DailyMed Label: Palynziq

DailyMed Label: Palynziq

2022

DailyMed Prescription

Palynziq

pegvaliase-pqpz

BioMarin Pharmaceutical Inc.

NDC: 68135-058

NDC: 68135-058

NDC: 68135-756

NDC: 68135-756

NDC: 68135-673

NDC: 68135-673

Pegvaliase-pqpz is a phenylalanine-metabolizing enzyme that is composed of recombinant phenylalanine ammonia lyase (rAvPAL) conjugated to N-hydroxysuccinimide (NHS)-methoxypolyethylene glycol (PEG). rAvPAL is manufactured in Escherichia coli bacteria transformed with a plasmid containing the phenylalanine ammonia lyase (PAL) gene derived from Anabaena variabilis . During the rAvPAL manufacturing process, fermentation is carried out in nutrient medium containing the antibiotic kanamycin. However, kanamycin is cleared in the manufacturing process and is not detectable in the final product. rAvPAL is a homotetrameric protein with a molecular weight of 62 kD per monomer. To produce pegvaliase-pqpz, an average of nine (9) 20 kD PEG molecules are covalently bound (or conjugated) to each monomer of rAvPAL. The total molecular weight of pegvaliase‑pqpz (rAvPAL‑PEG) is approximately 1000 kD. Palynziq (pegvaliase‑pqpz) injection, intended for subcutaneous injection, is a clear to slightly opalescent, colorless to pale yellow, sterile, preservative-free solution and is formulated at pH 6.6 to 7.4. Palynziq is provided in a single-dose prefilled syringe and is available in three dosage strengths: 2.5 mg/0.5 mL, 10 mg/0.5 mL, and 20 mg/mL. Palynziq contents for each dosage strength are summarized in Table 4. Table 4: Contents of Palynziq   Strength   Total Contents per Prefilled Syringe Palynziq 2.5 mg/0.5 mL prefilled syringe 2.5 mg pegvaliase-pqpz (expressed as the amount of rAvPAL conjugated to 7.25 mg of 20 kD PEG in 0.5 mL Water for Injection, USP) and contains the following inactive ingredients: sodium chloride (for tonicity adjustment), trans-cinnamic acid (0.07 mg), and tromethamine and tromethamine hydrochloride (for pH adjustment). Palynziq 10 mg/0.5 mL prefilled syringe 10 mg pegvaliase-pqpz (expressed as the amount of rAvPAL conjugated to 29 mg of 20 kD PEG in 0.5 mL Water for Injection, USP) and contains the following inactive ingredients: sodium chloride (for tonicity adjustment), trans-cinnamic acid (0.07 mg), and tromethamine and tromethamine hydrochloride (for pH adjustment).  Palynziq 20 mg/mL prefilled syringe 20 mg pegvaliase-pqpz (expressed as the amount of rAvPAL conjugated to 58 mg of 20 kD PEG in 1 mL Water for Injection, USP) and contains the following inactive ingredients: sodium chloride (for tonicity adjustment), trans-cinnamic acid (0.15 mg), and tromethamine and tromethamine hydrochloride (for pH adjustment).

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. Palynziq is a phenylalanine (Phe)‑metabolizing enzyme indicated to reduce blood Phe concentrations in adult patients with phenylketonuria who have uncontrolled blood Phe concentrations greater than 600 micromol/L on existing management. ( 1 )

Dosage ( 2.1 ) Obtain baseline blood Phe concentration before initiating treatment. The recommended initial dosage is 2.5 mg subcutaneously once weekly for 4 weeks. Titrate the dosage in a step-wise manner over at least 5 weeks based on tolerability to achieve a dosage of 20 mg once daily. See full prescribing information for titration regimen. Assess patient tolerability, blood Phe concentration, and dietary protein and Phe intake throughout treatment. Consider increasing the dosage to 40 mg once daily in patients who have been on 20 mg once daily continuously for at least 24 weeks and who have not achieved blood Phe control (blood phenylalanine concentration less than or equal to 600 micromol/L). Consider increasing the 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 and who have not achieved blood Phe control. 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. Reduce the dosage and/or modify dietary protein and Phe intake, as needed, to maintain blood Phe concentrations within a clinically acceptable range and above 30 micromol/L. Blood Phenylalanine Monitoring and Diet ( 2.2 ) Obtain blood Phe concentrations every 4 weeks until a maintenance dosage is established. Periodically monitor blood Phe concentrations during maintenance therapy. Counsel patients to monitor dietary protein and Phe intake, and adjust as directed by their healthcare provider. Premedication ( 2.3 , 5.1 , 5.3 ) Consider premedication for hypersensitivity reactions. Administration Instructions ( 2.4 ) Rotate injection sites. If more than one injection is needed for a single dose, the injection sites should be at least 2 inches away from each other. 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   Treatment   Palynziq Dosage   Duration Additional time may be required prior to each dosage escalation based on patient tolerability.  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 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)].  20 mg once daily  24 weeks   40 mg once daily  16 weeks  Maximum 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.    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. 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. For hypersensitivity reactions, consider premedication with an H 1 ‑receptor antagonist, H 2 ‑receptor antagonist, and/or antipyretic prior to Palynziq administration based upon individual patient tolerability [see Warnings and Precautions ( 5.1 , 5.3 )] . 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.

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 Injection: 2.5 mg/0.5 mL, 10 mg/0.5 mL, and 20 mg/mL in a single-dose prefilled syringe. ( 3 )

None. None. ( 4 )

Hypersensitivity Reactions, Other than Anaphylaxis: Management should be based on the severity of the reaction, recurrence, and clinical judgement, and may include dosage adjustment, temporary drug interruption, or treatment with antihistamines, antipyretics, and/or corticosteroids. ( 5.3 ) 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 H 1 -receptor antagonist, H 2 -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 )]. Palynziq is available only through a restricted program under a REMS called the Palynziq REMS, because of the risk of anaphylaxis [see Warnings and Precautions ( 5.1 )]. Notable requirements of the Palynziq REMS include the following: Prescribers must be certified with the program by enrolling in the program and completing training. Prescribers must prescribe auto‑injectable epinephrine with Palynziq. Pharmacies must be certified with the program and must dispense only to patients who are authorized to receive Palynziq. 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 with Palynziq. Patients must have auto‑injectable epinephrine available at all times while taking Palynziq. 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). Hypersensitivity reactions, other than anaphylaxis [see Warnings and Precautions ( 5.1 ), Adverse Reactions ( 6.1 , 6.2 )], have been reported in 204 out of 285 (72%) patients treated with Palynziq. The exposure adjusted rate of other hypersensitivity reactions was highest during the induction and titration phases (4.3 episodes/person-year; 50% of patients with at least one adverse reaction) and decreased in the maintenance phase (1.3 episodes/person-year; 61% of patients with at least one adverse reaction). Consider premedication with an H 1 ‑receptor antagonist, H 2 ‑receptor antagonist, and/or antipyretic prior to Palynziq administration based upon individual patient tolerability [see Dosage and Administration ( 2.3 )] . Management of hypersensitivity reactions should be based on the severity of the reaction, recurrence of the reaction, and the clinical judgement of the healthcare provider, and may include dosage adjustment, temporary drug interruption, or treatment with antihistamines, antipyretics, and/or corticosteroids.

The following serious adverse reactions are discussed below and in other sections of labeling:

Effect of Palynziq on Other PEGylated Products : Monitor for hypersensitivity reactions, including anaphylaxis, with concomitant treatment. ( 7.1 ) In a single dose study of Palynziq in adult patients with PKU, two patients receiving concomitant injections of medroxyprogesterone acetate suspension (a formulation containing PEG 3350) experienced a hypersensitivity reaction. One of the two patients experienced a hypersensitivity reaction on day 15 after a single Palynziq dosage of 0.67 mg within 15 minutes following medroxyprogesterone acetate injectable suspension, and subsequently experienced anaphylaxis on day 89 within 30 minutes after the next dose of medroxyprogesterone acetate injectable suspension. The other patient experienced a hypersensitivity reaction on day 40 after a single Palynziq dosage of 0.08 mg within 10 minutes following medroxyprogesterone acetate injectable suspension. Both patients had high anti‑PEG IgG antibody titers at or around the time of the hypersensitivity reactions. In Palynziq clinical trials, the majority of patients developed anti‑PEG IgM and IgG antibodies after treatment with Palynziq [see Adverse Reactions ( 6.2 )] . The clinical effects of concomitant treatment with different PEGylated products is unknown. Monitor patients treated with Palynziq and concomitantly with other PEGylated products for hypersensitivity reactions including anaphylaxis.

Pregnancy : May cause fetal harm. ( 8.1 ) Risk Summary Based on findings in studies of pregnant animals without PKU treated with pegvaliase-pqpz, Palynziq 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. There are risks to the fetus associated with poorly controlled phenylalanine concentrations in women with PKU during pregnancy including increased risk for miscarriage, major birth defects (including microcephaly, major cardiac malformations), intrauterine fetal growth retardation, and future intellectual disability with low IQ; therefore, phenylalanine concentrations should be closely monitored in women with PKU during pregnancy (see Clinical Considerations and Data). Advise pregnant women of the potential risks to the fetus. 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 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. The effects in rats occurred at 2.8 times the maximum recommended daily dose. In a pre-/post-natal 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 13 times the maximum recommended daily dose. The effects on rat embryo‑fetal and post-natal development were also associated with maternal toxicity. All pregnancies have a background risk of major birth defects, pregnancy loss, or other adverse pregnancy outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. The estimated background risk of major birth defects and miscarriage in pregnant women with PKU who maintain blood phenylalanine concentrations greater than 600 micromol/L during pregnancy is greater than the corresponding background risk for pregnant women without PKU. There is a pregnancy surveillance program for Palynziq. If Palynziq is administered during pregnancy, or if a patient becomes pregnant while receiving Palynziq or within one month following the last dose of Palynziq, healthcare providers should report Palynziq exposure by calling 1-866-906-6100. Clinical Considerations 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 and 360 micromol/L during pregnancy and during the 3 months before conception [see Dosage and Administration ( 2.2 )]. Dose Adjustments During Pregnancy and the Postpartum Period Phenylalanine concentrations below 30 micromol/L in pregnant women with PKU treated with Palynziq may be associated with adverse fetal outcomes. Monitor blood phenylalanine concentrations during pregnancy and adjust the dosage of Palynziq or modify dietary protein and phenylalanine intake to avoid blood phenylalanine concentrations below 30 micromol/L [see Dosage and Administration ( 2.2 )]. Data Human Data Uncontrolled Maternal PKU: Available data from the Maternal Phenylketonuria Collaborative Study on 468 pregnancies and 331 live births in pregnant women with PKU demonstrated that uncontrolled phenylalanine concentrations above 600 micromol/L are associated with an increased risk for miscarriage, major birth defects (including microcephaly, major cardiac malformations), intrauterine fetal growth retardation, and future intellectual disability with low IQ. Limited data from case reports of Palynziq use in pregnant women are insufficient to determine a drug‑associated risk of adverse developmental outcomes. Animal Data All developmental toxicity studies were conducted in animals (rats and rabbits) without PKU, in which treatment with pegvaliase-pqpz produced a dose-dependent reduction in maternal blood phenylalanine concentrations. At doses that produced maternal toxicity and/or effects on embryo-fetal development, the maternal plasma phenylalanine concentrations were markedly reduced compared to the control group. The contribution of maternal phenylalanine depletion to the incidence of embryo‑fetal developmental effects was not evaluated. Subcutaneous administration of 5 mg/kg/day pegvaliase‑pqpz (5 times the maximum recommended daily dose based on bodyweight [mg/kg]) in pregnant rabbits during the period of organogenesis produced embryo‑lethality (increased resorptions), marked reduction in fetal weight, and fetal malformations. The malformations included multiple external abnormalities of the head, body and limbs, multiple soft tissue malformations (reduced size or absence of kidneys, diaphragmatic hernia, corneal opacity, discoloration or reduced size of eyes, and reduced size of lungs) and multiple skeletal malformations of the craniofacial bones, vertebrae, sternebrae, ribs, pelvis, limbs, and digits. An increase in variations and delayed ossification was also observed in all skeletal regions. The adverse developmental effects were associated with maternal toxicity, as indicated by marked impairment of weight gain and food consumption. Deaths associated with weight loss and abortion occurred in 8% of the pregnant rabbits treated with 5 mg/kg/day pegvaliase‑pqpz. Subcutaneous administration of 2 mg/kg/day pegvaliase‑pqpz (2 times the maximum recommended daily dose based on bodyweight [mg/kg]) in pregnant rabbits had no adverse effects on embryo-fetal development. Systemic exposure to pegvaliase‑pqpz was detected in fetuses from rabbits treated with 2 or 5 mg/kg/day. Pegvaliase‑pqpz increased fetal alterations when administered daily in pregnant rats at doses of 8 mg/kg subcutaneously and higher (2.8 times the human steady-state area under the curve [AUC] at the maximum recommended daily dose) during a 28‑day premating period, mating, and through the period of organogenesis. The fetal alterations were limited to skeletal variations such as cervical ribs, bifid centra of lumbar and thoracic vertebrae, and incomplete ossification of squamosal bones, frontal bones, lumbar vertebra arch, and ribs. Daily administration of 20 mg/kg subcutaneously (13 times the human steady-state AUC at the recommended maximum daily dose) to pregnant rats produced reductions in litter sizes and fetal weights, which was associated with maternal toxicity (decreased body weight, ovarian weight, and food consumption). The decrease in litter sizes at 20 mg/kg subcutaneously was secondary to reductions in corpora lutea and implantations. Systemic exposure to pegvaliase‑pqpz was detected in fetuses from rats treated with 20 mg/kg of pegvaliase‑pqpz (13 times the human steady-state AUC at the recommended maximum daily dose). Subcutaneous administration of 2 mg/kg/day pegvaliase‑pqpz (less than the human steady state AUC at the maximum recommended daily dose) in pregnant rats had no adverse effects on embryo‑fetal development. Pegvaliase-pqpz decreased pup weight, litter size, and survival of offspring during lactation, and delayed sexual maturation of offspring when administered daily in rats at 20 mg/kg subcutaneously (13 times the human steady-state AUC at the recommended maximum daily dose), with dosing starting before mating and continuing through lactation. The effects in offspring were associated with maternal toxicity. No effects in offspring were observed at 8 mg/kg/day subcutaneously (2.8 times the human steady-state AUC at the recommended maximum daily dose). A follow-up study of the same design evaluated additional parameters of physical and neurobehavioral development in offsprings; No effects of pegvaliase‑pqpz were noted at the maternal NOAEL dose of 8 mg/kg/day. Risk Summary 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 pre-/post-natal 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 [see Use in Specific Populations ( 8.1 )] . However, systemic absorption of pegvaliase-pqpz was not detected in the rat pups . Palynziq may cause low phenylalanine concentrations in human milk . The developmental and health benefits of breastfeeding should be considered along with the clinical need for Palynziq treatment and any potential adverse effect on the breastfed infant from Palynziq or from the underlying condition (see Clinical Considerations) . Clinical Considerations Monitor blood phenylalanine concentrations in breastfeeding women treated with Palynziq. The safety and effectiveness of Palynziq in pediatric patients have not been established. Clinical studies of Palynziq did not include patients aged 65 years and older.

How Supplied Palynziq (pegvaliase-pqpz) injection is supplied as a preservative-free, sterile, clear to slightly opalescent, colorless to pale yellow solution. All dosage strengths of Palynziq are provided in a 1 mL glass syringe with a 26 gauge, 0.5 inch needle. Each carton contains 1 or 10 trays with single-dose prefilled syringe(s), Prescribing Information, Medication Guide, and Instructions for Use. The following packaging configurations are available. Table 6: Palynziq Packaging Configurations Pegvaliase‑pqpz 2.5 mg/0.5 mL 1 syringe/carton NDC 68135‑058‑90 Pegvaliase‑pqpz 10 mg/0.5 mL 1 syringe/carton   NDC 68135‑756‑20 Pegvaliase‑pqpz 20 mg/mL 1 syringe/carton 10 syringes/carton NDC 68135‑673‑40 NDC 68135‑673‑45 Storage and Handling Store in refrigerator at 36°F to 46°F (2°C to 8°C) in its original carton to protect from light. Do not freeze or shake. For patients : If needed, store Palynziq in the original carton at room temperature between 68°F to 77°F (20°C to 25°C) for up to 30 days. Record the date removed from refrigeration on the carton. Once stored at room temperature, do not return the product to the refrigerator. The shelf-life expires after storage at room temperature for 30 days, or after the expiration date on the product carton, whichever is earlier.

Pegvaliase-pqpz is a PEGylated phenylalanine ammonia lyase (PAL) enzyme that converts phenylalanine to ammonia and trans ‑cinnamic acid. It substitutes for the deficient phenylalanine hydroxylase (PAH) enzyme activity in patients with PKU and reduces blood phenylalanine concentrations. Palynziq treatment of adult patients with PKU resulted in the reduction of blood phenylalanine concentrations from pre-treatment baseline [see Clinical Studies ( 14 )] . The reduction of blood phenylalanine concentrations diminished with decreased pegvaliase‑pqpz plasma concentrations . The pharmacokinetics of pegvaliase‑pqpz exhibit high inter-patient and intra-patient variability due to the heterogeneity of the immune response in adult patients with PKU. Higher antibody titers correlated with higher apparent clearance of pegvaliase‑pqpz. In the first eight weeks of induction/titration treatment, plasma pegvaliase‑pqpz concentrations were low to not measurable. At steady state during maintenance treatment with Palynziq 20 mg, 40 mg, and 60 mg subcutaneously once daily, the mean ± SD (range) plasma trough pegvaliase‑pqpz concentrations were: 11.2 ± 9.0 (0.21 to 29.6) mg/L, 10.4 ± 12.7 (0.18 to 43.1) mg/L and 4.8 ± 10.7 (0 to 39.7) mg/L, respectively. The following pharmacokinetic parameters were observed in adult patients with PKU treated with Palynziq at maintenance dosages of 20 mg once daily and 40 mg once daily. Absorption The median T max was approximately 8 hours. The mean ± SD (range) peak concentration (C max ) at steady state was: 14.0 ± 16.3 (0.26 to 68.5) mg/L and 16.7 ± 19.5 (0.24 to 63.8) mg/L, respectively. Distribution The mean ± SD (range) apparent volume of distribution was 26.4 ± 64.8 (1.8 to 241) L and 22.2 ± 19.7 (3.1 to 49.5) L, respectively. Elimination The mean ± SD (range) apparent clearance at steady state was 0.39 ± 0.87 (0.018 to 3.66) L/h and 1.25 ± 2.46 (0.034 to 8.88) L/h, respectively. The mean ± SD (range) half-life was 47 ± 42 (14 to 132) hours and 60 ± 45 (14 to 127) hours, respectively. Metabolism The metabolism of phenylalanine ammonia lyase is expected to occur via catabolic pathways and be degraded into small peptides and amino acids. Excretion The route of elimination of pegvaliase‑pqpz has not been studied in humans.

Carcinogenicity and genotoxicity studies have not been performed with pegvaliase‑pqpz. Based on its mechanism of action, pegvaliase‑pqpz is not expected to be tumorigenic. Pegvaliase-pqpz produced impaired fertility in female rats at 20 mg/kg/day subcutaneously (13 times the human steady-state AUC at the maximum recommended daily dose), as indicated by decreases in corpora lutea, implantations, and litter size. These effects were associated with maternal toxicity (decreased body weight, ovarian weight, and food consumption). No effects on mating or fertility were observed in female rats with 8 mg/kg/day subcutaneously (2.8 times the human steady-state AUC at the maximum recommended daily dose) or in male rats with 20 mg/kg/day subcutaneously. In rats without PKU treated with pegvaliase-pqpz, dose-dependent vacuolation in multiple organs and tissues was observed in the 4‑ and 26‑week repeat dose toxicity studies at doses of 8 mg/kg subcutaneously or greater administered twice weekly (less than the human steady state AUC at the maximum recommended daily dose). Vacuolation occurred in renal tubule cells and in histiocytic cells of the liver, spleen, testes, adrenal cortex, mesenteric lymph node, and mandibular lymph node. Vacuolation in histiocytes of the affected organs and tissues persisted after cessation of treatment. The vacuolation observed in these studies was not associated with organ‑related toxicities as determined by clinical chemistry/urinalysis and histopathological examination. The clinical significance of these findings and functional consequences are unknown. In the 39‑week repeat dose toxicity study in monkeys, pegvaliase-pqpz 3 mg/kg subcutaneously twice weekly (2 times the human steady state AUC at the maximum recommended daily dose) produced systemic arteritis involving small arteries and arterioles in a wide range of organs and tissues (kidney, urinary bladder, pancreas, gallbladder, esophagus, stomach, duodenum, jejunum, ileum, cecum, colon, rectum, lung, heart, sciatic nerve, lacrimal gland, mandibular lymph node, epididymis, seminal vesicle, ovary, uterus, cervix, and vagina) and in subcutaneous injection sites. Arteritis was likely due to the immune-mediated response (e.g., immune complex deposition in blood vessels) associated with chronic administration of a foreign protein to the animals. The incidence and severity of systemic arteritis was dose-dependent. The vascular inflammation observed in this study was not associated with organ related toxicities as determined by clinical pathology parameters (hematology, clinical chemistry, and urinalysis) and histopathological examination. Studies of longer duration in rats and monkeys treated with pegvaliase‑pqpz have not been conducted.

Study 301: Induction/Titration/Maintenance Treatment Study 165‑301 (referred to as Study 301, NCT01819727) was an open-label randomized, multi-center study of adults with PKU to assess safety and tolerability of self-administered Palynziq in an induction/titration/maintenance regimen with a target maintenance dose of 20 mg subcutaneously once daily or 40 mg subcutaneously once daily. At Palynziq treatment initiation, 253 patients demonstrated inadequate blood phenylalanine control (blood phenylalanine concentration greater than 600 micromol/L) on existing management, and 8 patients had blood phenylalanine concentrations less than or equal to 600 micromol/L. Existing management options included prior or current restriction of dietary phenylalanine and protein intake, and/or prior treatment with sapropterin dihydrochloride. Patients previously treated with sapropterin dihydrochloride were required to discontinue use at least 14 days prior to the first dose. The 261 enrolled patients were aged 16 to 55 years (mean: 29 years) and had a baseline mean (range) blood phenylalanine of 1,233 (285, 2330) micromol/L. One hundred forty nine out of 261 (57%) patients were taking medical food at baseline and 41 out of 261 patients (16%) were on a protein-restricted diet at baseline (defined as receiving greater than 75% of total protein intake from medical food). Patients were randomized (1:1) to one of two target maintenance dosage arms: 20 mg once daily or 40 mg once daily. Patients were titrated to reach their randomized target dosage of 20 mg once daily or 40 mg once daily. The duration of titration varied among patients and was based on patient tolerability. Of the 261 enrolled patients, 195 (75%) patients reached their randomized maintenance dosage (103 in the 20 mg once daily arm, 92 in the 40 mg once daily arm). Among the patients who reached their randomized maintenance dosage, patients in the 20 mg once daily randomized arm reached their maintenance dosage at a median time of 10 weeks (range: 9 to 29 weeks) and patients in the 40 mg once daily arm reached their maintenance dosage at a median time of 11 weeks (range: 10 to 33 weeks). Of the 261 patients who enrolled in Study 301, 54 (21%) patients discontinued treatment during Study 301, 4 patients completed Study 301 and did not continue to Study 165‑302 (referred to as Study 302, NCT01889862), 152 patients continued to the eligibility period of Study 302, and 51 patients continued directly from Study 301 into the long‑term treatment period of Study 302. Study 302: Efficacy Assessment A total of 164 adult patients with PKU who were previously-treated with Palynziq (152 patients from Study 301 and 12 patients from other Palynziq trials) enrolled in Study 302 and continued treatment with Palynziq in Study 302 for up to 13 weeks to assess eligibility for randomized withdrawal period. Randomized Withdrawal Period Following this period of up to 13 weeks of additional Palynziq treatment in Study 302, eligibility for entry into the efficacy assessment period (randomized withdrawal period) was determined by whether a patient achieved at least a 20% reduction in blood phenylalanine concentration from pre-treatment baseline (when in previous studies). Eighty‑six out of 164 patients (52%) met this response target and continued into the randomized withdrawal period. In the double-blind, placebo-controlled, randomized withdrawal period, patients were randomized in a 2:1 ratio to either continue their maintenance Palynziq dosage or to receive matching placebo for a total of 8 weeks. The treatment difference in least squares (LS) mean change in blood phenylalanine concentration from the Study 302 randomized withdrawal baseline to randomized withdrawal Week 8 for each randomized study arm is shown in Table 5. Mean blood phenylalanine concentrations at pre-treatment baseline (Study 301 or other Palynziq trials) are also shown in Table 5. At Study 302 randomized withdrawal Week 8, Palynziq‑treated patients (20 mg once daily or 40 mg once daily) maintained their blood phenylalanine concentrations as compared to their randomized withdrawal baseline, whereas patients randomized to matching placebo (20 mg once daily or 40 mg once daily) returned to their pretreatment baseline blood phenylalanine concentrations (Figure 1). Table 5: Primary Endpoint: LS Mean Change in Blood Phenylalanine Concentration from Randomized Withdrawal Baseline to Week 8 in Adult Patients with PKU – Efficacy Assessment in Study 302 Randomized Study Arm Blood Phenylalanine Concentration (micromol/L) Mean (SD) LS Mean Change from Study 302 Randomized Withdrawal Baseline to Week 8 (95% CI)  Treatment Difference in LS Mean Change (95% CI) P‑value Based on the mixed model repeated measures (MMRM) method, with treatment arm, visit, and treatment arm-by-visit interaction as factors adjusting for baseline blood phenylalanine concentration. Pre‑treatment Baseline Study 302 Randomized Withdrawal Baseline Study 302 Randomized Withdrawal Week 8   Palynziq 20 mg once daily 1450.2 (310.5) n = 29 596.8 (582.8) n = 29  553.0 (582.4) n = 26 Patients who did not complete phenylalanine assessment within the window for Week 8 (Day 43 to 56) were excluded.   -23.3 (-156.2, 109.7) -973.0 (‑1204.2, ‑741.9) p < 0.0001  Placebo 20 mg once daily  1459.1 (354.7) n = 14 563.9 (504.6) n = 14  1509.0 (372.6) n = 13   949.8 (760.4, 1139.1)  Palynziq 40 mg once daily 1185.8 (344.0) n = 29 410.9 (440.0) n = 29 566.3 (567.5) n = 23   76.3 (-60.2, 212.8)  -588.5  (-830.1, -346.9) p < 0.0001 Placebo 40 mg once daily  1108.9 (266.8) n = 14   508.2 (363.7) n = 14 1164.4 (343.3) n = 10   664.8  (465.5, 864.1) Figure 1: Observed Mean (SE) Blood Phenylalanine Concentrations Over Time in Adult Patients with PKU in Study 302 Study 301 and 302 Continuous Treatment Of 118 patients from Study 301 with a pre‑treatment baseline blood phenylalanine concentration greater than 600 micromol/L who were randomized to and received at least one dose of 20 mg once daily Palynziq, 107 patients, 97 patients, 93 patients, 86 patients, and 77 patients were treated for at least 6 months, 12 months, 18 months, 24 months, and 36 months, respectively. During the continuous treatment period, patients were allowed to dose up to 60 mg once daily based on investigator discretion to achieve blood phenylalanine lowering (for example, to achieve blood phenylalanine concentrations between 120 and 360 micromol/L). Of the 118 patients, a majority (91 patients, 77%) reached their first response, defined as a blood phenylalanine concentration less than or equal to 600 micromol/L, at a time point prior to 36 months. Of the 91 patients, 9 patients (10%) achieved their first response at a dose less than 20 mg once daily, 44 patients (48%) achieved their first response at a dose of 20 mg once daily, 26 patients (29%) achieved their first response at a dose of 40 mg once daily, and 12 patients (13%) achieved their first response at a dose of 60 mg once daily. Of the 44 patients that achieved their first response at a dose of 20 mg once daily, 36 (82%) achieved it by 24 weeks of treatment. Of the 26 patients that achieved their first response at a dose of 40 mg once daily, 18 (69%) achieved it by 16 weeks of treatment. Of the 12 patients that achieved their first response at a dose of 60 mg once daily, 8 (67%) achieved it by 16 weeks of treatment. Of the 107 patients treated for at least 6 months, 28 (26%), 18 (17%), and 11 (10%) had a blood phenylalanine concentration less than or equal to 600, 360, and 120 micromol/L, respectively, at 6 months of treatment. Of the 97 patients treated for at least 12 months, 47 (48%), 41 (42%), and 31 (32%) had a blood phenylalanine concentration less than or equal to 600, 360, and 120 micromol/L, respectively, at 12 months of treatment. Of the 93 patients treated for at least 18 months, 64 (69%), 46 (49%), and 36 (39%) had a blood phenylalanine concentration less than or equal to 600, 360, and 120 micromol/L, respectively, at 18 months of treatment. Of the 86 patients treated for at least 24 months, 65 (76%), 57 (66%), and 43 (50%) had a blood phenylalanine concentration less than or equal to 600, 360, and 120 micromol/L, respectively, at 24 months of treatment. Of the 77 patients treated for at least 36 months, 58 (75%), 51 (66%), and 37 (48%) had a blood phenylalanine concentration less than or equal to 600, 360, and 120 micromol/L, respectively, at 36 months of treatment. Figure 1

NDC 68135-058-90                     Rx only Palynziq TM (pegvaliase-pqpz) Injection 2.5 mg/0.5 mL For Subcutaneous Use Only Contains one x 2.5 mg/0.5 mL single-dose prefilled syringe. Discard after use. ATTENTION: Dispense the enclosed Medication Guide to each patient. 2.5 mg Carton 2.5 mg Tray Cover 2.5 mg Syringe Label