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A Review of Available Antidotes for Chemotherapy Overdoses

Adam Peele, PharmD MHA BCOP BCPS
Director, Oncology Pharmacy Services
PGY-2 Oncology Pharmacy Residency Director
Cone Health—Oncology
Greensboro, NC

Maggie Shuda, PharmD
PGY-2 Oncology Pharmacy Resident
Cone Health—Oncology
Greensboro, NC

In 1999, the Institute of Medicine published a report known as To Err Is Human: Building a Safer Health System.1 The report emphasized the importance of a systematic approach to error prevention and the need for “well-designed processes of care [that] prevent, identify, and quickly recover from errors” in order to prevent patient harm. The delivery of oncology pharmacotherapy requires processes ensuring precise, meticulous, and detailed care.2 The rate of documented inpatient errors is not well defined, and numerous studies have identified error rates in ambulatory settings. Weingart and colleagues, in a review published in 2018, estimated that chemotherapy error rates with potential for harm may range from 1 to 4 per 1,000 chemotherapy orders.3 Although these error rates may be lower than rates seen in the general medicine population, the extent of harm they cause to patients is not known.

The narrow therapeutic range of oncology medications makes it vital to ensure that the correct dosage is given. Chemotherapy medications have a narrow therapeutic index and are often derived by complex dosing calculations to ensure that the patient is appropriately treated. Despite recommendations and guidelines to ensure safe oncology pharmacotherapy, errors still occur. One study noted that errors occurred throughout the entire medication process, with most centering on ordering and administration.2 Risks for prescribing errors arise, for example, when orders have three or more chemotherapies, are placed by physicians who do not commonly use computerized prescription order entry, or are placed by physicians new to practice.3 Special types of chemotherapy that should be carefully considered for error potential are intrathecal chemotherapy, oral chemotherapies, and chemotherapy treatments given over multiple days.

Our processes for ensuring safe medication use have improved over the years, but chemotherapy overdoses still occur. If a chemotherapy overdose does occur, one avenue to combat toxicities and prevent permanent sequelae is to administer antidotes. Unfortunately, direct antidotes do not exist for most chemotherapies, but it is important for pharmacists to understand the different agents that they could use if the need for one arose. With the exception of uridine triacetate, a U.S. Food and Drug Administration (FDA)–approved antidote for fluorouracil and capecitabine overdose and early-onset toxicity, data regarding antidotes for chemotherapy overdoses are limited to small studies and case reports.

Uridine Triacetate for Fluorouracil or Capecitabine Overdose or Early-Onset Toxicity
Uridine triacetate is currently indicated for treating fluorouracil (5-FU) or capecitabine overdose and for treating patients who develop early, life-threatening toxicities with these medications.4 Overdoses from these medications may be accidental or intentional. The potential for error is related to 5-FU chemotherapy pump malfunctions or misprogramming and to accidental ingestion of capecitabine tablets. Severe toxicities that may be seen in the event of an acute overdose include cytopenias, acute cardiomyopathy, altered mental status, mucositis, severe nausea, and severe diarrhea. Additionally, genetic enzyme variants may enhance toxic effects in some patients at doses that are usually well tolerated.5 Uridine triacetate was studied in two open-label compassionate-use trials.5 The goal of these studies was to evaluate the impact of uridine triacetate on patient outcomes in the setting of either an overt overdose, defined as administration of a larger dose of 5-FU (or a dose at a higher rate) than planned, or early-onset serious toxicity, defined as a patient’s development of severe toxicities within 96 hours of a 5-FU infusion or within the standard 14-day course of capecitabine treatment. Because it was considered unethical to include a placebo arm in the trial, outcomes for uridine triacetate treatment for overdose were compared with those for a historical cohort treated with best supportive care. Adult dosing consisted of uridine triacetate 10 g orally every 6 hours; pediatric patients received 6.2 g/m2 (max of 10 g) orally every 6 hours. A full treatment course consisted of 20 doses, ideally initiated within 96 hours of the last 5-FU or capecitabine dose. Patient survival or resumption of chemotherapy after 30 days was the primary end point, and adverse effects were documented to evaluate safety. The studies included 173 patients who were treated with uridine triacetate, 168 of whom were available for follow-up, and the historical comparator group included 25 patients. Efficacy results are displayed in (Table 1-see PDF). The most common adverse effects noted with uridine triacetate use were vomiting (8.1%), nausea (4.6%), and diarrhea (3.5%).

The study design had several limitations. Selecting patients to include in a historical cohort as the comparator group introduces risk for bias, given that severe cases may be more likely to be reported, although the authors did attempt to standardize toxicity severity and correlate it with expected outcomes. It is also difficult to directly compare the data between the historical cohort and the treatment cohorts. However, despite the limitations of this trial, the data demonstrated that uridine triacetate could play an important role in improving the survival of patients with early-onset toxicity or overdose from 5-FU or capecitabine, especially if it was initiated early after the chemotherapy was administered.

Uridine triacetate is distributed solely by Cardinal Health Specialty Pharmacy Distribution, and it is available for order 24 hours a day, 7 days a week.4 The medication should be added to the formulary to ensure that providers can order it efficiently when it is needed. Given the high cost of this medication, pharmacy and therapeutics (P&T) committees will need to decide whether to keep a certain quantity in stock or order it as needed. Use should be restricted to overt overdoses and life-threatening toxicities within 96 hours of administration or ingestion. Because uridine triacetate may reduce the effectiveness of 5-FU and capecitabine, it should not be used for treating mild to moderate toxicities. Depending on the degree of toxicities patients are experiencing and how quickly they recover, they may be eligible for outpatient treatment. In this case, uridine triacetate must be dispensed through a specialty pharmacy, and care must be taken to ensure that the patient completes the full 5-day course without missing doses.

Uridine triacetate is supplied as oral granules in single-use 10-gram packets.4 Granules should be mixed with soft food and taken within 30 minutes. It may also be given via nasogastric or gastric tubes in cases involving compromised mental status or severe mucositis. Uridine triacetate doses should be readministered if the patient vomits within 2 hours of administration.

Glucarpidase for Intravenous and Intrathecal Methotrexate Overdose
High-dose methotrexate (HDMTX), usually defined as intravenous (IV) doses at least 500 mg/m2 given over 2–36 hours, is an important therapy for treating several malignancies.6 Although leucovorin rescue, urine alkalinization, hydration, and avoidance of concomitant nephrotoxins reduce the risk of acute kidney injury associated with HDMTX, some patients may require the rescue agent glucarpidase to rapidly decrease methotrexate levels and prevent permanent sequelae of toxicities. Glucarpidase is FDA-approved for patients who experience toxic levels of systemic methotrexate secondary to severe HDMTX-induced renal impairment.7 The medication is a recombinant bacterial enzyme that works by deactivating methotrexate into two inactive metabolites. It works quickly, achieving a reduction in serum methotrexate levels of over 97% within 15 minutes of administration.7 Although the usual route of administration is IV, studies investigating administration via the intrathecal (IT) route in the setting of acute intrathecal methotrexate overdose have been conducted.

Overdoses of IT methotrexate are a rare but serious error and can occur when methotrexate doses meant for systemic administration are given intrathecally. Signs and symptoms suggestive of IT methotrexate overdose are likely dependent on the degree of overdose and may include severe headache, fatigue, and confusion; they may progress to seizures or death.8 No antidote for IT methotrexate overdose has been approved by the FDA, nor do consensus guidelines on how to manage these situations exist, but several small studies have used IT glucarpidase, along with cerebrospinal fluid (CSF) exchange, in an attempt to reverse methotrexate effects. Other supportive care strategies noted in the literature include systemic IV leucovorin to decrease systemic methotrexate impacts and IV dexamethasone to reduce the risk of arachnoiditis.8-12

One small case series was conducted by Widemann and colleagues and published in 2004.10 The investigators analyzed the effect of glucarpidase 2,000 units IT in seven pediatric and adult patients 3–9 hours after an IT methotrexate overdose occurred. Glucarpidase was given, along with standard supportive measures, which included leucovorin 100 mg IV every 6 hours and dexamethasone 4 mg IV every 6 hours, each for four doses. Four of the patients also received CSF exchange prior to receiving glucarpidase. In this study, all patients survived. Two patients had residual cognitive deficits, but five returned to their baseline cognitive function.

Another case report that used a similar treatment protocol was published in 2012.11 This case report detailed the course of a 66-year-old female who accidentally received IT methotrexate at 10 times the intended dose. After the mistake was recognized, CSF fluid was removed through the reservoir through which the drug had been administered. The patient was subsequently hospitalized and treated with the same regimen followed in the previous discussed study, including glucarpidase 2,000 units IT. The patient reportedly returned to her baseline mental status.

Evidence regarding glucarpidase IT as an antidote to methotrexate IT overdose is limited to a small case series and case reports, but the patients in these studies appeared to have favorable outcomes with regard to avoiding permanent neurologic sequelae. Because the published studies used many treatment modalities for toxicity management, it is difficult to estimate the degree that each medication or procedure played in overdose reversal. Small studies that used leucovorin IT in treating methotrexate IT overdose showed possible neurotoxic adverse effects, but glucarpidase did not demonstrate this effect in these very small studies.11,12

Glucarpidase is exclusively distributed by BTG Specialty Solutions Center.7 It may be ordered 24 hours a day, 7 days a week to stock pharmacy inventory or for on-demand use. Health system P&T committees may choose to add it to the formulary to improve efficiency in physician ordering. Facilities that administer HDMTX may be more likely to keep glucarpidase in stock because of its more defined role in therapy in this setting and because it should be administered within 60 hours of HDMTX exposure. For administration of glucarpidase IV following HDMTX, use should be restricted to patients who have toxic levels of methotrexate with severe renal impairment. Institutions should implement protocols that specify how toxic levels of methotrexate will be defined and who is eligible to receive glucarpidase. Glucarpidase inactivates both leucovorin and methotrexate, so leucovorin should be administered at least 2 hours after glucarpidase infusions.6 The protocol should also address how methotrexate levels will be monitored after glucarpidase administration. Because glucarpidase can falsely elevate methotrexate immunoassay measurements for about 48 hours after administration, a chromatographic method must be used during this time.

Facilities that do not administer HDMTX but do administer IT methotrexate injections will need to weigh the pros and cons of regularly stocking glucarpidase in anticipation of a rare but serious error. Pharmacists must be aware that the procedure for reconstituting glucarpidase for IT administration differs from that for IV administration (12 ml of preservative-free normal saline for 2,000 units of glucarpidase versus 1 ml of saline for each 1,000 units of glucarpidase, respectively).10,11 It may be helpful for facilities to develop protocols for procuring, reconstituting, and administering glucarpidase to aid the healthcare team in the rare event of an IT methotrexate overdose.

Sodium Thiosulfate for Cisplatin Overdose
Cisplatin overdoses can have multi-organ system effects, including but not limited to, acute renal failure, myelosuppression, nausea and vomiting, and neurological effects such as ototoxicity and seizures.13 No specific antidote for cisplatin overdose exists, and current treatment options are limited to aggressive supportive care.

Sodium thiosulfate, a medication originally used to treat acute cyanide poisoning, has been used to prevent cisplatin renal toxicity.14 The agent is postulated to have renal-protective effects by binding free serum platinum and improving renal clearance of inactive metabolites. Evidence regarding the use of sodium thiosulfate for reversal of acute kidney injury secondary to cisplatin overdose is limited to case reports.

Erdlenbruch and colleagues reported their experience using sodium thiosulfate in an acute cisplatin overdose that occurred in a 14-year-old patient.15 The patient received a cisplatin dose that was three times the intended amount. She subsequently developed hearing loss and acute renal failure and was treated with sodium thiosulfate 4 g/m2 IV once and then 2.7 g/m2/day IV in three divided doses for a total of 13 days. This treatment was initiated 70 hours after the cisplatin infusion, along with other supportive care measures such as aggressive hydration. The patient survived with residual hearing loss but did not develop chronic kidney damage. In two other published case reports, adult patients were treated with sodium thiosulfate, along with other modalities such as hemodialysis and plasmapheresis; in both reports the patient survived.13

The evidence for the use of sodium thiosulfate to treat cisplatin overdose is limited to case reports of single patients. This minimal evidence suggests that sodium thiosulfate could be used as a treatment modality, along with other supportive care measures.

Conclusion
The goal of oncology pharmacotherapy is to administer potentially lethal medications in a safe manner that will optimize therapeutic benefit and minimize harm. However, medication errors can still occur, and the goal in this scenario is to manage toxicity quickly in order to minimize harm to patients. After the FDA approval of uridine triacetate, the Institute of Safe Medication Practices (ISMP) published an article summarizing case reports of 5-FU overdoses and recommendations on how to manage these events.16 The article applied to 5-FU overdoses, but the concepts could be generalized to managing chemotherapy overdoses that have specific antidotes. ISMP recommends training nurses and other healthcare professionals on recognizing chemotherapy toxicities and creating a treatment protocol that defines how to efficiently procure an antidote and manage the patient’s toxicities. Pharmacists are uniquely positioned to serve as subject matter experts on chemotherapy agents and their respective antidotes and should be involved in developing chemotherapy antidote protocols.

References

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  4. Vistogard (uridine triaceate) [package insert]. Rockville, MD: Wellstat Therapeutics Corp.; 2018.
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  6. Ramsey LB, Balis FM, O’Brien MM, et al. Consensus guideline for use of glucarpidase in patients with high-dose methotrexate induced acute kidney injury and delayed methotrexate clearance. Oncologist. 2018;23(1):52-61.
  7. Voraxaze (glucarpidase) [package insert]. Brentwood, TN: BTG International Inc.; 2013.
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  9. Riva L, Conter V, Rizzari C, Jankovic M, Sala A, Milani M. Successful treatment of intrathecal methotrexate overdose with folinic acid rescue: A case report. Acta Paediatr. 1999;88:780-782.
  10. Widemann BC, Balis FM, Shalabi A, et al. Treatment of accidental intrathecal methotrexate overdose with intrathecal carboxypeptidase G2. J Natl Cancer Inst. 2004;96:1557-1559.
  11. Bradley AM, Buie LW, Kuykendal A, Voorhees PM. Successful use of intrathecal carboxypeptidase G2 for intrathecal methotrexate overdose: A case study and review of the literature. Clin Lymphoma Myeloma Leuk. 2013;13:166-170.
  12. Jardine LF, Ingram LC, Bleyer WA. Intrathecal leucovorin after intrathecal methotrexate overdose. J Pediatr Hematol Oncol. 1996;18:302-304.
  13. Song B, Yang C, Wang L. Fatal overdosage with cisplatin by accidental substitution for carboplatin: A case report. Int J Clin Exp Med. 2018;11:5275-5280.
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  16. Institute for Safe Medication Practices. Accidental overdoses involving fluorouracil infusions. June 18, 2015. Available at https://www.ismp.org/resources/accidental-overdoses-involving-fluorouracil-infusions. Accessed September 29, 2018.
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