These highlights do not include all the information needed to use AMBRISENTAN TABLETS safely and effectively. See full prescribing information for AMBRISENTAN TABLETS. AMBRISENTAN tablets, for oral use Initial U.S. Approval: 2007

WARNING: EMBRYO-FETAL TOXICITY

BOXED WARNING SECTION

Ambrisentan is contraindicated for use during pregnancy because it may cause major birth defects if used by pregnant patients, based on studies in animals [see Contraindications (4.1), Warnings and Precautions (5.1), and Use in Specific Populations (8.1)] . Therefore, for females of reproductive potential, exclude pregnancy before the initiation of treatment with ambrisentan. Advise use of effective contraception before initiation, during treatment, and for one month after treatment with ambrisentan [see Dosage and Administration (2.2) Contraindications (4.1), Warnings and Precautions (5.1), and Use in Specific Populations (8.1, 8.3)] . When pregnancy is detected, discontinue ambrisentan as soon as possible (5.1).

1 INDICATIONS AND USAGE

INDICATIONS & USAGE SECTION

Ambrisentan is indicated for the treatment of pulmonary arterial hypertension (PAH) (WHO Group 1) in adult patients: • To improve exercise ability and delay clinical worsening. Studies establishing effectiveness included predominantly patients with WHO Functional Class II–III symptoms and etiologies of idiopathic or heritable PAH (60%) or PAH associated with connective tissue diseases (34%).

2 DOSAGE AND ADMINISTRATION

DOSAGE & ADMINISTRATION SECTION

3 DOSAGE FORMS AND STRENGTHS

DOSAGE FORMS & STRENGTHS SECTION

5 mg and 10 mg film - coated tablets for oral administration Each 5 mg tablet is pale pink colored, round shape, biconvex beveled edge film-coated tablet debossed with “236” on one side and plain on the other side. Each 10 mg tablet is deep pink colored, oval shape, biconvex film-coated tablet debossed with “237” on one side and plain on the other side.

4 CONTRAINDICATIONS

CONTRAINDICATIONS SECTION

5 WARNINGS AND PRECAUTIONS

WARNINGS AND PRECAUTIONS SECTION

6 ADVERSE REACTIONS

ADVERSE REACTIONS SECTION

Clinically significant adverse reactions that appear in other sections of the labeling include: Embryo-fetal Toxicity [see Warnings and Precautions (5.1), Use in Specific Populations (8.1)] Fluid Retention [see Warnings and Precautions (5.2)] Pulmonary Edema with PVOD [see Warnings and Precautions (5.3)] Decreased Sperm Count [see Warnings and Precautions (5.4)] Hematologic Changes [see Warnings and Precautions (5.5)]

7 DRUG INTERACTIONS

DRUG INTERACTIONS SECTION

Multiple dose coadministration of ambrisentan and cyclosporine resulted in an approximately 2-fold increase in ambrisentan exposure in healthy volunteers; therefore, limit the dose of ambrisentan to 5 mg once daily when coadministered with cyclosporine [see Clinical Pharmacology (12.3)] .

8 USE IN SPECIFIC POPULATIONS

USE IN SPECIFIC POPULATIONS SECTION

10 OVERDOSAGE

OVERDOSAGE SECTION

There is no experience with overdosage of ambrisentan. The highest single dose of ambrisentan administered to healthy volunteers was 100 mg, and the highest daily dose administered to patients with PAH was 10 mg once daily. In healthy volunteers, single doses of 50 mg and 100 mg (5 to 10 times the maximum recommended dose) were associated with headache, flushing, dizziness, nausea, and nasal congestion. Massive overdosage could potentially result in hypotension that may require intervention.

11 DESCRIPTION

DESCRIPTION SECTION

Ambrisentan is an endothelin receptor antagonist. The chemical name of ambrisentan is (+)-(2S)-2-[(4,6-dimethylpyrimidin-2-yl)oxy]-3-methoxy-3,3-diphenylpropanoic acid. It has a molecular formula of C22H22N2O4 and a molecular weight of 378.42 and has the following structural formula: Figure 1 Ambrisentan Structural Formula Ambrisentan is a white to off-white, crystalline solid. It is a carboxylic acid with a pKa of 4.0. Ambrisentan is practically insoluble in water and in aqueous solutions at low pH. Solubility increases in aqueous solutions at higher pH. In the solid state ambrisentan is very stable, is not hygroscopic, and is not light sensitive. Ambrisentan is available as 5 mg and 10 mg film-coated tablets for once daily oral administration. The tablets include the following inactive ingredients: anhydrous lactose, colloidal silicon dioxide, croscarmellose sodium, magnesium stearate and microcrystalline cellulose. The tablets are film-coated with a coating material containing FD&C Red #40 aluminum lake, lecithin, polyethylene glycol, polyvinyl alcohol, talc, and titanium dioxide. Each round, pale pink ambrisentan tablet contains 5 mg of ambrisentan. Each oval, deep pink ambrisentan tablet contains 10 mg of ambrisentan. Ambrisentan tablets are unscored.

12 CLINICAL PHARMACOLOGY

CLINICAL PHARMACOLOGY SECTION

13 NONCLINICAL TOXICOLOGY

NONCLINICAL TOXICOLOGY SECTION

14 CLINICAL STUDIES

CLINICAL STUDIES SECTION

16 HOW SUPPLIED/STORAGE AND HANDLING

HOW SUPPLIED SECTION

Ambrisentan film-coated tablets are supplied as follows: Tablet Strength Package Configuration NDC No. Description of Tablet; Debossed on Tablet 5 mg 30 count carton (3 x 10 unit-dose) 47335-236-64 round biconvex; pale pink; debossed with “236” on one side and plain on the other side. 30 count bottle 47335-236-83 10 count bottle 47335-236-85 10 count carton (1 x 10 unit-dose) 47335-236-66 10 mg 30 count carton (3 x 10 unit-dose) 47335-237-64 Oval biconvex; deep pink; debossed with “237” on one side and plain on the other side. 30 count bottle 47335-237-83 10 count bottle 47335-237-85 10 count carton (1 x 10 unit-dose) 47335-237-66 Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° and 30°C (59° and 86°F). [see USP Controlled Room Temperature]. Store ambrisentan in its original packaging.

17 PATIENT COUNSELING INFORMATION

INFORMATION FOR PATIENTS SECTION

Advise patients to read the FDA-approved patient labeling (Medication Guide). Embryo-fetal Toxicity Instruct patients on the risk of fetal harm when ambrisentan is used in pregnancy [see Warnings and Precautions (5.1) and Use in Specific Populations (8.1)] . Instruct females of reproductive potential to immediately contact their physician if they suspect they may be pregnant. Educate and counsel patients who can become pregnant about the need to use effective contraception prior to treatment with ambrisentan, during treatment, and for one month after treatment discontinuation [see Warnings and Precautions (5.1) and Use in Specific Populations (8.1, 8.3)]. Patients who can become pregnant should have a negative pregnancy test prior to treatment with ambrisentan [see Dosage and Administration (2.2), Contraindications (4.1), Warnings and Precautions (5.1), Use in Specific Populations (8.1, 8.3)]. Counsel patients who can become pregnant about pregnancy planning and prevention, including emergency contraception, or designate counseling by another healthcare provider trained in contraceptive counseling [see Boxed Warning]. Hepatic Effects Advise patients of the symptoms of potential liver injury and instruct them to report any of these symptoms to their physician. Hematological Change Advise patients of the importance of hemoglobin testing. Other Risks Associated with ambrisentan Instruct patients that the risks associated with ambrisentan also include the following: Decreases in sperm count Fluid overload Administration Advise patients not to split, crush, or chew tablets.

Medication Guide

SPL MEDGUIDE SECTION

Dispense with Medication Guide available at https://www.sunpharma.com/usa/products Ambrisentan (am" bri senʹ tan) Tablets Read this Medication Guide before you start taking ambrisentan tablets and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking with your doctor about your medical condition or your treatment. What is the most important information I should know about ambrisentan tablets? Serious birth defects. Ambrisentan tablets can cause serious birth defects if taken during pregnancy. Females should not be pregnant when they start taking ambrisentan tablets or become pregnant during treatment with ambrisentan tablets. Females who are able to get pregnant should have a negative pregnancy test before beginning treatment with ambrisentan tablets. Talk to your doctor about your menstrual cycle. Your doctor will decide when to do a pregnancy test, and will order a pregnancy test for you depending on your menstrual cycle. Females who are able to get pregnant are females who: have entered puberty, even if they have not started their menstrual period, and have a uterus, and have not gone through menopause. Menopause means that you have not had a menstrual period for at least 12 months for natural reasons, or that you have had your ovaries removed. Females who are not able to get pregnant are females who: have not yet entered puberty, or do not have a uterus, or have gone through menopause. Menopause means that you have not had a menstrual period for at least 12 months for natural reasons, or that you have had your ovaries removed, or who are infertile for any other medical reason and this infertility is permanent and cannot be reversed Females who are able to get pregnant should use effective contraception before beginning ambrisentan tablets, during treatment with ambrisentan tablets, and for one month after stopping ambrisentan tablets because the medicine may still be in the body. Talk with your doctor or gynecologist (a doctor who specializes in female reproduction) to find out about options for acceptable forms of birth control that you may use to prevent pregnancy during treatment with ambrisentan tablets. If you decide that you want to change the form of birth control that you use, talk with your doctor or gynecologist to be sure that you choose another acceptable form of birth control. Do not have unprotected sex. Talk to your doctor or pharmacist right away if you have unprotected sex or if you think your birth control has failed. Your doctor may tell you to use emergency birth control. Tell your doctor right away if you miss a menstrual period or think you may be pregnant for any reason. If you are the parent or caregiver of a female child who started taking ambrisentan tablets before reaching puberty, you should check your child regularly to see if she is developing signs of puberty. Tell your doctor right away if you notice that she is developing breast buds or pubic hair. Your doctor should decide if your child has reached puberty . Your child may reach puberty before having her first menstrual period. What are ambrisentan tablets? Ambrisentan tablets are a prescription medicine used to treat pulmonary arterial hypertension (PAH), which is high blood pressure in the arteries of your lungs. Ambrisentan tablets can improve your ability to exercise and it can help slow down the worsening of your physical condition and symptoms. It is not known if ambrisentan tablets are safe and effective in children. Who should not take ambrisentan tablets? Do not take ambrisentan tablets if: you are pregnant, plan to become pregnant, or become pregnant during treatment with ambrisentan tablets. Ambrisentan tablets can cause serious birth defects. (See “What is the most important information I should know about ambrisentan tablets?” ). you have a condition called Idiopathic Pulmonary Fibrosis (IPF) What should I tell my doctor before taking ambrisentan tablets? Before you take ambrisentan tablets, tell your doctor if you: have been told that you have a low red blood cell level (anemia) have liver problems have any other medical conditions Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Ambrisentan tablets and other medicines may affect each other, causing side effects. Do not start any new medicines until you check with your doctor. Especially tell your doctor if you take the medicine cyclosporine (Gengraf*, Neoral*, Sandimmune*). Your doctor may need to change your dose of ambrisentan tablets. How should I take ambrisentan tablets? Take ambrisentan tablets exactly as your doctor tells you to take it. Do not stop taking ambrisentan tablets unless your doctor tells you to stop. You can take ambrisentan tablets with or without food. Do not split, crush or chew ambrisentan tablets. It will be easier to remember to take ambrisentan tablets if you take it at the same time each day. If you take more than your regular dose of ambrisentan tablets, call your doctor right away. If you miss a dose, take it as soon as you remember that day. Take your next dose at the regular time. Do not take two doses at the same time to make up for a missed dose. What should I avoid while taking ambrisentan tablets? Do not get pregnant while taking ambrisentan tablets. (See the serious birth defects section of the Medication Guide above called “What is the most important information I should know about ambrisentan tablets?” ) If you miss a menstrual period, or think you might be pregnant, call your doctor right away. It is not known if ambrisentan passes into your breast milk. You should not breastfeed if you are taking ambrisentan tablets. Talk to your doctor about the best way to feed your baby if you take ambrisentan tablets. What are the possible side effects of ambrisentan tablets? Ambrisentan tablets can cause serious side effects including: See “What is the most important information I should know about ambrisentan tablets?” Swelling all over the body (fluid retention) can happen within weeks after starting ambrisentan tablets. Tell your doctor right away if you have any unusual weight gain, tiredness, or trouble breathing while taking ambrisentan tablets. These may be symptoms of a serious health problem. You may need to be treated with medicine or need to go to the hospital. Decreased sperm count. Decreased sperm counts have happened in some men taking a medicine that is like ambrisentan tablets. A decreased sperm count may affect the ability to father a child. Tell your doctor if being able to have children is important to you. Low red blood cell levels (anemia) can happen during the first weeks after starting ambrisentan tablets. If this happens, you may need a blood transfusion. Your doctor will do blood tests to check your red blood cells before starting ambrisentan tablets. Your doctor may also do these tests during treatment with ambrisentan tablets. The most common side effects of ambrisentan tablets include: swelling of hands, legs, ankles and feet (peripheral edema) stuffy nose (nasal congestion) inflamed nasal passages (sinusitis) hot flashes or getting red in the face (flushing) Some medicines that are like ambrisentan tablets can cause liver problems. Tell your doctor if you get any of these symptoms of a liver problem while taking ambrisentan tablets: loss of appetite nausea or vomiting fever achiness generally do not feel well pain in the upper right stomach (abdominal) area yellowing of your skin or the whites of your eyes dark urine itching Tell your doctor if you have any side effect that bothers you or that does not go away. These are not all of the possible side effects of ambrisentan tablets. For more information, ask your doctor or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. For more information call 1-800-818-4555. How s...

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

NDC 47335-236-66 Ambrisentan Tablets 5 mg PHARMACIST: Dispense with Medication Guide to each patient. Rx only 10 Tablets (1 X 10 Unit-dose) SUN PHARMA

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

NDC 47335-237-66 Ambrisentan Tablets 10 mg PHARMACIST: Dispense with Medication Guide to each patient. Rx only 10 Tablets (1 X 10 Unit-dose) SUN PHARMA

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

NDC 47335-236-83 Ambrisentan Tablets 5 mg PHARMACIST: Dispense with Medication Guide to each patient. Rx only 30 Tablets SUN PHARMA

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

NDC 47335-237-83 Ambrisentan Tablets 10 mg PHARMACIST: Dispense with Medication Guide to each patient. Rx only 30 Tablets SUN PHARMA