2011 American Society of Consultant Pharmacists (ASCP) Annual Meeting and Exhibition
November 16-18, 2011; Pheonix, AZ
Optimizing Diabetes Management With Insulin Analogs Levemir and NovoLog
Diabetes, particularly the type 2 variant, is becoming more prevalent, increasing the burden on clinicians. Individuals with diabetes are more likely to require extended hospital stays, develop significant neuropathic pain, and experience depression. Effective management of diabetes in older patients requires overcoming several barriers, including comorbid diseases, preexisting complications of poorly managed diabetes, an elevated risk of hypoglycemia, and greater insulin resistance. As a result, many patients have difficulty achieving a glycated hemoglobin (A1c) level of <7%, which is the level the American Diabetes Association (ADA) considers evidence of optimal glucose control, said Brian Tulloch, MD, Clinical Endocrinologist and Associate Professor,
Diagnostic Clinic of Houston, TX. In a product theater sponsored by Novo Nordisk at the 2011 ASCP annual meeting, Tulloch discussed the benefits of two insulin analog therapies—Levemir (insulin detemer) and NovoLog (insulin aspart)—and addressed current standards for managing and treating diabetes.
Levemir is administered as a subcutaneous injection once or twice daily in diabetic patients who require basal insulin. Tulloch said the effectiveness of once-daily Levemir at controlling blood glucose was demonstrated in TITRATE, a 20-week, open-label, multicenter trial. TITRATE’s researchers randomized 244 insulin-naïve patients taking an oral antidiabetic drug (OAD) for type 2 diabetes to one of two groups. One group was instructed to self-titrate Levemir to achieve a target fasting glucose level of 70 mg/dL to 90 mg/dL, as measured with a fasting plasma glucose (FPG) test, and the target for the other group was set at 80 mg/dL to 110 mg/dL. Every 3 days, patients adjusted their insulin dose as needed to achieve the target, with the increase or decrease in insulin based on the mean FPG values from the prior 3 days. By the study’s conclusion, 64.3% of patients in the 70 md/dL to 90 mg/dL target group and 54.5% of patients in the 80 mg/dL to 110 mg/dL group had achieved A1c levels <7%. The mean A1c level for the groups combined was 6.9%. From baseline, A1c levels declined a mean of 1.2% for patients assigned to the group with the lower FPG target versus 0.9% for patients assigned to the group with the higher FPG target.
Tulloch explained that human insulin comprises 51 amino acids; 21 of these constitute the A polypeptide chain and the remaining 30 constitute the B polypeptide chain. A disulfide bond links the A chain to the B chain. Levemir was engineered to attach a fatty acid chain to amino acid B29. He said the fatty acid chain enhances Levemir’s ability to bind to albumin. Studies comparing Levemir with insulin glargine have observed a similar 24-hour effect on blood glucose with both agents but more consistent absorption and action and significantly less weight gain with Levemir. Unlike insulin glargine, Levemir is soluble at neutral pH.
The second analog discussed, NovoLog, is absorbed faster than human insulin and thus has a faster onset and shorter duration of action. Tulloch said NovoLog is typically injected 5 to 10 minutes before meals. In the 48-week randomized, multinational STEPwise trial, researchers compared two stepwise schedules for gradually increasing the NovoLog dose in adults (N=296) with type 2 diabetes that was poorly controlled despite the use of basal insulin and OADs. In the “SimpleSTEP” group, an initial injection of NovoLog was given with the largest meal, blood glucose was measured prior to subsequent meals, and additional doses were based on those results. Individuals assigned to the “ExtraSTEP” group took the initial NovoLog dose before the meal associated with the greatest increases in blood sugar as measured before and after the meal, with the primary NovoLog dose adjusted according to the level of glucose control achieved. Nearly one-third (31%) of patients in the SimpleSTEP group achieved the A1c goal of <7%. Tulloch said another study—the 3-year 4-T study—involving 708 insulin-naïve patients with type 2 diabetes found that a majority achieved and maintained the target A1c level when using NovoLog as part of a basal-bolus therapy.
A NovoLog 70/30 mix (70% insulin aspart protamine suspension, 30% insulin aspart injection) is also available. The mix has a faster onset than human insulin premix 70/30. The open-label, nonrandomized, observational IMPROVE study was used to demonstrate the effectiveness of this
During the presentation, Tulloch also demonstrated the convenience of the NovoLog FlexPen. He said NovoLog remains stable in the FlexPen, in the 3-mL PenFill cartridges, and in 10-mL vials for up to 28 days when stored at room temperature or until its expiration date if refrigerated.—David Despain
This product theater was sponsored by Novo Nordisk.
Xarelto Reduces Stroke Risk in Patients With Nonvalvular Atrial Fibrillation
Cinicians now have Xarelto (rivaroxaban) as an option for reducing the risk of stroke and noncentral nervous system systemic embolic events in patients with nonvalvular atrial fibrillation (AF). The US Food and Drug Administration approved Xarelto despite limited data on its effectiveness based on a lack of placebo-controlled trials. Associate Professor at the University of Sciences in Philadelphia, PA, Richard Stefanacci, DO, MGH, MBA, discussed use of the anticlotting drug, along with data from the ROCKET-AF trial in a product theater at the 2011 ASCP annual meeting. Stefanacci said AF affects more than 2.2 million individuals in the United States, and its prevalence is predicted to top 12 million by 2050. AF increases the risk of ischemic stroke, which is more likely to produce severe disability, to recur, or to prove fatal in individuals with AF.
According to Stefanacci, Xarelto’s mechanism of action and its convenience make it worth considering for treating patients who have demonstrated an inadequate response to warfarin. Xarelto selectively inhibits Factor Xa, acting upstream of the thrombin burst, and is administered as a single daily dose. He said that, unlike warfarin, routine coagulation monitoring (prothrombin time/international normalized ratio [INR] testing) is not required with Xarelto.
ROCKET-AF was a prospective, randomized, double-blind trial in which more than 14,000 patients (mean age, 71 years) with nonvalvular AF were randomized to receive 20 mg of Xarelto daily (15 mg for patients with moderate renal impairment) or warfarin targeted to an INR of 2 to 3. In this patient population, Xarelto was found to be noninferior to dose-adjusted warfarin in reducing the risk of stroke and noncentral nervous system embolic events. Stefanacci explained that the trial was not powered to demonstrate superiority with Xarelto and did not do so.
The rate of major bleeding events in ROCKET-AF was somewhat higher with Xarelto than with warfarin and consisted primarily of intracranial bleeds. The Xarelto group had lower rates of critical organ and fatal bleeding events, but higher rates of transfusion and gastrointestinal bleeding. The proportion of patients who discontinued because of treatment-related adverse events (bleeding and nonbleeding events) were similar between the two study arms.
Stefanacci cautioned that renal function should be assessed in patients 65 years and older before initiating treatment with Xarelto. Patients with creatinine clearance (CrCl) greater than 50 mL per minute should receive 20 mg daily, with a dose adjustment to 15 mg daily for patients with CrCl between 15 mL and 50 mL per minute; Xarelto should not be used in patients with CrCL <15 mL per minute. If a dose is missed, the patient should take the next dose as soon as possible on the same day and resume taking Xarelto once daily with the following day.
Black box warnings for Xarelto include the risk of epidural or spinal hematomas in surgical settings (eg, when undergoing anesthesia or spinal puncture). Stefanacci said these hematomas can also arise in patients who use an indwelling epidural catheter, in those who take concomitant medications that affect hemostasis (eg, nonsteroidal anti-inflammatory drugs [NSAIDs] and platelet inhibitors), and in patients with a history of traumatic or repeated epidural or spinal punctures or spinal surgery or who have spinal deformity. Contraindications discussed include active pathological bleeding and severe hypersensitivity to Xarelto.
Other warnings and precautions include the need to discontinue the drug in the absence of adequate alternative anticoagulation and the increased risk of serious or fatal bleeding for which no antidote is available. With overdose, Xarelto may cause untreatable hemorrhage. In such cases, clinicians should discontinue Xarelto immediately and provide appropriate therapy; activated charcoal may be an option for reducing absorption. The medicine is not thought to be dialyzable. Stefanacci discussed the possibility of drug-drug interactions, such as the use of Xarelto with medications that inhibit or induce CYP3A4 enzymes and drug transport systems; and with other drugs that increase the risk of bleeding, such as NSAIDs and Plavix.—David Despain
This product theater was sponsored by Janssen Pharmaceuticals, Inc.
In a product theater sponsored by Avanir Pharmaceuticals, a video is shown that features a patient with dementia being interviewed by her physician. She begins crying uncontrollably for seemingly no reason. This is a hallmark of pseudobulbar affect (PBA), which involves episodes of laughing and/or crying that are frequent, stereotypical, inappropriate to the situation (incongruent or exaggerated), and last seconds to minutes. Mary Catherine Yaggy, MSN, GNP-BC, Gerontological Nurse Practitioner, Extended Care Specialists, Fort Wayne, IN, discussed this patient and her treatment with Nuedexta (dextromethorphan hydrobromide 20 mg and low-dose quinidine sulfate 10 mg), the first approved therapy for PBA, at the 2011 ASCP annual meeting. Yaggy said after 10 days of taking Nuedexta, the patient saw a 50% reduction in the number of PBA episodes each day. Yaggy has been treating patients with Nuedexta since April, only a couple of months after it first became available, and said it has proven extremely effective in patients who previously received mood stabilizers. She expects it will serve a valuable role in the long-term care and behavior management arenas.
PBA is a disorder of disinhibition of emotional expression characterized by involuntary, sudden, and frequent crying and/or laughing. It occurs secondary to neurological conditions, including multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), Parkinson’s disease, Alzheimer’s disease, and traumatic brain injury. The symptoms can severely disrupt the lives of patients and caregivers and may lead to social phobia, withdrawal, and isolation. Historically, various terms have been used to describe the disorder, including excessive emotionality, affective instability, emotional dyscontrol, post-stroke emotionality, pathological laughing and crying, and pathological affect.
Dana Saffel, PharmD, DPh, CGP, FASCP, President and CEO, PharmaCare Strategies, Inc, discussed the etiology of PBA and the prescribing information for Nuedexta at the meeting. She said recent research suggests PBA results from lesions in the frontal cortex that cause disruption along the corticopontocerebellar pathways, which control emotional motor expression. Saffel said the treatment should not be seen as a cure, but it does help normalize signaling, allowing the patient to control these inappropriate, unprompted displays of laughing or crying. The dextromethorphan ingredient is thought to have two mechanisms of action: presynaptic inhibition of glutamate release and postsynaptic glutamate response modulation. The low-dose quinidine in the compound inhibits the CYP2D6 enzyme from metabolizing dextromethorpan and allows it to enter the brain.
The effectiveness of Nuedexta was established in studies involving patients with ALS and MS, patient populations with a high prevalence of PBA. The primary end point was the reduction in number of episodes. One randomized, double-blind, placebo-controlled, multicenter study randomized 326 patients to Nuedexta (n=107) or placebo (n=109) for 12 weeks. Patients in the Nuedexta group had significantly fewer episodes of laughing and crying compared with patients in the placebo group. Episodes in Nuedexta-treated patients were also significantly less severe compared with episodes in patients given placebo. Saffel said patients had an average 60% to 70% reduction in the number of episodes, a rate that was sustained over the 12-week duration of the study. Half the patients in the Nuedexta arm were episode-free during the final 14 days of the study. Adverse events that occurred in approximately 3% of patients treated with Nuedexta, and at a significantly greater rate than observed in the placebo arm, included diarrhea (13% vs 6%, respectively) and dizziness (10% vs 6%, respectively).
Saffel said the recommended starting dose of Nuedexta is one capsule daily, given by mouth. After 7 days of therapy, the dose is increased to two capsules daily (one every 12 hours). Nuedexta is contraindicated in patients who are taking quinidine and related drugs or monoamine oxidase inhibitors; in patients with a history of hypersensitivity to the drug or either of its ingredients; and in patients with hepatitis or QT abnormality.—David Despain
This product theater was sponsored by Avanir Pharmaceuticals.
With age, the risk of influenza increases because the immune system weakens, causing the body to produce fewer antibodies in response to vaccination. A decreased immunologic response may leave an individual more vulnerable to influenza infection and at an increased risk of severe complications. In a product theater for Fluzone, a high-dose (HD) injectable flu vaccine manufactured by Sanofi Pasteur, Inc, clinical pharmacist Frank Breve, President and CEO of Mid-Atlantic Pharma Tech in NJ, said older adults make up 15% of the US population, yet account for more than 60% of the estimated 226,000 annual hospitalizations and 90% of the 3000 to 49,000 annual deaths attributed to influenza and pneumonia. He said the presence of comorbidities—practically universal in elders—increases the risk of mortality from influenza and/or pneumonia dramatically. The disproportionate burden of these illnesses on older adults, which is an ever-growing segment of the population, highlights the need to improve influenza prevention.
The Fluzone HD vaccine contains four times the standard dose of antigen (60 mcg vs 15 mcg hemagglutinin), and its approval by the US Food and Drug Administration (FDA) was based on demonstrations of its ability to engender superior immune response in individuals aged 65 years and older. Although none of the data available to date demonstrate superior effectiveness of Fluzone at preventing influenza illnesses and complications, Breve said three clinical studies have shown that the mega-dose results in significantly higher antibody levels in older adults compared with the regular dose.
In 2009, Ann Falsey, MD, and colleagues, University of Rochester, Rochester, NY, published findings in The Journal of Infectious Diseases (JID) of a randomized, double-blind phase 3 trial that compared Fluzone HD (n=2575) with the standard dose (n=1262) in adults 65 years of age and older. The HD induced a statistically significant level of antibody response compared with the standard dose, meeting superiority criteria for influenza A strains H1N1 and H3N2 and noninferiority criteria for the influenza B strain.
The JID issue included a commentary by Gregory Poland, MD, a physician and researcher with the Mayo Clinic, Rochester, MN, and Mark Mulligan, MD, Professor of Medicine, Emory University, Atlanta, GA. In the commentary, they encouraged manufacturers to seek licensure from the FDA for HD vaccines. They said this step would be critical to reduce the annual epidemics of influenza and morbidity and mortality associated with influenza. Poland and Mulligan said it would be irresponsible for manufacturers not to make providing better options for influenza vaccination a priority.
According to Breve, data from multiple studies show that elevated levels of antibodies generally correlate with greater resistance to influenza, and it is important for patients to be aware of this fact and their option to receive Fluzone HD. He expects data demonstrating the vaccine’s ability to prevent influenza to come eventually, as regular vaccination has already been found to be successful at preventing the illness in older adults. Regular influenza vaccinations reduce the risk of hospitalization in adults aged 65 years and older by approximately 30% and nearly halve the risk of cause-specific mortality (including cardiovascular disease, stroke, renal disease, and diabetes).
The most common adverse effects seen with Fluzone HD are mild pain at the injection site, erythema, fever, headache, malaise, and myalgia. Safety information warns against giving the HD vaccination to anyone with a severe allergic reaction to eggs or egg products or to a previous dose of any influenza vaccine. HD vaccination should be discussed with a clinician if the patient has ever experienced Guillain-Barré syndrome.—David Despain
This product theater was sponsored by Sanofi Pasteur, Inc.