OR WAIT null SECS
This article reviews the 10 newly improved or investigational agents evaluated in this year's "Focus on" column and includes an update on the regulatory status of each drug.
Many thanks to editorial advisory board members Robert A. Quercia, MS, RPh, and Craig I. Coleman, PharmD, for their invaluable assistance in coordinating and overseeing these articles throughout the year. Mr Quercia is clinical manager, Department of Pharmacy Services, Hartford Hospital, Connecticut and adjunct associate professor, University of Connecticut School of Pharmacy, Storrs. Dr Coleman is associate professor of pharmacy practice, University of Connecticut School of Pharmacy, and director, Pharmacoeconomics and Outcomes Studies Group, Hartford Hospital.
Selective relaxant binding agent for neuromuscular block reversal. Neuromuscular blocking (NMB) drugs are used to facilitate endotracheal intubation for mechanical ventilation and to provide muscle relaxation in the operating room and intensive care unit. To decrease the risk for postoperative residual paralysis, NMB is reversed at the end of surgery. Sugammadex is a novel, first-in-class, selective relaxant binding agent that encapsulates the nondepolarizing aminosteroid muscle relaxants rocuronium and vecuronium, reversing and preventing their NMB action. Sugammadex is unique compared with other NMB reversal drugs in that it can reverse a light, moderate, or deep NMB, thus eliminating the need for acetylcholinesterase inhibitors such as neostigmine and cholinergic antagonists such as glycopyrrolate or atropine. Clinical trials have demonstrated that sugammadex is effective in reversing both rocuronium-and vecuronium-induced NMB, and the agent has been well tolerated in studies. An NDA for sugammadex was submitted in October 2007. In August 2008, the manufacturer announced that FDA had issued a nonapprovable letter for sugammadex; however, clinical trials with this agent remain ongoing. (Kovac AL. Focus on sugammadex: A selective relaxant binding agent for neuromuscular block reversal. Formulary. 2009;44:13–21.)
CURRENT STATUS: The manufacturer is maintaining an ongoing dialogue with FDA about sugammadex and met with the agency in December 2008 to gain an understanding of the issues and define a clear path forward. In order to address issues primarily related to hypersensitivity/allergic reactions, the manufacturer is conducting an allergy sensitivity study in approximately 450 healthy volunteers that involves repeat exposure to sugammadex. The study was initiated in August 2009 and is expected to be completed in February 2010. The manufacturer said it cannot speculate on possible timing for submitting data from this study to FDA or when it might gain US approval of sugammadex.
Multaq/Sanofi-Aventis Antiarrhythmic agent February 2009 issue
Antiarrhythmic agent for the management of cardiovascular hospitalization in patients with paroxysmal or persistent atrial fibrillation (AF) or atrial flutter (AFL) and a recent episode of AF/AFL and associated cardiovascular risk factors who are in sinus rhythm or who will be cardioverted. Associated cardiovascular risk factors include age over 70 years, hypertension, diabetes, prior cerebrovascular accident, left atrial diameter ≥50 mm or left ventricular ejection fraction (LVEF) <40%. Dronedarone is to be given twice daily as a 400-mg tablet and should be taken as one tablet with morning and evening meals. In the ATHENA study, dronedarone, in addition to standard therapy, reduced the combined endpoint of cardiovascular hospitalization or death from any cause by 24% (P<.001) when compared with placebo in patients with AL/AFL or a recent history of these conditions, meeting the study's primary endpoint. The primary endpoint was entirely driven by the reduction of cardiovascular hospitalizations. Dronedarone is pharmacologically related to amiodarone and the compounds share multi-channel blocking properties, but with a different relative effect on ion channels. Dronedarone does not contain the iodine radical as does amiodarone. Based on the clinical data available to date, dronedarone has not been associated with the extracardiac toxicities (i.e., thyroid effects, pulmonary fibrosis) that are associated with amiodarone. Surveillance will be continued during the commercialization phase. AF is a major cause of morbidity and mortality, and affects approximately 2.5 million people in the United States. Hospitalization associated with AF has increased dramatically (2-to 3-fold) in recent years in the United States. AF increases the risk of stroke up to 5-fold, worsens the prognosis of patients with cardiovascular risk factors, and doubles the risk of mortality. Initiation of dronedarone treatment is contraindicated in patients with severe heart failure (NYHA class IV) or NYHA class II-III heart failure with a recent decompensation requiring hospitalization or referral to a specialized heart failure clinic. Most common adverse reactions are diarrhea, nausea, vomiting, abdominal pain, asthenia (weakness), and cutaneous rash. Treatment with dronedarone can be initiated in an outpatient setting. (Coleman CI, White CM, Baker WL. Focus on dronedarone: An antiarrhythmic agent for the management of atrial fibrillation and atrial flutter. Formulary. 2009;44:40–46.)
CURRENT STATUS: Dronedarone was approved by FDA on July 1, 2009; the agent was granted priority review in August 2008.
Stelara/Centocor Ortho Biotech Human monoclonal antibody March 2009 issue
Human monoclonal antibody for the treatment of adults with moderate to severe plaque psoriasis. As a chronic inflammatory skin disorder, psoriasis can be effectively treated with biologic agents, which target immune pathways. Current approved biologic agents for psoriasis include agents that inhibit tumor necrosis factor (TNF)-alpha (eg, etanercept, infliximab, adalimumab) or T-cell activation (eg, alefacept). Ustekinumab works by selectively targeting the cytokines interleukin-12 (IL-12) and interleukin-23 (IL-23), naturally occurring proteins that are believed to play a role in the development of psoriasis. Subcutaneous administration of ustekinumab at weeks 0 and 4, followed by every 12-week maintenance dosing, demonstrated significant efficacy in two pivotal phase 3 trials with larger proportions of ustekinumab-treated patients (>60%) achieving 75% reduction in Psoriasis Area and Severity Index (PASI) scores compared with placebo-treated patients. Ustekinumab-treated patients also experienced greater improvements in health-related quality of life. Ustekinumab was generally well tolerated; the most commonly reported adverse events included cough, arthralgia, injection-site reaction, and headache. (Phung OJ, White CM, Coleman CI. Focus on ustekinumab: A human monoclonal antibody for the treatment of plaque psoriasis. Formulary. 2009;44:72–76.)
CURRENT STATUS: Ustekinumab received FDA approval on September 25, 2009, and is currently available by prescription.
Cleviprex/The Medicines Company Dihydropyridine calcium-channel blocker April 2009 issue
Intravenous dihydropyridine calcium-channel blocker approved by FDA (August 2008) for the treatment of acute hypertension. Clevidipine is an intravenous (IV) dihydropyridine calcium-channel blocker (CCB) with a rapid onset of action (2-4 min) and a short duration of action (5–15 min). This agent is approved for the reduction of blood pressure (BP) when oral therapy is not feasible or not desirable. Clevidipine is effective at reducing BP in the emergency room (ER), intensive care unit (ICU), and in the pre-, peri-, and postoperative settings, with approximately 90% of treated patients achieving their systolic BP (SBP) goals regardless of treatment setting. Direct comparisons of clevidipine with nitroglycerin, sodium nitroprusside, and nicardipine in the perioperative setting have demonstrated similar mortality and cardiovascular outcomes 30 days after surgery. Clevidipine is generally well tolerated; the most commonly reported adverse events in clinical trials were headache, nausea, and vomiting. (Phung OJ, Baker WL, White CM, et al. Focus on clevidipine: An intravenous dihydropyridine calcium-channel blocker for the treatment of acute hypertension. Formulary. 2009;44:102–107.)
CURRENT STATUS: Clevidipine was approved by the FDA on August 1, 2008, for the treatment of acute hypertension.
Novo Nordisk Human GLP-1 analogue May 2009 issue
Human GLP-1 analogue for the treatment of type 2 diabetes. Liraglutide is the second glucagon-like peptide-1 (GLP-1) analogue in its class being considered for the treatment of type 2 diabetes mellitus. Liraglutide stimulates insulin secretion and inhibits glucagon secretion, both in a glucose-dependent manner, slows gastric emptying, and reduces appetite. The use of liraglutide is also associated with enhanced pancreatic beta-cell function. The addition of a C-16 fatty acid chain gives liraglutide a longer half-life than that of exenatide, allowing for once-daily dosing. Across the Liraglutide Effect and Action in Diabetes (LEAD) trials, liraglutide demonstrated significant reductions in hemoglobin A1c (HbA1c) levels compared with other antidiabetics when used as a monotherapy or in combination with other oral agents. Reductions in weight were also noted. The most common adverse events associated with liraglutide have been gastrointestinal in nature. Reports of major hypoglycemia and pancreatitis have been rare. Although C-cell tumors have been seen in rodents with liraglutide administration, the relevance for humans is likely to be low but cannot be completely excluded. Additional studies are needed to determine liraglutide's full potential therapeutic role, but current trials show promising beneficial effects for this agent's use in type 2 diabetes. (Sakauye SD, Shah SA. Focus on liraglutide: A human GLP-1 analogue for the treatment of type 2 diabetes. Formulary. 2009;44:136–142.)
CURRENT STATUS: Liraglutide is currently under FDA review for the treatment of type 2 diabetes. The manufacturer expects to hear from the FDA in the fourth quarter of this year.
ARCA Beta-blocker June 2009 issue
Beta-blocker for the treatment of heart failure. Two beta-blockers are approved for the treatment of heart failure (HF): carvedilol and metoprolol XL. Bucindolol, an investigational agent under FDA review for the treatment of HF, is a pharmacologically unique beta-blocker and mild vasodilator. The largest and most comprehensive clinical trial evaluating the effect of bucindolol on HF outcomes was the Beta-Blocker Evaluation of Survival Trial (BEST). This randomized, placebo-controlled trial was terminated early based on totality of evidence derived from BEST and other beta-blocker studies and loss of investigator equipoise. Subsequent analyses from BEST have demonstrated benefits in discrete subgroups, including a genetically identified subgroup. If approved, bucindolol may become the first genetically targeted medication for the treatment of HF. (Reinhart KM, White CM. Focus on bucindolol: A beta-blocker for the treatment of heart failure. Formulary. 2009;44:166–171.).
CURRENT STATUS: NDA submitted September 2008; Complete response letter issued May 2009.
Savella/Forest/Cypress Serotonin and norepinephrine reuptake inhibitor July 2009 issue
Serotonin and norepinephrine reuptake inhibitor for the management of fibromyalgia syndrome. Fibromyalgia syndrome (FMS) is a condition classified by widespread chronic pain and is associated with fatigue, morning stiffness, and disordered sleep. Milnacipran is a serotonin and norepinephrine reuptake inhibitor (SNRI) that was recently approved by FDA on January 14, 2009, under the brand name Savella for the management of FMS. In clinical trials, milnacipran has demonstrated efficacy in reducing FMS symptoms, with patients exhibiting response rates of 25% to 33%. Milnacipran is generally well tolerated and has minimal interactions with concomitant drug therapies. Nausea was the adverse event most frequently reported in clinical trials. In patients with FMS who are unable to tolerate first-line tricyclic antidepressant therapy, milnacipran may be a reasonable alternative or adjunct therapy. (Cios DA, Kim JE. Focus on milnacipran: A serotonin and norepinephrine reuptake inhibitor for the management of fibromyalgia syndrome. Formulary. 2009;44:197–202.)
CURRENT STATUS: Milnacipran was approved by FDA on January 14, 2009, and became commercially available on April 20, 2009.
Bayer/Ortho-McNeil Direct factor Xa inhibitor August 2009 issue
Direct factor Xa inhibitor for VTE prophylaxis in patients undergoing total knee or hip replacement surgery. Rivaroxaban is a highly potent direct factor Xa inhibitor that is awaiting FDA approval for the indication of venous thromboembolism (VTE) prophylaxis in patients undergoing total knee replacement (TKR) or total hip replacement (THR) surgery. Unlike the currently prescribed VTE prophylactic agents, which require subcutaneous (SC) administration or exhibit an undesirable drug interaction/monitoring profile, this agent offers the convenience of once-daily oral dosing, without the inconvenience of laboratory monitoring. In multiple phase 3 trials, rivaroxaban has demonstrated superior efficacy compared with enoxaparin in preventing VTE in patients undergoing THR and TKR, with comparable rates of major bleeding. The most commonly reported adverse events associated with rivaroxaban treatment include anemia, nausea, and postprocedural bleeding. Future trials will clarify the long-term safety profile of rivaroxaban including the potential risk of precipitating adverse liver or cardiovascular events. (Nunokawa N, Wong H, Song JC. Focus on rivaroxaban: A direct factor Xa inhibitor for VTE prophylaxis in patients undergoing total knee or hip replacement surgery. Formulary. 2009;44:226–236.)
CURRENT STATUS: Rivaroxaban received a complete response letter in May 2009, requesting additional information from the manufacturer, but not requiring additional studies to be completed. The manufacturer expects to respond to the letter by the end of the year.
Simponi/Centocor Ortho Biotech Human anti-TNF-alpha monoclonal antibody approved for three indications at one time September 2009 issue
Human anti-TNF-alpha monoclonal antibody approved for the treatment of autoimmune joint diseases. Golimumab is a human anti-tumor necrosis factor (TNF)-alpha monoclonal antibody that was recently approved by FDA as a once-monthly injection for the treatment of rheumatoid arthritis (RA), psoriatic arthritis (PsA), and ankylosing spondylitis (AS). In clinical trials, subcutaneous (SC) golimumab injected every 4 weeks significantly improved clinically relevant end points in all 3 disease states. In patients with RA, golimumab is approved for use in combination with methotrexate (MTX); in patients with PsA, golimumab may be used with or without MTX; and is also approved for active AS. Golimumab is available in two dosage forms, either through a novel autoinjector or a prefilled syringe. Golimumab may increase the risk for upper respiratory tract infection, lymphoma, and injection-site reaction, but the incidence of these adverse events was low in clinical trials. (Phung OJ, Coleman CI. Focus on golimumab: A human anti-TNF-alpha monoclonal antibody for the treatment of autoimmune joint diseases. Formulary. 2009;44:264–272.)
CURRENT STATUS: Golimumab received FDA approval on April 24, 2009, and is currently available by prescription.
Acorda Potassium-channel blocker October 2009 issue
Potassium-channel blocker for the improvement of walking ability in patients with MS. Fampridine-SR is a sustained-release oral medication that is pending FDA approval for the treatment of multiple sclerosis (MS). Fampridine (4-aminopyridine) is a potassium-channel blocker that has been demonstrated to improve impulse conduction in nerve fibers in which myelin has been damaged, a hallmark of MS. Although fampridine-SR is not a disease-modifying therapy, this agent does offer a novel approach to target MS symptoms, specifically walking ability and lower-extremity strength. A recent phase 3 trial in patients with various types of MS demonstrated that fampridine-SR is associated with clinically meaningful improvements in some patients regardless of concomitant therapy. If approved by FDA, fampridine-SR would be the first drug specifically indicated for the improvement of walking ability in patients with MS. (Feret B. Focus on fampridine-SR: A potassium-channel blocker for the improvement of walking ability in patients with MS. Formulary. 2009;44:293–299.)
CURRENT STATUS: Fampridine-SR is being evaluated by FDA for the improvement of walking ability in patients with MS. On October 14, 2009, the FDA Peripheral and CNS Advisory Committee voted in favor of approval, however, final approval by FDA is still pending.