Table 5 Guidance statements and evidence grades: considerations for medical management

From: Evidence- and consensus-based recommendations for the use of pegvaliase in adults with phenylketonuria

Guidance statement(s)

Evidence grade

Monitoring of adverse events

 1. Patients should be assessed (in person or by telephone/telemedicine) for signs and symptoms of hypersensitivity reactions every 2–4 weeks during the introduction and initial titration of pegvaliase, and during additional dose changes

B (Based on data from the clinical trial program)

Prevention of adverse events

 2. To minimize the risk of hypersensitivity reactions, antihistamines (H1 and H2 receptor antagonists, including, but not limited to, ranitidine) and antipyretics, if tolerated, are recommended as premedication for use from the day before the first injection and then daily during introduction and titration of pegvaliase. Reduction or discontinuation of premedications may be considered, based on clinical judgment, once stable dosing is reached

Premedications: C (based on nonrandomized comparison of AE rates before/after a change of protocol to the phase 3 clinical trial)

Management of anaphylaxis

 3. The decision to interrupt or discontinue pegvaliase in the event of suspected systemic hypersensitivity reaction should be made at the discretion of the treating clinician and the patient

     a. Consider permanently discontinuing pegvaliase in patients with acute systemic hypersensitivity reactions (defined by grade 3 anaphylaxis eventsa as assessed by Brown’s Severity Grading)b

     b. Rechallenge can be considered in patients with less severe systemic hypersensitivity reactions (defined by grade 1/2 anaphylaxis events as assessed by Brown’s Severity Grading)b

     c. Rechallenge should be at a lower dose/frequency of pegvaliase than the last dose taken

     d. Rechallenge should be performed in a controlled medical setting to facilitate rapid response to acute systemic hypersensitivity/anaphylaxis

     e. Referral and/or supervision by an allergy/immunology specialist when rechallenging with pegvaliase may be considered at the discretion of the prescribing metabolic specialist

     f. Consider resuming premedications and reinstating the trained observerc to accompany the patient for 1 hour after each injection for the first week following acute systemic hypersensitivity/anaphylaxis

C (Based on a small number of cases following the clinical trial program)

Management of arthralgia

 4. Arthralgia can generally be managed without the need for discontinuation of pegvaliase; however, consideration should be given to delaying scheduled dose increases until symptoms improve

     a. Management of mild arthralgia should include the addition of nonsteroidal anti-inflammatory drugs (NSAIDs) or acetaminophen to existing premedications at maximum dose (as per product label[s]) every 6–12 hours depending on the medication used, while maintaining current pegvaliase dose

     b. Short-term use of oral corticosteroids (such as prednisolone) can be used to manage moderate-to-severe arthralgia

B (Based on data from the clinical trial program)

D (Opinion of the SC, based on their experience in the clinical trial program)

Management of injection site reactions

 5. Injection site and generalized skin reactions are often transient and benign, and therefore, pegvaliase dose adjustment is rarely required

B (Based on data from the clinical trial program)

 6. Management of persistent localized injection site reactions may include use of topical steroid creams and/or short-term use of topical antihistamines while maintaining current pegvaliase dose until symptoms improve

D (Opinion of the SC, based on their experience in the clinical trial program)

 7. For more severe generalized pruritic skin reactions, consider the addition of oral antihistamines (H1 receptor antagonist) to existing premedications and maintain current pegvaliase dose until symptoms improve

D (Opinion of the SC, based on their experience in the clinical trial program)

 8. Patients should be advised to rotate injection sites with each dose and to avoid injecting into pre-existing nodules/sites of previous injection site reaction

D (Opinion of the SC, based on their experience in the clinical trial program)

 9. Patients should be encouraged to record injection site reactions, preferably by taking a photo for discussion with their doctor (either remotely via telemedicine or face-to-face at their next clinic visit)

D (Opinion of the SC, based on their experience in the clinical trial program)

  1. AE adverse event, SC Steering Committee.
  2. Postconsensus comments by the SC in response to recent FDA approval of pegvaliase:
  3. aAcross all clinical trials of pegvaliase with induction/titration/maintenance dosing (n = 285), 26 patients (9%) experienced 37 anaphylaxis episodes. These were deemed to be type III non-IgE-mediated reactions: 24/25 patients who were tested for drug-specific IgE antibodies were negative (one patient was not tested); 18/26 patients who experienced anaphylaxis were successfully rechallenged with pegvaliase.21 As such, the SC recommends that patients with type III hypersensitivity can be rechallenged in a controlled medical setting.
  4. bBrown’s system is a simple grading system to assess the severity of anaphylaxis. A limitation of this system is that grading of anaphylaxis events was based on emergency department assessments rather than allergist review with confirmatory skin testing and specific IgE analysis, and as such, grading is not based on etiology.
  5. cPALYNZIQ was not licensed when the consensus program was conducted, and this recommendation was drafted based on experience from the clinical trial program, during which the presence of an observer was required. Postapproval, use of a trained observer is not considered mandatory.
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