Tri-Sprintec

Tri-Sprintec ® (norgestimate and ethinyl estradiol tablets) is a combination of norgestimate, a progestin, and ethinyl estradiol, an estrogen, indicated for use by females of reproductive potential to prevent pregnancy. () Tri-Sprintec ® (norgestimate and ethinyl estradiol tablets) 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. Tri-Sprintec ® (norgestimate and ethinyl estradiol tablets) should be used for the treatment of acne only if the patient desires an oral contraceptive for birth control. ()

1.1Oral Contraceptive Tri-Sprintec

® (norgestimate and ethinyl estradiol tablets) is indicated for use by females of reproductive potential to prevent pregnancy .

1.2Acne Tri-Sprintec

® (norgestimate and ethinyl estradiol tablets) 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. Tri-Sprintec ® (norgestimate and ethinyl estradiol tablets) should be used for the treatment of acne only if the patient desires an oral contraceptive for birth control .

2 DOSAGE AND ADMINISTRATION • Take one tablet daily by mouth at the same time every day. • Take tablets in the order directed on the blister pack. • Do not skip or delay tablet intake.

2.1Recommended Dosage and Administration Take

one tablet by mouth at the same time each day with or without food. Table 1 provides the recommended dosage and administration instructions for Tri-Sprintec ® (norgestimate and ethinyl estradiol tablets). Table 1: Instructions for Administration of Tri-Sprintec® 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: • Tri-Sprintec ® active tablets are gray (Day 1 to Day 7), light blue (Day 8 to Day 14) and blue (Day 15 to Day 21). • Tri-Sprintec ® has white inactive tablets (Day 22 to Day 28). Day 1 Start: • 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 white 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) Sunday Start: • 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 Tri-Sprintec ® . • Take subsequent active tablets once daily at the same time each day for a total of 21 days. • Take one white 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.

Switching to Tri-Sprintec ® 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 Tri-Sprintec ® Start Tri-Sprintec ® : • Transdermal patch • On the day when next application would have been scheduled • Vaginal ring • On the day when next insertion would have been scheduled • Injection • On the day when next injection would have been scheduled • Intrauterine contraceptive • On 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. • Implant • On the day of removal Complete instructions to facilitate patient counseling on proper tablet usage are located in the FDA-Approved Patient Labeling. Starting Tri-Sprintec ® after Abortion or Miscarriage First-trimester • After a first-trimester abortion or miscarriage, Tri-Sprintec ® may be started immediately.

An additional method of contraception is not needed if Tri-Sprintec ® is started immediately. • If Tri-Sprintec ® 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 Tri-Sprintec ® . Second-trimester • Do not start until 4 weeks after a second-trimester abortion or miscarriage, due to the increased risk of thromboembolic disease. Start Tri-Sprintec ® , 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 Tri-Sprintec ® . Starting Tri-Sprintec ® after Childbirth • Do not start until 4 weeks after delivery, due to the increased risk of thromboembolic disease.

Start contraceptive therapy with Tri-Sprintec ® following the instructions in Table 1 for women not currently using hormonal contraception. • Tri-Sprintec ® is not recommended for use in lactating women . • If the woman has not yet had a period postpartum, consider the possibility of ovulation and conception occurring prior to use of Tri-Sprintec ® .

2.2Recommendations Regarding Missed Doses Contraceptive

failure may occur when active tablets are missed. Table 2 describes instructions for Tri-Sprintec ® dosing and use of additional non-hormonal contraception (such as condoms) when active tablets are missed. Table 2: Instructions for Missed Tri-Sprintec® Tablets • If one active tablet is missed in Weeks 1, 2, or 3 Take the tablet as soon as possible.

Continue taking one tablet a day until the pack is finished. • If two active tablets are missed in Week 1 or Week 2 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. • If 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 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.

2.3Dosage Recommendations

if Vomiting or Diarrhea Occurs 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.

2.4Tri-Sprintec

® Use for Acne The timing of initiation of dosing with Tri-Sprintec ® for acne should follow the guidelines for use of Tri-Sprintec ® as an oral contraceptive. Consult the DOSAGE AND ADMINISTRATION section for instructions.

5 WARNINGS AND PRECAUTIONS • Thromboembolic Disorders and Other Vascular Problems: Stop Tri-Sprintec ® 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. () • Liver disease: Discontinue Tri-Sprintec ® if jaundice occurs. () • High blood pressure: If used in women with well-controlled hypertension, monitor blood pressure and stop Tri-Sprintec ® if blood pressure rises significantly. () • Carbohydrate and lipid metabolic effects: Monitor prediabetic and diabetic women taking Tri-Sprintec ® . Consider an alternate contraceptive method for women with uncontrolled dyslipidemia. () • Headache: Evaluate significant change in headaches and discontinue Tri-Sprintec ® if indicated. () • Bleeding Irregularities and Amenorrhea: Evaluate irregular bleeding or amenorrhea. ()

5.1Thromboembolic Disorders and Other Vascular Problems

• Stop Tri-Sprintec ® if an arterial thrombotic event or venous thromboembolic (VTE) event occurs. • Stop Tri-Sprintec ® if there is unexplained loss of vision, proptosis, diplopia, papilledema, or retinal vascular lesions. Evaluate for retinal vein thrombosis immediately . • If feasible, stop Tri-Sprintec ® 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 Tri-Sprintec ® 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

Tri-Sprintec ® is contraindicated in women with liver disease, such as acute viral hepatitis or severe (decompensated) cirrhosis of liver . 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 Tri-Sprintec ® if jaundice develops. Liver Tumors Tri-Sprintec ® is contraindicated in women with benign and malignant liver tumors . 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 Tri-Sprintec ® prior to starting therapy with the combination drug regimen ombitasvir/paritaprevir/ritonavir, with or without dasabuvir . Tri-Sprintec ® can be restarted approximately 2 weeks following completion of treatment with the Hepatitis C combination drug regimen.

5.4High Blood Pressure Tri-Sprintec

® is contraindicated in women with uncontrolled hypertension or hypertension with vascular disease . For women with well-controlled hypertension, monitor blood pressure and stop Tri-Sprintec ® 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 Tri-Sprintec ® . 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 Tri-Sprintec ® develops new headaches that are recurrent, persistent, or severe, evaluate the cause and discontinue Tri-Sprintec ® if indicated. Consider discontinuation of Tri-Sprintec ® 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 norgestimate and ethinyl estradiol, the frequency and duration of breakthrough bleeding and/or spotting was assessed in 4,826 patients (35,546 evaluable cycles). A total of 231 (4.8%) women discontinued norgestimate and ethinyl estradiol, at least in part, due to bleeding or spotting. Based on data from the clinical trials, 13 to 38% of women using norgestimate and ethinyl estradiol experienced unscheduled bleeding per cycle in the first year.

The percent of women who experienced breakthrough/unscheduled bleeding tended to decrease over time. Amenorrhea and Oligomenorrhea Women who use Tri-Sprintec ® 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.

5.9Depression Carefully

observe women with a history of depression and discontinue Tri-Sprintec ® if depression recurs to a serious degree.

5.10Malignant Neoplasms Breast Cancer Tri-Sprintec

® is contraindicated in females who currently have or have had breast cancer because breast cancer may be hormonally sensitive . 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 . Cervical Cancer 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.

5.11Effect 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.

5.12Monitoring 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.

5.13Hereditary Angioedema In

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

5.14Chloasma 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 Tri-Sprintec ® .

Tri-Sprintec ® 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 women who are known to: o Smoke, if over age 35 o Have deep vein thrombosis or pulmonary embolism, now or in the past o Have inherited or acquired hypercoagulopathies o Have cerebrovascular disease o Have coronary artery disease o Have thrombogenic valvular or thrombogenic rhythm diseases of the heart (for example, subacute bacterial endocarditis with valvular disease, or atrial fibrillation) o Have uncontrolled hypertension o Have diabetes mellitus with vascular disease o Have headaches with focal neurological symptoms or migraine headaches with aura ▪ Women over age 35 with any migraine headaches • Liver tumors, benign or malignant, or liver disease • Undiagnosed abnormal uterine bleeding • Current diagnosis of, or history of, breast cancer, which may be hormone-sensitive • Use of Hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, due to the potential for ALT elevations • A high risk of arterial or venous thrombotic diseases • Liver tumors or liver disease • Undiagnosed abnormal uterine bleeding • Breast cancer • Co-administration with Hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir

Lactating women: Not recommended; can decrease milk production. ()

8.1Pregnancy Risk Summary There

is no use for contraception in pregnancy, therefore, Tri-Sprintec ® should be discontinued during pregnancy. Epidemiologic studies and meta-analyses have not found an increased risk of genital or non-genital birth defects (including cardiac anomalies and limb reduction defects) following exposure to CHCs before conception or during early pregnancy. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4 percent and 15 to 20 percent, respectively.

8.2Lactation Risk Summary Contraceptive

hormones and/or metabolites are present in human milk. CHCs can reduce milk production in breastfeeding females. This reduction can occur at any time but is less likely to occur once breastfeeding is well-established. When possible, advise the nursing female to use other forms of contraception until she discontinues breast-feeding.

The developmental and health benefits of breast-feeding should be considered along with the mother’s clinical need for Tri-Sprintec ® and any potential adverse effects on the breast-fed child from Tri-Sprintec ® or from the underlying maternal condition.

8.4Pediatric Use Safety and

efficacy of Tri-Sprintec ® tablets has been established in women of reproductive age. Efficacy is expected to be the same for post‑pubertal adolescents under the age of 18 and for users 18 years and older. Use of this product before menarche is not indicated. There was no significant difference between Tri-Sprintec ® tablets and placebo in mean change in total lumbar spine (L1-L4) and total hip bone mineral density between baseline and Cycle 13 in 123 adolescent females with anorexia nervosa in a double-blind, placebo-controlled, multicenter, one-year treatment duration clinical trial for the Intent To Treat (ITT) population.

8.5Geriatric Use Tri-Sprintec

® has not been studied in postmenopausal women and is not indicated in this population.

8.6Hepatic Impairment The

pharmacokinetics of Tri-Sprintec ® has not been studied in subjects with hepatic impairment. However, steroid hormones may be poorly metabolized in patients with hepatic impairment. 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 .

8.7Renal Impairment The

pharmacokinetics of Tri-Sprintec ® has not been studied in women with renal impairment.

The following serious adverse reactions with the use of COCs are discussed elsewhere in labeling: • Serious cardiovascular events and stroke • Vascular events • Liver disease The most common adverse reactions reported during clinical trials (≥2%) were: 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). () To report SUSPECTED ADVERSE REACTIONS, contact Teva at 1-888-838-2872 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. The safety of norgestimate and ethinyl estradiol was evaluated in 4,826 healthy women of child-bearing potential who participated in 6 clinical trials and received at least 1 dose of norgestimate and ethinyl estradiol 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 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 1). Three studies compared breast cancer risk between current or recent COC users (<6 months since last use) and never users of COCs (Figure 1). 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 1: 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 additional adverse 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 : Anaphylactic reaction, 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. 1