Overview

Drug allergy overall algo.png

Contraindications

  • Do not re-challenge patients with a history of any of the following reactions triggered by the drug in question:
    • Autoimmune diseases
      • Bullous pemphigoid
      • Pemphigus vulgaris
      • Linear IgA bullous disease
      • Drug-induced lupus
    • Neutrophilic dermatosis
      • AGEP
      • Sweet’s syndrome - acute febrile neutrophilic dermatosis
    • Severe cutaneous drug reactions
      • SJS/TEN
      • DRESS
      • Exfoliative dermatitis
    • Drug-induced vasculitis
      • Leukocytoclastic vasculitis
      • Churg-Strauss
    • Organ-specific drug reactions
      • Cytopenias
      • Hepatitis
      • Nephritis
      • Pneumonitis
    • Serum sickness

  • Other considerations:
    • Is the drug truly needed (no suitable alternative)?
      • Are the alternatives potentially more toxic or less effective?
    • Do the available tests lack high negative predictive value?
    • What is individual risk-benefit?

  • Key components in history to document prior to testing:
    • Name of drug
    • When during course did reaction occur
    • Characteristics of reaction, systems involved
    • Previous exposure to same or similar drug
    • Reason for administration
    • Concurrent medications at time of reaction
    • Management required for reaction
    • Time elapsed since the reaction
    • Subsequent exposure to same or similar drug
    • Similar symptoms in absence of drug treatment



Graded Dose Challenge

  • Synonyms: drug provocation test, graded dose challenge, incremental challenge, test dosing
  • Objective is to cautiously introduce a drug in patients who are unlikely to be allergic to it
  • Drug is given in 2-3 steps (>4-5 steps may induce modifications of immune effector cells and therefore induce tolerance in the patient)
  • Protocols
    • Should be done under close monitoring with 1:1 nursing and rescue medications readily available
    • Choose starting dose:
Likelihood of true allergy to drug-------
Starting dose
Unlikely
1/100 or 1/1000th of final dose-------
Very unlikely
1/10 of final dose
Extremely unlikely
Full dose to negate history
    • Interval between doses depends on history of original reaction
      • Immediate - 20-30 minutes
      • Delayed - hours-days
    • The Brigham and Women’s Hospital protocol involves giving 1/10th the final therapeutic dose over 3 rapid intervals followed by administering the rest of the dose at an infusion rate of 80 mL/h
    • Boston Children’s Hospital protocol starts at 1/100th, then 1/10th, and finally 9/10th of the therapeutic dose given at 30 min intervals administered at the usual recommended infusion rate of the drug. The patient is then observed for 1 hr after the final dose.
    • If the graded challenge is tolerated, the patient may return to regular administration of the the drug




Desensitization (BWH)

Location

  • Consider risk stratification according to the severity of the patient's reaction history
    Brown HSR grading.png
  • Adults:
    • ICU for patients with history of grade 3 reactions and/or those with minimal cardiopulmonary reserve capacity
    • Outpatient infusion setting is acceptable for adults with history of grade 1-2 provided there is appropriate nursing/physician supervision
  • Children:
    • ICU step down unit for history of grade 1-2 reactions
    • ICU for grade 3 reactions

Premedication

Premedication
Adults
Children
Note
Diphenhydramine
25 mg PO/IV
1 mg/Kg PO/IV
  • 20 min prior to infusion
  • Because most reactions tend to occur toward the end of most desensitization protocols, it may be more advantageous to premedicate with 2nd/3rd generation antihistamines with longer half-lives over shorter-acting first-generation antihistamines
Famotidine
20 mg PO/IV
20 mg IV if >12 yo
  • 20 min prior to infusion
Ranitidine
50 mg IV
1.5 mg/Kg IV
  • 20 min prior to infusion
Dexamethasone
20 mg PO/IV
10 mg/m2 PO/IV
  • Given the previous night and the morning of desensitization for certain chemotherapeutic agents
Montelukast
10 mg PO
4 mg (0-5 yo), 5 mg (6-14 yo) PO
  • 1 hour prior to infusion
  • Consider if previously failed desensitization or experienced flushing reactions
ASA
325 mg PO
10-15 mg/Kg PO
  • 1 hour prior to infusion
  • Consider if previously failed desensitization or experienced flushing reactions
Acetaminophen
500 mg PO
15 mg/Kg PO
  • Acetaminophen (plus histamine blockers) recommended as prophylaxis for cytokine release reactions induced by monoclonal Abs used in cancer therapy

  • Consider effect of patient's other medications on desensitization
Mast_cell_degranulators.png

Charting

  • Document any reaction, including:
    • Symptoms, vital signs, peak flow, physical findings
    • At what step did the reaction occur and how many minutes into the infusion
    • Treatments administered, response to treatment, when the protocol desensitization was restarted
  • Recording time of symptom onset is helpful because a patient with a history of breakthrough reactions may receive additional antihistamine treatment before the step at which a previously experienced reactions occurred


Infusion Protocol


  • Patients who have had severe anaphylactic reactions or who have reacted early in the standard 12-step desensitization (outlined in the spreadsheet above) may experience fewer symptoms if desensitized using a 16-step protocol, which adds another bag containing 1/1000th of the full dose. The use of a 16-step (four bags) or a 20-step (five bags) protocol is reserved for high-risk patients


Treatment of Reactions

Mild/moderate reactions
  • Pruritus, flushing, urticaria, nausea, abdominal pain, back pain*, normal vital signs
    • Back pain typically only seen with chemotherapy or monoclonal antibody drugs
  • Stop the infusion and treat with IV diphenhydramine (25-50 mg adults, 1 mg/Kg children) and IV ranitidine (50 mg adults, 1.5 mg/Kg children)
    • For shortness of breath, chest tightness, throat tightness add nebulized albuterol +/- IV methylprednisolone 0.5 mg/Kg
  • Observe the patient until reaction subsides and then resume protocol at the point where the infusion was stopped
Severe reactions
  • Syncope, hypotension, stridor, upper airway compromise, status asthmaticus, respiratory distress, hypoxia
  • Stop the infusion and treat with epinephrine (0.3 mg IM adults, 0.01 mg/Kg children), diphenhydramine IV and methyprednisolone IV, oxygen, nebulized albuterol for bronchospasm, and IV fluids
  • Consider glucagon 1-2 mg bolus IV it patient has taken beta-blockers followed by infusion at 1-5 mg/hr
  • Immediately alert the house-staff and or allergist on call
  • When the patient is stable, the protocol may be resumed as instructed by allergist on call
    • When resuming, decrease the next dose at least 10-fold and repeat until no systemic reactions are observed
    • In some instances, the desensitization procedure may have to be aborted, and repeated in the future with a more conservative protocol or additional premedications
Management_of_desensitization_reactions.png
HSR - hypersensitivity reaction
(Castells 2009)


Note:
  • For medications given at intervals significantly greater than their half-lives, such as monoclonal antibodies and chemotherapy, desensitization needs to be repeated for each administration
  • Severe back or chest pain and a vague sense of impending doom have been described by patients who experience acute drug reactions to chemotherapy and monoclonal antibodies (especially taxanes)
  • Liposomal doxorubicin adverse effects can mimic hypersensitivity reactions and can present as palmoplantar erythrodysesthesia (“hand-foot syndrome”), stomatitis, and/or a diffuse follicular eruption with an intertriginous distribution
  • In the largest case series of rapid desensitizations to chemotherapeutic drugs: 67% proceeded without reaction, 27% had mild reactions (no chest pain, hypotension, dyspnea, hypoxia, or throat tightness), and 6% had severe reactions (no intubations or deaths, only 1 required epinephrine)
  • Clinical efficacy of short half-life chemotherapeutic drugs delivered slowly via desensitization (vs. normal delivery which should achieve higher peak serum levels) is unclear


PCN Desensitization





References