Table 2.

Example of a drug provocation test (DPT) or drug challenge with paclitaxel as per Ramon y Cajal University Hospital (RCUH) standard and cautious protocols for a total dose of 200 mg of paclitaxel that was intended to be administered in 250 ml over approximately 3 h

The standard approach to drug provocation test
Total dose	200 mg		Solution concentration		Drug
Solution A	250 ml		0.8 mg/ml		Paclitaxel
Step	Solution	Rate (ml/h)	Administered volume (ml)	Time (min)	Administered dose (mg)	Cumulative dose infused (mg)
1	A	80	250	187.5	200	200

The cautious approach to drug provocation testa:
Total dose	200 mg		Solution concentration		Drug
Solution A	250 ml		0.8 mg/ml		Paclitaxel
Step	Solution	Rate (ml/h)	Administered volume (ml)	Time (min)	Administered dose (mg)	Cumulative dose infused (mg)
1	A	40	20	30	24	24
2	A	80	230	172.5	176	200

Considerations:
(i) Safety is of the essence. DPT with intravenous chemotherapy should be limited to well-selected patients with a favorable risk assessment. It should be done ideally in an intensive care setting or equivalent (a well-equipped Allergy-dedicated Technical Area with complete crash cart, and rapid access to intensive care <1 min), 1:1 patient:nurse ratio, expert nursing staff (well trained in chemotherapy, allergy, and emergency treatment), constant monitoring, constant supervision with nurse and allergist at the bedside (including someone ready to stop the infusion rapidly), emergency anaphylaxis treatment at the ready (including pre-prepared intramuscular adrenaline). Observation after DPT should be at least 1 h after finishing the infusion (or longer, conditional to product information, local guidance, and type of reaction).
(ii) The recommended concentrations and rates for paclitaxel are rather wide and might depend on the condition of the patient or local standard operating procedures. Concentrations and infusion times need to be discussed according to local guidelines (including small details such as whether the line is flushed with the drug or with the solvent saline), and the protocol will need to be altered accordingly. Always check product information leaflets and local protocols for specific administration recommendations in specific populations.
(iii) DPT with chemotherapy agents should be done using standard posology and premedication recommendations as per product information. In the specific case of paclitaxel, the product information states that patients need to be premedicated with corticosteroids, H1 antihistamines, and H2 antihistamines. It is recommended to check local guidance, as there might be variations. This practice differs from guidelines on DPT with other drugs, which usually recommend against the use of premedication (especially with antihistamines or steroids), as it can alter tolerance and hide warning symptoms. However, Madrigal-Burgaleta et al.b have shown data on the usefulness of DPT with paclitaxel whilst still using the standard premedication with corticosteroids, H1 antihistamines, and H2 antihistamines for the DPT.
(iv) Product information leaflets should be available for all products from their manufacturers and must be compliant with the recommendations of the relevant regulatory body, such as www.ema.europa.eu, products.mhra.gov.uk, or https://www.fda.gov/.
(v) Follow recently published guidance on DPT with chemotherapy agentsc

DPT, drug provocation testing; RCUH, Ramon y Cajal University Hospital; RDD, rapid drug desensitization.

Note: The standard approach to DPT is as close as possible to a standard infusion as per product information to avoid the risk of unnecessarily affecting efficacy and to ensure that we confirm tolerance under normal conditions so that nothing alters tolerance to the drug. These drugs are meant to be infused over long periods, so the dose/minute ratio is already low on a standard infusion. In our experience, the key to safety is not necessarily on the infusion rate but on carrying out these techniques in a high-risk area and having experienced and trained staff at the bedside ready to stop the infusion and administrate medication at the first sign of a reaction.

Note on increasing premedication beyond routine premedication: The value of adding extra premedication or altering infusion times/rates beyond what is contemplated in the manufacturer's instructions is not recommended. Such practices have not been validated, and they could affect tolerance, mask early signs of a reaction, arguably further sensitize the patient, and create opportunity for human errors in the infusion center (e.g., by adding premedication that the staff are not used to give and, during a busy shift, are likely to forget). Thus, if the reaction of the patient were worrying enough that such measures (additional premedication or altering infusion rates beyond the manufacturer's instructions) were being contemplated, we would recommend avoiding the direct DPT diagnostic pathway and rather choose the RDD therapeutic pathway instead (with its specific infusion rates and range of premedication). After all, this could eventually lead to a diagnostic DPT further down the line, after confirming tolerance to progressively shorter RDD protocols.

^aThe cautious approach could potentially induce tolerance, and thus, a negative DPT using the cautious approach might benefit from later performing a standard DPT on the next scheduled chemotherapy session.

^bMadrigal-Burgaleta R, Bernal-Rubio L, Berges-Gimeno MP, Carpio-Escalona LV, Gehlhaar P, Alvarez-Cuesta E. A Large Single-Hospital Experience Using Drug Provocation Testing and Rapid Drug Desensitization in Hypersensitivity to Antineoplastic and Biological Agents. J Allergy Clin Immunol Pract. 2019;7(2):618–632. DOI:10.1016/j.jaip.2018.07.031.

^cPagani M, Bavbek S, Alvarez-Cuesta E, Dursun AB, Bonadonna P, Castells M, Cernadas J, Chiriac A, Sahar H, Madrigal-Burgaleta R, Sanchez Sanchez S. Hypersensitivity Reactions to Chemotherapy: an EAACI Position Paper. Allergy. 2021; in press. DOI: 10.1111/all.15113