Kalliga (desogestrel 0.15 mg ethinyl estradiol 0.03 mg) Dailymed

Generic: desogestrel and ethinyl estradiol is used for the treatment of Abortion, Spontaneous Acne Vulgaris Aged Breast Neoplasms Cerebrovascular Disorders Coronary Disease Diabetes Mellitus Endometriosis Heart Valve Diseases Hypertension Jaundice Liver Diseases Liver Neoplasms Menstruation Disturbances Pregnancy Thromboembolism Thrombophlebitis Tobacco Use Disorder Uterine Hemorrhage Endometrial Neoplasms Adenoma, Liver Cell Headache Disorders Cerebral Arterial Diseases Coronary Artery Disease Hypogonadism Menopause, Premature Menorrhagia Neoplasms, Hormone-Dependent Prostatic Neoplasms Osteoporosis, Postmenopausal Primary Ovarian Insufficiency Hot Flashes Tobacco Use

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Warning: Cardiovascular Risk Associated With Smoking

Cigarette smoking increases the risk of serious cardiovascular events from combination oral contraceptive use. This risk increases with age, particularly in women over 35 years of age, and with the number of cigarettes smoked. For this reason, combination oral contraceptives, including Kalliga^TM, should not be used by women who are over 35 years of age and smoke.

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

Description

Kalliga^TM tablets provide an oral contraceptive regimen of 21 white to off-white round tablets each containing 0.15 mg desogestrel (13-ethyl-11-methylene-18,19-dinor-17 alpha-pregn-4-en-20-yn-17-ol) and 0.03 mg ethinyl estradiol USP (19-nor-17 alpha-pregna-1,3,5 (10)-trien-20-yne-3,17,diol). Inactive ingredients include colloidal silicon dioxide, lactose monohydrate, potato starch, povidone, stearic acid, and vitamin E. Each green tablet contains the following inactive ingredients: anhydrous lactose, croscarmellose sodium, FD&C Blue No.2 Aluminum Lake, ferric oxide yellow, magnesium stearate, microcrystalline cellulose, and povidone.

Kalliga meets USP Dissolution Test 2.

Clinical Pharmacology

Pharmacodynamics

Combined 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 changes in the endometrium which reduce the likelihood of implantation. Receptor binding studies, as well as studies in animals, have shown that 3-keto-desogestrel, 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

Desogestrel is rapidly and almost completely absorbed and converted into 3-keto-desogestrel, its biologically active metabolite. Following oral administration, the relative bioavailability of desogestrel, as measured by serum levels of 3-keto-desogestrel, is approximately 84%. In the third cycle of use after a single dose of Kalliga^TM, maximum concentrations of 3-keto-desogestrel of 2,805 ± 1,203 pg/mL (mean ± SD) are reached at 1.4 ± 0.8 hours. The area under the curve (AUC_0-∞) is 33,858 ± 11,043 pg/mL⋅hr after a single dose. At steady state, attained from at least day 19 onwards, maximum concentrations of 5,840 ± 1,667 pg/mL are reached at 1.4 ± 0.9 hours. The minimum plasma levels of 3-keto-desogestrel at steady state are 1,400 ± 560 pg/mL. The AUC_0-24at steady state is 52,299 ± 17,878 pg/mL⋅hr. The mean AUC_0-∞ for 3-keto-desogestrel at single dose is significantly lower than the mean AUC_0-24 at steady state. This indicates that the kinetics of 3-keto-desogestrel are non-linear due to an increase in binding of 3-keto-desogestrel to sex hormone-binding globulin in the cycle, attributed to increased sex hormone-binding globulin levels which are induced by the daily administration of ethinyl estradiol. Sex hormone-binding globulin levels increased significantly in the third treatment cycle from day 1 (150 ± 64 nmol/L) to day 21 (230 ± 59 nmol/L). The elimination half-life for 3-keto-desogestrel is approximately 38 ± 20 hours at steady state. In addition to 3-keto-desogestrel, other phase I metabolites are 3α-OH-desogestrel, 3β-OH-desogestrel, and 3α-OH-5α-H-desogestrel. These other metabolites are not known to have any pharmacologic effects, and are further converted in part by conjugation (phase II metabolism) into polar metabolites, mainly sulfates and glucuronides. Ethinyl estradiol is rapidly and almost completely absorbed. In the third cycle of use after a single dose of Kalliga^TM, the relative bioavailability is approximately 83%. In the third cycle of use after a single dose of Kalliga^TM, maximum concentrations of ethinyl estradiol of 95 ± 34 pg/mL are reached at 1.5 ± 0.8 hours. The AUC_0-∞ is 1,471 ± 268 pg/mL⋅hr after a single dose. At steady state, attained from at least day 19 onwards, maximum ethinyl estradiol concentrations of 141 ± 48 pg/mL are reached at about 1.4 ± 0.7 hours. The minimum serum levels of ethinyl estradiol at steady state are 24 ± 8.3 pg/mL. The AUC_0-24at steady state is 1,117 ± 302 pg/mL⋅hr. The mean AUC_0-∞ for ethinyl estradiol following a single dose during treatment cycle 3 does not significantly differ from the mean AUC_0-24 at steady state. This finding indicates linear kinetics for ethinyl estradiol. The elimination half-life is 26 ± 6.8 hours at steady state. Ethinyl estradiol is subject to a significant degree of presystemic conjugation (phase II metabolism). Ethinyl estradiol escaping gut wall conjugation undergoes phase I metabolism and hepatic conjugation (phase II metabolism). Major phase I metabolites are 2-OH-ethinyl estradiol and 2-methoxy-ethinyl estradiol. Sulfate and glucuronide conjugates of both ethinyl estradiol and phase I metabolites, which are excreted in bile, can undergo enterohepatic circulation.

Indications And Usage

Kalliga^TM tablets are indicated for the prevention of pregnancy in women who elect to use oral contraceptives as a method of contraception.

Oral contraceptives are highly effective. Table 1 uls the typical accidental pregnancy rates for users of combined oral contraceptives and other methods of contraception. The efficacy of these contraceptive methods, except sterilization, the IUD, and the Norplant System depends upon the reliability with which they are used. Correct and consistent use of these methods can result in lower failure rates.

In a clinical trial with Kalliga^TM, 1,195 subjects completed 11,656 cycles and a total of 10 pregnancies were reported. This represents an overall user-efficacy (typical user-efficacy) pregnancy rate of 1.12 per 100 women-years. This rate includes patients who did not take the drug correctly.

Table 1: PERCENTAGE OF WOMEN EXPERIENCING AN UNINTENDED PREGNANCY DURING THE FIRST YEAR OF TYPICAL USE AND THE FIRST YEAR OF PERFECT USE OF CONTRACEPTION AND THE PERCENTAGE CONTINUING USE AT THE END OF THE FIRST YEAR. UNITED STATES.

% of Women Experiencing an Unintended Pregnancy within the First Year of Use % of Women Continuing Use at One Year^*

Method (1) Typical Use ^† (2) Perfect Use^‡ (3) (4)

Chance^# 85 85

Spermicides^Þ 26 6 40

Periodic abstinence 25 63

Calendar 9

Ovulation Method 3

Sympto-Thermal^ß 2

Post-Ovulation 1

Withdrawal 19 4

Cap^à

Parous Women 40 26 42

Nulliparous Women 20 9 56

Sponge

Parous Women 40 20 42

Nulliparous Women 20 9 56

Diaphragm^à 20 6 56

Condom^è

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 T380A 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%.^§

Lactation Amenorrhea Method: LAM is a highly effective, temporary method of contraception.^¶

Source: Trussell J. Contraceptive efficacy. In Hatcher RA, Trussell J, Stewart F, Cates W, Stewart GK, Kowel D, Guest F, Contraceptive Technology: Seventeenth Revised Edition. New York, NY; Irvington Publishers, 1998.

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

^†     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.

^‡     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 other reason.

^§The treatment schedule is one dose within 72 hours after unprotected intercourse, and a second dose 12 hours after the first dose. The FDA 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 4 yellow pills).

^¶     However, to maintain effective protection against pregnancy, another method of contraception must be used as soon as menstruation resumes, the frequency of duration of breastfeeds is reduced, bottle feeds are introduced, or the baby reaches 6 months of age.

^#     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 percent who would become pregnant within one year among women now relying on reversible methods of contraception if they abandoned contraception altogether.

^Þ    Foams, creams, gels, vaginal suppositories, and vaginal film.

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

^à    With spermicidal cream or jelly.

^è    Without spermicides.

Kalliga^TM has not been studied for and is not indicated for use in emergency contraception.

Table 1: PERCENTAGE OF WOMEN EXPERIENCING AN UNINTENDED PREGNANCY DURING THE FIRST YEAR OF TYPICAL USE AND THE FIRST YEAR OF PERFECT USE OF CONTRACEPTION AND THE PERCENTAGE CONTINUING USE AT THE END OF THE FIRST YEAR. UNITED STATES.
	% of Women Experiencing an Unintended Pregnancy within the First Year of Use	% of Women Continuing Use at One Year^*
Method (1)	Typical Use ^† (2)	Perfect Use^‡ (3)	(4)
Chance^#	85	85
Spermicides^Þ	26	6	40
Periodic abstinence	25		63
Calendar		9
Ovulation Method		3
Sympto-Thermal^ß		2
Post-Ovulation		1
Withdrawal	19	4
Cap^à
Parous Women	40	26	42
Nulliparous Women	20	9	56
Sponge
Parous Women	40	20	42
Nulliparous Women	20	9	56
Diaphragm^à	20	6	56
Condom^è
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 T380A	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

Contraindications

Kalliga^TM is contraindicated in females who are known to have or develop the following conditions:

Thrombophlebitis or thromboembolic disorders

A past history of deep vein thrombophlebitis or thromboembolic disorders

Known thrombophilic conditions

Cerebral vascular or coronary artery disease (current or history)

Valvular heart disease with complications

Persistent blood pressure values of ≥ 160 mm Hg systolic or ≥ 100 mg Hg diastolic¹⁰²

Diabetes with vascular involvement

Headaches with focal neurological symptoms

Major surgery with prolonged immobilization

Current diagnosis of, or history of, breast cancer, which may be hormone-sensitive

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

Acute or chronic hepatocellular disease with abnormal liver function

Hepatic adenomas or carcinomas

Known or suspected pregnancy

Hypersensitivity to any component of this product

Are receiving Hepatitis C drug combinations containing ombitasivir/paritaprevir/ritonavir, with or without dasabuvir, due to the potential for ALT elevations (see section 5 in WARNINGS, Risk of Liver Enzyme Elevations with Concomitant Hepatitis C Treatment ).

Warnings

Cigarette smoking increases the risk of serious cardiovascular events from combination oral contraceptive use. This risk increases with age, particularly in women over 35 years of age, and with the number of cigarettes smoked. For this reason, combination oral contraceptives, including Kalliga^TM, should not be used by women who are over 35 years of age and smoke. The use of oral contraceptives is associated with increased risks of several serious conditions including myocardial infarction, thromboembolism, stroke, hepatic neoplasia, and gallbladder disease, 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 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, epidemiological 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 (Adapted from refs. 2 and 3 with the author’s permission). For further information, the reader is referred to a text on epidemiological methods.

1. Thromboembolic Disorder and Other Vascular Problems

a. 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 to 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 gradually disappears after combined oral contraceptive (COC) use is stopped.²VTE risk is highest in the first year of use and when restarting hormonal contraception after a break of four weeks or longer.

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. In general, these studies indicate an approximate 2-fold increased risk, which corresponds to an additional 1 to 2 cases of venous thromboembolism per 10,000 women-years of use. However, data from additional studies have not shown this 2-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 The relative risk of venous thrombosis in women who have predisposing conditions is twice that of women without such medical conditions.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 also 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 breastfeed.

b. 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.^{4 to 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 infarctions 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, especially in those 35 years of age and older and in nonsmokers over the age of 40 among women who use oral contraceptives. (See Figure 1.)

Figure 1:    Circulatory Disease Mortality Rates per 100,000 Women-Years by Age, Smoking Status and Oral Contraceptive Use

(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 to 18} Oral contraceptives have been shown to increase blood pressure among users (see section 10 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.

There is some evidence that the risk of myocardial infarction associated with oral contraceptives is lower when the progestogen has minimal androgenic activity than when the activity is greater. Receptor binding and animal studies have shown that desogestrel or its active metabolite has minimal androgenic activity (see CLINICAL PHARMACOLOGY ), although these findings have not been confirmed in adequate and well-controlled clinical trials.

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, and smoking interacted to increase the risk of stroke.^{27 to 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

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.^{31 to 33} A decline in serum high density lipoproteins (HDL) has been reported with many progestational agents.^{14 to 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 estrogen content which is judged appropriate for the individual patient.

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 40 to 49 years old who had used oral contraceptives for five or more years, but this increased risk was not demonstrated in other age groups.⁸ In another study in Great Britain, the risk of developing cerebrovascular disease persisted for at least 6 years after discontinuation of oral contraceptives, although excess risk was very small.³⁴ However, both studies were performed with oral contraceptive formulations containing 0.05 mg or higher of estrogens.

2. Estimates of Mortality from Contraceptive Use

One study gathered data from a variety of sources which have estimated the mortality rate associated with different methods of contraception at different ages (Table 2). 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 an increase in risk of mortality with age for oral contraceptive users is based on data gathered in the 1970's.³⁵ Current clinical recommendation involves the use of lower estrogen dose formulations and a careful consideration of risk factors. In 1989, the Fertility and Maternal Health Drugs Advisory Committee was asked to review the use of oral contraceptives in women 40 years of age and over. The Committee concluded that although cardiovascular disease risk 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. 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 an oral contraceptive which contains the least amount of estrogen and progestogen that is compatible with a low failure rate and individual patient needs.

Table 2: 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
Adapted from H.W. Ory, ref. #35. ^* Deaths are birth-related ^†Deaths are method-related

Method of control and outcome 15 to 19 20 to 24 25 to 29 30 to 34 35 to 39 40 to 44

No fertility-control methods* 7 7.4 9.1 14.8 25.7 28.2

Oral contraceptives non-smoker^† 0.3 0.5 0.9 1.9 13.8 31.6

Oral contraceptives smoker^† 2.2 3.4 6.6 13.5 51.1 117.2

IUD^† 0.8 0.8 1 1 1.4 1.4

Condom* 1.1 1.6 0.7 0.2 0.3 0.4

Diaphragm/spermicide* 1.9 1.2 1.2 1.3 2.2 2.8

Periodic abstinence* 2.5 1.6 1.6 1.7 2.9 3.6

3. Malignant Neoplasms

Breast Cancer

Kalliga^TMis contraindicated in females who currently have or have had breast cancer because breast cancer may be hormonally sensitive [see Contraindications].

Epidemiology studies have not found a consistent association between use of combined oral contraceptives (COCs) and breast cancer risk. Studies do not show an association between ever (current or past) use of COCs and risk of breast cancer. However, some studies report a small increase in the risk of breast cancer among current or recent users (<6 months since last use) and current users with longer duration of COC use [see Postmarketing Experience].

Cervical Cancer

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 to 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.

4. Hepatic Neoplasia

Benign hepatic adenomas are associated with oral contraceptive use, although the incidence of benign tumors is rare in the United States. Indirect calculations have estimated the attributable risk to be in the range of 3.3 cases/100,000 for users, a risk that increases after four or more years of use especially with oral contraceptives of higher dose.⁴⁹ Rupture of benign, hepatic adenomas may cause death through intra-abdominal hemorrhage.^50,51

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.

5. Risk of Liver Enzyme Elevations with Concomitant Hepatitis C Treatment

During clinical trials with the Hepatitis C combination drug regimen that contains ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, ALT elevations greater than 5 times the upper limit of normal (ULN), including some cases greater than 20 times the ULN, were significantly more frequent in women using ethinyl estradiol-containing medications such as COCs. Discontinue Kalliga^TM prior to starting therapy with the combination drug regimen ombitasvir/paritaprevir/ritonavir, with or without dasabuvir (see CONTRAINDICATIONS ). Kalliga^TM can be restarted approximately 2 weeks following completion of treatment with the combination drug regimen.

6. 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.

7. Oral Contraceptive Use Before or During Early Pregnancy

Extensive epidemiological studies have revealed no increased risk of birth defects in women who have used oral contraceptives prior to pregnancy.^{56 to 57} The majority of recent studies also do not indicate 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 time of the first missed period. Oral contraceptive use should be discontinued if pregnancy is confirmed.

8. 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 to 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.

9. Carbohydrate and Lipid Metabolic Effects

Oral contraceptives have been shown to cause a decrease in glucose tolerance in a significant percentage of users.¹⁷ This effect has been shown to be directly related to estrogen dose.⁶⁵ In general, progestogens increase insulin secretion and create insulin resistance, this effect varying with different progestational agents.^17,66 In the nondiabetic 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.

10. Elevated Blood Pressure

Women with significant hypertension should not be started on hormonal contraception.⁹⁸ An increase in blood pressure has been reported in women taking oral contraceptives⁶⁸ and this increase is more likely in older oral contraceptive users⁶⁹ and with extended duration of use.⁶¹ Data from the Royal College of General Practitioners¹² and subsequent randomized trials have shown that the incidence of hypertension increases with increasing progestational activity and concentrations of progestogens. Women with a history of hypertension or hypertension-related diseases, or renal disease⁷⁰ should be encouraged to use another method of contraception. If these women elect to use oral contraceptives, they should be monitored closely and if a clinically significant persistent elevation of blood pressure (BP) occurs (≥ 160 mm Hg systolic or ≥ 100 mm Hg diastolic) and cannot be adequately controlled, oral contraceptives should be discontinued. In general, women who develop hypertension during hormonal contraceptive therapy should be switched to a non-hormonal contraceptive. If other contraceptive methods are not suitable, hormonal contraceptive therapy may continue combined with antihypertensive therapy. Regular monitoring of BP throughout hormonal contraceptive therapy is recommended.¹⁰² 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 among former and never users.^68,70,71

11. 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.

12. 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.

13. Ectopic Pregnancy

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

Precautions

1. General

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

2. Physical Examination and Follow-Up

It is good medical practice for all women to have annual history and physical examinations, including women using oral contraceptives. The physical examination, however, may be deferred until after initiation of oral contraceptives if requested by the woman and judged appropriate by the clinician. The physical examination should include special reference to blood pressure, breasts, abdomen and pelvic organs, including cervical cytology, and relevant laboratory tests. In case of undiagnosed, persistent or recurrent abnormal vaginal bleeding, appropriate measures should be conducted to rule out malignancy. Women with a strong family history of breast cancer or who have breast nodules should be monitored with particular care.

3. Lipid Disorders

Women who are being treated for hyperlipidemias should be followed closely if they elect to use oral contraceptives. Some progestogens may elevate LDL levels and may render the control of hyperlipidemias more difficult.

4. Liver Function

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.

5. Fluid Retention

Oral contraceptives may cause some degree of fluid retention. They should be prescribed with caution, and only with careful monitoring, in patients with conditions which might be aggravated by fluid retention.

6. Emotional Disorders

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

7. Contact Lenses

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

8. Drug Interactions

Consult the labeling of concurrently-used drugs to obtain further information about interactions with hormonal contraceptives or the potential for enzyme alterations. Effects of Other Drugs on Combined Hormonal Contraceptives Substances decreasing the plasma concentrations of COCs and potentially diminishing the efficacy of COCs: Drugs or herbal products that induce certain enzymes, including cytochrome P450 3A4 (CYP3A4), may decrease the plasma concentrations of COCs and potentially diminish the effectiveness of CHCs or increase breakthrough bleeding. Some drugs or herbal products that may decrease the effectiveness of hormonal contraceptives include phenytoin, barbiturates, carbamazepine, bosentan, felbamate, griseofulvin, oxcarbazepine, rifampicin, topiramate, rifabutin, rufinamide, aprepitant, and products containing St. John’s wort. Interactions between hormonal contraceptives and other drugs may lead to breakthrough bleeding and/or contraceptive failure. Counsel women to use an alternative method of contraception or a back-up method when enzyme inducers are used with CHCs, and to continue back-up contraception for 28 days after discontinuing the enzyme inducer to ensure contraceptive reliability. Substances increasing the plasma concentrations of COCs: Co-administration of atorvastatin or rosuvastatin and certain COCs containing EE increase AUC values for EE by approximately 20 to 25%. Ascorbic acid and acetaminophen may increase plasma EE concentrations, possibly by inhibition of conjugation. CYP3A4 inhibitors such as itraconazole, voriconazole, fluconazole, grapefruit juice, or ketoconazole may increase plasma hormone concentrations. Human immunodeficiency virus (HIV)/ Hepatitis C virus (HCV) protease inhibitors and non-nucleoside reverse transcriptase inhibitors: Significant changes (increase or decrease) in the plasma concentrations of estrogen and/or progestin have been noted in some cases of co-administration with HIV protease inhibitors (decrease [e.g., nelfinavir, ritonavir, darunavir/ritonavir, (fos)amprenavir/ritonavir, lopinavir/ritonavir, and tipranavir/ritonavir] or increase [e.g., indinavir and atazanavir/ritonavir]) /HCV protease inhibitors (decrease [e.g., boceprevir and telaprevir]) or with non-nucleoside reverse transcriptase inhibitors (decrease [e.g., nevirapine] or increase [e.g., etravirine]). Concomitant Use with HCV Combination Therapy – Liver Enzyme Elevation: Do not co-administer Kalliga^TM with HCV drug combinations containing ombitasvir/ paritaprevir/ritonavir, with or without dasabuvir, due to potential for ALT elevations (see section 5 in WARNINGS, Risk of Liver Enzyme Elevations with Concomitant Hepatitis C Treatment ). Colesevelam: Colesevelam, a bile acid sequestrant, given together with a combination oral hormonal contraceptive, has been shown to significantly decrease the AUC of EE. A drug interaction between the contraceptive and colesevelam was decreased when the two drug products were given 4 hours apart. Effects of Combined Hormonal Contraceptives on Other Drugs COCs containing EE may inhibit the metabolism of other compounds (e.g., cyclosporine, prednisolone, theophylline, tizanidine, and voriconazole) and increase their plasma concentrations. COCs have been shown to decrease plasma concentrations of acetaminophen, clofibric acid, morphine, salicylic acid, temazepam and lamotrigine. Significant decrease in plasma concentration of lamotrigine has been shown, likely due to induction of lamotrigine glucuronidation. This may reduce seizure control; therefore, dosage adjustments of lamotrigine may be necessary. Women on thyroid hormone replacement therapy may need increased doses of thyroid hormone because serum concentrations of thyroid-binding globulin increases with use of COCs.

9. Interactions with Laboratory Tests

Certain endocrine and liver function tests and blood components may be affected by oral contraceptives: a. Increased prothrombin and factors VII, VIII, IX, and X; decreased antithrombin 3; increased norepinephrine-induced platelet aggregability. b. 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. c. Other binding proteins may be elevated in serum. d. 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. e. Triglycerides may be increased and levels of various other lipids and lipoproteins may be affected. f.    Glucose tolerance may be decreased. g. 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.

10. Carcinogenesis

See WARNINGS .

11. Pregnancy

Pregnancy Category X. See CONTRAINDICATIONS and WARNINGS .

12. 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.

13. Pediatric Use

Safety and efficacy of Kalliga^TM 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.

14. 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 ).

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

Melasma which may persist

Breast changes: tenderness, enlargement, secretion

Change in weight (increase or decrease)

Change in cervical erosion and secretion

Diminution in lactation when given immediately postpartum

Cholestatic jaundice

Migraine

Allergic reaction, including rash, urticaria, and angioedema

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:

Pre-menstrual syndrome

Cataracts

Changes in appetite

Cystitis-like syndrome

Headache

Nervousness

Dizziness

Hirsutism

Loss of scalp hair

Erythema multiforme

Erythema nodosum

Hemorrhagic eruption

Vaginitis

Porphyria

Impaired renal function

Hemolytic uremic syndrome

Acne

Changes in libido

Colitis

Budd-Chiari Syndrome

Post Marketing Experience

Five studies that compared breast cancer risk between ever-users (current or past use) of COCs and never-users of COCs reported no association between ever use of COCs and breast cancer risk, with effect estimates ranging from 0.90 to 1.12 (Figure 2).

Three studies compared breast cancer risk between current or recent COC users (<6 months since last use) and never users of COCs (Figure 2). One of these studies reported no association between breast cancer risk and COC use. The other two studies found an increased relative risk of 1.19 to 1.33 with current or recent use. Both of these studies found an increased risk of breast cancer with current use of longer duration, with relative risks ranging from 1.03 with less than one year of COC use to approximately 1.4 with more than 8 to 10 years of COC use.

Figure 2: Risk of Breast Cancer with Combined Oral Contraceptive Use

RR = relative risk; OR = odds ratio; HR = hazard ratio. “ever COC” are females with current or past COC use; “never COC use” are females that never used COCs.

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 epidemiological studies which largely utilized oral contraceptive formulations containing estrogen doses exceeding 0.035 mg of ethinyl estradiol or 0.05 mg of mestranol.⁷³ ^{to 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, Kalliga^TM must be taken exactly as directed and at intervals not exceeding 24 hours. Kalliga^TM is available in the buler pack which is preset for a Sunday Start. Day 1 Start is also provided.

Day 1 Start

The dosage of Kalliga^TM for the initial cycle of therapy is one white to off-white “active” tablet administered daily from the 1st day through the 21st day of the menstrual cycle, counting the first day of menstrual flow as "Day 1". Tablets are taken without interruption as follows: One white to off-white “active” tablet daily for 21 days, then one green “reminder” tablet daily for 7 days. After 28 tablets have been taken, a new course is started and a white to off-white “active” tablet is taken the next day. The use of Kalliga^TM for contraception may be initiated 4 weeks postpartum in women who elect not to breastfeed. 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: Nursing Mothers .) If the patient starts on Kalliga^TM postpartum, and has not yet had a period, she should be instructed to use another method of contraception until a white to off-white “active” tablet has been taken daily for 7 days. The possibility of ovulation and conception prior to initiation of medication should be considered. If the patient misses one (1) white to off-white “active” tablet in Weeks 1, 2, or 3, the white to off-white “active” tablet should be taken as soon as she remembers. If the patient misses two (2) white to off-white “active” tablets in Week 1 or Week 2, the patient should take two (2) white to off-white “active” tablets the day she remembers and two (2) white to off-white “active” tablets the next day; and then continue taking one (1) white to off-white “active” tablet a day until she finishes the pack. The patient should be instructed to use a back-up method of birth control such as a condom or spermicide if she has sex in the seven (7) days after missing pills. If the patient misses two (2) white to off-white “active” tablets in the third week or misses three (3) or more white to off-white “active” tablets in a row, the patient should throw out the rest of the pack and start a new pack that same day. The patient should be instructed to use a back-up method of birth control if she has sex in the seven (7) days after missing pills.

Sunday Start

When taking Kalliga^TM, the first white to off-white “active” tablet should be taken on the first Sunday after menstruation begins. If the period begins on Sunday, the first white to off-white “active” tablet is taken on that day. If switching directly from another oral contraceptive, the first white to off-white “active” tablet should be taken on the first Sunday after the last ACTIVE tablet of the previous product. Tablets are taken without interruption as follows: One white to off-white “active” tablet daily for 21 days, then one green “reminder” tablet daily for 7 days. After 28 tablets have been taken, a new course is started and a white to off-white “active” tablet is taken the next day (Sunday). When initiating a Sunday start regimen, another method of contraception should be used until after the first 7 consecutive days of administration. The use of Kalliga^TM for contraception may be initiated 4 weeks postpartum. 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: Nursing Mothers .) If the patient starts on Kalliga^TM postpartum, and has not yet had a period, she should be instructed to use another method of contraception until a white to off-white “active” tablet has been taken daily for 7 days. The possibility of ovulation and conception prior to initiation of medication should be considered. If the patient misses one (1) white to off-white active tablet in Weeks 1, 2, or 3, the white to off-white “active” tablet should be taken as soon as she remembers. If the patient misses two (2) white to off-white “active” tablets in Week 1 or Week 2, the patient should take two (2) white to off-white “active” tablets the day she remembers and two (2) white to off-white “active” tablets the next day; and then continue taking one (1) white to off-white “active” tablet a day until she finishes the pack. The patient should be instructed to use a back-up method of birth control such as a condom or spermicide if she has sex in the seven (7) days after missing pills. If the patient misses two (2) white to off-white “active” tablets in the third week or misses three (3) or more white to off-white “active” tablets in a row, the patient should continue taking one white to off-white “active” tablet every day until Sunday. On Sunday the patient should throw out the rest of the pack and start a new pack that same day. The patient should be instructed to use a back-up method of birth control if she has sex in the seven (7) days after missing pills.

ADDITIONAL INSTRUCTIONS FOR ALL DOSING REGIMENS

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, nonfunctional causes should be borne in mind. In undiagnosed persistent or recurrent abnormal bleeding from the vagina, adequate diagnostic measures are indicated to rule out pregnancy or malignancy. If pathology has been excluded, time or a change to another formulation 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 oral contraceptives 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 oral contraceptive 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.

How Supplied

Kalliga^TM (desogestrel and ethinyl estradiol tablets USP) 0.15 mg/0.03 mg is available in cartons of 3 pouches and 6 pouches, each containing 28 tablets:

21 active tablets: White to off-white, round, biconvex, beveled-edge tablets, debossed with “S” on one side and “25” on other side.

7 inert tablets: Green, round, mottled, biconvex, beveled-edge tablets, debossed with “S” on one side and “7” on other side.

                          1 Pouch of 28 tablets                                      NDC 65862- 887-28

                          Carton of 3 Pouches                                       NDC 65862- 887-88

                          Carton of 6 Pouches                                       NDC 65862- 887-92

STORAGE

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

References

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New York, Raven Press, 1983; pp. 395-410. 67. Perlman JA, Roussell-Briefel RG, Ezzati TM, Lieberknecht G. Oral glucose tolerance and the potency of oral contraceptive progestogens. J Chronic Dis 1985; 38:857-864. 68. Royal College of General Practitioners' Oral Contraception Study: Effect on hypertension and benign breast disease of progestogen component in combined oral contraceptives. Lancet 1977; 1:624. 69. Fisch IR, Frank J. Oral contraceptives and blood pressure. JAMA 1977; 237:2499-2503. 70. Laragh AJ. Oral contraceptive induced hypertension - nine years later. Am J Obstet Gynecol 1976; 126:141-147. 71. Ramcharan S, Peritz E, Pellegrin FA, Williams WT. Incidence of hypertension in the Walnut Creek Contraceptive Drug Study cohort. In Pharmacology of Steroid Contraceptive Drugs. Garattini S, Berendes HW. Eds. New York, Raven Press, 1977; pp. 277-288. (Monographs of the Mario Negri Institute for Pharmacological Research, Milan). 72. Stockley I. Interactions with oral contraceptives. J Pharm 1976; 216:140-143. 73. The Cancer and Steroid Hormone Study of the Centers for Disease Control and the National Institute of Child Health and Human Development: Oral contraceptive use and the risk of ovarian cancer. JAMA 1983; 249:1596-1599. 74. The Cancer and Steroid Hormone Study of the Centers for Disease Control and the National Institute of Child Health and Human Development: Combination oral contraceptive use and the risk of endometrial cancer. JAMA 1987; 257:796-800. 75. Ory HW. Functional ovarian cysts and oral contraceptives: negative association confirmed surgically. JAMA 1974; 228: 68-69. 76. Ory HW, Cole P, Macmahon B, Hoover R. Oral contraceptives and reduced risk of benign breast disease. N Engl J Med 1976; 294:419-422. 77. Ory HW. The noncontraceptive health benefits from oral contraceptive use. Fam Plann Perspect 1982; 14:182-184. 78. Ory HW, Forrest JD, Lincoln R. Making Choices: Evaluating the health risks and benefits of birth control methods. New York, The Alan Guttmacher Institute, 1983; p.1. 79. Schlesselman J, Stadel BV, Murray P, Lai S. Breast Cancer in relation to early use of oral contraceptives. JAMA 1988; 259:1828-1833. 80. Hennekens CH, Speizer FE, Lipnick RJ, Rosner B, Bain C, Belanger C, Stampfer MJ, Willett W, Peto R. A case-controlled study of oral contraceptive use and breast cancer. JNCI 1984;72:39-42. 81. LaVecchia C, Decarli A, Fasoli M, Franceschi S, Gentile A, Negri E, Parazzini F, Tognoni G. Oral contraceptives and cancers of the breast and of the female genital tract. Interim results from a case-control study. Br. J. Cancer 1986; 54:311-317. 82. Meirik O, Lund E, Adami H, Bergstrom R, Christoffersen T, Bergsjo P. Oral contraceptive use in breast cancer in young women. A Joint National Case-control study in Sweden and Norway. Lancet 1986; 11:650-654. 83. Kay CR, Hannaford PC. Breast cancer and the pill-A further report from the Royal College of General Practitioners' oral contraception study. Br.J. Cancer 1988; 58:675-680. 84. Stadel BV, Lai S, Schlesselman JJ, Murray P. Oral contraceptives and premenopausal breast cancer in nulliparous women. Contraception 1988; 38:287-299. 85. Miller DR, Rosenberg L, Kaufman DW, Stolley P, Warshauer ME, Shapiro S. Breast cancer before age 45 and oral contraceptive use: New Findings. Am. J. Epidemiol 1989; 129:269-280. 86. The UK National Case-Control Study Group, Oral contraceptive use and breast cancer risk in young women. Lancet 1989; 1:973-982. 87. Schlesselman JJ. Cancer of the breast and reproductive tract in relation to use of oral contraceptives. Contraception 1989; 40:1-38. 88. Vessey MP, McPherson K, Villard-Mackintosh L, Yeates D. Oral contraceptives and breast cancer: latest findings in a large cohort study. Br. J. Cancer 1989; 59:613-617. 89. Jick SS, Walker AM, Stergachis A, Jick H. Oral contraceptives and breast cancer. Br. J. Cancer 1989; 59:618-621. 90. Godsland, I et al. The effects of different formulations of oral contraceptive agents on lipid and carbohydrate metabolism. N Engl J Med 1990; 323:1375-81. 91. Kloosterboer, HJ et al. Selectivity in progesterone and androgen receptor binding of progestogens used in oral contraception. Contraception 1988; 38:325-32. 92. Van der Vies, J and de Visser, J. Endocrinological studies with desogestrel. Arzneim Forsch/ Drug Res, 1983; 33(I),2:231-6. 93. Data on file, Organon Inc. 94. Fotherby, K. Oral contraceptives, lipids and cardiovascular diseases. Contraception 1985; Vol. 31; 4:367-94. 95. Lawrence, DM et al. Reduced sex hormone binding globulin and derived free testosterone levels in women with severe acne. Clinical Endocrinology 1981;15:87-91. 96. Collaborative Group on Hormonal Factors in Breast Cancer. Breast cancer and hormonal contraceptives: collaborative reanalysis of individual data on 53 297 women with breast cancer and 100 239 women without breast cancer from 54 epidemiological studies. Lancet 1996; 347:1713-1727. 97. Palmer JR, Rosenberg L, Kaufman DW, Warshauer ME, Stolley P, Shapiro S. Oral Contraceptive Use and Liver Cancer. Am J Epidemiol 1989; 130:878-882. 98. Improving access to quality care in family planning: Medical eligibility criteria for contraceptive use. Geneva, WHO, Family and Reproductive Health, 1996. 99. Bork K, Fischer B, DeWald G. Recurrent episodes of skin angioedema and severe attacks of abdominal pain induced by oral contraceptives or hormone replacement therapy. Am J Med 2003;114:294-298. 100. Van Giersbergen PLM, Halabi A, Dingemanse J. Pharmacokinetic interaction between bosentan and the oral contraceptives norethisterone and ethinyl estradiol. Int J Clin Pharmacol Ther 2006;44(3):113-118. 101. Christensen J, Petrenaite V, Atterman J, et al. Oral contraceptives induce lamotrigine metabolism: evidence from a double-blind, placebo-controlled trial. Epilepsia 2007;48(3):484-489. 102. Chobanian et al. Seventh report of the joint national committee on prevention, detection, evaluation, and treatment of high blood pressure. Hypertension 2003;42; 1206-1252. 103. Brown KS, Armstrong IC, Wang A, Walker JR, Noveck RJ, Swearingen D, Allison M, Kissling JC, Kisicki J, Salazar D. Effect of the bile acid sequestrant colesevelam on the pharmacokinetics of pioglitazone, repaglinide, estrogen estradiol, norethindrone, levothyroxine, and glyburide. J Clin Pharmacol 2010;50:554-565.

Brief Summary Patient Package Insert

Kalliga^TM (Desogestrel and Ethinyl Estradiol Tablets USP) This product (like all oral contraceptives) is intended to prevent pregnancy. It does not protect against HIV infection (AIDS) and other sexually transmitted diseases. Oral contraceptives, also known as "birth control pills" or "the pill," are taken to prevent pregnancy, and when taken correctly without missing any pills, have a failure rate of approximately 1% per year. The typical failure rate is approximately 5% per year when women who miss pills are included. For most women, oral contraceptives are also free of serious or unpleasant side effects. 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. 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

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

BOXED WARNING SECTION

Do not use Kalliga^TM if you smoke cigarettes and are over 35 years old. Smoking increases your risk of serious cardiovascular side effects (heart and blood vessel problems) from combination oral contraceptives, including death from heart attack, blood clots or stroke. This risk increases with age and the number of cigarettes you 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, headache, 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) or lungs (pulmonary embolism), stoppage or rupture of a blood vessel in the brain (stroke), blockage of blood vessels in the heart (heart attack or 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. In rare cases, oral contraceptives can cause benign but dangerous liver tumors. These benign liver tumors can rupture and cause fatal internal bleeding. In addition, some studies report an increased risk of developing liver cancer. However, liver cancers are rare. 3. High blood pressure, although blood pressure usually returns to normal when the pill is stopped. The symptoms associated with these serious side effects are discussed in the detailed patient labeling given to you with your supply of pills. Notify your healthcare professional if you notice any unusual physical disturbances while taking the pill. In addition, drugs such as rifampin, bosentan, as well as some seizure medicines and herbal preparations containing St. John’s wort (Hypericum perforatum) may decrease oral contraceptive effectiveness. Oral contraceptives may interact with lamotrigine (LAMICTAL^®), a seizure medicine used for epilepsy. This may increase the risk of seizures so your healthcare professional may need to adjust the dose of lamotrigine. There may be slight increases in the risk of breast cancer among current users of hormonal birth control pills with longer duration of use of 8 years or more. Some studies have found an increase in the incidence of cancer of the cervix in women who use oral contraceptives. However, this finding may be related to factors other than the use of oral contraceptives. There is insufficient evidence to rule out the possibility that the pill may cause such cancers. 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 professional. Your healthcare professional 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 professional believes that it is a good medical practice to postpone it. You should be reexamined at least once a year while taking oral contraceptives. The detailed patient information labeling gives you further information which you should read and discuss with your healthcare professional. This product (like all oral contraceptives) is intended to prevent pregnancy. It does not protect against transmission of HIV (AIDS) and other sexually transmitted diseases such as chlamydia, genital herpes, genital warts, gonorrhea, hepatitis B, and syphilis.

HOW TO TAKE THE PILL

______________________________________________________________________________________ IMPORTANT POINTS TO REMEMBER ______________________________________________________________________________________ BEFORE YOU START TAKING YOUR PILLS: 1.    BE SURE TO READ THESE DIRECTIONS:        Before you start taking your pills.        Anytime you are not sure what to do. 2.    THE RIGHT WAY TO TAKE THE PILL IS TO TAKE ONE PILL EVERY DAY AT THE SAME TIME.        If you miss pills you could get pregnant. This includes starting the pack late. The more pills you miss, the more likely you are to get pregnant. 3.    MANY WOMEN HAVE SPOTTING OR LIGHT BLEEDING, OR MAY FEEL SICK TO THEIR STOMACH DURING THE FIRST 1 to 3 PACKS OF PILLS. If you feel sick to your stomach, do not stop taking the pill. The problem will usually go away. If it doesn’t go away, check with your healthcare professional. 4.    MISSING PILLS CAN ALSO CAUSE SPOTTING OR LIGHT BLEEDING, even when you make up these missed pills.        On the days you take 2 pills to make up for missed pills, you could also feel a little sick to your stomach. 5.     IF YOU HAVE VOMITING OR DIARRHEA, or IF YOU TAKE SOME MEDICINES, your pills may not work as well.        Use a back-up method (such as a condom or spermicide) until you check with your healthcare professional. 6.     IF YOU HAVE TROUBLE REMEMBERING TO TAKE THE PILL, talk to your healthcare professional about how to make pill-taking easier or about using another method of birth control. 7.     IF YOU HAVE ANY QUESTIONS OR ARE UNSURE ABOUT THE INFORMATION IN THIS LEAFLET, call your healthcare professional. BEFORE YOU START TAKING YOUR PILLS 1.    DECIDE WHAT TIME OF DAY YOU WANT TO TAKE YOUR PILL.        It is important to take it at about the same time every day. 2.     LOOK AT YOUR PILL PACK:        The pill pack has 21 white to off-white “active” pills (with hormones) to take for 3 weeks, followed by 1 week of green “reminder” pills (without hormones). 3.     ALSO FIND:        1) where on the pack to start taking pills,        2) in what order to take the pills,        3) check picture of pill pack and additional instructions for using this package below. 4.     BE SURE YOU HAVE READY AT ALL TIMES:         ANOTHER KIND OF BIRTH CONTROL (such as a condom or spermicide) to use as a back-up method in case you miss pills.         AN EXTRA, FULL PILL PACK. ______________________________________________________________________________________ WHEN TO START THE FIRST PACK OF PILLS ______________________________________________________________________________________ You have a choice of which day to start taking your first pack of pills. Kalliga^TM is available in the buler pack which is preset for a Sunday Start. Day 1 Start is also provided. Decide with your healthcare professional which is the best day for you. Pick a time of day that will be easy to remember. DAY 1 START: 1.     Take the first white to off-white “active” pill of the first pack during the first 24 hours of your period. 2.     You will not need to use a back-up method of birth control, since you are starting the pill at the beginning of your period. SUNDAY START: 1.     Take the first white to off-white “active” pill of the first pack on the Sunday after your period starts, even if you are still bleeding. If your period begins on Sunday, start the pack that same day. 2.     Use another method of birth control such as a condom or spermicide as a back-up method if you have sex anytime from the Sunday you start your first pack until the next Sunday (7 days). ______________________________________________________________________________________ WHAT TO DO DURING THE MONTH ______________________________________________________________________________________

1.     TAKE ONE PILL AT THE SAME TIME EVERY DAY UNTIL THE PACK IS EMPTY.             Do not skip pills even if you are spotting or bleeding between monthly periods or feel sick to your stomach (nausea).             Do not skip pills even if you do not have sex very often. 2.     WHEN YOU FINISH A PACK OR SWITCH YOUR BRAND OF PILLS:             Start the next pack on the day after your last green "reminder" pill. Do not wait any days between packs. ______________________________________________________________________________________ WHAT TO DO IF YOU MISS PILLS ______________________________________________________________________________________ If you MISS 1 white to off-white "active" pill: 1.     Take it as soon as you remember. Take the next pill at your regular time. This means you may take 2 pills in 1 day. 2.     You do not need to use a back-up birth control method if you have sex. If you MISS 2 white to off-white "active" pills in a row in WEEK 1 OR WEEK 2 of your pack: 1.     Take 2 pills on the day you remember and 2 pills the next day. 2.     Then take 1 pill a day until you finish the pack. 3.     You COULD BECOME PREGNANT if you have sex in the 7 days after you miss pills. You MUST use another birth control method (such as a condom or spermicide) as a back-up method for those 7 days. If you MISS 2 white to off-white "active" pills in a row in THE 3RD WEEK: 1.     If you are a Day 1 Starter:         THROW OUT the rest of the pill pack and start a new pack that same day.         If you are a Sunday Starter :         Keep taking 1 pill every day until Sunday. On Sunday, THROW OUT the rest of the pack and start a new pack of pills that same day. 2.     You may not have your period this month but this is expected. However, if you miss your period 2 months in a row, call your healthcare professional because you might be pregnant. 3.     You COULD BECOME PREGNANT if you have sex in the 7 days after you miss pills. You MUST use another birth control method (such as a condom or spermicide) as a back-up method for those 7 days. If you MISS 3 OR MORE white to off-white "active" pills in a row (during the first 3 weeks): 1.     If you are a Day 1 Starter:         THROW OUT the rest of the pill pack and start a new pack that same day.         If you are a Sunday Starter:         Keep taking 1 pill every day until Sunday. On Sunday, THROW OUT the rest of the pack and start a new pack of pills that same day. 2.     You may not have your period this month but this is expected. However, if you miss your period 2 months in a row, call your healthcare professional because you might be pregnant. 3.     You COULD BECOME PREGNANT if you have sex in the 7 days after you miss pills. You MUST use another birth control method (such as a condom or spermicide) as a back-up method for those 7 days. A REMINDER: If you forget any of the 7 green "reminder" pills in Week 4: THROW AWAY the pills you missed. Keep taking 1 pill each day until the pack is empty. You do not need a back-up method. FINALLY, IF YOU ARE STILL NOT SURE WHAT TO DO ABOUT THE PILLS YOU HAVE MISSED: Use a BACK-UP METHOD anytime you have sex. KEEP TAKING ONE WHITE TO OFF-WHITE "ACTIVE" PILL EACH DAY until you can reach your healthcare professional.

INSTRUCTIONS FOR USE

1. The buler pack comes to you set up for Sunday Start. If your healthcare professional has instructed you to start pill-taking on the first SUNDAY after your menstrual period has begun, or has instructed you to start pill-taking on the first day of your menstrual period and that day is SUNDAY, go to the directions in Number 3. 2. If you are to start pill-taking on a day other than SUNDAY, the enclosed calendar label has been provided and will be placed over the calendar printed on the buler pack. To put label in place, identify your correct starting day, locate that day label present in the calendar label and affix that day label over the printed calendar on the buler pack. 3. The first white to off-white "active" pill you will take is indicated by START and lines up with the black Day Arrow as indicated on the buler pack. For details, see the directions in the following picture. DAY-1 STARTERS: If your period begins on a day other than Sunday, place the day label strip that starts with the first day of your period here. Push down on the first white to off-white “active” pill with your thumb or forefinger. The pill will come out through a hole in the back of the package. After you have taken all 21 white to off-white “active” pills, take one green “reminder” pill daily for 7 days. During this time your period should begin. After you have taken all the pills, start a new pack of pills even if your period is not yet over. STORAGE Store at 20º to 25°C (68° to 77º F) [see USP Controlled Room Temperature].

Detailed Patient Labeling

This product (like all oral contraceptives) is intended to prevent pregnancy. It does not protect against HIV infection (AIDS) and other sexually transmitted diseases. PLEASE NOTE: This labeling is revised from time to time as important new medical information becomes available. Therefore, please review this labeling carefully. The following oral contraceptive product contains a combination of a progestogen and estrogen, the two kinds of female hormones: Kalliga^TM (Desogestrel and Ethinyl Estradiol Tablets USP) Each white to off-white tablet contains 0.15 mg desogestrel and 0.03 mg ethinyl estradiol. Each green tablet contains inert ingredients. INTRODUCTION Any woman who considers using oral contraceptives (the birth control pill or the pill) should understand the benefits and risks of using this form of birth control. This patient labeling will give you much of the information you will need to make this decision and will also help you determine if you are at risk of developing any of the serious side effects of the pill. It will tell you how to use the pill properly so that it will be as effective as possible. However, this labeling is not a replacement for a careful discussion between you and your healthcare professional. You should discuss the information provided in this labeling with him or her, both when you first start taking the pill and during your revisits. You should also follow your healthcare professional’s advice with regard to regular check-ups while you are on the pill. EFFECTIVENESS OF ORAL CONTRACEPTIVES Oral contraceptives or "birth control pills" or "the pill" are used to prevent pregnancy and are more effective than most other non-surgical methods of birth control. When they are taken correctly without missing any pills, the chance of becoming pregnant is approximately 1%   (1 pregnancy per 100 women per year of use). Typical failure rates, including women who do not always take the pills exactly as directed, are approximately 5% per year. The chance of becoming pregnant increases with each missed pill during a menstrual cycle. In comparison, typical failure rates for other non-surgical methods of birth control during the first year of use are as follows:

Implant: <1% Male sterilization: <1%

Injection: <1% Cervical Cap with spermicides: 20 to 40%

IUD: 1 to 2% Condom alone (male): 14%

Diaphragm with spermicides: 20% Condom alone (female): 21%

Spermicides alone: 26% Periodic abstinence: 25%

Vaginal sponge: 20 to 40% Withdrawal: 19%

Female sterilization: <1% No methods: 85%

WHO SHOULD NOT TAKE ORAL CONTRACEPTIVES

BOXED WARNING SECTION

Do not use Kalliga^TM if you smoke cigarettes and are over 35 years old. Smoking increases your risk of serious cardiovascular side effects (heart and blood vessel problems) from combination oral contraceptives, including death from heart attack, blood clots or stroke. This risk increases with age and the number of cigarettes you smoke.

Some women should not use the pill. For example, you should not take the pill if you have any of the following conditions:

A history of heart attack or stroke

Blood clots in the legs (thrombophlebitis), lungs (pulmonary embolism), or eyes

A history of blood clots in the deep veins of your legs

An inherited problem that makes your blood clot more than normal

Chest pain (angina pectoris)

Known or suspected breast cancer or cancer of the lining of the uterus, cervix or vagina

Unexplained vaginal bleeding (until a diagnosis is reached by your healthcare professional)

Yellowing of the whites of the eyes or of the skin (jaundice) during pregnancy or during previous use of the pill

Liver tumor (benign or cancerous)

If you take any Hepatitis C drug combination containing ombitasvir/ paritaprevir/ritonavir, with or without dasabuvir. This may increase levels of the liver enzyme “alanine aminotransferase” (ALT) in the blood.

Known or suspected pregnancy

If you plan to have surgery with prolonged bed rest

Tell your healthcare professional if you have ever had any of these conditions. Your healthcare professional can recommend another method of birth control. OTHER CONSIDERATIONS BEFORE TAKING ORAL CONTRACEPTIVES Tell your healthcare professional if you have or have had:

Breast nodules, fibrocystic disease of the breast, an abnormal breast x-ray or mammogram

Diabetes

Elevated cholesterol or triglycerides

High blood pressure

Migraine or other headaches or epilepsy

Mental depression

Gallbladder, liver, heart or kidney disease

History of scanty or irregular menstrual periods

Women with any of these conditions should be checked often by their healthcare professional if they choose to use oral contraceptives. Also, be sure to inform your healthcare professional if you smoke or are on any medications.

RISKS OF TAKING ORAL CONTRACEPTIVES

1. Risk of Developing Blood Clots

Blood clots and blockage of blood vessels are one of the most serious side effects of taking oral contraceptives and can cause death or serious disability. Serious blood clots can happen especially if you smoke, are obese, or are older than 35 years of age. Serious blood clots are more likely to happen when you:

First start taking birth control pills

Restart the same or different birth control pills after not using them for a month or more

In particular, a clot in the legs can cause thrombophlebitis and a clot that travels to the lungs can cause a sudden blocking of the vessel carrying blood to the lungs. The risks of these side effects may be greater with desogestrel-containing oral contraceptives, such as Kalliga^TM, than with certain other low-dose pills. Rarely, clots occur in the blood vessels of the eye and may cause blindness, double vision, or impaired vision. If you take oral contraceptives and need elective surgery, need to stay in bed for a prolonged illness or injury or have recently delivered a baby, you may be at risk of developing blood clots. You should consult your healthcare professional about stopping oral contraceptives three to four weeks before surgery and not taking oral contraceptives for two weeks after surgery or during bed rest. You should also not take oral contraceptives soon after delivery of a baby. It is advisable to wait for at least four weeks after delivery if you are not breastfeeding. If you are breastfeeding, you should wait until you have weaned your child before using the pill. (See also the section on Breastfeeding in GENERAL PRECAUTIONS.) The risk of circulatory disease in oral contraceptive users may be higher in users of high-dose pills. The risk of venous thromboembolic disease associated with oral contraceptives does not increase with length of use and disappears after pill use is stopped. The risk of abnormal blood clotting increases with age in both users and nonusers of oral contraceptives, but the increased risk from the oral contraceptive appears to be present at all ages. For women aged 20 to 44 it is estimated that about 1 in 2,000 using oral contraceptives will be hospitalized each year because of abnormal clotting. Among nonusers in the same age group, about 1 in 20,000 would be hospitalized each year. For oral contraceptive users in general, it has been estimated that in women between the ages of 15 and 34 the risk of death due to a circulatory disorder is about 1 in 12,000 per year, whereas for nonusers the rate is about 1 in 50,000 per year. In the age group 35 to 44, the risk is estimated to be about 1 in 2,500 per year for oral contraceptive users and about 1 in 10,000 per year for nonusers. 2. Heart Attacks and Strokes Oral contraceptives may increase the tendency to develop strokes (stoppage or rupture of blood vessels in the brain) and angina pectoris and heart attacks (blockage of blood vessels in the heart). Any of these conditions can cause death or serious disability. Smoking greatly increases the possibility of suffering heart attacks and strokes. Furthermore, smoking and the use of oral contraceptives greatly increase the chances of developing and dying of heart disease. 3. Gallbladder Disease Oral contraceptive users probably have a greater risk than nonusers of having gallbladder disease, although this risk may be related to pills containing high doses of estrogens. 4. Liver Tumors In rare cases, oral contraceptives can cause benign but dangerous liver tumors. These benign liver tumors can rupture and cause fatal internal bleeding. In addition, some studies report an increased risk of developing liver cancer. However, liver cancers are rare. 5. Risk of Cancer It is not known if hormonal birth control pills causes breast cancer. Some studies, but not all, suggest that there could be a slight increase in the risk of breast cancer among current users with longer duration of use. If you have breast cancer now, or have had it in the past, do not use hormonal birth control because some breast cancers are sensitive to hormones. Some studies have found an increase in the incidence of cancer of the cervix in women who use oral contraceptives. However, this finding may be related to factors other than the use of oral contraceptives. There is insufficient evidence to rule out the possibility that pills may cause such cancers.

ESTIMATED RISK OF DEATH FROM A BIRTH CONTROL METHOD OR PREGNANCY

All methods of birth control and pregnancy are associated with a risk of developing certain diseases which may lead to disability or death. An estimate of the number of deaths associated with different methods of birth control and pregnancy has been calculated and is shown in the following table.

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
^*Deaths are birth-related ^† Deaths are method-related

Method of control and outcome 15 to 19 20 to 24 25 to 29 30 to 34 35 to 39 40 to 44

No fertility-control methods^* 7 7.4 9.1 14.8 25.7 28.2

Oral contraceptives non-smoker^† 0.3 0.5 0.9 1.9 13.8 31.6

Oral contraceptives smoker^† 2.2 3.4 6.6 13.5 51.1 117.2

IUD^† 0.8 0.8 1 1 1.4 1.4

Condom^* 1.1 1.6 0.7 0.2 0.3 0.4

Diaphragm/spermicide^* 1.9 1.2 1.2 1.3 2.2 2.8

Periodic abstinence^* 2.5 1.6 1.6 1.7 2.9 3.6

In the above table, the risk of death from any birth control method is less than the risk of childbirth, except for oral contraceptive users over the age of 35 who smoke and pill users over the age of 40 even if they do not smoke. It can be seen in the table that for women aged 15 to 39, the risk of death was highest with pregnancy (7 to 26 deaths per 100,000 women, depending on age). Among pill users who do not smoke, the risk of death is always lower than that associated with pregnancy for any age group, although over the age of 40, the risk increases to 32 deaths per 100,000 women, compared to 28 associated with pregnancy at that age. However, for pill users who smoke and are over the age of 35, the estimated number of deaths exceeds those for other methods of birth control. If a woman is over the age of 40 and smokes, her estimated risk of death is four times higher (117/100,000 women) than the estimated risk associated with pregnancy (28/100,000 women) in that age group. The suggestion that women over 40 who do not smoke should not take oral contraceptives is based on information from older, higher-dose pills. An Advisory Committee of the FDA discussed this issue in 1989 and recommended that the benefits of low-dose oral contraceptive use by healthy, non-smoking women over 40 years of age may outweigh the possible risks. Older women, as all women, who take oral contraceptives, should take an oral contraceptive which contains the least amount of estrogen and progestogen that is compatible with the individual patient needs. WARNING SIGNALS If any of these adverse effects occur while you are taking oral contraceptives, call your healthcare professional immediately:

Sharp chest pain, coughing of blood, or sudden shortness of breath (indicating a possible clot in the lung)

Pain in the calf (indicating a possible clot in the leg)

Crushing chest pain or heaviness in the chest (indicating a possible heart attack)

Sudden severe headache or vomiting, dizziness or fainting, disturbances of vision or speech, weakness, or numbness in an arm or leg (indicating a possible stroke)

Sudden partial or complete loss of vision (indicating a possible clot in the eye)

Breast lumps (indicating possible breast cancer or fibrocystic disease of the breast; ask your healthcare professional to show you how to examine your breasts)

Severe pain or tenderness in the stomach area (indicating a possibly ruptured liver tumor)

Difficulty in sleeping, weakness, lack of energy, fatigue, or change in mood (possibly indicating severe depression)

Jaundice or a yellowing of the skin or eyeballs, accompanied frequently by fever, fatigue, loss of appetite, dark colored urine, or light colored bowel movements (indicating possible liver problems)

SIDE EFFECTS OF ORAL CONTRACEPTIVES

1. Vaginal Bleeding Irregular vaginal bleeding or spotting may occur while you are taking the pills. Irregular bleeding may vary from slight staining between menstrual periods to breakthrough bleeding which is a flow much like a regular period. Irregular bleeding occurs most often during the first few months of oral contraceptive use, but may also occur after you have been taking the pill for some time. Such bleeding may be temporary and usually does not indicate any serious problems. It is important to continue taking your pills on schedule. If the bleeding occurs in more than one cycle or lasts for more than a few days, talk to your healthcare professional. 2. Contact Lenses If you wear contact lenses and notice a change in vision or an inability to wear your lenses, contact your healthcare professional. 3. Fluid Retention Oral contraceptives may cause edema (fluid retention) with swelling of the fingers or ankles and may raise your blood pressure. If you experience fluid retention, contact your healthcare professional. 4. Melasma A spotty darkening of the skin is possible, particularly of the face, which may persist. 5. Other Side Effects Other side effects may include nausea and vomiting, change in appetite, headache, nervousness, depression, dizziness, loss of scalp hair, rash, vaginal infections and allergic reactions. If any of these side effects bother you, call your healthcare professional.

GENERAL PRECAUTIONS

1. Missed Periods and Use of Oral Contraceptives Before or During Early Pregnancy There may be times when you may not menstruate regularly after you have completed taking a cycle of pills. If you have taken your pills regularly and miss one menstrual period, continue taking your pills for the next cycle but be sure to inform your healthcare professional before doing so. If you have not taken the pills daily as instructed and missed a menstrual period, you may be pregnant. If you missed two consecutive menstrual periods, you may be pregnant. Check with your healthcare professional immediately to determine whether you are pregnant. Stop taking oral contraceptives if pregnancy is confirmed. There is no conclusive evidence that oral contraceptive use is associated with an increase in birth defects, when taken inadvertently during early pregnancy. Previously, a few studies had reported that oral contraceptives might be associated with birth defects, but these findings have not been seen in more recent studies. Nevertheless, oral contraceptives should not be used during pregnancy. You should check with your healthcare professional about risks to your unborn child of any medication taken during pregnancy. 2. While Breastfeeding If you are breastfeeding, consult your healthcare professional before starting oral contraceptives. Some of the drug will be passed on to the child in the milk. A few adverse effects on the child have been reported, including yellowing of the skin (jaundice) and breast enlargement. In addition, oral contraceptives may decrease the amount and quality of your milk. If possible, do not use oral contraceptives while breastfeeding. You should use another method of contraception since breastfeeding provides only partial protection from becoming pregnant and this partial protection decreases significantly as you breastfeed for longer periods of time. You should consider starting oral contraceptives only after you have weaned your child completely. 3. Laboratory Tests If you are scheduled for any laboratory tests, tell your healthcare professional you are taking birth control pills. Certain blood tests may be affected by birth control pills. 4. Drug Interactions Tell your healthcare provider about all medicines and herbal products that you take. Some medicines and herbal products may make hormonal birth control less effective, including, but not limited to:

certain seizure medicines (carbamazepine, felbamate, oxcarbazepine, phenytoin, rufinamide, and topiramate)

aprepitant

barbiturates

bosentan

colesevelam

griseofulvin

certain combinations of HIV medicines (nelfinavir, ritonavir, ritonavir-boosted protease inhibitors)

certain non-nucleoside reverse transcriptase inhibitors (nevirapine)

rifampin and rifabutin

St. John’s wort

Use another birth control method (such as a condom and spermicide or diaphragm and spermicide) when you take medicines that may make Kalliga^TM less effective. Some medicines and grapefruit juice may increase your level of the hormone ethinyl estradiol if used together, including:

acetaminophen

ascorbic acid

medicines that affect how your liver breaks down other medicines (itraconazole, ketoconazole, voriconazole, and fluconazole)

certain HIV medicines (atazanavir, indinavir)

atorvastatin

rosuvastatin

etravirine

Hormonal birth control methods may interact with lamotrigine, a seizure medicine used for epilepsy. This may increase the risk of seizures, so your healthcare provider may need to adjust the dose of lamotrigine. Women on thyroid replacement therapy may need increased doses of thyroid hormone. Know the medicines you take. Keep a ul of them to show your doctor and pharmacist when you get a new medicine. 5. Sexually Transmitted Diseases This product (like all oral contraceptives) is intended to prevent pregnancy. It does not protect against transmission of HIV (AIDS) and other sexually transmitted diseases such as chlamydia, genital herpes, genital warts, gonorrhea, hepatitis B, and syphilis.

HOW TO TAKE THE PILL

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IMPORTANT POINTS TO REMEMBER

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BEFORE YOU START TAKING YOUR PILLS:

1. BE SURE TO READ THESE DIRECTIONS:

    Before you start taking your pills.

    Anytime you are not sure what to do.

2. THE RIGHT WAY TO TAKE THE PILL IS TO TAKE ONE PILL EVERY DAY AT THE SAME TIME.

    If you miss pills you could get pregnant. This includes starting the pack late. The more pills you miss, the more likely you are to get pregnant.

3. MANY WOMEN HAVE SPOTTING OR LIGHT BLEEDING, OR MAY FEEL SICK TO THEIR STOMACH DURING THE FIRST 1 to 3 PACKS OF PILLS. If you feel sick to your stomach, do not stop taking the pill. The problem will usually go away. If it doesn't go away, check with your healthcare professional.

4. MISSING PILLS CAN ALSO CAUSE SPOTTING OR LIGHT BLEEDING, even when you make up these missed pills.

    On the days you take 2 pills to make up for missed pills, you could also feel a little sick to your stomach.

5. IF YOU HAVE VOMITING OR DIARRHEA, or IF YOU TAKE SOME MEDICINES, your pills may not work as well.

    Use a back-up method (such as a condom or spermicide) until you check with your healthcare professional.

6. IF YOU HAVE TROUBLE REMEMBERING TO TAKE THE PILL, talk to your healthcare professional about how to make pill-taking easier or about using another method of birth control.

7. IF YOU HAVE ANY QUESTIONS OR ARE UNSURE ABOUT THE INFORMATION IN THIS LEAFLET, call your healthcare professional.

BEFORE YOU START TAKING YOUR PILLS

1. DECIDE WHAT TIME OF DAY YOU WANT TO TAKE YOUR PILL.

    It is important to take it at about the same time every day.

2. LOOK AT YOUR PILL PACK:

    The pill pack has 21 white to off-white “active” pills (with hormones) to take for 3 weeks, followed by 1 week of green “reminder” pills (without hormones).

3. ALSO FIND:

    1) where on the pack to start taking pills,

    2) in what order to take the pills.

    CHECK PICTURE OF PILL PACK AND ADDITIONAL INSTRUCTIONS FOR USING THIS PACKAGE IN THE BRIEF SUMMARY PATIENT PACKAGE INSERT.

4. BE SURE YOU HAVE READY AT ALL TIMES:

    ANOTHER KIND OF BIRTH CONTROL (such as a condom or spermicide) to use as a back-up method in case you miss pills.

    AN EXTRA, FULL PILL PACK.

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WHEN TO START THE FIRST PACK OF PILLS

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You have a choice of which day to start taking your first pack of pills. Kalliga^TM is available in the buler pack which is preset for a Sunday Start. Day 1 Start is also provided. Decide with your healthcare professional which is the best day for you. Pick a time of day that will be easy to remember.

DAY 1 START:

1. Take the first white to off-white “active” pill of the first pack during the first 24 hours of your period.

2. You will not need to use a back-up method of birth control, since you are starting the pill at the beginning of your period.

SUNDAY START:

1. Take the first white to off-white “active” pill of the first pack on the Sunday after your period starts, even if you are still bleeding. If your period begins on Sunday, start the pack that same day.

2. Use another method of birth control such as a condom or spermicide as a back-up method if you have sex anytime from the Sunday you start your first pack until the next Sunday (7 days).

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WHAT TO DO DURING THE MONTH

___________________________________________________________________

1. TAKE ONE PILL AT THE SAME TIME EVERY DAY UNTIL THE PACK IS EMPTY.

    Do not skip pills even if you are spotting or bleeding between monthly periods or feel sick to your stomach (nausea).

    Do not skip pills even if you do not have sex very often.

2. WHEN YOU FINISH A PACK OR SWITCH YOUR BRAND OF PILLS:

    Start the next pack on the day after your last green "reminder" pill. Do not wait any days between packs.

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WHAT TO DO IF YOU MISS PILLS

___________________________________________________________________

If you MISS 1 white to off-white "active" pill:

1. Take it as soon as you remember. Take the next pill at your regular time. This means you may take 2 pills in 1 day.

2. You do not need to use a back-up birth control method if you have sex.

If you MISS 2 white to off-white "active" pills in a row in WEEK 1 OR WEEK 2 of your pack:

1. Take 2 pills on the day you remember and 2 pills the next day.

2. Then take 1 pill a day until you finish the pack.

3. You COULD BECOME PREGNANT if you have sex in the 7 days after you miss pills. You MUST use another birth control method (such as a condom or spermicide) as a back-up method for those 7 days.

If you MISS 2 white to off-white "active" pills in a row in THE 3RD WEEK:

1. If you are a Day 1 Starter:

    THROW OUT the rest of the pill pack and start a new pack that same day.

    If you are a Sunday Starter:

    Keep taking 1 pill every day until Sunday. On Sunday, THROW OUT the rest of the pack and start a new pack of pills that same day.

2. You may not have your period this month but this is expected. However, if you miss your period 2 months in a row, call your healthcare professional because you might be pregnant.

3. You COULD BECOME PREGNANT if you have sex in the 7 days after you miss pills. You MUST use another birth control method (such as a condom or spermicide) as a back-up method for those 7 days.

If you MISS 3 OR MORE white to off-white "active" pills in a row (during the first 3 weeks):

1. If you are a Day 1 Starter:

    THROW OUT the rest of the pill pack and start a new pack that same day.

    If you are a Sunday Starter:

    Keep taking 1 pill every day until Sunday. On Sunday, THROW OUT the rest of the pack and start a new pack of pills that same day.

2. You may not have your period this month but this is expected. However, if you miss your period 2 months in a row, call your healthcare professional because you might be pregnant.

3. You COULD BECOME PREGNANT if you have sex in the 7 days after you miss pills. You MUST use another birth control method (such as a condom or spermicide) as a back-up method for those 7 days.

A REMINDER:

If you forget any of the 7 green "reminder" pills in Week 4:

THROW AWAY the pills you missed.

Keep taking 1 pill each day until the pack is empty.

You do not need a back-up method.

FINALLY, IF YOU ARE STILL NOT SURE WHAT TO DO ABOUT THE PILLS YOU HAVE MISSED:

Use a BACK-UP METHOD anytime you have sex.

KEEP TAKING ONE WHITE TO OFF-WHITE "ACTIVE" PILL EACH DAY until you can reach your healthcare professional.

PREGNANCY DUE TO PILL FAILURE

When taken correctly without missing any pills, oral contraceptives are highly effective; however the typical failure rate of large numbers of pill users is 5% per year when women who miss pills are included. If failure does occur, the risk to the fetus is minimal. PREGNANCY AFTER STOPPING THE PILL There may be some delay in becoming pregnant after you stop using oral contraceptives, especially if you had irregular menstrual cycles before you used oral contraceptives. It may be advisable to postpone conception until you begin menstruating regularly once you have stopped taking the pill and desire pregnancy. There does not appear to be any increase in birth defects in newborn babies when pregnancy occurs soon after stopping the pill. OVERDOSAGE Serious ill effects have not been reported following ingestion of large doses of oral contraceptives by young children. Overdosage may cause nausea and withdrawal bleeding in females. In case of overdosage, contact your healthcare professional. OTHER INFORMATION Your healthcare professional 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 professional believes that it is a good medical practice to postpone it. You should be reexamined at least once a year. Be sure to inform your healthcare professional if there is a family history of any of the conditions uled previously in this leaflet. Be sure to keep all appointments with your healthcare professional because this is a time to determine if there are early signs of side effects of oral contraceptive use. Do not use the drug for any condition other than the one for which it was prescribed. This drug has been prescribed specifically for you; do not give it to others who may want birth control pills. HEALTH BENEFITS FROM ORAL CONTRACEPTIVES In addition to preventing pregnancy, use of combined oral contraceptives may provide certain benefits. They are:

menstrual cycles may become more regular

blood flow during menstruation may be lighter and less iron may be lost. Therefore, anemia due to iron deficiency is less likely to occur.

pain or other symptoms during menstruation may be encountered less frequently.

ectopic (tubal) pregnancy may occur less frequently.

noncancerous cysts or lumps in the breast may occur less frequently.

acute pelvic inflammatory disease may occur less frequently.

oral contraceptive use may provide some protection against developing two forms of cancer: cancer of the ovaries and cancer of the lining of the uterus.

If you want more information about birth control pills, ask your healthcare professional or pharmacist. They have a more technical leaflet called the Professional Labeling, which you may wish to read. STORAGE Store at 20º to 25°C (68° to 77º F) [see USP Controlled Room Temperature]. Keep out of reach of children. The brands uled are trademarks of their respective owners and are not trademarks of Aurobindo Pharma Limited. The makers of these brands are not affiliated with and do not endorse Aurobindo Pharma Limited or its products. Distributed by: Aurobindo Pharma USA, Inc. 279 Princeton-Hightstown RoadEast Windsor, NJ 08520 Manufactured by: Aurobindo Pharma Limited Hyderabad-500 032, India Revised: 12/2021

Package Label-principal Display Panel - 0.15 Mg/0.03 Mg Pouch Label

NDC 65862-887-28 Kalliga^TM (Desogestrel and Ethinyl Estradiol Tablets USP) 0.15 mg/0.03 mg Each white to off-white tablet contains 0.15 mg desogestrel and 0.03 mg ethinyl estradiol USP. Each green tablet contains inert ingredients. Dosage: One tablet daily as prescribed. See package insert. Rx only                                               1 Pouch of 28 Tablets AUROBINDO

Package Label-principal Display Panel - 0.15 Mg/0.03 Mg Blister Carton

NDC 65862-887-92 Kalliga^TM (Desogestrel and Ethinyl Estradiol Tablets USP) 0.15 mg/0.03 mg Each white to off-white tablet contains 0.15 mg desogestrel and 0.03 mg ethinyl estradiol USP. Each green tablet contains inert ingredients. Dosage: One tablet daily as prescribed. See package insert. Rx only                                   6 Pouches Each Containing 28 Tablets AUROBINDO

Table 2: 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
Adapted from H.W. Ory, ref. #35. ^* Deaths are birth-related ^†Deaths are method-related
Method of control and outcome	15 to 19	20 to 24	25 to 29	30 to 34	35 to 39	40 to 44
No fertility-control methods*	7	7.4	9.1	14.8	25.7	28.2
Oral contraceptives non-smoker^†	0.3	0.5	0.9	1.9	13.8	31.6
Oral contraceptives smoker^†	2.2	3.4	6.6	13.5	51.1	117.2
IUD^†	0.8	0.8	1	1	1.4	1.4
Condom*	1.1	1.6	0.7	0.2	0.3	0.4
Diaphragm/spermicide*	1.9	1.2	1.2	1.3	2.2	2.8
Periodic abstinence*	2.5	1.6	1.6	1.7	2.9	3.6

Implant: <1%	Male sterilization: <1%
Injection: <1%	Cervical Cap with spermicides: 20 to 40%
IUD: 1 to 2%	Condom alone (male): 14%
Diaphragm with spermicides: 20%	Condom alone (female): 21%
Spermicides alone: 26%	Periodic abstinence: 25%
Vaginal sponge: 20 to 40%	Withdrawal: 19%
Female sterilization: <1%	No methods: 85%

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
^*Deaths are birth-related ^† Deaths are method-related
Method of control and outcome	15 to 19	20 to 24	25 to 29	30 to 34	35 to 39	40 to 44
No fertility-control methods^*	7	7.4	9.1	14.8	25.7	28.2
Oral contraceptives non-smoker^†	0.3	0.5	0.9	1.9	13.8	31.6
Oral contraceptives smoker^†	2.2	3.4	6.6	13.5	51.1	117.2
IUD^†	0.8	0.8	1	1	1.4	1.4
Condom^*	1.1	1.6	0.7	0.2	0.3	0.4
Diaphragm/spermicide^*	1.9	1.2	1.2	1.3	2.2	2.8
Periodic abstinence^*	2.5	1.6	1.6	1.7	2.9	3.6

DISCLAIMER:

"This tool does not provide medical advice, and is for informational and educational purposes only, and is not a substitute for professional medical advice, treatment or diagnosis. Call your doctor to receive medical advice. If you think you may have a medical emergency, please dial 911."

"Do not rely on openFDA to make decisions regarding medical care. While we make every effort to ensure that data is accurate, you should assume all results are unvalidated. We may limit or otherwise restrict your access to the API in line with our Terms of Service."

"This product uses publicly available data from the U.S. National Library of Medicine (NLM), National Institutes of Health, Department of Health and Human Services; NLM is not responsible for the product and does not endorse or recommend this or any other product."

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Kalliga (desogestrel 0.15 mg ethinyl estradiol 0.03 mg) Dailymed

Drug Classes

Version History

FDA Adverse Reactions

Warning: Cardiovascular Risk Associated With Smoking

Description

Clinical Pharmacology

Pharmacodynamics

Pharmacokinetics

Indications And Usage

Contraindications

Warnings

1. Thromboembolic Disorder and Other Vascular Problems

2. Estimates of Mortality from Contraceptive Use

3. Malignant Neoplasms

4. Hepatic Neoplasia

5. Risk of Liver Enzyme Elevations with Concomitant Hepatitis C Treatment

6. Ocular Lesions

7. Oral Contraceptive Use Before or During Early Pregnancy

8. Gallbladder Disease

9. Carbohydrate and Lipid Metabolic Effects

10. Elevated Blood Pressure

11. Headache

12. Bleeding Irregularities

13. Ectopic Pregnancy

Precautions

1. General

2. Physical Examination and Follow-Up

3. Lipid Disorders

4. Liver Function

5. Fluid Retention

6. Emotional Disorders

7. Contact Lenses

8. Drug Interactions

9. Interactions with Laboratory Tests

10. Carcinogenesis

11. Pregnancy

12. Nursing Mothers

13. Pediatric Use

14. Geriatric Use

INFORMATION FOR THE PATIENT

Adverse Reactions

Post Marketing Experience

Overdosage

Dosage And Administration

Day 1 Start

Sunday Start

ADDITIONAL INSTRUCTIONS FOR ALL DOSING REGIMENS

How Supplied

References

Brief Summary Patient Package Insert

BOXED WARNING SECTION

HOW TO TAKE THE PILL

INSTRUCTIONS FOR USE

Detailed Patient Labeling

BOXED WARNING SECTION

RISKS OF TAKING ORAL CONTRACEPTIVES

ESTIMATED RISK OF DEATH FROM A BIRTH CONTROL METHOD OR PREGNANCY

SIDE EFFECTS OF ORAL CONTRACEPTIVES

GENERAL PRECAUTIONS

HOW TO TAKE THE PILL

PREGNANCY DUE TO PILL FAILURE

Package Label-principal Display Panel - 0.15 Mg/0.03 Mg Pouch Label

Package Label-principal Display Panel - 0.15 Mg/0.03 Mg Blister Carton