Dosages
Side effects in children
Warnings & precautions in children
Contra-indications in children

Interactions
PK
Renal impairment
References

Theophylline

Generic name
Theophylline
Brand name
ATC Code
R03DA04

Pharmacokinetics in children

Half-lives:
Premature neonates
- Postnatal age 3-15 days: 30 hours (17-43 hours)
- Postnatal age 25-57 days: 20 hours (9.4-30.6 hours

Full-term neonates
- Postnatal age 1-2 days: 25.7 hours (25-26.5 hours)
- Postnatal age 3-30 weeks: 11 hours (6-29 hours)

children
- 1-4 years: 3.4 hours (1.2-5.6 hours)
- 4-6 years: not defined
- 6 to 17 years: 3.7 (1.5-5.9 hours)

Theophylline is metabolized in the liver. The clearance increases strongly with the maturation of the liver in the early years of life. A disadvantage of xanthine derivatives is the narrow therapeutic range. Therapeutic plasma levels for antiasthmatic effects are 8-15 mg/l.

In a population – PK-study in neonates with HIE (hypoxic-ischaemic encephalopathy) undergoing hypothermia, theophylline clearance was low with a 50% longer half-life ca. 40h compared to full-term normothermic neonates without HIE. [Frymoyer et al. 2020]
In ECMO-Patients (n=75 term neonates and children) of a population PK-Study the estimated clearance was significantly lower and the Vd higher than in non-ECMO patients of similar age. [Mulla et al. 2003]


 

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

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Available formulations

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Dosages

Therapy-resistant asthmatic status
  • Intravenous
    • 2 months up to 6 months
      • Initial dose: 5 - 10 mg/kg/dose, once only in 20-60 minutes.
      • Maintenance dose: 0.4 mg/kg/hour, continuous infusion.

      • Initial dose: 6 mg/kg/dose is usually sufficient
        Theophylline concentration maintenance treatment between 8 and 15 mg/l or potentially up to 20 mg/l.

        It should be noted that treatment with theophylline is not recommended due to a lack of added value in optimal therapy with short-acting βagonists and an increase in side effects. [GINA 2022]

         

        ...read more
    • 6 months up to 1 year
      • Initial dose: 5 - 10 mg/kg/dose, once only in 20-60 minutes.
      • Maintenance dose: 0.7 mg/kg/hour, continuous infusion.

      • Initial dose: 6 mg/kg/dose is usually sufficient
        Theophylline concentration maintenance dose between 8 and 15 mg/l or potentially up to 20 mg/l.

        It should be noted that treatment with theophylline is not recommended due to a lack of added value in optimal therapy with short-acting βagonists and an increase in side effects. [GINA 2022]

         

        ...read more
    • 1 year up to 7 years
      • Initial dose: 5 - 10 mg/kg/dose, once only in 20-60 minutes. 6 mg/kg/dose is usually sufficient.
      • Maintenance dose: 0.9 mg/kg/hour, continuous infusion.

      • Theophylline concentration maintenance dose between 8 and 15 mg/l or potentially up to 20 mg/l.

        It should be noted that treatment with theophylline is not recommended due to a lack of added value in optimal therapy with short-acting βagonists and an increase in side effects. [GINA 2022]

        ...read more
    • 7 years up to 16 years
      • Initial dose: 5 - 10 mg/kg/dose, once only in 20-60 minutes.
      • Maintenance dose: 0.7 mg/kg/hour, continuous infusion.

      • Initial dose: 6 mg/kg/dose is usually sufficient
        Theophylline concentration maintenance dose between 8 and 15 mg/l or potentially up to 20 mg/l.

        It should be noted that treatment with theophylline is not recommended due to a lack of added value in optimal therapy with short-acting βagonists and an increase in side effects. [GINA 2022]

        ...read more
    • ≥ 16 years
      • Initial dose: 5 - 10 mg/kg/dose, once only in 20-60 minutes.
      • Maintenance dose: 0.5 mg/kg/hour, continuous infusion.

      • Theophylline concentration maintenance dose between 8 and 15 mg/l or potentially up to 20 mg/l.

        It should be noted that treatment with theophylline is not recommended due to a lack of added value in optimal therapy with short-acting βagonists and an increase in side effects. [GINA 2022]

        ...read more
Bronchoconstriction (asthma, obstructive airway diseases)
  • Oral
    • Extended release tablet
      • ≥ 6 years and < 30 kg
        • 200 mg/day in 2 doses.
      • ≥ 6 years and ≥ 30 kg
        • 300 - 400 mg/day in 2 doses.
    • Extended release capsules, hard
      • 1 year up to 6 years
        • 24 mg/kg/day in 2 doses.

        • The contents of Bronchoretard 100 junior capsules can also be administered mixed with a chyme, but care must be taken to ensure that the medicinal pellets are swallowed whole and that the mixture is taken immediately after the corresponding dose has been prepared.
Diuresis, prevention of kidney dysfunction in asphyxia
  • Intravenous
    • Term neonate
      • 5 - 8 mg/kg/dose, once only during the first 60 minutes after birth.
Neonatal apnoea
  • Oral
    • Premature infants Gestational age < 37 weeks
      • Initial dose: 4 mg/kg/dose, once only.
      • Maintenance dose: 4 mg/kg/day in 2 doses.

      • Target level: 5-10 mg/l

        No scientific foundation for the use of theophylline in apnoea. It is applied in the above-mentioned dosage in practice.

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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.

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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

In high plasma concentrations, gastrointestinal effects, central effects (headaches, dizziness, nervousness and sleep disorders) and effects on the heart can occur (tachycardia and arrhythmias). Children in particular are susceptible to the central side effects, such as excitement; this is especially a risk in dehydration, such as vomiting, diarrhoea and increased diuresis. Toxic plasma concentrations (> 20-25 mg/l) can lead to convulsions. [SmPC Afpred-forte-THEO 200mg Injektionslösung (Glenwood GmbH 04-2019)]

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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

The dosage should be adjusted according to the plasma concentration and clinical picture in case of serious status asthmatics. Due to the narrow therapeutic range, it is important to restrict fluctuations in plasma concentrations as much as possible.
Interference with other clinical pictures is one of the determining factors for the theophylline plasma concentration, increase of the plasma concentration is reported in virus infections, cardiac failure and liver problems. Adjust the dose in cases of heart or liver failure. Young children are more sensitive than adults to central side effects, such as excitement; this is especially a risk in dehydration, such as vomiting, diarrhoea and increased diuresis. In smokers and young people (1-16 years), the elimination can be accelerated to such an extent that high dosages must be given. [SmPC Afpred-forte-THEO 200mg Injektionslösung (Glenwood GmbH 04-2019)]
 

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Interactions

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

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Leukotriene receptor antagonists
R03DC03
Other systemic drugs for obstructive airway diseases
R03DX09
R03DX05
R03DX11

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References

  1. National Heart,Lung,and Blood Institute Bethesda MD, Expert panel report 3: guidelines for the diagnosis and management of asthma. , 2007, Available from URL: http://www.nhlbi.nih.gov/guidelines/asthma/asthgdln.pdf.
  2. Ream RS, et al, Efficacy of IV theophylline in children with severe status asthmaticus., Chest., 2001, May;119(5), 1480-8
  3. Mitra A, et al, Intravenous aminophylline for acute severe asthma in children over two years receiving inhaled bronchodilators, Cochrane Database Syst Rev, 2005, (2), CD001276
  4. D'Avila RS, et al, Early administration of two intravenous bolus of aminophylline added to the standard treatment of children with acute asthma, Respir Med, 2008, Jan;102(1), 156-61
  5. Wheeler DS, et al, Theophylline versus terbutaline in treating critically ill children with status asthmaticus: a prospective, randomized, controlled trial, Pediatr Crit Care Med, 2005, Mar;6(2), 142-7
  6. Roberts G, et al, Intravenous salbutamol bolus compared with an aminophylline infusion in children with severe asthma: a randomised controlled trial, Thorax., 2003, Apr;58(4), 306-10
  7. Seddon P, et al, Oral xanthines as maintenance treatment for asthma in children, Cochrane Database Syst Rev, 2006, (1), CD002885
  8. Hogue SL, et al, Evaluation of three theophylline dosing equations for use in infants up to one year of age, J Pediatr, 1993, Oct;123(4), 651-6
  9. Karo Pharma AB, SmPC Theo-Dur ( Numre 6607 and 6608) 26-06-2020, www.legemiddelsok.no
  10. Jenik, AG., et al., A randomized, double-blind, placebo-controlled trial of the effects of prophylactic theophylline on renal function in term neonates with perinatal asphyxia., Pediatrics, 2000, 105(4), 511-4
  11. Frymoyer, A., et al., Theophylline dosing and pharmacokinetics for renal protection in neonates with hypoxic-ischemic encephalopathy undergoing therapeutic hypothermia., Pediatr Res, 2020, 88 (6), 871-877
  12. Bakr, A., et al., Prophylactic theophylline to prevent renal dysfunction in newborns exposed to perinatal asphyxia--a study in a developing country., Pediatr Nephrol, 2005, 20(9), 1249-52
  13. Bhat, GC., et al., Theophylline and aminophylline for prevention of acute kidney injury in neonates and children: a systematic review., Arch Dis Child, 2019, 104(7), 670-679
  14. Raina, A., et al., Treating perinatal asphyxia with theophylline at birth helps to reduce the severity of renal dysfunction in term neonates., Acta Paediatr, 2016, 105(10), e448-51
  15. Mulla, H., et al., Population pharmacokinetics of theophylline during paediatric extracorporeal membrane oxygenation., Br J Clin Pharmacol, 2003, 55(1), 23-31
  16. Eslami, Z., et al., Theophylline for prevention of kidney dysfunction in neonates with severe asphyxia., Iran J Kidney Dis, 2009, 3(4), 222-6
  17. National Heart,Lung,and Blood Institute Bethesda MD, Expert panel report 3: guidelines for the diagnosis and management of asthma., 2007, Available from URL: http://www.nhlbi.nih.gov/guidelines/asthma/asthgdln.pdf.
  18. Glenwood GmbH Pharmazeutische Erzeugnisse, SmPC Bronchoretard® 100 junior (5809.00.00), 10/2018

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Changes

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