NARCAN (Page 3 of 5)
12.2 Pharmacodynamics
When naloxone hydrochloride is administered intravenously, the onset of action is generally apparent within two minutes. The time to onset of action is shorter for intravenous compared to subcutaneous or intramuscular routes of administration. The duration of action is dependent upon the dose and route of administration of naloxone hydrochloride.
12.3 Pharmacokinetics
In a pharmacokinetic study in 30 healthy adult subjects, the relative bioavailability (BA) of one nasal spray in one nostril, consisting of a 2 mg total dose (0.1 mL of 20 mg/mL naloxone hydrochloride solution) and a 4 mg total dose (0.1 mL of 40 mg/mL naloxone hydrochloride solution), and two nasal sprays administered as one nasal spray in each nostril, consisting of a 4 mg total dose (0.1 mL of 20 mg/mL naloxone hydrochloride solution in each nostril) and an 8 mg total dose (0.1 mL of 40 mg/mL naloxone hydrochloride solution in each nostril), were compared to a single dose of 0.4 mg naloxone hydrochloride intramuscular injection. For intranasal administration, the subjects were instructed not to breathe through the nose during administration of the nasal spray, and remained fully supine for approximately one hour post-dose. For intramuscular administration, naloxone was administered as a single injection in the gluteus maximus muscle. The pharmacokinetic parameters obtained in the study are shown in Table 1.
Parameter | 2 mg – One Nasal Spray in one nostril 20 mg/ml (N=29) | 4 mg – Two Nasal Sprays, one in each nostril 20 mg/ml (N=29) | 4 mg – One Nasal Spray in one nostril 40 mg/ml (N=29) | 8 mg –Two Nasal Sprays, one in each nostril 40 mg/ml (N=29) | 0.4 mg Intramuscular Injection (N=29) |
---|---|---|---|---|---|
tmax (h)* | 0.33 (0.25, 1.00) | 0.33 (0.17, 0.57) | 0.50 (0.17, 1.00) | 0.33 (0.17, 1.00) | 0.38 (0.08, 2.05) |
Cmax (ng/mL) | 2.91 (35) | 6.30 (34) | 4.83 (43) | 9.70 (36) | 0.88 (31) |
AUCt (hr.ng/mL) | 4.60 (27) | 9.64 (24) | 7.87 (37) | 15.3 (23) | 1.75 (23) |
AUC0-inf (h*ng/mL) | 4.66 (27) | 9.74 (24) | 7.95 (37) | 15.5 (23) | 1.79 (23) |
t½ (h) | 1.85 (33) | 2.19 (33) | 2.08 (30) | 2.10 (32) | 1.24 (26) |
Dose normalized Relative BA (%) vs. IM | 51.7 (22) | 54.0 (23) | 44.2 (31)† | 43.1 (24) | 100 |
Figure 1 Mean ± SD Plasma Concentration of Naloxone, (a) 0-6 h and (b) 0-1h Following Intranasal Administration and Intramuscular Injection
(a) Figure 1 Mean ± SD Plasma Concentration of Naloxone, (a) 0-6 h and (b) 0-1h Following Intranasal Administration and Intramuscular Injection |
(b) Figure 1 Mean ± SD Plasma Concentration of Naloxone, (a) 0-6 h and (b) 0-1h Following Intranasal Administration and Intramuscular Injection |
The median naloxone tmax after intranasal administration of NARCAN Nasal Spray (one nasal spray in one nostril (2 mg or 4 mg) or two nasal sprays as one spray in each nostril (4 mg or 8 mg) was not significantly different compared to the 0.4 mg dose of naloxone hydrochloride intramuscular injection (Table 1).
The dose normalized relative bioavailability of one dose (2 mg or 4 mg) or two doses (4 mg or 8 mg) of NARCAN Nasal Spray as compared to the 0.4 mg dose of naloxone hydrochloride administered by intramuscular injection was 52%, 44%, 54%, and 43%, respectively.
Distribution
Following parenteral administration, naloxone is distributed in the body and readily crosses the placenta. Plasma protein binding occurs but is relatively weak. Plasma albumin is the major binding constituent, but significant binding of naloxone also occurs to plasma constituents other than albumin. It is not known whether naloxone is excreted into human milk.
Elimination
Following a single intranasal administration of NARCAN Nasal Spray (2 mg or 4 mg dose of naloxone hydrochloride), the mean plasma half-life of naloxone in healthy adults was approximately 1.85 (33% CV) hours and 2.08 (30% CV) hours; respectively, which was longer than that observed after administrations of a 0.4 mg naloxone hydrochloride intramuscular injection, where the half-life was 1.24 hours (26% CV). In a neonatal study of naloxone hydrochloride injection, the mean (± SD) plasma half-life was observed to be 3.1 (± 0.5) hours.
Metabolism
Naloxone hydrochloride is metabolized in the liver, primarily by glucuronide conjugation, with naloxone-3-glucoronide as the major metabolite.
Excretion
After an oral or intravenous dose, about 25-40% of naloxone is excreted as metabolites in urine within 6 hours, about 50% in 24 hours, and 60-70% in 72 hours.
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