Indications and Usage

Reclipsen™ (desogestrel and ethinyl estradiol tablets USP) is 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 lists 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 Reclipsen (desogestrel and ethinyl estradiol tablets USP), 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 ^c
Method (1)	Typical Use ^a (2)	Perfect Use ^b (3)	(4)
Chance ^d	85	85
Spermicides ^e	26	6	40
Periodic abstinence	25	63
Calendar	9
Ovulation Method	3
Sympto-Thermal ^f	2
Post-Ovulation	1
Withdrawal	19	4
Cap ^g
Parous Women	40	26	42
Nulliparous Women	20	9	56
Sponge
Parous Women	40	20	42
Nulliparous Women	20	9	56
Diaphragm ^g	20	6	56
Condom ^h
Female (Reality^®)	21	5	56
Male	14	3	61
Pill	5	71
Progestin Only	0.5
Combined	0.1
IUD
Progesterone T	2.0	1.5	81
Copper 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	0.10	100
Emergency Contraceptive Pills: Treatment initiated within 72 hours after unprotected intercourse reduces the risk of pregnancy by at least 75%. ⁱ Lactation Amenorrhea Method: LAM is a highly effective, temporary method of contraception. ^j Source: Trussel 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. ^a. 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. ^b. 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. ^c. Among couples attempting to avoid pregnancy, the percentage who continue to use a method for one year. ^d. 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. ^e. Foams, creams, gels, vaginal suppositories, and vaginal film. ^f. Cervical mucus (ovulation) method supplemented by calendar in the pre-ovulatory and basal body temperature in the post-ovulatory phases. ^g. With spermicidal cream or jelly. ^h. Without spermicides. ^i. 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). ^j. 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.

Reclipsen (desogestrel and ethinyl estradiol tablets USP) has not been studied for and is not indicated for use in emergency contraception.

Dosage and Administration

To achieve maximum contraceptive effectiveness, Reclipsen must be taken exactly as directed and at intervals not exceeding 24 hours. Reclipsen is available in the Tablet Dispenser which is preset for a Sunday Start. Day 1 Start is also provided.

Day 1 Start

The dosage of Reclipsen for the initial cycle of therapy is one rose-colored “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 rose-colored “active” tablet daily for 21 days, then one white “reminder” tablet daily for 7 days. After 28 tablets have been taken, a new course is started and a rose-colored “active” tablet is taken the next day.

The use of Reclipsen 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 Reclipsen postpartum, and has not yet had a period, she should be instructed to use another method of contraception until a rose-colored “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) rose-colored “active” tablet in Weeks 1, 2, or 3, the rose-colored “active” tablet should be taken as soon as she remembers. If the patient misses two (2) rose-colored “active” tablets in Week 1 or Week 2, the patient should take two (2) rose-colored “active” tablets the day she remembers and two (2) rose-colored “active” tablets the next day; and then continue taking one (1) rose-colored “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) rose-colored “active” tablets in the third week or misses three (3) or more rose-colored “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 Reclipsen, the first rose-colored “active” tablet should be taken on the first Sunday after menstruation begins. If the period begins on Sunday, the first rose-colored “active” tablet is taken on that day. If switching directly from another oral contraceptive, the first rose-colored “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 rose-colored “active” tablet daily for 21 days, then one white “reminder” tablet daily for 7 days. After 28 tablets have been taken, a new course is started and a rose-colored “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 Reclipsen 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 Reclipsen postpartum, and has not yet had a period, she should be instructed to use another method of contraception until a rose-colored “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) rose-colored “active” tablet in Weeks 1, 2, or 3, the rose-colored “active” tablet should be taken as soon as she remembers. If the patient misses two (2) rose-colored “active” tablets in Week 1 or Week 2, the patient should take two (2) rose-colored “active” tablets the day she remembers and two (2) rose-colored “active” tablets the next day; and then continue taking one (1) rose-colored “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) rose-colored “active” tablets in the third week or misses three (3) or more rose-colored “active” tablets in a row, the patient should continue taking one rose-colored “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.

Contraindications

Reclipsen 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 ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, due to the potential for ALT elevations (see WARNINGS, Risk of Liver Enzyme Elevations with Concomitant Hepatitis C Treatment).

Adverse Reactions

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 0.90-1.12 (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 1.19-1.33 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 8-10 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.

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

figure 2

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.

Description

Reclipsen™ (desogestrel and ethinyl estradiol tablets USP) blister cards provide an oral contraceptive regimen of 21 rose-colored, 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, FD&C Blue No. 2 Aluminum Lake, FD&C Red No. 40 Aluminum Lake, hydroxypropyl methylcellulose, lactose monohydrate, polyethylene glycol, polysorbate 80, povidone, pregelatinized corn starch, stearic acid, titanium dioxide, and vitamin E.

Reclipsen blister cards also contain 7 white “inactive” tablets for oral administration, containing the following inactive ingredients: lactose anhydrous, magnesium stearate, microcrystalline cellulose and pregelatinized corn starch.

Desogestrel

C₂₂H₃₀O M.W. 310.48

Ethinyl Estradiol, USP

C₂₀H₂₄O₂ M.W. 296.40

The 21 rose-colored tablets meet USP Dissolution Test 2.

structural formula 1 structural formula 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 Reclipsen, 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_0-24 at 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, 3ß-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 Reclipsen, the relative bioavailability is approximately 83%.

In the third cycle of use after a single dose of Reclipsen, 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_0-24 at 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.

How Supplied / Storage and Handling

Reclipsen™ (desogestrel and ethinyl estradiol tablets USP) 28 tablets blister cards contain 21 rose-colored, round, film-coated, unscored, biconvex, tablets and 7 round, unscored white tablets. Each rose-colored tablet (debossed with “dp” on one side and “575” on the other side) contains 0.15 mg desogestrel and 0.03 mg ethinyl estradiol, USP. Each white tablet (debossed with “dp” on one side and “570” on the other side) contains inert ingredients.

Cartons of 6 blister cards (NDC: 0093-3304-16).

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

KEEP THIS AND ALL MEDICATIONS OUT OF THE REACH OF CHILDREN.

Patient Counseling Information

See Patient Labeling printed below.

Professional Information — Reclipsen 28 Day