Pharmacokinetics in children

The following kinetic parameters have been observed (Aggarwal, Lipman, Peltola, Rubio and Zhao):

	Age	Dose	Cmax ss (mg/l)	T½ ss (hours)	Cl (l/hour/kg)	V (l/kg)
ORAL	> 3 months to 7 years	30 mg/kg	1.95-3.57	4.2-5.1	0.98-1.46	-
	5-17 years with CF	40 mg/kg	3.4-4.4	3.3-3.6	0.98-1.23	-
IV	0-3 months	20 mg/kg	2.3-3	-	0.04-0.81	0.4-3.55
	>3 months to 5 years	20 mg/kg	5.81-9.03	2.82-4.23	0.49-0.68	1.43-2.06
	5-17 years with CF	30 mg/kg	3.6-5.5	2.6-2.8	0.81-0.91	-

From the study by Payen et al. (N=55, 1 day – 24 years) it can be seen that the clearance in CF children is about twice as high as that in non-CF children.

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

Complicated urinary tract infections, pyelonephritis, sepsis and febrile neutropenia

Oral 1 month up to 18 years [14] [15] [27] [28] 30 mg/kg/day in 2 doses. Max: 1.500 mg/day. Duration of treatment: see the treatment protocol for each indication. The duration of treatment can vary from 7-21 days. Intravenous Premature infants Postmenstrual age < 34 weeks [24] 15 mg/kg/day in 2 doses. The scientific foundations for using ciprofloxacin in premature infants are limited; this dosage is based on a population pharmacokinetics model (Zhao). Premature infants Postmenstrual age ≥ 34 weeks [24] 25 mg/kg/day in 2 doses. The scientific foundations for using ciprofloxacin in premature infants are limited; this dosage is based on a population pharmacokinetics model (Zhao). 1 month up to 18 years [14] [15] [27] [28] 20 - 30 mg/kg/day in 2 - 3 doses. Max: 1.200 mg/day. Max single dose: 400 mg/dose. Duration of treatment: see the treatment protocol for each indication. The duration of treatment can vary from 7-21 days.

Bronchopulmonary infections in cystic fibrosis, caused by Pseudomonas aeruginosa

Oral 1 month up to 18 years [4] [18] [19] [25] 40 mg/kg/day in 2 doses. Max: 2.000 mg/day. Duration of treatment: See treatment protocol. The duration of treatment can vary from 10-21 days Intravenous 1 month up to 18 years [4] [18] [19] [25] 30 mg/kg/day in 2 - 3 doses. Max: 1.200 mg/day. Duration of treatment: See treatment protocol. The duration of treatment can vary from 10-14 days; switch to oral administration in sequential treatment after a number of days

Selective bowel decontamination for immunocompromised patients with aplasia
Oral 1 month up to 18 years [14] [15] [21] 30 mg/kg/day in 2 doses. Max: 1.000 mg/day. Intravenous 1 month up to 18 years [14] [15] 30 mg/kg/day in 2 doses. Max: 800 mg/day. Max single dose: 400 mg/dose.

Post-exposure prophylaxis and treatment of anthrax

Oral 1 month up to 18 years [9] [10] [13] [27] 30 mg/kg/day in 2 doses. Max: 1.000 mg/day. Duration of treatment: See the treatment protocol: often 60 days in a proven B. anthracis infection. Stop the prophylaxis if B. anthracis is not demonstrably present. Intravenous 1 month up to 18 years [9] [10] [13] [28] 20 mg/kg/day in 2 doses. Max: 800 mg/day. Duration of treatment: See the treatment protocol: often 60 days in a proven B. anthracis infection. Stop the prophylaxis if B. anthracis is not demonstrably present.

Perianal fistulae in Crohn’s disease
Oral 1 month up to 18 years [26] 20 mg/kg/day in 2 doses. Max: 1.000 mg/day.

Tularemia, plague

Oral 1 month up to 18 years [29] [30] 30 mg/kg/day in 2 doses. Max: 1.000 mg/day. Duration of treatment: Plague: treatment 10 days; prophylaxis 7 days Tularemia: treatment at least 10 days, prophylaxis at least 14 days. Tularemia: in a very large number of victims as a result of large-scale exposure and as post-exposure prophylaxis. Intravenous 1 month up to 18 years [29] [30] 30 mg/kg/day in 2 doses. Max: 800 mg/day. Duration of treatment: Plague: treatment 10 days; Tularemia: treatment at least 10 days. Tularemia: in incidental cases or a limited number of victims as a result of a bioterrorist attack.

Infections (without clinical suspicion of meningitis) caused by microorganisms susceptible at increased exposure ('I')
Oral 1 month up to 18 years [27] [46] [47] 30 - 40 mg/kg/day in 2 doses. Max: 1.500 mg/day. Intravenous 1 month up to 18 years [28] [46] [47] 30 mg/kg/day in 3 doses. Max: 1.200 mg/day.

Renal impaiment in children > 3 months

Adjustment in renal impairment as specified:

GFR 50-80 ml/min/1.73 m2

Adjustment not necessary.

GFR 30-50 ml/min/1.73 m2

Dose adjustment not needed.

GFR 10-30 ml/min/1.73 m2

100 percentage of single dose and dosing interval : 24 uur

GFR < 10 ml/min/1.73 m2

100 percentage of single dose and dosing interval : 24 uur

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

Gastrointestinal problems such as stomach pain, abdominal pain, anorexia, nausea, vomiting, diarrhoea, pseudomembranous colitis, dyspepsia, flatulence. Central side effects such as headaches, sleep disorders, dizziness, drowsiness, transpiration, paraesthesia, peripheral neuropathy, vision disorders, confusion, convulsions, restlessness, panic reaction, hallucinations, olfactory and colour vision and taste disturbances, anxiety, depression, tiredness. Arthralgia, arthropathy, hepatic and/or renal function disorders, thrombophlebitis, abnormal blood counts, tachycardia, hypotension, anaemia, asthenia, fever, pain in the extremities. Two cases of dental dyschromia have been described in the literature.

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

Slow infusion into a large vein or through a central line is desirable to minimize patient discomfort due to the low PH of the infusion solution and to reduce the risk of venous irritation.

Caution is needed when giving quinolones to children in the growth phase. Using them should be restricted to cases in which there are no other therapeutic possibilities.

In the primary healthcare sector, ciprofloxacin should not be given to children because of resistance issues.

Quinolones are known to trigger epileptic seizures or to lower the threshold for epileptic seizures. Ciprofloxacin must be used with caution in patients with conditions of the CNS that can have a tendency to cause epileptic seizures.

In experimental animal research, arthropathy was observed to a varying extent when very high doses were given to young dogs. These side effects have never been reported in humans either: fluoroquinolones are therefore being used to an increasing extend in children if there are no other therapeutic possibilities or if there are serious objections against the use of other broad-spectrum antibiotics.

Do not administer together with dairy product due to the interaction with calcum salts.
 

Interactions

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

• ANTIINFECTIVES FOR SYSTEMIC USE
• ANTIBACTERIALS FOR SYSTEMIC USE

QUINOLONE ANTIBACTERIALS

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

Fluoroquinolones
	Levofloxacin Related Medicines Menu">	J01MA12

References

1. Aggarwal P, et al, Multiple dose pharmacokinetics of ciprofloxacin in preterm babies, Indian Pediatr., 2004, 41, 1001-7
2. CBO, Richtlijn Diagnostiek en behandeling Cystic Fibrosis, www.cbo.nl, 2007
3. Belet N, et al, Ciprofloxacin treatment in newborns with multi-drug-resistant nosocomial Pseudomonas infections., Biol Neonate., 2004, 85, 263-8
4. Church DA, Sequential ciprofloxacin therapy in pediatric cystic fibrosis: Comparative study vs. ceftazidime/tobramycin in the treatment of acute pulmonary, Pediatr Infect Dis J, 1997, 16, 97-105
5. Chyský V, et al, Safety of ciprofloxacin in children: worldwide clinical experience based on compassionate use. Emphasis on joint evaluation., Infection, 1991, 19, 289-96
6. Drossou-Agakidou V, et al, Use of ciprofloxacin in neonatal sepsis: lack of adverse effects up to one year, Pediatr Infect Dis J, 2004, 23, 346-9
7. Grady R, Safety profile of quinolone antibiotics in the pediatric population, Pediatr Infect Dis J, 2003, 22, 1128-32
8. Hampel B, et al, Ciprofloxacin in pediatrics: worldwide clinical experience based on compassionate use--safety report., Pediatr Infect Dis J, 1997, 16, 127-9
9. Inglesby TV, et al, Anthrax as a biological weapon, 2002: updated recommendations for management, JAMA, 2002, 287, 2236-52
10. Inglesby TV, et al, Plague as a biological weapon: medical and public health management. Working Group on Civilian Biodefense, JAMA, 2000, May 3 283(17), 2281-90
11. Koyle MA, et al, Pediatric urinary tract infections: the role of fluoroquinolones, Pediatr Infect Dis J, 2003, 22, 1133-7
12. Lipman J, et al, Ciprofloxacin pharmacokinetic profiles in paediatric sepsis: how much ciprofloxacin is enough?, Intensive Care Med., 2002, 28, 493-500
13. Meyerhoff A, et al, US Food and Drug Administration approval of ciprofloxacin hydrochloride for management of postexposure inhalational anthrax., Clin Infect Dis, 2004, 39, 303-8
14. Mullen CA, Ciprofloxacin in treatment of fever and neutropenia in pediatric cancer patients., Pediatr Infect Dis J, 2003, 22, 1138-42
15. Paganini H, et al, Oral ciprofloxacin in the management of children with cancer with lower risk febrile neutropenia, Cancer., 2001, 91, 1563-7
16. Peltola H, et al, Single-dose and steady-state pharmacokinetics of a new oral suspension of ciprofloxacin in children, Pediatrics, 1998, 101, 658-62
17. Payen S, et al, Population pharmacokinetics of ciprofloxacin in pediatric and adolescent patients with acute infections, Antimicrob Agents Chemother., 2003, 47, 3170-8
18. Rubio TT, et al, Pharmacokinetic disposition of sequential intravenous/oral ciprofloxacin in pediatric cystic fibrosis patients with acute pulmonary exacerbation, Pediatr Infect Dis J, 1997, 16, 112-7
19. Schaad UB, et al, Ciprofloxacin as antipseudomonal treatment in patients with cystic fibrosis., Pediatr Infect Dis J., 1997, 16, 106-111
20. van den Oever HL, et al, Ciprofloxacin in preterm neonates: case report and review of the literature, Eur J Pediatr, 1998, 157, 843-5
21. R. Pieters, et al, Richtlijnen supportive care kinderoncologie Erasmus MC – Sophia Kinderziekenhuis., Geraadpleegd op 29 maart 2010, http://www.erasmusmc.nl/alkg-cs/242905/242981/supcare?version=1
22. NHG, Standaard Urineweginfecties, H&W , 2005, 48, 341-53
23. Van Pinxteren B et al, NHG Standaard Urineweginfecties (derde herziening), Huisarts Wet, 2013, 56(6), 270-80
24. Zhao W et al, Population pharmacokinetics of ciprofloxacin in neonates and young infants less than three months of age. , Antimicrob Agents Chemother., 2014, Nov;58(11), 6572-80
25. Guillot E et al, Suboptimal ciprofloxacin dosing as a potential cause of decreased Pseudomonas aeruginosa susceptibility in children with cystic fibrosis., Pharmacotherapy, 2010, Dec;30(12), 1252-8
26. Ruemmele FM et al, Consensus guidelines of ECCO/ESPGHAN on the medical management of pediatric Crohn’s disease., J Crohns Colitis, 2014, Oct;8(10), 1179-207
27. Bayer B.V., SmPC Ciproxin suspensie (RVG 19342) 01-08-2022, www.geneesmiddeleninformatiebank.nl
28. Mylan BV, SmPC Ciprofloxacine infusie (RVG 29032) 27-11-2020, www.geneesmiddeleninformatiebank.nl
29. LCI, Richtlijn tularemie (laatst gewijzigd 2017), http://www.rivm.nl/Onderwerpen/L/LCI_Richtlijnen
30. LCI, Richtlijn pest (publicatiedatum 10-12-2013), http://www.rivm.nl/Onderwerpen/L/LCI_Richtlijnen
31. Yildirim P., Association Patterns in Open Data to Explore Ciprofloxacin Adverse Events, Appl Clin Inform., 2015 Dec, 16;6(4), 728-47
32. Hexal AG, SmPC CiproHEXAL Infusionslösung (58855.00.00/ 58856.00.00), 11/2015
33. Fresenius Kabi Deutschland GmbH, SmPC Ciprofloxacin Kabi Infusionlösung (64688.00.00/ 64689.00.00/ 64690.00.00), 04/2017
34. Hikma Pharma GmbH, SmPC Ciprofloxacin Hikma 2 mg/ml Infusionslösung (64983.00.00), 10/2014
35. Bayer Vital GmbH, SmPC Ciprobay 400 mg (8242.05.02), 12/2015
36. Bayer Vital GmbH, SmPC Ciprobay Saft 10% (36212.01.00), 05/2016
37. Aliud Pharma GmbH, SmPC Ciprofloxacin AL (51992.00.00 / 51993.00.00 / 51993.01.00 / 51993.02.00), 03/2017
38. Ratiopharm GmbH, SmPC Ciprofloxacin-ratiopharm 100/ 250/ 500/ 750 mg Filmtabletten (50514.00.00 / 50514.01.00 / 50514.02.00 / 50514.03.00), 11/2015
39. Bayer Vital GmbH, SmPC Ciprobay 750 mg (8242.03.00), 12/2015
40. Bayer Vital GmbH, SmPC Ciprobay 500 mg (8242.02.00), 12/2015
41. Bayer Vital GmbH, SmPC Ciprobay 250 mg (8242.01.00), 12/2015
42. Bayer Vital GmbH, SmPC Ciprobay Saft 5% (36212.00.00), 05/2016
43. Bayer Vital GmbH, SmPC Ciprobay 200 mg (8242.04.02), 12/2015
44. Bayer Int, DHPC Fluorochinolonen, 29 maart 2019
45. BfArM., Rote-Hand-Brief zu Fluorchinolon-Antibiotika. 08.04.2019. https://www.bfarm.de/SharedDocs/Risikoinformationen/Pharmakovigilanz/DE/RHB/2019/rhb-fluorchinolone.pdf;jsessionid=4D7FF38A3DCDA1F9795930B56FD1B5E8.2_cid329?__blob=publicationFile&v=3, zuletzt aufgerufen am 12.04.2019.
46. Dutch Working Party on Antibiotic Policy (SWAB) - Special Interest Group Pediatrics, Expert opinion on high dosing for infections caused by microorganisms susceptible to increased doses., Dec 6, 2022
47. European Committee on Antimicrobial Susceptibility Testing - EUCAST, Clinical breakpoints - breakpoints and guidance, https://www.eucast.org/clinical_breakpoints, Jan2, 2023

Changes

Therapeutic Drug Monitoring

Overdose