Drug Pipeline

Researchers conducted a study to determine if self-reported sleep deprivation is associated with an increased risk of coronary events.

In each issue, the 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 in 2004, along with updates on the status of each agent.

As initiatives to legalize the importation of prescription drugs draw more attention, the concern over counterfeit drugs is growing. The possibility of receiving counterfeit drugs has created an emerging dilemma for health-care professionals. FDA is relying on pharmacists to help ensure the integrity of drug products before they reach health-care consumers. Pharmacy and therapeutics committees can play a key role in achieving this goal by reviewing policies for medication acquisition and ensuring that necessary controls are in place to help prevent the acquisition of counterfeit drugs. FDA is also taking steps to help alleviate counterfeiting by mandating bar codes on all hospital drug packaging and implementing electronic pedigree papers to track distribution. FDA leaders project that by 2007, all prescription drugs will be tracked electronically to help ensure their authenticity. Formulary decision-makers, pharmacy directors, and clinicians must continue to be educated about the problem to help prevent counterfeit drugs from polluting the drug supply.

Government, industry provide pharmaceutical policy outlook for 2005; $139 million to advance information technology, records; Rofecoxib hearings point to failures in clinical testing design, decision-making transparency; New guidance for generic drugs clarifies protocol, increases speed to market

Worldwide study finds that fluoroquinolones are still effective against CAP; Weekly nesiritide may have greatest benefit in highest-risk heart failure patients

Valdecoxib meta-analysis finds increased cardiovascular risk

Agencies encourage development of more affordable treatments and take steps to ensure safer product use

Chronic obstructive pulmonary disease (COPD) is a disease state characterized by the progressive development of airflow limitation that is not fully reversible. The airflow limitation is associated with an abnormal inflammatory response of the lungs to noxious particles or gases. It affects approximately 15 million Americans and is associated with high morbidity and mortality. Previously, pharmacologic therapeutic options were limited by relatively short durations of action in the first-line medications and limited efficacy data and/or a high rate of adverse effects in the second-line medications. Today, there are several new and emerging medications to treat this disease state, and new guidelines have been published for disease management. This review examines current therapeutic options, compares efficacy data, and highlights the recommendations from international guidelines.

Nebivolol is a beta-blocker under FDA review for the treatment of hypertension. Nebivolol has unique pharmacologic properties, including high specificity for the beta-1 receptor and a nitric oxide-mediated vasodilatory effect. The agent provides significant blood pressure reduction from baseline values and as compared to placebo. Clinical trials have demonstrated that nebivolol reduces blood pressure similarly to atenolol, bisoprolol, amlodipine, nifedipine, lisinopril, and hydrochlorothiazide. The tolerability of nebivolol is similar to or better than that of these agents. If approved, nebivolol would likely be a viable alternative therapy for hypertension; however, additional studies are needed in patients with heart failure and coronary artery disease.

Suit alleges FDA overstepped jurisdiction in regulating compounding pharmacies; Report lists steps to improve product quality regulatory system; ASHP, AMCP recommend criteria for Medicare formulary design, formulary decision-maker responsibilities; Illinois, Wisconsin specify safeguards, provisions in state-sponsored WWW prescription drug pharmacy

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There has been a nationwide increase in the incidence of vancomycin-resistant Enterococcus (VRE) reported over the last decade and a half. The heightened concern caused by VRE and the possibility of vancomycin resistance gene transfer to other gram positive organisms, especially methicillin-resistant Staphylococcus aureus (MRSA), led the Centers for Disease Control and Prevention (CDC) and the Hospital Infection Control Practices Advisory Committee (HICPAC) to publish recommendations for the prevention and control of vancomycin resistance. However, in 2002, the first documented case of vancomycin-resistant S aureus (VRSA) was reported in Michigan in an immunocompromised patient with a history of diabetes, peripheral vascular disease, and renal failure. Since then, 2 other cases have been reported: 1 in Pennsylvania in October 2002 and 1 in New York in March 2004. The limited availability of effective antimicrobial agents against vancomycin-resistant strains of Enterococcus and Staphylococcus species and the morbidity, mortality, and cost associated with resistance represent serious reasons for concern. This article presents a general overview of the current literature on the prevention and control of vancomycin resistance and a review of potential antimicrobial agents used in the treatment of VRE, vancomycin intermediate S aureus (VISA), and VRSA infections.

Rofecoxib voluntarily withdrawn from market due to cardiovascular risk

Secondary hyperparathyroidism is a common sequelae of chronic kidney disease. Treatment of this condition with traditional agents such as phosphate binders and vitamin D analogs is often complicated by the development of hypercalcemia and hyperphosphatemia. Cinacalcet (Sensipar, Amgen) is the first agent in a new class of drugs called calcimimetics. The agent sensitizes the calcium-sensing receptors in the parathyroid gland to extracellular calcium and directly lowers arathyroid hormone levels. Cinacalcet is FDA-approved for the treatment of secondary hyperparathyroidism in patients with chronic kidney disease on dialysis. In this patient population, cinacalcet reduces plasma intact parathyroid hormone (iPTH) levels, serum calcium and phosphorus levels, and the calcium-phosphorus product without associated hypercalcemia and hyperphosphatemia. Cinacalcet appears to be well-tolerated, with nausea, vomiting, and hypocalcemia as the main adverse events. The drug is also approved for the treatment of hypercalcemia in patients with parathyroid carcinoma and holds promise for the treatment of primary hyperparathyroidism.

FDA combats illegal WWW drug sales; Electronic database allows greater public access to studies; ‘Roadmap’ developed to prepare for and respond to pandemic; Government seeks posting of clinical trial results online; Purchasing pools yield more options, savings for states; New efforts to increase antimicrobial research gain momentum

Initiating high-dose simvastatin (Zocor, Merck) early after an acute coronary syndrome (ACS) event does not result in significantly superior clinical outcomes compared to delayed initiation of low-dose simvastatin.This major finding of phase Z of the A to Z Trial is in contrast to the results of 2 previous clinical trials in which aggressive therapy with atorvastatin (Lipitor, Pfizer) was found to be superior to less aggressive statin therapy in reducing the risk of adverse clinical events in ACS patients.

A telephone survey investigating comedication rates of aspirin, acetaminophen, or nonaspirin NSAIDs (ibuprofen and naproxen) among long-term cyclooxygenase 2 (COX-2) inhibitor users (at least a 90-day supply of a COX-2 inhibitor) (N=325, mean age 71, 67% female) revealed that 50% used aspirin concurrently despite its apparent GI adverse effects. Aspirin use was higher for those aged ?56 years (50%) than for those aged 37 to 55 years (25%) (P=.03).

The Warfarin/Aspirin Study in Heart Failure provided no evidence that aspirin is effective or safe in heart failure patients.

A study presented on August 25 at the 20th International Conference on Pharmacoepidemiology & Therapeutic Risk Management in Bordeaux, France, revealed that higher-dose rofecoxib (>25 mg/d) was associated with a greater risk of acute myocardial infarction (AMI) and sudden cardiac death (SCD) compared to other NSAIDs. The risk of AMI and SCD was also increased with lower-dose rofecoxib (25 mg/d) when compared with celecoxib. The maximum recommended daily doses of rofecoxib in the management of pain associated with osteoarthritis, rheumatoid arthritis, primary dysmenorrhea, and migraine attacks with or without aura are 25, 25, 50, and 50 mg/d, respectively.

A study presented on August 25 at the 20th International Conference on Pharmacoepidemiology & Therapeutic Risk Management in Bordeaux, France, revealed that higher-dose rofecoxib (>25 mg/d) was associated with a greater risk of acute myocardial infarction (AMI) and sudden cardiac death (SCD) compared to other NSAIDs. The risk of AMI and SCD was also increased with lower-dose rofecoxib (25 mg/d) when compared with celecoxib. The maximum recommended daily doses of rofecoxib in the management of pain associated with osteoarthritis, rheumatoid arthritis, primary dysmenorrhea, and migraine attacks with or without aura are 25, 25, 50, and 50 mg/d, respectively.

Once-daily injections of liraglutide, a long-acting, acylated, glucagon-like peptide 1 analog, have proven to be effective in the treatment of patients with type 2 diabetes.

Investigators in the Trial of Atorvastatin in Rheumatoid Arthritis (TARA) assessed whether statins would reduce inflammatory symptoms in patients with RA. Patients with RA (N=116) were randomized in the double-blind, placebo-controlled trial to receive 40 mg of atorvastatin or placebo in addition to their current disease-modifying antirheumatic drug (DMARD) therapy.

Epilepsy therapy approved for migraine prophylaxis

SSNRI approved for the treatment of major depressive disorder

Current treatment options for acute coronary syndromes as well as chronic stable angina often include the use of percutaneous coronary intervention (PCI) with routine stenting. The clear benefits of stents have lead to their routine use for prevention of restenosis. However, the benefits of stenting demonstrated on some aspects of restenosis are compromised by the induction of restenosis by neointimal hyperplasia that is stimulated by standard bare metal stents. FDA has approved 2 drug-eluting stents (DES). DES create a local delivery system at the vascular site to reduce restenosis by neointimal hyperplasia. Multiple clinical trials have demonstrated the safety and efficacy of the use of DES. This article reviews the use of PCI in coronary artery disease, the evolution and pathophysiology of restenosis, and multiple aspects of DES technology. While DES may not be a direct pharmacy and therapeutics committee responsibility, committee members are being called upon to provide insights into pathway processes for medical technology review committees evaluating DES since these products contain a key pharmacologic component. There are also important adjunctive antiplatelet therapy protocols that need to be developed and adhered to in conjunction with DES in order to ensure optimal outcomes.

Although statins have been shown to reduce LDL-C and coronary heart disease (CHD) morbidity and mortality, it is not uncommon for patients to fail to reach the treatment goals recommended by the National Cholesterol Education Program (NCEP) guidelines. Some statins cannot lower LDL-C sufficiently in FDA-approved doses; other statins cannot be titrated optimally due to potential drug interactions and adverse effects. Ezetimibe/simvastatin(Vytorin, Merck/Schering-Plough) is an intestinal cholesterol absorption inhibitor and statin combination product that received FDA approval in July 2004. The combination has been found to reduce LDL-C and triglycerides by an additional 22% and17%, respectively, and to increase HDL-C by up to 5% compared to statin monotherapy. The 40 mg simvastatin/10 mg ezetimibe dose of the combination product is one of onlya few cholesterol-lowering regimens that can reduce LDL-C >55% and is also one of the most economical. Adding ezetimibe to a statin does not reduce tolerability. Since ezetimibelacks cytochrome P450 isoenzyme interactions, the additional drug interaction risk with combination therapy is low.

Another activity that will support FDA's e-labeling initiative is the establishment of a "paperless label" system.

Two studies evaluating the efficacy and long-term safety of the inhalable, rapid-acting dry powder insulin formulation (Exubera, Pfizer/Aventis) demonstrate that the drug was able to sustain glycemic control and pulmonary function in patients with type 2 diabetes

Etanercept/anakinra combination therapy for the treatment of rheumatoid arthritis (RA) provides no added benefit and has an increased risk compared to etanercept alone, according to a study published in Arthritis & Rheumatism, the journal of the American College of Rheumatology (ACR).

Four commonly prescribed antidepressants carry an equal risk of quadrupling the chance of suicidal behavior during the first 9 days of treatment, according to a study from the United Kingdom published in the Journal of the American Medical Association. The authors cautioned, however, that the risk is likely only temporary and may be attributed to the time period in which the drugs have not yet taken effect in those patients already considering suicide.