WARNING: EMBRYO-FETAL TOXICITY Do not administer ambrisentan to a pregnant female because it may cause fetal harm. Ambrisentan is very likely to produce serious birth defects if used by pregnant females, as this effect has been seen consistently when it is 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. Females of reproductive potential must use acceptable methods of contraception during treatment with ambrisentan and for one month after treatment. Obtain monthly pregnancy tests during treatment and 1 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, females can only receive ambrisentan through a restricted program called the Ambrisentan REMS program [see Warnings and Precautions (5.2) ] . WARNING: EMBRYO-FETAL TOXICITY See full prescribing information for complete boxed warning. Do not administer ambrisentan to a pregnant female because it may cause fetal harm ( 4.1 , 5.1 , 8.1 ). Females of reproductive potential: Exclude pregnancy before the start of treatment, monthly during treatment, and 1 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 ). For all female patients, ambrisentan is available only through a restricted program called the Ambrisentan Risk Evaluation and Mitigation Strategy (REMS) ( 5.2 ).
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warnings and cautions
5 WARNINGS AND PRECAUTIONS Fluid retention may require intervention ( 5.3 ). If patients develop acute pulmonary edema during initiation of therapy with ambrisentan, consider underlying pulmonary veno-occlusive disease and discontinue treatment if necessary ( 5.4 ). Decreases in sperm count have been observed in patients taking endothelin receptor antagonists ( 5.5 ). Decreases in hemoglobin have been observed within the first few weeks; measure hemoglobin at initiation, at 1 month, and periodically thereafter ( 5.6 ). 5.1. Embryo-fetal Toxicity Ambrisentan may cause fetal harm when administered during pregnancy and is 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 is only available for females through a restricted program under a REMS [see Warnings and Precautions (5.2) ] . 5.2. Ambrisentan REMS Program For all females, ambrisentan is available only through a restricted program 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) ] . Notable requirements of the Ambrisentan REMS program include the following: Prescribers must be certified with the program by enrolling and completing training. All females, regardless of reproductive potential, must enroll in the Ambrisentan REMS program prior to initiating ambrisentan. Male patients are not enrolled in the REMS. Females of reproductive potential must comply with the pregnancy testing and contraception requirements [see Use in Specific Populations (8.3) ]. Pharmacies that dispense ambrisentan must be certified with the program and must dispense to female patients who are authorized to receive ambrisentan. Further information is available at www.ambrisentanrems.us.com or 1-888-417-3172. 5.3. Fluid Retention Peripheral edema is a known class effect of endothelin receptor antagonists, and is also a 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 5 or 10 mg ambrisentan 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. Patients required intervention with a 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 or underlying heart failure, and the possible need for specific treatment or discontinuation of ambrisentan therapy. Peripheral edema/fluid retention is more common with ambrisentan plus tadalafil than with ambrisentan or tadalafil alone. 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, the possibility of PVOD should be considered, and if confirmed ambrisentan 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 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. These decreases were observed within the first few weeks of treatment with ambrisentan, and stabilized thereafter. The mean decrease in hemoglobin from baseline to end of treatment for those patients receiving ambrisentan in the 12-week placebo-controlled studies was 0.8 g/dL. Marked decreases in hemoglobin (>15% decrease from baseline resulting in a value below the lower limit of normal) were observed in 7% of all patients receiving ambrisentan (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 4 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, at one month, and periodically thereafter. Initiation of ambrisentan therapy is not recommended for patients with clinically significant anemia. If a clinically significant decrease in hemoglobin is observed and other causes have been excluded, consider discontinuing ambrisentan.
6 ADVERSE REACTIONS 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 (5.3) ] Pulmonary Edema with PVOD [see Warnings and Precautions (5.4) ] Decreased Sperm Count [see Warnings and Precautions (5.5) ] Hematologic Changes [see Warnings and Precautions (5.6) ] Most common adverse reactions (>3% compared to placebo) are peripheral edema, nasal congestion, sinusitis, and flushing ( 6.1 ). When used in combination with tadalafil, most common adverse reactions (>5% compared with either Monotherapy) are peripheral edema, headache, nasal congestion, cough, anemia, dyspepsia, and bronchitis ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Sigmapharm Laboratories, LLC, Pharmacovigilance at 1-855-332-0731 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1. Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Safety data for ambrisentan are presented from two 12-week, placebo-controlled studies (ARIES-1 and ARIES-2) in patients with pulmonary arterial hypertension (PAH), and one randomized, double-blind, active-controlled trial in 605 patients with PAH (AMBITION) comparing ambrisentan plus tadalafil to ambrisentan or tadalafil alone. The exposure to ambrisentan in these studies ranged from 1 day to 4 years (N=357 for at least 6 months and N=279 for at least 1 year). In ARIES-1 and ARIES-2, a total of 261 patients received ambrisentan 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 than receiving placebo are shown in Table 1. Table 1 Adverse Reactions with Placebo-Adjusted Rates >3% in ARIES-1 and ARIES-2 Placebo (N = 132) Ambrisentan (N = 261) Adverse Reaction n (%) n (%) Placebo-adjusted (%) Peripheral edema 14 (11) 45 (17) 6 Nasal congestion 2 (2) 15 (6) 4 Sinusitis 0 (0) 8 (3) 3 Flushing 1 (1) 10 (4) 3 Most 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 (14%; 29/205) or placebo (13%; 13/104), and was greater in elderly patients (≥65 years) receiving ambrisentan (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 (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 (5%; 13/261 patients). During 12-week controlled clinical trials, the incidence of aminotransferase elevations >3 x upper limit of normal (ULN) were 0% on ambrisentan and 2.3% on placebo. In practice, cases of hepatic injury should be carefully evaluated for cause. Combination Use with Tadalafil The mean exposure to ambrisentan + tadalafil in the AMBITION study was 78.7 weeks. The adverse reactions that occurred in >5% more patients receiving ambrisentan + tadalafil than receiving ambrisentan or tadalafil monotherapy in AMBITION are shown in Table 2. Table 2 Adverse Reactions Reported More Commonly (>5%) on Ambrisentan + Tadalafil than on Ambrisentan or Tadalafil Monotherapy (ITT) in AMBITION Adverse Reactions Ambrisentan + Tadalafil Combination Therapy (N=302) n (%) Ambrisentan Monotherapy (N=152) n (%) Tadalafil Monotherapy (N=151) n (%) Peripheral edema 135 (45%) 58 (38%) 43 (28%) Headache 125 (41%) 51 (34%) 53 (35%) Nasal congestion 58 (19%) 25 (16%) 17 (11%) Cough 53 (18%) 20 (13%) 24 (16%) Anemia 44 (15%) 11 (7%) 17 (11%) Dyspepsia 32 (11%) 5 (3%) 18 (12%) Bronchitis 31 (10%) 6 (4%) 13 (9%) Peripheral edema was more frequent on combination therapy; however, there was no notable difference observed in the incidence of peripheral edema in elderly patients (≥65 years) versus younger patients (<65 years) on combination therapy (44% vs. 45%) or ambrisentan monotherapy (37% vs. 39%) in AMBITION. Treatment discontinuations due to adverse events while on randomized treatment were similar across treatment groups: 16% for ambrisentan + tadalafil, 14% for ambrisentan alone, and 13% for tadalafil alone. 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 x ULN were treated with ambrisentan. Prior elevations were predominantly moderate, with 64% of the ALT elevations <5 x ULN, but 9 patients had elevations >8 x ULN. Eight patients had been re-challenged with bosentan and/or the investigational ERA and all eight had a 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 5 (PDE5) inhibitor therapy. Two patients discontinued early (including one of the patients with a prior 8 x ULN elevation). Of the remaining 34 patients, one patient experienced a mild aminotransferase elevation at 12 weeks on ambrisentan 5 mg that resolved with decreasing the dosage to 2.5 mg, and that did not recur with later escalations to 10 mg. With a median follow-up of 13 months and with 50% of patients increasing the dose of ambrisentan 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 led to fewer aminotransferase elevations than would have been seen with those drugs, the study indicates that ambrisentan 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. Because these reactions were reported voluntarily from a population of uncertain size, it is not possible to estimate reliably the frequency or to establish a 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 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) ] . To report SUSPECTED ADVERSE REACTIONS , contact Sigmapharm Laboratories, LLC, Pharmacovigilance at 1-855-332-0731 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.