Sirolimus

Generic name
Sirolimus
Brand name
ATC Code
L04AH01
Dosages
Side effects in children
Warnings & precautions in children
Contra-indications in children

Interactions
PK
Renal impairment
References

Pharmacokinetics in children

Published pharmacokinetic data on sirolimus in children are limited, especially in patients with vascular malformations. Most pharmacokinetic data have been obtained in transplanted pediatric patients (Tejani 2004; Ettenger 2001; Sindhi 2001; Schachter 2004; Schubert 2004; Goyal 2013). The pharmacokinetics of sirolimus is characterized by large interindividual variability. Therefore, meticulous TDM is advised (TDM monograph NVZA 2018). A shorter T1/2, especially in transplanted pediatric patients, and increased CL/F were seen in younger children (specific age group is not clear), compared to older pediatric patients and adults (Tejani 2004; Ettenger 2001; Sindhi 2001; Schachter 2004; Schubert 2004; Goyal 2013, Cheng 2020). This could be related to the enzyme activity of CYP3A4, which exceeds adult values after 2-3 years (Anderson 2002). A clear explanation is not given in the studies. In contrast, there is less clearance in neonates and young infants, which is related to age due to developmental and maturation changes (Anderson 2002; Kearns 2003).

Reference

Disease

N=

Age 

Dose 

Trough level

CL 

(whole blood)

Vd 

(whole blood)

T1/2

Tejani 2004

Stable chronic renal failure patients 

24

5 – 11y

12 – 18y

1.0, 3.0, 9.0, 15.0 mg/m2

 

1.0 mg/m2:

5-11y: 273 mL/h/kg 

12-18y: NA

3.0 mg/m2:

5-11y: 478 mL/h/kg

12-18y: 316 mL/h/kg

9.0 mg/m2:

5-11y: NA

12-18y: 631 mL/h/kg

15 mg/m2:

5-11y: 726 mL/h/kg

12-18y: 470 mL/h/kg

 

1.0 mg/m2:

5-11y: 107 h

12-18y: NA

3.0 mg/m2:

5-11y: 54.0 h

12-18y: 65.5 h

9.0 mg/m2:

5-11y: NA

12-18y: 53.5 h

15 mg/m2:

5-11y: 52.4 h

12-18y: 47.7 h

Ettenger 2001

Stable renal transplant patients  

4

Children: mean 7.2y

Adolescents: mean 16.4y

Adults: NA

Children: 4.6-5.7 mg/m2

Adolescents: 0.6-6.1 mg/m2

Adults: 1-13 mg/m2

 

Children: 485 mL/h/kg

Adolescents: 376 mL/h/kg

Adults: 208 mL/h/kg

 

Children: 49.1 h

Adolescents: 70.3 h

Adults: 62.0 h

Sindhi 2001

Various 

transplant patients

21

19 days – 21y (mean: 11.6)

1–2 mg/m2/day

Mean: 6.7 ng/mL

 

 

11.8 h

Schachter 2004

Stable renal transplant patients 

13

3.1 – 21.7y  (median 15.3)

Month 1:

4.2 – 26.1 mg/m2/day (median: 15.0)

Month 3: 

3.3 – 16.0 mg/m2/day (median: 9.0) 

Goal: 25 ng/mL (12h)

 

 

Month 1: 9.7 h

Month 3: 10.8 h 

 

<6y: 11.5 h

>6y: 9.6 h 

Schubert 2004

Renal transplant patients 

34

0.9 – 23.6y (median: 13.3)

2.1 mg/m2 once daily, 

3.3 mg/m2 twice daily

 

Mean 4.3 ng/mL 

8.61 ml/min/kg

 

12h: 13.7 h (twice daily)

24h: 21.8 h (once daily)

Goyal 2013

Blood and marrow transplant patients 

33

4 – 22y (median: 10.1)

 

1 – 5 mg/day

(mean: 2.5)  

Mean 9.1 ng/mL (24h)

5.7 L/h

0.19 L/h/kg

201.3 L

6.64 L/kg

26.6 h 

Scott 2013

Neurofibromatosis type 1 

44

3 – 18y (mean: 8.4)

Starting dose: 

0.8 mg/ m2 twice daily

Therapeutic dose:

2.0 mg/ m2 once daily

Goal: 10 – 15  ng/mL

11.8 L/h

0.17 L/h/kg (therapeutic dose)

After allometric scaling:

>4y: 24.2 L/h/70kg 

(Adult values approx. 28 L/h))

 

 

Cheng 2020

Immune cytopenia

27

1 – 15y (mean: 8.16)

1.5 mg/m2/day

Goal: 5 – 15 ng/mL 

5.63 L/h

144.16 L

 

Wang 2022

Tuberous Sclerosis Complex

15

1 – 14y (mean: 6.15)
 

 

Goal: 5 – 15 ng/mL

0.18 – 0.10 L/h/kg, 5 – 60 kg, respectively

124 L

 

Li 2022

Tuberous Sclerosis Complex

64

0 – 18y (median: 4)

0.25 – 1 mg/m2 once daily

Goal: 5 – 15 ng/mL

2.79 L/h

 

Median body weight of 16.7 kg: 0.17 L/h/kg 

69.48 L

 

Emoto 2015

Complicated vascular anomalies

44

1m – 18y (median: 5)

0.8 mg/m2 twice daily

Goal: 10 – 15 ng/mL

1 – 8m: 11 L/h

1y: 17 L/h

2y: 21 L/h

3 – 18y: 18 L/h

 

 

Chen 2021

Lymphangioma

15

0.12 – 16.39y (mean: 7.29)

 

Goal: 5-15 ng/mL

11.3 l/h/70 kg

388 L/70 kg

 

Wang 2019

Kaposiform hemangioendothelioma

17

0.2 – 6y (mean: 1.21)

0.8 mg/m2 twice daily

Goal: 10 – 15 ng/mL

3.19 L/h

165 L

 

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

Vascular malformations, Kaposiform haemangioendothelioma (KHE)
  • Oral
    • Term neonate
      • Starting dose: 0.2 mg/m²/day in 2 doses. with a dosing interval of 12 hours.
    • 1 month up to 3 months
      • Starting dose: 0.3 mg/m²/day in 2 doses. with a dosing interval of 12 hours.
    • 3 months up to 6 months
      • Starting dose: 0.4 mg/m²/day in 2 doses. with a dosing interval of 12 hours.
    • 6 months up to 12 months
      • Starting dose: 0.6 mg/m²/day in 2 doses. with a dosing interval of 12 hours.
    • ≥ 12 months
      • Starting dose: 0.8 mg/m²/day in 2 doses. with a dosing interval of 12 hours.
CAUTION:
  • Oral
    • 0 years up to 18 years
        • Pharmacokinetic modeling data with 5 – 10 ng/mL target levels support these doses. However, lower target levels (2 - 6 ng/mL) are currently aimed in clinical practice and are supported by limited evidence suggesting that lower target levels have equal efficacy and an improved toxicity profile. Therefore, the pharmacokinetic modeling data doses were translated to target levels of 2 - 6 ng/mL. Even lower doses than those presented here are used in clinical practice when aiming for a target level of 2 - 6 ng/mL. 
        • Blood levels of sirolimus higher than 10 ng/mL are associated with a higher risk of toxicity.
        • Titrate to a serum trough concentration of 2 - 6 ng/mL. Close TDM continues until steady-state and goal exposure is achieved.

        CAVE: Sirolimus tablets and oral solution are not bioequivalent. See warning and precautions.

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 kinetics of sirolimus do not change with renal impairment. There is minimal renal excretion (2%) of the drug.

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

Side effects tend to be dose dependent. The most common adverse event is mucositis (Hammill 2011; Ji 2021; Mack 2019). Other common side effects are gastrointestinal upset, headaches, bone marrow suppression, and metabolic/laboratory disturbances (Sandbank 2019; Adams 2016; Adams 2019). Most cases have been reversible and improving with decreasing drug level (Hammill 2011; Ji 2021). Higher levels of sirolimus or other concomitant drugs, including corticosteroids, may provide a risk for Pneumocystis jirovecii pneumonia (PJP). PJP is a rare but life-threatening side effect of sirolimus therapy. PJP prophylaxis should be considered for patients receiving sirolimus (Scott 2013; Djebli 2006; Wiegand 2022).

In some cases, sirolimus-induced pneumonitis occurred. Therefore, during sirolimus therapy, continuous and regular pulmonary function tests are needed to evaluate the respiratory status of pediatric patients to prevent the occurrence of fatal pneumonitis (Ji 2021; Zhang 2022)

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

  • Sirolimus tablets and oral solution are not bioequivalent, due to differences in absorption. When switching from oral solution to tablets and vice versa, maintain the same dosage and check trough levels after 1 to 2 weeks to ensure they remain within the recommended target range. Monitoring of the trough level is also recommended when switching between different tablet strengths (KNMP Oralia preparation).
  • The solution of 1 mg/ml contains 350 mg/ml propylene glycol and 25 mg/ml ethanol. It can be used safely in children >1 month (see background info). Propylene glycol can cause serious side effects with prolonged use and/or use of high doses, especially with a reduced metabolism, such as in young children. Propylene glycol must be evaluated individually to determine the permissible amount. When there is no alternative, the potential for severe adverse effects must be evaluated against the treatment's effectiveness.
  • The solution form is preferred for young children as they are unable to swallow pills. It is not possible to crush the tablets because bioavailability of sirolimus from crushed, chewed or broken tablets has not been established. Due to the lipophilic coating, the tablets do not disintegrate quickly in water. There are no practical data on the disintegration of sirolimus coated tablets in water (KNMP Oralia preparation).

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
L04AH02
Complement inhibitors
L04AJ01
L04AJ02
Dihydroorotate dehydrogenase (DHODH) inhibitors
L04AK02

References

  1. Koninklijke Nederlandse Maatschappij ter bevordering der Pharmacie (KNMP)., Oralia VTGM. Sirolimus., Available from: https://kennisbank.knmp.nl
  2. Mack JM, et al., Effect of sirolimus on coagulopathy of slow-flow vascular malformations, Pediatr Blood Cancer., 2019, 66(10), e27896
  3. Chen X, et al., Optimization of Initial Dose Regimen for Sirolimus in Pediatric Patients With Lymphangioma, Front Pharmacol, 2021, 12, 668952
  4. Adams DM, et al., Efficacy and Safety of Sirolimus in the Treatment of Complicated Vascular Anomalies., Pediatrics., 2016, 137(2), e20153257
  5. Scott JR, et al., Population pharmacokinetics of sirolimus in pediatric patients with neurofibromatosis type 1, Ther Drug Monit., 2013, 35(3), 332-7
  6. Zhang Z, et al., Safety Evaluation of Oral Sirolimus in the Treatment of Childhood Diseases: A Systematic Review., Children (Basel), 2022, 9(9)
  7. Tejani A, et al., Safety and pharmacokinetics of ascending single doses of sirolimus (Rapamune, rapamycin) in pediatric patients with stable chronic renal failure undergoing dialysis., Pediatr Transplant, 2004, 8(2), 151-60
  8. Ettenger RB, et al, Safety and efficacy of TOR inhibitors in pediatric renal transplant recipients., Am J Kidney Dis, 2001, 38(4 Suppl 2), S22-8
  9. Sindhi R, et al., Sirolimus for rescue and primary immunosuppression in transplanted children receiving Tacrolimus, Transplantation, 2001, 72, 851 – 5
  10. Schachter AD, et al., Short sirolimus half-life in pediatric renal transplant recipients on a calcineurin inhibitor-free protocol., Pediatr Transplant., 2004, 8(2), 171-7
  11. Goyal RK, et al., Sirolimus pharmacokinetics in early postmyeloablative pediatric blood and marrow transplantation., Biol Blood Marrow Transplant., 2013, 19(4), 569-75
  12. Harbers VEM, et al., Effective low-dose sirolimus regimen for kaposiform haemangioendothelioma with Kasabach-Merritt phenomenon in young infants., Br J Clin Pharmacol., 2022, 88(6), 2769-81
  13. Schubert M, et al., Pharmacokinetics of sirolimus and tacrolimus in pediatric transplant patients, Am J Transplant., 2004, 4(5), 767-73
  14. Cheng X, et al., The first study in pediatric: Population pharmacokinetics of sirolimus and its application in Chinese children with immune cytopenia, Int J Immunopathol Pharmacol., 2020, 34, 2058738420934936
  15. Wang DD, et al, Initial Dosage Recommendation for Sirolimus in Children With Tuberous Sclerosis Complex., Front Pharmacol, 2020, 11, 890
  16. Ji Y, et al., A prospective multicenter study of sirolimus for complicated vascular anomalies., J Vasc Surg., 2021, 74(5), 1673-81.e3
  17. Wiegand S, et al.., Efficacy of sirolimus in children with lymphatic malformations of the head and neck, Eur Arch Otorhinolaryngol, 2022, 279(8), 3801-10
  18. Emoto C, et al., Development of a Pediatric Physiologically Based Pharmacokinetic Model for Sirolimus: Applying Principles of Growth and Maturation in Neonates and Infants, CPT Pharmacometrics Syst Pharmacol., 2015, 4(2), e17
  19. Mizuno T. et al, Developmental pharmacokinetics of sirolimus: Implications for precision dosing in neonates and infants with complicated vascular anomalies. , Pediatr Blood Cancer., 2017, 64(8)
  20. Sandbank S, et al., Oral and Topical Sirolimus for Vascular Anomalies: A Multicentre Study and Review., Acta Derm Venereol, 2019, 99(11), 990-6.
  21. Wang D, et al, Population pharmacokinetics of sirolimus in pediatric patients with kaposiform hemangioendothelioma: A retrospective study., Oncol Lett, 2019, 18(3), 2412-9
  22. Nederlandse Vereniging voor Ziekenhuis Apothekers, TDM monografie Sirolimus, Available from: https://tdm-monografie.org/sirolimus/, 2018, November 15
  23. Anderson GD., Children versus adults: pharmacokinetic and adverse-effect difference, Epilepsia, 2002, 43 Suppl 3, 53-9
  24. Hammill AM, et al., Sirolimus for the treatment of complicated vascular anomalies in children., Pediatr Blood Cancer., 2011, 57(6), 1018-24
  25. Kearns GL, et al, Developmental pharmacology--drug disposition, action, and therapy in infants and children, N Engl J Med., 2003, 349(12), 1157-67
  26. Triana P. et al, Oral Sirolimus: An Option in the Management of Neonates with Life-Threatening Upper Airway Lymphatic Malformations., Lymphat Res Biol., 2019, 17(5), 504-11
  27. Czechowicz JA, et al. , Sirolimus for management of complex vascular anomalies - A proposed dosing regimen for very young infants. , Int J Pediatr Otorhinolaryngol. , 2018, 105, 48-51
  28. Adams DM, et al, Vascular Anomalies: Diagnosis of Complicated Anomalies and New Medical Treatment Options, Hematol Oncol Clin North Am, 2019, 33(3), 455-70
  29. Djebli N, et al., Sirolimus population pharmacokinetic/pharmacogenetic analysis and bayesian modelling in kidney transplant recipients., Clin Pharmacokinet., 2006, 45(11), 1135-48
  30. Scott JR, et al., Population pharmacokinetics of sirolimus in pediatric patients with neurofibromatosis type 1, Ther Drug Monit., 2013, 35(3), 332-7
  31. Czechowicz JA, et al., Sirolimus for management of complex vascular anomalies - A proposed dosing regimen for very young infants., Int J Pediatr Otorhinolaryngol., 2018, 105, 48-51
  32. Mizuno T. et al, Developmental pharmacokinetics of sirolimus: Implications for precision dosing in neonates and infants with complicated vascular anomalies., Pediatr Blood Cancer., 2017, 64(8)

Changes

Therapeutic Drug Monitoring


Overdose