Document resource
Situation Baby LRB was born very preterm (31+2 weeks gestation, weight 1.382Kg). She had an antenatal diagnosis of cardiac rhabdomyoma with a high mortality risk. She required respiratory support and remained clinically stable.The postnatal cardiac echocardiogram demonstrated a ‘giant’ intracardiac tumour. The cardiologists proposed treatment with sirolimus, a mammalian Target Of Rapamycin (mTOR) inhibitor. The parents were counselled about the risks of treatment and wished to proceed.Review of the licensed product, Rapamune® 1mg/ml oral solution,1 by the neonatal pharmacist identified that at the recommended starting dose of 1mg/m2 once daily,2 the quantity of the excipient propylene glycol exceeded the European Medicines Agency’s (EMA) maximum recommended intake of 1mg/kg3, by more than 30 times.Documented adverse effects from propylene glycol in a neonate include central nervous system (CNS) depression, hyperosmolality, metabolic acidosis and renal impairment.3 Ethanol, which Rapamune® also contains1, can increase the risk of these effects3.As LRB was not ‘in extremis’, the parents were fully counselled about the risks of the excipients before treatment was commenced. The parents wished to proceed; a dose of 0.12mg 24 hourly was prescribed.The action plan to mitigate the potential risks from the propylene glycol included increasing the total fluid allowance to reduce the risk of hyperosmolality and renal impairment, and regular assessment for CNS depression with titration of the morphine infusion.In addition, there were risks of sirolimus toxicity. Sirolimus is extensively metabolised by the cytochrome P450 3A4 isozyme; there is increased expression and activity for this isoenzyme from fetal, to newborn and then infant life.4 The limited published data of use in very preterm infants, and knowledge of the metabolic pathway, prompted a toxicity check after 2 doses; the incidence of adverse effects may increase with high sirolimus levels1.Difficulties in laboratory testing over a weekend resulted in 3 further doses being given before this initial result was reported, at 51.4nanogram/ml (pre 3rd dose level).The target therapeutic trough level was 5-10nanogram/ml2. Treatment was discontinued on receipt of this report and another level taken, however, by this time, a total of 5 daily doses had been administered. The 2nd level was reported at 52.4nanogram/ml.Sirolimus levels continued to be monitored; 18 days after the last dose the level was finally within the target therapeutic range (7.6nanogram/ml).During treatment, LRB experienced neutropenia, thrombocytopaenia, anaemia, oedema, sepsis and hypokalaemia; it is not possible to determine whether these were due to sirolimus, propylene glycol or prematurity.Initially, a one-month treatment course had been anticipated, however a repeat cardiac echocardiogram performed 12 days after the 1st dose was administered showed that the tumour had shrunk. No further treatment was required.Lessons Learned Data for sirolimus use in very preterm infants was sparse; case reports had demonstrated safe and successful treatment in neonates. This case demonstrates that the use of novel drugs outside of their license requires additional considerations and specialist knowledge from the whole multi-disciplinary team to ensure successful treatment and minimise the risks of adverse effects, from both the drug and excipients.References Pfizer Limited. Rapamune 1mg/ml Oral Solution SmPC [online]. 2023. https://www.medicines.org.uk/emc/product/8116/smpc (accessed 01 July 2025).Chen XQ, Wang YY, Zhang MN, et al. Sirolimus can increase the disappearance rate of cardiac rhabdomyomas associated with tuberous sclerosis: a prospective cohort and self-controlled case series study. The Journal of Paediatrics 2021;233:150–155.Neonatal and Paediatric Pharmacy Group (UK). Choosing an oral liquid medicine for children [online]. 2020. https://nppg.org.uk/choosing-an-oral-liquid-for-a-child/(accessed 01 July 2025).Sadler NC, Nandhikonda P, Webb-Robertson BJ, et al. Hepatic cytochrome P450 activity, abundance, and expression throughout human development. Drug Metabolism and Disposition 2016;44(7):984–91.