Jinteli

Ethinyl estradiol and norethindrone combination is used to prevent pregnancy. It is a birth control pill that contains two types of hormones, ethinyl estradiol and norethindrone, and when taken properly, prevents pregnancy. It works by stopping a woman's egg from fully developing each month. The egg can no longer accept a sperm and fertilization is prevented.

No contraceptive method is 100 percent effective. Birth control methods such as having surgery to become sterile or not having sex are more effective than birth control pills. Discuss your options for birth control with your doctor.

This medicine does not prevent HIV infection or other sexually transmitted diseases. It will not help as emergency contraception, such as after unprotected sexual contact.

This medicine is available only with your doctor's prescription.

It is very important that your doctor check your progress at regular visits to make sure this medicine is working properly and does not cause unwanted effects. These visits will usually be every 6 to 12 months, but some doctors require them more often. Your doctor may also want to check your blood pressure while taking this medicine.

Although you are using this medicine to prevent pregnancy, you should know that using this medicine while you are pregnant could harm the unborn baby. If you think you have become pregnant while using the medicine, tell your doctor right away. Make sure your doctor knows if you have had a baby within 4 weeks before you start using this medicine.

Vaginal bleeding of various amounts may occur between your regular menstrual periods during the first 3 months of use. This is sometimes called spotting when slight, or breakthrough bleeding when heavier.

• If this should occur, continue with your regular dosing schedule.
• The bleeding usually stops within 1 week. Check with your doctor if the bleeding continues for more than 1 week.
• If the bleeding continues after you have been taking hormonal contraceptives on schedule and for more than 3 months, check with your doctor.

Check with your doctor right away if you miss a menstrual period. Missed periods may occur if you skip one or more tablets and have not taken your pills exactly as directed. If you miss two periods in a row, talk to your doctor. You might need a pregnancy test.

If you suspect that you may be pregnant, stop taking this medicine immediately and check with your doctor.

Do not use this medicine if you smoke cigarettes or if you are over 35 years of age. If you smoke while using birth control pills, you increase your risk of having a blood clot, heart attack, or stroke. Your risk is even higher if you are over age 35, if you have diabetes, high blood pressure, high cholesterol, or if you are overweight. Talk with your doctor about ways to stop smoking. Keep your diabetes under control. Ask your doctor about diet and exercise to control your weight and blood cholesterol level.

Using this medicine may increase your risk of having blood clotting problems. Check with your doctor right away if you have pain in the chest, groin, or legs, especially the calves, difficulty with breathing, a sudden, severe headache, slurred speech, a sudden, unexplained shortness of breath, a sudden unexplained shortness of breath, a sudden loss of coordination, or vision changes while using this medicine.

Using this medicine may increase your risk of breast cancer or cervical cancer. Talk with your doctor about this risk. Check with your doctor immediately if your experience abnormal vaginal bleeding.

Check with your doctor immediately if you wear contact lenses or if blurred vision, difficulty in reading, or any other change in vision occurs during or after treatment. Your doctor may want an eye doctor to check your eyes.

Check with your doctor right away if you have pain or tenderness in the upper stomach, dark urine or pale stools, or yellow eyes or skin. These could be symptoms of a serious liver problem.

Using this medicine may increase your risk for gallbladder surgery. Talk with your doctor about this risk.

Check with your doctor before refilling an old prescription, especially after a pregnancy. You will need another physical examination and your doctor may change your prescription.

Make sure any doctor or dentist who treats you knows that you are using this medicine. The results of some medical tests may be affected by this medicine. You may also need to stop using this medicine at least 4 weeks before and 2 weeks after having major surgery.

Do not eat grapefruit or drink grapefruit juice while you are using this medicine. Grapefruit and grapefruit juice may change the amount of this medicine that is absorbed in the body.

Do not take other medicines unless they have been discussed with your doctor. This includes prescription or nonprescription (over-the-counter [OTC]) medicines and herbal (eg, St. John's wort) or vitamin supplements.

Overdosage of estrogen plus progestin 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 with institution of appropriate symptomatic care.

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.

Pharmacodynamics

Currently, there is no pharmacodynamic data known for Jinteli.

Pharmacokinetics

Absorption

Norethindrone acetate (NA) is completely deacetylated to norethindrone after oral administration, and the disposition of norethindrone acetate is indistinguishable from that of orally administered norethindrone. Norethindrone acetate and ethinyl estradiol (EE) are absorbed from Jinteli tablets, with maximum plasma concentrations of norethindrone and ethinyl estradiol generally occurring 1 to 2 hours postdose. Both are subject to first-pass metabolism after oral dosing, resulting in an absolute bioavailability of approximately 64 percent for norethindrone and 55 percent for ethinyl estradiol. Bioavailability of Jinteli tablets is similar to that from solution for norethindrone and slightly less for ethinyl estradiol. Administration of Jinteli tablets with a high fat meal decreases rate but not extent of ethinyl estradiol absorption. The extent of norethindrone absorption is increased by 27 percent following administration of Jinteli tablets with food.

The full pharmacokinetic profile of Jinteli tablets was not characterized due to assay sensitivity limitations. However, the multiple-dose pharmacokinetics were studied at a dose of 1 mg NA/10 mcg EE in 18 postmenopausal women. Mean plasma concentrations are shown below (Figure 1) and pharmacokinetic parameters are found in Table 2. Based on a population pharmacokinetic analysis, mean steady-state concentrations of norethindrone for 1 mg NA/5 mcg EE and 1/10 are slightly more than proportional to dose when compared to 0.5 mg NA/2.5 mcg EE tablets. It can be explained by higher SHBG concentrations. Mean steady-state plasma concentrations of ethinyl estradiol for the Jinteli 0.5/2.5 tablets and Jinteli 1/5 tablets are proportional to dose, but there is a less than proportional increase in steady-state concentrations for the NA/EE 1/10 tablet.

Figure 1. Mean Steady-State (Day 87) Plasma Norethindrone and Ethinyl Estradiol

Concentrations Following Continuous Oral Administration of 1 mg NA/10 mcg EE Tablets

* Cmax = Maximum plasma concentration; tmax = time of Cmax; AUC (0 to 24) = Area under the plasma concentration-time curve over the dosing interval; and CL/F = Apparent oral clearance; t1/2 = Elimination half-life † ND = Not determined
Table 2. Mean (SD) Single-Dose (Day 1) and Steady-State (Day 87) Pharmacokinetic Parameters*Following Administration of 1 mg NA/10 mcg EE Tablets
	Cmax	tmax	AUC (0 to 24)	CL/F	t1/2
NORETHINDRONE	ng/mL	hr	ng·hr/mL	mL/min	hr
Day 1 Day 87	6.0 (3.3) 10.7 (3.6)	1.8 (0.8) 1.8 (0.8)	29.7 (16.5) 81.8 (36.7)	588 (416) 226 (139)	10.3 (3.7) 13.3 (4.5)
ETHINYL ESTRADIOL	pg/mL	hr	pg·hr/mL	mL/min	hr
Day 1 Day 87	33.5 (13.7) 38.3 (11.9)	2.2 (1.0) 1.8 (0.7)	339 (113) 471 (132)	ND† 383 (119)	ND† 23.9 (7.1)

Based on a population pharmacokinetic analysis, average steady-state concentrations (Css) of norethindrone and ethinyl estradiol for Jinteli 1/5 tablets are estimated to be 2.6 ng/mL and 11.4 pg/mL, respectively. Css values of norethindrone and ethinyl estradiol for Jinteli 0.5/2.5 tablets are estimated to be 1.1 ng/mL and 5.4 ng/mL, respectively.

The pharmacokinetics of norethindrone acetate and ethinyl estradiol were not affected by age, (age range 40 to 62 years), in the postmenopausal population studied.

Distribution

The distribution of exogenous estrogens is similar to that of endogenous estrogens. Estrogens are widely distributed in the body and are generally found in higher concentrations in the sex hormone target organs. Estrogens circulate in the blood largely bound to SHBG and albumin.

Volume of distribution of norethindrone and ethinyl estradiol ranges from 2 to 4 L/kg. Plasma protein binding of both steroids is extensive (greater than 95 percent); norethindrone binds to both albumin and SHBG, whereas ethinyl estradiol binds only to albumin. Although ethinyl estradiol does not bind to SHBG, it induces SHBG synthesis.

Metabolism

Exogenous estrogens are metabolized in the same manner as endogenous estrogens. Circulating estrogens exist in a dynamic equilibrium of metabolic interconversions. These transformations take place mainly in the liver. Estradiol is converted reversibly to estrone, and both can be converted to estriol, which is a major urinary metabolite. Estrogens also undergo enterohepatic recirculation via sulfate and glucuronide conjugation in the liver, biliary secretion of conjugates into the intestine, and hydrolysis in the intestine followed by reabsorption. In postmenopausal women, a significant proportion of the circulating estrogens exist as sulfate conjugates, especially estrone sulfate, which serves as a circulating reservoir for the formation of more active estrogens.

Norethindrone undergoes extensive biotransformation, primarily via reduction, followed by sulfate and glucuronide conjugation. The majority of metabolites in the circulation are sulfates, with glucuronides accounting for most of the urinary metabolites. A small amount of norethindrone acetate is metabolically converted to ethinyl estradiol, such that exposure to ethinyl estradiol following administration of 1 mg of norethindrone acetate is equivalent to oral administration of 2.8 mcg ethinyl estradiol. Ethinyl estradiol is also extensively metabolized, both by oxidation and by conjugation with sulfate and glucuronide. Sulfates are the major circulating conjugates of ethinyl estradiol and glucuronides predominate in urine. The primary oxidative metabolite is 2-hydroxy ethinyl estradiol, formed by the CYP3A4 isoform of cytochrome P450. Part of the first-pass metabolism of ethinyl estradiol is believed to occur in gastrointestinal mucosa. Ethinyl estradiol may undergo enterohepatic circulation.

Excretion

Estradiol, estrone, and estriol are excreted in the urine along with glucuronide and sulfate conjugates.

Norethindrone and ethinyl estradiol are excreted in both urine and feces, primarily as metabolites. Plasma clearance values for norethindrone and ethinyl estradiol are similar (approximately 0.4 L/hr/kg). Steady-state elimination half-lives of norethindrone and ethinyl estradiol following administration of 1 mg NA/10 mcg EE tablets are approximately 13 hours and 24 hours, respectively.

Use in Specific Populations

No pharmacokinetic studies were conducted in specific populations, including women with renal or hepatic impairment.

  Jinteli®
(norethindrone acetate and ethinyl estradiol tablets USP)

Read this Patient Information before you start taking 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 the most important information I should know about Jinteli (a combination of estrogen and progestin)? • Do not use estrogens with progestins to prevent heart disease, heart attacks, strokes or dementia (decline of brain function). • Using estrogens with progestins may increase your chances of getting a heart attack, strokes, breast cancer, or blood clots. • Using estrogens with progestins may increase your chance of getting dementia, based on a study of women 65 years of age or older. • Do not use estrogen-alone to prevent heart disease, heart attacks, strokes or dementia. • Using estrogen-alone may increase your chance of getting cancer of the uterus (womb). • Using estrogen-alone may increase your chances of getting strokes or blood clots. • Using estrogen-alone may increase your chance of getting dementia, based on a study of women 65 years of age or older. • You and your healthcare provider should talk regularly about whether you still need treatment with Jinteli.

What is Jinteli?

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

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 take Jinteli?

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

Jinteli contains a progestin to decrease the chance of getting cancer of the uterus. If you do not have a uterus, you do not need a progestin and you should not take Jinteli.

Do not take Jinteli if you:

  • have 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.

  • currently have or have had certain cancers.

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

  • had a stroke or heart attack • currently have or have had blood clots • currently have or have had liver problems • have been diagnosed with a bleeding disorder • are allergic to Jinteli or any of its ingredients.

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

  • think you may be pregnant

Jinteli is not for pregnant women. If you think you may be pregnant, you should have a pregnancy test and know the results. Do not take Jinteli if the test is positive and talk to your healthcare provider.

What should I tell my healthcare provider before I take Jinteli?

Before you take Jinteli, tell your healthcare provider 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

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 taking Jinteli. • 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 non-prescription medicines, vitamins, and herbal supplements. Some medicines may affect how Jinteli works. 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 a new medicine.

How should I take 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:

  • heart attack • stroke • blood clots • dementia • breast cancer • cancer of the lining of the uterus (womb) • cancer of the ovary • high blood pressure • high blood sugar • gallbladder disease • liver problems • changes in your thyroid hormone levels • enlargement of benign tumors of the uterus (“fibroids”)

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

Less serious, but common side effects include:

  • headache • breast pain • irregular vaginal bleeding or spotting • stomach or abdominal cramps, bloating • hair loss • fluid retention • vaginal yeast infection

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 does not go away.

Call your doctor for medical advice about side effects. You may report side effects to 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 taking Jinteli. • If you have a uterus, talk with your healthcare provider about whether the addition of a progestin is right for you. • The addition of a progestin is generally 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 develop vaginal bleeding while taking 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 20° to 25°C (68° to 77°F).

Keep Jinteli out of the reach of children.

General information about the safe and effective use of Jinteli.

Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not take 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.

This leaflet summarizes the most important information about Jinteli. If you would like more information, talk with your healthcare provider or pharmacist. 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 in Jinteli?

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.

TEVA PHARMACEUTICALS USA, INC.

North Wales, PA 19454

Rev. C 2/2016