Pharmacokinetics in children

The following kinetic parameters were found on day 7 and in month 3 respectively after administration of 0.8 mg/m² everolimus twice daily:
Cmax: 13.5 ng/ml and 10.1 ng/ml respectively
Cl/F: 10.2 l/hour/m² and 12.3 l/hour/m² respectively
tmax: 1 hour and 1 hour respectively
The following half-lives were found after administration of 2.1, 3, 5 and 6.5 mg/m² respectively:
t½: 18, 15.9, 17.7, 15.2 hours respectively.

Limited data in patients aged < 3 years (n=13) indicates that the BSA-normalized clearance is approximately twice as high in patients with a small body size (BSA 0.556 m²) as in adults. 
 

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

Prophylaxis for rejection of a transplanted kidney
Oral 1 year up to 18 years [1] [4] [6] [7] [12] 1.6 - 3 mg/m²/day in 2 doses. The dose must be titrated to achieve trough concentrations of 3-8 ng/ml

Subependymal giant cell astrocytoma (SEGA) associated with tuberous sclerosis complex (TSC)

Oral 1 year up to 3 years [5] 7 mg/m²/day in 1 dose The dose must be titrated to achieve trough concentrations of 5–15 ng/ml. The dose may be increased in order to obtain a greater trough concentration in the whole blood that is then within the target range for obtaining the optimum efficacy, taking account of the tolerability. 3 years up to 18 years [5] 4.5 mg/m²/day in 1 dose The dose must be titrated to achieve trough concentrations of 5–15 ng/ml. The dose may be increased in order to obtain a greater trough concentration in the whole blood that is then within the target range for obtaining the optimum efficacy, taking account of the tolerability.

Refractory epileptic seizures associated with TSC WITHOUT CYP3A4/PgP inducer

Oral < 6 years [5] [11] Initially: 6 mg/m²/day in 1 dose Increase the starting dose in steps of 1-4 mg, depending on the concentrations.. The dose must be titrated to achieve trough concentrations of 5–15 ng/ml. The dose may be increased in order to obtain a greater trough concentration in the whole blood that is then within the target range for obtaining the optimum efficacy, taking account of the tolerability. ≥ 6 years [5] [11] Initially: 5 mg/m²/day in 1 dose Increase the starting dose in steps of 1-4 mg, depending on the concentrations.. The dose must be titrated to achieve trough concentrations of 5–15 ng/ml. The dose may be increased in order to obtain a greater trough concentration in the whole blood that is then within the target range for obtaining the optimum efficacy, taking account of the tolerability.

Refractory epileptic seizures associated with TSC combined with CYP3A4/PgP inducer

Oral < 6 years [5] [11] Initially:  9 mg/m²/day in 1 dose Increase the starting dose in steps of 1-4 mg, depending on the concentrations.. The dose must be titrated to achieve trough concentrations of 5–15 ng/ml. The dose may be increased in order to obtain a greater trough concentration in the whole blood that is then within the target range for obtaining the optimum efficacy, taking account of the tolerability. ≥ 6 years [5] [11] Initially: 8 mg/m²/day in 1 dose Increase the starting dose in steps of 1-4 mg, depending on the concentrations.. The dose must be titrated to achieve trough concentrations of 5–15 ng/ml. The dose may be increased in order to obtain a greater trough concentration in the whole blood that is then within the target range for obtaining the optimum efficacy, taking account of the tolerability.

Renal impaiment in children > 3 months

No information available on dose adjustment in renal impairment.

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

Mouth ulcers [Franz 2016]. Cases of exacerbation (Wiemer-Kruel and Krueger) and even initiation (Krueger) of epileptic seizures when everolimus is used have been described. Infections are more common in children and more serious. 

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

Contra-indications in children

Impaired liver function.

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

If the patient has not yet completed the National Vaccination Programme, it is preferable to complete it first, if possible and accelerated if necessary.

Interactions

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

Other immunosuppressants
	Azathioprine Related Medicines Menu">	L04AX01
	Methotrexate Related Medicines Menu">	L04AX03

Tumor necrosis factor alpha (TNF-alpha) inhibitors
	Adalimumab Related Medicines Menu">	L04AB04
	Etanercept Related Medicines Menu">	L04AB01
	Infliximab Related Medicines Menu">	L04AB02

Calcineurin inhibitors
	Ciclosporin Related Medicines Menu">	L04AD01
	Tacrolimus Related Medicines Menu">	L04AD02

References

1. Ettenger R et al, Multicenter trial of everolimus in pediatric renal transplant recipients: results at three year, Pediatr Transplant, 2008 , Jun;12(4), 456-63
2. Fouladi M et al, Phase I study of everolimus in pediatric patients with refractory solid tumors, J Clin Oncol, 2007 , Oct 20;25(30), 4806-12
3. Franz DN et al, Efficacy and safety of everolimus for subependymal giant cell astrocytomas associated with tuberous sclerosis complex (EXIST-1): a multicentre, randomised, placebo-controlled phase 3 trial, Lancet, 2013, Jan 12;381(9861), 125-32
4. Hoyer PF et al, Everolimus in pediatric de nova renal transplant patients, Transplantation, 2003, Jun 27;75(12), 2082-5
5. Novartis. , SPC Votubia EU/1/11/710/001-003 31-07-2017, www.EMA.europa.eu
6. Pape L et al, Pediatric kidney transplantation followed by de novo therapy with everolimus, low-dose cyclosporine A, and steroid elimination: 3-year data, Transplantation, 2011, Sep 27;92(6), 658-62
7. Grushkin C et al., De novo therapy with everolimus and reduced-exposure cyclosporine following pediatric kidney transplantation: a prospective, multicenter, 12-month study, Pediatr Transplant, 2013, May;17(3), 237-43
8. Wiemer-Kruel A et al, Everolimus for the treatment of subependymal giant cell astrocytoma probably causing seizure aggravation in a child with tuberous sclerosis complex: a case report. , Neuropediatrics. , 2014, Apr;45(2), 129-31
9. Krueger DA et al, Everolimus for subependymal giant-cell astrocytomas in tuberous sclerosis, N Engl J Med, 2010, 4;363(19), 1801-11
10. Franz DN et al., Long-Term Use of Everolimus in Patients with Tuberous Sclerosis Complex: Final Results from the EXIST-1 Study, PLoS One., 2016, Jun 28;11(6), e0158476
11. French JA et al, Adjunctive everolimus therapy for treatment-resistant focal-onset seizures associated with tuberous sclerosis (EXIST-3): a phase 3, randomised, double-blind, placebo-controlled study., Lancet, 2016, Oct 29;388(10056), 2153-2163
12. Billing H et al., Longitudinal growth on an everolimus- versus an MMF-based steroid-free immunosuppressive regimen in paediatric renal transplant recipients, Transpl Int. , 2013 , Sep;26(9), 903-9

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