TriNessa (norgestimate 0.25 mg ethinyl estradiol 0.035 mg) Dailymed

Recent Major Changes Section

Contraindications (4)	08/2017
Warnings and Precautions (5.3)	08/2017

1 Indications And Usage

MonoNessa and TriNessa are estrogen/progestin COCs, indicated for use by women to prevent pregnancy. (1.1)

TriNessa is also indicated for the treatment of moderate acne vulgaris in females at least 15 years of age, who have no known contraindications to oral contraceptive therapy and have achieved menarche.

TriNessa should be used for the treatment of acne only if the patient desires an oral contraceptive for birth control. (1.2)

1.1Oral Contraceptive

MonoNessa and TriNessa Tablets are indicated for use by females of reproductive potential to prevent pregnancy [see Clinical Studies (14)].

1.2Acne

TriNessa is indicated for the treatment of moderate acne vulgaris in females at least 15 years of age, who have no known contraindications to oral contraceptive therapy and have achieved menarche. TriNessa should be used for the treatment of acne only if the patient desires an oral contraceptive for birth control [see Clinical Studies (14)].

2 Dosage And Administration

• •Take one tablet daily by mouth at the same time every day. (2.2)
• •Take tablets in the order directed on the buler pack. (2.2)
• •Do not skip or delay tablet intake. (2.2)

2.1How to Start MonoNessa or TriNessa

MonoNessa and TriNessa are dispensed in a VERIDATE Tablet Dispenser [see How Supplied/Storage and Handling (16)]. MonoNessa and TriNessa may be started using either a Day 1 start or a Sunday start (see Table 1). For the first cycle of a Sunday Start regimen, an additional method of contraception should be used until after the first 7 consecutive days of administration.

2.2How to Take MonoNessa or TriNessa

MonoNessa active tablets are blue (Day 1 to Day 21).

TriNessa active tablets are white (Day 1 to Day 7), light blue (Day 8 to Day 14) and blue (Day 15 to Day 21).

MonoNessa and TriNessa both have dark green inactive tablets (Day 22 to Day 28).Take first active tablet without regard to meals on the first day of menses.

Take subsequent active tablets once daily at the same time each day for a total of 21 days.

Take one dark green inactive tablet daily for 7 days and at the same time of day that active tablets were taken.

Begin each subsequent pack on the same day of the week as the first cycle pack (i.e., on the day after taking the last inactive tablet)Take first active tablet without regard to meals on the first Sunday after the onset of menses. Due to the potential risk of becoming pregnant, use additional non-hormonal contraception (such as condoms and spermicide) for the first seven days of the patient's first cycle pack of MonoNessa or TriNessa.

Take subsequent active tablets once daily at the same time each day for a total of 21 days.

Take one dark green inactive tablet daily for the following 7 days and at the same time of day that active tablets were taken.

Begin each subsequent pack on the same day of the week as the first cycle pack (i.e., on the Sunday after taking the last inactive tablet) and additional non-hormonal contraceptive is not needed.Transdermal patchOn the day when next application would have been scheduledVaginal ringOn the day when next insertion would have been scheduledInjectionOn the day when next injection would have been scheduledIntrauterine contraceptiveOn the day of removal

If the IUD is not removed on first day of the patient's menstrual cycle, additional non-hormonal contraceptive (such as condoms and spermicide) is needed for the first seven days of the first cycle pack.ImplantOn the day of removal

Table 1: Instructions for Administration of MonoNessa or TriNessa

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Complete instructions to facilitate patient counseling on proper tablet usage are located in the FDA-Approved Patient Labeling.
Starting COCs in women not currently using hormonal contraception (Day 1 Start or Sunday Start) Important: Consider the possibility of ovulation and conception prior to initiation of this product. Tablet Color:
	Day 1 Start:
Sunday Start:
Switching to MonoNessa or TriNessa from another oral contraceptive	Start on the same day that a new pack of the previous oral contraceptive would have started.
Switching from another contraceptive method to MonoNessa or TriNessa	Start MonoNessa or TriNessa:

Starting MonoNessa or TriNessa after Abortion or Miscarriage

First-trimester

• •After a first-trimester abortion or miscarriage, MonoNessa or TriNessa may be started immediately. An additional method of contraception is not needed if MonoNessa or TriNessa is started immediately.
• •If MonoNessa or TriNessa is not started within 5 days after termination of the pregnancy, the patient should use additional non-hormonal contraception (such as condoms and spermicide) for the first seven days of her first cycle pack of MonoNessa or TriNessa.

Second-trimester

• •Do not start until 4 weeks after a second-trimester abortion or miscarriage, due to the increased risk of thromboembolic disease. Start MonoNessa or TriNessa, following the instructions in Table 1 for Day 1 or Sunday start, as desired. If using Sunday start, use additional non-hormonal contraception (such as condoms and spermicide) for the first seven days of the patient's first cycle pack of MonoNessa or TriNessa. [see Contraindications (4), Warnings and Precautions (5.1), and FDA-Approved Patient Labeling.]

Starting MonoNessa or TriNessa after Childbirth

• •Do not start until 4 weeks after delivery, due to the increased risk of thromboembolic disease. Start contraceptive therapy with MonoNessa or TriNessa following the instructions in Table 1 for women not currently using hormonal contraception.
• •MonoNessa or TriNessa are not recommended for use in lactating women [see Use in Specific Populations (8.3)].
• •If the woman has not yet had a period postpartum, consider the possibility of ovulation and conception occurring prior to use of MonoNessa or TriNessa. [See Contraindications (4), Warnings and Precautions (5.1), Use in Specific Populations (8.1 and 8.3), and FDA-Approved Patient Labeling].

VERIDATE^® Tablet Dispenser

• •Place the refill in the VERIDATE Tablet Dispenser so that the V notch in the refill is at the top of the dispenser. Press the refill down so that it fits firmly under all the nibs (see illustration below).
• •If the patient starts pill-taking on Sunday, the first active pill should be taken on the first Sunday after the patient's menstrual period begins. Remove the first active pill at the top of the dispenser (Sunday) by pressing the pill through the hole in the bottom of the dispenser.

MonoNessa:

• •If the patient will start pill-taking on "Day 1," choose a blue pill that corresponds with the day of the week the patient will take the first pill. Remove that blue pill by pressing the pill through the hole in the bottom of the dispenser.

TriNessa:

• •If the patient will start pill-taking on a day other than Sunday, a calendar label has been provided and should be placed over the calendar in the center of the VERIDATE. To place the label correctly, identify the correct starting day, locate that day printed in blue on the label, and line that day up with the first white pill directly under the V notch at the top of the dispenser. Remove the label from the backing. Press the center of the label down onto the center of the printed calendar. Remove that white pill by pressing the pill through the hole in the bottom of the dispenser.
• •After all the dark green pills have been taken, insert a new refill into the VERIDATE. The patient should take the first pill on the next day, even if the patient's period is not over yet.

To Insert New Refill (MonoNessa or TriNessa):

• •Lift the empty refill out of the VERIDATE Tablet Dispenser.
• •Insert the new refill so that the V notch in the refill is at the top of the dispenser. Press the refill down so that it fits firmly under the nibs.

2.3Missed Tablets

If one active tablet is missed in Weeks 1, 2, or 3If two active tablets are missed in Week 1 or Week 2If two active tablets are missed in the third week or three or more active tablets are missed in a row in Weeks 1, 2, or 3

Table 2: Instructions for Missed MonoNessa or TriNessa Tablets

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Take the tablet as soon as possible. Continue taking one tablet a day until the pack is finished.

Take the two missed tablets as soon as possible and the next two active tablets the next day. Continue taking one tablet a day until the pack is finished. Additional non-hormonal contraception (such as condoms and spermicide) should be used as back-up if the patient has sex within 7 days after missing tablets.

Day 1 start: Throw out the rest of the pack and start a new pack that same day. Sunday start: Continue taking one tablet a day until Sunday, then throw out the rest of the pack and start a new pack that same day. Additional non-hormonal contraception (such as condoms and spermicide) should be used as back-up if the patient has sex within 7 days after missing tablets.

2.4Advice in Case of Gastrointestinal Disturbances

In case of severe vomiting or diarrhea, absorption may not be complete and additional contraceptive measures should be taken. If vomiting or diarrhea occurs within 3 to 4 hours after taking an active tablet, handle this as a missed tablet [see FDA-Approved Patient Labeling].

2.5TriNessa Use for Acne

The timing of initiation of dosing with TriNessa for acne should follow the guidelines for use of TriNessa as an oral contraceptive. Consult the DOSAGE AND ADMINISTRATION section (2.1) for instructions.

Do not prescribe MonoNessa or TriNessa to women who are known to have the following conditions:

• •A high risk of arterial or venous thrombotic diseases. Examples include women who are known to:
  • •Smoke, if over age 35 [see Boxed Warning and Warnings and Precautions (5.1)]
  • •Have deep vein thrombosis or pulmonary embolism, now or in the past [see Warnings and Precautions (5.1)]
  • •Have inherited or acquired hypercoagulopathies [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 uncontrolled hypertension [see Warnings and Precautions (5.4)]
  • •Have diabetes mellitus with vascular disease [see Warnings and Precautions (5.6)]
  • •Have headaches with focal neurological symptoms or migraine headaches with aura [see Warnings and Precautions (5.7)]
    • •Women over age 35 with any migraine headaches [see Warnings and Precautions (5.7)]
• •Liver tumors, benign or malignant, or liver disease [see Warnings and Precautions (5.2)]
• •Undiagnosed abnormal uterine bleeding [see Warnings and Precautions (5.8)]
• •Pregnancy, because there is no reason to use COCs during pregnancy [see Warnings and Precautions (5.9) and Use in Specific Populations (8.1)]
• •Breast cancer or other estrogen- or progestin-sensitive cancer, now or in the past [see Warnings and Precautions (5.11)]
• • 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 (4)
• •Undiagnosed abnormal uterine bleeding (4)
• •Pregnancy (4)
• •Breast cancer or other estrogen- or progestin-sensitive cancer (4)
• •Co-administration with Hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir (4)

5 Warnings And Precautions

• • Thromboembolic Disorders and Other Vascular Problems: Stop MonoNessa or TriNessa if a thrombotic 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. (5.1)
• • Liver disease: Discontinue MonoNessa or TriNessa if jaundice occurs. (5.2)
• • High blood pressure: If used in women with well-controlled hypertension, monitor blood pressure and stop MonoNessa or TriNessa if blood pressure rises significantly. (5.4)
• • Carbohydrate and lipid metabolic effects: Monitor prediabetic and diabetic women taking MonoNessa or TriNessa. Consider an alternate contraceptive method for women with uncontrolled dyslipidemia. (5.6)
• • Headache: Evaluate significant change in headaches and discontinue MonoNessa or TriNessa if indicated. (5.7)
• • Bleeding Irregularities and Amenorrhea: Evaluate irregular bleeding or amenorrhea. (5.8)

5.1Thromboembolic Disorders and Other Vascular Problems

• •Stop MonoNessa or TriNessa if an arterial thrombotic event or venous thromboembolic (VTE) event occurs.
• •Stop MonoNessa or TriNessa if there is unexplained loss of vision, proptosis, diplopia, papilledema, or retinal vascular lesions. Evaluate for retinal vein thrombosis immediately [see Adverse Reactions (6.2)].
• •If feasible, stop MonoNessa or TriNessa at least 4 weeks before and through 2 weeks after major surgery or other surgeries known to have an elevated risk of VTE as well as during and following prolonged immobilization.
• •Start MonoNessa or TriNessa no earlier than 4 weeks after delivery, in women who are not breastfeeding. The risk of postpartum VTE decreases after the third postpartum week, whereas the risk of ovulation increases after the third postpartum week.
• •The use of COCs increases the risk of VTE. However, pregnancy increases the risk of VTE as much or more than the use of COCs. The risk of VTE in women using COCs is 3 to 9 cases per 10,000 woman-years. The risk of VTE is highest during the first year of use of COCs and when restarting hormonal contraception after a break of 4 weeks or longer. The risk of thromboembolic disease due to COCs gradually disappears after use is discontinued.
• •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. COCs have been shown to increase both the relative and attributable risks of cerebrovascular events (thrombotic and hemorrhagic strokes). This risk increases with age, particularly in women over 35 years of age who smoke.
• •Use COCs with caution in women with cardiovascular disease risk factors.

5.2Liver Disease

Impaired Liver Function

Do not use MonoNessa or TriNessa in women with liver disease, such as acute viral hepatitis or severe (decompensated) cirrhosis of liver [see Contraindications (4)]. 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. Discontinue MonoNessa or TriNessa if jaundice develops.

Liver Tumors

MonoNessa and TriNessa are contraindicated in women with benign and malignant liver tumors [see Contraindications (4)]. 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 risk of liver cancers in COC users is less than one case per million users.

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

5.4High Blood Pressure

MonoNessa and TriNessa are contraindicated in women with uncontrolled hypertension or hypertension with vascular disease [see Contraindications (4)]. For women with well-controlled hypertension, monitor blood pressure and stop MonoNessa and TriNessa 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 with extended duration of use. The incidence of hypertension increases with increasing concentrations of progestin.

5.5Gallbladder Disease

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

5.6Carbohydrate and Lipid Metabolic Effects

Carefully monitor prediabetic and diabetic women who take MonoNessa or TriNessa. COCs may decrease glucose tolerance.

Consider alternative contraception for women with uncontrolled dyslipidemia. 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.

5.7Headache

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

Consider discontinuation of MonoNessa or TriNessa in the case of increased frequency or severity of migraine during COC use (which may be prodromal of a cerebrovascular event).

5.8Bleeding Irregularities and Amenorrhea

Unscheduled Bleeding and Spotting

Unscheduled (breakthrough or intracyclic) bleeding and spotting sometimes occur in patients on COCs, especially during the first three months of use. If bleeding persists or occurs after previously regular cycles, 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 contraceptive product.

In clinical trials of MonoNessa and TriNessa, the frequency and duration of breakthrough bleeding and/or spotting was assessed in 1,647 patients (21,275 evaluable cycles) and 4,826 patients (35,546 evaluable cycles), respectively. A total of 100 (7.5%) women discontinued MonoNessa and 231 (4.8%) women discontinued TriNessa, at least in part, due to bleeding or spotting. Based on data from the clinical trials, 14–34% of women using MonoNessa experienced unscheduled bleeding per cycle in the first year; for TriNessa, the respective numbers were 13–38%. The percent of women who experienced breakthrough/unscheduled bleeding tended to decrease over time.

Amenorrhea and Oligomenorrhea

Women who use MonoNessa or TriNessa may experience amenorrhea. Some women may experience amenorrhea or oligomenorrhea after discontinuation of COCs, especially when such a condition was pre-existent.

If scheduled (withdrawal) bleeding does not occur, consider the possibility of pregnancy. If the patient has not adhered to the prescribed dosing schedule (missed one or more active tablets or started taking them on a day later than she should have), consider the possibility of pregnancy at the time of the first missed period and take appropriate diagnostic measures. If the patient has adhered to the prescribed regimen and misses two consecutive periods, rule out pregnancy.

5.9COC 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. Studies also do not suggest a teratogenic effect, particularly in so far as cardiac anomalies and limb reduction defects are concerned, when oral contraceptives are taken inadvertently during early pregnancy. Discontinue MonoNessa or TriNessa use if pregnancy is confirmed.

Administration of COCs to induce withdrawal bleeding should not be used as a test for pregnancy [see Use in Specific Populations (8.1)].

5.10Depression

Carefully observe women with a history of depression and discontinue MonoNessa or TriNessa if depression recurs to a serious degree.

5.11Carcinoma of Breast and Cervix

• •MonoNessa and TriNessa are contraindicated in women who currently have or have had breast cancer because breast cancer may be hormonally sensitive [see Contraindications (4)].
•  There is substantial evidence that COCs do not increase the incidence of breast cancer. Although some past studies have suggested that COCs might increase the incidence of breast cancer, more recent studies have not confirmed such findings.
• •Some studies suggest that COC use has been associated with an increase in the risk of cervical cancer or intraepithelial neoplasia. However, there continues to be controversy about the extent to which such findings may be due to differences in sexual behavior and other factors.

5.12Effect on Binding Globulins

The estrogen component of COCs 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.

5.13Monitoring

A woman who is taking COCs should have a yearly visit with her healthcare provider for a blood pressure check and for other indicated healthcare.

5.14Hereditary Angioedema

In women with hereditary angioedema, exogenous estrogens may induce or exacerbate symptoms of angioedema.

5.15Chloasma

Chloasma may occasionally occur, especially in women with a history of chloasma gravidarum. Women with a tendency to chloasma should avoid exposure to the sun or ultraviolet radiation while taking MonoNessa or TriNessa.

6 Adverse Reactions

The following serious adverse reactions with the use of COCs are discussed elsewhere in 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)]

Adverse reactions commonly reported by COC users are:

• •Irregular uterine bleeding
• •Nausea
• •Breast tenderness
• •Headache

The most common adverse reactions reported during clinical trials (≥2%) were:

MonoNessa: headache/migraine, abdominal/gastrointestinal pain, vaginal infection, genital discharge, breast issues (including breast pain, discharge, and enlargement), mood disorders (including depression and mood altered), flatulence, nervousness, rash. (6.1)

TriNessa: headache/migraine, breast issues (including breast pain, enlargement, and discharge), vaginal infection, abdominal/gastrointestinal pain, mood disorders (including mood alteration and depression), genital discharge, changes in weight (including weight increased or decreased). ( 6.1 )To report SUSPECTED ADVERSE REACTIONS, contact Actavis at 1-800-272-5525 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1Clinical 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 rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

MonoNessa

The safety of MonoNessa was evaluated in 1,647 healthy women of child-bearing potential who participated in 3 clinical trials and received at least 1 dose of MonoNessa for contraception. Two trials were randomized active-controlled trials and 1 was an uncontrolled open-label trial. In all 3 trials, subjects were followed for up to 24 cycles.

Common Adverse Reactions (≥ 2% of subjects): The most common adverse reactions reported by at least 2% of the 1,647 women were the following in order of decreasing incidence: headache/migraine (32.9%), abdominal/gastrointestinal pain (7.8%), vaginal infection (8.4%), genital discharge (6.8%), breast issues (including breast pain, discharge, and enlargement) (6.3%), mood disorders (including depression and mood altered) (5.0%), flatulence (3.2%), nervousness (2.9%), and rash (2.6%).

Adverse Reactions Leading to Study Discontinuation: Over the three trials, between 11 to 21% of subjects discontinued the trial due to an adverse reaction. The most common adverse reactions (≥1%) leading to discontinuation were: metrorrhagia (6.9%), nausea/vomiting (5.0%), headache (4.1%), mood disorders (including depression and mood altered) (2.4%), premenstrual syndrome (1.7%), hypertension (1.4%), breast pain (1.4%), nervousness (1.3%), amenorrhea (1.1%), dysmenorrhea (1.1%), weight increased (1.1%), and flatulence (1.1%).

Serious Adverse Reactions: breast cancer (1 subject), mood disorders including depression, irritability, and mood swings (1 subject), myocardial infarction (1 subject), and venous thromboembolic events including pulmonary embolism (1 subject) and deep vein thrombosis (DVT) (1 subject).

TriNessa

The safety of TriNessa was evaluated in 4,826 healthy women of child-bearing potential who participated in 6 clinical trials and received at least 1 dose of TriNessa for contraception. Two trials were randomized active-controlled trials and 4 were uncontrolled open-label trials. In 3 trials, subjects were followed for up to 24 cycles; in 2 trials, subjects were followed for up to 12 cycles; and in 1 trial, subjects were followed for up to 6 cycles.

Common Adverse Reactions (≥ 2% of subjects): The most common adverse reactions reported by at least 2% of the 4,826 women were the following in order of decreasing incidence: headache/migraine (33.6%), breast issues (including breast pain, enlargement, and discharge) (8.0%), vaginal infection (7.1%), abdominal/gastrointestinal pain (5.6%), mood disorders (including mood alteration and depression) (3.8%), genital discharge (3.2%), and changes in weight (including weight fluctuation, increased or decreased) (2.5%).

Adverse Reactions Leading to Study Discontinuation: Over the trials, between 9 to 27% of subjects discontinued the trial due to an adverse reaction. The most common adverse reactions (≥1%) leading to discontinuation were: metrorrhagia (4.3%), nausea/vomiting (2.8%), headache/migraine (2.4%), mood disorders (including depression and mood altered) (1.1%), and weight increased (1.1%).

Serious Adverse Reactions: breast cancer (1 subject), carcinoma of the cervix in situ (1 subject), hypertension (1 subject), and migraine (2 subjects).

6.2Postmarketing Experience

The following additional adverse drug reactions have been reported from worldwide postmarketing experience with norgestimate/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.

Infections and Infestations: Urinary tract infection;

Neoplasms Benign, Malignant and Unspecified (Incl. Cysts and Polyps): Breast cancer, benign breast neoplasm, hepatic adenoma, focal nodular hyperplasia, breast cyst;

Immune System Disorders: Hypersensitivity;

Metabolism and Nutrition Disorders: Dyslipidemia;

Psychiatric Disorders: Anxiety, insomnia;

Nervous System Disorders: Syncope, convulsion, paresthesia, dizziness;

Eye Disorders: Visual impairment, dry eye, contact lens intolerance;

Ear and Labyrinth Disorders: Vertigo;

Cardiac Disorders: Tachycardia, palpitations;

Vascular Events: Deep vein thrombosis, pulmonary embolism, retinal vascular thrombosis, hot flush, venous thrombosis (including Budd Chiari Syndrome and hepatic vein thrombosis);

Arterial Events: Arterial thromboembolism, myocardial infarction, cerebrovascular accident;

Respiratory, Thoracic and Mediastinal Disorders: Dyspnea;

Gastrointestinal Disorders: Pancreatitis, abdominal distension, diarrhea, constipation;

Hepatobiliary Disorders: Hepatitis;

Skin and Subcutaneous Tissue Disorders: Angioedema, erythema nodosum, hirsutism, night sweats, hyperhidrosis, photosensitivity reaction, urticaria, pruritus, acne;

Musculoskeletal, Connective Tissue, and Bone Disorders: Muscle spasms, pain in extremity, myalgia, back pain;

Reproductive System and Breast Disorders: Ovarian cyst, suppressed lactation, vulvovaginal dryness;

General Disorders and Administration Site Conditions: Chest pain, asthenic conditions.