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Mechanism Of Action
Naloxone hydrochloride is an opioid antagonist that antagonizes opioid effects by competing for the same receptor sites.
Naloxone hydrochloride reverses the effects of opioids, including respiratory depression, sedation, and hypotension. Also, it can reverse the psychotomimetic and dysphoric effects of agonist-antagonists such as pentazocine.
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.
In a pharmacokinetic study in 30 healthy subjects, a single 0.4 mg subcutaneous or intramuscular naloxone injection administered using EVZIO provides equivalent naloxone AUC and 15% greater naloxone Cmax in comparison to a single 0.4 mg subcutaneous or intramuscular naloxone injection administered using a standard syringe.
Following a single 0.4 mg EVZIO injection, the median Tmax of naloxone was reached at 0.25 hours (range 0.08 to 1.23 hours), with a mean Cmax value of 1.24 (51.4% CV) ng/mL. The mean plasma half-life of naloxone in healthy adults was 1.28 (38.0% CV) hours. In the same study, following administration of a single dose of 0.4 mg naloxone injection using a standard syringe, the median Tmax was 0.33 hours (range 0.08 to 2.03 hours) and the mean Cmax value was 1.07 (45.1% CV) ng/mL. The mean plasma half-life was 1.36 (23.5% CV) hours.
A second pharmacokinetic study in 24 healthy subjects using a crossover design, evaluated a single 0.4 mg EVZIO injection, a single 2 mg EVZIO injection, and two 0.4 mg EVZIO injections administered two minutes apart (0.8 mg naloxone hydrochloride total). The pharmacokinetic parameters obtained in this study are shown in Table 1 and the plasma concentration time profiles of naloxone are in Figure 1.
Table 1 Mean Pharmacokinetic Parameters (%CV) for Naloxone Following EVZIO (Naloxone HCl) Intramuscular/Subcutaneous Administration to Healthy Subjects
|Parameter||0.4 mg EVZIO
|0.8 mg (two 0.4 mg EVZIO)
|2 mg EVZIO
|Tmax (h)†||0.25 (0.09, 0.84)||0.21 (0.09, 0.85)||0.25 (0.13, 0.67)|
|Cmax (ng/mL)||1.33 (62.9)||2.16 (47.4)||7.91 (45.8)|
|AUC0-t (ng.h/mL)||1.82 (16.0)||3.50 (19.8)||9.66 (15.4)|
|AUC0-inf (ng.h/mL)||2.00 (16.3) ††||3.78 (19.1) ††||10.33 (15.2)|
|T1/2 (h)||1.58 (28.9) ††||1.52 (23.7) ††||1.53 (25.0)|
|† Tmax reported as median (minimum, maximum)
†† N=23 for AUC0-inf and T1/2
Figure 1 Mean ± SD Plasma Concentration of Naloxone, (a) 0-6 h and (b) 0-1h Following Intramuscular/Subcutaneous Administration using EVZIO
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.
Following a single 0.4 mg EVZIO injection, the mean plasma half-life of naloxone in healthy adults was 1.58 (28.9% CV) hours and 1.53 (25% CV) hours following a single 2 mg EVZIO injection. In a neonatal study of naloxone injection, the mean (± SD) plasma half-life was observed to be 3.1 (± 0.5) hours.
Naloxone hydrochloride is metabolized in the liver, primarily by glucuronide conjugation with naloxone-3glucoronide as the major metabolite.
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.
Last reviewed on RxList: 10/31/2016
This monograph has been modified to include the generic and brand name in many instances.
Additional Evzio Information
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