Whether practicing pharmacy in the ambulatory or inpatient setting, professionals devote a substantial amount of energy and time to appropriate dosing of medications for renal impairment. This is appropriate, considering that about 14% of the general population is affected by chronic kidney disease, and those with this disease likely have more frequent exposure to the health care system.

 However, considerably less attention has been focused on the opposite end of the spectrum, those patients who may exhibit a hyperdynamic state of renal clearance. This phenomenon is commonly referred to as augmented renal clearance (ARC), and only within the past decade has it begun to gain attention in the medical community.

 The definition of ARC varies in the literature with respect to actual filtration rate, duration of hyperdynamic filtration, and cutoff creatinine clearance (CrCl) values. The most widely accepted definition of ARC is a CrCl greater than 130 mL/min/1.73 m2. However, there is no consensus on grading or stratification of severity with escalating CrCl values.

Much remains unknown regarding the mechanism of ARC. However, available evidence suggests that multiple changes to nephron physiology may be at play.

 One model proposes that systemic inflammation in critically ill patients results in vasodilation and reduction of systemic vascular resistance. This decrease in resistance, when coupled with the administration of intravenous fluids and increases in heart rate, leads to increased cardiac output, increasing renal preload. This hyperdynamic state results in the increased glomerular filtration rates seen in ARC.

 The incidence of ARC may be as high as 30% to 65% in critically ill patients with normal serum creatinine. The most consistent patient factors associated with ARC across multiple studies are an age of younger than 50 years and trauma.

 Other associated factors include being a man, modified sequential organ failure assessment (SOFA) scores ≤4, and lower Acute Physiology and Chronic Health Evaluation or Simplified Acute Physiology scores.

In order to more effectively and rapidly identify patients with ARC, multiple groups have attempted to develop and validate scoring tools. The 2 most popular ones are the ARC scoring system and the Attitudes Related to Trauma- Informed Care (ARCTIC) scoring system. The ARC scoring system uses the criteria of age, a SOFA score, and trauma to assign patients an ARC score. Scores from 0 to 6 predict a low ARC risk, whereas scores of 7 to 10 are associated with a high risk of ARC.

 This tool was validated in a separate study that showed a sensitivity and specificity of 100% and 71%, respectively.

 The ARCTIC scoring system uses the criteria of age, gender, and serum creatinine and has an associated sensitivity of 84% and specificity of 68%.

 Despite the reductions in sensitivity and specificity, the ARCTIC scoring system is the more realistically feasible of the 2. This is largely because the use of the SOFA score within the ARC scoring system adds a layer of complexity and may make the calculation of an ARC score much more difficult in clinical practice. These scoring tools may help identify patients with suspected ARC. However, to confirm the presence and quantify the degree of ARC, a patient-specific CrCl is required. This should be performed using an 8-to-24-hour urine collection when possible, with subsequent CrCl calculation.

Given the importance of early goal-directed therapy in sepsis, coupled with the associated high mortality rate of patients presenting with sepsis, the impacts of ARC on the pharmacokinetics/pharmacodynamics (PK/PD) of antimicrobials may have a profound impact on patients admitted to intensive care units (ICUs).

 Many available antibiotics are extensively cleared by the kidneys, which is worrisome when evaluated within the context of ARC. Antibiotic dosing regimens are usually determined from studies in healthy individuals during PK/PD phase 2 trials and rarely, if ever, do they include critically ill patients or those likely to be experiencing ARC.

 The increased rate of drug clearance seen in patients with ARC may be detrimental to the PK/ PD of antibiotics with time-dependent killing mechanisms by leading to suboptimal time that serum concentration of the drug remains above the organism’s minimum inhibitory concentration (MIC).

 In a study by Carlier et al, investigators began to quantify the changes imposed by ARC on the PK/PD properties of b-lactam antibiotics. The fraction of time during a 24-hour period that free concentrations of antibiotics remained above the target MIC (fT>MIC) for Pseudomonas aeruginosa was measured in 61 patients exposed to extended infusion meropenem or piperacillin/tazobactam. Of the 19 patients who did not achieve the PK/PD target of 50% fT>MIC, 7 displayed a CrCl >130 mL/min. This study included a limited number of subjects, but it does raise the question: Are patients with ARC receiving antibiotic dosing regimens that fail to meet optimal pharmacodynamic targets?

 A slightly larger study by Claus et al evaluated a population of 128 patients with a total of 599 antimicrobial therapy days in the ICU. They examined therapeutic failure, defined as an impaired clinical response that required the need for alternative therapy.

 ARC was present for at least 1 antimicrobial therapy day in 66 patients.

 ARC patients experienced more therapeutic failure (27.3% vs 12.9%).

 Additionally, in those patients with ARC, 4 developed antibiotic resistance, as opposed to just 1 in the non-ARC patient group.

 Antibiotic failure in patients with ARC occurred only in those patients receiving time-dependent b-lactam antibiotics, including amoxicillin/clavulanic acid, cefuroxime, meropenem, and piperacillin/tazobactam.

Vancomycin, one of the most commonly prescribed antibiot- ics for patients with sepsis, was excluded in both of the above studies. This may be explainable, given that vancomycin trough levels are typically closely monitored in the hospital setting. Subtherapeutic vancomycin levels are commonly explained by patient-specific PK/PD characteristics that deviate from the expected population values, and regimens are adjusted when the values are found to be outside the target concentrations. In 2015, Chu et al aimed to evaluate whether some of the variance seen in vancomycin levels in inpatients was due to ARC. They retrospectively examined 148 patients who received 1000 mg every 12 hours. Not surprisingly, nearly 63% of patients with a CrCl >130 mL/min had trough concentrations <10 mcg/ mL.12 No patient with a CrCl <80 mL/min obtained a trough <10 mcg/mL, and just 27.8% of patients with a CrCl between 80 and <130 mL/min achieved such a trough.

The relationship is made stronger when looking at patients with supratherapeutic levels. Just 1 patient with a CrCl >130 mL/min had a trough of >20 mcg/mL, compared with 31.5% of patients with a CrCl <130 mL/min.

Clinicians should carefully consider the impact that ARC may have on treatments being administered in the inpatient care setting. When patients may be demonstrating a hyperdynamic state of renal clearance, a tool such as the ARC or ARCTIC score may be useful to help determine those in whom an 8-to-24-hour urine creatinine collection may be appropriate.

Knowledge of the impact of ARC on antibiotic PK/PD and overall treatment success is relatively limited. Once identified, patients with ARC should have close attention paid to their antimicrobial dosing, particularly those receiving drugs that depend on either area under the concentration time curve: MIC ratio or fT>MIC pharmacodynamics or those receiving antimicrobials for which therapeutic drug monitoring is available. Dosing adjustments may be necessary to assure adequate pharmacodynamic target achievement.

Ryan W. Stevens, PharmD, BCPS, is an infectious diseases clinical specialist at Providence Alaska Medical Center in Anchorage.

Nicholas A. Smith, PharmD, is a PGY1 pharmacy practice resident at Providence Alaska Medical Center in Anchorage.

1. National Institute of Diabetes and Digestive and Kidney Diseases. Kidney disease statistics for the United States. niddk.nih.gov/health-information/health- statistics/kidney-disease. Accessed November 1, 2017.

2. Mahmoud SH, Shen C. Augmented renal clearance in critical illness: an important consideration in drug dosing. 

. 2017;9(3):36. doi: 10 .3390/pharmaceutics9030036.

3. Sime FB, Udy AA, Roberts JA. Augmented renal clearance in critically ill patients: etiology, definition, and implications for beta-lactam dose optimization. 

. 2015;24:1-6. doi: 10.1016/j.coph.2015.06.002.

4. Hobbs AL, Shea KM, Roberts KM, Daley MJ. Implications of augmented renal clearance on drug dosing in critically ill patients: a focus on antibiotics. 

 2015;35(11):1063-1075. doi: 10.1002/phar.1653.

5. Udy AA, Roberts JA, Shorr AF, Boots RJ, Lipman J. Augmented renal clearance in septic and traumatized patients with normal plasma creatinine concentrations: identifying at-risk patients. 

6. Minville V, Asehnoune K, Ruiz S, et al. Increased creatinine clearance in polytrauma patients with normal serum creatinine: a retrospective observational study. 

7. Akers KS, Niece KL, Chung KK, Cannon JW, Cota JM, Murray CK. Modified augmented renal clearance score predicts rapid piperacillin and tazobactam clearance in critically ill surgery and trauma patients. 

. 2014;77:(3)(suppl 2):S163-170. doi: 10.1097/TA.0000000000000191.

8. Barletta JF, Mangram AJ, Byrne M, et al. Identifying augmented renal clearance in trauma patients: validation of the augmented renal clearance in intensive care scoring system. 

. 2017;82(4):665-671. doi: 10.1097/ TA.0000000000001387.

9. Claus BO, Hoste EA, Colpaert K, Robays H, Decruyenaere J, De Waele JJ. Augmented renal clearance is a common finding with worse clinical outcome in critically ill patients receiving antimicrobial therapy. 

 2013;28(5):695- 700. doi: 10.1016/j.jcrc.2013.03.003.

10. Rivers E, Nguyen B, Havstad S, et al. Early goal-directed therapy in the treatment of severe sepsis and septic shock. 

. 2001;345(19):1368-1377. doi: 10.1056/NEJMoa010307.

11. Carlier M, Carrette S, Roberts JA, et al. Meropenem and piperacillin/tazobactam prescribing in critically ill patients: Does augmented renal clearance affect pharmacokinetic/pharmacodynamic target attainment when extended infusions are used? 

12. Chu Y, Luo Y, Qu L, Zhao C, Jiang M. Application of vancomycin in patients with varying renal function, especially those with augmented renal clearance. 

. 2016;54(12):2802-2806. doi: 10.1080/13880209.2016.1183684.

Articles

Infectious Diseases Focus

Whether practicing pharmacy in the ambulatory or inpatient setting, professionals devote a substantial amount of energy and time to appropriate dosing of medications for renal impairment.

Augmented Renal Clearance and the Impact on Antimicrobial Therapy

A study published recently in the Journal of Pain Research reported the prevalence of neuropathic pain at 10% in the US population.

 The National Institute of Neurological Disorders and Stroke (NINDS) reported that 20 million Americans have some type of peripheral neuropathy.

 Neuropathic pain is defined as “pain caused by a lesion or disease of the somatosensory nervous system.”

 Although nociceptive pain results from nociceptor response to tissue injury, neuropathic pain occurs as a consequence of nociceptor damage. Originating from damage within nerve cells themselves, neuropathic pain is often complex, with many treatment challenges. Because of its numerous etiologies and minimal response to opioids, careful evaluation and multimodal treatment should be anticipated in managing neuropathy.

Neuropathic pain is associated with many symptoms and classifications. With more than 100 types of neuropathy recorded, each case is unique.

 Those with neuropathic pain can present with mononeuropathy or polyneuropathy of axonal or myelin origin.

 Axonal refers to pain originating from axonal damage, while myelin origin results from demyelination of a nerve cell myelin sheath. Neuropathies may occur secondary to damage of either origin or a combination of both axonal and myelin. Mononeuropathy is when an individual incurs damage to a single nerve (eg, carpal tunnel), and polyneuropathy is a “diffuse peripheral nerve disorder that is not confined to the distribution of a single nerve or a single limb.”

 Polyneuropathies typically present as symmetrical and bilateral, with sensory loss, weakness, or burning.

Neuropathic pain generally occurs as chronic pain that escalates. However, neuropathy can be acute or chronic. Chronic manifestations commence with subtle pain and develop gradually. By contrast, pain in an acute form develops spontaneously, advances quickly, and resolves slowly as the injured nerve cells begin to heal.

 Guillain-Barr syndrome, a commonly known acute neuropathy, results from an individual’s immune system attacking its own peripheral nerves. Unlike chronic neuropathic pain, this syndrome typically lasts a few weeks, with most patients suffering no long-term complications.

General manifestations of neuropathy include allodynia, anesthesia dolorosa, hyperalgesia, and hyperpathia.

 However, symptoms of neuropathic pain can vary greatly, depending on the type of nerve that is damaged. Autonomic, motor, and sensory nerve damage each have unique characteristics, which may help identify an underlying origin (online table 1).

Symptoms can also be classified as negative or positive based on their physiological effect. Negative symptoms, including the loss of sensation and numbness, are common in diabetic neuropathy and are a major contributing factor to the high rate of amputations in patients with diabetes. Positive symptoms include increased pain sensation, spontaneous pain, and paresthesia (burning or prickling sensations).

Most often, nerve damage results in chronic symptoms that resolve only if the cause is recognized and can be rectified. However, symptoms may persist, despite treating the underlying cause, because of changes in the central nervous system (CNS).

NINDS has identified 4 main causes (or risk factors) that are associated with neuropathic pain. These are diseases and disorders, exposure to toxins, genetic mutations, and physical injury (online table 2).

 The 4 categories show the diversity of neuropathic pain etiologies and explain why neuropathic pain can be difficult to treat. Peripheral neuropathy is most often associated with diabetic neuropathy, as well as neuropathic cancer pain, postherpetic neuralgia, and trigeminal neuralgia.

 Central neuropathy is often correlated to multiple sclerosis, a spinal cord injury, or a stroke.

The transmission of pain involves complex signaling pathways and numerous endogenous neurotrans- mitters (NTs), including calcium, gamma aminobutyric acid (GABA), glutamate, potassium, and sodium.

 Glutamate is the major excitatory NT with the ability to increase pain, and GABA is the major inhibitory NT that decreases pain. In the nociceptive pain pathway, nociceptors are stimulated, leading to a process called transduction in which the activation of nociceptors converts the stimuli to electrical activity. Then, through transmission and modulation, the electrical message is sent and potentially altered as it travels through the nervous system (dorsal root ganglion, spinothalamic tract, thalamus). Once the stimulus reaches the higher cortical structure, the somatosensory cortex, perception occurs and the stimulus becomes a conscious pain experience. However, in neuropathic pain, a direct stimulus is not involved and dysfunctional nerves lead to unnecessary generation of pain.

Unlike nociceptive pain, neuropathic pain is most often classified as chronic pain, which may increase in intensity over time. Although the mechanisms behind neuropathic pain are not completely understood, several mechanisms that influence the peripheral nervous system (PNS) and CNS have been identified. Three primary mechanisms that may be responsible for PNS neuropathy include unprompted firing of damaged nerves, increased sensitivity of the afferent pathways because of denervation (the loss of nerve supply), and sympathetically sustained pain.

 By contrast, neuropathic pain of CNS origin may result from sensitization at the synapses or restructuring of higher-processing operations.

Neuropathic pain is usually suspected based on the presence of symptoms.

 As mentioned, patients can present with varying signs and symptoms depending on the mechanism causing the neuropathy, but the underlying cause may or may not be apparent.

 A clinical examination is necessary for a diagnosis of neuropathic pain.

Patients undergo neurological examination, with a review of their medical history.

 A physical exam and sensory testing are performed to assess muscle strength and the ability to detect light touch, temperature, body position, and pain.

 Additional tests, which are outlined in online table 3, may be conducted.

The management of neuropathic pain is typically a multimodal process (online table 4).

 Treatment plans should be discussed with patients and include the reason why pharmacologic therapy is being selected, the benefits and adverse events (AEs) of therapy, the dose titration schedule, how to manage AEs, and nonpharmacologic therapies.

 Patients should be referred to a pain specialist or a specialist in the underlying condition if their pain is severe or significantly debilitating or if the underlying condition worsens.

Pharmacological agents used to manage neuropathy are outlined in online table 5 and online table 6.

The main drug classes used are antidepressants, anticonvulsants, and opioids. Tricyclic antidepressants (TCAs) have many AEs because they bind to other receptors, such as alpha-adrenergic, histaminergic, and muscarinic.

 Patients tend to tolerate desipramine better than amitriptyline. However, there are not enough data to support the use of desipramine in diabetic neuropathy.

 Serotonin-norepinephrine reuptake inhibitors have fewer AEs compared with TCAs because of their higher specificity to binding sites.

 Gabapentin and pregabalin have a similar mechanism of action, but pregabalin has more stable pharmacokinetics.

 Other anticonvulsants are available as alternative options (carbamazepine, oxcarbazepine, and topiramate). However, these agents are generally not recommended and should not be used unless patients are being managed by a specialist. Notably, carbamazepine is for the first-line treatment of trigeminal neuralgia, for which typical doses are 200 to 400 mg twice daily.7,8 The recommended first-, second-, and third-line therapies are outlined in online table 7.

Health care providers play a pivotal role in the management of neuropathic pain, from diagnosis to drug therapy. They are responsible for identifying the cause, establishing patient goals, developing an appropriate treatment plan, and assessing a patient’s well-being. In addition to physical pain, there is a significant emotional burden that accompanies neuropathy. Studies have shown that neuropathic pain negatively affects patients’ quality of life, physical functioning, and emotional well-being.

 During a public meeting held by the FDA in 2016, individuals X living with chronic neuropathic pain shared their perspectives about the disorder. Neuropathic pain constantly disrupted their sleep and affected their careers and relationships.

 Patients also seemed more prone to worry about the future.

 Slowly losing the ability to function takes a toll on patients daily, both physically and emotionally. To decrease physical pain and improve quality of life, the source of pain must be identified, multimodal treatment should be used, and emotional support must be given.

Neuropathic pain is a multifaceted disease requiring multimodal treatment. With patients’ symptoms ranging from mild discomfort to intense unabating pain, health care providers must balance their patients’ emotional and physical needs with effective drug therapy. Successful treatment requires individualized treatment plans, with the use of anticonvulsants, antidepressants, and other pharmacological therapies. The role of the provider will be as both a medication prescriber and an empathic discerner of the  patient’s priority of treatment needs to improve quality of life.

Jerry A. Barbee Jr, PharmD, BCPS, CPh, and Matthew Savoie, PharmD, are clinical hospital pharmacists in Pensacola, Florida.

Catherine M. Kew is a PharmD candidate at Auburn University in Alabama.

Alexis Smith is a PharmD candidate at the University of Maryland Eastern Shore in Princess Anne.

More neurology resources can be found on 

DiBonaventura MD, Sadosky A, Concialdi K, et al. The prevalence of probable neuropathic pain in the US: results from a multimodal general-population health survey. 

. 2017;10:2525-2538. doi: 10.2147/JPR.S127014.

Peripheral neuropathy fact sheet. National Institute of Neurologcal Disorders and Stroke website. ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Peripheral-Neuropathy-Fact-Sheet. Published December 2014. Accessed December 13, 2017.

Finnerup N, Attal N, Haroutounian S, et al. Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis. 

. 2015;14(2):162-173. doi: 10.1016/S1474-4422(14)70251-0.

Rubin M. Polyneuropathy. Merck Manual Professional Version

 merckmanuals.com/professional/neurologic-disorders/peripheral-nervous-system-and-motor-unit-disorders/polyneuropathy. Updated September 2016. Accessed December 13, 2017.

 uptodate.com/contents/overview-of-polyneuropathy. Updated September 29, 2017. Accessed December 13, 2017.

Guillain—Barré syndrome. World Health Organization website. who.int/mediacentre/factsheets/guillain-barre-syndrome/en/. Updated October 2016. Accessed December 13, 2017.

National Institute for Health and Care Excellence. Neuropathic pain — pharmacological management. https://www. 

nice.org.uk/guidance/cg173/evidence/neuropathic-pain-pharmacological-management-full-guideline-191621341

. Updated February 2017. Accessed December 13, 2017.

Markman J, Narasimhan SK. Neuropathic pain. Merck Manual Professional Version

 merckmanuals.com/professional/neurologic-disorders/pain/neuropathic-pain. Updated April 2014. Accessed December 1, 2017.

About peripheral nerve disorders. ColumbiaDoctors, Neurological Surgery website. columbianeurosurgery.org/conditions/peripheral-nerve-disorders/. Accessed December 13, 2017.

Autonomic neuropathy. MedlinePlus website. medlineplus.gov/ency/article/000776.htm. Updated December 5, 2017. Accessed December 13, 2017.

Svokos K. The pathophysiology of neuropathic pain. Practical Pain Management website. practicalpainmanagement.com/pain/neuropathic/pathophysiology-neuropathic-pain. Updated December 29, 2011. Accessed December 13, 2017.

Toxic neuropathy. Foundation for Peripheral Neuropathy website. foundationforpn.org/what-is-peripheral-neuropathy/causes/toxins/. Accessed December 13, 2017.

Swenson R, Cohen J, Fadul C, Jenkyn L, Ward T. Disorders of the Nervous System. dartmouth.edu/~dons/part_2/chapter_19.html. Published 2008. Accessed December 13, 2017.

Dworkin RH, O’Connor AB, Audette J, et al. Recommendations for the pharmacological management of neuropathic pain: an overview and literature update. 

. 2010;85(suppl 3):S3-S14. doi: 10.4065/mcp.2009.0649.

Fudin J, Bettinger J, Wegrzyn E. Treatment of neuropathic pain. 

pharmacytimes.com/publications/health-system-edition/2017/march2017/treatment-of-neuropathic-pain

. Published April 16, 2017. Accessed December 13, 2017.

Bril V, England J, Franklin GM, et al. Evidence-based guideline: treatment of painful diabetic neuropathy: report of the American Academy of Neurology, the American Association of Neuromuscular and Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation. 

 2011;76(20):1758-1765. doi: 10.1212/WNL.0b013e3182166ebe.

FDA. The voice of the patient. https://www. 

fda.gov/downloads/ForIndustry/UserFees/PrescriptionDrugUserFee/UCM542169.pdf

. Published February 2017. Accessed December 13, 2017.

Clinical Care Focus

Originating from damage within nerve cells themselves, neuropathic pain is often complex, with many treatment challenges.

Neuropathic Pain: A Glimpse Inside the Unabating Affliction

In response to the numerous concerns regarding antineoplastic drugs and other medications that may threaten the health of patients and health care workers, the National Institute for Occupational Safety and Health (NIOSH) developed a list, updated biennially, of hazardous drugs. Cancer chemotherapy, antivirals, and hormone therapies are only some of drugs listed in the 2016 NIOSH list.

NIOSH classifies hazardous drugs as those that exhibit any of the following 6 characteristics in humans or animals:

Teratogenicity/other developmental toxicity

Structure and toxicity profiles of new drugs that mimic existing drugs previously determined hazardous

A key takeaway is that because NIOSH classifies hazardous drugs based on the 1990 definition provided by the American Society of Hospital Pharmacists (ASHP, now known as the American Society of Health-System Pharmacists), the institute may not accurately classify newer pharmaceuticals, such as bioengineered drugs that are target specific. Moreover, NIOSH has not attempted to perform risk assessments on each drug or determine exposure limits.

NIOSH groups hazardous drugs into 3 categories (table 1) that are primarily focused on classifying the potential for reproductive and developmental toxicity, based on the needed dose to produce toxicity in animals and/or whether adverse effects are observed in animals at or near the maximum recommended human dose.

Three tables in the 2016 list outline the haz- ardous drugs and their properties, compiled from the updated 2014 NIOSH list of hazardous drugs and the 2016 update, which included 34 new drugs (table 2). There were no deletions from the 2014 list.

The NIOSH tables include a Supplemental Information column, which describes potential black box warnings and/or the FDA pregnancy category. Although the FDA removed the pregnancy letter categories for prescription labeling in 2015, the 2016 NIOSH list continues to use that lettering system.1 Most of the drugs categorized as X and D meet the ASHP criteria for hazardous drugs and are recorded in the 2016 NIOSH list.

The FDA definitions of the 2 most prevalent categories are given in table 3.

NIOSH recommends that in addition to using the information provided in the 2016 list of Antineoplastic and Other Hazardous Drugs in Healthcare Settings, organizations create their own list based on their formulary.

 The third section of the NIOSH alert provides detailed information on how to create a hazardous drug list.

Health care personnel must be aware of the risk of altering formulations. Coated tablets or capsules that are administered without modification may not pose a hazard, but if they are crushed or placed in an automated counting machine, the dust that results may pose a risk via inhalation or skin contact.

Overall, approximately 8 million US health care workers are potentially subjected to the risks of hazardous drugs; moreover, the use of antineoplastic agents and drugs is increasing quickly. It is imperative that organizations identify the hazardous drugs on their formulary, as well as implement procedures and policies that protect their patients and workers.

Marina Reed is a PharmD candidate at the University of Wisconsin—Madison School of Pharmacy.

1. The National Institute for Occupational Safety and Health. NIOSH list of antineoplastic and other hazardous drugs in healthcare settings, 2016. Centers for Disease Control and Prevention website. cdc.gov/niosh/docket/review/ docket233a/pdfs/2016-161finalpublication.pdf. Published September 2016. Accessed June 22, 2017.

2. Content and format of labeling for human prescription drug and biological products; requirements for pregnancy and lactation labeling. Fed Regist. 2008;73(104):30831-30868. To be codified at 21 CFR §201.

3. The National Institute for Occupational Safety and Health. Hazardous drug exposures in health care. Centers for Disease Control and Prevention website. cdc.gov/niosh/topics/hazdrug/default.html. Updated August 25, 2017. Accessed July 6, 2017.

Safe Handling

In response to the numerous concerns regarding antineoplastic drugs and other medications that may threaten the health of patients and
health care workers, the National Institute for Occupational Safety and Health (NIOSH) developed a list, updated biennially, of hazardous drugs. 

Key Points From the 2016 NIOSH List of Antineoplastic and Hazardous Drugs in Health Care Settings

Anticoagulants are among the most frequently prescribed drugs in the United States. They are indicated for prevention and treatment of venous thromboembolism (VTE) and pulmonary embolism (PE), stroke prevention in the setting of atrial fibrillation (AF), prevention of thromboembolism in patients with prosthetic heart valves, prophylaxis after joint replacement surgery, and reduction in the risk of thromboembolic events after myocardial infarction.

About 900,000 people are affected by VTE/ PE in the United States each year, and about 100,000 people die as a result, according to the CDC.

 One-third of those with VTE/PE will have a recurrence within 10 years.

 AF affects up to 6 million Americans every year, and this number is expected to increase with the aging of the population.

Historically, warfarin has been the most commonly prescribed oral anticoagulant. Approved by the FDA in 1954, the vitamin K antagonist (VKA) has been extensively studied, and the benefits and risks are well known.

 Although warfarin is an effective anticoagulant, management and safe use can be challenging, especially in certain populations. Since 2010, 5 direct oral anticoagulants (DOACs) have been approved that target the activity of thrombin or factor Xa: apixaban, betrixaban, dabigatran, edoxaban, and rivaroxaban.

 Collectively, as a class, the DOACs have less need for laboratory monitoring, minimal drug—drug and food interactions, and more predictable dosing.

 However, they come with a higher cost and varying degrees of risk, and most lack a reversal agent.

Hemostasis is the normal physiologic response that promotes blood clot formation at the site of vascular injury to prevent blood loss and promote healing.

 Clot formation involves several different system reactions, including activation of the coagulation cascade, platelet plug formation, and vasoconstriction.

 The response must be localized and tightly regulated to prevent widespread clotting. Once blood flow has ceased, tissue repair can begin.

The coagulation cascade involves a series of biochemical reactions that lead to the activation of thrombin. The cascade is divided into 2 pathways, extrinsic and intrinsic, which converge to a common pathway at the activation of factor X, which converts prothrombin to thrombin. Thrombin then converts fibrinogen to fibrin, which forms the matrix of the clot.

In thrombosis, coagulation reactions are inappropriately regulated so that the clot expands and occludes the lumen of the blood vessel. Three major factors, called Virchow’s triad, predispose to thrombus formation: blood hypercoagulability, vascular wall damage or injury, and venous stasis.

VKAs, such as warfarin, inhibit the vitamin K— dependent synthesis of clotting factors II, VII, IX, and X, as well as the regulatory proteins C, S, and Z.

 Warfarin has a narrow therapeutic window, and doses are individually tailored, based on laboratory monitoring of the international normalized ratio (INR), the universal monitoring index based on prothrombin time. The half-life of warfarin ranges from 20 to 60 hours, and the duration of effect is 2 to 5 days. It is primarily metabolized through the cytochrome P450 system, and induction or inhibition of the enzymes involved in metabolism can increase the INR significantly.

Dabigatran acts as an oral direct thrombin inhibitor that prevents thrombin from cleaving fibrinogen to fibrin. The half-life is about 12 to 17 hours in patients with normal renal function, with maximum anticoagulant effects 2 to 3 hours after ingestion.

Direct factor Xa inhibitors, which prevent factor Xa from converting prothrombin to thrombin by binding directly to factor Xa, are metabolized by the kidney and liver, and severe liver disease can result in accumulation. The DOACs have more predictable pharmacokinetic profiles than warfarin, with shorter half-lives and less need for routine laboratory monitoring, as drug levels are foreseeable for a given dose.

Betrixaban, dabigatran, and edoxaban are substrates for P-glycoprotein (P-gp), and concomitant use with P-gp inducers (eg, rifampin) reduces the anticoagulant effect.

 In patients with renal failure, concomitant use with P-gp may increase the anticoagulant effect. Apixaban and rivaroxaban interact with inhibitors of CYP3A4 and P-gp, such as ketoconazole and ritonavir, and inducers, such as carbamazepine and rifampin.

Anticoagulants have varying degrees of efficacy, depending on the clinical setting. There are also differences in adverse effects, cost, dosing, and monitoring. For these reasons, recommendations must be individualized, based on the indication and patient.

When a DOAC is preferred, individual patient characteristics will determine which should be prescribed, as no head-to-head trials have been done that compare their clinical outcomes.

VKAs are preferred over DOACs in several different settings. DOACs are not used in patients with prosthetic heart valves because of a greater risk of valve thrombosis.

 In patients with renal insufficiency, warfarin may be the preferred oral agent. For patients with creatinine clearance (CrCl) <30 mL/min, there is insufficient evidence compared with warfarin, and the DOACs must be dose adjusted. DOACs are not recommended in patients with CrCl <15 mL/min.

DOACs also are not used during pregnancy because of the lack of clinical experience. In pregnant women, low molecular weight heparin (LMWH) is usually the preferred agent.

Randomized, double-blind, double-dummy, noninferiority trials have investigated the newer anticoagulants compared with warfarin for indications of nonvalvular AF and VTE. Based on the findings, the 2016 American College of Chest Physicians guidelines for antithrombotic therapy recommended that in patients with VTE or PE and no cancer, the use of apixaban, dabigatran, edoxaban, or rivaroxaban be selected over VKA therapy, and in patients with VTE or PE and cancer, LMWH be used over apixaban, dabigatran, edoxaban, rivaroxaban, or VKA therapy.

Bevixaban was not included in the recommendations because it had not been approved at the time. It received approval with an indication for VTE prophylaxis in hospitalized adults in 2017.

Intracerebral bleeding is a major concern with warfarin, especially in older adults who have AF and are at risk of falling. The bleeding risk of dabigatran has been noted in several large observational studies, and findings have shown that overall bleeding with dabigatran is similar to warfarin, with lower rates of death and intracranial hemorrhage.

 Major bleeding risk of apixaban (5 or 2.5 mg) twice daily and edoxaban (30 or 60 mg) daily has been shown to be similar compared with warfarin and rivaroxaban (20 or 15 mg) daily and dabigatran (150 mg) twice daily, which had similar risks versus warfarin.

 The risk of gastrointestinal bleeding is slightly higher with dabigatran when using the dose of 150 mg twice daily and rivaroxaban (20 or 15 mg) daily versus warfarin.

 The risk of intracranial bleeding was reduced with all DOACs versus warfarin.

The anticoagulant effect sometimes requires rapid reversal if major bleeding occurs or emergency surgery is needed. Warfarin toxicity can be treated by holding doses or administering fresh frozen plasma, phytonadione (vitamin K), or prothrombin complex concentrate. Guidelines have been developed to help select treatment based on the INR and if bleeding is present.

Idarucizumab received FDA approval in 2017 as a reversal agent for dabigatran. The drug is a humanized monoclonal antibody fragment that binds to dabigatran with a higher affinity than to thrombin, thus neutralizing its activity. Reversal agents for other DOACs are in development.

A 2017 report involving more than 1500 patients who were being treated for VTE with a DOAC highlighted the lack of clinician familiarity with recommended dosing.

Pharmacists are well positioned to educate and guide providers on the benefits and risks of each oral anticoagulant. Patients also need to be counseled on adherence, drug interactions, and what to do when doses are missed.

New oral anticoagulants offer many advantages over warfarin, with faster onset, predictable anticoagulant effects, fewer drug interactions and dietary restrictions, lack of required monitoring, and a lower risk of intracranial bleeding. However, they do have higher costs and depend on renal elimination, and some lack an effective reversal agent.

Joanna Lewis, PharmD, MBA, is a clinical pharmacist and an active member of the American Society of Health-System Pharmacists. She has worked in a variety of practice settings, most recently as a coordinator at Duke University Hospital in Durham, North Carolina.

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