ADVERSE REACTIONS SECTION.


6 ADVERSE REACTIONS Clinically significant adverse reactions that appear in other sections of the labeling include:oEmbryo-fetal Toxicity [see Warnings and Precautions (5.1), Use in Specific Populations (8.1)]oFluid Retention [see Warnings and Precautions (5.3)]oPulmonary Edema with PVOD [see Warnings and Precautions (5.4)]oDecreased Sperm Count [see Warnings and Precautions (5.5)]oHematologic Changes [see Warnings and Precautions (5.6)]. oEmbryo-fetal Toxicity [see Warnings and Precautions (5.1), Use in Specific Populations (8.1)]. oFluid Retention [see Warnings and Precautions (5.3)]. oPulmonary Edema with PVOD [see Warnings and Precautions (5.4)]. oDecreased Sperm Count [see Warnings and Precautions (5.5)]. oHematologic Changes [see Warnings and Precautions (5.6)]. oMost common adverse reactions (> 3% compared to placebo) are peripheral edema, nasal congestion, sinusitis, and flushing (6.1). To report SUSPECTED ADVERSE REACTIONS, contact Mylan at 1-877-446-3679 (1-877-4-INFO-RX) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. oMost common adverse reactions (> 3% compared to placebo) are peripheral edema, nasal congestion, sinusitis, and flushing (6.1).. 6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.Safety data for ambrisentan tablets are presented from two 12-week, placebo-controlled studies (ARIES-1 and ARIES-2) in patients with pulmonary arterial hypertension (PAH). The exposure to ambrisentan in these studies ranged from days to 100 days.In ARIES-1 and ARIES-2, total of 261 patients received ambrisentan tablets at doses of 2.5, 5, or 10 mg once daily and 132 patients received placebo. The adverse reactions that occurred in 3% more patients receiving ambrisentan tablets than receiving placebo are shown in Table 1.Table 1: Adverse Reactions with Placebo-Adjusted Rates 3% in ARIES-1 and ARIES-2Placebo (N 132)Ambrisentan Tablets (N 261)Adverse Reactionn (%)n (%)Placebo-adjusted (%)Peripheral edema14 (11)45 (17)6Nasal congestion2 (2)15 (6)4Sinusitis0 (0)8 (3)3Flushing1 (1)10 (4)3Most adverse drug reactions were mild to moderate and only nasal congestion was dose-dependent.Few notable differences in the incidence of adverse reactions were observed for patients by age or sex. Peripheral edema was similar in younger patients (< 65 years) receiving ambrisentan tablets (14%; 29/205) or placebo (13%; 13/104), and was greater in elderly patients (>= 65 years) receiving ambrisentan tablets (29%; 16/56) compared to placebo (4%; 1/28). The results of such subgroup analyses must be interpreted cautiously.The incidence of treatment discontinuations due to adverse events other than those related to PAH during the clinical trials in patients with PAH was similar for ambrisentan tablets (2%; 5/261 patients) and placebo (2%; 3/132 patients). The incidence of patients with serious adverse events other than those related to PAH during the clinical trials in patients with PAH was similar for placebo (7%; 9/132 patients) and for ambrisentan tablets (5%; 13/261 patients).During 12-week controlled clinical trials, the incidence of aminotransferase elevations 3 upper limit of normal (ULN) were 0% on ambrisentan tablets and 2.3% on placebo. In practice, cases of hepatic injury should be carefully evaluated for cause.. Use in Patients with Prior Endothelin Receptor Antagonist (ERA) Related Serum Liver Enzyme Abnormalities. In an uncontrolled, open-label study, 36 patients who had previously discontinued endothelin receptor antagonists (ERAs: bosentan, an investigational drug, or both) due to aminotransferase elevations 3 ULN were treated with ambrisentan tablets. Prior elevations were predominantly moderate, with 64% of the ALT elevations 5 ULN, but patients had elevations 8 ULN. Eight patients had been re-challenged with bosentan and/or the investigational ERA and all eight had recurrence of aminotransferase abnormalities that required discontinuation of ERA therapy. All patients had to have normal aminotransferase levels on entry to this study. Twenty-five of the 36 patients were also receiving prostanoid and/or phosphodiesterase type (PDE5) inhibitor therapy. Two patients discontinued early (including one of the patients with prior x ULN elevation). Of the remaining 34 patients, one patient experienced mild aminotransferase elevation at 12 weeks on ambrisentan tablets mg that resolved with decreasing the dosage to 2.5 mg, and that did not recur with later escalations to 10 mg. With median follow-up of 13 months and with 50% of patients increasing the dose of ambrisentan tablets to 10 mg, no patients were discontinued for aminotransferase elevations. While the uncontrolled study design does not provide information about what would have occurred with re-administration of previously used ERAs or show that ambrisentan tablets led to fewer aminotransferase elevations than would have been seen with those drugs, the study indicates that ambrisentan tablets may be tried in patients who have experienced asymptomatic aminotransferase elevations on other ERAs after aminotransferase levels have returned to normal.. 6.2 Postmarketing Experience. The following adverse reactions were identified during post-approval use of ambrisentan tablets. Because these reactions were reported voluntarily from population of uncertain size, it is not possible to estimate reliably the frequency or to establish causal relationship to drug exposure: anemia requiring transfusion [see Warnings and Precautions (5.6)], heart failure (associated with fluid retention), symptomatic hypotension, and hypersensitivity (e.g., angioedema, rash).Elevations of liver aminotransferases (ALT, AST) have been reported with ambrisentan tablets use; in most cases alternative causes of the liver injury could be identified (heart failure, hepatic congestion, hepatitis, alcohol use, hepatotoxic medications). Other endothelin receptor antagonists have been associated with elevations of aminotransferases, hepatotoxicity, and cases of liver failure [see Adverse Reactions (6.1)].

BOXED WARNING SECTION.


WARNING: EMBRYO-FETAL TOXICITY Do not administer ambrisentan tablets to pregnant female because they may cause fetal harm. Ambrisentan tablets are very likely to produce serious birth defects if used by pregnant females, as this effect has been seen consistently when they are administered to animals [see Contraindications (4.1), Warnings and Precautions (5.1), and Use in Specific Populations (8.1)]. Exclude pregnancy before the initiation of treatment with ambrisentan tablets. Females of reproductive potential must use acceptable methods of contraception during treatment with ambrisentan tablets and for one month after treatment. Obtain monthly pregnancy tests during treatment and month after discontinuation of treatment [see Dosage and Administration (2.2) and Use in Specific Populations (8.3)]. Because of the risk of embryo-fetal toxicity, for all female patients, ambrisentan tablets are only available through restricted program under Risk Evaluation and Mitigation Strategy (REMS) called the Ambrisentan REMS [see Warnings and Precautions (5.2)]. WARNING: EMBRYO-FETAL TOXICITY See full prescribing information for complete boxed warning.oDo not administer ambrisentan tablets to pregnant female because they may cause fetal harm (4.1, 5.1, 8.1).oFemales of reproductive potential: Exclude pregnancy before the start of treatment, monthly during treatment, and month after stopping treatment. Prevent pregnancy during treatment and for one month after stopping treatment by using acceptable methods of contraception (2.2, 8.3).oBecause of the risk of embryo-fetal toxicity, for all female patients, ambrisentan tablets are only available through restricted program under Risk Evaluation and Mitigation Strategy (REMS) called the Ambrisentan REMS (5.2).. oDo not administer ambrisentan tablets to pregnant female because they may cause fetal harm (4.1, 5.1, 8.1).. oFemales of reproductive potential: Exclude pregnancy before the start of treatment, monthly during treatment, and month after stopping treatment. Prevent pregnancy during treatment and for one month after stopping treatment by using acceptable methods of contraception (2.2, 8.3).. oBecause of the risk of embryo-fetal toxicity, for all female patients, ambrisentan tablets are only available through restricted program under Risk Evaluation and Mitigation Strategy (REMS) called the Ambrisentan REMS (5.2).

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.


13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Oral carcinogenicity studies of up to two years duration were conducted at starting doses of 10, 30, and 60 mg/kg/day in rats (8 to 48 times the maximum recommended human dose [MRHD] on mg/m2 basis) and at 50, 150, and 250 mg/kg/day in mice (28 to 140 times the MRHD). In the rat study, the high- and mid-dose male and female groups had their doses lowered to 40 and 20 mg/kg/day, respectively, in week 51 because of effects on survival. The high-dose males and females were taken off drug completely in weeks 69 and 93, respectively. The only evidence of ambrisentan-related carcinogenicity was positive trend in male rats, for the combined incidence of benign basal cell tumor and basal cell carcinoma of skin/subcutis in the mid-dose group (high-dose group excluded from analysis), and the occurrence of mammary fibroadenomas in males in the high-dose group. In the mouse study, high-dose male and female groups had their doses lowered to 150 mg/kg/day in week 39 and were taken off drug completely in week 96 (males) or week 76 (females). In mice, ambrisentan was not associated with excess tumors in any dosed group.Positive findings of clastogenicity were detected, at drug concentrations producing moderate to high toxicity, in the chromosome aberration assay in cultured human lymphocytes. There was no evidence for genetic toxicity of ambrisentan when tested in vitro in bacteria (Ames test) or in vivo in rats (micronucleus assay, unscheduled DNULL synthesis assay).The development of testicular tubular atrophy and impaired fertility has been linked to the chronic administration of endothelin receptor antagonists in rodents. Testicular tubular degeneration was observed in rats treated with ambrisentan for two years at doses >= 10 mg/kg/day (8-fold MRHD). Increased incidences of testicular findings were also observed in mice treated for two years at doses >= 50 mg/kg/day (28-fold MRHD). Effects on sperm count, sperm morphology, mating performance, and fertility were observed in fertility studies in which male rats were treated with ambrisentan at oral doses of 300 mg/kg/day (236-fold MRHD). At doses of >= 10 mg/kg/day, observations of testicular histopathology in the absence of fertility and sperm effects were also present.

CLINICAL PHARMACOLOGY SECTION.


12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action. Endothelin-1 (ET-1) is potent autocrine and paracrine peptide. Two receptor subtypes, ETA and ETB, mediate the effects of ET-1 in the vascular smooth muscle and endothelium. The primary actions of ETA are vasoconstriction and cell proliferation, while the predominant actions of ETB are vasodilation, antiproliferation, and ET-1 clearance.In patients with PAH, plasma ET-1 concentrations are increased as much as 10-fold and correlate with increased mean right atrial pressure and disease severity. ET-1 and ET-1 mRNULL concentrations are increased as much as 9-fold in the lung tissue of patients with PAH, primarily in the endothelium of pulmonary arteries. These findings suggest that ET-1 may play critical role in the pathogenesis and progression of PAH.Ambrisentan is high-affinity (Ki 0.011 nM) ETA receptor antagonist with high selectivity for the ETA versus ETB receptor (> 4000-fold). The clinical impact of high selectivity for ETA is not known.. 12.2 Pharmacodynamics. Cardiac Electrophysiology. In randomized, positive- and placebo-controlled, parallel-group study, healthy subjects received either ambrisentan tablets 10 mg daily followed by single dose of 40 mg, placebo followed by single dose of moxifloxacin 400 mg, or placebo alone. Ambrisentan tablets 10 mg daily had no significant effect on the QTc interval. The 40 mg dose of ambrisentan tablets increased mean QTc at tmax by ms with an upper 95% confidence limit of ms. For patients receiving ambrisentan tablets 5-10 mg daily and not taking metabolic inhibitors, no significant QT prolongation is expected.. 12.3 Pharmacokinetics. The pharmacokinetics of ambrisentan (S-ambrisentan) in healthy subjects is dose proportional. The absolute bioavailability of ambrisentan is not known. Ambrisentan is absorbed with peak concentrations occurring approximately hours after oral administration in healthy subjects and PAH patients. Food does not affect its bioavailability. In vitro studies indicate that ambrisentan is substrate of P-gp. Ambrisentan is highly bound to plasma proteins (99%). The elimination of ambrisentan is predominantly by non-renal pathways, but the relative contributions of metabolism and biliary elimination have not been well characterized. In plasma, the AUC of 4-hydroxymethyl ambrisentan accounts for approximately 4% relative to parent ambrisentan AUC. The in vivo inversion of S-ambrisentan to R-ambrisentan is negligible. The mean oral clearance of ambrisentan is 38 mL/min and 19 mL/min in healthy subjects and in PAH patients, respectively. Although ambrisentan has 15-hour terminal half-life, the mean trough concentration of ambrisentan at steady-state is about 15% of the mean peak concentration and the accumulation factor is about 1.2 after long-term daily dosing, indicating that the effective half-life of ambrisentan is about hours.. Drug Interactions. In Vitro Studies. Studies with human liver tissue indicate that ambrisentan is metabolized by CYP3A, CYP2C19, and uridine 5-diphosphate glucuronosyltransferases (UGTs) 1A9S, 2B7S, and 1A3S. In vitro studies suggest that ambrisentan is substrate of the Organic Anion Transporting Polypeptides OATP1B1 and OATP1B3, and P-glycoprotein (P-gp). Drug interactions might be expected because of these factors; however, clinically relevant interaction has been demonstrated only with cyclosporine [see Drug Interactions (7)]. In vitro studies found ambrisentan to have little to no inhibition of human hepatic transporters. Ambrisentan demonstrated weak dose-dependent inhibition of OATP1B1, OATP1B3, and NTCP (IC50 of 47 uM, 45 uM, and approximately 100 uM, respectively) and no transporter-specific inhibition of BSEP, BRCP, P-gp, or MRP2. Ambrisentan does not inhibit or induce drug metabolizing enzymes at clinically relevant concentrations.. In Vivo Studies. The effects of other drugs on ambrisentan pharmacokinetics and the effects of ambrisentan on the exposure to other drugs are shown in Figure and Figure 3, respectively.Figure 2: Effects of Other Drugs on Ambrisentan Pharmacokinetics Figure 3: Effects of Ambrisentan on Other Drugs Figure 2: Effects of Other Drugs on Ambrisentan Pharmacokinetics. Figure 3: Effects of Ambrisentan on Other Drugs.

CLINICAL STUDIES SECTION.


14 CLINICAL STUDIES 14.1 Pulmonary Arterial Hypertension (PAH). Two 12-week, randomized, double-blind, placebo-controlled, multicenter studies were conducted in 393 patients with PAH (WHO Group 1). The two studies were identical in design except for the doses of ambrisentan tablets and the geographic region of the investigational sites. ARIES-1 compared once-daily doses of mg and 10 mg ambrisentan tablets to placebo, while ARIES-2 compared once-daily doses of 2.5 mg and mg ambrisentan tablets to placebo. In both studies, ambrisentan tablets or placebo was added to current therapy, which could have included combination of anticoagulants, diuretics, calcium channel blockers, or digoxin, but not epoprostenol, treprostinil, iloprost, bosentan, or sildenafil. The primary study endpoint was 6-minute walk distance. In addition, clinical worsening, WHO functional class, dyspnea, and SF-36(R) Health Survey were assessed.Patients had idiopathic or heritable PAH (64%) or PAH associated with connective tissue diseases (32%), HIV infection (3%), or anorexigen use (1%). There were no patients with PAH associated with congenital heart disease.Patients had WHO functional class (2%), II (38%), III (55%), or IV (5%) symptoms at baseline. The mean age of patients was 50 years, 79% of patients were female, and 77% were Caucasian.. Submaximal Exercise Ability. Results of the 6-minute walk distance at 12 weeks for the ARIES-1 and ARIES-2 studies are shown in Table and Figure 4.Table 3: Changes from Baseline in 6-Minute Walk Distance (meters) (ARIES-1 and ARIES-2)Mean +- standard deviationARIES-1ARIES-2Placebo(N 67)5 mg(N 67)10 mg(N 67)Placebo(N 65)2.5 mg(N 64)5 mg(N 63)Baseline342 +- 73340 +- 77342 +- 78343 +- 86347 +- 84355 +- 84Mean change from baseline-8 +- 7923 +- 8344 +- 63-10 +- 9422 +- 8349 +- 75Placebo-adjusted mean change from baseline31513259Placebo-adjusted median change from baseline27393045p-valuep- values are Wilcoxon rank sum test comparisons of ambrisentan tablets to placebo at Week 12 stratified by idiopathic or heritable PAH and non-idiopathic, non-heritable PAH patients 0.008< 0.0010.022< 0.001 Figure 4: Mean Change in 6-Minute Walk Distance (ARIES-1 and ARIES-2) In both studies, treatment with ambrisentan tablets resulted in significant improvement in 6-minute walk distance for each dose of ambrisentan tablets and the improvements increased with dose. An increase in 6-minute walk distance was observed after weeks of treatment with ambrisentan tablets, with dose-response observed after 12 weeks of treatment. Improvements in walk distance with ambrisentan tablets were smaller for elderly patients (age >= 65) than younger patients and for patients with secondary PAH than for patients with idiopathic or heritable PAH. The results of such subgroup analyses must be interpreted cautiously.. Figure Mean Change in 6-Minute Walk Distance (ARIES-1 and ARIES-2). Clinical Worsening. Time to clinical worsening of PAH was defined as the first occurrence of death, lung transplantation, hospitalization for PAH, atrial septostomy, study withdrawal due to the addition of other PAH therapeutic agents, or study withdrawal due to early escape. Early escape was defined as meeting two or more of the following criteria: 20% decrease in the 6-minute walk distance; an increase in WHO functional class; worsening right ventricular failure; rapidly progressing cardiogenic, hepatic, or renal failure; or refractory systolic hypotension. The clinical worsening events during the 12-week treatment period of the ambrisentan tablets clinical trials are shown in Table and Figure 5.Table 4: Time to Clinical Worsening (ARIES-1 and ARIES-2)Intention-to-treat population.Note: Patients may have had more than one reason for clinical worsening. Nominal p-valuesARIES-1ARIES-2Placebo(N 67)Ambrisentan Tablets(N 134)Placebo(N 65)Ambrisentan Tablets(N 127)Clinical worsening, no. (%)7 (10%)4 (3%)13 (22%)8 (6%)Hazard ratio0.280.30p-value, Log-rank test0.0300.005Figure 5: Time to Clinical Worsening (ARIES-1 and ARIES-2) Figure Time to Clinical Worsening (ARIES-1 and ARIES-2). 14.3 Long-term Treatment of PAH. In long-term follow-up of patients who were treated with ambrisentan tablets (2.5 mg, mg, or 10 mg once daily) in the two pivotal studies and their open-label extension (N 383), Kaplan-Meier estimates of survival at 1, 2, and years were 93%, 85%, and 79%, respectively. Of the patients who remained on ambrisentan tablets for up to years, the majority received no other treatment for PAH. These uncontrolled observations do not allow comparison with group not given ambrisentan tablets and cannot be used to determine the long-term effect of ambrisentan tablets on mortality.. 14.4 Adverse Effects in Idiopathic Pulmonary Fibrosis (IPF). randomized controlled study in patients with IPF, with or without pulmonary hypertension (WHO Group 3), compared ambrisentan tablets (N 329) to placebo (N 163). The study was terminated after 34 weeks for lack of efficacy, and was found to demonstrate greater risk of disease progression or death on ambrisentan tablets. More patients taking ambrisentan tablets died (8% vs. 4%), had respiratory hospitalization (13% vs. 6%), and had decrease in FVC/DLCO (17% vs. 12%) [see Contraindications (4.2)].

CONTRAINDICATIONS SECTION.


4 CONTRAINDICATIONS oPregnancy (4.1)oIdiopathic Pulmonary Fibrosis (4.2). oPregnancy (4.1). oIdiopathic Pulmonary Fibrosis (4.2). 4.1 Pregnancy. Ambrisentan tablets may cause fetal harm when administered to pregnant female. Ambrisentan tablets are contraindicated in females who are pregnant. Ambrisentan tablets were consistently shown to have teratogenic effects when administered to animals. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to fetus [see Warnings and Precautions (5.1, 5.2) and Use in Specific Populations (8.1)]. 4.2 Idiopathic Pulmonary Fibrosis. Ambrisentan tablets are contraindicated in patients with Idiopathic Pulmonary Fibrosis (IPF), including IPF patients with pulmonary hypertension (WHO Group 3) [see Clinical Studies (14.4)].

DESCRIPTION SECTION.


11 DESCRIPTION Ambrisentan tablets are an endothelin receptor antagonist that is selective for the endothelin type-A (ETA) receptor. The chemical name of ambrisentan is (+)-(2S)-2-[(4,6-dimethylpyrimidin-2-yl)oxy]-3-methoxy-3,3-diphenylpropanoic acid. It has molecular formula of C22H22N2O4 and molecular weight of 378.42. It contains single chiral center determined to be the (S) configuration and has the following structural formula:Figure 1: Ambrisentan Structural Formula Ambrisentan is white to off-white powder. It is carboxylic acid with 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 tablets are available as mg and 10 mg film-coated tablets for once daily oral administration. The tablets include the following inactive ingredients: anhydrous lactose, croscarmellose sodium, FD&C Blue No. Aluminum Lake, FD&C Red No. 40 Aluminum Lake, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polyvinyl alcohol, talc and titanium dioxide. Each round, pink ambrisentan tablet contains mg of ambrisentan. Each capsule shaped, pink ambrisentan tablet contains 10 mg of ambrisentan. Ambrisentan tablets are unscored.. Ambrisentan Structural Formula.

DOSAGE & ADMINISTRATION SECTION.


2 DOSAGE AND ADMINISTRATION oInitiate treatment at mg once daily (2.1).oTitrate at 4-week intervals as needed and tolerated (2.1).oDo not split, crush, or chew tablets (2.1).. oInitiate treatment at mg once daily (2.1).. oTitrate at 4-week intervals as needed and tolerated (2.1).. oDo not split, crush, or chew tablets (2.1).. 2.1 Adult Dosage. Initiate treatment at mg once daily. At 4-week intervals, the dose of ambrisentan tablets can be increased, as needed and tolerated, to 10 mg.Do not split, crush, or chew tablets.. 2.2 Pregnancy Testing in Females of Reproductive Potential. Initiate treatment with ambrisentan tablets in females of reproductive potential only after negative pregnancy test. Obtain monthly pregnancy tests during treatment [see Use in Specific Populations (8.3)].

DOSAGE FORMS & STRENGTHS SECTION.


3 DOSAGE FORMS AND STRENGTHS Ambrisentan Tablets are available containing mg or 10 mg of ambrisentan.oThe mg tablets are pink, film-coated, round, unscored tablets debossed with on one side of the tablet and AN on the other side.oThe 10 mg tablets are pink, film-coated, capsule shaped, unscored tablets debossed with on one side of the tablet and AN1 on the other side.. oThe mg tablets are pink, film-coated, round, unscored tablets debossed with on one side of the tablet and AN on the other side.. oThe 10 mg tablets are pink, film-coated, capsule shaped, unscored tablets debossed with on one side of the tablet and AN1 on the other side.. Tablet: mg and 10 mg (3).

DRUG INTERACTIONS SECTION.


7 DRUG INTERACTIONS 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 mg once daily when coadministered with cyclosporine [see Clinical Pharmacology (12.3)]. Cyclosporine increases ambrisentan exposure; limit ambrisentan dose to mg once daily (7).

FEMALES & MALES OF REPRODUCTIVE POTENTIAL SECTION.


8.3 Females and Males of Reproductive Potential. Pregnancy Testing. Female patients of reproductive potential must have negative pregnancy test prior to initiation of treatment, monthly pregnancy test during treatment, and pregnancy test month after stopping treatment with ambrisentan tablets. Advise patients to contact their healthcare provider if they become pregnant or suspect they may be pregnant. Perform pregnancy test if pregnancy is suspected for any reason. For positive pregnancy tests, counsel patient on the potential risk to the fetus and patient options [see Boxed Warning and Dosage and Administration (2.2)]. Contraception. Female patients of reproductive potential must use acceptable methods of contraception during treatment with ambrisentan tablets and for month after stopping treatment with ambrisentan tablets. Patients may choose one highly effective form of contraception (intrauterine device [IUD], contraceptive implant, or tubal sterilization) or combination of methods (hormone method with barrier method or two barrier methods). If partners vasectomy is the chosen method of contraception, hormone or barrier method must be used along with this method. Counsel patients on pregnancy planning and prevention, including emergency contraception, or designate counseling by another healthcare provider trained in contraceptive counseling [see Boxed Warning]. Infertility. Males In 6-month study of another endothelin receptor antagonist, bosentan, 25 male patients with WHO functional class III and IV PAH and normal baseline sperm count were evaluated for effects on testicular function. There was decline in sperm count of at least 50% in 25% of the patients after or months of treatment with bosentan. One patient developed marked oligospermia at months, and the sperm count remained low with follow-up measurements over the subsequent weeks. Bosentan was discontinued and after months the sperm count had returned to baseline levels. In 22 patients who completed months of treatment, sperm count remained within the normal range and no changes in sperm morphology, sperm motility, or hormone levels were observed. Based on these findings and preclinical data [see Nonclinical Toxicology (13.1)] from endothelin receptor antagonists, it cannot be excluded that endothelin receptor antagonists such as ambrisentan tablets have an adverse effect on spermatogenesis. Counsel patients about the potential effects on fertility [see Warnings and Precautions (5.5)].

GERIATRIC USE SECTION.


8.5 Geriatric Use. In the two placebo-controlled clinical studies of ambrisentan tablets, 21% of patients were >= 65 years old and 5% were >= 75 years old. The elderly (age >= 65 years) showed less improvement in walk distances with ambrisentan tablets than younger patients did, but the results of such subgroup analyses must be interpreted cautiously. Peripheral edema was more common in the elderly than in younger patients.

HOW SUPPLIED SECTION.


16 HOW SUPPLIED/STORAGE AND HANDLING Ambrisentan Tablets are available containing mg or 10 mg of ambrisentan.The mg tablets are pink, film-coated, round, unscored tablets debossed with on one side of the tablet and AN on the other side. They are available as follows:NDC 0378-4270-93bottles of 30 tabletsThe 10 mg tablets are pink, film-coated, capsule shaped, unscored tablets debossed with on one side of the tablet and AN1 on the other side. They are available as follows:NDC 0378-4271-93bottles of 30 tabletsStore at 20 to 25C (68 to 77F). [See USP Controlled Room Temperature.] Store ambrisentan tablets in their original packaging.Dispense only in original container.PHARMACIST: Dispense Medication Guide with each prescription.

INDICATIONS & USAGE SECTION.


1 INDICATIONS AND USAGE Ambrisentan tablets are indicated for the treatment of pulmonary arterial hypertension (PAH) (WHO Group 1):oTo 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%).. oTo improve exercise ability and delay clinical worsening. Ambrisentan tablets are an endothelin receptor antagonist indicated for the treatment of pulmonary arterial hypertension (PAH) (WHO Group 1):To improve exercise ability and delay clinical worsening. Studies establishing effectiveness included trials predominantly in patients with WHO Functional Class II-III symptoms and etiologies of idiopathic or heritable PAH (60%) or PAH associated with connective tissue diseases (34%) (1).

INFORMATION FOR PATIENTS SECTION.


17 PATIENT COUNSELING INFORMATION Advise patients to read the FDA-approved patient labeling (Medication Guide).Embryo-fetal Toxicity: Instruct patients on the risk of fetal harm when ambrisentan tablets are used in pregnancy [see Warnings and Precautions (5.1) and Use in Specific Populations (8.1)]. Female patients must enroll in the Ambrisentan REMS. Instruct females of reproductive potential to immediately contact their physician if they suspect they may be pregnant.Ambrisentan Risk Evaluation and Mitigation Strategy (REMS): For female patients, ambrisentan tablets are only available through restricted program called the Ambrisentan REMS [see Contraindications (4.1), Warnings and Precautions (5.2)]. Male patients are not enrolled in the Ambrisentan REMS.Inform female patients (and their guardians, if applicable) of the following notable requirements:oAll female patients must sign an enrollment form.oFemale patients of reproductive potential must comply with the pregnancy testing and contraception requirements [see Use in Specific Populations (8.3)].oFemales of reproductive potential must be counseled on the use of emergency contraception in the event of unprotected sex or known or suspected contraceptive failure.oPre-pubertal females must report any changes in their reproductive status immediately to their prescriber.Ambrisentan tablets are available only from certified pharmacies participating in the program. Therefore, provide patients with the telephone number and website for information on how to obtain the product.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 Tablets: Instruct patients that the risks associated with ambrisentan tablets also include the following:oDecreases in sperm countoFluid overloadAdministration: Advise patients not to split, crush, or chew tablets.. oAll female patients must sign an enrollment form.. oFemale patients of reproductive potential must comply with the pregnancy testing and contraception requirements [see Use in Specific Populations (8.3)].. oFemales of reproductive potential must be counseled on the use of emergency contraception in the event of unprotected sex or known or suspected contraceptive failure.. oPre-pubertal females must report any changes in their reproductive status immediately to their prescriber.. oDecreases in sperm count. oFluid overload.

LACTATION SECTION.


8.2 Lactation Risk Summary. It is not known whether ambrisentan is present in human milk. Because many drugs are present in human milk and because of the potential for serious adverse reactions in breastfed infants from ambrisentan tablets, decision should be made whether to discontinue breastfeeding or discontinue ambrisentan tablets, taking into account the importance of the drug to the mother.

MECHANISM OF ACTION SECTION.


12.1 Mechanism of Action. Endothelin-1 (ET-1) is potent autocrine and paracrine peptide. Two receptor subtypes, ETA and ETB, mediate the effects of ET-1 in the vascular smooth muscle and endothelium. The primary actions of ETA are vasoconstriction and cell proliferation, while the predominant actions of ETB are vasodilation, antiproliferation, and ET-1 clearance.In patients with PAH, plasma ET-1 concentrations are increased as much as 10-fold and correlate with increased mean right atrial pressure and disease severity. ET-1 and ET-1 mRNULL concentrations are increased as much as 9-fold in the lung tissue of patients with PAH, primarily in the endothelium of pulmonary arteries. These findings suggest that ET-1 may play critical role in the pathogenesis and progression of PAH.Ambrisentan is high-affinity (Ki 0.011 nM) ETA receptor antagonist with high selectivity for the ETA versus ETB receptor (> 4000-fold). The clinical impact of high selectivity for ETA is not known.

NONCLINICAL TOXICOLOGY SECTION.


13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Oral carcinogenicity studies of up to two years duration were conducted at starting doses of 10, 30, and 60 mg/kg/day in rats (8 to 48 times the maximum recommended human dose [MRHD] on mg/m2 basis) and at 50, 150, and 250 mg/kg/day in mice (28 to 140 times the MRHD). In the rat study, the high- and mid-dose male and female groups had their doses lowered to 40 and 20 mg/kg/day, respectively, in week 51 because of effects on survival. The high-dose males and females were taken off drug completely in weeks 69 and 93, respectively. The only evidence of ambrisentan-related carcinogenicity was positive trend in male rats, for the combined incidence of benign basal cell tumor and basal cell carcinoma of skin/subcutis in the mid-dose group (high-dose group excluded from analysis), and the occurrence of mammary fibroadenomas in males in the high-dose group. In the mouse study, high-dose male and female groups had their doses lowered to 150 mg/kg/day in week 39 and were taken off drug completely in week 96 (males) or week 76 (females). In mice, ambrisentan was not associated with excess tumors in any dosed group.Positive findings of clastogenicity were detected, at drug concentrations producing moderate to high toxicity, in the chromosome aberration assay in cultured human lymphocytes. There was no evidence for genetic toxicity of ambrisentan when tested in vitro in bacteria (Ames test) or in vivo in rats (micronucleus assay, unscheduled DNULL synthesis assay).The development of testicular tubular atrophy and impaired fertility has been linked to the chronic administration of endothelin receptor antagonists in rodents. Testicular tubular degeneration was observed in rats treated with ambrisentan for two years at doses >= 10 mg/kg/day (8-fold MRHD). Increased incidences of testicular findings were also observed in mice treated for two years at doses >= 50 mg/kg/day (28-fold MRHD). Effects on sperm count, sperm morphology, mating performance, and fertility were observed in fertility studies in which male rats were treated with ambrisentan at oral doses of 300 mg/kg/day (236-fold MRHD). At doses of >= 10 mg/kg/day, observations of testicular histopathology in the absence of fertility and sperm effects were also present.

OVERDOSAGE SECTION.


10 OVERDOSAGE There is no experience with overdosage of ambrisentan tablets. The highest single dose of ambrisentan tablets 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.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.


PRINCIPAL DISPLAY PANEL 5 mg NDC 0378-4270-97AmbrisentanTablets5 mgPHARMACIST: Dispense the accompanyingMedication Guide to each patient.Rx only 10 TabletsEach film-coated tablet contains:Ambrisentan mgUsual Dosage: See accompanyingprescribing information.Do not split, crush or chew your tablets.Keep this and all medication out of thereach of children.Store at 20 to 25C (68 to 77F). [SeeUSP Controlled Room Temperature.]Manufactured for: Mylan Pharmaceuticals Inc. Morgantown, WV 26505 U.S.A.Made in IndiaMylan.comRMX4270AMDispense only in original container.Keep container tightly closed.Code No.: MH/DRUGS/25/NKD/89. Ambrisentan Tablets mg Bottle Label.

PEDIATRIC USE SECTION.


8.4 Pediatric Use. Safety and effectiveness of ambrisentan tablets in pediatric patients have not been established.. Juvenile Animal Data. In juvenile rats administered ambrisentan orally once daily during postnatal day to 26, 36, or 62, decrease in brain weight (-3% to -8%) with no morphologic or neurobehavioral changes occurred after breathing sounds, apnea, and hypoxia were observed, at exposures approximately 1.8 to 7.0 times human pediatric exposures at 10 mg, based on AUC.

PHARMACODYNULLMICS SECTION.


12.2 Pharmacodynamics. Cardiac Electrophysiology. In randomized, positive- and placebo-controlled, parallel-group study, healthy subjects received either ambrisentan tablets 10 mg daily followed by single dose of 40 mg, placebo followed by single dose of moxifloxacin 400 mg, or placebo alone. Ambrisentan tablets 10 mg daily had no significant effect on the QTc interval. The 40 mg dose of ambrisentan tablets increased mean QTc at tmax by ms with an upper 95% confidence limit of ms. For patients receiving ambrisentan tablets 5-10 mg daily and not taking metabolic inhibitors, no significant QT prolongation is expected.

PHARMACOKINETICS SECTION.


12.3 Pharmacokinetics. The pharmacokinetics of ambrisentan (S-ambrisentan) in healthy subjects is dose proportional. The absolute bioavailability of ambrisentan is not known. Ambrisentan is absorbed with peak concentrations occurring approximately hours after oral administration in healthy subjects and PAH patients. Food does not affect its bioavailability. In vitro studies indicate that ambrisentan is substrate of P-gp. Ambrisentan is highly bound to plasma proteins (99%). The elimination of ambrisentan is predominantly by non-renal pathways, but the relative contributions of metabolism and biliary elimination have not been well characterized. In plasma, the AUC of 4-hydroxymethyl ambrisentan accounts for approximately 4% relative to parent ambrisentan AUC. The in vivo inversion of S-ambrisentan to R-ambrisentan is negligible. The mean oral clearance of ambrisentan is 38 mL/min and 19 mL/min in healthy subjects and in PAH patients, respectively. Although ambrisentan has 15-hour terminal half-life, the mean trough concentration of ambrisentan at steady-state is about 15% of the mean peak concentration and the accumulation factor is about 1.2 after long-term daily dosing, indicating that the effective half-life of ambrisentan is about hours.. Drug Interactions. In Vitro Studies. Studies with human liver tissue indicate that ambrisentan is metabolized by CYP3A, CYP2C19, and uridine 5-diphosphate glucuronosyltransferases (UGTs) 1A9S, 2B7S, and 1A3S. In vitro studies suggest that ambrisentan is substrate of the Organic Anion Transporting Polypeptides OATP1B1 and OATP1B3, and P-glycoprotein (P-gp). Drug interactions might be expected because of these factors; however, clinically relevant interaction has been demonstrated only with cyclosporine [see Drug Interactions (7)]. In vitro studies found ambrisentan to have little to no inhibition of human hepatic transporters. Ambrisentan demonstrated weak dose-dependent inhibition of OATP1B1, OATP1B3, and NTCP (IC50 of 47 uM, 45 uM, and approximately 100 uM, respectively) and no transporter-specific inhibition of BSEP, BRCP, P-gp, or MRP2. Ambrisentan does not inhibit or induce drug metabolizing enzymes at clinically relevant concentrations.. In Vivo Studies. The effects of other drugs on ambrisentan pharmacokinetics and the effects of ambrisentan on the exposure to other drugs are shown in Figure and Figure 3, respectively.Figure 2: Effects of Other Drugs on Ambrisentan Pharmacokinetics Figure 3: Effects of Ambrisentan on Other Drugs Figure 2: Effects of Other Drugs on Ambrisentan Pharmacokinetics. Figure 3: Effects of Ambrisentan on Other Drugs.

PREGNULLNCY SECTION.


8.1 Pregnancy. Risk Summary. Based on data from animal reproduction studies, ambrisentan tablets may cause fetal harm when administered to pregnant woman and is contraindicated during pregnancy. There are limited data on ambrisentan tablets use in pregnant women. In animal reproduction studies, ambrisentan tablets were teratogenic in rats and rabbits at doses which resulted in exposures of 3.5 and 1.7 times, respectively, the human dose of 10 mg per day [see Animal Data]. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, advise the patient of the potential hazard to fetus [see Contraindications (4.1), Warnings and Precautions (5.1)]. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.. Data. Animal Data Ambrisentan tablets were teratogenic at oral dosages of >= 15 mg/kg/day (AUC 51.7 houg/mL) in rats and >= mg/kg/day (24.7 houg/mL) in rabbits; it was not studied at lower dosages. These dosages are of 3.5 and 1.7 times, respectively, the human dose of 10 mg per day (14.8 houg/mL) based on AUC. In both species, there were abnormalities of the lower jaw and hard and soft palate, malformation of the heart and great vessels, and failure of formation of the thymus and thyroid. preclinical study in rats has shown decreased survival of newborn pups (mid and high dosages) and effects on testicle size and fertility of pups (high dosage) following maternal treatment with ambrisentan from late gestation through weaning. The mid and high dosages were 51 x, and 170 (on mg/m2 body surface area basis) the maximum oral human dose of 10 mg and an average adult body weight of 70 kg. These effects were absent at maternal dosage 17 the human dose based on mg/m2.

RISKS.


Risk Summary. Based on data from animal reproduction studies, ambrisentan tablets may cause fetal harm when administered to pregnant woman and is contraindicated during pregnancy. There are limited data on ambrisentan tablets use in pregnant women. In animal reproduction studies, ambrisentan tablets were teratogenic in rats and rabbits at doses which resulted in exposures of 3.5 and 1.7 times, respectively, the human dose of 10 mg per day [see Animal Data]. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, advise the patient of the potential hazard to fetus [see Contraindications (4.1), Warnings and Precautions (5.1)]. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

SPL MEDGUIDE SECTION.


Medication Guide Ambrisentan Tablets(am bri sen tan)Read this Medication Guide before you start taking ambrisentan tablets and each time you get 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 should know about ambrisentan tablets oSerious birth defects. Ambrisentan tablets can cause serious birth defects if taken during pregnancy. oFemales must not be pregnant when they start taking ambrisentan tablets or become pregnant during treatment with ambrisentan tablets. oFemales who are able to get pregnant must have negative pregnancy test before beginning treatment with ambrisentan tablets, each month during treatment with ambrisentan tablets, and one month after stopping ambrisentan tablets. Talk to your doctor about your menstrual cycle. Your doctor will decide when to do pregnancy test, and will order pregnancy test for you depending on your menstrual cycle. Females who are able to get pregnant are females who: ohave entered puberty, even if they have not started their menstrual period, and ohave uterus, and ohave not gone through menopause. Menopause means that you have not had 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: ohave not yet entered puberty, or odo not have uterus, or ohave gone through menopause. Menopause means that you have not had menstrual period for at least 12 months for natural reasons, or that you have had your ovaries removed, orowho are infertile for any other medical reason and this infertility is permanent and cannot be reversed Females who are able to get pregnant must use two acceptable forms of birth control during treatment with ambrisentan tablets, and for one month after stopping ambrisentan tablets because the medicine may still be in the body. oIf you have had tubal sterilization or have an IUD (intrauterine device) or progesterone implant, these methods can be used alone and no other form of birth control is needed. oTalk 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. oIf 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. See the chart below for Acceptable Birth Control Options during treatment with ambrisentan tablets.oDo 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. oTell your doctor right away if you miss menstrual period or think you may be pregnant for any reason. If you are the parent or caregiver of 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. Females can only receive ambrisentan tablets through restricted program under Risk Evaluation and Mitigation Strategy (REMS) called the Ambrisentan REMS. If you are female who can get pregnant, you must talk to your doctor, understand the benefits and risks of ambrisentan tablets, and agree to all of the instructions in the Ambrisentan REMS. Males can receive ambrisentan tablets without taking part in the Ambrisentan REMS. What are ambrisentan tablets oAmbrisentan tablets are prescription medicine used to treat pulmonary arterial hypertension (PAH), which is high blood pressure in the arteries of your lungs. oAmbrisentan tablets can improve your ability to exercise and it can help slow down the worsening of your physical condition and symptoms. oIt is not known if ambrisentan tablets are safe and effective in children. Who should not take ambrisentan tablets Do not take ambrisentan tablets if: oyou 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 should know about ambrisentan tablets)Serious birth defects from ambrisentan tablets happen early in pregnancy.oyou have condition called Idiopathic Pulmonary Fibrosis (IPF) What should tell my doctor before taking ambrisentan tabletsBefore you take ambrisentan tablets, tell your doctor if you:ohave been told that you have low red blood cell level (anemia)ohave liver problemsohave any other medical conditionsTell 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(R), Neoral(R), Sandimmune(R)). Your doctor may need to change your dose of ambrisentan tablets.How should take ambrisentan tablets oAmbrisentan tablets will be mailed to you by certified pharmacy. Your doctor will give you complete details. oTake ambrisentan tablets exactly as your doctor tells you to take them. Do not stop taking ambrisentan tablets unless your doctor tells you to stop.oYou can take ambrisentan tablets with or without food.oDo not split, crush or chew ambrisentan tablets.oIt will be easier to remember to take ambrisentan tablets if you take them at the same time each day. oIf you take more than your regular dose of ambrisentan tablets, call your doctor right away.oIf you miss 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 missed dose. What should avoid while taking ambrisentan tablets oDo 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 should know about ambrisentan tablets) If you miss menstrual period, or think you might be pregnant, call your doctor right away. oIt 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: oSee What is the most important information should know about ambrisentan tabletsoSwelling 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 serious health problem. You may need to be treated with medicine or need to go to the hospital. oDecreased sperm count. Decreased sperm counts have happened in some men taking medicine that is like ambrisentan tablets. decreased sperm count may affect the ability to father child. Tell your doctor if being able to have children is important to you. oLow red blood cell levels (anemia) can happen during the first weeks after starting ambrisentan tablets. If this happens, you may need 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: oswelling of hands, legs, ankles and feet (peripheral edema)ostuffy nose (nasal congestion)oinflamed nasal passages (sinusitis)ohot 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 liver problem while taking ambrisentan tablets:oloss of appetiteonausea or vomitingofeveroachinessogenerally do not feel well opain in the upper right stomach (abdominal) areaoyellowing of your skin or the whites of your eyesodark urineoitchingTell 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.How should store ambrisentan tablets Store ambrisentan tablets at room temperature between 20 to 25C (68 to 77F), in the package they come in. Keep ambrisentan tablets and all medicines out of the reach of children.General information about the safe and effective use of ambrisentan tablets Medicines are sometimes prescribed for purposes other than those listed in Medication Guide. Do not use ambrisentan tablets for condition for which they were not prescribed. Do not give ambrisentan tablets to other people, even if they have the same symptoms that you have. They may harm them. This Medication Guide summarizes the most important information about ambrisentan tablets. If you would like more information, ask your doctor. You can ask your doctor or pharmacist for information about ambrisentan tablets that is written for health professionals. What are the ingredients in ambrisentan tablets Active Ingredient: ambrisentan Inactive Ingredients: anhydrous lactose, croscarmellose sodium, FD&C Blue No. Aluminum Lake, FD&C Red No. 40 Aluminum Lake, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polyvinyl alcohol, talc and titanium dioxide. Manufactured for: Mylan Pharmaceuticals Inc., Morgantown, WV 26505Manufactured by: Mylan Laboratories Limited, Hyderabad 500 096, India The brands listed are trademarks of their respective owners. For more information, call Mylan at 1-877-446-3679 (1-877-4-INFO-RX).This Medication Guide has been approved by the U.S. Food and Drug Administration. Manufactured for: Mylan Pharmaceuticals Inc. Morgantown, WV 26505 U.S.A.Manufactured by: Mylan Laboratories Limited Hyderabad -- 500 096, India75069501Revised: 8/2019MX:AMBR:R5. oSerious birth defects. Ambrisentan tablets can cause serious birth defects if taken during pregnancy. oFemales must not be pregnant when they start taking ambrisentan tablets or become pregnant during treatment with ambrisentan tablets. oFemales who are able to get pregnant must have negative pregnancy test before beginning treatment with ambrisentan tablets, each month during treatment with ambrisentan tablets, and one month after stopping ambrisentan tablets. Talk to your doctor about your menstrual cycle. Your doctor will decide when to do pregnancy test, and will order pregnancy test for you depending on your menstrual cycle. Females who are able to get pregnant are females who: ohave entered puberty, even if they have not started their menstrual period, and ohave uterus, and ohave not gone through menopause. Menopause means that you have not had 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: ohave not yet entered puberty, or odo not have uterus, or ohave gone through menopause. Menopause means that you have not had menstrual period for at least 12 months for natural reasons, or that you have had your ovaries removed, orowho are infertile for any other medical reason and this infertility is permanent and cannot be reversed oFemales must not be pregnant when they start taking ambrisentan tablets or become pregnant during treatment with ambrisentan tablets. oFemales who are able to get pregnant must have negative pregnancy test before beginning treatment with ambrisentan tablets, each month during treatment with ambrisentan tablets, and one month after stopping ambrisentan tablets. Talk to your doctor about your menstrual cycle. Your doctor will decide when to do pregnancy test, and will order pregnancy test for you depending on your menstrual cycle. Females who are able to get pregnant are females who: ohave entered puberty, even if they have not started their menstrual period, and ohave uterus, and ohave not gone through menopause. Menopause means that you have not had 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: ohave not yet entered puberty, or odo not have uterus, or ohave gone through menopause. Menopause means that you have not had menstrual period for at least 12 months for natural reasons, or that you have had your ovaries removed, orowho are infertile for any other medical reason and this infertility is permanent and cannot be reversed Females who are able to get pregnant are females who: ohave entered puberty, even if they have not started their menstrual period, and ohave uterus, and ohave not gone through menopause. Menopause means that you have not had menstrual period for at least 12 months for natural reasons, or that you have had your ovaries removed. ohave entered puberty, even if they have not started their menstrual period, and ohave uterus, and ohave not gone through menopause. Menopause means that you have not had 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: ohave not yet entered puberty, or odo not have uterus, or ohave gone through menopause. Menopause means that you have not had menstrual period for at least 12 months for natural reasons, or that you have had your ovaries removed, orowho are infertile for any other medical reason and this infertility is permanent and cannot be reversed ohave not yet entered puberty, or odo not have uterus, or ohave gone through menopause. Menopause means that you have not had menstrual period for at least 12 months for natural reasons, or that you have had your ovaries removed, or. owho are infertile for any other medical reason and this infertility is permanent and cannot be reversed Females who are able to get pregnant must use two acceptable forms of birth control during treatment with ambrisentan tablets, and for one month after stopping ambrisentan tablets because the medicine may still be in the body. oIf you have had tubal sterilization or have an IUD (intrauterine device) or progesterone implant, these methods can be used alone and no other form of birth control is needed. oTalk 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. oIf 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. oIf you have had tubal sterilization or have an IUD (intrauterine device) or progesterone implant, these methods can be used alone and no other form of birth control is needed. oTalk 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. oIf 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. oDo 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. oTell your doctor right away if you miss menstrual period or think you may be pregnant for any reason. oAmbrisentan tablets are prescription medicine used to treat pulmonary arterial hypertension (PAH), which is high blood pressure in the arteries of your lungs. oAmbrisentan tablets can improve your ability to exercise and it can help slow down the worsening of your physical condition and symptoms. oIt is not known if ambrisentan tablets are safe and effective in children. oyou 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 should know about ambrisentan tablets)Serious birth defects from ambrisentan tablets happen early in pregnancy.. oyou have condition called Idiopathic Pulmonary Fibrosis (IPF) ohave been told that you have low red blood cell level (anemia). ohave liver problems. ohave any other medical conditions. oAmbrisentan tablets will be mailed to you by certified pharmacy. Your doctor will give you complete details. oTake ambrisentan tablets exactly as your doctor tells you to take them. Do not stop taking ambrisentan tablets unless your doctor tells you to stop.. oYou can take ambrisentan tablets with or without food.. oDo not split, crush or chew ambrisentan tablets.. oIt will be easier to remember to take ambrisentan tablets if you take them at the same time each day. oIf you take more than your regular dose of ambrisentan tablets, call your doctor right away.. oIf you miss 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 missed dose. oDo 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 should know about ambrisentan tablets) If you miss menstrual period, or think you might be pregnant, call your doctor right away. oIt 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. oSee What is the most important information should know about ambrisentan tablets. oSwelling 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 serious health problem. You may need to be treated with medicine or need to go to the hospital. oDecreased sperm count. Decreased sperm counts have happened in some men taking medicine that is like ambrisentan tablets. decreased sperm count may affect the ability to father child. Tell your doctor if being able to have children is important to you. oLow red blood cell levels (anemia) can happen during the first weeks after starting ambrisentan tablets. If this happens, you may need 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. oswelling of hands, legs, ankles and feet (peripheral edema). ostuffy nose (nasal congestion). oinflamed nasal passages (sinusitis). ohot flashes or getting red in the face (flushing). oloss of appetite. onausea or vomiting. ofever. oachiness. ogenerally do not feel well opain in the upper right stomach (abdominal) area. oyellowing of your skin or the whites of your eyes. odark urine. oitching. Acceptable Birth Control Options.

SPL UNCLASSIFIED SECTION.


2.1 Adult Dosage. Initiate treatment at mg once daily. At 4-week intervals, the dose of ambrisentan tablets can be increased, as needed and tolerated, to 10 mg.Do not split, crush, or chew tablets.

USE IN SPECIFIC POPULATIONS SECTION.


8 USE IN SPECIFIC POPULATIONS oBreastfeeding: Choose ambrisentan tablets or breastfeeding (8.2).oNot recommended in patients with moderate or severe hepatic impairment (8.7).. oBreastfeeding: Choose ambrisentan tablets or breastfeeding (8.2).. oNot recommended in patients with moderate or severe hepatic impairment (8.7).. 8.1 Pregnancy. Risk Summary. Based on data from animal reproduction studies, ambrisentan tablets may cause fetal harm when administered to pregnant woman and is contraindicated during pregnancy. There are limited data on ambrisentan tablets use in pregnant women. In animal reproduction studies, ambrisentan tablets were teratogenic in rats and rabbits at doses which resulted in exposures of 3.5 and 1.7 times, respectively, the human dose of 10 mg per day [see Animal Data]. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, advise the patient of the potential hazard to fetus [see Contraindications (4.1), Warnings and Precautions (5.1)]. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.. Data. Animal Data Ambrisentan tablets were teratogenic at oral dosages of >= 15 mg/kg/day (AUC 51.7 houg/mL) in rats and >= mg/kg/day (24.7 houg/mL) in rabbits; it was not studied at lower dosages. These dosages are of 3.5 and 1.7 times, respectively, the human dose of 10 mg per day (14.8 houg/mL) based on AUC. In both species, there were abnormalities of the lower jaw and hard and soft palate, malformation of the heart and great vessels, and failure of formation of the thymus and thyroid. preclinical study in rats has shown decreased survival of newborn pups (mid and high dosages) and effects on testicle size and fertility of pups (high dosage) following maternal treatment with ambrisentan from late gestation through weaning. The mid and high dosages were 51 x, and 170 (on mg/m2 body surface area basis) the maximum oral human dose of 10 mg and an average adult body weight of 70 kg. These effects were absent at maternal dosage 17 the human dose based on mg/m2.. 8.2 Lactation Risk Summary. It is not known whether ambrisentan is present in human milk. Because many drugs are present in human milk and because of the potential for serious adverse reactions in breastfed infants from ambrisentan tablets, decision should be made whether to discontinue breastfeeding or discontinue ambrisentan tablets, taking into account the importance of the drug to the mother.. 8.3 Females and Males of Reproductive Potential. Pregnancy Testing. Female patients of reproductive potential must have negative pregnancy test prior to initiation of treatment, monthly pregnancy test during treatment, and pregnancy test month after stopping treatment with ambrisentan tablets. Advise patients to contact their healthcare provider if they become pregnant or suspect they may be pregnant. Perform pregnancy test if pregnancy is suspected for any reason. For positive pregnancy tests, counsel patient on the potential risk to the fetus and patient options [see Boxed Warning and Dosage and Administration (2.2)]. Contraception. Female patients of reproductive potential must use acceptable methods of contraception during treatment with ambrisentan tablets and for month after stopping treatment with ambrisentan tablets. Patients may choose one highly effective form of contraception (intrauterine device [IUD], contraceptive implant, or tubal sterilization) or combination of methods (hormone method with barrier method or two barrier methods). If partners vasectomy is the chosen method of contraception, hormone or barrier method must be used along with this method. Counsel patients on pregnancy planning and prevention, including emergency contraception, or designate counseling by another healthcare provider trained in contraceptive counseling [see Boxed Warning]. Infertility. Males In 6-month study of another endothelin receptor antagonist, bosentan, 25 male patients with WHO functional class III and IV PAH and normal baseline sperm count were evaluated for effects on testicular function. There was decline in sperm count of at least 50% in 25% of the patients after or months of treatment with bosentan. One patient developed marked oligospermia at months, and the sperm count remained low with follow-up measurements over the subsequent weeks. Bosentan was discontinued and after months the sperm count had returned to baseline levels. In 22 patients who completed months of treatment, sperm count remained within the normal range and no changes in sperm morphology, sperm motility, or hormone levels were observed. Based on these findings and preclinical data [see Nonclinical Toxicology (13.1)] from endothelin receptor antagonists, it cannot be excluded that endothelin receptor antagonists such as ambrisentan tablets have an adverse effect on spermatogenesis. Counsel patients about the potential effects on fertility [see Warnings and Precautions (5.5)]. 8.4 Pediatric Use. Safety and effectiveness of ambrisentan tablets in pediatric patients have not been established.. Juvenile Animal Data. In juvenile rats administered ambrisentan orally once daily during postnatal day to 26, 36, or 62, decrease in brain weight (-3% to -8%) with no morphologic or neurobehavioral changes occurred after breathing sounds, apnea, and hypoxia were observed, at exposures approximately 1.8 to 7.0 times human pediatric exposures at 10 mg, based on AUC. 8.5 Geriatric Use. In the two placebo-controlled clinical studies of ambrisentan tablets, 21% of patients were >= 65 years old and 5% were >= 75 years old. The elderly (age >= 65 years) showed less improvement in walk distances with ambrisentan tablets than younger patients did, but the results of such subgroup analyses must be interpreted cautiously. Peripheral edema was more common in the elderly than in younger patients.. 8.6 Renal Impairment. The impact of renal impairment on the pharmacokinetics of ambrisentan has been examined using population pharmacokinetic approach in PAH patients with creatinine clearances ranging between 20 and 150 mL/min. There was no significant impact of mild or moderate renal impairment on exposure to ambrisentan [see Clinical Pharmacology (12.3)]. Dose adjustment of ambrisentan tablets in patients with mild or moderate renal impairment is therefore not required. There is no information on the exposure to ambrisentan in patients with severe renal impairment.The impact of hemodialysis on the disposition of ambrisentan has not been investigated.. 8.7 Hepatic Impairment. Pre-existing Hepatic Impairment. The influence of pre-existing hepatic impairment on the pharmacokinetics of ambrisentan has not been evaluated. Because there is in vitro and in vivo evidence of significant metabolic and biliary contribution to the elimination of ambrisentan, hepatic impairment might be expected to have significant effects on the pharmacokinetics of ambrisentan [see Clinical Pharmacology (12.3)]. Ambrisentan tablets are not recommended in patients with moderate or severe hepatic impairment. There is no information on the use of ambrisentan tablets in patients with mild pre-existing impaired liver function; however, exposure to ambrisentan may be increased in these patients.. Elevation of Liver Transaminases. Other endothelin receptor antagonists (ERAs) have been associated with aminotransferase (AST, ALT) elevations, hepatotoxicity, and cases of liver failure [see Adverse Reactions (6.1, 6.2)]. In patients who develop hepatic impairment after ambrisentan tablets initiation, the cause of liver injury should be fully investigated. Discontinue ambrisentan tablets if elevations of liver aminotransferases are 5 ULN or if elevations are accompanied by bilirubin 2 ULN, or by signs or symptoms of liver dysfunction and other causes are excluded.

WARNINGS AND PRECAUTIONS SECTION.


5 WARNINGS AND PRECAUTIONS oFluid retention may require intervention (5.3).oIf patients develop acute pulmonary edema during initiation of therapy with ambrisentan tablets, consider underlying pulmonary veno-occlusive disease and discontinue treatment if necessary (5.4).oDecreases in sperm count have been observed in patients taking endothelin receptor antagonists (5.5).oDecreases in hemoglobin have been observed within the first few weeks; measure hemoglobin at initiation, at month, and periodically thereafter (5.6).. oFluid retention may require intervention (5.3).. oIf patients develop acute pulmonary edema during initiation of therapy with ambrisentan tablets, consider underlying pulmonary veno-occlusive disease and discontinue treatment if necessary (5.4).. oDecreases in sperm count have been observed in patients taking endothelin receptor antagonists (5.5).. oDecreases in hemoglobin have been observed within the first few weeks; measure hemoglobin at initiation, at month, and periodically thereafter (5.6).. 5.1 Embryo-fetal Toxicity. Ambrisentan tablets may cause fetal harm when administered during pregnancy and are contraindicated for use in females who are pregnant. In females of reproductive potential, exclude pregnancy prior to initiation of therapy, ensure use of acceptable contraceptive methods, and obtain monthly pregnancy tests [see Dosage and Administration (2.2), and Use in Specific Populations (8.1, 8.3)].Ambrisentan tablets are only available for females through restricted program under REMS [see Warnings and Precautions (5.2)].. 5.2 Ambrisentan Risk Evaluation and Mitigation Strategy (REMS) For all females, ambrisentan tablets are available only through restricted program under REMS called the Ambrisentan REMS because of the risk of embryo-fetal toxicity [see Contraindications (4.1), Warnings and Precautions (5.1), and Use in Specific Populations (8.1, 8.3)].Important requirements of the Ambrisentan REMS include the following:oPrescribers must be certified with the Ambrisentan REMS by enrolling and completing training.oAll females, regardless of reproductive potential, must enroll in the Ambrisentan REMS prior to initiating ambrisentan tablets. Male patients are not enrolled in the REMS.oFemales of reproductive potential must comply with the pregnancy testing and contraception requirements [see Use in Specific Populations (8.3)].oPharmacies that dispense ambrisentan tablets must be certified with the Ambrisentan REMS and must dispense to female patients who are authorized to receive ambrisentan tablets.Further information is available at www.ambrisentanrems.us.com or 1-888-417-3172.. oPrescribers must be certified with the Ambrisentan REMS by enrolling and completing training.. oAll females, regardless of reproductive potential, must enroll in the Ambrisentan REMS prior to initiating ambrisentan tablets. Male patients are not enrolled in the REMS.oFemales of reproductive potential must comply with the pregnancy testing and contraception requirements [see Use in Specific Populations (8.3)].. oFemales of reproductive potential must comply with the pregnancy testing and contraception requirements [see Use in Specific Populations (8.3)].. oPharmacies that dispense ambrisentan tablets must be certified with the Ambrisentan REMS and must dispense to female patients who are authorized to receive ambrisentan tablets.. 5.3 Fluid Retention. Peripheral edema is known class effect of endothelin receptor antagonists, and is also clinical consequence of PAH and worsening PAH. In the placebo-controlled studies, there was an increased incidence of peripheral edema in patients treated with doses of or 10 mg ambrisentan tablets compared to placebo [see Adverse Reactions (6.1)]. Most edema was mild to moderate in severity.In addition, there have been postmarketing reports of fluid retention in patients with pulmonary hypertension, occurring within weeks after starting ambrisentan tablets. Patients required intervention with diuretic, fluid management, or, in some cases, hospitalization for decompensating heart failure.If clinically significant fluid retention develops, with or without associated weight gain, further evaluation should be undertaken to determine the cause, such as ambrisentan tablets or underlying heart failure, and the possible need for specific treatment or discontinuation of ambrisentan tablets therapy.. 5.4 Pulmonary Edema with Pulmonary Veno-occlusive Disease (PVOD). If patients develop acute pulmonary edema during initiation of therapy with vasodilating agents such as ambrisentan tablets, the possibility of PVOD should be considered, and if confirmed ambrisentan tablets should be discontinued.. 5.5 Decreased Sperm Counts. Decreased sperm counts have been observed in human and animal studies with another endothelin receptor antagonist and in animal fertility studies with ambrisentan. Ambrisentan tablets may have an adverse effect on spermatogenesis. Counsel patients about potential effects on fertility [see Use in Specific Populations (8.6) and Nonclinical Toxicology (13.1)]. 5.6 Hematological Changes. Decreases in hemoglobin concentration and hematocrit have followed administration of other endothelin receptor antagonists and were observed in clinical studies with ambrisentan tablets. These decreases were observed within the first few weeks of treatment with ambrisentan tablets, and stabilized thereafter. The mean decrease in hemoglobin from baseline to end of treatment for those patients receiving ambrisentan tablets in the 12-week placebo-controlled studies was 0.8 g/dL.Marked decreases in hemoglobin (> 15% decrease from baseline resulting in value below the lower limit of normal) were observed in 7% of all patients receiving ambrisentan tablets (and 10% of patients receiving 10 mg) compared to 4% of patients receiving placebo. The cause of the decrease in hemoglobin is unknown, but it does not appear to result from hemorrhage or hemolysis.In the long-term open-label extension of the two pivotal clinical studies, mean decreases from baseline (ranging from 0.9 to 1.2 g/dL) in hemoglobin concentrations persisted for up to years of treatment.There have been postmarketing reports of decreases in hemoglobin concentration and hematocrit that have resulted in anemia requiring transfusion.Measure hemoglobin prior to initiation of ambrisentan tablets, at one month, and periodically thereafter. Initiation of ambrisentan tablets therapy is not recommended for patients with clinically significant anemia. If clinically significant decrease in hemoglobin is observed and other causes have been excluded, consider discontinuing ambrisentan tablets.