Drug Pipeline

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.

Inhaled insulin (Exubera, Pfizer/Sanofi-Aventis) could be an effective therapy and alternative to rosiglitazone (Avandia, GlaxoSmithKline) for individuals who are early into the course of type 2 diabetes, according to a study published in Diabetes Care.

The ACE inhibitor perindopril significantly reduced left ventricular remodeling in a well-treated population of older patients with acute myocardial infarction (MI) and preserved ejection fraction, said Roberto Ferrari, MD, PhD, lead investigator of the Perindopril Remodeling in Elderly with Acute Myocardial Infarction (PREAMI).

FEDERAL AND STATE GOVERNMENT ACTIONS AND THEIR IMPACT ON DRUG DECISION-MAKERS

The growing trend for women to wait later in life before having their first child has placed many women at a higher risk for difficult conception. There are numerous classes of medications available to assist women who have been diagnosed with infertility.Agents that are used in the treatment of infertility include: clomiphene citrate, aromatase inhibitors, gonadotropins, chorionic gonadotropins, gonadotropin-releasing hormone, gonadotropin-releasing hormone agonists, gonadotropin-releasing hormone antagonists, follitropins, and other miscellaneous agents. Medications chosen for a patient will vary depending on the identified cause of the infertility. Additionally, economic factors will play a role. It is important for healthcare professionals to be aware of treatment options and have a basic understanding of the role these medications play in the treatment of infertility. (Formulary. 2005;40:329–341.)

Ranolazine (Ranexa, CV Therapeutics) is a partial fatty acid oxidase inhibitor that increases the amount of ATP produced from glucose and increases the ability of the myocardium to retain functionality despite a reduced oxygen supply. 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 have emerged that merit an update in this 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 tachyarrhythmias-specifically Torsade de Pointes-remains an important safety finding. (Formulary. 2005;40:323–328.)

Initiating therapy with the ACE inhibitor quinapril within the first 7 days after coronary artery bypass graft (CABG) surgery does not lead to better outcomes among patients already receiving optimal therapy, said Wiek H. van Gilst, MD, lead investigator of IMAGINE (Ischemia Management with Accupril Post Bypass Graft via Inhibition of Angiotensin Converting Enzyme).

Early use of clopidogrel, started prior to rather than at the time of angioplasty, reduces the risk of death, MI, or stroke by nearly half, reported Marc S. Sabatine, MD, MPH, lead investigator of PCI-CLARITY (Clopidogrel as Adjunctive Reperfusion Therapy).

An antihypertensive regimen of amlodipine with added perindopril significantly reduces all-cause mortality and most major adverse cardiovascular outcomes compared with a regimen of atenolol with the addition of a diuretic, according to the final results of ASCOT-BPLA (Anglo-Scandinavian Cardiac Outcomes Trial Blood Pressure Lowering Arm).

The factor Xa inhibitor fondaparinux prevents death, MI, and refractory ischemia at 9 days as well as the low-molecular-weight heparin enoxaparin in patients with acute coronary syndromes (ACS), while reducing the incidence of bleeding.

A beta blocker first strategy appears to be as safe and effective as an ACE inhibitor first strategy for the treatment of older patients with heart failure, and may confer an early survival advantage.

The ACE inhibitor perindopril significantly reduced left ventricular remodeling in a well-treated population of older patients with acute myocardial infarction (MI) and preserved ejection fraction, said Roberto Ferrari, MD, PhD, lead investigator of the Perindopril Remodeling in Elderly with Acute Myocardial Infarction (PREAMI).

Clonazepam orally disintegrating tablets 0.125, 0.25, 0.5, 1, and 2 mg (equiv to Klonopin rapidly disintegrating tablets).

This non-benzodiazepine hypnotic is delivered in 2 stages through the use of a bi-layered tablet.

Infliximab, a chimeric monoclonal antibody, exerts its effect through inhibition of human tumor necrosis factor alpha (TNF alpha).

This NSAID is believed to exert its therapeutic effect through inhibition of prostaglandin synthesis, primarily via inhibition of cyclooxygenase-2 (COX-2). Celecoxib was approved on July 29, 2005, for the relief of the signs and symptoms of ankylosing spondylitis (AS).

FDA's Pulmonary-Allergy Drugs Advisory Committee voted unanimously that the long-acting beta 2-agonists salmeterol (Serevent and Advair, GlaxoSmithKline) and formoterol (Foradil, Novartis) should remain on the market despite concern over reports of asthma-related deaths associated with the use of salmeterol.

Muraglitazar (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 (HbA 1c), muraglitazar treatment is associated with a substantial reduction in triglycerides (TGs), 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. (Formulary. 2005;40:285–293.)

This study compares the cost-effectiveness of the 4 most common empiric antimicrobial regimens used for the treatment of adults with community-acquired pneumonia (CAP) at a community health system during a 6-month period. Associations between initial antimicrobials and total hospital costs were determined. Cost-effectiveness ratios were determined by dividing the total hospital costs by the percent survival. A total of 415 patients met criteria for the Pneumonia Severity Index (PSI) risk class IV or V. Costs (adjusted for inflation) were as follows (median, 25th and 75th percentile): total hospital costs ($5,078 [$3,218–$8,144]), pharmacy costs ($753 [$455–$1,357]), and antibiotic costs ($139 [$82–$229]). The most favorable cost-effectiveness ratio was observed for patients who received levofloxacin monotherapy ($4,635 per life saved), followed by ceftriaxone plus a macrolide ($5,278), ceftriaxone monotherapy ($5,368), and ceftriaxone plus levofloxacin ($6,317).

Desmopressin tablets 0.1 and 0.2 mg (equiv to DDAVP tablets).

Pioglitazone acts primarily by decreasing insulin resistance, while metformin improves glucose tolerance in patients with type 2 diabetes, lowering both basal and postprandial plasma glucose.

This NSAID is believed to exert its therapeutic effect through inhibition of prostaglandin synthesis, primarily via inhibition of cyclooxygenase-2 (COX-2). Celecoxib was approved on July 29, 2005, for the relief of the signs and symptoms of ankylosing spondylitis (AS).

Phase 3 clinical trial results have demonstrated that the dual alpha/gamma peroxisome proliferator-activated receptor (PPAR) agonist muraglitazar achieves significant beneficial lipid effects compared with pioglitazone, and the agent also provides long-term glycemic control in type 2 diabetics. The results were reported during the American Diabetes Association (ADA) 65th Annual Meeting in San Diego, Calif.

A study was conducted to evaluate the clinical and economic burden of overactive bladder (OAB) among patients <60 years of age in a managed care population, especially with regard to the prevalence of related comorbidities and associated annual medical costs.

The human monoclonal antibody adalimumab induces significant Crohn's disease remission compared with placebo, according to trial results presented during Digestive Disease Week (DDW) in Chicago, Ill. Adalimumab is approved for the treatment of rheumatoid arthritis.

Phase 3 clinical trial results have demonstrated that the dual alpha/gamma peroxisome proliferator-activated receptor (PPAR) agonist muraglitazar achieves significant beneficial lipid effects compared with pioglitazone, and the agent also provides long-term glycemic control in type 2 diabetics. The results were reported during the American Diabetes Association (ADA) 65th Annual Meeting in San Diego, Calif.

Levothyroxine, a critical medication for millions of Americans, has had a long and turbulent history. In the face of tougher FDA regulations and especially its reclassification as a "new drug" in 1997, manufacturers have struggled to carve out their niche in an expansive market. The principal concern of physicians, patients, endocrinologists, manufacturers, and FDA is levothyroxine's relative bioequivalence. Even after FDA classified several products as bioequivalent, a single brand name product still holds most of the market share, despite the fact that it is more costly. Current issues surrounding levothyroxine include: controversy about research, the number and types of recalls, the lack of a single reference-listed drug for comparison, and conflicting claims about the bioequivalence of various formulations. (Formulary. 2005;40:258–271.)

After months of delay, the Senate confirmed Lester M. Crawford, DVM, PhD, in July as the official head of FDA. Despite efforts by some Senators to hold up the vote pending resolution of some FDA policies, most legislators agreed with Republican and Democratic leaders that the agency would be better off with a permanent chief than without.

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 and was approved for these indications in June 2005. The most common adverse events associated with tigecycline's administration during clinical trials were..

Efficacy. The efficacy of ramelteon in the treatment of chronic insomnia was evaluated in 2 randomized, double-blind trials employing polysomnography (PSG).