Ashlyna: Package Insert and Label Information

ASHLYNA- levonorgestrel and ethinyl estradiol and ethinyl estradiol
Glenmark Pharmaceuticals Inc., USA

1 INDICATIONS AND USAGE

Ashlyna is indicated for use by women to prevent pregnancy.

2 DOSAGE AND ADMINISTRATION

Take one tablet by mouth at the same time every day. The dosage of Ashlyna is one light blue to blue tablet containing levonorgestrel and ethinyl estradiol daily for 84 consecutive days, followed by one light yellow to yellow ethinyl estradiol tablet for 7 days. To achieve maximum contraceptive effectiveness, Ashlyna must be taken exactly as directed and at intervals not exceeding 24 hours.

Instruct the patient to begin taking Ashlyna on the first Sunday after the onset of menstruation. If menstruation begins on a Sunday, the first light blue to blue tablet is taken that day. One light blue to blue tablet should be taken daily for 84 consecutive days, followed by one light yellow to yellow tablet for 7 consecutive days. A non-hormonal back-up method of contraception (such as condoms or spermicide) should be used until a light blue to blue tablet has been taken daily for 7 consecutive days. A scheduled period should occur during the 7 days that the light yellow to yellow tablets are taken.

Begin the next and all subsequent 91-day cycles without interruption on the same day of the week (Sunday) on which the patient began her first dose of Ashlyna, following the same schedule: 84 days taking a light blue to blue tablet followed by 7 days taking a light yellow to yellow tablet. If the patient does not immediately start her next pill pack, she should protect herself from pregnancy by using a non-hormonal back-up method of contraception until she has taken a light blue to blue tablet daily for 7 consecutive days.

If unscheduled spotting or bleeding occurs, instruct the patient to continue on the same regimen. If the bleeding is persistent or prolonged, advise the patient to consult her healthcare provider.

For patient instructions regarding missed pills, see FDA-Approved Patient Labeling.

For postpartum women who are not breastfeeding, start Ashlyna no earlier than four to six weeks postpartum due to increased risk of thromboembolism. If the patient starts on Ashlyna postpartum and has not yet had a period, evaluate for possible pregnancy, and instruct her to use an additional method of contraception until she has taken a light blue to blue tablet for 7 consecutive days.

3 DOSAGE FORMS AND STRENGTHS

Ashlyna^® (Levonorgestrel and Ethinyl Estradiol Tablets, USP 0.15 mg/0.03 mg and Ethinyl Estradiol Tablets, USP 0.01 mg) are available in extended-cycle tablet dispensers, each containing a 13-week supply of tablets: 84 light blue to blue tablets, each containing 0.15 mg of levonorgestrel, USP and 0.03 mg ethinyl estradiol, USP and 7 light yellow to yellow tablets, each containing 0.01 mg of ethinyl estradiol, USP. The light blue to blue tablets are round, film-coated, biconvex, unscored tablets debossed with “E1” on one side. The light yellow to yellow tablets are round, biconvex, film-coated, unscored tablets debossed with “D8” on one side.

4 CONTRAINDICATIONS

Ashlyna is contraindicated in females who are known to have or develop the following conditions:

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A high risk of arterial or venous thrombotic diseases. Examples include women who are known to:

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Smoke, if over age 35 [see Boxed Warning and Warnings and Precautions (5.1)].

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Have deep vein thrombosis or pulmonary embolism, now or in the past [see Warnings and Precautions (5.1)].

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Have cerebrovascular disease [see Warnings and Precautions (5.1)]

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Have coronary artery disease [see Warnings and Precautions (5.1)].

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Have thrombogenic valvular or thrombogenic rhythm diseases of the heart (for example, subacute bacterial endocarditis with valvular disease, or atrial fibrillation) [see Warnings and Precautions (5.1)].

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Have inherited or acquired hypercoagulopathies [see Warnings and Precautions (5.1)].

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Have uncontrolled hypertension [see Warnings and Precautions (5.5)].

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Have diabetes with vascular disease [see Warnings and Precautions (5.7)].

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Have headaches with focal neurological symptoms or have migraine headaches with or without aura if over age 35 [see Warnings and Precautions (5.8)].

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Undiagnosed abnormal genital bleeding [see Warnings and Precautions (5.9)].

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Current diagnosis of, or history of, breast cancer, which may be hormone-sensitive [see Warnings and Precautions (5.2)].

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Liver tumors, benign or malignant, or liver disease [see Warnings and Precautions (5.3) and Use in Specific Populations (8.6)].

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Pregnancy, because there is no reason to use COCs during pregnancy [see Warnings and Precautions (5.10) and Use in Specific Populations (8.1)].

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Use of Hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, due to the potential for ALT elevations [see Warnings and Precautions (5.4)]

5 WARNINGS AND PRECAUTIONS

5.1 Thrombotic and Other Vascular Events

Stop levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets if an arterial or deep venous thrombotic event occurs. Although the use of COCs increases the risk of venous thromboembolism, pregnancy increases the risk of venous thromboembolism as much or more than the use of COCs. The risk of venous thromboembolism in women using COCs is 3 to 9 per 10,000 woman-years. The excess risk is highest during the first year of use of a COC. Use of COCs also increases the risk of arterial thromboses such as strokes and myocardial infarctions, especially in women with other risk factors for these events. The risk of thromboembolic disease due to COCs gradually disappears after COC use is discontinued.

Use of levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets provides women with more hormonal exposure on a yearly basis than conventional monthly oral contraceptives containing the same strength synthetic estrogens and progestins (an additional 9 and 13 weeks of exposure to progestin and estrogen, respectively, per year).

If feasible, stop levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets at least 4 weeks before and through 2 weeks after major surgery or other surgeries known to have an elevated risk of thromboembolism.

Start levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets no earlier than 4 to 6 weeks after delivery, in women who are not breastfeeding. The risk of postpartum thromboembolism decreases after the third postpartum week, whereas the risk of ovulation increases after the third postpartum week.

COCs 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 of age), and hypertensive women who also smoke. COCs also increase the risk for stroke in women with other underlying risk factors.

Oral contraceptives must be used with caution in women with cardiovascular disease risk factors.

Stop levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets if there is unexplained loss of vision, proptosis, diplopia, papilledema, or retinal vascular lesions. Evaluate for retinal vein thrombosis immediately.

5.2 Malignant Neoplasms

​ Breast Cancer

​ Ashlyna is contraindicated in females who currently have or have had breast cancer because breast cancer may be hormonally sensitive [see Contraindications (4) ​ ].

​ 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 (6.2) ​ ] ​ .

Cervical Cancer

Some studies suggest that COCs are associated with an increase in the risk of cervical cancer or intraepithelial neoplasia. However, there is controversy about the extent to which these findings are due to differences in sexual behavior and other factors.

5.3 Liver Disease

Discontinue levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets if jaundice develops. Steroid hormones may be poorly metabolized in patients with impaired liver function. Acute or chronic disturbances of liver function may necessitate the discontinuation of COC use until markers of liver function return to normal and COC causation has been excluded.

Hepatic adenomas are associated with COC use. An estimate of the attributable risk is 3.3 cases/100,000 COC users. Rupture of hepatic adenomas may cause death through intra-abdominal hemorrhage.

Studies have shown an increased risk of developing hepatocellular carcinoma in long-term (> 8 years) COC users. However, the attributable risk of liver cancers in COC users is less than one case per million users.

Oral contraceptive-related cholestasis may occur in women with a history of pregnancy-related cholestasis. Women with a history of COC-related cholestasis may have the condition recur with subsequent COC use.

5.4 Risk of Liver Enzyme Elevations with Concomitant Hepatitis C Treatment

During clinical trials with the Hepatitis C combination drug regimen that contains obmitasvir/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 levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets prior to starting therapy with the combination drug regimen ombitasvir/paritaprevir/ritonavir, with or without dasabuvir [see Contraindications (4)]. Levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets can be restarted approximately 2 weeks following completion of treatment with the Hepatitis C combination drug regimen.

5.5 High Blood Pressure

For women with well-controlled hypertension, monitor blood pressure and stop levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets if blood pressure rises significantly. Women with uncontrolled hypertension or hypertension with vascular disease should not use COCs.

An increase in blood pressure has been reported in women taking COCs, and this increase is more likely in older women and with extended duration of use. The incidence of hypertension increases with increasing concentration of progestin.

5.6 Gallbladder Disease

Studies suggest a small increased relative risk of developing gallbladder disease among COC users.

5.7 Carbohydrate and Lipid Metabolic Effects

Carefully monitor prediabetic and diabetic women who are taking levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets. COCs may decrease glucose tolerance in a dose-related fashion.

Consider alternative contraception for women with uncontrolled dyslipidemias. A small proportion of women will have adverse lipid changes while on COCs.

Women with hypertriglyceridemia, or a family history thereof, may be at an increased risk of pancreatitis when using COCs.

5.8 Headache

If a woman taking levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets develops new headaches that are recurrent, persistent, or severe, evaluate the cause and discontinue levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets if indicated.

An increase in frequency or severity of migraine during COC use (which may be prodromal of a cerebrovascular event) may be a reason for immediate discontinuation of the COC.

5.9 Bleeding Irregularities

Unscheduled (breakthrough) bleeding and spotting sometimes occur in patients on COCs, especially during the first 3 months of use. If bleeding persists, check for causes such as pregnancy or malignancy. If pathology and pregnancy are excluded, bleeding irregularities may resolve over time or with a change to a different COC.

When prescribing levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets, the convenience of fewer planned menses (4 per year instead of 13 per year) should be weighed against the inconvenience of increased unscheduled bleeding and/or spotting. The primary clinical trial (PSE-301) that evaluated the efficacy of levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets also assessed unscheduled bleeding. The participants in the 12-month clinical trial (N=1,006) completed the equivalent of 8,681 28-day cycles of exposure and were composed primarily of women who had used oral contraceptives previously (89%) as opposed to new users (11%). A total of 82 (8.2%) of the women discontinued levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets, at least in part, due to bleeding or spotting.

Scheduled (withdrawal) bleeding and/or spotting remained fairly constant over time, with an average of 3 days of bleeding and/or spotting per each 91-day cycle. Unscheduled bleeding and unscheduled spotting decreased over successive 91-day cycles. Table 1 below presents the number of days with unscheduled bleeding in treatment cycles 1 and 4. Table 2 presents the number of days with unscheduled spotting in treatment cycles 1 and 4.

Table 1: Total Number of Days with Unscheduled Bleeding

91-Day Treatment Cycle	Days per 84-Day Interval				Days per 28-Day Interval
	Q1	Median	Q3	Mean	Mean
1st	1	4	10	6.9	1.7
4th	0	1	4	3.2	0.8

Q1=Quartile 1: 25% of women had this number of days of unscheduled bleeding

Median: 50% of women had ≤ this number of days of unscheduled bleeding

Q3=Quartile 3: 75% of women had ≤ this number of days of unscheduled bleeding

Table 2: Total Number of Days with Unscheduled Spotting

91-Day Treatment Cycle	Days per 84-Day Interval				Days per 28-Day Interval
	Q1	Median	Q3	Mean	Mean
1st	1	4	11	7.4	1.9
4th	0	2	7	4.4	1.1

Q1=Quartile 1: 25% of women had ≤ this number of days of unscheduled spotting

Median: 50% of women had ≤ this number of days of unscheduled spotting

Q3=Quartile 3: 75% of women had ≤ this number of days of unscheduled spotting

Figure 1 shows the percentage of levonorgestrel and ethinyl estradiol tablets and ethinyl estradiol tablets subjects participating in trial PSE-301 with ≥ 7 days or ≥ 20 days of unscheduled bleeding and/or spotting, or only unscheduled bleeding, during each 91-day treatment cycle.

Figure 1: Percent of Women Taking Levonorgestrel and Ethinyl Estradiol Tablets and Ethinyl Estradiol Tablets who Reported Unscheduled Bleeding and/or Spotting or only Unscheduled Bleeding

Amenorrhea sometimes occurs in women who are using COCs. Pregnancy should be ruled out in the event of amenorrhea. Some women may encounter amenorrhea or oligomenorrhea after stopping COCs, especially when such a condition was pre-existent.