Pharmaceutical Approval Update: Ambrisentan (Letairis)
Indications: Ambrisentan is an endothelin receptor antagonist indicated for the treatment of pulmonary arterial hypertension (PAH) (World Health Organization Group 1) in patients with WHO class II or III symptoms to improve exercise capacity and delay clinical worsening. PAH is a rare, life-threatening condition characterized by continuous high blood pressure within the arteries of the lungs.
Drug Class: Ambrisentan, an endothelin receptor antagonist, is selective for the endothelin type-A (ETA) receptor. The chemical name is (+)-(2S)-2-[(4,6-dimethylpyrimidin-2-yl)oxyj-3-methoxy-3,3-diphenylpropanoic acid.
Uniqueness of Drug: Endothelin-1 (ET-1) is a potent auto-crine 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 vaso-constriction and cell proliferation, whereas 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 they correlate with increased mean right atrial pressure and disease severity. ET-1 and ET-1 messenger RNA concentrations are increased as much as nine-fold in the lung tissue of patients with PAH, primarily in the endothelium of pulmonary arteries. These findings suggest that ET-1 may play a critical role in the pathogenesis and progression of PAH.
Ambrisentan is a high-affinity (Ki = 0.011 nM) ETA receptor antagonist with a high selectivity for the ETA versus ETB receptor (more than 4,000-fold). The clinical impact of high selectivity for ETA is not known.
Potential liver toxicity: Ambrisentan can cause elevation of liver alanine and aspartate aminotransferases (ALT and AST) to at least three times the upper limit of normal (ULN). Ambrisentan treatment was associated with aminotransferase elevations above three times the ULN in 0.8% of patients in 12-week trials and in 2.8% of patients, including long-term open-label trials, out to one year.
One case of aminotransferase elevations above three times the ULN has been accompanied by bilirubin elevations greater than twice the ULN. Because these changes are a marker for potentially serious liver injury, serum aminotransferase levels—and bilirubin if aminotransferase levels are elevated— must be measured prior to the initiation of treatment and then monthly. kamagra tablets
In the postmarketing period, in studies of another endothelin receptor antagonist, bosentan (Tracleer, Actelion), rare cases of unexplained hepatic cirrhosis were reported after prolonged therapy of more than12 months. In at least one case with bosentan, a late presentation (after more than 20 months of treatment) included pronounced elevations in aminotrans-ferases and bilirubin levels accompanied by nonspecific symptoms, all of which resolved slowly over time after discontinuation of the suspect drug. This case reinforces the importance of strict adherence to the monthly monitoring schedule for the duration of treatment.
Patients with elevations in aminotransferases require close attention. Ambrisentan should generally be avoided in patients with elevated aminotransferases (greater than three times the ULN) at baseline, because monitoring liver injury may be more difficult. If liver aminotransferase elevations are accompanied by clinical symptoms of liver injury (such as nausea, vomiting, fever, abdominal pain, jaundice, or unusual lethargy or fatigue) or increases in bilirubin greater than twice the ULN, treatment should be stopped. There is no experience with the re-introduction of ambrisentan in these circumstances.
Pregnancy: Because ambrisentan consistently produced serious birth defects in animals, it is like to have a similar effect in pregnant women. Pregnancy must be excluded before ambrisentan is started. Thereafter, patients should avoid pregnancy by using at least two reliable methods of contraception. If a tubal sterilization has been performed or an intrauterine device (IUD), such as the Copper T 380A IUD or the levo-norgestrel (LNg-20) has been inserted, no other contraception is needed. Pregnancy tests should be performed monthly.
Because of the risks of liver injury and birth defects, ambrisentan is available only through a restricted distribution program called the Letairis Education and Access Program (LEAP) (phone number: 1-866-664-LEAP). Only health care professionals and pharmacies registered with LEAP may prescribe and distribute ambrisentan. This medication may be dispensed only to patients who are enrolled in and who meet all conditions of LEAP. Warnings and Precautions:
Potential liver injury:Treatment with endothelin receptor antagonists has been associated with dose-dependent liver injury manifested primarily by elevated serum aminotrans-ferase (ALT or AST) levels, but is sometimes accompanied by abnormal liver function (elevated bilirubin). The combination of aminotransferase levels above three times the ULN and total bilirubin levels greater than twice the ULN are markers for potentially serious hepatic injury.
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In all clinical studies with ambrisentan, liver function tests were closely monitored. For all ambrisentan-treated patients (N = 483), the 12-week incidence of aminotransferase levels that were above three times the ULN was 0.8%; the incidence of levels above eight times the ULN was 0.2%.
For placebo-treated patients, the 12-week incidence of aminotransferase levels that were more than three times the ULN was 2.3%; the incidence of levels above eight times the
ULN was 0.0%.
The one-year rate of aminotransferase elevations that were above three times the ULN with ambrisentan was 2.8%; the rate above eight times the ULN was 0.5%.
One case of aminotransferase elevations above three times the ULN was accompanied by bilirubin elevations greater than two times the ULN.
Liver chemistry values must be measured before ambri-sentan therapy is initiated and at least every month thereafter. If aminotransferase levels are elevated between three and five times the ULN, they should be measured again.
If the confirmed level of aminotransferase is between three and five times the ULN, the daily dose should be reduced or interrupted. These levels should continue to be monitored every two weeks until they are below three times the ULN.
If aminotransferase elevations are between five and eight times the ULN, ambrisentan should be discontinued and monitoring should be performed until levels are below three times the ULN. Ambrisentan can then be reinitiated, and amino-transferase levels should be monitored more frequently. kamagra soft tabs
If aminotransferase elevations are more than eight times the ULN, treatment should be stopped and should not be introduced again.
Ambrisentan is not recommended in patients with elevated aminotransferase levels (above three times the ULN) at baseline, because monitoring liver injury may be more difficult. If aminotransferase elevations are accompanied by clinical symptoms of liver injury (anorexia, nausea, vomiting, fever, malaise, fatigue, right upper quadrant abdominal discomfort, itching, or jaundice) or if increases in bilirubin exceed twice the ULN, ambrisentan treatment should be stopped. Reintroducing ambrisentan therapy has not been studied in these circumstances.
Hematological changes: Decreased hemoglobin concentrations and hematocrit have occurred following the administration of other endothelin receptor antagonists, and these changes have been observed with ambrisentan. These decreases were apparent within the first few weeks of am-brisentan treatment, but they stabilized after that. The mean decrease in hemoglobin from the baseline to the end of treatment for patients receiving ambrisentan in the 12-week placebo-controlled studies was 0.8 g/dL. Marked decreases in hemoglobin (more than 15% decrease from baseline, resulting in a value below the lower limit of normal) were observed in 7% of all patients receiving ambrisentan (and in 10% of patients receiving 10 mg), compared with 4% of patients receiving placebo. kamagra oral jelly uk
The cause of the decrease in hemoglobin is unknown, but it does not appear to result from hemorrhage or hemolysis. Hemoglobin levels must be measured before ambrisentan therapy begins, and they should be measured at one month and periodically thereafter. If a clinically significant decrease in hemoglobin occurs and if other causes have been excluded, discontinuation of treatment should be considered.