Source: Health Products Regulatory Authority (IE) Revision Year: 2020 Publisher: DNE Pharma AS, Karihaugveien 22, 1086 Oslo, Norway
Pharmacotherapeutic group: Antidotes
ATC code: V03AB15
Naloxone is a semi-synthetic morphine derivative (N-allyl-noroxymorphon) and a specific opioid antagonist that antagonises opioid effects by competing for the same receptor sites. The effect is due to antagonism of mu, kappa, delta opioid receptors. The antagonism of the mu receptor restores respiration.
Naloxone reverses the effects of opioids, including respiratory depression, sedation, and hypotension. It has a very high affinity to opioid receptors and as a result displaces both opioid agonists and partial antagonist like e.g. pentazocine and nalorphine. Naloxone does not reverse CNS depression caused by hypnotics or other non-opioids and does not have agonistic or morphine-like effects as other opioid antagonists.
In cases of opioid dependency, administration of naloxone will increase the symptoms of physical dependency. The pharmacological effects of naloxone will typically be observed within 2 minutes following administration. The duration of the antagonistic effect is dose dependant but is typically 1-4 hours. The need for repeated dosing depends on the amount, type and route of administration of the opioid to be antagonised.
In a pharmacokinetic study in 22 healthy adult subjects, the relative bioavailability of one nasal spray in one nostril (1.4 mg total dose naloxone hydrochloride, equivalent to 1.26 mg naloxone base, given as 0.1 ml of 14 mg/ml naloxone hydrochloride) and two nasal sprays administered in the same nostril (2.8 mg total dose naloxone hydrochloride, equivalent to two times 1.26 mg naloxone base, given as 2 × 0.1 ml of 14 mg/ml naloxone hydrochloride) was compared to a single dose of 0.8 mg naloxone hydrochloride intramuscular injection and 0.4 mg naloxone hydrochloride intravenous injection. Absolute bioavailability of the nasal spray was on average 0.49 ±0.24. Results are presented in Table 1 below.
Table 1. Mean pharmacokinetic parameters for naloxone following administration of Ventizolve, intramuscular and intravenous naloxone hydrochloride to healthy subjects:
| Parameter | 1.4 mg/dose intranasal – one dose | 1.4 mg/dose intranasal – two doses | 0.8 mg intramuscular injection | 0.4 mg intravenous injection |
|---|---|---|---|---|
| tmax (min) | 20.16 | 20.7 | 13.62 | 3.48* |
| Cmax (ng/ml) | 2.356 | 4.181 | 3.734 | 7.437* |
| AUC0-last (h*ng/ml) | 2.622 | 5.232 | 3.091 | 1.839 |
| AUC0-inf (h*ng/ml) | 2.842 | 5.469 | 3.431 | 2.087 |
| t1/2 (h) | 1.216 | 1.162 | 1.414 | 1.239 |
| Dose normalised relative bioavailability (%) IN vs. IM | 0.52 |
* Time and concentration at first sampling point = 2 minutes
Mean plasma concentrations of naloxone after 2 and 5 minutes following 1.4 mg IN Ventizolve were 0.5475 ng/mL (23% of Cmax) and 0.9519 ng/mL (40% of Cmax), respectively. Onset of action following intranasal administration can reasonably be expected to occur in each individual before the tmax is reached. The corresponding mean plasma concentrations of naloxone after 2 and 5 minutes following 0.8 mg IM naloxone were 1.4979 ng/mL (40% of Cmax) and 3.1551 ng/mL (85% of Cmax), respectively.
Naloxone is a highly lipophilic compound and following parenteral administration it is rapidly and extensively distributed into body fluids and tissues including the brain. Naloxone readily crosses the placenta. It is not known whether naloxone is excreted into human milk.
Plasma protein binding occurs but is relatively weak (32-45%). Plasma albumin is the major binding constituent, but significant binding of naloxone also occurs to plasma constituents other than albumin.
Naloxone is metabolized in the liver, primarily by glucuronide conjugation, with naloxone-3-glucoronide as the major metabolite.
In adults, the elimination half-life is approximately 1 to 1.5 hours after parenteral administration. In a pharmacokinetic study, there was no significant difference in elimination following administration of Ventizolve and 0.8 mg IM and 0.4 mg IV formulations.
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, acute and repeated dose toxicity.
Naloxone was weakly positive in the Ames mutagenicity and in the in vitro human lymphocyte chromosome aberration test but was negative in the in vitro Chinese hamster V79 cell HGPRT mutagenicity assay and in the in vivo rat bone marrow chromosome aberration study. Overall, the weight of evidence indicates that naloxone poses minimal, if any, risk for human genotoxicity and carcinogenicity.
Naloxone had no effect on fertility and reproduction in the rat, or on early embryonic development of the rat and mouse. Naloxone is not teratogenic in animals.
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