Cancer Chemother Pharmacol (2014) 73:435–436 DOI 10.1007/s00280-013-2331-6

COMMENTARY

Assessing physico‑chemical compatibility of concomitantly diluted antiemetics including palonosetron‑HCl and fosaprepitant dimeglumine Hans‑Peter Lipp · Wieland Gfrörer 

Received: 16 August 2013 / Accepted: 16 October 2013 / Published online: 13 November 2013 © Springer-Verlag Berlin Heidelberg 2013

Very recently, Sun et al. [1] presented physico-chemical compatibility data of intravenous fosaprepitant with different 5-HT3 antagonists and corticosteroids in the same infusion solution. After 24-h storage under ambient conditions, samples were assayed for degradation. Compatibility was defined as (1) <0.2 % increase in degradate level and (2) particulate levels according to United States Pharmacopeia (USP). Whereas any particulates were below the USP recommended limits, degradate formation was concluded to be unacceptable in the case of palonosetron-HCl combined with fosaprepitant based on an increased rate of fosaprepitant degradation products between 0.3 and 1.1 % compared to 0.0 % with granisetron-HCl with or without corticosteroids in the ad hoc mixture. We have proceeded a similar compatibility study [2] with an all-in-one admixture, when we combined palonosetron-HCl 0.25 mg, dexamethasone dihydrogen phosphate 12 mg and fosaprepitant 150 mg (as corresponding dimeglumine) in 50 mL NaCl 0.9 %. When we measured drug levels to different time points after admixture (Table 1) by HPLC, we concluded the addition of all three drugs to be compatible and physico-chemically stable for at least 24 h at room temperature. However, a slow release of low amounts of the active compound aprepitant by hydrolysis over time can be observed (Table 1), which results in a precipitation after several days when a critical concentration level is exceeded. We performed this experiment based on the fact that (1) ad hoc admixtures, e.g., of antiemetic drugs in the same IV infusion solution, can alleviate the everyday clinical practice particularly in ambulatory settings, (2) H.-P. Lipp (*) · W. Gfrörer  Department of Hospital Pharmacy, University Clinic of Tübingen, Tübingen, Germany e-mail: hans‑[email protected]‑tuebingen.de

palonosetron, dexamethasone, and fosaprepitant may represent the most potent antiemetic regimen for first-line treatment in case of highly emetogenic chemotherapy (HEC) as well as salvage regimens in moderately emetogenic chemotherapy (MEC), and (3) the structurally related granisetronHCl (range of pH stability: 4.0–6.0) has been shown to be compatible with a broad spectrum of other agents in the same infusion solution including dexamethasone sodium phosphate (range of optimal pH stability: 7–8.5). Why should therefore a great difference to palonosetron-HCl to be expected (range of pH stability: 4.5–5.5)? In this context, we were surprised, when Sun et al. [1] described an obvious difference between granisetron-HCl and palonosetron-HCl in the similar ad hoc admixtures. However, a general comment may be needed in respect to the definition “compatibility”. The study group defined >0.2 % in degradation level as unacceptable which is somewhat surprising. It is convenient, to accept a limit up to even 10 % decrease in the parent compound, when stability and compatibility are monitored during experimental studies (e.g., ondansetron-HCl and dexamethasone sodium phosphate in infusion bags and syringes for 32 days), however, with non-toxic, inactive degradation products as a prerequisite [3, 4]. In contrast, such a limit is deeply unacceptable in the case of dacarbazine based on the fact that already small amounts, e.g., <1 %, of the toxic degradation product azahypoxanthine have been shown to increase allover drug intolerability enormously [5]. However, toxic degradation products are very unlikely to occur during enzymatic or non-enzymatic hydrolysis of the prodrug fosaprepitant dimeglumine which is in accordance with our study results. Indeed, a slow release of the active compound aprepitant, which is less soluble in aqueous solutions, has to be expected during storage of fosaprepitant in NaCl 0.9 % 50 mL over a longer period of time [6].

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Cancer Chemother Pharmacol (2014) 73:435–436

Table 1  Physico-chemical compatibility and stability of palonosetron-HCl (5 mL), dexamethasone dihydrogen phosphate (3 mL), and fosaprepitant (5 mL) added to NaCl 0.9 % 50 mL up to 24 h Drug

t0h (%)

t2h (%)

t4h (%)

t6h (%)

t24h (%)

Palonosetron-HCl Dexamethasone Fosaprepitant

100.9 100.0 101.5

100.4 100.4 101.9

100.5 99.6 100.3

99.6 98.7 101.7

100.0 98.9 102.8

Aprepitant

0.25

0.32

0.38

0.45

0.90

Palonosetron-HCl 0.25 mg (ALOXI®), dexamethasone dihydrogen phosphate 12 mg (corresponding disodium salt: FORTECORTIN 8 mg and 4 mg), fosaprepitant 150 mg (corresponding dimeglumine: IVEMEND 150 mg); aprepitant, slowly released from fosaprepitant by hydrolysis (referred to an internal standard)

As a consequence, if Sun et al. might have defined a limit of at least 1 % rather 0.2 % to be accepted, they would have raised a deeply changed conclusion. In addition, it remains unclear and perhaps confusing why such a difference has been detected between granisetron-HCl and palonosetron-HCl in spite of highly overlapping ranges of pH stability values in aqueous solutions. To be true, we had some small differences in our experiments compared to Sun et al.: 1. We used fosaprepitant 150 mg rather than 115 mg, based on the fact that the former dose is meanwhile generally recommended to be used [7]. 2. After proper reconstitution of fosaprepitant dimeglumine (lyophylisate) according to the manufacturer, we added the concentrate to 50 mL NaCl 0.9 % with a higher concentration of the final solution as a consequence, whereas 1 mg/mL has been recommended by the manufacturer when fosaprepitant has to be added to 145 mL NaCl 0.9 %. However, our procedure may simplify everyday clinical practice and does not result in any obvious incompatibility according to our HPLC analysis with at least 3 probes measured per time point. Based on our results (Table 1), we concluded a threein-one IV admixture of 0.25 mg palonosetron-HCl,

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150 mg fosaprepitant, and 12 mg dexamethasone dihydrogen phosphate to be physico-chemically stable and compatible after addition into NaCl 0.9 % 50 mL for at least 24 h at room temperature when we accepted a limit of 0.2 % to be exceeded. In our opinion, this allin-one ready-to-use admixture may be clearly helpful in oncology units to improve antiemetic prophylaxis in everyday clinical practice. In conclusion, we suggest that the all-in-one admixture palonosetron-HCl 0.25 mg, fosaprepitant 150 mg, and dexamethasone dihydrogen phosphate 12 mg is physicochemically stable and compatible for at least 24 h when the different components are added to 50 mL NaCl 0.9 %, however, on condition that the released amount of aprepitant is accepted to exceed a limit of 0.2 %.

References 1. Sun S, Schaller J, Placek J et al (2013) Compatibility of intravenous fosaprepitant with intravenous 5-HT3 antagonists and corticosteroids. Cancer Chemother Pharmacol [Epub ahead of print] 2. Lipp HP, Gfrörer W, Herbst N (2011) Physico-chemical compatibility of palonosetron HCI, fosaprepitant dimeglumine and dexamethasone-21-dihydrogene-phosphate IV admixtures over at least 24 hours. Support Care Cancer 19(Suppl.2):67–370 3. Trissel LA (ed) (2013) Handbook of injectable drugs, 17th edn. American Society of Health-System Pharmacists 4. Hagan RL, Mallett MS, Fox JL (1996) Stability of ondansetron hydrochloride and dexamethasone sodium phosphate in infusion bags and syringes for 32 days. Am J Health Syst Pharm 53:1431–1435 5. El Aatmani M, Poujol S, Astre C et al (2002) Stability of dacarbazine in amber glass vials and polyvinyl chloride bags. Am J Health Syst Pharm 59:1351–1356 6. Skrdla PJ, Abrahim A, Wu Y (2006) An HPLC chromatographic reactor approach for investigating the hydrolytic stability of a pharmaceutical compound. J Pharm Biomed Anal 41:883–890 7. Celio L, Ricchini F, De Braud F (2013) Safety, efficacy, and patient acceptability of single-dose fosaprepitant regimen for the prevention of chemotherapy-induced nausea and vomiting. Patient Prefer Adherence 7:391–400