Postoperative pain management presents a major challenge to patients and health care providers. Inadequate pain management can lead to delays in rehabilitation and hospital discharge as well as lower patient satisfaction. According to the National Institute of Medicine, more than 805  patients experience postoperative pain, with fewer than 50% receiving adequate pain management.

Nociception and pain involve complex neurohormonal signaling pathways. Despite advances in the understanding of postoperative pain, including the need for a multimodal approach, opioid monotherapy remains common as initial, first-line pain management, despite known risks such as oversedation and long-term dependence and abuse associated with opioid use. Opioid-related adverse events have been shown to be associated with increased hospitalization costs and an increase in the overall length of hospital stay.

The use of multimodal treatment strategies in the management of postoperative pain has been explored in a variety of surgical fields. Treatment with multimodal analgesia has been shown to reduce opioid use, reduce the incidence of opioid-associated adverse events, and improve pain control when compared with using opioid monotherapy.

 Non-opioid analgesic options include acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs), local anesthetics, gabapentinoids, ketamine, and glucocorticoids. The most well studied combination of non-opioid analgesics includes acetaminophen with NSAIDs.

 Other combinations of non-opioid analgesics are not well studied, and most non-opioid analgesic options are also associated with particular adverse effects as well.

Another mode of postoperative pain management involves the use of regional anesthetic techniques including epidural and perineural and local anesthetics. Epidural analgesia involves the injection of a local anesthetic such as bupivacaine with or without an opioid such as fentanyl into the epidural space within the spinal column. It has traditionally been used in various thoracic, abdominal, and gynecological surgeries. Epidural analgesia is not without risks, including the development of epidural hematoma and abscesses.

 Perineural nerve blocks can be used to inject anesthetics into areas adjacent to the nerve or plexus of various locations depending on the type of surgery performed. A 2006 meta-analysis found that use of peripheral nerve blocks was associated with better pain management and a reduction in opioid-associated adverse events compared with opioid monotherapy in postoperative pain management.

 A potential disadvantage of epidural and perineural techniques is the requirement of intra- and postoperative management of the drug delivery catheter, and that it is contraindicated in patients taking antiplatelet or anticoagulant medications as well as individuals with coagulopathies. Nevertheless, they represent a potential strategy for optimizing pain management and limiting opioid use postoperatively.

EK is a 30-year-old male with a past medical history significant for posttraumatic stress disorder and polysubstance abuse who presented as a red trauma after being involved in a motor vehicle accident. His injuries were significant for bilateral rib fractures (right 1-12, left 1-8), bilateral hemopneumothoraxes with pulmonary contusions, and cerebral contusions with questionable traumatic subarachnoid hemorrhage and subdural hemorrhage. During his hospital course, management of his pain and agitation was a significant issue. By hospital day 10, the patient was receiving hydromorphone 5 mg per hour, dexmedetomidine 1.2 mcg/kg per hour, lorazepam 1 mg every 8 hours, oxycodone 15 mg every 4 hours, acetaminophen 1000 mg every 6 hours, gabapentin 300 mg every 8 hours, and lidocaine patches with uncontrolled pain and sedation. The patient was scheduled for rib plating; however, there was significant concern regarding management of postoperative pain. The decision was made to place an epidural catheter prior to his surgical procedure. He was initiated on bupivacaine 0.125% at 8 ml per hour. EK’s operative procedure proceeded without complication. He was extubated on postoperative day 2, at which time he received a patient-controlled analgesia, and his epidural was removed on postoperative day 3.

Given the extent of EK’s injuries, as well as his underlying substance abuse disorder, management of his pain, agitation, and withdrawal with opioids alone would not have been reasonable. Initially, multimodal pharmacotherapy involving opioids, gabapentinoids, NSAIDs, and acetaminophen was attempted. However, this strategy did not sufficiently manage EK’s pain. Although multimodal systemic therapy did not completely control EK’s pain, it was still a reasonable choice in an effort to decrease opioid use and opioid-related adverse events.

An epidural was used in this case, as EK had extensive bilateral injuries and did not have any contraindications to epidural use such as coagulopathy or antiplatelet/anticoagulant use. Use of a peripheral nerve block may have been a reasonable alternative. EK did not have any complications associated with his epidural use. However, it is important to weigh the risks and benefits of regional analgesics for each patient.

Postoperative pain management is a complicated topic and requires an individualized approach depending on patient characteristics, the type of surgery performed, and the expected course of postoperative recovery.

ELLEN HUANG, PHARMD, is the cardiothoracic and surgical ICU clinical specialist at Augusta University Medical Center.

PHILLIP S. OWEN, PHARMD, BCPS, practices as the cardiothoracic intensive care unit clinical pharmacy specialist at the University of North Carolina Medical Center. He also is a member of the inpatient lung transplant and thoracic and vascular surgery services.

Institute of Medicine. Relieving pain in America: A blueprint for transforming prevention, care, education, and research nationalacademies.org/hmd/Reports/2011/Relieving-Pain-in-America-A-Blueprint-for-Transforming-Prevention-Care-Education-Research.aspx. Published June 2011. Accessed July 27, 2017.

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Lee SK, Lee JW, Choy WS. Is multimodal analgesia as effective as postoperative patient-controlled analgesia following upper extremity surgery? 

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Hyllested M, Jones S, Pedersen JL, Kehlet H. Comparative effect of paracetamol, NSAIDs or their combination in postoperative pain management: a qualitative review. 

Mathiesen O, Wetterslev J, Kontinen VK, et al. Adverse effects of perioperative paracetamol, NSAIDs, glucocorticoids, gabapentinoids and their combinations: a topical review. 

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Richman JM, Liu SS, Courpas G, et al. Does continuous peripheral nerve block provide superior pain control to opioids? A meta-analysis. 

Mei S, Jin S, Chen Z, et al. Analgesia for total knee arthroplasty: A meta-analysis comparing local infiltration and femoral nerve block. 

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Articles

Case Report

Postoperative pain management presents a major challenge to patients and health care providers.

Postoperative Pain Management

 cases are type 2, which is a major cause of morbidity and mortality. Because it is a progressive multi-organ disease, effective therapies

are critical. Current guidelines recommend a patient-centered approach aimed at minimizing adverse effects, such as hypoglycemia and weight gain, while maximizing efficacy.

 Most patients start with metformin monotherapy. If the condition remains uncontrolled, therapy is intensified with either oral or injectable agents. Patients who are unlikely to achieve a glycated hemoglobin (A1C) goal with 1 agent may be initiated on combination therapy at diagnosis.

The combination of a glucagon-like peptide-1 receptor agonist (GLP-1 RA)

 and basal insulin is increasing in popularity because these pharmacologic actions complement one another. Although a basal and GLP-1 RA regimen requires fewer daily injections, compared with basal and bolus (prandial) insulin therapy, using the 2 agents separately still requires multiple injections.

Fixed-ratio combination products decrease the number of injections to once a day. Both the American Diabetes Association and the American Association of Clinical Endocrinologists support the use of basal insulin plus a GLP-1 RA in combination with metformin.

 The 2 components work synergistically to reduce blood sugar and A1C. Insulin stimulates peripheral glucose uptake by muscle and fat cells and inhibits hepatic glucose production. GLP-1 RAs increase glucose-dependent insulin release and, thus, work only in the presence of hyperglycemia,

 leading to a low risk of hypoglycemia. The GLP-1 RA component may mitigate weight gain that can occur with basal insulin and may instead cause weight loss. The combination of basal insulin and a GLP-1 RA addresses 7 of the 8 core defects found in advanced type 2 diabetes.

The GLP-1 RA lixisenatide has a more profound effect on postprandial blood glucose levels than liraglutide

does. Postprandial reduction occurs primarily via delayed gastric emptying and reduced glucagon release. Lixisenatide’s half-life is 2 to 4 hours. Hence, this drug is dosed prior to the first meal of the day. With a half-life of 13 hours, liraglutide

 can be dosed once a day at any time. It has activity on both postprandial and fasting glucose levels. Insulin glargine has a protracted action through post-injection precipitation, which slows absorption and results in a half-life of about 12 hours, allowing once-daily dosing in most patients. Insulin degludec attains its protracted action through multi-hexamer formation in the subcutaneous injection depot. It has a half-life of about 25 hours, so with once-daily dosing, a steady state is achieved.

To improve glycemic control in adults with type 2 diabetes inadequately controlled on basal insulin (<60 units) or lixisenatide, the FDA approved 2 fixed-ratio combination products in November 2016: Soliqua 100/33

 is a combination of glargine insulin and lixisenatide, and Xultophy

 combines degludec insulin and liraglutide. Both combinations are dosed according to the basal insulin.

In the clinical development programs for these combination agents, different titration regimens were used. However, the 2 products are both titrated as a basal insulin. When titrated gradually (table), gastrointestinal adverse effects may be minimized or avoided. No head-to-head trials of these 2 agents have been done, and comparisons between outcomes should not be made because of different study designs, interventions, definitions, and patient populations.

Patients to consider for using one of these combination products to intensify therapy include those who did not reach their A1C target with either component alone. The combination targets both fasting and postprandial blood sugar values and, in clinical trials, led to more patients achieving A1C goals. The fixed-dose combination decreases the number of injections daily; minimizes hypoglycemia risk and weight gain; and, more important, makes pharmacologic sense. This availability may also potentially increase adherence, though insurance coverage is not well known.

Drs. Patel and Goldman are both professors of pharmacy practice at Massachusetts College of Pharmacy and Health Sciences School of Pharmacy, in Boston.

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Berlie H, Hurren KM, Pinelli NR. Glucagon-like peptide-1 receptor agonists as add-on therapy to basal insulin in patients with type 2 diabetes: a systematic review. 

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Garber AJ. Abrahamson MJ, Barzilay JI, et al. Consensus statement by the American Association of Clinical Endocrinologists and American College of Endocrinology on the comprehensive type 2 diabetes management algorithm—2016 executive summary. 

2016;22(1):84-113. doi: 10.4158/EP151126.CS.

Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycemia in type 2 diabetes, 2015: a patient-centered approach: update to a position statement of the American Diabetes Association and the European Association for the Study of Diabetes. 

2015;38(1):140-149. doi: 10.2337/dc14-2441.

Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. 

2016;375(4):311-322. doi: 10.1056/NEJMoa1603827.

Soliqua [prescribing information]. Bridgewater, NJ: Sanofi-Aventis U.S. LLC; 2016.   

Sanofi receives FDA approval of Soliqua 100/33 for the treatment of adults with type 2 diabetes. [news release]. Paris, France: Sanofi; November 21, 2016. 

news.sanofi.us/2016-11-21-Sanofi-Receives-FDA-Approval-of-Soliqua-100-33-for-the-Treatment-of-Adults-with-Type-2-Diabetes

Novo Nordisk receives FDA approval for Xultophy 100/3.6 (insulin degludec and liraglutide injection) [news release]. Plainsboro, NJ: Novo Nordisk; November 21, 2016. 

press.novonordisk-us.com/2016-11-21-Novo-Nordisk-Receives-FDA-Approval-for-Xultophy-100-3-6-insulin-degludec-and-liraglutide-injection

Meier JJ, Rosenstock J, Hincelin-Méry A, et al. Contrasting effects of lixisenatide and liraglutide on postprandial glycemic control, gastric emptying, and safety parameters in patients with type 2 diabetes on optimized insulin glargine with or without metformin: a randomized, open-label trial. 

2015;38(7):1263-1273. doi: 10.2337/dc14-1984.

Clinical Care Focus

Ninety percent of diabetes cases are type 2, which is a major cause of morbidity and mortality.

Fixed-Ratio Combination of Basal Insulin and GLP-1 Receptor Agonist

Pharmacists need to be experts on follow-on biologics (FOBs), including biosimilars, so they can provide education to health professionals about safe prescribing

and use, which ultimately affects patient care. Seamless interchangeability among biosimilars and FOBs may not be permissible under the law, or as appropriate, as it is with brand and generic chemically derived drugs.

Several biologic patents expire in the next few years, and other manufacturers will offer alternatives with reduced costs. Health care practitioners will encounter many questions as biosimilars and FOBs enter the market. Many prescribers may not fully understand the differences between a biosimilar and the reference licensed biologic product.

Experts anticipate a 20% to 30% price reduction on biosimilars compared with the reference biologic, a price drop that would be necessary to create a viable biosimilar market through increased patient access.

 Payers anticipate biosimilars, and FOBs will be part of a strategy to reduce drug prices.

Depending on market dynamics and the competitive landscape, price reductions may come directly from the list price, rebates, or a combination of both. Some believe this represents a compelling business opportunity.

 Meanwhile, patients and providers face a challenge understanding immunogenicity, interchangeability, and pharmacy substitutions related to biosimilars.

Differing biologic formulations may pose concerns for efficacy and safety due to changes in manufacturing processes, protocols, packaging, and cold storage delivery.

 Keeping this in mind, pharmacists will be important contributors to the biosimilar and FOB information cascade shared with prescribers and patients as they make product decision choices.

There are important differences between biologics and biosimilars compared with chemically derived small molecules and their generics. First, biologics are produced in living cells or organisms and may comprise any virus, therapeutic serum, toxin, antitoxin, or analogous product, including therapeutic proteins that are not chemically synthesized polypeptides.

 These biologic products are typically used in the prevention, treatment, or cure of a disease. The first biologic product approved as a “drug” in 1982 was Humulin R (recombinant human insulin) from Eli Lilly and Company.10 Today, biopharmaceuticals include vaccines, blood products, allergenic extracts, human cells and tissues, gene therapies, and more.

Second, biologics differ from chemical drugs because they are larger, more complex molecules manufactured from living cells or organisms, susceptible to instability from external conditions, and associated with immunologic properties.

 A biosimilar is highly similar to an already approved licensed biologic molecule in which the manufacturing process details are proprietary information. This is the reason why manufacturers of a proposed biosimilar must develop an entirely new process that can lead to small differences in structure, stability, impurities, and excipients compared with the reference biologic.

 Approval processes require that these changes have no clinically meaningful significance. Therefore, biosimilars are similar to the reference biologic, not identical, so they are not generically equivalent.

Different terminology describes biosimilars and FOBs, and it is important for pharmacists to understand how the terms relate to federal and state regulations. In the United States, biosimilars are approved under Section 351 of the Public Health Service Act (PHS Act). Interchangeability is an FDA regulatory designation that the manufacturer requests, suggesting that a biosimilar draft a higher level of regulation than biosimilarity. However, specific FDA guidance on interchangeability has not yet been finalized. At least 35 states have passed legislation regarding the rules for biosimilar substitution (ncsl.org/research/health/state-laws-and-legislation-related-to-biologic-medications-and-substitution- of-biosimilars.aspx). Therefore, substitution occurs at the pharmacy and is regulated by state legislatures.

States may define the practice of substitution so that the pharmacist is able to substitute an FDA-licensed interchangeable biosimilar for a referenced biologic or vice versa without direct prescriber consult based on state-specific regulations.

 Interchangeability refers to a decision by a regulatory authority, based on scientific data submitted by the manufacturer, that the biosimilar product is appropriate for substitution for the reference biological product under local laws and pharmacy practices.

Switching occurs when the prescriber chooses to change a patient’s therapy from a registered licensed biologic to a biosimilar product, or vice versa.

 Additional terms of importance include “not similar,” “similar,” “highly similar,” and “highly similar with fingerprint-like similarity.” These categories described by the FDA further quantify the degree of similarity between 2 products.

 In the United States, some follow-on biologics may be similar versions of already approved listed drugs upon which the new drug application (NDA) is filed under section 505(b)(2) of the Food, Drug, and Cosmetic Act. Biologics filed through the 505(b)(2) pathway are also obligated to meet safety and efficacy requirements as defined by the FDA.

 Biosimilars and FOBs are not generics; therefore, they are not “bioequivalent” to the listed drug relied upon. For biologics, 2 products manufactured by different companies (without technology transfer) cannot be said to contain the identical active ingredient or to be bioequivalent.

Biosimilar regulations continue to evolve, but pharmacists should be familiar with some regulatory pathways currently in place. The 351(k) pathway is an abbreviated pathway for licensing of products shown to be biosimilar to an FDA-approved reference product.

 Zarxio (filgrastim-sndz), the first approved biosimilar in the United States, went through this pathway.

 The totality-of-evidence approach is used to demonstrate biosimilarity and requires structural and functional characterization, nonclinical evaluation, human pharmacokinetics (PK) and pharmacodynamics (PD) data, clinical immunogenicity data, and comparative clinical study data. Clinically meaningful differences could include a difference in the expected range of safety, purity, or potency of the proposed product and the reference product. In contrast, slight differences in rates of occurrence of certain adverse events (AEs) between the 2 products ordinarily would not be considered a clinically meaningful difference.

Alternatively, the 505(b)(2) pathway is used in cases where the listed drug relied upon made its application under section 505. These submissions require an NDA and have been used by insulins, calcitonin, and human growth hormone.

 In 2010, the Affordable Care Act (ACA) required all biologics and biosimilars to file a biologics license application (BLA) and previously approved products to be subject to a transition period until 2020. Between now and 2020, similar biologics will either be filed under the 351(k) pathway or the 505(b)(2) pathway pending transition to a biologics or biosimilar designation on March 23, 2020.

 Basaglar (insulin glargine injection) was recently approved and filed through the 505(b)(2) pathway.

Since the introduction of biologic licensing under the PHS Act, the FDA introduced a new resource, 

. This resource provides lists of licensed biological products with reference product exclusivity and biosimilarity or interchangeability evaluations. Besides providing key dates and lists of reference products, a portion of 

 assigns 1 of 2 grades to biologics, biosimilar (B) or interchangeable (I) to the reference product. Interchangeable would require additional data for approval compared with a biosimilar designation.

 This resource is meant to closely model 

, which describes the therapeutic equivalence and safety between 2 related drug products.

 will add all new biologic products approved through the 351(k) pathway, with the first entry being Zarxio (filgrastim-sndz).

 Biopharmaceuticals submitted for approval through the 505(b)(2) pathway are not yet reflected in 

. However, as of March 23, 2020, these products will be transitioned to obtain their BLA previously mentioned under 351 and, hence, they will be defined in the resource.

Meanwhile, pharmacists will have to pay close attention to regulations around biologic products.

Within the 351(k) pathway, there are still many questions regarding biosimilar naming and labeling in the United States. The FDA has asked for input on draft guidances on biosimilar naming and labeling.

 On August 28, 2015, the FDA announced the availability of a draft guidance, entitled “Nonproprietary Naming of Biological Products.” The draft guidance describes current thinking on the need for biologic products licensed under the PHS Act to bear a nonproprietary name that includes an FDA-designated suffix.

 This guidance has been applied to Zarxio (filgrastim-sndz), the first biosimilar approved in March 2015.

 Inflectra (infliximab-dyyb) is the second example of an approved biosimilar in the United States.

An approach to streamline naming could be to decide that the nonproprietary names are similar, but not the same. Utilizing the same nonproprietary name could imply the product is identical and approved for all of the same indications, whereas the biosimilar could be approved only for a subset of the reference biologic’s indications.

Therefore, each product would hold its own brand name to further help to prevent confusion on which product should be dispensed.

Prescribers and pharmacists need to prepare for the adoption of biosimilars in practice to support their patients appropriately. As previously mentioned, biosimilars are not interchangeable unless specifically requested by the manufacturer and approved by the FDA under the higher regulatory standard of interchangeability.

If a regulatory authority determines the biosimilar to be interchangeable, this would allow for direct substitution. Pharmacists will then have to know which products can be directly substituted and those that would require prescriber consultation. Additionally, pharmacists must follow individual state regulations. Prescribers will want accurate documentation of which biosimilar their patient is utilizing.

 Although complicated, this provides an opportunity for pharmacists to be a valued source of education to prescribing health care professionals. Pharmacists can be the local biosimilar experts and implement sound pharmacovigilance practices, as well as have the knowledge of niche therapeutic options and potential cost advantages for patients, prescribers, and health care systems.

Basaglar (insulin glargine injection) was recently approved through a 505(b)(2)) submission with no differentiation in the non-proprietary name associated with Lantus (Sanofi; Paris, France). Biologics manufactured by different companies (without technology transfer) are not identical despite having the same primary amino acid structure or being bioequivalent.

 The 2 molecules are not considered bioequivalent, resulting in 2 products that are not automatically substitutable unless listed as such in 

. Prescribers maintain the option to transition patients from one product to the other as a matter of choice, but should do so when prescribing by brand name to enable management of potential clinical and safety issues that may occur. Somatropin, a growth hormone, marketed under several brand names, has the same nonproprietary name resulting in similar challenges.

If biosimilars and FOBs are not prescribed by their brand name, pharmacists and prescribers should be aware of the potential confusion that may be generated by electronic medical records, e-prescribing, prescription dispensing practices, AE reporting, and patient discussions. When a prescription is written for the nonproprietary name, pharmacists should verify with the prescriber of the intended brand. To further complicate matters, Merck and Mylan are anticipated to seek approval of their versions of insulin glargine sometime in the near future.

There are a number of factors that can influence the development of an immune response from a biologic or biosimilar, and they can be product-, patient-, or treatment-related.

 The body has the ability to detect foreign proteins and produce (neutralizing) antibodies. Therefore, the immunologic profile of a biosimilar or an FOB should be more important than cost considerations when determining their place in therapy.

Payers may desire interchangeable biologic products analogous to AB-rated bioequivalent generics, but product complexity complicates this circumstance. Small changes in the manufacturing process or product excipients may impact the PD and PK, efficacy, structure, stability, impurities, immunogenicity, and AEs associated with the biotherapeutic.

 One must remember that biologics are inherently immunogenic. An example of this was Coagulation Factor VIII. This biotherapeutic clearly showed a link between the manufacturing process and the product profile. A degradation product of factor VIII led to increased immunogenicity.

Despite issues pertaining to complexity and risk, biosimilar or FOB agents can safely be produced using different manufacturing processes and protocols. Health care professionals facilitating patient care should be properly educated on the background of biotechnological manufacturing and how these processes can differ between manufacturers.

BIOSIMILARS AND FOLLOW-ON BIOLOGICS IN PRACTICE SITES

Pharmacists need to prepare for the introduction of biosimilars and FOBs for use in both the institutional and outpatient settings. Starting with hospital formularies, the adoption of these products will have different challenges to overcome compared with chemical drugs. This will continue into the outpatient setting, where payer formularies and product availability may differ from the prescribing institution. The more complex adoption into a health-system formulary may require clarity of past manufacturing issues, supply chain availability, patient monitoring, and increased provider and patient education. The institutional setting may need to invest resources into evaluating and monitoring the use of the reference product over that of a single, or even multiple, FOB products.

As the medication expert, pharmacists have the opportunity to offer guidance in all stages and areas of biologic use. This is especially true as collaborative practice agreements and pharmacist credentialing and certifications continue to develop. Prescribers will need to appreciate how better access to biotherapeutics may impact patient adherence to treatment regimens and begin taking steps now to address these potential issues.

 Patient adherence may also be affected by device ease of use, patient support programs, and product affordability.

 Patient perceptions of biosimilar and FOB therapeutics will be a barrier if the patient perceives these alternatives as inferior to the reference product. If they are providing meaningful patient education, pharmacists must be knowledgeable about a biotherapeutic’s efficacy, immunogenicity, and AEs that may be uncommon compared with the listed drug relied upon.

 Postmarketing surveillance also is critical to confirm the regulatory decision of biosimilarity, and it is important for the pharmacist to report AEs in conjunction with the prescriber’s responsibility.

As previously stated, experts anticipate that a 20% to 30% price reduction from the reference biologic would create a viable biosimilar and FOB market through increased patient access. This has the potential to impact what a patient pays out-of-pocket (OOP). Reductions in list price will impact patients in benefit design, such as high-deductible plans and co-insurance, where OOP costs are determined by a percentage of a medication’s list price instead of a fixed co-pay. For example, a patient who is in a high-deductible plan will pay 100% of the list price for each prescription until they reach their OOP benefit maximum, which can be as high as $6500 for a single plan and $13,000 for a family plan, as mandated by the ACA. For a patient with coinsurance, their OOP may be 10% or 20% of the list price. Therefore, the introduction of biosimilars and FOBs may impact the patient’s cost, whereby if the biosimilar list price or the FOB price is lower than the reference product, the patient’s OOP costs will be lower.

In benefit designs where patient OOP is a fixed co-pay, price concessions from manufacturers may not impact a patient’s OOP expenses. Considering all the factors discussed, pharmacists have the opportunity to proactively direct patients and prescribers to the lower-priced biologic.

Biopharmaceuticals offer management options and solutions for a vast number of conditions and diseases. Ultimately, they help improve patient lives. Increasing availability of biosimilars and FOBs should increase prescriber choice of, and patient access to, biotherapeutics. Improving prescriber confidence in biosimilars and FOBs will help to overcome negative patient perceptions that may mirror what generics faced when initially compared with brand thereapeutics.

 Prescriber education on immunogenicity profiles and clarity on product names and documentation will demand interprofessional communication in the process. Payers may dictate access to different products, and it will be up to the health care team to be knowledgeable of available options. Products may not be interchangeable based on approval status, so the pharmacist has a responsibility to ensure the accuracy and appropriateness of their patient’s regimen. If pharmacists understand the regulations and biosimilar/FOB marketplace, they will be able to offer pertinent recommendations to prescribers and meaningful consultation to patients.

Michael McShea, RPh, graduated from the University of South Carolina, College of Pharmacy with his BS in Pharmacy. His experiences span marketing, account management, hospital and retail pharmacy, long term care, and diabetes and hospital account sales. He joined Eli Lilly & Co. in 1989 and is currently in Channel Strategy focusing on the Endocrine platform. His responsibilities include identifying and understanding the environment and capabilities in various traditional Trade and emerging Specialty Channels, including distribution and pharmacy, as well as the evolving capabilities of the organizations and vendor partners actively participating in those channels. He is also currently a member of the advisory panel for Specialty Pharmacy Times and Pharmacy Times. He places importance on connecting patients with product within the pharmacy channel to ultimately enhance patient experiences and care in support of improved patient outcomes.

Mark Borns, PharmD, graduated from The Ohio State University in 2016 with his Doctorate of Pharmacy and also has a BS in Pharmaceutical Sciences. He is currently a Visiting Scientist Fellow at Eli Lilly and Company in Indianapolis, Indiana, focused in Global Pricing, Reimbursement and Access. He is devoted to the value of biopharmaceutical innovation and the importance of patient access to medications.

Roy Daniel Pollom, MD, received his MD from Indiana University School of Medicine in 1977 and completed his residency in Internal Medicine in 1980. For the last 15 years, Dr. Pollom worked at Diabetes, Internal Medicine & Endocrinology, a multi-physician group practice at Community Health Network in Indianapolis, Indiana, specializing in the care of children and adults with diabetes. Additionally, he served as Medical Director at the Indiana Heart Hospital providing leadership in the management of diabetes and hyperglycemia in hospitalized patients with cardiovascular disease. His work with cardiovascular and peripheral vascular surgeons helped to establish evidence-based glycemic guidelines to improved outcomes in surgical patients. He joined Eli Lilly & Co. as a Sr. Medical Advisor in 2013 after more than 30 years of treating people with diabetes in private practice. His areas of expertise include type 1 and type 2 diabetes management, diabetes in pregnancy, continuous insulin pump and glucose sensor technology, stress hyperglycemia management during hospitalization and electronic glucose data analysis.

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US Food and Drug Administration. Information for Consumers (Biosimilars). 2015. http://www.fda.gov/drugs/developmentapprovalprocess/howdrugsaredevelopedandapproved/approvalapplications/therapeuticbiologicapplications/biosimilars/ucm241718.htm. Accessed: 18 Aug 2015.

Celebrating a Milestone: FDA's Approval of First Genetically-Engineered Product. http://www.fda.gov/AboutFDA/WhatWeDo/History/ProductRegulation/SelectionsFromFDLIUpdateSeriesonFDAHistory/ucm081964.htm. April 4 2009. Accessed: 18 August 2015.

FDA Basics - What is a biological product? http://www.fda.gov/AboutFDA/Transparency/-Basics/ucm194516.htm. Accessed: 18 Aug 2015.

Edelman S, Polonsky WH, Parkin CG. Biosimilar insulins are coming: what they are, what you need to know. Curr Med Res Opin. 2014; 30(11):2217-2222.

Owens DR, Landgraf W, Schmidt A, Bretzel RG, Kuhlmann MK. The emergence of biosimilar insulin preparations--a cause for concern? Diabetes Technol Ther. 2012 Nov; 14(11):989-996. doi: 10.1089/dia.2012.0105.

Lutz R. Biosimilar Substitution A Primer for Pharmacists. Pharmacy Times. 2015 Jul 16.

US Food and Drug Administration. Guidance for industry: Scientific considerations in demonstrating biosimilarity to a reference product. 2012. http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm291128.pdf. Accessed: 18 Aug 2014

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BioPharma Reporter 11.20.2015. New Jersey permits pharmacy-level substitution

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FDA approves first biosimilar Zarxio (filgrastim-sndz) from Sandoz. http://www.biosimilarnews.com/fda-approves-first-biosimilar-zarxio-filgrastim-sndz-from-sandoz. Accessed: 18 Aug 2015.

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Biosimilars. Purple Book. Lists of Licensed Biological Products with Reference Product Exclusivity and Biosimilarity or Interchangeability Evaluations. Accessed: 30 Jun 2016.

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Guest Feature

Pharmacists must be experts on follow-on biologics (FOBs), including biosimilars, so they can provide education to health professionals about safe prescribing
and use, which ultimately affects patient care.

Biosimilars and Follow-on Biologics

Money makes the world go round, right? Perhaps to a degree, but a common misconception about formulary management is that money is the driving force behind the entire operation. Although economic considerations play a role in the decision-making process, we would argue that formulary management is more than medication cost. The creation and continuous evaluation of a hospital’s formulary facilitates superior patient care, achieves therapeutic goals, and improves patient safety while curtailing expenses.

As a basis for this discussion, it must be understood that there are 2 main types of formularies: open and closed. An open formulary places no limits on a clinician’s prescribing abilities. Any brand, generic, class, strength, dosage form, etc., of a medication may be requested, and the pharmacy will stock or obtain the particular therapy. It should be no surprise that this type of formulary system is rarely used because of expense and safety issues. Most institutions implement a closed hospital formulary—a predetermined list of medications that clinicians can prescribe to their patients. In a closed formulary system, usually only 1 or 2 drugs in a given therapeutic class are available to clinicians. Some institutions choose to further restrict prescribing abilities of specific medications to certain physicians or practice specialties (ie, infectious disease or cardiology).

 However, even in a closed system, clinicians may request medications not available on the formulary. These requests should be reserved for medications required to achieve therapeutic goals not attainable with current formulary medications.

The pharmacy and therapeutics (PT) committee is a well-balanced multidisciplinary team composed of physicians, pharmacists, nurses, hospital administrators, quality assurance staff, and other hospital staff. These individuals are key stakeholders who bear the responsibility of formulary management. P&T committees are not about cost and limitation but rather play a vital role in patient care decisions throughout a hospital. One of the committee’s goals is to promote the rational, appropriate, and safe use of drugs while fostering cost-effective therapy. The joint commission standard states, “The hospital develops and approves criteria for selecting medications, which, at a minimum, include the following: indications for use, effectiveness, drug interaction, potential for errors and abuse, adverse drug events, sentinel event advisories, population(s) served (eg, pediatrics, geriatrics), other risks, costs.”

 The assessment of formulary medications does not stop upon a medication’s addition to the formulary, but the P&T committee maintains effective formulary management through reviewing new data regarding safety and evaluating medication use.

Formulary medications can provide patients with an equipotent alternative to their home medication through approved therapeutic interchanges. Often only 1 or 2 medications in a given class will be considered formulary, and there should be guidance regarding conversion of other medications in that class to the formulary medication. The conversion of a patient’s home medications to the hospital formulary medications, and then the interchange back to the community-outpatient-setting medications, should be undertaken with the utmost care. From the point of initial triage in the emergency department to the discharge of a patient back into the community setting, efficient and effective medication reconciliation is a crucial patient care process. Clinicians should review each step carefully; the importance of safe interchange of these medications is critical.

Antibiotic use represents another essential component of any formulary system. This group of medications affects cost and patient outcomes in health care. In the United States, more than 50% of patients in an inpatient setting receive some type of antimicrobial therapy, and 20% to 50% of the antibiotics prescribed have been found to be “unnecessary” or “inappropriate.”

 The need to ameliorate antibiotic use in hospitals is not only an individual patient care issue but also an escalating public health matter.

 Antibiotic resistance is on the rise; therefore, implementation of antibiotic stewardship programs is essential in hospitals. Antibiotic stewardship can start with an effective hospital formulary. “Formulary restriction is also a first step toward stewardship because, very simply, making only certain drugs available is a way to steer clinicians toward the use of those drugs,” according to the CDC.

 Clinicians must streamline and manage antibiotic use to improve patient outcomes and reduce health care costs. Effective formulary management and strategic restrictions of medication use are an initial step in the right direction toward improving antibiotic stewardship.

We believe that involving key stakeholders via a P&T committee to create a closed formulary system creates an environment that improves patient care. Safe and appropriate home medication therapeutic interchange and antibiotic stewardship are important in providing superior patient care. Medication cost is one factor in determining whether a medication is formulary, but that factor should be superseded by the impact it has on patient care. The effective implementation of a formulary system can improve the use of health care resources for a pharmacy and a facility and can improve patient outcomes.

Jerry Barbee Jr, PharmD, BCPS, CPh, is a clinical pharmacist at HCA West Florida Hospital.

Katy Lauderdale, PharmD, BCPS, is a clinical pharmacist at HCA West Florida Hospital.

Alexis Smith is a 2018 PharmD candidate at the University of Maryland Eastern Shore.

Chase KA, Brown TR, Holdford DA. Medication management. In: 

Introduction to hospital and health-system pharmacy practice

. Bethesda, MD: American Society of Health-System Pharmacists; 2010.

Joint Commission Perspectives. January 2012.

Trends in US antibiotic use: new data needed to improve prescribing, combat threat of antibiotic resistance. Pew Charitable Trusts website. pewtrusts.org/en/research-and-analysis/issue-briefs/2017/03/trends-in-us-antibiotic-use. Published March 22, 2017. Accessed June 2, 2017.

Core elements of hospital antibiotic stewardship programs. CDC website. cdc.gov/getsmart/healthcare/implementation/core-elements.html. Published February 23, 2017. Accessed June 2, 2017.

Viewpoints

The creation and continuous evaluation of a hospital’s formulary facilitates superior patient care, achieves therapeutic goals, and improves patient safety while curtailing expenses.

Hospital Formulary Management

Biologics, drug products made from living organisms, have revolutionized the treatment of life-threatening illnesses and chronic diseases, including cancer, rheumatoid arthritis, 

, and autoimmune disorders. The market for biologics continues to increase and is expected to reach $390 billion by 2020 and represent 28% of the value of the world’s pharmaceutical products. In 2014, 10 of the top 25 drugs in the United States were biologics. Biologics play a significant role in patient care, but because of the high cost of these medications, they may be inaccessible to patients and increase health care costs.

The emergence of biosimilars (a biological product that is highly similar to the reference product and only has minor differences in clinically inactive compounds, and no meaningful differences in terms of safety, purity, and potency from the reference product) into the US market gives clinicians more affordable options that are safe and effective. The Biologics Price Competition and Innovation Act (BCPIA, part of the Affordable Care Act) in 2010 provided an abbreviated pathway for FDA approval of biologics that are shown to be similar to or interchangeable with an FDA-approved biologic whose patent protection has expired, referred to as the reference drug. Similar to the Drug Price Competition and Patent Term Restoration Act (Hatch-Waxman Act, Public Law 98-417) in 1984 for small-molecule generics, BCPIA provides the opportunity for lower-cost alternatives and marketplace competition that ultimately results in health care savings.

For a product to gain FDA approval as a biosimilar, a manufacturer must be able to show the pharmacokinetic (PK) and pharmacodynamic (PD) similarities and differences between the proposed biosimilar product and the reference product. Through comparative, head-to-head studies with the reference product, the manufacturer also must demonstrate that small changes to the biosimilar do not affect its profile or immunogenicity.

Biologics and biosimilars are made from living organisms such as bacteria, yeast, and mammalian cells, rather than from the simpler atomic units of small molecule generics, and as a result they are not as easy to copy and will have a degree of microheterogeneity. The large size and complexity of the molecules and the inherent variability of the manufacturing process make it difficult to be identical to the reference product (table).

Sandoz’s filgrastim-sndz (Zarxio), a copy of the granulocyte-colony-stimulating factor (G-CSF) filgrastim (Neupogen), was the first biosimilar approved by the FDA and differs from filgrastim by 1 inactive compound. FDA approval of filgrastim-sndz was based on PK and PD studies that demonstrated similar clinical safety and efficacy profiles. The studies evaluated subcutaneous doses of 1 to 10 mcg/kg in healthy patients and the area under the curve and peak plasma concentration were within the 90% accepted confidence interval. These studies also evaluated absolute neutrophil counts and CD34+ counts as relevant PD factors for neutropenia and mobilization of hematopoietic stem cells. These end points were within the 95% confidence interval and predefined limits of 80% to 125%.

THERAPEUTIC USE, DOSING, AND ADMINISTRATION

Biologics play a significant role in patient care, but because of the high cost of these medications, they may be inaccessible to patients and increase health care costs.

September 2017

Postoperative Pain Management

Fixed-Ratio Combination of Basal Insulin and GLP-1 Receptor Agonist

Biosimilars and Follow-on Biologics

Hospital Formulary Management

Biosimilars: A Similar Frontier

Managing Chemotherapy-Induced Nausea and Vomiting (CINV) to Improve Patient Care

Cancer and Pain: Opportunities to Optimize Patient Care