QUARTETTE (levonorgestrel 0.15 mg ethinyl estradiol 0.025 mg) Dailymed

3 Dosage Forms And Strengths

QUARTETTE (levonorgestrel/ethinyl estradiol and ethinyl estradiol) tablets are available as round, film-coated, biconvex tablets debossed with TV on one side, packaged in Extended-Cycle Tablet Dispensers, each containing a 13-week supply of tablets in the following order:

• 42 light pink tablets, each containing 0.15 mg of levonorgestrel and 0.02 mg ethinyl estradiol: debossed with 076 on the other side
• 21 pink tablets containing 0.15 mg of levonorgestrel and 0.025 mg ethinyl estradiol: debossed with 075 on the other side
• 21 purple tablets containing 0.15 mg of levonorgestrel and 0.03 mg ethinyl estradiol: debossed with 074 on the other side and
• 7 yellow tablets containing 0.01 mg of ethinyl estradiol: debossed with 077 on the other side

QUARTETTE consists of 91 tablets in the following order (3):

• 42 light pink tablets containing 0.15 mg levonorgestrel and 0.02 mg ethinyl estradiol,
• 21 pink tablets containing 0.15 mg of levonorgestrel and 0.025 mg ethinyl estradiol, and
• 21 purple tablets containing 0.15 mg of levonorgestrel and 0.03 mg ethinyl estradiol, and
• 7 yellow tablets containing 0.01 mg of ethinyl estradiol.

4 Contraindications

QUARTETTE is 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 (5.5)].
  • Have diabetes mellitus and are over age 35, diabetes mellitus with hypertension or with 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 (5.8)].
• 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)].

• A high risk of arterial or venous thrombotic diseases (4)
• Undiagnosed abnormal uterine bleeding (4)
• Breast cancer (4)
• Liver tumors or liver disease (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 females with well-controlled hypertension, monitor blood pressure and stop use if blood pressure rises significantly. (5.3)
• Gallbladder disease: May cause or worsen gallbladder disease. (5.6)
• Carbohydrate and lipid metabolic effects: Monitor glucose in prediabetic and diabetic women taking QUARTETTE. Consider an alternate contraceptive method for women with uncontrolled dyslipidemias. (5.6)
• Headache: Evaluate significant change in headaches and discontinue if indicated. (5.7)
• Uterine bleeding: May cause irregular bleeding or amenorrhea. Evaluate for other causes if symptoms persist. (5.8)

5.1 Thromboembolic Disorders and Other Vascular Conditions

• Stop QUARTETTE if an arterial or deep venous thromboembolic event occurs.
• Stop QUARTETTE if there is unexplained loss of vision, proptosis, diplopia, papilledema, or retinal vascular lesions. Evaluate for retinal vein thrombosis immediately.
• Discontinue QUARTETTE during prolonged immobilization. If feasible, stop QUARTETTE at least 4 weeks before and through 2 weeks after major surgery or other surgeries known to have an elevated risk of thromboembolism.
• Start QUARTETTE 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 risk of ovulation increases after the third postpartum week.
• Before starting QUARTETTE evaluate any past medical history or family history of thrombotic or thromboembolic disorders and consider whether the history suggests an inherited or acquired hypercoagulopathy. QUARTETTE is contraindicated in females with a high risk of arterial or venous/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.

QUARTETTE 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, 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.

Use of QUARTETTE 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). In the clinical trial, three cases of deep vein thrombosis were reported.

5.2 Liver Disease

Elevated Liver Enzymes

QUARTETTE 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 QUARTETTE until liver tests return to normal and QUARTETTE causation has been excluded. Discontinue QUARTETTE if jaundice develops.

Liver Tumors

QUARTETTE is contraindicated in females with benign or 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 from 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 Hypertension

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

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 effect of COCs on blood pressure may vary according to the progestin in the COC.

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

5.5 Age-related Considerations

The risk for cardiovascular disease and prevalence of risk factors for cardiovascular disease increases 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 QUARTETTE 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 QUARTETTE, may also worsen existing gallbladder disease.

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

5.7 Adverse Carbohydrate and Lipid MetabolicEffects

Hyperglycemia

QUARTETTE 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 duration [see Contraindications (4)]. QUARTETTE may decrease glucose tolerance. Carefully monitor prediabetic and diabetic females who are taking QUARTETTE.

Dyslipidemia

Consider alternative contraception for females with uncontrolled dyslipidemias. QUARTETTE may cause adverse lipid changes.

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

5.8 Headache

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

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

Consider discontinuation of QUARTETTE in the case of 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 (light pink, pink and purple) of each extended-cycle regimen is considered “unscheduled” bleeding/spotting. Bleeding that occurs during the time a woman takes the seven tablets (yellow) containing 10 mcg of ethinyl estradiol is considered “scheduled” bleeding.

Unscheduled and Scheduled Bleeding and Spotting

Females using QUARTETTE 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 on Quartette, evaluate for causes such as pregnancy or malignancy.

When prescribing QUARTETTE, consider the occurrence of fewer scheduled menses (4 per year instead of 13 per year) against the occurrence of increased unscheduled bleeding and/or spotting. A 12-month open-label study of the efficacy of QUARTETTE in preventing pregnancy assessed scheduled and unscheduled bleeding [see Clinical Studies (14)] in 3,597 women who completed 34,087 28-day cycles of exposure. A total of 178 (4.9%) of the women discontinued QUARTETTE, at least in part, due to bleeding and/or spotting.

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

Table 2:          Number of Unscheduled Bleeding, Spotting and Bleeding and/or Spotting Days per 91-day Cycle

Cycle(N)	Days of Unscheduled Bleeding per 84-Day Interval				Median Days Per Subject-Month
	Mean	Q1	Median	Q3
1 (3330)	7.2	0	4	10	1.0
2 (2820)	3.3	0	0	4	0.0
3 (2433)	2.5	0	0	3	0.0
4 (2213)	2.2	0	0	2	0.0
Cycle (N)	Days of Unscheduled Spotting per 84-Day Interval				Median Days Per Subject-Month
	Mean	Q1	Median	Q3
1 (3330)	10.7	2	7	15	1.8
2 (2820)	6.7	0	3	9	0.8
3 (2433)	5.2	0	2	6	0.5
4 (2213)	4.4	0	1	5	0.3
Cycle (N)	Days of Unscheduled Bleeding and/or Spotting per 84-Day Interval				Median Days Per Subject-Month
	Mean	Q1	Median	Q3
1 (3330)	17.9	5	14	27	3.5
2 (2820)	10.0	1	5	14	1.3
3 (2433)	7.7	0	3	10	0.8
4 (2213)	6.6	0	3	8	0.8

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

Figure 2 shows the percent of QUARTETTE subjects in the primary clinical trial with ≥7 days or ≥20 days of unscheduled bleeding and/or spotting, or just unscheduled bleeding, during each 91-day treatment cycle.

Figure 2: Percent of Women Taking QUARTETTE Who Reported Unscheduled Bleeding and/or Spotting

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.

Amenorrhea and Oligomenorrhea

Females who use QUARTETTE may experience absence of scheduled (withdrawal) bleeding, even if they are not pregnant. Based on data from the clinical trial, amenorrhea occurred in approximately 1.9% of women during Cycle 1, 7.7% during Cycle 2, 10.7% during Cycle 3, and 10.1% during Cycle 4 using Quartette.

Rule out pregnancy in the event of amenorrhea. Some women may experience amenorrhea or oligomenorrhea after stopping QUARTETTE, especially if these conditions were pre-existent.

5.10 Depression

Carefully observe females with a history of depression and discontinue QUARTETTE if depression recurs to a serious degree. Six cases of suicidality (suicide attempts and suicidal behavior) were reported in the clinical trial; several of these cases occurred in women with a psychiatric history.

Data on the association of COCs with onset of depression or exacerbation of existing depression are limited.

5.11Malignant Neoplasms

Breast Cancer

Quartette 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.

5.12 Effect on Binding Globulins

The estrogen component of QUARTETTE 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 women with hereditary angioedema, exogenous estrogens, including QUARTETTE, may induce or exacerbate symptoms of hereditary angioedema.

5.14 Chloasma

Chloasma may occur with QUARTETTE 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 QUARTETTE.

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

• Serious cardiovascular events [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%) in clinical trials for QUARTETTE were headaches, heavy/irregular vaginal bleeding, nausea/vomiting, acne, dysmenorrhea, weight increased, mood changes, anxiety/panic attack, breast pain and migraines. (6)

To report SUSPECTED ADVERSE REACTIONS, contact Teva Pharmaceuticals at 1-888-483-8279 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 practice.

The safety data described below are from a 12-month, US, open-label study, which enrolled women aged 18-40, of whom 3,597 took at least one dose of QUARTETTE (2,661 woman-years of exposure) [see Clinical Studies (14)].

Adverse Reactions Leading to Study Discontinuation: 13.3% of the women discontinued from the clinical trial due to an adverse reaction; the most common adverse reactions (≥1% of women) leading to discontinuation were heavy/irregular bleeding (5.0%), mood swings/alteration/affect lability (1.4%), headaches/migraines (1.3%), weight increased (1.3%) and acne (1.0%).

Common Adverse Reactions (≥2% of women): headaches (12.2%), heavy/irregular vaginal bleeding (9.7%), nausea/vomiting (8.8%), acne (5.4%), dysmenorrhea (5.4%), weight increased (4.6%), mood changes (depression, depressed mood, crying, major depression, affective disorder, depression suicidal, dysthymic disorder) (2.9%), anxiety/panic attack (2.4%), breast tenderness/pain/discomfort (2.2%), migraine (2.0%).

Serious Adverse Reactions (≥2 women): Abortion Spontaneous, Suicide Attempt, Cholecystitis/ Cholelithiasis, Deep Vein Thrombosis, Ectopic Pregnancy.

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 - 1.12 (Figure 3).

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 3: Relevant Studies of Risk of Breast Cancer with Combined Oral Contraceptives



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 extended-cycle COCs containing levonorgestrel and ethinyl estradiol. Because these reactions are reported voluntarily from a population of uncertain size, it is not always 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 disorders: hypersensitivity reaction

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

Respiratory, thoracic and mediastinal disorders: pulmonary embolism, pulmonary thrombosis

Skin and subcutaneous tissue disorders: alopecia

Vascular disorders: thrombosis