Pharmacokinetics in children

There is a general lack of published pharmacokinetic data on the use of piritramide in children. Compared to infants, young children, and adults, neonates showed a higher initial concentration and a clearly prolonged elimination. Since infants and young children's elimination rates are higher than those of adults, therefore the duration of effects will be shortened (Muller 2006)).

The following pharmacokinetic parameters were found in children (n=39) in the intensive care unit (ICU) setting (Muller 2006):

parameter Median ± SE (Range)	Population
	neonates (N = 8)	infants group 1 (N = 7)	infants group 2 (N = 14)	children (N = 10)
age	10,6 ± 10,7 days (1 – 27 days)	11,4 ± 4,4 weeks (5,4 – 16,9 weeks)	9,0 ± 2,3 months (5,2 – 12,2 months)	2,4 ± 0,9 years (1,61 – 4,02 years)
Cmax (µg/l)	79 ± 240 (5 – 723)	36 ± 367 (6 – 855)	12 ± 81 (3 – 315)	16 ± 9 (9 – 35)
T½β (min)	701,5 ± 720 (88 – 1950)	157 ± 102 (106 – 394)	160 ± 68 (114 – 335)	165 ± 143 (101 – 512)
Clt (ml/kg/min)	5,0 ± 4,8 (0,7 – 15,6)	9,8 ± 12,3 (1,3 – 32,1)	26,7 ± 42,7 (2,8 – 172,1)	24,0 ± 11,6 (5,7 – 41,1)
Vdss (l/kg)	1,96 ± 4,93 (0,07 – 13,9)	1,70 ± 2,5 (0,12 – 5,78)	6,95 ± 5,15 (0,58 – 17,02)	6,70 ± 2,15 (1,20 – 8,10)

 

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.

Due to lack of data on piritramide, the dose is extrapolated from morphine. Piritramid is less potent than morphine. In clinical practice equal doses for morphine and piritramide are used.

 

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Dosages

Severe pain

Intramuscular ≥ 5 years 0.05 - 0.2 mg/kg/dose, as required, max. 4x daily. Subcutaneous 1 month up to 3 years VENTILATED PATIENTS Starting dose: 100 microgram/kg/dose, bolus Maintenance dose, continuous infusion: 4-9 kg: 10-15 microgram/kg/hour, titrated up to 40 microgram/kg/hour 10-15kg: 15-20 microgram/kg/hour, titrated up to 40 microgram/kg/hour In case insufficient pain control, repeat bolus of 50 – 100 microgram/kg/dose and increase continuous infusion dose  NON-VENTILATED PATIENTS Starting dose:  PICU: 15 microgram/kg/dose, bolus. Repeat 3 times if needed. In case of insufficient pain control after repeating, start with continuous infusion. PACU: 10-50 microgram/kg/dose (repeat dose if necessary) under continuous monitoring until sufficient pain control is reached, then continuous infusion can be started.  Maintenance dose, continuous infusion: 4-9 kg: 10-15 microgram/kg/hour, titrated up to 40 microgram/kg/hour 10-15kg: 15-20 microgram/kg/hour, titrated up to 40 microgram/kg/hour 3 years up to 18 years and ≥ 15 kg VENTILATED PATIENTS Starting dose: 100 microgram/kg/dose, bolus Maintenance dose, continuous infusion:10-40 microgram/kg/hour In case insufficient pain control, repeat bolus of 50 – 100 microgram/kg/dose and increase continuous infusion dose  NON-VENTILATED PATIENTS Starting dose:  PICU: 15 microgram/kg/dose, bolus. Repeat 3 times if needed. In case of insufficient pain control after repeating, start with continuous infusion. PACU: 10-50 microgram/kg/dose (repeat dose if necessary) under continuous monitoring until sufficient pain control is reached, then continuous infusion can be started.  Maintenance dose, continuous infusion: 10-40 microgram/kg/hour  Intravenous 1 month up to 3 years VENTILATED PATIENTS Starting dose: 100 microgram/kg/dose, bolus Maintenance dose, continuous infusion: 4-9 kg: 10-15 microgram/kg/hour, titrated up to 40 microgram/kg/hour 10-15kg: 15-20 microgram/kg/hour, titrated up to 40 microgram/kg/hour In case insufficient pain control, repeat bolus of 50 – 100 microgram/kg/dose and increase continuous infusion dose  NON-VENTILATED PATIENTS Starting dose:  PICU: 15 microgram/kg/dose, bolus. Repeat 3 times if needed. In case of insufficient pain control after repeating, start with continuous infusion. PACU: 10-50 microgram/kg/dose (repeat dose if necessary) under continuous monitoring until sufficient pain control is reached, then continuous infusion can be started.  Maintenance dose, continuous infusion: 4-9 kg: 10-15 microgram/kg/hour, titrated up to 40 microgram/kg/hour 10-15kg: 15-20 microgram/kg/hour, titrated up to 40 microgram/kg/hour 3 years up to 18 years and ≥ 15 kg VENTILATED PATIENTS Starting dose: 100 microgram/kg/dose, bolus Maintenance dose, continuous infusion:10-40 microgram/kg/hour In case insufficient pain control, repeat bolus of 50 – 100 microgram/kg/dose and increase continuous infusion dose  NON-VENTILATED PATIENTS Starting dose:  PICU: 15 microgram/kg/dose, bolus. Repeat 3 times if needed. In case of insufficient pain control after repeating, start with continuous infusion. PACU: 10-50 microgram/kg/dose (repeat dose if necessary) under continuous monitoring until sufficient pain control is reached, then continuous infusion can be started.  Maintenance dose, continuous infusion: 10-40 microgram/kg/hour

Severe pain: administration via PCA pump
Subcutaneous 5 years up to 18 years BOLUS: 15-20 microgram/kg, lockout interval 15-30 minutes, Background infusion (CONTINUOUS INFUSION): 0 - 15 microgram/kg/hour, max. 100 microgram/kg/hour Intravenous 5 years up to 18 years BOLUS: 15-20 microgram/kg, lockout interval 10 minutes, Background infusion (CONTINUOUS INFUSION) 0 - 15 microgram/kg/hour, max. 100 microgram/kg/hour

CAUTION:
Route of administration not applicable 0 years up to 18 years Due to lack of data on piritramide, the dose is extrapolated from morphine. Piritramid is less potent than morphine. In clinical practice equal doses for morphine and piritramide are used.

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

Spontaneously breathing neonates in particular may be at risk of respiratory depression because of prolonged elimination half-life and decreased clearance in this age group. [SmPC Dipidolor, Muller 2006]

 

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

It may take up to 24 hours for the patient to benefit from the full analgesic effect of the given dose of Dipidolor. Increasing the dose of piritramide should be done cautiously to avoid accumulation of piritramide. This could, in fact, increase the risk of respiratory depression (Huenseler 2008; SmPC ).

When postoperative respiratory depression occurs, naloxone IV can be administrated (see naloxone  for dose recommendations). 

Interactions

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

• NERVOUS SYSTEM
• ANALGESICS

OPIOIDS

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

Natural opium alkaloids
	Hydromorfon Related Medicines Menu">	N02AA03
	Morphine Related Medicines Menu">	N02AA01
	Oxycodone Related Medicines Menu">	N02AA05
	Paracetamol + codeine Related Medicines Menu">	N02AA59

Phenylpiperidine derivatives
	Fentanyl, nasal Related Medicines Menu">	N02AB03
	Fentanyl (transdermal and nasal) Related Medicines Menu">	N02AB03
	Pethidine Related Medicines Menu">	N02AB02

Diphenylpropylamine derivatives
	Levomethadon	N02AC06

Oripavine derivatives
	Buprenorphine Related Medicines Menu">	N02AE01

Morphinan derivatives
	Nalbufine Related Medicines Menu">	N02AF02

Other opioids
	Tapentadol Related Medicines Menu">	N02AX06
	Tilidin Related Medicines Menu">	N02AX01
	Tramadol Related Medicines Menu">	N02AX02

Opioids in combination with non-opioid analgesics
	Paracetamol + tramadol Related Medicines Menu">	N02AJ13

References

1. Piramal Critical Care B.V., SmPC Dipidolor (RVG 09129) 23-03-2021, www.geneesmiddeleninformatiebank.nl
2. Janssen-Cilag NV, SmPC Dipidolor (BE119402) 30-03-2017, http://bijsluiters.fagg-afmps.be
3. Association of Paediatric Anaesthetists of Great, B. and Ireland., Good practice in postoperative and procedural pain management, 2nd edition., Paediatr Anaesth, 2012, 22 Suppl 1, 1-79
4. Huenseler C, et al., Prospective evaluation of the pharmacodynamics of piritramide in neonates and infants, Eur J Pediatr, 2008, 167(8), 867-72
5. Müller C, et al., Pharmacokinetics of piritramide in newborns, infants and young children in intensive care units, Eur J Pediatr, 2006, 165(4), 229-39
6. Krekels, E.H., et al., Evidence-based morphine dosing for postoperative neonates and infants., Clin Pharmacokinet, 2014, 53(6), 553-63
7. Friedrichsdorf, S.J. and T.I. Kang,, The management of pain in children with life-limiting illnesses, Pediatr Clin North Am, 2007, 54(5), 645-72
8. Experts opinion Editorial Board Kinderformularium NL, Meeting 10-03-2023
9. Knibbe, C.A., et al;, Morphine glucuronidation in preterm neonates, infants and children younger than 3 years, Clin Pharmacokinet., 2009, 48(6), 371-85
10. Berde, C.B. and N.F. Sethna,, Analgesics for the treatment of pain in children, N Engl J Med, 2002, 47(14), 1094-103
11. Karl, H.W., et al, Controlled trial of morphine vs hydromorphone for patient-controlled analgesia in children with postoperative pain, Pain Med, 2012, 13(12), 1658-9
12. Peters, J.W., et al.,, Patient controlled analgesia in children and adolescents: a randomized controlled trial., Paediatr Anaesth, 1999, 9(3), 235-41
13. Goulooze, S.C., et al., Quantifying the Pharmacodynamics of Morphine in the Treatment of Postoperative Pain in Preverbal Children., J Clin Pharmacol, 2022, 62(1), 99-109
14. Ceelie, I., et al., Effect of intravenous paracetamol on postoperative morphine requirements in neonates and infants undergoing major noncardiac surgery: a randomized controlled trial., JAMA, 2013, 309(2), 49-54
15. van Dijk, M., et al., Efficacy of continuous versus intermittent morphine administration after major surgery in 0-3-year-old infants; a double-blind randomized controlled trial, Pain, 2002, 98(3), 305-313
16. Lynn, A.M., et al., Intravenous morphine in postoperative infants: intermittent bolus dosing versus targeted continuous infusions., Pain, 2000, 8(1), 89-95
17. Bouwmeester, N.J., et al., Developmental pharmacokinetics of morphine and its metabolites in neonates, infants and young children., Br J Anaesth, 2004, 92(2), 208-17
18. Duedahl, T.H. and E.H. Hansen., A qualitative systematic review of morphine treatment in children with postoperative pain, Paediatr Anaesth, 2007, 17(8), 756-74
19. Doyle, E., et al, Comparison of patient-controlled analgesia in children by i.v. and s.c. routes of administration, Br J Anaesth, 1994, 72(5), 533-6
20. McNeely, J.K. and N.C. Trentadue., Comparison of patient-controlled analgesia with and without nighttime morphine infusion following lower extremity surgery in children., J Pain Symptom Manage, 1997, 15(5), 268-73
21. Walker, S.M., et al., Intravenous opioids for chemotherapy-induced severe mucositis pain in children: Systematic review and single-center case series of management with patient- or nurse-controlled analgesia (PCA/NCA)., Paediatr Anaesth, 2022, 32(1), 17-34
22. Berde, C.B., et al.,, Patient-controlled analgesia in children and adolescents: a randomized, prospective comparison with intramuscular administration of morphine for postoperative analgesia., J Pediatr,, 1991, 118(3), 460-6
23. Doyle, E., Iet al, Patient-controlled analgesia with low dose background infusions after lower abdominal surgery in children, Br J Anaesth, 1993, 71(6), 818-22
24. Ozalevli, M., et al., Comparison of morphine and tramadol by patient-controlled analgesia for postoperative analgesia after tonsillectomy in children, Paediatr Anaesth, 2005, 15(11), 979-84

Changes

Therapeutic Drug Monitoring

Overdose