The Drug Quality and Security Act (DQSA) created a pathway for pharmacy compounders to be registered with the FDA as outsourced 503B compounding facilities.

This effort was largely in response to the outbreak of fungal meningitis among patients who received contaminated preservative-free methylprednisolone acetate steroid injections because of poor quality control at the New England Compounding Center in September 2012.

 Section 503B of the DQSA aims to establish federal standards for product integrity, quality assurance testing, reporting, and safety when producing large volumes of compounded sterile products (CSPs).

Pharmacies compound millions of sterile and nonsterile drug doses for patients each year, and many are pursuant to a patient-specific prescription order from a physician or other prescriber. However, anticipatory batch compounding is where pharmacies will produce CSPs in advance of a patient-specific order. Although this process can supposedly save money and time for pharmacies, it is not the ideal practice, given new compounding standards and the limits of the drug's beyond-use-date, as well as requirements for batch testing, analysis, and reporting.

This is where the standards come in to help pharmacists with anticipatory batch compounding. 503B outsourcing facilities have streamlined anticipatory batch compounding by making the process much easier, more cost-effective, and safer when producing large-volume CSPs instead of pharmacies trying to do everything themselves. The mission of 503B suppliers is to provide effective and safe compounded drug products that are not otherwise commercially available. 503B suppliers must comply with current good manufacturing practice (cGMP) requirements, pass an FDA inspection according to a risk-based schedule, meet certain other conditions, report adverse events, and provide the FDA with specific information about the products they compound. They also must hold up to scrutiny by many others, including state pharmacy boards, departments of health, the Joint Commission, and other regulatory bodies.

The scale and size of investment required to operate at cGMP requirements is significant and makes it largely impracticable for community and hospital pharmacies to duplicate this operating model. The cGMP requirements reduce variability, which significantly reduces risk to the public. Although requiring such rigor to produce CSPs raises quality, it also makes it quite expensive to operate. But the process is highly repeatable. There are many 503B suppliers operating within the United States, and many serve all 50 states. These suppliers are incredibly efficient at driving down waste and lowering cost, and at the same time, offer more ready-to-use products. This, in turn, translates into an easy-to-understand return on investment calculation for providers. By lowering providers' costs and raising quality, 503B suppliers produce a win-win solution for the public.

Although the advent of 503B compliance has raised standards and is producing great benefits for Americans, it would be impractical for all CSPs to be manufactured at a 503B outsourcing facility. Providers should seek a 503B supplier to assist them with only the truly laborious CSPs to produce. These may include such products as continuous ambulatory delivery device pumps, controlled substances and narcotics, elastomeric pumps, high-risk compounds, and infrequently used medications. 503B suppliers can also assist pharmacists working with active pharmaceutical ingredients (APIs) or nonsterile drugs and can help sterilize the final product. This assistant permits these difficult-to-handle medications to be produced with a high degree of certainty and quality, and at the same time, allows the local pharmacy team bandwidth and time to focus on the patient-specific CSPs that are needed acutely and on a smaller scale.

503B outsourcing facilities benefit the public by producing medications found on the FDA's drug shortage list. By working with APIs and raw materials with a cGMP standard, patients and providers have access to drugs that would otherwise be unavailable. Drug shortages across the United States continue to be a problem, but the impact of these shortages has been negated to some extent by 503B outsourcing facilities. Another tangible benefit of this impact is the vital role that 503B suppliers played in supplying hospitals with shortage medications required to treat critically ill patients with COVID-19 during the peak of the pandemic.

503B compliance has raised the bar on quality and safety for patients and providers alike in the United States. As more companies enter this space, there will be competition to further lower prices while improving quality. The benefit of the DQSA to the public is being realized.

1. Compounding laws and pharmacies. FDA. September 10, 2020. Accessed April 29, 2021. https://www.fda.gov/drugs/human-drug-compounding/compounding-laws-and-policies

2. Multistate outbreak of fungal meningitis and other infections. CDC. October 30, 2015. Accessed April 29, 2021. https://www.cdc.gov/hai/outbreaks/meningitis.html

is vice president of field pharmacy services at Premier, Inc in Charlotte, North Carolina.

Articles

As more companies enter this space, expect competition to further lower prices while improving quality.

How Does 503B Compliance Benefit the Public?

The FDA recently approved Cabenuva, the first long-acting injectable for the treatment of HIV. Cabenuva is a 2-drug copackaged product containing cabotegravir (CAB) and rilpivirine (RPV) and requires 2 intramuscular (IM) gluteal injections once monthly. It is indicated as maintenance therapy for individuals who are virologically suppressed, defined as HIV-1 RNA with less than 50 copies/ mL, on a stable regimen with no history of treatment failure and no known or suspected resistance to either drug.

The FDA approved the regimen on the basis on results from 2 phase 3, multi-center, randomized, noninferiority trials: FLAIR (NCT02938520) and ATLAS (NCT02951052). Both met noninferiority for the primary end point of the proportion of participants with plasma HIV-1 RNA greater than or equal to 50 copies/mL at week 48. FLAIR compared monthly IM CAB/RPV with daily oral dolutegravir/abacavir/lamivudine therapy (primary end point, 2.1% vs 2.5%, respectively; adjusted difference, –0.4 percentage points; 95% CI, –2.8 to 2.1), whereas ATLAS compared monthly IM CAB/RPV with patients’ current daily antiretroviral regimen (primary end point, 1.6% vs 1.0%, respectively; adjusted difference, 0.6 percentage points; 95% CI, –1.2 to 2.5).

To ensure tolerability prior to transitioning to the long-acting injectable formulation, an oral lead-in with one 30-mg tablet of CAB (Vocabria) and two 25-mg tablets of RPV (Edurant) once daily with food for at least 1 month is recommended.

 The long-acting injectables are then initiated on the last day of oral lead-in therapy and dosed once monthly. Interestingly, both CAB/RPV are slowly absorbed following IM administration, in which the absorption rate half-lives are about 40 days and 90 to 200 days, respectively. Thus, a less frequent IM administration may be needed.

 The phase 3, multicenter, randomized, noninferiority ATLAS-2M study (NCT03299049) compared CAB 400 mg/RPV 600 mg every 4 weeks with CAB 600 mg/RPV 900 mg every 8 weeks. The primary outcome was the same as in the FLAIR and ATLAS trials, which was the proportion of participants with plasma HIV-1 RNA greater than or equal to 50 copies/mL at week 48. Findings from this study established that administration every 8 weeks was noninferior to dosing every 4 weeks (2% vs 1%, respectively; adjusted difference, 0.8; 95% CI –0.6 to 2.2). Although the study met its primary end point, an extension phase is under way and will follow patients through week 100. Pending FDA review, dosing every 8 weeks may be recommended.

 Regardless of the dosing regimen, patients who are unable to obtain their injectables in clinic on the exact targeted administration day have a buffer period of 7 days to receive the next dose.

Given that the product is administered as an IM injection, a notable advantage is its ability to overcome drug-drug interactions present with the oral formulation of RPV. Proton pump inhibitors (PPIs) increase gastric pH, resulting in the reduction of RPV plasma concentration when given orally. When RPV is given in combination with omeprazole, RPV area under the curve, maximum plasma concentration, and minimum plasma concentration decrease by 40%, 40%, and 33%, respectively.

 As a result, PPIs are contraindicated in patients who take oral RPV.

However, given the IM formulation, this is no longer an issue. This also holds true for histamine-2 receptor antagonists and antacids.

Practitioners should note certain prescribing considerations for the use of Cabenuva. For the oral lead-in phase, only a single specialty pharmacy, TheraCom, is contracted to provide a 30-day supply, which can be shipped directly to a patient’s home or a prescriber’s office. Once patients demonstrate tolerability of oral therapy, they can switch to the long-acting, once-monthly IM injections, which must be administered in a health care setting, such as a prescriber’s office. The first IM kit contains CAB 600 mg and RPV 900 mg, whereas subsequent monthly dosing consists of CAB 400 mg and RPV 600 mg. If a patient misses 1 to 2 months of Cabenuva, resume with CAB 400-mg and RPV 600-mg IM monthly injections as soon as possible.7 But if a patient misses more than 2 months of Cabenuva, reinitiate with CAB 600-mg and RPV 900-mg IM injections, then continue to follow the CAB 400-mg and RPV 600-mg IM monthly injection dosing schedule. If patients are unable to access or continue Cabenuva, switching to an oral antiretroviral regimen is permissible under the supervision of a health care provider.

Although practitioners must consider many factors when prescribing Cabenuva, the agent has the potential to revolutionize the treatment landscape for HIV and, with hope, will play a fundamental role in ending the HIV epidemic.

 is an infectious diseases resident at The University of Texas MD Anderson Cancer Center in Houston.

Melissa Badowski, PharmD, MPH, FCCP, BCIDP, BCPS, AAHIVP, 

is a clinical associate professor at the University of Illinois Chicago College of Pharmacy.

FDA approves Cabenuva and Vocabria for the treatment of HIV-1 infection. News release. FDA. January 27, 2021. Accessed April 12, 2021. https://www.fda.gov/drugs/human-immunodeficiency-virus-hiv/fda-approves-cabenuva-and-vocabria-treatment-hiv-1-infection 

Orkin C, Arasteh K, Hernandez-Mora MG, et al. Long-acting cabotegravir and rilpivirine after oral induction for HIV-1 infection. N Engl J Med. 2020;382(12):1124-1135. doi:10.1056/ NEJMoa1909512

Swindells S, Andrade-Villanueva JF, Richmond GJ, et al. Long-Acting cabotegravir and rilpivirine for maintenance of HIV-1 suppression. N Engl J Med. 2020;382(12):1112-1123. doi:10.1056/NEJMoa1904398

Vocabria. Prescribing information. ViiV Healthcare; 2021. Accessed April 12, 2021. https:// gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Vocabria/pdf/ VOCABRIA-PI-PIL.PDF

Letendre SL, Mills A, Hagins D, et al. Pharmacokinetics and antiviral activity of cabotegravir and rilpivirine in cerebrospinal fluid following long-acting injectable administration in HIV -infected adults. J Antimicrob Chemother. 2020;75(3):648-655. doi:10.1093/jac/dkz504

Overton ET, Richmond G, Rizzardini G, et al. Long-acting cabotegravir and rilpivirine dosed every 2 months in adults with HIV-1 infection (ATLAS-2M), 48- week results: a randomized, multirecentre, open-label, phase 3b, non-inferiority study. Lancet. 2020;396(10267):1994-2005. doi:10.1016/S0140-6736(20)32666-0

Cabenuva. Prescribing information. ViiV Healthcare; 2021. Accessed April 12, 2021. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/212888s000lbl.pdf

Edurant. Prescribing information. Tibotec Therapeutics; 2011. Accessed April 12, 2021. https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/202022s000lbl.pdf

Infectious Diseases Focus

FDA approval of 2-drug injectable Cabenuva is a game changer in maintaining viral suppression in patients.

Long-Acting HIV Regimen May Prove Revolutionary

Small cell lung cancer (SCLC) accounts for approximately 15% of all lung cancer cases, with almost all cases attributed to tobacco smoke exposure.

SCLC is generally characterized by an aggressive, rapidly growing disease course with a high rate of metastasis. Although this rapid growth and proliferation translate into higher response rates to chemotherapy and radiation, patients relapse quickly with increased rates of disease progression.

Clinical staging for SCLC has historically been classified using the Veterans Administration Lung Study Group's 2-stage system to categorize patients to having either limited-stage SCLC (LS-SCLC) or extensive-stage SCLC (ES-SCLC) disease.

 This system differs from most solid tumor staging, which uses the American Joint Committee on Cancer TNM staging system. The National Comprehensive Cancer Network (NCCN) uses a combined approach for staging SCLC using the TNM staging criteria but ultimately classifies patients with SCLC as having LS-SCLC or ES-SCLC.

 Patients with ES-SCLC have a more advanced disease course. Therefore, the goal of treatment for these patients shifts from curative intent to an intent geared toward disease control and palliation.

For several decades, first-line treatment for ES-SCLC has consisted of systemic chemotherapy with a platinum agent (carboplatin or cisplatin) plus etoposide. Because of the favorable toxicity profile of carboplatin over cisplatin and comparable efficacy rates between the 2 platinum agents, carboplatin was preferred over cisplatin in ES-SCLC treatment regimens. Although response rates were reported as high as 80%, median overall survival rates for patients treated with carboplatin and etoposide were approximately 10 months.

In recent years, immune checkpoint inhibitors have revolutionized oncology treatment with 7 checkpoint inhibitors approved by the FDA to treat various types of cancer, including melanoma, non–small cell lung cancer, renal cell carcinoma, urothelial carcinoma, and many others. By manipulating physiologic immune checkpoint pathways in place to reduce autoimmunity, cancer cells can evade recognition and targeting by cytotoxic T lymphocytes (CTLs). Immune checkpoint inhibitors target these pathways, either by inhibiting CTL antigen-4 (CTLA-4) or the interaction between PD-1 receptors and its ligands, PD-L1/L2.

Two immune checkpoint inhibitors, atezolizumab (Tecentriq; Genentech) and durvalumab (Imfinzi; AstraZeneca), were recently studied in the first-line setting for patients with ES-SCLC in combination with a platinum agent and etoposide. This addition of immunotherapy to chemotherapy represents the first change in ES-SCLC treatment since the 1990s. Both atezolizumab and durvalumab are humanized, IgG monoclonal antibodies targeting PD-L1 on the surface of tumor cells.

Atezolizumab was studied in combination with carboplatin and etoposide for first-line treatment in ES-SCLC in the phase 1/3 IMpower133 trial.

 In a 1:1 fashion, 403 patients with untreated ES-SCLC were randomized to receive treatment with carboplatin, etoposide, and atezolizumab or a matching placebo every 21 days for 4 cycles. After the initial 4-cycle induction phase of treatment, patients received maintenance therapy with atezolizumab or a placebo every 21 days until loss of clinical benefit, disease progression, or unacceptable toxicity.

After a median follow-up of 13.9 months, patients in the atezolizumab arm had a longer median overall survival (12.3 months) compared with the placebo arm (10.3 months).

=.007), suggesting a 30% lower risk of death with the addition of atezolizumab to standard carboplatin-etoposide therapy. In February 2021, an updated analysis was published after a median follow-up of 22.9 months, supporting the original results of the IMpower133 trial.

 The update reported a median overall survival of 12.3 months in the atezolizumab arm compared with 10.3 months in the placebo arm (HR, 0.76; 95% CI, 0.60-0.95; 

Durvalumab was the second PD-L1 inhibitor approved by the FDA based on the results of the CASPIAN trial.

 In this trial, 805 patients with untreated ES-SCLC were randomized 1:1:1 to receive treatment with a platinum agent (carboplatin or cisplatin) and etoposide; platinum-etoposide plus durvalumab; or platinum-etoposide plus durvalumab and tremelimumab, a CTLA-4 inhibitor. Initial treatment was given for 4 cycles (up to 6 cycles in the platinum-etoposide arm), followed by maintenance durvalumab every 4 weeks until disease progression or unacceptable toxicity. 

The published results of the CASPIAN trial included analysis of the platinum-etoposide and platinum-etoposide-durvalumab arms.

 After a median follow-up of 25.1 months, updated results were published showing that the median overall survival was longer in the platinum-etoposide-durvalumab arm (12.9 months) compared with the platinum-etoposide arm (10.5 months).

=.0032), similar to the results from the IMpower133 trial. 

As with other checkpoint inhibitors, treatment with both atezolizumab and durvalumab is associated with a unique immune-mediated toxicity profile, ranging from mild toxicities to potentially life-threatening toxicities. With a heterogeneous clinical presentation, immune-mediated toxicities can affect any organ system, most commonly the gastrointestinal tract, liver, skin, and thyroid gland. Immune-mediated toxicities should be identified as early as possible for close monitoring, prompt initiation or high-dose corticosteroids, and supportive care.

Based on the results of both the CASPIAN and IMpower133 trials, the addition of atezolizumab or durvalumab to platinum-etoposide therapy is considered the standard of care for patients with untreated ES-SCLC, as recommended by the NCCN guidelines. Pharmacists should recognize the role of adding atezolizumab and durvalumab to first-line treatment for ES-SCLC, along with the unique toxicities with which these patients may present.

1. Rudin CM, Brambilla E, Faivre-Finn C, Sage J. Small-cell lung cancer. Nat Rev Dis Primers. 2021;7(1):3. doi:10.1038/s41572-020-00235-0

2. Pesch B, Kendzia B, Gustavsson P, et al. Cigarette smoking and lung cancer-relative risk estimates for the major histological types from a pooled analysis of case-control studies. Int J Cancer. 2012;131(5):1210-1219. doi:10.1002/ijc.27339

3. Jett JR, Schild SE, Kesler KA, Kalemkerian GP. Treatment of small cell lung cancer: diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2013;143(suppl5):e400S-e419S. doi:10.1378/chest.12-2363

4. Recently updated guidelines. National Comprehensive Cancer Network. Accessed April 28, 2021. https://www.nccn.org/guidelines/recently-published-guidelines

5. Socinski MA, Smit EF, Lorigan P, et al. Phase III study of pemetrexed plus carboplatin compared with etoposide plus carboplatin in chemotherapy-naive patients with extensive-stage small-cell lung cancer. J Clin Oncol. 2009;27(28):4787-4792. doi:10.1200/JCO.2009.23.1548

6. Horn L, Mansfield NS, Szczesna A, et al. First-line atezolizumab plus chemotherapy in extensive-stage small-cell lung cancer. N Engl J Med. 2018;379(23):2220-2229. doi:10.1056/NEJMoa1809064

7. Liu SV, Reck M, Mansfield AS, et al. Updated overall survival and PD-L1 subgroup analysis of patients with extensive-stage small-cell lung cancer treated with atezolizumab, carboplatin, and etoposide (IMpower133). J Clin Oncol. 2021;39(6):619-630. doi:10.1200/JCO.20.01055

8. Paz-Ares L, Dvorkin ML, Chen Y, et al. Durvalumab plus platinum-etoposide versus platinum-etoposide in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): a randomised, controlled, open-label, phase 3 trial. Lancet. 2019;394(10212):1929-1939. doi:10.1016/S0140-6736(19)32222-6

9. Goldman JW, Dvorkin M, Chen Y, et al. Durvalumab, with or without tremelimumab, plus platinum-etoposide versus platinum-etoposide alone in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): updated results from a randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 2021;22(1):51-65. doi:10.1016/S1470-2045(20)30539-8

 is an oncology clinical pharmacy specialist at University of Rochester Medical Center in New York.

Oncology Focus

Addition of atezolizumab and durvalumab to chemotherapy is a win for patients with extensive-stage small cell lung cancer

Immunotherapy Revolutionizes Treatment of ES-SCLC

Technology has changed the practice of pharmacy. Many systems are now part of an ever-increasingly interfaced or integrated health care system allowing the electronic exchange of prescriptions from electronic health records (EHRs) to the pharmacy information system and bidirectional data exchange for many items, such as lab results and test information. With meaningful use of automated distribution cabinet databases, EHR efforts, electronic data exchange, and smart pump technology, the availability of data to use for addressing and preventing adverse medication events has grown.

 Use of these systems has allowed a data-rich environment to store and retrieve reporting. Mining data is becoming easier and can be used as a tool to identify adverse medication events or potential events.

The EHR supports an enterprise-wide view of patient care delivered in both the inpatient and outpatient settings.

 Achieving meaningful use and interoperability with EHRs has improved 2 critical aspects of the medication management system: conducting a medication reconciliation and reducing transcription errors during medication ordering. However, even with increased legibility and transcription, EHRs can only be as good as the data entered, the review process, and their sources.

To catch potential medication errors using EHRs, pharmacy staff members generate reports to determine the number of profiles or identified patient populations who are high-risk. Employees review data to determine whether communication handoffs exist among the varying levels of care and whether data received at the time of admission or care were accurate.

An EHR can be built during the ordering process to include dose range, drug information resources, frequency, lab result limits, medication route, and required testing. In addition, a drug interaction screening system is often layered to prevent medication misadventures. Staff members can analyze data from the EHR to look at tool use, such as the number of times the standard orders were not being used and the number of required interventions allowed for education and quality improvement in the medication use system. Order sets should be maintained, and as such, a process for continual review and updating must be identified to ensure optimal value and prevent other issues from arising.

Other areas to review are medications being administered within the time frame set by policy and whether there is an associated reason for the change in medication administration time. A review can include documentation that an independent double-check was conducted when required by organization policy. 

Automated distribution cabinets (ADCs) decentralize and streamline the entire physician order and medication delivery process. The results have been better supply chain management, improved reporting, more effective communication between nursing and pharmacy staff, and timelier patient care.

 With the implementation of technology, pharmacy staff members load systems via barcodes, and nurses select the correct medication for the appropriate patient using barcode e-verification. The system is integrated with the medication administration record in the EHRs.

To prevent medication problems, pharmacists can monitor null transactions, wrong bin openings, returns, forced entry detection, and overrides. Pharmacy staff can review for documentation of independent double-check, if it is required by the organization, for medications that have been removed from the ADC using the override function.

Radiofrequency identification technology offers tools to help reduce errors in patient care, assisting with medication selection, facilitating tracing and tracking of equipment and patients, and promising better management of health care assets and improvement in the process of audits and forecasting capacity.

 These systems offer data mining and reporting capabilities when used in conjunction with an administration or dispensing system.

INTELLIGENT INFUSION (SMART PUMP) TECHNOLOGY

Computerized intravenous infusion pumps have become a standard method of improving medication safety.

 Software included in these pumps can alert the operator when a pump setting is put into the system outside approved organizational guidelines. However, the tool's effectiveness depends on creating a database to put in document alerts, rules, and safety "guardrails."

 Features must be kept up-to-date with continual maintenance of data when new medications are added or when there has been a change in concentrations or formulations. In addition, staff members must be educated about changes and determine pump use. Review of pump usage should include common medications excluded during the data build process, the number of overrides and guardrail warnings, and what medications have been programmed outside the data dictionary. Also, data transfer should be reviewed for accuracy during the most recent update to the pump.

Pharmacists must use data intentionally to prevent medication errors. Using technology in the medication use process in an increasingly interconnected system helps achieve the common goal of effective and safe medication use.

1. Reisman M. EHRs: the challenge of making electronic data usable and interoperable. P T. 2017;42(9);572-575.

2. Arzt NH. The interoperability of things. J Healthcare Information Manag. 2015;29(4):6-8.

3. Kellermann AL, Jones SS. What it will take to achieve the as-yet-unfulfilled promises of health information technology. Health Aff (Millwood). 2013;32(1):63-68. doi:10.1377/hlthaff.2012.0693

4. ASHP Section of Pharmacy Informatics and Technology Executive Committee, 2008-09. Technology-enabled practice: a vision statement by the ASHP Section of Pharmacy Informatics and Technology. Am J Health Syst Pharm. 2009;66(17):1573-1577. doi:10.2146/ajhp090073

5. Interoperability in healthcare. Healthcare Information and Management Systems Society. Accessed April 12, 2021. https://www.himss.org/resources/interoperability-healthcare

6. Federico F. 15 years after to err is human: the status of patient safety in the US and the UK. Institute for Healthcare Improvement. December 6, 2015. Accessed April 20, 2021. http://www.ihi.org/communities/blogs/15-years-afterto-err-is-human-the-status-of-patient-safety-in-the-us-and-the-uk

7. Gurwitz JH, Field TS, Harrold LR, et al. Incidence and preventability of adverse drug events among older persons in the ambulatory setting. JAMA. 2003;289(9):1107-1116. doi:10.1001/jama.289.9.1107

8. Zhan C, Roughead E, Liu L, Pratt N, Li J. A data-driven method to detect adverse drug events from prescription data. J Biomed Inform. 2018;85:10-20. doi:10.1016/j.jbi.2018.07.013

9. Desselle S. Mitigating information chaos during prescription handoffs. McGraw Hill Medical. April 8, 2021. Accessed April 12, 2021. https://www.accessmedicinenetwork.com/posts/41355-mitigating-information-chaos-during-prescription-handoffs?channel_id=1754-pharmacy-management-tip-of-the-week

10. Braswell A, Duggar S. The new look of bedside technology. The point-of-care evolution drives providers to rethink nursing workflow and medication management. Nurs Manag. 2006;(suppl):14,16-18,32.

11. Pedersen CA, Schneider PJ, Ganio MC, Scheckelhoff DJ. ASHP national survey of pharmacy practice in hospital settings: dispensing and administration-2020. Am J Health Syst Pharm. 2021;zxab120. doi:10.1093/ajhp/zxab120

12. ISMP issues updated guidelines for the safe use of automated dispensing cabinets. Institute for Safe Medication Practices. February

13, 2019. Accessed April 12, 2021. https://www.ismp.org/news/ismp-issues-updated-guidelines-safe-use-automated-dispensing-cabinets

13. Seckman C, Bauer A, Moser T, Paaske S. The benefits and barriers to RFID technology in healthcare. Healthcare Information and Management Systems Society. June 26, 2017. Accessed April 20, 2021. https://www.himss.org/resources/benefits-and-barriers-rfid-technology-healthcare

14. Lehr J, Vitoux RR, Zavotsky KE, Pontieri-Lewis V, Colineri L. Achieving outcomes with innovative smart pump technology. J Nurs Care Qual. 2019;34(1):9-15. doi:10.1097/NCQ.0000000000000326

15. Franklin BD. ‘Smart’ intravenous pumps: how smart are they? BMJ Qual Saf. 2017;26(2):93-94. doi:10.1136/bmjqs-2016-00530

 is vice president of operations support CompleteRx in Houston, Texas.

 is director of experiential learning, manager of clinical support services, and associate professor of pharmacy practice, adminsitration, and research at Marshall University School of Pharmacy in Huntington, West Virginia.

Alberto Coustasse-Hencke, MD, DrPh, MBA, MPH,

 is a professor health care administration at the Management and Healthcare Administration division at Lewis College of Business at Marshall University.

Safe Handling

Digital tools can help pharmacists and other health care providers ensure effective and safe drug use.

Detect Adverse Events and Medication Errors Using Technology

In recent years, scientists have made remarkable strides in unlocking the mysteries of the brain. They are using artificial intelligence to map the visual cortex. Positron emission tomography scans allow investigators to track surges in brain activity, and electrical implants are helping some patients with paralysis to walk again.

Although much progress has been made over the past decade, there is still much more to be understood about the brain’s inner workings, specifically on how to prevent or reverse cognitive decline.

The CDC defines dementia as a general term used to describe the impaired ability to remember, think, or make decisions in a way that interferes with everyday activities.

 An estimated 5 million individuals in the United States have dementia with Alzheimer disease (AD), the most common form.

 Interest in brain health is high, with recent survey results showing that about 25% of adults over age 50 years take a supplement to improve their brain health with the promise of enhanced memory and sharper attention and focus.

Age has long been known as the strongest predictor of developing dementia, but there are other risk factors. An individual with a family history is more likely to develop dementia. Black individuals are twice as likely, and Hispanic individuals are 1.5 times more likely to have dementia compared with White individuals.

Hypertension in midlife may increase the risk of cognitive decline in older age, because it damages blood vessels, which leads to vascular dementia.

 Other conditions, such as diabetes and traumatic brain injury, have links to dementia as well.

Dementia treatment includes addressing the underlying cause, whether that is a chronic disease, medication, or other factors. AD has no cure, but some medications can slow the process and treat symptoms of anxiety or behavioral changes. Although there are still many unanswered questions about dementia, there are proven strategies that can be adopted throughout life to slow cognitive decline in older age.

The research results have demonstrated the link between brain health and exercise, and several studies have looked at the effect on cognitive decline in older age. The results of a study of more than 30,000 participants found that those who were physically fit throughout the 10-year study were almost 50% less likely to develop dementia in older age than the least fit study participants.

 The study results also showed that participants who were out of shape in middle age who became fitter throughout the study showed the same substantial risk reduction for dementia as their counterparts who were fit at the outset of the study.

 This shows that it is never too late to start exercising to receive cognitive benefits. Other studies have looked at the intensity and length of exercise, and results found that regular moderate- to high-intensity exercise and weight resistance training are most beneficial.

Changes in the brain can happen years before symptoms appear, and nutrition has been studied as a possible way to slow the aging process, specifically through the Mediterranean and Mediterranean-DASH Intervention for Neurodegenerative Delay diets. The Mediterranean diet emphasizes fish, fruits, grains, legumes, vegetables, and whole grains. Not only does good nutrition help with chronic disease risk factors, such as cardiovascular disease and diabetes, but it also may protect the brain through anti-inflammatory and antioxidant processes. So far, there is no hard evidence that avoiding or eating certain foods lowers the risk of AD, but eating fish and green, leafy vegetables and following a low-salt and -sugar diet may reduce the risk of developing dementia.

Although investigators are still debating whether dementia leads to poor sleep or poor sleep exacerbates dementia, they agree that there is a link. The National Institutes of Health reported in 2018 that sleep deficits might increase the β-amyloid proteins in the brain that are linked to AD.

 The results of another study that followed individuals older than 25 years showed a 30% increased dementia risk in 50-, 60-, and 70-year-olds who slept 6 or fewer hours a night.

Most supplements are not tested in clinical, controlled, randomized trials, and the FDA does not regulate supplements. Because of this, their efficacy and safety are largely unknown, as is how supplements interact with other medications. There are several supplements that individuals regularly use that have shown small benefits in the results of some studies.

The most common of these are omega-3 and vitamins E and B

. Omega-3s are found in fatty fish, such as mackerel and salmon, and nuts, seeds, and vegetable oils, which have all shown anti-inflammatory and antioxidant effects on the brain. The results of a 2014 study showed that vitamin E might help individuals with AD continue to perform daily functions. However, vitamin E does not prevent AD or reduce other symptoms.

 Vitamin E is thought to contribute to brain health by reducing oxidative stress. The vitamins B

 help break down homocysteine, which has been shown to contribute to AD and dementia. Most people get enough vitamin B in their diets, but if they don’t, the deficit is reversible through supplementation, which is rarely needed long term.

There is also an herb specifically indicated for memory, Gingko biloba, but research does not conclusively back the claim. One of the largest studies trying to connect it to memory was the Ginkgo Evaluation of Memory study. With 3000 participants taking a supplement over 6 years, the results did not show that Gingko biloba lowered the risk of developing overall dementia.

Lifestyle choices, such as diet and exercise, may help prevent AD and support brain health, as well as lower the risk of other diseases, such as diabetes and heart disease, which have been linked to AD. Healthy lifestyle choices can improve health and possibly protect the brain.

1. What is dementia? CDC. April 5, 2019. Accessed April 22, 2021. https://www.cdc.gov/aging/dementia/index.html

2. Levine H. AARP’s survey on supplements for brain health. AARP. June 11, 2019. Accessed April 22, 2021. https://www.aarp.org/health/drugs-supplements/info-2019/brain-supplements-survey.html

3. Peila R, White LR, Masaki K, Petrovitch H, Launer LJ. Reducing the risk of dementia: efficacy of long-term treatment of hypertension. Stroke. 2006;37(5):1165-1170. doi:10.1161/01.STR.0000217653.01615.93

4. Livingston G, Huntley J, Sommerlad A, et al. Dementia prevention, intervention, and care: 2020 report of the Lancet Commission. Lancet. 2020;396(10248):413-446. doi:10.1016/S0140-6736(20)30367-6

5. Exercise improves memory, boosts blood flow to the brain. News release. UT Southwestern Medical Center. May 20, 2020. Accessed April 25, 2021. https://www.utsouthwestern.edu/newsroom/articles/year-2020/exercise-improves-memory-boosts-blood-flow-to-brain.html

6. Sleep deprivation increases Alzheimer’s protein. National Institutes of Health. April 24, 2018. Accessed April 23, 2021. https://www.nih.gov/news-events/nih-research-matters/sleep-deprivation-increases-alzheimers-protein

7. Sabia S, Fayosse A, Dumurgier J, et al. Association of sleep duration in middle and old age with incidence of dementia. Nat Commun. 2021;12(1):2289. doi:10.1038/s41467-021-22354-2

8. La Fata G, Weber P, Mohajeri MH. Effects of vitamin E on cognitive performance during ageing and in Alzheimer’s disease. Nutrients. 2014;6(12):5453-5472. doi:10.3390/nu6125453

9. DeKosky ST, Fitzpatrick A, Ives DG, et al. The Ginkgo Evaluation of Memory (GEM) study: design and baseline data of a randomized trial of Ginkgo biloba extract in prevention of dementia. Contemp Clin Trials. 2006;27(3):238-253. doi:10.1016/j.cct.2006.02.007

 is the 340B compliance coordinator at Baptist Health in Jacksonville, Florida.

Clinical Care Focus

Exercise, nutrition, sleep, and supplements can help slow cognitive decline in older individuals.

Lifestyle Modifications Support Brain Health

Pain management in the intensive care unit (ICU) is not a one-size-fits-all discipline. There are many factors to consider, including location and type of pain, breakthrough pain despite adequate management, and patient history of opioid use. But preventing pain instead of reacting to it is key. 

It is important to keep in mind that pain management medications are not without the risks of oversedation and, ultimately, respiratory depression. Hence, it is imperative to find a balance in addressing pain by using medications that have different mechanisms of action.

The first class of medication that providers turn to is local anesthetics. Guidelines do not recommend the use of topical anesthetics in ICU patients. However, topical anesthetics can provide great advantages when other routes of administration are not plausible. Lidocaine is a local anesthetic that binds reversibly to sodium channels, blocking nerve depolarization by locking nerves in the open state.

 One study evaluated pretreatment with lidocaine 5% patches in acute potthoracotomy population pain. Results found that lidocaine was effective in reducing pain intensity and total morphine consumption. Therefore, lidocaine 5% patches could be considered as an adjunct treatment to intravenous (IV) morphine to control postthoracotomy pain.

 Nevertheless, the results of another study assessing the efficacy of topical lidocaine 5% patches in ICU patients in poststernotomy or postthoracotomy pain concluded that lidocaine did not reduce acute pain.

Because of their low risk of systemic effects, minimal drug interactions, and safety profiles, lidocaine patches are considered a suitable treatment for the elderly population. However, variable skin properties in individuals may influence absorption and distribution. Additionally, many studies of topical medications lack quality; thus, further studies are needed to analyze effectiveness and long-term effects.

The guidelines also suggest using low-dose ketamine for pain relief in post-operative adults in the ICU.

-aspartate and glutamate receptor antagonist. It is recommended as an adjunct to opioid therapy to reduce opioid consumption in ICU patients with postsurgical pain. Common adverse effects (AEs) include confusion, diplopia, drowsiness, dysphoria, and, in some rare cases, hallucinations.

Although opioids remain the mainstay of therapy in the ICU, the guidelines also recognize the negative effects that opioids pose and encourage the use of multi-modal therapies whenever possible to decrease opioid use.

 Two other classes of medications used in the ICU are nonsteroidal anti-inflammatory drugs (NSAIDs), and acetaminophen, an analgesic, and antipyretic medication. NSAIDs work by inhibiting prostaglandin synthesis through COX-1 and COX-2 inhibition.

 Patients must have stable renal functions and not be on concomitant nephrotoxic medications while receiving NSAIDs. These drugs should also be avoided in patients with gastric ulcers, active gastrointestinal (GI) bleeds, or a history of GI bleeds, and congestive heart failure.

 Additionally, in patients with severe cirrhosis or liver impairment, alternatives should be considered.

Acetaminophen is the preferred initial agent of choice for ICU patients.

 According to the guidelines, IV, oral, or rectal acetaminophen should be used for pain control and to decrease opioid use in the critically ill population.

 Acetaminophen has proved to have comparable effects to opioids and demonstrated an opioid-sparing effect in multiple investigations. In 1 study looking at moderate to severe pain after orthopedic surgery, results showed  that IV acetaminophen at a dose of 1 g, administered over 24 hours, reduced opioid need, and was well tolerated.

 The results of another study showed that the addition of acetaminophen to meperidine provided adequate pain control in patients and reduced their opioid need.

 Results from another trial demonstrated adequate pain control and opioid-sparing effects through the combined use of acetaminophen and tramadol in patients who have cardiac surgery.

Similar opioid-sparing effects can be seen with NSAIDs, such as ibuprofen and ketorolac. Study results showed that using 800 mg of IV ibuprofen every 6 hours in patients who had postabdominal pain effectively controlled their pain and reduced their opioid requirements.

 The results of one controlled, randomized trial comparing IV morphine 4 mg with IV ketorolac 4 mg showed that pain scores were similar after chest tube removal. These results indicated that NSAIDs could be used as an alternative to opioid therapy in the critically ill population for certain procedures.

 When using ketorolac, it is imperative to maintain therapy for no more than 5 days, as prolonged therapy can increase the risk of AEs, particularly GI bleeding.

 Patients should be evaluated to determine whether they are good candidates for either acetaminophen of NSAID therapy alone or in combination with opioids to decrease AEs and opioid burden and help prevent pain.

Neuropathic pain is derived from damaged nerves and is often treated by medications, such as carbamazepine, gabapentin, and pregabalin. Their analgesic properties are exhibited through mechanisms of binding to voltage-gated calcium channels and inhibiting the release of excitatory neurotransmitters.

 Neuropathic agents are recommended as adjuncts to opioids to lower the intensity of neuropathic and postcardiovascular surgery pain in critically ill adults. These agents are also recommended for patients with diabetes who have nerve pain.

 Gabapentin has structural similarities to γ-aminobutyric acid (GABA) but does not bind to GABA receptors and has minimal effect on degradation or uptake of GABA. It has proved to be useful in postherpetic neuralgia, as well as in peripheral nerve injuries.

Because of Pain Agitation Delirium Immobility Sleep guidelines on analagosedation, opioid use remains the mainstay for pain management in most ICU settings because of the greater analgesic effects they produce over acetaminophen and NSAIDs, especially in the setting of mechanical ventilation or postsurgical analgesia.

 Opioids produce analgesia by activating G protein–coupled receptors, particularly μ-opioid receptors, located in the brain and spinal cord regions, which are involved in transmission and modulation of pain. Activation of G protein–coupled receptors alters pain perception, increases pain threshold, and inhibits ascending pain pathways.

The most common opioids used in the ICU setting include fentanyl, hydromorphone, and morphine, because of their titratability as either bolus doses or infusions. With renal failure, morphine is used cautiously because of the significant accumulation of morphine metabolites, morphine-3-glucuronide and morphine-6-glucuronide. Morphine is also associated with histamine release, which can lead to vasodilation and decreased blood pressure.

 Fentanyl, a synthetic derivative of morphine, is 100 times more potent than morphine and is not associated with histamine release, making it preferred in the setting of hemodynamic instability.

 Hydromorphone, a semisynthetic derivative or morphine, is 5 to 10 times more potent than morphine and is an appropriate alternative to either fentanyl or morphine.

Although opioids are considered the mainstay of therapy, they are associated with negative AEs.

All opioids carry a risk for fatal, life-threatening, or serious respiratory depression and more common AEs, including constipation, drowsiness, nausea, sedation, and vomiting.

 As a result, the guidelines endorse multimodal analgesia to reduce opioid requirements, as well as bowel regimens to manage constipation in the ICU.

Adequate pain assessment and management in the ICU is a complex process. It is further complicated by patients' unstable health statuses, making them unable to communicate their pain accurately. To overcome these barriers between health care providers and patients, proper identification of pain is important. Universal pain management is not possible in the ICU; therefore, it is critical to find the right drug or combination of drugs for each patient, monitor progress throughout the therapy, and adjust as needed. Each class of medications comes with its own set of indications and AEs, which is why pain must be managed carefully and remain under the supervision of an interprofessional team (see table).

1. Lidocaine (systemic). Drugs.com. Updated October 20, 2020. Accessed April 11, 2021. https://www.drugs.com/ppa/lidocaine-systemic.html

2. Fiorelli A, Pace C, Cascone R, et al. Preventive skin analgesia with lidocaine patch for management of post-thoracotomy pain: results of a randomized, double blind, placebo controlled study. Thorac Cancer. 2019;10(4):631-641. doi:10.1111/1759-7714.12975

3. Liu M, Wai M, Nunez J. Topical lidocaine patch for postthoracotomy and poststernotomy pain in cardiothoracic intensive care unit adult patients. Crit Care Nurse. 2019;39(5):51-57. doi:10.4037/ccn2019849

4. Jorge LL, Feres CC, Teles VE. Topical preparations for pain relief: efficacy and patient adherence. J Pain Res. 2010;4:11-24. doi:10.2147/JPR.S9492

5. Devlin JW, Skrobik Y, Gélinas C, et al. Executive summary: clinical practice guidelines for the prevention and management of pain, agitation/sedation, delirium, immobility, and sleep disruption in adult patients in the ICU. Crit Care Med. 2018;46(9):1532-1548. doi:10.1097/CCM.0000000000003259

6. Ketamine. Drugs.com. Updated October 26, 2020. Accessed April 26, 2021. https://www.drugs.com/monograph/ketamine.html

7. Ibuprofen. Drugs.com. Updated November 9, 2020. Accessed April 26, 2021. https://www.drugs.com/monograph/ibuprofen.html

8. Ketorolac (systemic). Drugs.com. Updated November 9, 2020. Accessed April 26, 2021. https://www.drugs.com/monograph/ketorolac-systemic.html

9. Acetaminophen. Drugs.com. Updated January 22, 2021. Accessed April 26, 2021. https://www.drugs.com/acetaminophen.html

10. Shi SB, Wang XB, Song JM, Guo SF, Chen ZX, Wang Y. Efficacy of intravenous acetaminophen in multimodal management for pain relief following total knee arthroplasty: a meta-analysis. J Orthop Surg Res. 2018;13(1):250. doi:10.1186/s13018-018-0950-7

11. Sinatra RS, Jahr JS, Reynolds LW, Viscusi ER, Groudine SB, Payen-Champenois C. Efficacy and safety of single and repeated administration of 1 gram intravenous acetaminophen injection (paracetamol) for pain management after major orthopedic surgery. Anesthesiology. 2005;102(4):822-831. doi:10.1097/00000542-200504000-00019

12. Memis D, Inal MT, Kavalci G, Sezer A, Sut N. Intravenous paracetamol reduced the use of opioids, extubation time, and opioid-related adverse effects after major surgery in intensive care unit. J Crit Care. 2010;25(3):458-462. doi:10.1016/j.jcrc.2009.12.012

13. Cattabriga I, Pacini D, Lamazza G, et al. Intravenous paracetamol as adjunctive treatment for postoperative pain after cardiac surgery: a double blind randomized controlled trial. Eur J Cardiothorac Surg. 2007;32(3):527-531. doi:10.1016/j.ejcts.2007.05.017

14. Benyamin R, Trescot AM, Datta S, et al. Opioid complications and side effects. Pain Physician. 2008;11(suppl 2):S105-S120.

15. Rose MA, Kam PCA. Gabapentin: pharmacology and its use in pain management. Anaesthesia. 2002;57(5):451-462. doi:10.1046/j.0003-2409.2001.02399.x

16. Backonja M, Glanzman RL. Gabapentin dosing for neuropathic pain: evidence from randomized, placebo-controlled clinical trials. Clin Ther. 2003;25(1):81-104. doi:10.1016/s0149-2918(03)90011-7

17. Gabapentin. Drugs.com. Updated December 3, 2020. . Accessed April 26, 2021. https://www.drugs.com/monograph/gabapentin.html

18. Devlin JW, Skrobik Y, Gélinas C, et al. Clinical practice guidelines for the prevention and management of pain, agitation/sedation, delirium, immobility, and sleep disruption in adult patients in the ICU. Crit Care Med. 2018;46(9):e825-e873 doi:10.1097/CCM.0000000000003299

19. Schumacher MA, Basbaum AI, Naidu RK. Opioid agonists and antagonists. In: Katzung BG, Vanderah TW, eds. Basic and Clinical Pharmacology. 15th ed. McGraw-Hill Professional Publishing: 2021;573-594.

20. Morphine. Drugs.com. Updated March 29, 2021. Accessed April 26, 2021. https://www.drugs.com/monograph/morphine.html

Finding the right medication or drug combination for individual patients is critical.

May 2021

How Does 503B Compliance Benefit the Public?

Long-Acting HIV Regimen May Prove Revolutionary

Immunotherapy Revolutionizes Treatment of ES-SCLC

Detect Adverse Events and Medication Errors Using Technology

Lifestyle Modifications Support Brain Health

Pain Management in the ICU Is Complex

Pandemic Has Unanticipated Consequences