A year of novel pharmacologic agents in review

In each issue, Formulary's "Focus on" article reviews a newly approved or investigational drug of interest to pharmacy and therapeutics committee members. Because so many readers have told the editors of Formulary that they reference this column frequently when making formulary decisions for their hospitals, health systems, or managed care organizations, the editors have compiled this review of all the "Focus on" articles published so far in 2005, along with updates on the status of each agent.

Many thanks to editorial advisory board members Robert A. Quercia, MS, RPh, and Craig I. Coleman, PharmD, for their valued assistance in coordinating and overseeing these articles. Mr Quercia is director of Drug Information Services at Hartford Hospital in Hartford, Conn, and an associate clinical professor, University of Connecticut School of Pharmacy, Storrs, Conn. Dr Coleman is director of the Pharmacoeconomics and Outcomes Studies Group at Hartford Hospital and an assistant professor of pharmacy practice, University of Connecticut School of Pharmacy.

POSACONAZOLESchering-PloughTriazole antifungalJanuary 2005 issueA triazole antifungal for the treatment of invasive fungal infections. Serious fungal infections have emerged as a prominent cause of infectious morbidity and mortality globally. Posaconazole, a novel broad-spectrum triazole antifungal, is undergoing FDA review for the treatment of invasive fungal infections. Posaconazole possesses potent in vitro and in vivo activity against Candida species, Aspergillus species, and other rare and emerging fungal pathogens, including Zygomycetes. In clinical trials, posaconazole demonstrated efficacy in immunocompromised patients with invasive infections caused by these fungi that were refractory to standard therapies. If approved, posaconazole will be available as an oral suspension, which, when taken with food, has demonstrated excellent bioavailability. Additionally, posaconazole appears to be safe and well-tolerated over prolonged durations of treatment and has a promising drug interaction profile compared with other available azoles. If approved, the eventual cost and further clinical experience with this antifungal will ultimately determine its utility in the treatment of invasive fungal infections. (Sircar-Ramsewak F, Kuti JL, Nicolau DP. Focus on posaconazole: A novel triazole antifungal for the treatment of invasive fungal infections. Formulary. 2005;40:13–21.)

CILANSETRONCalmactin, Solvay Pharmaceuticals5HT₃ receptor antagonistFebruary 2005 issue

A 5-HT₃ receptor antagonist for the treatment of irritable bowel syndrome. If approved, cilansetron (Calmactin, Solvay Pharmaceuticals) would be the second selective 5-HT₃ antagonist introduced for the treatment of irritable bowel syndrome (IBS). Based on 2 main clinical trials, cilansetron 2 mg orally 3 times daily appears to be effective in the relief of IBS-D symptoms (abdominal pain/discomfort) and abnormal bowel habits in both male and female patients. Adverse effects were minor, with constipation being the most commonly reported adverse effect. No information is currently available on cilansetron's potential for drug interactions, need for dose adjustments in renal or hepatic insufficiency, long-term safety, or cost. Cilansetron was granted priority review status by FDA on September 1, 2004, for the treatment of diarrhea-predominant IBS in men and women. Currently marketed agents for the treatment of IBS are only approved for use in female patients. (Zimmermann AE. Focus on cilansetron: A novel 5-HT3 receptor antagonist for the treatment of irritable bowel syndrome. Formulary. 2005;40:44–48.)

CURRENT STATUS: In April 2005, a non-approvable letter was issued by FDA for cilansetron.

EXENATIDEByetta, Amylin/LillyIncretin mimeticMarch 2005 issueAn incretin mimetic hormone for the treatment of type 2 diabetes. A number of clinical approaches are utilized in managing the overlapping aspects of poor glycemic control in patients with type 2 diabetes. Exenatide (Byetta, Amylin/Lilly), a novel drug in a new medication class known as the incretin mimetic agents, offers a new mechanism to achieve glycemic control. Through stimulation of the glucagon-like peptide receptor, exenatide stimulates the body's ability to produce insulin in response to elevated concentrations of blood glucose, inhibits the release of glucagon following meals, slows the rate of gastric emptying and secondarily the rate of nutrient absorption into the bloodstream, and reduces food intake. Clinical studies have demonstrated improved glycemic control with exenatide therapy in patients who are not using insulin and are not achieving target glucose levels with diet and oral medications. An NDA for exenatide was submitted to FDA in June 2004. (Gryskiewicz KA, Coleman CI. Focus on exenatide: A novel incretin mimetic hormone for the treatment of type 2 diabetes. Formulary. 2005;40:86–90.)

CURRENT STATUS: Exenatide was approved on April 28, 2005.

TIPRANAVIRAptivus, Pfizer/Boehringer IngelheimProtease inhibitor April 2005 issueA nonpeptidic protease inhibitor for the treatment of HIV infection. If approved, tipranavir (Boehringer Ingelheim) will be the ninth protease inhibitor (PI) available and the first nonpeptidic PI available in the United States. Designed by structure-based analysis, tipranavir is more flexible at the binding site, allowing for a potent and durable antiretroviral response. The tipranavir (TPV) and ritonavir (RTV) PI regimen (TPV/r) studied in clinical trials had a moderate pill burden, requiring 4 pills to be taken twice daily (2 RTV 100 mg and 2 TPV 250 mg). In phase 3 clinical studies, TPV/r provided enhanced immunologic and virologic responses versus comparator PI and ritonavir regimens. Resistance to tipranavir was uncommon, even among PI-resistant isolates. Decreased virologic response to TPV/r has been infrequent and has usually been observed when greater than 2 primary PI mutations were present. Further, treatment with tipranavir did not appear to alter viral resistance to other PIs. The adverse effects associated with tipranavir appear similar to those of other PIs, including nausea, vomiting, and diarrhea, as well as hepatic and metabolic laboratory abnormalities. (Ellis JM, Ross JW. Focus on tipranavir: A novel nonpeptidic protease inhibitor. Formulary. 2005;40:104–113.)

CURRENT STATUS: Tipranavir was granted accelerated approval by FDA on June 22, 2005.

RAMELTEONRozerem, Takeda PharmaceuticalsMelatonin receptor agonistMay 2005 issueA melatonin receptor agonist for the treatment of insomnia. Ramelteon (Takeda Pharmaceuticals) is a selective melatonin receptor agonist awaiting FDA approval for the treatment of insomnia. Unlike the currently prescribed hypnotic agents that work by targeting gamma-aminobutyric acid (GABA) receptors, ramelteon offers a novel mechanism of action, specifically targeting the MT₁ and MT₂ receptors in the brain, which are thought to play a role in regulating sedation and circadian rhythms. Ramelteon is characterized by undergoing extensive first-pass metabolism along with having high oral bioavailability. Results of phase 2 clinical trials have demonstrated that ramelteon-treated patients had significantly shorter sleep onset latencies and longer total sleep times than placebo-treated patients. Furthermore, ramelteon therapy did not appear to impair patient cognition, memory recall, levels of alertness, or ability to concentrate. Data from animal studies suggest that ramelteon is not likely to cause abuse or physical dependence. Unlike the current FDA-approved hypnosedatives, ramelteon has been evaluated in trials for periods of up to 1 year. The most commonly reported adverse effects include somnolence, headache, fatigue, nausea, and dizziness. (Nguyen NN, Yu SS, Song JC. Focus on ramelteon: A novel melatonin receptor agonist for the treatment of insomnia. Formulary. 2005;40:146–155.)

CURRENT STATUS: Ramelteon was approved on July 22, 2005.

ALVIMOPANEntereg, Adolor/GlaxoSmithKlineOpioid mu receptor antagonistJune 2005 issueAn M₃-selective muscarinic antagonist for the treatment of overactive bladder. Post-operative ileus causes significant patient morbidity and is a major contributor to patient discomfort and increased length of hospitalization post-operatively. Alvimopan (Entereg, Adolor/GlaxoSmithKline), a peripherally selective opioid mu receptor antagonist with gastrointestinal (GI) tract-specific activity, is undergoing FDA review for the treatment of post-operative ileus. There are currently no other drugs marketed for this indication. In clinical trials, alvimopan was effective in decreasing the time to return of normal GI function after major abdominal surgery without antagonizing the analgesic effect of a systemically administered opioid. Alvimopan appears to be safe and well-tolerated when administered for a short duration of therapy up to 7 days after surgery. To date, the only significant interaction documented with alvimopan is the precipitation of local GI adverse effects in chronic opioid users, possibly indicating a localized opioid withdrawal. Alvimopan is administered orally at least 2 hours before a surgical procedure and twice daily starting on Day 1 post-surgery. Further clinical experience will dictate the full utility of alvimopan in the management of post-operative ileus and other dysmotility conditions of the GI tract. (Udeh E, Goldman M. Focus on alvimopan: A peripherally selective opioid mu receptor antagonist Formulary. 2005;40:176–183.)

CURRENT STATUS: FDA issued an approvable letter for alvimopan on July 22, 2005.

DAPOXETINEAlza/Ortho-McNeilSerotonin reuptake inhibitorJuly 2005 issueA fast-acting serotonin reuptake inhibitor. Dapoxetine (Alza/Ortho-McNeil) is a novel oral medication undergoing FDA review for premature ejaculation, one of the most common disorders of sexual dysfunction in men. Dapoxetine is a fast-acting inhibitor of the serotonin reuptake transporter. It has a short half-life and is structurally related to the antidepressant fluoxetine, allowing for on-demand dosing. Recent phase 3 clinical trials in patients with premature ejaculation have shown dapoxetine to be effective in improving the time to ejaculation without any major adverse events, except nausea. If approved, dapoxetine would be the first drug specifically indicated for premature ejaculation, and it may offer patients a safer and more tolerable alternative compared to traditional selective serotonin reuptake inhibitors (SSRIs), which are currently used off-label to treat this condition.?(Feret B. Focus on dapoxetine: A novel, fast-acting serotonin reuptake inhibitor. Formulary. 2005;40:227–230.)

CURRENT STATUS: FDA issued a non-approvable letter for dapoxetine in October 2005. At press time, the manufacturer had stated that it planned to address concerns raised by FDA.

TIGECYCLINETygacil, WyethGlycylcycline antibioticAugust 2005 issueA glycylcycline antibiotic. Highly resistant strains of both gram-positive and gram-negative bacteria are becoming commonplace in both the inpatient and outpatient setting. Recently developed antimicrobials have targeted resistant gram-positive pathogens, but the problem of resistant gram-negative pathogens remains. Tigecycline (Tygacil, Wyeth) is an injectable antimicrobial and the first in a new class of agents (the glycylcyclines) that possesses activity against key gram-positive and gram-negative bacterial pathogens. Tigecycline overcomes common tetracycline resistance mechanisms and has shown in vitro and in vivo activity against multidrug-resistant organisms. Tigecycline treatment produced clinical and microbiologic outcomes similar to standard comparator agents in patients with complicated skin and skin structure infections and complicated intra-abdominal infections. The most common adverse events associated with tigecycline's administration during clinical trials were gastrointestinal in nature. Tigecycline appears to be a promising alternative agent for the management of infections in which resistant pathogens are suspected or documented. (Smith KL, McCabe SM, Aeschlimann JR. Focus on tigecycline: A novel glycylcycline antibiotic. Formulary. 2005;40:245–254.)

CURRENT STATUS: Tigecycline was approved on June 15, 2005.

MURAGLITAZARPargluva, Bristol-Myers Squibb/MerckPeroxisome proliferator-activated receptor agonist September 2005 issueA dual peroxisome proliferator-activated receptor agonist. Muraglitazar (Pargluva, Bristol-Myers Squibb/Merck) is a new agent under investigation for the treatment of patients with type 2 diabetes. It belongs to a novel class of drugs that target the peroxisome proliferator-activated receptors, both alpha and gamma subtypes. Available clinical data describe improvements in glycemic parameters similar to available thiazolidinediones. In addition to improvements in blood glucose and hemoglobin A_1c (HbA_1c), muraglitazar treatment is associated with a substantial reduction in triglycerides, an increase in HDL-C, and a modest decrease in LDL-C levels. Safety data are limited, but in available abstracts, there are reports of moderately elevated rates of edema, weight gain, and hypoglycemia with muraglitazar compared with placebo or pioglitazone. When used in combination with metformin or glyburide, chronic heart failure events have been reported with muraglitazar. If approved, muraglitazar will provide a convenient alternative for the treatment of type 2 diabetes. (Kirwin J, Van Amburgh J. Focus on muraglitazar: A dual peroxisome proliferator-activated receptor agonist. Formulary. 2005;40:285–293.)

CURRENT STATUS: FDA's Endocrinologic and Metabolic Drugs Advisory Committee voted to recommend approval of muraglitazar in September 2005. FDA issued an approvable letter for the drug on October 18, 2005, requesting more data on the drug's cardiovascular safety profile. At press time, the drug's developers were considering their next course of action.

RANOLAZINERanexa, CV TherapeuticsAntianginal agentOctober 2005 issueAn update on the novel antianginal agent. Ranolazine's (Ranexa, CV Therapeutics) anti-ischemic activity is thought to be due to selectively inhibiting the aberrant increases in late Na+ current and the resulting intracellular calcium overload seen during myocardial ischemia (more information regarding the proposed mechanism of action can be found in the Letter to the Editor). Ranolazine is under FDA review for the treatment of chronic stable angina (CSA). Ranolazine was first reviewed in the August 2003 issue of Formulary. Since the initial review of ranolazine by FDA, additional data emerged that merited an updated review article in the journal. Clinical trials have demonstrated the efficacy of ranolazine as both monotherapy and combination therapy in patients with CSA. Recently published clinical trials (MARISA and CARISA) have shown an improvement in symptom-limited exercise duration. The results of the ERICA trial demonstrated a reduction in weekly anginal attacks when ranolazine was added to maximum-dose amlodipine therapy. Headache and generalized weakness were the most commonly reported adverse events in clinical trials. Prolongation of the QT interval has raised concerns; however, a lack of development of ventricular tachy-arrhythmias-specifically Torsade de Pointes-remains an important safety finding. (McBride BF, White CM. Focus on ranolazine: A novel metabolic modulator for the treatment of chronic stable angina. Formulary. 2003;38: 461–476.) (Henyan NN, White CM. Focus on ranolazine: An update on the novel antianginal agent. Formulary. 2005; 40:323–328.) (Sweeney M. Letter to the editor. Formulary. 2005;40:386.)

CURRENT STATUS: In 2003, FDA issued an approvable letter for ranolazine, citing the need for further clinical data. Since then, three additional phase 3 trials have been completed. At press time, the approval of ranolazine was still under consideration by FDA, pending the review of the additional clinical data.

ATRASENTANXinlay, AbbottEndothelin-A receptor antagonistNovember 2005A selective endothelin-A receptor antagonist. Accumulating data have demonstrated that the endothelin axis plays a role in the progression of many malignancies. Endothelin-1, which is produced by prostate cancer cells, can stimulate new bone formation. It can also act synergistically with a number of growth factors promoting cancer cells growth and proliferation. Over-expression of endothelin-1 and diminished capacity for its clearance have been seen in prostate cancer cell lines. The highest concentration of endothelin-1 is found in patients with hormone refractory metastatic disease. Atrasentan (Xinlay, Abbott) is a member of a new class of drugs called the selective endothelin-A receptor antagonists (SERAs). The safety and efficacy of atrasentan in hormone refractory prostate cancer (HRPC) have been evaluated in several clinical trials. Atrasentan demonstrated some efficacy in delaying the progression of disease and improving patients' quality of life while having an acceptable safety profile. An NDA for atrasentan was submitted in December 2004 for the treatment of patients with HRPC metastatic to bone. A response from FDA is anticipated later this year. (Abdelghany O. Focus on atrasentan: A novel selective endothelin-A receptor antagonist. Formulary. 2005;40: 376–381.)

CURRENT STATUS: An NDA was filed for atrasentan in February 2005. The drug was still undergoing FDA review at press time.