PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

Package/Label Display Panel

NDC 0093-3122-42

Jinteli®

(norethindrone acetate and ethinyl estradiol tablets, USP)

1 mg/5 mcg

This package contains 5 pouches. Each pouch contains one blister
card of 28 tablets. Each white tablet contains 1 mg norethindrone
acetate, USP and 5 mcg ethinyl estradiol, USP.

Usual Dosage: One tablet daily. See enclosed Full Prescribing Information.

PHARMACIST: Each foil pouch contains one “PATIENT INFORMATION" sheet which is to be provided to the patient with each prescription.

Rx only

5 Blister Cards,
28 Tablets Each

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RECENT MAJOR CHANGES SECTION

Highlight: Boxed Warning 5/2023

Warnings and Precautions, Malignant Neoplasms (5.2) 11/2023

RECENT MAJOR CHANGES

Boxed Warning 5/2023

Warnings and Precautions, Malignant Neoplasms (5.2) 11/2023

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DESCRIPTION SECTION

11 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

C22H28O3 M.W. 340.46 C20H24O2 M.W. 296.40

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DOSAGE FORMS & STRENGTHS SECTION

Highlight: * Tablet: 1 mg norethindrone acetate and 5 mcg ethinyl estradiol (3)

3 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 stylizedb on one side and125 on the other side.

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CONTRAINDICATIONS SECTION

Highlight: * 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)

4 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 Precautions (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.

BOXED WARNING SECTION

WARNING: CARDIOVASCULAR DISORDERS, PROBABLE DEMENTIA, BREAST CANCER, and

ENDOMETRIAL CANCER

WARNINGS AND PRECAUTIONS SECTION

Highlight: * 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 WARNINGS AND PRECAUTIONS

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 placebo2 [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 persisted3 [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 years4 [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)]. Among women who reported prior use of hormone therapy, the relative risk of invasive breast cancer was 1.86 and the absolute risk was 46 versus 25 cases per 10,000 women- years for CE plus MPA compared with placebo. Among women who reported no prior use of hormone therapy, the relative risk of invasive breast cancer was 1.09, and the absolute risk was 40 versus 36 cases per 10,000 women-years for CE plus MPA compared with placebo. In the same substudy, invasive breast cancers were larger, were more likely to be node positive, and were diagnosed at a more advanced stage in the CE (0.625 mg) plus MPA (2.5 mg) group compared with the placebo group. Metastatic disease was rare with no apparent difference between the two groups. Other prognostic factors, such as histologic subtype, grade and hormone receptor status did not differ between the groups5 [see Clinical Studies (14.5)].

The WHI substudy of daily CE (0.625 mg)-alone provided information about breast cancer in estrogen-alone users. In the WHI estrogen-alone substudy, after an average follow up of 7.1 years, daily CE-alone was not associated with an increased risk of invasive breast cancer (relative risk [RR] 0.80) compared to placebo6 [see Clinical Studies (14.5)].

Consistent with the WHI clinical trials, observational studies have also reported an increased risk of breast cancer for estrogen plus progestin therapy, and a smaller increased risk for estrogen-alone therapy, after several years of use. One large meta-analysis of prospective cohort studies reported increased risks that were dependent upon duration of use and could last up to >10 years after discontinuation of estrogen plus progestin therapy and estrogen-alone therapy. Extension of the WHI trials also demonstrated increased breast cancer risk associated with estrogen plus progestin therapy. Observational studies also suggest that the risk of breast cancer was greater, and became apparent earlier, with estrogen plus progestin therapy as compared to estrogen-alone therapy. These studies have not generally found significant variation in the risk of breast cancer among different estrogen plus progestin combinations, doses, or routes of administration.

The use of estrogen-alone and estrogen plus progestin has been reported to result in an increase in abnormal mammograms requiring further evaluation.

All women should receive yearly breast examinations by a healthcare provider and perform monthly breast self-examinations. In addition, mammography examinations should be scheduled based on patient age, risk factors and prior mammogram results.

Endometrial Cancer

Endometrial hyperplasia (a possible precursor of endometrial cancer) has been reported to occur at a rate of approximately 1 percent or less with Jinteli.

An increased risk of endometrial cancer has been reported with the use of unopposed estrogen therapy in a woman with a uterus. The reported endometrial cancer risk among unopposed estrogen users is about 2 to 12 times greater than in non-users, and appears dependent on duration of treatment and on estrogen dose. Most studies show no significant increased risk associated with use of estrogens for less than 1 year. The greatest risk appears associated with prolonged use, with increased risks of 15- to 24-fold for 5 to 10 years or more. This risk has been shown to persist for at least 8 to 15 years after estrogen therapy is discontinued.

Clinical surveillance of all women using estrogen-alone or estrogen plus progestogen therapy is important. Adequate diagnostic measures, including directed or random endometrial sampling when indicated, should be undertaken to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal genital bleeding.

There is no evidence that the use of natural estrogens results in a different endometrial risk profile than synthetic estrogens of equivalent estrogen dose. Adding a progestogen to estrogen therapy in postmenopausal women has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer.

Ovarian Cancer

The CE plus MPA substudy of WHI reported that estrogen plus progestin increased the risk of ovarian cancer. After an average follow-up of 5.6 years, the relative risk for ovarian cancer for CE plus MPA versus placebo was 1.58 (95 percent CI, 0.77 to 3.24), but it was not statistically significant. The absolute risk for CE plus MPA versus placebo was 4 versus 3 cases per 10,000 women-years.7

A meta-analysis of 17 prospective and 35 retrospective epidemiology studies found that women who used hormonal therapy for menopausal symptoms had an increased risk for ovarian cancer. The primary analysis, using case-control comparisons, included 12,110 cancer cases from the 17 prospective studies. The relative risks associated with current use of hormonal therapy was 1.41 (95% confidence interval [CI] 1.32 to 1.50); there was no difference in the risk estimates by duration of the exposure (less than 5 years [median of 3 years] vs. greater than 5 years [median of 10 years] of use before the cancer diagnosis). The relative risk associated with combined current and recent use (discontinued use within 5 years before cancer diagnosis) was 1.37 (95% CI 1.27 to 1.48), and the elevated risk was significant for both estrogen-alone and estrogen plus progestin products. The exact duration of hormone therapy use associated with an increased risk of ovarian cancer, however, is unknown.

5.3 Probable Dementia

In the WHI Memory Study (WHIMS) estrogen plus progestin ancillary study, a population of 4,532 postmenopausal women 65 to 79 years of age was randomized to daily CE (0.625 mg) plus MPA (2.5 mg) or placebo.

After an average follow-up of 4 years, 40 women in the CE plus MPA group and 21 women in the placebo group were diagnosed with probable dementia. The relative risk of probable dementia for CE plus MPA versus placebo was 2.05 (95 percent CI, 1.21 to 3.48). The absolute risk of probable dementia for CE plus MPA versus placebo was 45 versus 22 cases per 10,000 women-years8 [see Use in Specific Populations (8.5), and Clinical Studies (14.6)].

In the WHIMS estrogen-alone ancillary study, a population of 2,947 hysterectomized women 65 to 79 years of age was randomized to daily CE (0.625 mg)-alone or placebo.

After an average follow-up of 5.2 years, 28 women in the estrogen-alone group and 19 women in the placebo group were diagnosed with probable dementia. The relative risk of probable dementia for CE-alone versus placebo was 1.49 (95 percent CI, 0.83 to 2.66). The absolute risk of probable dementia for CE-alone versus placebo was 37 versus 25 cases per 10,000 women-years8 [see Use in Specific Populations (8.5), and Clinical Studies (14.6)].

When data from the two populations in the WHIMS estrogen-alone and estrogen plus progestin ancillary studies were pooled as planned in the WHIMS protocol, the reported overall relative risk for probable dementia was 1.76 (95 percent CI, 1.19 to 2.60). Since both ancillary substudies were conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women8 [see Use in Specific Populations (8.5), and Clinical Studies (14.6)].

5.4 Gallbladder Disease

A 2- to 4-fold increase in the risk of gallbladder disease requiring surgery in postmenopausal women receiving estrogens has been reported.

5.5 Hypercalcemia

Estrogen administration may lead to severe hypercalcemia in women with breast cancer and bone metastases. Discontinue estrogens, including Jinteli, if hypercalcemia occurs, and take appropriate measures to reduce the serum calcium level.

5.6 Visual Abnormalities

Retinal vascular thrombosis has been reported in women receiving estrogens. Discontinue Jinteli pending examination if there is sudden partial or complete loss of vision, or a sudden onset of proptosis, diplopia, or migraine. Permanently discontinue estrogens, including Jinteli, if examination reveals papilledema or retinal vascular lesions.

5.7 Addition of a Progestogen When a Woman Has Not Had a Hysterectomy

Studies of the addition of a progestogen for 10 or more days of a cycle of estrogen administration or daily with estrogen in a continuous regimen, have reported a lowered incidence of endometrial hyperplasia than would be induced by estrogen treatment alone. Endometrial hyperplasia may be a precursor to endometrial cancer.

There are, however, possible risks that may be associated with the use of progestogens with estrogens compared to estrogen-alone regimens. These include an increased risk of breast cancer.

5.8 Elevated Blood Pressure

In a small number of case reports, substantial increases in blood pressure have been attributed to idiosyncratic reactions to estrogens. In a large, randomized, placebo-controlled clinical trial, a generalized effect of estrogen therapy on blood pressure was not seen.

5.9 Exacerbation of Hypertriglyceridemia

In women with pre-existing hypertriglyceridemia, estrogen therapy may be associated with elevations of plasma triglycerides leading to pancreatitis. Discontinue Jinteli if pancreatitis occurs.

5.10 Hepatic Impairment and/or a Past History of Cholestatic Jaundice

Estrogens may be poorly metabolized in women with hepatic impairment. Exercise caution in any woman with a history of cholestatic jaundice associated with past estrogen use or with pregnancy. In the case of recurrence of cholestatic jaundice, discontinue Jinteli.

5.11 Exacerbation of Hypothyroidism

Estrogen administration leads to increased thyroid-binding globulin (TBG) levels. Women with normal thyroid function can compensate for the increased TBG by making more thyroid hormone, thus maintaining free T4 and T3 serum concentrations in the normal range. Women dependent on thyroid hormone replacement therapy who are also receiving estrogen may require increased doses of their thyroid replacement therapy. Monitor thyroid function in these women during treatment with Jinteli to maintain their free thyroid hormone levels in an acceptable range.

5.12 Fluid Retention

Estrogens plus progestogens may cause some degree of fluid retention. Monitor any woman with a condition(s) that might predispose her to fluid retention, such as cardiac or renal impairment. Discontinue estrogen plus progestogen therapy, including Jinteli, with evidence of medically concerning fluid retention.

5.13 Hypocalcemia

Estrogen-induced hypocalcemia may occur in women with hypoparathyroidism. Consider whether the benefits of estrogen therapy, including Jinteli, outweigh the risks in such women.

5.14 Exacerbation of Endometriosis

A few cases of malignant transformation of residual endometrial implants have been reported in women treated post-hysterectomy with estrogen-alone therapy.

5.15 Hereditary Angioedema

Exogenous estrogens may exacerbate symptoms of angioedema in women with hereditary angioedema. Consider whether the benefits of estrogen therapy, including Jinteli, outweigh the risks in such women.

5.16 Exacerbation of Other Conditions

Estrogen therapy, including Jinteli, may cause an exacerbation of asthma, diabetes mellitus, epilepsy, migraine, porphyria, systemic lupus erythematosus, and hepatic hemangiomas. Consider whether the benefits of estrogen therapy outweigh the risks in women with such conditions.

5.17 Laboratory Tests

Serum follicle stimulating hormone (FSH) and estradiol levels have not been shown to be useful in the management of postmenopausal women with moderate to severe vasomotor symptoms.

5.18 Drug-Laboratory Test Interactions

• Accelerated prothrombin time, partial thromboplastin time, and platelet aggregation time; increased platelet count; increased factors II, VII antigen, VIII antigen, VIII coagulant activity, IX, X, XII, VII-X complex, II-VII-X complex, and beta-thromboglobulin; decreased levels of antifactor Xa and antithrombin III, decreased antithrombin III activity; increased levels of fibrinogen and fibrinogen activity; increased plasminogen antigen and activity.
• Increased TBG levels leading to increased circulating total thyroid hormone levels as measured by protein-bound iodine (PBI), T4 levels (by column or by radioimmunoassay) or T3 levels by radioimmunoassay. T3 resin uptake is decreased, reflecting the elevated TBG. Free T4 and free T3 concentrations are unaltered. Women on thyroid replacement therapy may require higher doses of thyroid hormone.
• Other binding proteins may be elevated in serum, for example, corticosteroid binding globulin (CBG), sex hormone-binding globulin (SHBG), leading to increased total circulating corticosteroids and sex steroids, respectively. Jinteli 1/5 tablets was associated with an SHBG increase of 22 percent. Free hormone concentrations, such as testosterone and estradiol, may be decreased. Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha-1-antitrypsin, ceruloplasmin).
• Increased plasma high-density lipoprotein (HDL) and HDL2 cholesterol subfraction concentrations, reduced low-density lipoprotein (LDL) cholesterol concentration, increased triglycerides levels.
• Impaired glucose tolerance.

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DRUG INTERACTIONS SECTION

Highlight: * Inducers and/or inhibitors of CYP3A4 may affect estrogen drug metabolism and decrease or increase the estrogen plasma concentration. (7)

7 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.

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ADVERSE REACTIONS SECTION

Highlight: 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 ADVERSE REACTIONS

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)].

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*

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.

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OVERDOSAGE SECTION

10 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.

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NONCLINICAL TOXICOLOGY SECTION

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term continuous administration of natural and synthetic estrogens in certain animal species increases the frequency of carcinomas of the breast, uterus, cervix, vagina, testis, and liver.

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SPL PATIENT PACKAGE INSERT SECTION

PATIENT INFORMATION

JINTELI**®**

(Norethindrone Acetate and Ethinyl Estradiol Tablets)

Read this Patient Information before you start using Jinteli and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your menopausal symptoms or your treatment.

What is Jinteli?

Jinteli is a prescription medicine that contains two kinds of hormones, an estrogen and a progestogen.

What is Jinteli used for?

Jinteli is used after menopause to:

*Reduce moderate to severe hot flushes

Estrogens are hormones made by a woman’s ovaries. The ovaries normally stop making estrogens when a woman is between 45 and 55 years old. This drop in body estrogen levels causes the “change of life” or menopause, the end of monthly menstrual periods. Sometimes both ovaries are removed during an operation before natural menopause takes place. The sudden drop in estrogen levels causes “surgical menopause”.

When estrogen levels begin dropping, some women get very uncomfortable symptoms, such as feelings of warmth in the face, neck, and chest, or sudden intense episodes of heat and sweating (“hot flashes” or “hot flushes”). In some women the symptoms are mild, and they will not need to take estrogens. In other women, symptoms can be more severe.

*Help reduce your chances of getting osteoporosis (thin weak bones)

If you use Jinteli only to prevent osteoporosis from menopause, talk with your healthcare provider about whether a different treatment or medicine without estrogens might be better for you. You and your healthcare provider should talk regularly about whether you still need treatment with Jinteli.

Who should not use Jinteli?

****Do not use Jinteli if you have had your uterus (womb) removed (hysterectomy).

****Jinteli contains a progestogen to decrease the chance of getting cancer of the uterus (womb). If you do not have a uterus, you do not need a progestogen and you should not use Jinteli.

Do not start using Jinteli if you:

*have any unusual vaginal bleeding.

Vaginal bleeding after menopause may be a warning sign of cancer of the uterus (womb). Your healthcare provider should check any unusual vaginal bleeding to find out the cause.

*have been diagnosed with a bleeding disorder. *currently have or have had certain cancers.

Estrogens may increase the chances of getting certain types of cancers, including cancer of the breast or uterus (womb). If you have or have had cancer, talk with your healthcare provider about whether you should use Jinteli.

*had a stroke or heart attack *currently have or have had blood clots *currently have or have had liver problems *are allergic to Jinteli or any of its ingredients.

See the list of ingredients in Jinteli at the end of this leaflet.

Before you use Jinteli, tell your healthcare provider about all of your medical conditions, including if you:

*have any unusual vaginal bleeding

Vaginal bleeding after menopause may be a warning sign of cancer of the uterus (womb). Your healthcare provider should check any unusual vaginal bleeding to find out the cause.

*have any other medical conditions that may become worse while you are using norethindrone acetate and ethinyl estradiol tablets.

Your healthcare provider may need to check you more carefully if you have certain conditions, such as asthma (wheezing), epilepsy (seizures), diabetes, migraine, endometriosis, lupus, angioedema (swelling of face and tongue), or problems with your heart, liver, thyroid, kidneys, or have high calcium levels in your blood.

*are going to have surgery or will be on bed rest

Your healthcare provider will let you know if you need to stop using Jinteli.

*are pregnant or think you may be pregnant.

Jinteli is not for pregnant women.

*are breastfeeding

The hormones in Jinteli can pass into your breast milk.

**Tell your healthcare provider about all the medicines you take,**including prescription and over-the-counter medicines, vitamins, and herbal supplements. Some medicines may affect how Jinteli works. Some other medicines and food products may increase or decrease the concentrations of the hormones in Jinteli in the blood. Jinteli may also affect how your other medicines work. Keep a list of your medicines and show it to your healthcare provider and pharmacist when you get new medicine.

How should I use Jinteli?

• Take Jinteli exactly as your healthcare provider tells you to take it.
• Take 1 Jinteli tablet at the same time each day.
• You and your healthcare provider should talk regularly (every 3 to 6 months) about the dose you are taking and whether or not you still need treatment with Jinteli.

What are the possible side effects of Jinteli?

Side effects are grouped by how serious they are and how often they happen when you are treated.

Serious, but less common side effects include:

Call your healthcare provider right away if you get any of the following warning signs or any other unusual symptoms that concern you:

• new breast lumps
• unusual vaginal bleeding
• changes in vision or speech
• sudden new severe headaches
• severe pains in your chest or legs with or without shortness of breath, weakness and fatigue

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Common side effects of****Jinteli include:

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These are not all the possible side effects of Jinteli. For more information, ask your healthcare provider or pharmacist. Tell your healthcare provider if you have any side effects that bother you or do not go away.

You may report side effects to Teva at 1-888-838-2872 or FDA at 1-800-FDA-1088.

What can I do to lower my chances of a serious side effect with Jinteli?

• Talk with your healthcare provider regularly about whether you should continue using Jinteli.

• If you have a uterus, talk with your healthcare provider about whether Jinteli is right for you.

• In general, the addition of a progestogen is recommended for a woman with a uterus to reduce the chance of getting cancer of the uterus (womb).

• See your healthcare provider right away if you get vaginal bleeding while using Jinteli.

• Have a pelvic exam, breast exam and mammogram (breast x-ray) every year unless your healthcare provider tells you something else.

• If members of your family have had breast cancer or if you have ever had breast lumps or an abnormal mammogram (breast x-ray), you may need to have breast exams more often.

• If you have high blood pressure, high cholesterol (fat in the blood), diabetes, are overweight, or use tobacco, you may have a higher chance for getting heart disease.

Ask your healthcare provider for ways to lower your chances of getting heart disease.

How should I store****Jinteli?

• Store Jinteli at room temperature between 68°F to 77°F (20°C to 25°C).

Keep Jinteli out of the reach of children.

General information about the safe and effective use ofJinteli.

Medicines are sometimes prescribed for conditions that are not mentioned in a Patient Information leaflet. Do not use Jinteli for conditions for which it was not prescribed. Do not give Jinteli to other people, even if they have the same symptoms you have. It may harm them.

You can ask your pharmacist or healthcare provider for information about Jinteli that is written for health professionals.

For more information call 1-888-838-2872.

What are the ingredients inJinteli?

Active Ingredients: norethindrone acetate and ethinyl estradiol

Inactive Ingredients: calcium stearate, lactose monohydrate, microcrystalline cellulose, pregelatinized corn starch, and sodium starch glycolate

This Patient Information has been approved by the U.S Food and Drug Administration.

Manufactured For:

Teva Pharmaceuticals

Parsippany, NJ 07054

Rev. D 11/2023

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REFERENCES SECTION

15 REFERENCES

1. Rossouw JE, et al. Postmenopausal Hormone Therapy and Risk of Cardiovascular Disease by Age and Years Since Menopause. JAMA. 2007;297:1465-1477.
2. Hsia J, et al. Conjugated Equine Estrogens and Coronary Heart Disease. Arch Int Med. 2006;166:357-365.
3. Cushman M, et al. Estrogen Plus Progestin and Risk of Venous Thrombosis. JAMA. 2004;292:1573-1580.
4. Curb JD, et al. Venous Thrombosis and Conjugated Equine Estrogen in Women Without a Uterus. Arch Int Med. 2006;166:772-780.
5. Chlebowski RT, et al. Influence of Estrogen Plus Progestin on Breast Cancer and Mammography in Healthy Postmenopausal Women. JAMA. 2003;289:3234-3253.
6. Stefanick ML, et al. Effects of Conjugated Equine Estrogens on Breast Cancer and Mammography Screening in Postmenopausal Women With Hysterectomy. JAMA. 2006;295:1647-1657.
7. Anderson GL, et al. Effects of Estrogen Plus Progestin on Gynecologic Cancers and Associated Diagnostic Procedures. JAMA. 2003;290:1739-1748.
8. Shumaker SA, et al. Conjugated Equine Estrogens and Incidence of Probable Dementia and Mild Cognitive Impairment in Postmenopausal Women. JAMA. 2004;291:2947-2958.
9. Jackson RD, et al. Effects of Conjugated Equine Estrogen on Risk of Fractures and BMD in Postmenopausal Women With Hysterectomy: Results From the Women’s Health Initiative Randomized Trial. J Bone Miner Res. 2006;21:817-828.
10. Hendrix SL, et al. Effects of Conjugated Equine Estrogen on Stroke in the Women’s Health Initiative. Circulation. 2006;113:2425-2434.

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