Pharmacokinetics in children

In adults, 80% of each eye drop passes through the nasolacrimal system, from where it is rapidly absorbed into the systemic circulation via the nasal mucosa, conjunctiva, lacrimal duct, oropharynx and intestines, or via the skin through tear flow. Because blood volume is lower in children than in adults, a potentially higher circulation concentration must be taken into account. In addition, enzyme metabolism is not yet fully developed in newborns, which may result in a prolonged elimination half-life and an increased likelihood of side effects. Limited data indicate that plasma timolol levels in children after a dose of 0.25% are much higher than those in adults after 0.5%, particularly in infants; this is thought to lead to an increased risk of side effects such as bronchospasm and bradycardia [SmPC Timolol Sandoz].

The absorption of topically applied timolol was investigated in 40 infants (median age 18 weeks (range 2-25). They were treated with topical timolol gel 0.5% twice daily. Urinalysis was positive in 20/24 patients and serum timolol levels were median 0.16 ng/mL [range 0.1–0.18 ng/mL] (n=3) [Weibel 2016].

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

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

Opthalmic
Because of the relatively high concentrations in the blood, the risk of side effects is greater in (younger) children [SmPC Timolol].

Transdermal
Dyspnea and insomnia [Tawfik 2015], sleep disturbance [Chakkittakandiyil 2012; Xia 2025], respiratory problems, localized skin irritation (desquamation, erythema, itching) and residual skin lesions [Xia 2025; Püttgen 2016]. It should be noted that the study by Xia (2025) was conducted during the COVID-19 pandemic, which may have contributed to the reported respiratory problems.

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

Opthalmic

• Be extremely cautious with neonates, infants and young children because of the risk of apnoea and Cheyne-Stokes respiration.
• Particularly in younger children on strict indication
• Especially in neonates, closely monitor the child for ocular and systemic side effects for 1–2 hours after the first dose. Keep the tear duct closed for 3–5 minutes.
• The eye gel (Timogel) and eye drops that form a gel after administration (Timoptol “XE”) have not been studied in children.
• For use in children, a concentration of 0.1% active ingredient may be sufficient.

Topical timolol for infantile haemangiomas 

• Use caution when treating premature infants who have not yet reached a postmenstrual age (PMA) of 44 weeks, as well as infants with a documented history of apnea or bradycardia. In premature and low-birthweight infants with complicated haemangiomas, we recommend close monitoring of temperature, blood pressure, and heart rate when initiating topical timolol and throughout treatment [Frommelt 2016]. 
• Use caution when treating ulcerated haemangiomas, as application may be painful and impaired skin barrier may increase systemic absorption. There are documented cases of bradycardia and hypothermia in infants receiving timolol on high permeability areas, such as ulcerated haemangiomas and haemangiomas involving the eyelid, diaper region, or mucosal surfaces [Frommelt 2016]. Efficacy in ulcerated haemangiomas is limited. Measuring heart rate 2–4 hours after application is recommended, particularly in preterm or young infants [Püttgen 2016; Weibel 2016]. 
• Caution is also warranted when timolol is used under occlusion. Occlusive application is expected to substantially increase absorption, reaching levels comparable to ophthalmic use, with a risk of therapeutic or supratherapeutic serum levels. Certain hemangioma locations may further increase systemic exposure and toxicity risk, including intraocular sites, ulcerated lesions, mucosal surfaces, and eyelid skin [Weibel 2016; Frommelt 2016]
• The gel-forming solution may reduce systemic absorption due to its higher viscosity compared to the liquid solution [Khan 2017]. Consequently, the systemic absorption of timolol maleate gel formulation is significantly less than that of timolol maleate solution and hence has been favoured in more recent studies [Chan 2013]. 

Interactions

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

References

1. Rademaker C.M.A. et al, Geneesmiddelen-Formularium voor Kinderen, 2007
2. MSD BV, SPC Timoptol (RVG 17017) 31-03-2015, www.cbg-meb.nl
3. Frommelt P, et al, Adverse Events in Young and Preterm Infants Receiving Topical Timolol for Infantile Hemangioma, Pediatr Dermatol., 2016
4. Cheng J, et al, Randomised controlled trial: Can topical timolol maleate prevent complications for small superficial infantile haemangiomata in high-risk areas?, Pediatr Res, 2020
5. Chakkittakandiyil A, et al, Timolol Maleate 0.5% or 0.1% Gel‐Forming Solution for Infantile Hemangiomas: A Retrospective, Multicenter, Cohort Study, Pediatric Dermatology, 2012
6. Püttgen K, et al, Topical Timolol Maleate Treatment of Infantile Hemangiomas., Pediatrics., 2016
7. Gong H, et al, Evaluation of the efficacy and safety of propranolol, timolol maleate, and the combination of the two, in the treatment of superficial infantile haemangiomas., Br J Oral Maxillofac Surg., 2015
8. Yu L, et al, Treatment of superficial infantile hemangiomas with timolol: Evaluation of short-term efficacy and safety in infants., Exp Ther Med., 2013
9. Chan H, et al, RCT of timolol maleate gel for superficial infantile hemangiomas in 5- to 24-week-olds, Pediatrics, 2013
10. Khan M, et al, The Role of Topical Timolol in the Treatment of Infantile Hemangiomas: A Systematic Review and Meta-analysis, Acta Derm Venereol., 2017
11. Moehrle M, et al, Topical Timolol for Small Hemangiomas of Infancy., Pediatric Dermatology., 2013
12. Ni N, et al, Topical Timolol for Periocular Hemangioma: Report of Further Study., Archives of Ophthalmology., 2011
13. Park K, et al, Topical timolol maleate 0.5% for infantile hemangioma; it’s effectiveness and/or adjunctive pulsed dye laser – single center experience of 102 cases in Korea., Journal of Dermatological Treatment., 2015
14. Tawfik A, et al, Topical timolol solution versus laser in treatment of infantile hemangioma: a comparative study., Pediatr Dermatol., 2015
15. Xu D, et al, Topical timolol maleate for superficial infantile hemangiomas: an observational study., Oral Maxillofac Surg., 2015
16. Weibel L, et al, Topical Timolol for Infantile Hemangiomas: Evidence for Efficacy and Degree of Systemic Absorption., Pediatr Dermatol., 2016
17. Xia M, et al, The timing and safety of topical timolol treatment for superficial infantile hemangioma: a retrospective cohort study., European Journal of Pediatrics., 2025
18. Sandoz B.V., SmPC Timolol Sandoz 2,5 mg/ml (RVG 57608, 57609), www.cbg-meb.nl, 8-2024

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