).

The administration of oral contraceptives to induce withdrawal bleeding should not be used as a test for pregnancy. Oral contraceptives should not be used during pregnancy to treat threatened or habitual abortion.

It is recommended that for any patient who has missed two consecutive periods, pregnancy should be ruled out before continuing oral-contraceptive use. 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. Oral-contraceptive use should be discontinued if pregnancy is confirmed.

8. Gallbladder Disease

Earlier studies have reported an increased lifetime relative risk of gallbladder surgery in users of oral contraceptives and estrogens. More recent studies, however, have shown that the relative risk of developing gallbladder disease among oral-contraceptive users may be minimal. The recent findings of minimal risk may be related to the use of oral-contraceptive formulations containing lower hormonal doses of estrogens and progestogens.

9. Carbohydrate And Lipid Metabolic Effects

Oral contraceptives have been shown to cause glucose intolerance in a significant percentage of users. Oral contraceptives containing greater than 75 micrograms of estrogens cause hyperinsulinism, while lower doses of estrogen cause less glucose intolerance. Progestogens increase insulin secretion and create insulin resistance, this effect varying with different progestational agents. However, in the nondiabetic woman, oral contraceptives appear to have no effect on fasting blood glucose. Because of these demonstrated effects, prediabetic and diabetic women should be carefully observed while taking oral contraceptives.

A small proportion of women will have persistent hypertriglyceridemia while on the pill. As discussed earlier (see "WARNINGS," 1a. and 1d.), changes in serum triglycerides and lipoprotein levels have been reported in oral-contraceptive users.

10. Elevated Blood Pressure

An increase in blood pressure has been reported in women taking oral contraceptives, and this increase is more likely in older oral-contraceptive users and with continued use. Data from the Royal College of General Practitioners and subsequent randomized trials have shown that the incidence of hypertension increases with increasing quantities of progestogens.

Women with a history of hypertension or hypertension-related diseases, or renal disease, should be encouraged to use another method of contraception. If women with hypertension elect to use oral contraceptives, they should be monitored closely, and if significant elevation of blood pressure occurs, oral contraceptives should be discontinued (See "CONTRAINDICATIONS" section). For most women, elevated blood pressure will return to normal after stopping oral contraceptives, and there is no difference in the occurrence of hypertension among ever- and never-users.

11. Headache

The onset or exacerbation of migraine or development of headache with a new pattern that is recurrent, persistent, or severe requires discontinuation of oral contraceptives and evaluation of the cause. (See "WARNINGS," 1c.)

12. Bleeding Irregularities

Breakthrough bleeding and spotting are sometimes encountered in patients on oral contraceptives, especially during the first three months of use. The type and dose of progestogen may be important. If bleeding persists or recurs, nonhormonal causes should be considered and adequate diagnostic measures taken to rule out malignancy or pregnancy in the event of breakthrough bleeding, as in the case of any abnormal vaginal bleeding. If pathology has been excluded, time or a change to another formulation may solve the problem. In the event of amenorrhea, pregnancy should be ruled out if the oral contraceptive has not been taken according to directions prior to the first missed withdrawal bleed or if two consecutive withdrawal bleeds have been missed.

Some women may encounter post-pill amenorrhea or oligomenorrhea (possibly with anovulation), especially when such a condition was preexistent.

Precautions

1. General

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

2. Physical Examination And Follow-Up

A periodic personal and family medical history and complete physical examination are appropriate for all women, including women using oral contraceptives. The physical examination, however, may be deferred until after initiation of oral contraceptives if requested by the woman and judged appropriate by the clinician. The physical examination should include special reference to blood pressure, breasts, abdomen and pelvic organs, including cervical cytology, and relevant laboratory tests. In case of undiagnosed, persistent, or recurrent abnormal vaginal bleeding, appropriate measures should be conducted to rule out malignancy. Women with a strong family history of breast cancer or who have breast nodules should be monitored with particular care.

3. Lipid Disorders

Women who are being treated for hyperlipidemias should be followed closely if they elect to use oral contraceptives. Some progestogens may elevate LDL levels and may render the control of hyperlipidemias more difficult. (See "WARNINGS," 1d.)

In patients with familial defects of lipoprotein metabolism receiving estrogen-containing preparations, there have been case reports of significant elevations of plasma triglycerides leading to pancreatitis.

4. Liver Function

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

5. Fluid Retention

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

6. Emotional Disorders

Patients becoming significantly depressed while taking oral contraceptives should stop the medication and use an alternate method of contraception in an attempt to determine whether the symptom is drug related. Women with a history of depression should be carefully observed and the drug discontinued if depression recurs to a serious degree.

7. Contact Lenses

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

8. Gastrointestinal Motility

Diarrhea and/or vomiting may reduce hormone absorption.

9. Drug Interactions

Interactions between ethinyl estradiol and other substances may lead to decreased or increased serum ethinyl estradiol concentrations.

Decreased ethinyl estradiol plasma concentrations may cause an increased incidence of breakthrough bleeding and menstrual irregularities and may possibly reduce efficacy of the combination oral contraceptive.

Reduced ethinyl estradiol concentrations have been associated with concomitant use of substances that induce hepatic microsomal enzymes, such as rifampin, rifabutin, barbiturates, phenylbutazone, phenytoin sodium, griseofulvin, topiramate, some protease inhibitors, modafinil, and possibly St. John's wort.

Substances that may decrease plasma ethinyl estradiol concentrations by other mechanisms include any substance that reduces gut transit time and certain antibiotics (e.g. ampicillin and other penicillins, tetracyclines) by a decrease of enterohepatic circulation of estrogens. During concomitant use of ethinyl estradiol containing products and substances that may lead to decreased plasma steroid hormone concentrations, it is recommended that a nonhormonal back-up method of birth control be used in addition to the regular intake of Trivora (levonorgestrel and ethinyl estradiol tablets-triphasic regimen). If the use of a substance which leads to decreased ethinyl estradiol plasma concentrations is required for a prolonged period of time, combination oral contraceptives should not be considered the primary contraceptive.

After discontinuation of substances that may lead to decreased ethinyl estradiol plasma concentrations, use of a nonhormonal back-up method of birth control is recommended for 7 days. Longer use of a back-up method is advisable after discontinuation of substances that have led to induction of hepatic microsomal enzymes, resulting in decreased ethinyl estradiol concentrations. It may take several weeks until enzyme induction has completely subsided, depending on dosage, duration of use, and rate of elimination of the inducing substance.

Some substances may increase plasma ethinyl estradiol concentrations. These include:

  • Competitive inhibitors for sulfation of ethinyl estradiol in the gastrointestinal wall, such as ascorbic acid (vitamin C) and acetaminophen.
  • Substances that inhibit cytochrome P450 3A4 isoenzymes such as indinavir, fluconazole, and troleandomycin. Troleandomycin may increase the risk of intrahepatic cholestasis during coadministration with combination oral contraceptives.
  • Atorvastatin (unknown mechanism).

Ethinyl estradiol may interfere with the mechanism of other drugs by inhibiting hepatic microsomal enzymes or by inducing hepatic drug conjugation, particularly glucuronidation. Accordingly, tissue concentrations may be either increased (e.g. cyclosporine, theophylline, corticosteroids) or decreased.

The prescribing information of concomitant medications should be consulted to identify potential interactions.

Concomitant Use with HCV Combination Therapy – Liver Enzyme Elevation

Do not co-administer Trivora with HCV drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, due to potential for ALT elevations (see Warnings RISK OF LIVER ENZYME ELEVATIONS WITH CONCOMITANT HEPATITIS C TREATMENT).

10. Interactions With Laboratory Tests

Certain endocrine- and liver-function tests and blood components 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-binding globulins are increased and result in elevated levels of total circulating sex steroids and corticoids; however, free or biologically active levels remain unchanged.
  5. Triglycerides may be increased.
  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.

11. Carcinogenesis

See "WARNINGS" section.

12. Pregnancy

See "CONTRAINDICATIONS" and "WARNINGS" sections.

13. Nursing Mothers

Small amounts of oral-contraceptive steroids and/or metabolites have been identified in the milk of nursing mothers, and a few adverse effects on the child have been reported, including jaundice and breast enlargement. In addition, combination oral contraceptives given in the postpartum period may interfere with lactation by decreasing the quantity and quality of breast milk. If possible, the nursing mother should be advised not to use combination oral contraceptives but to use other forms of contraception until she has completely weaned her child.

14. Pediatric Use

Safety and efficacy of Trivora (levonorgestrel and ethinyl estradiol tablets—triphasic regimen) have been established in women of reproductive age. Safety and efficacy are expected to be the same for postpubertal adolescents under the age of 16 and users 16 and older. Use of this product before menarche is not indicated.

Information For The Patient

See Patient Labeling Printed Below.

Adverse Reactions

An increased risk of the following serious adverse reactions (see "WARNINGS" section for additional information) has been associated with the use of oral contraceptives.

Thromboembolic disorders and other vascular problems (including thrombophlebitis, arterial thromboembolism, pulmonary embolism, myocardial infarction, cerebral hemorrhage, cerebral thrombosis), carcinoma of the reproductive organs, hepatic neoplasia (including hepatic adenomas or benign liver tumors), ocular lesions (including retinal vascular thrombosis), gallbladder disease, carbohydrate and lipid effects, elevated blood pressure, and headache.

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

  •  Nausea.
  •  Vomiting.
  •  Gastrointestinal symptoms (such as abdominal pain, cramps and bloating).
  •  Breakthrough bleeding.
  •  Spotting.
  •  Change in menstrual flow.
  •  Amenorrhea.
  •  Temporary infertility after discontinuation of treatment.
  •  Edema/fluid retention.
  •  Melasma/chloasma which may persist.
  •  Breast changes: tenderness, pain, enlargement, secretion.
  •  Change in weight or appetite (increase or decrease).
  •  Change in cervical erosion and secretion.
  •  Diminution in lactation when given immediately postpartum.
  •  Cholestatic jaundice.
  •  Rash (allergic).
  •  Mood changes, including depression.
  •  Vaginitis, including candidiasis.
  •  Change in corneal curvature (steepening).
  •  Intolerance to contact lenses.
  •  Mesenteric thrombosis.
  •  Decrease in serum folate levels.
  •  Exacerbation of systemic lupus erythematosus.
  •  Exacerbation of porphyria.
  •  Exacerbation of chorea.
  •  Aggravation of varicose veins.
  •  Anaphylactic/anaphylactoid reactions, including urticaria, angioedema, and severe reactions with respiratory and circulatory symptoms.

The following adverse reactions have been reported in users of oral contraceptives, and the association has been neither confirmed nor refuted:

  •  Congenital anomalies.
  •  Premenstrual syndrome.
  •  Cataracts.
  •  Optic neuritis, which may lead to partial or complete loss of vision.
  •  Cystitis-like syndrome.
  •  Nervousness.
  •  Dizziness.
  •  Hirsutism.
  •  Loss of scalp hair.
  •  Erythema multiforme.
  •  Erythema nodosum.
  •  Hemorrhagic eruption.
  •  Impaired renal function.
  •  Hemolytic uremic syndrome.
  •  Budd-Chiari syndrome.
  •  Acne.
  •  Changes in libido.
  •  Colitis.
  •  Sickle-cell disease.
  •  Cerebral-vascular disease with mitral valve prolapse.
  •  Lupus-like syndromes.
  •  Pancreatitis.
  •  Dysmenorrhea.

Overdosage

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

NONCONTRACEPTIVE HEALTH BENEFITS

The following noncontraceptive health benefits related to the use of oral contraceptives are supported by epidemiological studies which largely utilized oral-contraceptive formulations containing doses exceeding 0.035 mg of ethinyl estradiol or 0.05 mg of 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.

Effects from long-term use

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.

Trivora Dosage and Administration

To achieve maximum contraceptive effectiveness, Trivora® Tablets (levonorgestrel and ethinyl estradiol tablets—triphasic regimen) must be taken exactly as directed and at intervals not exceeding 24 hours.

Trivora Tablets are a three-phase preparation plus 7 inert tablets. The dosage of Trivora Tablets is one tablet daily for 28 consecutive days per menstrual cycle in the following order: 6 blue tablets (phase 1), followed by 5 white tablets (phase 2), followed by 10 pink tablets (phase 3), plus 7 peach inert tablets, according to the prescribed schedule.

It is recommended that Trivora Tablets be taken at the same time each day, preferably after the evening meal or at bedtime. During the first cycle of medication, the patient should be instructed to take one Trivora Tablet daily in the order of 6 blue, 5 white, 10 pink tablets, and then 7 peach inert tablets for twenty-eight (28) consecutive days, beginning on day one (1) of her menstrual cycle. (The first day of menstruation is day one.) Withdrawal bleeding usually occurs within 3 days following the last pink tablet and may not have finished before the next pack is started. (If Trivora Tablets are first taken later than the first day of the first menstrual cycle of medication or postpartum, contraceptive reliance should not be placed on Trivora Tablets until after the first 7 consecutive days of administration and a nonhormonal back-up method of birth control should be used during those 7 days. The possibility of ovulation and conception prior to initiation of medication should be considered.)

When switching from another oral contraceptive, Trivora Tablets should be started on the first day of bleeding following the last active tablet taken of the previous oral contraceptive.

The patient may switch any day from a progestin-only pill and should begin Trivora the next day. If switching from an implant or injection, the patient should start Trivora on the day of implant removal or, if using an injection, the day the next injection would be due. In switching from a progestin-only pill, injection, or implant, the patient should be advised to use a non-hormonal back-up method of birth control for the first 7 days of tablet-taking.

The patient begins her next and all subsequent 28-day courses of Trivora Tablets on the same day of the week that she began her first course, following the same schedule. She begins taking her blue tablets on the next day after ingestion of the last peach tablet, regardless of whether or not a menstrual period has occurred or is still in progress. Any time a subsequent cycle of Trivora Tablets is started later than the next day, the patient should be protected by another means of contraception until she has taken a tablet daily for seven consecutive days.

If spotting or breakthrough bleeding occurs, the patient is instructed to continue on the same regimen. This type of bleeding is usually transient and without significance; however, if the bleeding is persistent or prolonged, the patient is advised to consult her physician. Although the occurrence of pregnancy is highly unlikely if Trivora Tablets are taken according to directions, if withdrawal bleeding does not occur, the possibility of pregnancy must be considered. If the patient has not adhered to the prescribed schedule (missed one or more tablets or started taking them on a day later than she should have), the probability of pregnancy should be considered at the time of the first missed period and appropriate diagnostic measures taken before the medication is resumed. If the patient has adhered to the prescribed regimen and misses two consecutive periods, pregnancy should be ruled out before continuing the contraceptive regimen.

The risk of pregnancy increases with each active (blue, white, or pink) tablet missed. For additional patient instructions regarding missed pills, see the "WHAT TO DO IF YOU MISS PILLS" section in the DETAILED PATIENT LABELING below. If breakthrough bleeding occurs following missed active tablets, it will usually be transient and of no consequence. If the patient misses one or more peach tablets, she is still protected against pregnancy provided she begins taking blue tablets again on the proper day.

Trivora may be initiated no earlier than day 28 postpartum in the non-lactating mother or after a second trimester abortion due to the increased risk for thromboembolism (see "CONTRAINDICATIONS", "WARNINGS" and "PRECAUTIONS" concerning thromboembolic disease). The patient should be advised to use a nonhormonal back-up method for the first 7 days of tablet-taking. However, if intercourse has already occurred, pregnancy should be excluded before the start of combined oral contraceptive use or the patient must wait for her first menstrual period. In the case of first-trimester abortion, if the patient starts Trivora immediately, additional contraceptive measures are not needed. It is to be noted that early resumption of ovulation may occur if Parlodel® (bromocriptine mesylate) has been used for the prevention of lactation.

How is Trivora Supplied

Trivora® Tablets (levonorgestrel and ethinyl estradiol tablets—triphasic regimen) are available in 28-tablet blister cards. Six blister cards are packaged in a carton. Each cycle contains 28 tablets as follows:

  • Six blue tablets containing 0.05 mg of levonorgestrel and 0.03 mg of ethinyl estradiol. The blue tablets are unscored, round in shape with "WATSON" debossed on one side and "50/30" on the other side.
  • Five white tablets containing 0.075 mg of levonorgestrel and 0.04 mg of ethinyl estradiol. The white tablets are unscored, round in shape with "WATSON" debossed on one side and "75/40" on the other side.
  • Ten pink tablets containing 0.125 mg of levonorgestrel and 0.03 mg of ethinyl estradiol. The pink tablets are unscored, round in shape with "WATSON" debossed on one side and "125/30" on the other side.
  • Seven peach inert tablets. The peach inert tablets are unscored, round in shape with "WATSON" debossed on one side and "P1" on the other side.

Store at 20° - 25°C (68° - 77°F). [See USP controlled room temperature.]

References available upon request.

BRIEF SUMMARY PATIENT PACKAGE INSERT

This product (like all oral contraceptives) is intended to prevent pregnancy. It does not protect against HIV infection (AIDS) and other sexually transmitted diseases.

Oral contraceptives, also known as "birth-control pills" or "the pill," are taken to prevent pregnancy, and when taken correctly, have a failure rate of less than 1.0% per year when used without missing any pills. The average failure rate of large numbers of pill users is 5% per year when women who miss pills are included. For most women oral contraceptives are also free of serious or unpleasant side effects. However, forgetting to take pills considerably increases the chances of pregnancy.

For the majority of women, oral contraceptives can be taken safely. But there are some women who are at high risk of developing certain serious diseases that can be life-threatening or may cause temporary or permanent disability or death. The risks associated with taking oral contraceptives increase significantly if you:

  • smoke.
  • have high blood pressure, diabetes, high cholesterol, or a tendency to form blood clots, or are obese.
  • have or have had clotting disorders, heart attack, stroke, angina pectoris, cance

    Editorial References and Review

    Medically reviewed by USARx EDITORIAL TEAM Last updated on 1/1/2020.

    Source: Drugs.com Trivora-28 (www.drugs.com/trivora.html).

Trivora-28 Side Effects

Note: This document contains side effect information about ethinyl estradiol / levonorgestrel. Some of the dosage forms listed on this page may not apply to the brand name Trivora.

For the Consumer

Applies to ethinyl estradiol / levonorgestrel: oral tablet

Warning

Oral route (Tablet)

Cigarette smoking increases the risk of serious cardiovascular events from combination oral contraceptives (COC) use. This risk increases with age, particularly in women older than 35 years, and with the number of cigarettes smoked. Women who use oral contraceptives should be strongly advised not to smoke.

Along with its needed effects, ethinyl estradiol/levonorgestrel may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur while taking ethinyl estradiol / levonorgestrel:

Incidence not known

Some side effects of ethinyl estradiol / levonorgestrel may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

Incidence not known

For Healthcare Professionals

Applies to ethinyl estradiol / levonorgestrel: oral tablet

General

The most frequently reported side effects were headache, heavy/irregular vaginal bleeding, nausea/vomiting, acne, dysmenorrhea, weight increased, mood changed, anxiety/panic attack, breast pain, and migraines.

Genitourinary

Very common (10% or more): Irregular/heavy uterine bleeding (up to 17%), menorrhagia (up to 11.6%), breast pain (up to 11.2%), dysmenorrhea (up to 11%), breakthrough bleeding/spotting

Common (1% to 10%): Breast tenderness/discomfort, vaginitis, candidiasis, breast enlargement, breast secretion, breast tension, intermenstrual bleeding/metrorrhagia

Uncommon (0.1% to 1%): Breast enlargement, breast hypertrophy, menstrual flow changed

Rare (less than 0.1%): Breast discharge, vaginal discharge, amenorrhea

Frequency not reported: Uterine myoma, temporary infertility, cervical erosion changed, cervical secretion changed, diminution in lactation

Postmarketing reports: Menstrual flow reduced, withdrawal bleeding missed, post pill amenorrhea

Cardiovascular

Uncommon (0.1% to 1%): Blood pressure increased

Rare (less than 0.1%): Venous thromboembolism, arterial thromboembolism

Frequency not reported: Deep vein thrombosis, hypertension, myocardial infarction, varicose veins exacerbated, thrombophlebitis, cerebral vascular disease, mitral valve prolapse

Postmarketing reports: Thrombosis

Nervous system

Very common (10% or more): Headache (up to 33%)

Common (1% to 10%): Migraine, dizziness

Very rare (less than 0.01%): Chorea exacerbated

Frequency not reported: Loss of consciousness, epilepsy, Sydenham's chorea, transient ischemic attack, ischemic stroke, hemorrhagic stroke, stroke, cerebral hemorrhage, cerebral thrombosis

Gastrointestinal

Very common (10% or more): Nausea/vomiting (up to 11%)

Common (1% to 10%): Abdominal pain/cramps, diarrhea

Very rare (less than 0.01%): Pancreatitis

Frequency not reported: Crohn's disease, ulcerative colitis, bloating, mesenteric thrombosis

Postmarketing reports: Abdominal distention

Oncologic

Rare (less than 0.1%): Benign liver tumor, malignant liver tumor, breast cancer

Hepatic

Rare (less than 0.1%): Cholestatic jaundice

Very rare (less than 0.01%): Gallbladder disease, gallbladder disease exacerbated

Frequency not reported: Cholecystitis, cholelithiasis, Budd-Chiari syndrome

Postmarketing reports: Liver function disturbance

Hematologic

Frequency not reported: Hemolytic uremic syndrome

Psychiatric

Common (1% to 10%): Mood changed, mood swings/alteration/affect lability, depression, anxiety/panic attack, nervousness, libido decreased, libido increased, depression

Frequency not reported: Major depressive disorder, suicide attempt, depressed mood, crying, major depression, affective disorder, depression suicidal, dysthymic disorder

Postmarketing reports: Insomnia

Immunologic

Rare (less than 0.1%): Hypersensitivity reaction, anaphylactic/anaphylactoid reaction

Very rare (less than 0.01%): Systemic lupus erythematosus exacerbated

Ocular

Rare (less than 0.1%): Contact lens intolerance

Very rare (less than 0.01%): Retinal vein thrombosis

Frequency not reported: Cataract, corneal curvature changed/steepening

Postmarketing reports: Optic neuritis

Metabolic

Common (1% to 10%): Appetite increased, fluid retention/edema

Uncommon (0.1% to 1%): Appetite decreased, serum lipid levels changed, hypertriglyceridemia

Rare (less than 0.1%): Glucose tolerance changed

Frequency not reported: Tolerance to carbohydrates reduced

Dermatologic

Common (1% to 10%): Acne

Uncommon (0.1% to 1%): Urticaria, rash, chloasma

Rare (less than 0.1%): Erythema nodosum, erythema multiforme, hereditary angioedema exacerbated

Frequency not reported: Herpes gestationis, hirsutism, alopecia, melasma

Postmarketing reports: Alopecia, itching, angioedema

Other

Common (1% to 10%): Weight gain, weight changed, flu syndrome

Rare (less than 0.1%): Weight decreased

Very rare (less than 0.01%): Porphyria exacerbated

Frequency not reported: Ectopic pregnancy, spontaneous abortion, porphyria, congenital anomaly, cystitis-like syndrome

Postmarketing reports: Chest pain, fatigue, malaise, edema peripheral, pain, serum folate decreased

Musculoskeletal

Common (1% to 10%): Back pain

Frequency not reported: Systemic lupus erythematosus

Postmarketing reports: Muscle spasm, pain in extremity

Renal

Frequency not reported: Pulmonary embolism

Postmarketing reports: Pulmonary thrombosis

Editorial References and Review

Medically reviewed by USARx EDITORIAL TEAM Last updated on 1/1/2020.

Source: Drugs.com Trivora-28 (www.drugs.com/trivora.html).

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