Caziant: Indications, Dosage, Precautions, Adverse Effects
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Caziant – Product Information

Manufacture: Watson Laboratories Inc. (Allergan)
Country: United States
Condition: Birth Control (Contraception), Contraception (Birth Control)
Class: Contraceptives
Form: Tablets
Ingredients: desogestrel, ethinyl estradiol

Desogestrel and Ethinyl Estradiol Tablets USP

Description

CAZIANT (desogestrel/ethinyl estradiol) Tablets are a triphasic oral contraceptive containing two active components, desogestrel and ethinyl estradiol. Each 28-day treatment cycle pack consists of three active dosing phases: 7 white tablets containing 0.100 mg desogestrel (13-ethyl-11-methylene-18,19- dinor-17α -pregn-4-en-20-yn-17-ol) and 0.025 mg ethinyl estradiol (19-nor-17α pregna-1,3,5(10)-trien- 20-yne-3, 17-diol); 7 light blue tablets containing 0.125 mg desogestrel and 0.025 mg ethinyl estradiol, and 7 blue tablets containing 0.150 mg desogestrel and 0.025 mg ethinyl estradiol. Inactive ingredients include vitamin E, corn starch, colloidal silicon dioxide, stearic acid, lactose anhydrous, povidone, FD&C Blue #1 aluminum lake (0.125 mg/0.025 mg and 0.15 mg/0.025 mg only). The CAZIANT® blister pack also contains 7 green tablets with the following inert ingredients: Vitamin E, lactose anhydrous, magnesium stearate, microcrystalline cellulose, D&C Yellow #10 aluminum lake, and FD&C Blue No. 2 aluminumlake. The molecular weights for desogestrel and ethinyl estradiol are 310.48 and 296.40, respectively. The structural formulas are as follows:


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

Absorption

Desogestrel is rapidly and almost completely absorbed and converted into etonogestrel, its biologically active metabolite. Following oral administration, the relative bioavailability of desogestrel, based on the lowest and highest tablet strengths, 0.100 mg desogestrel/0.025 mg ethinyl estradiol and 0.150 mg desogestrel/0.025 mg ethinyl estradiol, compared to solution, as measured by serum levels of etonogestrel, is approximately 100%. Ethinyl estradiol is rapidly and almost completely absorbed.

When the lowest and highest tablet strengths, 0.100 mg desogestrel/0.025 mg ethinyl estradiol and 0.15 mg desogestrel/0.025 mg ethinyl estradiol, were compared to solution, the relative bioavailability of ethinyl estradiol was 92% and 98%, respectively. The effect of food on the bioavailability of desogestrel and ethinyl estradiol tablets following oral administration has not been evaluated.

The pharmacokinetics of etonogestrel and ethinyl estradiol following multiple dose administration of desogestrel and ethinyl estradiol tablets were determined during the third cycle in 21 subjects. After multiple dosing with desogestrel and ethinyl estradiol tablets, plasma concentrations of etonogestrel reached steady-state after four days of treatment during dosing Phases 1 and 3. During dosing Phase 2, steady-state was reached after five days of treatment. The dose-normalized AUC0-24 for etonogestrel was increased approximately 20% from Phase 1 to Phase 2 and approximately 10% from Phase 2 to Phase 3. SHBG concentrations were shown to be induced by the daily administration of ethinyl estradiol. Steady state for ethinyl estradiol was reached after four days of dosing in all dosing phases. The pharmacokinetic parameters of etonogestrel and ethinyl estradiol during the third cycle following multiple dose administration of desogestrel and ethinyl estradiol tablets are summarized in Table I.

TABLE I: MEAN (SD) PHARMACOKINETIC PARAMETERS OF DESOGESTREL AND ETHINYL ESTRADIOL TABLETS OVER A 28-DAY DOSING PERIOD IN THE THIRD CYCLE (n=21)

Etonogestrel
Phase (days) Dose**/* mg Cmax pg/mL Tmax h n-AUC0-24 pg•hr/mL/μg CL/F L/h
1 (1-7)0.1002163.3(856.4)1.6 (0.7)196.0 (75.4)6.1 (2.3)
2 (8-14)0.1253241.5(1296.5)a 1.1 (0.3) a 234.4 (85.0) a5.1 (1.9) a
2 (8-14)0.1253241.5(1296.5) a1.1 (0.3)a234.4 (85.0) a5.1 (1.9) a
3 (15-21)0.1503855.7(1273.1)1.5 (0.8)256.6 (104.0)4.6 (1.6)
**/* Desogestrel
Ethinyl Estradiol
Phase (days) Dose**/* mg Cmax pg/mL Tmax h n-AUC0-24 pg•hr/mL/μg CL/F L/h
1 (1-7)0.02585.4 (51.7)1.5 (0.8)26.4 (11.5)43.5 (15.0)
2 (8-14)0.02591.3 (52.2)a1.2 (1.2)a29.0 (15.5)a41.7 (15.5)a
3 (15-21)0.02590.1 (48.2)1.2 (0.7)28.3 (13.2)42.5 (18.7)
a n=20
Cmax – measured peak concentration
tmax – time at which maximum serum drug concentration occurs
n-AUC0-24 – area under the concentration–vs. time curve -0 to 24 hours normalized to 1 μg administered
CL/F – apparent clearance
Note: for information on t½ for Day 21, see the Excretion section.

Distribution

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 (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 -13ethyldihydroxylated 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 2OH-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.

Excretion

Etonogestrel and ethinyl estradiol are primarily eliminated in urine, bile and feces. At steady state, on Day 21, the elimination half-lives of etonogestrel and ethinyl estradiol are 37.1 ± 14.8 hours and 28.2 ± 10.5 hours, respectively.

Special Populations

Race

There is no information to determine the effect of race on the pharmacokinetics of desogestrel and ethinyl estradiol tablets.

Hepatic Insufficiency

No formal studies were conducted to evaluate the effect of hepatic disease on the disposition of desogestrel and ethinyl estradiol tablets. 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 ofdesogestrel and ethinyl estradiol tablets.

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 desogestrel and ethinyl estradiol tablets (see PRECAUTIONS).

Indications and usage

CAZIANT® (desogestrel/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 II 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 II: 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 Accidental Pregnancy within the First Year of Use% of Women Continuing Use at One Year3
Method (1) Typical Use1 (2) Perfect Use2 (3) (4)
Chance4 8585
Spermicides 526640
Periodic abstinence 2563
Calendar 9
Ovulation method 3
Sympto-thermal 62
Post-ovulation 1
Post-ovulation 194
Cap7
Parous women 402042
Nulliparous women 20956
Sponge
Parous women 402042
Nulliparous women 20956
Diaphragm 720656
Condom 8
Female (Reality)21556
Male 14361
Pill 571
Progestin only 0.5
Combined 0.1
IUD
Progesterone T 2.02.01.581
Copper T380A 0.80.678
Lng 200.10.181
Depo-Provera0.30.370
Norplantand Norplant-20.050.0588
Female sterilization 0.5 0.5100
Male sterilization 0.150.10100

Emergency Contraceptive Pills : Treatment initiated within 72 hours after unprotected intercourse reduces risk of pregnancy by at least 75% 9

Lactational Amenorrhea Method: LAM is a highly effective, temporary method of contraception. 10

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.

1Among typical couples who initiate use of a method (not necessarily for the first time), the percentage who experience an accidental pregnancy during the first year if they do not stop use for any other reason.

2Among couples who initiate use of a method (not necessarily for the first time) and who use it perfectly (both consistently and correctly), the percentage who experience an accidental pregnancy during the first year if they do not stop use for any other reason.

3Among couples attempting to avoid pregnancy, the percentage who continue to use a method for one year.

4The percentage of women becoming pregnant noted in columns (2) and (3) are based on data from populations where contraception is not used and from women who cease using contraception in order to become pregnant. Among such populations, about 89% become pregnant within one year. This estimate was lowered slightly (to 85%) to represent the percent who would become pregnant within one year among women now relying on reversible methods of contraception if they abandoned contraception altogether.

5Foams, creams, gels, vaginal suppositories, and vaginal film.

6Cervical mucus (ovulation) method supplemented by calendar in the pre-ovulatory and basal body temperature in the post-ovulatory phases.

7With spermicidal cream or jelly.

8Without spermicides.

9The treatment schedule is one dose within 72 hours after unprotected intercourse and a second dose 12 hours after the first dose. The Food and Drug Administration has declared the following brands of oral contraceptives to be safe and effective for emergency contraception: Ovral® (1 dose is 2 white pills), Alesse® (1 dose is 5 pink pills), Nordette® or Levlen® (1 dose is 2 light orange pills), Lo/Ovral® (1 dose is 4 white pills), Triphasil® or Tri-Levlen® (1 dose is 4 yellow pills)

10However, to maintain effective protection against pregnancy, another method of contraception must be used as soon as menstruation resumes, the frequency or duration of breastfeeds is reduced, bottle feeds are introduced or the baby reaches six months of age

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 CAZIANT®

Warnings

Cigarette smoking increases the risk of serious cardiovascular s ide 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 are strongly advised not to smoke.

The use of oral contraceptives is associated with increased risk of several serious conditions including venous and arterial thrombotic and thromboembolic events (such as myocardial infarction, thromboembolism, and stroke) hepatic neoplasia, and 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 epidemiological methods.

THROMBOEMBOLIC DISORDERS AND OTHER VASCULAR PROBLEMS

Thromboembolism

An 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 weeks after delivery in women who elect not to breast feed.

Myocardial infarction

An increased risk of myocardial infarction has been attributed to oral contraceptive use. This risk is primarily in smokers or women with other underlying risk factors for coronary artery disease such as hypertension, hypercholesterolemia, morbid obesity, and diabetes. The relative risk of heart attack for current oral contraceptive users has been estimated to be two tosix (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 III) among women who use oral contraceptives.

TABLE III: CIRCULATORY DISEASE MORTALITY RATES PER 100,000 WOMEN YEARS BY AGE, SMOKING STATUS, AND ORAL CONTRACEPTIVE USE

AGE EVER-USERS NON-SMOKERS EVER-USERS SMOKERS CONTROLS NON-SMOKERS CONTROLS SMOKERS
15-240.010.50.00.0
25-344.414.22.74.2
35-4421.563.46.415.2
45+52.4206.711.427.9

Adapted from P.M. Layde and V. Beral, ref. #12.

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.

Cerebrovascular diseases

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

Dose-related risk of vascular disease from oral contraceptives

A positive association has been observed between the amount of estrogen and progestogen in oral contraceptives and the risk of vascular disease (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 preparations containing the lowest hormone content that provides satisfactory results in the individual.

Persistence of risk of vascular disease

There are two studies which have shown persistence 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 50 micrograms or more of estrogens.

ESTIMATES OF MORTALITY FROM CONTRACEPTIVE USE

One study gathered data from a variety of sources which have estimated the mortality rate associated with different methods of contraception at different ages (Table IV). These estimates include the combined risk of death associated with contraceptive methods plus the risk attributable to pregnancy in the event of method failure. Each method of contraception has its specific benefits and risks. The study concluded that with the exception of oral contraceptive users 35 and older who smoke and 40 and older who do not smoke, mortality associated with all methods of birth control is 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 (100,101), 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 IV: 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 AGE
15 to 1920 to 2425 to 2930 to 3435 to 3940 to 44
No fertility control methods*7.07.49.114.825.728.2
Oral contraceptives nonsmoker**0.30.50.91.913.831.6
Oral contraceptives smoker**2.23.46.613.551.1117.2
lUD**0.80.8111.41.4
Condom*1.11.60.70.20.30.4
Diaphragm/ spermicide*1.91.21.21.32.22.8
Periodic abstinence*2.51.61.61.72.93.6
* Deaths are birth related
** Deaths are method related
Adapted from H.W. Ory, ref.#35

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 oral contraceptive use has been associated with an increase in the risk of cervical intraepithelial 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.

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 intra-abdominal hemorrhage (50,51).

Studies from Britain have shown an increased risk of developing hepatocellular carcinoma (5254) 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.

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.

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.

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.

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 estrogens 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.

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 quantities 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 ever- and never-users (68,70,71).

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.

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.

ECTOPIC PREGNANCY

Ectopic as well as intrauterine pregnancy may occur in contraceptive failures.

Precautions

SEXUALLY TRANSMITTED DISEASES

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

PHYSICAL EXAMINATION AND FOLLOW UP

It is good medical practice for all women to have an 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.

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.

LIVER FUNCTION

If jaundice develops in any woman receiving oral contraceptives, the medication should be discontinued. The hormones in CAZIANT®Tablets may be poorly metabolized in patients with impaired liver function.

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.

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.

CONTACT LENSES

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

Drug interactions

Changes in contraceptive effectiveness associated with co-administration of other drugs:

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.

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. Health care providers should refer to the label of the individual anti-HIV protease inhibitors for further drug- drug interaction information.

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 and ethinyl estradiol tablets.

INTERACTIONS WITH LABORATORY TESTS

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

Increased prothrombin and factors VII, VIII, IX and X; decreased antithrombin 3; increased norepinephrine-induced platelet aggregability.

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.

Other binding proteins may be elevated in serum.

Sex hormone-binding globulins are increased and result in elevated levels of total circulating sex steroids; however, free or biologically active levels either decrease or remain unchanged.

Triglycerides may be increased, and levels of various other lipids and lipoproteins may be affected.

Glucose tolerance may be decreased.

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.

CARCINOGENESIS

See WARNINGS section.

PREGNANCY

Pregnancy Category X (see CONTRAINDICATIONS and WARNINGS sections).

NURSING MOTHERS

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, 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.

PEDIATRIC USE

Safety and efficacy of desogestrel 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 this product before menarche is not indicated.

GERIATRIC USE

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

Information for the patient

See Patient Labeling Printed Below

Adverse reactions

An increased risk of the following serious adverse reactions has been associated with the use of oral contraceptives (see WARNINGS section):

  • Thrombophlebitis and venous thrombosis with or without embolism
  • Arterial thromboembolism
  • Pulmonary embolism
  • Myocardial infarction
  • Cerebral hemorrhage
  • Cerebral thrombosis
  • Hypertension
  • Gallbladder disease
  • Hepatic adenomas or benign liver tumors

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

  • Mesenteric thrombosis
  • Retinal thrombosis

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

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

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

  • Pre-menstrual syndrome
  • Cataracts
  • Cystitis-like syndrome
  • Headache
  • Nervousness
  • Dizziness
  • Hirsutism
  • Loss of scalp hair
  • Erythema multiforme
  • Dysmenorrhea
  • Pancreatitis
  • Erythema nodosum
  • Hemorrhagic eruption
  • Impaired renal function
  • Hemolytic uremic syndrome
  • Acne
  • Changes in libido
  • Colitis
  • Budd-Chiari Syndrome
  • Optic neuritis, which may lead to partial or complete loss of vision

Overdosage

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

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 (73-78).

Effects on menses:

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

Effects related to inhibition of ovulation:

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

Effects from long-term use:

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

Dosage and administration

To achieve maximum contraceptive effectiveness, CAZIANT® Tablets must be taken exactly as directed, at the same time every day, and at intervals not exceeding 24 hours. CAZIANT® Tablets may be initiated using either a Sunday start or a Day 1 start.

NOTE: Each tablet 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 tablet 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 CAZIANT® Tablets should be considered. A woman can begin to take CAZIANT® 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, CAZIANT® should be started on the same day that a new pack of the previous oral contraceptive would have been started.

SUNDAY START

When initiating a Sunday start regimen, another method of contraception, such as condoms or spermicide, should be used until after the first 7 consecutive days of taking CAZIANT®.

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 7 days, followed by 1 light blue tablet daily for 7 days, 1 blue tablet daily for 7 days, and then 1 green (inactive) tablet daily for 7 days. For all subsequent cycles, the patient then begins a new 28tablet regimen on the next day (Sunday) after taking the last green tablet. [If switching from a Sunday Start oral contraceptive, the first CAZIANT® tablet should be taken on the second Sunday after the last tablet of a 21 day oral contraceptive regimen or should be taken on the first Sunday after the last inactive tablet of a 28 day regimen.]

If a patient misses one 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 active 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 missing pills. If the patient misses 2 consecutive blue (active) tablets in the third week or misses 3 or more active tablets in a row at any time during the cycle, the patient should keep taking 1 active 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 the 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 ("How to Take the Pill" section).

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 7 days, then 1 light blue tablet daily for 7 days, followed by 1 blue tablet daily for 7 days and then 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 after taking the last green 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 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 active 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 blue tablets in the third week or if the patient misses 3 or more active 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 she restarts her pills.

Complete instructions to facilitate patient counseling on proper pill usage can be found in Detailed or Brief Patient Labeling ("How to Take the Pill" section).

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 CAZIANT® in the Event of a Missed Menstrual Period:

  1. 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 CAZIANT® use should be discontinued if pregnancy is confirmed.
  2. If the patient has adhered to the prescribed regimen and misses two consecutive periods, pregnancy should be ruled out. CAZIANT® should be discontinued if pregnancy is confirmed.

Use of CAZIANT® Postpartum

The use of CAZIANT® 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 (see CONTRAINDICATIONS and WARNINGS concerning thromboembolic disease. See also PRECAUTIONS for “Nursing Mothers”).

If the patient starts on CAZIANT® 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.

How supplied

CAZIANT® Tablets (Triphasic Regimen) are available in a 28-day blister card within a recyclable plastic dispenser. Each 28-day treatment cycle pack consists of four different dosing phases: 7 uncoated, round, convex, beveled edge white tablets (debossed with WATSON on one side and 960 on the other side) containing 0.1 mg desogestrel and 0.025 mg ethinyl estradiol; 7 uncoated, round, convex, beveled edge light blue tablets (debossed with WATSON on one side and 961 on the other side) containing 0.125 mg desogestrel and 0.025 mg ethinyl estradiol; and 7 uncoated, round, convex, beveled edge blue tablets (debossed with WATSON on one side and 962 on the other side) containing 0.15 mg desogestrel and 0.025 mg ethinyl estradiol. Seven round, convex, beveled edge green tablets (debossed with WATSON on one side and P on the other side) contain inert ingredients.

CAZIANT® Tablets (Triphasic Regimen) are available in cartons of 3 tablet dispensers.

Storage

Store at 20°-25°C (68°-77°F). [See USP Controlled Room Temperature.]