Safety of Test Doses for Evaluating Adverse Drug Reactions

January 8, 2016
Melissa Iammatteo, MD
Melissa Iammatteo, MD

Melissa Iammatteo, MD, is a first-year Allergy and Immunology fellow at Montefiore Health System/Albert Einstein College of Medicine. She recently completed her Internal Medicine residency at Massachusetts General Hospital, where she served as a Clinical Fellow in Medicine at Harvard Medical School. Her research focuses on the evaluation of adverse drug reactions, particularly through the use of protocols involving test doses.

Graded drug challenges are considered the gold standard for evaluating patients with a low-risk history of a prior adverse drug reactions – like a mild rash or unknown reaction to penicillin as a child.

Graded drug challenges are considered the gold standard for evaluating patients with a low-risk history of a prior adverse drug reactions — like a mild rash or unknown reaction to penicillin as a child.

Graded challenges also allow for the evaluation of cross-reactivity of structurally related compounds among different drug classes.

They are not recommended for patients with a history consistent with a severe reaction, such as Stevens-Johnson syndrome, toxic epidermal necrolysis, interstitial nephritis, hepatitis, or hemolytic anemia.

Performed in a controlled manner with administration of progressively increasing doses of a medication until a full therapeutic dose is reached, the intention of graded challenges is to exclude an immediate adverse drug reaction in a patient with a low likelihood of reacting to a medication.

Although graded challenges are considered the gold standard for evaluating these reactions, no evidence-based guidelines exist to guide the optimal number of steps. There is also concern that a challenge consisting of four or more steps may actually be inducing tolerance rather than challenging a patient.

As such, in an article “Safety and Outcomes of Test Doses at a Single Institution: A 5-Year Retrospective Review” published in The Journal of Allergy and Clinical Immunology: In Practice, my colleagues and I determined the safety of test doses among patients with a history of adverse drug reactions by comparing the outcomes to multistep graded challenges.

A one-step test dose is defined as the administration of the full dose of a medication followed by a specific time period (i.e., 60 minutes) of observation, while a two-step test dose is defined as 1/10th of the full dose for a parenteral medication or ¼ of a pill for an oral medication followed by administration of the full dose after a specific period of observation.

We compared the outcomes of one- or two-step test doses with multi-step graded challenges comprised three or four steps performed between May 2008 and May 2013 at Massachusetts General Hospital.

Adverse drug reactions were classified by type and graded by severity. We identified 456 unique patients who underwent 497 one- or two-step test doses — Beta-lactams were the most common drug prompting test doses followed by NSAIDs. The majority of patients (n=444, 89%) did not experience any adverse drug reactions like non-immune-mediated reactions (45%), including localized tingling sensation, nausea, drowsiness, chills, dry throat and headache, or mild IgE-mediated reactions (32%), such as hives (n=5), pruritus (n=6), and angioedema (n=1) during test doses.

All reactions were mild; no anaphylactic reactions occurred.

This study concluded that one- or two-step test doses are safe in appropriately selected patients for the evaluation of adverse drug reactions, and the overwhelming majority of test doses do not result in adverse drug reactions.

Furthermore, when reactions did occur, they were mild and often did not require any treatment. Multi-step challenges do not confer additional safety, but may be performed when caution is required, such as in patients with anxiety or multiple co-morbid conditions.

Advantages of test doses over multistep challenges include:

· The absence of concern for induction of tolerance or desensitization given the limited number of steps

· The need for fewer resources such as staffing and time

· The ability for patients, especially inpatients, to reach therapeutic dosing more rapidly.

Test doses also allow for a more efficient means to provide patients with the optimal drug required to treat their disease. For instance, patients who reported a penicillin allergy were more likely to receive alternative antibiotics that were broad-spectrum and potentially more toxic and less effective.

Although penicillin allergy is reported in approximately 10% of the population, only 90% of these patients were deemed to truly be allergic. By performing a test dose in patients who reported a low-risk history of penicillin allergy, the optimal antibiotic of choice could be evaluated and administered to the patient within two hours.

The next time you evaluate a patient who reports a history of a mild adverse drug reaction — remember to promptly involve an allergist to assess the patient’s suitability for a test dose rather than opting to administer an alternative antibiotic that may be more toxic or less effective.