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

Manufacture: Watson (Allergan)
Country: United States
Condition: Birth Control (Contraception), Contraception (Birth Control)
Class: Contraceptives
Form: Tablets
Ingredients: drospirenone, ethinyl estradiol, lactose monohydrate, corn starch, pregelatinized starch, magnesium stearate, Vitamin E

Description

ZARAH™ (Drospirenone and ethinyl estradiol tablets) provides an oral contraceptive regimen consisting of 21 active tablets each containing 3 mg of drospirenone and 0.030 mg of ethinyl estradiol and 7 inert tablets. The inactive ingredients are lactose monohydrate, corn starch, pregelatinized starch, magnesium stearate, Vitamin E, FD&C Blue #1 Aluminum Lake. The inert tablets contain lactose anhydrous, microcrystalline cellulose, FD&C Yellow #6 Aluminum Lake and magnesium stearate.

Drospirenone (6R,7R,8R,9S,10R,13S,14S,15S,16S,17S)-1,3’,4’,6,6a,7,8,9,10,11,12,13,14,15,15a,16-hexadecahydro-10,13-dimethylspiro-[17H-dicyclopropa-6,7:15,16]cyclopenta[a]phenanthrene- 17,2’(5H)-furan]-3,5’(2H)-dione) is a synthetic progestational compound and has a molecular weight of 366.5 and a molecular formula of C24H30O3. Ethinyl estradiol (19-nor-17α-pregna 1,3,5(10)-triene-20- yne-3,17-diol) is a synthetic estrogenic compound and has a molecular weight of 296.4 and a molecular formula of C20H24O2.The structural formulas are as follows:


Clinical pharmacology

Pharmacodynamics

Combination oral contraceptives (COCs) 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 increases the difficulty of sperm entry into the uterus) and the endometrium (which reduces the likelihood of implantation).

Drospirenone is a spironolactone analogue with antimineralocorticoid activity. Preclinical studies in animals and in vitro have shown that drospirenone has no androgenic, estrogenic, glucocorticoid, and antiglucocorticoid activity. Preclinical studies in animals have also shown that drospirenone has antiandrogenic activity.

Pharmacokinetics

Absorption

The absolute bioavailability of drospirenone (DRSP) from a single entity tablet is about 76%. The absolute bioavailability of ethinyl estradiol (EE) is approximately 40% as a result of presystemic conjugation and first-pass metabolism. The absolute bioavailability of a combination tablet of drospirenone and ethinyl estradiol has not been evaluated. Serum concentrations of DRSP and EE reached peak levels within 1 to 3 hours after administration of drospirenone and ethinyl estradiol. After single dose administration of drospirenone and ethinyl estradiol, the relative bioavailability, compared to a suspension, was 107% and 117% for DRSP and EE, respectively.

The pharmacokinetics of DRSP are dose proportional following single doses ranging from 1 to 10 mg. Following daily dosing of drospirenone and ethinyl estradiol, steady-state DRSP concentrations were observed after 10 days. There was about 2 to 3 fold accumulation in serum Cmax and AUC (0 to 24h) values of DRSP following multiple dose administration of drospirenone and ethinyl estradiol (see Table 1).

For EE, steady-state conditions are reported during the second half of a treatment cycle. Following daily administration of drospirenone and ethinyl estradiol serum Cmax and AUC (0 to 24h) values of EE accumulate by a factor of about 1.5 to 2.0.

TABLE 1: Mean Pharmacokinetic Parameters of Drospirenone and Ethinyl Estradiol (3 mg / 0.03 mg)

Drospirenone Mean (%CV) Values
Cycle / Day No. of Subjects Cmax (ng/mL) Tmax (h) AUC(0 to 24h) (ng•h/mL) t½ (h)
1/1 12 36.9 (13) 1.7 (47) 288 (25) NA
1/21 12 87.5 (59) 1.7 (20) 827 (23) 30.9 (44)
6/21 12 84.2 (19) 1.8 (19) 930 (19) 32.5 (38)
9/21 12 81.3 (19) 1.6 (38) 957 (23) 31.4 (39)
13/21 12 78.7 (18) 1.6 (26) 968 (24) 31.1 (36)
Ethinyl Estradiol Mean (%CV) Values
Cycle / Day No. of Subjects Cmax (pg/mL) Tmax (h) AUC(0 to 24h) (pg•h/mL) t½ (h)
1/1 11 53.5 (43) 1.9 (45) 280.3 (87)) NA
1/21 11 92.1 (35) 1.5 (40) 461.3 (94) NA
6/21 11 99.1 (45) 1.5 (47) 346.4 (74) NA
9/21 11 87.0 (43) 1.5 (42) 485.3 (92) NA
13/21 10 90.5 (45) 1.6 (38) 469.5 (83) NA
NA = Not available

Effect of Food

The rate of absorption of DRSP and EE following single administration of two drospirenone and ethinyl estradiol tablets was slower under fed conditions with the serum Cmax being reduced about 40% for both components. The extent of absorption of DRSP, however, remained unchanged. In contrast the extent of absorption of EE was reduced by about 20% under fed conditions.

Distribution

DRSP and EE serum levels decline in two phases. The apparent volume of distribution of DRSP is approximately 4 L/kg and that of EE is reported to be approximately 4 to 5 L/kg.

DRSP does not bind to sex hormone binding globulin (SHBG) or corticosteroid binding globulin (CBG) but binds about 97% to other serum proteins. Multiple dosing over 3 cycles resulted in no change in the free fraction (as measured at trough levels). EE is reported to be highly but non-specifically bound to serum albumin (approximately 98.5 %) and induces an increase in the serum concentrations of both SHBG and CBG. EE induced effects on SHBG and CBG were not affected by variation of the DRSP dosage in the range of 2 to 3 mg.

Metabolism

The two main metabolites of DRSP found in human plasma were identified to be the acid form of DRSP generated by opening of the lactone ring and the 4,5-dihydrodrospirenone-3-sulfate. These metabolites were shown not to be pharmacologically active. In in vitro studies with human liver microsomes, DRSP was metabolized only to a minor extent mainly by Cytochrome P450 3A4 (CyP3A4)

EE has been reported to be subject to presystemic conjugation in both small bowel mucosa and the liver. Metabolism occurs primarily by aromatic hydroxylation but a wide variety of hydroxylated and methylated metabolites are formed. These are present as free metabolites and as conjugates with glucuronide and sulfate. CYP3A4 in the liver are responsible for the 2-hydroxylation which is the major oxidative reaction. The 2-hydroxy metabolite is further transformed by methylation and glucuronidation prior to urinary and fecal excretion.

Excretion

DRSP serum levels are characterized by a terminal disposition phase half-life of approximately 30 hours after both single and multiple dose regimens. Excretion of DRSP was nearly complete after ten days and amounts excreted were slightly higher in feces compared to urine. DRSP was extensively metabolized and only trace amounts of unchanged DRSP were excreted in urine and feces. At least 20 different metabolites were observed in urine and feces. About 38 to 47% of the metabolites in urine were glucuronide and sulfate conjugates. In feces, about 17 to 20 % of the metabolites were excreted as glucuronides and sulfates.

For EE the terminal disposition phase half life has been reported to be approximately 24 hours. EE is not excreted unchanged. EE is excreted in the urine and feces as glucuronide and sulfate conjugates and undergoes enterohepatic circulation.

Special Populations

Race

The effect of race on the disposition of drospirenone and ethinyl estradiol has not been evaluated.

Hepatic Dysfunction

Drospirenone and ethinyl estradiol is contraindicated in patients with hepatic dysfunction (also see BOLDED WARNING). The mean exposure to DRSP in women with moderate liver impairment is approximately three times the exposure in women with normal liver function.

Renal Insufficiency

Drospirenone and ethinyl estradiol is contraindicated in patients with renal insufficiency (also see BOLDED WARNING).

The effect of renal insufficiency on the pharmacokinetics of DRSP (3 mg daily for 14 days) and the effect of DRSP on serum potassium levels were investigated in female subjects (n = 28, age 30 to 65) with normal renal function and mild and moderate renal impairment. All subjects were on a low potassium diet. During the study 7 subjects continued the use of potassium sparing drugs for the treatment of the underlying illness. On the 14th day (steady-state) of DRSP treatment, serum DRSP levels in the group with mild renal impairment (creatinine clearance CLcr, 50 to 80 mL/min) were comparable to those in the group with normal renal function (CLcr, > 80 mL/min). The serum DRSP levels were on average 37% higher in the group with moderate renal impairment (CLcr, 30 to 50 mL/min) compared to those in the group with normal renal function. DRSP treatment was well tolerated by all groups. DRSP treatment did not show any clinically significant effect on serum potassium concentration. Although hyperkalemia was not observed in the study, in five of the seven subjects who continued use of potassium sparing drugs during the study, mean serum potassium levels increased by up to 0.33 mEq/L. Therefore, potential exists for hyperkalemia to occur in subjects with renal impairment whose serum potassium is in the upper reference range, and who are concomitantly using potassium sparing drugs.

Indications and usage

ZARAH (Drospirenone and ethinyl estradiol tablets) is indicated for the prevention of pregnancy in women who elect to use an oral contraceptive.

Oral contraceptives are highly effective. Table 2 lists the typical accidental pregnancy rates for users of combination oral contraceptives and other methods of contraception. The efficacy of these contraceptive methods, except sterilization, depends upon the reliability with which they are used. Correct and consistent use of methods can result in lower failure rates.

TABLE 2: Percentage of women experiencing an unintended pregnancy during the firs t year of typical use and firs t year of perfect use of contraception and the percentage continuing use at the end of the firs t 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 85 85
Spermicides 5 26 6 40
Calendar 9
Ovulation method 3
Sympto-thermal 6 2
Post-ovulation 40 26 42
Withdrawal 19 4
Cap7 2
Parous women 40 26 42
Nulliparous women 20 9 56
Sponge
Parous women 40 20 42
Nulliparous women 20 9 56
Diaphragm 7 20 6 56
Condom 8
Female (Reality®*) 21 5 56
Male 14 3 61
Pill 5
Progestin only 0.5
Combined 0.1
IUD
Progesterone T 2.0 1.5 81
Copper T380A 0.8 0.6 78
Lng 20 0.3 0.3 70
Depo-Provera®*
Norplant®* and Norplant®* II 0.05 0.05 88
Female sterilization 0.5 0.5 100
Male sterilization 0.15 0.10 100

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

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

  1. Among 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.
  2. Among 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 reason.
  3. Among couples attempting to avoid pregnancy, the percentage who continue to use a method for one year.
  4. The percents becoming pregnant 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 percentage who would become pregnant within one year among women now relying on reversible methods of contraception if they abandoned contraception altogether.
  5. Foams, creams, gels, vaginal suppositories, and vaginal film.
  6. Cervical mucus (ovulation) method supplemented by calendar in the pre-ovulatory and basal body temperature in the post-ovulatory phases.
  7. With spermicidal cream or jelly.
  8. Without spermicides.
  9. The 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).
  10. However, 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.

In clinical efficacy studies of drospirenone and ethinyl estradiol tablets of up to 2 years duration, 2,629 subjects completed 33,160 cycles of use without any other contraception. The mean age of the subjects was 25.5 ± 4.7 years. The age range was 16 to 37 years. The racial demographic was: 83% Caucasians, 1% Hispanic, 1% Black, < % Asian, < 1% other, < 1% missing data, 14% not inquired and < 1% unspecified. Pregnancy rates in the clinical trials were less than one per 100 woman-years of use.

Contraindications

Drospirenone and ethinyl estradiol tablets should not be used in women who have the following:

  • Renal insufficiency
  • Hepatic dysfunction
  • Adrenal Insufficiency
  • Thrombophlebitis or thromboembolic disorders
  • A past history of deep-vein thrombophlebitis or thromboembolic disorders
  • Cerebral-vascular or coronary-artery disease
  • Valvular heart disease with thrombogenic complications
  • Severe hypertension
  • Diabetes with vascular involvement
  • Headaches with focal neurological symptoms
  • Known or suspected carcinoma of the breast
  • Carcinoma of the endometrium or other known or suspected estrogen-dependent neoplasia
  • Undiagnosed abnormal genital bleeding
  • Cholestatic jaundice of pregnancy or jaundice with prior pill use
  • Liver tumor (benign or malignant) or active liver disease
  • Known or suspected pregnancy
  • Heavy smoking (> 15 cigarettes per day) and over age 35

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 should be strongly advised not to smoke.

Drospirenone and ethinyl estradiol tablets contain 3 mg of the progestin drospirenone that has antimineralocorticoid activity, including the potential for hyperkalemia in high-risk patients, comparable to a 25 mg dose of spironolactone. Drospirenone and ethinyl estradiol tablets should not be used in patients with conditions that predispose to hyperkalemia (i.e. renal insufficiency, hepatic dysfunction and adrenal insufficiency). Women receiving daily, long-term treatment for chronic conditions or diseases with medications that may increase serum potassium should have their serum potassium level checked during the firs t treatment cycle. Drugs that may increase serum potassium include ACE inhibitors, angiotensin – II receptor antagonists, potassium- sparing diuretics, heparin, aldosterone antagonists, and NSAIDs.

The use of oral contraceptives is associated with increased risks of several serious conditions including myocardial infarction, thromboembolism, 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 hypertension, hyperlipidemias, obesity and diabetes.

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

The information contained in this package insert is based principally on studies carried out in patients who used oral contraceptives with higher formulations of estrogens and progestogens than those in common use today. The effect of long-term use of the oral contraceptives with lower formulations of both estrogens and progestogens remains to be determined.

Throughout this labeling, 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 nonusers. The relative risk does not provide information on the actual clinical occurrence of a disease. Cohort studies provide a measure of attributable risk, which is the difference in the incidence of disease between oral contraceptive users and nonusers. The attributable risk does provide information about the actual occurrence of a disease in the population. For further information, the reader is referred to a text on epidemiologic methods.

  1. THROMBOEMBOLIC DISORDERS AND OTHER VASCULAR PROBLEMS
  2. a. Myocardial infarction

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

    Smoking in combination with oral contraceptive use has been shown to contribute substantially to the incidence of myocardial infarctions in women in their mid-thirties or older with smoking accounting for the majority of excess cases. Mortality rates associated with circulatory disease have been shown to increase substantially in smokers over the age of 35 and nonsmokers over the age of 40 (Table 3) among women who use oral contraceptives.

    TABLE 3: (Adapted from P.M. Layde and V. Beral) 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 CONTROL SMOKERS
    15 to 24 0.0 10.5 0.0 0.0
    25 to 34 4.4 14.2 2.7 4.2
    35 to 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. In particular, some progestogens are known to decrease HDL cholesterol and cause glucose intolerance, while estrogens may create a state of hyperinsulinism. Oral contraceptives have been shown to increase blood pressure among users (see section 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.

  3. b. Thromboembolism
  4. 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 nonusers to be 3 for the first episode of superficial venous thrombosis, 4 to 11 for deep vein thrombosis or pulmonary embolism, and 1.5 to 6 for women with predisposing conditions for venous thromboembolic disease. Cohort studies have shown the relative risk to be somewhat lower, about 3 for new cases and about 4.5 for new cases requiring hospitalization. The risk of thromboembolic disease due to oral contraceptives is not related to length of use and disappears after pill use is stopped.

    A two- to four-fold increase in the relative risk of post-operative thromboembolic complications has been reported with the use of oral contraceptives. The relative risk of venous thrombosis in women who have predisposing conditions is twice that of women without such medical conditions. If feasible, oral contraceptives should be discontinued from at least four weeks prior to and for two weeks after elective surgery of a type associated with an increase in risk of thromboembolism and during and following prolonged immobilization. Since the immediate postpartum period is also associated with an increased risk of thromboembolism, oral contraceptives should be started no earlier than four to six weeks after delivery.

    Several studies have investigated the relative risks of thromboembolism in women using drospirenone and ethinyl estradiol tablets compared to those in women using COCs containing other progestins. Two prospective cohort studies, both evaluating the risk of venous and arterial thromboembolism and death, were initiated at the time of drospirenone and ethinyl estradiol tablets approval.1, 2 The first (EURAS) showed the risk of thromboembolism (particularly venous thromboembolism) and death in drospirenone and ethinyl estradiol tablets users to be comparable to that of other oral contraceptive preparations, including those containing levonorgestrel (a so-called second generation COC). The second prospective cohort study (Ingenix) also showed a comparable risk of thromboembolism in drospirenone and ethinyl estradiol tablets users compared to users of other COCs, including those containing levonorgestrel. In the second study, COC comparator groups were selected based on their having similar characteristics to those being prescribed drospirenone and ethinyl estradiol tablets.

    Two additional epidemiological studies, one case-control study (van Hylckama Vlieg et al.3) and one retrospective cohort study (Lidegaard et al.4) suggested that the risk of venous thromboembolism occurring in drospirenone and ethinyl estradiol tablets users was higher than that for users of levonorgestrel-containing COCs and lower than that for users of desogestrel/gestodene-containing COCs (so-called third generation COCs). In the case-control study, however, the number of drospirenone and ethinyl estradiol tablets cases was very small (1.2% of all cases) making the risk estimates unreliable. The relative risk for drospirenone and ethinyl estradiol tablets users in the retrospective cohort study was greater than that for users of other COC products when considering women who used the products for less than one year. However, these one-year estimates may not be reliable because the analysis may include women of varying risk levels. Among women who used the product for 1 to 4 years, the relative risk was similar for users of drospirenone and ethinyl estradiol tablets to that for users of other COC products.

    c. Cerebrovascular diseases

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

    In a large study, the relative risk of thrombotic strokes has been shown to range from 3 for normotensive users to 14 for users with severe hypertension. The relative risk of hemorrhagic stroke is reported to be 1.2 for nonsmokers who used oral contraceptives, 2.6 for smokers who did not use oral contraceptives, 7.6 for smokers who used oral contraceptives, 1.8 for normotensive users and 25.7 for users with severe hypertension. The attributable risk is also greater in older women.

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

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

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

    e. Persistence of risk of vascular disease

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

  5. ESTIMATES OF MORTALITY FROM CONTRACEPTIVE USE
  6. 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 4). 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 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. However, current clinical practice involves the use of lower estrogen dose formulations combined with careful restriction of oral contraceptive use to women who do not have the various risk factors listed in this labeling.

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

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

    TABLE 4: Annual Number of Birth-Related or Method-Related Deaths Associated With Control of Fertility per 100,000 Nonsterile Women, by Fertility Control Method According to Age

    Method of Control and Outcome AGE
    15 to 19 20 to 24 25 to 29 30 to 34 35 to 39 40 to 44
    No fertility control methods\1\ 7.0 7.4 9.1 14.8 25.7 28.2
    Oral contraceptives
    Nonsmoker \2\ 0.3 0.5 0.9 1.9 13.8 31.6
    Oral contraceptives
    Smoker \2\ 2.2 3.4 6.6 13.5 51.1 117.2
    lUD \2\ 0.8 0.8 1 1 1.4 1.4
    Condom \1\ 1.1 1.6 0.7 0.2 0.3 0.4
    Diaphragm/ spermicide \1\ 1.9 1.2 1.2 1.3 2.2 2.8
    Periodic abstinence \1\ 2.5 1.6 1.6 1.7 2.9 3.6
    \1\ Deaths are birth related

    \2\ Deaths are method related

    Adapted from H.W. Ory, Family Planning Perspectives, 15:57 to 63, 1983.

  7. CARCINOMA OF THE REPRODUCTIVE ORGANS AND BREASTS
  8. Numerous epidemiological studies have been performed on the incidence of breast, endometrial, ovarian and cervical cancer in women using oral contraceptives.

    The risk of having breast cancer diagnosed may be slightly increased among current and recent users of COCs. However this excess risk appears to decrease over time after COC discontinuation and by 10 years after cessation the increased risk disappears. The risk does not appear to increase with duration of use and no consistent relationships have been found with dose or type of steroid. Most studies show a similar pattern of risk with COC use regardless of a woman’s reproductive history or her family breast cancer history. Some studies have found a small increase in risk for women who first use COCs before age 20.

    Breast cancers diagnosed in current or previous oral contraceptive users tend to be less clinically advanced than in nonusers.

    Women who currently have or have had breast cancer should not use oral contraceptives because breast cancer is a hormonally-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. 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.

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

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

  11. OCULAR LESIONS
  12. 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.

  13. ORAL CONTRACEPTIVE USE BEFORE OR DURING EARLY PREGNANCY
  14. Extensive epidemiological studies have revealed no increased risk of birth defects in women who have used oral contraceptives prior to pregnancy. Studies also do not suggest a teratogenic effect, particularly in so far as cardiac anomalies and limb-reduction defects are concerned, when 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 dosing schedule, the possibility of pregnancy should be considered at the time of the first missed period. Oral contraceptive use should be discontinued if pregnancy is confirmed.

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

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

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

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

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

  21. HEADACHE
  22. 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.

  23. BLEEDING IRREGULARITIES

Breakthrough bleeding and spotting are sometimes encountered in patients on oral contraceptives, especially during the first three months of use. Nonhormonal causes should be considered and adequate diagnostic measures taken to rule out malignancy or pregnancy in the event of breakthrough bleeding, as in the case of any abnormal vaginal bleeding. If pathology has been excluded, time or a change to another formulation may solve the problem. In the event of amenorrhea, pregnancy should be ruled out.

Some women may encounter post-pill amenorrhea or oligomenorrhea, especially when such a condition was pre-existent.

Precautions

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

  3. PHYSICAL EXAMINATION AND FOLLOW-UP
  4. 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.

  5. LIPID DISORDERS
  6. 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.

  7. LIVER FUNCTION
  8. If jaundice develops in any woman receiving oral contraceptives, the medication should be discontinued. Steroid hormones may be poorly metabolized in patients with impaired liver function.

  9. FLUID RETENTION
  10. 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.

  11. EMOTIONAL DISORDERS
  12. Women with a history of depression should be carefully observed and the drug discontinued if depression recurs to a serious degree.

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

  15. DRUG INTERACTIONS
  16. Effects of Other Drugs on Combined Hormonal Contraceptives

    Rifampin: Metabolism of ethinyl estradiol and some progestins (e.g., norethindrone) is increased by rifampin. A reduction in contraceptive effectiveness and an increase in menstrual irregularities have been associated with concomitant use of rifampin.

    Anticonvulsants: Anticonvulsants such as phenobarbital, phenytoin, and carbamazepine have been shown to increase the metabolism of ethinyl estradiol and/or some progestins, which could result in a reduction of contraceptive effectiveness.

    Antibiotics: Pregnancy while taking combined hormonal contraceptives has been reported when the combined hormonal contraceptives were administered with antimicrobials such as ampicillin, tetracycline, and griseofulvin. However, clinical pharmacokinetic studies have not demonstrated any consistent effects of antibiotics (other than rifampin) on plasma concentrations of synthetic steroids.

    Atorvastatin: Coadministration of atorvastatin and an oral contraceptive increased AUC values for norethindrone and ethinyl estradiol by approximately 30% and 20%, respectively.

    St. John’s Wort: 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 oral contraceptives and emergency contraceptive pills. This may also result in breakthrough bleeding.

    Other: Ascorbic acid and acetaminophen may increase plasma concentrations of some synthetic estrogens, possibly by inhibition of conjugation. A reduction in contraceptive effectiveness and an increased incidence of menstrual irregularities has been suggested with phenylbutazone.

    Effects of Drospirenone on Other Drugs

    • Metabolic Interactions
    • Metabolism of DRSP and potential effects of DRSP on hepatic cytochrome P450 (CYP) enzymes have been investigated in in vitro and in vivo studies (see Metabolism). In in vitro studies DRSP did not affect turnover of model substrates of CYP1A2 and CYP2D6, but had an inhibitory influence on the turnover of model substrates of CYP1A1, CYP2C9, CYP2C19 and CYP3A4 with CYP2C19 being the most sensitive enzyme. The potential effect of DRSP on CYP2C19 activity was investigated in a clinical pharmacokinetic study using omeprazole as a marker substrate. In the study with 24 postmenopausal women [including 12 women with homozygous (wild type) CYP2C19 genotype and 12 women with heterozygous CYP2C19 genotype] the daily oral administration of 3 mg DRSP for 14 days did not affect the oral clearance of omeprazole (40 mg, single oral dose). Based on the available results of in vivo and in vitro studies it can be concluded that, at clinical dose level, DRSP shows little propensity to interact to a significant extent with cytchrome P450 enzymes.

    • Interactions with Drugs that Have the Potential to Increase Serum Potassium

    There is a potential for an increase in serum potassium in women taking drospirenone and ethinyl estradiol with other drugs (see BOLDED WARNING). Of note, occasional or chronic use of NSAID medication was not restricted in any of the drospirenone and ethinyl estradiol clinical trials. A drug-drug interaction study of DRSP 3 mg/estradiol (E2) 1 mg versus placebo was performed in 24 mildly hypertensive postmenopausal women taking enalapril maleate 10 mg twice daily. Potassium levels were obtained every other day for a total of 2 weeks in all subjects. Mean serum potassium levels in the DRSP/E2 treatment group relative to baseline were 0.22 mEq/L higher than those in the placebo group. Serum potassium concentrations also were measured at multiple timepoints over 24 hours at baseline and on Day 14. On Day 14, the ratios for serum potassium Cmax and AUC in the DRSP/E2 group to those in the placebo group were 0.955 (90% CI: 0.914, 0.999) and 1.010 (90% CI: 0.944, 1.080), respectively. No patient in either treatment group developed hyperkalemia (serum potassium concentrations > 5.5 mEq/L).

    Effects of Combined Hormonal Contraceptives on Other Drugs

    Combined oral contraceptives containing 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. In addition, oral contraceptives may induce the conjugation of other compounds. Decreased plasma concentrations of acetaminophen and increased clearance on temazepam, salicylic acid, morphine, and clofibric acid have been noted when these drugs were administered with oral contraceptives.

  17. INTERACTIONS WITH LABORATORY TESTS
  18. 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 and corticoids; however, free or biologically active levels remain unchanged.
    • Triglycerides may be increased.
    • 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.
  19. CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY
  20. In a 24 month oral carcinogenicity study in mice dosed with 10 mg/kg/day drospirenone alone or 1 + 0.01, 3 + 0.03 and 10 + 0.1 mg/kg/day of drospirenone and ethinyl estradiol, 0.1 to 2 times the exposure (AUC of drospirenone) of women taking a contraceptive dose, there was an increase in carcinomas of the harderian gland in the group that received the high dose of drospirenone alone. In a similar study in rats given 10 mg/kg/day drospirenone alone or 0.3 + 0.003, 3 + 0.03 and 10 + 0.1 mg/kg/day drospirenone and ethinyl estradiol, 0.8 to 10 times the exposure of women taking a contraceptive dose, there was an increased incidence of benign and total (benign and malignant) adrenal gland pheochromocytomas in the group receiving the high dose of drospirenone. Drospirenone was not mutagenic in a number of in vitro (Ames, Chinese Hamster Lung gene mutation and chromosomal damage in human lymphocytes) and in vivo (mouse micronucleus) genotoxicity tests. Drospirenone increased unscheduled DNA synthesis in rat hepatocytes and formed adducts with rodent liver DNA but not with human liver DNA. See WARNINGS

  21. PREGNANCY
  22. Pregnancy category X. See CONTRAINDICATIONS and WARNINGS Sections. Estrogens and progestins should not be used during pregnancy. Fourteen pregnancies that occurred with drospirenone and ethinyl estradiol exposure in utero (none with more than a single cycle of exposure) have been identified. One infant was born with esophageal atresia. A causal association with drospirenone and ethinyl estradiol is unknown.

    A teratology study in pregnant rats given drospirenone orally at doses of 5, 15 and 45 mg/kg/day, 6 to 50 times the human exposure based on AUC of drospirenone, resulted in an increased number of fetuses with delayed ossification of bones of the feet in the two higher doses. A similar study in rabbits dosed orally with 1, 30 and 100 mg/kg/day drospirenone, 2 to 27 times the human exposure, resulted in an increase in fetal loss and retardation of fetal development (delayed ossification of small bones, multiple fusions of ribs) at the high dose only. When drospirenone was administered with ethinyl estradiol (100:1) during late pregnancy (the period of genital development) at doses of 5, 15 and 45 mg/kg, there was a dose dependent increase in feminization of male rat fetuses. In a study in 36 cynomolgous monkeys, no teratogenic or feminization effects were observed with orally administered drospirenone and ethinyl estradiol (100:1) at doses up to 10 mg/kg/day drospirenone, 30 times the human exposure.

  23. NURSING MOTHERS
  24. 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.

    After oral administration of drospirenone and ethinyl estradiol about 0.02% of the drospirenone dose was excreted into the breast milk of postpartum women within 24 hours. This results in a maximal daily dose of about 3 mcg drospirenone in an infant.

  25. PEDIATRIC USAGE

Safety and efficacy of drospirenone and ethinyl estradiol 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.

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
  • 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, although additional confirmatory studies are needed:

  • 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
  • Melasma which may persist
  • Breast changes: tenderness, enlargement, secretion
  • Change in weight (increase or decrease)
  • Change in cervical ectropion and secretion
  • Diminution in lactation when given immediately postpartum
  • Cholestatic jaundice
  • Migraine
  • Rash (allergic)
  • Mental depression
  • Reduced tolerance to carbohydrates
  • Vaginal candidiasis
  • Change in corneal curvature (steepening)
  • Intolerance to contact lenses

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

  • Acne
  • Budd-Chiari syndrome
  • Cataracts
  • Changes in appetite
  • Changes in libido
  • Colitis
  • Cystitis-like syndrome
  • Dizziness
  • Erythema multiforme
  • Erythema nodosum
  • Headache
  • Hemolytic uremic syndrome
  • Hemorrhagic eruption
  • Hirsutism
  • Impaired renal function
  • Loss of scalp hair
  • Nervousness
  • Porphyria
  • Pre-menstrual syndrome
  • Vaginitis

The following are the most common adverse events reported with use of drospirenone and ethinyl estradiol during the clinical trials, occurring in > 1% of subjects and which may or may not be drug related: Headache, Menstrual Disorder, Breast Pain, Abdominal Pain, Nausea, Leukorrhea, Flu Syndrome, Acne, Vaginal Moniliasis, Depression, Diarrhea, Asthenia, Dysmenorrhea, Back Pain, Infection, Pharyngitis, Intermenstrual Bleeding, Migraine, Vomiting, Dizziness, Nervousness, Vaginitis, Sinusitis, Cystitis, Bronchitis, Gastroenteritis, Allergic Reaction, Urinary Tract Infection, Pruritus, Emotional Lability, Surgery, Rash, Upper Respiratory Infection.

Overdosage

Serious ill effects have not been reported following acute ingestion of large doses of other oral contraceptives by young children. Overdosage may cause nausea, and withdrawal bleeding may occur in females. Drospirenone, however is a spironolactone analogue which has antimineralcorticoid properties. Serum concentration of potassium and sodium, and evidence of metabolic acidosis, should be monitored in cases of overdose.

NON-CONTRACEPTIVE HEALTH BENEFITS

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

Effects on menses:

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

Effects related to inhibition of ovulation:

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

Effects from long-term use:

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

Dosage and administration

To achieve maximum contraceptive effectiveness, ZARAH must be taken exactly as directed at intervals not exceeding 24 hours.

ZARAH consist of 21 tablets of a monophasic combined hormonal preparation plus 7 inert tablets. The dosage of ZARAH is one blue tablet daily for 21 consecutive days followed by 7 peach inert tablets per menstrual cycle. A patient should begin to take ZARAH either on the first day of her menstrual period (Day 1 Start) or on the first Sunday after the onset of her menstrual period (Sunday Start).

Day 1 Start. During the first cycle of ZARAH use, the patient should be instructed to take one blue ZARAH daily, beginning on day one (1) of her menstrual cycle. (The first day of menstruation is day one). She should take one blue ZARAH daily for 21 consecutive days, followed by one peach inert tablet daily on menstrual cycle days 22 through 28. It is recommended that ZARAH be taken at the same time each day, preferably after the evening meal or at bedtime. If ZARAH is first taken later than the first day of the menstrual cycle, ZARAH should not be considered effective as a contraceptive until after the first 7 consecutive days of product administration. The possibility of ovulation and conception prior to initiation of medication should be considered.

Sunday Start. During the first cycle of ZARAH use, the patient should be instructed to begin to take one blue ZARAH daily, beginning on the first Sunday after the onset of her menstrual period. She should take one blue ZARAH daily for 21 consecutive days, followed by one peach inert tablet daily on menstrual cycle days 22 through 28. It is recommended that ZARAH be taken at the same time each day, preferably after the evening meal or at bedtime. ZARAH should not be considered effective as a contraceptive until after the first 7 consecutive days of product administration. The possibility of ovulation and conception prior to initiation of medication should be considered.

The patient should begin her next and all subsequent 28-day regimens of ZARAH on the same day of the week that she began her first regimen, following the same schedule. She should begin taking her blue tablets on the next day after ingestion of the last peach tablet, regardless of whether or not a menstrual period has occurred or is still in progress. Anytime a subsequent cycle of ZARAH is started later than the day following administration of the last peach tablet, the patient should use another method of contraception until she has taken a blue ZARAH daily for seven consecutive days.

When switching from another oral contraceptive, ZARAH should be started on the same day that a new pack of the previous oral contraceptive would have been started.

Withdrawal bleeding usually occurs within 3 days following the last blue tablet. If spotting or breakthrough bleeding occurs while taking ZARAH, the patient should be instructed to continue taking her ZARAH as instructed and by the regimen described above. She should be instructed that this type of bleeding is usually transient and without significance; however, if the bleeding is persistent or prolonged, the patient should be advised to consult her physician.

Although the occurrence of pregnancy is unlikely if ZARAH is taken according to directions, if withdrawal bleeding does not occur, the possibility of pregnancy must be considered. If the patient has not adhered to the prescribed dosing schedule (missed one or more active tablets or started taking them on a day later than she should have), the possibility of pregnancy should be considered at the time of the first missed period and appropriate diagnostic measures taken. If the patient has adhered to the prescribed regimen and misses two consecutive periods, pregnancy should be ruled out. Hormonal contraceptives should be discontinued if pregnancy is confirmed.

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

In the nonlactating mother, ZARAH may be initiated 4 weeks postpartum, for contraception. When the tablets are administered in the postpartum period, the increased risk of thromboembolic disease associated with the postpartum period must be considered. (See "CONTRAINDICATIONS", "WARNINGS", and "PRECAUTIONS" concerning thromboembolic disease.)

How supplied

ZARAH™ tablets are available in packages of 3 tablet dispensers (NDC 52544-981-31).

Each tablet dispenser contains one blister of 21 active blue round, unscored tablets each containing 3 mg drospirenone and 0.03 mg ethinyl estradiol with 981 on one side and WATSON on the other side, and 7 inert peach round, unscored tablets with 983 on one side and WATSON on the other side.

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

References

  1. Dinger JC, Heinemann LAJ, et al: The safety of a drospirenone-containing oral contraceptive: final results from the European active surveillance study on oral contraceptives based on 142,475 women-years of observation. Contraception 2007;75:344-354.
  2. Seeger JD, Loughlin J, Eng PM, et al: Risk of thromboembolism in women taking ethinylestradiol/drospirenone and other oral contraceptives. Obstetrics & Gynecology 2007;110(3):587-593.
  3. van Hylckama Vlieg A, Helmerhorst FM, Vandenbroucke JP, et al: The venous thrombotic risk of oral contraceptives, effects of oestrogen dose and progestogen type: results of the MEGA case- control study. BMJ 2009;339:b2921.
  4. Lidegaard O, Lokkegaard E, Svendsen AL, et al: Hormonal contraception and risk of venous thromboembolism: national follow-up study. BMJ 2009; 339:b2890.

Brief summary patient package insert

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

ZARAH is different from other birth control pills because they contain the progestin drospirenone. Drospirenone may increase potassium. Therefore, you should not take ZARAH if you have kidney, liver or adrenal disease because this could cause serious heart and health problems. Other drugs may also increase potassium. If you are currently on daily, long-term treatment for a chronic condition with any of the medications below, you should consult your healthcare provider about whether ZARAH is right for you, and during the firs t month that you take drospirenone and ethinyl estradiol tablets, you should have a blood test to check your potassium level.

  • NSAIDs (ibuprofen [Motrin®*, Advil®*], naprosyn [Aleve®* and others] when taken long- term and daily for treatment of arthritis or other problems)
  • Potassium-sparing diuretics (spironolactone and others)
  • Potassium supplementation
  • ACE inhibitors (Capoten®*, Vasotec®*, Zestril®* and others)
  • Angiotensin-II receptor antagonists (Cozaar®*, Diovan®*, Avapro®*, and others)
  • Heparin
  • Oral contraceptives, also known as "birth control pills" or "the pill", are taken to prevent pregnancy, and when taken correctly, have a failure rate of less than 1% per year when used without missing any pills. The typical failure rate of large numbers of pill users is less than 5% per year when women who miss pills are included. However, forgetting to take pills considerably increases the chances of pregnancy.

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

    • smoke
    • have high blood pressure, diabetes, high cholesterol
    • have or have had clotting disorders, heart attack, stroke, angina pectoris, cancer of the breast or sex organs, jaundice, or malignant or benign liver tumors.

    You should not take the pill if you suspect you are pregnant or have unexplained vaginal bleeding.

    Cigarette smoking increases the risk of serious adverse effects on the heart and blood vessels 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 not smoke.

    Most side effects of the pill are not serious. The most common such effects are nausea, vomiting, bleeding between menstrual periods, weight gain, breast tenderness, and difficulty wearing contact lenses. These side effects, especially nausea and vomiting may subside within the first three months of use.

    The serious side effects of the pill occur very infrequently, especially if you are in good health and are young. However, you should know that the following medical conditions have been associated with or made worse by the pill:

    1. Blood clots in the legs (thrombophlebitis), lungs (pulmonary embolism), blockage or rupture of a blood vessel in the brain (stroke), blockage of blood vessels in the heart (heart attack and angina pectoris) or other organs of the body. As mentioned above, smoking increases the risk of heart attacks and strokes and subsequent serious medical consequences.
    2. Liver tumors, which may rupture and cause severe bleeding. A possible but not definite association has been found with the pill and liver cancer. However, liver cancers are extremely rare. The chance of developing liver cancer from using the pill is thus even rarer.
    3. High blood pressure, although blood pressure usually returns to normal when the pill is stopped.
    4. Cancer of the breast. Various studies give conflicting reports on the relationship between breast cancer and oral contraceptive use. Oral contraceptive use may slightly increase your chance of having breast cancer diagnosed, particularly after using hormonal contraceptives at a younger age. After you stop using hormonal contraceptives, the chances of getting breast cancer begin to go back down. You should have regular breast examinations by a healthcare provider and examine your own breasts monthly. Tell your healthcare provider if you have a family history of breast cancer or if you have had breast nodules or an abnormal mammogram. Women who currently have or have had breast cancer should not use oral contraceptives because breast cancer is a hormone-sensitive tumor.

    The symptoms associated with these serious side effects are discussed in the detailed leaflet given to you with your supply of pills. Notify your doctor or healthcare provider if you notice any unusual physical disturbances while taking the pill. In addition, drugs such as rifampin, as well as some anticonvulsants, some antibiotics and some herbal products such as St. John’s Wort, may decrease oral contraceptive effectiveness.

    Taking the pill provides some important non-contraceptive benefits. These include less painful menstruation, less menstrual blood loss and anemia, fewer pelvic infections, and fewer cancers of the ovary and the lining of the uterus.

    Be sure to discuss any medical condition you may have with your healthcare provider. Your healthcare provider will take a medical and family history before prescribing oral contraceptives and will examine you. The physical examination may be delayed to another time if you request it and the healthcare provider believes that it is appropriate to postpone it. You should be reexamined at least once a year while taking oral contraceptives. The detailed patient information gives you further information which you should read and discuss with your healthcare provider.

    This product (like all oral contraceptives) is intended to prevent pregnancy. It does not protect against HIV infection (AIDS) and other sexually transmitted diseases such as chlamydia, genital herpes, genital warts, gonorrhea, hepatitis B, and syphilis.