Naloxone

Generic name
Naloxone
Brand name
ATC Code
V03AB15
Dosages
Side effects in children
Warnings & precautions in children
Contra-indications in children

Interactions
PK
Renal impairment
References

Pharmacokinetics in children

Naloxone is primarily metabolized in the liver trough dealkylation with reduction of the 6-ketogroup and conjugation with glucuronic acid, and excreted with the urine, in unchanged form and in the form of metabolites [SmPC].  

The following pharmacokinetic parameters have been found in term neonates (n=29) with respiratory depression due to administration of opioids to mother within 4 hours before birth, after IV (via umbilical vein) and IM administration with different doses [Moreland 1980]:

PK parameters

(mean + SD)

Dose: 35 µg IV

n=6

Dose: 70 µg IV

n=6

Dose: 200 µg IM

n=17

Cmax (ng/ml)

8,2 ± 4,91

13,7 ± 4,81

18,6 ± 8,02,3

T1/2 (hr)

3,53 ± 2,20

2,65 ± 1,30

NR

Vd (l/kg)

2,20 ± 1,18

1,78 ± 0,73

NR

Clplasma (ml/kg/hr)

564 ± 488 

576 ± 372

NR

1 Time to reach peak plasma level varied. In five cases peak levels were reached within 5 min. of administration but in the remainder, plasma levels continued to rise for up to 40 min.

2 Time to reach peak plasma levels ranged from 0.5 – 2 hr (mean 1.2 hr).

IM administration resulted in a longer time to peak levels compared to IV doses, possibly due to a drug depot forming at the injection site. The T1/2 after IV administration was two to three times longer than in adults (1 – 1.5 hr), likely due to the reduced ability of neonates to metabolize drugs, as naloxone is primarily eliminated via glucuronidation, which is not yet fully developed in neonates. The relatively long time to reach peak levels observed in some neonates is likely due to naloxone remaining in the umbilical vein after injection, delaying the onset and reducing the magnitude of the pharmacologic effect of naloxone [Moreland 1980].

The following pharmacokinetic parameters have been found in preterm neonates (n=10) with narcotic-induced central nervous system depression or apnea treatment, after IV administration [Stile 1987]:

PK parameters

mean ± SD (range)

Dose: 0.04 mg/kg IV

n=10

Cmax (ng/ml)

18,7 ± 4,2

T1/2 (min)

70,8 ± 35,6 (29 – 122)

Vd (l/kg)1

3,52 ± 1,20 (2,39 – 6,09)

Cltotal (ml/kg/min)

39,13 ± 14,53 (24,6 – 74,0)

1 Vd significantly correlated with birth weight.

The pharmacokinetic parameters in preterm neonates indicate that the T1/2 of naloxone is comparable to that observed in adults (1 – 1.5 hr), in contrast to term neonates, which could be partially attributed to the administration method (via umbilical vein) used in term neonates. The short T1/2 in preterm neonates may indicate that naloxone is metabolized by a different pathway. Although capacity to metabolize substances by glucuronidation and dealkylation is reduced, other reactions such as sulfate and glycine conjugation appear to be present in activities similar to those found in adults [Stile 1987].

dose recommendation of formulary compared to licensed use (on-label versus off-label)

No information is present at this moment.

Available formulations

No information is present at this moment.

Dosages

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Opiate overdose, known or suspected (e.g.anesthesia/postoperative analgesia)
  • Endotracheal
    • 1 month up to 18 years
      • 50 microg./kg/dose, as required repeat. repeat after 3 minutes if there is no effect.
  • Nasal
    • ≥ 14 years
      [6]
      • 1.8 mg/dose, as required May be repeated after 2-3 minutes if needed.
        • Administer into one nostril.
        • Further doses should be administered in alternate nostrils.
  • intravenous / intramuscular / subcutaneously
    • Preterm (GA < 37 weeks) and Term neonate
      [9] [14]
      • 10 microg./kg/dose, bolus. Max: 400 microg./dose. Repeat as necessary with increased dose of 100 microg/kg if there is no effect after 3 min..
    • 1 month up to 18 years
      [2]
      • 10 microg./kg/dose, bolus. Max: 400 microg./dose. Repeat as necessary with increased dose of 100 microg/kg if there is no effect after 3 min..
Itching as a result of terminal hepatic/renal insufficiency
  • Intravenous
    • 1 month up to 18 years
      • 0.5 microg./kg/hour, continuous infusion.
Complete or partial recovery of the CNS, particulary respiratory depression caused by natural or synthetic opiates
  • intravenous / intramuscular / subcutaneously
    • Preterm (GA< 37 weeks) and Term neonate
      [2] [12] [13] [14]
      • 1.5 - 3 microg./kg/dose, as required. Titrate slowly and repeat dose every 2 – 3 minutes until respiratory function is restored to a satisfactory level..
        • Start as low as possible in chronic opioid users to prevent acute opioid withdrawal
        • Because the duration of action of opioids may exceed that of naxolone, continuous monitoring of respiration is essential, and repeated naloxone administrations (IM/SC) or continuous infusion (IV) at  1 – 2 mcg/kg/hr may be necessary to prevent recurrent apneas.
    • 1 month up to 18 years
      [2] [12] [13] [14]
      • 1.5 - 3 microg./kg/dose, as required. Titrate slowly and repeat dose every 2 – 3 minutes until respiratory function is restored to a satisfactory level..
        • Start as low as possible in chronic opioid users to prevent acute opioid withdrawal
        • Because the duration of action of opioids may exceed that of naxolone, continuous monitoring of respiration is essential, and repeated naloxone administrations (IM/SC) or continuous infusion IV at  1 – 2 mcg/kg/hr may be necessary to prevent recurrent apneas.
Respiratory depression resulting from administration of opioids to mother less than 4 hours before the birth
  • intravenous / intramuscular / subcutaneously
    • Preterm (GA <37 weeks) and Term neonate
      • 10 microg./kg/dose, as required repeat after 2-3 minutes if there is no effect.
        • Because the duration of effect of opioids may exceed that of naloxone, continuous respiratory monitoring is essential and repeated administrations of naloxone may be needed in order to prevent recurrent apnoea. For this reason, monitoring is desirable for 24 hours after administering naloxone.
        • Do not administer naloxone to a new-born whose mother may be a user of addictive drugs, as naloxone may then cause acute withdrawal symptoms.

Renal impaiment in children > 3 months

GFR ≥10 ml/min/1.73m2: Dose adjustment not required.

GFR <10 ml/min/1.73m2: A general recommendation on dose adjustment cannot be provided.

The complete list of all undesirable drug reactions can be found in the national Summary of Product Characteristics (SmPC) – click here

Side effects in children

Naloxone, at doses up to 10 mcg/kg, is safe in infants (< 6 months) in terms of not causing unwanted stimulant effects on the opioid receptors or the cardiovascular system. It effectively blocks opioid effects without causing additional changes in heart rate or blood pressure [Fischer 1974].

The complete list of all contra-indications can be found in the national Summary of Product Characteristics (SmPC) – click here

Contra-indications

No information available on specific contra indications in children.

The complete list of all warnings and precautions can be found in the national Summary of Product Characteristics (SmPC) – click here

Warnings & precautions in children

Rapid injection has a strong emetic effect. The effect of naloxone lasts less long than the effect of opoids: longer-term observation is needed because a rebound effect can occur. In such situations, consider administering a continuous infusion [Vila 1979; Karl 1996].

In neonates: ensure proper ventilation first. Naloxone should preferably not be administered to a new-born whose mother is a user of addictive substances due to acute withdrawal symptoms. Can also be administered subcutaneously or intramuscularly if the peripheral circulation of the neonate is sufficient. Monitor for 24 hours after administration.

Administer cautiously to persons with known or suspected dependence on opioids, including neonates of mothers on whom such dependence is known. In such cases, abrupt and complete removal of narcotic effects may result in acute abstinence syndrome (hypertension, cardiac arrhythmias, cardiac arrest, pulmonary edema), this may also occur in the newborn children of such patients [Deshpande 2009].

Excessive dosage may lead to complete removal of analgesia, nervousness and increase in blood pressure. Too rapid a lifting of the effects of opioids may cause nausea, vomiting, sweating, hyperventilation, dizziness, hypertension, tachycardia, tremors, convulsions and cardiac arrest.

In obese children, dosing based on TBW is preferred [Ross 2015; Wells 2020].

Interactions

The complete list of all interactions can be found in the national Summary of Product Characteristics (SmPC) – click here

ALL OTHER THERAPEUTIC PRODUCTS

This pages provides a list of drugs from the same ATC class for comparison. This does not necessarily mean that these drugs are interchangeable.

Antidotes
V03AB14
Iron chelating agents
V03AC03
V03AC02
V03AC01
Detoxifying agents for antineoplastic treatment
V03AF03
V03AF01
V03AF07
Drugs for treatment of hypoglycemia
V03AH01
DETOXIFYING AGENTS FOR ANTINEOPLASTIC TREATMENT
V03AF03
V03AF01
V03AF07

References

  1. Rademaker C.M.A. et al, Geneesmiddelen-Formularium voor Kinderen, 2007
  2. Hameln Pharmaceuticals gmbh, SmPC Naloxon ( RVG 28360) 29-05-2020, www.geneesmiddeleninformatiebank.nl
  3. NVK, Richtlijn pijnmeting en behandeling pijn bij kinderen, www.nvk.nl, 2007, http://www.nvk.nl/Kwaliteit/Richtlijnenenindicatoren/Richtlijnen/Pijnmetingenbehandelingvan/tabid/348/language/nl-NL/Default.aspx, 99
  4. NVK, Richtlijn Reanimatie van de pasgeborene, www.nvk.nl, 2008, http://www.nvk.nl/Kwaliteit/Richtlijnenenindicatoren/Richtlijnen/Reanimatievanpasgeborenen/tabid/352/language/nl-NL/Default.aspx, 29-30
  5. Kamps WA et al, Werkboek ondersteundende behandeling kinderoncologie, VU Uitgeverij, 2005
  6. Mundipharma Corporation (Ireland) Limited, SmPC Nyxoid (EU/1/17/1238) Rev 7, 22-09-2022, www.ema.europa.eu
  7. Deshpande G, et al., Cardiac arrest following naloxone in an extremely preterm neonate., Eur J Pediatr, 2009, 168(1, 115-7
  8. Stile IL, et al., The pharmacokinetics of naloxone in the premature newborn, Dev Pharmacol Ther., 1987, 10(6), 454-9
  9. Elmekkawi A,et al. , Use of naloxone to minimize extubation failure after premedication for INSURE procedure in preterm neonates., J Neonatal Perinatal Med, 2016, 9(4), 363-70
  10. Moreland TA, et al., Naloxone pharmacokinetics in the newborn, Br J Clin Pharmacol., 1980, 9(6), 609-12
  11. Fischer CG, et al. , The respiratory and narcotic antagonistic effects of naloxone in infants., Anesth Analg, 1974, 53(6), 849-52
  12. Vilà R, et al., Respiratory depression following epidural morphine in an infant of three months of age., Paediatr Anaesth, 1997, 7(1), 61-4
  13. Karl HW, et al., Respiratory depression after low-dose caudal morphine, Can J Anaesth, 1996, 43(10), 1065-7
  14. Amomed Pharma GmbH. , SmPC Naloxon Amomed 0,4 mg/ml Injektionslösung. (Z.Nr 1-27262) , www.basg.gv.at, 05/2022
  15. Ross EL, et al., Development of recommendations for dosing of commonly prescribed medications in critically ill obese children., Am J Health Syst Pharm, 2015, 72(7), 542-56
  16. Wells M, et al., The utility of pediatric age-based weight estimation formulas for emergency drug dose calculations in obese children., J Am Coll Emerg Physicians Open., 2020, 1(5), 947-54
  17. Mundipharma Pharmaceuticals B.V. , SmPC Nyxoid 1,8 mg neusspray, (EU/1/17/1238/001) Rev 8; 24-02-2023, www.ema.europa.eu
  18. van Vonderen JJ, et al., Effects of naloxone on the breathing pattern of a newborn exposed to maternal opiates. , Acta Paediatr., 2012, 101(7), e309-12

Changes

Therapeutic Drug Monitoring


Overdose