drospirenone and ethinyl estradiol
Dosage Form: tablets
Ocella™ 28 TABLETS
(drospirenone and ethinyl estradiol)
PHYSICIAN LABELING
Rx only
PATIENTS SHOULD BE COUNSELED THAT THIS PRODUCT DOES NOT PROTECT AGAINST HIV INFECTION (AIDS) AND OTHER SEXUALLY TRANSMITTED DISEASES.
Description
Ocella provides an oral contraceptive regimen consisting of 21 active film coated tablets each containing 3 mg of drospirenone and 0.03 mg of ethinyl estradiol and 7 inert film coated tablets. The inactive ingredients are lactose monohydrate NF, corn starch NF, modified starch NF, povidone 25000 USP, magnesium stearate NF, hydroxylpropylmethyl cellulose USP, macrogol 6000 NF, talc USP, titanium dioxide USP, ferric oxide pigment, yellow NF. The inert film coated tablets contain lactose monohydrate NF, corn starch NF, povidone 25000 USP, magnesium stearate NF, hydroxylpropylmethyl cellulose USP, talc USP, titanium dioxide USP.
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:
Ocella - 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 Ocella which is a combination tablet of drospirenone and ethinyl estradiol has not been evaluated. Serum concentrations of DRSP and EE reached peak levels within 1–3 hours after administration of Ocella. After single dose administration of Ocella, 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 1–10 mg. Following daily dosing of Ocella, steady state DRSP concentrations were observed after 10 days. There was about 2 to 3 fold accumulation in serum Cmax and AUC (0–24h) values of DRSP following multiple dose administration of Ocella (see TABLE I).
For EE, steady-state conditions are reported during the second half of a treatment cycle. Following daily administration of Ocella serum Cmax and AUC(0–24h) values of EE accumulate by a factor of about 1.5 to 2.
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Drospirenone Mean (%CV) Values | |||||
Cycle / Day | No. of Subjects | Cmax (ng/mL) | Tmax (h) | AUC(0–24h) (ng•h/mL) | t1/2 (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(0–24h) (pg•h/mL) | t1/2 (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 (43) | 1.5 (42) | 485.3 (92) | NA* |
| 13/21 | 10 | 90.5 (45) | 1.6 (38) | 469.5 (83) | NA* |
Effect of Food
The rate of absorption of DRSP and EE following single administration of two Ocella 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 4–5 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 38–47% of the metabolites in urine were glucuronide and sulfate conjugates. In feces, about 17–20% 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 Ocella has not been evaluated.
Hepatic Dysfunction
Ocella is contraindicated in patients with hepatic dysfunction (also see BOLDED WARNINGS). 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
Ocella is contraindicated in patients with renal insufficiency (also see WARNINGS).
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 30–65) 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, the serum DRSP levels in the group with mild renal impairment (creatinine clearance CLcr, 50–80 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, 30–50 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 for Ocella
Ocella is indicated for the prevention of pregnancy in women who elect to use an oral contraceptive.
Oral contraceptives are highly effective. TABLE II lists the typical accidental pregnancy rates for users of combination oral contraceptives and other methods of contraception. The efficacy of these contraceptive methods, except sterilization, depends upon the reliability with which they are used. Correct and consistent use of methods can result in lower failure rates.
| 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. | |||
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% of Women Experiencing an Accidental Pregnancy Within the First Year of Use | % of Women Continuing Use At One Year* | ||
Method (1) | Typical Use† (2) | Perfect Use‡ (3) | (4) |
| Chance§ | 85 | 85 | |
| Spermicides¶ | 26 | 6 | 40 |
| Periodic abstinence | 25 | 63 | |
| Calendar | 9 | ||
| Ovulation method | 3 | ||
| Sympto-thermal# | 2 | ||
| Post-ovulation | 1 | ||
| Withdrawal | 19 | 4 | |
| CapÞ | |||
| Parous women | 40 | 26 | 42 |
| Nulliparous women | 20 | 9 | 56 |
| Sponge | |||
| Parous women | 40 | 20 | 42 |
| Nulliparous women | 20 | 9 | 56 |
| DiaphragmÞ | 20 | 6 | 56 |
| Condomß | |||
| Female (Reality) | 21 | 5 | 56 |
| Male | 14 | 3 | 61 |
| Pill | 5 | 71 | |
| progestin only | 0.5 | ||
| combined | 0.1 | ||
| IUD | |||
| Progesterone T: | 2 | 1.5 | 81 |
| Copper T 380A | 0.8 | 0.6 | 78 |
| Lng 20 | 0.1 | 0.1 | 81 |
| Depo Provera | 0.3 | 0.3 | 70 |
| Norplant and Norplant-2 | 0.05 | 0.05 | 88 |
| Female Sterilization | 0.5 | 0.5 | 100 |
| Male Sterilization | 0.15 | 0.1 | 100 |
| Emergency Contraceptive Pills: Treatment initiated within 72 hours after unprotected intercourse reduces the risk of pregnancy by at least 75%à | |||
| Lactational Amenorrhea Method: LAM is highly effective, temporary method of contraceptionè | |||
In clinical efficacy studies of Ocella 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% Caucasian, 1% Hispanic, 1% Black, <1% 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
Ocella 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 side effects from oral contraceptive use. This risk increases with age and with heavy smoking (15 or more cigarettes per day) and is quite marked in women over 35 years of age. Women who use oral contraceptives should be strongly advised not to smoke.
Ocella contains 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. Ocella 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 first 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
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 III) among women who use oral contraceptives.
| (Adapted from P.M. Layde and V. Beral) | ||||
| AGE | EVER-USERS NON-SMOKERS | EVER-USERS SMOKERS | CONTROL NON-SMOKERS | CONTROL SMOKERS |
| 15–24 | 0 | 10.5 | 0 | 0 |
| 25–34 | 4.4 | 14.2 | 2.7 | 4.2 |
| 35–44 | 21.5 | 63.4 | 6.4 | 15.2 |
| 45+ | 52.4 | 206.7 | 11.4 | 27.9 |
Oral contraceptives may compound the effects of well-known risk factors, such as hypertension, diabetes, hyperlipidemias, age and obesity. 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.
b. 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 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 Ocella 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 Ocella approval.1,2 The first (EURAS) showed the risk of thromboembolism (particularly venous thromboembolism) and death in Ocella 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 Ocella 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 Ocella.
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 Ocella 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 Ocella cases was very small (1.2% of all cases) making the risk estimates unreliable. The relative risk for Ocella 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 Ocella 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.
2. ESTIMATES OF MORTALITY FROM CONTRACEPTIVE USE
One study gathered data from a variety of sources which have estimated the mortality rate associated with different methods of contraception at different ages (Table 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 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.
| Adapted from H.W. Ory, Family Planning Perspectives, 15:57-63, 1983. | ||||||
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| Method of Control and Outcome | 15–19 | 20–24 | 25–29 | 30–34 | 35–39 | 40–44 |
| No fertility control methods* | 7 | 7.4 | 9.1 | 14.8 | 25.7 | 28.2 |
| Oral contraceptives nonsmoker† | 0.3 | 0.5 | 0.9 | 1.9 | 13.8 | 31.6 |
| Oral contraceptives smoker† | 2.2 | 3.4 | 6.6 | 13.5 | 51.1 | 117.2 |
| lUD† | 0.8 | |||||
