Version May 2024
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 Palynziq REMS.
Note: Due to risk of hypersensitivity, prescribe an epinephrine auto-injector to all patients. Administer initial dose or first dose following anaphylaxis under the supervision of a health care provider equipped to manage anaphylaxis, and closely observe patients for ≥60 minutes following injection. Consider premedication with antihistamines (H1 antagonist, H2 antagonist) and/or antipyretic to prevent hypersensitivity reactions (based on patient tolerability).
Phenylketonuria:
Induction and titration: SUBQ:
Note: Measure baseline blood phenylalanine concentration prior to initiation. Additional time may be required prior to each dosage escalation based on patient tolerability.
|
SUBQ dose |
Typical duration | |
|---|---|---|
|
Induction |
2.5 mg once weekly |
4 weeks |
|
Titration (after 4-week induction) |
2.5 mg twice weekly |
1 week |
|
10 mg once weekly |
1 week | |
|
10 mg twice weekly |
1 week | |
|
10 mg 4 times weekly |
1 week | |
|
10 mg once daily |
1 week, then transition to maintenance dosing |
Maintenance (after induction and titration): SUBQ: 20 mg once daily for at least 24 weeks. Individualize dose to the lowest effective and tolerated dose to achieve response (blood phenylalanine concentration ≤600 micromole/L), taking daily protein intake into consideration. May increase to 40 mg once daily if a response has not been achieved after administering 20 mg once daily for 24 weeks. May consider further increase to 60 mg once daily if a response has not been achieved after administering 40 mg once daily continuously for at least 16 weeks without achieving blood phenylalanine control. Maximum dose: 60 mg/day.
Dosage adjustment:
Reduce dose and/or modify diet to avoid serum phenylalanine concentrations <30 micromole/L.
Temporary reduction (reducing the dose 1 or 2 steps back in the dosing regimen) is recommended to prevent further events in patients experiencing a hypersensitivity reaction during the titration phase (Ref).
Discontinuation of therapy: If an adequate response has not been achieved after administering 60 mg once daily for 16 weeks of continuous treatment, discontinue therapy.
There are no dosage adjustments provided in the manufacturer's labeling.
There are no dosage adjustments provided in the manufacturer's labeling.
Refer to adult dosing.
(For additional information see "Pegvaliase: Pediatric drug information")
Note: Due to risk of hypersensitivity, all patients should be prescribed an epinephrine autoinjector. Consider premedication with antihistamines (ie, H1-antagonist, H2-antagonist), and/or antipyretic to prevent hypersensitivity reactions (based on patient tolerability). Administer initial dose or first dose following anaphylaxis under the supervision of a health care provider equipped to manage anaphylaxis, and closely observe patients for ≥60 minutes following injection.
Phenylketonuria (PKU): Limited data available:
Note: Should only be administered under the supervision of a qualified health care provider experienced in the management of PKU. Measure baseline blood phenylalanine concentration prior to initiation. Dose should be individualized to maintain a serum phenylalanine concentration ≤600 micromol/L, taking into consideration patient tolerability and dietary protein intake. Reduce dose or modify diet to avoid serum phenylalanine concentrations <30 micromol/L.
Induction and Titration: Adolescents ≥16 years: SubQ: Pegvaliase should be titrated in a stepwise manner as per the following table based on tolerability and dietary protein intake; additional time may be needed at each step.
|
Dose |
Typical Duration | |
|---|---|---|
|
Induction |
2.5 mg once weekly |
4 weeks |
|
Titration |
2.5 mg twice weekly |
1 week |
|
10 mg once weekly |
1 week | |
|
10 mg twice weekly |
1 week | |
|
10 mg 4 times weekly |
1 week | |
|
10 mg once daily |
1 week then transition to maintenance dosing |
Maintenance: Individualize dose to achieve a serum phenylalanine concentration ≤600 micromol/L, taking patient tolerance and daily protein intake into consideration; use lowest effective and tolerated dose.
Adolescents ≥16 years: SubQ: 20 mg once daily; if after 24 weeks response not achieved (ie, control of blood phenylalanine concentrations), may further increase dose to 40 mg once daily; if after 16 weeks response not achieved may consider further dose increase to 60 mg once daily. Discontinue therapy if a response has not been achieved after administering 60 mg once daily for 16 weeks. Maximum daily dose: 60 mg/day.
There are no dosage adjustments provided in the manufacturer's labeling.
There are no dosage adjustments provided in the manufacturer's labeling.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Incidence ranges include induction, titration, and maintenance dosing.
>10%:
Dermatologic: Alopecia (5% to 19%), pruritus (20% to 27%), skin changes (21% to 47%)
Gastrointestinal: Abdominal pain (14% to 30%), diarrhea (9% to 27%), nausea (18% to 31%), vomiting (13% to 30%)
Hematologic & oncologic: Change in serum protein (below LLN: complement factor C3 [68% to 84%]; complement factor C4 [49% to 62%]), C-reactive protein increased (64% to 71%), hypophenylalaninemia (16% to 65%)
Hypersensitivity: Hypersensitivity reaction (54% to 72%)
Immunologic: Antibody development (100%; neutralizing antibodies to PAL enzyme activity: 89%)
Local: Injection site reaction (72% to 88%)
Nervous system: Anxiety (5% to 21%), dizziness (16% to 21%), fatigue (13% to 24%), headache (36% to 56%)
Neuromuscular & skeletal: Arthralgia (68% to 86%; severe arthralgia: 4%), increased creatine phosphokinase in blood specimen (18% to 48%)
Respiratory: Cough (9% to 30%), nasal congestion (4% to 27%), oropharyngeal pain (13% to 29%)
1% to 10%:
Hypersensitivity: Anaphylaxis (10%), angioedema (8%), serum sickness (2%)
Neuromuscular & skeletal: Joint stiffness (8%), joint swelling (8%), muscle rigidity (7%)
There are no contraindications listed in the manufacturer's US labeling.
Canadian labeling: Previous severe hypersensitivity (eg, severe serum sickness, severe angioedema, severe anaphylactic reactions) or a recurrence of a mild to moderate anaphylactic reaction to pegvaliase or any component of the formulation; history of anaphylactic reaction to products containing polyethylene glycol (PEG) or any other products containing PEGylated ingredients.
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. Signs and 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 also been reported, including angioedema, injection site reactions, and arthralgias; dose adjustment or temporary drug interruption may be considered. Consider premedication prior to administration. Patients with a history of anaphylaxis or severe allergic reactions to PEGylated drugs should be assessed by an allergist/immunologist prior to starting pegvaliase (Caballero 2021; Hausmann 2019).
• REMS program: [US Boxed Warning]: Because of the risk of anaphylaxis, pegvaliase is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the Palynziq REMS. Prescribers and pharmacies must be certified with the program and prescribers must prescribe auto-injectable epinephrine. Patients must enroll in the program, be educated about the risk of anaphylaxis, and carry auto-injectable epinephrine at all times during treatment. Further information is available at www.PALYNZIQREMS.com or at 1-855-758-7367.
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)
No
Solution Prefilled Syringe (Palynziq Subcutaneous)
2.5 mg/0.5 mL (per 0.5 mL): $738.00
10 mg/0.5 mL (per 0.5 mL): $738.00
20 mg/mL (per mL): $738.00
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Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution Prefilled Syringe, Subcutaneous:
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)
Perform initial administration or readministration (after anaphylaxis) under close observation by a health care provider for ≥60 minutes following injection. Consider the use of an observer to be present during and for at least 60 minutes after each administration when patient is self-injecting, at least for the first several months of treatment (ie, first 6 months) (Ref).
SUBQ administration: Administer SUBQ in the front middle of thighs or the abdomen (at least 2 inches [5 cm] 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 (5 cm) away from the first injection site; second site may be on the same or a different body part as the first injection. Pegvaliase should not be injected into moles, birthmarks, bruises, rashes, or areas where the skin is hard, tender, red, damaged, burned, inflamed, or tattooed.
Note: Consider premedication with antihistamines (ie, H1-antagonist, H2-antagonist) and/or an antipyretic to prevent hypersensitivity reactions (based on patient tolerability). Perform initial administration or readministration (after anaphylaxis) under close observation by a health care provider for ≥60 minutes following injection.
Parenteral: SubQ: Allow sealed tray containing prefilled syringe to sit at room temperature for ≥30 minutes before injecting. Administer subcutaneously. If self-injecting, administer in the front middle thigh or the abdomen at least 2 inches (5 cm) away from navel; if a caregiver is administering, the back of the upper arms or 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; the second site may be on the same or a different body part as the first injection. Avoid injection sites that have moles, scars, birthmarks, bruises, tattoos, or rashes or areas where the skin is hard, tender, red, damaged, burned, or inflamed.
Missed dose: If a dose is missed, it should be skipped, and the next dose administered as scheduled.
An FDA-approved patient medication guide, which is available with the product information and as follows, must be dispensed with this medication:
Palynziq: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/761079s000lbl.pdf#page=23
Phenylketonuria: To reduce blood phenylalanine concentrations in adult patients with phenylketonuria who have uncontrolled blood phenylalanine concentrations >600 micromole/L on existing management.
None known.
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
MedroxyPROGESTERone: May enhance the adverse/toxic effect of Pegvaliase. Specifically, the risk of anaphylaxis or hypersensitivity reactions may be increased. Risk C: Monitor therapy
PEGylated Drug Products: May enhance the adverse/toxic effect of Pegvaliase. Specifically, the risk of anaphylaxis or hypersensitivity reactions may be increased. Risk C: Monitor therapy
Family planning is recommended for females with phenylalanine hydroxylase deficiency (ACOG 802 2020). Phenylalanine concentrations should be normalized 3 months prior to conception (ACOG 802 2020; Vockley 2014). Women planning a pregnancy should discontinue pegvaliase and allow for a 4-week washout period prior to conception (Longo 2019). In one case report, pegvalaise was discontinued over a period of 10 weeks to allow dietary transition and decrease maternal adverse events; conception occurred 4 weeks after pegvaliase was fully discontinued (Rohr 2020).
Pegvaliase is not contraindicated in males planning to father a child (Longo 2019).
Information related to the use of pegvaliase in pregnant women is limited.
Uncontrolled maternal phenylalanine concentrations are associated with adverse pregnancy outcomes. Phenylalanine (PHE) concentrations >600 micromole/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. Pregnancy outcomes are comparable to the general population when appropriate maternal PHE concentrations are maintained (van Wegberg 2017). Fetal development is optimal when maternal PHE concentrations <360 micromole/L (6 mg/dL) are achieved prior to conception (ACOG 802 2020; Vockley 2014). Maternal plasma concentrations of PHE 120 to 360 micromole/L (2 to 6 mg/dL) are recommended throughout pregnancy (ACOG 802 2020).
Pegvaliase is not currently recommended for use during pregnancy. Treatments other than pegvaliase are currently recommended for the treatment of phenylketonuria in pregnant women (Longo 2019; Vockley 2014).
Data collection to monitor pregnancy and infant outcomes following exposure to pegvaliase is ongoing. 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).
It is not known if pegvaliase is present in breast milk.
Phenylalanine ammonia lyase activity was not found to be different in the breast milk of a postpartum lactating woman taking pegvaliase and a lactating woman without phenylketonuria, indicating a lack of pegvaliase activity within the breast milk (Rohr 2020).
Maternal use of pegvaliase may influence milk concentrations of phenylalanine. According to the manufacturer, the decision to breastfeed during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and benefits of treatment to the mother; monitor maternal phenylalanine blood levels. Prior to breastfeeding, the infant’s phenylalanine status should be considered (ACOG 802 2020).
Dietary protein and phenylalanine intake may need to be adjusted based on blood phenylalanine concentrations.
Blood phenylalanine concentration prior to initiation, every 4 weeks until maintenance dosage is established, then periodically thereafter; signs and symptoms of anaphylaxis/hypersensitivity for ≥60 minutes after initial dose or upon re-initiation of therapy (after a previous episode of anaphylaxis). Maintain serum phenylalanine concentrations between 120 and 360 micromole/L for 3 months prior to conception and during pregnancy.
A PEGylated phenylalanine ammonia lyase (PAL) enzyme that converts phenylalanine to ammonia and trans-cinnamic acid, thereby reducing blood phenylalanine concentrations.
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
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