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…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.

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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)].

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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 H1 -receptor antagonist, H2 -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.

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As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Palynziq in the studies described below with the incidence of antibodies in other studies or to other products may be misleading.

All patients treated with Palynziq developed a sustained total anti-drug antibody (TAb) response with a majority of patients (91%; N = 235/258) developing that response by Week 4 of treatment. Mean TAb titers peaked 2 weeks after Palynziq initiation and remained elevated throughout treatment (greater than  3 years after treatment initiation). Anti-phenylalanine ammonia lyase (PAL) IgM antibodies were detected in a majority of patients (98%; N = 265/270) by 2 months after treatment initiation, with incidence declining over time to 67% at 36 months (N = 114/171). Anti-PAL IgG antibodies were detected in almost all patients (N = 226/227) by 4 months after treatment initiation. Mean anti-PAL IgM and IgG titers peaked at approximately 3 and 6 months, respectively, after treatment initiation and remained elevated throughout treatment (greater than 3 years after treatment initiation). Drug-induced anti-PEG IgM and IgG antibodies were detected in the majority of patients (98%; N = 277/284 for IgM; and 278/284 for IgG) with mean titers for both peaking at 1 to 3 months after treatment initiation [see Drug Interactions (7.1)]. Neutralizing antibodies (NAb) capable of inhibiting PAL enzyme activity were detected on at least one measurement in the majority of patients (89%; N = 253/284) over time. Mean NAb titers peaked and reached a plateau at 16 to 20 weeks of treatment and then remained present throughout treatment (greater than 3 years after treatment initiation).

Twenty-seven of 29 patients who had anaphylaxis were tested for anti-pegvaliase-pqpz IgE antibodies, which recognize the PEGylated protein product. Of the 27 patients tested for anti-pegvaliase-pqpz IgE antibodies, 26 patients tested negative. The one patient who tested positive for anti-pegvaliase-pqpz IgE antibodies on the screening test did not have sufficient sample to confirm IgE positivity. This patient tested negative for anti-pegvaliase-pqpz IgE at routine visits prior to and after the anaphylaxis episode (not at times of anaphylaxis). Sixty-seven of 285 patients in clinical trials were tested for both anti-PAL IgE antibodies, which recognize the recombinant PAL protein, and for anti-pegvaliase-pqpz IgE antibodies during routine study visits (not at times of anaphylaxis episodes) or during additional visits for hypersensitivity reactions. Of those 67 patients, 5 (8%) tested positive at least once for anti-PAL IgE antibodies but negative for anti-pegvaliase-pqpz IgE antibodies.

The highest frequency of hypersensitivity reactions (consistent with a Type III immune complex- mediated hypersensitivity mechanism) occurred within the first 6 months of Palynziq treatment when the mean circulating immune complex (CIC) concentrations were at their highest and mean complement C3 and C4 concentrations were at their lowest. Mean CIC concentrations decreased and complement levels increased over time as the exposure-adjusted rate of hypersensitivity reactions decreased. IgG and IgM CIC concentrations were above the upper limit of normal in 63% (N = 164/259) and 42% of patients (N = 109/259), respectively, at 12 weeks of Palynziq treatment and returned towards baseline with long-term treatment (greater than 3 years after treatment initiation). 61% of patients (N = 110/180) had complement C3 concentrations less than lower limit of normal (LLN) at 6 months after treatment initiation and 38% of patients (N = 94/248) had complement C4 concentrations less than LLN at 3 months after treatment initiation. The incidence of low complement C3 and C4 concentrations decreased over time, but approximately 35% (N = 34/96) and 12% (N = 11/96) of patients had low C3 and C4 concentrations, respectively, at 36 months after treatment initiation.

Higher antibody responses for all antibody analytes, including NAb, were associated with lower mean trough pegvaliase-pqpz concentrations and with higher blood phenylalanine concentrations.

Hypersensitivity reactions occurred more frequently in patients with higher antibody titers for some but not all antibody analytes. Patients with higher mean change in IgG CIC concentrations from pre-treatment baseline tended to have higher discontinuation rates than patients with lower mean change in IgG CIC concentrations. Mean antibody titers for anti-PAL IgG and IgM, TAb, and NAb remained relatively stable with long-term treatment.

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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.

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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.

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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). This study lacked a complete evaluation of physical and neurobehavioral development in offspring; however, no effects of pegvaliase-pqpz were noted in tests of learning and memory.

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