Коротко
- «БайоМарин фармасьютикал» (BioMarin Pharmaceutical) добилась разрешения Управления по санитарному надзору за качеством пищевых продуктов и медикаментов США (FDA) на «Палинзик» (Palynziq, пегвалиаза), предназначенный взрослым пациентам с фенилкетонурией для снижения фенилаланина в крови, концентрация которого, будучи неконтролируемой при имеющихся вариантах терапии, превышает 600 мкмоль/л.
- Фенилкетонурия — редкое генетическое аутосомно-рецессивное метаболическое заболевание, проявляющееся в детском возрасте и оказывающее кумулятивный токсический эффект на головной мозг. Причиной патологии является мутация гена PAH, отвечающего за фенилаланингидроксилазу, катализирующую гидроксилирование ароматической боковой цепи фенилаланина с превращением в тирозин. Аминокислота фенилаланин, присутствующая во всех формах белков, не распадается и накапливается, что приводит к серьезным неврологическим и нейропсихиатрическим проблемам. Пациентам с фенилкетонурией приходится следовать жесткой диете, в том числе избегая потребления белков, недостаточность которых восполняется аминокислотными смесями без фенилаланина.
- Подкожно вводимая пегвалиаза (pegvaliase) — пегилированная рекомбинантная фенилаланин-аммиак-лиаза (PAL), превращающая L-фенилаланин в аммиак и транс-изомер коричной кислоты (транс-бета-фенилакриловую кислоту). Пегилирование необходимо в том числе для уменьшения иммуногенности. Фактически речь идет о первой ферментозаместительной терапии фенилкетонурии, когда недостаточность естественной фенилаланингидроксилазы (PAH) компенсируется аналогичным энзимом.
Подробности
«Палинзик» — второе лекарственное средство, выпущенное «БайоМарин» для ведения фенилкетонурии. Первый препарат, «Куван» (Kuvan, сапроптерин), одобренный в 2007 году, работает только на определенной популяции пациентов и должен использоваться на фоне строгой диеты, ограничивающей поступление фенилаланина в организм. В 2020 году «Пар фармасьютикал» (Par Pharmaceutical), принадлежащая «Эндо интернешнл» (Endo International), предложит первый дженерик «Кувана».
Регуляторное одобрение «Палинзика» отталкивалось от результатов опорных клинических испытаний PRISM-2 фазы III, засвидетельствовавших, что назначение пегвалиазы обеспечило существенную разницу с плацебо (p<0,0001) в отношении снижения концентрации фенилаланина в крови. Новинка работает эффективнее сапроптерина, причем без соблюдения ограничивающего режима питания.
Между тем «Палинзику» не удалось продемонстрировать улучшений когнитивной деятельности у пациентов.
Профиль безопасности пегвалиазы характеризуется проблемами. Во-первых, существует риск развития анафилактического шока, и потому первоначальная доза препарата должна вводиться под наблюдением специалиста. Во-вторых, 69% участников (n=196/285) столкнулись с аллергическими реакциями на пегвалиазу. Пациентам рекомендовано всегда иметь с собой автоинъектор норадреналина, например «ЭпиПен» (EpiPen, эпинефрин). Назначение «Палинзика» должно осуществляться в соответствии со сложной схемой дозирования, включающей фазы индукции, увеличения и поддержания дозы. Следует превентивно принимать антагонисты гистаминового H1– или H2-рецептора, а также жаропонижающие.
Цена «Палинзика» в преднаполненных шприцах заявлена в 192 тыс. долларов в год с учетом скидок против 150 тыс. долларов для «Кувана». Исходя из того, что из 11 тыс. взрослых больных фенилкетонурией в Соединенных Штатах только где-то 1,4 тыс. человек адекватно отвечают на терапию «Куваном», спрос на «Палинзик» прогнозируется приличным. Сама «БайоМарин» полагает, что пегвалиаза в конечном итоге станет бестселлером, перешагнув отметку в 1 млрд долларов ежегодных продаж. Согласно оценкам EvaluatePharma, реализация «Палинзика» выйдет к 370 млн долларов в 2024 году, тогда как интерес к «Кувану» упадет до 166 млн долларов. Последний, будучи пероральным, останется препаратом выбора пациентов педиатрического возраста.
В 2019 году намечен старт клинических испытаний генной терапии фенилкетонурии: есть надежда, что будет достаточно одной инъекции, чтобы покончить с заболеванием раз и навсегда.
Важная информация
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Люди, страдающие редким генетическим заболеванием фенилкетонурия (ФКУ), в том случае, когда стандартная терапия не помогает контролировать концентрацию фенилаланина в крови, теперь имеют возможность получить принципиально новую ферментотерапию: 24 мая 2018 г. в США был одобрен препарат Palynzig (pegyaliase-pqpz) для применения у взрослых. Пациенты с ФКУ рождаются с неспособностью расщеплять фенилаланин – аминокислоту, содержащуюся в продуктах, богатых белками, а также в подсластителях высокой интенсивности, которые широко применяются в пищевой промышленности.
По словам доктора Джулии Бейтц, директора управления по оценке лекарственных средств III Центра Экспертизы и изучения лекарств, FDA, USA, эта инновационная ферментозаместительная терапия должна быть очень востребована у тех пациентов, страдающих ФКУ, у которых не получается достичь ответа на существующие методы лечения.
Болезнь Феллинга в Соединенных Штатах поражает в среднем одного из 10 000-15 000 человек. Если ФКУ не лечить, это приводит к нарушениям нервно-психического характера, а также физической и умственной недееспособности. Пациенты должны всю жизнь придерживаться строгой диеты и избегать потребления продуктов, содержащие фенилаланин, так как его накопление в организме может приводить к долгосрочным последствиям с нарушением работы центральной нервной системы.
Безопасность и эффективность препарата Palynziq изучалась в ходе двух последовательных клинических испытаний с участием пациентов, страдающих ФКУ с содержанием фенилаланина в крови свыше 600 моль/л.
Большинство участников находились на нежесткой диете как до начала испытаний, так и во время их проведения. Первое исследование было рандомизированным и открытым, когда пациенты получали увеличенные дозы препарата Palynziq в виде подкожных инъекций до достижения необходимой дозировки 20 мг/день либо 40 мг/день. Второе исследование было рандомизированным, плацебо-контролируемым, с отменой препарата, и длилось 8 недель с участием тех же пациентов, принимавших ранее препарат Palynziq. Результаты испытаний показали статистически значимое снижение уровня фенилаланина в крови по сравнению с показателями его концентрации до начала испытаний.
Самые распространенные побочные явления, отмечавшиеся во время клинических испытаний, включали местные реакции, суставную боль, гиперчувствительность, головную боль, общие кожные реакции длительностью не менее 14 дней, зуд, тошноту, головокружение, боль в области живота, горла, усталость, рвоту, кашель, диарею.
Самое тяжелое побочное явление было зафиксировано в виде анафилаксии, которая наблюдалась наиболее часто при титровании повышаемой дозы в течение первого года приема препарата. По этой причине инструкция к применению препарата Palynziq содержит специальную предупреждающую информацию, а сам препарат доступен только в рамках медицинских программ.
Одобрение препарата Palynziq получила фармацевтическая компания BioMarin Pharmaceutical Inc.
Dosing & Uses
AdultPediatric
Dosage Forms & Strengths
injectable solution, single-dose prefilled syringe
- 2.5mg/0.5mL
- 10mg/0.5mL
- 20mg/mL
Phenylketonuria
Indicated to reduce blood phenylalanine concentrations in adults with phenylketonuria (PKU) who have uncontrolled blood phenylalanine concentrations >600 micromol/L on existing management
Induction
- Initial dose: 2.5 mg SC once weekly for 4 weeks
Titration
- Based on tolerability, titrate dose in a stepwise manner over at least 5 weeks, to achieve a dosage of 20 mg SC qDay
-
Weekly titration schedule
- Week 1: 2.5 mg twice weekly
- Week 2: 10 mg once weekly
- Week 3: 10 mg twice weekly
- Week 4: 10 mg 4x/week
- Week 5: 10 mg once daily
- Additional time may be needed for dose escalation depending on tolerability
Maintenance
- Therapeutic response may not be achieved until patient is titrated to an effective maintenance dosage
- Use lowest effective and tolerated dose
- Assess patient tolerability, blood phenylalanine concentrations, and dietary protein and phenylalanine intake throughout treatment
- Individualize maintenance dosage to achieve blood phenylalanine control (blood phenylalanine concentrations <600 micromol/L)
- Maintain at 20 mg SC qDay for at least 24 weeks; consider increasing to 40 mg/day in patients who have been maintained continuously on 20 mg qDay for at least 24 weeks without achieving blood phenylalanine control
- Consider increasing to maximum of 60 mg/day in those who have been on 40 mg/day for at least 16 weeks without achieving blood phenylalanine control
Discontinuation
- Discontinue in patients who have not achieved a response after 16 weeks of continuous treatment with maximum dosage 60 mg/day
Dosage Modifications
Dose reduction for low phenylalanine concentrations
- Blood phenylalanine concentrations <30 micromol/L: Reduce dose and/or modify dietary protein and phenylalanine intake to maintain blood phenylalanine concentrations within a clinically acceptable range and >30 micromol/L
Readministration following anaphylaxis
- If dose is readministered 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 for >60 minutes following the dose
- Based on patient tolerability and therapeutic response, subsequent dose titration
Dosing Considerations
Obtain baseline blood phenylalanine concentration before initiating therapy
After initiating treatment, obtain blood phenylalanine concentrations q4weeks until a maintenance dosage is established
After a maintenance dosage is established, periodic blood phenylalanine monitoring is recommended to assess blood phenylalanine control
Monitor dietary protein and phenylalanine intake throughout treatment and counsel patients on adjusting their dietary intake, as needed, based on blood phenylalanine concentrations
Safety and efficacy not been established
Interactions
Interaction Checker
Enter a drug name to check for any interactions. and pegvaliase
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Interactions Found
Contraindicated
Serious
Significant — Monitor Closely
Minor
All Interactions Sort By:
Contraindicated (0)
Serious (0)
Monitor Closely (17)
- certolizumab pegol
pegvaliase, certolizumab pegol. Other (see comment). Use Caution/Monitor.
Comment: The majority of patients treated with pegvaliase develop anti-polyethylene glycol (PEG) IgM and IgG antibodies. Risk of coadministration with different PEGylated products is unknown. There is a case report of anaphylaxis following a medroxyprogesterone acetate injectable suspension that contained PEG 3350. Carefully read all drug labels, including OTC drugs to check contents for PEG. Note: Unable to include an exhaustive product list for this interaction. - Factor IX, recombinant
pegvaliase, Factor IX, recombinant. Other (see comment). Use Caution/Monitor.
Comment: The majority of patients treated with pegvaliase develop anti-polyethylene glycol (PEG) IgM and IgG antibodies. Risk of coadministration with different PEGylated products is unknown. There is a case report of anaphylaxis following a medroxyprogesterone acetate injectable suspension that contained PEG 3350. Carefully read all drug labels, including OTC drugs to check contents for PEG. Note: Unable to include an exhaustive product list for this interaction. - griseofulvin
pegvaliase, griseofulvin. Other (see comment). Use Caution/Monitor.
Comment: The majority of patients treated with pegvaliase develop anti-polyethylene glycol (PEG) IgM and IgG antibodies. Risk of coadministration with different PEGylated products is unknown. There is a case report of anaphylaxis following a medroxyprogesterone acetate injectable suspension that contained PEG 3350. Carefully read all drug labels, including OTC drugs to check contents for PEG. Applies to ultramicrosized griseofulvin containing PEG 400 and 8000. Note: Unable to include an exhaustive product list for this interaction. - methoxy polyethylene glycol / epoetin beta
pegvaliase, methoxy polyethylene glycol / epoetin beta. Other (see comment). Use Caution/Monitor.
Comment: The majority of patients treated with pegvaliase develop anti-polyethylene glycol (PEG) IgM and IgG antibodies. Risk of coadministration with different PEGylated products is unknown. There is a case report of anaphylaxis following a medroxyprogesterone acetate injectable suspension that contained PEG 3350. Carefully read all drug labels, including OTC drugs to check contents for PEG. Note: Unable to include an exhaustive product list for this interaction. - pegademase
pegvaliase, pegademase. Other (see comment). Use Caution/Monitor.
Comment: The majority of patients treated with pegvaliase develop anti-polyethylene glycol (PEG) IgM and IgG antibodies. Risk of coadministration with different PEGylated products is unknown. There is a case report of anaphylaxis following a medroxyprogesterone acetate injectable suspension that contained PEG 3350. Carefully read all drug labels, including OTC drugs to check contents for PEG. Note: Unable to include an exhaustive product list for this interaction. - pegaptanib
pegvaliase, pegaptanib. Other (see comment). Use Caution/Monitor.
Comment: The majority of patients treated with pegvaliase develop anti-polyethylene glycol (PEG) IgM and IgG antibodies. Risk of coadministration with different PEGylated products is unknown. There is a case report of anaphylaxis following a medroxyprogesterone acetate injectable suspension that contained PEG 3350. Carefully read all drug labels, including OTC drugs to check contents for PEG. Note: Unable to include an exhaustive product list for this interaction. - pegaspargase
pegvaliase, pegaspargase. Other (see comment). Use Caution/Monitor.
Comment: The majority of patients treated with pegvaliase develop anti-polyethylene glycol (PEG) IgM and IgG antibodies. Risk of coadministration with different PEGylated products is unknown. There is a case report of anaphylaxis following a medroxyprogesterone acetate injectable suspension that contained PEG 3350. Carefully read all drug labels, including OTC drugs to check contents for PEG. Note: Unable to include an exhaustive product list for this interaction. - pegfilgrastim
pegvaliase, pegfilgrastim. Other (see comment). Use Caution/Monitor.
Comment: The majority of patients treated with pegvaliase develop anti-polyethylene glycol (PEG) IgM and IgG antibodies. Risk of coadministration with different PEGylated products is unknown. There is a case report of anaphylaxis following a medroxyprogesterone acetate injectable suspension that contained PEG 3350. Carefully read all drug labels, including OTC drugs to check contents for PEG. Note: Unable to include an exhaustive product list for this interaction. - peginterferon alfa 2a
pegvaliase, peginterferon alfa 2a. Other (see comment). Use Caution/Monitor.
Comment: The majority of patients treated with pegvaliase develop anti-polyethylene glycol (PEG) IgM and IgG antibodies. Risk of coadministration with different PEGylated products is unknown. There is a case report of anaphylaxis following a medroxyprogesterone acetate injectable suspension that contained PEG 3350. Carefully read all drug labels, including OTC drugs to check contents for PEG. Note: Unable to include an exhaustive product list for this interaction. - peginterferon alfa 2b
pegvaliase, peginterferon alfa 2b. Other (see comment). Use Caution/Monitor.
Comment: The majority of patients treated with pegvaliase develop anti-polyethylene glycol (PEG) IgM and IgG antibodies. Risk of coadministration with different PEGylated products is unknown. There is a case report of anaphylaxis following a medroxyprogesterone acetate injectable suspension that contained PEG 3350. Carefully read all drug labels, including OTC drugs to check contents for PEG. Note: Unable to include an exhaustive product list for this interaction. - peginterferon beta-1a
pegvaliase, peginterferon beta-1a. Other (see comment). Use Caution/Monitor.
Comment: The majority of patients treated with pegvaliase develop anti-polyethylene glycol (PEG) IgM and IgG antibodies. Risk of coadministration with different PEGylated products is unknown. There is a case report of anaphylaxis following a medroxyprogesterone acetate injectable suspension that contained PEG 3350. Carefully read all drug labels, including OTC drugs to check contents for PEG. Note: Unable to include an exhaustive product list for this interaction. - pegloticase
pegvaliase, pegloticase. Other (see comment). Use Caution/Monitor.
Comment: The majority of patients treated with pegvaliase develop anti-polyethylene glycol (PEG) IgM and IgG antibodies. Risk of coadministration with different PEGylated products is unknown. There is a case report of anaphylaxis following a medroxyprogesterone acetate injectable suspension that contained PEG 3350. Carefully read all drug labels, including OTC drugs to check contents for PEG. Note: Unable to include an exhaustive product list for this interaction. - pegvisomant
pegvaliase, pegvisomant. Other (see comment). Use Caution/Monitor.
Comment: The majority of patients treated with pegvaliase develop anti-polyethylene glycol (PEG) IgM and IgG antibodies. Risk of coadministration with different PEGylated products is unknown. There is a case report of anaphylaxis following a medroxyprogesterone acetate injectable suspension that contained PEG 3350. Carefully read all drug labels, including OTC drugs to check contents for PEG. Note: Unable to include an exhaustive product list for this interaction. - polyethylene glycol & electrolytes
pegvaliase, polyethylene glycol & electrolytes. Other (see comment). Use Caution/Monitor.
Comment: The majority of patients treated with pegvaliase develop anti-polyethylene glycol (PEG) IgM and IgG antibodies. Risk of coadministration with different PEGylated products is unknown. There is a case report of anaphylaxis following a medroxyprogesterone acetate injectable suspension that contained PEG 3350. Carefully read all drug labels, including OTC drugs to check contents for PEG. Note: Unable to include an exhaustive product list for this interaction. - polyethylene glycol 400/propylene glycol ophthalmic
pegvaliase, polyethylene glycol 400/propylene glycol ophthalmic. Other (see comment). Use Caution/Monitor.
Comment: The majority of patients treated with pegvaliase develop anti-polyethylene glycol (PEG) IgM and IgG antibodies. Risk of coadministration with different PEGylated products is unknown. There is a case report of anaphylaxis following a medroxyprogesterone acetate injectable suspension that contained PEG 3350. Carefully read all drug labels, including OTC drugs to check contents for PEG. Note: Unable to include an exhaustive product list for this interaction. - polyethylene glycol/electrolytes/sodium ascorbate/ascorbic acid
pegvaliase, polyethylene glycol/electrolytes/sodium ascorbate/ascorbic acid. Other (see comment). Use Caution/Monitor.
Comment: The majority of patients treated with pegvaliase develop anti-polyethylene glycol (PEG) IgM and IgG antibodies. Risk of coadministration with different PEGylated products is unknown. There is a case report of anaphylaxis following a medroxyprogesterone acetate injectable suspension that contained PEG 3350. Carefully read all drug labels, including OTC drugs to check contents for PEG. Note: Unable to include an exhaustive product list for this interaction. - sodium sulfate/potassium chloride/magnesium sulfate/polyethylene glycol
pegvaliase, sodium sulfate/potassium chloride/magnesium sulfate/polyethylene glycol. Other (see comment). Use Caution/Monitor.
Comment: The majority of patients treated with pegvaliase develop anti-polyethylene glycol (PEG) IgM and IgG antibodies. Risk of coadministration with different PEGylated products is unknown. There is a case report of anaphylaxis following a medroxyprogesterone acetate injectable suspension that contained PEG 3350. Carefully read all drug labels, including OTC drugs to check contents for PEG. Note: Unable to include an exhaustive product list for this interaction.
Minor (0)
Adverse Effects
>10% (Induction/titration)
Injection site reactions (88%)
Arthralgia (74%)
Complement factor C3 below LLN (68%)
C-reactive protein (CRP) above ULN (64%)
Complement factor C4 below LLN (62%)
Hypersensitivity reactions (53%)
Headache (35%)
Generalized skin reaction lasting at least 14 days (21%)
Pruritus (20%)
Hypophenylalaninemia on a single measurement (19%)
Blood creatine phosphokinase (CPK) above ULN (18%)
Nausea (18%)
Hypophenylalaninemia on 2 or more consecutive measurements (16%)
Dizziness (16%)
Abdominal pain (14%)
Oropharyngeal pain (13%)
Fatigue (13%)
Vomiting (13%)
Hs-CRP above 0.287 mg/dL over a 6-month period (12%)
>10% (Maintenance)
Complement factor C3 below LLN (84%)
Injection site reactions (72%)
CRP above ULN (68%)
Arthralgia (61%)
Hypersensitivity reactions (61%)
Hypophenylalaninemia on a single measurement (61%)
Headache (50%)
Complement factor C4 below LLN (48%)
CPK above ULN (43%)
Hypophenylalaninemia on 2 or more consecutive measurements (42%)
Generalized skin reaction lasting at least 14 days (37%)
Nausea (26%) Vomiting (26%) Abdominal pain (25%)
Pruritus (24%) Oropharyngeal pain (23%)
Cough (22%)
Diarrhea (22%)
Fatigue (22%)
Anxiety (18%)
Nasal congestion (18%)
Dizziness (17%)
Alopecia (17%)
1-10%
Induction/titration
- Cough (9%)
- Diarrhea (9%)
- Anxiety (5%)
- Alopecia (5%)
- Nasal congestion (4%)
Maintenance
- Hs-CRP above 0.287 mg/dL over a 6 month period (10%)
Warnings
Black Box Warnings
Anaphylaxis
- Anaphylaxis reported after administration and may occur at any time during treatment
- Administer the initial dose after an anaphylaxis episode under the supervision of a healthcare provider equipped to manage anaphylaxis, and closely observe >60 minutes following injection
- Prior to self-injection, confirm patient competency with self-administration, and patient’s and observer’s (if applicable) ability to recognize signs and symptoms of anaphylaxis and administer autoinjectable epinephrine, if needed
- Prescribe autoinjectable epinephrine, and instruct patient and observer (if applicable) on how to recognize the signs and symptoms of anaphylaxis, how to properly administer autoinjectable epinephrine, and to seek immediate medical care upon its use
- Consider a caregiver for patients who may need assistance in recognizing and managing anaphylaxis
- If an caregiver is needed, present caregiver during and for >60 minutes after each administration should be able to administer autoinjectable epinephrine, and to call for emergency medical support upon its use
- Consider the risks and benefits of readministering pegvaliase-pqpz following an episode of anaphylaxis
- If treatment is readministered, administer the first dose under the supervision of a healthcare provider equipped to manage anaphylaxis and closely observe >60 minutes following the dose
- Because of the risk of anaphylaxis, treatment is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called Palynziq REMS
Contraindications
None
Cautions
In clinical trials with induction/titration/maintenance dosing, 26 (9%) of 285 patients experienced a total of 37 anaphylaxis episodes (see Black Box Warnings)
Management of hypersensitivity reactions should be based on severity of reaction, recurrence of reaction, and clinical judgment of healthcare provider, and may include dosage adjustment, temporary drug interruption, or treatment with antihistamines, antipyretics, and/or corticosteroids
REMS program
- Treatment is available only through a restricted program under Palynziq REMS, because of the risk of anaphylaxis
- Hypersensitivity reactions, other than anaphylaxis, reported
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Requirements of the REMS program
- Prescribers must be certified with the program by enrolling in the program and completing training
- Prescribers must prescribe autoinjectable epinephrine
- Pharmacies must be certified with the program and must dispense only to patients who are authorized to receive treatment
- 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
- Patients must have autoinjectable epinephrine available at all times
- 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)
Drug interactions overview
- The majority of patients treated with pegvaliase develop anti-polyethylene glycol (PEG) IgM and IgG antibodies
- Risk of coadministration with different PEGylated products is unknown; however, there is a case report of anaphylaxis following a medroxyprogesterone acetate injectable suspension that contained PEG 3350
- Carefully read all drug labels, including OTC drugs to check contents for PEG
Pregnancy & Lactation
Pregnancy
Based on findings in studies of pregnant animals without phenylketonuria (PKU), pegvaliase-pqpz 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
Risks to the fetus associated with poorly controlled phenylalanine concentrations in women with PKU during pregnancy include increased risk for miscarriage, major birth defects (eg, microcephaly, major cardiac malformations), intrauterine fetal growth restriction, and future intellectual disability with low IQ; therefore, closely phenylalanine concentrations in women with PKU during pregnancy
Advise pregnant women of the potential risks to the fetus
Animal data
- 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 7.5 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; effects in rats occurred at 4.2 times the maximum recommended daily dose
- In a prenatal/postnatal 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 19.4 times the maximum recommended daily dose; effects on rat embryo-fetal and postnatal development were associated with maternal toxicity
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 120-360 micromol/L during pregnancy and during the 3 months before conception
Dose adjustments during pregnancy and the postpartum period
- Phenylalanine concentrations <30 micromol/L in pregnant women with PKU may be associated with adverse fetal outcomes; monitor blood phenylalanine concentrations during pregnancy and adjust dose or modify dietary protein and phenylalanine intake to avoid blood phenylalanine concentrations below 30 micromol/L (see Dosage Modifications)
Lactation
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 prenatal/postnatal 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
Pregnancy Categories
A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.
C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.
D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.
X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.
NA: Information not available.
Pharmacology
Mechanism of Action
Pegylated phenylalanine ammonia lyase (PAL), which is an enzyme that catalyzes phenylalanine (Phe) to ammonia and trans-cinnamic acid
PKU is an inborn error of amino acid metabolism, which is caused by a deficiency of the enzyme phenylalanine hydroxylase (PAH) that leads to accumulation of phenylalanine in body fluids
Absorption
Median peak plasma time: ~8 hr
Peak plasma concentration, steady state: 14 mg/L (20 mg/day); 16.7 mg/L (40 mg/day)
Distribution
Vd: 26.4 L (20 mg/day); 22.2 L (40 mg/day)
Metabolism
Metabolism of phenylalanine ammonia lyase is expected to occur via catabolic pathways and be degraded into small peptides and amino acids
Excretion
Half-life: 47 hr (20 mg/day); 60 hr (40 mg/day)
Clearance: 0.39 L/hr (20 mg/day); 1.25 L/hr (40 mg/day)
Route of elimination of pegvaliase-pqpz not studied in humans
Administration
SC Administration
Subcutaneous administration only
Single use only
Visually inspect for particulate matter and discoloration prior to administration; solution appears clear to slightly opalescent, colorless to pale yellow
Discard if discolored, cloudy, or if particulate matter is present
Recommended injection sites: Front middle of thighs and the abdomen >2 inches (5 cm) away from the navel
If a caregiver is administering the injection, the top of buttocks and the back of the upper arms are also appropriate injection sites
Do not inject 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 injection sites; if >1 injection is needed for a single dose, injection sites should be >2 inches away from each other; second injection site can be on the same part of the body or a different part of the body
Premedication
- Consider premedication with an H1-receptor antagonist, H2-receptor antagonist, and/or antipyretic prior to administration based upon tolerability
Missed dose
- If a dose is missed, instruct patients to take their next dose as scheduled and to not take 2 doses to make up for the missed dose
Storage
Syringes
- Refrigerate at 28°C (36-46°F) in its original carton to protect from light; do not freeze or shake
- If needed, store at room temperature between 20-25°C (68-77°F) for <30 days; record date removed from refrigeration on the carton
- Once stored at room temperature, do not return the product to the refrigerator
- Shelf-life expires after storage at room temperature for 30 days, or after the expiration date on the product carton, whichever is earlier
Images
| BRAND | FORM. | UNIT PRICE | PILL IMAGE |
|---|---|---|---|
| Palynziq subcutaneous
— |
2.5 mg/0.5 mL solution |
Copyright © 2010 First DataBank, Inc.
Patient Handout
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Formulary
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- Application under evaluation
- CHMP opinion
- European Commission decision
Overview
Palynziq is a medicine that is used to treat phenylketonuria (PKU) in adults and adolescents from 16 years of age.
Patients with this genetic disease cannot process the amino acid phenylalanine from dietary protein, and as a result the amino acid builds up in the blood to abnormally high levels, causing problems in the nervous system. Palynziq is used in patients whose blood levels of phenylalanine have not been adequately controlled with other treatments.
Palynziq was designated an ‘orphan medicine’ (a medicine used in rare diseases) on 28 January 2010.
Further information on the orphan designation can be found EU/3/09/708.
Palynziq contains the active substance pegvaliase.
The medicine can only be obtained with a prescription and treatment should be started and supervised by a doctor who has experience in treating PKU. Phenylalanine blood levels must be measured before starting treatment. During treatment, monthly measurements are recommended. Palynziq is intended for long-term use.
Palynziq is available as pre-filled syringes (2.5, 10 and 20 mg) for injection under the skin. The recommended starting dose is 2.5 mg once a week for 4 weeks. The dose and frequency of injection are then increased gradually (up to a maximum dose of 60 mg once a day) to achieve adequate control of phenylalanine blood levels. Palynziq must be used with stringent measures to manage any serious allergic reactions, especially in the first few months.
For more information about using Palynziq, see the package leaflet or contact your doctor or pharmacist.
The active substance in Palynziq, pegvaliase, is a bacterial enzyme that can break down phenylalanine, thereby stopping phenylalanine from building up in the body and helping to relieve the symptoms of phenylketonuria. The enzyme in pegvaliase is ‘pegylated’ (attached to a chemical called PEG), allowing it to remain in the body and to act for longer.
The main study investigating Palynziq in patients with PKU consisted of different parts. Throughout the study, patients were required to maintain a constant level of dietary protein intake, to ensure that changes in blood phenylalanine levels could be attributed to treatment rather than to changes in protein intake.
During the first part, all patients were given Palynziq at a dose of 20 or 40 mg for up to 13 weeks. Eighty-six patients who responded to treatment (i.e. whose blood phenylalanine levels were reduced by at least 20%) where then either kept on the same dose of Palynziq or were given placebo (a dummy treatment). After 8 weeks of treatment, blood phenylalanine levels remained under control in patients taking Palynziq but they returned to pre-treatment levels in patients on placebo, showing that Palynziq was more effective than placebo in reducing blood phenylalanine levels and keeping them within an acceptable range.
In the extension phase of the study patients received an individual optimized dose of Palynziq. It was shown that for the majority of patients continued treatment with Palynziq for 18 months was effective at keeping blood phenylalanine levels under control (below 600 micromoles per litre).
The most common side effects with Palynziq (which may affect more than 7 in 10 people) are reactions at the injection site, pain in the joints and allergic reactions. The most significant allergic reactions include acute systemic allergic reaction, angioedema (swelling under the skin in areas such as the face, throat, arms and legs), and serum sickness (allergic reaction caused by animal proteins or serum). For the full list of side effects of Palynziq, see the package leaflet.
Palynziq must not be used in patients who have had an allergic reaction to pegvaliase, to any of the other components of Palynziq or to any other pegylated medicine.
Palynziq was shown to be effective at reducing levels of blood phenylalanine and keeping them under control. The safety of Palynziq is considered acceptable, and important side effects such as allergic reactions are considered manageable with additional stringent measures (see below). The European Medicines Agency therefore decided that Palynziq’s benefits are greater than its risks and it can be authorised for use in the EU.
The company that markets Palynziq will provide information material for doctors and for patients and carers about the risk of allergic reactions with Palynziq, including how to identify them promptly and what to do in case such a reaction occurs.
Recommendations and precautions to be followed by healthcare professionals and patients for the safe and effective use of Palynziq have also been included in the summary of product characteristics and the package leaflet.
As for all medicines, data on the use of Palynziq are continuously monitored. Side effects reported with Palynziq are carefully evaluated and any necessary action taken to protect patients.
Palynziq received a marketing authorisation valid throughout the EU on 3 May 2019.
Product information
Latest procedure affecting product information:
R/0038
19/04/2024
This medicine’s product information is available in all official EU languages.
Select ‘available languages’ to access the language you need.
Product information documents contain:
- summary of product characteristics (annex I);
- manufacturing authorisation holder responsible for batch release (annex IIA);
- conditions of the marketing authorisation (annex IIB);
- labelling (annex IIIA);
- package leaflet (annex IIIB).
Product details
-
Name of medicine
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Palynziq
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Active substance
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Pegvaliase
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International non-proprietary name (INN) or common name
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pegvaliase
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Therapeutic area (MeSH)
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Phenylketonurias
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Anatomical therapeutic chemical (ATC) code
-
A16AB19
Pharmacotherapeutic group
Other alimentary tract and metabolism products
Therapeutic indication
Palynziq is indicated for the treatment of patients with phenylketonuria (PKU) aged 16 years and older who have inadequate blood phenylalanine control (blood phenylalanine levels greater than 600 micromol/l) despite prior management with available treatment options.
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EMA product number
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EMEA/H/C/004744
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This medicine was designated an orphan medicine. This means that it was developed for use against a rare, life-threatening or chronically debilitating condition or, for economic reasons, it would be unlikely to have been developed without incentives. For more information, see Orphan designation.
-
Marketing authorisation holder
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BioMarin International Limited
Shanbally
Ringaskiddy
County Cork
P43 R298
Ireland -
Opinion adopted
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28/02/2019
-
Marketing authorisation issued
-
03/05/2019
-
Revision
-
8
Assessment history
Topics
This page was last updated on
BOXED WARNING: RISK OF ANAPHYLAXIS
- Anaphylaxis has been reported after administration of PALYNZIQ and may occur at any time during treatment
- Administer the initial dose of PALYNZIQ under the supervision of a healthcare provider equipped to manage anaphylaxis, and closely observe patients for at least 60 minutes following injection. Prior to self-injection, confirm patient competency with self-administration, and patient’s and observer’s (if applicable) ability to recognize signs and symptoms of anaphylaxis and to administer auto-injectable epinephrine, if needed
- 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 call for emergency medical support upon its use
- Prescribe auto-injectable epinephrine. Prior to the first dose, instruct the patient and observer (if applicable) on its appropriate use. Instruct the patient to seek immediate medical care upon its use. Instruct patients to carry auto-injectable epinephrine with them at all times during PALYNZIQ treatment
- PALYNZIQ is available only through a restricted program called PALYNZIQ REMS (Risk Evaluation and Mitigation Strategy). Further information, including a list of qualified pharmacies, is available at www.PALYNZIQREMS.com or by telephone at 1-855-758-REMS (1-855-758-7367)
WARNINGS AND PRECAUTIONS
Anaphylaxis
- Signs and symptoms of anaphylaxis reported include 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)
- Anaphylaxis generally occurred within 1 hour after injection; however, delayed episodes occurred up to 48 hours after PALYNZIQ 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 PALYNZIQ administration, should be able to administer auto-injectable epinephrine, and 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
- Consider premedication with an H1-receptor antagonist, H2-receptor antagonist, and/or antipyretic prior to PALYNZIQ administration based upon individual patient tolerability
Other Hypersensitivity Reactions
- Hypersensitivity reactions other than anaphylaxis have been reported in 204 of 285 (72%) patients treated with PALYNZIQ in clinical trials
- Management of hypersensitivity reactions should be based on the severity of the reaction, recurrence of the reaction, and the clinical judgment of the healthcare provider, and may include dosage adjustment, temporary drug interruption, or treatment with antihistamines, antipyretics, and/or corticosteroids
ADVERSE REACTIONS
- The most common adverse reactions (at least 20% of patients in either treatment phase) were injection site reactions, arthralgia, hypersensitivity reactions, headache, generalized skin reactions lasting at least 14 days, nausea, abdominal pain, vomiting, cough, oropharyngeal pain, pruritus, diarrhea, nasal congestion, fatigue, dizziness, and anxiety
- Of the 285 patients exposed to PALYNZIQ in an induction/titration/maintenance regimen in clinical trials, 44 (15%) patients discontinued treatment due to adverse reactions. The most common adverse reactions leading to treatment discontinuation were hypersensitivity reactions (6% of patients) including anaphylaxis (3% of patients), angioedema (1% of patients), arthralgia (4% of patients), generalized skin reactions lasting at least 14 days (2% of patients), and injection site reactions (1% of patients)
- The most common adverse reactions leading to dosage reduction were arthralgia (15% of patients), hypersensitivity reactions (9% of patients), injection site reactions (4% of patients), alopecia (3% of patients), and generalized skin reactions lasting at least 14 days (2% of patients)
- The most common adverse reactions leading to temporary drug interruption were hypersensitivity reactions (14% of patients), arthralgia (13% of patients), anaphylaxis (4% of patients), and injection site reactions (4% of patients)
- Angioedema and serum sickness: 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 face edema) occurring independent of anaphylaxis. In clinical trials, serum sickness was reported in 7 out of 285 (2%) patients
Blood Phenylalanine Monitoring and Diet
- 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
DRUG INTERACTIONS
Effect of PALYNZIQ on Other PEGylated Products
- 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 anaphylaxis
- The clinical effects of concomitant treatment with different PEGylated products are unknown. Monitor patients treated with PALYNZIQ and concomitantly with other PEGylated products for hypersensitivity reactions including anaphylaxis
USE IN SPECIFIC POPULATIONS
Pregnancy and Lactation
- PALYNZIQ may cause fetal harm when administered to a pregnant woman
- Advise women who are exposed to PALYNZIQ during pregnancy or who become pregnant within one month following the last dose of PALYNZIQ that there is a pregnancy surveillance program that monitors pregnancy outcomes. Healthcare providers should report PALYNZIQ exposure and encourage these patients to report their pregnancy to BioMarin (1-866-906-6100)
- Monitor blood Phe levels in breastfeeding women treated with PALYNZIQ
Pediatric Use
- The safety and effectiveness of PALYNZIQ in pediatric patients have not been established
Geriatric Use
- Clinical studies of PALYNZIQ did not include patients aged 65 years and older
You are encouraged to report suspected adverse reactions to BioMarin at 1-866-906-6100, or to the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
Please see full Prescribing Information, with Boxed Warning for risk of anaphylaxis, and Medication Guide here.
INDICATION
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.