In addition to gastrointestinal (GI) symptoms associated with pegvaliase hypersensitivity, nausea, abdominal pain, vomiting, and diarrhea were reported during clinical trials. Nausea was the most common GI adverse event occurring in 52 of 285 (18%) patients during the induction/titration phase and 69 of 223 (31%) patients during the maintenance phase. Abdominal pain, which includes upper abdominal pain and abdominal discomfort, occurred in 39 of 285 (14%) patients during the induction/titration phase and 67 of 223 (30%) patients during the maintenance phase. Vomiting (13% during induction/titration phase; 30% during maintenance phase) and diarrhea (9% during induction/titration phase; 27% during maintenance phase) were also reported.[63190]

Pegvaliase can cause serious hypersensitivity reactions or anaphylaxis, including anaphylactoid reactions, anaphylactic shock, and angioedema. During clinical trials, 29 of 285 patients experienced anaphylactic reactions during induction/titration/maintenance dosing. Anaphylaxis usually occurred within 1 hour after injection (81%; 34/42 episodes); however, delayed episodes occurred up to 48 hours after pegvaliase administration. The exposure-adjusted rate of anaphylaxis was highest during the induction and titration phases and decreased in the maintenance phase. Manifestations included syncope, hypotension, hypoxia, dyspnea, wheezing, chest discomfort/chest tightness, tachycardia, angioedema, throat tightness, skin flushing, urticaria, pruritus, and gastrointestinal symptoms (vomiting, nausea, diarrhea). Most episodes of anaphylaxis occurred within the first year of dosing (69%), but cases occurred up to 1,604 days (4.4 years) into treatment. In clinical trials, management of anaphylaxis included administration of auto-injectable epinephrine, corticosteroids, antihistamines, and/or oxygen. Out of the patients who experienced anaphylaxis, 72% (21/29) were rechallenged with pegvaliase and 29% (6/21) had recurrence of anaphylaxis. All anaphylaxis episodes resolved without sequelae. Hypersensitivity reactions, other than anaphylaxis have been reported in 204 out of 285 (72%) patients treated with pegvaliase. The exposure-adjusted rate of hypersensitivity reactions was highest during the induction and titration phases and decreased in the maintenance phase. In clinical trials, 22 out of 285 (8%) patients experienced 45 episodes of angioedema (symptoms included: pharyngeal edema, swollen tongue, lip swelling, mouth swelling, eyelid edema and facial edema) occurring independently of anaphylaxis. Angioedema was more frequent during the induction/titration phase (0.14 episodes/patient-year) and decreased over time (0.04 episodes/patient-year in the maintenance phase). Three patients discontinued treatment; all episodes resolved. Pruritus (20% induction/titration phase; 27% maintenance phase) was also reported during clinical trials. Hypersensitivity reactions were reported in 153 of 285 (54%) patients treated with pegvaliase during the induction/titration phase and 145 of 223 (64%) of patients during the maintenance phase. Hypersensitivity reaction reports included urticaria, anaphylaxis, rash (generalized), hypersensitivity, rash erythematous, maculopapular rash, rash pruritic, swelling face, contact dermatitis, swollen tongue, lip swelling, rash macular, pharyngeal edema, injection site hypersensitivity, eczema or atopic dermatitis, drug eruption, allergic dermatitis, tongue edema, palatal edema, mouth edema, multiple allergies, lip edema, eye edema, exfoliative rash, drug hypersensitivity, dermatitis acneiform (acneiform rash), allergic pruritus, mouth swelling, injection site rash, gingival swelling, face edema, eyelid edema (blepharedema), ocular swelling, dermatitis psoriaiform (psoriaform rash), dermatitis infected, allergic conjunctivitis, bronchospasm, angioedema, allergic sinusitis, and allergic-related coughing. Serum sickness (duration ranged from 1 to 8 days) was reported in 7 of 285 (2%) patients. Serum sickness was more frequent during the induction/titration phase (0.04 episodes/patient-year) and decreased over time (less than 0.01 episodes/patient-year in the maintenance phase). All serum sickness reactions resolved without sequelae. Out of the 7 patients who experienced serum sickness, 5 patients continued treatment without a recurrence and managed serum sickness with drug interruption, dosage reduction, and/or medication. Two patients discontinued treatment. During clinical trials, the most common adverse reactions leading to treatment discontinuation were hypersensitivity reactions (6%) including anaphylaxis (3%) and angioedema (1%). Hypersensitivity reactions (9%) were some of the most common reactions leading to dosage reduction and hypersensitivity reactions (14%) and anaphylaxis (4%) were 2 of the most common adverse reactions leading to temporary drug interruption.[63190]

A generalized skin reaction lasting at least 14 days occurred in 61 to 134 of 285 (21% to 47%) patients receiving pegvaliase during the induction/titration phase and 93 of 225 (41%) patients during the maintenance phase. Generalized skin reactions were more frequent during the induction/titration phase (0.7 episodes/patient-years) and decreased over time (0.3 episodes/patient-years in the maintenance phase). The mean time from first dose to onset of skin reactions was 373 days (median: 213 days; range: 2 to 1,970 days). The mean duration of the skin reaction was 58 days (median: 35 days; range: 14 to 638 days). Of these reactions, 5% persisted at least 180 days and 85% resolved at the time of last observation (up to 59 months of follow-up). During clinical trials, generalized skin reactions lasting at least 14 days (2% of patients) were one of the most common adverse reactions leading to treatment discontinuation and leading to temporary drug interruption. In some cases, the appearance of these reactions was similar to those reported with hypersensitivity events. A generalized skin reaction included reports of pruritus, rash, urticaria, dry skin (xerosis), rash erythematous, erythema, cellulitis, rash macular, generalized itching, petechiae, dermatitis allergic, skin infection or infected dermatitis, skin induration, rash maculopapular, rash (generalized), pharyngeal edema, macule, granulomatous dermatitis, exfoliative dermatitis or rash, drug eruption, atopic dermatitis or eczema, dermatitis, xanthogranuloma, skin mass, skin lesion, skin hypopigmentation, skin hypertrophy, skin hyperpigmentation, skin exfoliation, septal panniculitis, scleroderma, scar, rash pruritic, rash papular, skin plaque (psoriasis) or psoriaform rash or dermatitis, psoriatic arthropathy, papule, necrobiosis lipoidica diabeticorum, furuncle, ecchymosis, and blister.[63190]

Subcutaneous administration of pegvaliase can cause an injection site reaction that includes symptoms such as erythema, pruritus, pain, bruising, rash, swelling, urticaria, induration, hemorrhage, edema, mass, inflammation, nodule, discoloration, warmth, hematoma, irritation, vesicles, hypersensitivity, papule, discomfort, scar, paresthesias, hypertrophy, extravasation, and dryness. During clinical trials, injection site reactions occurred in 252 of 285 (88%) patients receiving pegvaliase during the induction/titration phase and 166 of 223 (74%) patients during the maintenance phase. Injection site reactions occurred as early as after the first pegvaliase dose and occurred at any time during treatment. Injection site reactions were most frequent during the induction/titration phase (21 episodes/patient-years) and decreased over time (3.3 episodes/patient-years in the maintenance phase). The mean duration of injection site reaction was 10 days (median: 2 days, range 1 to 1,612 days), and 8% of injection site reactions had a duration of at least 14 days. At the time of the last observation (up to 77 months of follow-up), 99% of injection site reactions were resolved. Three injection site reactions consistent with granulomatous skin lesions were reported (each reaction occurring in 1 patient). These included granulomatous dermatitis (occurred after 464 days of pegvaliase treatment; lasted 16 days), xanthogranuloma (occurred after 378 days of pegvaliase treatment; lasted 638 days) and necrobiosis lipoidica diabeticorum (occurred after 281 days of pegvaliase treatment and lasted 281 days). Xanthogranuloma was treated with a topical antihistamine, corticosteroid, and pegvaliase treatment was discontinued. Necrobiosis lipoidica diabeticorum was treated with steroid injections and complicated by Pseudomonas infection. All 3 infections resolved. One patient reported soft tissue infection (occurred after 196 days of pegvaliase treatment; lasted 8 days) associated with mesenteric panniculitis treated with antibiotics, which resulted in treatment discontinuation. During clinical trials, one of the most common adverse reactions leading to treatment discontinuation was injection site reaction (1% patients). Additionally, injection site reactions (4% patients) were some of the most common reactions leading to dosage reduction and leading to temporary drug interruption.[63190]

Arthralgia occurred in 211 to 245 of 285 (74% to 86%) patients receiving pegvaliase during the induction/titration phase and 154 of 223 (64%) patients during the maintenance phase. Included in reports classified as arthralgia were reports of pain in extremity, back pain, musculoskeletal pain, and neck pain. Arthralgia episodes were more frequent during the induction/titration phase (7.4 episodes/patient-year) and decreased over time (1.4 episodes/patient-year in the maintenance phase). Out of 285 patients, 44 (15%) patients had 1 episode of arthralgia, 32 (11%) patients had 2 episodes of arthralgia, 18 (6%) had 3 episodes of arthralgia, and 146 (51%) had 4 or more episodes of arthralgia. Arthralgia occurred as early as after the first dose of pegvaliase and anytime after treatment. The mean duration of arthralgia was 16 days (median 3 days, range 1 to 936 days); 19% of arthralgia episodes had a duration of at least 14 days. Severe arthralgia, defined as severe pain limiting self-care activities of daily living, was reported by 11 (4%) patients. Other joint-related signs and symptoms that were reported included joint swelling (24 patients; 8%), joint stiffness (22 patients; 8%), and musculoskeletal stiffness (20 patients; 7%). Arthralgia episodes were managed with medications (e.g., nonsteroidal anti-inflammatory drugs, glucocorticoids, and acetaminophen), dosage reduction (4% of episodes), temporary drug interruption (4% of episodes), or treatment discontinuation (0.6% of episodes). At the time of last observation (up to 77 months of follow-up), 97% of arthralgia episodes were reported as resolved.[63190]

Alopecia occurred in 13 of 285 (5%) patients receiving pegvaliase during the induction/titration phase and 43 of 223 (19%) patients during the maintenance phase. Alopecia (3% patients) was a common adverse reaction leading to dosage reduction during clinical trials.[63190]

Neurologic adverse events were reported by patients receiving treatment with pegvaliase during clinical trials. Headache occurred in 102 of 285 (36%) patients receiving pegvaliase during the induction/titration phase and 126 of 223 (56%) patients during the maintenance phase. Dizziness occurred in 47 of 285 (16%) patients during the induction/titration phase and 48 of 223 (21%) patients during the maintenance phase. Fatigue (13% during induction/titration phase; 24% during maintenance phase) and anxiety (5% during induction/titration phase; 21% during maintenance phase) were also reported.[63190]

Respiratory adverse reactions that have been reported in at least 15% of patients treated with pegvaliase include oropharyngeal pain (sore throat or pharyngitis, 13% during induction/titration phase; 29% during maintenance phase), cough (9% during induction/titration phase; 30% during maintenance phase), and nasal congestion (4% during induction/titration phase; 27% during maintenance phase).[63190]

As with all therapeutic proteins, there is a potential for immunogenicity with pegvaliase, and, antibody formation has been reported in patients receiving the drug. All patients treated with pegvaliase developed a sustained total anti-drug antibody (TAb) response with most patients (91%; n = 235/258) developing that response by week 4 of treatment. Mean TAb titers peaked 2 weeks after pegvaliase initiation and remained elevated throughout treatment (more than 3 years after treatment initiation). Anti-phenylalanine ammonia lyase (anti-PAL) IgM antibodies were detected in all patients; most patients (98%; n = 265/270) were positive for anti-PAL IgM by 2 months after treatment initiation. 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 2 and 6 months, respectively, after treatment initiation and remained elevated throughout treatment (more than 3 years after treatment initiation). Drug-induced anti-PEG IgM and IgG antibodies were detected in most patients (98%; n = 277/284 for IgM; and 278/284 for IgG), and mean titers for both peaked at 1 to 3 months after treatment initiation. Neutralizing antibodies (NAb) that are capable of inhibiting PAL enzyme activity were detected on at least 1 measurement in most patients (88%; n = 249/284) over time. Mean NAb titers peaked and leveled off at 16 to 20 weeks of treatment and then remained present throughout treatment (more than 3 years after treatment initiation). In clinical trials, 27 out of 29 patients who had anaphylaxis were tested for anti-pegvaliase IgE antibodies. Only 1 patient tested positive on the screening test, but the screening test was not sufficient to confirm IgE positivity. This patient tested negative for anti-pegvaliase IgE at routine visits prior to and after the anaphylaxis episode. In clinical trials, 67 of 285 patients were tested for both anti-PAL IgE antibodies and for anti-pegvaliase IgE antibodies during routine study visits or during additional visits for hypersensitivity reactions. Only 5 of those 68 patients (8%) tested positive at least once for anti-PAL IgE antibodies, but negative for anti-pegvaliase IgE antibodies. Higher antibody responses for all antibody analytes, including NAb, were associated with lower mean trough pegvaliase concentrations and with higher blood phenylalanine (Phe) concentrations. Hypersensitivity reactions occurred more frequently in patients with higher antibody titers for some, but not all antibody analytes. Mean antibody titers for anti-PAL IgG and IgM, TAb, and NAb remained relatively stable with long-term treatment.[63190]

Pegvaliase is associated with a risk of serious hypersensitivity reactions or anaphylaxis. Premedication with a histamine antagonist selective for H1- or H2-receptors and/or antipyretic prior to injection should be considered. Administration of the initial dose of pegvaliase requires an experienced clinician prepared to manage anaphylaxis; monitor the patient for at least 60 minutes following the first administration. Personnel, medications, and equipment necessary to manage an acute pegvaliase hypersensitivity reaction should be readily available. Anaphylaxis requires immediate treatment with auto-injectable epinephrine. Prior to the first pegvaliase dose, the treated patient should be prescribed auto-injectable epinephrine. Consider the risks and benefits of readministering the drug to individual patients after a severe reaction. If the decision is made to readminister pegvaliase, administration should be preformed under the supervision of an experienced clinician that is equipped to manage anaphylaxis and the patient should be closely monitored for a minimum of 60 minutes after administration. An adult observer may be helpful for patients who may need assistance in recognizing and managing anaphylaxis during pegvaliase treatment. Patient and observer should be instructed on how to recognize the signs and symptoms of anaphylaxis, how to properly administer auto-injectable epinephrine, and to seek immediate medical care. The observer should be present during and for at least 60 minutes after each pegvaliase administration.[63190]

Based on animal studies, pegvaliase can cause fetal harm when administered during human pregnancy. No adequate studies of pegvaliase exist in pregnant women; the limited available data on pegvaliase use in pregnant women are not sufficient to inform a drug-associated risk. Poorly controlled phenylalanine (Phe) concentrations in women with phenylketonuria (PKU) during pregnancy can lead to adverse pregnancy outcomes for the fetus; therefore, Phe concentrations should be closely monitored in women with PKU during pregnancy. To reduce the risk of hyperphenylalaninemia-induced fetal adverse effects, blood Phe concentrations should be maintained between 120 and 360 micromol/L during pregnancy and during the 3 months before conception. Phe concentrations below 30 micromol/L in pregnant women with PKU treated with pegvaliase may be associated with adverse fetal outcomes. Embryo-fetal toxicities (increased resorptions and reduced fetal weight) occurred in pregnant rabbits when pegvaliase was administered at 7.5 times the maximum recommended daily dose. Additionally, there was a high incidence of fetal malformations throughout the skeletal system, and in kidneys, lungs, and eyes. Maternal toxicity was also noted and included marked reduction in weight gain and food consumption and death. An animal reproduction study in pregnant rats found an increase in skeletal variations, with no malformations observed at 4.2-times the maximum recommended human dose (MRHD) of pegvaliase. In a pre-/post-natal development study in female rats, administration of pegvaliase at 19.4-times the MRHD produced reduced survival of offspring during lactation, decreased pup weight and litter size, and delayed sexual maturation of offspring. The decrease in litter size was secondary to reductions in corpora lutea and implantations. Maternal toxicity (decreased body weight, ovarian weight, and food consumption) was also noted. No effects on mating or fertility were observed in female rats receiving 4.2-times the MHRD. To monitor fetal outcomes of pregnant women exposed to pegvaliase, the manufacturer maintains a pregnancy registry surveillance program. If pegvaliase is administered during pregnancy, or if a patient becomes pregnant while receiving pegvaliase or within 1 month following the last dose, report exposure by calling 1-866-906-6100.[63190]

There are no data on the presence of pegvaliase in human milk, the effects on the breast-fed infant, or the effects on milk production. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. A pre-/post-natal study in rats showed that pegvaliase is present in rat milk and that pegvaliase administration during lactation decreases pup weight and survival. Systemic absorption of pegvaliase was not detected in the rat pups. Pegvaliase may cause low phenylalanine (Phe) concentrations in human milk; monitor blood phenylalanine concentrations in breast-feeding women treated with pegvaliase.[63190]