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

Interactions
PK
Renal impairment
References

Doxapram

Generic name
Doxapram
Brand name
ATC Code
R07AB01

Pharmacokinetics in children

Premature neonates:

Vd mean 4-7,3 L/kg
T1/2 mean 6,6-9,9 uur

Oral bioavailability of doxapram in preterm infants was estimated at 74%, using a popPK model.(Flint 2021)

Doxapram is primarily metabolized by CYP3A4, and to a lesser extent by CYP3A5, into keto-doxapram, which has a pharmacological activity of ~80% compared to doxapram.(Bairam 1991; Ogawa 2015; Bairam 1990)

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

No information is present at this moment.

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Available formulations

No information is present at this moment.

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Dosages

Idiopathic apnoea (not responsive to the maximum dose of caffeine)
  • Intravenous
    • • Pregnancy duration < 37 weeks Postnatal age 0 days up to 14 days
      • Initial dose: 2.5 mg/kg/dose, bolus in10 min.
      • Maintenance dose: Then  0.5 mg/kg/hour, continuous infusion. Thereafter, adjust maintenance dose based on effect to 0.5-2 mg/kg/hour, continuous infusion..

      • Always in combination with caffeine.

    • • Pregnancy duration < 37 weeks Postnatal age ≥ 14 days
      • Initial dose: 2.5 mg/kg/dose, bolus in10 min.
      • Maintenance dose: Then  1 mg/kg/hour, continuous infusion. Thereafter, increase or decrease maintenance dose based on effect to 0.5-2 mg/kg/hour, continuous infusion..

      • Always in combination with caffeine.

  • Oral
    • Gestational age < 37 weeks
      • Due to gastrointestinal side effects, oral administration is not preferred.   12 - 48 mg/kg/day in 4 - 24 doses. or continuous, orally..

      • Always in combination with caffein therapy. 

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Renal impaiment in children > 3 months

No information available on dose adjustment in renal impairment.

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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

There are insufficient data about the short and long term safety of doxapram   with unknown risks for neurodevelopment. (Possible) side effects are:  Hypokalemia, prolonged QT interval. Neurological effects (Restlessness[ , irritability, motor restlessness, decreased sleep/wake cycles and convulsive activity), gastrointestinal effects (nutritional retention / feeding problems vomiting, necrotizing enterocolitis) . High doses cause many side effects: hypertension, hyperexitability, , gastrointestinal tract irritation. Intoxication symptoms: hypothermia, salivation, teardrop, tremors, motor restlessness, hyperactivity, hepatic dysfunction.(Vliegenthart et al 2017)

 

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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

Discontinue if there is sudden hypotension or dyspnoea.

Some injections contain benzyl alcohol. Dozampram may could lead to extension of the QT interval. Treatment with doxapram doesn't always show a good response in terms op decreased hypoxia  or r improved respiratory condition (Poppe 2020).

Based on a popPK study by Flint et al, a similar exposure would be reached in all neonates when adjusting the dose according to the popPK model that was developed. Both PNA and GA were found to be the best predictors for changes in CL parameters. However,  target concentrations at different PNA’s and GA’s are yet unknown. Therefore, dosages need to be titrated based on individual effects. For this reason the dose recommendations are a simplification of the popPK outcomes in addition to other available literature (see references). 


 

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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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Lung surfactants
R07AA02
R07AA05
Other respiratory system products
R07AX02
R07AX32
R07AX30
R07AX31

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References

  1. Beaudry MA, et al, Pharmacokinetics of doxapram in idiopathic apnea of prematurity, Dev Pharmacol Ther, 1988, 11(2), 65-72
  2. Jamali F, et al, Doxapram dosage regimen in apnea of prematurity based on pharmacokinetic data, Dev Pharmacol Ther, 1988, 11(5), 253-7
  3. Barrington KJ, et al, Dose-response relationship of doxapram in the therapy for refractory idiopathic apnea of prematurity, Pediatrics, 1987, Jul;80(1), 22-7
  4. Miyata M, et al, Dynamic QT/RR relationship of cardiac conduction in premature infants treated with low-dose doxapram hydrochloride, J Perinat Med, 2007, 35(4), 330-3
  5. Dani C, et al, Brain hemodynamic effects of doxapram in preterm infants, Biol Neonate, 2006, 89(2), 69-74
  6. Henderson-Smart DJ, et al, Doxapram treatment for apnea in preterm infants, Cochrane Database Syst Rev, 2001, (4), CD000074
  7. Maillard C, et al, QT interval lengthening in premature infants treated with doxapram, Clin Pharmacol Ther, 2001, Dec;70(6), 540-5
  8. Roll C, et al, Effect of doxapram on cerebral blood flow velocity in preterm infants, Neuropediatrics., 2004, Apr;35(2), 126-9
  9. Henderson-Smart DJ, et al, Doxapram versus methylxanthine for apnea in preterm infants, Cochrane Database Syst Rev, 2000, (2), CD000075
  10. Barbe F, et al, Severe side effects and drug plasma concentrations in preterm infants treated with doxapram. , Ther Drug Monit., 1999, Oct;21(5), 547-52
  11. Poets CF, et al, Effect of doxapram on episodes of apnoea, bradycardia and hypoxaemia in preterm infants, Biol Neonate, 1999, Oct;76(4):, 207-13
  12. Moller JC, et al, A comparative study about the therapeutic effect of theophylline and doxapram in apnoeic disorders, Klin Padiatr., 1999, Mar-Apr;211(2):, 86-91
  13. De Villiers GS, et al, Second-degree atrioventricular heart block after doxapram administration, J Pediatr, 1998, Jul;133(1), 149-50
  14. Huon C, et al, Low-dose doxapram for treatment of apnoea following early weaning in very low birthweight infants: a randomized, double-blind study, Acta Paediatr, 1998, Nov;87(11), 1180-4
  15. Barrington KJ, et al, Randomized, controlled, blinded trial of doxapram for extubation of the very low birthweight infant, Acta Paediatr, 1998, Feb;87(2), 191-4
  16. Romeo MG, et al, Oral administration of doxapram in preterm neonates with aminophylline-resistant idiopathic apnea crisis, Pediatr Med Chir, 1995, Mar-Apr;17(2), 123-6
  17. Bairam A, et al, Doxapram for the initial treatment of idiopathic apnea of prematurity, Biol Neonate, 1992, 61(4):, 209-13
  18. Brion LP, et al, Low-dose doxapram for apnea unresponsive to aminophylline in very low birthweight infants, J Perinatol., 1991, Dec;11(4), 359-64
  19. Kumita H, et al, Low-dose doxapram therapy in premature infants and its CSF and serum concentrations, Acta Paediatr Scand, 1991, Aug-Sep;80(8-9), 786-91
  20. Tay-Uyboco J, et al, Clinical and physiological responses to prolonged nasogastric administration of doxapram for apnea of prematurity, Biol Neonate, 1991, 59(4), 190-200
  21. Jamali F, et al, Lack of a pharmacokinetic interaction between doxapram and theophylline in apnea of prematurity, Dev Pharmacol Ther, 1991, 16(2), 78-82
  22. Bairam A, et al, Low-dose doxapram for apnoea of prematurity, Lancet., 1986, Apr 5;1(8484), 793-4
  23. Eyal F, et al, Aminophylline versus doxapram in idiopathic apnea of prematurity: a double-blind controlled study, Pediatrics, 1985, Apr;75(4), 709-13
  24. Peliowski A, et al, A blinded, randomized, placebo-controlled trial to compare theophylline and doxapram for the treatment of apnea of prematurity., J Pediatr., 1990, Apr 16(4), 648-53
  25. Bairam A, et al, Gastrointestinal absorption of doxapram in neonates, Am J Perinatol, 1991, Mar 8 (2), 110-3
  26. Rademaker, CMA et al, Geneesmiddelen-Formularium voor Kinderen, 2007
  27. Flint R, et al., Retrospecive study shows that doxapram therapy avoided the need for endotracheal intubation in most premature neonates, Acta Paediatr, 2017, 106, 733-9
  28. Fischer C, et al., Doxapram and hypokalaemia in very preterm infants., Arch Dis Child Fetal Neonatal., 2013, 98, F416-418
  29. Shimokaze T, et al., Blood potassium and urine aldosterone after doxapram therapy for preterm infants., J Perinatol., 2018, 38, 702-7
  30. Flint RB, et al., The bioavailability and maturing clearance of doxapram in preterm infants., Pediatr Res, 2021, 89(5), 1268-77
  31. Bairam A, et al., Doxapram metabolism in human fetal hepatic organ culture, Clin Pharmacol Ther., 1991, 50(1), 32-8
  32. Ogawa Y, et al., Population pharmacokinetics of doxapram in low-birth-weight Japanese infants with apnea. , Eur J Pediatr., 2015, 174(4), 509-18
  33. Bairam A, et al, Pharmacodynamic effects and pharmacokinetic profiles of keto-doxapram and doxapram in newborn lambs, Pediatr Res., 1990, 28(2), 142-6
  34. Vliegenthart RJ,, Doxapram Treatment for Apnea of Prematurity: A Systematic Review., Neonatology., 2017, 111(2), 162-71
  35. Poppe JA, et al., Precision Dosing of Doxapram in Preterm Infants Using Continuous Pharmacodynamic Data and Model-Based Pharmacokinetics: An Illustrative Case Series., Front Pharmacol., 2020, 11, 665.
  36. Ogawa Y, et al., Population pharmacokinetics of doxapram in low-birth-weight Japanese infants with apnea., Eur J Pediatr., 2015, 174(4), 509-18
  37. Barbe F, et al, Severe side effects and drug plasma concentrations in preterm infants treated with doxapram., Ther Drug Monit., 1999, Oct;21(5), 547-52
  38. Moller JC, et al, A comparative study about the therapeutic effect of theophylline and doxapram in apnoeic disorders, Klin Padiatr., 1999, Mar-Apr;211(2):, 86-91

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