Boxed Warning
Anaphylaxis
Anaphylaxis has been reported after administration of pegvaliase and may occur at any time during treatment. Administer the initial dose of pegvaliase under the supervision of a health care provider equipped to manage anaphylaxis, and closely observe patients for at least 60 minutes following injection. Prior to self-injection, confirm patient competency with self-administration, and patient’s and observer’s (if applicable) ability to recognize signs and symptoms of anaphylaxis and administer auto-injectable epinephrine, if needed. Consider having an adult observer for patients who may need assistance in recognizing and managing anaphylaxis during pegvaliase treatment. If an adult observer is needed, the observer should be present during and for at least 60 minutes after pegvaliase administration, should be able to administer auto-injectable epinephrine, and call for emergency medical support upon its use. Prescribe auto-injectable epinephrine to all patients treated with pegvaliase. Prior to the first dose, instruct the patient and observer (if applicable) how to recognize the signs and symptoms of anaphylaxis, how to properly administer auto-injectable epinephrine, and to seek immediate medical care upon its use. Instruct patients to carry auto-injectable epinephrine with them at all times during treatment with pegvaliase. Consider the risks and benefits of readministering pegvaliase following an episode of anaphylaxis. If the decision is made to readminister pegvaliase, readminister the first dose under the supervision of a health care provider equipped to manage anaphylaxis and closely observe the patient for at least 60 minutes following the dose. Because of the risk of anaphylaxis, pegvaliase is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the pegvaliase REMS
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution Prefilled Syringe, Subcutaneous [preservative free]:
Palynziq: pegvaliase-pqpz 20 mg/mL (1 mL); pegvaliase-pqpz 10 mg/0.5 mL (0.5 mL); pegvaliase-pqpz 2.5 mg/0.5 mL (0.5 mL)
Pharmacology
Mechanism of Action
A PEGylated phenylalanine ammonia lyase (PAL) enzyme that converts phenylalanine to ammonia and trans-cinnamic acid, thereby reducing blood phenylalanine concentrations.
Pharmacokinetics/Pharmacodynamics
Absorption
Tmax: ~8 hours
Distribution
Vd: 20 mg/dose: 1.8 to 241 L; 40 mg/dose: 3.1 to 49.5 L
Metabolism
Via catabolic pathways and degrades into small peptides and amino acids
Half-Life Elimination
20 mg/dose: 14 to 132 hours; 40 mg/dose: 14 to 127 hours
Use: Labeled Indications
Phenylketonuria (PKU): To reduce blood phenylalanine concentrations in adult patients with phenylketonuria (PKU) who have uncontrolled blood phenylalanine concentrations >600 micromol/L on existing management..
Contraindications
There are no contraindications listed in the manufacturer's labeling.
Dosage and Administration
Dosing: Adult
Note: Prescribe an epinephrine auto-injector to all patients. Measure baseline blood phenylalanine concentration prior to initiation. Consider premedication with antihistamines (H1-antagonist, H2-antagonist) and/or antipyretic to prevent hypersensitivity reactions (based on patient tolerability). Reduce dose or modify diet to avoid serum phenylalanine concentrations <30 micromol/L.
Phenylketonuria (PKU): SubQ:
Induction: 2.5 mg once weekly for 4 weeks
Titration (after 4-week induction): 2.5 mg twice weekly for 1 week, then 10 mg once weekly for 1 week, then 10 mg twice weekly for 1 week, then 10 mg 4 times/week for 1 week, then 10 mg once daily for 1 week. Additional time may be required prior to each dosage escalation based on patient tolerability.
Maintenance (after induction and titration): 20 mg once daily for at least 24 weeks. May increase to 40 mg once daily if a response (20% reduction from baseline in blood phenylalanine or blood phenylalanine concentration 600 micromol/L or less) has not been achieved after administering 20 mg once daily for 24 weeks. Discontinue therapy if a response has not been achieved after administering 40 mg once daily for 16 weeks. Use lowest effective and tolerated dose. Maximum dose: 40 mg/day
Dosing: Geriatric
Refer to adult dosing.
Administration
SubQ administration: Administer subcutaneously in the front middle thighs or the abdomen (at least 2 inches away from navel) if self-injecting; if a caregiver is administering the injection, the back of the upper arms and the top of the buttocks may also be used. Rotate injection sites; if more than 1 injection is needed for a single dose, administer the second injection at least 2 inches away from the first injection site; second site may be on the same or a different body part as the first injection. Perform initial administration or readministration (after anaphylaxis) under close observation by a health care provider for ≥60 minutes following injection.
Dietary Considerations
Dietary protein and phenylalanine intake may need to be adjusted based on blood phenylalanine concentrations.
Storage
Store in refrigerator at 2°C to 8°C (36°F to 46°F) in original carton to protect from light; do not freeze or shake.
If needed, product may be stored in original carton at room temperature at 20°C to 25°C (68°F to 77°F) for up to 30 days. Do not return the product to the refrigerator once stored at room temperature. Discard after 30 days at room temperature or after the expiration date, whichever comes first.
Drug Interactions
MedroxyPROGESTERone: May enhance the adverse/toxic effect of Pegvaliase. Specifically, the risk of anaphylaxis or hypersensitivity reactions may be increased. Monitor therapy
PEGylated Drug Products: May enhance the adverse/toxic effect of Pegvaliase. Specifically, the risk of anaphylaxis or hypersensitivity reactions may be increased. Monitor therapy
Adverse Reactions
Incidence ranges include induction, titration, and maintenance dosing.
>10%:
Central nervous system: Headache (35% to 50%), fatigue (13% to 22%), anxiety (5% to 18%), dizziness (16% to 17%)
Dermatologic: Skin changes (21% to 44%), pruritus (20% to 24%), alopecia (5% to 17%)
Gastrointestinal: Nausea (18% to 26%), vomiting (13% to 26%), abdominal pain (14% to 25%), diarrhea (9% to 22%)
Hematologic & oncologic: Change in serum protein (below LLN: complement factor C3 8% to 84%; complement factor C4 48% to 62%), C-reactive protein increased (64% to 68%), hypophenylalaninemia (16% to 61%)
Hypersensitivity: Anaphylaxis (9% to 84%), hypersensitivity reaction (53% to 69%)
Immunologic: Antibody development (100%; neutralizing antibodies to PAL enzyme activity: 88%)
Local: Injection site reaction (72% to 88%)
Neuromuscular & skeletal: Arthralgia (61% to 83%), increased creatine phosphokinase (18% to 43%)
Respiratory: Oropharyngeal pain (13% to 23%), cough (9% to 22%), nasal congestion (4% to 18%)
1% to 10%:
Hypersensitivity: Angioedema (8%), serum sickness (2%)
Neuromuscular & skeletal: Joint stiffness (8%), joint swelling (8%), musculoskeletal disease (7%)
Warnings/Precautions
Concerns related to adverse effects:
- Hypersensitivity reactions: [US Boxed Warning]: Anaphylaxis has been reported and may occur at any time during treatment; administer initial dose under the supervision of a health care provider equipped to manage anaphylaxis, and closely observe patients for at least 60 minutes following injection. Prior to self-injection, confirm patient competency with self-administration; prescribe auto-injectable epinephrine to all patients treated with pegvaliase and instruct patients to carry auto-injectable epinephrine with them at all times during treatment. Symptoms of anaphylaxis include syncope, hypotension, hypoxia, dyspnea, wheezing, chest discomfort/tightness, tachycardia, angioedema, throat tightness, skin flushing, rash, urticaria, pruritus, and GI symptoms; delayed episodes of anaphylaxis occurred up to 48 hours after administration (most episodes occurred within first year; some cases reported after 2 years). Hypersensitivity reactions (other than anaphylaxis) have been also been reported; dose adjustment or temporary drug interruption may be considered. Consider premedication prior to administration.
Monitoring Parameters
Blood phenylalanine concentration prior to initiation, every 4 weeks until maintenance is achieved, then periodically throughout treatment; signs and symptoms of anaphylaxis/hypersensitivity for ≥60 minutes after initial dose or upon reinitiation of therapy (after a previous episode of anaphylaxis). Maintain serum phenylalanine concentrations between 120 and 360 micromol/L for 3 months prior to conception and during pregnancy.
Pregnancy
Pregnancy Considerations
Uncontrolled maternal phenylalanine concentrations are associated with adverse pregnancy outcomes. Phenylalanine concentrations >600 micromol/L (10 mg/dL) may increase the risk of miscarriage, birth defects (including microcephaly and major cardiac malformations), intrauterine growth retardation, and future intellectual disability. Maternal phenylalanine concentrations should be controlled during pregnancy and for 3 months prior to conception to reduce the risk of adverse fetal events. Dietary control is currently recommended (ACOG 2015; Vockley 2014); information related to the use of pegvaliase in pregnant women is insufficient.
Health care providers are encouraged to enroll women exposed to pegvaliase during pregnancy or within 1 month following the last dose to the pregnancy surveillance program (866-906-6100).
Patient Education
- Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)
- Patient may experience joint pain, headache, abdominal pain, mouth pain, sore throat, cough, loss of strength and energy, anxiety, hair loss, or stuffy nose. Have patient report immediately to prescriber chest pain, dizziness, passing out, fast heartbeat, flushing, leaking of urine, leaking of stool, skin rash, itching, facial edema, chest tightness, throat tightness, wheezing, difficulty breathing, severe nausea, vomiting, diarrhea, skin reaction, or severe injection site irritation (HCAHPS).
- Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.
Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.
