Pharmacokinetic properties of intranasal and injectable formulations of naloxone for community use: a systematic review
2018; Future Medicine; Volume: 8; Issue: 3 Linguagem: Inglês
10.2217/pmt-2017-0060
ISSN1758-1877
Autores Tópico(s)Poisoning and overdose treatments
ResumoPain ManagementVol. 8, No. 3 Systematic ReviewOpen AccessPharmacokinetic properties of intranasal and injectable formulations of naloxone for community use: a systematic reviewShawn A Ryan & Robert B DunneShawn A Ryan*Author for correspondence: Tel.: +1 513 834 7063; Fax: +1 513 873 1567; E-mail Address: s.ryan@brightviewhealth.com Department of Emergency Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, 45267 USA BrightView Health, Cincinnati, OH, 45206 USA & Robert B Dunne Department of Emergency Medicine, Wayne State University School of Medicine, Detroit, MI, 48202 USAPublished Online:23 Apr 2018https://doi.org/10.2217/pmt-2017-0060AboutSectionsView ArticleView PDFView PDF Plus ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinkedInRedditEmail View articleAbstractAim: To assess the pharmacokinetic properties of community-use formulations of naloxone for emergency treatment of opioid overdose. Methods: Systematic literature review based on searches of established databases and congress archives. Results: Seven studies met inclusion criteria: two of US FDA-approved intramuscular (im.)/subcutaneous (sc.) auto-injectors, one of an FDA-approved intranasal spray, two of unapproved intranasal kits (syringe with atomizer attachment) and two of intranasal products in development. Conclusion: The pharmacokinetics of im./sc. auto-injector 2 mg and approved intranasal spray (2 and 4 mg) demonstrated rapid uptake and naloxone exposure exceeding that of the historic benchmark (0.4 mg im.), indicating that naloxone exposure was adequate for reversal of opioid overdose.Keywords: auto-injectorbioavailabilitycommunity usedrug overdoseintramuscularintranasalnaloxonenasal spraypharmacokineticsreversalPractice pointsThe US FDA has approved two naloxone products for use by laypersons in community settings for emergency treatment of known or suspected opioid overdose: an intranasal spray with a concentrated naloxone dose of 2 or 4 mg in 0.1 ml and an auto-injector for intramuscular (im.) or subcutaneous (sc.) use with a naloxone dose of 0.4 or 2 mg.In the absence of head-to-head, comparative efficacy studies, which are not feasible for ethical and logistical reasons, pharmacokinetic data provide important information about effective doses and routes of administration of naloxone for opioid overdose reversal.In pharmacokinetic studies, both the approved intranasal spray and the im./sc. auto-injector demonstrated bioequivalence with a previously approved formulation, indicating that naloxone exposure was adequate to reverse an opioid overdose.Both the approved intranasal spray and the im./sc. auto-injector demonstrated sufficient plasma exposure within the first 15–20 min after administration.Usability studies with laypersons in simulated overdose conditions have found that more than 90% of participants were able to successfully administer naloxone using the approved intranasal spray or im./sc. auto-injector without prior training; however, these studies have identified critical errors with the proper assembly and use of unapproved intranasal kits, even when training had been provided.Approved intranasal naloxone is appropriate for most patients, with the exception of those with known nasal pathology (e.g., polyps and chronic intranasal drug use).Providing prescriptions for community-use naloxone may reduce future risk in patients who are receiving chronic opioid therapy for pain control or who have histories of illicit opioid use.BackgroundDrug poisoning is the leading cause of accidental death in the USA and is driven largely by overdose of prescription or illicit opioids [1–3]. From 2000 to 2014, the rate of opioid-related (e.g., prescription analgesics and heroin) overdose deaths tripled [2], with a further increase of 16% observed from 2014 to 2015 [3]. A sharp increase was noted in overdose deaths related to fentanyl and fentanyl derivatives, potent synthetic opioid analgesics that can be manufactured or purchased illicitly [4–6]. Of 52,404 deaths caused by drug overdose in the USA in 2015, 63.1% (33,091 deaths) involved an opioid [3].Each year, there are more than one million emergency department visits for drug poisoning in the USA [7]. From 2008 through 2011, 14% of emergency department visits for unintentional overdose were opioid related [7]. An analysis of the 2010 Nationwide Emergency Department Sample found that 67.8% of emergency department visits for opioid overdose involved prescription opioids, and 16.1% involved heroin (13.4% were unspecified and 2.7% involved multiple opioid types) [8].ImportanceSince its introduction more than 40 years ago, the opioid antagonist naloxone has been used to reverse respiratory and central nervous system depression resulting from opioid overdose [9]. Until 2014, naloxone was approved by the US FDA only in injectable formulations for use by trained healthcare professionals [10]. In response to the increase in fatalities caused by opioid overdose, government agencies and community organizations have worked to establish wider access to naloxone [11–13]. Unapproved intranasal kits contain an injectable formulation of naloxone (e.g., prefilled syringe); to enable intranasal administration, the user must first attach an atomizer (manufactured by another company but provided in the kit) to the syringe [14]. Such kits have been increasingly available for public use [14] and have been employed successfully by first responders (e.g., emergency medical service personnel, police officers and bystanders) to reverse opioid overdose [15–20]. Although these products are FDA approved as injectables, they are not FDA approved for intranasal administration when included in a kit with an atomizer. Furthermore, little data have been collected on the bioavailability of naloxone when administered using these unapproved intranasal kits [14]. Importantly, human factors studies have found that many laypersons (i.e., individuals with no medical training) were unable to employ unapproved intranasal kits correctly, even after training [21,22]. For example, a prospective usability study of 42 healthy adults found that no participants (0%) could successfully administer a dose of naloxone using an unapproved intranasal kit before training, and fewer than 60% of participants were able to successfully administer a dose of naloxone using this kit after receiving training [21].The FDA has approved two naloxone products for use by laypersons in community settings for emergency treatment of known or suspected opioid overdose: an auto-injector for intramuscular (im.) or subcutaneous (sc.) use with a naloxone dose of 0.4 or 2 mg (EVZIO®; Kaléo, Inc., VA, USA) [23,24] and an intranasal spray with a concentrated naloxone dose of 2 or 4 mg in 0.1 ml (NARCAN®; Adapt Pharma, Inc., PA, USA) [25]. The efficacy of naloxone for reversing opioid overdose is well established; therefore, FDA approval of these products was based on other data, including: compliance with good manufacturing practice requirements for combination products (drug + device) [26], human factors studies demonstrating label comprehension and ease of use [27,28] and pharmacokinetic studies demonstrating adequate bioavailability [27].Goals of this investigationThe purpose of this systematic review is to summarize the pharmacokinetic properties of formulations of naloxone for community use (i.e., formulations currently available or in commercial development for use by laypersons for opioid overdose reversal) as a means for understanding the speed of onset, adequacy and duration of the clinical effects. With the increasing availability of highly potent synthetic opioids, the naloxone dose required to reverse opioid overdose has increased, and multiple dosing has also become common [29,30]. Consequently, the approved naloxone products and products in development offer larger naloxone doses in the devices. Therefore, it is important to evaluate the pharmacokinetic properties of these new formulations to understand their potential role in highly potent opioid overdose reversal. A secondary aim is to establish selection of optimal naloxone product based on patient-specific and product-specific factors such as route of administration, formulation and dosing considerations for community use. Community-use formulations include the im./sc. auto-injector, approved intranasal spray, unapproved intranasal kits and intranasal in-development products.MethodsSearches of the MEDLINE and Embase® databases were conducted on 9 November 2017. Search terms included 'naloxone' and ('pharmacokinetic' OR 'pharmacokinetics'), with the dates of publication set as 2000 to present. Congress programs and abstract archives from January 2012 through October 2017 were accessed online for scientific meetings of pain medicine (American Academy of Pain Medicine and PAINWeek), addiction medicine (American Society of Addiction Medicine and Society for the Study of Addiction) and emergency medicine (American College of Emergency Physicians, National Association of EMS Physicians and Society for Academic Emergency Medicine) professionals. These scientific meetings were selected for review based on the authors' clinical and research expertise and the volume of material presented at these conferences relevant to the topic. Abstract and presentation titles were searched electronically for 'naloxone'. In addition, briefing documents from the 2016 FDA advisory committee meeting on naloxone and FDA product labels for naloxone products for community use were hand searched for pharmacokinetic studies not reported in other published or congress sources.This review included original research studies that were published in English and that reported prespecified pharmacokinetic parameters for a community-use formulation of naloxone administered to either human volunteers or patients. The PRISMA guidelines checklist was followed to comply with the systematic review methodology. Prespecified pharmacokinetic variables included maximum plasma concentration (Cmax; ng/ml), time to Cmax (tmax; hours), area under the plasma concentration–time curve (AUC; ng•h/ml), terminal elimination half-life (t½; hours) and bioavailability (%). Cmax and AUC assess peak and overall drug exposure, respectively. Tmax is an indicator of the speed of onset, whereas t½ is an indicator of the duration of effect. Most studies with AUC data reported AUC from baseline extrapolated to infinity (AUC0-∞); therefore, AUC0-∞ was selected as the primary assessment of total naloxone exposure. If AUC0-∞ was not reported, AUC from baseline to the last measurable concentration (AUC0-t) was used. Relative bioavailability was based on AUC0-∞ data unless otherwise specified. For the prespecified pharmacokinetic variables, measures of central tendency (mean, geometric mean and median) and variability (percent coefficient of variation, 95% CI and range) were extracted from each study report and summarized. Pharmacokinetic variables reported in units that differed from those described above were converted as appropriate.ResultsThe literature search and study selection are described in Figure 1 [24,31–37]. Seven studies were included in this review [24,31–36]. Three studies with naloxone pharmacokinetic data [38–40] were excluded because they used study-specific, investigator-compounded agents that did not represent formulations or doses currently available for community use (or in development for community use). Table 1 provides a summary of the study designs and formulations/doses used. Naloxone pharmacokinetic data were obtained from two studies of im./sc. auto-injector, one study of the approved intranasal product, two studies of unapproved intranasal kits and two studies of intranasal products in development. Results for the prespecified pharmacokinetic variables (Cmax, tmax, AUC, t½ and bioavailability) from each study are shown in Table 2 [24,31–36].Figure 1. Flow chart of study selection.†One study was initially included in the systematic review based on information presented as a poster [37]; however, this study was published after the search was performed [35].iv.: Intravenous; PI: Prescribing information; PK: Pharmacokinetic.Table 1. Summary of included studies.Naloxone formulationStudy (year)Naloxone dose(s)Comparator product(s)Study designNRef.US FDA-approved formulations for community useim./sc. auto-injector (EVZIO®)Edwards et al. (2015)0.4 mg (midanterolateral thigh)0.4-mg im. standard syringe and needle (midanterolateral thigh)R, single-blind, single-dose, 2-period, 2-sequence, crossover30 healthy adult volunteers[31]im./sc. auto-injector (EVZIO®)Product PI0.4 mg (1 injection)0.8 mg (2 injections of 0.4 mg administered 2 min apart)2 mg (1 injection)–Crossover (other design details not specified)24 healthy volunteers (age not specified)[24]Approved intranasal (NARCAN®)Krieter et al. (2016)2 mg (1 spray of 2 mg/0.1 ml)4 mg (1 spray of 4 mg/0.1 ml)4 mg (1 spray of 2 mg/0.1 ml in each nostril)8 mg (1 spray of 4 mg/0.1 ml in each nostril)0.4-mg im. standard syringe and needle (0.4 mg/1 ml, gluteus maximus)R, OL, 5-period, 5-treatment, 5-sequence, crossover30 healthy adult volunteers[32]Unapproved intranasal kitsUnapproved intranasal (LMA® MAD Nasal™)†Edwards et al. (2016)2 mg (1 mg/ml in each nostril)2-mg im. standard syringe and needle (1 mg/1 ml in each thigh)R, OL, single-dose, 3-period, crossover36 adults with chronic rhinitis but no significant nasal abnormalities, surgery, polyps or trauma[33]Unapproved intranasal (MAD)‡Dowling et al. (2008)0.8 mg (1 spray of 0.4 mg/1 ml in each nostril)2 mg (1 spray of 1 mg/2.5 ml in each nostril)0.8-mg iv.2-mg iv.0.8-mg im. standard syringe and needle (gluteus maximus)OL, crossover6 healthy adult volunteers[34]Community-use formulations in developmentIntranasal in development (Mundipharma)McDonald et al. (2017)1 mg (1 spray of 1 mg/0.1 ml)2 mg (1 spray of 2 mg/0.1 ml)4 mg (2 sprays of 2 mg/0.1 ml)0.4-mg im. standard syringe and needle (primary reference; deltoid muscle)0.4-mg iv.R, OL, 5-way, crossover38 healthy adult volunteers[35]Intranasal in development (dne pharma)Tylleskar et al. (2017)0.8 mg (1 spray of 0.8 mg/0.1 ml)1.6 mg (2 sprays of 0.8 mg/0.1 ml)1.0-mg iv.R, OL, 3-way crossover12 healthy adult volunteers[36]†Teleflex, Inc. NC, USA.‡Wolf-Tory Medical, UT, USA.im.: Intramuscular; iv.: Intravenous; LMA: Laryngeal mask airway; MAD: Mucosal atomizer device; OL: Open label; PI: Prescribing information; R: Randomized; sc.: Subcutaneous.Table 2. Pharmacokinetic parameters for community-use formulations of naloxone.Naloxone formulationNMean (%CV) Cmax, ng/mlMean (%CV) AUC0-∞, ng•h/mlMedian (range) tmax, hMean (%CV) t1/2, hBioavailability, %US FDA-approved formulations for community useim./sc. auto-injector naloxone0.4-mg dose [31]301.2 (51.4)1.9 (23.4)0.25 (0.08–1.23)1.3 (38.0)98.3†0.4-mg dose [24]241.3 (62.9)2.0 (16.3)0.25 (0.09–0.84)1.6 (28.9)NA0.8-mg (two 0.4-mg) dose [24]242.2 (47.4)3.8 (19.1)0.21 (0.09–0.85)1.5 (23.7)NA2-mg dose [24]247.9 (45.8)10.3 (15.2)0.25 (0.13–0.67)1.5 (25.0)NAApproved intranasal spray [32]2 mg (1 spray of 2 mg/0.1 ml)293.1 (36.1)4.7 (29.8)0.3 (0.3–1.0)1.9 (34.6)51.9†4 mg (1 spray of 4 mg/0.1 ml)295.3 (44.6)8.5 (39.0)0.5 (0.2–1.0)2.2 (29.1)46.2†4 mg (2 sprays of 2 mg/0.1 ml)296.5 (32.3)9.7 (26.7)0.3 (0.2–0.6)2.4 (31.7)53.5†8 mg (2 sprays of 4 mg/0.1 ml)2910.3 (38.1)15.8 (23.1)0.3 (0.2–1.0)2.2 (39.0)43.9†Unapproved intranasal kitsUnapproved intranasal [33]2 mg/2 ml‡36§1.3 (48.3)1.5 (31.6)0.25 (0.07–0.68)1.5 (18.5)14.6¶2 mg/2 ml‡ + vasoconstrictor#36§0.7 (52.0)1.1 (35.1)0.33 (0.08–1.00)1.5 (22.9)11.1¶Community-use formulations in developmentIntranasal in development (Mundipharma) [35]1 mg (1 spray of 1 mg/0.1 ml)321.5†† (50.2)2.7†† (40.5)0.25 (0.2–1.0)1.3 (NA)50.8†2 mg (1 spray of 2 mg/0.1 ml)322.9†† (49.6)5.0†† (38.5)0.5 (0.1–1.0)1.4 (NA)47.1†4 mg (2 sprays of 2 mg/0.1 ml)326.0†† (54.5)10.1†† (35.8)0.25 (0.2–1.0)1.7 (NA)48.3†Intranasal in development (dne pharma) [36]0.8 mg (1 spray of 0.8 mg/ml)121.4 (1.1–1.8)‡‡1.6 (1.3–2.0)‡‡§§0.3 (0.2–0.4)††1.5 (1.3–1.7)††54¶¶1.6 mg (2 sprays of 0.8 mg/ml)112.6 (1.5–3.7)‡‡3.1 (2.0–4.1)‡‡§§0.3 (0.2–0.4)††1.3 (1.1–1.5)††52¶¶†Relative to 0.4-mg im. standard syringe/needle.‡1 mg/ml in each nostril using the LMA® MAD Nasal™ atomizer.§Adults with chronic rhinitis; all other studies were of healthy adults.¶Relative to 2-mg im. standard syringe/needle (1 mg in each thigh).#Oxymetazoline HCl 0.05% nasal solution (Afrin®).††Geometric mean.‡‡Data shown as mean (95% CI).§§AUC0-t.¶¶Relative to 1.0-mg iv., based on AUC0-t.%CV: Percent coefficient of variation; AUC0-∞: Area under the plasma concentration–time curve from baseline extrapolated to infinity; AUC0-t: Area under the plasma concentration–time curve from baseline to the last measurable concentration; Cmax: Time concentration; im.: Intramuscular; iv.: Intravenous; LMA: Laryngeal mask airway; MAD: Mucosal atomizer device; NA: Not available; sc.: Subcutaneous; t1/2: Terminal elimination half-life; tmax: Time to maximum plasma concentration.FDA-approved products for community useNaloxone pharmacokinetics for the im./sc. auto-injector were evaluated in two studies that varied with regard to the naloxone doses included. A study of 30 healthy volunteers assessed 0.4 mg of naloxone via im./sc. auto-injector, with 0.4 mg of naloxone im. via standard syringe and needle as the reference product [31]. Pharmacokinetic parameters of the im./sc. auto-injector and im. syringe and needle were similar for mean Cmax (1.2 and 1.1 ng/ml, respectively), median tmax (0.25 and 0.33 h, respectively), mean AUC0-∞ (1.9 and 2.0 ng•h/ml, respectively) and mean t½ (1.3 and 1.4 h, respectively). The relative bioavailability of naloxone for the im./sc. auto-injector compared with im. syringe and needle was 98.3% (Table 2).A separate study of 24 healthy volunteers evaluated im./sc. auto-injector doses of 0.4, 0.8 mg (administered as two injections of 0.4 mg) and 2 mg [24]. Mean Cmax and AUC0-∞ were dose proportional (Table 2) [24]. Median tmax and mean t½ were similar across doses.Naloxone pharmacokinetics for the approved intranasal spray were evaluated at various doses (2 mg [1 spray], 4 mg [as 1 or 2 sprays] and 8 mg [2 sprays]) in a study of 30 healthy volunteers, with 0.4 mg of naloxone im. via standard syringe and needle as the reference product [32]. Mean Cmax and AUC0-∞ were dose proportional for the approved intranasal spray (Table 2). Mean Cmax, AUC0-∞ and t½ were greater for all doses of the approved intranasal spray compared with the im. reference. Mean Cmax was 3.1 and 5.3 ng/ml, respectively, for the approved intranasal (single spray) 2 and 4 mg, compared with 0.9 ng/ml for the im. reference (Figure 2) [32]. Mean AUC0-∞ was 4.7 and 8.5 ng•h/ml, respectively, for the approved intranasal (single spray) 2 and 4 mg, compared with 1.8 ng•h/ml for the im. reference. In addition, the mean t½ was 1.9 and 2.2 h, respectively, for the approved intranasal (single spray) 2 and 4 mg, compared with 1.3 h for the im. reference. Median tmax was generally similar for the approved intranasal spray (0.3–0.5 h) and im. reference (0.4 h). Early-stage plasma concentrations for the 4-mg dose of the approved intranasal spray relative to the im. reference are shown in Figure 3 [25]. Compared with im. administration, the relative bioavailability of naloxone for the approved intranasal spray was 51.9% for 2 mg, 46.2% for 4 mg administered in one spray, 53.5% for 4 mg administered in two sprays of 2 mg and 43.9% for 8 mg (administered in two sprays of 4 mg).Figure 2. Mean naloxone plasma concentration–time curves for approved intranasal spray versus intramuscular standard syringe: overall.im.: Intramuscular.Reprinted with permission from [32] © John Wiley & Sons, Inc. (2016).Figure 3. Mean naloxone plasma concentration–time curves for approved intranasal spray versus intramuscular standard syringe: early-stage (0–1 h).Error bars represent standard deviation.im.: Intramuscular.Reprinted with permission from [25] © Adapt Pharma, Inc. (2017).Unapproved intranasal kitsA study of 36 adults with chronic rhinitis assessed a commercially available, unapproved intranasal kit (2-mg naloxone as 1 mg/ml in each nostril) compared with 2-mg im. (1 mg/ml in each thigh via standard needle and syringe) [33]. Cmax and AUC0-∞ were lower for the unapproved intranasal kit compared with the 2-mg im. (mean Cmax of 1.3 vs 4.5 ng/ml, respectively; mean AUC0-∞ of 1.5 vs 9.8 ng•h/ml, respectively) (Table 2) [33]; however, the im. reference dose was five-times greater than that used in other pharmacokinetic studies [31,32,35]. For both formulations, median tmax (0.25 h) and mean t½ (1.5 h) were similar. Relative bioavailability (which takes dose into account) was 14.6% for the unapproved intranasal compared with im. naloxone. The use of an intranasal vasoconstrictor (30 min prior) reduced the naloxone exposure obtained using the unapproved intranasal kit (Table 2).A study of six volunteers used a population-pharmacokinetic modeling and simulation approach to evaluate unapproved intranasal, im. and intravenous (iv.) delivery of naloxone (commercially available, 0.4 mg/ml) [34]. Pharmacokinetic parameters were not reported separately for each formulation, with the exception of relative bioavailability (derived from the modeling/simulation), which was 4% for unapproved intranasal compared with iv. administration. The relative bioavailability of im. versus iv. administration was 36%.Community-use formulations in developmentNaloxone pharmacokinetics for the two intranasal products in development were evaluated in one study each. A study of 38 healthy volunteers assessed an intranasal spray (Mundipharma) at doses of 1, 2 and 4 mg, with 0.4 mg of naloxone im. via standard syringe and needle as the primary reference product (and also 0.4-mg iv. naloxone) [35]. Geometric mean Cmax was 2.9 ng/ml for the 2-mg intranasal in-development product compared with 1.3 ng/ml for 0.4-mg im. (standard needle and syringe) and 5.9 ng/ml for 0.4-mg iv. (Figure 4) [35]. Also, geometric mean AUC0-∞ was 5.0 ng•h/ml for the 2-mg intranasal in-development product compared with 2.1 ng•h/ml for both the 0.4-mg im. (standard needle and syringe) and the 0.4-mg iv. product. Median tmax was somewhat longer for the 2-mg intranasal in-development product (0.5 h) compared with 0.4-mg im. (0.2 h) naloxone; whereas, mean t½ was similar (1.4 h for both). Early-stage plasma concentrations for the intranasal in-development product relative to the iv. and im. reference products are shown in Figure 5. Compared with im. administration, the bioavailability for intranasal in-development naloxone was 50.8% for 1 mg, 47.1% for 2 mg and 48.3% for 4 mg (administered as two sprays of 2 mg).Figure 4. Mean naloxone plasma concentration–time curves for intranasal formulation in-development, intramuscular standard syringe and intravenous administration: overall (2 h).Error bars represent standard deviation.im.: Intramuscular; iv.: Intravenous.Adapted with permission from [35] (2018) via a CreativeCommons Attribution-NonCommercial license.Figure 5. Mean naloxone plasma concentration–time curves for intranasal formulation in-development, intramuscular standard syringe and intravenous administration: early stage (20 min).Error bars represent standard deviation.im.: Intramuscular; iv.: Intravenous.Adapted with permission from [35] (2018) via a CreativeCommons Attribution-NonCommercial license.A different intranasal in-development product (manufactured by dne pharma) was assessed in 12 healthy volunteers; naloxone doses were 0.8 and 1.6 mg (2 sprays of 0.8 mg), with 1.0-mg iv. naloxone as the reference product [36]. Mean Cmax was 2.6 ng/ml for the 1.6-mg intranasal in-development product compared with 14.2 ng/ml for iv. administration (Figure 6) [36]. Mean AUC0-t was 3.1 ng•h/ml for intranasal in-development product 1.6 mg compared with 4.0 ng/ml for 1.0 mg iv. Mean tmax was longer for intranasal in-development product 1.6 mg (0.3 h) compared with iv. (0.04 h) naloxone; whereas, mean t½ was similar (1.3 and 1.2 h, respectively). Compared with iv. administration, the bioavailability for the intranasal in-development naloxone was 54% for the 0.8-mg dose and 52% for the 1.6-mg dose.Figure 6. Time course of plasma concentrations (mean [error bars 95% confidence interval]) of naloxone after intravenous (1.0 mg) and intranasal (0.8 and 1.6 mg) administration in healthy human volunteers (n = 12 for intravenous and intranasal 0.8 mg, n = 11 for intranasal 1.6 mg).Squares are the 0.8 mg intranasal, dots are the 1.6 mg intranasal and triangles are the 1.0 mg iv. [36].CI: Confidence interval; iv.: Intravenous.Adapted with permission from [36] © Springer (2017).DiscussionTwo naloxone products for community use have been approved by the FDA for emergency treatment of known or suspected opioid overdose, based on pharmacokinetic and human factors studies: an im./sc. auto-injector and a concentrated naloxone dose via an intranasal spray (no device assembly required) [23–25]. In the absence of head-to-head, comparative efficacy studies in the community-use setting, which are not feasible for ethical and logistical reasons, pharmacokinetic data provide important information about effective doses and routes of administration of naloxone for opioid overdose reversal.In pharmacokinetic studies, both the im./sc. auto-injector and the approved intranasal spray demonstrated bioequivalence with a previously approved formulation, indicating that naloxone exposure was adequate to reverse an opioid overdose [31,32]. By contrast, unapproved intranasal kits (syringe with atomizer attachment) using a commercially available naloxone solution intended for iv. use (0.4 mg/ml, 2 mg/2 ml [predominantly used]) have shown low bioavailability of naloxone relative to iv. (4%) [34] or im. (15%) [33] administration; additionally, the unapproved kits lack the label comprehension or human-use study data needed for FDA approval of a combination drug/device product. The poor bioavailability for the unapproved intranasal kits is likely related to the large volume of the solution that has to be atomized and absorbed in the nasal cavity, which may result in a loss of naloxone from the site of absorption (via drainage, either into the nasopharynx or externally) [41,42]. As a consequence of nasopharyngeal drainage, intranasal administration of a large volume of solution fails to bypass the extensive first-pass metabolism associated with oral administration of naloxone [43]. The approved intranasal spray addresses this issue by using a highly concentrated solution of naloxone such that the volume of each spray is only 0.1 ml [25]. Consistently, an explorative review integrating patent application data for noninjectable naloxone for opioid overdose and scientific publications reported that bioavailability of intranasal naloxone products has a positive association with dose and negative association with volume [44]. Although there are concerns of overantagonism with higher doses of naloxone resulting in severe withdrawal symptoms [45,46], the risk of inadequate reversal, especially with overdose of potent opioids such as fentanyl, is far greater than the risk of unpleasant opioid withdrawal reactions [46]. No studies have yet assessed the initial dose of naloxone required to reverse a fentanyl-related overdose.Rapid uptake of naloxone is critically important because opioid overdose may result in respiratory depression with hypoxia, which leads to cardiopulmonary arrest and long-term damage to the central nervous system or death [47]. The need for both rapid onset and adequate duration of the naloxone effect is especially significant in light of the increase in overdose deaths involving high-potency, synthetic opioids [2–4]. Both the im./sc. auto-injector and the approved intranasal spray demonstrated sufficient plasma exposure within the first 15–20 min after administration to garner FDA approval. By contrast, a different intranasal spray was denied approval, potentially because of inadequate early-stage uptake of naloxone [48]. The duration of action is shorter for naloxone compared with most opioids; additional dose(s) may be required if the initial response is inadequate or if signs of overdose (e.g., respiratory depression) recur [23,25,27,49].The optimal naloxone dose is one that successfully reverses opioid overdose without precipitating acute withdrawal symptoms [50]. However, most of the information necessary to make a precise dose determination (e.g., mu receptor affinity of the opioid taken and dose taken) is unavailable at the time that naloxone is administered, and varying naloxone dosing algorithms have been suggested [43,49,50]. The recent increase in overdose deaths related to potent opioids such as fentanyl [4] has tipped the balance toward the need for adequately high naloxone doses to prevent overdose fatalities. The FDA stance on naloxone dosing is evident in the approval of a new, higher dose (2 mg) for the im./sc. naloxone injector and a limited indication for the lower dose (2 mg) of intranasal naloxone (only for opioid-dependent patients expected to be at risk for severe opioid withdrawal [assuming this information is known at the time of naloxone administration]). The higher dose of the im./sc. auto-injector was developed to ensure that adequate naloxone would be provided for reversing overdose of various types of opioids, including potent opioids such as fentanyl [24]. In fact, an FDA advisory committee voted in 2016 to increase the current pharmacokinetic benchmark (0.4-mg im.) for approval of naloxone products for community use [51,52]. The makers of the im./sc. auto-injector intend to discontinue manufacturing the lower (0.4-mg) dose [53].Approved intranasal spray initially received FDA approval i
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