December 2013 FAQs

What is the comparative efficacy of brand Plavix and generic clopidogrel bisulfate?

Introduction

The Food and Drug Administration (FDA) defines a generic drug as “one that is comparable to an innovator drug product in dosage form, strength, route of administration, quality, performance characteristics, and intended use.1 The approval process for a brand name product involves completing a new drug application (NDA) and presenting preclinical and clinical data to the FDA, while the approval process of a generic medication involves establishing bioequivalence with the innovator product and completing an abbreviated NDA (ANDA).

The FDA considers products bioequivalent if statistical tests assessing peak concentration (Cmax) and area under the concentration time curve (AUC) of the generic product fall within a 20% range of the brand.2 This means that the 90% confidence interval (CI) for these 2 parameters should fall between 80% and 125% of the innovator product. Data from 1 unpublished bioequivalence study comparing brand and generic clopidogrel found that the 90% CI for Cmax was 82 to 124.2 and for AUC was 86.4 to 122.6. These results, while within the prespecified CI for bioequivalence, indicated great variability with generic product use. It is unclear at this time if this variability affects clinical outcomes.

Although bioequivalence of brand and generic medications is a requirement from the FDA, many clinicians are hesitant to use generics as there are limited to no clinical data supporting their efficacy.3 Concern for the efficacy of generic products has been observed for therapies such as thyroid medications, antiepileptic drugs, and immunosuppressants.4 A similar concern has surfaced for the brand name product Plavix and its generic, clopidogrel bisulfate (clopidogrel hydrogen sulfate). Generic clopidogrel became available in May 2012 and is currently manufactured by 12 companies. 3 Despite the fact that the available clopidogrel generic products have received AB bioequivalency ratings from the FDA, there has been discussion regarding the lack of clinical outcomes for generic versions of this life-sustaining medication.

A summary of the methods used to evaluate platelet activity as well as findings from studies describing surrogate and clinical outcomes of brand and generic clopidogrel are described below.

Clopidogrel characteristics

Clopidogrel is a prodrug which undergoes metabolism by cytochrome (CYP) 2C19 to its active form. 5After being metabolized, it irreversibly binds to platelet P2Y12 receptors to prevent platelet activation and aggregation. Brand name Plavix is approved for use in patients with acute coronary syndromes (ACS), recent myocardial infarction (MI), stroke, and peripheral artery disease. It has been shown to reduce the recurrence of MI and stroke, stent thrombosis, and the rate of cardiovascular death. All patients should be monitored for the occurrence of bleeding events and the use of Plavix should be avoided in patients with an active bleed.

Clopidogrel bisulfate is the only salt form of clopidogrel available in the United States; however, in other countries the available salt forms include clopidogrel hydrochloride and clopidogrel besylate.

Comparative platelet aggregation studies

Plavix vs. generic clopidogrel bisulfate

Light transmittance aggregometry (LTA) is the gold standard for assessing platelet aggregation and is used in studies to test for the anti-platelet effects of aspirin, P2Y12, and glycoprotein IIb/IIIa inhibitors.6 It requires that blood samples be centrifuged to obtain platelet rich plasma (PRP). The turbidity of PRP is measured using light. Upon the addition of an aggregation stimulant such as adenosine diphosphate (ADP), the platelets aggregate thus allowing more light to travel through the PRP sample.7

The VerifyNow P2Y12 assay assesses platelet aggregation based on how fibrinogen activated beads aggregate with platelets when a platelet agonist such as ADP is present.7 This test is a point of care test that provides immediate results.

A small, prospective, crossover, controlled study evaluated the differences in platelet aggregation between Plavix and Plavitor, a generic form of clopidogrel bisulfate available in Korea.8 Patients in this study had undergone percutaneous coronary intervention (PCI) with placement of a drug eluting stent and had been receiving Plavix 75 mg for a minimum of 6 months. All 20 patients that were enrolled in this study were transitioned to Plavitor for 30 days. Platelet function was assessed with the LTA and the VerifyNow P2Y12 assay before and after patients received Plavitor to assess the differences in platelet aggregation between the 2 therapies. Platelet aggregation was tested using 2 concentrations of the ADP stimulus. No differences were found between the 2 treatments for either ADP concentration (p=0.280 and p=0.667, respectively). Although the findings were not statistically significant there was a large variability in results which the author speculated could result in different clinical outcomes.

Plavix vs. non-bisulfate generic clopidogrel salts

The following studies are comparisons between the various salt forms of clopidogrel that are available throughout the world. These studies include clopidogrel bisulfate as a treatment as well as other salt forms not available in the U.S.

In a small study conducted in Greece, 86 patients who had been initiated on Plavix 75 mg for ACS and presented to the hospital for 1 month follow-up were randomized to either continued Plavix or Clovelen (generic clopidogrel besylate) 75 mg for 6 months.9 Light transmittance aggregometry was used to evaluate platelet aggregation between the 2 salt formulations (primary endpoint). Three different agonists were used to stimulate platelet aggregation. There was no difference in aggregation between the 2 groups at 1 month and 6 months. Clinical outcomes were not reported.

An open-label, randomized, crossover study in the United Kingdom compared the platelet function of 17 healthy males receiving Plavix or clopidogrel hydrochloride.10 The healthy volunteers were given a 300 mg loading dose on day 1, followed by 75 mg maintenance dose on days 2 to 8. Participants underwent a 2 week wash-out period before each salt form was initiated. A point of care technique known as thrombelastography (TEG) was used in platelet assessment on day 8 of therapy with each agent. Using the results of the TEG the authors concluded that there was no difference in platelet reactivity between the 2 treatment groups.

Plavix vs. generic clopidogrel (unknown salt form)

The effect of Plavix and Apolets (generic clopidogrel) on platelet aggregation was compared in patients undergoing coronary angiography with or without PCI.11 The salt formulation of Apolets was not specified. Forty nine patients in Thailand were randomized to receive a 600 mg loading dose of either agent 1 hour before cardiac catheterization. Platelet aggregation was measured using LTA. No differences in platelet aggregation were found between the 2 study medications at 6 hours after administration.

Comparative clinical outcomes studies

Plavix vs. generic clopidogrel (unknown salt form)

In a retrospective analysis conducted in Korea, clinical outcomes of 428 patients were compared between those taking brand Plavix and Platless (generic clopidogrel).12 The salt formulation of Platless was not specified. Patients who underwent PCI prior to 2008 received Plavix, while those after 2008 received Platless. The primary endpoint was major adverse cardiovascular and cerebrovascular events at 1 year, defined as a composite of death, MI, and target vessel revascularization (TVR). There was no statistically significant difference in the primary endpoint between the 2 treatment groups (p=0.66). Four noncardiac deaths occurred in the Plavix group, while 2 deaths occurred in the Platless group. These deaths were attributed to heart failure exacerbation and sudden cardiac collapse. One patient in the Plavix group experienced an MI compared to 4 patients in the Platless group. Stroke occurred in 2 patients in each treatment group. Although the salt form of Platless is unknown, this is the only study that statistically compares clinical outcomes between brand and generic clopidogrel. No difference was found in the primary endpoint suggesting that Platless and Plavix have similar efficacy.

A double-blind, randomized, multicenter study conducted in Iran compared the clinical outcomes of Plavix to Osvix (generic clopidogrel).13 The salt formulation of Osvix was not provided. Four hundred twenty two patients were randomized to receive a 300 mg loading dose of either Plavix or Osvix followed by 75 mg daily of the same product for 30 days if patients received a bare metal stent or 6 months if patients received a drug eluding stent. The primary endpoint was the occurrence of major adverse cardiovascular events. This included death, Q wave and non-Q wave MI, stroke, target lesion revascularization, TVR, and in-stent thrombosis. No difference was found in the primary endpoint (p-values were not reported). The incidence of MI was 0.4% in the Osvix and 1.4% in the Plavix groups. In-stent thrombosis occurred in 0.4% and 0.5% of patients in the Osvix and Plavix groups, respectively. In addition, there were no statistically significant differences seen in episodes of angina, heart failure, and bleeding. The authors concluded that Osvix improved clinical outcomes compared to Plavix based on the rates of events experienced by the 2 groups and the trend in increased complications in the Plavix group. Therefore, Osvix is preferred in Iran due to cost.

Conclusion

Overall, studies comparing platelet aggregation and clinical outcomes between brand and generic clopidogrel formulations have shown no statistically significant differences. However, several limitations exist in each of these clinical trials. They include small study populations, lack of information regarding non-U.S. salt formulations, short study durations, and limited data regarding clinical outcomes including safety. The few studies that provide comparative data on clinical outcomes did not find statistical differences. There were numerical differences that may suggest greater efficacy of the brand name product but this preliminary finding needs to be confirmed with further studies before any conclusion can be made. The question of whether generic clopidogrel is as effective as brand Plavix remains unanswered due to the limited number of studies available. While no difference has been found in platelet reactivity between formulations, it is unclear if these results equate to similar clinical outcomes. Currently available data suggest that there is no difference between brand and generic clopidogrel, with generic products providing an additional benefit of reduced financial burden.

References

1. Abbreviated New Drug Application (ANDA): Generics. US Food and Drug Administration Website. http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/AbbreviatedNewDrugApplicationANDAGenerics/default.htm . Updated July 17, 2013. Accessed October 7, 2013.

2. Doll J, Zeitler E, Becker R. Generic clopidogrel: time to substitute? JAMA. 2013;310(2):145-146.

3. Al-Jazairi AS, Bhareth S, Eqtefan IS, Al-Suwayeh SA. Brand and generic medications: are they interchangeable? Ann Saudi Med. 2008;28(1):33-41.

4. Approved Drug Products with Therapeutic Equivalence Evaluations. 2013. US Food and Drug Administration Website. http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/UCM071436.pdf . Accessed October 7, 2013.

5. Plavix [package insert]. Bridgewater, NJ: Sanofi Aventis/Bristol Meyers Squibb; 2013.

6. Gurbel P, Becker R, Mann K, et al. Platelet function monitoring in patients with coronary artery disease. J Am Coll Cardiol. 2007;50(19):1822-1834.

7. Harrison P. Platelet function testing. UpToDate Website. http://www.uptodate.com/contents/platelet-function-testing?detectedLanguage=en&source=search_result&search=verifynow&selectedTitle=1~6&provider=noProvider . Updated September 28, 2012. Accessed October 7, 2013.

8. Jeong YH, Koh J, Kang M, et al. The impact of generic clopidogrel bisulfate on platelet inhibition in patients with coronary artery stents: results of the ACCEL-GENERIC Study. Korean J Intern Med. 2010;25(2):154-161.

9. Tsoumani ME, Kalantzi KI, Dimitriou AA, et al. Antiplatelet efficacy of long-term treatment with clopidogrel besylate in patients with a history of acute coronary syndromes: comparison with clopidogrel hydrogen sulfate. Angiology. 2012;63(7):547-551.

10. Sambu N, Radhakrishnan A, Curzen N. A randomized crossover study comparing the antiplatelet effect of Plavix versus generic clopidogrel . J Cardiovasc Pharmacol. 2012;60(6):495-501.

11. Srimahachota S, Rojnuckarin P, Udayachalerm W, et al. Comparison of original and generic clopidogrel 600 mg loading dose in the patients who planned undergoing coronary angiography. J Med Assoc Thai. 2012;95(12):1495-1499.

12. Park YM, Ahn T, Lee K, et al. A comparison of two brands of clopidogrel in patients with drug-eluting stent implantation. Korean Circ J . 2012;42(7):458-463.

13. Khosravi AR, Pourmoghadas M, Ostovan M, et al. The impact of generic form of clopidogrel on cardiovascular events in patients with coronary artery stent: results of the OPCES study. J Res Med Sci. 2011;16(5):640-650.

Prepared by:

Esha Bhargava, PharmD

PGY1 Community Pharmacy Resident

NorthShore University HealthSystem

December 2013

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Are there data to support the use of medroxyprogesterone for postpartum hemorrhage?

Introduction

Postpartum hemorrhage is a medical emergency and a significant cause of maternal morbidity and mortality.1 It has been reported to occur in 1% to 5% of all deliveries, and accounts for 99% of maternal deaths in developing countries.1,2 Though postpartum hemorrhage is a type of abnormal uterine bleeding, the etiology, risk factors, and therapy differ from those of non-organic causes of abnormal uterine bleeding.1 Medroxyprogesterone is a progestogen available in multiple formulations and is used for several types of abnormal uterine bleeding.3 However, its use in postpartum hemorrhage has not been described. A discussion of the differences between these types of bleeding and the associated role of medroxyprogesterone is summarized below.

Medroxyprogesterone mechanism and uses

Medroxyprogesterone is a synthetic progestogen which is responsible for transforming the endometrium from a proliferative to secretory form in women with endogenous estrogen production.3 It is available in tablet and parenteral formulations. The indications and pharmacokinetics vary depending on the specific formulation and route of administration. These are summarized in the Table.

Table. Indications and pharmacokinetic parameters for medroxyprogesterone.3-6

FDA=Food and Drug Administration; Tmax=time to maximum concentration.

The peak absorption and elimination half-life is shortest with the oral formulations followed by the subcutaneous (SC) formulation, and longest with the intramuscular (IM) formulation.3 Due to the prolonged duration of action of the injectable formulations, they are not recommended for use to treat the indications of the oral dosage form. In SC and IM dosing, medroxyprogesterone works to inhibit pituitary gonadotropin secretion and prevention of follicular maturation, ultimately leading to thinning of the endometrium and prevention of ovulation.5,6 The ability to suppress estradiol produces a beneficial effect on endometriosis-associated pain. Administration via the oral route, in doses of 5 to 10 mg, does not share the same mechanism or therapeutic effects of the injectable agents, but does transform the endometrium into the secretory form.3,6 The mechanism of action against endometrial and renal carcinoma has not been elucidated.3 In higher doses, luteinizing hormone and follicle-stimulating hormone secretion from the pituitary gland are inhibited, preventing the usual gonadotropin spikes during the menstrual cycle.

Medroxyprogesterone has several off-label uses, including paraphilia in males, precocious puberty, relief of post-menopausal symptoms, hypersomnolence, obstructive sleep apnea, and hirsutism.3 However, some institutions have reported seeing its use in the setting of postpartum or post-Cesarean section bleeding.

Types and etiologies of abnormal uterine bleeding

Abnormal uterine bleeding results from organic causes such as systemic or reproductive tract diseases, or from hormonal causes, which can be either anovulatory or ovulatory.7 Systemic diseases can lead to anovulatory bleeding, but the most common cause of hormone-related uterine bleeding is altered neuroendocrinologic functioning. In younger patients, this is usually due to immaturity of the hypothalamic-pituitary-ovarian (HPO) axis, but in older women this is a result of HPO axis dysregulation occurring near ovarian failure, or menopause.7,8 In these cases, unopposed estrogen release causes endometrial hyperplasia and inhibition of prostaglandins, thereby reducing platelet activation.8 Anovulatory bleeding manifests with several patterns depending on HPO axis fluctuations. Polycystic ovarian disease is the most common cause of anovulatory bleeding.

Ovulatory bleeding, on the other hand, manifests as prolonged menstruation in the absence of any organic causes.7 The etiology relates to overproduction of prostacyclins which leads to reduced platelet adhesion and uterine contractility. Ovulatory bleeding can be managed with a number of agents, including estrogens and progestogens, non-steroidal anti-inflammatory drugs, tranexamic or aminocaproic acid, danazol, or gonadotropin-releasing hormone agonists.

In contrast, diseases of the reproductive tract are not managed with progestogens.7 In fact, certain hormonal and nonhormonal contraceptive therapies can actually induce uterine bleeding. Reproductive causes of abnormal uterine bleeding include endometrial and cervical cancer, estrogen-producing tumors in the ovaries, anatomic abnormalities of the uterus, and the most common cause – accidents of pregnancy. Specific therapies exist to target these issues, based on their etiology.

Management of postpartum hemorrhage

The most common etiology of postpartum hemorrhage is uterine atony, which is a lack of natural contraction that normally occurs after placental delivery in order to control bleeding.1 Other causes include retained placenta, coagulation diseases, infection, and lacerations. Pharmacologic therapy with uterotonics is first-line therapy for uterine atony. Correction of coagulopathy may be the best approach if this is the determined etiology of the hemorrhage. Physical uterine maneuvers can be used to aid in controlling the bleeding temporarily while preparation for fluid and blood resuscitation can be made.

Utilization of medroxyprogesterone in any formulation is not mentioned in the American College of Obstetrics and Gynecology (ACOG) and World Health Organization (WHO) guidelines for postpartum bleeding.9,10 According to WHO, the uterotonic oxytocin, given intravenously or intramuscularly, is strongly recommended for prevention of postpartum hemorrhage in both vaginal and Caesarian deliveries.9 If oxytocin is not available, agents such as misoprostol (Cytotec), methylergonovine (Methergine) or prostaglandin F-2α (Hemabate) may be used. In the setting of refractory persistent or trauma related bleeding, tranexamic acid may be considered, though the evidence for this recommendation was only in trauma settings. According to ACOG, excessive bleeding despite oxytocin requires the addition of methylergonovine or prostaglandin F2α directly into the uterus.10 In both guidelines, surgical interventions should only be made if pharmacological management fails.9,10 A recent Cochrane review from November 2013 concluded that there is strong evidence for using oxytocin prophylactically when compared to no prophylaxis at all.2 Compared to ergot alkaloids, oxytocin is still preferred due to less maternal gastrointestinal side effects.

Conclusion

Abnormal uterine bleeding is a term that encompasses reproductive, systemic, anovulatory, and ovulatory types. The treatment approach differs based on the etiology. Although medroxyprogesterone is appropriate to use for abnormal uterine bleeding, its benefit is limited to such bleeding caused by non-organic triggers in nonpregnant patients. Medroxyprogesterone is not an appropriate therapy for uterine bleeding from organic causes such as postpartum hemorrhage, since these are usually not hormonal in nature. Postpartum hemorrhage is most commonly caused by uterine atony, so uterotonics are the mainstay of treatment.

References

1. Francois KE, Foley MR. Antepartum and postpartum hemorrhage. In: Gabbe ST, Niebyl JR, Simpson JL, et al, eds. Obstetrics: Normal and Problem Pregnancies. 6th ed. St. Louis, MO: Saunders; 2012. http://www.mdconsult.com/books/about.do?about=true&eid=4-u1.0-B978-1-4377-1935-2..C2009-0-44892-X–TOP&isbn=978-1-4377-1935-2&uniqId=430625157-2 . Accessed November 19, 2013.

2. Westhoff G, Cotter AM, Tolosa JE. Prophylactic oxytocin for the third stage of labour to prevent postpartum haemorrhage. Cochrane Database Syst Rev. 2013;10:CD001808.

3. Micromedex Healthcare Series [database online]. Greenwood Village, CO: Thomson Reuters (Healthcare), Inc; 2013. http://www.thomsonhc.com/hcs/librarian. Accessed November 19, 2013.

4. Provera [package insert]. New York, NY: Pfizer Inc; 2013.

5. depo-subQ provera 104 [package insert]. New York, NY: Pfizer Inc; 2013.

6. Depo-Provera [package insert]. New York, NY: Pfizer Inc; 2013.

7. Lobo RA. Abnormal uterine bleeding. In: Lentz GM, Lobo RA, Gershenson DM, Katz VL, eds. Comprehensive Gynecology. 6th ed. Philadelphia, PA: Mosby; 2012. http://www.mdconsult.com/books/about.do?about=true&eid=4-u1.0-B978-0-323-06986-1..C2009-0-48752-X–TOP&isbn=978-0-323-06986-1&uniqId=430625157-2 . Accessed November 19, 2013.

8. Cirilli AR, Cipot SJ. Emergency evaluation and management of vaginal bleeding in the nonpregnant patient. Emerg Med Clin North Am. 2012;30(4):991-1006.

9. WHO recommendations for the prevention and treatment of postpartum haemorrhage. The WHO Reproductive Health Library website. http://apps.who.int/rhl/guidelines/postpartum_haemorrhage/en/index.html . Accessed November 19, 2013.

10. American College of Obstetricians and Gynecologists. ACOG practice bulletin: clinical management guidelines for obstetrician-gynecologists number 76, October 2006: postpartum hemorrhage. Obstet Gynecol. 2006;108(4):1039-1047.

December 2013

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Can dexmedetomidine be used off-label in the management of

alcohol withdrawal syndromes?

Introduction

Alcohol withdrawal syndrome (AWS) is a major cause of morbidity and healthcare utilization.1 It is estimated that 500,000 episodes of AWS severe enough to require pharmacologic treatment occur each year, and approximately 20% of inpatients are admitted with AWS.2,3 Management of AWS focuses on symptom alleviation and prevention of neurologic complications through use of sedative-hypnotic agents such as benzodiazepines (BZDs). 2,4 A growing body of literature describes the use of the α2-receptor agonist dexmedetomidine in AWS. It is currently approved by the Food and Drug Administration (FDA) for sedation of mechanically ventilated intensive care unit (ICU) patients and procedural sedation of nonintubated patients for up to 24 hours.5 The purpose of this article is to review the mechanism, supporting data, and recommendations for the off-label use of dexmedetomidine in AWS.

Pathophysiology and management of AWS

Chronic users of alcohol adapt to its central nervous system (CNS) depressant effects by developing insensitivity to the major stimulatory neurotransmitter gamma-aminobutyric acid (GABA) and hypersensitivity to the major excitatory neurotransmitter glutamate.2 Thus, cessation of chronic alcohol consumption in an adapted user leads to CNS hyperexcitation due to disrupted GABA signaling and rebound increases in glutamate concentrations.6 This manifests as AWS, which can result in seizures, delirium tremens, and alcohol withdrawal delirium (AWD), the most severe form of AWS.2,4,7 To treat symptoms of this hyperexcited state, BZDs have been used as standard therapy due to their augmentation of the inhibitory effects of GABA. 6,8,9 While effective, concerns with BZDs include the risk of drug-induced delirium and GABA-mediated respiratory depression, the latter of which may require mechanical ventilation.10 Similarly, other CNS-depressing drugs, such as propofol or barbiturates, may be beneficial in BZD-refractory AWS.4 However, respiratory depression requiring mechanical ventilation may occur with these as well, and propofol has been associated with hypertriglyceridemia and infusion reactions.11

Other adaptations to chronic alcohol ingestion include downregulation of α2-receptors.9 Activation of α2-receptors completes a negative feedback loop to decrease further release of norepinephrine. Therefore, α2-receptor agonists such as dexmedetomidine are believed to alleviate hyperexcitation in patients with AWS and offer benefit as adjunctive therapy. Favorable properties of dexmedetomidine include its absence of GABAergic effects, obviating the need for mechanical ventilation.12 Nonetheless, concern still remains regarding dose- and duration-dependent adverse effects, such as bradycardia and tachyphylaxis, which are believed to occur with bolus administration and infusions longer than 24 hours, respectively. Despite its promising properties, little data have described the off-label use of dexmedetomidine in patients with AWS.

Literature review

The only published prospective data on dexmedetomidine use in patients with AWS comes from one analysis, though it provides limited insight on efficacy. 13 Eighteen patients with AWD received dexmedetomidine as adjunctive therapy to oral or intravenous diazepam, lorazepam, or haloperidol or as monotherapy if any of these were not tolerated. The mean ± standard deviation (SD) maximum infusion rate of dexmedetomidine was 1.5 ± 1.2 mcg/kg/h. Descriptive analyses found the mean ± SD time to resolution of AWD was 3.8 ± 1.3 days, while length of ICU stay was 7.1 ± 2.7 days. Richmond Agitation Sedation Scale (RASS) scores decreased from a mean ± SD of 1.4 ± 1.5 at initiation of dexmedetomidine to 0.3 ± 1.4 twenty-four hours later. The maximum infusion duration and rate were 75 hours and 4.6 mcg/kg/h, respectively, which is well beyond the FDA-approved maximum infusion duration (24 hours) and rate (0.7 mcg/kg/h). Eleven patients experienced at least 1 of the predefined complications, including pneumonia, other infection, respiratory failure, and noninvasive ventilation. No patients experienced bradycardia, but tachyphylaxis was not assessed. While these findings provide some data on the safety of dexmedetomidine in AWD, limited information on efficacy is gained as no hypothesis testing was performed.

A retrospective evaluation statistically compared measurements 24 hours before and after dexmedetomidine administration in ICU patients with AWS. 6 This review analyzed 20 patients who received dexmedetomidine at a mean infusion rate of 0.53 mcg/kg/h (95% confidence interval, 0.44 to 0.62 mcg/kg/h). After 24 hours of dexmedetomidine administration, statistically significant percent decreases occurred for mean values of alcohol withdrawal score (21.1%), dose of BZD received (61.5%), heart rate (HR; 22.8%), systolic blood pressure (SBP; 9.6%), hours with HR >100 bpm (22.8%), and hours with SBP >140 mm Hg (42.3%). Confidence in the clinical significance of these differences should be scrutinized, though, as intervals were wide due to the small sample. Specifically, conclusions on improvement in AWS severity score lacks external validity, as scores were determined from a scale less validated and widely used than the Ramsay and RASS scales.14 Additionally, analysis of this outcome was limited to 11 of the 20 patients who had complete scoring data. While this comparison sheds more light on efficacy, safety concerns were apparent, as 2 occurrences of asystole occurred in a patient who received an average dexmedetomidine infusion rate of 0.75 mcg/kg/h.

Other than the literature described above, use of dexmedetomidine used in AWS is limited to smaller case series and case reports.12,15-19 The majority of these reported positive outcomes with few major safety concerns. However, most patients did not receive bolus loading doses and were treated for approximately 3 or fewer days, which may contribute to positive conclusions of safety.

Place in therapy

Despite the growing body of literature, significant questions still remain regarding the evidence-based use of dexmedetomidine in AWS. Appropriate candidates appear to be those with AWS that is severe, complicated, or refractory to BZD treatment, as these are the typical patients represented by published literature. In contrast, the optimal dosage of dexmedetomidine in AWS is unclear, as infusion rates have varied from 0.2 to 4.6 mcg/kg/h. 13 Furthermore, patients have shown successful responses as well as adverse events along this entire dosage range. Lastly, the maximum FDA-approved duration of dexmedetomidine infusion is 24 hours, but the longest reported infusion duration in AWS was 8 days in a patient with traumatic brain injury and refractory agitation.5,16 However, the majority of reports described a duration of use of 3 or fewer days. 12,13,15,17,19

More definitive guidance on the use of dexmedetomidine in AWS should emerge with the publication of 2 prospective, randomized controlled trials (RCTs). 20,21 One completed, but unpublished, trial in ICU patients with severe AWS evaluated adjunctive dexmedetomidine at 0.4 and 1.2 mcg/kg/h for up to 5 days for the primary outcome of need for other sedative, analgesic, or neuroleptic treatment.20 Another ongoing trial in critically ill patients with severe AWS and AWD will evaluate dexmedetomidine at 1.4 mcg/kg/h for the primary outcome of length of ICU stay.21 These RCTs will provide the first prospective data from controlled intervention with dexmedetomidine in AWS.

Conclusion

Current literature describing the use of dexmedetomidine in AWS is limited. One prospective observational analysis and 1 retrospective comparison study suggest dexmedetomidine may decrease scores on agitation scales. However, the totality of literature indicates that patients with AWS may respond to, as well as experience, adverse events with a wide range of dexmedetomidine infusion rates and durations. Based on current literature, judicious use of dexmedetomidine in AWS may be limited to patients with severe or refractory AWS for the shortest required duration at the minimum effective infusion rate. Future RCTs should provide more data on the safety and efficacy of dexmedetomidine in AWS at doses and durations beyond those listed in its FDA-approved product labeling.

References

1. Nelson LS, Gold JA. Chapter 78. Ethanol Withdrawal. In: Nelson LS, Gold JA, eds. Goldfrank's Toxicologic Emergencies. 9th ed. New York: McGraw-Hill; 2011. http://www.accesspharmacy.com/content.aspx?aID=6521734. Accessed October 30, 2013.

2. Hoffman RS. Weinhouse GL. Management of moderate and severe alcohol withdrawal syndromes. In: Basow DS, ed. UpToDate. Waltham, MA: UpToDate; 2013.

3. Powell JE, Mcinness E. Alcohol use among older hospital patients: findings from an Australian study. Drug Alcohol Rev. 1994;13(1):5-12.

4. Mayo-smith MF, Beecher LH, Fischer TL, et al. Management of alcohol withdrawal delirium. An evidence-based practice guideline. Arch Intern Med. 2004;164(13):1405-1412.

5. Precedex [package insert]. Lake Forest, IL: Hospira, Inc.; 2012.

6. Rayner SG, Weinert CR, Peng H, Jepsen S, Broccard AF. Dexmedetomidine as adjunct treatment for severe alcohol withdrawal in the ICU. Ann Intensive Care. 2012;2(1):12. doi: 10.1186/2110-5820-2-12.

7. Mckeon A, Frye MA, Delanty N. The alcohol withdrawal syndrome. J Neurol Neurosurg Psychiatr. 2008;79(8):854-862.

8. Mihic SJ, Harris RA. Chapter 17. Hypnotics and Sedatives. In: Chabner BA, Knollmann BC, eds. Goodman & Gilman's The Pharmacological Basis of Therapeutics. 12nd ed. New York: McGraw-Hill; 2011. http://www.accesspharmacy.com/content.aspx?aID=16663643. Accessed November 1, 2013.

9. Muzyk AJ, Fowler JA, Norwood DK, Chilipko A. Role of α2-agonists in the treatment of acute alcohol withdrawal. Ann Pharmacother. 2011;45(5):649-657.

10. Rothberg MB, Herzig SJ, Pekow PS, Avrunin J, Lagu T, Lindenauer PK. Association between sedating medications and delirium in older inpatients. J Am Geriatr Soc. 2013;61(6):923-930.

11. Mccowan C, Marik P. Refractory delirium tremens treated with propofol: a case series. Crit Care Med. 2000;28(6):1781-1784.

12. Darrouj J, Puri N, Prince E, Lomonaco A, Spevetz A, Gerber DR. Dexmedetomidine infusion as adjunctive therapy to benzodiazepines for acute alcohol withdrawal. Ann Pharmacother. 2008;42(11):1703-1705.

13. Tolonen J, Rossinen J, Alho H, Harjola VP. Dexmedetomidine in addition to benzodiazepine-based sedation in patients with alcohol withdrawal delirium. Eur J Emerg Med. 2013;20(6):425-427.

14. Ely EW. Chapter 62. Delirium in the Intensive Care Unit. In: Hall JB, Schmidt GA, Wood LD, eds. Principles of Critical Care. 3rd ed. New York: McGraw-Hill; 2005. http://www.accessmedicine.com/content.aspx?aID=2292550. Accessed October 30, 2013.

15. Rovasalo A, Tohmo H, Aantaa R, Kettunen E, Palojoki R. Dexmedetomidine as an adjuvant in the treatment of alcohol withdrawal delirium: a case report. Gen Hosp Psychiatry. 2006;28(4):362-363.

16. Tang JF, Chen PL, Tang EJ, May TA, Stiver SI. Dexmedetomidine controls agitation and facilitates reliable, serial neurological examinations in a non-intubated patient with traumatic brain injury. Neurocrit Care. 2011;15(1):175-181.

17. Maccioli GA. Dexmedetomidine to facilitate drug withdrawal. Anesthesiology. 2003;98(2):575-577.

18. Demuro JP, Botros DG, Wirkowski E, Hanna AF. Use of dexmedetomidine for the treatment of alcohol withdrawal syndrome in critically ill patients: a retrospective case series. J Anesth. 2012;26(4):601-605.

19. Muzyk AJ, Revollo JY, Rivelli SK. The use of dexmedetomidine in alcohol withdrawal. J Neuropsychiatry Clin Neurosci. 2012;24(3):E45-46.

20. Dexmedetomidine as Adjunctive Therapy for Alcohol Withdrawal (DATA). Clinicaltrials.gov website. http://clinicaltrials.gov/ct2/show/NCT00936377?term=dexmedetomidine+alcohol&rank=2. Updated November 20, 2012. Accessed October 31, 2013.

21. Dexmedetomidine (Precedex®) for Severe Alcohol Withdrawal Syndrome (AWS) and Alcohol Withdrawal Delirium (AWD). Clinicaltrials.gov website. http://clinicaltrials.gov/ct2/show/NCT01362205?term=dexmedetomidine+alcohol&rank=1. Updated July 24, 2013. Accessed October 30, 2013.

December 2013

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