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Pegvaliase-pqpz

Class: Enzymes
Chemical Name: Pegylated recombinant Anabaena variabilis-derived phenylalanine ammonia lyase
Molecular Formula: C15H30N2O5
CAS Number: 1585984-95-7
Brands: Palynziq

Medically reviewed by Drugs.com. Last updated on Jan 13, 2020.

Warning

    Anaphylaxis
  • Risk of anaphylaxis; may occur at any time during therapy. (See Anaphylaxis under Cautions.)

  • Administer initial dose under supervision of a healthcare provider capable of managing anaphylaxis and closely monitor patient for ≥60 minutes following injection.

  • Prior to self-administration, confirm patient competency, including ability to recognize signs and symptoms of anaphylaxis and administer an epinephrine autoinjector. Consider having an adult observer present during and for ≥60 minutes after administration for patients who may require assistance recognizing and managing anaphylaxis; the adult observer should be able to administer an epinephrine autoinjector and call for emergency medical support upon its use.

  • Prescribe an epinephrine autoinjector for patients to have available at all times during pegvaliase therapy; instruct patients and/or caregivers on how to recognize signs and symptoms of anaphylaxis, and how to administer the epinephrine autoinjector.

  • If anaphylaxis occurs, assess risks and benefits of continuing therapy. If decision is made to continue therapy, administer first dose under supervision of a healthcare provider prepared to manage anaphylaxis; closely monitor patient for ≥60 minutes after administration.

  • Because of risk of anaphylaxis, pegvaliase-pqpz is available only through a restricted distribution program (REMS). (See REMS and also see Restricted Distribution Program under Dosage and Administration.)

Risk Evaluation and Mitigation Strategy (REMS):

FDA approved a REMS for pegvaliase-pqpz to ensure that the benefits of a drug outweigh the risks. The REMS may apply to one or more preparations of pegvaliase-pqpz and consists of the following: elements to assure safe use and implementation system. See https://www.accessdata.fda.gov/scripts/cder/rems/.

Introduction

Phenylalanine-metabolizing enzyme; conjugated with polyethylene glycol (PEG) and biosynthetic (recombinant DNA origin) phenylalanine ammonia lyase (PAL).

Uses for Pegvaliase-pqpz

Phenylketonuria

Used to reduce blood phenylalanine concentrations in patients with phenylketonuria (PKU) who have inadequately controlled blood phenylalanine concentrations (>600 µmol/L) despite existing management (e.g., phenylalanine-restricted diet, protein-restricted diet, treatment with sapropterin). Designated an orphan drug by FDA for treatment of hyperphenylalaninemia.

Pegvaliase-pqpz Dosage and Administration

General

  • Carefully monitor blood phenylalanine concentrations during therapy. Measure blood phenylalanine concentrations prior to initiating therapy, every 4 weeks until a maintenance dosage is established, and then periodically afterwards.

  • Monitor dietary protein and phenylalanine intake periodically throughout treatment; adjust dietary intake as required based on blood phenylalanine concentrations.

  • Monitor patients closely during administration for signs and symptoms of anaphylaxis. Administer first injection of therapy (and first injection following an anaphylactic episode) under the supervision of a clinician who is capable of managing anaphylaxis. Monitor patient during and for ≥60 minutes following injection. (See Boxed Warning.)

  • Consider premedication with an H1-receptor antagonist, H2-receptor antagonist, and/or antipyretic.

  • Before initiating therapy, prescribe an epinephrine autoinjector for patients to have available at all times. (See Boxed Warning.)

Restricted Distribution Program

  • Distribution of pegvaliase-pqpz (Palynziq) is restricted. (See Boxed Warning and also see Anaphylaxis under Cautions.)

  • Must be obtained through the Palynziq Risk Evaluation and Mitigation Strategy (REMS) program designed to minimize risk of anaphylaxis. Clinicians, pharmacies, and patients must enroll in and comply with all requirements of the program.

  • Additional information available at 1-855-758-7367 or [Web].

Administration

Sub-Q Injection

Available in single-dose, prefilled syringes equipped with a 26-gauge, ½-inch needle.

Administer by sub-Q injection into middle front thigh or abdomen (except within 2 inches of navel); if a caregiver is administering injection, may also use top of buttocks or back of upper arm. Rotate injection sites. If multiple injections are required for a single dose, separate injection sites by ≥2 inches. Do not inject into areas where the skin is tender, swollen, bruised, inflamed, red, burned, damaged, tattooed, or hard, or into moles, scars, or birthmarks.

Do not shake the injection.

Intended for use under the guidance and supervision of a clinician, but may be self-administered if clinician determines that the patient and/or their caregiver is competent to safely administer the drug after appropriate training and with medical follow-up as necessary.

If a dose is missed, administer next dose at regularly scheduled time; do not take 2 doses to make up for a missed dose.

Dosage

Adults

Phenylketonuria
Sub-Q

Individualize dosage based on patient tolerability, blood phenylalanine concentrations, and dietary protein and phenylalanine intake. (See General under Dosage and Administration.)

Dosing regimen consists of an induction, titration, and maintenance phase.

Initially, 2.5 mg once weekly for 4 weeks.

Increase dosage slowly, as tolerated, over ≥5 weeks, to a target maintenance dosage of 20 mg once daily. Manufacturer provides a suggested schedule for dosage titration (see Table 1); however, titrate dosage based on individual response and tolerability. Slower titration may be required in patients who experience adverse effects.

Table 1: Recommended Pegvaliase Dosage Titration Regimen

Treatment Phase

Dosage

Duration

Induction

2.5 mg once weekly

4 weeks

Titration

2.5 mg twice weekly

1 week

Titration

10 mg once weekly

1 week

Titration

10 mg twice weekly

1 week

Titration

10 mg four times per week

1 week

Titration

10 mg once daily

1 week

Maintenance

20 mg once daily

24 weeks

Therapeutic response may not be achieved until effective maintenance dosage is achieved; use lowest effective and tolerated dosage.

If a response is not obtained (i.e., blood phenylalanine concentrations do not decrease by ≥20% from baseline or remain elevated at >600 µmol/L) after 24 weeks of treatment with dosage of 20 mg once daily, may increase to 40 mg once daily. If blood phenylalanine concentrations still do not decrease by ≥20% from baseline or remain elevated at >600 µmol/L after 16 weeks at a dosage of 40 mg once daily, discontinue therapy.

If blood phenylalanine concentrations decrease to <30 µmol/L during titration or maintenance therapy, reduce dosage and/or modify dietary intake of protein or phenylalanine to maintain blood phenylalanine concentrations within a clinically acceptable range above 30 µmol/L.

If anaphylaxis occurs and a decision is made to continue pegvaliase therapy, titrate subsequent dosage based on patient tolerability and therapeutic response. (See Anaphylaxis under Cautions.)

Prescribing Limits

Adults

Phenylketonuria
Sub Q

Maximum 40 mg once daily.

Special Populations

Hepatic Impairment

No specific dosage recommendations.

Renal Impairment

No specific dosage recommendations.

Geriatric Patients

No specific dosage recommendations.

Pregnancy

Monitor blood phenylalanine concentrations during pregnancy; adjust dosage or dietary intake of protein or phenylalanine to maintain blood phenylalanine concentrations >30 µmol/L. (See Pregnancy under Cautions.)

Cautions for Pegvaliase-pqpz

Contraindications

  • No known contraindications.

Warnings/Precautions

Sensitivity Reactions

Anaphylaxis

Anaphylaxis (e.g., syncope, hypotension, hypoxia, dyspnea, wheezing, chest discomfort, chest tightness, tachycardia, angioedema, throat tightness, flushing, rash, urticaria, pruritus, vomiting, nausea, diarrhea) reported. (See Boxed Warning.)

Occurred most frequently within first year of therapy, primarily during induction and titration phases, but may occur at any time during therapy, including after 1–2 years of therapy. Onset usually within 1 hour following sub-Q injection; however, delayed reactions (within 48 hours of administration) also reported. Recurrence observed following rechallenge in some patients. All episodes of anaphylaxis resolved with appropriate management (e.g., administration of epinephrine, corticosteroids, antihistamines, and/or oxygen).

Monitor patients closely during administration. Consider premedication. (See General under Dosage and Administration.) If signs and symptoms of anaphylaxis occur, immediate treatment with an epinephrine autoinjector is required.

If anaphylaxis occurs, assess risks and benefits of continuing therapy. (See Boxed Warning.)

Other Hypersensitivity Reactions

Hypersensitivity reactions other than anaphylaxis (e.g., injection site reactions, serum sickness, eczema, dermatitis, allergic conjunctivitis, allergic sinusitis, allergic cough) reported, occurring most frequently during induction and titration phases of therapy.

Consider premedication with antihistamines and/or antipyretics. (See General under Dosage and Administration.) If a hypersensitivity reaction occurs, administer medications (e.g., antihistamines, corticosteroids, and/or antipyretics), adjust dosage, or interrupt therapy based on severity of the reaction and whether the reaction has recurred.

Immunogenicity

In clinical studies, all patients developed an antibody response. Antibodies that developed included anti-pegvaliase total antibodies, IgG antibodies to phenylalanine ammonia lyase (PAL), IgM antibodies to PAL, and antibodies to PEG. Neutralizing antibodies capable of inhibiting enzyme activity of drug also detected in the majority of patients. Antibodies usually detected within 1–4 months after treatment initiation and remained present during therapy.

Antibodies binding to the PEG portion of the drug may cross-react with other pegylated drugs. (See Interactions.)

High antibody titers associated with reduced serum trough concentrations of the drug and higher blood phenylalanine concentrations. Possible correlation between hypersensitivity reactions and immune response; however, additional study is needed.

Specific Populations

Pregnancy

May cause fetal harm based on animal findings. Insufficient data in pregnant women. In animal studies, embryofetal toxicity and maternal toxicity observed.

Poorly controlled blood phenylalanine concentrations before and during pregnancy associated with fetal harm and adverse effects on postnatal development (e.g., intellectual disability, low IQ). In addition, blood phenylalanine concentrations <30 µmol/L during pregnancy can increase risk of adverse fetal outcome. Closely monitor blood phenylalanine concentrations during pregnancy; adjust dosage or dietary phenylalanine and protein intake as necessary.

Pregnancy registry at 1-866-906-6100 for pregnant women and women who become pregnant within 1 month following their last dose of pegvaliase.

Lactation

Distributed into milk in rats; increased pup mortality and impaired weight gain observed when the drug was administered to lactating rats. Not known whether distributed into human milk, affects milk production, or affects nursing infants.

Consider benefits of breast-feeding along with importance of the drug to the woman and any potential adverse effects on the breast-fed infant from the drug or underlying maternal condition.

May decrease phenylalanine concentrations in human milk. Monitor blood phenylalanine concentrations in breast-feeding women during therapy.

Pediatric Use

Safety and efficacy not established in pediatric patients.

Geriatric Use

Not studied in geriatric patients ≥65 years of age.

Common Adverse Effects

Injection site reactions, arthralgia (e.g., back pain, musculoskeletal pain, pain in extremities, neck pain), hypersensitivity reactions, pruritus, headache, generalized skin reactions lasting ≥14 days, nausea, vomiting, abdominal pain, diarrhea, oropharyngeal pain, cough, nasal congestion, fatigue, anxiety, dizziness, alopecia.

Interactions for Pegvaliase-pqpz

Pegylated Agents

The clinical consequence of using pegvaliase with other pegylated drugs is not known; however, some evidence suggests that such concomitant use may increase the risk of hypersensitivity reactions. If pegvaliase is used concomitantly with other pegylated drugs, monitor patients for hypersensitivity reactions, including anaphylaxis.

Specific Drugs

Drug

Interaction

Comments

Medroxyprogesterone acetate

Hypersensitivity reactions, including anaphylaxis, observed in a few patients following concomitant use

Monitor for hypersensitivity reactions

Pegvaliase-pqpz Pharmacokinetics

Absorption

Plasma Concentrations

Median time to reach peak plasma concentrations approximately 8 hours; however, pharmacokinetics highly variable due to individual immune response.

Elimination

Metabolism

Expected to undergo protein catabolism and degradation into small peptides and amino acids.

Elimination Route

Unknown.

Half-life

Mean half-life is 47 or 60 hours following sub-Q administration of 20 or 40 mg once daily, respectively.

Stability

Storage

Parenteral

Injection

2–8°C in original container to protect from light; do not freeze or shake.

May store at room temperature (20–25°C) in the original carton for <30 days; do not return to refrigerator once stored at room temperature.

Actions

  • Biosynthetic (recombinant DNA origin) phenylalanine ammonia lyase (PAL) covalently bound to N-hydroxysuccinimide (NHS)-methoxypolyethylene glycol (PEG).

  • Used as an enzyme substitution therapy for the deficient phenylalanine hydroxylase enzyme in patients with PKU; provides an alternate pathway for the breakdown of phenylalanine in such patients by converting phenylalanine to ammonia and trans-cinnamic acid, thereby reducing blood phenylalanine concentrations.

  • Prepared using a strain of Escherichia coli genetically modified to incorporate the PAL gene derived from Anabaena variabilis.

  • Pegylation of the PAL enzyme reduces immunogenicity and improves drug stability.

Advice to Patients

  • Importance of patients reading the manufacturer's patient information (medication guide) and instructions for use.

  • Importance of instructing patients and/or their caregivers on how to prepare and administer pegvaliase injections, including the use of aseptic technique, and proper disposal of needles and syringes.

  • Importance of informing patients that hypersensitivity reactions, including anaphylaxis, can occur at any time during therapy. Importance of advising patients to monitor for signs and symptoms of anaphylaxis (e.g., wheezing; difficulty breathing; swelling of the lips, eyes, throat, or tongue; throat tightness; dizziness; fainting; fast or weak heartbeat; flushing; chest discomfort or pain; sudden confusion; urticaria; rash; itching; nausea, vomiting or diarrhea) and to immediately discontinue therapy and seek medical care if anaphylaxis occurs. Inform patients that the drug should be resumed after an anaphylactic reaction only at the instruction of a clinician.

  • Importance of instructing patients to carry an epinephrine autoinjector with them at all times during pegvaliase therapy. Instruct patients and/or their caregivers on the appropriate use of the autoinjector.

  • Importance of patients monitoring their dietary intake of phenylalanine and protein throughout treatment and adjusting their intake as directed by their clinician. Importance of monitoring blood phenylalanine concentrations.

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed. Importance of informing patients of the existence of a pregnancy registry for PKU patients.

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, vitamins, and herbal supplements.

  • Importance of informing clinicians of concomitant medical conditions.

  • Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Pegvaliase-pqpz (Palynziq) is available only through a restricted distribution program (Palynziq REMS Program). (See Restricted Distribution Program under Dosage and Administration: General.)

Pegvaliase-pqpz

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

Injection, for subcutaneous use

2.5 mg/0.5 mL

Palynziq (available as single-dose prefilled syringes)

BioMarin

10 mg/0.5 mL

Palynziq (available as single-dose prefilled syringes)

BioMarin

20 mg/mL

Palynziq (available as single-dose prefilled syringes)

BioMarin

AHFS DI Essentials™. © Copyright 2021, Selected Revisions January 13, 2020. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

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