Pharmacokinetics in children

The following pharmacokinetic parameters (mean (range)) have been found in neonates (n = 10, after loading dose of 10 mg / kg, monotherapy) (Singh et al. 1996):

Cmax (mg/l)	Tmax (uur)	t½ (uur)	Cl (ml/min/kg)	Vd (l/kg)
8.1 ± 0.8 (7.1 - 9.9)	9.2 ± 4.2 (4 – 16)	24.5 ± 13.9 (9.6 - 60.2)	0.5 ± 0.2 (0.21 - 0.85)	0.9 ± 0.1 (0.64 - 1.13)

When carbamazepine is combined with other anti-epileptic drugs, such as phenobarbital and phenytoin, the t½ decreases (MacKintosh, Baird-Lampert, and Buchanan 1987, Rey et al. 1979).

The following pharmacokinetic parameters (mean, range) were found in older children (2-21 years of age) (Carlsson et al. 2005):

t½ (uur) (range)	Cl (ml/min/kg) (range)	Vd (l/kg) (range)
6.5 (4.2 - 15.4)	1.72 (0.60 - 3.63)	0.88 (0.35 - 1.81)

The bioavailability of the suspension is higher than that of the tablets. When converting from tablet to suspension, give the same daily dose in mg applies, with in smaller, more frequent doses. If carbamazepine is administered rectally, a 25% higher dose is required than the oral dose.

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

Epilepsy

Oral Preterm neonates Gestational age < 37 weeks [33] Initial dose: 7 - 10 mg/kg/day in 2 doses. Maintenance dose: Increase weekly based on effect up to 15 mg/kg/day in 2 doses. Titrate down if there are side effects. Caution is needed in patients with a Chinese, Japanese or Thai backgorund; different HLA variations can lead to Steven Johnson Syndrome. See further warnings and precautions for children. Term neonate [29] Initial dose: 7 - 10 mg/kg/day in 2 doses. Maintenance dose: Increase weekly based on effect up to 15 mg/kg/day in 2 doses. Titrate down if there are side effects. Caution is needed in patients with a Chinese, Japanese or Thai backgorund; different HLA variations can lead to Steven Johnson Syndrome. See further warnings and precautions for children. 1 month up to 5 years [5] [7] [9] [10] [29] [36] Initial dose: 10 mg/kg/day in 2 - 3 doses. Maintenance dose: Increase weekly by 5 mg/kg/day until the desired effect is achieved. Usual maintenance dose 10 - 20 mg/kg/day in 2 - 3 doses. Max: 35 mg/kg/day. Titrate down if there are side effects. Caution is needed in patients with a Chinese, Japanese or Thai backgorund; different HLA variations can lead to Steven Johnson Syndrome. See further warnings and precautions for children. 5 years up to 12 years [4] [5] [6] [7] [8] [9] [10] [11] [12] Initial dose: 10 mg/kg/day in 2 - 3 doses. Maintenance dose: Increase weekly by 5 mg/kg/day until the desired effect is achieved. Usual maintenance dose 10 - 25 mg/kg/day in 2 - 3 doses. Max: 1.000 mg/day. Tablet with regulated release can be used: divide daily dose in 2 doses Titrate down if there are side effects. Caution is needed in patients with a Chinese, Japanese or Thai backgorund; different HLA variations can lead to Steven Johnson Syndrome. See further warnings and precautions for children. 12 years up to 16 years [14] Initial dose: 200 mg/day in 2 doses. Maintenance dose: Increase weekly by 200 mg/day until the desired effect is achieved. Usual maintenance dose 200 - 1.000 mg/day in 2 - 4 doses. Max: 1.000 mg/day. Tablet with regulated release can be used: divide daily dose in 2 doses Titrate down if there are side effects. Caution is needed in patients with a Chinese, Japanese or Thai backgorund; different HLA variations can lead to Steven Johnson Syndrome. See further warnings and precautions for children. 16 years up to 18 years [14] Initial dose: 200 mg/day in 2 doses. Maintenance dose: Increase weekly by 200 mg/day until the desired effect is achieved. Usual maintenance dose 200 - 1.200 mg/day in 2 - 4 doses. Max: 1.200 mg/day. Tablet with regulated release can be used: divide daily dose in 2 doses Titrate down if there are side effects. Caution is needed in patients with a Chinese, Japanese or Thai backgorund; different HLA variations can lead to Steven Johnson Syndrome. See further warnings and precautions for children. Rectal < 5 years [37] Initial dose: 12.5 mg/kg/day in 2 - 3 doses. Maintenance dose: Increase weekly by 6.25 mg/kg/day until the desired effect is achieved. Usual maintenance dose 25 mg/kg/day in 2 - 3 doses. Max: 43.75 mg/kg/day. Titrate down if there are side effects. Caution is needed in patients with a Chinese, Japanese or Thai backgorund; different HLA variations can lead to Steven Johnson Syndrome. See further warnings and precautions for children. 5 years up to 12 years [37] Initial dose: 12.5 mg/kg/day in 2 - 3 doses. Maintenance dose: Increase weekly by 6.25 mg/kg/day until the desired effect is achieved. Usual maintenance dose 12.5 - 31.25 mg/kg/day in 2 - 3 doses. Max: 1.250 mg/day. Titrate down if there are side effects Caution is needed in patients with a Chinese, Japanese or Thai backgorund; different HLA variations can lead to Steven Johnson Syndrome. See further warnings and precautions for children. 12 years up to 16 years [37] Initial dose: 250 mg/day in 2 doses. Maintenance dose: Increase weekly by 250 mg/day until the desired effect is achieved 250 - 1.250 mg/day in 2 doses. Max: 1.250 mg/day. Titrate down if there are side effects Caution is needed in patients with a Chinese, Japanese or Thai backgorund; different HLA variations can lead to Steven Johnson Syndrome. See further warnings and precautions for children. 16 years up to 18 years [37] Initial dose: 250 mg/day in 2 doses. Maintenance dose: Increase weekly by 250 mg/day until the desired effect is achieved 250 - 1.500 mg/day in 2 doses. Max: 1.500 mg/day. Titrate down if there are side effects Caution is needed in patients with a Chinese, Japanese or Thai backgorund; different HLA variations can lead to Steven Johnson Syndrome. See further warnings and precautions for children.

Trigeminus neuralgia
Oral 1 month up to 18 years [3] [31] [35] Initial dose: 1.5 - 3 mg/kg/day in 1 dose Maintenance dose: Increase with weekly increments to 5 - 10 mg/kg/day in 2 - 4 doses. Max: 10 mg/kg/day. Caution is needed in patients with a Chinese, Japanese or Thai backgorund; different HLA variations can lead to Steven Johnson Syndrome. See further warnings and precautions for children.

Bipolar disorder

Oral < 25 kg Initial dose: 100 mg/day in 2 - 3 doses. Maintenance dose: Increase the starting dose step by step (every 5 days) to 400 mg/day in 2 - 3 doses. Max: 20mg/kg/day, but not exceeding 400 mg/day. The effective concentrations in the blood are between 4 and 12 mg/l. Treatment by or after consulting a paediatric specialist (child and youth psychiatrist) who has experience using carbamazepine for this indication. 25 up to 40 kg Initial dose: 200 mg/day in 2 - 3 doses. Maintenance dose: Increase the starting dose step by step (every 5 days) to 800 mg/day in 2 - 3 doses. Max: 800 mg/day. The effective concentrations in the blood are between 4 and 12 mg/l. Treatment by or after consulting a paediatric specialist (child and youth psychiatrist) who has experience using carbamazepine for this indication. ≥ 40 kg [28] [34] Initial dose: 400 mg/day in 2 - 3 doses. Maintenance dose: Increase the starting dose step by step (every 5 days) to 1.200 mg/day in 2 - 3 doses. Max: 1.200 mg/day. Caution is needed in patients with a Chinese, Japanese or Thai backgorund; different HLA variations can lead to Steven Johnson Syndrome. See further warnings and precautions for children. Carbamazepine must be prescribed for this indication by a specialist in child and adolescent psychiatry. The dose should be determined individually and the lowest possible dose should be applied

Renal impaiment in children > 3 months

Adjustment in renal impairment as specified:

GFR 50-80 ml/min/1.73 m2

No dose adjustment needed

GFR 30-50 ml/min/1.73 m2

No dose adjustment needed

GFR 10-30 ml/min/1.73 m2

Adjust dose in epilepsia based in plasma concentration levels. Adjust dose in other indications for use based on clinical effect and side effects.

GFR < 10 ml/min/1.73 m2

A general recommendation is not provided

Clinical consequences

Symptoms of overdose: sedation, dizziness with nystagmus, ataxia, nausea, vomiting, blurred vision and hallucinations.
The carbamazepine-10,11-epoxide metabolite is more hydrophilic than the parent compound and may accumulate with renal impairment.
At a normal carbamazepine level, the metabolite carbamazepine 10,11-epoxide may still be increased. Different carbamazepine plasma concentration levels are used. Refer to local hospital, policy. 

Patients on dialysis

Adjust dose in epilepsia based in plasma concentration levels. Adjust dose in other indications for use based on clinical effect and side effects.

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

Headaches, gastrointestinal complaints, sedation, dizziness, skin rash (Verity 1995) Increase of absences and myocloni.
Overdose: ataxia, diplopia
 

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

Contra-indications in children

Do not use carbamazepine in generalized tonic-clonic seizures with myocloni or absences because they can have an adverse effect in these types of seizures.

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

Caution is needed in cases of severe cardiovascular disease, impaired liver function, haematological side effects of other medicines in the previous history. For the indication ‘epilepsy’: carbamazepine can cause an increase of absences and myocloni
The FDA has warned about possible fatal bone marrow depression and agranulocytosis correlated to the use of carbamazepine (incidence of both is 1:100,000).
Patients of Chinese, Japanese or Thai backgrounds with HLA-A*3101, HLA-B*1502 or HLA-B*1511 appear to have a high risk of Stevens-Johnson syndrome. Do not use in this group unless there are no alternatives. Genotyping may be considered. 
Increased risk of suicide 1 week after start of treatment.
Lower levels of carbamazepine with several enzyme inducers, but take the active metabolite into account to prevent toxicity.

Interactions

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

Barbiturates and derivatives
	Phenobarbital Related Medicines Menu">	N03AA02

Hydantoin derivatives
	Phenytoin Related Medicines Menu">	N03AB02

Succinimide derivatives
	Ethosuximide Related Medicines Menu">	N03AD01

Fatty acid derivatives
	Valproic acid (sodiumvalproate) Related Medicines Menu">	N03AG01

Other antiepileptics
	Lamotrigine Related Medicines Menu">	N03AX09
	Levetiracetam Related Medicines Menu">	N03AX14

References

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