pegvaliase (Rx)

Brand and Other Names:pegylated phenylalanine ammonia lyase (PAL), pegvaliase-pqpz, more...Palynziq
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Dosing & Uses

AdultPediatric

Dosage Forms & Strengths

injectable solution, single-dose prefilled syringe

  • 2.5mg/0.5mL
  • 10mg/0.5mL
  • 20mg/mL

Phenylketonuria

Indicated to reduce blood phenylalanine concentrations in adults with phenylketonuria (PKU) who have uncontrolled blood phenylalanine concentrations >600 micromol/L on existing management

Also see Administration

Induction

  • Initial dose: 2.5 mg SC once weekly for 4 weeks

Titration

  • Based on tolerability, titrate dose in a stepwise manner over at least 5 weeks, to achieve a dosage of 20 mg SC qDay
  • Weekly titration schedule
    • Week 1: 2.5 mg twice weekly
    • Week 2: 10 mg once weekly
    • Week 3: 10 mg twice weekly
    • Week 4: 10 mg 4x/week
    • Week 5: 10 mg once daily
    • Additional time may be needed for dose escalation depending on tolerability

Maintenance

  • Therapeutic response may not be achieved until patient is titrated to an effective maintenance dosage
  • Use lowest effective and tolerated dose
  • Assess patient tolerability, blood phenylalanine concentrations, and dietary protein and phenylalanine intake throughout treatment
  • Maintain at 20 mg SC qDay for at least 24 weeks; may increase, but not exceed 40 mg/day in patients who have been maintained continuously on 20 mg qDay for at least 24 weeks and who have not achieved either a 20% reduction in blood phenylalanine concentration from pretreatment baseline or a blood phenylalanine concentration ≤600 micromol/L

Discontinuation

  • Discontinue in patients who have not achieved a response (at least a 20% reduction in blood phenylalanine concentration from pretreatment baseline or a blood phenylalanine concentration ≤600 micromol/L) after 16 weeks of continuous treatment with maximum dosage 40 mg/day

Dosage Modifications

Dose reduction for low phenylalanine concentrations

  • Blood phenylalanine concentrations <30 micromol/L: Reduce dose and/or modify dietary protein and phenylalanine intake to maintain blood phenylalanine concentrations within a clinically acceptable range and >30 micromol/L

Readministration following anaphylaxis

  • If dose is readministered after an anaphylaxis episode, administer the first dose following the anaphylaxis episode under the supervision of a healthcare provider equipped to manage anaphylaxis and closely observe for >60 minutes following the dose
  • Based on patient tolerability and therapeutic response, subsequent dose titration

Dosing Considerations

Obtain baseline blood phenylalanine concentration before initiating therapy

After initiating treatment, obtain blood phenylalanine concentrations q4weeks until a maintenance dosage is established

After a maintenance dosage is established, periodic blood phenylalanine monitoring is recommended to assess blood phenylalanine control

Monitor dietary protein and phenylalanine intake throughout treatment and counsel patients on adjusting their dietary intake, as needed, based on blood phenylalanine concentrations

Safety and efficacy not been established

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Interactions

Interaction Checker

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            Adverse Effects

            >10% (Induction/titration)

            Injection site reactions (88%)

            Arthralgia (74%)

            Complement factor C3 below LLN (68%)

            C-reactive protein (CRP) above ULN (64%)

            Complement factor C4 below LLN (62%)

            Hypersensitivity reactions (53%)

            Headache (35%)

            Generalized skin reaction lasting at least 14 days (21%)

            Pruritus (20%)

            Hypophenylalaninemia on a single measurement (19%)

            Blood creatine phosphokinase (CPK) above ULN (18%)

            Nausea (18%)

            Hypophenylalaninemia on 2 or more consecutive measurements (16%)

            Dizziness (16%)

            Abdominal pain (14%)

            Oropharyngeal pain (13%)

            Fatigue (13%)

            Vomiting (13%)

            Hs-CRP above 0.287 mg/dL over a 6-month period (12%)

            >10% (Maintenance)

            Complement factor C3 below LLN (84%)

            Injection site reactions (72%)

            CRP above ULN (68%)

            Arthralgia (61%)

            Hypersensitivity reactions (61%)

            Hypophenylalaninemia on a single measurement (61%)

            Headache (50%)

            Complement factor C4 below LLN (48%)

            CPK above ULN (43%)

            Hypophenylalaninemia on 2 or more consecutive measurements (42%)

            Generalized skin reaction lasting at least 14 days (37%)

            Nausea (26%) Vomiting (26%) Abdominal pain (25%)

            Pruritus (24%) Oropharyngeal pain (23%)

            Cough (22%)

            Diarrhea (22%)

            Fatigue (22%)

            Anxiety (18%)

            Nasal congestion (18%)

            Dizziness (17%)

            Alopecia (17%)

            1-10%

            Induction/titration

            • Cough (9%)
            • Diarrhea (9%)
            • Anxiety (5%)
            • Alopecia (5%)
            • Nasal congestion (4%)

            Maintenance

            • Hs-CRP above 0.287 mg/dL over a 6 month period (10%)
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            Warnings

            Black Box Warnings

            Anaphylaxis

            • Anaphylaxis reported after administration and may occur at any time during treatment
            • Administer the initial dose after an anaphylaxis episode under the supervision of a healthcare provider equipped to manage anaphylaxis, and closely observe >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 autoinjectable epinephrine, if needed
            • Prescribe autoinjectable epinephrine, and instruct patient and observer (if applicable) on how to recognize the signs and symptoms of anaphylaxis, how to properly administer autoinjectable epinephrine, and to seek immediate medical care upon its use
            • Consider a caregiver for patients who may need assistance in recognizing and managing anaphylaxis
            • If an caregiver is needed, present caregiver during and for >60 minutes after each administration should be able to administer autoinjectable epinephrine, and to call for emergency medical support upon its use
            • Consider the risks and benefits of readministering pegvaliase-pqpz following an episode of anaphylaxis
            • If treatment is readministered, administer the first dose under the supervision of a healthcare provider equipped to manage anaphylaxis and closely observe >60 minutes following the dose
            • Because of the risk of anaphylaxis, treatment is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called Palynziq REMS

            Contraindications

            None

            Cautions

            In clinical trials with induction/titration/maintenance dosing, 26 (9%) of 285 patients experienced a total of 37 anaphylaxis episodes (see Black Box Warnings)

            Management of hypersensitivity reactions should be based on severity of reaction, recurrence of reaction, and clinical judgment of healthcare provider, and may include dosage adjustment, temporary drug interruption, or treatment with antihistamines, antipyretics, and/or corticosteroids

            REMS program

            • Treatment is available only through a restricted program under Palynziq REMS, because of the risk of anaphylaxis
            • Hypersensitivity reactions, other than anaphylaxis, reported
            • Requirements of the REMS program
              • Prescribers must be certified with the program by enrolling in the program and completing training
              • Prescribers must prescribe autoinjectable epinephrine
              • Pharmacies must be certified with the program and must dispense only to patients who are authorized to receive treatment
              • Patients must enroll in the program and be educated about the risk of anaphylaxis by a certified prescriber to ensure they understand the risks and benefits of treatment
              • Patients must have autoinjectable epinephrine available at all times
              • Further information, including a list of qualified pharmacies, is available at www.PALYNZIQREMS.com or by telephone 1-855-758-REMS (1-855-758-7367)

            Drug interactions overview

            • The majority of patients treated with pegvaliase develop anti-polyethylene glycol (PEG) IgM and IgG antibodies
            • Risk of coadministration with different PEGylated products is unknown; however, there is a case report of anaphylaxis following a medroxyprogesterone acetate injectable suspension that contained PEG 3350
            • Carefully read all drug labels, including OTC drugs to check contents for PEG
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            Pregnancy

            Pregnancy

            Based on findings in studies of pregnant animals without phenylketonuria (PKU), pegvaliase-pqpz may cause fetal harm when administered to a pregnant woman

            Limited available data with pegvaliase-pqpz use in pregnant women are insufficient to inform a drug-associated risk of adverse developmental outcomes

            Risks to the fetus associated with poorly controlled phenylalanine concentrations in women with PKU during pregnancy include increased risk for miscarriage, major birth defects (eg, microcephaly, major cardiac malformations), intrauterine fetal growth restriction, and future intellectual disability with low IQ; therefore, closely phenylalanine concentrations in women with PKU during pregnancy

            Advise pregnant women of the potential risks to the fetus

            Animal data

            • A reproduction study in pregnant rabbits treated with pegvaliase-pqpz demonstrated a high incidence of fetal malformations throughout the skeletal system, and in kidneys, lungs, and eyes
            • Embryo-fetal toxicity (increased resorptions and reduced fetal weight) was also observed
            • These effects occurred at 7.5 times the maximum recommended daily dose and were associated with strong signs of maternal toxicity, including marked reductions in weight gain and food consumption, and death
            • A reproduction study in pregnant rats treated with pegvaliase-pqpz demonstrated an increase in skeletal variations, with no malformations observed; effects in rats occurred at 4.2 times the maximum recommended daily dose
            • In a prenatal/postnatal development study in rats, pegvaliase-pqpz produced reduced survival of offspring during lactation, decreases in pup weight and litter size, and delayed sexual maturation of offspring when administered daily at 19.4 times the maximum recommended daily dose; effects on rat embryo-fetal and postnatal development were associated with maternal toxicity

            Disease-associated maternal and/or embryo-fetal risk

            • Uncontrolled blood phenylalanine concentrations before and during pregnancy are associated with an increased risk of adverse pregnancy outcomes and fetal adverse effects; to reduce the risk of hyperphenylalaninemia-induced fetal adverse effects, blood phenylalanine concentrations should be maintained between 120-360 micromol/L during pregnancy and during the 3 months before conception

            Dose adjustments during pregnancy and the postpartum period

            • Phenylalanine concentrations <30 micromol/L in pregnant women with PKU may be associated with adverse fetal outcomes; monitor blood phenylalanine concentrations during pregnancy and adjust dose or modify dietary protein and phenylalanine intake to avoid blood phenylalanine concentrations below 30 micromol/L (see Dosage Modifications)

            Lactation

            There are no data on the presence of pegvaliase-pqpz in human milk, the effects on the breastfed infant, or the effects on milk production

            A prenatal/postnatal study in rats showed that pegvaliase-pqpz is present in rat milk and that administration of pegvaliase-pqpz during lactation decreased pup weight and survival

            Pregnancy Categories

            A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

            B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

            C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

            D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

            X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

            NA: Information not available.

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            Pharmacology

            Mechanism of Action

            Pegylated phenylalanine ammonia lyase (PAL), which is an enzyme that catalyzes phenylalanine (Phe) to ammonia and trans-cinnamic acid

            PKU is an inborn error of amino acid metabolism, which is caused by a deficiency of the enzyme phenylalanine hydroxylase (PAH) that leads to accumulation of phenylalanine in body fluids

            Absorption

            Median peak plasma time: ~8 hr

            Peak plasma concentration, steady state: 14 mg/L (20 mg/day); 16.7 mg/L (40 mg/day)

            Distribution

            Vd: 26.4 L (20 mg/day); 22.2 L (40 mg/day)

            Metabolism

            Metabolism of phenylalanine ammonia lyase is expected to occur via catabolic pathways and be degraded into small peptides and amino acids

            Excretion

            Half-life: 47 hr (20 mg/day); 60 hr (40 mg/day)

            Clearance: 0.39 L/hr (20 mg/day); 1.25 L/hr (40 mg/day)

            Route of elimination of pegvaliase-pqpz not studied in humans

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            Administration

            SC Administration

            Subcutaneous administration only

            Single use only

            Visually inspect for particulate matter and discoloration prior to administration; solution appears clear to slightly opalescent, colorless to pale yellow

            Discard if discolored, cloudy, or if particulate matter is present

            Recommended injection sites: Front middle of thighs and the abdomen >2 inches (5 cm) away from the navel

            If a caregiver is administering the injection, the top of buttocks and the back of the upper arms are also appropriate injection sites

            Do not inject into moles, scars, birthmarks, bruises, rashes, or areas where the skin is hard, tender, red, damaged, burned, inflamed, or tattooed

            Check the injection site for redness, swelling, or tenderness

            Rotate injection sites; if >1 injection is needed for a single dose, injection sites should be >2 inches away from each other; second injection site can be on the same part of the body or a different part of the body

            Premedication

            • Consider premedication with an H1-receptor antagonist, H2-receptor antagonist, and/or antipyretic prior to administration based upon tolerability

            Missed dose

            • If a dose is missed, instruct patients to take their next dose as scheduled and to not take 2 doses to make up for the missed dose

            Storage

            Syringes

            • Refrigerate at 28°C (36-46°F) in its original carton to protect from light; do not freeze or shake
            • If needed, store at room temperature between 20-25°C (68-77°F) for <30 days; record date removed from refrigeration on the carton
            • Once stored at room temperature, do not return the product to the refrigerator
            • Shelf-life expires after storage at room temperature for 30 days, or after the expiration date on the product carton, whichever is earlier
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            Formulary

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            The above information is provided for general informational and educational purposes only. Individual plans may vary and formulary information changes. Contact the applicable plan provider for the most current information.

            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
            2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
            3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
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            NC NOT COVERED – Drugs that are not covered by the plan.
            Code Definition
            PA Prior Authorization
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