TRI-VYLIBRA- norgestimate and ethinyl estradiol
RPK Pharmaceuticals, Inc.
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HIGHLIGHTS OF PRESCRIBING INFORMATIONThese highlights do not include all the information needed to use Tri-VyLibra safely and effectively. See full prescribing information for Tri-VyLibra.
Tri-VyLibra® (norgestimate and ethinyl estradiol) tablets, for oral use Initial U.S. Approval: 1989 WARNING: CIGARETTE SMOKING and SERIOUS CARDIOVASCULAR EVENTSSee full prescribing information for complete boxed warning.RECENT MAJOR CHANGESWarnings and Precautions (5.11) 04/2022 INDICATIONS AND USAGETri-VyLibra is estrogen/progestin COC, indicated for use by women to prevent pregnancy. (1.1) Tri-VyLibra 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. Tri-VyLibra should be used for the treatment of acne only if the patient desires an oral contraceptive for birth control. (1.2) DOSAGE AND ADMINISTRATIONDOSAGE FORMS AND STRENGTHSTri-VyLibra consists of 28 round, biconvex tablets in the following order (3):
CONTRAINDICATIONSWARNINGS AND PRECAUTIONS
ADVERSE REACTIONSThe 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). (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Afaxys Pharma, LLC at 1-855-888-2467 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. DRUG INTERACTIONSDrugs or herbal products that induce certain enzymes including CYP3A4, may decrease the effectiveness of COCs or increase breakthrough bleeding. Counsel patients to use a back-up or alternative method of contraception when enzyme inducers are used with COCs. (7.1) USE IN SPECIFIC POPULATIONSNursing mothers: Not recommended; can decrease milk production. (8.3) See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling. Revised: 6/2022 |
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 (4)].
Tri-VyLibra tablets are indicated for use by females of reproductive potential to prevent pregnancy [see Clinical Studies (14)].
Tri-VyLibra 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-VyLibra should be used for the treatment of acne only if the patient desires an oral contraceptive for birth control [see Clinical Studies (14)].
Tri-VyLibra is available in blister pack [see How Supplied/Storage and Handling (16)]. Tri-VyLibra 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.
Table 1: Instructions for Administration of Tri-VyLibra
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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:
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Sunday Start:
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Switching to Tri-VyLibra 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-VyLibra
| Start Tri-VyLibra:
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● 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.
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Starting Tri-VyLibra after Abortion or Miscarriage
First-trimester
Second-trimester
Starting Tri-VyLibra after Childbirth
How to Use the Blister Pack:
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.
1. 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 pack over the preprinted days of the week and make sure it lines up with the pills.
2. Your 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 white “active” pills, 7 light blue “active” pills, 7 dark blue “active” pills, and 7 green “reminder” pills. Refer to the sample of the blister pack below:
3. After taking the last green pill, start a new blister pack 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 green pill, start taking the first white pill from the blister pack the very next day.
4. Take the pills in each new package as before. Start with the white pill on row #1 and take one pill each day, left to right, until the last green pill has been taken.
Three Ways to Remember in What Order to take the Pills
Table 2: Instructions for Missed Tri-VyLibra 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.
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| 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. |
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].
The timing of initiation of dosing with Tri-VyLibra for acne should follow the guidelines for use of Tri-VyLibra as an oral contraceptive. Consult the DOSAGE AND ADMINISTRATION section (2.1) for instructions.
Tri-VyLibra tablets are available in blister packs. Each blister pack contains 28 tablets in the following order:
Tri-VyLibra is contraindicated in females who are known to have or develop the following conditions:
Impaired Liver Function
Do not use Tri-VyLibra 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 Tri-VyLibra if jaundice develops.
Liver Tumors
Tri-VyLibra is 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.
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-VyLibra prior to starting therapy with the combination drug regimen ombitasvir/paritaprevir/ritonavir, with or without dasabuvir [see Contraindications (4)]. Tri-VyLibra can be restarted approximately 2 weeks following completion of treatment with the Hepatitis C combination drug regimen.
Tri-VyLibra is 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 Tri-VyLibra 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.
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.
Carefully monitor prediabetic and diabetic women who take Tri-VyLibra. 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.
If a woman taking Tri-VyLibra develops new headaches that are recurrent, persistent, or severe, evaluate the cause and discontinue Tri-VyLibra if indicated.
Consider discontinuation of Tri-VyLibra in the case of increased frequency or severity of migraine during COC use (which may be prodromal of a cerebrovascular event).
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-VyLibra, 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-VyLibra, at least in part, due to bleeding or spotting. Based on data from the clinical trials, 13 to 38% of women using Tri-VyLibra 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-VyLibra 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.
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-VyLibra 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)].
Carefully observe women with a history of depression and discontinue Tri-VyLibra if depression recurs to a serious degree.
Breast Cancer
Tri-VyLibra is contraindicated in females who currently have or have had breast cancer because breast cancer may be hormonally sensitive [see Contraindications (4)].
Epidemiology studies have not found a consistent association between use of combined oral contraceptives (COCs) and breast cancer risk. Studies do not show an association between ever (current or past) use of COCs and risk of breast cancer. However, some studies report a small increase in the risk of breast cancer among current or recent users (<6 months since last use) and current users with longer duration of COC use [see Postmarketing Experience (6.2)].
Cervical Cancer
Some studies suggest that COC 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.
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.
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.
The following serious adverse reactions with the use of COCs are discussed elsewhere in labeling:
Adverse reactions commonly reported by COC users are:
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-VyLibra 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-VyLibra 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).
Five studies that compared breast cancer risk between ever-users (current or past use) of COCs and never-users of COCs reported no association between ever use of COCs and breast cancer risk, with effect estimates ranging from 0.90 to 1.12 (Figure 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 to 1.33 with current or recent use. Both of these studies found an increased risk of breast cancer with current use of longer duration, with relative risks ranging from 1.03 with less than one year of COC use to approximately 1.4 with more than 8 to 10 years of COC use.
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 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.
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-VyLibra.
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 non-nucleoside 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]).
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.
The use of contraceptive steroids may influence the results of certain laboratory tests, such as coagulation factors, lipids, glucose tolerance, and binding proteins.
Do not co-administer Tri-VyLibra with HCV drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, due to potential for ALT elevations [see Warnings and Precautions (5.3)].
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 non-genital 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.
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.
Safety and efficacy of Tri-VyLibra Tablets have 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-VyLibra 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.
Tri-VyLibra has not been studied in postmenopausal women and is not indicated in this population.
The pharmacokinetics of Tri-VyLibra 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 (4) and Warnings and Precautions (5.2)].
There have been no reports of serious ill effects from overdosage of oral contraceptives, including ingestion by children. Overdosage may cause withdrawal bleeding in females and nausea.
Tri-VyLibra is a combination oral contraceptive containing the progestational compound norgestimate and the estrogenic compound ethinyl estradiol. Norgestimate is designated as (18,19-Dinor-17-pregn-4-en-20-yn-3-one,17-(acetyloxy)-13-ethyl-, oxime, (17α)-(+)-) and ethinyl estradiol is designated as (19-nor-17α-pregna,1,3,5(10)-trien-20-yne-3,17-diol).
Each active white tablet contains 0.180 mg of norgestimate USP and 0.035 mg of ethinyl estradiol USP. Inactive ingredients include croscarmellose sodium, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, and titanium dioxide.
Each active light blue tablet contains 0.215 mg of norgestimate USP and 0.035 mg of ethinyl estradiol USP. Inactive ingredients include croscarmellose sodium, FD&C #2/Indigo carmine aluminum lake, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, and titanium dioxide.
Each active dark blue tablet contains 0.250 mg of norgestimate USP and 0.035 mg of ethinyl estradiol USP. Inactive ingredients include croscarmellose sodium, FD&C #2/Indigo carmine aluminum lake, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, and titanium dioxide.
Each green tablet contains only inert ingredients, as follows: anhydrous lactose, FD&C Blue No. 2 aluminum lake, ferric oxide yellow, magnesium stearate, microcrystalline cellulose, and povidone.
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 is a skin condition with a multifactorial etiology, including androgen stimulation of sebum production. While the combination of ethinyl estradiol and norgestimate increases sex hormone-binding 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.
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-VyLibra. 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).
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 |
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Mean (SD) Pharmacokinetic Parameters of Tri-VyLibra During a Three Cycle Study
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Analyte | Cycle | Day | Cmax
| tmax (h) | AUC0-24h
| t1/2 (h) |
NGMN | 3 | 7 | 1.80 (0.46) | 1.42 (0.73) | 15.0 (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 | 3.00 (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) |
Food Effect
The effect of food on the pharmacokinetics of Tri-VyLibra 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-5β-17-pregnan-20-yn,3α,17β-dihydroxy-13-ethyl,(17α), various hydroxylated metabolites and conjugates of these metabolites.
[See Warnings and Precautions (5.2, 5.11) and Use in Specific Populations (8.1).]
In four clinical trials with Tri-VyLibra, 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 women-years.
Tri-VyLibra was evaluated for the treatment of acne vulgaris in two randomized, double-blind, placebo-controlled, multicenter, six- (28 day) cycle studies. Two hundred twenty-one patients received Tri-VyLibra 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-VyLibra 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-VyLibra showed a statistically significant improvement in total lesions compared to those treated with placebo.
*LOCF: Last Observation Carried Forward |
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| Tri-VyLibra (N=221) | Placebo (N=234) | Difference in Counts between Tri-VyLibra and Placebo at 6 Months |
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# 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: 2.0, 11.9) |
Sixth Month Mean | 31 | 42% | 38 | 27% |
Tri-VyLibra tablets are available in a blister pack.
Each blister pack (28 tablets) contains in the following order:
The blister packs are available in the following packages:
• The blister packs are packaged in mono cartons
Carton of 1 Blister Pack NDC 50102-233-11
Carton of 3 Blister packaged in mono cartons NDC 50102-233-13
See FDA-approved patient labeling (Patient Information and Instructions for Use).
Counsel patients about the following information:
Manufactured For:
Afaxys Pharma, LLC
Charleston, SC, 29403, USA.
Manufactured by:
Aurobindo Pharma Limited
Unit-VII (SEZ)
Mahaboob Nagar (Dt)-509302, India
Revised: 06/2022
Tri-VyLibra
(norgestimate and ethinyl estradiol tablets USP)
What is the most important information I should know about Tri-VyLibra?
Do not use Tri-VyLibra if you smoke cigarettes and are over 35 years old. Smoking increases your risk of serious cardiovascular side effects from hormonal birth control pills, including death from heart attack, blood clots or stroke. This risk increases with age and the number of cigarettes you smoke.
What is Tri-VyLibra?
Tri-VyLibra is a birth control pill (oral contraceptive) used by women to prevent pregnancy.
Tri-VyLibra is also used to treat moderate acne vulgaris in females 15 years of age and older, who have no known history of allergies or problems taking birth control pills, and have started their menstrual cycle (“period”). Tri-VyLibra should only be used to treat acne in women who want to take birth control pills to prevent pregnancy.
How does Tri-VyLibra work for contraception?
Your chance of getting pregnant depends on how well you follow the directions for taking your birth control pills. The better you follow the directions, the less chance you have of getting pregnant.
Based on the results of clinical studies, about 1 out of 100 women may get pregnant during the first year they use Tri-VyLibra.
The following chart shows the chance of getting pregnant for women who use different methods of birth control. Each box on the chart contains a list of birth control methods that are similar in effectiveness. The most effective methods are at the top of the chart. The box on the bottom of the chart shows the chance of getting pregnant for women who do not use birth control and are trying to get pregnant.
Who should not take Tri-VyLibra?
Do not take Tri-VyLibra if you:
If any of these conditions happen while you are taking Tri-VyLibra, stop taking Tri-VyLibra right away and talk to your healthcare provider. Use non-hormonal contraception when you stop taking Tri-VyLibra.
What should I tell my healthcare provider before taking Tri-VyLibra?
Tell your healthcare provider if you:
Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins and herbal supplements.
Tri-VyLibra may affect the way other medicines work, and other medicines may affect how well Tri-VyLibra works.
Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine.
How should I take Tri-VyLibra?
Read the Instructions for Use at the end of this Patient Information.
What are the possible serious side effects of Tri-VyLibra?
Serious blood clots can happen especially if you smoke, are obese, or are older than 35 years of age. Serious blood clots are more likely to happen when you:
Call your healthcare provider or go to a hospital emergency room right away if you have:
Other serious side effects include:
What are the most common side effects of Tri-VyLibra?
These are not all the possible side effects of Tri-VyLibra. For more information, ask your healthcare provider or pharmacist.
You may report side effects to the FDA at 1-800-FDA-1088.
What else should I know about taking Tri-VyLibra?
How should I store Tri-VyLibra?
General information about the safe and effective use of Tri-VyLibra.
Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use Tri-VyLibra for a condition for which it was not prescribed. Do not give Tri-VyLibra to other people, even if they have the same symptoms that you have.
This Patient Information summarizes the most important information about Tri-VyLibra. You can ask your pharmacist or healthcare provider for information about Tri-VyLibra that is written for health professionals.
For more information, call Afaxys Pharma, LLC at 1-855-888-2467
Do birth control pills cause cancer?
It is not known if hormonal birth control pills cause breast cancer. Some studies, but not all, suggest that there could be a slight increase in the risk of breast cancer among current users with longer duration of use.
If you have breast cancer now, or have had it in the past, do not use hormonal birth control because some breast cancers are sensitive to hormones.
Women who use birth control pills may have a slightly higher chance of getting cervical cancer. However, this may be due to other reasons such as having more sexual partners.
What if I want to become pregnant?
You may stop taking the pill whenever you wish. Consider a visit with your healthcare provider for a pre-pregnancy checkup before you stop taking the pill.
What should I know about my period when taking Tri-VyLibra?
Your periods may be lighter and shorter than usual. Some women may miss a period. Irregular vaginal bleeding or spotting may happen while you are taking Tri-VyLibra, especially during the first few months of use. This usually is not a serious problem. It is important to continue taking your pills on a regular schedule to prevent a pregnancy.
What are the ingredients in Tri-VyLibra?
Active ingredients: Each white, light blue, and dark blue pill contains norgestimate and ethinyl estradiol.
Inactive ingredients:
White pills: croscarmellose sodium, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, and titanium dioxide.
Light blue pills: croscarmellose sodium, FD&C#2/Indigo carmine aluminum lake, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, and titanium dioxide.
Dark blue pills: croscarmellose sodium, FD&C#2/Indigo carmine aluminum lake, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, and titanium dioxide.
Green pills: anhydrous lactose, FD&C Blue No. 2 aluminum lake, ferric oxide yellow, magnesium stearate, microcrystalline cellulose, and povidone.
Tri-VyLibra
(norgestimate and ethinyl estradiol tablets USP)
Important Information about taking Tri-VyLibra
Before you start taking Tri-VyLibra:
When should I start taking Tri-VyLibra?
If you start taking Tri-VyLibra and you have not used a hormonal birth control method before:
If you start taking Tri-VyLibra and you are switching from another birth control pill:
If you start taking Tri-VyLibra and previously used a vaginal ring or transdermal patch:
If you start taking Tri-VyLibra and you are switching from a progestin-only method such as an implant or injection:
If you start taking Tri-VyLibra and you are switching from an intrauterine device or system (IUD or IUS):
Keep a calendar to track your period:
If this is the first time you are taking birth control pills, read, “When should I start taking Tri-VyLibra?” above.
Follow these instructions for either a Sunday Start or a Day 1 Start.
Sunday Start:
You will use a Sunday Start if your healthcare provider told you to take your first pill on a Sunday.
Day 1 Start:
You will use a Day 1 Start if your doctor told you to take your first pill (Day 1) on the first day of your period.
How to Use the Blister Pack:
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.
1. 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 pack over the preprinted days of the week and make sure it lines up with the pills.
2. Your 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 white “active” pills, 7 light blue “active” pills, 7 dark blue “active” pills, and 7 green “reminder” pills. Refer to the sample of the blister pack below:
3. After taking the last green pill, start a new blister pack 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 green pill, start taking the first white pill from the blister pack the very next day.
4. Take the pills in each new package as before. Start with the white pill on row #1 and take one pill each day, left to right, until the last green pill has been taken.
Three Ways to Remember in What Order to take the Pills
1. Follow the sticker with the days of the week (placed above the pills).
2. Always go from left to right.
3. Always finish all your pills.
What should I do if I miss any Tri-VyLibra pills?
If you miss 1 pill in Weeks 1, 2, or 3, follow these steps:
If you miss 2 pills in Week 1 or Week 2 of your pack, follow these steps:
If you miss 2 pills in a row in Week 3, or you miss 3 or more pills in a row during Weeks 1, 2, or 3 of the pack, follow these steps:
If you have any questions or are unsure about the information in this leaflet, call your healthcare provider.
Manufactured For:
Afaxys Pharma, LLC
Charleston, SC, 29403, USA.
Manufactured by:
Aurobindo Pharma Limited
Unit-VII (SEZ)
Mahaboob Nagar (Dt)-509302, India
This Patient Information and Instructions for Use has been approved by the U.S. Food and Drug Administration.
Revised: 06/2022
TRI-VYLIBRA
norgestimate and ethinyl estradiol kit |
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Labeler - RPK Pharmaceuticals, Inc. (147096275) |
Establishment | |||
Name | Address | ID/FEI | Business Operations |
---|---|---|---|
RPK Pharmaceuticals, Inc. | 147096275 | RELABEL(53002-1776) |