levonorgestrel and ethinyl estradiol (levonorgestrel 0.15 mg ethinyl estradiol 0.03 mg) Dailymed

Levonorgestrel and ethinyl estradiol tablets are contraindicated in females who are known to have or develop the following conditions:

• •A high risk of arterial or venous thrombotic diseases. Examples include females who are known to:
  • ∘Smoke, if over age 35 [see Boxed Warning and Warnings and Precautions (5.1)].
  • ∘Have current or history of deep vein thrombosis or pulmonary embolism [see Warnings and Precautions (5.1)].
  • ∘Have cerebrovascular disease [see Warnings and Precautions (5.1)].
  • ∘Have coronary artery disease [see Warnings and Precautions (5.1)].
  • ∘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)].
  • ∘Have inherited or acquired hypercoagulopathies [see Warnings and Precautions (5.1)].
  • ∘Have uncontrolled hypertension or hypertension with vascular disease [see Warnings and Precautions (5.4)].
  • ∘Have diabetes mellitus and are over age of 35, diabetes mellitus with hypertension or vascular disease or other end-organ damage, or diabetes mellitus of >20 years duration [see Warnings and Precautions (5.7)].
  • ∘Have headaches with focal neurological symptoms, migraine headaches with aura, or over age 35 with any migraine headaches [see Warnings and Precautions (5.8)].
• •Current diagnosis of, or history of breast cancer, which may be hormone sensitive [see Warnings and Precautions (5.11)].
• •Liver tumors, acute viral hepatitis, or severe (decompensated) cirrhosis [see Warnings and Precautions (5.2) and Use in Specific Populations (8.6)].
• • Undiagnosed abnormal uterine bleeding [see Warnings and Precautions ( 5.9 )].
• • 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 (5.3)].

• •A high risk of arterial or venous thrombotic diseases (4)
• •Liver tumors or liver disease, acute viral hepatitis or decompensated cirrhosis (4)
• •Undiagnosed abnormal uterine bleeding (4)
• •Breast cancer (4)
• •Co-administration with Hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir (4)

5 Warnings And Precautions

• •Vascular risks: Stop if a thrombotic or thromboembolic event occurs. Stop at least 4 weeks before and through 2 weeks after major surgery. Start no earlier than 4 weeks after delivery, in women who are not breastfeeding. Consider cardiovascular risk factors before initiating in all females, particularly those over 35 years. (5.1, 5.5)
• •Liver disease: Discontinue if jaundice occurs. (5.2)
• •Hypertension: If used in women with well-controlled hypertension, monitor blood pressure and stop if blood pressure rises significantly. (5.4)
• •Gallbladder disease: May cause or worsen gallbladder disease. (5.5)
• •Adverse carbohydrate and lipid effects: Monitor glucose in prediabetic and diabetic women taking levonorgestrel and ethinyl estradiol. Consider an alternate contraceptive method for women with uncontrolled dyslipidemia. (5.7)
• •Headache: Evaluate significant change in headaches and discontinue if indicated. (5.8)
• •Uterine bleeding: May cause irregular bleeding or amenorrhea. Evaluate for other causes if symptoms persist. (5.9)

5.1 Thromboembolic Disorders and Other Vascular Conditions

• •Stop levonorgestrel and ethinyl estradiol if an arterial or venous thrombotic/thromboembolic event occurs.
• •Stop levonorgestrel and ethinyl estradiol if there is unexplained loss of vision, proptosis, diplopia, papilledema, or retinal vascular lesions. Evaluate for retinal vein thrombosis immediately.
• •Discontinue levonorgestrel and ethinyl estradiol during prolonged immobilization. If feasible, stop levonorgestrel and ethinyl estradiol 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 no earlier than 4 weeks after delivery in females who are not breastfeeding. The risk of postpartum thromboembolism decreases after the third postpartum week, whereas the likelihood of ovulation increases after the third postpartum week.
• •Before starting levonorgestrel and ethinyl estradiol evaluate any past medical history or family history of thrombotic or thromboembolic disorders and consider whether the history suggests an inherited or acquired hypercoagulopathy. Levonorgestrel and ethinyl estradiol is contraindicated in females with a high risk of arterial or venous thrombotic/thromboembolic diseases [see Contraindications (4)].

Arterial Events

COCs increase the risk of cardiovascular events and cerebrovascular events, such as myocardial infarction and stroke. The risk is greater among older women (> 35 years of age), smokers, and females with hypertension, dyslipidemia, diabetes, or obesity.

Levonorgestrel and ethinyl estradiol is contraindicated in women over 35 years of age who smoke [see Contraindications (4)]. Cigarette smoking increases the risk of serious cardiovascular events from COC use. This risk increases with age, particularly in women over 35 years of age, and with the number of cigarettes smoked.

Venous Events

Use of COCs increases the risk of venous thromboembolic events (VTEs), such as deep vein thrombosis and pulmonary embolism. Risk factors for VTEs include smoking, obesity, and family history of VTE, in addition to other factors that contraindicate use of COCs [see Contraindications (4)]. While the increased risk of VTE associated with use of COCs is well-established, the rates of VTE are even greater during pregnancy, and especially during the postpartum period (see Figure 1). The rate of VTE in females using COCs has been estimated to be 3 to 9 cases per 10,000 woman years.

The risk of VTE is highest during the first year of use of a COC and when restarting hormonal contraception after a break of four weeks or longer. The risk of thromboembolic disease due to COCs gradually disappears after COC use is discontinued.

Figure 1 shows the risk of developing a VTE for females who are not pregnant and do not use oral contraceptives, for females who use oral contraceptives, for pregnant females and for females in the postpartum period. To put the risk of developing a VTE into perspective: If 10,000 females who are not pregnant and do not use oral contraceptives are followed for one year, between 1 and 5 of these females will develop a VTE.

Figure 1: Likelihood of Developing a VTE

* Pregnancy data based on actual duration of pregnancy in the reference studies. Based on a model assumption that pregnancy duration is nine months, the rate is 7 to 27 per 10,000 WY.

Use of levonorgestrel and ethinyl estradiol provides women with more hormonal exposure on a yearly basis than conventional monthly COCs containing the same strength synthetic estrogens and progestins (an additional 9 weeks of exposure per year). In the clinical trial, one case of pulmonary embolism was reported. Postmarketing adverse reactions of VTE have been reported in women who used levonorgestrel and ethinyl estradiol.

5.2 Liver Disease

Elevated Liver Enzymes

Levonorgestrel and ethinyl estradiol is contraindicated in females with acute viral hepatitis or severe (decompensated) cirrhosis of the liver [see Contraindications (4)]. Acute liver test abnormalities may necessitate the discontinuation of levonorgestrel and ethinyl estradiol until the liver tests return to normal and levonorgestrel and ethinyl estradiol causation has been excluded. Discontinue levonorgestrel and ethinyl estradiol if jaundice develops.

Liver Tumors

Levonorgestrel and ethinyl estradiol is contraindicated in females with benign and malignant liver tumors [see Contraindications (4)]. COCs increase the risk of hepatic adenomas. 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. The attributable risk of liver cancers in COC users is less than one case per million users.

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

5.4 Hypertension

Levonorgestrel and ethinyl estradiol is contraindicated in females with uncontrolled hypertension or hypertension with vascular disease [see Contraindications (4)]. For all women, including those with well-controlled hypertension, monitor blood pressure at routine visits and stop levonorgestrel and ethinyl estradiol if blood pressure rises significantly.

An increase in blood pressure has been reported in females taking COCs, and this increase is more likely in older women and with extended duration of use. The effect of COCs on blood pressure may vary according to the progestin in the COC.

5.5 Age-related Considerations

The risk for cardiovascular disease and prevalence of risk factors for cardiovascular disease increase with age. Certain conditions, such as smoking and migraine headache without aura, that do not contraindicate COC use in younger females, are contraindications to use in women over 35 years of age [see Contraindications (4) and Warnings and Precautions (5.1)]. Consider the presence of underlying risk factors that may increase the risk of cardiovascular disease or VTE, particularly before initiating levonorgestrel and ethinyl estradiol for women over 35 years, such as:

• •Hypertension
• •Diabetes
• •Dyslipidemia
• •Obesity

5.6 Gallbladder Disease

Studies suggest a small increased relative risk of developing gallbladder disease among COC users. Use of COCs, including levonorgestrel and ethinyl estradiol, may worsen existing gallbladder disease.

A past history of COC-related cholestasis predicts an increased risk with subsequent COC use. Females with a history of pregnancy-related cholestasis may be at an increased risk for COC-related cholestasis.

5.7 Adverse Carbohydrate and Lipid Metabolic Effects

Hyperglycemia

Levonorgestrel and ethinyl estradiol is contraindicated in diabetic women over age 35, or females who have diabetes with hypertension, nephropathy, retinopathy, neuropathy, other vascular disease or females with diabetes of >20 years of duration [see Contraindications (4)]. Levonorgestrel and ethinyl estradiol may decrease glucose tolerance. Carefully monitor prediabetic and diabetic females who are using levonorgestrel and ethinyl estradiol.

Dyslipidemia

Consider alternative contraception for females with uncontrolled dyslipidemia. Levonorgestrel and ethinyl estradiol may cause adverse lipid changes.

Females with hypertriglyceridemia, or a family history thereof, may have an increase in serum triglyceride concentrations when using levonorgestrel and ethinyl estradiol, which may increase the risk of pancreatitis.

5.8 Headache

Levonorgestrel and ethinyl estradiol is contraindicated in females who have headaches with focal neurological symptoms or have migraine headaches with aura, and in women over age 35 years who have migraine headaches with or without aura [see Contraindications (4)].

If a female taking levonorgestrel and ethinyl estradiol develops new headaches that are recurrent, persistent, or severe, evaluate the cause and discontinue levonorgestrel and ethinyl estradiol if indicated. Consider discontinuation of levonorgestrel and ethinyl estradiol if there is an increased frequency or severity of migraine during COC use (which may be prodromal of a cerebrovascular event) [see Contraindications (4)] .

5.9 Bleeding Irregularities and Amenorrhea

Bleeding and/or spotting that occurs at any time while taking the first 84 tablets of each extended-cycle regimen is considered "unscheduled" bleeding/spotting. Bleeding that occurs during the time a woman takes the seven white to off-white inert tablets is considered "scheduled" bleeding.

Unscheduled Bleeding and Spotting

Females using levonorgestrel and ethinyl estradiol may experience unscheduled (breakthrough or intracyclic) bleeding and spotting especially during the first 3 months of use. Bleeding irregularities may resolve over time or by changing to a different contraceptive product. If unscheduled bleeding persists or occurs after previously regular cycles, evaluate for causes such as pregnancy or malignancy.

Before prescribing levonorgestrel and ethinyl estradiol, advise the woman to weigh the occurrence of fewer scheduled menses (4 per year instead of 13 per year) against the occurrence of increased unscheduled bleeding and/or spotting.

The clinical trial of the efficacy of levonorgestrel and ethinyl estradiol (91-day cycles) in preventing pregnancy also assessed scheduled and unscheduled bleeding. The participants in the study were composed primarily of women who had used oral contraceptives previously as opposed to new users. Women with a history of breakthrough bleeding/spotting ≥ 10 consecutive days on oral contraceptives were excluded from the study. More levonorgestrel and ethinyl estradiol subjects, compared to subjects on the comparator 28-day cycle regimen, discontinued prematurely for unacceptable bleeding (7.7% [levonorgestrel and ethinyl estradiol] vs. 1.8% [28-day cycle regimen]).

Unscheduled bleeding and unscheduled spotting decreased over successive 91-day cycles. Table 3 below presents the number of days with unscheduled bleeding and/or spotting for each respective 91-day cycle.

Table 3: Number of Unscheduled Bleeding and/or Spotting Days per 91-day Cycle

Cycle (N)	Days of Unscheduled Bleeding and/or Spotting per 84-Day Interval				Median Days Per Subject-Month
	Mean	Q1	Median	Q3
1 (446)	15.1	3	12	23	3
2 (368)	11.6	2	6	17.5	1.5
3 (309)	10.6	1	6	15	1.5
4 (282)	8.8	1	4	14	1

Q1=Quartile 1: 25% of women had ≤ this number of days of unscheduled bleeding/spotting Median: 50% of women had ≤ this number of days of unscheduled bleeding/spotting

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

Table 4 shows the percentages of women with ≥7 days and ≥20 days of unscheduled spotting and/or bleeding in the levonorgestrel and ethinyl estradiol and the 28-day cycle treatment groups.

Table 4: Percentage of Subjects with Unscheduled Bleeding and/or Spotting

Days of unscheduled bleeding and/or spotting	Percentage of Subjects a
a Based on spotting and/or bleeding on days 1 to 84 of a 91 day cycle in the levonorgestrel and ethinyl estradiol subjects and days 1 to 21 of a 28 day cycle over 4 cycles in the 28-day dosing regimen.
Levonorgestrel and ethinyl estradiol	Cycle 1 (N=385)	Cycle 4 (N=261)
≥ 7 days	65%	42%
≥ 20 days	35%	15%
28-day regimen	Cycles 1 to 4 (N=194)	Cycles 10 to 13 (N=158)
≥ 7 days	38%	39%
≥ 20 days	6%	4%

Total days of bleeding and/or spotting (scheduled plus unscheduled) were similar over one year of treatment for levonorgestrel and ethinyl estradiol subjects and subjects on the 28-day cycle regimen.

Amenorrhea and Oligomenorrhea

Females who use levonorgestrel and ethinyl estradiol may experience absence of scheduled (withdrawal) bleeding, even if they are not pregnant. Based on data from the clinical trial of levonorgestrel and ethinyl estradiol, amenorrhea occurred in approximately 0.8% of females during Cycle 1, 1.2% of females during Cycle 2, 3.7% of females during Cycle 3, and 3.4% of females during Cycle 4.

Because females using levonorgestrel and ethinyl estradiol will likely have scheduled bleeding only 4 times per year, rule out pregnancy at the time of any missed menstrual period.

After discontinuation of levonorgestrel and ethinyl estradiol, amenorrhea or oligomenorrhea may occur, especially if these conditions were pre-existent.

5.10 Depression

Carefully observe females with a history of depression and discontinue levonorgestrel and ethinyl estradiol if depression recurs to a serious degree. Data on the association of COCs with onset of depression or exacerbation of existing depression are limited.

5.11 Malignant Neoplasms

Breast Cancer

Levonorgestrel and ethinyl estradiol 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 COC are associated with an increase in the risk of cervical cancer or intraepithelial neoplasia. However, there is controversy about the extent to which such findings may be due to differences in sexual behavior and other factors.

5.12 Effect on Binding Globulins

The estrogen component of levonorgestrel and ethinyl estradiol may raise the serum concentrations of thyroxine-binding globulin, sex hormone-binding globulin and cortisol-binding globulin. The dose of replacement thyroid hormone or cortisol therapy may need to be increased.

5.13 Hereditary Angioedema

In females with hereditary angioedema, exogenous estrogens, including levonorgestrel and ethinyl estradiol, may induce or exacerbate symptoms of hereditary angioedema.

5.14 Chloasma

Chloasma may occur with levonorgestrel and ethinyl estradiol use, especially in females with a history of chloasma gravidarum. Advise females with a history of chloasma to avoid exposure to the sun or ultraviolet radiation while taking levonorgestrel and ethinyl estradiol.

The following serious adverse reactions with the use of COCs are discussed elsewhere in the labeling:

• •Serious cardiovascular events and stroke [see Boxed Warning and Warnings and Precautions (5.1)]
• •Vascular events [see Warnings and Precautions (5.1)]
• •Liver disease [see Warnings and Precautions (5.2)]

The most common adverse reactions (≥2%) reported during clinical trials were headache, menorrhagia, nausea, dysmenorrhea, acne, migraine, breast tenderness, weight increased, and depression. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Glenmark Pharmaceuticals Inc., USA at 1 (888) 721-7115 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trial Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to the rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

The clinical trial that evaluated the safety and efficacy of levonorgestrel and ethinyl estradiol was a 12-month, randomized, multicenter, open-label study, which enrolled women aged 18 to 40, of whom 456 took at least one dose of levonorgestrel and ethinyl estradiol (345.14 woman-years of exposure) [see Clinical Studies (14)].

Adverse Reactions Leading to Study Discontinuation: 14.9% of the women discontinued from the clinical trial due to an adverse reaction; the most common adverse reactions (≥ 1% of women) leading to discontinuation in the levonorgestrel and ethinyl estradiol group were menorrhagia (5.7%), mood swings (1.9%), weight/appetite increase (1.5%), and acne (1.3%).

Common Adverse Reactions (≥ 2% of women): headache (20.6%), menorrhagia (11.6%), nausea (7.5%), dysmenorrhea (5.7%), acne (4.6%), migraine (4.4%), breast tenderness (3.5%), weight increased (3.1%), and depression (2.1%).

Serious Adverse Reactions: pulmonary embolus, cholecystitis.

6.2 Postmarketing 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.

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.

The following adverse reactions have been identified during post-approval use of levonorgestrel and ethinyl estradiol. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Gastrointestinal disorders: abdominal distension, vomiting

General disorders and administration site conditions: chest pain, fatigue, malaise, edema peripheral, pain

Immune system disorder: hypersensitivity reactions, including itching, rash, and angioedema

Investigations: blood pressure increased

Musculoskeletal and connective tissue disorders: muscle spasms, pain in extremity

Nervous system disorders: dizziness, loss of consciousness

Psychiatric disorders: insomnia

Reproductive and breast disorders: dysmenorrhea

Skin and subcutaneous tissue disorders: alopecia

Vascular disorders: thrombosis, pulmonary embolism, pulmonary thrombosis