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P T. 2016;41(1): 10, 11, 12, 13, 14, 15, 16, 21, 22, 23, 24, 53

New Drugs/Drug News/New Medical Devices January 2016

NEW DRUG APPROVALS

Alectinib for NSCLC

The FDA has approved alectinib (Alecensa, Genentech) to treat patients with advanced (metastatic) anaplastic lymphoma kinase (ALK)-positive non–small-cell lung cancer (NSCLC) whose disease has worsened after, or who could not tolerate, treatment with crizotinib (Xalkori, Pfizer).

ALK gene mutations are present in approximately 5% of patients with NSCLC. Alectinib is an oral medication that blocks the activity of the ALK protein, which may prevent NSCLC cells from growing and spreading.

The safety and efficacy of alectinib were studied in two single-arm clinical trials of patients with metastatic ALK-positive NSCLC whose disease was no longer controlled by treatment with crizotinib. The participants received alectinib twice daily. In the first study, 38% of participants experienced a partial shrinkage of their NSCLC tumors, an effect that lasted for an average of 7.5 months. In the second study, 44% of participants experienced a partial shrinkage of their NSCLC tumors, lasting for an average of 11.2 months. Sixty-one percent of participants in the two trials who had measurable brain metastases experienced a complete or partial reduction in their brain tumors, lasting an average of 9.1 months.

Alectinib may cause serious adverse effects, including liver problems, severe or life-threatening inflammation of the lungs, bradycardia, and severe muscle problems. Treatment with alectinib may cause sunburn when patients are exposed to sunlight.

Source: FDA, December 11, 2015

Portrazza for Lung Cancer

Necitumumab (Portrazza, Eli Lilly) in combination with two forms of chemotherapy (gemcitabine and cisplatin) has secured FDA approval for the treatment of patients with metastatic squamous non–small-cell lung cancer (NSCLC) who have not previously received medications specifically for treating their advanced lung cancer.

Necitumumab is a monoclonal antibody that blocks the activity of epidermal growth factor receptor (EGFR), a protein commonly found on squamous NSCLC tumors.

The safety and efficacy of necitumumab were evaluated in a randomized, open-label clinical study of 1,093 participants with advanced squamous NSCLC who received the chemotherapies gemcitabine and cisplatin with or without necitumumab. Patients treated with necitumumab plus gemcitabine and cisplatin lived longer on average (11.5 months) compared with those receiving only gemcitabine and cisplatin (9.9 months). Necitumumab was not an effective treatment in patients with nonsquamous NSCLC.

Source: FDA, November 24, 2015

Tagrisso for Lung Cancer

The FDA has granted accelerated approval for an oral medication to treat patients with advanced non–small-cell lung cancer (NSCLC). Osimertinib (Tagrisso, AstraZeneca) was approved for patients whose tumors have a specific epidermal growth factor receptor (EGFR) mutation (T790M) and whose disease has gotten worse after treatment with other EGFR-blocking therapy.

The FDA also approved the first companion diagnostic test (cobas EGFR Mutation Test v2) to detect the type of EGFR resistance mutation that osimertinib is known to target. The newly approved version of the test adds the T790M mutation to the clinically relevant mutations detected by the original cobas EGFR Mutation Test (v1), which is marketed by Roche Molecular Systems.

Source: FDA, November 13, 2015

Empliciti for Multiple Myeloma

Elotuzumab (Empliciti, Bristol-Myers Squibb) has won FDA approval in combination with lenalidomide (Revlimid, Celgene Corp.) and dexamethasone to treat patients with multiple myeloma who have received one to three prior medications. Elotuzumab activates the body’s immune system to attack and kill multiple myeloma cells.

The safety and efficacy of elotuzumab were evaluated in a randomized, open-label study of 646 participants whose multiple myeloma recurred after, or did not respond to, previous treatment. Those taking elotuzumab plus lenalidomide and dexamethasone experienced a delay in the amount of time before their disease worsened (19.4 months) compared with participants taking only lenalidomide and dexamethasone (14.9 months). In addition, 78.5% of those taking elotuzumab with lenalidomide and dexamethasone saw a complete or partial shrinkage of their tumors, compared with 65.5% of those taking lenalidomide and dexamethasone.

Source: FDA, November 30, 2015

Ninlaro for Multiple Myeloma

The FDA has granted approval for ixazomib (Ninlaro, Takeda), used in combination with lenalidomide (Revlimid, Celgene Corp.) and dexamethasone, to treat people with multiple myeloma who have received at least one prior therapy.

Ixazomib is a proteasome inhibitor that blocks enzymes from multiple myeloma cells, inhibiting their ability to grow and survive.

The safety and efficacy of ixazomib were demonstrated in an international, randomized, double-blind clinical study of 722 patients with multiple myeloma that recurred after, or did not respond to, previous treatment. The participants received either ixazomib in combination with lenalidomide and dexamethasone or placebo plus lenalidomide and dexamethasone. Those treated with the ixazomib combination lived longer without disease progression (average, 20.6 months) compared with those receiving the placebo combination (average, 14.7 months).

Source: FDA, November 20, 2015

Darzalex for Multiple Myeloma

The FDA has given accelerated approval to daratumumab (Darzalex, Janssen Biotech) to treat patients with multiple myeloma who have received at least three prior treatments. Daratumumab was the first monoclonal antibody approved for treating multiple myeloma.

Daratumumab injection, given as an infusion, works by helping certain cells in the immune system attack cancer cells. Its safety and efficacy were demonstrated in two open-label studies. In one study involving 106 participants, 29% of the subjects receiving daratumumab experienced a complete or partial reduction in their tumor burden, which lasted for an average of 7.4 months. In the second study, which involved 42 participants, 36% of those treated with daratumumab had a complete or partial reduction in their tumor burden.

Source: FDA, November 16, 2015

Tafinlar/Mekinist for Melanoma

The FDA has approved the combination of dabrafenib (Tafinlar) and trametinib (Mekinist) for the treatment of patients with BRAF V600E/K mutation-positive unresectable or metastatic melanoma, as detected by an FDA-approved test. This is the first targeted therapy combination demonstrating more than two years overall survival in patients with the most aggressive form of skin cancer. Novartis markets both products.

In January 2014, the dabrafenib/trametinib combination received provisional approval for use in patients with BRAF V600E/K mutation-positive unresectable or metastatic melanoma. This approval was contingent on the results of the phase 3 COMBI-d study, which was designed to evaluate the clinical benefit of the combination in patients with unresectable or metastatic melanoma with a BRAF V600E/K mutation.

Updated results from the COMBI-d trial showed that dabrafenib/trametinib achieved a statistically significant overall survival benefit compared with dabrafenib alone (median, 25.1 months versus 18.7 months, respectively; P = 0.01). The analysis also showed median progression-free survival of 9.3 months compared with 8.8 months in the two treatment groups (P = 0.035). The overall response rates were 66% and 51% for dabrafenib/trametinib and dabrafenib monotherapy, respectively.

Source: Novartis, November 20, 2015

Bridion to Reverse Neuromuscular Blockade

The FDA has approved sugammadex injection (Bridion, Merck) to reverse the effects of neuromuscular blockade induced by rocuronium bromide and vecuronium bromide, which are used during certain types of surgery in adults.

Rocuronium bromide and vecuronium bromide are neuromuscular blocking drugs that cause temporary paralysis by interfering with the transmission of nerve impulses to the muscles. They can be used to paralyze the vocal cords when patients require tracheal intubation; to prevent patients from moving during surgery under general anesthesia; and to prevent the body from breathing automatically when a patient must be placed on a ventilator.

The safety and efficacy of sugammadex were evaluated in three phase 3 trials involving 456 participants. The return to recovery time was faster overall for the sugammadex treatment groups compared with the comparator groups.

The FDA declined to approve sugammadex in 2008, citing concerns about potential allergic reactions and bleeding. Sugammadex was subsequently evaluated in a randomized, double-blind, parallel-group, repeat-dose trial. Of 299 participants treated with sugammadex, one person experienced an anaphylactic reaction.

Cases of marked bradycardia, some of which have resulted in cardiac arrest, have been observed within minutes after the administration of sugammadex. Patients should be closely monitored for hemodynamic changes during and after the reversal of neuromuscular blockade. The most common adverse events observed in clinical trials included vomiting, hypotension, pain, headache, and nausea.

Sources: FDA and Reuters, December 15, 2015

Kanuma for Lysosomal Acid Lipase Deficiency

Sebelipase alfa (Kanuma, Alexion Pharmaceuticals) has secured FDA approval as the first treatment for patients with lysosomal acid lipase (LAL) deficiency.

Patients with LAL deficiency (a rare condition also known as Wolman disease and cholesteryl ester storage disease) have no or little LAL enzyme activity. This results in a build-up of fats within the cells of various tissues, which can lead to liver and cardiovascular disease and other complications. Sebelipase provides a recombinant human LAL protein that functions in place of the missing, partially active, or inactive LAL protein in the patient.

Treatment is provided via intravenous infusion once weekly in patients with rapidly progressive LAL deficiency presenting in the first six months of life, and once every other week in all other patients.

Source: FDA, December 8, 2015

Otiprio for Otitis Media

The FDA has approved ciprofloxacin otic suspension (Otiprio, Otonomy, Inc.) for the treatment of pediatric patients with bilateral otitis media with effusion undergoing tympanostomy tube placement.

Otiprio, a single-dose fluoroquinolone antibacterial agent, is the first product approved by the FDA for this indication. It is given by a physician as a single 0.1-mL (6-mg) intratympanic administration into each affected ear after suctioning of the middle-ear effusion. The thermosensitive suspension exists as a liquid at or below room temperature and gels when warmed.

In two phase 3 trials, a single intraoperative administration of Otiprio demonstrated a statistically significant reduction in the cumulative proportion of study treatment failures compared with tubes alone (P < 0.001).

Source: Otonomy, Inc., December 11, 2015

Vonvendi for Bleeding Episodes

The FDA has given the green light to Vonvendi (von Willebrand factor [recombinant], Baxalta U.S., Inc.), for use in adults 18 years of age and older who have von Willebrand disease (VWD). Vonvendi, the first FDA-approved recombinant von Willebrand factor, is approved for the on-demand (as-needed) treatment and control of bleeding episodes in adults diagnosed with VWD. VWD is the most common inherited bleeding disorder, affecting approximately 1% of the U.S. population.

Source: FDA, December 8, 2015

Fluad Vaccine for Influenza

The FDA has approved Fluad (Seqirus/Novartis), the first seasonal influenza vaccine containing an adjuvant. The vaccine is produced from three influenza virus strains (two subtype A and one type B) and is approved for the prevention of seasonal flu in people 65 years of age and older.

Fluad, which is manufactured using an egg-based process, is formulated with the adjuvant MF59, an oil-in-water emulsion of squalene oil. Squalene is a naturally occurring substance found in humans, animals, and plants. Adjuvants are incorporated into some vaccine formulations to enhance or direct the immune response of the vaccinated individual.

In a clinical study conducted in the U.S. and internationally, Fluad induced antibody levels that were comparable with the levels induced by Agriflu (Novartis), an unadjuvanted trivalent seasonal flu vaccine, in 7,082 subjects ages 65 years and older.

Source: FDA, November 24, 2015

Adynovate for Hemophilia

Adynovate (antihemophilic factor [recombinant], PEGylated, Baxalta U.S., Inc.) has received FDA approval for use in adults and adolescents, ages 12 years and older, who have hemophilia A. The product is modified to last longer in the blood and potentially to require less-frequent injections compared with unmodified antihemophilic factor when used to reduce the frequency of bleeding.

Adynovate is approved for on-demand (as-needed) treatment and control of bleeding episodes and to reduce the frequency of bleeding episodes (prophylaxis) in patients with hemophilia A. The product consists of the full-length coagulation factor VIII molecule (also known as antihemophilic factor) linked to other polyethylene glycol molecules (PEGylated). This link makes the product last longer in the patient’s blood.

Source: FDA, November 13, 2015

Generic Approvals

Imatinib Mesylate Tablets

A subsidiary of the Mumbai-based company Sun Pharmaceutical Industries has received final approval from the FDA for its abbreviated new drug application for a generic version of imatinib mesylate tablets 100 mg and 400 mg (Gleevec, Novartis). The tablets are indicated for the treatment of chronic myeloid leukemia.

Under the terms of a settlement agreement with Novartis, the Sun Pharma subsidiary will launch its version of generic Gleevec in the U.S. on February 1, 2016.

Gleevec (sold in some other nations as Glivec) had global sales of $4.7 billion in 2014, according to Novartis.

Sources: Sun Pharmaceutical Industries, December 7, 2015, and Novartis

Sildenafil Citrate

The FDA has granted final approval for the manufacture and marketing of 20-mg sildenafil tablets (Aurobindo Pharma Ltd.). The product is bioequivalent and therapeutically equivalent to 20-mg Revatio tablets (sildenafil citrate, Pfizer). Sildenafil is a phosphodiesterase-5 inhibitor indicated for the treatment of pulmonary arterial hypertension (WHO Group I) in adults to improve exercise ability and delay clinical worsening.

Source: Aurobindo Pharma, November 21, 2015, and Revatio prescribing information

Dutasteride

Breckenridge Pharmaceutical, Inc., has received final FDA approval for its 0.5-mg dutasteride soft gelatin capsules, the generic version of Avodart (GlaxoSmithKline). Dutasteride is indicated for the treatment of symptomatic benign prostatic hyperplasia in men with an enlarged prostate.

Source: Breckenridge Pharmaceutical, November 20, 2015

Rabeprazole DR

The FDA has approved rabeprazole sodium delayed-release (DR) tablets (Breckenridge Pharmaceutical, Inc.). The generic version of AcipHex (Eisai) will be available in 20-mg strengths. AcipHex is indicated for the treatment, healing, and maintenance of gastroesophageal reflux disease in adults and adolescents 12 years of age and older and for the healing of duodenal ulcers in adults.

Source: Breckenridge Pharmaceutical, November 19, 2015

NEW INDICATIONS

Caldolor Injection for Pain and Fever in Children

The FDA has approved Caldolor (ibuprofen injection, Cumberland Pharmaceuticals) for pediatric patients 6 months of age and older. The approval was based on data submitted to the agency as part of a post-marketing commitment after the approval of Caldolor for use in adults in 2009. The product is the only injectable nonsteroidal anti-inflammatory drug (NSAID) approved for use in pediatric patients.

Caldolor is indicated in adults and pediatric patients for the management of mild-to-severe pain as an adjunct to opioid analgesics, as well as for the reduction of fever. It is contraindicated in patients with known hypersensitivity to ibuprofen or other NSAIDs, or in patients with a history of asthma or other allergic-type reactions after taking aspirin or other NSAIDs. Caldolor is also contraindicated for use during the perioperative period in the setting of coronary artery bypass graft surgery.

Source: Cumberland Pharmaceuticals, November 23, 2015

Opdivo for Kidney Cancer

Nivolumab (Opdivo, Bristol-Myers Squibb) has won FDA approval for the treatment of patients with metastatic renal cell carcinoma (RCC) who have received prior anti-angiogenic therapy.

Nivolumab targets the programmed death-1/programmed death ligand-1 (PD-1/PD-L1) proteins found on immune cells and some cancer cells. By blocking this pathway, nivolumab may help the body’s immune system fight cancer cells.

The safety and efficacy of nivolumab for this use were demonstrated in an open-label, randomized study of 821 patients with advanced RCC whose disease worsened during or after treatment with an anti-angiogenic agent. Patients were treated with nivolumab or everolimus (Afinitor, Novartis). Those receiving nivolumab lived an average of 25.0 months after starting treatment compared with 19.6 months in those treated with everolimus.

Nivolumab was previously approved for the treatment of melanoma and non–small-cell lung cancer. The FDA is also giving priority review to an application for the use of nivolumab in the treatment of patients with advanced renal-cell carcinoma who have received prior anti-angiogenic therapy. The projected FDA action date is March 16, 2016.

Sources: FDA, November 23, 2015, and Bristol-Myers Squibb, November 17, 2015

Yervoy for Melanona

Based on results from a European Organization for Research and Treatment of Cancer (EORTC) study, the FDA has expanded its approval of ipilimumab (Yervoy, Bristol-Myers Squibb) in advanced melanoma to include adjuvant treatment of patients with stage III disease at high risk of recurrence after complete resection. Adjuvant ipilimumab significantly improved recurrence-free survival in patients with completely resected stage III melanoma at high risk of disease recurrence, but the treatment was also associated with a high rate of immune-related adverse events.

Source: EORTC, November 13, 2015

Harvoni for Hepatitis C

The FDA has approved ledipasvir/sofosbuvir (Harvoni, Gilead Sciences) for expanded use in patients with genotype 4, 5, and 6 chronic hepatitis C virus (HCV) infection and in patients coinfected with human immunodeficiency virus. In addition, ledipasvir/sofosbuvir plus ribavirin for 12 weeks was approved as an alternate therapy to 24 weeks of ledipasvir/sofosbuvir for treatment-experienced, genotype-1 patients with cirrhosis.

Harvoni received regulatory approval for the treatment of chronic HCV genotype-1 infection in adults in October 2014.

Source: Gilead Sciences, November 12, 2015

NEW FORMULATIONS

Short-infusion Bendamustine For Leukemia and Lymphoma

Bendeka injection (Teva Pharmaceutical Industries/Eagle Pharmaceuticals), a liquid, low-volume (50-mL), short-time (10-minute) infusion formulation of bendamustine hydrochloride, has received FDA approval. The drug is meant for the treatment of patients with chronic lymphocytic leukemia (CLL) and for the treatment of patients with indolent B-cell non-Hodgkin lymphoma that has progressed during or within six months of treatment with rituximab or a rituximab-containing regimen.

The efficacy of Bendeka in patients with CLL relative to first-line therapies other than chlorambucil has not been established.

Source: Teva Pharmaceutical Industries, December 8, 2015

Narcan for Opioid Overdose

The FDA has given the green light to Narcan nasal spray (Adapt Pharma, Inc.), the first approved nasal-spray version of naloxone hydrochloride, a life-saving medication that can stop or reverse the effects of an opioid overdose. Until this approval, naloxone was approved only in injectable forms, most commonly delivered by syringe or auto-injector.

In clinical trials, administering Narcan nasal spray in one nostril delivered approximately the same levels or higher of naloxone as a single dose of an FDA-approved naloxone intramuscular injection, and achieved these levels in approximately the same time frame.

The FDA had granted the product a fast-track designation and priority review.

Source: FDA, November 18, 2015

DRUGS UNDER REVIEW

Breakthrough Therapies

Avelumab for Merkel Cell Carcinoma

The FDA has granted avelumab (Merck/Pfizer) a breakthrough therapy designation for the treatment of patients with metastatic Merkel cell carcinoma (MCC) who have progressed after at least one previous chemotherapy regimen. Avelumab is an investigational fully human anti-programmed death ligand 1 (PD-L1) immunoglobulin 1 (IgG1) monoclonal antibody.

Each year, approximately 1,500 new cases of MCC are diagnosed in the U.S. There is no approved treatment for metastatic MCC.

Source: Pfizer, November 18, 2015

Orphan Drug Status

TPIV 200 for Ovarian Cancer

An orphan drug designation has been granted to the cancer vaccine TPIV 200 (TapImmune, Inc.) for the treatment of patients with ovarian cancer.

TPIV 200 is a multi-epitope peptide vaccine that targets folate receptor alpha, which is overexpressed in several cancers, including more than 90% of ovarian cancer cells. In phase 1 clinical studies conducted at the Mayo Clinic in patients with breast and ovarian cancer, the vaccine was shown to be safe and well tolerated and to achieve cellular immune responses in 20 out of 21 evaluable patients.

Source: TapImmune, Inc., December 9, 2015

ARM210 for Duchenne MD

The FDA has granted orphan drug status and a rare pediatric disease designation to ARM210 (Armgo Pharma) for the treatment of patients with Duchenne muscular dystrophy (DMD). ARM210 targets the ryanodine receptor, an intracellular calcium-release channel that becomes leaky in disease states, including DMD, contributing to muscle damage and the loss of function. In animal models of DMD, ARM210 showed significant improvements in exercise capacity, muscle-specific force, grip strength, and muscle histology compared with vehicle-treated controls.

Source: Armgo Pharma, December 9, 2015

Ubenimex for PAH

The FDA has granted orphan drug status to ubenimex (Eiger BioPharmaceuticals) for the treatment of pulmonary arterial hypertension (PAH). The compound is an oral, small-molecule, dual inhibitor of aminopeptidase and leukotriene A4 hydrolase (LTA4H), the enzyme responsible for catalyzing the committed step in the formation of the pro-inflammatory mediator LTB4.

Source: Eiger BioPharmaceuticals, November 30, 2015

Complete Response Letters

Enclomiphene for Hypogonadism

Repros Therapeutics has received a complete response letter (CRL) from the FDA on its new drug application (NDA) for enclomiphene for the treatment of secondary hypogonadism in overweight men wishing to restore normal testicular function. A CRL informs a company that its NDA cannot be approved in its present form. In the letter, the FDA stated that, based on recent scientific developments, the design of the phase 3 studies of enclomiphene is no longer adequate to demonstrate clinical benefit. The agency recommended that Repros conduct an additional phase 3 trial (or trials) to support approval in the target population. The FDA also expressed concerns regarding study-entry criteria, titration, and bioanalytical method validation in the phase 3 program.

Source: Repros Therapeutics, December 1, 2015

Makena for Preterm Birth

AMAG Pharmaceuticals has received a complete response letter for its new drug application seeking approval for a single-dose vial of Makena (hydroxyprogester-one caproate injection) to reduce the risk of preterm birth in certain at-risk patients. In its letter, the FDA requested additional information. Makena is a progestin indicated to reduce the risk of preterm birth in women with a singleton pregnancy who have a history of singleton spontaneous preterm birth. The product is currently marketed in a multidose vial containing five weekly injections.

Source: AMAG Pharmaceuticals, November 18, 2015

FDA Advisors Reject MCNA

The FDA’s Cellular, Tissue, and Gene Therapies Advisory Committee and Oncologic Drugs Advisory Committee voted against a biologics license application for MCNA (Telesta Therapeutics) at a combined meeting in November.

The advisory committee cast 18 no votes and 6 yes votes, with no abstentions, on the following question: “Does MCNA have an overall favorable benefit–risk profile for the treatment of non–muscle-invasive bladder cancer at high risk of recurrence or progression in adult patients who failed prior BCG immunotherapy, e.g., in patients who are BCG-refractory or BCG-relapsing?”

MCNA is a biologic therapy developed to provide a therapeutic alternative to surgery for high-risk patients with non–muscle-invasive bladder cancer who are refractory to or relapsing from first-line therapy with BCG (bacillus Calmette-Guérin). MCNA is derived from the cell-wall fractionation of a nonpathogenic bacterium. Its activity is believed to be through a dual mechanism of immune stimulation and direct anticancer effects.

The FDA’s review goal date for MCNA is February 27, 2016.

Source: Telesta Therapeutics, November 19, 2015

Biosimilar of Neulasta in Review

The FDA has accepted a biologics license application for a proposed biosimilar version of pegfilgrastim (Neulasta, Amgen), a recombinant human granulocyte colony-stimulating factor. The new product’s developer, Sandoz, is seeking approval for the same indication as the reference product. Pegfilgrastim is used to help reduce the risk of infection due to a low white blood cell count in patients with cancer (nonmyeloid) who receive chemotherapy that can cause fever and febrile neutropenia.

Source: Sandoz, November 18, 2015

DRUG SAFETY ISSUES

Risk of Ketoacidosis With SGLT2 Inhibitors

An FDA safety review has resulted in adding warnings to the labels of sodium-glucose cotransporter-2 (SGLT2) inhibitors about the risks of ketoacidosis and serious urinary tract infections, both of which can result in hospitalization. SGLT2 inhibitors are FDA-approved for use with diet and exercise to lower blood sugar in adults with type-2 diabetes. Medications in the SGLT2 inhibitor class include canagliflozin, dapagliflozin, and empagliflozin.

The FDA issued a drug safety communication in May 2015 warning about the risk of ketoacidosis with SGLT2 inhibitors. A review of the FDA’s Adverse Event Reporting System (FAERS) database from March 2013 to May 2015 identified 73 cases of ketoacidosis in patients with type-1 or type-2 diabetes treated with SGLT2 inhibitors. The FDA also identified 19 cases of life-threatening urosepsis and pyelonephritis that started as urinary tract infections with the SGLT2 inhibitors reported to FAERS from March 2013 through October 2014. All 19 patients were hospitalized, and a few required admission to an intensive care unit or dialysis to treat kidney failure.

As a result, the FDA added new warnings and precautions to the labels of all SGLT2 inhibitors to describe these two safety issues, and to provide prescribing and monitoring recommendations.

Source: FDA, December 4, 2015

FDA Modifies Clozapine Neutropenia Monitoring

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

There are two parts to the changes in the requirements for treating patients with clozapine. First, the FDA clarified and enhanced the prescribing information for clozapine that explains how to monitor patients for neutropenia and how to manage clozapine treatment. Second, the FDA approved a new, shared risk evaluation and mitigation strategy (the Clozapine REMS Program). The revised prescribing information and the Clozapine REMS Program are intended to improve the monitoring and management of patients with severe neutropenia. The shared REMS is also expected to reduce the burden and possible confusion related to having separate registries for individual clozapine medications. The requirements to monitor, prescribe, dispense, and receive all clozapine medications are now incorporated into the Clozapine REMS Program.

Source: FDA, November 19, 2015

Iodine Contrast Agents May Affect Infants’ Thyroids

Rare cases of underactive thyroid have been reported in infants after the use of contrast media containing iodine, also called “contrast dye,” for x-rays and other medical imaging procedures, according to the FDA. In all of the reported cases, the infants were either premature or had other serious underlying medical conditions. This rare occurrence was usually temporary and resolved without treatment or any lasting effects.

The FDA approved changes to the labels of all iodinated contrast media products to include information about these cases. No changes to current prescribing, administration, or monitoring practices were recommended.

Source: FDA, November 17, 2015

RESEARCH BRIEFS

Is Tablet Splitting Safe For Dementia Patients?

Many patients—particularly older ones—may split tablets, usually for economic reasons but also because they want a smaller dose. Studies have shown that some tablets can be safely split without diminishing the drug’s effects or endangering the patient. But is tablet splitting safe for elderly patients with dementia? They are often taking psychotropic drugs that may not be commercially available in the doses prescribed for neuropsychiatric symptoms, say researchers from Universidade de Brasília.

In a study of geriatric outpatients at a referral center for dementia management, the researchers found dementia was significantly associated with prescriptions that implied a directive to split tablets. Among the 88 patients who split tablets, nearly two-thirds split tablets of psychotropic drugs. The oldest patients (80 years and older) were most likely to split tablets and were more likely to have severe dementia.

If the medication seems to vary in effectiveness, it is important to consider the possibility that tablet splitting, not drug–drug interactions, is the cause, the researchers warn. On the other hand, nearly one-third of patients who split psychotropic drugs in this study had interactions that could change the effectiveness of the split medications. The most significant interactions were between acetylcholinesterase inhibitors and anticholinergics—drugs used to control behavioral disturbances in dementia patients.

The researchers found that the number of clinic visits was associated with tablet splitting, although they say this may be a consequence of a greater number of prescribed medications (and thus a higher rate of tablet splitting).

The researchers advise consulting a clinical pharmacist about the effects of splitting the tablets, availability of different tablet concentrations, and the potential interactions that might interfere with treatment. The pharmacist can also help teach patients how to split tablets correctly.

Source: Clinical Therapeutics, October 2015

Anticoagulant Prediction Test

Is it possible to predict who will do well—and who will not—on a vitamin K antagonist in the “real world”? The SAMe-TT2R2 test may enhance decision-making, say researchers from the University of Murcia, Spain, and City Hospital, Birmingham, United Kingdom.

SAMe-TT2R2 stands for Sex, Age (less than 60 years), Medical history (at least two of the following: hypertension, diabetes, coronary artery disease/myocardial infarction, peripheral arterial disease, congestive heart failure, previous stroke, pulmonary disease, hepatic or renal disease), Treatment (interacting drugs), current Tobacco use, and Race. Each factor is scored 1 point, except for tobacco use and race, both of which get 2 points.

The researchers calculated the baseline SAMe-TT2R2 score in 459 outpatients with nonvalvular atrial fibrillation who were starting oral anticoagulation on the vitamin K antagonist acenocoumarol. At six months, they calculated time in therapeutic range. All patients had at least eight visits to the outpatient clinic.

A high SAMe-TT2R2 score doubled the risk of suboptimal oral anticoagulation. The median SAMe-TT2R2 score was 2; 55% of patients had a score less than 2. Only 18 patients had a score of more than 3. The mean time in therapeutic range at six months was 64%. More than half of patients (54%) had a time in therapeutic range value more than 65%. After six months, patients with a SAMe-TT2R2 score of less than 2 had a mean time in therapeutic range value of 67%, compared with 61% among patients with a score of 2 or less.

The use of this simple scoring system, the researchers say, can help patients avoid the “warfarin stress test,” in which patients undergo a trial to find out whether they can meet the standard of time spent in therapeutic range value. Patients with a high SAMe-TT2R2 score can be “justifiably” started on an oral anticoagulant other than a vitamin K antagonist without a warfarin test, while those with a low score can be started on a vitamin K antagonist. Even small differences in time in the therapeutic range could translate to a lower risk of adverse events while taking a vitamin K antagonist, the researchers say.

Source: American Journal of Medicine, November 2015

Contraceptives, IBD, and VTE

Patients with inflammatory bowel disease (IBD), such as Crohn’s disease and ulcerative colitis, have a higher risk of venous thromboembolism (VTE), per-haps from active inflammatory processes. Is it safe for women with IBD to use oral contraceptives, which also carry a risk of VTE?

Researchers from Second University of Naples, Italy, looked into the possibility of an adverse synergistic effect. They compared 146 IBD patients (in remission) with 290 patients without IBD. They excluded patients with active IBD because a prothrombotic state often accompanies active flares.

One patient with Crohn’s disease developed VTE, and one patient in the control group developed deep-vein thrombosis. No patients developed pulmonary embolism. Over about seven years of follow-up, the incidence of VTE associated with oral contraceptives was 0.5%, slightly higher than the 0.6% found in the general population. Patients receiving immunosuppressant and biologic drugs showed a nonsignificant trend toward increased risk of VTE. Being an active smoker significantly and considerably raised the risk of VTE, although the study group was too small for definitive conclusions about smoking and IBD.

Surgical patients were excluded from the study; the researchers note that surgery plays a “relevant role” for IBD patients, who often need complex or repeated procedures. The study results may have been weakened by the exclusion, the researchers say.

Source: Annals of Medicine and Surgery, November 3, 2015

Digital Pneumonia Diagnosis

Watching a child’s breathing and counting the breaths can be challenging, especially when the child is breathing fast or moving. That may make “mPneumonia”—a mobile-based application designed by researchers from PATH, University of Washington, and Kintampo Health Research Centre in Ghana—a welcome addition. It combines a digital version of the World Health Organization’s Integrated Management of Childhood Illness (IMCI) protocols with a software-based breath counter.

The health care practitioner (HCP) records breathing by tapping the screen for each breath observed over one minute. Visual, audio, and vibration indicators provide feedback at each tap, as well as when the measurement period ends. The application, which uses Android technology, does not require a network or wireless connection. It can store information until it is connected to a network, after which data files can be uploaded to a central server. A reusable pulse oximeter can be connected.

The researchers designed their application with lesser-trained HCPs in low-resource settings in mind and tested its usability at a community health clinic in Ghana. Based on their experience with seven HCPs (five of whom had never used a touch-screen device), the researchers incorporated more user-friendly features (such as images of palmar pallor) to allow them to answer the algorithm questions quickly without having to read the text. The step-by-step software increases adherence to the algorithm by not allowing HCPs to skip essential assessment questions, which means less experienced users can identify children with pneumonia who are in greatest need of treatment.

Given that clinicians average 8.2 minutes per child for a consultation using the paper-based IMCI protocol, the researchers concede that the 43 minutes the testers typically took would not be practical for most HCPs. They say it will be important to find out how daily routine use and more familiarity with the application will cut that time.

Source: PLoS One, October 16, 2015

Panic Disorder and CHD

The connection between panic disorder (PD) and coronary heart disease (CHD) has been noted for decades, but the nature of that connection is unknown. People with PD often report symptoms that overlap those of CHD, say researchers from The University of Adelaide, University of Freiburg, and University of Ulm. Or is it a case of misdiagnosis, in which people with PD are having somatic symptoms of undiagnosed coronary conditions?

The researchers reviewed 12 published studies involving 1,131,612 patients and 58,111 cardiac events (major adverse cardiac events [MACE], structural coronary artery disease, ischemic heart disease, or other diagnosed CHD). Incident myocardial infarction (MI) was the most common individual endpoint, with 18,541 MI events reported in 953,888 patients in six studies.

PD was associated with incident CHD even after excluding angina. The researchers found that high-quality evidence suggested that PD was an independent risk factor for incident MI; moderate evidence supported an association between PD and MACE. Only low-quality evidence indicated a link between PD and CHD, and no association was seen between PD and fatal CHD. However, the researchers say the findings are tempered by heterogeneity between study estimates and risk of biases.

The risk for CHD was significant after excluding depression. The researchers note, though, that some of their review suggests that both depression and generalized anxiety could be associated with incident CHD. Adjusting for depression and antidepressant medication attenuated CHD risk attributable to PD by 24% in studies that included depression as a factor. Previous studies have reported CHD risks in the range of 30% to 90% for patients with depression.

Cognitive-behavioral therapy, serotonergic reuptake inhibitors, benzodiazepines, and combinations of them may help lower the incidence of CHD, but the effects are unclear. The IMPACT trial showed that collaborative depression care reduced MACE by 48% at seven-year follow-up in patients without established CHD.

Source: Psychological Medicine, October 2015

Ebola Virus Remains in Semen

Fragments of Ebola virus have been found in semen nine months after onset of symptoms, according to a study by the Sierra Leone Ministry of Health and Sanitation, the World Health Organization, and the U.S. Centers for Disease Control and Prevention (CDC).

In the study, 93 men from Freetown, Sierra Leone, enrolled between two and 10 months after their illness began. Of nine men who were tested in the first three months after initial symptoms, all were positive for Ebola virus. Of 40 who were tested between four and six months after onset, 26 (65%) were positive, as were 11 of 43 (26%) tested seven to nine months after onset.

The researchers say it isn’t clear why some participants had cleared the virus earlier than others. The CDC is conducting further tests of the samples to determine whether the virus is live and potentially infectious. Cases of Ebola virus linked to sexual transmission have been rare, the researchers say. But until more is known, men who survive the Ebola virus should be counseled to be tested regularly, and to abstain from all types of sex or use condoms.

Source: CDC, October 14, 2015

Telomeres and Heart Disease

Telomeres (DNA protein complexes that shorten with cell division) have been associated with coronary heart disease. They’ve also been posited as surrogate markers of the aging process and bio-markers of age-related chronic cardiovascular disease. But researchers who measured these “mitotic clocks” in peripheral blood leukocytes say they didn’t find evidence that classic coronary risk factors contribute to telomere attrition.

The researchers measured mean telomere length (TL) in blood from 343 blood donors. Although age and sex were significantly associated with TL, glucose, total cholesterol, low-density lipoprotein-cholesterol, and fibrinogen were not. However, the researchers did find positive associations between TL and erythrocyte and leukocyte counts, hematocrit, and hemoglobin, as well as a borderline significant association with thrombocytes. One liver enzyme (glutamic-pyruvate transaminase) was significantly inversely associated with TL. The data suggest that telomere attrition may be a marker for reduced global cellular reserve, the researchers say.

Progressive telomere shortening has been observed in vascular regions susceptible to atherosclerosis, the researchers say, which may enhance atherogenesis. They also theorize that the chronic systemic inflammation seen in atherogenesis may “secondarily” lead to increased cell turnover and telomere attrition.

Source: PLoS One, October 7, 2015

One CPR Method Has Better Results

Cardiopulmonary resuscitation (CPR) guidelines allow for either continuous chest compressions or interrupted compressions with ventilation. Because both methods are accepted, treatment can vary from one community to another, according to a report from the National Heart, Lung, and Blood Institute (NHLBI). However, it adds, such variation “could soon become a thing of the past.”

In a study funded in part by the NHLBI and the U.S. Army Medical Research and Materiel Command, researchers compared survival rates among 23,709 adults with cardiac arrest treated by emergency medical service (EMS) crews at 114 agencies. Survival to discharge was similar with both methods. But patients given standard CPR (compressions plus pauses for ventilation) had significantly more days alive and out of hospital during the first 30 days following cardiac arrest. The benefits of interrupted compressions, the researchers say, may be due to improved blood flow and oxygenation.

The study is the largest of its kind to evaluate CPR practices among firefighters and paramedics, says NHLBI. The findings were presented at the American Heart Association 2015 Scientific Sessions.

Source: National Institutes of Health, November 9, 2015

Flesh-Eating Bacteria Drug Trial Now Enrolling Patients

Patients are being enrolled in a phase 3 study to evaluate AB103 (Atox Bio)––the first pharmaceutical candidate developed for the treatment of necrotizing soft-tissue infections (NSTIs), also known as “flesh-eating bacteria.” The ACCUTE trial expects to enroll 290 subjects at approximately 40 centers in the U.S.

NSTIs are caused by bacteria, such as streptococcus, staphylococcus, and others, that enter the body via a minor cut, surgery, an insect bite, or other route and spread to the connective tissue below the skin. The infection moves aggressively, causing significant tissue destruction, and can quickly become systemic, leading to multiple organ dysfunction.

AB103 is a short peptide that modulates the patient’s inflammatory response through binding to the CD28 dimer interface. By targeting the host rather than the bacteria, AB103 has the potential to be effective across the spectrum of pathogen species and avoids antibiotic resistance.

Source: Atox Bio, December 7, 2015

Positive Data for Telotristat In Carcinoid Syndrome Trial

Positive results have been reported from the phase 3 TELECAST trial of telotristat etiprate (Lexicon Pharmaceuticals) in treating carcinoid syndrome in cancer patients with metastatic neuroendocrine tumors. Telotristat etiprate (250 mg or 500 mg) met the study’s primary efficacy endpoint––the percent change from baseline in urinary 5-hydroxyindoleacetic acid (the main metabolite of serotonin)––at week 12 (P < 0.001 for both dose arms compared with placebo). In addition, the drug achieved statistically significant reductions in the frequency of daily bowel movements during the 12 weeks of the study (P = 0.004 for the 250-mg arm and P < 0.001 for the 500-mg arm compared with placebo).

Telotristat etiprate is the first investigational drug in clinical studies to target tryptophan hydroxylase, an enzyme that triggers the excess serotonin production within mNET cells that leads to carcinoid syndrome. The treatment received fast-track and orphan drug designations from the FDA.

Source: Lexicon Pharmaceuticals, December 1, 2015

Positive Results For Cancer Vaccine

Positive findings from clinical studies of a WT1 gene-targeted cancer vaccine (Sellas Life Sciences Group) were reported at the International WT1 Conference, held in November in Kyoto, Japan. Clinically meaningful prolonged survival was demonstrated in patients with malignant pleural mesothelioma (MPM) as well as in those with acute myeloid leukemia (AML). A median overall survival (OS) of 52.5 months was achieved in a phase 2 study of the WT1 vaccine in adult patients with AML. Similarly, in a previous phase 1 AML study, the WT1 vaccine provided a median OS of more than five years. When combined, the results from both studies demonstrated two-year OS in adult AML patients of 79%. Historical two-year OS results in similar patient populations range from 30% to 45%.

In addition, a randomized, double-blind, placebo-controlled phase 2 study in MPM patients at the Memorial Sloan Kettering Cancer Center and at the MD Anderson Cancer Center showed a median OS of 21.4 months for WT1 vaccine-treated patients compared with 16.6 months for patients in the placebo arm. The WT1 cancer vaccine also provided median progression-free survival of 11.4 months, double that of the placebo arm (5.7 months), in patients with MPM.

Source: Sellas Life Sciences Group, November 30, 2015

Lyrica Flops in Pain Study

A phase 3 trial evaluating the efficacy and safety of pregabalin (Lyrica, Pfizer) in adults with chronic post-traumatic peripheral neuropathic pain failed to meet its primary efficacy endpoint (the mean pain reduction from baseline compared with placebo, based on pain scores from patients’ daily pain diaries).

The safety profile observed in this 15-week, double-blind, placebo-controlled, parallel-group study was consistent with that known for pregabalin. The most common adverse events were dizziness, somnolence, nausea, and fatigue.

Pregabalin is approved for five indications in the U.S., four of which are in the therapeutic area of pain. There is no FDA-approved treatment for post-traumatic neuropathic pain.

Source: Pfizer, November 25, 2015

Spinal Cord Stimulator Helps Relieve Back Pain

New study results evaluating the Precision Spectra Spinal Cord Stimulator (SCS) system (Boston Scientific Corporation) demonstrate that the device provides more than 70% greater low back pain relief compared with the previous-generation Precision Plus SCS system.

The study showed a significant decrease in average pain scores sustained over a two-year period. In addition, when the Precision Spectra SCS was used with Boston Scientific’s CoverEdge surgical lead, 12-month data demonstrated further pain relief in patients with low back pain. The improved outcomes were achieved using the Precision Spectra proprietary Illumina 3D neural targeting algorithm, which is designed to enable precise control with simple point-and-click targeting.

Source: Boston Scientific Corp., December 11, 2015

Monarch eTNS System Aids Traumatic Brain Injuries

Positive preliminary findings have been reported from a clinical study using noninvasive external trigeminal nerve stimulation with the Monarch eTNS system to treat combat veterans. The results mark the first report about using eTNS in patients with traumatic brain injury (TBI).

The Monarch eTNS System is composed of a cell-phone-sized pulse generator and a single-use electric patch that is applied to the forehead. Signals are transmitted through lead wires to the patch to stimulate the trigeminal nerve in the skin of the forehead; triggering these nerve fibers sends signals to targeted brain regions and changes the activity there. Patients self-administer the Monarch eTNS system at home and typically use the device while sleeping.

According to the device’s developer (NeuroSigma, Inc.), neuroimaging data indicated that eight weeks of nightly eTNS treatment produced a lasting effect on the activity of specific brain areas that are linked to TBI, along with improvements in memory, anxiety, and other symptoms that are common in patients with TBI.

Source: NeuroSigma, Inc., December 10, 2015

NuQ Blood Test Detects 91% of Colorectal Cancers

An investigational blood test (NuQ, VolitionRx Ltd.) accurately detected 91% of colorectal cancer cases in a prospective clinical trial.

The study included 121 patients referred for colonoscopy at a university hospital in Belgium. The subjects either presented with symptoms suggesting the presence of colorectal cancer or were at high risk for cancer. Of these subjects, 23 were found to have colorectal cancer. The investigators tested blood samples taken from subjects before their colonoscopies to determine whether a NuQ test could accurately predict the colonoscopy’s findings.

The results showed that a panel test of four NuQ biomarker assays, adjusted for age, detected 91% of colorectal cancer cases at 90% specificity. The results also showed equally accurate detection of early- and late-stage cancers. In addition, the same panel test detected 67% of the type of polyps most likely to develop into cancer, demonstrating a potential for NuQ tests to accurately detect the spectrum of cancer development from precancerous polyps through early-stage to late-stage colorectal cancer.

Source: VolitionRx Ltd., December 8, 2015

Positive Results for Enbrel Biosimilar

CHS-0214 (CoHerus Biosciences/Baxalta Inc.), a proposed biosimilar version of etanercept (Enbrel, Amgen), met its primary endpoints in a confirmatory, double-blind, randomized, controlled, phase 3 study. The ongoing 52-week trial is evaluating the efficacy and safety of CHS-0214 compared with that of etanercept in patients with moderate-to-severe chronic plaque psoriasis.

At week 12, the study’s primary endpoints—the mean percent change in Psoriasis Activity Severity Index (PASI) scores from baseline and the proportion of subjects achieving 75% improvement in PASI scores from baseline—were within the prespecified margins for demonstrating the equivalence of CHS-0214 compared with etanercept. There were no clinically meaningful differences in the safety profiles of the two products.

Source: Coherus Biosciences, November 11, 2015

DEVICE APPROVALS

Cooling Cap to Prevent Hair Loss During Chemotherapy

The first cooling cap to reduce alopecia in female breast cancer patients undergoing chemotherapy has received FDA clearance for U.S. marketing.

The Dignitana DigniCap Cooling System (Dignitana, Inc.) is indicated to reduce the frequency and severity of alopecia during chemotherapy in breast cancer patients in which alopecia-inducing chemotherapeutic agents and doses are used. It is a computer-controlled system that circulates cooled liquid to a head-worn cooling cap during chemotherapy treatment. The cooling cap is covered by a second cap made from neoprene, which holds the cooling cap in place and acts as an insulation cover to prevent the loss of cooling.

The cooling action is intended to constrict blood vessels in the scalp, which, in theory, reduces the amount of chemotherapy that reaches cells in the hair follicles. The cold also decreases the activity of the hair follicles, which slows down cell division and makes the follicles less affected by chemotherapy. The combined actions are thought to reduce the effect chemotherapy has on the cells, which may reduce hair loss. The device may not work with some chemotherapy regimens.

Source: FDA, December 8, 2015

Encompass SRS Immobilization System

The Encompass SRS immobilizations system (Qfix) has received 510(k) clearance from the FDA for use in stereotactic radiosurgery (SRS).

The Encompass SRS system has been used for intracranial radiotherapy treatments for nearly a year and is now cleared for submillimeter immobilization to treat multiple lesions with a single isocenter.

The system uses a posterior thermoplastic and anterior open-view mask that is compatible with optical tracking systems. It is available as a kVue Insert for use in simulation on kVue CT and for treatment on kVue Couch Top, a standalone device for use with non-kVue CT simulation and treatment surfaces. It is also available in a magnetic resonance imaging (MRI)-compatible standalone device for MR imaging and treatment.

Source: Qfix, December 4, 2015

INOmax DSIR Plus MRI Device Cleared for Nitric Oxide Delivery

The FDA has approved the use of the INOmax DSIR Plus MRI device (Mallinck-rodt) for the delivery of INOmax (nitric oxide) for inhalation during magnetic resonance imaging (MRI) procedures.

The INOmax DSIR Plus MRI system is indicated for delivery of the gas into the patient-breathing circuit to provide a constant concentration of nitric oxide to the patient. The device is indicated for use only with magnetic resonance conditional ventilators validated to be compatible, as identified in the device labeling.

Source: Mallinckrodt, November 16, 2015

DEVICE SAFETY ISSUES

Custom Ultrasonics Recalls Endoscope Reprocessors

The FDA has ordered Custom Ultrasonics to recall all of its automated endoscope reprocessors (AERs) from health care facilities because of the firm’s continued violations of federal law and a consent decree entered with the company in 2007. The identified violations could result in an increased risk of infection transmission.

The FDA ordered the recall under the terms of the consent decree. The agency also issued a safety communication recommending that health care facilities using Custom Ultrasonics AERs begin shifting to alternative methods to reprocess flexible endoscopes as soon as possible.

The FDA’s most recent inspection of Custom Ultrasonics’ facility in April 2015 documented continued violations, which included the inability to validate that the AERs can adequately wash and disinfect endoscopes to mitigate the risk of patient infection. In the months following the inspection, the FDA provided the company with an opportunity to correct inspection violations and requested additional validation data. After a review of the company’s submissions, the agency determined that Custom Ultrasonics has not adequately addressed its continued violations.

Source: FDA, November 13, 2015

Needle Mechanism Failure With OmniPod Insulin System

Insulet Corporation initiated a voluntary field safety notification in early November for 15 lots of the OmniPod Insulin Management System that were distributed in the U.S. This notification was due to a slight increase in reported cases in which the pod’s needle mechanism failed to deploy or there was a delay in the deployment of the needle mechanism. In the event a needle mechanism fails to deploy, the needle will not be inserted and insulin delivery will not begin. The interruption of insulin delivery may cause hyperglycemia, which, if left untreated, can result in diabetic ketoacidosis.

Source: FDA, December 1, 2015

Risk of Shaft Separation With Chariot Guiding Sheath

Boston Scientific has voluntarily recalled all material numbers (UPNs) of the Chariot Guiding Sheaths. The recall was initiated on November 19, 2015, because of the risk of shaft separation.

Boston Scientific has received 14 complaints about shaft separation, four of which involved separation of the distal shaft. These events occurred during device preparation or use. The most severe outcome of this failure is embolism of device fragments, which could lead to obstruction of blood flow or additional intervention to remove a device fragment. Obstruction of blood flow can result in injuries such as stroke, kidney damage, or damage to the intestines or limbs.

The Chariot guiding sheath is intended for the introduction of interventional devices during peripheral vascular procedures.

Source: Boston Scientific, December 11, 2015