June 2019 FAQs

What evidence is available for the use of capsaicin in cannabinoid hyperemesis syndrome?

Introduction

Marijuana, also referred to as cannabis, is commonly used in the United States, with an estimated 22.2 million users each month according to a 2015 survey.¹ More states are beginning to legalize marijuana for medicinal and recreational use, potentially increasing both the number of marijuana users and the number of patients seeking care for marijuana-related health problems.^2,3 Chronic marijuana use has been associated with several adverse effects, including dependence/addiction, lung problems, and impairment of cognitive function.^3,4 Another increasingly prevalent adverse effect of chronic marijuana use is cannabinoid hyperemesis syndrome (CHS).²

Cannabinoid hyperemesis syndrome, a variant of cyclic vomiting syndrome first described in 2004, is characterized by recurrent, paroxysmal episodes of nausea, vomiting, and abdominal pain in the setting of chronic marijuana use.⁵ Symptoms are relieved by frequent hot baths or showers, but often refractory to opioids and commonly used antiemetics.^4,5 Patients with CHS often present to the emergency department with nonspecific symptoms, requiring repeat visits and multiple tests before a diagnosis is made.⁵ If untreated, this syndrome can lead to significant complications, including acute renal failure, electrolyte abnormalities, esophageal injury, and pneumomediastinum. This article will discuss some of the treatment modalities for CHS, with a specific focus on the role of capsaicin.

Pathophysiology and diagnosis of CHS

The pathophysiology of CHS is still unclear.⁴ The development of this syndrome with cannabis use seems paradoxical, because cannabis is frequently used as an antiemetic in patients on chemotherapy, as well as an appetite stimulant for patients with chronic disease states like HIV/AIDS.^2,5 The major active component in marijuana, 9Δ-tetrahydrocannabinol, activates CB₁ receptors in the medulla, inhibiting gastric motor function and proemetic dopamine activity; it also inhibits serotonin release through its action on CB₁ receptors, and inhibits emetogenic 5-hydroxytryptamine-3 (5-HT₃) serotonin receptors.

Chronic cannabis use may result in downregulation, desensitization, or internalization of cannabinoid receptors, causing an imbalance in the endogenous cannabinoid system.^2,5,6 Endogenous cannabinoids are important for reestablishing homeostasis after a stressful event, so an imbalance in the endogenous cannabinoid system may lead to abnormal processing of stressful stimuli and abnormal regulation/activation of the hypothalamic-pituitary-adrenal (HPA) axis and sympathetic nervous system.⁷  It is thought that this dysregulation plays a role in the development of CHS.

Cannabinoid hyperemesis syndrome consists of 3 phases: prodromal, hyperemetic, and recovery.⁸ The prodromal phase is characterized by early-morning nausea and mild abdominal discomfort; this may last for months to years. The hyperemetic phase typically lasts for 24 to 48 hours; this acute, highly symptomatic phase may be precipitated by stress or fasting.^5,8 In the hyperemetic phase, patients experience severe, unrelenting abdominal pain and repeated episodes of vomiting and retching.⁸ Patients may be unable to tolerate oral intake during this phase, resulting in dehydration, weight loss, and electrolyte abnormalities. Symptoms are typically relieved by hot water, and many patients will report compulsive hot water bathing during the hyperemetic phase in order to gain relief. In the recovery phase, patients regain lost weight and return to a normal state of health. However, if patients do not discontinue marijuana use, this phase will be short-lived. Diagnosis of CHS is based on patient symptoms and history. Patients will have a history of regular, frequent marijuana use, and typically present with severe nausea and vomiting that recurs cyclically over months. Other supportive findings include relief of symptoms with hot water bathing, age younger than 50 years, weight loss greater than 5 kg, colicky abdominal pain with normal bowel habits, morning predominance of symptoms, and resolution of symptoms with marijuana cessation.

Treatment options for CHS

Supportive care and complete cessation of marijuana use are the mainstays of treatment for CHS.⁸ After marijuana cessation, symptoms typically resolve within 7 to 10 days, but may recur with re-exposure.² Intravenous fluids should be given for dehydration, and medication should be given to help relieve vomiting symptoms. Conventional antiemetics, such as ondansetron, promethazine, and metoclopramide, are commonly used, but often ineffective as monotherapy for patients with CHS.^2,5,9 Benzodiazepines and diphenhydramine have also been used in the treatment of this condition, although reports of effectiveness are mixed. Multiple case reports have shown the efficacy of haloperidol in CHS symptom relief; olanzapine may also be considered, although the evidence for its use is more limited. In recent years, topical capsaicin has emerged as a potential first-line treatment option for this disease state.² The remainder of this article will focus on capsaicin and the evidence supporting its use in CHS.

Proposed mechanism and evidence for capsaicin in CHS

Topical capsaicin has typically been used in the treatment of nociceptive and neuropathic musculoskeletal pain.⁶ When applied, it binds to and activates transient receptor potential vanilloid 1 (TRPV1) receptors on peripheral nociceptive neurons, leading to influx of calcium and sodium, release of inflammatory neuropeptides, and transient burning, stinging, or itching at the site. The TRPV1 receptors also respond to other noxious stimuli, such as heat, acids, pain, and change in osmolarity. Because hot showers/baths and capsaicin have both been reported to decrease CHS symptoms, it is thought that the activation of TRPV1 receptors may be what leads to CHS symptom relief with these treatment modalities. It is still unclear exactly how the TRPV1 receptors and the endocannabinoid system interact in CHS, but some endocannabinoids have been found to bind with TRPV1 as well as cannabinoid receptors. A counter-regulatory interplay between the cannabinoid and TRPV1 receptors is thought to play a role in nausea, emesis, nociception, anxiety-related behaviors, and stress maladaptation.

Evidence for topical capsaicin use in CHS is limited to case reports and case series (Table 1), but these reports have generally shown rapid relief of symptoms after application.^10-16 Capsaicin has also been effective in patients with symptoms that were refractory to standard antiemetics and other treatments.  Application sites for capsaicin have varied, but the abdomen is commonly used. Various capsaicin strengths have been used, ranging from 0.025% to 1.5%.

Table 1. Summary of reports describing topical capsaicin use for CHS.^10-16

Conclusion

Topical capsaicin cream has been effective for treating symptoms of CHS in several case reports, including cases where symptoms were refractory to conventional antiemetics and other therapies. Although the level of evidence for capsaicin in CHS is low, an expert consensus guideline from the San Diego Emergency Medicine Oversight Commission, the County of San Diego Health and Human Services Agency, and the San Diego Kaiser Permanente Division of Medical Toxicology recommends topical capsaicin cream as a first-line treatment for diagnosed CHS, due to its low cost, mild side effect profile, and widespread availability.² Capsaicin cream is available over-the-counter in several strengths (0.025%, 0.035%, 0.075%, 0.1%, and 0.25%).¹⁷ The consensus guideline recommends using the 0.075% strength, and applying to the abdomen or back of arms 3 to 4 times daily.² Further studies are necessary to establish the optimal dosing regimen for capsaicin, as well as the efficacy of capsaicin relative to other treatments.

References

1. Marijuana fast facts and fact sheets. Centers for Disease Control and Prevention website. https://www.cdc.gov/marijuana/fact-sheets.htm. Updated May 12, 2017. Accessed May 7, 2019.
2. Lapoint J, Meyer S, Yu CK, et al. Cannabinoid hyperemesis syndrome: public health implications and a novel model treatment guideline. West J Emerg Med. 2018;19(2):380-386.
3. Wilkinson ST, Yarnell S, Radhakrishnan R, Ball SA, D’Souza DC. Marijuana legalization: impact on physicians and public health. Annu Rev Med. 2016;67:453-466.
4. Lapoint JM. Cannabinoids. In: Nelson LS, Howland M, Lewin NA, Smith SW, Goldfrank LR, Hoffman RS, eds. Goldfrank’s Toxicologic Emergencies. 11th ed. New York, NY: McGraw-Hill; 2019. https://accesspharmacy.mhmedical.com/content.aspx?bookid=2569&sectionid=210259605. Accessed May 7, 2019.
5. Richards JR. Cannabinoid hyperemesis syndrome: pathophysiology and treatment in the emergency department. J Emerg Med. 2018;54(3):354-363.
6. Richards JR, Lapoint JM, Burillo-Putze G. Cannabinoid hyperemesis syndrome: potential mechanisms for the benefit of capsaicin and hot water hydrotherapy in treatment. Clin Toxicol (Phila). 2018;56(1):15-24.
7. Richards JR. Cannabinoid hyperemesis syndrome: a disorder of the HPA axis and sympathetic nervous system? Med Hypotheses. 2017;103:90-95.
8. Williams MV. Cannabinoids: emerging evidence in use and abuse. Emerg Med Pract. 2018;20(8):1-20.
9. Khattar N, Routsolias JC. Emergency department treatment of cannabinoid hyperemesis syndrome: a review. Am J Ther. 2018;25(3):e357-e361.
10. Sharma U. Cannabis hyperemesis syndrome. BMJ Case Rep. 2018;2018:bcr-2018-226524.
11. Moon AM, Buckley SA, Mark NM. Successful treatment of cannabinoid hyperemesis syndrome with topical capsaicin. ACG Case Rep J. 2018;5:e3.
12. Dezieck L, Hafez Z, Conicella A, et al. Resolution of cannabis hyperemesis syndrome with topical capsaicin in the emergency department: a case series. Clin Toxicol (Phila). 2017;55(8):908-913.
13. Graham J, Barberio M, Wang GS. Capsaicin cream for treatment of cannabinoid hyperemesis syndrome in adolescents: a case series. Pediatrics. 2017;140(6):e20163795.
14. Hafez ZT, Liss DB, Schwarz ES, Mullins ME. Capsaicin cream in the treatment of cannabinoid hyperemesis syndrome: relief from the “joint” pain. Clin Toxicol (Phila). 2017;55(5):443.
15. Lapoint J. Case series of patients treated for cannabinoid hyperemesis syndrome with capsaicin cream. Clin Toxicol (Phila). 2014;52(7):707.
16. Biary R, Oh A, Lapoint J, Nelson LS, Hoffman RS, Howland MA. Topical capsaicin cream used as a therapy for cannabinoid hyperemesis syndrome. Clin Toxicol (Phila). 2014;52(7):787.
17. Clinical Pharmacology [database online]. Tampa, FL: Elsevier, Inc.; 2019. http://clinicalpharmacology.com/. Accessed May 13, 2019.

Prepared by:
Laura Koppen, PharmD, BCPS
Clinical Assistant Professor, Drug Information Specialist
University of Illinois at Chicago College of Pharmacy

June 2019

The information presented is current as of May 2, 2019. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.

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What is the evidence for using haloperidol for migraines in the emergency department?

Background

Migraine is a recurrent headache disorder that typically lasts from 4 to 72 hours each time.¹ During a migraine attack, headache is typically unilateral, pulsating, associated with moderate to severe pain, and/or aggravated by physical activity such as walking. Patients usually experience nausea, vomiting, photophobia, and/or phonophobia. Some migraines present with aura, which are neurological symptoms (ie, visual, sensory, speech, motor, brainstem, and/or retinal symptoms) preceding or accompanying the headache.

The mechanism behind migraines is complex and multifactorial. Migraines start with changes in the connectivity and activity of the hypothalamus several hours prior to the headache.² Changes also occur in thalamic and thalamocortical circuits and in the connectivity of the cortex, thalamus, hypothalamus, brainstem, amygdala, and cerebellum that may lead to photophobia, pain, anxiety, and mood alterations. Calcitonin gene-related peptides (CGRPs) and pituitary adenylate cyclase-activating polypeptides (PACAPs) serve as migraine mediators when they are released into the circulation.

Migraines accounted for 1.2 million visits to U.S. emergency departments (EDs) in 2010.³ Opioids were administered in 59% of those visits with hydromorphone being the most common parenteral agent. With the increased awareness of the opioid epidemic and rising opioid overdose deaths over the last decade, healthcare providers have an interest in exploring and understanding the evidence behind other non-opioid treatment options such as haloperidol.⁴

Haloperidol (Haldol) is a butyrophenone with an unclear mechanism of action.⁵ The Food and Drug Administration approved the use of this agent for schizophrenia and the control of tics and vocal utterances of Tourette’s disorder. Haloperidol has been studied in several off-label indications including migraines. In migraines, haloperidol may elicit its effects through binding to D1 dopamine, 5-HT2 serotonin, H1 histamine, and α2 adrenergic receptors in the brain.^6,7

Current guidelines

The American Headache Society (AHS) published a guideline on the use of parenteral pharmacotherapies in adults with acute migraine in the ED in 2016.⁸ The guideline states that intravenous (IV) metoclopramide, IV prochlorperazine, or subcutaneous sumatriptan should be offered to patients presenting with migraine to the ED who have never received an injectable migraine medication before. Intravenous haloperidol belongs to the category of “may offer”, which also includes agents such as IV acetaminophen, IV acetylsalicylic acid, IV chlorpromazine, IV dexketoprofen, IV diclofenac, IV dipyrone, IV droperidol, IV ketorolac, and IV valproate. The guideline recommends counseling patients about drowsiness and akathisia with IV haloperidol. In patients who have received a previous IV therapy for acute migraine attacks, providers should consider a prior response to IV therapies as well as the risk for adverse events when selecting an IV agent.

Evidence for haloperidol

The AHS recommendations regarding IV haloperidol are based on 2 randomized controlled trials.⁸ The trial by Gaffigan and colleagues received the strongest classification as class 1 in the AHS recommendations.^8,9 The double-blind, randomized, controlled trial compared the use of IV metoclopramide 10 mg and IV haloperidol 5 mg in 64 adult patients with migraine headaches presenting to the ED.⁹ The results showed similar pain relief using visual analog scale (VAS), side effects, and satisfaction with treatment. However, patients in the IV haloperidol group needed significantly lower frequency of rescue medication administration (3% versus 24%, p<0.02) but experienced more restlessness (43% versus 10%, p<0.015) compared with patients in the IV metoclopramide group.

The AHS rated the trial by Honkaniemi and colleagues as class 3, the lowest classification for the strength of evidence.^6,8 The randomized, double-blind, placebo-controlled trial in 40 patients with acute migraine found significantly lower pain as assessed by VAS values (p<0.0001) and significantly more patients with pain relief (p<0.0001) with IV haloperidol versus placebo.⁶ About 80% to 88% of patients receiving IV haloperidol experienced side effects. The most common side effects were motor agitation (50% to 53%) and sedation (33% to 53%).

A meta-analysis, published in 2011, included 3 randomized studies to measure headache relief with parenteral butyrophenones, droperidol or haloperidol, versus placebo in patients presenting to the ED with migraines.¹⁰ Compared with placebo, butyrophenones were more effective in headache relief, defined as >50% improvement in VAS scores (pooled odds ratio (OR), 8.08; 95% confidence interval (CI), 1.54 to 42.30). The rates of side effects ranged from 10% to 45%. The most common side effects were akathisia and sedation.

The case reports published by Fisher in 1995 were the initial evidence for the use of haloperidol for migraines in the ED.^7,11 The administration of haloperidol 5 mg led to the cessation of migraine within 25 to 65 minutes in 6 patients. Haloperidol also aided with nausea and vomiting. Only 1 patient reported anxiousness after receiving a haloperidol dose, which resolved within minutes. The rest of the patients did not report any adverse effects.

A safety study of 47 patients with migraines receiving IV haloperidol 5 mg over 2 to 3 hours revealed akathisia in 21% (n=10) of patients.¹² Mild drowsiness was the only other side effect reported. If patients developed akathisia, the providers stopped haloperidol infusion and administered IV diphenhydramine or IV dihydroergotamine.

Dosing and administration of haloperidol

In the available studies, all patients with migraines received IV haloperidol 5 mg in the ED.^6,7,9,11,12 However, the preparation and administration of IV haloperidol vary among studies. Depending on the study, IV haloperidol 5 mg was administered over 2 to 3 minutes, over 20 to 30 minutes when diluted in 500 mL of normal saline, or over 2 to 3 hours when diluted in 250 mL of dextrose 5%. Interestingly, the package insert for haloperidol injection does not include recommended dilution volume, diluent, or administration time.⁵ Pre-treatment with IV diphenhydramine 25 mg may be necessary to prevent akathisias and to provide an antiemetic effect.^9,11,12

Conclusion

According to 2010 data, migraines were responsible for 1.2 million visits to EDs in the United States, and opioids were administered in more than half of these cases.³ With the increasing awareness regarding the opioid epidemic, an interest in evidence behind non-opioid agents such as haloperidol exists. The AHS guideline states that IV haloperidol may be offered to patients presenting with migraines to the ED.⁸ The published evidence regarding IV haloperidol for this indication is somewhat limited but provides insights into its similar efficacy compared with IV metoclopramide and superior efficacy compared with placebo. Unfortunately, IV haloperidol has a high risk for causing side effects, with the notable side effects being agitation, sedation, restlessness, and akathisia. Pre-treatment with IV diphenhydramine may prevent akathisia as well as reduce the risk of nausea associated with migraines. Patients presenting with migraines to the ED may receive IV haloperidol 5 mg, but the preparation and administration rate of the agent differed in the published literature. Further studies may be necessary to outline the efficacy and safety of IV haloperidol compared to other agents used for migraines in ED, to identify its place in therapy, and to determine the optimal preparation and administration of the agent.

References

1. Headache Classification Committee of the International Headache Society (IHS): the international classification of headache disorders, 3rd edition. Cephalalgia. 2018;38(1):1-211.
2. Charles A. The pathophysiology of migraine: implications for clinical management. Lancet Neurol. 2018;17(2):174-182.
3. Friedman BW, West J, Vinson DR, Minen MT, Restivo A, Gallagher EJ. Current management of migraine in US emergency departments: an analysis of the National Hospital Ambulatory Medical Care Survey. Cephalalgia. 2015;35(4):301-309.
4. Opioid overdose. Centers for Disease Control and Prevention website. https://www.cdc.gov/drugoverdose/index.html. Updated October 19, 2018. Accessed May 28, 2019.
5. Haloperidol injection [package insert]. Eatontown, NJ: West-Ward Pharmaceuticals; June 2018.
6. Honkaniemi J, Liimatainen S, Rainesalo S, Sulavuori S. Haloperidol in the acute treatment of migraine: a randomized, double-blind, placebo-controlled study. Headache. 2006;46(5):781-787.
7. Fisher H. A new approach to emergency department therapy of migraine headache with intravenous haloperidol: a case series. J Emerg Med. 1995;13(1):119-122.
8. Orr SL, Friedman BW, Christie S, et al. Management of adults with acute migraine in the emergency department: The American Headache Society evidence assessment of parenteral pharmacotherapies. Headache. 2016;56(6):911-940.
9. Gaffigan ME, Bruner DI, Wason C, Pritchard A, Frumkin K. A randomized controlled trial of intravenous haloperidol vs. intravenous metoclopramide for acute migraine therapy in the emergency department. J Emerg Med. 2015;49(3):326-334.
10. Leong LB, Kelly AM. Are butyrophenones effective for the treatment of primary headache in the emergency department? CJEM. 2011;13(2):96-104.
11. Fisher H. Comment on a randomized controlled trial of intravenous haloperidol versus intravenous metoclopramide for acute migraine therapy in the emergency department. J Emerg Med. 2017;52(3):e75.
12. Nelson JP. Safety experience with IV haloperidol for abortive treatment of migraine. Headache. 2010;10(suppl 1):76.

Prepared by:
Janna Afanasjeva, PharmD, BCPS
Clinical Assistant Professor, Drug Information Specialist
University of Illinois at Chicago College of Pharmacy

June 2019

The information presented is current as of May 28, 2019. This information is intended as an educational piece and should not be used as the sole source for clinical decision making.

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Update: What is the safety information available on the use of DOACs in patients with renal impairment?

Introduction

In 2015, the Drug Information Group reviewed the literature related to the safety of using direct oral anticoagulants (DOACs) in patients with renal impairment, which can be accessed here.¹ Since the publication of the review, more recent literature has emerged on the topic. Therefore, the purpose of this review is to describe updated literature on the safety of DOACs in patients with renal impairment since the last FAQ, including a recent meta-analysis, observational data (not included in the meta-analysis), case reports, and pharmacokinetic data.

Meta-analysis

Although several meta-analyses have been published on the use of DOACs in patients with renal impairment in the last few years, only 1 includes updated trial information since 2015.² The remaining 3 meta-analyses all review various trials that were already discussed as part of the meta-analyses covered in the previous FAQ, and thus, will not be included in the current discussion.^3-5 In 2018, Chokesuwattanaskul et al published a meta-analysis of 5 observational studies that included over 50,000 patients with stage 4 or 5 chronic kidney disease (CKD) or end-stage renal disease (ESRD) on dialysis.² All of the included studies assessed the safety associated with use of apixaban in the population of interest; 3 studies compared apixaban to warfarin and 2 studies did not have a comparater group. The main outcome assessed was major bleeding, which was increased overall in patients with CKD or ESRD on dialysis that were taking apixaban (4 studies; event rate, 0.082; 95% CI, 0.048 to 0.135; p=0.000). When data from the 3 studies that compared major bleeding in patients prescribed apixaban or warfarin were pooled, major bleeding was significantly decreased in patients taking apixaban vs warfarin (odds ratio [OR], 0.42; 95% CI, 0.28 to 0.61; p=0.00). Limited data (not pooled) showed that the incidence of stroke was similar between patients treated with apixaban and warfarin (1 study). A second study did not record any thromboembolic events over a period of 64 months. One limitation to the meta-analysis is the fact that all of the studies included were observational in nature, bleeding was defined differently in different trials, and specific information about the dosing of apixaban and warfarin were not available. In addition, the results were largely driven by 1 retrospective database study that included more than 49,000 patients, all of which had atrial fibrillation.

Observational studies

Additional observational studies outside of those discussed in the meta-analysis by Chokesuwattanaskul et al have either been published more recently, or involve DOACs other than apixaban; they are further described in Table 1 below.^6-9 All of the studies assessed the effects of various DOACs in patients with renal impairment: 2 studies compared the use of apixaban to warfarin, 1 uncontrolled study evaluated safety with administration of edoxaban 30 mg daily, and 1 case-control study compared incidence of major hemorrhage in patients exposed to rivaroxaban, dabigatran, or warfarin with CKD to control patients that did not experience hemorrhage. In general, major bleeding rates were similar when comparing any DOAC to warfarin, and were even decreased when apixaban was compared to warfarin.

Table 1. Observational studies evaluating DOAC use in patients with renal impairment.^6-9

Case reports

Apixaban

A 62-year old African-American woman with non-valvular atrial fibrillation treated with warfarin for approximately 4 years was admitted to the hospital for what was later confirmed as warfarin-assocated calciphylaxis.¹⁰ The patient had a number of comorbidities at the time of admission including ESRD, which required chronic hemodialysis (HD) three times per week. Based on a CHA₂DS₂-VASc score of 4 and a HAS-BLED score of 2, the decision to continue anticoagulation was made and apixaban 2.5 mg twice daily was initiated. Enoxaparin-calibrated antifactor Xa levels were monitored, with a peak concentration measured approximately 3 hours after the 11^th dose, and a trough concentration measured approximately 11 hours after the 13^th dose. Both concentrations were >2 IU/mL, which was above the upper limit of detection of the hospital’s antifactor Xa assay. The patient’s hemoglobin remained stable at about 7 g/dL until day 7 of treatment with apixaban, when the patient developed hematochezia and her hemoglobin dropped to 5.6 mg/dL. A fecal occult blood test was also positive. Apixaban was discontinued and the patient received 2 units of packed red blood cells; her hemoglobin increased back to baseline and anticoagulation was held indefinitely. The patient subsequently died 44 days after the acute bleeding event due to complications of septic shock.

Dabigatran

Two more recent case reports describing the use of dabigatran in patients with renal insufficiency have been published, and are similar to those that were described in the 2015 review.^11,12 In both of the case reports, the patients were elderly (87 and 89 years old), had multiple comorbidities, and had moderate renal impairment at the time that dabigatran was initiated. Both patients were previously prescribed warfarin for atrial fibrillation; 1 patient was switched due to difficulty with maintaining a therapeutic international normalized ratio (INR) and the second was switched because of development of an acute ischemic stroke while on warfarin. In both cases, dabigatran was initiated at a dose of 110 mg twice daily. After initiating dabigatran, 1 patient presented with melena and hematemesis, and the other developed multiple bruises and a blood clot in her nasogastric tube after just 2 days of treatment. In both cases, laboratory findings were abnormal and included prolonged activated partial thromboplastin time (aPTT), increased INR, and worsening renal function. One of the patients stabilized after discontinuation of dabigatran; the second stabilized, but developed recurrent bleeding and later died, with the primary cause determined to be gastrointestinal bleeding.

Pharmacokinetic studies

Apixaban

Three additional studies, including 1 pooled pharmacokinetic analysis, have been published since 2015 to assess the pharmacokinetics and/or pharmacodynamics of apixaban in patients with renal impairment or in those with ESRD on HD.^13-15 A population-based pharmacokinetic study pooled data from 11 phase I through phase III studies to determine the impact of renal impairment: 8 phase I studies, 1 phase II study, and 2 phase III clinical trials.¹³ Pharmacokinetic modeling showed that treatment of venous thromboembolism (VTE) with apixaban in patients with severe renal impairment (creatinine clearance [CrCl] <15 mL/min) would result in a 36% reduction in overall clearance and a 40% increase in the area under the curve (AUC) compared to those with normal renal function.

An additional study evaluated the effect of a single 5 mg oral dose of apixaban in 8 patients with ESRD, given on 2 separate occasions and separated by at least 7 days, compared to 8 healthy controls.¹⁴ The first 5 mg dose was given 2 hours before HD, followed by a 4-hour HD session to mimic the effect of the dose in patients on HD. The second 5 mg dose was given after a washout period, immediately after a 4-hour HD session, to determine the pharmacokinetics of apixaban between dialysis sessions. Multiple blood samples were taken in intervals up to 72 hours post-dose. The study found that a single dose of apixaban 5 mg led to a 10% decrease in the maximum serum concentration (C_max) of apixaban and 36% increase in AUC in patients with ESRD off HD; patients given their dose immediately after HD had a 13% reduction in C_max and 14% reduction in AUC. The percentage change in various coagulation-related laboratory parameters, including the prothrombin time (PT), INR, aPTT, and the anti-factor Xa activity were similar in patients with and without ESRD.

A second pharmacokinetic study tested the effects of administering apixaban 2.5 mg twice daily for 8 days in patients with ESRD; patients then took part in a 5 day washout period followed by administration of apixaban 5 mg twice daily for an additional 8 days.¹⁵ The 2.5 mg twice daily dose, when measured at 0 and 24 hours post-dose, resulted in an increase in AUC from 628 ng h/mL to 2054 ng h/mL (p<0.001), and an increase in trough levels from 45 ng/mL to 132 ng/mL (p<0.001). Apixaban levels were measured each hour during dialysis on day 9, and only 4% of the drug was found to be removed during dialysis. Exposure to a 5 mg twice daily dose resulted in drug exposures that were above the 90^th percentile for patients with normal renal function. The authors concluded that a 2.5 mg twice daily dose of apixaban in patients with ESRD resulted in similar exposures to a 5 mg twice daily dose in patients with normal renal function, and that a higher dose of 5 mg twice daily should be avoided in patients on dialysis due to supratherapeutic levels.

Dabigatran

In a prospective, open-label pharmacokinetic study at a single institution, 15 patients with severe CKD (CrCl between 15 to 30 mL/min) were administered dabigatran 75 mg twice daily for 15 doses, followed by a 4-day washout period.¹⁶ The median values for the maximum plasma concentration of dabigatran after administration of the first dose, immediately before the last dose, and at steady-state were 59.2 ng/mL, 176 ng/mL, and 215 ng/mL, respectively. The AUC at steady-state was 2,270 ng h/mL and the terminal half-life at steady state for the last dose administered was approximately 28 hours. The observed concentration-time profile in this study was compared with predicted values using 2 different pharmacokinetic models that were used in previous studies that allowed for Food and Drug Administration (FDA)-approval of lower-dose dabigatran (75 mg twice daily) in patients with atrial fibrillation and a CrCl between 15 to 30 mL/min. Observed values from this study and predicted values using the previously developed models were comparable, further supporting the FDA-approved dosage recommendations.

A second study used a previously developed pharmacometric model to simulate dose-exposure relationships for various once- and twice-daily dosages of dabigatran in patients on HD and calculate the AUC.¹⁷ The simulated AUC values were then compared to values simulated in a typical patient with non-valvular atrial fibrillation (eg, Caucasian elderly male weighing 80 kg with CrCl of approximately 69 mL/min receiving 150 mg per day) from the RE-LY trial. The simulation showed that all of the twice-daily dosages that were investigated (75 mg, 110 mg, and 150 mg) led to exposures above those seen in the average patient in the RE-LY trial. In contrast, once-daily doses of 75 mg or 110 mg produced AUC values that were comparable to those seen in the typical patient in the RE-LY trial (-13.3% and +4.4%, respectively).

Edoxaban

A previously developed population pharmacokinetic model (the ENGAGE PopPK model) was updated to include data from 3 phase III studies completed in Japan that included 90 patients with non-valvular atrial fibrillation and concomitant severe renal impairment (CrCl <30 mL/min).¹⁸ After validation, the model was used to predict drug exposures for subgroups of patients from the Japanese studies in renal impairment. Pharmacokinetic parameters were the highest in patients receiving a 60 mg dose; the steady-state AUC was similar between patients with severe renal insufficiency who received a 15 mg dose and patients with normal or mild renal insufficiency who received a 30 mg dose.

A population pharmacokinetic model was developed based on a previously published study of edoxaban use (15 mg given as a single dose) in patients with various levels of renal function, including patients with renal impairment.¹⁹ The final model was used to predict AUC values for a 70 kg patient with varying levels of renal functionality. Compared to a patient with normal renal function (ie, CrCl 100 mL/min), AUC values of 57%, 35%, and 11.61% were calculated for a patient with a CrCl of 30 mL/min, 50 mL/min, and 80 mL/min, respectively. Projected AUC increases were similar for edoxaban’s active metabolite M4.

Rivaroxaban

In 2016, a study was conducted in 16 adult patients (8 patients with ESRD on HD and 8 healthy controls with normal renal function) to evaluate the pharmacokinetics, pharmacodynamics, and safety of a single dose of rivaroxaban 15 mg.²⁰ Patients in the ESRD group were given a single dose of rivaroxaban approximately 2 hours prior to their dialysis session, and blood sampling was performed before, during, and after dialysis. Afterwards, patients completed a 7- to 14-day washout period, and were given another single dose of rivaroxaban 3 hours after completion of a 4-hour dialysis session, with blood samples taken before and after the session. Control patients received a single dose of rivaroxaban with pharmacokinetic/pharmacodynamic sampling performed before and after the dose was administered. The authors found that dosing 3 hours after dialysis led to a decrease in overall clearance of 35% and an increase in AUC of 56% compared to healthy controls. Administration of rivaroxaban prior to HD resulted in a 5% reduction in AUC.

An open-label dose-finding study was conducted in 18 adult patients on HD to determine the pharmacokinetics and pharmacodynamics of rivaroxaban in patients on chronic HD.²¹ A single dose of rivaroxaban 10 mg was given to 12 patients immediately after 3 consecutive dialysis sessions; blood sampling showed that the AUC from 0 to 44 hours in ESRD patients was similar to the AUC from 0 to 48 hours after a single 20 mg dose in patients with normal renal function. Rivaroxaban 10 mg was also given as a single dose in 12 patients, given 6 to 8 hours prior to dialysis, and blood samples samples were collected throughout dialysis and immediately afterwards. Results showed that dialysis had no obvious effect on PT values or on the plasma concentration of rivaroxaban. Finally, multiple dose administration was tested by giving 6 patients rivaroxaban 10 mg once daily over 7 days with dialysis performed on days 2, 4, and 6. Laboratory values were comparable from day 1 to day 7 for the AUC from 0 to 24 hours (1,449 mcg/L/h on day 1 vs 1,851 mcg/L/h on day 7), the C_max (mean 152.8 mcg/L vs 192 mcg/L), and the half-life (mean 6.6 hours vs mean 7.3 hours).

Betrixaban

A new DOAC has been approved since the previous FAQ was published. Betrixaban (Bevyxxa) was approved in June 2017 for extended VTE prophylaxis in adult, acutely ill patients that are hospitalized and at risk of VTE.²² Betrixaban has been shown to have a lower renal clearance than other DOACs (approximately 5 to 7%), and patients with severe renal impairment were included in the initial trials that led to its approval.²³ In the APEX trial, hospitalized medically ill patients at an increased risk of VTE were randomized to subcutaneous enoxaparin daily plus betrixaban 160 mg by mouth for the first day followed by 80 mg once daily or enoxaparin plus placebo.²⁴ Patients with a CrCl between 15 to 30 mL/min were given a reduced dose of 80 mg for 1 dose followed by 40 mg once daily thereafter. Of the patients that received a reduced dose of betrixaban, 0 patients had a CrCl <15 mL/min and approximately 21% had a CrCl between 15 to 30 mL/min. The mean concentration of betrixaban was similar in patients with normal renal function (CrCl 90 to 120 mL/min) who were given the full dose and in patients with severe renal impairment (CrCl 15 to 30) who were given the reduced dose (mean 19.47 ng/mL ± 16.61 vs 14.52 ± 12.98, respectively). Betrixaban is not currently approved for any other indications; therefore, its role in therapy compared to other DOACs is unclear.

Conclusion

Since the publication of the preceding FAQ on the use of DOACs in patients with renal impairment, only 1 meta-analysis has been published with new trial information from 5 observational studies, specifically investigating apixaban. The results of the meta-analysis and 2 additional observational studies have shown apixaban to have an improved safety profile among patients with renal impairment or ESRD on dialysis when compared to warfarin, with a lower incidence of major bleeding reported with apixaban. Additional observational studies have shown dabigatran and rivaroxaban to have similar safety profiles to warfarin and an uncontrolled study has also shown that edoxaban may be safe for use in patients with renal impairment; however, the data for these agents is limited. A few case reports indicate that apixaban and dabigatran may lead to significant bleeding events, especially in patients that are elderly or have multiple comorbidities. Several new pharmacokinetic/pharmacodynamic studies have been published since this topic was last reviewed; they generally show that HD has a limited effect on DOAC clearance, and that renal impairment causes a decreased clearance and an increased exposure to the DOACs. Dosage adjustment in patients with renal impairment can lead to similar exposures to patients with normal renal function who are given full doses. Overall, this new data strengthens previous reports that the DOACs may be safe for use in patients with renal impairment, with the strongest evidence existing for apixaban. Future studies will be important to further delineate the roles of the various DOACs among patients with renal impairment, especially betrixaban, which appears to be a safer option in renally impaired patients but is not currently approved for any of the same indications as other DOACs.

References

1. What is the safety information available on the use of NOACs in patients with renal impairment? UIC Drug Information Group website. https://pharmacy.uic.edu/departments/pharmacy-practice/centers-and-sections/drug-information-group/2014/2015-faqs/july-2015-faqs. Published July 2015. Accessed May 22, 2019.
2. Chokesuwattanaskul R, Thongprayoon C, Tanawuttiwat T, Kaewput W, Pachariyanon P, Cheungpasitporn W. Safety and efficacy of apixaban versus warfarin in patients with end-stage renal disease: Meta-analysis. Pacing Clin Electrophysiol. 2018;41(6):627-634.
3. Kimachi M, Furukawa TA, Kimachi K, Goto Y, Fukuma S, Fukuhara S. Direct oral anticoagulants versus warfarin for preventing stroke and systemic embolic events among atrial fibrillation patients with chronic kidney disease. Cochrane Database Syst Rev. 2017;11:CD011373.
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5. Raccah BH, Perlman A, Danenberg HD, Pollak A, Muszkat M, Matok I. Major bleeding and hemorrhagic stroke with direct oral anticoagulants in patients with renal failure: systematic review and meta-analysis of randomized trials. Chest. 2016;149(6):1516-1524.

6. Fazio G, Dentamaro I, Gambacurta R, Alcamo P, Colonna P. Safety of edoxaban 30 mg in elderly patients with severe renal impairment. Clin Drug Investig. 2018;38(11):1023-1030.
7. Siontis KC, Zhang X, Eckard A, et al. Outcomes associated with apixaban use in patients with end-stage kidney disease and atrial fibrillation in the United States. Circulation. 2018;138(15):1519-1529.
8. Reed D, Palkimas S, Hockman R, Abraham S, Le T, Maitland H. Safety and effectiveness of apixaban compared to warfarin in dialysis patients. Res Pract Thromb Haemost. 2018;2(2):291-298.
9. Harel Z, Mamdani M, Juurlink DN, et al. Novel oral anticoagulants and the risk of major hemorrhage in elderly patients with chronic kidney disease: a nested case-control study. Can J Cardiol. 2016;32(8):986.e17-e22.
10. Kufel WD, Zayac AS, Lehmann DF, Miller CD. Clinical application and pharmacodynamics monitoring of apixaban in a patient with end-stage renal disease requiring chronic hemodialysis. Pharmacotherapy. 2016;36(11):e166-e171.
11. Havig SM, Lea D, Krpo M, Skari RM, Gustavsen I, Høiseth G. Fatal adverse event with dabigatran in elderly patient with reduced kidney function. Basic Clin Pharmacol Toxicol. 2018;123(2):221-226.
12. Lee MJ, Jang HM, Jeong WK, Bang OY. The need for a coagulation assay after initiation of new oral anticoagulants in patients with renal dysfunction: a case report. J Clin Neurol. 2015;11(4):395-397.
13. Byon W, Sweeney K, Frost C, Boyd RA. Population pharmacokinetics, pharmacodynamics, and exploratory exposure-response analyses of apixaban in subjects treated for venous thromboembolism. CPT Pharmacometrics Syst Pharmacol. 2017;6(5):340-349.
14. Wang X, Tirucherai G, Marbury TC, et al. Pharmacokinetics, pharmacodynamics, and safety of apixaban in subjects with end-stage renal disease on hemodialysis. J Clin Pharmacol. 2016;56(5):628-636.
15. Mavrakanas TA, Samer CF, Nessim SJ, Frisch G, Lipman ML. Apixaban pharmacokinetics at steady state in hemodialysis patients. J Am Soc Nephrol. 2017;28(7):2241-2248.
16. Kooiman J, van der Hulle T, Maas H, et al. Pharmacokinetics and pharmacodynamics of dabigatran 75 mg b.i.d. in patients with severe chronic kidney disease. J Am Coll Cardiol. 2016;67(20):2442-2444.
17. Liesenfeld KH, Clemens A, Kreuzer J, Brueckmann M, Schulze F. Dabigatran treatment simulation in patients undergoing maintenance haemodialysis. Thromb Haemost. 2016;115(3):562-569.
18. Shimzu T, Tachibana M, Kimura T, Kumakura T, Yoshihara K. Population pharmacokinetics of edoxaban in Japanese atrial fibrillation patients with severe renal impairment. Clin Pharmacol Drug Dev. 2017;6(5):484-491.
19.  Jönsson S, Simonsson US, Miller R, Karlsson MO. Population pharmacokinetics of edoxaban and its main metabolite in a dedicated renal impairment study. J Clin Pharmacol. 2015;55(11):1268-1279.
20. Dias C, Moore KT, Murphy J, et al. Pharmacokinetics, pharmacodynamics, and safety of single-dose rivaroxaban in chronic hemodialysis. Am J Nephrol. 2016;43(4):229-236.
21. De Vriese AS, Caluwé R, Bailleul E, et al. Dose-finding study of rivaroxaban in hemodialysis patients. Am J Kidney Dis. 2015;66(1):91-98.
22. Bevyxxa [package insert]. South San Francisco, CA: Portola Pharmaceuticals, Inc.; 2017.
23. Weber J, Olyaei A, Shatzel J. The efficacy and safety of direct oral anticoagulants in patients with chronic renal insufficiency: a review of the literature. Eur J Haematol. 2019;102(4):312-318.
24. Gibson CM, Halaby R, Korjian S, et al; APEX investigators. The safety and efficacy of full- versus reduced-dose betrixaban in the acute medically ill VTE (venous thromboembolism) prevention with extended-duration betrixaban (APEX) trial. Am Heart J. 2017;185:93-100.

Prepared by:
Jessica Zacher, PharmD, BCPS
Clinical Assistant Professor, Drug Information Specialist
University of Illinois At Chicago College of Pharmacy

June 2019

The information presented is current as of May 22, 2019. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making

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