Jinteli

norethindrone acetate and ethinyl estradiol · Tablet · Oral

Boxed warning. WARNING: CARDIOVASCULAR DISORDERS, PROBABLE DEMENTIA, BREAST CANCER, and ENDOMETRIAL CANCER Estrogen Plus Progestin Therapy Cardiovascular Disorders and Probable Dementia The Women’s Health Initiative (WHI) estrogen plus progestin substudy reported increased risks of pulmonary embolism (PE), deep vein thrombosis (DVT), stroke, and myocardial infarction (MI) in postmenopausal women (50 to 79 years of age) during 5.6 years of treatment with daily oral conjugated estrogens (CE) [0.625 mg] combined with medroxyprogesterone acetate (MPA) [2.5 mg], relative to placebo [see Warnings and Precautions ( 5.1 ), and Clinical Studies ( 14.5 )] . The WHI Memory Study (WHIMS) estrogen plus progestin ancillary study of WHI reported an increased risk of developing probable dementia in postmenopausal women 65 years of age and older during 4 years of treatment with daily CE (0.625 mg) combined with MPA…

Uses

Jinteli is a combination of an estrogen and progestin indicated in a woman with a uterus for: Treatment of Moderate to Severe Vasomotor Symptoms due to Menopause ( 1.1 ) Prevention of Postmenopausal Osteoporosis ( 1.2 ) 1.1 Treatment of Moderate to Severe Vasomotor Symptoms due to Menopause 1.2 Prevention of Postmenopausal Osteoporosis Limitation of Use When prescribing solely for the prevention of postmenopausal osteoporosis, first consider the use of non-estrogen medications. Consider estrogen therapy only for women at significant risk of osteoporosis.

Dosage and administration

Use estrogen, alone or in combination with a progestogen, at the lowest effective dose and the shortest duration consistent with treatment goals and risks for the individual woman. Re-evaluate postmenopausal women periodically as clinically appropriate to determine whether treatment is still necessary. One tablet orally once daily ( 2.1 , 2.2 ) 2.1 Treatment of Moderate to Severe Vasomotor Symptoms due to Menopause Take a single Jinteli, 1 mg/5 mcg, orally once daily. 2.2 Prevention of Postmenopausal Osteoporosis Take a single Jinteli tablet 1 mg/5 mcg, orally once daily.

Dosage forms and strengths

Jinteli ® (norethindrone acetate and ethinyl estradiol tablets, USP) 1 mg/5 mcg: white, round, flat-faced, beveled-edge, unscored tablet; debossed with stylized b on one side and 125 on the other side. Tablet: 1 mg norethindrone acetate and 5 mcg ethinyl estradiol ( 3 )

Contraindications

Jinteli is contraindicated in women with any of the following conditions: Undiagnosed abnormal genital bleeding [see Warnings and Precautions ( 5.2 )]. Breast cancer or a history of breast cancer [see Warnings and Pr ecautions ( 5.2 )]. Estrogen-dependent neoplasia [see Warnings and Precautions ( 5.2 )]. Active DVT, PE or a history of these conditions [see Warnings and Precautions ( 5.1 )]. Active arterial thromboembolic disease (for example, stroke and MI), or a history of these conditions [see Warnings and Precautions ( 5.1 )]. Known anaphylactic reaction, angioedema, or hypersensitivity to Jinteli Hepatic impairment or disease. Protein C, protein S, or antithrombin deficiency, or other known thrombophilic disorders. Undiagnosed abnormal genital bleeding ( 4 , 5.2 ) Breast cancer or a history of breast cancer ( 4 , 5.2 ) Estrogen-dependent neoplasia ( 4 , 5.2 ) Active DVT, PE, or history of these conditions ( 4 , 5.1 ) Active arterial thromboembolic disease (for example, stroke and MI), or a history of these conditions ( 4 , 5.1 ) Known anaphylactic reaction, angioedema, or hypersensitivity to Jinteli ( 4 ) Hepatic impairment or disease ( 4 , 5.10 ) Protein C, protein S, or antithrombin deficiency, or other known thrombophilic disorders ( 4 )

Warnings and precautions

Estrogens increase the risk of gallbladder disease ( 5.4 ) Discontinue estrogen if severe hypercalcemia, loss of vision, severe hypertriglyceridemia or cholestatic jaundice occurs ( 5.5 , 5.6 , 5.9 , 5.10 ) Monitor thyroid function in women on thyroid replacement therapy ( 5.11 , 5.18 ) 5.1 Cardiovascular Disorders Increased risks of PE, DVT, stroke, and MI are reported with estrogen plus progestin therapy. Increased risks of stroke and DVT are reported with estrogen-alone therapy. Immediately discontinue estrogen with or without progestogen therapy if any of these occur or are suspected. Manage appropriately any risk factors for arterial vascular disease (for example, hypertension, diabetes mellitus, tobacco use, hypercholesterolemia, and obesity) and/or venous thromboembolism (VTE) (for example, personal history or family history of VTE, obesity, and systemic lupus erythematosus). Stroke The WHI estrogen plus progestin substudy reported a statistically significant increased risk of stroke in women 50 to 79 years of age receiving daily CE (0.625 mg) plus MPA (2.5 mg) compared to women in the same age group receiving placebo (33 versus 25 strokes per 10,000 women-years, respectively) [see Clinical Studies ( 14.5 )] . The increase in risk was demonstrated after the first year and persisted. 1 Immediately discontinue estrogen with or without progestogen therapy if a stroke occurs or is suspected. The WHI estrogen-alone substudy reported a statistically significant increased risk of stroke in women 50 to 79 years of age receiving daily conjugated estrogens CE (0.625 mg)-alone compared to women in the same age group receiving placebo (45 versus 33 strokes per 10,000 women-years, respectively). The increase in risk was demonstrated in year 1 and persisted [see Clinical Studies ( 14.5 )] . Immediately discontinue estrogen-alone therapy if a stroke occurs or is suspected. Subgroup analyses of women 50 to 59 years of age suggest no increased risk of stroke for those women receiving CE (0.625 mg)-alone versus those receiving placebo (18 versus 21 per 10,000 women-years). 1 Coronary Heart Disease The WHI estrogen plus progestin substudy reported an increased risk (not statistically significant) of coronary heart disease (CHD) events (defined as nonfatal MI, silent MI, or CHD death) in those women receiving daily CE (0.625 mg) plus MPA (2.5 mg) compared to women receiving placebo (41 versus 34 per 10,000 women-years). 1 An increase in relative risk was demonstrated in year 1, and a trend toward decreasing relative risk was reported in years 2 through 5 [see Clinical Studies ( 14.5 )]. The WHI estrogen-alone substudy reported no overall effect on CHD events in women receiving estrogen-alone compared to placebo 2 [see Clinical Studies ( 14.5 )]. Subgroup analyses of women 50 to 59 years of age, who were less than 10 years since menopause, suggest a reduction (not statistically significant) of CHD events in those women receiving CE (0.625 mg)-alone compared to placebo (8 versus 16 per 10,000 woman-years). 1 In postmenopausal women with documented heart disease (n = 2,763), average 66.7 years of age, in a controlled clinical trial of secondary prevention of cardiovascular disease (Heart and Estrogen/Progestin Replacement Study; HERS), treatment with daily CE (0.625 mg) plus MPA (2.5 mg) demonstrated no cardiovascular benefit. During an average follow-up of 4.1 years, treatment with CE plus MPA did not reduce the overall rate of CHD events in postmenopausal women with established CHD. There were more CHD events in the CE plus MPA-treated group than in the placebo group in year 1, but not during the subsequent years. Two thousand, three hundred and twenty-one (2,321) women from the original HERS trial agreed to participate in an open label extension of HERS, HERS II. Average follow-up in HERS II was an additional 2.7 years, for a total of 6.8 years overall. Rates of CHD events were comparable among women in the CE plus MPA group and the placebo group in HERS, HERS II, and overall. Venous Thromboembolism The WHI estrogen plus progestin substudy reported a statistically significant 2-fold greater rate of VTE (DVT and PE) in women receiving daily CE (0.625 mg) plus MPA (2.5 mg) compared to women receiving placebo (35 versus 17 per 10,000 women-years). Statistically significant increases in risk for both DVT (26 versus 13 per 10,000 women-years) and PE (18 versus 8 per 10,000 women-years) were also demonstrated. The increase in VTE risk was demonstrated during the first year and persisted 3 [see Clinical Studies ( 14.5 )] . Immediately discontinue estrogen plus progestogen therapy if a VTE occurs or is suspected. In the WHI estrogen-alone substudy, the risk of VTE was increased for women receiving daily CE (0.625 mg)-alone compared to placebo (30 versus 22 per 10,000 women-years), although only the increased risk of DVT reached statistical significance (23 versus 15 per 10,000 women-years). The increase in VTE risk was demonstrated during the first 2 years 4 [see Clinical Studies (14.5)] . Immediately discontinue estrogen-alone therapy if a VTE occurs or is suspected. If feasible, discontinue estrogens at least 4 to 6 weeks before surgery of the type associated with an increased risk of thromboembolism or during periods of prolonged immobilization. 5.2 Malignant Neoplasms Breast Cancer After a mean follow-up of 5.6 years, the WHI substudy of daily CE (0.625 mg) plus MPA (2.5 mg) reported an increased risk of invasive breast cancer in women who took daily CE plus MPA compared to placebo. In this substudy, prior use of estrogen-alone or estrogen plus progestin therapy was reported by 26 percent of the women. The relative risk of invasive breast cancer was 1.24, and the absolute risk was 41 versus 33 cases per 10,000 women-years for CE plus MPA compared with placebo [see Clinical Studies ( 14.5 )] .

Side effects

The following serious adverse reactions are discussed elsewhere in the labeling: Cardiovascular Disorders [see Boxed Warning, Warnings and Precautions ( 5.1 )] . Malignant Neoplasms [see Boxed Warning, Warnings and Precautions ( 5.2 )] . The most common adverse reactions with Jinteli (incidence greater than or equal to 5 percent) are: headache, abdominal pain, breast pain, and edema (generalized) ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Teva at 1-888-838-2872 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials 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 practice. Adverse reactions reported by ≥ 5 percent of women in controlled clinical studies of Jinteli are shown in Table 1. Table 1. Associated Adverse Reactions Reported by ≥ 5 Percent of Women by Body System* BODY SYSTEM/ Adverse Reaction Number (Percent) of Subjects Placebo Jinteli 0.5/2.5 Jinteli 1/5 N = 247 N = 244 N = 258 BODY AS A WHOLE 23 (12.8) 30 (16.9) 30 (15.7) Edema - Generalized 10 (4.0) 12 (4.9) 11 (4.3) Headache 12 (4.9) 14 (5.7) 16 (6.2) DIGESTIVE SYSTEM 8 (4.4) 17 (9.6) 25 (13.1) Abdominal Pain 3 (1.2) 13 (5.3) 14 (6.8) UROGENITAL SYSTEM 20 (11.1) 34 (19.2) 45 (23.6) Breast Pain 9 (3.6) 22 (9.0) 20 (7.8) * The total number of women for each body system may be less than the number of women with AEs in that body system because a woman may have had more than one AE per body system 6.2 Postmarketing Experience The following additional adverse reactions have been identified during post-approval use of Jinteli. 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. Genitourinary System Changes in vaginal bleeding pattern and abnormal withdrawal bleeding or flow; breakthrough bleeding; spotting; increase in size of uterine leiomyomata, vaginitis, including vaginal candidiasis; change in amount of cervical secretion; changes in cervical ectropion; ovarian cancer; endometrial hyperplasia; endometrial cancer; uterine cancer; vaginal hemorrhage; ovarian cyst; irregular menstruation; metrorrhagia; menorrhagia; dysmenorrhea; uterine enlargement. Breasts Tenderness, enlargement, breast pain, nipple pain, nipple discharge, galactorrhea; fibrocystic breast changes; breast cancer; breast disorder; breast mass; breast enlargement. Cardiovascular Deep and superficial venous thrombosis; pulmonary embolism; thrombophlebitis; thrombosis; chest pain; myocardial infarction; cerebrovascular accident (stroke); transient ischemic attack; hemiparesis; increase in blood pressure; irregular heart rate; palpitations; dyspnea. Gastrointestinal Nausea, vomiting; cholestatic jaundice; pancreatitis, enlargement of hepatic hemangiomas; bloating, abdominal cramps; abdominal pain; increased incidence of gallbladder disease; cholecystitis; cholelithiasis. Skin Chloasma or melasma that may persist when drug is discontinued; generalized erythema; erythema multiforme; erythema nodosum; hemorrhagic eruption; loss of scalp hair; hirsutism; rash, pruritus. Eyes Retinal vascular thrombosis; visual impairment; intolerance to contact lenses. Central Nervous System (CNS) Headache; migraine; dizziness; depression; chorea; nervousness; mood disturbances; irritability; exacerbation of epilepsy, dementia; paresthesia; insomnia. Miscellaneous Increase or decrease in weight; reduced carbohydrate tolerance; aggravation of porphyria; edema; arthralgias; leg cramps; back pain; changes in libido; urticaria, angioedema, anaphylactoid/anaphylactic reactions; hypocalcemia; exacerbation of asthma; increased triglycerides; blood glucose abnormal; fatigue; myalgia; hypersensitivity.

Drug interactions

In vitro and in vivo studies have shown that estrogens are metabolized partially by cytochrome P450 3A4 (CYP3A4). Therefore, inducers or inhibitors of CYP3A4 may affect estrogen and progestin drug metabolism. Inducers of CYP3A4 such as St. John’s wort (Hypericum perforatum) preparations, phenobarbital, carbamazepine and rifampin may decrease the plasma concentration of estrogens and progestins, possibly resulting in a decrease in therapeutic effects and/or changes in the uterine bleeding profile. Inhibitors of CYP3A4 such as erythromycin, clarithromycin, ketoconazole, itraconazole, ritonavir and grapefruit juice may increase the plasma concentration of the estrogen or the progestin or both and may result in adverse reactions. Coadministration of atorvastatin and certain hormonal products containing ethinyl estradiol increase AUC values for ethinyl estradiol approximately 20 percent. Ascorbic acid and acetaminophen may increase the plasma ethinyl estradiol concentration, possibly by inhibition of conjugation. Combination hormonal products have been shown to significantly decrease the plasma concentration of lamotrigine likely due to induction of lamotrigine glucuronidation. This may reduce seizure control; therefore, dosage adjustments of lamotrigine may be necessary. Inducers and/or inhibitors of CYP3A4 may affect estrogen drug metabolism and decrease or increase the estrogen plasma concentration. ( 7 )

Use in specific populations

8.1 Pregnancy Risk Summary Jinteli is not indicated for use in pregnancy. There are no data with the use of Jinteli in pregnant women; however, 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 combined (estrogens and progestins) product before conception or during early pregnancy. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. 8.2 Lactation Risk Summary Estrogens plus progestogens are present in human milk and can reduce milk production in breastfeeding women. This reduction can occur at any time but is less likely to occur once breastfeeding is well-established. The development and health benefits of breastfeeding should be considered along with the mother’s clinical need for Jinteli and any potential adverse effects on the breastfed child from Jinteli or from the underlying maternal condition. 8.4 Pediatric Use Jinteli is not indicated for use in pediatric patients. Clinical studies have not been conducted in the pediatric population. 8.5 Geriatric Use There have not been sufficient numbers of geriatric women involved in clinical studies utilizing Jinteli to determine whether those over 65 years of age differ from younger subjects in their response to Jinteli. The Women’s Health Initiative Studies In the WHI estrogen plus progestin substudy (daily CE [0.625 mg] plus MPA [2.5 mg] versus placebo), there was a higher relative risk of nonfatal stroke and invasive breast cancer in women greater than 65 years of age [see Clinical Studies ( 14.5 )] . In the WHI estrogen-alone substudy (daily CE [0.625 mg]-alone versus placebo), there was a higher relative risk of stroke in women greater than 65 years of age [see Clinical Studies ( 14.5 )] . The Women’s Health Initiative Memory Study In the WHIMS ancillary studies of postmenopausal women 65 to 79 years of age, there was an increased risk of developing probable dementia in women receiving estrogen plus progestin or estrogen-alone when compared to placebo [see Warnings and Precautions ( 5.3 ), and Clinical Studies ( 14.6 )] . Since both ancillary studies were conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women 8 [see Warnings and Precautions ( 5.3 ), and Clinical Studies ( 14.6 )] .

Pregnancy

Pediatric use

8.4 Pediatric Use Jinteli is not indicated for use in pediatric patients. Clinical studies have not been conducted in the pediatric population.

Geriatric use

8.5 Geriatric Use There have not been sufficient numbers of geriatric women involved in clinical studies utilizing Jinteli to determine whether those over 65 years of age differ from younger subjects in their response to Jinteli. The Women’s Health Initiative Studies In the WHI estrogen plus progestin substudy (daily CE [0.625 mg] plus MPA [2.5 mg] versus placebo), there was a higher relative risk of nonfatal stroke and invasive breast cancer in women greater than 65 years of age [see Clinical Studies ( 14.5 )] . In the WHI estrogen-alone substudy (daily CE [0.625 mg]-alone versus placebo), there was a higher relative risk of stroke in women greater than 65 years of age [see Clinical Studies ( 14.5 )] . The Women’s Health Initiative Memory Study In the WHIMS ancillary studies of postmenopausal women 65 to 79 years of age, there was an increased risk of developing probable dementia in women receiving estrogen plus progestin or estrogen-alone when compared to placebo [see Warnings and Precautions ( 5.3 ), and Clinical Studies ( 14.6 )] . Since both ancillary studies were conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women 8 [see Warnings and Precautions ( 5.3 ), and Clinical Studies ( 14.6 )] .

Overdosage

Overdosage of estrogen plus progestogen may cause nausea, vomiting, breast tenderness, abdominal pain, drowsiness and fatigue, and withdrawal bleeding may occur in women. Treatment of overdose consists of discontinuation of Jinteli therapy with institution of appropriate symptomatic care.

Description

Jinteli ® (norethindrone acetate and ethinyl estradiol tablets, USP) are a continuous dosage regimen of a progestin-estrogen combination for oral administration. Each white tablet contains 1 mg norethindrone acetate, USP [19-Norpregn-4-en-20-yn-3-one,7(acetyloxy)-, (17α)-] and 5 mcg ethinyl estradiol, USP [19-Norpregna-1,3,5(10)-trien-20-yne-3,17-diol, (17α)-]. Each tablet also contains the following inactive ingredients: calcium stearate, lactose monohydrate, microcrystalline cellulose, pregelatinized corn starch, and sodium starch glycolate. The structural formulas are as follows: Norethindrone Acetate, USP Ethinyl Estradiol, USP C 22 H 28 O 3 M.W. 340.46 C 20 H 24 O 2 M.W. 296.40 new

Mechanism of action

12.1 Mechanism of Action Endogenous estrogens are largely responsible for the development and maintenance of the female reproductive system and secondary sexual characteristics. Although circulating estrogens exist in a dynamic equilibrium of metabolic interconversions, estradiol is the principal intracellular human estrogen and is substantially more potent than its metabolites, estrone and estriol, at the receptor level. The primary source of estrogen in normally cycling adult women is the ovarian follicle, which secretes 70 to 500 mcg of estradiol daily, depending on the phase of the menstrual cycle. After menopause, most endogenous estrogen is produced by conversion of androstenedione, which is secreted by the adrenal cortex, to estrone in the peripheral tissues. Thus, estrone and the sulfate conjugated form, estrone sulfate, are the most abundant circulating estrogens in postmenopausal women. The pharmacologic effects of ethinyl estradiol are similar to those of endogenous estrogens. Estrogens act through binding to nuclear receptors in estrogen-responsive tissues. To date, two estrogen receptors have been identified. These vary in proportion from tissue to tissue. Circulating estrogens modulate the pituitary secretion of the gonadotropins, luteinizing hormone (LH) and FSH through a negative feedback mechanism. Estrogens act to reduce the elevated levels of these hormones seen in postmenopausal women. Progestin compounds enhance cellular differentiation and generally oppose the actions of estrogens by decreasing estrogen receptor levels, increasing local metabolism of estrogens to less active metabolites, or inducing gene products that blunt cellular responses to estrogen. Progestins exert their effects in target cells by binding to specific progesterone receptors that interact with progesterone response elements in target genes. Progesterone receptors have been identified in the female reproductive tract, breast, pituitary, hypothalamus, bone, skeletal tissue and central nervous system. Progestins produce similar endometrial changes to those of the naturally occurring hormone progesterone.

How supplied

16.1 How Supplied Jinteli ® (norethindrone acetate and ethinyl estradiol tablets, USP) is available in the following strength and package sizes: 1 mg/5 mcg - White, round, flat-faced, beveled-edge, unscored tablets, debossed with stylized b on one side and 125 on the other side. Bottle of 90 tablets (NDC 0093- 3122 -98) 5 Blister Cards of 28 tablets per carton (NDC 0093- 3122 -42) 16.2 Storage and Handling Store at 20ºC to 25ºC (68ºF to 77ºF); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Keep this and all medications out of the reach of children.

Patient information

Advise women to read the FDA-approved patient labeling (Patient Information) Vaginal Bleeding Inform postmenopausal women to report any vaginal bleeding to their healthcare provider as soon as possible [see Warnings and Precautions ( 5.2 )] . Possible Serious Adverse Reactions with Estrogen Plus Progestogen Therapy Inform postmenopausal women of possible serious adverse reactions of estrogen plus progestogen therapy including Cardiovascular Disorders, Malignant Neoplasms, and Probable Dementia [see Warnings and Precautions ( 5.1 , 5.2 , 5.3 )] . Possible Common Adverse Reactions with Estrogen Plus Progestogen Therapy Inform postmenopausal women of possible less serious but common adverse reactions of estrogen plus progestogen therapy such as headache, breast pain and tenderness, nausea and vomiting. Manufactured For: Teva Pharmaceuticals Parsippany, NJ 07054 Rev. E 2/2024

Label text from the FDA structured product label by Teva Pharmaceuticals USA, Inc. (revised Feb 27, 2024). Long sections are shortened; the complete label is on DailyMed.

Active ingredients

Norethindrone Acetate in 1 product
Ethinyl Estradiol in 1 product

Jinteli NDC products (1)

NDC	Strength & form	Labeler	Type
0093-3122	Norethindrone Acetate 1 mg/1; Ethinyl Estradiol 5 ug/1 Tablet	Teva Pharmaceuticals USA, Inc.	ANDA

Frequently asked questions

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Who makes Jinteli?

Jinteli is listed by 1 labeler in the FDA NDC directory, including Teva Pharmaceuticals USA, Inc..