Alvimopan for Postoperative Ileus
Alvimopan for Postoperative Ileus
The most common adverse effects of alvimopan are GI related. Nausea, vomiting, and nasogastric tube reinsertion occur more frequently with placebo than with alvimopan in patients with postoperative ileus. In 3015 patients receiving alvimopan (n = 1650) or placebo (n = 1365) in nine placebo-controlled trials, the following adverse effects occurred ≥1% more often with alvimopan than placebo: constipation (9.7% versus 7.6%), dyspepsia (5.9% versus 4.8%), flatulence (8.7% versus 7.7%), back pain (3.4% versus 2.6%), and urinary retention (3.5% versus 2.3%). Although hypokalemia was more common in the subset of bowel resection patients (n = 1985) receiving alvimopan (9.5%) compared with placebo (8.5%), hypokalemia was actually less frequent with alvimopan in the overall surgical population (6.9% versus 7.5%).
Perhaps the most concerning adverse effects of alvimopan became apparent in long-term studies. When FDA issued an approvable letter for alvimopan for the treatment of postoperative ileus, it required additional safety data and a risk management plan as a result of preliminary findings from a Phase III, blinded, placebo-controlled, 12-month safety evaluation of alvimopan 0.5 mg twice daily in patients with chronic non-cancer pain and OIBD (study 014). A 6-month interim analysis revealed an increased rate of serious cardiovascular events in the alvimopan-treated group. The affected patients were considered at high risk for developing cardiovascular complications, and the onset of the events did not appear correlated to the duration of alvimopan exposure.
The full study results were reported in a press release in early 2007. A total of 805 patients had been enrolled and randomized in a 2:1 ratio of alvimopan:placebo. A "numerical imbalance" was noted between the alvimopan (n = 538) and placebo (n = 267) groups in terms of cardiovascular events and neoplasms. Myocardial infarction occurred in 1.3% and 0% of the alvimopan and placebo groups, respectively, and all cardiovascular adverse effects occurred in 2.6% and 1.1% of the respective groups. When the data from this study were combined with those from other studies of OIBD in patients with noncancer pain (studies 011, 012, 013, 217, and 304), the rates of all cardiovascular events were 1.6% with alvimopan (n = 1728) and 1.0% with placebo (n = 790). All patients with events had established or were at high risk for developing cardiovascular disease. Most myocardial infarctions occurred within the first 12 weeks of treatment. A fourfold greater frequency of neoplasms was recorded in the alvimopan group (2.8%) versus placebo (0.7%). The rate of fracture was also greater with alvimopan (3.7% versus 1.1%). Most fractures were noted in the ribs, ankles, and feet.
Adverse Effects
The most common adverse effects of alvimopan are GI related. Nausea, vomiting, and nasogastric tube reinsertion occur more frequently with placebo than with alvimopan in patients with postoperative ileus. In 3015 patients receiving alvimopan (n = 1650) or placebo (n = 1365) in nine placebo-controlled trials, the following adverse effects occurred ≥1% more often with alvimopan than placebo: constipation (9.7% versus 7.6%), dyspepsia (5.9% versus 4.8%), flatulence (8.7% versus 7.7%), back pain (3.4% versus 2.6%), and urinary retention (3.5% versus 2.3%). Although hypokalemia was more common in the subset of bowel resection patients (n = 1985) receiving alvimopan (9.5%) compared with placebo (8.5%), hypokalemia was actually less frequent with alvimopan in the overall surgical population (6.9% versus 7.5%).
Perhaps the most concerning adverse effects of alvimopan became apparent in long-term studies. When FDA issued an approvable letter for alvimopan for the treatment of postoperative ileus, it required additional safety data and a risk management plan as a result of preliminary findings from a Phase III, blinded, placebo-controlled, 12-month safety evaluation of alvimopan 0.5 mg twice daily in patients with chronic non-cancer pain and OIBD (study 014). A 6-month interim analysis revealed an increased rate of serious cardiovascular events in the alvimopan-treated group. The affected patients were considered at high risk for developing cardiovascular complications, and the onset of the events did not appear correlated to the duration of alvimopan exposure.
The full study results were reported in a press release in early 2007. A total of 805 patients had been enrolled and randomized in a 2:1 ratio of alvimopan:placebo. A "numerical imbalance" was noted between the alvimopan (n = 538) and placebo (n = 267) groups in terms of cardiovascular events and neoplasms. Myocardial infarction occurred in 1.3% and 0% of the alvimopan and placebo groups, respectively, and all cardiovascular adverse effects occurred in 2.6% and 1.1% of the respective groups. When the data from this study were combined with those from other studies of OIBD in patients with noncancer pain (studies 011, 012, 013, 217, and 304), the rates of all cardiovascular events were 1.6% with alvimopan (n = 1728) and 1.0% with placebo (n = 790). All patients with events had established or were at high risk for developing cardiovascular disease. Most myocardial infarctions occurred within the first 12 weeks of treatment. A fourfold greater frequency of neoplasms was recorded in the alvimopan group (2.8%) versus placebo (0.7%). The rate of fracture was also greater with alvimopan (3.7% versus 1.1%). Most fractures were noted in the ribs, ankles, and feet.