Crushed Posaconazole Delayed-Release Tablets Via Enteral Feeding Tubes: A Cautionary Tale

Several retrospective case series have evaluated the use of crushed posaconazole (POS) delayed-release tablets (DRTs) administered via enteral feeding tubes (EFTs) and have reported achievement of therapeutic POS concentrations with no alarming signals in clinical outcomes or safety.^1-4 This is despite a package insert warning to avoid crushing POS DRTs. ⁵ Based on these favorable reports of crushed POS DRTs, our institution permitted administration of crushed POS DRTs via EFTs in October 2022. Nursing staff followed a standard process for crushing oral medications with the RXCrush pill crusher. The timing of held enteral nutrition regimens was not standardized or specified within the POS order.

To assess the safety of this practice, we conducted a single-center, retrospective review of patients who had POS therapeutic drug monitoring (TDM) while receiving crushed POS DRTs via EFTs from October 1, 2022, to April 15, 2023. POS levels were obtained as trough concentrations and assessed based on indication-specific goals for prophylaxis (>700 ng/mL) and treatment (>1000 ng/mL). ⁶ This study was conducted with approval from the University of North Carolina at Chapel Hill (UNC) institutional review board.

A total of 10 patients met inclusion criteria with baseline characteristics and clinical course information as described in Table 1. Most patients transitioned from an alternative POS regimen to crushed POS DRTs (80%) and required intensive care unit (ICU)-level care at the time of crushed POS DRT initiation (90%). This group of ICU patients received a variety of supportive care measures. During the period that crushed POS DRTs were administered, five were mechanically ventilated, three received vasopressor support, two were paralyzed to improve oxygenation, and one received renal replacement therapy. EFT sites of administration included nasogastric (70%), nasoduodenal (20%), and gastric (10%) tubes.

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Table 1.

Characteristics of Patients Receiving Crushed Posaconazole (POS) Delayed-Release Tablets (DRTs) Via Enteral Feeding Tubes (EFTs).

#	Age/sex diagnosis indication	Location a DDIs b nutrition/diarrhea	Initial POS regimen		Crushed POS DRT via EFT regimen		Subsequent POS regimen		Outcomes and comments
			Dosage and frequency (duration)	POS level (time from POS start to level)	Dosage and frequency	POS level (time from crushed start to level)	Adjusted dosage and frequency	POS level(s) (time from dose change to level)
1	80/F Burn injury Treatment	ICU None TF/No	N/A—started on crushed POS DRT	N/A	300 mg NG daily	217 ng/mL (6 days)	300 mg BID IV for 1 day, then 300 mg IV daily	1751 ng/mL (6 days)	Completed course on IV POS
2	12/M AML Prophylaxis	ICU None TF + TPN/No	200 mg PO qAM and 300 mg PO qPM (16 days)	1511 ng/mL (7 days)	200 mg NG qAM and 300 mg NG qPM	689 ng/mL (3 days)	N/A	N/A	Died on POS therapy
3	60/M Burn injury Prophylaxis	ICU None TF/Yes	300 mg IV daily (6 days)	325 ng/mL (6 days)	300 mg NG daily	225 ng/mL (6 days)	N/A	N/A	Antifungal therapy discontinued
4	21/M IPA Treatment	ICU None TF/No	300 mg PO daily (29 days)	3217 ng/mL (28 days)	200 mg NG daily	2042 ng/mL (5 days)	100 mg NG daily	1250 (10 days)	Died on POS therapy
5	74/M ROCA Treatment	Floor None TF/No	300 mg PO daily (2 days), then 200 mg TID (1 day)	N/A	300 mg ND daily	301 ng/mL (3 days)	400 mg NG daily	499 ng/mL (4 days); 683 ng/mL (7 days)	Transitioned to ISA
6	29/M Burn injury Treatment	ICU None TF/No	300 mg IV BID (1 day)	N/A	300 mg ND daily	241 ng/mL (4 days)	N/A	N/A	Transitioned to VRC
7	39/F BOLT Prophylaxis	ICU TAC TF/No	N/A—started on crushed POS DRT	N/A	300 mg NG daily	693 ng/mL (5 days)	400 mg NG daily	924 ng/mL (2 days); 697 ng/mL (3 days)	Transitioned to PO POS DRTs
8	26/F BOLT Prophylaxis	ICU TAC TF/No	400 mg PO daily (~4 years)	771 ng/mL (~4 years)	300 mg post-pyloric daily	<100 ng/mL (5 days)	300 mg IV daily	163 ng/mL (1 day)	Died on IV POS therapy
9	81/M IPA Treatment	ICU PPI, CsA TF/No	300 mg PO BID (1 day), 300 mg PO daily (6 days)	1034 ng/mL (4 days)	300 mg NG daily	1491 ng/mL (3 days)	300 mg PO daily	N/A	Antifungal therapy discontinued
10	74/M IPA Treatment	ICU TAC TF/No	300 mg PO daily (3 days)	N/A	300 mg NG daily	947 ng/mL (6 days)	N/A	N/A	Died on POS therapy

Abbreviations: AML, acute myeloid leukemia; BID, twice daily; BOLT, bilateral orthotopic lung transplant; CsA, cyclosporine A; DDIs, drug-drug interactions; DRT, delayed release tablets; EFT, enteral feeding tubes; IPA, invasive pulmonary aspergillosis; ISA, isavuconazole; IV, intravenous; N/A, not applicable; ND, nasoduodenal; NG, nasogastric; PO, by mouth; POS, posaconazole; PPI, proton pump inhibitor; qAM, every morning; qPM, every evening; ROCA, rhino-orbital-cerebral aspergillosis; TAC, tacrolimus; TF, tube feeds; TID, three times daily; TPN, total parenteral nutrition; VRC, voriconazole.

a

Location: ICU or floor status at the time of crushed POS DRT via EFT initiation/first level.

b

DDIs: clinically relevant drug-drug interactions that may have resulted in reduced posaconazole concentrations.

Upon initial TDM, obtained 3-6 days after the initiation of crushed POS DRTs, only 2 patients (20%; patients 4 and 9) achieved their indication-specific goals. Both of those patients had confirmed therapeutic levels prior to crushed POS DRT initiation. Only 3 patients (30%) achieved levels >700 ng/mL, consistent with the prophylactic TDM goal at our institution. All patients (4/4) who had a prior POS concentration measured while receiving IV or non-crushed oral POS experienced a decrease in POS level. Escalation of crushed POS DRT doses occurred in 2 patients (patients 5 and 7), but neither achieved and/or maintained a therapeutic POS level after dose escalation. Two patients (patients 1 and 8) who transitioned from crushed POS DRT to a noncrushed POS regimen, with subsequent TDM, experienced increased serum POS levels.

The high rate of subtherapeutic POS concentrations observed in this study conflicts with the limited existing literature.^1-4 The two largest studies that investigated crushed POS DRTs demonstrated successful attainment of therapeutic POS levels upon first assessment in most patients: 10/14 by Dieringer et al ² and 19/19 by Manesh et al. ³ However, crushed POS DRTs via EFTs resulted in subtherapeutic initial levels for most patients in this study. It is unclear whether the patients in this study would have subsequently achieved therapeutic levels with dose titration, as few patients had their doses adjusted. Notably, all four patients that received tacrolimus or cyclosporine with concomitant immunosuppression TDM, while on crushed POS DRTs, achieved therapeutic or supratherapeutic immunosuppression levels. These limited observations are not consistent with universal malabsorption from the enteric tract. Our data demonstrate consistent reduction in serum POS levels with crushed POS DRTs in patients that transitioned to or from IV or oral POS administration.

The reasons for these discrepancies are likely multifactorial including drug and food interactions, feeding type, patient-specific absorption factors, and inconsistent preparation of crushed POS DRTs.^4,7 It is important to note that most patients in this study were critically ill, which has been associated with reduced and variable POS levels.^8,9 However, this does not solely explain the discrepancy in outcomes, as successful implementation of crushed POS DRTs was demonstrated by Dieringer et al, ² in a similarly ill patient population.

In the absence of further pharmacokinetic and clinical outcomes data, it is unclear what role crushed POS DRTs should have in therapy. Based on this study, our institution no longer recommends the use of crushed POS if other routes are available. We recommend institutions review internal data to assess target attainment with crushed POS. Frequent POS TDM should be considered if patients are transitioned to crushed POS DRTs.