AMBRISENTAN
Generic: AMBRISENTAN
Basic Information
Manufacturer
Sigmapharm Laboratories, LLC
Product Type
HUMAN PRESCRIPTION DRUG
Route of Administration
ORAL
FDA Set ID
e20ab2fe-bc9f-48a3-b15a-e4bc9532c2ac
Indications & Usage
1 INDICATIONS AND USAGE Ambrisentan tablets are indicated for the treatment of pulmonary arterial hypertension (PAH) (WHO Group 1): To improve exercise ability and delay clinical worsening.
In combination with tadalafil to reduce the risks of disease progression and hospitalization for worsening PAH, and to improve exercise ability [ see Clinical Studies (14.2) ].
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%).
Ambrisentan is an endothelin receptor antagonist indicated for the treatment of pulmonary arterial hypertension (PAH) (WHO Group 1): To improve exercise ability and delay clinical worsening.
In combination with tadalafil to reduce the risks of disease progression and hospitalization for worsening PAH, and to improve exercise ability.
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 ).
In combination with tadalafil to reduce the risks of disease progression and hospitalization for worsening PAH, and to improve exercise ability [ see Clinical Studies (14.2) ].
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%).
Ambrisentan is an endothelin receptor antagonist indicated for the treatment of pulmonary arterial hypertension (PAH) (WHO Group 1): To improve exercise ability and delay clinical worsening.
In combination with tadalafil to reduce the risks of disease progression and hospitalization for worsening PAH, and to improve exercise ability.
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 ).
Adverse Reactions
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.
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.