Contributing Editor Christine Blank is a freelance writer based in Florida.

Christine Blank

Apixaban (Eliquis) had the lowest overall risks out of direct oral anticoagulants (DOACs) versus warfarin (Coumadin) in a large study.

Researchers at the University of Nottingham in the United Kingdom set out to investigate the associations between DOACs and risks of bleeding, ischemic stroke, venous thromboembolism, and all-cause mortality compared with warfarin, in the 

Using two UK primary care databases-QResearch and Clinical Practice Research Datalink (CPRD) -the researchers evaluated 132,231 patients taking warfarin, 7,744 on dabigatran, 37,863 on rivaroxaban, and 18,223 on apixaban without anticoagulant prescriptions for twelve months before study entry. The patients were subgrouped into 103,270 with atrial fibrillation (AF) and 92,791 without AF.

Apixaban was found to be the safest drug, with reduced risks of major, intracranial, and gastrointestinal bleeding compared with warfarin, the researchers state.

“Anticoagulants are prescribed for a wide range of indications although the adverse events have been studied mostly in patients with atrial fibrillation. Our study has shown that the risk of major bleeding is lower in patients taking apixaban-regardless of the reason for prescribing,” writes Yana Vinogradova, PhD, research statistician in the School of Medicine at the University of Nottingham.

In patients with atrial fibrillation, apixaban was associated with a lower risk of major bleed than warfarin and rivaroxaban (Xarelto). Dabigatran (Pradaxa) and apixaban were associated with lower risks of intracranial bleed than warfarin, and rivaroxaban was associated with a higher risk of intracranial bleeding compared to apixaban.

In the subgroup of patients without AF, apixaban was associated with lower risks of major bleed (adjusted hazard ratio 0.60) than warfarin or rivaroxaban. Rivaroxaban was associated with a lower risk of intracranial bleed (0.54) compared with warfarin, and apixaban use resulted in lower risks of all gastrointestinal (0.55) and upper gastrointestinal bleeds (0.55).

The risk of primary ischemic stroke did not differ between any of the anticoagulants studied. In addition, the risk of primary venous thromboembolism in patients with AF was not different between any drugs. However, in the group without AF compared with warfarin, there was a higher risk in patients taking rivaroxaban and lower risks in patients taking dabigatran.

For both patients with and without AF, the risk of mortality was increased in patients taking rivaroxaban compared with warfarin, the researchers find. “Both rivaroxaban and low-dose apixaban were associated with increased risks of all-cause mortality compared with warfarin,” they write.

An important limitation of the study is the lack of information on patient adherence to their prescribed drugs, according to Vinogradova. “It is not known when exactly a patient stopped taking anticoagulants … Warfarin has been shown to have the highest non-persistence [adherence rate] and apixaban and rivaroxaban the lowest.”

Articles

Study Shows Comparative Risks for DOACs

	Sometimes, despite your best efforts, you can't stay up on the latest news. Staying up on local and national politics is hard enough, but what about the latest pharmacy news? Almost impossible.

That's why every month we bring you Small Doses. They're easy-to-swallow little pills (candy-coated!) of information tailored for the busy pharmacist. There's a lot happening out there, but here's the short version of what we think you need to know. 

	This month, read more on depression in the pharmacy, vaccine errors, naloxone, and more. And when you're done, hopefully you'll be well-versed enough to share the news around the water cooler-

assuming you even have time for a water break

	Up next: More pharmacy residents depressed than medical residents.

	More Pharmacy Residents Depressed than Medical Residents

	Pharmacy residents typically carry a high stress load and can become depressed, but more accurate data on depression rates are needed. “We haven’t really studied this a lot,” says Janet A. Silvester, PharmD, vice president of accreditation services for 

. “On the medical side, they have been looking at [the impacts of stress on residents] longer.”

	To obtain more accurate data on pharmacy resident stress, Evan Williams, PharmD, BCPS, assistant professor of pharmacy practice at 

 in Henderson, NV, along with pharmacists who work for Albertsons and Rite Aid, surveyed more than 1,900 pharmacy residents using the depression screening component of the Patient Health Questionnaire (PHQ-9).

, published in the March 2018 issue of the 

American Journal of Health-System Pharmacy

, found 39% reported moderate to severe depressive symptoms during March 2016. Rates among medical residents have been reported to be about 30%. In the general population, the depression rate ranges from 6.6% to 7.6%.

	“The rate was higher than what I expected,” says Williams.

	Now, he and his colleagues are working to reproduce the results in a two-year study, surveying pharmacy residents about their 

 rates at various times of the year. “Hopefully, we are able to publish this and get more of a cluster of data, to describe how frequently we think this is happening,” Williams says.

Pharmacy School Helps Community with Naloxone Training

 at Auburn University in Alabama is looking to expand the 

	The school’s pharmacy residents and pharmacists are supplying the city’s police and firefighters with naloxone, and training them to use the opioid overdose reversal medication.

	“The Auburn pharmacy faculty and students are working to be proactive, and prepare the Auburn community to react and respond if and when the United States opioid epidemic extends to the Auburn community,” says Kimberly Braxton-Lloyd, PharmD, assistant dean in Auburn’s Department of Pharmacy Health Services. “We want to increase awareness and preparedness among our students, faculty, advisors, and first responders, so we can act quickly and decisively in emergencies and potentially save lives.”

	Braxton-Lloyd is working to raise funds for 

. “We would like to continue to expand this program to further educate and equip others who may be in a position to respond during an opioid overdose,” Braxton-Lloyd says. “We believe the more people who are trained and equipped throughout campus, the more likely it will be that we are prepared when an overdose situation does occur on our campus.”

	Alabama leads the country in opioid prescribing, according to the CDC, with an estimated 96 to 142 prescriptions per 100 people per year.

	Specialty drugs will contribute all of the growth in drug spending in 2018. In fact, these medicines are expected to reach 48% of total spending in developed markets by 2022, according to a 

 from the IQVIA Institute for Human Data Science.

	This year, the $318 billion specialty medicines market will represent 41% of developed market spending, up from $172 billion in 2013, IQVIA said in its 

2018 and Beyond: Outlook and Turning Points 

study. However, the growth of spending on specialty medicines will be constrained by cost and access controls and a greater focus on assessments of value, IQVIA notes.

Considering Specialty Pharmacy? Make Your Move

	Biosimilar drugs will also have a much bigger impact on drug spending in 2018 and beyond. In 2018, $19 billion of current biotech spending in developed markets will have competition from biosimilars for the first time. “That amount is significantly greater than the $3 billion in biosimilar revenue that became exposed in 2017, and it adds to the $26 billion already facing competition,” IQVIA says. “The new exposure to competition in 2018 is the largest single-year change to date and signals the start of the next large wave of biosimilars.”

	The study also found that real net per capita spending on medicines in the United States will decline in 2018 and continue almost unchanged at roughly $800 per person through 2022. “Spending will remain flat after factoring in the robust pipeline of new drugs, moderating brand price increases of 2% to 5% on a net basis (7% to 10% on a list price basis) and the impact of brand losses of exclusivity, which will be greater in the next five years than the last five,” according to an IQVIA statement.

	Patients taking over-the-counter medications such as acetaminophen reported less pain intensity than patients taking prescription opioids such as Vicodin, during a recent study.

, involved Veterans Affairs patients who had moderate to severe chronic back pain, or hip or knee osteoarthritis pain, despite analgesic use.

	Researchers compared patients’ pain intensity, pain-related function, and the adverse effects between opioids such as morphine, oxycodone, or fentanyl patches, versus nonopioids, including generic Tylenol, ibuprofen, and prescription nerve and muscle pain drugs.

	While the two groups did not significantly differ on pain-related function over a 12-month period, pain intensity was significantly better in the nonopioid group. The 

 (BPI) severity was 4.0 for the opioid group and 3.5 for the nonopioid group.

	Adverse medication-related symptoms were significantly more common in the opioid group over 12 months:1.8 in the opioid group versus 0.9 in the nonopioid group.

Treatment with opioids was not superior to treatment with nonopioid medications for improving pain-related function over 12 months,” the researchers wrote. “Results do not support initiation of opioid therapy for moderate to severe chronic back pain or hip or knee osteoarthritis pain.”

Errors Reported with Herpes Zoster Vaccines

	Confusion over the two herpes zoster vaccines on the market, has led to a “small number of error reports” involving differences between the two vaccines, the Institute for Safe Medication Practices (ISMP) reports.

 (zoster vaccine recombinant, adjuvanted) from GlaxoSmithKline, referred to as RZV by the CDC, was approved by the FDA last October. However, for more than 10 years, healthcare professionals have been accustomed to the storage and administration requirements of Merck’s Zostavax (zoster vaccine live, or ZVL).

	“Shingrix and Zostavax have different storage requirements, components/diluents, and routes of administration,” according to 

ISMP Medication Safety Alert! Community/Ambulatory Care Edition.

	Both components of the Shingrix vaccine, its lyophilized gE antigen component and its adjuvant suspension component, should be stored under refrigeration before and after reconstitution, according to ISMP. If the lyophilized component or its adjuvant suspension are improperly stored in a freezer, they must be discarded.

, the lyophilized vaccine (attenuated varicellazoster virus) should be stored in a freezer, and the Merck-supplied sterile water diluent can be stored in a refrigerator or at room temperature.

	“The product components are not interchangeable. A system should be employed to ensure the Shingrix lyophilized component and adjuvant suspension vials are stored with one another to reduce the risk of using a diluent from another vaccine,” ISMP says.

	Another major difference is that Shingrix is given intramuscularly, while Zostavax is given subcutaneously.

 (ACA) recently acquired the pharmacy buying group The Compounders Group (TCG) to help independent pharmacists stay competitive in today’s marketplace, ACA says.

	“The costs of running an independent pharmacy continue to escalate, especially with challenges like USP 800. It’s more important than ever that independent pharmacies work together,” says ACA Executive Vice President Donnie Calhoun, who is also a longtime member of TCG. “We will see more collaboration as TCG grows to an even larger, stronger group, leveraging its buying power and helping independent pharmacies face the challenging pharmacy landscape.”

	Since the acquisition, TCG has experienced an almost 20% increase in membership and has expanded to 52 vendors.

	“The founders of TCG have watched it grow over the past six years, from serving primarily compounders with an increasing number of members that own hybrid, specialty, and traditional pharmacies. With ACA at the helm, TCG’s goal of helping its members buy smarter and stronger will remain the same,” says David Rochefort, one of TCG’s five founding members.

ASHP: 340B Provides Access to Pharmacy Services

 lauded the benefits of the government’s 340B Drug Discount Program during a Senate hearing on drug pricing in mid-March.

	“The increasing shift throughout healthcare toward ambulatory care, including more outpatient pharmacy services, has contributed to the growth of the 340B program and has allowed for better access to medications by low-income and uninsured patients,” Joe Hill, director of 

, told the Senate Health, Education, Labor, and Pensions Committee. “It is important to note that drugs subject to the 340B drug-pricing program make up a fraction of the nation’s total drug expenditures.”

	The 340B program also reduces government expenditures and lessens the burden on taxpayers who would otherwise be financing the indigent care federal 340B-participating hospitals provide, said Hill. He added that the 340B program results in savings that:

		Improve access to primary care, behavioral health services, and pharmacist-led substance abuse treatment;

		Enable discounts or free prescription medications; and

		Provide many other services for uninsured and underinsured patients.

Easy-to-swallow bits of news and studies for the busy pharmacist.

Small Doses: News for Pharmacists in April

	The Centers for Medicare & Medicaid Services’ new Medicare Part D proposal calls for a seven-day supply limit on opioid prescriptions and other efforts to help battle the opioid epidemic.

, which would go into effect in 2019, includes new hard formulary levels at pharmacies that would restrict the amount of initial fills on prescription opioids to seven days for the treatment of acute pain with or without a daily dose maximum (such as 50 MME).

	CMS would also expect all sponsors to implement soft POS safety edits (which can be overridden by a pharmacist) based on duplicative therapy of multiple long-acting opioids, and request feedback on concurrent prescription opioid and benzodiazepine soft edits, the agency said in a 

	CMS also proposes enhancing the Overutilization Monitoring System (OMS) by identifying high risk beneficiaries who use “potentiator” drugs such as gabapentin (brand names Neurontin, Gralise, and others) and pregabalin (brand name Lyrica) in combination with prescription opioids to “ensure that plans provide appropriate case management,” CMS said.

	OMS already flags concurrent benzodiazepine use by plan enrollees.

 executives have not been able to fully review the proposal, the organization in general advocates for “a change in public policy to create a seven-day supply limit for initial opioid prescriptions issued for acute pain, which is consistent with the Centers for Disease Control and Prevention (CDC) Guideline for Prescribing Opioids for Chronic Pain,” Chris Krese, spokesman for NACDS, told 

	“CDC’s clinical evidence suggests that a greater amount of initial opioid exposure is associated with a greater risk for long-term use and addiction. More than 20 states already have taken action, and federal action is needed for consistent patient care,” Krese added.

	Meanwhile, NACDS is reviewing the exact details of CMS' Medicare Part D, to determine if they are consistent with NACDS’s position. “Following that review, NACDS will submit comments to CMS,” Krese said.

	In related news, the National Conference of Pharmaceutical Organizations (NCPO) 

 “immediate action on components of the President’s Commission on Combating Drug Addiction and the Opioid Crisis report” and requested the opportunity to dialogue with the President and others in the Administration for continued collaboration on opioid-related issues.

	The coalition of 11 trade associations and professional societies includes NACDS, NCPA, ASHP, and APhA.

	“Pharmacy has significant insights about the complexity of this issue, given the role of pharmacists on the front lines of healthcare every day, and we are committed to working proactively with NCPO members and with all levels and branches of government for the safety of our families and communities,” said NACDS President and CEO Steven C. Anderson.

Pharmacy groups are praising new Medicare Part D opioid limits.

CMS Proposes Part D Opioid Limits, Pharmacy Reacts

	Saying that pharmacists are busy is like saying that water is wet. In the middle of all the craziness you go through every day, are you really taking the time to sit down and read all the latest pharmacy news?

	But there are some things you should know. Things like Amazon’s entry into the pharmaceutical business, how the U.S. government is cracking down on illegal ovoid withdrawal supplements, and how hospitals are handling the ongoing IV saline shortage are all important issues that impact pharmacists’ daily business.

	In these six “Small Doses” articles, 

 gives you easy-to-swallow bits of information that could make a huge impact on you and your patients. 

	Up next: FDA cracks down on false claims

	FDA, FTC Warn Opioid Cessation Supplement Makers

	The FDA and the Federal Trade Commission 

 the marketers and distributors of 12 opioid cessation products for illegally marketing unapproved products with claims about their ability to help treat opioid addiction and withdrawal.

	The marketers include Opiate Freedom Center; U4Life, LLC; CalmSupport, LLC; TaperAid; Medicus Holistic Alternatives LLC; NutraCore Health Products, LLC; Healthy Healing, LLC; Soothedrawal, Inc.; Choice Detox Center, Inc.; GUNA, Inc.; and King Bio, Inc. 

	All of them use online platforms to make illegal claims about their products' ability to cure, treat, or prevent a disease, according to FDA. Examples of claims include: “#1 Selling Opiate Withdrawal Brand” and “Safe and effective natural supplements that work to ease many physical symptoms of opiate withdrawal.”

	If the companies don’t correct violations, they could face law enforcement actions, such as seizure or injunction.

	Publix Pharmacies Feature Walk-In Care Centers

	Lakeland, Florida-based Publix and BayCare Health System teamed up to provide Telehealth systems at 26 in-store Publix Pharmacy locations by the end of this year.

	The “Walk-In Care” telehealth centers at Publix, which operates 1,168 stores, feature a private room where shoppers can receive non-urgent medical care from board-certified physicians through teleconferencing and medical diagnostic equipment.

	“The kiosk, which is interactive and user-friendly, allows patients to easily enter their symptoms and work with medical tools such as thermometers, otoscopes, blood pressure cuffs, and high definition cameras to help doctors make an accurate diagnosis,” BayCare Health said in a statement.

	Publix Pharmacy support staff are available to assist patients, if needed. 

	“Pharmacists are a part of many patients’ wellness plans, and our Publix Pharmacists have been serving our communities through a variety of services like vaccinations, health screenings, free and discounted medications, and more,” said Maria Brous, Publix’s director of media and community relations. “This Walk-In Care clinic takes our partnership with physicians to a new level. Together, we’ll help keep our community feeling well.”

	Amazon’s exploratory pharmacy business leadership team has expanded to between 30 and 40 people, according to a report from financial research firm Leerink.

	Amazon also held exploratory talks in November with generic drug manufacturers such as Sandoz and Mylan, leading analyst to speculate that Amazon will sell generic drugs.

	Leerink believes that Amazon’s entry into the pharmaceutical business is a matter of “when” not “if.” CNBC 

. "Amazon saw the inclusion of pharmaceutical drugs as a natural add-on to its existing product offerings,” Leerink’s report stated.

	Amazon’s latest high-profile health care hire is Martin Levine, a doctor who specializes in new models of patient care, CNBC said.

	The Flu’s Impact on IV Saline Shortages

	This year’s severe flu season may continue to further impact the IV saline shortage, which worsened last fall after Hurricanes Maria and Irma struck Puerto Rico. “The tight supply of saline products has been exacerbated by an increased demand for saline we’re seeing as a result of the worse-than-typical flu season. ... As such, we encourage healthcare organizations and hospitals to 

 directly if they aren’t receiving the products they need,” said FDA Commissioner Scott Gottlieb, MD, in a 

Pharmacy Supply Lines Are Still Shaking After Storm Passes

	FDA is also asking IV saline manufacturers to submit data to extend expiration dates for products. “If expiration dates can be safety extended, it would allow some near-expiry product that remains at the hospital level to be used,” Gottlieb said.

	Updates, including new supply sources and extensions of expiration dating, will be posted on the FDA’s drug shortage 

	Cannabidiol Drug for Epilepsy Expected Later This Year

 therapy-the first in a new category of antiepileptic drugs-is expected to launch in the second half of this year, after its manufacturer’s New Drug Application was accepted by FDA.

	Epidiolex, manufactured by GW Pharmaceuticals, demonstrated a reduced monthly drop in seizure frequency compared to placebo in highly-treatment-resistant patients with Lennox-Gastaut syndrome (LGS), a rare form of epilepsy, according to a study published in 

. Over a 14-week treatment period, 44% of patients taking Epidiolex saw a significant reduction in seizures, compared with 22% of the placebo group.

	"LGS is one of the most difficult types of epilepsy to treat, and the majority of patients do not have an adequate response to existing therapies," said Elizabeth Thiele, MD, PhD, a professor of Neurology at Harvard Medical School, and lead author of the Lancet study. "These results show that Epidiolex may provide clinically meaningful benefits for patients with LGS."

	FDA accepted the NDA for Epidiolex to treat LGS and Draven syndrome, another rare childhood-onset epilepsy, in December.

	Publix Launches Low-Cost Generics Program

	Publix Pharmacy’s new low-cost generic program will provide up to a 90-day supply of some of the most commonly prescribed generic drugs for $7.50.

	The Lakeland, FL-based chain of 1,168 stores will offer 29 generic medications with a total of 85 dosage options for $7.50 each. They include highly-prescribed treatments for heart health and cardiovascular conditions, diabetes, high cholesterol, mental health, seizure disorders, Parkinson’s disease, Alzheimer’s disease, osteoporosis, and several other medical conditions.

	 “Healthcare costs continue to rise, so sometimes people have a hard time filling their prescriptions as regularly as they should. We believe this low price will help encourage customers to follow their doctor’s orders, so they can experience better health outcomes,” said Maria Brous, director of media and community relations for Publix.

Easy-to-swallow bits of information from around the world of pharmacy.

Small Doses: 6 Stories You Need to Know in January

	Medicare Part D direct and indirect (DIR) fee reform is gaining momentum in Congress this year, as more than 115 organizations and a bipartisan group of 80 U.S. Representatives 

 a proposal changing how the fees are charged.

	The new provision, part of the Centers for Medicare and Medicaid Services’ 2019 proposed Medicare Part D rule, would apply pharmacy DIR fees at the point-of-sale rather than after the fact.

	“The Center for Medicare and Medicaid Services would provide these pharmacies with fairness and transparency by effectively ending retroactive Direct and Indirect Remuneration (DIR) fees,” said Rep. Morgan Griffith (R-VA). “This reform will help community pharmacists continue their important work serving patients.”

	In addition, more than 115 pharmacy retailers, health care organizations, and others signed a 

 to CMS supporting the point-of-sale change. Albertsons, Price Chopper, Sav-Mor Drugs, and Bartell Drugs, along with other drug stores, numerous state pharmacy associations, drug distrubutors like McKesson, several major hospitals, and national associations such as NCPA and ASHP, signed the letter.

	“Via this letter, more than 115 health care stakeholders make a case for why the proposed rule is good policy, and urge CMS not to waver on it. The current system, which allows pharmacy benefit managers to claw back an undetermined amount of money from pharmacies weeks or months after the transaction, is unfair to patients and unsustainable for small-business pharmacy owners,” said NCPA CEO B. Douglas Hoey, RPh, MBA, in a statement.

	While NACDS agrees with requiring the inclusion of all potential pharmacy price concessions in the point-of-sale negotiated price, the organization is asking CMS to clarify “whether it would expect the negotiated price, including all pharmacy price concessions, to be used for determining pharmacy reimbursement for prescription drugs at point of sale, or if CMS would expect such a negotiated price to be used solely for determining beneficiary payment at the point-of-sale,” NACDS wrote in comments submitted to Health and Human Services.

The Drug Topics 2017 Pharmacist Salary Survey

	“While we support the inclusion of all potential pharmacy price concessions in the negotiated price, under this scenario we would urge CMS to consider that the negotiated price be used solely for determining beneficiary payment at the point of sale and not for determining pharmacy reimbursement at point-of-sale. We also believe performance-based payments should not be incorporated into the negotiated price,” NACDS wrote.

	"In addition, we ask CMS to clarify that the negotiated price would still be determined on a contractual basis and not be the same negotiated price among all pharmacies within a network,” the organization added.

	The National Association of Specialty Pharmacy also urged CMS to “consider pharmacy reimbursement in totality when moving pharmacy price concessions to the calculation of negotiated price,” the organization said in comments to HHS.

	The agency should also tweak the definitions of mail order and retail pharmacies, NASP said, as well as “codify and enforce that unreasonably low reimbursement rates, when offered in an initial network contract, occurring as a result of mid-year rate changes and/or after rebates/concessions are factored in to the final reimbursement rate subverts the convenient access standards.”

CMS is considering big changes to DIR fees and pharmacists are excited.

New DIR Proposal Supported by Chains, Pharmacy Organizations

	The FDA will no longer allow opioid-containing cough and cold medicines to be prescribed for children younger than 18 years.

	The agency is ordering the safety labeling changes in cough and cold medicines containing codeine or hydrocodone “because the serious risks of these medicines outweigh their potential benefits in this population,” the agency said in a 

	After safety labeling changes are made, the products will no longer be indicated for use to treat cough in any pediatric population, and will be labeled for use only in adults aged 18 years and older.

	“Given the epidemic of opioid addiction, we’re concerned about unnecessary exposure to opioids, especially in young children. We know that any exposure to opioid drugs can lead to future addiction. It’s become clear that the use of prescription, opioid-containing medicines to treat cough and cold in children comes with serious risks that don’t justify their use in this vulnerable population,” said FDA Commissioner Scott Gottlieb, MD.

	At the same time, the FDA is taking steps to help reassure parents that treating the common cough and cold is possible without using opioid-containing products, Gottlieb added.

	Labeling for the medications is also being updated with additional safety information for adult use. The cough and cold drugs will now include an expanded Boxed Warning - the FDA’s most prominent warning - notifying about the risks of misuse, abuse, addiction, overdose, death, and slowed or difficult breathing that can result from exposure to codeine or hydrocodone.

	“The new labeling will provide safety warnings on these products that are consistent with the labeling of other opioid-containing drug products, including immediate-release opioid analgesics and extended-release and long-acting opioid analgesics,” FDA said.

 of a contraindication to the labeling of prescription codeine products alerting that codeine should not be used to treat pain or cough in children younger than 12 years, due to a specific risk of ultra-rapid metabolism in certain patients.

	The FDA also held an expert roundtable and convened a meeting of its Pediatric Advisory Committee to look at all the risks associated with the use of codeine- or hydrocodone-containing cough and cold products in children and adolescents younger than 18 years old.

	“Experts indicated that although some pediatric cough symptoms do require treatment, cough due to a cold or upper respiratory infection typically does not require treatment. Moreover, the risks of using prescription opioid cough products in children of all ages generally outweigh the potential benefits,” FDA said.

The agency’s ruling also added an additional Boxed Warning.