In order to determine the safety of administration of formulations of etoposide via intrathecal routes an attempt was made to distil the relevant evidence from the literature and expert clinical opinion. A thorough literature search (Embase and Medline) reviewing all studies or case reports in which etoposide had been administered into the cerebrospinal fluid (including intracerebral, intracerebroventricular, intraspinal, intrathecal and intratumoral administration) was conducted. Where possible the product, excipients, and administration technique utilised, as well as any safety concerns raised, were extracted from the references.
Summary
Within the UK the Eposin (medac GmBH) brand of etoposide has been utilised for intraventricular administration, despite concerns relating to the use of a complex solvent system (including benzyl alcohol) which may cause leaching of substances from syringe components and may have a directly toxic effect on the central nervous system. It would appear that the Teva product is the most similar to ETO-GRY which has been proposed by Pajtler et al4 and in personal communication as the most suitable product for intrathecal administration due to an absence of benzyl alcohol. Though the Teva and ETO-GRY products contain the same excipients it should be noted that concentrations of these excipients are unknown.
The general consensus is that excipients in intrathecal products should be minimised wherever possible, with particular reference to concerns relating to inclusion of benzyl alcohol. Two products currently marketed in the UK (Actavis and Teva) do not contain benzyl alcohol. However it should be noted that all products contain macrogol (polyethylene glycol) and ethanol which may also pose a risk on administration into the CSF. Macrogol 300 is present in all UK products except for the Teva product which contains macrogol 400. It should also be noted that all of the products identified within the literature contain macrogol 300.
Toxicity and Adverse Effects
Fleishhack et al.1 observed 2 cases of transient headache and 2 cases of infective meningitis. They also noted 1 case of recurrent headache and vomiting leading to temporary confusion, seizures and transient coma, however, this was attributed to progressive disease of which the patient died one month later. Chamberlain et al.2 documented cases of transient arachnoiditis in 4 patients (15%) and 15 of 112 treatment cycles. Chronic fatigue was also noted as a common adverse event (10 patients, 37%). Despite chronic fatigue being noted as a symptom of neoplastic meningitis, the authors proposed that chronic fatigue may be attributable to cumulative toxicity of intra-CSF etoposide. The Pajtler4 study demonstrated possible etoposide-related adverse events in 28% (19/68) patients. Infection of the reservoir and/or meningitis (n=6) was noted to have occurred only in patients who had received systemic chemotherapy before (within 4 weeks) or during treatment and in the same group seizures (n=4) and transient impaired consciousness (n=2) also occurred. All groups demonstrated mild transient headaches (n=7) and occurrence of fever without other signs of infection (n=6). Longer term adverse events included three patients who developed one or more neuro-psychological symptoms (impaired concentration, short term memory disturbance or disorientation); one patient who developed dysarthria, ataxia and fatigue and one patient who developed an acute myeloid leukaemia following long term treatment with intraventricular etoposide.
Email correspondence
Nottingham University Hospital administer etoposide intracerebroventricularly as below:
Product: Eposin brand etoposide (Medac, GmBH)
Excipients: 30mg/mL benzyl alcohol, macrogol 300, polysorbate 80, benzyl alcohol, ethanol, citric acid (anhydrous).
Administration: 0.5mg in 2mL NaCl 0.9% each day for 5 days via Ommaya reservoir (not recommended for intrathecal use) repeated every 3-4 weeks
Personal Communication from the Chair of the NHS Pharmaceutical Aseptic Services Group:
There is likely to be an incompatibility issue with the rubber grommet and lubricant used in Surety non-luer syringes due to the use of complex solvent systems (including macrogol 300 {polyethylene glycol}, polysorbate 80, ethanol plus citric acid). This is likely to leach substances from rubber components and lubricant in syringes in a time dependent manner. In use expiry of etoposide diluted for use in bone marrow transplantation has been described as limited to a few hours.
It is also noteworthy that Nottingham University Hospital has observed that no issues were observed during in house stability/precipitation testing and that they were not aware of any issues in clinical practice. The principal investigator for the INTREPID trial investigating the continuous intrathecal infusion of etoposide was also contacted; however, this trial has not yet started due to concerns surrounding excipients in the products currently on the market and unavailability of the ETO-GRY product referred to by Pajtler et al.4
Notable additional information
Fleishhack et al.1 postulated that intraventricular administration of etoposide does not penetrate the parenchyma following two patients in their study developing new cerebral parenchymal metastases. Pajtler4 et al. comment that immunocompromise due to concurrent administration of systemic therapy increased occurrence of central infections. They also suggest that the seizures and impaired consciousness observed during therapy appeared to be related to disease progression rather than treatment itself. Slavc et al5 note that etoposide was never administered intra-lumbarly for fear that CSF flow obstruction might result in unpredictably high levels of etoposide and its solvents thus producing damage to the spinal cord. Stapleton and Blaney9 highlight a number of the studies identified in a review paper, in which they also warn that further studies are required to determine the safety of intrathecal etoposide due to formulations containing benzyl alcohol, absolute ethyl alcohol and polyethylene glycol. A 2012 review of leptomeningeal metastases10 also notes etoposide as a “novel agent for intrathecal administration” whilst commenting that the Chamberlain study2 showed no better results than standard treatment.
It should be noted that the scope of this review did not include any appraisal of the clinical efficacy of this treatment modality.
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Overview of studies identified
Reference / Product / Excipients / Administration / DetailFeasibility of intraventricular administration of etoposide in patients with metastatic brain tumours1 / Vepesid (Bristol-Myers Squibb, Germany), 100mg etoposide in 5mL / 150mg benzyl alcohol, 3250mg macrogol 300, 1210mg absolute ethyl alcohol, citric acid and polysorbate 80 / Product diluted with preservative-free saline to a concentration of 0.1mg/mL and administered via an Ommaya or Rickham Reservoir. / Fleischhack et al. conducted an open label comparative multicentre study investigating the feasibility of intraventricular administration of etoposide. Fourteen patients (aged 2.1-33.2 years) were treated with etoposide 0.5mg daily for five consecutive days every 2-5 weeks over a period of 0-11 months. A total of fifty nine courses of etoposide were administered.
Intraventricular etoposide safety and toxicity profile in children and young adults with refractory or recurrent malignant brain tumors4 / Initially:
Vepesid (Bristol-Myers Squibb, Germany) / 150mg benzyl alcohol, 3250mg macrogol 300, 1210mg absolute ethyl alcohol, citric acid and polysorbate 80. / Intraventricular administration by Ommaya-Rickham reservoir. / Sub-group analysis of 68 patients enrolled on the HIT-REZ-97 study (unable to locate this study) who received intraventricular etoposide. Patients received etoposide at a dose of 0.25, 0.5 or 1mg, in cycles of 5 or 10 days, at a frequency of 12 or 24 hourly, and duration between cycles of 2-5 weeks. A total of 93 courses were administered.
Post-1999:
ETO-GRY (Teva, Germany) / Ethanol, macrogol 300, polysorbate 80 and citric acid
Feasibility of long-term intraventricular therapy with mafosfamide (n=26) and etoposide (n=11): experience in 26 children with disseminated brain tumours5 / Etoposid Ebewe (BASF Pharma, Austria). Etoposide 20mg/mL / 20mg/mL benzyl alcohol, 260mg/mL ethanol, macrogol 300, polysorbate 80, citric acid and nitrogen. / 5mg diluted to 20mL (Conc 0.25mg/mL) injected via Ommaya or Rickham reservoir. / Etoposide was administered at a dose of 0.5mg daily for five consecutive days, repeated every 3-6 weeks. The trial looked at 11 patients administered intraventricular etoposide, two of whom switched from mafosfamide treatment due to disease progression and adverse effects. The remaining 9 patients received alternating etoposide and mafosfamide. No immediate toxicities were attributable to intrathecal therapy.
Phase II trial of intracerebrospinal fluid etoposide in the treatment of neoplastic meningitis2 / Shering-Plough, Kenilworth NJ. / Unknown, and product no longer marketed / Intraventricular injection (no further detail available). / Open label trial of intratraventricular etoposide to treat neoplastic meningitis. The study included 27 patients (median age, 55) who received etoposide 0.5mg daily for five days per week on alternate weeks for an 8 week induction phase, responding patients continued to receive etoposide 5 consecutive days every four weeks. The study was closed early due to a failure to achieve greater than 5 patients alive and progression free at 6 months.
Prolonged response of meningeal carcinomatosis from non-small cell lung cancer to salvage intrathecal etoposide subsequent to failure of first-line methotrexate: a case report and literature review7 / EPS (Boryung Pharm Co, Korea), etoposide 100mg in 5mL / Unknown / 0.2mg/mL (diluted with normal saline) administered via Ommaya reservoir. / This is a case report of one patient treated with etoposide via Ommaya reservoir at a dose of 1mg once weekly. The case described no adverse effects, and a “durable response” to this newly described treatment regimen. Considered by the author to be a simpler and more convenient practice.
Cerebrospinal fluid pharmacokinetics after different dosage regimens of intraventricular etoposide3 / Unknown / Unknown / Intraventricular administration via Ommaya reservoir. / This study investigated pharmacokinetic parameters of etoposide in CSF following intraventricular administration utilising different dosage schedules in 9 patients aged 3-32 years. Pharmacokinetics of etoposide following intraventricular administration exhibited a linear two-compartment model.
Intrathecal administration of etoposide in the treatment of malignant meningitis: feasibility and pharmacokinetic data6 / Unknown - “i.v. etoposide formulation” / Unknown / 1st patient: 0.5mg diluted in 2mL of saline administered intraventricularly via subcutaneous reservoir.
2nd patient: 0.5mg diluted in 2mL of saline administered intrathecally (unclear where this administration took place). / This reference describes two case reports of patients’ treated with 0.5mg etoposide on five consecutive days, followed by a second course of 0.5mg etoposide twice daily (2 hours apart for the first patient, 12 hours apart for the second) for 5 days, 21 days after the first course. No systemic toxicities were demonstrated in either patient.
Comparison of UK Marketed Products with Products Used in References
Note: Products with the same, or similar excipients, may utilise different concentrations.
Vepesid, Bristol-Myers Squibb, Germany1,4 / Etoposid Ebewe, BASF Pharma, Austria5 / ETO-GRY, Teva, Germany4Absolute ethyl alcohol, Benzyl alcohol, Citric acid, Macrogol 300, Polysorbate 80 / Benzyl alcohol, Citric acid, Ethanol, Macrogol 300, Nitrogen, Polysorbate 80 / Citric acid, Ethanol, Macrogol 300, Polysorbate 80
Teva UK Limited
Most similar to the ETO-GRY product suggested within the literature to be the “safest”. / Citric acid, Ethanol, Macrogol 300, Polysorbate 80 / Similar content except:
· UK product does not contain benzyl alcohol – potentially beneficial / Similar content except:
· UK product does not contain benzyl alcohol – potentially beneficial
· Austrian product also includes nitrogen as an excipient – impact unclear / Same content
medac GmbH(Eposin)
Currently used in UK practice. / Benzyl alcohol, Citric acid, anhydrous, Ethanol, Macrogol 300, Polysorbate 80 / Same content / Similar content:
· Austrian product also includes nitrogen as an excipient – impact unclear / · UK product contains benzyl alcohol
· Other excipients may be different concentrations
Accord Healthcare Limited / Benzyl alcohol, Citric acid, anhydrous, Ethanol, anhydrous, Macrogol 300, Polysorbate 80 / Same content / Similar content except:
· Austrian product also includes nitrogen – impact unclear / · UK product contains benzyl alcohol
· Other excipients may be different concentrations
Actavis UK Ltd / Citric acid, anhydrous, Ethanol, anhydrous, Macrogol 400, Polysorbate 80 / Similar content except:
· UK product does not contain benzyl alcohol – potentially beneficial
· UK product utilises macrogol 400 instead of macrogol 300 – impact unclear / Similar content except:
· UK product does not contain benzyl alcohol – potentially beneficial
· UK product utilises macrogol 400 instead of macrogol 300 – impact unclear
· Austrian product also includes nitrogen – impact unclear / Similar content except:
· UK product utilises macrogol 400 instead of macrogol 300 – impact unclear
Cipla (EU) Limited / Benzyl alcohol, Citric acid, anhydrous, Ethanol, Macrogol 300, Polysorbate 80 / Same content / Similar content:
· Austrian product also includes nitrogen as an excipient – impact unclear / · UK product contains benzyl alcohol
· Other excipients may be different concentrations
Fresenius Kabi Oncology Plc. / Benzyl alcohol, Citric acid, Ethanol Anhydrous, Macrogol 300, Polysorbate 80 / Same content / Similar content:
· Austrian product also includes nitrogen as an excipient – impact unclear / · UK product contains benzyl alcohol
· Other excipients may be different concentrations
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References
1. Fleischhack, G. et al. (2001). Feasibility of intraventricular administration of etoposide in patients with metastatic brain tumours. British Journal of Cancer, 84(11), pp. 1453-9.
2. Chamberlain, M. et al. (2006). Phase II trial of intracerebrospinal fluid etoposide in the treatment of neoplastic meningitis. Cancer, 106(9), pp. 2021-7.
3. Sirisangtragul, C. et al. (2003). Cerebrospinal fluid pharmacokinetics after different dosage regimens of intraventricular etoposide. International Journal of Clinical Pharmacology and Therapeutics, 41(12), pp. 606-7.
4. Pajtler, K. et al. (2016). Intraventricular etoposide safety and toxicity profile in children and young adults with refractory or recurrent malignant brain tumors. Journal of Neurooncology, 128, pp.463-71.