Solia® (desogestrel and ethinyl estradiol) Tablets provide 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. Solia® also contains 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. The structural formulas are as follows:
Solia - Clinical Pharmacology
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 (91,92). The relevance of this latter finding in humans is unknown.
Pharmacokinetics
AbsorptionDesogestrel 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 Solia® (desogestrel and ethinyl estradiol) Tablets, maximum concentrations of etonogestrel of 2805±1203 pg/mL (mean±SD) are reached at 1.4±0.8 hours. The area under the curve (AUC0–∞) is 33,858±11,043 pg/mL∙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 AUC0–24 at steady state is 52,299±17,878 pg/mL∙hr. The mean AUC0–∞ for etonogestrel at single dose is significantly lower than the mean AUC0–24 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 Solia®, the relative bioavailability is approximately 83%.
In the third cycle of use after a single dose of Solia®, maximum concentrations of ethinyl estradiol of 95±34 pg/mL are reached at 1.5±0.8 hours. The AUC0–∞ is 1471±268 pg/mL∙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 AUC0–24, at steady state is 1117±302 pg/mL∙hr. The mean AUC0–∞ for ethinyl estradiol following a single dose during treatment cycle 3 does not significantly differ from the mean AUC0–24 at steady state. This finding indicates linear kinetics for ethinyl estradiol.
DistributionEtonogestrel, 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 (96–99).
Metabolism Desogestrel
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., 3α-OH-desogestrel, 3β-OH-desogestrel, and 3α-OH-5α-H-desogestrel) also have been identified and these metabolites may undergo glucuronide and sulfate conjugation.
Ethinyl estradiol
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.
ExcretionEtonogestrel 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.
Special Populations Race
There is no information to determine the effect of race on the pharmacokinetics of Solia® (desogestrel and ethinyl estradiol) Tablets.
Hepatic Insufficiency
No formal studies were conducted to evaluate the effect of hepatic disease on the disposition of Solia®. However, steroid hormones may be poorly metabolized in patients with impaired liver function (see PRECAUTIONS).
Renal Insufficiency
No formal studies were conducted to evaluate the effect of renal disease on the disposition of Solia®.
Drug–Drug Interactions
Interactions between desogestrel/ethinyl estradiol and other drugs have been reported in the literature. No formal drug-drug interaction studies were conducted with Solia® (see PRECAUTIONS).
Indications and Usage for Solia
Solia® (desogestrel and ethinyl estradiol) Tablets are indicated for the prevention of pregnancy in women who elect to use this product as a method of contraception.
Oral contraceptives are highly effective. Table 1 lists the typical 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.
TABLE 1: PERCENTAGE OF WOMEN EXPERIENCING AN UNINTENDED PREGNANCY DURING THE FIRST YEAR OF TYPICAL USE AND THE FIRST YEAR OF PERFECT USE OF CONTRACEPTION AND THE PERCENTAGE CONTINUING USE AT THE END OF THE FIRST YEAR: UNITED STATES.
|
% of Women Experiencing an Unintended Pregnancy within the First Year of Use |
% of Women Continuing Use at One Year |
|---|
| Method |
Typical Use |
Perfect Use |
|---|
| (1) |
(2) |
(3) |
(4) |
|---|
Emergency Contraceptive Pills: Treatment initiated within 72 hours after unprotected intercourse reduces risk of pregnancy by at least 75%.
Lactational Amenorrhea Method: LAM is a highly effective, temporary method of contraception.
Source: Trussell J, Stewart F, Contraceptive Efficacy. In Hatcher RA, Trussell J, Stewart F, Cates W, Stewart GK, Kowal D, Guest F, Contraceptive Technology: Seventeenth Revised Edition. New York, NY: Irvington Publishers, 1998. |
|
| Chance |
85 |
85 |
|
| Spermicides |
26 |
6 |
40 |
| Periodic abstinence |
25 |
|
63 |
| Calendar |
|
9 |
|
| Ovulation Method |
|
3 |
|
| Sympto-Thermal |
|
2 |
|
| Post-Ovulation |
|
1 |
|
| Withdrawal |
19 |
4 |
|
| Cap |
|
|
|
| Parous Women |
40 |
26 |
42 |
| Nulliparous Women |
20 |
9 |
56 |
| Sponge |
|
|
|
| Parous Women |
40 |
20 |
42 |
| Nulliparous Women |
20 |
9 |
56 |
| Diaphragmà |
20 |
6 |
56 |
| Condom |
|
|
|
| Female (Reality) |
21 |
5 |
56 |
| Male |
14 |
3 |
61 |
| Pill |
5 |
|
71 |
| Progestin Only |
|
0.5 |
|
| Combined |
|
0.1 |
|
| IUD |
|
|
|
| Progesterone T |
2.0 |
1.5 |
81 |
| Copper T 380A |
0.8 |
0.6 |
78 |
| LNg 20 |
0.1 |
0.1 |
81 |
| Depo-Provera |
0.3 |
0.3 |
70 |
| Norplant and Norplant-2 |
0.05 |
0.05 |
88 |
| Female sterilization |
0.5 |
0.5 |
100 |
| Male sterilization |
0.15 |
0.10 |
100 |
Contraindications
Oral contraceptives should not be used in women who currently have the following conditions:
- Thrombophlebitis or thromboembolic disorders
- A past history of deep vein thrombophlebitis or thromboembolic disorders
- Cerebral vascular or coronary artery disease (current or history)
- Valvular heart disease with thrombogenic complications
- Severe hypertension
- Diabetes with vascular involvement
- Headaches with focal neurological symptoms
- Major surgery with prolonged immobilization
- Known or suspected carcinoma of the breast (or personal history of breast cancer)
- Carcinoma of the endometrium or other known or suspected estrogen-dependent neoplasia
- Undiagnosed abnormal genital bleeding
- Cholestatic jaundice of pregnancy or jaundice with prior hormonal contraceptive use
- Hepatic tumors (benign or malignant) or active liver disease
- Known or suspected pregnancy
- Heavy smoking (≥15 cigarettes per day) and over age 35
- Hypersensitivity to any of the components of Solia® (desogestrel and ethinyl estradiol) Tablets
Warnings
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.
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. THROMBOEMBOLIC DISORDERS AND OTHER VASCULAR PROBLEMS
a. ThromboembolismAn increased risk of 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 non-users 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 (2,3,19–24). 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 (25). The risk of thromboembolic disease associated with oral contraceptives is not related to length of use and disappears after pill use is stopped (2).
Several epidemiologic studies indicate that third generation oral contraceptives, including those containing desogestrel, are associated with a higher risk of venous thromboembolism than certain second generation oral contraceptives (102–104). In general, these studies indicate an approximate two-fold increased risk, which corresponds to an additional 1–2 cases of venous thromboembolism per 10,000 women-years of use. However, data from additional studies have not shown this two-fold increase in risk.
A two- to four-fold increase in relative risk of post-operative thromboembolic complications has been reported with the use of oral contraceptives (9,26). The relative risk of venous thrombosis in women who have predisposing conditions is twice that of women without such medical conditions (9,26). 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 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.
b. Myocardial infarctionAn 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 (4–10). The risk is very low in women under the age of 30.
Smoking in combination with oral contraceptive use has been shown to contribute substantially to the incidence of myocardial infarction in women in their mid-thirties or older with smoking accounting for the majority of excess cases (11). Mortality rates associated with circulatory disease have been shown to increase substantially in smokers over the age of 35 and non-smokers over the age of 40 (Table 2) among women who use oral contraceptives.
TABLE 2: CIRCULATORY DISEASE MORTALITY RATES PER 100,000 WOMAN-YEARS BY AGE, SMOKING STATUS, AND ORAL CONTRACEPTIVE USE.
| AGE |
EVER-USERS NON-SMOKERS |
EVER-USERS SMOKERS |
CONTROLS NON-SMOKERS |
CONTROLS SMOKERS |
|---|
| Adapted from P.M. Layde and V. Beral, ref. #12. |
| 15–24 |
0.0 |
10.5 |
0.0 |
0.0 |
| 25–34 |
4.4 |
14.2 |
2.7 |
4.2 |
| 35–44 |
21.5 |
63.4 |
6.4 |
15.2 |
| 45+ |
52.4 |
206.7 |
11.4 |
27.9 |
Oral contraceptives may compound the effects of well-known risk factors, such as hypertension, diabetes, hyperlipidemias, age, and obesity (13). In particular, some progestogens are known to decrease HDL cholesterol and cause glucose intolerance, while estrogens may create a state of hyperinsulinism (14–18). Oral contraceptives have been shown to increase blood pressure among users (see section 9 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.
c. Cerebrovascular diseasesOral 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 of hemorrhagic stroke (27–29).
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 (30). The relative risk of hemorrhagic stroke is reported to be 1.2 for non-smokers 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 (30). The attributable risk is also greater in older women (3). 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 contraceptivesA positive association has been observed between the amount of estrogen and progestogen in oral contraceptives and the risk of vascular disease (31–33). A decline in serum high-density lipoproteins (HDL) has been reported with many progestational agents (14–16). 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 progestogens used in the contraceptives. 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 a product containing the lowest hormone content that is judged appropriate for the individual.
e. Persistence of risk of vascular diseaseThere 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 40–49 years old who had used oral contraceptives for five or more years, but this increased risk was not demonstrated in other age groups (8). 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 (34). However, both studies were performed with oral contraceptive formulations containing 0.05 mg 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 3). 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 low and below 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 (35). However, current clinical practice involves the use of lower estrogen 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 (103,104), 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 non-smoking women (even with the newer low-dose formulations), there are also 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 low-dose oral contraceptive use by healthy non-smoking 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 and meets the individual patient needs.
TABLE 3: ANNUAL NUMBER OF BIRTH-RELATED OR METHOD-RELATED DEATHS ASSOCIATED WITH CONTROL OF FERTILITY PER 100,000 NON-STERILE 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, ref. #35. |
|
| No fertility control methods |
7.0 |
7.4 |
9.1 |
14.8 |
25.7 |
28.2 |
| Oral contraceptives non-smoker |
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 epidemiologic studies have been performed on the incidence of breast, endometrial, ovarian, and cervical cancer in women using oral contraceptives. Although the risk of breast cancer may be slightly increased among current users of oral contraceptives (RR = 1.24), this excess risk decreases over time after oral contraceptive discontinuation and by 10 years after cessation the increased risk disappears. The risk does not increase with duration of use, and no relationships have been found with dose or type of steroid. The patterns of risk are also similar regardless of a woman's reproductive history or her family breast cancer history. The subgroup for whom risk has been found to be significantly elevated is women who first used oral contraceptives before age 20, but because breast cancer is so rare at these young ages, the number of cases attributable to this early oral contraceptive use is extremely small. Breast cancers diagnosed in current or previous oral contraceptive users tend to be less advanced clinically than in never-users. Women who currently have or have had breast cancer should not use oral contraceptives because breast cancer is a hormone-sensitive tumor.
Some studies suggest that combination oral contraceptive use has been associated with an increase in the risk of cervical intra-epithelial neoplasia in some populations of women (45–48). 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 especially with oral contraceptives of higher dose (49). Rupture of rare, benign, hepatic adenomas may cause death through intraabdominal hemorrhage (50,51).
Studies from Britain have shown an increased risk of developing hepatocellular carcinoma (52–54) in long-term (>8 years) oral contraceptive users. However, these cancers are extremely rare in the US and the attributable risk (the excess incidence) of liver cancers in oral contraceptive users approaches less than one per million users.
5. OCULAR LESIONS
There have been clinical case reports of retinal thrombosis associated with the use of oral contraceptives. 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 epidemiologic studies have revealed no increased risk of birth defects in women who have used oral contraceptives prior to pregnancy (55–57). Studies also do not suggest a teratogenic effect, particularly in so far as cardiac anomalies and limb reduction defects are concerned (55,56,58,59), when oral contraceptives are taken inadvertently during early pregnancy.
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 first missed period. Oral contraceptive use should be discontinued if pregnancy is confirmed.
7. GALLBLADDER DISEASE
Earlier studies have reported an increased lifetime relative risk of gallbladder surgery in users of oral contraceptives and estrogens (60,61). More recent studies, however, have shown that the relative risk of developing gallbladder disease among oral contraceptive users may be minimal (62–64). 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 a decrease in glucose tolerance in a significant percentage of users (17). Oral contraceptives containing greater than 75 micrograms of estrogen cause hyperinsulinism, while lower doses of estrogen cause less glucose intolerance (65). Progestogens increase insulin secretion and create insulin resistance, this effect varying with different progestational agents (17,66). However, in the non-diabetic woman, oral contraceptives appear to have no effect on fasting blood glucose (67). Because of these demonstrated effects, prediabetic and diabetic women should be carefully monitored while taking oral contraceptives.
A small proportion of women will have persistent hypertriglyceridemia while on the pill. As discussed earlier (see WARNINGS 1.a. and 1.d.), changes in serum triglycerides and lipoprotein levels have been reported in oral contraceptive users.
9. ELEVATED BLOOD PRESSURE
Women with severe hypertension should not be started on hormonal contraceptives. An increase in blood pressure has been reported in women taking oral contraceptives (68) and this increase is more likely in older oral contraceptive users (69) and with continued use (61). Data from the Royal College of General Practitioners (12) and subsequent randomized trials have shown that the incidence of hypertension increases with increasing concentrations of progestogens.
Women with a history of hypertension or hypertension-related diseases, or renal disease (70) should be encouraged to use another method of contraception. If women elect to use oral contraceptives, they should be monitored closely and if significant elevation of blood pressure occurs, oral contraceptives should be discontinued. For most women, elevated blood pressure will return to normal after stopping oral contraceptives (69), and there is no difference in the occurrence of hypertension between everand never-users (68,70,71).
10. HEADACHE
The onset or exacerbation of migraine or development of headache with a new pattern which is recurrent, persistent, or severe requires discontinuation of oral contraceptives and evaluation of the cause.
11. BLEEDING IRREGULARITIES
Breakthrough bleeding and spotting are sometimes encountered in patients on oral contraceptives, especially during the first three months of use. If bleeding persists or recurs, non-hormonal causes should be considered and adequate diagnostic measures taken to rule out malignancy or pregnancy, 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, especially when such a condition was pre-existent.
12. ECTOPIC PREGNANCY
Ectopic as well as intrauterine pregnancy may occur in contraceptive failures.
Precautions 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 Solia® (desogestrel and ethinyl estradiol) Tablets 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.
8. DRUG INTERACTIONS
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 drugsCo-administration of atorvastatin and certain ethinyl estradiol containing oral contraceptives
