Palynziq: Package Insert and Label Information

PALYNZIQ- pegvaliase injection, solution
BioMarin Pharmaceutical Inc.

1 INDICATIONS AND USAGE

Palynziq is indicated to reduce blood phenylalanine concentrations in adult patients with phenylketonuria (PKU) who have uncontrolled blood phenylalanine concentrations greater than 600 micromol/L on existing management.

2 DOSAGE AND ADMINISTRATION

2.1 Dosage

• Treatment with Palynziq should be managed by a healthcare provider experienced in the management of PKU.

• Obtain baseline blood phenylalanine concentration before initiating treatment.

Induction

The recommended initial induction dosage for Palynziq is 2.5 mg subcutaneously once weekly for 4 weeks. Administer the initial dose under the supervision of a healthcare provider [see Dosage and Administration (2.4)].

Titration

Titrate the Palynziq dosage in a step-wise manner, based on tolerability, over at least 5 weeks, to achieve a dosage of 20 mg subcutaneously once daily according to Table 1.

Maintenance

Therapeutic response may not be achieved until the patient is titrated to an effective maintenance dosage of Palynziq. Use the lowest effective and tolerated dosage of Palynziq.

Assess patient tolerability, blood phenylalanine concentrations, and dietary protein and phenylalanine intake throughout treatment.

​ Individualize the maintenance dosage to achieve blood phenylalanine control (blood phenylalanine concentrations less than or equal to 600 micromol/L), taking into account patient tolerability to Palynziq and dietary protein intake (see Table 1).

​ Maintain the Palynziq dosage at 20 mg once daily for at least 24 weeks. Consider increasing the Palynziq dosage to 40 mg once daily in patients who have been on 20 mg once daily continuously for at least 24 weeks without achieving blood phenylalanine control. Consider increasing the Palynziq dosage to a maximum of 60 mg once daily in patients who have been on 40 mg once daily continuously for at least 16 weeks without achieving blood phenylalanine control.

Discontinuation

​ Discontinue Palynziq in patients who have not achieved an adequate response after 16 weeks of continuous treatment with the maximum dosage of 60 mg once daily [see Clinical Studies (14)].

Table 1: Recommended Dosing Regimen

* Additional time may be required prior to each dosage escalation based on patient tolerability. † Individualize treatment to the lowest effective and tolerated dosage. Consider increasing to 40 mg once daily in patients who have not achieved a response with 20 mg once daily continuous treatment for at least 24 weeks. Consider increasing to a maximum of 60 mg once daily in patients who have not achieved a response with 40 mg once daily continuous treatment for at least 16 weeks [see Clinical Studies (14)]. ‡ Discontinue Palynziq in patients who have not achieved an adequate response after 16 weeks of continuous treatment at the maximum dosage of 60 mg once daily.
​ Treatment	​ Palynziq Dosage	​ 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 four times per week	​ 1 week
	​ 10 mg once daily	​ 1 week
​ Maintenance †	​ 20 mg once daily	​ 24 weeks
	​ 40 mg once daily	​ 16 weeks
​ Maximum ‡	​ 60 mg once daily	​ 16 weeks

​

Dose Reduction for Low Phenylalanine Concentrations

During titration and maintenance of Palynziq treatment, patients may experience blood phenylalanine concentrations below 30 micromol/L. For blood phenylalanine concentrations below 30 micromol/L, the dosage of Palynziq may be reduced and/or dietary protein and phenylalanine intake may be modified to maintain blood phenylalanine concentrations within a clinically acceptable range and above 30 micromol/L [see Dosage and Administration (2.2)].

Readministration Following Anaphylaxis

If the decision is made to readminister Palynziq 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 the patient for at least 60 minutes following the dose. Subsequent dose titration should be based on patient tolerability and therapeutic response [see Warnings and Precautions (5.1)].

Missed Dose

If a dose is missed, instruct patients to take their next dose as scheduled and to not take two doses of Palynziq to make up for the missed dose.

2.2 Blood Phenylalanine Monitoring and Diet

After initiating treatment with Palynziq, obtain blood phenylalanine concentrations every 4 weeks until a maintenance dosage is established. After a maintenance dosage is established, periodic blood phenylalanine monitoring is recommended to assess blood phenylalanine control.

Monitor patients’ dietary protein and phenylalanine intake throughout treatment with Palynziq and counsel them on how to adjust their dietary intake, as needed, based on blood phenylalanine concentrations.

2.3 Premedication

For hypersensitivity reactions, consider premedication with an H₁ ‑receptor antagonist, H₂ ‑receptor antagonist, and/or antipyretic prior to Palynziq administration based upon individual patient tolerability [see Warnings and Precautions (5.1, 5.3)].

2.4 Administration Instructions

• Each prefilled syringe of Palynziq is intended for use as a single subcutaneous injection.
  
• Inspect Palynziq visually for particulate matter and discoloration prior to administration. Palynziq is a clear to slightly opalescent, colorless to pale yellow solution. Discard if discolored, cloudy, or if particulate matter is present.
  
• Prior to first dose of Palynziq, prescribe auto-injectable epinephrine, and instruct the patient and observer (if applicable) on 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.
  
• Perform initial administration(s) and/or readministration after an anaphylaxis episode under the supervision of a healthcare provider equipped to manage anaphylaxis, and closely observe patients for at least 60 minutes following injection [see Warnings and Precautions (5.1)]. Prior to self-injection, confirm patient competency with self‑administration.
  
• Consider having an adult observer for patients who may need assistance in recognizing and managing anaphylaxis during Palynziq treatment. If an adult observer is needed, the observer should be present during and for at least 60 minutes after each Palynziq administration, should be able to administer auto-injectable epinephrine, and to call for emergency medical support upon its use [see Warnings and Precautions (5.1)].
  
• The recommended injection sites for Palynziq are: the front middle of thighs and the abdomen at least 2 inches (five centimeters) away from the navel. If a caregiver is giving the injection, the top of buttocks and the back of the upper arms are also appropriate injection sites.
  
• Do not inject Palynziq 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 sites for subcutaneous injections of Palynziq. If more than one injection is needed for a single dose of Palynziq, the injection sites should be at least 2 inches away from each other. The second injection site can be on the same part of the body or a different part of the body.

3 DOSAGE FORMS AND STRENGTHS

Palynziq is a clear to slightly opalescent, colorless to pale yellow solution available as follows:

• Injection: 2.5 mg/0.5 mL single-dose prefilled syringe
• Injection: 10 mg/0.5 mL single-dose prefilled syringe
• Injection: 20 mg/mL single-dose prefilled syringe

4 CONTRAINDICATIONS

None.

5 WARNINGS AND PRECAUTIONS

5.1 Anaphylaxis

In clinical trials of Palynziq with induction/titration/maintenance dosing, 29 out of 285 (10%) patients experienced a total of 42 anaphylaxis episodes [see Adverse Reactions (6.1, 6.2)]. The exposure-adjusted rate of anaphylaxis was highest during the induction and titration phases (0.25 episodes/person‑years; 5% of patients with at least one episode) and decreased in the maintenance phase (0.05 episodes/person‑years; 7% of patients with at least one episode). Signs and symptoms of anaphylaxis reported in clinical trials of Palynziq included syncope, hypotension, hypoxia, dyspnea, wheezing, chest discomfort/chest tightness, tachycardia, angioedema (swelling of face, lips, eyes, tongue), throat tightness, skin flushing, rash, urticaria, pruritus, and gastrointestinal symptoms (vomiting, nausea, diarrhea). In clinical trials of Palynziq, anaphylaxis generally occurred within 1 hour after injection (81%; 34/42 episodes); however, delayed episodes also occurred up to 48 hours after Palynziq administration. Most episodes of anaphylaxis occurred within the first year of dosing (69%, 29/42 episodes), but cases also occurred after one year of dosing and up to 1604 days (4.4 years) into treatment. Management of anaphylaxis in Palynziq clinical trials included: administration of auto-injectable epinephrine (48%; 20/42 episodes), corticosteroids (55%; 23/42 episodes), antihistamines (57%; 24/42 episodes), and/or oxygen (5%; 2/42 episodes). Twenty one out of the 29 (72%) patients who experienced anaphylaxis were rechallenged with Palynziq and 6 out of the 21 patients who were rechallenged (29%) had recurrence of anaphylaxis. All anaphylaxis episodes resolved without sequelae.

Consider having an adult observer for patients who may need assistance in recognizing and managing anaphylaxis during Palynziq treatment. If an adult observer is needed, the observer should be present during and for at least 60 minutes after Palynziq administration, should be able to administer auto‑injectable epinephrine, and to call for emergency medical support upon its use.

Anaphylaxis requires immediate treatment with auto-injectable epinephrine. Prescribe auto‑injectable epinephrine to all patients receiving Palynziq and instruct patients to carry auto‑injectable epinephrine with them at all times during Palynziq treatment. Prior to the first dose, instruct the patient and observer (if applicable) on 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. Consider the risks associated with auto-injectable epinephrine use when prescribing Palynziq. Refer to the auto‑injectable epinephrine prescribing information for complete information.

Consider the risks and benefits of readministering Palynziq following an episode of anaphylaxis. If the decision is made to readminister Palynziq, administer the first dose under the supervision of a healthcare provider equipped to manage anaphylaxis and closely observe the patient for at least 60 minutes following the dose. Subsequent Palynziq dose titration should be based on patient tolerability and therapeutic response [see Dosage and Administration (2.4)].

Consider premedication with an H₁ -receptor antagonist, H₂ -receptor antagonist, and/or antipyretic prior to Palynziq administration based upon individual patient tolerability [see Dosage and Administration (2.3)].

Palynziq is available only through a restricted program under a REMS [see Warnings and Precautions (5.2)].