Everolimus

Generic name
Everolimus
Brand name
ATC Code
L04AH02
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Everolimus

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 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
      • 1.6 - 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
      • 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
      • 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 combined with CYP3A4/PgP inducer
  • Oral
    • < 6 years
      • 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
      • 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.

    • < 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

IMMUNOSUPPRESSANTS

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

Selective immunosuppressants
L04AA24
L04AA32
L04AA13
L04AA02
L04AA06
L04AA31
L04AA04
L04AA44
Other immunosuppressants
L04AX01
L04AX03
Tumor necrosis factor alpha (TNF-alpha) inhibitors
L04AB04
L04AB01
L04AB06
L04AB02
Interleukin inhibitors
L04AC03
L04AC02
L04AC08
L04AC13
L04AC19
L04AC10
L04AC22
L04AC07
L04AC05
Calcineurin inhibitors
L04AD01
L04AD02
Sphingosine-1-phosphate (S1P) receptor modulators
L04AE01
Janus-associated kinase (JAK) inhibitors
L04AF02
L04AF02
L04AF08
L04AF01
Monoclonal antibodies
L04AG04
Mammalian target of rapamycin (mTOR) kinase inhibitors
L04AH01
Complement inhibitors
L04AJ01
L04AJ02
Dihydroorotate dehydrogenase (DHODH) inhibitors
L04AK02

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
  13. 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

Changes

Therapeutic Drug Monitoring


Overdose