Clonidine

Generic name
Clonidine
Brand name
ATC Code
C02AC01
Dosages
Side effects in children
Warnings & precautions in children
Contra-indications in children

Interactions
PK
Renal impairment
References

Pharmacokinetics in children

The following kinetic parameters were found after oral administration (Arenas-Lopez et al. 2014, Xie et al. 2011 and Larsson et al. 2011):

  n= Cmax (ng/ml) Tmax (min) Cl (l/kg/hour) Vd (l/kg)
Neonates 36 - - 0.22 5.59
1 month to 1 year 46 0.73 (3 µg/kg) 190 0.20 2.59
3-10 yrs 8 0.77 (4 µg/kg) 62 0.26 1.61
ECMO (3 days-6 years) 22 - - 0.43 6.49

In children on ECMO, the clearance is doubled and the volume of distribution increased (Kleiber 2017).

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

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Premedication before the induction of anaesthesia
  • Oral
    • 1 month up to 18 years
      • Clonidinehydrochloride: 4 microg./kg/dose, once only. Max: 150 microg./dose.
    • Term neonate
      • Clonidinehydrochloride: 4 microg./kg/dose, once only. Max: 150 microg./dose.
    • 1 month up to 18 years
      [29] [30] [31] [32] [33] [36] [37]
      • Clonidinehydrochloride: 4 microg./kg/dose, once only. Max: 150 microg./dose.
    • Term neonate
      [35]
      • Clonidinehydrochloride: 4 microg./kg/dose, once only. Max: 150 microg./dose.
ADHD with or without behavioural problems or tics
  • Oral
    • 6 years up to 18 years and < 25 kg
      • Initial dose: 25 microg./day in 1 dose as an evening dose.
      • Maintenance dose: Start with a dose of 50 micrograms every three days and increase to the usual maintenance dose of 3 - 5 microg./kg/day in 3 doses.

      • Clonidine must be discontinued gradually (reduce by 25 micrograms per 3 days) to avoid rebound hypertension.
        Treatment by or after consulting a specialist in child and youth psychiatry who has experience of using clonidine for this indication.

    • 6 years up to 18 years and ≥ 25 kg
      • Initial dose: Clonidinehydrochloride: 50 microg./day in 1 dose as an evening dose.
      • Maintenance dose: Start with a dose of 50 micrograms every three days and increase to the usual maintenance dose of 3 - 5 microg./kg/day in 3 doses.

      • Clonidine must be discontinued gradually (reduce by 25 micrograms per 3 days) to avoid rebound hypertension.

        Treatment by or after consulting a specialist in child and youth psychiatry who has experience of using clonidine for this indication.
Problems getting to sleep in ADHD
  • Oral
    • 4 years up to 18 years
      • Clonidinehydrochloride: In the evening: 25 microg./dose in 1 dose. Max: 75 microg./day.

      • Clonidine must be discontinued gradually (reduce by 25 micrograms per 3 days) to avoid rebound hypertension.

        Treatment by or after consulting a specialist in child and youth psychiatry who has experience of using clonidine for this indication.
Growth hormone secretion test
  • Oral
    • 1 month up to 18 years
      [17] [18] [24]
      • Clonidinehydrochloride: 150 microg./m²/dose, once only. Max: 150 microg./dose.

      • For a calculated dose <75 microg. round up to 75 microg.
        For a calculated dose >75 microg. round up to 150 microg.
Neonatal abstinence syndrome (NAS)
  • Oral
    • Term neonate
      [3] [4] [19] [20] [21]
      • Initial dose: Clonidinehydrochloride: 0.5 - 1 microg./kg/dose, once only.
      • Maintenance dose: Slowly increase the starting dose, depending on withdrawal symptoms and blood pressure, over 1 to 2 days to 6 - 9 microg./kg/day in 4 - 6 doses.

      • Clonidine must be discontinued gradually (reduce the daily dose by 10% every day) in order to avoid rebound hypertension.

         
Hypertension
  • Oral
    • 1 month up to 18 years
      [26] [27]
      • Initial dose: 5 - 10 microg./kg/day in 3 - 4 doses.
      • Maintenance dose: Depending on the effect, the initial dose may be increased every 4-7 days to a maximum of 25 microg./kg/day in 3 - 4 doses. Max: 900 microg./day.

      • Clonidine must be discontinued gradually in order to avoid rebound hypertension.
As an adjuvant with other analgesics
  • Caudal
    • 6 months up to 18 years
      • Clonidinehydrochloride: 0.5 - 1 microg./kg/dose, once only. Max: 2 microg./kg/dose.

      • Only use the higher dose of 2 µg / kg if sedation is not a problem.

  • Epidural
    • 6 months up to 18 years
      • Clonidinehydrochloride:  0.5 - 1 microg./kg/dose, once only. Max: 2 microg./kg/dose. Administer through catheter:.
        • The higher dose of 2 µg/kg can cause sedation
        • Clonidine can be administered through an epidural continuous infusion, dose 0,12-0,16 µg/kg/hour. [SKA expert opinion 2018]
Sedation in IC: Adjuvant with benzodiazepines
  • Intravenous
    • 1 month up to 18 years
      • Initial dose: Clonidinehydrochloride: 0.5 microg./kg/hour, continuous infusion.
      • Maintenance dose: Increase the initial dose until the desired effect is obtained, to a maximum of 3 microg./kg/hour, continuous infusion.
        • If an effect is needed rapidly, a loading dose of 2-5 mcg/kg can be given in 15 minutes.
        • Clonidine must be discontinued gradually in order to avoid rebound hypertension.
    • Term neonate
      • Initial dose: Clonidinehydrochloride: 0.5 microg./kg/hour, continuous infusion.
      • Maintenance dose: Increase the initial dose until the desired effect is obtained, to a maximum of 3 microg./kg/hour, continuous infusion.
        • If an effect is needed rapidly, a loading dose of 1 mcg/kg can be given in 15 minutes.
        • Clonidine must be discontinued gradually in order to avoid rebound hypertension.

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

When used as a psychopharmaceutical: Hypotension, bradycardia, sedation, dizziness, depressive symptoms (sad, listless, irritated behaviour), headaches and obstipation. Clear ECG changes have not been observed.

The most common side effects in pediatric studies were drowsiness, dry mouth, headache, dizziness, and sleeping disorders. In children and adolescents, these side effects could have a significant impact on everyday behavior [SmPC Catapresan tablets].

In overdoses in children: Respiratory depression, loss of consciousness, cardiac side effects, severe hypotension, paradoxical blood pressure increases, hyperglycaemia, hypothermia.

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

Contra-indications in children

Severe bradyarrhythmias (sick sinus syndrome, second or third-degree AV block).

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

  • Sudden interruption of treatment: a rebound phenomenon may occur, with an acute increase in blood pressure, tachycardia, restlessness, nervousness, tremors, headaches and/or nausea. Clonidine should not be discontinued abruptly and/or without replacement.
  • Combination with beta-blockers: first slwoly discontinue beta-receptor blocker, afterwards clonidine dosis. This prevents threatening undesirable effects (sympathetic overreactivity).

Checks to see if there are any existing cardiac problems (in the tension or rhythm) in the child or their family before treatment commences. In the event of dizziness or heart palpitations, or if arrhythmia is suspected, the blood pressure and pulse rate (rhythm and regularity) should be checked, both before and during treatment. The systolic and diastolic blood pressure drop with clonidine by approximately 10 mmHg; however, this has no clinical relevance. Complaints that arise during physical effort should be investigated thoroughly, though. ECG is indicated if there are any doubts about the cardiovascular condition.

To avoid sudden drops and rises in the blood pressure, it is recommended that clonidine should be commenced gradually at the start of the therapy and gradually discontinued (over several days) if the treatment is discontinued. The blood pressure and pulse rate should be checked regularly during the treatment.

When used as a psychopharmaceutical:
Mild sedation often occurs in the first weeks. If the side effects (sedation, dizziness) are too disruptive, the dose should be lowered. The sedation generally disappears. Clonidine is mostly given in three doses (with breakfast and lunch, and before going to bed). It can take up to 3 months for clonidine to have its full effect. The parents and the child must be aware of this. If there is no clear effect yet after a month, the dose can be increased. If there is still no effect at all after a second month, clonidine is then deemed to be ineffective. If a decision is made after two or three months to continue the medication, six-monthly medication checks (effects, side effects and weight) are recommended. A check to see if the medication can be discontinued can be made every year.

Extra alertness is needed in patients with depression symptoms, as these can be exacerbated.


Interactions

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

ANTIADRENERGIC AGENTS, CENTRALLY ACTING

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

Imidazoline receptor agonists
C02AC02

References

  1. Rademaker C.M.A. et al, Geneesmiddelen-Formularium voor Kinderen, 2007
  2. Landelijk Kenniscentrum Kind-enJeugdpsychiatrie (Ketelaars), Adrenerge middelen, 2009
  3. Hoder EL, et al, Clonidine treatment of neonatal narcotic abstinence syndrome, Psychiatry Res., 1984, 13, 243-51
  4. Osborn DA, et al., Sedatives for opiate withdrawal in newborn infants, Cochrane Database Syst Rev., 2010, Oct 6;(10), CD002053
  5. Potts AL, et al, Clonidine disposition in children; a population analysis, Paediatr Anaesth., 2007, 17, 924-33
  6. CBO, ADHD- Richtlijn voor de diagnostiek en behandeling van ADHD bij kinderen en jeugdigen, www.cbo.nl, 2005
  7. Ambrose C et al., Intravenous clonidine infusion in critically ill children: dose-dependent sedative effects and cardiovascular stability. , Br J Anaesth , 2000, 84(6), 794-6
  8. Arenas-Lopez S et al., Use of oral clonidine for sedation in ventilated paediatric intensive care patients., Intensive Care Med, 2004, 30(8), 1625-9
  9. Duffett M et al., Clonidine in the sedation of mechanically ventilated children: A pilot randomized trial. , J Crit Care, 2014, 29(5), 758-63
  10. Hünseler C et al., Continuous infusion of clonidine in ventilated newborns and infants: a randomized controlled trial., Pediatr Crit Care Med, 2014, 15(6), 511-22
  11. Pohl-Schickinger A et al. , Intravenous clonidine infusion in infants after cardiovascular surgery., Paediatr Anaesth, 2008, 18(3), 217-22
  12. Wolf A et al., Prospective multicentre randomised, double-blind, equivalence study comparing clonidine and midazolam as intravenous sedative agents in critically ill children: the SLEEPS study., Health Technol Assess, 2014, 18(71), 1-212
  13. Connor DF et al., A meta-analysis of clonidine for symptoms of attention-deficit hyperactivity disorder., J Am Acad Child Adolesc Psychiatry., 1999, Dec;38(12), 1551-9
  14. Palumbo DR et al., Clonidine for attention-deficit/hyperactivity disorder: I. Efficacy and tolerability outcomes., J Am Acad Child Adolesc Psychiatry., 2008, Feb;47(2), 180-8
  15. Tourette's Syndrome Study Group. , Treatment of ADHD in children with tics: a randomized controlled trial. , Neurology. , 2002 , Feb 26;58(4), 527-36
  16. Prince JB et al., Clonidine for sleep disturbances associated with attention-deficit hyperactivity disorder: a systematic chart review of 62 cases., J Am Acad Child Adolesc Psychiatry., 1996, May;35(5), 599-605
  17. Noordam C et al., Werkboek Kinderendocrinologie. , Digitale publicatie op www.nvk.nl (alleen leden). , 2010
  18. Romer TE et al., Oral clonidine for screening of growth hormone deficiency., Panminerva Med., 1982, Jul-Sep;24(3), 231-5.
  19. Agthe AG et al., Clonidine as an adjunct therapy to opioids for neonatal abstinence syndrome: a randomized, controlled trial., Pediatrics., 2009, May;123(5), e849-56
  20. Surran B et al. , Efficacy of clonidine versus phenobarbital in reducing neonatal morphine sulfate therapy days for neonatal abstinence syndrome. A prospective randomized clinical trial. , J Perinatol., 2013, Dec;33(12), 954-9
  21. Hudak ML et al., Neonatal drug withdrawal. , Pediatrics., 2012 , Feb;129(2), e540-60
  22. Larsson P et al., Oral bioavailability of clonidine in children., Paediatr Anaesth., 2011, Mar;21(3), 335-40
  23. Xie HG et al, Clonidine clearance matures rapidly during the early postnatal period: a population pharmacokinetic analysis in newborns with neonatal abstinence syndrome, J Clin Pharmacol., 2011, Apr;51(4), 502-11
  24. Klein RH et al., Pharmacokinetics and pharmacodynamics of orally administered clonidine: a model-based approach., Horm Res Paediatr., 2013, 79(5), 300-9
  25. Sheng Y et al. , Pharmacokinetic reason for negative results of clonidine sedation in long-term-ventilated neonates and infants. , Pediatr Crit Care Med, 2015, 16(1), 92-3
  26. Lurbe E et al. , 2016 European Society of Hypertension guidelines for the management of high blood pressure in children and adolescents. , J Hypertens., 2016, Oct;34(10):, 1887-920
  27. NVK, Sectie kindernefrologie. , Expertopinie dosering hypertensie. , 18-12-2017
  28. Kleiber N et al. , Population pharmacokinetics of intravenous clonidine for sedation during paediatric extracorporeal membrane oxygenation and continuous venovenous hemofiltration. , Br J Clin Pharmacol., 2017, Jun;83(6), 1227-1239
  29. Akin, A. et al, The effects of caudal or intravenous clonidine on postoperative analgesia produced by caudal levobupivacaine in children, Paediatr Anaesth, 2010, 20(4), 350-5
  30. Cao, J. et al, Effects of premedication of midazolam or clonidine on perioperative anxiety and pain in children, Biosci Trends, 2009, 3(3), 115-8
  31. Inomata, S. et al, The hypnotic and analgesic effects of oral clonidine during sevoflurane anesthesia in children: a dose-response study, 2002, 94(6), 1479-83
  32. Ivani, G. at el, Spinal versus peripheral effects of adjunct clonidine: comparison of the analgesic effect of a ropivacaine-clonidine mixture when administered as a caudal or ilioinguinal-iliohypogastric nerve blockade for inguinal surgery in children, Paediatr Anaesth, 2002, 12(8), 680-4
  33. Lambert, P. et al, Clonidine premedication for postoperative analgesia in children, Cochrane Database Syst, 2014, Rev (1), Cd009633
  34. Sharpe, P. et al, Analgesia for circumcision in a paediatric population: comparison of caudal bupivacaine alone with bupivacaine plus two doses of clonidine., Paediatr Anaesth, 2001, 11(6), 695-700
  35. Sectie kinderanesthesiologie, Expert opinie SKA november 2018
  36. Tazeroualti, N. et al, Oral clonidine vs midazolam in the prevention of sevoflurane-induced agitation in children. a prospective, randomized, controlled trial., Br J Anaesth, 2007, 98(5), 667-71
  37. Vetter, T.R. et al, A comparison of single-dose caudal clonidine, morphine, or hydromorphone combined with ropivacaine in pediatric patients undergoing ureteral reimplantation, Anesth Analg, 2007, 104(6), 1356-63
  38. Boehringer Ingelheim, SmPC Catapresan 0,15 mg Tbl. (13874), 03/2018
  39. Lurbe E et al., 2016 European Society of Hypertension guidelines for the management of high blood pressure in children and adolescents., J Hypertens., 2016, Oct;34(10):, 1887-920
  40. Duffett M et al., Clonidine in the sedation of mechanically ventilated children: A pilot randomized trial., J Crit Care, 2014, 29(5), 758-63
  41. Kleiber N et al., Population pharmacokinetics of intravenous clonidine for sedation during paediatric extracorporeal membrane oxygenation and continuous venovenous hemofiltration., Br J Clin Pharmacol., 2017, Jun;83(6), 1227-1239
  42. Sheng Y et al., Pharmacokinetic reason for negative results of clonidine sedation in long-term-ventilated neonates and infants., Pediatr Crit Care Med, 2015, 16(1), 92-3
  43. Tourette's Syndrome Study Group., Treatment of ADHD in children with tics: a randomized controlled trial., Neurology., 2002, Feb 26;58(4), 527-36
  44. Noordam C et al., Werkboek Kinderendocrinologie., Digitale publicatie op www.nvk.nl (alleen leden)., 2010
  45. Hudak ML et al., Neonatal drug withdrawal., Pediatrics., 2012, Feb;129(2), e540-60
  46. Surran B et al., Efficacy of clonidine versus phenobarbital in reducing neonatal morphine sulfate therapy days for neonatal abstinence syndrome. A prospective randomized clinical trial., J Perinatol., 2013, Dec;33(12), 954-9
  47. NVK, Sectie kindernefrologie., Expertopinie dosering hypertensie., 18-12-2017
  48. Ambrose C et al., Intravenous clonidine infusion in critically ill children: dose-dependent sedative effects and cardiovascular stability., Br J Anaesth, 2000, 84(6), 794-6
  49. Pohl-Schickinger A et al., Intravenous clonidine infusion in infants after cardiovascular surgery., Paediatr Anaesth, 2008, 18(3), 217-22

Changes

Therapeutic Drug Monitoring


Overdose