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Levonorgestrel and Ethinyl Estradiol
Overview
What is AUBRA?
Each active, light yellow tablet (21) contains 0.1 mg of levonorgestrel, d(-)-13β-ethyl-17α-ethinyl-17β-hydroxygon-4-en-3-one, a totally synthetic progestogen, and 0.02 mg of ethinyl estradiol, 17α-ethinyl-1,3,5(10)-estratriene-3,17β-diol. The inactive ingredients present are croscarmellose sodium, ferric oxide of iron (yellow), ferric oxide of iron (red), lactose monohydrate, magnesium stearate, microcrystalline cellulose, povidone K-25, and sodium lauryl sulfate.
Each inactive, brown tablet (7) contains the following inactive ingredients: croscarmellose sodium, ferric oxide of iron (brown), lactose monohydrate, magnesium stearate, microcrystalline cellulose, and povidone K-25.
What does AUBRA look like?
What are the available doses of AUBRA?
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What should I talk to my health care provider before I take AUBRA?
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How should I use AUBRA?
Aubra is indicated for the prevention of pregnancy in women who elect to use oral contraceptives as a method of contraception.
Oral contraceptives are highly effective. Table II lists the typical accidental pregnancy rates for users of combination oral contraceptives and other methods of contraception. The efficacy of these contraceptive methods, except sterilization, the IUD, and Norplant System, depends upon the reliability with which they are used. Correct and consistent use of methods can result in lower failure rates.
Emergency Contraceptive Pills: The FDA has concluded that certain combined oral contraceptives containing ethinyl estradiol and norgestrel or levonorgestrel are safe and effective for use as postcoital emergency contraception. Treatment initiated within 72 hours after unprotected intercourse reduces the risk of pregnancy by at least 75%.
Lactation Amenorrhea Method: LAM is a highly effective, temporary method of contraception.
Source: Trussell J. Contraceptive efficacy. In: Hatcher RA, Trussell J, Stewart F, Cates W, Stewart GK, Kowel D, Guest F. Contraceptive Technology: Seventeenth Revised Edition. New York NY: Irvington Publishers; 1998.
In a clinical trial with levonorgestrel and ethinyl estradiol tablets, 1,477 subjects had 7,720 cycles of use and a total of 5 pregnancies were reported. This represents an overall pregnancy rate of 0.84 per 100 woman-years. This rate includes patients who did not take the drug correctly. One or more pills were missed during 1,479 (18.8%) of the 7,870 cycles; thus all tablets were taken during 6,391 (81.2%) of the 7,870 cycles. Of the total 7,870 cycles, a total of 150 cycles were excluded from the calculation of the Pearl index due to the use of backup contraception and/or missing 3 or more consecutive pills.
To achieve maximum contraceptive effectiveness, Aubra (levonorgestrel and ethinyl estradiol tablets) must be taken exactly as directed and at intervals not exceeding 24 hours. The dosage of Aubra is one light yellow tablet daily for 21 consecutive days, followed by one brown inert tablet daily for 7 consecutive days, according to the prescribed schedule. It is recommended that Aubra tablets be taken at the same time each day.
During The First Cycle Of Use
The possibility of ovulation and conception prior to initiation of medication should be considered. The patient should be instructed to begin taking Aubra on either the first Sunday after the onset of menstruation (Sunday Start) or on Day 1 of menstruation (Day 1 Start).
Sunday start
The patient is instructed to begin taking Aubra on the first Sunday after the onset of menstruation. If menstruation begins on a Sunday, the first tablet (light yellow) is taken that day. One light yellow tablet should be taken daily for 21 consecutive days, followed by one brown inert tablet daily for 7 consecutive days. Withdrawal bleeding should usually occur within 3 days following discontinuation of light yellow tablets and may not have finished before the next pack is started. During the first cycle, contraceptive reliance should not be placed on Aubra until a light yellow tablet has been taken daily for 7 consecutive days, and a nonhormonal back-up method of birth control should be used during those 7 days.
Day 1 start
During the first cycle of medication, the patient is instructed to begin taking Aubra during the first 24 hours of her period (day one of her menstrual cycle). One light yellow tablet should be taken daily for 21 consecutive days, followed by one brown inert tablet daily for 7 consecutive days. Withdrawal bleeding should usually occur within 3 days following discontinuation of light yellow tablets and may not have finished before the next pack is started. If medication is begun on day one of the menstrual cycle, no back-up contraception is necessary. If Aubra tablets are started later than day one of the first menstrual cycle or postpartum, contraceptive reliance should not be placed on Aubra 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.
After the first cycle of use
The patient begins her next and all subsequent courses of tablets on the day after taking her last brown tablet. She should follow the same dosing schedule: 21 days on light yellow tablets followed by 7 days on brown tablets. If in any cycle the patient starts tablets later than the proper day, she should protect herself against pregnancy by using a nonhormonal back-up method of birth control until she has taken a light yellow tablet daily for 7 consecutive days.
Switching from another hormonal method of contraception
When the patient is switching from a 21-day regimen of tablets, she should wait 7 days after her last tablet before she starts Aubra. She will probably experience withdrawal bleeding during that week. She should be sure that no more than 7 days pass after her previous 21-day regimen. When the patient is switching from a 28-day regimen of tablets, she should start her first pack of Aubra on the day after her last tablet. She should not wait any days between packs. The patient may switch any day from a progestin-only pill and should begin Aubra the next day. If switching from an implant or injection, the patient should start Aubra 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 nonhormonal back-up method of birth control for the first 7 days of tablet-taking.
If spotting or breakthrough bleeding occurs
If spotting or breakthrough bleeding occur, 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.
Risk of pregnancy if tablets are missed
While there is little likelihood of ovulation occurring if only one or two light yellow tablets are missed, the possibility of ovulation increases with each successive day that scheduled light yellow tablets are missed. Although the occurrence of pregnancy is unlikely if Aubra is 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. If the patient has adhered to the prescribed regimen and misses two consecutive periods, pregnancy should be ruled out.
The risk of pregnancy increases with each active (light yellow) tablet missed. For additional patient instructions regarding missed tablets, see the section in the below.
Use after pregnancy, abortion or miscarriage
Aubra may be initiated no earlier than day 28 postpartum in the nonlactating mother or after a second trimester abortion due to the increased risk for thromboembolism (see and concerning thromboembolic disease). The patient should be advised to use a non-hormonal back-up method for the first 7 days of tablet taking.
Aubra may be initiated immediately after a first trimester abortion or miscarriage. If the patient starts Aubra immediately, back-up contraception is not needed.
What interacts with AUBRA?
Combination oral contraceptives should not be used in women with any of the following conditions:
Thrombophlebitis or thromboembolic disorders
A history of deep-vein thrombophlebitis or thromboembolic disorders
Cerebrovascular or coronary artery disease (current or past history)
Valvular heart disease with thrombogenic complications
Thrombogenic rhythm disorders
Hereditary or acquired thrombophilias
Major surgery with prolonged immobilization
Diabetes with vascular involvement
Headaches with focal neurological symptoms
Uncontrolled hypertension
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
Hepatic adenomas or carcinomas, or active liver disease
Known or suspected pregnancy
Hypersensitivity to any of the components of levonorgestrel and ethinyl estradiol tablets
Are receiving Hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, due to the potential for ALT elevations (see Warnings, .
What are the warnings of AUBRA?
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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, diabetes, and surgery or trauma with increased risk of thrombosis (see ).
Practitioners prescribing oral contraceptives should be familiar with the following information relating to these risks.
The information contained in this package insert is principally based on studies carried out in patients who used oral contraceptives with higher doses of estrogens and progestogens than those in common use today. The effect of long-term use of the oral contraceptives with lower doses 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
b. Venous thrombosis and thromboembolism
c. Cerebrovascular diseases
d. Dose-related risk of vascular disease from oral contraceptives
e. Persistence of risk of vascular disease
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 III). 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 III: ANNUAL NUMBER OF BIRTH-RELATED OR METHOD-RELATED DEATHS ASSOCIATED WITH CONTROL OF FERTILITY PER 100,000 NONSTERILE WOMEN, BY FERTILITY-CONTROL METHOD AND ACCORDING TO AGE
Array
*
**
Adapted from H.W. Ory, Family Planning Perspectives, 57-63, 1983.
| Method of control and outcome | 15 - 19 | 20 - 24 | 25 - 29 | 30 - 34 | 35 - 39 | 40 - 44 |
| No fertility-control methods | 7.0 | 7.4 | 9.1 | 14.8 | 25.7 | 28.2 |
| Oral contraceptives | ||||||
| nonsmoker | 0.3 | 0.5 | 0.9 | 1.9 | 13.8 | 31.6 |
| Oral contraceptives | ||||||
| smoker | 2.2 | 3.4 | 6.6 | 13.5 | 51.1 | 117.2 |
| 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 and Breasts
Numerous epidemiological studies have examined the association between the use of oral contraceptives and the incidence of breast and cervical cancer.
The risk of having breast cancer diagnosed may be slightly increased among current and recent users of combination oral contraceptives. However, this excess risk appears to decrease over time after combination oral contraceptive discontinuation and by 10 years after cessation the increased risk disappears. Some studies report an increased risk with duration of use while other studies do not and no consistent relationships have been found with dose or type of steroid. Some studies have reported a small increase in risk for women who first use combination oral contraceptives at a younger age. Most studies show a similar pattern of risk with combination oral contraceptive use regardless of a woman's reproductive history or her family breast cancer history.
Breast cancers diagnosed in current or previous OC users tend to be less clinically advanced than in nonusers.
Women with known or suspected carcinoma of the breast or personal history of breast cancer should not use oral contraceptives because breast cancer is usually a hormonally-sensitive tumor. 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 combination 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 these 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.
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 CHCs. Discontinue levonorgestrel and ethinyl estradiol prior to starting therapy with the combination drug regimen ombitasvir/paritaprevir/ritonavir, with or without dasabuvir [see Contraindications (4)]. Levonorgestrel and ethinyl estradiol can be restarted approximately 2 weeks following completion of treatment with the combination drug regimen.
5. 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.
6. Oral-Contraceptive Use Before or During Early Pregnancy
Extensive epidemiological studies have revealed no increased risk of birth defects in infants born to 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 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. 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.
7. Gallbladder Disease
Combination oral contraceptives may worsen existing gallbladder disease and may accelerate the development of this disease in previously asymptomatic women. 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.
8. 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 mcg 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 and ), changes in serum triglycerides and lipoprotein levels have been reported in oral-contraceptive users.
9. 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 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.
10. 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 and )
11. 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 persist 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.
Some women may encounter post-pill amenorrhea or oligomenorrhea (possibly with anovulation), especially when such a condition was preexistent.
12. Ectopic Pregnancy
Ectopic as well as intrauterine pregnancy may occur in contraceptive failures.
What are the precautions of AUBRA?
1. General
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Patients should be counseled that oral contraceptives do not protect against transmission of HIV (AIDS) and other sexually transmitted diseases (STDs) such as chlamydia, genital herpes, genital warts, gonorrhea, hepatitis B, and syphilis.
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 diagnostic 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
and )
A small proportion of women will have adverse lipid changes while taking oral contraceptives. Nonhormonal contraception should be considered in women with uncontrolled dyslipidemias. Persistent hypertriglyceridemia may occur in a small population of combination oral contraceptive users. Elevations of plasma triglycerides may lead to pancreatitis and other complications.
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
Diarrhea and /or vomiting may reduce hormone absorption resulting in decreased serum concentrations.
9. Drug Interactions
10. Interactions with Laboratory Tests
Certain endocrine- and liver-function tests and blood components may be affected by oral contraceptives:
a. Increased prothrombin and factors VII, VIII, IX, and X; decreased antithrombin 3; increased norepinephrine-induced platelet aggregability.
b. Increased thyroid-binding globulin (TBG) leading to increased circulating total thyroid hormone, as measured by protein-bound iodine (PBI), T4 by column or by radioimmunoassay. Free T3 resin uptake is decreased, reflecting the elevated TBG; free T4 concentration is unaltered.
c. Other binding proteins may be elevated in serum i.e. corticosteroid binding globulin (CBG), sex hormone-binding globulins (SHBG) leading to increased levels of total circulating corticosteroids and sex steroids respectively. Free or biologically active hormone concentrations are unchanged.
d. Triglycerides may be increased and levels of various other lipids and lipoproteins may be affected.
e. Glucose tolerance may be decreased.
f. 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 section.
12. Pregnancy
Pregnancy Category X. See and 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 levonorgestrel and ethinyl estradiol tablets have been established in women of reproductive age. Safety and efficacy are expected to be the same for postpubertal adolescents under the age of 16 and for users 16 years and older. Use of levonorgestrel and ethinyl estradiol tablets before menarche is not indicated.
15. Geriatric use
Levonorgestrel and ethinyl estradiol tablets have not been studied in women over 65 years of age and are not indicated in this population.
16. Information for the Patient
See Patient Labeling Printed Below.
What are the side effects of AUBRA?
An increased risk of the following serious adverse reactions (see section for additional information) has been associated with the use of oral contraceptives:
Thromboembolic and thrombotic disorders and other vascular problems (including thrombophlebitis and venous thrombosis with or without pulmonary embolism, mesenteric thrombosis, arterial thromboembolism, myocardial infarction, cerebral hemorrhage, cerebral thrombosis), carcinoma of the reproductive organs and breasts, 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 including migraine.
The following adverse reactions have been reported in patients receiving oral contraceptives and are believed to be drug related (alphabetically listed):
Acne
Amenorrhea
Anaphylactic/anaphylactoid reactions, including urticaria, angioedema and severe reactions with respiratory and circulatory symptoms
Breast changes: tenderness, pain, enlargement, secretion
Budd-Chiari syndrome
Cervical erosion and secretion, change in
Cholestatic jaundice
Chorea, exacerbation of
Colitis
Contact lenses, intolerance to
Corneal curvature (steepening), change in
Dizziness
Edema/fluid retention
Erythema multiforme
Erythema nodosum
Gastrointestinal symptoms (such as abdominal pain, cramps, and bloating)
Hirsutism
Infertility after discontinuation of treatment, temporary
Lactation, diminution in, when given immediately postpartum
Libido, change in
Melasma/chloasma which may persist
Menstrual flow, change in
Mood changes, including depression
Nausea
Nervousness
Pancreatitis
Porphyria, exacerbation of
Rash (allergic)
Scalp hair, loss of
Serum folate levels, decrease in
Spotting
Systemic lupus erythematosus, exacerbation of
Unscheduled bleeding
Vaginitis, including candidiasis
Varicose veins, aggravation of
Vomiting
Weight or appetite (increase or decrease), change in
The following adverse reactions have been reported in users of oral contraceptives:
Cataracts
Cystitis-like syndrome
Dysmenorrhea
Hemolytic uremic syndrome
Hemorrhagic eruption
Optic neuritis, which may lead to partial or complete loss of vision
Premenstrual syndrome
Renal function, impaired
What should I look out for while using AUBRA?
Combination oral contraceptives should not be used in women with any of the following conditions:
Thrombophlebitis or thromboembolic disorders
A history of deep-vein thrombophlebitis or thromboembolic disorders
Cerebrovascular or coronary artery disease (current or past history)
Valvular heart disease with thrombogenic complications
Thrombogenic rhythm disorders
Hereditary or acquired thrombophilias
Major surgery with prolonged immobilization
Diabetes with vascular involvement
Headaches with focal neurological symptoms
Uncontrolled hypertension
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
Hepatic adenomas or carcinomas, or active liver disease
Known or suspected pregnancy
Hypersensitivity to any of the components of levonorgestrel and ethinyl estradiol tablets
Are receiving Hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, due to the potential for ALT elevations (see Warnings, .
What might happen if I take too much AUBRA?
Symptoms of oral contraceptive overdosage in adults and children may include nausea, vomiting, and drowsiness/fatigue; withdrawal bleeding may occur in females. There is no specific antidote and further treatment of overdose, if necessary, is directed to the symptoms.
How should I store and handle AUBRA?
Aubra tablets (0.1 mg levonorgestrel and 0.02 mg ethinyl estradiol) are available in a 28 Tablets Blister, arranged in 3 rows of 7 active tablets and 1 row of inert tablets, as follows:21 active tablets: light yellow colored, uncoated, round, unscored, flat tablets debossed with 201 on one side and blank on the other side.7 inert tablets: brown colored, uncoated, round, unscored flat tablets debossed with 271 on one side and blank on the other side.Aubra tablets are available as follows:Package (NDC-50102-120-10)Carton (NDC-50102-120-03) containing 3 Packageseach containing one blister pack of 28 tablets.Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].Aubra tablets (0.1 mg levonorgestrel and 0.02 mg ethinyl estradiol) are available in a 28 Tablets Blister, arranged in 3 rows of 7 active tablets and 1 row of inert tablets, as follows:21 active tablets: light yellow colored, uncoated, round, unscored, flat tablets debossed with 201 on one side and blank on the other side.7 inert tablets: brown colored, uncoated, round, unscored flat tablets debossed with 271 on one side and blank on the other side.Aubra tablets are available as follows:Package (NDC-50102-120-10)Carton (NDC-50102-120-03) containing 3 Packageseach containing one blister pack of 28 tablets.Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].Aubra tablets (0.1 mg levonorgestrel and 0.02 mg ethinyl estradiol) are available in a 28 Tablets Blister, arranged in 3 rows of 7 active tablets and 1 row of inert tablets, as follows:21 active tablets: light yellow colored, uncoated, round, unscored, flat tablets debossed with 201 on one side and blank on the other side.7 inert tablets: brown colored, uncoated, round, unscored flat tablets debossed with 271 on one side and blank on the other side.Aubra tablets are available as follows:Package (NDC-50102-120-10)Carton (NDC-50102-120-03) containing 3 Packageseach containing one blister pack of 28 tablets.Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].Aubra tablets (0.1 mg levonorgestrel and 0.02 mg ethinyl estradiol) are available in a 28 Tablets Blister, arranged in 3 rows of 7 active tablets and 1 row of inert tablets, as follows:21 active tablets: light yellow colored, uncoated, round, unscored, flat tablets debossed with 201 on one side and blank on the other side.7 inert tablets: brown colored, uncoated, round, unscored flat tablets debossed with 271 on one side and blank on the other side.Aubra tablets are available as follows:Package (NDC-50102-120-10)Carton (NDC-50102-120-03) containing 3 Packageseach containing one blister pack of 28 tablets.Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].Aubra tablets (0.1 mg levonorgestrel and 0.02 mg ethinyl estradiol) are available in a 28 Tablets Blister, arranged in 3 rows of 7 active tablets and 1 row of inert tablets, as follows:21 active tablets: light yellow colored, uncoated, round, unscored, flat tablets debossed with 201 on one side and blank on the other side.7 inert tablets: brown colored, uncoated, round, unscored flat tablets debossed with 271 on one side and blank on the other side.Aubra tablets are available as follows:Package (NDC-50102-120-10)Carton (NDC-50102-120-03) containing 3 Packageseach containing one blister pack of 28 tablets.Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].Aubra tablets (0.1 mg levonorgestrel and 0.02 mg ethinyl estradiol) are available in a 28 Tablets Blister, arranged in 3 rows of 7 active tablets and 1 row of inert tablets, as follows:21 active tablets: light yellow colored, uncoated, round, unscored, flat tablets debossed with 201 on one side and blank on the other side.7 inert tablets: brown colored, uncoated, round, unscored flat tablets debossed with 271 on one side and blank on the other side.Aubra tablets are available as follows:Package (NDC-50102-120-10)Carton (NDC-50102-120-03) containing 3 Packageseach containing one blister pack of 28 tablets.Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].Aubra tablets (0.1 mg levonorgestrel and 0.02 mg ethinyl estradiol) are available in a 28 Tablets Blister, arranged in 3 rows of 7 active tablets and 1 row of inert tablets, as follows:21 active tablets: light yellow colored, uncoated, round, unscored, flat tablets debossed with 201 on one side and blank on the other side.7 inert tablets: brown colored, uncoated, round, unscored flat tablets debossed with 271 on one side and blank on the other side.Aubra tablets are available as follows:Package (NDC-50102-120-10)Carton (NDC-50102-120-03) containing 3 Packageseach containing one blister pack of 28 tablets.Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].Aubra tablets (0.1 mg levonorgestrel and 0.02 mg ethinyl estradiol) are available in a 28 Tablets Blister, arranged in 3 rows of 7 active tablets and 1 row of inert tablets, as follows:21 active tablets: light yellow colored, uncoated, round, unscored, flat tablets debossed with 201 on one side and blank on the other side.7 inert tablets: brown colored, uncoated, round, unscored flat tablets debossed with 271 on one side and blank on the other side.Aubra tablets are available as follows:Package (NDC-50102-120-10)Carton (NDC-50102-120-03) containing 3 Packageseach containing one blister pack of 28 tablets.Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].
Clinical Information
Chemical Structure
No Image foundClinical Pharmacology
Absorption
No specific investigation of the absolute bioavailability of levonorgestrel and ethinyl estradiol tablets in humans has been conducted. However, literature indicates that levonorgestrel is rapidly and completely absorbed after oral administration (bioavailability about 100%) and is not subject to first-pass metabolism. Ethinyl estradiol is rapidly and almost completely absorbed from the gastrointestinal tract but, due to first-pass metabolism in gut mucosa and liver, the bioavailability of ethinyl estradiol is between 38% and 48%.
After a single dose of levonorgestrel and ethinyl estradiol tablets to 22 women under fasting conditions, maximum serum concentrations of levonorgestrel are 2.8 ± 0.9 ng/mL (mean ± SD) at 1.6 ± 0.9 hours. At steady state, attained from day 19 onwards, maximum levonorgestrel concentrations of 6.0 ± 2.7 ng/mL are reached at 1.5 ± 0.5 hours after the daily dose. The minimum serum levels of levonorgestrel at steady state are 1.9 ± 1.0 ng/mL. Observed levonorgestrel concentrations increased from day 1 (single dose) to days 6 and 21 (multiple doses) by 34% and 96%, respectively (Figure I). Unbound levonorgestrel concentrations increased from day 1 to days 6 and 21 by 25% and 83%, respectively. The kinetics of total levonorgestrel are non-linear due to an increase in binding of levonorgestrel to sex hormone binding globulin (SHBG), which is attributed to increased SHBG levels that are induced by the daily administration of ethinyl estradiol.
Following a single dose, maximum serum concentrations of ethinyl estradiol of 62 ± 21 pg/mL are reached at 1.5 ± 0.5 hours. At steady state, attained from at least day 6 onwards, maximum concentrations of ethinyl estradiol were 77 ± 30 pg/mL and were reached at 1.3 ± 0.7 hours after the daily dose. The minimum serum levels of ethinyl estradiol at steady state are 10.5 ± 5.1 pg/mL. Ethinyl estradiol concentrations did not increase from days 1 to 6, but did increase by 19% from days 1 to 21 (FIGURE I).
FIGURE I: Mean (SE) levonorgestrel and ethinyl estradiol serum concentrations in 22 subjects receiving levonorgestrel and ethinyl estradiol tablets (100 µg levonorgestrel and 20 µg ethinyl estradiol)
Table I provides a summary of levonorgestrel and ethinyl estradiol pharmacokinetic parameters.
TABLE I: MEAN (SD) PHARMACOKINETIC PARAMETERS OF
LEVONORGESTREL AND ETHINYL ESTRADIOL TABLETS OVER A 21-DAY DOSING PERIOD
Distribution
Levonorgestrel in serum is primarily bound to SHBG. Ethinyl estradiol is about 97% bound to plasma albumin. Ethinyl estradiol does not bind to SHBG, but induces SHBG synthesis.
Metabolism
Levonorgestrel: The most important metabolic pathway occurs in the reduction of the Δ4-3-oxo group and hydroxylation at positions 2α, 1β, and 16β, followed by conjugation. Most of the metabolites that circulate in the blood are sulfates of 3α, 5β-tetrahydro-levonorgestrel, while excretion occurs predominantly in the form of glucuronides. Some of the parent levonorgestrel also circulates as 17β-sulfate. Metabolic clearance rates may differ among individuals by several-fold, and this may account in part for the wide variation observed in levonorgestrel concentrations among users.
Ethinyl estradiol: Cytochrome P450 enzymes (CYP3A4) in the liver are responsible for the 2-hydroxylation that is the major oxidative reaction. The 2-hydroxy metabolite is further transformed by methylation and glucuronidation prior to urinary and fecal excretion. Levels of Cytochrome P450 (CYP3A) vary widely among individuals and can explain the variation in rates of ethinyl estradiol 2-hydroxylation. Ethinyl estradiol is excreted in the urine and feces as glucuronide and sulfate conjugates, and undergoes enterohepatic circulation.
Excretion
The elimination half-life for levonorgestrel is approximately 36 ± 13 hours at steady state. Levonorgestrel and its metabolites are primarily excreted in the urine (40% to 68%) and about 16% to 48% are excreted in feces. The elimination half-life of ethinyl estradiol is 18 ± 4.7 hours at steady state.
Non-Clinical Toxicology
Combination oral contraceptives should not be used in women with any of the following conditions:Thrombophlebitis or thromboembolic disorders
A history of deep-vein thrombophlebitis or thromboembolic disorders
Cerebrovascular or coronary artery disease (current or past history)
Valvular heart disease with thrombogenic complications
Thrombogenic rhythm disorders
Hereditary or acquired thrombophilias
Major surgery with prolonged immobilization
Diabetes with vascular involvement
Headaches with focal neurological symptoms
Uncontrolled hypertension
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
Hepatic adenomas or carcinomas, or active liver disease
Known or suspected pregnancy
Hypersensitivity to any of the components of levonorgestrel and ethinyl estradiol tablets
Are receiving Hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, due to the potential for ALT elevations (see Warnings, .
Topiramate
Some patients may experience a large increase in amitriptyline concentration in the presence of topiramate and any adjustments in amitriptyline dose should be made according to the patient's clinical response and not on the basis of plasma levels.
Drugs Metabolized by P450 2D6
The biochemical activity of the drug metabolizing isozyme cytochrome P450 2D6 (debrisoquin hydroxylase) is reduced in a subset of the caucasian population (about 7 to 10% of Caucasians are so called “poor metabolizers”); reliable estimates of the prevalence of reduced P450 2D6 isozyme activity among Asian, African and other populations are not yet available. Poor metabolizers have higher than expected plasma concentrations of tricyclic antidepressants (TCAs) when given usual doses. Depending on the fraction of drug metabolized by P450 2D6, the increase in plasma concentration may be small, or quite large (8 fold increase in plasma AUC of the TCA).
In addition, certain drugs inhibit the activity of this isozyme and make normal metabolizers resemble poor metabolizers. An individual who is stable on a given dose of TCA may become abruptly toxic when given one of these inhibiting drugs as concomitant therapy. The drugs that inhibit cytochrome P450 2D6 include some that are not metabolized by the enzyme (quinidine; cimetidine) and many that are substrates for P450 2D6 (many other antidepressants, phenothiazines, and the Type 1C antiarrhythmics propafenone and flecainide). While all the selective serotonin reuptake inhibitors (SSRIs), e.g., fluoxetine, sertraline, and paroxetine, inhibit P450 2D6, they may vary in the extent of inhibition. The extent to which SSRI-TCA interactions may pose clinical problems will depend on the degree of inhibition and the pharmacokinetics of the SSRI involved. Nevertheless, caution is indicated in the coadministration of TCAs with any of the SSRIs and also in switching from one class to the other. Of particular importance, sufficient time must elapse before initiating TCA treatment in a patient being withdrawn from fluoxetine, given the long half-life of the parent and active metabolite (at least 5 weeks may be necessary).
Concomitant use of tricyclic antidepressants with drugs that can inhibit cytochrome P450 2D6 may require lower doses than usually prescribed for either the tricyclic antidepressant or the other drug. Furthermore, whenever one of these other drugs is withdrawn from co-therapy, an increased dose of tricyclic antidepressant may be required. It is desirable to monitor TCA plasma levels whenever a TCA is going to be coadministered with another drug known to be an inhibitor of P450 2D6.
Monoamine oxidase inhibitors – see section. Guanethidine or similarly acting compounds; thyroid medication; alcohol, barbiturates and other CNS depressants; and disulfiram – see section.
When amitriptyline is given with anticholinergic agents or sympathomimetic drugs, including epinephrine combined with local anesthetics, close supervision and careful adjustment of dosages are required.
Hyperpyrexia has been reported when amitriptyline is administered with anticholinergic agents or with neuroleptic drugs, particularly during hot weather.
Paralytic ileus may occur in patients taking tricyclic antidepressants in combination with anticholinergic-type drugs.
Cimetidine is reported to reduce hepatic metabolism of certain tricyclic antidepressants, thereby delaying elimination and increasing steady-state concentrations of these drugs. Clinically significant effects have been reported with the tricyclic antidepressants when used concomitantly with cimetidine. Increases in plasma levels of tricyclic antidepressants, and in the frequency and severity of side effects, particularly anticholinergic, have been reported when cimetidine was added to the drug regimen. Discontinuation of cimetidine in well-controlled patients receiving tricyclic antidepressants and cimetidine may decrease the plasma levels and efficacy of the antidepressants.
Caution is advised if patients receive large doses of ethchlorvynol concurrently. Transient delirium has been reported in patients who were treated with one gram of ethchlorvynol and 75 to 150 mg of amitriptyline hydrochloride.
ID349
Patients should be counseled that oral contraceptives do not protect against transmission of HIV (AIDS) and other sexually transmitted diseases (STDs) such as chlamydia, genital herpes, genital warts, gonorrhea, hepatitis B, and syphilis.
An increased risk of the following serious adverse reactions (see section for additional information) has been associated with the use of oral contraceptives:
Thromboembolic and thrombotic disorders and other vascular problems (including thrombophlebitis and venous thrombosis with or without pulmonary embolism, mesenteric thrombosis, arterial thromboembolism, myocardial infarction, cerebral hemorrhage, cerebral thrombosis), carcinoma of the reproductive organs and breasts, 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 including migraine.
The following adverse reactions have been reported in patients receiving oral contraceptives and are believed to be drug related (alphabetically listed):
Acne
Amenorrhea
Anaphylactic/anaphylactoid reactions, including urticaria, angioedema and severe reactions with respiratory and circulatory symptoms
Breast changes: tenderness, pain, enlargement, secretion
Budd-Chiari syndrome
Cervical erosion and secretion, change in
Cholestatic jaundice
Chorea, exacerbation of
Colitis
Contact lenses, intolerance to
Corneal curvature (steepening), change in
Dizziness
Edema/fluid retention
Erythema multiforme
Erythema nodosum
Gastrointestinal symptoms (such as abdominal pain, cramps, and bloating)
Hirsutism
Infertility after discontinuation of treatment, temporary
Lactation, diminution in, when given immediately postpartum
Libido, change in
Melasma/chloasma which may persist
Menstrual flow, change in
Mood changes, including depression
Nausea
Nervousness
Pancreatitis
Porphyria, exacerbation of
Rash (allergic)
Scalp hair, loss of
Serum folate levels, decrease in
Spotting
Systemic lupus erythematosus, exacerbation of
Unscheduled bleeding
Vaginitis, including candidiasis
Varicose veins, aggravation of
Vomiting
Weight or appetite (increase or decrease), change in
The following adverse reactions have been reported in users of oral contraceptives:
Cataracts
Cystitis-like syndrome
Dysmenorrhea
Hemolytic uremic syndrome
Hemorrhagic eruption
Optic neuritis, which may lead to partial or complete loss of vision
Premenstrual syndrome
Renal function, impaired
Reference
This information is obtained from the National Institute of Health's Standard Packaging Label drug database.
"https://dailymed.nlm.nih.gov/dailymed/"
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Clonazepam Description Each single-scored tablet, for oral administration, contains 0.5 mg, 1 mg, or 2 mg Clonazepam, USP, a benzodiazepine. Each tablet also contains corn starch, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and povidone. Clonazepam tablets USP 0.5 mg contain Yellow D&C No. 10 Aluminum Lake. Clonazepam tablets USP 1 mg contain Yellow D&C No. 10 Aluminum Lake, as well as FD&C Blue No. 1 Aluminum Lake. Chemically, Clonazepam, USP is 5-(o-chlorophenyl)-1,3-dihydro-7-nitro-2H-1,4-benzodiazepin-2-one. It is a light yellow crystalline powder. It has the following structural formula: C15H10ClN3O3 M.W. 315.72Tips
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