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CLINICAL PHARMACOLOGY Mechanism Of Action Oral Contraception COCs lower the risk of becoming pregnant primarily by suppressing ovulation. Other possible mechanisms may include cervical mucus changes that inhibit sperm penetration and endometrial changes that reduce the likelihood of implantation. Acne Acne is a skin condition with a multifactorial etiology, including androgen stimulation of sebum production. While the combination of ethinyl estradiol and norgestimate increases sex hormonebinding globulin (SHBG) and decreases free testosterone, the relationship between these changes and a decrease in the severity of facial acne in otherwise healthy women with this skin condition has not been established. Pharmacodynamics No specific pharmacodynamic studies were conducted with Tri-Sprintec. Pharmacokinetics Absorption Norgestimate (NGM) and EE are rapidly absorbed following oral administration. NGM is rapidly and completely metabolized by first pass (intestinal and/or hepatic) mechanisms to norelgestromin (NGMN) and norgestrel (NG), which are the major active metabolites of norgestimate. Peak serum concentrations of NGMN and EE are generally reached by 2 hours after administration of Tri-Sprintec. Accumulation following multiple dosing of the 250 mcg NGM / 35 mcg EE dose is approximately 2-fold for NGMN and EE compared with single dose administration. The pharmacokinetics of NGMN is dose-proportional following NGM doses of 180 mcg to 250 mcg. Steady-state concentration of EE is achieved by Day 7 of each dosing cycle. Steady-state concentrations of NGMN and NG are achieved by Day 21. Non-linear accumulation (approximately 8 fold) of NG is observed as a result of high-affinity binding to SHBG, which limits its biological activity (Table 3). Table 3: Summary of NGMN, NG and EE pharmacokinetic parameters . Mean (SD) Pharmacokinetic Parameters of Tri-Sprintec During a Three Cycle Study Analyte Cycle Day Cmax tmax (h) AUC0-24h T1/2(h) NGMN 3 7 1.8 (0.46) 1.42 (0.73) 15 (3.88) NC 14 2.12 (0.56) 1.21 (0.26) 16.1 (4.97) NC 21 2.66 (0.47) 1.29 (0.26) 21.4 (3.46) 22.3 (6.54) NG 3 7 1.94 (0.82) 3.15 (4.05) 34.8 (16.5) NC 14 3 (1.04) 2.21 (2.03) 55.2 (23.5) NC 21 3.66 (1.15) 2.58 (2.97) 69.3 (23.8) 40.2 (15.4) EE 3 7 124 (39.5) 1.27 (0.26) 1130 (420) NC 14 128 (38.4) 1.32 (0.25) 1130 (324) NC 21 126 (34.7) 1.31 (0.56) 1090 (359) 15.9 (4.39) Cmax = peak serum concentration, tmax = time to reach peak serum concentration, AUC0-24h = area under serum concentration vs time curve from 0 to 24 hours, t1/2 = elimination half-life, NC = not calculated. NGMN and NG: Cmax = ng/mL, AUC0-24h = h•ng/mL EE: Cmax = pg/mL, AUC0-24h = h•pg/mL Food Effect The effect of food on the pharmacokinetics of Tri-Sprintec has not been studied. Distribution NGMN and NG are highly bound (>97%) to serum proteins. NGMN is bound to albumin and not to SHBG, while NG is bound primarily to SHBG. EE is extensively bound (>97%) to serum albumin and induces an increase in the serum concentrations of SHBG. Metabolism NGM is extensively metabolized by first-pass mechanisms in the gastrointestinal tract and/or liver. NGM’s primary active metabolite is NGMN. Subsequent hepatic metabolism of NGMN occurs and metabolites include NG, which is also active, and various hydroxylated and conjugated metabolites. Although NGMN and its metabolites inhibit a variety of P450 enzymes in human liver microsomes, under the recommended dosing regimen, the in vivo concentrations of NGMN and its metabolites, even at the peak serum levels, are relatively low compared to the inhibitory constant (Ki). EE is also metabolized to various hydroxylated products and their glucuronide and sulfate conjugates. Excretion The metabolites of NGMN and EE are eliminated by renal and fecal pathways. Following administration of 14C-norgestimate, 47% (45 to 49%) and 37% (16 to 49%) of the administered radioactivity was eliminated in the urine and feces, respectively. Unchanged NGM was not detected in the urine. In addition to 17-deacetyl norgestimate, a number of metabolites of NGM have been identified in human urine following administration of radiolabeled NGM. These include 18, 19-Dinor-17-pregn-4-en-20- yn-3-one,17-hydroxy-13-ethyl,(17α)-(-);18,19-Dinor-5β17-pregnan-20-yn,3α,17β-dihydroxy-13- ethyl,(17α), various hydroxylated metabolites and conjugates of these metabolites. Clinical Studies Contraception In four clinical trials with Tri-Sprintec, 4,756 women aged 15 to 41 years were studied for 24 cycles, providing a total of 45,244 cycles of exposure. The racial demographic was about 87 to 90% Caucasian, 6 to 10% African-American, with the remainder Asian (≤1%) or Other (2 to 5%). There were no exclusions on the basis of weight; the weight range for women treated was 80 to 310 lbs, with a mean weight of about 132 lbs. The pregnancy rate was approximately 1 pregnancy per 100 womenyears. Acne Tri-Sprintec was evaluated for the treatment of acne vulgaris in two randomized, double-blind, placebocontrolled, multicenter, six- (28 day) cycle studies. Two hundred twenty-one patients received Tri- Sprintec and 234 patients received placebo. Mean age at enrollment for both groups was 28 years. At the end of 6 months, the mean total lesion count changed from 55 to 31 (42% reduction) in patients treated with Tri-Sprintec and from 54 to 38 (27% reduction) in patients similarly treated with placebo. Table 4 summarizes the changes in lesion count for each type of lesion. Based on the investigator’s global assessment conducted at the final visit, patients treated with Tri-Sprintec showed a statistically significant improvement in total lesions compared to those treated with placebo. Table 4: Acne Vulgaris Indication. Combined Results: Two Multicenter, Placebo-Controlled Trials . Observed Means at Six Months (LOCF)* and at Baseline. Intent-to-Treat Population. Tri-Sprintec (N=221) Placebo (N=234) Difference in Counts between Tri- Sprintec and Placebo at 6 Months # of Lesions Counts % Reduction Counts % Reduction INFLAMMATORY LESIONS Baseline Mean 19 19 Sixth Month Mean 10 48% 13 30% 3 (95% CI: -1.2, 5.1) NON INFLAMMATORY LESIONS Baseline Mean 36 35 Sixth Month Mean 22 34% 25 21% 3 (95% CI: -0.2, 7.8) TOTAL LESIONS Baseline Mean 55 54 7 (95% CI: 2,11.9) Sixth Month Mean 31 42% 38 27% * LOCF: Last Observation Carried Forward

Find Lowest Prices on TRI-SPRINTEC®(norgestimate/ethinyl estradiol) Tablets WARNING CIGARETTE SMOKING AND SERIOUS CARDIOVASCULAR EVENTS Cigarette smoking increases the risk of serious cardiovascular events from combination oral contraceptive (COC) use. This risk increases with age, particularly in women over 35 years of age, and with the number of cigarettes smoked. For this reason, COCs are contraindicated in women who are over 35 years of age and smoke [see CONTRAINDICATIONS]. DESCRIPTION Tri-Sprintec® (norgestimate and ethinyl estradiol tablets USP) is a combination oral contraceptive containing the progestational compound norgestimate, USP and the estrogenic compound ethinyl estradiol, USP. Each gray tablet contains 0.18 mg of the progestational compound, norgestimate, USP (18,19-Dinor-17- pregn-4-en-20-yn-3-one, 17-(acetyloxy)-13-ethyl-, oxime, (17α)-(+)-) and 0.035 mg of the estrogenic compound, ethinyl estradiol, USP (19-Nor-17α-pregna,1,3,5(10)-trien-20-yne-3, 17-diol), and the inactive ingredients include anhydrous lactose, lactose monohydrate, lake blend black LB 636 (ingredients include aluminum sulfate solution, aluminum-chloride solution, FD&C blue no. 2, FD&C red no. 40, FD&C yellow no. 6, sodium bicarbonate and sodium carbonate), magnesium stearate, and pregelatinized corn starch. Each light blue tablet contains 0.215 mg of the progestational compound norgestimate, USP (18,19- Dinor-17-pregn-4-en-20-yn-3-one,17-(acetyloxy)-13-ethyl-, oxime, (17α)-(+)-) and 0.035 mg of the estrogenic compound, ethinyl estradiol, USP (19-Nor-17α-pregna,1,3,5(10)-trien-20-yne-3, 17-diol), and the inactive ingredients include anhydrous lactose, FD&C blue no. 2 aluminum lake (ingredients include aluminum sulfate solution, aluminum-chloride solution, FD&C blue no. 2, sodium bicarbonate and sodium carbonate), lactose monohydrate, magnesium stearate, and pregelatinized corn starch. Each blue tablet contains 0.25 mg of the progestational compound norgestimate, USP (18,19-Dinor-17- pregn-4-en-20-yn-3-one, 17-(acetyloxy)-13-ethyl-, oxime, (17α)-(+)-) and 0.035 mg of the estrogenic compound, ethinyl estradiol, USP (19-Nor-17α-pregna,1,3,5(10)-trien-20-yne-3, 17-diol), and the inactive ingredients include anhydrous lactose, FD&C blue no. 2 aluminum lake (ingredients include aluminum sulfate solution, aluminum-chloride solution, FD&C blue no. 2, sodium bicarbonate and sodium carbonate), lactose monohydrate, magnesium stearate, and pregelatinized corn starch. Each white tablet contains only inert ingredients as follows: anhydrous lactose, hypromellose, magnesium stearate, and microcrystalline cellulose. The structural formulas are as follows: C23H31NO3 M.W. 369.50 C20H24O2 M.W. 296.40

INDICATIONS Oral Contraceptive Tri-Sprintec® (norgestimate and ethinyl estradiol tablets USP) is indicated for use by females of reproductive potential to prevent pregnancy [see Clinical Studies]. Acne Tri-Sprintec® (norgestimate and ethinyl estradiol tablets USP) 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 USP) should be used for the treatment of acne only if the patient desires an oral contraceptive for birth control [see Clinical Studies]. DOSAGE AND ADMINISTRATION How To Start Tri-Sprintec Tri-Sprintec is dispensed in a blister pack tablet dispenser [see HOW SUPPLIED]. Tri-Sprintec 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. How To Take Tri-Sprintec 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 15) and blue (Day 16 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 nonhormonal contraception (such as condoms and spermicide) for the firsts even 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: Trans dermal 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 nonhormonal 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 us age 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. [See CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, and FDA-Approved Patient Labeling.] 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 [see Use In Specific Populations]. If the woman has not yet had a period postpartum, consider the possibility of ovulation and conception occurring prior to use of Tri-Sprintec. [See CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, Use In Specific Populations, and FDA-Approved Patient Labeling]. How To Use The Blister Cards There are two ways to start taking birth control pills, Sunday Start or Day 1 Start. Your healthcare professional will tell you which to use. Pick the Days of the Week Sticker that starts the first day of your period. (This is the day you begin bleeding or spotting, even if it is midnight when bleeding begins.) When you have picked the right sticker, throw away the others and place the sticker on the blister card over the preprinted days of the week and make sure it lines up with the pills. Your blister package consists of three parts, the foil pouch, wallet, and a blister pack containing 28 individually sealed pills. Note that the pills are arranged in four numbered rows of 7 pills, with the pre-printed days of the week printed above them. There are 7 gray “active” pills, 7 light blue “active” pills, 7 blue “active” pills, and 7 white “reminder” pills. Refer to the sample of the blister card below: After taking the last white pill, start a new blister card the very next day no matter when your period started. You will be taking a pill every day without interruption. Anytime you start the pills later than directed, protect yourself by using another method of birth control until you have taken a pill a day for seven consecutive days. After taking the last white pill, start taking the first gray pill from the blister card the very next day. Take the pills in each new package as before. Start with the gray pill on row #1 and take one pill each day, left to right, until the last white pill has been taken. Three Ways To Remember In What Order To Take The Pills Follow the sticker with the days of the week (placed above the pills). Always go from left to right. Always finish all your pills. Missed Tablets 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 nonhormonal contraception (such as condoms and spermicide) should be used as back-up if the patient has sex within 7 days after missing tablets . Advice 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-ApprovedPatient Labeling]. Tri-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 (2.1) for instructions. HOW SUPPLIED Dosage Forms And Strengths Tri-Sprintec tablets are available in blister cards. Each blister card contains 28 tablets in the following order: 7 gray, round, flat-faced, beveled-edge, unscored tablets debossed with stylized b on one side and 985 on the other side contains 0.18 mg norgestimate /0.035 mg ethinyl estradiol 7 light blue, round, flat-faced, beveled-edge, unscored tablets debossed with stylized b on one side and 986 on the other side contains 0.215 mg norgestimate /0.035 mg ethinyl estradiol 7 blue, round, flat-faced, beveled-edge, unscored tablets debossed with stylized b on one side and 987 on the other side contains 0.25 mg norgestimate /0.035 mg ethinyl estradiol 7 white, round, flat-faced, beveled-edge, unscored tablets debossed with stylized b on one side and 143 on the other side contains inert ingredients Storage And Handling Tri-Sprintec® (norgestimate and ethinyl estradiol tablets USP) 0.18 mg/0.035 mg are gray, round, flatfaced, beveled-edge, unscored tablets debossed with stylized b on one side and 985 on the other side; 0.215 mg/0.035 mg are light blue, round, flat-faced, beveled-edge, unscored tablets debossed with stylized b on one side and 986 on the other side; 0.25 mg/0.035 mg are blue, round, flat-faced, bevelededge, unscored tablets debossed with stylized b on one side and 987 on the other side; placebo tablets are white, round, flat-faced, beveled-edge, unscored tablets, debossed with stylized b on one side and 143 on the other side. Tri-Sprintec® (norgestimate and ethinyl estradiol tablets USP) are packaged in cartons of six blister cards. Each card contains 28 tablets as follows: Each gray tablet contains 0.18 mg of the progestational compound, norgestimate, USP, together with 0.035 mg of the estrogenic compound, ethinyl estradiol, USP. Each light blue tablet contains 0.215 mg of the progestational compound, norgestimate, USP, together with 0.035 mg of the estrogenic compound, ethinyl estradiol, USP. Each blue tablet contains 0.25 mg of the progestational compound, norgestimate, USP, together with 0.035 mg of the estrogenic compound, ethinyl estradiol, USP, and the 7 white placebo tablets contain inert ingredients. NDC: 0555-9018-58 KEEP THIS AND ALL MEDICATIONS OUT OF THE REACH OF CHILDREN. Storage Conditions Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature]. PROTECT FROM LIGHT. Manufactured by: TEVA PHARMACEUTICALS USA, INC. North Wales, PA 19454. Revised: Aug 2016

SIDE EFFECTS The following serious adverse reactions with the use of COCs are discussed elsewhere in labeling: Serious cardiovascular events and stroke [see BOX WARNING and WARNINGS AND PRECAUTIONS] Vascular events [see WARNINGS AND PRECAUTIONS] Liver disease [see WARNINGS AND PRECAUTIONS] Adverse reactions commonly reported by COC users are: Irregular uterine bleeding Nausea Breast tenderness Headache 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 rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The safety of Tri-Sprintec was evaluated in 4,826 healthy women of child-bearing potential who participated in 6 clinical trials and received at least 1 dose of Tri-Sprintec 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%), 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). Postmarketing 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; 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. DRUG INTERACTIONS Consult the labeling of concurrently used drugs to obtain further information about interactions with hormonal contraceptives or the potential for enzyme alterations. No drug-drug interaction studies were conducted with Tri-Sprintec. Effects Of Other Drugs On Combined Oral Contraceptives Substances Decreasing The Plasma Concentrations Of COCs: Drugs or herbal products that induce certain enzymes, including cytochrome P450 3A4 (CYP3A4), may decrease the plasma concentrations of COCs and potentially diminish the effectiveness of COCs or increase breakthrough bleeding. Some drugs or herbal products that may decrease the effectiveness of hormonal contraceptives include phenytoin, barbiturates, carbamazepine, bosentan, felbamate, griseofulvin, oxcarbazepine, rifampicin, topiramate, rifabutin, rufinamide, aprepitant, and products containing St. John’s wort. Interactions between hormonal contraceptives and other drugs may lead to breakthrough bleeding and/or contraceptive failure. Counsel women to use an alternative method of contraception or a back-up method when enzyme inducers are used with COCs, and to continue back-up contraception for 28 days after discontinuing the enzyme inducer to ensure contraceptive reliability. Colesevelam Colesevelam, a bile acid sequestrant, given together with a COC, has been shown to significantly decrease the AUC of EE. The drug interaction between the contraceptive and colesevelam was decreased when the two drug products were given 4 hours apart. Substances Increasing The Plasma Concentrations Of COCs: Co-administration of atorvastatin or rosuvastatin and certain COCs containing ethinyl estradiol (EE) increase AUC values for EE by approximately 20 to 25%. Ascorbic acid and acetaminophen may increase plasma EE concentrations, possibly by inhibition of conjugation. CYP3A4 inhibitors such as itraconazole, voriconazole, fluconazole, grapefruit juice, or ketoconazole may increase plasma hormone concentrations. Human Immunodeficiency Virus (HIV)/Hepatitis C Virus (HCV) Protease Inhibitors And Nonnucleoside Reverse Transcriptase Inhibitors: Significant changes (increase or decrease) in the plasma concentrations of estrogen and/or progestin have been noted in some cases of co-administration with HIV protease inhibitors (decrease [e.g., nelfinavir, ritonavir, darunavir/ritonavir, (fos)amprenavir/ritonavir, lopinavir/ritonavir, and tipranavir/ritonavir] or increase [e.g., indinavir and atazanavir/ritonavir])/HCV protease inhibitors (decrease [e.g., boceprevir and telaprevir]) or with non-nucleoside reverse transcriptase inhibitors (decrease [e.g., nevirapine] or increase [e.g., etravirine]). Effects Of Combined Oral Contraceptives On Other Drugs COCs containing EE may inhibit the metabolism of other compounds (e.g., cyclosporine, prednisolone, theophylline, tizanidine, and voriconazole) and increase their plasma concentrations. COCs have been shown to decrease plasma concentrations of acetaminophen, clofibric acid, morphine, salicylic acid, temazepam and lamotrigine. Significant decrease in plasma concentration of lamotrigine has been shown, likely due to induction of lamotrigine glucuronidation. This may reduce seizure control; therefore, dosage adjustments of lamotrigine may be necessary. Women on thyroid hormone replacement therapy may need increased doses of thyroid hormone because the serum concentration of thyroid-binding globulin increases with use of COCs. Interference With Laboratory Tests The use of contraceptive steroids may influence the results of certain laboratory tests, such as coagulation factors, lipids, glucose tolerance, and binding proteins.

WARNINGS Included as part of the "PRECAUTIONS" Section PRECAUTIONS Thromboembolic 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 [see ADVERSE REACTIONS]. 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. Liver Disease Impaired Liver Function Do not use Tri-Sprintec in women with liver disease, such as acute viral hepatitis or severe (decompensated) cirrhosis of liver [see CONTRAINDICATIONS]. 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 [see CONTRAINDICATIONS]. 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. High Blood Pressure Tri-Sprintec is contraindicated in women with uncontrolled hypertension or hypertension with vascular disease [see CONTRAINDICATIONS]. 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. Gallbladder 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. Carbohydrate 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. Headache 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). Bleeding 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 Tri-Sprintec, 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 Tri-Sprintec, at least in part, due to bleeding or spotting. Based on data from the clinical trials, 13 to 38% of women using Tri-Sprintec 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. COC 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 Tri-Sprintec 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]. Depression Carefully observe women with a history of depression and discontinue Tri-Sprintec if depression recurs to a serious degree. Carcinoma Of Breast And Cervix Tri-Sprintec is contraindicated in women who currently have or have had breast cancer because breast cancer may be hormonally sensitive [see CONTRAINDICATIONS]. 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. Effect 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. Monitoring 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. Hereditary Angioedema In women with hereditary angioedema, exogenous estrogens may induce or exacerbate symptoms of angioedema. Chloasma 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. Patient Counseling Information See FDA-approved patient labeling (PATIENT INFORMATION and Instructions for Use). Counsel patients about the following information: Cigarette smoking increases the risk of serious cardiovascular events from COC use, and that women who are over 35 years old and smoke should not use COCs [see BOX WARNING]. Increased risk of VTE compared to non-users of COCs is greatest after initially starting a COC or restarting (following a 4-week or greater pill-free interval) the same or a different COC [see WARNINGS AND PRECAUTIONS]. Tri-Sprintec does not protect against HIV infection (AIDS) and other sexually transmitted infections. Tri-Sprintec is not to be used during pregnancy; if pregnancy occurs during use of Tri-Sprintec instruct the patient to stop further use [see WARNINGS AND PRECAUTIONS]. Take one tablet daily by mouth at the same time every day. Instruct patients what to do in the event tablets are missed [see DOSAGE AND ADMINISTRATION]. Use a back-up or alternative method of contraception when enzyme inducers are used with Tri- Sprintec [see DRUG INTERACTIONS]. COCs may reduce breast milk production; this is less likely to occur if breastfeeding is well established [see Use In Specific Populations]. Women who start COCs postpartum, and who have not yet had a period, should use an additional method of contraception until they have taken an active tablet for 7 consecutive days [see DOSAGE AND ADMINISTRATION]. Amenorrhea may occur. Consider pregnancy in the event of amenorrhea at the time of the first missed period. Rule out pregnancy in the event of amenorrhea in two or more consecutive cycles [see WARNINGS AND PRECAUTIONS]. Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment Of Fertility [See WARNINGS AND PRECAUTIONS and Use In Specific Populations] Use In Specific Populations Pregnancy There is little or no increased risk of birth defects in women who inadvertently use COCs during early pregnancy. Epidemiologic studies and meta-analyses have not found an increased risk of genital or nongenital birth defects (including cardiac anomalies and limb reduction defects) following exposure to low dose COCs prior to conception or during early pregnancy. Do not administer COCs to induce withdrawal bleeding as a test for pregnancy. Do not use COCs during pregnancy to treat threatened or habitual abortion. Nursing Mothers Advise the nursing mother to use other forms of contraception, when possible, until she has weaned her child. COCs can reduce milk production in breastfeeding mothers. This is less likely to occur once breastfeeding is well-established; however, it can occur at any time in some women. Small amounts of oral contraceptive steroids and/or metabolites are present in breast milk. Pediatric Use Safety and efficacy of Tri-Sprintec Tablets has been established in women of reproductive age. Efficacy is expected to be the same for postpubertal 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. Geriatric Use Tri-Sprintec has not been studied in postmenopausal women and is not indicated in this population. Hepatic 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. [See CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS] Renal Impairment The pharmacokinetics of Tri-Sprintec has not been studied in women with renal impairment.