National drug shortages are a common occurrence with a multitude of causes, which include manufacturing difficulties related to sterile injectables, shortage of raw ingredients, delays due to the production of multiple different therapeutic agents on the same supply line, inability of competing manufacturers to quickly increase output in response to production delay or discontinuation by another manufacturer, and lack of excess inventory throughout a complex distribution network.14 Given the several recent occurrences of IV sodium bicarbonate shortages, strategies to allow for the safe administration of HDMTX is imperative for the treatment of patients with hematologic malignancies. There have been limited attempts at modifying IV sodium bicarbonate regimens with PO substitutes or other alternatives outlined in Table 6. This study demonstrates that a PO alkalization regimen with PO sodium bicarbonate and PO acetazolamide is feasible and reduces the cost of treatment medications, albeit with increased pill burden. PO alkalization regimens in literature were limited at the time of the national shortage. Roy et al recently published another institution’s protocol for PO alkalization in the time of the national shortage.15 Their HDMTX “shortage” protocol included PO sodium bicarbonate at 3250 mg every 2 hrs in addition to PO or IV acetazolamide 250–500 mg every 6 hrs as needed. There were no statistically significant differences in MTX clearance, hospital length of stay, AKI, or hepatotoxicity. However, there was increased time of urine pH <7 and significant increase in length of stay. Shamash et al used monotherapy acetazolamide to keep patients’ urine alkalized and found no increase in AKI or difficulties with MTX clearance.8 The study demonstrated that if acetazolamide is used as single agent greater than 48 hrs, adverse effects occur. When used alone, prolonged carbonic anhydrase inhibition with acetazolamide results in depletion of the bicarbonate-carbon dioxide buffer in blood and could eventually lead to loss of urine alkalization followed by worsening MTX crystallization in the kidney tubules. Roy et al investigated an PO alkalization regimen similar to ours with sodium bicarbonate and PO acetazolamide; however, they used higher doses and more frequent PO sodium bicarbonate and reserved acetazolamide for use as needed when urine pH was <7.5.15
We demonstrated in our study no significant difference in MTX clearance rate, which is similar to previous studies using PO sodium bicarbonate.7 There are several limitations to this study. HDMTX at doses exceeding 5 g/m2 were excluded because there were too few treatment courses at this dose that utilized the PO regimen for urine alkalization. The analysis was done in a prospective design; however, it was not a randomized controlled trial and was not analyzed with case match controls. We did not establish and incidence of mucositis or other potential toxicities due to inconsistent reporting in the EMR. However, there were no re-admissions for mucositis toxicity from HDMTX administration. In addition, cytopenias were difficult to assess in the setting of patients getting multi-agent chemotherapy for most regimens with ALL and CNS lymphoma. Cytopenias that occur were likely due to the combination effect of chemotherapy, rather than HDMTX. There was no documented evidence of MTX-induced rash or pneumonitis. No patients received glucarpidase or dialysis for the treatment of delayed methotrexate clearance and AKI.
Our studied intervention of PO sodium bicarbonate and acetazolamide was a well-tolerated. Compared to previously published PO treatment regimens, this study had a smaller sodium bicarbonate pill burden. The protocol was designed to accommodate patient sleep schedule and reduce wake times for pill administration. Finally, this is the first study of a PO regimen for urine alkalization to include a cost analysis, which demonstrated the PO regimen to be associated with potential significant savings if implemented in a large patient population.