DESOGESTREL with ETHINYL ESTRADIOL
|| See TERMINOLOGY & ABBREVIATIONS ||
Cigarette smoking increases the risk of serious cardiovascular side effects from oral contraceptive use. This risk increases with age and with heavy smoking (15 or more cigarettes per day) and is quite marked in women over 35 years of age. Women who use oral contraceptives should be strongly advised not to smoke.
Desogestrel and Ethinyl Estradiol tablets (e.g. DESOGEN®) provides an oral contraceptive regimen of 21 white round tablets each containing 0.15 mg desogestrel (13-ethyl-11-methylene-18,19-dinor-17 alpha-pregn-4-en-20-yn-17-ol) and 0.03 mg ethinyl estradiol (19-nor-17 alpha-pregna-1,3,5 (10)-trien-20-yne-3,17-diol). Inactive ingredients include vitamin E, corn starch, povidone, stearic acid, colloidal silicon dioxide, lactose, hydroxypropyl methylcellulose, polyethylene glycol, titanium dioxide, and talc. The product may also contain 7 green round tablets containing the following inert ingredients: lactose, corn starch, magnesium stearate, FD&C Blue No. 2 aluminum lake, ferric oxide, hydroxypropyl methylcellulose, polyethylene glycol, titanium dioxide, and talc. The molecular weights for desogestrel and ethinyl estradiol are 310.48 and 296.40, respectively.
|Indication(s) and Health Benefits||
Desogestrel and Ethinyl Estradiol (e.g. DESOGEN®) is indicated for the prevention of pregnancy in women who elect to use this product as a method of contraception.
Oral contraceptives are highly effective. Table 1 lists the typical unintended pregnancy rates for users of combination oral contraceptives and other methods of contraception. The efficacy of these contraceptive methods, except sterilization, the IUD, and implants, depends upon the reliability with which they are used. Correct and consistent use of these methods can result in lower failure rates.
|Non-contraceptive Health benefits
The following non-contraceptive health benefits related to the use of oral contraceptives are supported by epidemiologic studies which largely utilized oral contraceptive formulations containing estrogen doses exceeding 0.035 mg of ethinyl estradiol or 0.05 mg of mestranol.
Effects on menses:
Effects related to inhibition of ovulation:
Effects from long-term use:
|Dosage & Administration||
To achieve maximum contraceptive effectiveness, Desogestrel/Ethinyl Estradiol tablet (e.g. DESOGEN®) must be taken exactly as directed, at the same time every day, and at intervals not exceeding 24 hours. Desogestrel/Ethinyl Estradiol tablet may be initiated using either a Sunday start or a Day 1 start.
NOTE: Each cycle pack dispenser is preprinted with the days of the week, starting with Sunday, to facilitate a Sunday start regimen. Six different "day label strips" are provided with each cycle pack dispenser in order to accommodate a Day 1 start regimen. In this case, the patient should place the self-adhesive "day label strip" that corresponds to her starting day over the preprinted days.
DURING THE FIRST CYCLE OF USE
IMPORTANT: The possibility of ovulation and conception prior to initiation of use of Desogestrel/Ethinyl Estradiol tablet should be considered. A woman can begin to take Desogestrel/Ethinyl Estradiol tablet either on the first Sunday after the onset of her menstrual period (Sunday Start) or on the first day of her menstrual period (Day 1 Start). When switching from another oral contraceptive, Desogestrel/Ethinyl Estradiol tablet should be started on the same day that a new pack of the previous oral contraceptive would have been started.
When initiating a Sunday start regimen, another method of contraception, such as condoms or spermicide, should be used for the first 7 consecutive days of taking Desogestrel/Ethinyl Estradiol tablet.
Using a Sunday start, tablets are taken daily without interruption as follows: The first white tablet should be taken on the first Sunday after menstruation begins (if menstruation begins on Sunday, the first white tablet is taken on that day). Tablets are then taken sequentially following the arrows marked on the dispenser. One white tablet is taken daily for 21 days, followed by 1 green (inactive) tablet daily for 7 days. For all subsequent cycles, the patient then begins a new 28-tablet regimen on the next day (Sunday) after taking the last green (inactive) tablet. [If switching from a different Sunday Start oral contraceptive, the first Desogestrel/Ethinyl Estradiol tablet tablet should be taken on the same day that a new pack of the previous oral contraceptive would have been started.]
If a patient misses 1 white (active) tablet in Weeks 1, 2, or 3, she should take the missed tablet as soon as she remembers. If the patient misses 2 consecutive white tablets in Week 1 or Week 2, the patient should take 2 tablets the day she remembers and 2 tablets the next day; thereafter, the patient should resume taking 1 tablet daily until she finishes the cycle pack. The patient should be instructed to use a back-up method of birth control (such as condoms or spermicide) if she has intercourse in the 7 days after she restarts her pills. If the patient misses 2 consecutive white tablets in the third week or misses 3 or more white tablets in a row at any time during the cycle, the patient should keep taking 1 white tablet daily until the next Sunday. On Sunday the patient should throw out the rest of that cycle pack and start a new cycle pack that same day. The patient should be instructed to use a back-up method of birth control if she has intercourse in the 7 days after restarting her pills.
Complete instructions to facilitate patient counseling on proper pill usage can be found in Detailed or Brief Patient Labeling.
DAY 1 START
Counting the first day of menstruation as "Day 1", the first white tablet should be taken on the first day of menstrual bleeding. Tablets are then taken sequentially without interruption as follows: One white tablet daily for 21 days, then one green (inactive) tablet daily for 7 days. For all subsequent cycles, the patient then begins a new 28-tablet regimen on the next day after taking the last green (inactive) tablet. [If switching directly from another oral contraceptive, the first white tablet should be taken on the same day that a new pack of the previous oral contraceptive would have been started.]
If a patient misses 1 white tablet, she should take the missed tablet as soon as she remembers. If the patient misses 2 consecutive white tablets in Week 1 or Week 2, the patient should take 2 tablets the day she remembers and 2 tablets the next day; thereafter, the patient should resume taking 1 tablet daily until she finishes the cycle pack. The patient should be instructed to use a back-up method of birth control (such as condoms or spermicide) if she has intercourse in the 7 days after she restarts her pills. If the patient misses 2 consecutive white tablets in the third week or misses 3 or more white tablets in a row at any time during the cycle, the patient should throw out the rest of that cycle pack and start a new cycle pack that same day. The patient should be instructed to use a back-up method of birth control if she has intercourse in the 7 days after restarting her pills.
Complete instructions to facilitate patient counseling on proper pill usage can be found in Detailed or Brief Patient Labeling.
ADDITIONAL INSTRUCTIONS FOR BOTH SUNDAY AND DAY 1 STARTS
If Spotting or Breakthrough Bleeding Occurs
Breakthrough bleeding, spotting, and amenorrhea are frequent reasons for patients discontinuing oral contraceptives. In breakthrough bleeding, as in all cases of irregular bleeding from the vagina, non-functional causes should be considered. In undiagnosed persistent or recurrent abnormal bleeding from the vagina, adequate diagnostic measures are indicated to rule out pregnancy or malignancy. If both pregnancy and pathology have been excluded, time or a change to another preparation may solve the problem. Changing to an oral contraceptive with a higher estrogen content, while potentially useful in minimizing menstrual irregularity, should be done only if necessary since this may increase the risk of thromboembolic disease.
Use of Desogestrel/Ethinyl Estradiol tablet in the Event of a Missed Menstrual Period
If the patient has not adhered to the prescribed schedule, the possibility of pregnancy should be considered at the time of the first missed period and Desogestrel/Ethinyl Estradiol tablet use should be discontinued if pregnancy is confirmed.
If the patient has adhered to the prescribed regimen and misses two consecutive periods, pregnancy should be ruled out. Desogestrel/Ethinyl Estradiol tablet should be discontinued if pregnancy is confirmed.
Use of Desogestrel/Ethinyl Estradiol tablet Postpartum
The use of Desogestrel/Ethinyl Estradiol tablet for contraception may be initiated 4 to 6 weeks postpartum in women who elect not to breast-feed. When the tablets are administered during the postpartum period, the increased risk of thromboembolic disease associated with the postpartum period must be considered.
If the patient starts on Desogestrel/Ethinyl Estradiol tablet postpartum, and has not yet had a period, she should be instructed to use another method of contraception until a white tablet has been taken daily for 7 consecutive days.
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.
Oral contraceptives should not be used in women who currently have the following conditions:
|Warnings & Precaution(s)||
Oral contraceptives should not be used in women who currently have the following conditions:
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 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 principally based on studies carried out in patients who used oral contraceptives with formulations of higher doses of estrogens and progestogens than those in common use today. The effect of long-term use of the oral contraceptives with formulations of lower doses of both estrogens and progestogens remains to be determined.
Throughout this labeling, epidemiologic 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 a disease, namely, a ratio of the incidence of a disease among oral contraceptive users to that among non-users. 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 non-users. The attributable risk does provide information about the actual occurrence of a disease in the population (Adapted from refs. 2 and 3 with the authors' permission). For further information, the reader is referred to a text on epidemiologic methods.
1. SEXUALLY TRANSMITTED DISEASES
Patients should be counseled that this product does not protect against HIV infection (AIDS) and other sexually transmitted diseases.
2. PHYSICAL EXAMINATION AND FOLLOW UP
It is good medical practice for all women to have annual history and physical examinations, including women using oral contraceptives. The physical examination, however, may be deferred until after initiation of oral contraceptives if requested by the woman and judged appropriate by the clinician. The physical examination should include special reference to blood pressure, breasts, abdomen and pelvic organs, including cervical cytology, and relevant laboratory tests. In case of undiagnosed, persistent or recurrent abnormal vaginal bleeding, appropriate measures should be conducted to rule out malignancy. Women with a strong family history of breast cancer or who have breast nodules should be monitored with particular care.
3. LIPID DISORDERS
Women who are being treated for hyperlipidemias should be followed closely if they elect to use oral contraceptives. Some progestogens may elevate LDL levels and may render the control of hyperlipidemias more difficult.
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 oral contraceptives, the medication should be discontinued. The hormones in Desogestrel/Ethinyl Estradiol tablet may be poorly metabolized in patients with impaired liver function.
5. FLUID RETENTION
Oral contraceptives may cause some degree of fluid retention. They should be prescribed with caution, and only with careful monitoring, in patients with conditions which might be aggravated by fluid retention.
6. EMOTIONAL DISORDERS
Women with a history of depression should be carefully observed and the drug discontinued if depression recurs to a serious degree. 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.
|Adverse Drug Reaction(s)||
An increased risk of the following serious adverse reactions has been associated with the use of oral contraceptives:
There is evidence of an association between the following conditions and the use of oral contraceptives:
The following adverse reactions have been reported in patients receiving oral contraceptives and are believed to be drug-related:
The following adverse reactions have been reported in users of oral contraceptives and the association has been neither confirmed nor refuted:
Changes in contraceptive effectiveness associated with co-administration of other drugs
a. Anti-infective agents and anticonvulsants
Contraceptive effectiveness may be reduced when hormonal contraceptives are coadministered with some antibiotics, anticonvulsants, and other drugs that increase metabolism of contraceptive steroids. This could result in unintended pregnancy or breakthrough bleeding. Examples include barbiturates, rifampin, phenylbutazone, phenytoin, carbamazepine, felbamate, oxcarbazepine, topiramate and griseofulvin.
Since desogestrel is mainly metabolized by the cytochrome P450 2C9 enzyme (CYP 2C9) to form etonogestrel, the active progestin, there is a possibility of interaction with CYP 2C9 substrates or inhibitors (such as: ibuprofen, piroxicam, naproxen, phenytoin, fluconazole, diclofenac, tolbutamide, glipizide, celecoxib, sulfamethoxazole, isoniazid, torsemide, irbesartan, losartan, and valsartan). The clinical relevance of these interactions is unknown.
b. Anti-HIV protease inhibitors
Several of the anti-HIV protease inhibitors have been studied with co-administration of oral combination hormonal contraceptives; significant changes (increase and decrease) in the plasma levels of the estrogen and progestin have been noted in some cases. The efficacy and safety of these oral contraceptive products may be affected with co-administration of anti-HIV protease inhibitors. healthcare providers should refer to the label of the individual anti-HIV protease inhibitors for further drug-drug interaction information.
c. Herbal products
Herbal products containing St. John's wort (hypericum perforatum) may induce hepatic enzymes (cytochrome P450) and p-glycoprotein transporter and may reduce the effectiveness of contraceptive steroids. This may also result in breakthrough bleeding.
Increase in plasma hormone levels associated with co-administered drugs
Co-administration of atorvastatin and certain ethinyl estradiol containing oral contraceptives increased AUC values for ethinyl estradiol by approximately 20%. Ascorbic acid and acetaminophen may increase plasma ethinyl estradiol levels, possibly by inhibition of conjugation. CYP 3A4 inhibitors such as itraconazole or ketoconazole may increase plasma hormone levels.
Changes in plasma levels of co-administered drugs
Combination hormonal contraceptives containing some synthetic estrogens (e.g., ethinyl estradiol) may inhibit the metabolism of other compounds. Increased plasma concentrations of cyclosporine, prednisolone, and theophylline have been reported with concomitant administration of oral contraceptives. Decreased plasma concentrations of acetaminophen and increased clearance of temazepam, salicylic acid, morphine, and clofibric acid, have been noted when these drugs were administered with oral contraceptives.
No formal drug-drug interaction studies were conducted with Desogestrel/Ethinyl Estradiol tablet.
Lab test result
Certain endocrine and liver function tests and blood components may be affected by oral contraceptives:
|Pregnancy Category (FDA) and use in Specific Population||
Pregnancy Category X.
Small amounts of oral contraceptive steroids have been identified in the milk of nursing mothers and a few adverse effects on the child have been reported, including jaundice and breast enlargement. In addition, 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 oral contraceptives but to use other forms of contraception until she has completely weaned her child.
Safety and efficacy of Desogestrel/Ethinyl Estradiol tablet has been established in women of reproductive age. Safety and efficacy are expected to be the same for postpubertal adolescents under the age of 16 and for users 16 years and older. Use of this product before menarche is not indicated.
GERIATRIC USEThis product has not been studied in women over 65 years of age and is not indicated in this population.
Combination oral contraceptives act by suppression of gonadotropins. Although the primary mechanism of this action is inhibition of ovulation, other alterations include changes in the cervical mucus (which increase the difficulty of sperm entry into the uterus) and the endometrium (which reduce the likelihood of implantation).
Receptor-binding studies, as well as studies in animals, have shown that etonogestrel, the biologically active metabolite of desogestrel, combines high progestational activity with minimal intrinsic androgenicity. The relevance of this latter finding in humans is unknown.
Desogestrel is rapidly and almost completely absorbed and converted into etonogestrel, its biologically active metabolite. Following oral administration, the relative bioavailability of desogestrel, as measured by serum levels of etonogestrel, is approximately 84%.
In the third cycle of use after a single dose of Desogestrel/Ethinyl Estradiol tablet, maximum concentrations of etonogestrel of 2805±1203 pg/mL (mean±SD) are reached at 1.4±0.8 hours. The area under the curve (AUC0â€“âˆž) is 33,858±11,043 pg/mLâˆ™hr after a single dose. At steady state, attained from at least day 19 onwards, maximum concentrations of 5840±1667 pg/mL are reached at 1.4±0.9 hours. The minimum plasma levels of etonogestrel at steady state are 1400±560 pg/mL. The AUC0â€“24 at steady state is 52,299±17,878 pg/mLâˆ™hr. The mean AUC0â€“âˆž for etonogestrel at single dose is significantly lower than the mean AUC0â€“24 at steady state. This indicates that the kinetics of etonogestrel are non-linear due to an increase in binding of etonogestrel to SHBG in the cycle, attributed to increased SHBG levels which are induced by the daily administration of ethinyl estradiol. SHBG levels increased significantly in the third treatment cycle from day 1 (150±64 nmol/L) to day 21 (230±59 nmol/L).
Ethinyl estradiol is rapidly and almost completely absorbed. In the third cycle of use after a single dose of Desogestrel/Ethinyl Estradiol tablet, the relative bioavailability is approximately 83%.
In the third cycle of use after a single dose of Desogestrel/Ethinyl Estradiol tablet, maximum concentrations of ethinyl estradiol of 95±34 pg/mL are reached at 1.5±0.8 hours. The AUC0â€“âˆž is 1471±268 pg/mLâˆ™hr after a single dose. At steady state, attained from at least day 19 onwards, maximum ethinyl estradiol concentrations of 141±48 pg/mL are reached at about 1.4±0.7 hours. The minimum serum levels of ethinyl estradiol at steady state are 24±8.3 pg/mL. The AUC0â€“24, at steady state is 1117±302 pg/mLâˆ™hr. The mean AUC0â€“âˆž for ethinyl estradiol following a single dose during treatment cycle 3 does not significantly differ from the mean AUC0â€“24 at steady state. This finding indicates linear kinetics for ethinyl estradiol.
Etonogestrel, the active metabolite of desogestrel, was found to be 98% protein bound, primarily to sex hormone-binding globulin (SHBG). Ethinyl estradiol is primarily bound to plasma albumin. Ethinyl estradiol does not bind to SHBG, but induces SHBG synthesis. Desogestrel, in combination with ethinyl estradiol, does not counteract the estrogen-induced increase in SHBG, resulting in lower serum levels of free testosterone.
Desogestrel is rapidly and completely metabolized by hydroxylation in the intestinal mucosa and on first pass through the liver to etonogestrel. In vitro data suggest an important role for the cytochrome P450 CYP2C9 in the bioactivation of desogestrel. Further metabolism of etonogestrel into 6β-hydroxy, etonogestrel and 6β-13ethyl-dihydroxylated metabolites as major metabolites is catalyzed by CYP3A4. Other metabolites (i.e., 3Î±-OHdesogestrel, 3β-OH-desogestrel, and 3Î±-OH-5Î±-H-desogestrel) also have been identified and these metabolites may undergo glucuronide and sulfate conjugation.
Ethinyl estradiol is subject to a significant degree of presystemic conjugation (phase II metabolism). Ethinyl estradiol, escaping gut wall conjugation, undergoes phase I metabolism and hepatic conjugation (phase II metabolism). Major phase I metabolites are 2-OH-ethinyl estradiol and 2-methoxy-ethinyl estradiol. Sulfate and glucuronide conjugates of both ethinyl estradiol and phase I metabolites, which are excreted in bile, can undergo enterohepatic circulation.
Etonogestrel and ethinyl estradiol are primarily eliminated in urine, bile and feces. The elimination half-life of etonogestrel is approximately 38±20 hours at steady state. The elimination half-life of ethinyl estradiol is 26±6.8 hours at steady state.
|ATC Classification||G03AC09 - desogestrel; Belongs to the class of progestogens. Used as systemic contraceptives.|
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