NEW DRUG APPROVALS Cotellic for Melanoma The FDA has approved cobimetinib (Cotellic, Genentech) for use in combination with vemurafenib (Zelboraf, Genentech) to treat advanced (metastatic), unresectable melanoma with a BRAF V600E or V600K mutation. Cobimetinib blocks the activity of the MEK enzyme, which is part of a larger signaling pathway. Abnormal activity of signaling pathways can lead to cancer. Cobimetinib prevents or slows cancer cell growth. Vemurafenib is a BRAF inhibitor that affects a different part of the same pathway and was approved in 2011 to treat melanoma that has metastasized and is unresectable in patients whose tumors express the BRAF V600E gene mutation, as detected by an FDA-approved test. Health care providers should confirm the presence of a BRAF V600E or V600K mutation in their patients’ tumor specimens using one of these tests before starting treatment with cobimetinib in combination with vemurafenib. Source: FDA, November 10, 2015

Genvoya for HIV Genvoya (Gilead Sciences), a fixeddose combination tablet containing elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide, has received FDA approval as a complete regimen for the treatment of human immunodeficiency virus-1 (HIV-1) infection in adults and pediatric patients. Specifically, the treatment is approved for use in treatment-naïve, HIV-infected adults and children 12 years of age and older weighing at least 35 kg (77 pounds) and for HIV-infected adults whose HIV-1 virus is currently suppressed. Genvoya is not recommended for patients with severe renal impairment, but it can be taken by those with moderate renal impairment. Genvoya contains a new form of tenofo-

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vir that has not previously been approved. This new form of tenofovir provides lower levels of drug in the bloodstream, but higher levels within the cells where HIV-1 replicates. Genvoya appears to be associated with less renal toxicity and decreases in bone density than previously approved tenofovir-containing regimens. Source: FDA, November 5, 2015

Nucala for Severe Asthma The FDA has cleared mepolizumab (Nucala, GlaxoSmithKline) for use with other asthma medications in the maintenance treatment of asthma in patients 12 years of age and older. Nucala is approved for patients who have a history of severe asthma attacks (exacerbations) despite receiving other asthma medications. A health care professional administers mepolizumab once every four weeks by subcutaneous injection into the upper arm, thigh, or abdomen. The product is a humanized interleukin-5 antagonist monoclonal antibody produced by recombinant DNA technology in Chinese hamster ovary cells. Mepolizumab reduces severe asthma attacks by reducing the levels of blood eosinophils, which contribute to the development of asthma. The most common adverse events associated with mepolizumab include headache, injection-site reactions (pain, redness, swelling, itching, or burning), back pain, and fatigue.  Source: FDA, November 4, 2015

Utibron and Seebri for COPD The FDA has approved the dual combination bronchodilator indacaterol/glycopyrrolate (Utibron Neohaler, Novartis), an inhalation powder for the long-term maintenance treatment of airflow obstruction in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and/or emphysema. Utibron Neohaler is a twice-daily fixed-

dose combination of the long-acting beta2adrenergic agonist (LABA) indacaterol 27.5 mcg and the long-acting muscarinic antagonist (LAMA) glycopyrrolate 15.6 mcg. The FDA also approved Seebri Neohaler (glycopyrrolate) inhalation powder 15.6 mcg as a stand-alone monotherapy for the same COPD indication. Novartis expects that Seebri Neohaler will be available in the first quarter of 2016. Utibron and Seebri are not used to treat sudden symptoms of COPD and won’t replace a rescue inhaler. Utibron is not for the treatment of asthma. Source: Novartis, October 30, 2015

Imlygic for Melanoma Talimogene laherparepvec (Imlygic, Amgen) has become the first FDAapproved oncolytic virus therapy for the treatment of melanoma lesions in the skin and lymph nodes. Talimogene laherparepvec, a genetically modified live oncolytic herpes virus therapy, is used to treat melanoma lesions that cannot be removed completely by surgery. The therapy is injected directly into the melanoma lesions, where it replicates inside cancer cells and causes the cells to rupture and die.   A treatment course with Imlygic consists of a series of injections into the melanoma lesions. After the initial injection, a second dose is administered three weeks later, followed by additional doses every two weeks for at least six months, unless other treatment is required or until there are no remaining injectable lesions to treat. Source: FDA, October 27, 2015

Belbuca for Chronic Pain The FDA has approved buprenorphine hydrochloride buccal film (Belbuca, BioDelivery Sciences International/Endo Pharmaceuticals) for use in patients with chronic pain severe enough to require

daily, around-the-clock, long-term opioid treatment for which alternative treatment options are inadequate.  Buprenorphine is a Schedule III controlled substance, which means that it has been defined as having a lower abuse potential than Schedule II drugs, a category that includes most opioid analgesics. Belbuca is expected to become commercially available in the U.S. during the first quarter of 2016. Source: BioDelivery Sciences International, October 26, 2015

Strensiq for Hypophosphatasia Asfotase alfa (Strensiq, Alexion Pharmaceuticals) has been cleared by the FDA for the treatment of patients with perinatal-, infantile-, and juvenile-onset hypophosphatasia (HPP). Asfotase, an enzyme replacement therapy, is the first treatment approved in the U.S. for patients with HPP, a genetic, chronic, and progressive ultra-rare metabolic disease characterized by low alkaline phosphatase activity and defective bone mineralization. HPP can lead to deformity of the bones and other skeletal abnormalities, as well as systemic complications such as profound muscle weakness, seizures, pain, and respiratory failure leading to premature death in infants. The FDA’s approval was based on data from four clinical trials and supporting extension studies comprising patients with perinatal-, infantile- and juvenileonset HPP who received treatment with asfotase for up to 6.5 years. Source: Alexion Pharmaceuticals, October 23, 2015

Yondelis for Soft-Tissue Sarcomas The FDA has approved trabectedin (Yondelis, Janssen Products), a chemotherapy for specific soft-tissue sarcomas (STS)—liposarcoma and leiomyosarcoma—that are unresectable or advanced (metastatic). The treatment is approved

for patients who previously received chemotherapy that contained anthracycline. The efficacy and safety of trabectedin were demonstrated in 518 clinical trial participants with metastatic or recurrent leiomyosarcoma or liposarcoma who were randomly assigned to receive either trabectedin (n = 345) or dacarbazine (n = 173). Progression-free survival was approximately 4.2 months for trabectedin compared with 1.5 months for dacarbazine. The most common adverse events associated with trabectedin included nausea, fatigue, vomiting, diarrhea, constipation, decreased appetite, dyspnea, headache, peripheral edema, neutropenia, thrombocytopenia, anemia, elevated liver enzymes, and decreased albumin. Source: FDA, October 23, 2015

Vivlodex for OA Pain Meloxicam capsules (Vivlodex, Iroko Pharmaceuticals) have secured FDA approval for managing the pain of osteoarthritis (OA) in 5-mg and 10-mg doses administered once daily. The treatment was developed to align with recommendations from the FDA and professional medical organizations that nonsteroidal anti-inflammatory drugs (NSAIDs) be used at the lowest effective dose for the shortest possible duration. Vivlodex, developed using proprietary fine-particle technology, contains meloxicam as submicron particles that are approximately 10 times smaller than their original size. The reduction in particle size provides an increased surface area, leading to faster dissolution.  The FDA approval was based on data from a phase 3, double-blind, placebocontrolled study of 402 adults (40 years of age or older) with pain due to OA of the knee or hip, who were randomly assigned to receive treatment with oncedaily Vivlodex 5 mg, Vivlodex 10 mg, or placebo for 12 weeks. The Vivlodex doses

achieved efficacy at 33% lower doses than currently available meloxicam products.  Source: Iroko Pharmaceuticals, October 23, 2015

Onivyde for Pancreatic Cancer The FDA has approved irinotecan liposome injection (Onivyde, Merrimack Pharmaceuticals), in combination with fluorouracil and leucovorin, to treat patients with advanced (metastatic) pancreatic cancer who have previously been treated with gemcitabine-based chemotherapy. The effectiveness of irinotecan liposome injection was demonstrated in a three-arm, randomized, open-label study of 417 patients with metastatic pancreatic adenocarcinoma whose cancer had grown after receiving gemcitabine or a gemcitabine-based therapy. Patients treated with irinotecan plus fluorouracil/leucovorin lived an average of 6.1 months, compared with 4.2 months for those treated with fluorouracil/ leucovorin. There was no sur vival improvement for those who received only irinotecan compared with those who received fluorouracil/leucovorin. The labeling for Onivyde includes a boxed warning about the risks of severe neutropenia and diarrhea. Source: FDA, October 22, 2015

Veltassa for Hyperkalemia Patiromer for oral suspension (Veltassa, Relypsa Inc.) has been approved by the FDA for the treatment of hyperkalemia. Patiromer, a powder that patients mix with water and take by mouth, works by binding potassium in the gastrointestinal tract, thereby decreasing its absorption. In clinical trials, Veltassa was effective in lowering potassium levels in hyperkalemic subjects with chronic kidney disease who were being treated with at least one drug that inhibited the renin– angiotensin–­aldosterone system.

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In clinical trials, the most common adverse events reported by participants treated with patiromer were constipation, hypomagnesemia, diarrhea, nausea, abdominal discomfort, and flatulence. The use of patiramer is not appropriate for rapid correction of severe hyperkalemia because lowering of serum potassium may take hours to days. Source: FDA, October 21, 2015

Coagadex for Factor X Deficiency The FDA has approved coagulation factor X, human (Coagadex, Bio Products Laboratory Ltd.) for hereditary factor X deficiency. Prior to this orphan drug approval, no specific coagulation factor replacement therapy was available for patients with factor X deficiency. Coagadex, which is derived from human plasma, is indicated for individuals 12 years of age and older with hereditary factor X deficiency for on-demand treatment and control of bleeding episodes, and for perioperative management of bleeding in patients with mild hereditary factor X deficiency. Patients with factor X deficiency are usually treated with fresh-frozen plasma or plasma-derived prothrombin complex concentrates (plasma products containing a combination of vitamin K-dependent proteins) to stop or prevent bleeding. Source: FDA, October 20, 2015

Dyanavel XR for ADHD The FDA has approved an extendedrelease oral-suspension formulation of amphetamine, CII (Dyanavel XR, Tris Pharma) for the treatment of attentiondeficit/hyperactivity disorder (ADHD) in children 6 years of age and older. The approval was based on results from a phase 3, randomized, placebocontrolled, laboratory classroom efficacy study conducted in 108 children (ages 6 to 12 years) who met DSM-IV criteria for ADHD. The study, which included a

five-week, open-label, dose-optimization phase followed by a one-week, doubleblind treatment phase, met its primary endpoint of a change from predose in the Swanson, Kotkin, Agler, M-Flynn, and Pelham (SKAMP) combined score at four hours after dosing. Dyanavel XR also met key secondary endpoints by demonstrating an onset of clinical effect at one hour that persisted through 13 hours after dosing compared with placebo. The most common adverse events included epistaxis, allergic rhinitis, and upper abdominal pain. Source: Tris Pharma, October 20, 2015

Enstilar for Plaque Psoriasis The FDA has approved calcipotriene and betamethasone dipropionate foam (Enstilar, Leo Pharma) for the topical treatment of plaque psoriasis in adults 18 years of age and older. Enstilar is a once-daily, alcohol-free foam formulation in a pressurized spray can. In a pivotal phase 3 clinical study, more than half of the patients treated with Enstilar were clear or almost clear by week 4, as indicated by the Investigator’s Global Assessment score of disease severity. In addition, more than half of the patients treated with Enstilar achieved a 75% improvement in scores on the Psoriasis Area and Severity Index from baseline. Adverse events—reported in less than 1% of patients treated with Enstilar—included application-site irritation, application-site pruritus, folliculitis, skin hypopigmentation, hypercalcemia, urticaria, and exacerbation of psoriasis. Source: Leo Pharma, October 19, 2015

Generic Approvals Memantine Oral Solution Silarx Pharmaceuticals and Macleods Pharmaceuticals have received FDA approval to produce memantine hydrochloride oral solution 2 mg/mL, the first generic equivalents to Namenda oral solu-

tion 2 mg/mL (Forest Pharmaceuticals).  The drug is used to treat dementia associated with Alzheimer’s disease. Sources: Lannett Company, October 14, 2015, and FDA, October 15, 2015

Palonosetron Hydrochloride The FDA has approved the first generic formulations of palonosetron hydrochloride injection, marketed as Aloxi Injection by Helsinn Healthcare. Teva Pharmaceuticals USA can sell the drug in 0.25 mg/5 mL and 0.075 mg/1.5 mL formulations, while Sandoz Inc. can sell the 0.25 mg/5 mL product. Aloxi is a serotonin 5-HT3 receptor antagonist indicated for prevention of nausea and vomiting associated with chemotherapy or following surgery. Sources: FDA, October 13, 2015, and Aloxi prescribing information

Itraconazole Oral Solution The FDA has approved Amneal Pharmaceuticals’ itraconazole oral solution, 10 mg/mL, the first generic version of Sporanox oral solution (Janssen Pharmaceuticals ). Itraconazole oral solution is an azole antifungal agent indicated for empiric therapy of febrile neutropenic patients with suspected fungal infections and for the treatment of oropharyngeal and esophageal candidiasis. Sources: FDA, October 30, 2015, and Sporanox prescribing information

Morphine Sulfate Oral Solution Vintage Pharmaceuticals has received FDA permission to market morphine sulfate oral solution, 20 mg/5 mL (4 mg/mL). According to the FDA, this is the first generic version of Roxane Laboratories’ Morphine Sulfate Oral Solution. Source: FDA, October 30, 2015

Potassium Chloride Extended-Release A generic version of KlorCon (potassium chloride, Upsher-Smith Laboratories/Sandoz Pharmaceuticals) extendedcontinued on page 799

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release tablets (600 mg and 750 mg) has been approved by the FDA for the treatment and prevention of hypokalemia. The new product is manufactured by Perrigo Company. Source: Perrigo Company, November 10, 2015

NEW INDICATION Yervoy for Stage III Melanoma The FDA has expanded the approved use of ipilimumab (Yervoy, Bristol-Myers Squibb) to include a new use as adjuvant therapy for patients with stage III melanoma to lower the risk that the melanoma will return after surgery. Ipilimumab, administered intravenously, was approved in 2011 to treat late-stage, unresectable melanoma. The product is a monoclonal antibody that blocks cytotoxic T-lymphocyte antigen (CTLA-4), a molecule that may interfere with the immune system’s ability to fight off cancerous cells. Ipilimumab is believed to work by allowing the immune system to recognize, target, and attack cells in melanoma tumors. Source: FDA, October 28, 2015

DRUGS UNDER REVIEW Fast-Track Designation CAM2038 for Opioid Addiction The FDA has granted a fast-track designation for the CAM2038 weekly and monthly buprenorphine subcutaneous injection products under development for the treatment of opioid addiction. So far, the products have been evaluated in 176 healthy volunteers and patients in three short-term clinical trials.  According to the developers (Braeburn Pharmaceuticals/Camurus), CAM2038 has the potential to improve medication adherence and to help patients avoid relapse, a critical aspect of a comprehensive approach to treating opioid addiction. The first patient has been dosed in a phase 2 study designed to assess the

effectiveness of CAM2038 in blocking the effects of other opioids.  Source: Braeburn Pharmaceuticals, November 5, 2015

Breakthrough Therapies

TGCT for whom surgical removal of the tumor would be associated with potentially worsening functional limitation or severe morbidity. Source: Daiichi Sankyo, October 30, 2015

SD-809 for Tardive Dyskinesia The FDA has granted breakthrough therapy status to SD-809 (deutetrabenazine, Teva Pharmaceutical Industries Ltd.) for the treatment of patients with moderate-to-severe tardive dyskinesia, a hyperkinetic movement disorder. Deutetrabenazine is an investigational, oral, small-molecule inhibitor of vesicular monoamine 2 transporter that is designed to regulate levels of the neurotransmitter dopamine in the brain. It is being developed for the treatment of chorea associated with Huntington’s disease, a neurodegenerative movement disorder that affects cognition, behavior, and movements. Source: Teva Pharmaceuticals, November 9, 2015

Pembrolizumab for Colorectal Cancer

Pexidartinib for Giant Cell Tumor

Pembrolizumab (Keytruda, Merck), an anti-programmed death-1 therapy, has received an FDA breakthrough therapy designation for the treatment of patients with microsatellite instability high metastatic colorectal cancer. Pembrolizumab previously received breakthrough therapy status for advanced melanoma and advanced non–small-cell lung cancer. The designation for advanced colo­ rectal cancer was based on data from a phase 2 study evaluating the activity of pembrolizumab in cancers with microsatellite instability, a well-established feature seen in cells with certain types of DNA repair defects. The findings were published in the New England Journal of Medicine. Source: Merck, November 2, 2015

The FDA has granted a breakthrough therapy designation to pexidartinib (Daiichi Sankyo/Plexxikon) for the treatment of tenosynovial giant cell tumor (TGCT) where surgical removal of the tumor would be associated with potentially worsening functional limitation or severe morbidity. Pexidartinib is an investigational, oral small molecule that selectively inhibits the colony-stimulating factor 1 receptor, which is a primary growth driver of abnormal cells in the synovium that causes TGCT. The breakthrough therapy designation was granted based on results from an extension cohort of a single-arm, phase 1 study that assessed the safety and efficacy of pexidartinib. A pivotal, phase 3 study of pexidartinib (ENLIVEN) is enrolling patients with symptomatic

The investigational antibody–drug conjugate inotuzumab ozogamicin has received a breakthrough therapy designation from the FDA for the treatment of patients with acute lymphoblastic leukemia (ALL). The designation was based on the results from the phase 3 INO-VATE ALL trial, which enrolled 326 adults with relapsed or refractory CD22-positive ALL and compared inotuzumab ozogamicin with standard-of-care chemotherapy. Top-line results from this study were announced in April 2015. Inotuzumab ozogamicin consists of a monoclonal antibody that targets CD22, a cell-surface antigen expressed on approximately 90% of B-cell malignancies linked to a cytotoxic agent. When inotuzumab

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ozogamicin binds to the CD22 antigen on malignant B cells, it is internalized into the cell, where the cytotoxic agent calicheamicin is released to destroy the cell. Source: Pfizer, October 19, 2015

Orphan Drug Designation

and commercialization rights to Evomela from Ligand Pharmaceuticals in March 2013. Spectrum assumed responsibility for completing a pivotal phase 2 clinical trial, and was responsible for filing the NDA.  Source: Spectrum Pharmaceuticals, October 23, 2015

Exenatide for Short Bowel Syndrome NB1001 (Xten-GLP-1, Naia Rare Diseases), a long-acting glucagon-like peptide-1 (GLP-1) receptor agonist, has been granted orphan drug status for the treatment of patients with short bowel syndrome. NB1001 combines exenatide with a proprietary extended half-life technology. If approved, NB1001 will be administered as a replacement therapy (replacing endogenous GLP-1 lost by bowel resection), in contrast to GLP-1 agonists used to treat type-2 diabetes, which are administered at pharmacological levels to lower blood sugar. It is expected that lower doses of NB1001 combined with a longer half-life will provide a safe and effective therapeutic approach for these patients. Source: Naia Ltd., October 20, 2015

Complete Response Letters Evomela for Multiple Myeloma The biotechnology company Spectrum Pharmaceuticals has received a complete response letter (CRL) from the FDA about its propylene glycol-free melphalan formulation (Evomela) for multiple myeloma. A CRL is a communication from the FDA that tells companies that a new drug application (NDA) cannot be approved in its present form. In the letter, the FDA did not identify any clinical deficiencies in the NDA package. Evomela’s formulation eliminates the need to use a propylene glycol-­containing diluent, which is required with other intravenous melphalan formulations and has been reported to cause renal and cardiac adverse effects.  Spectrum obtained global development

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Lifitegrast for Dry Eye Disease The FDA has requested an additional clinical study as part of a complete response letter (CRL) to the new drug application for lifitegrast (Shire) for the signs and symptoms of dry eye disease in adults. Shire recently completed a phase 3 study of lifitegrast (OPUS-3) that is expected to support the company’s response to the CRL. The FDA also requested more information about product quality, which Shire will address in its CRL response. Top-line results are expected from OPUS-3 before the end of 2015, and, if positive, Shire plans to include the data in its resubmission to the FDA during the first quarter of 2016. Lifitegrast is a small-molecule integrin inhibitor. It binds to the integrin LFA-1 (lymphocyte function-associated antigen-1), a cell-surface protein found on leukocytes, and blocks the interaction of LFA-1 with its cognate ligand ICAM-1 (intercellular adhesion molecule-1). ICAM-1 is overexpressed in corneal and conjunctival tissues in dry eye disease. Source: Shire, October 16, 2015

DRUG SAFETY ISSUES Mortality Unchanged After Long-Term Plavix Treatment An FDA review has determined that long-term use of the blood-thinner clopidogrel (Plavix) does not increase or decrease the overall risk of death in patients with or at risk for heart disease. The FDA evaluation of the Dual Antiplatelet Therapy (DAPT) trial and several other clinical trials also does not

suggest that clopidogrel increases the risk of cancer or death from cancer. To investigate the increased risk of death and cancer-related death reported with clopidogrel in the DAPT trial, the FDA examined the results of this study and other large, long-term clinical studies of clopidogrel with data available on rates of death, death from cancer, or cancer reported as an adverse event. The FDA performed meta-analyses of other long-term clinical trials to assess the effects of clopidogrel on death rates from all causes. The results indicate that long-term (12 months or longer) dual antiplatelet therapy with clopidogrel and aspirin do not appear to change the overall risk of death compared with shortterm (six months or less) clopidogrel and aspirin or aspirin alone. In addition, there was no apparent increase in the risks of cancer-related deaths or cancer-related adverse events with long-term treatment. The FDA is working with the manufacturers of clopidogrel (Bristol-Myers Squibb/Sanofi) to update the label to reflect the results of the mortality meta-analysis. Source: FDA, November 6, 2015

FDA: Cardiovascular Risk Is No Higher With Comtan An FDA safety review has found no clear evidence of an increased risk of heart attacks, stroke, or other cardiovascular events associated with the use of entacapone (Comtan, Novartis) for the treatment of patients with Parkinson’s disease. As a result, recommendations for using entacapone and a combination of entacapone, carbidopa, and levodopa (Stalevo) will remain the same in the drug labels. The FDA alerted health care professionals about a possible increased risk for cardiovascular events and death with Stalevo in August 2010. The agency required the manufacturer, Novartis, to study the potential for cardiovascular risk with

the entacapone component of the drug. The FDA examined the results from this required study and from one additional study and concluded that they did not show an increased risk of cardiovascular adverse events with entacapone.  Source: FDA, October 26, 2015

Kayexalate Drug Interactions The FDA is requiring Concordia Pharmaceuticals, the manufacturer of the potassium-lowering drug Kayexalate (sodium polystyrene sulfonate), to conduct studies to investigate that product’s potential to bind to other medications administered by mouth—drug interactions that could affect how well the other medications work. The approved labeling for Kayexalate describes its potential to reduce the absorption of lithium and thyroxine; however, extensive drug–drug interaction studies with Kayexalate have not been performed. During the FDA’s review of another potassium-lowering drug, patiromer (Veltassa, Relypsa, Inc.), the agency found that patiromer bound to about half of the medications tested, some of which are commonly used in patients who require potassium-lowering drugs. Such binding could decrease the effects of these medications, according to the FDA. Similar to patiromer, Kayexalate may also bind to other medications administered by mouth. To reduce this potential risk, prescribers and patients should consider separating Kayexalate dosing from other medications taken by mouth by at least six hours. This includes both prescription medications, such as anti­ biotics, blood pressure-lowering agents, and blood thinners, and those purchased over-the-counter without a prescription, such as antacids and laxatives. Health care professionals should monitor blood levels or clinical response to the other medications when appropriate. Source: FDA, October 22, 2015

HCV Drugs May Harm Liver The FDA has warned that the hepatitis C treatments Viekira Pak and Technivie can cause serious liver injury, mostly in patients with underlying advanced liver disease. The agency is requiring the manufacturer of both products (AbbVie) to add information about serious liverinjury adverse events to sections of the two products’ labels. Viekira Pak is a fixed-dose combination of dasabuvir, ombitasvir, paritaprevir, and ritonavir used with or without ribavirin. Technivie is a fixed-dose combination of ombitasvir, paritaprevir, and ritonavir, used in combination with ribavirin. FDA review of adverse events reported to the FDA Adverse Event Reporting System (FAERS) database and to AbbVie identified cases of hepatic decompensation and liver failure in patients with underlying liver cirrhosis who were taking these medications. Some of these events resulted in liver transplantation or death. These serious outcomes were reported mostly in patients taking Viekira Pak who had evidence of advanced cirrhosis before starting treatment. Source: FDA, October 22, 2015

Sanofi Recalls Auvi-Q Injections Sanofi has recalled all Auvi-Q (epinephrine injection, USP) on the market, including both the 0.15-mg and 0.3-mg strengths for hospitals, retailers, and consumers. This includes lot numbers 2299596 through 3037230, which expire March 2016 through December 2016. The products were found to potentially have inaccurate dosage delivery. Auvi-Q is used to treat life-threatening allergic reactions (anaphylaxis) in people who are at risk for or have a history of these reactions. The product is packaged with two active devices and one trainer device in a corrugated box. Source: Sanofi, October 28, 2015

OTHER DRUG NEWS Track and Trace Rules Delayed The FDA announced in late October that it would delay enforcement of “track and trace” requirements, which had been scheduled to start on November 1, 2015, until March 1, 2016. Provisions of the Drug Supply Chain Security Act (DSCSA) require that prescription drug data be tracked through the supply chain, from the manufacturer to the end user or dispenser. Hospitals and health systems must collect and store information provided by manufacturers that identifies drug products to the lot level. The requirements were originally scheduled to take effect on July 1, 2015. Representatives of the American Society of Health-System Pharmacists (ASHP) met with FDA officials to discuss concerns with implementation, including unresolved questions about certain exceptions from the DSCSA requirements. The ASHP had sent a letter to agency officials describing significant challenges to compliance with the requirements, including the time needed by institutions to put in place data collection and storage processes. Sources: FDA and ASHP, October 29, 2015

Oncology Group Rates Blood Cancer Regimens The National Comprehensive Cancer Network (NCCN) has issued ratings aimed at helping doctors and patients assess the costs and benefits of current therapies for chronic myelogenous leukemia (CML) and multiple myeloma. Ratings for the primary CML treatments—dasatinib (Sprycel, Bristol-Myers Squibb), matinib (Gleevec, Novartis), and nilotinib (Tasigna, Novartis)—were nearly identical. All three were scored as highly effective but very expensive. For newly diagnosed myeloma patients eligible for a stem cell transplant, the

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NCCN listed six “preferred” regimens— four containing bortezomib (Velcade, Takeda) and various chemotherapies; one with lenalidomide (Revlimid, Celegen Corp.); and another that combines bortezomib and lenalidomide. A bortezomib/ lenalidomide/dexamethasone regimen was rated as the most effective and the most expensive. The NCCN listed carfilzomib (Kyprolis, Amgen) with lenalidomide and dexamethasone as another first-line myeloma regimen, but it was not “preferred” because pivotal trial results are still pending. The carfilzomib regimen was rated as highly effective, mildly toxic, and very expensive. Source: Reuters, October 16, 2015

Beloranib Study to Continue Zafgen, Inc., will proceed with efficacy and safety analyses and close the randomized portion of its phase 3 ZAF-311 trial of the weight-loss drug beloranib in patients with Prader-Willi syndrome (PWS) and its ZAF-203 phase 2b trial of beloranib in patients with severe obesity complicated by type-2 diabetes. Previously, Zafgen learned of a patient death in the ZAF-311 trial, and it subsequently received notice from the FDA that beloranib had been placed on a partial clinical hold. The cause of the subject’s death was determined to be respiratory failure due to pulmonary emboli; it is not known whether this was related to beloranib treatment. Beloranib is a first-in-class injectable small-molecule therapy with a mechanism of action that reduces hunger while stimulating the use of stored fat as an energy source. The drug is a potent inhibitor of MetAP2, an enzyme that modulates the activity of key cellular processes that control metabolism. Source: Zafgen, Inc., October 22, 2015

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RESEARCH BRIEFS Buy Food, or Medicine? Deciding whether to spend limited money on food or medicine may be seen mainly as a problem of the elderly, but similar issues affect households of younger adults, according to researchers from California State University Northridge, the University of California at Los Angeles, and the U.S. Department of Agriculture. The researchers analyzed data from 67,539 respondents to the 2011 and 2012 National Health Interview Survey. Of those, 26% reported at least one instance in the previous 12 months of cost-related medication underuse, such as skipping doses, taking less medication than prescribed, and delaying filling a prescription. The likelihood of engaging in all the behaviors rose with increasing food insecurity (the limited or uncertain availability of food). Among the food secure, fewer than 5% reported skipping medication to save money, compared with 30% of those with very low food security. Other factors associated with costrelated medication underuse were being female; being a single parent; having no or partial health care coverage; and having a chronic condition, functional or other limitation, or severe mental illness. But while other factors might be present, the authors say, food insecurity prevailed. Using a more detailed food-security measure, they found a dose–response relationship between food security and cost-related medication underuse. Even among the fully insured, the authors wrote, “health insurance cannot fully overcome the economic hardships faced by food-insecure households.” Source: American Journal of Public Health, October 2015

Young Patient With Old Hearts Three out of four U.S. adults have a predicted heart age five years or more older than their actual age, according to a study

from the Centers for Disease Control and Prevention (CDC). Using findings from the Framingham Heart Study and data collected from every U.S. state, CDC projections show that around 69 million adults who haven’t had a heart attack or stroke have an “older” heart—on average, seven years older. In men, the average is eight years older; in women, five years. The hearts of African-Americans were an average of 11 years older for both sexes. Mississippi, West Virginia, Louisiana, Kentucky, and Alabama had the highest percentage of adults with heart ages five or more years older than their actual age. Utah, Colorado, California, Massachusetts, and Hawaii had the lowest percentage. The “heart age” concept, the CDC says, was created to more effectively communicate a person’s risk of dying from heart attack or stroke, and to show what can be done to lower the risk. The CDC advises using calculators such as the one it provides ( heartage.htm) or others recommended by national guidelines to assess cardiovascular risk and heart age for patients ages 30 to 74, and then discussing preventive steps with your health care provider. Source: CDC, September 2015

Alcohol, Insomnia: a Bad Mix Excessive drinking and insomnia are bad enough on their own, but combined they may aggravate psychosocial problems, according to a University of Pennsylvania study. In the study, 75% of 123 participants reported having insomnia: 36 mild cases and 56 moderate-to-severe cases. On average, participants said they’d had 15.7 drinks per day over the previous 90 days. The only difference between the insomnia groups was on the number of heavy-drinking days: Those with moderate-to-severe insomnia had a significantly higher number. Insomniacs also reported

a higher need for addiction treatment, compared with the no-insomnia subjects. Individuals with moderate-to-severe insomnia had significantly higher scores on the total Short Index of Problems scale, as well as higher subscale scores for physical problems, social problems, and impulse control problems. They had the highest scores for serious conflict with others over the previous month and lifetime conflicts with spouses and mothers. Employment problems increased significantly with severity of insomnia symptoms. Insomnia is associated with psycho­ social problems, the researchers note. It’s possible, they say, that people plagued with insomnia and its related symptoms of irritability and anxiety are self-­ medicating with alcohol. They add that suicidal ideation is common among this group of patients and may be exacerbated by insomnia. Source: Addictive Behaviors, November 2015

Vaccination Persuasion When health care providers talk with parents about vaccinations, “subtle modifications” in approach can make a big difference, say researchers from the University of Washington, Portland State University, the University of California at Los Angeles, and Seattle Children’s Research Institute. The researchers sought to learn whether a participator y format (e.g., “What do you want to do about shots?”) was more likely to influence parents to get their children vaccinated than a presumptive format (e.g., “Well, we have to do some shots today.”). They videotaped 16 interactions between pediatric providers and parents at nine primary care practices. The researchers sur veyed eligible parents (89% mothers) for “vaccine hesitancy.” They described their objective generally as simply seeking to understand

parent-provider communication. They also embedded the Parent Attitudes About Childhood Vaccines survey into a larger survey about common childhood topics. The parents completed questionnaires after the visit, before leaving the clinic. Most of the time, providers initiated the discussion, usually (74%) using the presumptive format. Parents voiced resistance to vaccine recommendations in 38 encounters (41%); providers immediately continued to advocate for their original vaccine recommendations in 19 cases (50%). Overall, 64% of parents accepted all recommended vaccines and 72% rated their visit experience highly. When parents voiced initial resistance but the provider stuck with the original recommendation, significantly more parents accepted all vaccines. Providers were more likely to pursue their recommendations if they began with the presumptive format. Significantly fewer parents accepted all vaccines when providers used the participatory format—but significantly more parents rated their visit experience highly when the participatory format was used. Practitioners might need to “leverage the inherent value” of the participatory format to cultivate a strong relationship with parents, the researchers suggest, thus helping ensure acceptance of vaccines in the long run as opposed to a more forceful short-term approach. Managing that fine line isn’t easy, the researchers admit. Source: American Journal of Public Health, October 2015

Entresto Reduces Readmissions A new analysis shows that fewer heart failure patients with reduced ejection fraction treated with sacubitril/valsartan tablets (Entresto, Novartis) were readmitted to the hospital for heart failure or for any cause within 30 days of discharge from a heart failure hospitalization compared with patients treated with enalapril (Vasotec, Valeant Pharmaceuticals), Novartis says.

In a post hoc analysis of findings from the PARADIGM-HF trial—the largest clinical study ever conducted in heart failure—44% fewer patients treated with sacubitril/valsartan were readmitted for heart failure, and 36% fewer patients were readmitted for any cause, within 30 days. In general, about one in four patients is readmitted within 30 days of a hospitalization for heart failure. Entresto was approved in July 2015 to reduce the risk of cardiovascular death and hospitalization for heart failure in patients with chronic heart failure (New York Heart Association class II to IV) and reduced ejection fraction. Source: Novartis, November 10, 2015

Sovaldi May Slow Heartbeats The hepatitis C drug sofosbuvir (Sovaldi, Gilead Sciences) may trigger an abnormally slow heartbeat and put patients at risk of passing out, according to French doctors. Their report, in a letter to the New England Journal of Medicine, detailed episodes of a slowing heart rate that developed within the first 10 days of sofosbuvir therapy in three of 415 patients treated in 2014 at the Hôpital Cochin’s hepatology and cardiology group in Paris. All three patients received pacemakers within a week to ensure that their hearts maintained a healthy rhythm.  The affected patients were also taking other antiviral drugs for their hepatitis C infections, with two receiving daclatasvir (Daklinza, Bristol-Myers Squibb) plus a handful of additional medications for various ailments. The third patient was receiving the antiarrhythmic agent amiodarone. Source: Bloomberg Business, November 4, 2015

Saxenda Leads to Weight Loss Treatment with liraglutide (Saxenda, Novo Nordisk) in combination with a reduced-calorie diet and increased physi-

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cal activity resulted in significant and sustained weight loss over a three-year period, according to data presented at ObesityWeek 2015. A three-year extension of the phase 3a SCALE trial involved 2,254 adults who were obese or overweight with comorbidities and had prediabetes at baseline. The extension data compared treatment with liraglutide, a reduced-calorie diet, and increased physical activity to treatment with a placebo (i.e., reduced-calorie diet and increased physical activity alone). At week 160, the average body weight loss from baseline was 6.1% among subjects randomly assigned to treatment with liraglutide (n = 1,505) compared with 1.9% among placebo-treated subjects (n = 749); 49.6% of adults treated with liraglutide achieved at least 5% weight loss, compared with 23.7% of adults given placebo. In addition, 24.8% lost more than 10% of their body weight when treated with liraglutide, compared with 9.9% of those treated with placebo. Moreover, 52.6% of adults treated with liraglutide completed the 160-week extension trial compared with 45.0% of those in the placebo group. Source: Novo Nordisk, November 4, 2015

Crisaborole for Atopic Dermatitis A phase 3 safety study yielded positive results for Crisaborole topical ointment, 2% (Anacor Pharmaceuticals), a nonsteroidal anti-inflammatory phosphodiesterase 4 (PDE-4) inhibitor in development for the potential treatment of mild-to-moderate atopic dermatitis in children and adults. No treatment-related serious adverse events were reported, and most adverse events were transient and mild in severity. The most common treatment-related adverse events were atopic dermatitis (3.1%) and application-site pain (2.3%). The open-label study was designed to evaluate the long-term safety of cri-

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saborole in subjects as young as 2 years of age. Crisaborole was administered to patients in four-week treatment periods for up to 12 months. The study enrolled 517 subjects, 396 of whom completed six months of intermittent treatment and 271 of whom completed 12 months of intermittent treatment. Source: Anacor Pharmaceuticals, October 29, 2015

Pembrolizumab Outdoes Chemo in NSCLC Patients A top-line analysis of data from the phase 2/3 KEYNOTE-010 study showed that treatment with pembrolizumab (Keytruda, Merck) was associated with longer survival than docetaxel in patients with advanced non–small-cell lung cancer (NSCLC). The randomized, pivotal study compared two doses of pembrolizumab (the FDA-approved 2-mg/kg dose and a higher, investigational 10-mg/kg dose, each given every three weeks) with docetaxel (75 mg/m2 every three weeks) in 1,034 NSCLC patients. All of the patients had failed prior systemic therapy for advanced NSCLC and had tumors with programmed death ligand-1 (PD-L1) expression tumor proportion scores (TPS) of 1% or more. Tumor response was assessed at week 12 and every six weeks thereafter. The top-line analysis showed that pembrolizumab was associated with longer overall survival than docetaxel. In addition, treatment with pembrolizumab at both doses provided superior progression-free survival compared with that achieved after treatment with docetaxel in patients whose tumors had TPS values equal to or greater than 50%. Source: Merck, October 26, 2015

Genvoya Effective for HIV Gilead Sciences has announced 96-week results from two phase 3 studies evaluating its once-daily, single-tablet

regimen Genvoya (elvitegravir 150 mg, cobicistat 150 mg, emtricitabine 200 mg, and tenofovir alafenamide 10 mg) for the treatment of human immunodeficiency virus-1 (HIV-1) infection in 1,733 treatment-naïve adults. The data were presented at the 15th European AIDS Conference in Barcelona, Spain. Genvoya was found to be statistically noninferior to Stribild (elvitegravir 150 mg, cobicistat 150 mg, emtricitabine 200 mg, and tenofovir disoproxil fumarate 300 mg, Gilead), based on percentages of patients with HIV-1 RNA levels of less than 50 copies/mL (87% versus 85%, respectively). Patients treated with Genvoya also had improved renal and bone laboratory parameters compared with those treated with Stribild. Source: Gilead Sciences, October 22, 2015

Natalizumab Fails MS Study A phase 3 trial investigating natalizumab (Tysabri) in the treatment of secondary progressive multiple sclerosis (SPMS) did not achieve its primary and secondary endpoints, according to Biogen, the drug’s manufacturer. ASCEND evaluated the ability of natalizumab to slow the accumulation of disability progression unrelated to relapse in SPMS patients—an unmet medical need. The study’s composite primary endpoint evaluated the percentage of patients whose disability had progressed on one or more of three disability measurements. In the U.S., natalizumab is indicated as monotherapy for patients with relapsing forms of MS. Source: Biogen, October 21, 2015

Ustekinumab in Crohn’s Disease Treatment with ustekinumab (Stelara, Janssen) induced a clinical response and clinical remission in patients with moderate-to-severe Crohn’s disease who had failed conventional therapy, phase 3

data have shown. Most of the patients were naïve to treatment with antitumor necrosis factor (TNF)-alpha. In the UNITI-2 trial, ustekinumab treatment groups demonstrated significantly higher clinical response rates at week 6 compared with the placebo group. Clinical response and clinical remission at week 8 were also significantly higher among patients receiving ustekinumab compared with patients receiving placebo.  Ustekinumab, approved for the treatment of moderate-to-severe plaque psoriasis and active psoriatic arthritis in many countries, is a monoclonal antibody that targets interleukin (IL)-12 and IL-23 cytokines, which are believed to play a role in immune-mediated diseases, including Crohn’s disease.  Source: Janssen, October 19, 2015

Wearable Ventilator for COPD The use of a wearable ventilator system by patients with chronic obstructive pulmonary disease (COPD) with chronic respiratory insufficiency was associated with a significant improvement in overall respiratory health, according to data presented at the annual meeting of the American College of Chest Physicians (CHEST 2015). The study evaluated 16 stable oxygen-dependent patients with moderate to very severe COPD who were using a one-pound wearable Non-Invasive Open Ventilation (NIOV) system (Breathe Technologies) as a complement to their standard medical regimen. COPD Assessment Test (CAT) and modified Medical Research Council (mMRC) scores improved significantly in the post-NIOV implementation period. In addition, the researchers estimated total cost reductions across the study population of between 68% and 96%. Source: Scio Health Analytics, October 26, 2015

DEVICE APPROVALS LiverMultiscan MRI Device The LiverMultiScan imaging device, which can detect early liver disease using magnetic resonance imaging (MRI), has received 510(k) clearance from the FDA. The device was formally launched at the 2015 American Association for the Study of Liver Disease (AASLD) Liver Meeting, held in San Francisco in November. Used in the clinical management of patients with chronic liver disease, LiverMultiScan is the only imaging test cleared to detect early-stage liver disease. The technology offers a quantitative liver assessment in a noninvasive 15-minute MRI scan. Analysis is based on the assessment of native properties of liver tissue, accurate measurement of liver fat, and other metrics without the need for additional diagnostic technologies or contrast agents. Source: Perspectum Diagnostics, November 12, 2015

Kator Suture Anchors The FDA has granted 501(k) clearance to the Kator suture anchor system for tissue-to-bone attachment. When applied to arthroscopic rotator cuff repair surgery, the system provides knotless fixation with suture anchors that are loaded with four high-strength sutures, with the ability to independently tension each suture. According to the system’s manufacturer (Kator LLC), the system allows surgeons to repair torn rotator cuffs using fewer suture anchors, thereby preserving more bone and increasing the “footprint” area available for tendon healing. Source: Kator, November 10, 2015

Expandable Opticage The FDA has approved the Opticage expandable interbody fusion device, an enhanced version of the original Opticage system that was approved in 2012. According to the manufacturer (Inter-

ventional Spine, Inc.), the new device offers an improved ability to deliver graft material through the implant after expansion, has a streamlined profile compared with that of the previous implant, and has improved ergonomics. Source: Inter ventional Spine, Inc., November 10, 2015

Cellvizio in Cancer Surgery Cellvizio, a confocal laser endomicroscopy platform, has received 510(k) clearance from the FDA for use in surgery. Using the Celioflex probe, surgeons can obtain real-time microscopic images of tissue during a procedure, allowing them to identify cancerous tissue and to guide treatment during surgery. According to the manufacturer (Mauna Kea Technologies), the Celioflex probe may be delivered endoscopically or laparoscopically through a trocar and manipulated in the surgical field with standard laparoscopic hand-held instruments. With real-time visualization of tissue during surgery, surgeons may be better able to confirm the absence or presence of metastasis that may not be visible using preoperative imaging. Cellvizio may also make it easier to identify the extent of tumor margins and to evaluate appropriate responses to treatment. Source: Mauna Kea Technologies, October 27, 2015

ER-REBOA Catheters The FDA has granted 510(k) clearance for the sale and distribution of ER-REBOA catheters (Pryor Medical Devices). REBOA (Resuscitative Endovascular Balloon Occlusion of the Aorta) is a minimally invasive technique used by the trauma, critical care, and emergency medicine community to temporarily occlude large vessels using a balloon. Key ER-REBOA features include its small size (7 Fr), which precludes the need for additional surgical repair at the

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access site. In addition, the ER-REBOA catheter does not require multiple wire exchanges; has a soft, atraumatic tip; and allows simultaneous arterial pressure monitoring. Source: Pryor Medical Devices, October 26, 2015

SmartLinx Patient Monitoring SmartLinx Vitals Plus, a patient monitoring system that integrates vital-signs monitoring and clinical documentation into one platform, has received 510(k) clearance from the FDA. According to the manufacturer (Qualcomm Life, Inc.), the system offers an alternative to traditional low-acuity monitors, allowing hospitals and other health care facilities to streamline user authentication, patient identification, vital-signs measurement, and clinical documentation by integrating vital-signs modules and components directly to the SmartLinx Neuron 2 mobile clinical computer.   Source: Qualcomm Incorporated, October 21, 2015

CO2RE Use Expanded

The FDA has granted numerous additional indications for use of the CO2RE device. The new indications include gynecology applications (including vaginal treatments), wrinkles, scars, and dermatology and plastic surgery indications. A previously FDA-cleared version of the device was initially launched in 2010. According to the manufacturer (Syneron Medical Ltd.), the CO2RE device incorporates advanced scanner technology, high peak power, and a highbrightness CO2 laser. The device delivers precisely fractionated beam patterns to treat two layers of the epidermis and dermis simultaneously. Source: Syneron Medical, November 5, 2015

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iFuse Implant System The FDA has allowed the iFuse implant system (Si-Bone, Inc.) to add the following to its indication statement: “Clinical studies have demonstrated that treatment with the iFuse implant system improved pain, patient function, and quality of life at 12 months post-implantation.” This addition was based on data from prospective and retrospective clinical studies, which demonstrated consistent improvement in pain, patient function, and quality of life at 12 months in patients treated with iFuse. The minimally invasive surgical device is indicated for fusion for certain disorders of the sacroiliac joint. Source: Si-Bone, Inc., November 9, 2015

DEVICE SAFETY ISSUES Heater–Cooler Infections The use of heater–cooler devices has been associated with nontuberculous mycobacteria (NTM) infections, primarily in patients undergoing cardiothoracic surgical procedures. NTM organisms usually are not harmful, but in rare cases they may cause infections in very ill patients and/or in individuals with compromised immune systems. Heater–cooler devices are used during cardiothoracic surgeries as well as other medical and surgical procedures to warm or cool a patient to optimize medical care and improve patient outcomes. These devices include water tanks that provide temperature-controlled water to external heat exchangers or warming/ cooling blankets through closed circuits. Although the water in the circuits does not come into direct contact with the patient, there is the potential for contaminated water to enter other parts of the device or for the transmission of bacteria through the air through the device’s exhaust vent into the environment and to the patient. Between January 2010 and August

2015, the FDA received 32 medical device reports of infections associated with heater–cooler devices or of bacterial contamination of these devices. Eight reports were related to infections occurring at U.S. health care facilities. The remaining 24 reports involved facilities outside the U.S., mostly in Western Europe. In some cases, patients presented with infections several months to years after their surgical procedures. The FDA is not aware of NTM infections acquired by hospital staff. Source: FDA, October 15, 2015

MPS Recall Quest Medical, Inc., has initiated a nationwide recall of 31 lots of Myocardial Protection System (MPS) delivery sets, models 5001102, 5001102-AS, and 7001102. Seals were found to fail intermittently during use, which potentially could result in patient blood loss. Recalled products were distributed from June 2015 to September 2015; a list of affected lots is available at The identified lots of MPS delivery sets showed a possible seal failure along the blood source channel of the main pump cassette, resulting in blood loss from the bypass circuit and interrupted delivery of cardioplegia solution. Quest Medical received 20 complaints of seal failures, which resulted in 16 instances of patient blood loss during surgery. There were no reports of patient injuries Source: FDA, October 28, 2015 n

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