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P T. 2015;40(11): 716-718, 721-725, 774

New Drugs/Drug News/New Medical Devices November 2015

NEW DRUG APPROVALS

Aristada for Schizophrenia

The FDA has approved aripiprazole lauroxil extended-release injection (Aristada, Alkermes, Inc.) to treat adults with schizophrenia. Aristada is injected in the arm or buttocks by a health care professional every four to six weeks.

The efficacy of extended-release (ER) aripiprazole was demonstrated in part by a 12-week clinical trial involving 622 participants. In participants with acute schizophrenia who had been stabilized with oral aripiprazole, the ER formulation was found to maintain the treatment effect compared with a placebo.

Aristada is a longer-acting injectable version of the schizophrenia pill Abilify (Otsuka Pharmaceuticals), making the treatment available in two doses.

Aripiprazole and other second-generation antipsychotic drugs used to treat schizophrenia have a boxed warning about an increased risk of death associated with the off-label use of these drugs to treat behavioral problems in older people with dementia-related psychosis. No drug in this class is approved to treat patients with dementia-related psychosis. ER aripiprazole must be dispensed with a patient medication guide that describes important information about the drug’s uses and risks.

The most common side effect reported by participants receiving ER aripiprazole in clinical trials was akathisia.

Sources: Alkermes, Inc., and Reuters, October 5, 2015

Pradaxa Reversal Agent

Idarucizumab (Praxbind, Boehringer Ingelheim) has received FDA approval for use in patients treated with dabigatran etexilate (Pradaxa, Boehringer Ingelheim) when dabigatran’s anticoagulant effects must be reversed for emergency surgery, for urgent procedures, or in life-threatening or uncontrolled bleeding.

Idarucizumab had been granted breakthrough therapy and priority review designations. It was approved under an accelerated approval pathway based on results of studies and an interim analysis that found that idarucizumab’s reversal effects were evident within minutes after administration of a 5-g dose.

Boehringer Ingelheim is continuing to evaluate idarucizumab in RE-VERSE AD, a phase 3 global study that includes patients taking dabigatran etexilate who have uncontrolled bleeding or require emergency procedures.

Idarucizumab is a humanized antibody fragment designed as a specific reversal agent to dabigatran. It binds only to dabigatran molecules, neutralizing their anticoagulant effect without interfering with the coagulation cascade.

Source: Boehringer Ingelheim, October 19, 2015

Tresiba, Ryzodeg for Diabetes

The FDA has approved insulin degludec injection (Tresiba) and insulin degludec/insulin aspart injection (Ryzodeg 70/30) to improve glucose control in adults with diabetes mellitus. Novo Nordisk manufactures both products.

Tresiba is a long-acting insulin analog indicated to improve glycemic control in adults with type-1 and type-2 diabetes mellitus. It is administered subcutaneously once daily at any time of day.

The efficacy and safety of Tresiba used in combination with mealtime insulin for the treatment of patients with type-1 diabetes were evaluated in two 26-week and one 52-week active-controlled clinical trials involving 1,102 participants exposed to Tresiba. The efficacy and safety of Tresiba used in combination with mealtime insulin or used as an add-on to common oral antidiabetic drugs for the treatment of patients with type-2 diabetes were evaluated in four 26-week and two 52-week active-controlled clinical trials involving 2,702 participants exposed to Tresiba. In participants with type-1 and type-2 diabetes who had inadequate blood sugar control at trial entry, treatment with Tresiba provided reductions in hemoglobin A1c (HbA1c) or glycosylated hemoglobin in line with reductions achieved with other, previously approved long-acting insulin.

Ryzodeg 70/30 is a mixture of insulin degludec, a long-acting insulin analog, and insulin aspart, a rapid-acting human insulin analog. It is indicated to improve glycemic control in adults with diabetes mellitus.

The efficacy and safety of Ryzodeg 70/30 used in combination with mealtime insulin for the treatment of patients with type-1 diabetes were evaluated in one 26-week active-controlled clinical trial involving 362 participants exposed to Ryzodeg 70/30. The efficacy and safety of Ryzodeg 70/30 administered once or twice daily for the treatment of patients with type-2 diabetes were evaluated in four active-controlled 26-week clinical trials involving 998 participants exposed to Ryzodeg 70/30. In participants with type-1 and type-2 diabetes who had inadequate blood sugar control at trial entry, treatment with Ryzodeg 70/30 provided reductions in HbA1c that were equivalent to reductions achieved with other, previously approved long-acting or premixed insulin.

Source: FDA, September 25, 2015

Generic Approvals

Rivastigmine Patch

The FDA has approved the application of Alvogen Pine Brook, Inc., to market the rivastigmine transdermal system in 24-hour strengths of 4.6 mg, 9.5 mg, and 13.3 mg. Alvogen was the first filer for the 13.3-mg strength, making it the first generic formulation of the Exelon transdermal system (Novartis). Exelon’s U.S. sales were approximately $400 million during 2014, according to IMS data. The rivastigmine patch is an acetylcholinesterase inhibitor indicated for treatment of mild-to-moderate dementia related to Alzheimer’s or Parkinson’s diseases.

Sources: Alvogen Pine Brook, Inc., September 4, 2015, and Exelon prescribing information

Balsalazide Disodium

Balsalazide disodium tablets, 1.1 g, can be marketed by Par Pharmaceutical Inc. (now part of Endo Pharmaceutical PLC), the FDA has ruled. This is the first generic version of Giazo (Valeant Pharmaceuticals), a locally acting aminosalicylate indicated for the treatment of mildly to moderately active ulcerative colitis in males 18 years of age and older.

Sources: FDA, September 8, 2015, and Giazo prescribing information

Fluvastatin Sodium ER

Mylan Pharmaceuticals now sells fluvastatin sodium extended-release tablets, 80 mg, the first generic formulation of Lescol XL (Novartis). This medication is indicated to reduce elevated total cholesterol, low-density lipoprotein-cholesterol, apolipoprotein B, and triglyceride and to increase high-density lipoprotein-cholesterol in adults with primary hypercholesterolemia and mixed dyslipidemia, as an adjunct to diet, when response to diet and other nonpharmacological treatments is inadequate. The product had U.S. sales of approximately $37.6 million for the 12 months ending June 30, 2015, according to IMS data.

Source: Mylan, September 18, 2015

Clozapine ODT

The first generic version of clozapine orally disintegrating tablets, 25 mg and 100 mg, can be marketed by Mylan Pharmaceuticals, the FDA has ruled. The brand-name product, the second-generation antipsychotic drug FazaClo ODT (Jazz Pharmaceuticals), is a tricyclic dibenzodiazepine derivative.

Sources: FDA, September 15, 2015, and FazaClo prescribing information

Pimozide

The FDA has approved the marketing of pimozide tablets USP, 1 mg and 2 mg, by Par Pharmaceutical, Inc. (now part of Endo Pharmaceutical PLC). This is the first generic formulation of Orap Tablets (Teva), an orally active antipsychotic agent of the diphenyl-butylpiperidine series indicated for the suppression of motor and phonic tics in patients with Tourette’s disorder who have failed to respond satisfactorily to standard treatment.

Sources: FDA, September 28, 2015, and Orap prescribing information

Adapalene/Benzoyl Peroxide Gel

The FDA has permitted Actavis Mid Atlantic, LLC, to sell adapalene/benzoyl peroxide gel, 0.1%/2.5%. This is the first generic version of Galderma Laboratories’ Epiduo Topical Gel, which is indicated for the topical treatment of acne vulgaris in patients 12 years of age and older.

Sources: FDA, September 30, 2015, and Epiduo prescribing information

NEW INDICATIONS

Letairis for PAH

Ambrisentan (Letairis, Gilead Sciences) has received FDA approval in combination with tadalafil for the treatment of pulmonary arterial hypertension (PAH) to reduce the risks of disease progression and hospitalization for worsening PAH and to improve the ability to exercise.

Letairis is an endothelin receptor antagonist that was approved in 2007 as monotherapy for PAH to improve exercise ability and to delay clinical worsening. Tadalafil is a phosphodiesterase type 5 inhibitor that was initially approved for PAH in 2009 to improve exercise ability. PAH represents Group 1 in the World Health Organization (WHO) pulmonary hypertension classification system.

The new labeling is supported by data from the AMBITION trial, a randomized, double-blind study of first-line combination therapy with ambrisentan and tadalafil in PAH patients. The study’s primary endpoint was the time to first occurrence of death, hospitalization for worsening PAH, and a decrease from baseline in the six-minute walk distance of greater than 15% combined with WHO functional class III or IV symptoms sustained over 14 days (short-term clinical worsening) or over six months (inadequate long-term clinical response).

Ambrisentan/tadalafil demonstrated superiority in reducing the risk of the composite primary endpoint compared with monotherapy with ambrisentan or tadalafil. Combination therapy also demonstrated a reduced risk of hospitalization for worsening PAH compared with ambrisentan or tadalafil alone.

Source: Gilead Sciences, October 2, 2015

Opdivo/Yervoy for Melanoma

The FDA has approved nivolumab (Opdivo) in combination with ipilimumab (Yervoy) for the treatment of patients with BRAF V600 wild-type unresectable or metastatic melanoma. The decision marks the first FDA approval of a regimen of two immuno-oncology agents. Bristol-Myers Squibb manufactures both drugs.

The approval was based on data from the pivotal CheckMate 069 trial, which reported outcomes with nivolumab plus ipilimumab in 140 previously untreated patients with unresectable or metastatic melanoma. The results from this study demonstrated a statistically significant increase in the confirmed objective response rate (the trial’s primary endpoint) in patients with BRAF wild-type melanoma treated with the nivolumab/ipilimumab combination compared with those treated with ipilimumab monotherapy (60% versus 11%, respectively).

Complete responses were seen in 17% of the nivolumab/ipilimumab patients. Partial responses were seen in 43% of the nivolumab/ipilimumab group and in 11% of the ipilimumab monotherapy group. The nivolumab/ipilimumab regimen demonstrated a 60% reduction in the risk of disease progression compared with ipilimumab monotherapy. Median progression-free survival was 8.9 months with the combination regimen and 4.7 months with ipilimumab alone.

Source: Bristol-Myers Squibb, October 1, 2015

Opdivo for NSCLC

The FDA has approved nivolumab intravenous injection (Opdivo, Bristol-Myers Squibb) for the treatment of patients with metastatic non–small-cell lung cancer (NSCLC) with progression during or after platinum-based chemotherapy. Patients with epidermal growth factor receptor mutation or anaplastic lymphoma kinase translocation should show disease progression during appropriate targeted therapy before receiving nivolumab.

This approval was based on the results of the CheckMate 057 trial, a phase 3 study that demonstrated a superior overall survival benefit for nivolumab compared with docetaxel in patients with previously treated metastatic NSCLC. Biomarker testing is not required for nivolumab, a programmed cell death-1 therapy.

Source: Bristol-Myers Squibb, October 10, 2015

NEW FORMULATION

Abuse-Deterrent ER MorphaBond

The FDA has approved morphine sulfate extended-release (ER) tablets for oral use, CII (MorphaBond, Inspirion Delivery Technologies LLC), an abuse-deterrent formulation of ER morphine using physical and chemical barriers without aversive agents or opioid antagonists.

MorphaBond’s inactive ingredients make the tablet more difficult to adulterate for misuse and abuse while maintaining ER characteristics even if the tablet is subjected to physical manipulation and/or chemical extraction.

The formulation has been tested in vitro using methods of manipulation that drug abusers commonly use for the preparation of ER opioids for administration by various routes, including oral consumption, intranasal insufflation, injection, and smoking. The laboratory test data demonstrated that, relative to other morphine sulfate ER tablets, MorphaBond has increased resistance to cutting, crushing, or breaking using a variety of tools. When subjected to a liquid environment, the manipulated MorphaBond formulation forms a viscous material that resists passage through a needle.

Source: Inspirion Delivery Technologies LLC, October 6, 2015

DRUGS UNDER REVIEW

Priority Reviews

Daclatasvir for More HCV Indications

The FDA has accepted for filing and review three supplemental new drug applications for daclatasvir (Daklinza, Bristol-Myers Squibb), a nonstructural protein 5A replication complex inhibitor, for use with sofosbuvir (Sovaldi, Gilead Sciences) with or without ribavirin. The applications are for the treatment of patients with chronic hepatitis C virus (HCV) coinfected with human immunodeficiency virus-1 (HIV-1), patients with advanced cirrhosis (including decompensated cirrhosis), and patients with the recurrence of HCV after liver transplant. The FDA granted priority review status to all three applications. Daclatasvir was approved in July 2015 for use with sofosbuvir in the treatment of patients with chronic HCV genotype 3 infection. In May 2015, daclatasvir with sofosbuvir received a breakthrough therapy designation for HCV genotype 1 patients with advanced cirrhosis (Child-Pugh class B or C) and for those who develop genotype 1 HCV recurrence after liver transplant.

Source: Bristol-Myers Squibb, October 6, 2010

Kyprolis for Relapsed Multiple Myeloma

The FDA has accepted for priority review a supplemental new drug application for carfilzomib (Kyprolis, Onyx Pharmaceuticals/Amgen) for patients with relapsed multiple myeloma. The application is designed to expand the current indication to include carfilzomib in combination with dexamethasone for patients who have received at least one prior therapy. The Prescription Drug User Fee Act target action date is January 22, 2016.

The FDA recently approved the drug in combination with lenalidomide (Revlimid, Celgene) and dexamethasone for the treatment of patients with relapsed multiple myeloma who have received one to three prior lines of therapy.

The application was based on data from the phase 3 ENDEAVOR study, which showed that patients with relapsed multiple myeloma treated with carfilzomib and low-dose dexamethasone lived twice as long without their disease worsening, demonstrating statistically and clinically significant superiority over bortezomib and low-dose dexamethasone. Median progression-free survival was 18.7 months versus 9.4 months, respectively (P < 0.0001).

Source: Amgen, September 18, 2015

Defibrotide for Hepatic Veno-Occlusive Disease

The FDA has accepted for filing with priority review a new drug application for defibrotide (Jazz Pharmaceuticals). Defibrotide is an investigational agent proposed for the treatment of patients with hepatic veno-occlusive disease (VOD), also known as sinusoidal obstruction syndrome, with evidence of multiorgan dysfunction (MOD) after hematopoietic stem-cell transplantation (HSCT). Based on the Prescription Drug User Fee Act, FDA review of the application is expected to be completed by March 31, 2016.

The application includes safety and efficacy data from three clinical studies of defibrotide for the treatment of hepatic VOD with MOD following HSCT, as well as a retrospective review of registry data from the Center for International Blood and Marrow Transplant Research. The safety database includes more than 900 patients exposed to defibrotide in the clinical development program for the treatment of hepatic VOD.

The most frequent adverse events observed during premarketing use of defibrotide were hemorrhage, hypotension, and coagulopathy

Source: Jazz Pharmaceuticals, September 30, 2015

Fast-Track Designations

Cinryze After Renal Transplants

The FDA has granted a fast-track designation for the investigation of C1 esterase inhibitor, human (Cinryze, Shire) for intravenous (IV) administration in subjects with antibody-mediated rejection (AMR) following renal transplants. The product is being studied as an adjunct to donor-specific antibody (DSA) reduction therapy in kidney transplant patients with acute AMR.

Shire plans a phase 3, randomized, double-blind, placebo-controlled study to evaluate the efficacy of Cinryze as an adjunct to DSA reduction therapy (i.e., plasmapheresis, plasma exchange, and/or immune adsorption treatments and IV immunoglobulin) for the treatment of acute AMR in kidney transplant recipients.

Cinryze is currently approved for routine prophylaxis against angioedema attacks in adolescent and adult patients with hereditary angioedema.

Source: Shire, October 13, 2015

Angiotensin for DMD

The FDA has granted a fast-track designation to TXA127 (angiotensin 1–7) to reduce skeletal muscle damage and fibrosis, thereby improving muscle strength, in patients with Duchenne muscular dystrophy (DMD). The product’s developer, Tarix Orphan LLC, expects to initiate a phase 2 safety and efficacy study in early 2016. The planned trial will be a 48-week, double-blind, randomized, placebo-controlled study of TXA127 in 45 ambulatory patients with DMD, followed by a 96-week open-label extension study.

TXA127 previously received orphan drug status for DMD in the U.S.

TXA127 is a formulation of the naturally occurring peptide angiotensin (1–7), which is being developed for the treatment of several orphan and genetic diseases with an initial focus on DMD. TXA127 is part of the alternative renin–angiotensin system (RAS) and counteracts the classical RAS, which promotes hypertension, fibrosis, hypertrophy, and inflammation.

Source: Tarix Orphan LLC, October 6, 2010

Breakthrough Therapies

RBX2660 for Recurrent C. Difficile

The FDA has designated RBX2660 (Rebiotix Inc.), a microbiota restoration therapy (MRT), as a breakthrough therapy for the treatment of recurrent Clostridium difficile infection, a difficult-to-treat gastrointestinal infection. MRT delivers healthy, live, human-derived microbes into a sick patient’s intestinal tract to treat disease.

Studies have shown that most cases of C. difficile infection occur after the normal microorganisms that reside in the gut have been disrupted by antibiotic use. Restoring the balance of microbes is thought to be the key to breaking the cycle of recurrence.

Source: Rebiotix Inc., October 12, 2015

Abemaciclib for Breast Cancer

The FDA has granted a breakthrough therapy designation to abemaciclib (LY2835219, Eli Lilly), a cyclin-dependent kinase (CDK) 4 and 6 inhibitor, for patients with refractory hormone-receptor–positive (HR+) advanced or metastatic breast cancer. This designation is based on data from the breast cancer cohort expansion of a phase 1 trial that studied the efficacy and safety of abemaciclib in women with advanced or metastatic breast cancer. Patients in this cohort had received a median of seven prior systemic treatments.

Abemaciclib is designed to block the growth of cancer cells by specifically inhibiting CDK 4 and 6. Although abemaciclib inhibits both, results from cell-free enzymatic assays have shown that it was most active against cyclin D1 and CDK 4. Results from preclinical and early-stage clinical studies supported the further evaluation of abemaciclib for the treatment of human cancers—including breast cancer and lung cancer—in which aberrant CDK 4 and 6 pathways enhance cancer cell growth.

Abemaciclib has now entered phase 3 development with two trials in HR+ breast cancer and one in lung cancer.

Source: Eli Lilly; October 8, 2015

OTHER DRUG NEWS

Evacetrapib Work Halted

Eli Lilly and Company has discontinued development of the investigational medication evacetrapib for the treatment of patients with high-risk atherosclerotic cardiovascular disease (ASCVD).

An independent data monitoring committee recommended terminating the phase 3 ACCELERATE trial of evacetrapib because of insufficient efficacy. The committee based its recommendation on findings from periodic data reviews, which suggested that there was a low probability the study would achieve its primary endpoint based on the current results.

The ACCELERATE study was designed to evaluate the efficacy and safety of evacetrapib in participants with high-risk ASCVD. The randomized, double-blind, placebo-controlled trial involved 12,095 patients. The primary outcome measure was the time to first occurrence of any component of the composite cardiovascular events of cardiovascular death, myocardial infarction, stroke, coronary revascularization, or hospitalization for unstable angina.

Source: Lilly, October 12, 2015

Neutropenia Risk With Clozapine

The FDA is changing the requirements for monitoring, prescribing, dispensing, and receiving the schizophrenia medication clozapine to address safety concerns about severe neutropenia.

There are two parts to the changes. First, the FDA has clarified the prescribing information for clozapine that explains how to monitor patients for neutropenia and manage clozapine treatment. Second, the agency has approved a new, shared risk evaluation and mitigation strategy (REMS). The requirements to monitor, prescribe, dispense, and receive all clozapine medications are now incorporated into the clozapine REMS program, which replaces six clozapine registries maintained by individual manufacturers. To prescribe and dispense clozapine, prescribers and pharmacies must be certified in the clozapine REMS program according to a specific transition schedule starting on October 12, 2015.

Under the new monitoring recommendations for neutropenia caused by clozapine treatment, neutropenia will be monitored only by the absolute neutrophil count (ANC) rather than in conjunction with the white blood cell count. Moreover, in the clozapine REMS program, the ANC requirements are being modified so that patients will be able to continue on clozapine treatment with a lower ANC. In addition, patients with benign ethnic neutropenia who previously were not eligible for clozapine treatment will now be eligible to receive the medication.

Source: FDA, September 15, 2015

RESEARCH BRIEFS

Game Reduces Drug Craving

Playing Tetris reduces the strength of drug cravings, according to researchers from Plymouth University in the United Kingdom and Queensland University of Technology in Australia.

Craving, a criterion for substance abuse disorders, contributes to continued drug use and to relapse. Laboratory research has shown that cravings can be suppressed by distracting tasks, such as those that involve visuospatial or olfactory processing.

The researchers sought to learn whether visual-imagery cognitive tasks that target the working memory would reduce cravings for drugs, food, and other potential addictions. They chose Tetris because the game is easily accessible, engaging, and has a strong visual component involving movement.

For a week, 31 students carried iPods and played the game at predetermined intervals. They were prompted seven times a day to report craving targets, the strength of the craving, whether they indulged the craving, and whether they were under the influence of alcohol. Those randomly assigned to the intervention then played Tetris for three minutes and reported their cravings again.

Playing Tetris, even for a few minutes, reduced craving strength for addictive substances (nicotine, caffeine, and alcohol), food, and drink, as well as sex, gaming, exercise, and social interaction, by nearly 14 percentage points. The researchers say this finding shows that using a working memory task to interfere with cravings is effective in the field as well as the lab. The impact of Tetris on craving remained steady throughout the week—“potentially important,” the researchers say, because an intervention that works solely because it is novel will have diminishing benefits as participants become familiar with it.

Tetris did not reduce the pregame craving scores across the week. Longer studies are needed to show whether Tetris (or similar interventions) can help manage cravings or just weaken them while the task is being performed.

Source: Addictive Behaviors, December 2015

ED Patients’ Views on Pain

Up to 70% of patients in the emergency department (ED) who present with acute pain don’t receive analgesics, University of Pennsylvania researchers say. To learn patients’ perspectives, the researchers surveyed 23 ED patients with acute pain.

Some patients said they were hesitant about receiving medication, often due to concern about potential addiction. Some modified their prescribed regimen on their own (taking fewer pills, for instance) to reduce the risk of addiction. However, some believed that taking the medicine as prescribed or as needed prevents addiction. There seemed to be a perception that some people chose to be addicted because they didn’t take their medicine as prescribed or because they “enjoyed” the medication. Many patients felt they could avoid addiction “by simply declaring that they do not want to become addicted.”

Patients see the tension among practitioners who are trying to balance pain management with addiction risks. Some patients feel they suffer because other patients have become addicted, causing practitioners to avoid prescribing medication to people who need it.

The patients wanted engagement in treatment plans. They noted that poor communication leads to dissatisfaction and misunderstanding. For instance, when a physician has ruled out causes of a complaint, the patients want that information.

Instead of the classic 1-to-10 pain scale, the patients wished physicians could “delve into what the pain means” with questions about how it affects their home and work life, for instance. Patients also notice when care is fragmented by teams, nurses, and physicians failing to communicate with one another. And when health care practitioners don’t acknowledge the patient’s perspective, patients feel patronized and disrespected.

Source: Annals of Emergency Medicine, September 2015

The Top H. Pylori Treatment

Researchers who examined the evidence on 14 treatment regimens for Helicobacter pylori infection found the commonly recommended seven days of standard triple treatment was the least effective.

The “most comprehensive and systematic comparative meta-analysis of eradication treatments for H. pylori” analyzed data from 99 studies and ranked the treatments in order of effectiveness. Concomitant treatments, 10 or 14 days of probiotic-supplemented triple treatment, 10 or 14 days of levofloxacin-based triple treatment, 14 days of hybrid treatment, and 10 or 14 days of sequential treatment came first. Standard triple treatment—seven days of a simultaneous proton pump inhibitor plus clarithromycin and amoxicillin or metronidazole—ranked last.

Longer treatments in most cases were better for efficacy and worse for adverse events. Patients on probiotic-supplemented treatment or seven-day levofloxacin treatment had the lowest frequency of headaches (with or without vomiting) and diarrhea. Levofloxacin-based triple treatment and bismuth-based quadruple treatment were associated with the least taste alteration.

Seven days of probiotic-supplemented triple treatment and seven days of levofloxacin-based triple treatment (both of which were significantly better than the standard triple treatment) ranked best in terms of tolerance. For patients with epigastric or abdominal pain, ranitidine bismuth citrate–based triple treatments and 10 or 14 days of probiotic-supplemented triple treatment might be “relatively optimal choices,” the researchers say.

The researchers caution that treatments have different results in different areas of the world, in part because antibiotic resistance varies among geographical zones. One single “most effective” treatment is unlikely to surface, they suggest, since the treatments will need to be tailored to regional resistance profiles.

Source: BMJ, August 19, 2015

Central Sleep Apnea Mortality

Patients with heart failure often have central sleep apnea (Cheyne–Stokes respiration), breathing interruptions, and hyperventilation that can be dangerous for a failing heart. In fact, central sleep apnea is an independent marker for poor prognosis and death in heart failure, so suppressing these apneas and hypopneas sounds like a good idea.

But the results of the SERV-HF trial suggest otherwise. The researchers found adaptive servo-ventilation increased all-cause and cardiovascular mortality.

Researchers followed 1,325 patients for a median of 31 months. Of those, 666 patients were in the adaptive servo-ventilation group; 60% used it for an average of three hours per night or more during the study period. Despite effective control of central sleep apnea during the therapy, the risk of cardiovascular death rose by 34% in the intervention group—a risk that was sustained throughout the trial. Moreover, researchers found no beneficial effect on quality of life or symptoms of heart failure.

Two possible mechanisms may be at work, the researchers say. First, positive airway pressure therapy (not specifically adaptive servo-ventilation) might have adverse consequences on cardiac function in some patients. Second, some aspects of Cheyne–Stokes respiration may actually be useful to the patient, so removing it may remove a compensatory mechanism.

Source: New England Journal of Medicine, September 17, 2015

Pneumonia’s Lasting Effects

Perhaps survivors of community-acquired pneumonia (CAP) should be managed like patients with other common high-risk chronic conditions, according to Canadian researchers. In their study comparing 6,078 CAP patients with 29,402 people without CAP, they found the legacy of CAP was a “tremendous burden” for the patient in the long term.

CAP increased the risk of death in 10 years by more than 50%. Over the study period, 2,858 patients with CAP died compared with 9,399 control subjects. Moreover, patients with CAP were hospitalized more often, had more emergency department visits, and had a nearly fourfold absolute increase in subsequent CAP-related events. The analyses suggested that the survival curves for CAP patients, compared with control subjects, continue to worsen and accelerate with time.

Although older people had the highest absolute rates of CAP-associated morbidity and mortality, the very young had the highest relative rates.

While outcomes have improved for patients with other common conditions, no such significant improvements have been seen for patients with pneumonia. The reasons behind the poor prognosis aren’t fully known. Some research has indicated pneumonia may alter underlying biological processes or might be a manifestation of an underlying biological process rather than the cause of death per se.

Source: American Journal of Respiratory and Critical Care Medicine, September 1, 2015

DEVICE APPROVALS

Bioabsorbable Drug-Eluting Stent

The FDA has approved the Synergy system (Boston Scientific) for the treatment of coronary artery disease, making it the first bioabsorbable polymer drug-eluting stent with this indication.

Both the drug coating and the polymer—which modulates drug release—are fully absorbed shortly after drug elution is complete at three months.

The Synergy system is designed to enable more-rapid and complete arterial healing, thereby reducing the risk of complications associated with long-term polymer exposure compared with currently used drug-eluting stents with permanent polymers.

Results from the pivotal EVOLVE II trial—a global, randomized, single-blind, noninferiority study—demonstrated 0% definite stent thrombosis after 24 hours. Four-year EVOLVE trial data demonstrated a continued 0% stent-thrombosis rate and a target lesion revascularization rate of 1.1%.

Source: Boston Scientific, October 5, 2015

Laser-Based Hearing Aid

The FDA has allowed marketing of a new hearing aid that uses a laser diode and direct vibration of the eardrum to amplify sound. The combination of laser light pulses and a custom-fit device component that comes into direct contact with the eardrum is designed to use the patient’s own eardrum as a speaker and enables amplification over a wider range of frequencies for some hearing-impaired persons.

The EarLens Contact Hearing Device (EarLens Corporation) is indicated for use by adults with mild-to-severe sensorineural hearing impairment. The device consists of two parts: a tympanic membrane transducer (TMT), which is nonsurgically placed deeply into the ear canal on the eardrum, and a behind-the-ear (BTE) audio processor that sits on the outer ear and is connected to an ear tip that is placed in the ear canal.

External sound waves received by the BTE processor are converted to electronic signals, digitally processed, amplified, and sent to the ear tip, which contains a laser diode. There, the electronic signals of amplified sound are converted to pulses of light. The laser light pulses then shine onto a photodetector in the TMT, which converts the light back into electronic signals, transmitting sound vibrations directly to the eardrum by direct contact.

Source: FDA, September 29, 2015

Betaconnect Autoinjector for MS

The FDA has approved Betaconnect (Bayer HealthCare), the first electronic autoinjector for the treatment of relapsing-remitting multiple sclerosis. The device will be available exclusively to patients receiving Betaseron (Bayer’s interferon beta-1b) beginning in early 2016.

The autoinjector has an optional backup reminder function that lets patients know when it is time for their next injection. In addition, the automatic needle insertion and retraction with a visual and audio end-of-dose indication lets patients know when the injection is complete.

Source: Bayer HealthCare, September 25, 2015

Labor-Monitoring Device

The FDA has given the nod to a new fetal heart-rate monitoring unit, which will be integrated into the TrueLabor maternal fetal monitor (OB-Tools Ltd.).

The TrueLabor monitor uses electrodes attached to the abdomen and measures the electrical signals emitted by uterine contractions and fetal heart beats. These signals are unaffected by body movement, coughing, or obesity. The system is designed to work with any monitoring system or electronic medical records.

Source: OB-Tools Ltd., September 30, 2015

Test for CNS Infections

The FDA has allowed marketing of the first cerebrospinal fluid (CSF) nucleic acid-based test for simultaneous detection of multiple pathogens that can cause central nervous system (CNS) infections.

The FilmArray meningitis/encephalitis panel (BioFire Diagnostics) is designed to simultaneously test for 14 bacterial, viral, and yeast pathogens using CSF samples from patients who have signs and/or symptoms of meningitis or encephalitis. The test can provide results in about one hour. It is intended to aid in the diagnosis of those diseases when used in conjunction with other clinical and laboratory findings.

Currently, testing CSF for multiple organisms is not always possible because it can be difficult to obtain enough fluid from a patient to run multiple tests. Identification of the cause of bacterial CNS infections may take up to three days using current methods. Testing for viral infections may take even longer because many hospital laboratories do not perform such tests and must ship specimens to specialized laboratories for testing.

Source: FDA, October 8, 2015

Exablate for Uterine Fibroids

The FDA has approved the Exablate system (Insightec Ltd.) to treat symptomatic uterine fibroids and has changed the labeling to allow consideration for women who desire to maintain fertility. The updated labeling specifies that ablation of uterine fibroid tissue can now be considered for women with symptomatic uterine fibroids who want to retain fertility and spare their uterus.

The Exablate platform combines focused ultrasound, which is used to ablate the fibroid tissue, and magnetic resonance imaging, which is used to guide the ultrasound waves to the specific target tissue and to provide real-time feedback on treatment progress and outcome.

The Exablate platform was approved by the FDA for the treatment of the entire symptomatic fibroid tissue in 2009.

Source: Insightec Ltd., October 7, 2015

Brain Cancer Device

The FDA has approved an expanded indication for the Optune device (Novocure Inc.) to treat patients with newly diagnosed glioblastoma multiforme (GBM), an aggressive brain cancer. The device is used along with the chemotherapy drug temozolomide (TMZ) after standard treatments, which include surgery, chemotherapy, and radiation therapy.

In the clinical study used to support the expanded indication, patients treated with the device and TMZ lived on average three months longer than those treated with the drug alone.

The device was approved in 2011 to treat patients with GBM that recurred or progressed after chemotherapy. With the expanded indication, the device can now be used as part of a standard treatment for GBM before the disease progresses.

When using the device, health care professionals place electrodes on the surface of the patient’s scalp to deliver low-intensity, alternating electrical fields called tumor treatment fields (TTFs). The unique shape and special characteristics of rapidly dividing tumor cells make them susceptible to damage when exposed to TTFs, which may halt tumor growth.

The Optune device is portable and can be powered with batteries or plugged into an electrical outlet. Patients can use the device at home or work, allowing them to continue their normal daily activities.

Source: FDA, October 5, 2015

DEVICE SAFETY ISSUES

Bioprosthetic Aortic Valves

Despite reports of reduced leaflet motion in some bioprosthetic aortic valves, the FDA believes they “remain reasonably safe and effective when used according to their approved indications.”

Reduced leaflet motion has been reported in both surgical aortic valve replacement (SAVR) and transcatheter aortic valve replacement (TAVR) devices. Most cases were discovered by advanced imaging studies in patients without symptoms of abnormal valve function. These studies have shown that in valves with reduced motion of one or more individual leaflets, there was acceptable forward blood flow through the valve opening without evidence of stenosis.

Although no definitive cause is known, evidence from imaging studies suggests that thrombus deposits on the leaflets may restrict motion.

The FDA says its view that the valves remain reasonably safe is supported by the favorable risk–benefit profile observed in SAVR devices during the 30 years that they have been on the market and in TAVR devices during the eight years that they have been in use.

Source: FDA, October 5, 2015

Infections and Bronchoscopes

The FDA is recommending steps to ensure the safe use of bronchoscopes.

In March 2015, the agency listed bronchoscopes among the devices that pose a greater likelihood of microbial transmission and represent a high risk of infection if they are not adequately reprocessed. The FDA analyzed medical device reports (MDRs) from manufacturers and health care facilities and found that it had received 109 MDRs concerning infections or device contamination associated with flexible bronchoscopes between January 2010 and June 2015.

Compared with the annual number of U.S. bronchoscopy procedures, this is considered a small number of MDRs. However, in 2014, the FDA received 50 MDRs that mentioned infections or device contamination associated with reprocessed flexible bronchoscopes. An FDA analysis identified two recurrent themes: failure to meticulously follow manufacturer instructions for reprocessing, and continued use of devices despite integrity, maintenance, and mechanical issues. The FDA recommends that facilities that reprocess flexible bronchoscopes take the following precautions:

  • Strictly adhere to the manufacturer’s reprocessing instructions.
  • Immediately remove from service for assessment and repair or replacement any bronchoscope that fails a leak test or shows visible signs of damage.
  • Follow the manufacturer’s recommendations for preventive maintenance and repair of the device.
  • Implement a comprehensive reprocessing quality control program.
  • After reprocessing, store bronchoscopes in a way that minimizes the chance of contamination or the collection and retention of moisture according to the manufacturer’s instructions.

Source: FDA, September 17, 2015

Clutch Failure in Cranial Drills

The failure of automatic clutch mechanisms to stop cranial perforators from drilling into the brain caused more than 200 injuries over a decade, the FDA says.

Most cranial perforators are designed to stop drilling automatically after penetrating the skull to prevent the tip from entering the brain. However, this clutch mechanism may fail to disengage if proper use, patient considerations, and device selection are not followed in accordance with the manufacturer’s instructions.

From January 2005 through August 2015, the FDA received more than 300 medical device reports associated with the use of cranial perforators with an automatic clutch mechanism failing to disengage. Injuries included perforation of the dura mater, hemorrhage, brain contusion, cerebral tissue damage, and neurological deficit. The outcomes from these injuries included seizures, aphasia, delayed or prolonged hospital stays, and the need for additional procedures.

An FDA analysis suggests that failure to disengage is not specific to any manufacturer or brand of devices. The risk of these devices failing to disengage can be mitigated through proper use, patient considerations, and device selection in accordance with the device’s instructions for use.

Source: FDA, September 28, 2015

Freedom Driver Systems Recalled

The FDA has notified health care professionals of a class I recall of the Freedom Driver Systems used with the Syn-Cardia temporary total artificial heart. A specific part of the drive mechanism may fail and cause the device to stop pumping. Patients do not receive an advance warning that the device may fail. If it does fail, a red light in the center of the driver, toward the top, will stay red, and a loud continuous alarm will sound.

However, if the Freedom Driver stops pumping, the patient will lose consciousness almost immediately, so the warning light and alarm may not be helpful. The patient will likely experience serious injury or death if not immediately switched to a backup driver by a caregiver.

Source: FDA, September 18, 2015