Pharmacokinetics in children

Tramadol is metabolized into the active metabolite O-desmethyltramadol (M1) by CYP2D6 and into N-desmethyltramadol (M2) by CYP2D6 and CYP3A4.

Neonates and Infants (< 1 years)

The formation rate of O-desmethyltramadol via CYP2D6 increase over the neonatal period, reaches adult CYP2D6 activity levels around 1 year of age. In addition, the immature glucuronidation (e.g. UGT2B7) and renal function may result in slower elimination and accumulation of O-desmethyltramadol in children less than 1 year of age, especially in the first week of postnatal life. 

A population-PK-study by Allegaert et. al. 2005 the following age-related PK parameters were predicted with based on the covariate models (Allegaert 2005):

Age (weight (kg)1)	25 wks PCA (0.6 kg)	30 wks PCA (1.3 kg)	35 wks PCA (2.5 kg)	40 wks PCA (3.3 kg)	45 wks PCA (4.5 kg)	50 wks PCA (5.5 kg)	60 wks PCA (7,5kg)	1 yr PNA (10kg)	3 yrs PNA (14kg)	Adult (70kg)
Cl (ml/min/kg)	4.32	7.08	8.12	8.96	9.19	9.4	9.32	9.22	8.54	5.71
Central Vd (L/kg)	3.66	3.51	3.38	3.26	3.15	3.05	2.88	2.54	2.18	2.13
Peripheral Vd (L/kg)	0.57	0.57	0.57	0.57	0.57	0.57	0.57	0.57	0.57	0.57

^{1. Weight is estimated within each age group, based on weight of participants within studies until 50 wks PCA.  
PCA= postconceptional age
PNA = postnatal age}

1 year to 16 years

The pharmacokinetics of tramadol and O-desmethyltramadol after single and multiple oral dosing were generally similar to those in adults when dose-adjusted based on body weight, but with a higher inter-subject correlation variability in children aged ≤8 years  (SmPC Tramal Injection fluid 01/2022)

Reference	Route of administration	Dose	Population	CL (ml/min/kg) Tramadol	Vd  (l/kg)	Tramadol			active O-desmethyl-metabolite
						Cmax (ng/ml) (mean+SD)	Tmax (h) (mean+SD)	T ½ (h)	Cmax (ng/ml) (mean+SD)	Tmax (h) (mean+SD)	T ½ (h)
Vandenbosche et al. 2015	Oral  (immediate release tablets)	mean 1.5mg/kg/dose every 6 hours for 3 days	7-11 years (n=6)	8,2±1,0		362±94	1,7±0,5		89±40	1,8±0,8
			12-16 years (n=11)	9,7±3,3		242±116	1,9±0,8		89±33	2,1±1,0
Payne et al. 2002	oral (single administration, drops)	1.5 mg/kg	4-7 years (n=24)	5,6±2,7	4,1±1,2		< 0,5	3,6±1,1	37,5±5,2	4,5±1,5	5,8±1,7
Zwaveling et al. 2004 1	Rectal (single administration)	1-1.9 mg/kg	1-6 years (n=12)	15.5	6.1	200±60	2,4±1,0	4,3±0,22	35±15	3,9±1,1

1. The age-related PK parameters were predicted in population-PK study.
2. (mean±SEM)

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

Pain

Intravenous Term neonates and 1 month up to 1 year 1 - 2 mg/kg/dose as needed depending on clinical efficacy, safety and tolerability. Max: 8 mg/kg/day.  . Alternative: 1-2 mg/kg over 30 min, then 0.1 - 0.2 mg/kg/h as continuous infusion. Max. 8 mg/kg/day Preterm neonates Gestational age < 34 weeks 1 - 2 mg/kg/dose as needed depending on clinical efficacy, safety and tolerability. Max: 8 mg/kg/day.  . Alternative: 1-2 mg/kg over 30 min, then 0.1 - 0.15 mg/kg/h as continuous infusion. Max. 8 mg/kg/day Preterm neonates Gestational age ≥ 34 weeks 1 - 2 mg/kg/dose as needed depending on clinical efficacy, safety and tolerability. Max: 8 mg/kg/day. Alternative: 1-2 mg/kg over 30 min, then 0.1 - 0.2mg/kg/h as continuous infusion. Max. 8 mg/kg/day. Normal preparation (immediate release) 1 year up to 12 years 1 - 2 mg/kg/dose As required based on effect and tolerance.. Max: 8mg/kg/day, but not exceeding 400 mg/day.  . Alternative: continuous infusion: 0,5-1 mg/kg as a bolus, then 0.1-0.25 mg/kg/hour as a continuous infusion, max 400 mg/day Regulated release 12 years up to 18 years 50 - 100 mg/dose As required based on effect and tolerance. Max: 400 mg/day.  . Alternative: continuous infusion: 0,5-1 mg/kg as a bolus, then 0.1-0.25 mg/kg/hour as a continuous infusion, max 400 mg/day Oral Normal preparation (immediate release) 1 year up to 12 years 1 - 2 mg/kg/dose as required based on effect and tolerance max 4 times daily. Max: 8mg/kg/day, but not exceeding 400 mg/day. Max single dose: 100 mg/dose. 12 years up to 18 years 50 - 100 mg/dose as required based on effect and tolerance max 4 times daily.. Max: 400 mg/day. Regulated release 12 years up to 18 years 50 - 100 mg/dose as required increase dose gradually based on effect and tolerance to 150-200 mg 2 dd. Max: 400 mg/day. The "once daily" tablets: 200 mg 1dd, increase gradually based on effect and tolerance to max 400 mg/day Rectal 1 year up to 12 years 1 - 2 mg/kg/dose, as required, max. 4x daily. Max single dose: 100 mg/dose. Regulated release 12 years up to 18 years 100 mg/dose As required based on effect and tolerance up to 4 times daily.

Renal impaiment in children > 3 months

Adjustment in renal impairment as specified:

GFR 50-80 ml/min/1.73 m2

Dose adjustment is not required

GFR 30-50 ml/min/1.73 m2

Dose adjustment is not required

GFR 10-30 ml/min/1.73 m2

100 percentage of single dose and dosing interval : 12 uur

GFR < 10 ml/min/1.73 m2

Generalized recommendations cannot be given.

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

Nausea, vomiting, headache.

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

Contra-indications in children

• The effervescent tablet should not be used in children with phenylketonuria at doses of > 200 mg.
• Post-operative pain relief in the home situation after tonsillectomy and adenoidectomy.

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

Children are more likely to suffer respiratory depression when using tramadol in all procedures/conditions in which the airway could be obstructed in any way (FDA safety announcement 20-Apr-2017, Anderson et al. 2017).

Oral administration
Careful with dosing the droplet solution, as some preparations have a very high concentrations (e.g. 100 mg/ml, 1 droplet contains 2.5 mg tramadol). 

In chronic pain, always prescribe in combination with a laxative.

Pharmacogenetics.
The occurrence of serious adverse reactions or lack of effect may be due to abnormal drug metabolism. CYP2D6 may determine the variation in response. Genotyping may be considered.

Interactions

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

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
	Piritramide Related Medicines Menu">	N02AC03

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

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

References

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