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.