Tri-Vylibra

Do not prescribe Tri-Vylibra to women who are known to have the following conditions:

• A high risk of arterial or venous thrombotic diseases. Examples include women who are known to:
  • Smoke, if over age 35 [see Boxed Warning and Warnings and Precautions (5.1)]
  • Have deep vein thrombosis or pulmonary embolism, now or in the past [see Warnings and Precautions (5.1)]
  • Have inherited or acquired hypercoagulopathies [see Warnings and Precautions (5.1)]
  • Have cerebrovascular disease [see Warnings and Precautions (5.1)]
  • Have coronary artery disease [see Warnings and Precautions (5.1)]
  • Have thrombogenic valvular or thrombogenic rhythm diseases of the heart (for example, subacute bacterial endocarditis with valvular disease, or atrial fibrillation) [see Warnings and Precautions (5.1)]
  • Have uncontrolled hypertension [see Warnings and Precautions (5.4)]
  • Have diabetes mellitus with vascular disease [see Warnings and Precautions (5.6)]
  • Have headaches with focal neurological symptoms or migraine headaches with aura [see Warnings and Precautions (5.7)]
    • Women   over   age   35   with   any   migraine   headaches   [see  Warnings   and Precautions (5.7)]
  • Liver tumors, benign or malignant, or liver disease [see Warnings and Precautions (5.2)]
  • Undiagnosed abnormal uterine bleeding [see Warnings and Precautions (5.8)]
  • Pregnancy, because there is no reason to use COCs during pregnancy [see Warnings and Precautions (5.9) and Use in Specific Populations (8.1)]
  • Breast  cancer  or  other  estrogen-  or  progestin-sensitive  cancer,  now  or  in  the  past [see Warnings and Precautions (5.11)]
  • Use of Hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, due to the potential for ALT elevations [see Warnings and Precautions (5.3)]

Thromboembolic Disorders and Other Vascular Problems

• Stop Tri-Vylibra if an arterial thrombotic event or venous thromboembolic (VTE) event occurs.
• Stop Tri-Vylibra if there is unexplained loss of vision, proptosis, diplopia, papilledema, or retinal vascular lesions. Evaluate for retinal vein thrombosis immediately [see Adverse Reactions (6.2)].
• If feasible, stop Tri-Vylibra  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-Vylibra 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-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.

Risk of Liver Enzyme Elevations with Concomitant Hepatitis C Treatment

During clinical trials with the Hepatitis C combination drug regimen that contains ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, ALT elevations greater than 5 times the upper limit of normal (ULN), including some cases greater than 20 times the ULN, were significantly more frequent in women using ethinyl estradiol-containing medications, such as 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.

High Blood Pressure

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.

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-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.

Headache

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).

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-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.

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-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)].

Depression

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

Carcinoma of Breast and Cervix

• Tri-Vylibra is contraindicated in women who currently have or have had breast cancer because breast cancer may be hormonally sensitive [see Contraindications (4)].

There is substantial evidence that COCs do not increase the incidence of breast cancer. Although some past studies have suggested that COCs might increase the incidence of breast cancer, more recent studies have not confirmed such findings.

• Some studies suggest that COC use has been associated with an increase in the risk of cervical cancer or intraepithelial neoplasia. However, there continues to be controversy about the extent to which such findings may be due to differences in sexual behavior and other factors.

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-Vylibra.

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.

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 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.

Pharmacodynamics

No specific pharmacodynamic studies were conducted with Tri-Vylibra.

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-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).

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.

How Supplied

Tri-Vylibra tablets are available in a blister pack.

Each blister pack (28 tablets) contains in the following order:

• 7 white, round, biconvex, coated tablets, debossed with “S” on one side and “19” on other side of the tablet contains 0.180 mg norgestimate USP and 0.035 mg ethinyl estradiol USP
• 7 light blue, round, biconvex, coated tablets, debossed with “S” on one side and “21” on other side of the tablet contains 0.215 mg norgestimate USP and 0.035 mg ethinyl estradiol USP
• 7 dark blue, round, biconvex, coated tablets, debossed with “S” on one side and “22” on other side of the tablet contains 0.250 mg norgestimate USP and 0.035 mg ethinyl estradiol USP
• 7 green, round, mottled biconvex, uncoated tablets (non-hormonal Placebo), debossed with “S” on one side and “24” on other side of the tablet.

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           

Storage Conditions

• Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].
• Protect from light.
• Keep out of the reach of children.