Palynziq

ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 

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▼This medicinal product is subject to additional monitoring. This will allow quick identification of 
new safety information. Healthcare professionals are asked to report any suspected adverse reactions. 
See section 4.8 for how to report adverse reactions. 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Palynziq 2.5 mg solution for injection in pre-filled syringe 
Palynziq 10 mg solution for injection in pre-filled syringe 
Palynziq 20 mg solution for injection in pre-filled syringe 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each 2.5 mg pre-filled syringe contains 2.5 mg pegvaliase in 0.5 ml solution. 
Each 10 mg pre-filled syringe contains 10 mg pegvaliase in 0.5 ml solution. 
Each 20 mg pre-filled syringe contains 20 mg pegvaliase in 1 ml solution. 
 
The strength indicates the quantity of the phenylalanine ammonia lyase (rAvPAL) moiety of 
pegvaliase without consideration of the PEGylation. 
 
The active substance is a covalent conjugate of the protein phenylalanine ammonia lyase (rAvPAL)* 
with NHS-methoxypolyethylene glycol (NHS-PEG). 
 
* Anabaena variabilis rAvPAL produced by recombinant DNA technology in Escherichia coli. 
 
The potency of this medicinal product should not be compared to any other PEGylated or 
non-PEGylated protein of the same therapeutic class. For more information, see section 5.1. 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Solution for injection (injection). 
 
Colourless to pale yellow, clear to slightly opalescent solution with pH 6.6 – 7.4. 
 
2.5 mg pre-filled syringe: 
Osmolality: 260 – 290 mOsm/kg 
 
10 mg and 20 mg pre-filled syringe: 
Osmolality: 285 – 315 mOsm/kg, viscous solution 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
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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4.2 Posology and method of administration 
 
Treatment with Palynziq should be directed by physicians experienced in the management of PKU. 
 
Posology 
 
Before initiating treatment, blood phenylalanine level must be obtained. Monitoring of blood 
phenylalanine level is recommended once a month. 
 
Dietary phenylalanine intake should remain consistent until a maintenance dose is established. 
 
Dosing regimens 
 
Induction 
The recommended starting dose of Palynziq is 2.5 mg administered once per week for 4 weeks. 
 
Titration 
The dose should be escalated gradually based on tolerability to the daily maintenance dose required to 
achieve blood phenylalanine level of 120 to 600 micromol/l according to Table 1.  
 
Maintenance 
The maintenance dose is individualised to achieve patient’s blood phenylalanine control (i.e., a 
phenylalanine level between 120 to 600 micromol/l) taking into account patient tolerability to 
Palynziq and dietary protein intake (see Table 1). 
 

Table 1: Recommended dosing regimen 
 

 Dose1 administered subcutaneously 
 

Duration prior to next dose increase  

Induction 2.5 mg once weekly  4 weeks2 
2.5 mg twice weekly 1 week2 
10 mg once weekly 1 week2 
10 mg twice weekly 1 week2 
10 mg four times a week 1 week2 

Titration 

10 mg daily 1 week2 
20 mg daily 12 weeks to 24 weeks2  
40 mg daily 
(2 consecutive injections of 20 mg 
pre-filled syringe)4 

16 weeks2  
Maintenance3 

60 mg daily  
(3 consecutive injections of 20 mg 
pre-filled syringe)4 

Maximum recommended dose 

1 If blood phenylalanine levels are below 30 micromol/l, dietary protein intake should be increased 
to appropriate levels, and then, if needed, the dose of Palynziq should be reduced (see section 4.4, 
Hypophenylalaninaemia). 

2 Additional time may be required prior to each dose escalation based on patient tolerability with 
Palynziq. 

3 The maintenance dose is individualised to achieve blood phenylalanine levels between 120 to 
600 micromol/l. 

4 If multiple injections are needed for a single dose, injections should be administered at the same 
time of day and injection sites should be at least 5 cm away from each other. Doses should not be 
divided over the course of the day (see Method of administration). 

 
Dose adjustments 
During titration and maintenance of Palynziq treatment, patients may develop blood phenylalanine 
levels below 30 micromol/l. To manage hypophenylalaninaemia, dietary protein intake should be 
increased to appropriate levels, and then, if needed, the dose of Palynziq should be reduced. In patients 

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experiencing hypophenylalaninaemia despite appropriate levels of protein intake, dose reductions are 
expected to be most effective in managing hypophenylalaninaemia (see section 5.2, Exposure-effect). 
Patients should be monitored every 2 weeks until blood phenylalanine levels are within a clinically 
acceptable range (see section 4.4, Hypophenylalaninaemia).  
 
If hypophenylalaninaemia develops prior to reaching daily dosing, the dose may be reduced to the 
previous titration dose. If hypophenylalaninaemia develops once daily dosing is reached, the dose may 
be reduced by at least 10 mg decrements to achieve and maintain blood phenylalanine levels in the 
clinically acceptable range. In patients experiencing hypophenylalaninaemia on 10 mg/day, the dose 
may be reduced to 5 mg/day.  
 
Special populations 
 
Paediatric population 
The safety and efficacy of Palynziq in paediatric patients from birth to less than 16 years have not 
been established. No data are available.  
 
Currently available data on patients aged 16 up to 18 years are described in section 4.8 and 5.1. 
Posology is the same in these patients as in adults.  
 
Method of administration 
 
Subcutaneous use. Each pre-filled syringe is for single use only.  
 
Due to the potential for an acute systemic hypersensitivity reaction, premedication prior to each dose 
is required during induction and titration (time prior to reaching blood phenylalanine levels less than 
600 micromol/l while on a stable dose; see section 4.8). Patients should be instructed to pre-medicate 
with an H1-receptor antagonist, H2-receptor antagonist, and antipyretic. During maintenance, 
premedication may be reconsidered for subsequent injections based on patient tolerability to Palynziq. 
 
Initial administration(s) should be performed under supervision of a healthcare professional and 
patients should be closely observed for at least 60 minutes following each of these initial injection(s) 
(see sections 4.4 and 4.8). 
 
Prior to first dose of Palynziq, the patient should be trained on the signs and symptoms of an acute 
systemic hypersensitivity reaction and to seek immediate medical care if a reaction occurs, and how to 
properly administer adrenaline injection device (auto-injector or pre-filled syringe/pen). 
 
Patients should be instructed to carry adrenaline injection device with them at all times during 
Palynziq treatment.  
 
For at least the first 6 months of treatment when the patient is self-injecting (i.e. when administration 
is not under healthcare professional supervision), an observer must be present during and for at least 
60 minutes after each administration. An observer is someone who:  
 would be present with the patient during and after Palynziq administration,  
 is able to recognise the signs and symptoms of an acute systemic hypersensitivity reaction,  
 can call for emergency medical support and administer adrenaline, if warranted.  
 
After 6 months of Palynziq treatment, the need for an observer may be reconsidered. 
 
Prior to independent self-injection, a healthcare professional should: 
 train the patient and assess patient competency on proper self-administration of this medicinal 

product.  
 train the observer to recognise signs and symptoms of an acute systemic hypersensitivity 

reaction and to seek immediate medical care if a reaction occurs, and how to properly 
administer adrenaline injection device (auto-injector or pre-filled syringe/pen). 

 

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Readministration following mild to moderate acute systemic hypersensitivity reactions: The 
prescribing physician should consider the risks and benefits of readministering the medicinal product 
following resolution of the first mild to moderate acute systemic hypersensitivity reaction (see 
sections 4.3 and 4.4). Readministration for the first dose must be done under supervision of a 
healthcare professional with the ability to manage acute systemic hypersensitivity reactions.  
 
The recommended injection sites on the body are: the front middle of the thighs and the lower part of 
the abdomen except for 5 cm directly around the navel. If a caregiver is giving the injection, the top of 
the buttocks and the back of the upper arms are also appropriate injection sites. 
 
Palynziq should not be injected into moles, scars, birthmarks, bruises, rashes, or areas where the skin 
is hard, tender, red, damaged, burned, inflamed, or tattooed. The injection site should be checked for 
redness, swelling, or tenderness. 
 
Patients or caregiver should be advised to rotate sites for subcutaneous injections. If more than one 
injection is needed for a single dose, each injection site should be at least 5 cm away from another 
injection site.  
 
Palynziq is a clear to slightly opalescent, colourless to pale yellow solution. The solution should not be 
used if discoloured or cloudy or if visible particles are present. 
 
4.3 Contraindications 
 
Severe systemic hypersensitivity reaction or recurrence of a mild to moderate acute systemic 
hypersensitivity reaction to pegvaliase, any of the excipients listed in section 6.1, or another 
PEGylated medicinal product (see section 4.4). 
 
4.4 Special warnings and precautions for use 
 
Hypersensitivity reactions 
 
Hypersensitivity reactions, including acute systemic hypersensitivity reactions, angioedema, and 
serum sickness, have been reported in patients treated with Palynziq and can occur at any time during 
treatment. Palynziq may also increase hypersensitivity to other PEGylated injectable medicinal 
products (see Effect of Palynziq on other PEGylated injectable medicinal products).  
 
In clinical trials, 16 out of 285 (6%) patients experienced 25 acute systemic hypersensitivity reactions 
of any severity. Acute systemic hypersensitivity reactions were managed by administration of 
adrenaline (44%; 11/25 episodes), corticosteroids (56%; 14/25 episodes), antihistamines (56%; 
14/25 episodes), and/or oxygen (8%; 2/25 episodes). Four out of 16 (1%; 4/285) patients experienced 
a total of 5 episodes of acute systemic hypersensitivity reactions that were considered severe (see 
sections 4.3 and 4.8). The underlying mechanism for acute systemic hypersensitivity reactions 
observed in clinical trials was non-IgE mediated Type III (immune-complex mediated) 
hypersensitivity (see section 4.8). 
 
In clinical trials, serum sickness was reported in 7 out of 285 (2%) patients. Three out of 7 (1%) 
patients had severe serum sickness (see section 4.8).  
 
Management of hypersensitivity reactions should be based on the severity of the reaction; in clinical 
trials, this has included dose adjustment, treatment interruption, additional antihistamines, antipyretics, 
and/or corticosteroids.  
 
Acute systemic hypersensitivity reactions require treatment with adrenaline and immediate medical 
care. An adrenaline injection device (auto-injector or pre-filled syringe/pen) should be prescribed to 
patients receiving this medicinal product. Patients should be instructed to carry adrenaline injection 
device with them at all times during Palynziq treatment. Patients and the observer should be instructed 
to recognise the signs and symptoms of acute systemic hypersensitivity reactions, in the proper 

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emergency use of the adrenaline injection device, and the requirement to seek immediate medical care. 
The risks associated with adrenaline use should be considered when prescribing Palynziq. Refer to the 
adrenaline product information for complete information.  
 
Due to the potential for an acute systemic hypersensitivity reaction, premedication prior to each dose 
is required during induction and titration (see section 4.2, Method of administration). Patients should 
be instructed to pre-medicate with an H1-receptor antagonist, H2-receptor antagonist, and antipyretic. 
During maintenance, premedication may be considered for subsequent injections based on patient 
tolerability to Palynziq. For at least the first 6 months of treatment when the patient is self-injecting 
(i.e. when administration is not under healthcare professional supervision), an observer must be 
present during and for at least 60 minutes after each administration (see section 4.2, Method of 
administration).  
 
For severe systemic hypersensitivity reactions or recurrence of a mild to moderate acute systemic 
hypersensitivity reaction, patients should seek immediate medical care and Palynziq should be 
permanently discontinued (see section 4.3). The prescribing physician should consider the risks and 
benefits of readministering the medicinal product following resolution of the first mild to moderate 
acute systemic hypersensitivity reaction. Upon readministration, the first dose must be administered 
with premedication under the supervision of a healthcare professional with the ability to manage acute 
systemic hypersensitivity reactions. Prescribing physician should continue or consider resuming use of 
premedication. 
 
Dose titration and time to achieve response 
 
Time to response (achieving blood phenylalanine levels ≤ 600 micromol/l) varies among patients. The 
time to reach a response ranged from 0.5 to 30 months. The majority of patients (66%) reached a 
response by 18 months of total treatment. An additional 7% of patients responded to Palynziq after 
18 months of treatment. If a patient does not reach a clinically relevant blood phenylalanine reduction 
after 18 months of treatment, continuation should be reconsidered. The physician may decide, with the 
patient, to continue Palynziq treatment in those patients who show other beneficial effects (e.g. ability 
to increase protein intake from intact food or improvement of neurocognitive symptoms). 
 
Effect of Palynziq on other PEGylated injectable medicinal products 
 
PEGylated proteins have the potential to elicit an immune response. Because antibodies bind to the 
PEG portion of pegvaliase, there may be potential for binding with other PEGylated therapeutics and 
increased hypersensitivity to other PEGylated injectables. In a single dose study of Palynziq in adult 
patients with PKU, two patients receiving concomitant injections of medroxyprogesterone acetate 
suspension containing PEG experienced hypersensitivity reactions. One of the two patients 
experienced a hypersensitivity reaction on day 15 after a single Palynziq dose within 15 minutes 
following medroxyprogesterone acetate, and subsequently experienced an acute systemic 
hypersensitivity reaction on day 89 within 30 minutes after the next dose of medroxyprogesterone 
acetate injectable suspension. The second patient experienced a hypersensitivity reaction on day 40 
after a single Palynziq dose within 10 minutes following medroxyprogesterone acetate injectable 
suspension. In Palynziq clinical trials, the majority of patients developed anti-PEG IgM and IgG 
antibodies after treatment with Palynziq (see section 4.8). The impact of anti-PEG antibodies on the 
clinical effects of other PEG-containing medicinal products is unknown. 
 
Hypophenylalaninaemia  
 
In clinical trials, 125 out of 285 (44%) patients developed a total of 237 episodes of 
hypophenylalaninaemia (blood phenylalanine levels below 30 micromol/l on two consecutive 
measurements). Hypophenylalaninaemia occurred during titration and maintenance phase, as early as 
51 days and up 1405 days into Palynziq treatment (median: 393 days from Palynziq treatment 
initiation). The median duration was 161 days (range: 35, 1408). Patients who developed 
hypophenylalaninaemia during the studies were advised to increase their protein intake from intact 
foods and/or reduce Palynziq dose. 

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Monitoring of blood phenylalanine level is recommended once a month. If a patient has a confirmed 
phenylalanine level below 30 micromol/l, dietary protein intake should be increased to appropriate 
levels, and then, if needed, the dose of Palynziq should be reduced (see section 4.2). In patients 
experiencing hypophenylalaninaemia despite appropriate levels of protein intake, dose reductions are 
expected to be most effective in managing hypophenylalaninaemia. Patients who develop 
hypophenylalaninaemia should be monitored every 2 weeks until blood phenylalanine level is within a 
clinically acceptable range. The long-term clinical consequences of chronic hypophenylalaninaemia 
are unknown.  
 
Based on animal studies, hypophenylalaninaemia in pregnant women with PKU treated with Palynziq 
may be associated with adverse foetal outcomes (see sections 4.6 and 5.3). Blood phenylalanine levels 
should be monitored more frequently prior to and during pregnancy.  
 
Sodium 
 
This medicine contains less than 1 mmol sodium (23 mg) per pre-filled syringe, that is to say 
essentially ‘sodium-free’. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
No interaction studies have been performed. 
 
4.6 Fertility, pregnancy and lactation 
 
Pregnancy 
 
There are no or limited amount of data from the use of Palynziq in pregnant women. Animal studies 
have shown maternal reproductive toxicity that was associated with decreased blood phenylalanine 
concentrations below normal levels (see section 5.3). 
 
Uncontrolled blood phenylalanine levels (hyperphenylalaninaemia) before and during pregnancy are 
associated with increased risk for miscarriage, major birth defects (including microcephaly and major 
cardiac malformations), intrauterine foetal growth retardation and future intellectual disability with 
low IQ. In case of hypophenylalaninaemia during pregnancy, there is a risk of intrauterine foetal 
growth retardation. Additional risk to the unborn child due to hypophenylalaninaemia is not 
established. 
 
Maternal blood phenylalanine levels must be strictly controlled between 120 and 360 micromol/l both 
before and during pregnancy. Palynziq is not recommended during pregnancy, unless the clinical 
condition of the woman requires treatment with pegvaliase and alternative strategies to control 
phenylalanine levels have been exhausted.  
 
Breast-feeding 
 
It is unknown whether pegvaliase is excreted in human milk. Available toxicological data in animals 
have shown excretion of pegvaliase in milk. In the pups of these animals, systemic exposure of 
pegvaliase was not detected. A risk to infants cannot be excluded. Due to lack of human data, Palynziq 
should only be administered to breast-feeding women if the potential benefit is considered to outweigh 
the potential risk to the infant. 
 
Fertility 
 
No human data are available. Reduced implantations were observed in normal female rats after 
administration of Palynziq (see section 5.3). 
 

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4.7 Effects on ability to drive and use machines 
 
Palynziq has a minor influence on the ability to drive and use machines. Hypersensitivity reactions 
that include symptoms such as dizziness or syncope may affect the ability to drive and use machines.  
 
4.8 Undesirable effects 
 
Summary of the safety profile 
 
In clinical trials, the majority of patients experienced injection site reactions (93%), arthralgia (85%), 
and hypersensitivity reactions (75%). The most clinically significant hypersensitivity reactions include 
acute systemic hypersensitivity reaction (6%), angioedema (7%), and serum sickness (2%) 
(see sections 4.3 and 4.4).  
 
In clinical trials, adverse reaction rates were highest in induction and titration phases (time prior to 
reaching blood phenylalanine levels less than 600 micromol/l while on a stable dose) coinciding with 
the period when titres of IgM and anti-PEG antibodies were highest. Rates decreased over time as the 
immune response matured (see Description of selected adverse reactions section).  
 
Tabulated list of adverse reactions 
 
Table 2 provides adverse reactions in patients treated with Palynziq. 
 
Frequencies are defined as: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 
to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000) and not known (cannot be estimated 
from the available data). Within each frequency grouping, adverse reactions are presented in order of 
decreasing seriousness. 
 

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Table 2: Adverse reactions in patients treated with Palynziq 
 

System organ class Adverse reaction(s) Induction/Titration1 Maintenance 
Blood and lymphatic system 
disorders 

Lymphadenopathy 
 

Common 
(9.8%) 

Very common 
(12%) 

Hypersensitivity 
reaction2 
 

Very common 
(65%) 

Very common 
(58%) 

Acute systemic 
hypersensitivity 
reaction3 

Common 
(4.6%) 

Common 
(1.7%) 

Angioedema3 
 

Common 
(5.6%) 

Common 
(2.9%) 

Immune system disorders 

Serum sickness3 
 

Common 
(2.1%) 

Uncommon 
(0.6%) 

Nervous system disorders Headache 
 

Very common 
(42%) 

Very common 
(46%) 

Respiratory, thoracic and 
mediastinal disorders 

Cough2 
 

Very common 
(19%) 

Very common 
(21%) 

Abdominal pain2,4 
 

Very common 
(19%) 

Very common 
(27%) 

Nausea 
 

Very common 
(25%) 

Very common 
(27%) 

Gastrointestinal disorders 

Vomiting 
 

Very common 
(19%) 

Very common 
(25%) 

Alopecia 
 

Common  
(6.7%) 

Very common 
(22%) 

Urticaria 
 

Very common 
(25%) 

Very common 
(21%) 

Rash 
 

Very common 
(33%) 

Very common 
(23%) 

Pruritus 
 

Very common 
(25%) 

Very common 
(22%) 

Erythema 
 

Very common 
(11%) 

Common 
(5.7%) 

Skin exfoliation 
 

Uncommon 
(0.4%) 

Common 
(1.7%) 

Skin and subcutaneous 
tissue disorders 
 

Maculo-papular rash 
 

Common 
(3.5%) 

Common 
(2.9%) 

Arthralgia3 
 

Very common 
(78%) 

Very common 
(62%) 

Myalgia 
 

Very common 
(11%) 

Very common 
(11%) 

Joint swelling Common 
(6.0%) 

Common 
(3.4%) 

Musculoskeletal stiffness Common 
(4.2%) 

Common 
(5.1%) 

Musculoskeletal and 
connective tissue disorders 

Joint stiffness 
 

Common 
(6.3%) 

Common 
(2.3%) 

General disorders and 
administration site 
conditions 

Injection site reaction3 
 

Very common 
(90%) 

Very common 
(64%) 

Hypophenylalaninaemia 
 

Very common 
(15%) 

Very common 
(61%) 

Investigations 

Complement factor 
C3 decreased5 

Very common 
(66%) 

Very common 
(73%) 

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System organ class Adverse reaction(s) Induction/Titration1 Maintenance 
Complement factor 
C4 decreased5 

Very common 
(64%) 

Very common 
(35%) 

High sensitivity CRP 
levels increased6 

Very common 
(17%) 

Common 
(9.1%) 

1 Induction and titration phase reflects the time prior to reaching blood phenylalanine levels less than 
600 micromol/l while on a stable dose. Once blood phenylalanine levels less than 600 micromol/l on 
stable dose was reached, patients were considered to be in the maintenance phase thereafter. 

2 Hypersensitivity reactions cover a group of terms, including acute systemic hypersensitivity 
reactions, and can manifest as a range of symptoms including angioedema, serum sickness, rash, 
and urticaria. 

3 Refer to Description of selected adverse reactions section. 
4 Abdominal pain reflects the following terms: abdominal pain, abdominal pain upper and abdominal 

discomfort. 
5 Complement factor C3/C4 decrease is defined changing from normal or high baseline complement 

value to low post-baseline complement value. 
6 Reflects high sensitivity CRP (hsCRP) levels above upper limit of normal (greater than 

0.287 mg/dl) over a 6 month period. 
 
Description of selected adverse reactions 
 
Hypersensitivity reactions 
In clinical trials, 213 out of 285 (75%) patients experienced hypersensitivity reactions. The most 
common hypersensitivity reactions (occurring in at least 10% of patients) were rash, urticaria, and 
hypersensitivity. Hypersensitivity reactions were most frequent during induction and titration phase 
(65% of patients; 921 episodes over mean treatment duration of 12 months) and decreased in 
maintenance phase (58% of patients; 491 episodes over mean treatment duration of 28 months). The 
risk of a hypersensitivity reaction occurring is 2.6-fold higher in induction/titration phase compared to 
maintenance phase. 
 
Hypersensitivity reactions occurred as early as the first dose and can occur at any time during 
treatment. Hypersensitivity reactions were managed with dose reduction (3% of episodes), treatment 
interruption (5% of episodes), treatment withdrawal (2% of episodes), and/or concomitant medicinal 
products. The mean duration of hypersensitivity reactions was 7 days, and ranged less than 1 day to 
227 days; 89% of hypersensitivity reactions had a duration of less than 14 days, 0.4% of 
hypersensitivity reactions persisted at least 180 days, and 99% of hypersensitivity reactions resolved 
by the time of the data cut-off. 
 
Acute systemic hypersensitivity reactions 
In clinical trials, 16 out of 285 (6%) patients experienced 25 acute systemic hypersensitivity reactions 
of any severity based on acute onset of skin and/or mucosal tissue manifestations and at least either 
respiratory compromise or reduced blood pressure (or associated symptoms of end-organ dysfunction). 
Manifestations included a combination of the following acute signs and symptoms: syncope, 
hypotension, hypoxia, dyspnoea, wheezing, chest discomfort/chest tightness, tachycardia, angioedema 
(swelling of face, lips, eyes, and tongue), flushing, rash, urticaria, pruritus, and gastrointestinal 
symptoms (vomiting, nausea, and diarrhoea). Four out of 16 (1%; 4/285) patients experienced a total 
of 5 episodes of acute systemic hypersensitivity reactions considered severe based on the presence of: 
cyanosis or oxygen saturation (SpO2) less than or equal to 92%, hypotension (systolic blood pressure 
below 90 mm Hg in adults) or syncope.  
 
Acute systemic hypersensitivity reactions were most frequent during induction and titration phase (5% 
of patients; 19 episodes over mean treatment duration of 12 months) and decreased in maintenance 
phase (2% of patients; 6 episodes over mean treatment duration of 28 months). The risk of an acute 
systemic hypersensitivity reaction occurring is 7-fold higher in induction/titration phase compared to 
maintenance phase. 
 

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Acute systemic hypersensitivity reactions generally occurred within the first hour after injection (88%; 
22/25 episodes); however, reactions have occurred up to 24 hours after dosing. Reactions were 
managed by administration of adrenaline (10/16 patients; 11/25 episodes), corticosteroids, 
antihistamines, and/or oxygen under emergency medical care. Ten out of the 16 patients who 
experienced an acute systemic hypersensitivity reaction were rechallenged and 4 patients had at least 
one recurrence. Seven out of the 16 patients discontinued treatment. All episodes resolved without 
sequelae (see Immunogenicity section).  
 
Angioedema 
In clinical trials, 21 out of 285 (7%) patients experienced 37 episodes of mild to moderate episodes of 
angioedema (symptoms include one or more of the following: pharyngeal oedema, swollen tongue, lip 
swelling, mouth swelling, eyelid oedema and face oedema) occurring independent of acute systemic 
hypersensitivity reactions. Angioedema was most frequent during induction and titration phase (6% of 
patients; 27 episodes over mean treatment duration of 12 months) and decreased in maintenance phase 
(3% of patients; 10 episodes over mean treatment duration of 28 months). The risk of angioedema 
occurring is 4.5-fold higher in induction/titration phase compared to maintenance phase. 
 
Angioedema occurred as early as 4 days and up to 1222 days into Palynziq treatment (median: 91 days 
from Palynziq treatment initiation). Of the 9 angioedema episodes where time to onset was evaluable, 
5 episodes occurred within 24 hours of injection, 4 episodes occurred between 24 hours and up to 
29 days of injection. Eighteen out of 21 patients who experience angioedema were re-challenged and 
5 patients had at least one recurrence. Angioedema was managed with dose reduction (3 episodes; 
8%), treatment interruption (5 episodes; 14%), treatment withdrawal (3 episodes; 8%), and/or 
concomitant medicinal products. All episodes resolved without sequelae.  
 
Angioedema can also present as one of the symptoms of an acute systemic hypersensitivity reaction. 
 
Serum sickness 
In clinical trials, serum sickness was reported in 7 out of 285 (2%) patients. Serum sickness was most 
frequent during induction and titration phase (2% of patients; 6 episodes over mean treatment duration 
of 12 months) and decreased in maintenance phase (0.6% of patients; 1 episode over mean treatment 
duration of 28 months). The risk of serum sickness occurring is greater than 2-fold higher in 
induction/titration phase compared to maintenance phase.  
 
Serum sickness occurred as early as 10 days and up to 232 days into Palynziq treatment (median: 
13 days from Palynziq treatment initiation). Of the 5 serum sickness episodes where time to onset was 
evaluable, 1 episode occurred within 1 hour of injection and 4 episodes occurred between 24 hours 
and up to 5 days following injection. The mean duration of serum sickness was 5 days and ranged 
from 1 to 8 days.  
 
Three of these patients experienced severe serum sickness (3/285; 1%), which resulted in treatment 
discontinuation (2 patients) or treatment interruption (1 patient). Five out of the 7 patients who 
experienced serum sickness continued treatment without a recurrence, and managed serum sickness 
with treatment interruption, dose reduction and/or concomitant medicinal products. All serum sickness 
reactions resolved without sequelae.  
 
Arthralgia and other joint related signs and symptoms 
In clinical trials, 241 out of 285 (85%) patients experienced episodes consistent with arthralgia 
(including back pain, musculoskeletal pain, pain in extremity, and neck pain). Arthralgia occurred as 
early as the first dose and can occur at any time during treatment. Arthralgia was most frequent during 
induction and titration phase (78% of patients; 1264 episodes over mean treatment duration of 
12 months) and decreased in maintenance phase (62% of patients; 612 episodes over mean treatment 
duration of 28 months). The risk of arthralgia occurring is 2.9-fold higher in induction/titration phase 
compared to maintenance phase.  
 
The mean duration of arthralgia was 15 days and ranged 1 day to 936 days; 78% of arthralgia episodes 
had a duration of less than 14 days, and 1% of arthralgia episodes persisted at least 180 days. Severe 

11 



arthralgia (severe pain limiting self-care activities of daily living) was experienced in 14 (5%) patients. 
Arthralgia episodes were managed with concomitant medicinal products (e.g., nonsteroidal 
anti-inflammatory drugs, glucocorticoids, and/or antipyretic), dose reduction (4% of episodes), 
treatment interruption (4% of episodes), or treatment withdrawal (0.6% of episodes), and 97% of 
arthralgia episodes resolved by the time of the data cut-off. 
 
Persistent arthralgia (lasting at least 6 months) occurred in 19 (7%) patients with a total of 24 episodes. 
Persistent arthralgia occurred as early as 6 days and up to 1526 days into Palynziq treatment (median: 
554 days from Palynziq treatment initiation). Dose was not changed for 23 (96%) episodes and dose 
was reduced for 1 (4%) episode. All persistent arthralgia episodes resolved without sequelae. 
 
Injection site reactions 
Injection site reactions were reported in 266 out of 285 (93%) patients. The most common injection 
site reactions (occurring in at least 10% of patients) were reaction, erythema, bruising, pruritus, pain, 
swelling, rash, induration, and urticaria. Injection site reactions were most frequent during induction 
and titration phase (90% of patients; 3899 episodes over mean treatment duration of 12 months) and 
decreased in maintenance phase (64% of patients; 1110 episodes over mean treatment duration of 
28 months). The risk of injection site reactions occurring is 4.9-fold higher in induction/titration phase 
compared to maintenance phase. 
 
Injection site reactions occurred as early as the first dose and can occur at any time during treatment. 
The mean duration of injection site reaction was 9 days, and ranged 1 day to 970 days; 91% of 
injection site reactions had a duration of less than 14 days, 0.8% of injection site reactions persisted at 
least 180 days, and 99% of injection site reactions resolved by the time of the data cut-off.  
 
Three injection site reactions consistent with granulomatous skin lesions were reported (each reaction 
occurring in one patient): granulomatous dermatitis (occurred 15 months after Palynziq treatment and 
lasted 16 days), xanthogranuloma (occurred 12 months after Palynziq treatment and lasted 21 months), 
and necrobiosis lipoidica diabeticorum (occurred 9 months after Palynziq treatment and lasted 
9 months). Necrobiosis lipoidica diabeticorum was treated with steroid injections and complicated by 
Pseudomonas infection. All of these injection site reactions resolved. One patient reported soft tissue 
infection associated with mesenteric panniculitis, which resulted in treatment discontinuation. 
 
Cutaneous reactions (not limited to the injection site) lasting ≥ 14 days 
In clinical trials, 133 out of 285 (47%) patients treated with Palynziq experienced cutaneous reactions 
(not limited to the injection site) lasting at least 14 days. Cutaneous reactions lasting at least 14 days 
were most frequent during induction and titration phase (31% of patients; 137 episodes over mean 
treatment duration of 12 months) and decreased in maintenance phase (38% of patients; 129 episodes 
over mean treatment duration of 28 months). The risk of cutaneous reactions lasting at least 14 days 
occurring is 1.5-fold higher in induction/titration phase compared to maintenance phase.  
 
The most common cutaneous reactions (at least 5% of patients) reported were pruritus (37 patients; 
13%), rash (33 patients; 12%), erythema (15 patients; 5%), and urticaria (15 patients; 5%). Other 
reactions reported included skin exfoliation, generalised rash, erythematous rash, maculo-papular rash, 
and pruritic rash. The mean (SD) time from first dose of pegvaliase to onset was 372 (384) days. The 
mean (SD) duration of these reactions was 64 (78) days, and the maximum duration was 638 days, 5% 
of these reactions persisted at least 180 days, and 86% of these reactions resolved by the time of the 
data cut-off. 
 
Immunogenicity 
 
All patients treated with Palynziq developed a sustained total anti-pegvaliase antibody (TAb) response 
with a majority of patients (91%) becoming positive by Week 4. Mean TAb titres peaked 2 weeks 
after initiation of pegvaliase and then were sustained through long-term treatment (greater than 1 year 
after treatment initiation). Anti-phenylalanine ammonia lyase (PAL) IgM was detected in all patients 
with a majority of treated patients (98%) becoming positive by 2 months. Anti-PAL IgG was detected 
in almost all patients by 4 months. Mean anti-PAL (IgM and IgG) titres peaked 3 to 6 months post 

12 



treatment initiation and were relatively stable through long-term treatment (greater than 1 year after 
pegvaliase initiation). Pegvaliase induced anti-PEG IgM and IgG responses were detected in the 
majority of patients (98%) and titres peaked at 1 to 3 months after treatment initiation and then 
returned to baseline levels in most patients by 6 to 9 months after treatment initiation (see section 4.5). 
Neutralising antibodies (NAb) capable of inhibiting PAL enzyme activity were detected in a majority 
of patients over time with 78% of patients testing positive for NAb at one year after treatment 
initiation and maintaining stable NAb titres through long-term treatment.  
 
All 16 patients who experienced acute systemic hypersensitivity reactions tested negative for 
pegvaliase-specific IgE at or near the time of the acute systemic hypersensitivity reactions episode. 
These reactions were consistent with a Type III immune-complex mediated hypersensitivity 
mechanism and were most frequent in the early phases of treatment (during the induction and titration 
periods) when the early immune response was dominated by PEG IgM, PEG IgG and PAL IgM 
responses and C3/C4 levels were at their lowest. Hypersensitivity reactions decreased over time in 
maintenance as the incidence of these antibodies decreased, and C3/C4 returned towards baseline. 
Presence of antibody titres were not predictive of hypersensitivity reactions.  
 
In clinical trials, a direct correlation between pegvaliase plasma exposure and blood phenylalanine 
reduction was observed. Pegvaliase plasma exposure was primarily driven by immune response to 
pegvaliase. Patients with lower antibody titres for all antibody analytes including NAb had higher 
pegvaliase concentrations due to less immune-mediated pegvaliase clearance. As a consequence, these 
patients were more likely to develop hypophenylalaninaemia. Patients with higher antibody titres 
required higher doses to overcome clearance and achieve blood phenylalanine reduction. However, 
due to the substantial variability in antibody titres between patients, no specific antibody titre was 
predictive of pegvaliase dose required to reach substantial blood phenylalanine reduction, or the 
development of hypophenylalaninaemia. During early treatment (less than 6 months after Palynziq 
administration) when immune-mediated clearance was high, and doses were low, patients with higher 
antibody titres achieved less blood phenylalanine reduction. Following maturation of the early 
immune response (more than 6 months after Palynziq administration), and dose adjustment for 
managing blood phenylalanine control in long-term treatment, mean blood phenylalanine levels 
continued to decrease in patients who continued treatment (see section 5.1). Antibody titres were 
stable with long-term treatment and dose increases were not associated with increased antibody titres. 
Thus, mean dose levels also stabilized with long-term treatment with sustained therapeutic effect. 
 
Paediatric population 
 
No data are available in paediatric patients less than 16 years of age.  
 
Twelve patients (11 patients from Study 301) aged 16 up to 18 years received Palynziq treatment. 
Adverse reactions were similar in type and frequency to that of adult patients.  
 
Reporting of suspected adverse reactions 
 
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V. 
 
4.9 Overdose 
 
In clinical trials, doses of pegvaliase were explored up to 150 mg/day and no specific signs or 
symptoms were identified following these higher doses. No differences in the safety profile were 
observed. For management of adverse reactions, see sections 4.4 and 4.8. 
 
 

13 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: Other alimentary tract and metabolism products, Enzymes, ATC code: 
A16AB19 
 
Pegvaliase is rAvPAL conjugated with linear 20 kDa NHS-PEG at a degree of substitution of 28 to 
44 moles of polymer/mole of protein. The average molecular mass is approximately 1,000 kDa of 
which the protein moiety constitutes approximately 248 kDa. 
 
Mechanism of action 
 
Pegvaliase is a PEGylated recombinant phenylalanine ammonia lyase enzyme that converts 
phenylalanine to ammonia and trans-cinnamic acid that are primarily eliminated by liver metabolism. 
 
Clinical efficacy and safety 
 
The effects of Palynziq in the treatment of PKU have been demonstrated in patients with 
phenylketonuria in Study 301, an open-label study to initiate Palynziq treatment, and Study 302, a 
follow-on study for efficacy assessment. 
 
Study 301: Treatment initiation (Induction and Titration)  
Study 301 an open-label randomised (1:1), multi-centre study of patients with PKU to assess the safety 
and tolerability of self-administered Palynziq in an induction/titration/maintenance dose regimen. The 
261 enrolled patients were aged 16 to 55 years (mean: 29 years) and had a baseline mean blood 
phenylalanine of 1233 micromol/l. At treatment initiation, 253 (97%) patients had inadequate blood 
phenylalanine control (blood phenylalanine levels above 600 micromol/l) and 8 patients had blood 
phenylalanine levels less than or equal to 600 micromol/l. Patients previously treated with sapropterin 
were required to discontinue treatment at least 14 days prior to first dose of Palynziq. At baseline, 
149 (57%) patients were receiving part of their total protein intake from medical food and 41 out of 
261 (16%) patients were on a phenylalanine-restricted diet (defined as receiving greater than 75% of 
total protein intake from medical food). Patients initiated Palynziq treatment with an induction 
regimen (2.5 mg once week for 4 weeks) and were titrated in a stepwise manner (increased dose and 
frequency) to reach their randomised target dose of 20 mg once daily or 40 mg once daily. The 
duration of titration varied among patients and was based on patient tolerability (up to 30 weeks). For 
this study, the maintenance period was defined as at least 3 weeks dosing at randomised 20 mg or 
40 mg once daily.  
 
Of the 261 enrolled patients, 195 (75%) patients reached their randomised maintenance dose 
(103 patients in the 20 mg once daily arm, 92 patients in the 40 mg once daily arm). Patients in the 
20 mg once daily randomised arm reached their maintenance dose at a median time of 10 weeks 
(range: 9 to 29 weeks) and patients in the 40 mg once daily arm reached their maintenance dose at a 
median time of 11 weeks (range: 10 to 33 weeks). Of the 261 patients who enrolled in Study 301, 
152 patients continued to the eligibility period of Study 302, and 51 patients continued directly from 
Study 301 into the long-term extension period of Study 302. 
 
Study 302: Efficacy assessment  
Study 302 was a follow-on study (from Study 301) and included: an open label eligibility period; a 
double-blind, placebo-controlled randomised discontinuation trial period (RDT), and a long-term 
open-label extension period.  
 
Eligibility period  
A total of 164 previously-treated Palynziq patients (152 patients from Study 301, and 12 patients from 
other Palynziq trials) continued treatment for up to 13 weeks.  
 

14 



Of the 164 patients that entered the eligibility period of Study 302, 86 patients met the eligibility 
criterion (achieved at least 20% mean blood phenylalanine reduction from pre-treatment baseline at 
their randomised dose within 13 weeks) and continued to the RDT, 12 patients discontinued treatment, 
and 57 patients did not enter the RDT and continued Palynziq treatment in the long-term extension 
period of Study 302, where they were allowed to increase dose. 
 
Randomised discontinuation trial (RDT) period 
In the double-blind, placebo-controlled RDT, patients were randomised in a 2:1 ratio to either continue 
their randomised dosing (20 mg/day or 40 mg/day) or receive matching placebo for 8 weeks. 
 
The primary endpoint was change from RDT baseline to RDT Week 8 in blood phenylalanine levels. 
Palynziq-treated patients were able to maintain their blood phenylalanine reductions compared to the 
placebo patients whose blood phenylalanine levels returned to their pre-treatment baseline levels after 
8 weeks (p < 0.0001, see Table 3).  
 

Table 3: LS Mean change from RDT baseline in blood phenylalanine 
concentration (micromol/l) at RDT Week 8 in patients with PKU (Study 302) 

 
Blood phenylalanine concentration 

(micromol/l) 
Mean (SD) 

Randomised 
study arm 

Pre-
treatment 
baseline1 

 

Study 302 
RDT 

baseline 
 

Study 302  
RDT Week 8

 

LS mean 
change from  

Study 302 
RDT baseline 

to Week 8  
(95% CI) 

Treatment  
difference  

in LS mean 
change 

(95% CI)  
P-value2 

Palynziq 
20 mg once 

daily3 

1450.2 (310.5) 
n = 29 

596.8 (582.8) 
n = 29 

553.0 (582.4) 
n = 26 

-23.3 
(-156.2, 109.7) 

Placebo 
20 mg once 

daily4 

1459.1 (354.7) 
n = 14 

563.9 (504.6) 
n = 14 

1509.0 (372.6) 
n = 13 

949.8 
(760.4, 1139.1) 

-973.0 
(-1204.2, -741.9) 

p < 0.0001 

Palynziq 
40 mg once 

daily3 

1185.8 (344.0) 
n = 29 

410.9 (440.0) 
n = 29 

566.3 (567.5) 
n = 23 

76.3 
(-60.2, 212.8) 

Placebo 
40 mg once 

daily4 

1108.9 (266.8) 
n = 14 

508.2 (363.7) 
n = 14 

1164.4 (343.3) 
n = 10 

664.8  
(465.5, 864.1) 

-588.5  
(-830.1, -346.9) 

p < 0.0001 

1 Blood phenylalanine level prior to initiating treatment with Palynziq. 
2 Based on the mixed model repeated measures (MMRM) method, with treatment arm, visit, and 
treatment arm-by-visit interaction (the time profile of blood phenylalanine changes is assessed 
separately for each treatment arm) as factors adjusting for baseline blood phenylalanine 
concentration. 

3 Nine patients were excluded from the Week 8 analysis from the Palynziq treatment arms 
(20 mg/day or 40 mg/day): 4 patients did not complete the RDT due to adverse events (1 patient 
discontinued treatment and 3 patients transitioned to the long-term extension period) and the 
remaining 5 patients who did not complete phenylalanine assessment within the window for 
Week 8 (Day 43 to 56).  

4 Five patients were excluded from the Week 8 analysis from the placebo arms (20 mg/day or 
40 mg/day):  
1 patient did not complete the RDT due to adverse event transitioned to the long-term extension 
period and the remaining 4 patients who did not complete phenylalanine assessment within the 
window for Week 8 (Day 43 to 56). 
 

Symptoms of inattention and mood were also evaluated during this period. No differences were 
observed in inattention and mood between patients randomised to placebo versus those randomised to 
Palynziq during this 8-week duration.  
 

15 



Long-term extension period 
Patients continued Palynziq treatment in the long-term open-label extension period and dose was 
adjusted (5, 10, 20, 40 and 60 mg/day) by the physician to achieve further blood phenylalanine 
reductions and maintain previously achieved phenylalanine levels.  
 
Overall treatment experience from Study 301 and Study 302 
At the time of the data cut-off, 188 out of the 261 patients received treatment for at least 1 year, 
4 patients completed treatment, and 69 discontinued treatment in the first year. Of these 188 patients, 
164 patients received treatment for at least 2 years, 2 patients continued treatment but had not yet 
reached 2 years of treatment, and 22 patients discontinued in the second year, and 9 patients 
discontinued after 2 years of treatment. Of the 100 patients who discontinued treatment, 40 patients 
discontinued due to an adverse event, 29 patients discontinued due to patient decision, 10 patients 
discontinued due to physician decision, and 21 patients discontinued to other reasons (e.g. lost to 
follow-up, pregnancy, or protocol deviation). 
 
Efficacy results over time are presented in Table 4 and Figure 1.  
 
Phenylalanine levels over time 
Mean blood phenylalanine levels reduced from 1233 micromol/l at baseline to 565 micromol/l at 
Month 12 (n=164) and 345 micromol/l at Month 24 (n=90), and these reductions in mean blood 
phenylalanine levels were maintained through Month 36 (341 micromol/l; n=48) (see Table 4 and 
Figure 1). Median change from baseline was -634 micromol/l at Month 12, -965 micromol/l at 
Month 24, and -913 micromol/l at Month 36. 
 
ADHD inattention and PKU-POMS confusion over time 
Symptoms of inattention were assessed using the inattention subscale of the investigator-rated 
Attention Deficient Hyperactivity Disorder Rating Scale (ADHD-RS IV). The ADHD-RS IV 
inattention subscale ranges from 0 to 27, higher scores indicate a greater degree of impairment, and a 
score below 9 indicates that the patient is asymptomatic (i.e. has a score that is in the normative 
range). Results for ADHD inattention subscale over time are shown in Table 4. Mean reduction 
(suggesting improvement) from baseline ADHD-RS inattention was above the minimally clinically 
important difference (MCID) for adults with ADHD (defined as a reduction of at least 5.2) at 
Month 18 (n=168; a reduction of 5.3), Month 24 (n=160; a reduction of 5.9) and Month 36 (n=92; a 
reduction of 6.7). In patients with baseline ADHD inattention scores > 9 (suggesting symptoms of 
inattention at baseline), mean reduction in ADHD inattention score from baseline (suggesting 
improvement) was above the MCID estimated for adults with ADHD at Month 12 (n=80; a reduction 
of 7.8), Month 18 (n=78; a reduction of 8.9), Month 24 (n=76; a reduction of 9.6) and Month 36 
(n=45; a reduction of 10.6).  
 
Symptoms of mood (confusion, fatigue, depression, tension-anxiety, vigour, and anger domains) were 
evaluated using the Profile of Mood States (POMS) tool that has been modified to be specific to PKU 
(PKU-POMS). The PKU-POMS confusion subscale (ranging from 0 to 12 points with higher scores 
indicating greater degree of impairment) was considered most sensitive to changes in blood 
phenylalanine levels. Results for PKU-POMS confusion subscale over time are shown in Table 4. 
Mean change from baseline PKU-POMS confusion subscale (suggesting improvement) was above 
MCID (defined as a reduction of at least 1) at Month 12 (n=130; a reduction of 1.6), Month 18 
(n=123; a reduction of 2), Month 24 (n=117; a reduction of 2.2) and Month 36 (n=51; a reduction of 
2.2).  
 

16 



Changes in protein intake from intact food over time 
Median protein intake from intact food increased at Month 12 (4 g increase from baseline), and 
Month 24 (14 g increase from baseline) and Month 36 (25 g increase from baseline). 
 

Figure 1: Mean (SE) phenylalanine levels over time 

 
 

17 



Table 4: Efficacy results at Month 12, Month 18, Month 24 and Month 36 in Palynziq-treated 
patients 

 
 Baseline Month 12 Month 18 Month 24 Month 36 
Blood phenylalanine1 
N 261 1642 1252 902 482 
Mean (SD) blood phenylalanine 
(micromol/l) 

1233 (386) 565 (531) 390 (469) 345 (453) 341 (465) 

Change from baseline (micromol/l) 
Mean (SD) 
Median 

-  
-662 (588) 

-634 

 
-883 (565) 

-920 

 
-873 (566) 

-965 

 
-956 (536) 

-913 
ADHD inattention3 subscale (investigator-rated) 
N 253 178 175 167 97 
Mean (SD) inattention score  9.8 (6.1) 5 (4.9) 4.6 (4.7) 4.2 (4.6) 3.7 (5) 
Change from baseline inattention 
score (n)4 
Mean (SD) 
Median 

- n=172 
-4.7 (5.6) 

-4 

n=168 
-5.3 (5.9) 

-5 

n=160 
-5.9 (6.1) 

-5 

n=92 
-6.7 (6.4) 

-5.5 

ADHD inattention3 subscale (investigator-rated) with baseline score > 9 
N 116 80 78 76 45 
Mean (SD) inattention score  15.3 (4.1) 7.6 (4.9) 6.6 (5) 5.9 (4.9) 5.1 (5.6) 
Change from baseline inattention 
score (n)4 
Mean (SD) 
Median 

- n=80 
-7.8 (5.5) 

-7 

n=78 
-8.9 (5.8) 

-9 

n=76 
-9.6 (5.9) 

-10 

n=45 
-10.6 (6.4) 

-12 

PKU-POMS confusion3 subscale (self-rated) 
N 170 181 178 169 100 
Mean (SD) confusion score  4 (2.7) 2.4 (2.1) 2.1 (2.2) 2 (2.1) 1.8 (2.1) 
Change from baseline confusion 
score (n)4 
Mean (SD) 
Median 

- n=130 
-1.6 (2.5) 

-1 

n=123 
-2 (2.8) 

-2 

n=117 
-2.2 (2.7) 

-2 

n=51 
-2.2 (3.1) 

-2 

Protein intake from intact food (g) 
N 250 160 111 84 46 
Mean (SD)  39 (28) 47 (29) 50 (27) 54 (27) 72 (27) 
Change from baseline protein 
intake (n)4 
Mean (SD) 
Median 

- n=154 
9 (25) 

4 

n=106 
12 (25) 

9 

n=81 
16 (28) 

14 

n=44 
27 (34) 

25 

1 Post-baseline phenylalanine values were mapped to the closest monthly visit (i.e. within a 1-month 
window). 

2 Reflects number of patients who reached time point (Month 12/Month 18/Month 24/Month 36) of 
treatment at the time of the data cut-off and had a scheduled phenylalanine assessment for that time 
point. 

3 Post-baseline ADHD-inattention/PKU-POMS confusion values were mapped to the closest 3-month 
visit (i.e. within a 3-month window). 

4 Change from baseline was based on subjects with available measurements at both time points. Not all 
subjects had a baseline ADHD inattention score and POMS confusion score taken at the start of the 
study. 

 
Of 253 patients who had inadequate blood phenylalanine control (blood phenylalanine levels 
above 600 micromol/l) at baseline in Study 301: 
 54% of patients, 69% of patients, and 72% of patients reached blood phenylalanine level 

≤ 600 micromol/l by 12 months, 24 months, and 36 months, respectively;  
 44% of patients, 62% of patients, and 66% of patients reached blood phenylalanine level 

≤ 360 micromol/l by 12 months, 24 months, and 36 months, respectively. 

18 



 
Impact blood phenylalanine reduction on ADHD inattention and PKU-POMS confusion 
An analysis of ADHD inattention and PKU-POMS confusion subscales by change in blood 
phenylalanine from baseline quartiles showed that patients with the largest phenylalanine reductions 
experienced the greatest improvements in ADHD inattention and PKU-POMS confusion subscales.  
 
Paediatric population 
 
No data are available in paediatric patients less than 16 years of age.  
 
Of the 261 patients in Study 301, 11 patients were aged between 16 and 18 years at enrolment. All 
11 patients had inadequate blood phenylalanine control (blood phenylalanine levels above 
600 micromol/l) at baseline. These patients received the same induction/titration/maintenance regimen 
as patients aged 18 years and older in this study. Mean (SD) change from baseline was 
20 (323) micromol/l at Month 12 (n=9), -460 (685) micromol/l at Month 24 (n=5), 
and -783 (406) micromol/l at Month 36 (n=5). Of the 11 patients initially enrolled in Study 301, 
3 patients reached blood phenylalanine levels ≤ 600 micromol/l by 12 months, 7 patients reached this 
threshold by 24 months, and 8 patients reached this threshold by 36 months. 
 
The European Medicines Agency has deferred the obligation to submit the results of studies with 
Palynziq in one or more subsets of the paediatric population for the treatment of 
hyperphenylalaninaemia (see section 4.2 for information on paediatric use). 
 
5.2 Pharmacokinetic properties 
 
Pegvaliase is a PEGylated recombinant phenylalanine ammonia lyase (rAvPAL), derived from the 
cyanobacterium Anabaena variablis expressed in Escherichia coli. The purpose of the PEGylation of 
rAvPAL is to reduce immune recognition of the rAvPAL bacterial protein, and increase the half-life. 
 
The pharmacokinetics of pegvaliase exhibit high inter-patient and intra-patient variability due to the 
heterogeneity of the immune response in adult patients with PKU. Immune response affects clearance 
and time to reach steady state. The immune response stabilises over 6 to 9 months of total treatment.  
 
Absorption 
 
Following a single subcutaneous dose (0.01, 0.03 or 0.1 mg/kg), pegvaliase is absorbed slowly with a 
median tmax of 3.5 to 4 days (individual range of 2.5 to 7 days). The bioavailability is not affected by 
the different injection sites on the body (see section 4.2). The absolute bioavailability in humans is 
unknown. 
 
Distribution 
 
Mean (SD) for apparent volume of distribution (Vz/F) at steady state following 20 mg and 40 mg 
doses was 26.4 L (64.8 L) and 22.2 L (19.7 L) respectively. 
 
Biotransformation 
 
Following cellular uptake, the metabolism of phenylalanine ammonia lyase (PAL) is expected to occur 
via catabolic pathways and be degraded into small peptides and amino acids; the PEG molecule is 
metabolically stable and expected to be separated from PAL protein and primarily eliminated by renal 
filtration. 
 
Elimination 
 
Pegvaliase is primarily cleared by immune-mediated mechanisms following repeat dosing. In clinical 
studies, anti-PAL, anti-PEG and anti-pegvaliase have been identified as IgG and IgM mainly. 
Relatively low titres of IgE has also been observed. In maintenance phase of the treatment, steady state 

19 



is expected 4 to 24 weeks after maintenance dose started. A mean (SD) half-life at 20 mg and 40 mg 
were 47.3 hours (41.6 hours) and 60.2 hours (44.6 hours), respectively. Individual values for half-life 
range from 14 to 132 hours. The PEG molecule is expected to be primarily eliminated by renal 
filtration.  
 
Linearity/nonlinearity 
 
During dose escalation from 20 mg/day to 40 mg/day and 40 mg/day to 60 mg/day, a greater dose 
proportional increase in exposure was observed.  
 
Specific populations 
 
Analysis of pegvaliase concentration data from clinical trials indicated that body weight, gender and 
age did not have a notable effect on pegvaliase pharmacokinetics. No clinical studies have been 
conducted to evaluate the effect of renal or hepatic impairment on the pharmacokinetics of pegvaliase. 
 
Exposure-effect  
 
A PK/PD analysis using the Phase III data demonstrated an inverse pegvaliase exposure-phenylalanine 
response relationship, which could be influenced by dietary phenylalanine intake. At lower plasma 
pegvaliase Ctrough concentrations < 10,000 ng/ml, patients with higher dietary phenylalanine intake 
tend to have higher blood phenylalanine levels compared to patients with the same Ctrough 
concentration and lower dietary phenylalanine intake, suggesting saturation of the enzyme 
(i.e. rAvPAL). At high pegvaliase Ctrough concentrations ≥ 10,000 ng/ml, the majority of the blood 
phenylalanine levels (97%) are ≤ 30 micromol/l, even when dietary phenylalanine intake is high. 
Therefore, a reduction in pegvaliase dose should be considered in patients experiencing 
hypophenylalaninaemia despite appropriate levels of protein intake (see section 4.2). 
 
5.3 Preclinical safety data 
 
Dose-dependent reductions in body weight gain attributed to decreased plasma phenylalanine levels to 
below normal levels in normal animals (monkeys, rats and rabbits) was observed in single and repeat 
dose toxicology studies as well as developmental and reproductive toxicity studies with pegvaliase. 
Decreased plasma phenylalanine and reduced body weight gain was reversible after cessation of 
treatment.  
 
In cynomolgus monkeys, the incidence and severity of arterial inflammation was dose dependent and 
observed in a wide range of organs and tissues at clinically relevant exposures in the 4- and 39-week 
repeat-dose toxicology studies. The arterial inflammation observed in these studies involved small 
arteries and arterioles in a wide range of organs and tissues and in subcutaneous injection sites. 
Arteritis was attributed to the immune-mediated response associated with chronic administration of 
foreign protein to the animals. The vascular inflammation observed in these studies was reversible 
upon cessation of treatment. 
 
In rats, dose dependent vacuolation attributed to pegvaliase treatment was observed at clinically 
relevant exposures in the 4- and 26-week repeat-dose toxicity studies in rats in multiple organs and 
tissues, but not in cynomolgus monkeys. No vacuolation was observed in the brain. Vacuoles in all 
tissues, with the exception of the kidney, resolved or were diminished by the end of the recovery 
period, suggesting partial reversibility. The vacuolation observed in these studies was not associated 
with any organ related toxicities as determined by clinical chemistry/urinalysis and histopathological 
analysis. The clinical significance of these findings and functional consequences are unknown. 
 
Adverse reproductive and developmental effects of pegvaliase in rats and rabbits were dose dependent 
and included reduced implantation rate, smaller litter size, lower foetal weights, and increased foetal 
alterations. Additional findings in rabbits included increased abortions, foetal malformations and 
embryo/foetal lethality. These findings occurred in the presence of maternal toxicity (decreased body 
weights, decreased ovarian weights, and decreased food consumption) and were associated with 

20 



markedly decreased maternal blood phenylalanine below normal levels in non-PKU animals. The 
contribution of maternal phenylalanine depletion to the incidence of embryo-foetal developmental 
effects was not evaluated. 
 
In the peri/postnatal study, pegvaliase 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. The effects in offspring were associated with maternal toxicity.  
 
Long-term studies in animals to evaluate carcinogenic potential or studies to evaluate mutagenic 
potential have not been performed with pegvaliase. Based on its mechanism of action, pegvaliase is 
not expected to be tumorigenic. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Trometamol 
Trometamol hydrochloride 
Sodium chloride 
trans-cinnamic acid 
Water for injections 
 
6.2 Incompatibilities 
 
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal 
products. 
 
6.3 Shelf life 
 
2 years 
 
Palynziq may be stored in its sealed tray outside the refrigerator (below 25°C) for a single period up to 
30 days with protection from sources of heat. After removal from the refrigerator, the product must not 
be returned to the refrigerator. 
 
6.4 Special precautions for storage 
 
Store in a refrigerator (2°C - 8°C). Do not freeze. 
 
See section 6.3 for additional information on storage outside the refrigerator (below 25°C). 
 
6.5 Nature and contents of container  
 
1 ml pre-filled syringe made of Type I borosilicate glass, equipped with a stainless steel 26 gauge 
needle, needle safety device, polypropylene plunger rod, and chlorobutyl rubber syringe stopper with 
fluoropolymer coating. The automatic needle guard is composed of a polycarbonate transparent needle 
guard and a stainless steel spring inside the needle guard. After injection, the spring expands causing 
the needle to be covered by the needle guard. 
 
Pre-filled syringe 2.5 mg (white plunger): 
Each carton contains 1 pre-filled syringe. 
 
Pre-filled syringe 10 mg (green plunger): 
Each carton contains 1 pre-filled syringe. 
 

21 



Pre-filled syringe 20 mg (blue plunger): 
Each carton contains 1 or 10 pre-filled syringes.  
 
Not all pack sizes may be marketed. 
 
6.6 Special precautions for disposal and other handling 
 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. After injection, the needle automatically retracts into the needle guard safely covering 
the needle. 
 
Instructions for the preparation and administration of Palynziq are given in the package leaflet. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
BioMarin International Limited 
Shanbally, Ringaskiddy 
County Cork 
Ireland 
P43 R298 
 
 
8. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/19/1362/001 1 x 2.5 mg pre-filled syringe 
EU/1/19/1362/002 1 x 10 mg pre-filled syringe 
EU/1/19/1362/003 1 x 20 mg pre-filled syringe 
EU/1/19/1362/004 10 x 20 mg pre-filled syringes 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: {DD month YYYY} 
 
 
10. DATE OF REVISION OF THE TEXT 
 
MM/YYYY 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu. 
 

22 

http://www.ema.europa.eu/


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX II 
 

A. MANUFACTURER(S) OF THE BIOLOGICAL ACTIVE SUBSTANCE(S) 
AND MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE 

 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 

 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 
 

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 
EFFECTIVE USE OF THE MEDICINAL PRODUCT 

 
 

23 



A. MANUFACTURER(S) OF THE BIOLOGICAL ACTIVE SUBSTANCE(S) AND 
MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE 

 
Name and address of the manufacturer(s) of the biological active substance(s)  
 
BioMarin Pharmaceutical Inc. 
Galli Drive Facility 
46 Galli Drive 
Novato 
CA 94949 
United States 
 
Name and address of the manufacturer(s) responsible for batch release 

 
BioMarin International Limited 
Shanbally, Ringaskiddy  
County Cork  
Ireland 
 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
 
Medicinal product subject to restricted to medical prescription. (see Annex I: Summary of Product 
Characteristics, section 4.2) 
 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 
 
 Periodic safety update reports  

 
The requirements for submission of periodic safety update reports for this medicinal product are set 
out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 
2001/83/EC and any subsequent updates published on the European medicines web-portal. 
 
The marketing authorisation holder shall submit the first periodic safety update report for this product 
within 6 months following authorisation.  
 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 
 

 Risk Management Plan (RMP) 
 

The MAH shall perform the required pharmacovigilance activities and interventions detailed in the 
agreed RMP presented in Module 1.8.2 of the marketing authorisation and any agreed subsequent 
updates of the RMP. 
 
An updated RMP should be submitted: 
 

 At the request of the European Medicines Agency; 
 

 Whenever the risk management system is modified, especially as the result of new 
information being received that may lead to a significant change to the benefit/risk profile 
or as the result of an important (pharmacovigilance or risk minimisation) milestone being 
reached.  

 

24 



 Additional risk minimisation measures  
 

Prior to launch of Palynziq in each Member State, the Marketing Authorisation Holder (MAH) must 
agree about the content and format of the educational programme, including communication media, 
distribution modalities, and any other aspects of the programme, with the National Competent 
Authority.  
 
The MAH shall ensure that in each Member State where Palynziq is marketed, all healthcare 
professionals and patients, carers and observers who are expected to prescribe, use or oversee the 
administration of Palynziq have access to/are provided with the following educational package: 
 

 Physician educational material 
 Patient information pack 

 
 The physician educational material should contain: 

o The Summary of Product Characteristics 
o Guide for healthcare professionals 

 
 The Guide for healthcare professionals shall contain the following key elements: 

o Information on the risk of acute systemic hypersensitivity reactions and details of 
the risk minimisation measures necessary to minimise this risk (i.e. premedication, 
trained observer, prescription of adrenaline injection device). 

o Management of acute systemic hypersensitivity reactions and information on 
retreatment 

o Key messages that must be conveyed and elements that must be addressed prior to 
self-injection by the patient, in particular: 
o training of patients to recognise the signs and symptoms of acute systemic 

hypersensitivity reactions and the action to be taken if such a reaction occurs 
o prescription of adrenaline injection device and training on its use  
o premedication requirements 
o provision of appropriate instruction on self-administration of pegvaliase  
o assessment of competency in self-injection by patient 
o requirement for a trained observer for at least the first 6 months of treatment 
o training of the observer to recognise the signs and symptoms of acute 

systemic hypersensitivity reactions, to seek immediate medical care if a 
reaction occurs, and how to properly administer adrenaline injection device  

o provision of the guide for patients and trained observers and patient alert 
card 

o Information about the observational study to evaluate long term safety and the 
importance of contributing to such a study where applicable 

 
 The patient information pack should contain: 

o The patient information leaflet 
o The guide for patients and trained observers 
o The patient alert card 

 
 The guide for patients and trained observers shall contain the following key messages: 

o Description of the signs and symptoms of severe allergic reactions 
o Information on the action to be taken by the patient and/or trained observer in the 

event of the occurrence of a severe allergic reaction 
o Description of the risk minimisation measures necessary to minimise the risk of 

severe allergic reactions, in particular: 
 Premedication requirements 
 Requirement to carry adrenaline injection device at all times 
 Requirement for trained observer for at least the first 6 months of treatment 

o The need to contact the prescriber in the event of a severe allergic reaction prior to 
continuing treatment 

25 



o The importance of carrying the patient alert card 
 

 The patient alert card shall contain the following key messages:  
o A warning message for HCPs treating the patient at any time, that the patient is 

using Palynziq and severe allergic reactions have been associated with this product 
o Signs or symptoms of the severe allergic reactions and action to be taken in the 

event of such a reaction 
o The importance of carrying an adrenaline injection device and the patient alert card 

at all times 
o Emergency contact details for the patient and contact details of the prescriber  

26 



 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 

27 



 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 

28 



PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
2.5 MG CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Palynziq 2.5 mg solution for injection in pre-filled syringe 
pegvaliase 
 
 
2.  STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each pre-filled syringe contains 2.5 mg pegvaliase in 0.5 ml solution. 
 
 
3. LIST OF EXCIPIENTS 
 
Excipients: trometamol, trometamol hydrochloride, sodium chloride, trans-cinnamic acid, water for 
injections. See leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Solution for injection 
 
1 pre-filled syringe 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
For single use only. 
Read the package leaflet before use. 
Subcutaneous use 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator. Do not freeze. 
 
Can be stored outside the refrigerator (below 25°C) for a single period up to 30 days. 

29 



 
Date removed from refrigeration: _____/_____/______ 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
BioMarin International Limited 
Shanbally, Ringaskiddy 
County Cork 
Ireland 
P43 R298 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/19/1362/001 2.5 mg pre-filled syringe 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Palynziq 2.5 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC: 
SN: 
NN: 
 
 

30 



PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
10 MG CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Palynziq 10 mg solution for injection in pre-filled syringe 
pegvaliase 
 
 
2.  STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each pre-filled syringe contains 10 mg pegvaliase in 0.5 ml solution. 
 
 
3.  LIST OF EXCIPIENTS 
 
Excipients: trometamol, trometamol hydrochloride, sodium chloride, trans-cinnamic acid, water for 
injections. See leaflet for further information. 
 
 
4.  PHARMACEUTICAL FORM AND CONTENTS 
 
Solution for injection 
 
1 pre-filled syringe 
 
 
5.  METHOD AND ROUTE(S) OF ADMINISTRATION 
 
For single use only. 
Read the package leaflet before use. 
Subcutaneous use 
 
 
6.  SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7.  OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8.  EXPIRY DATE 
 
EXP 
 
 
9.  SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator. Do not freeze. 
 
Can be stored outside the refrigerator (below 25°C) for a single period up to 30 days. 

31 



 
Date removed from refrigeration: _____/_____/______ 
 
 
10.  SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11.  NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
BioMarin International Limited 
Shanbally, Ringaskiddy 
County Cork 
Ireland 
P43 R298 
 
 
12.  MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/19/1362/002 10 mg pre-filled syringe 
 
 
13.  BATCH NUMBER 
 
Lot 
 
 
14.  GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15.  INSTRUCTIONS ON USE 
 
 
16.  INFORMATION IN BRAILLE 
 
Palynziq 10 mg 
 
 
17.  UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18.  UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC: 
SN: 
NN: 
 
 

32 



PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
20 MG CARTON 
 
 
1.  NAME OF THE MEDICINAL PRODUCT 
 
Palynziq 20 mg solution for injection in pre-filled syringe 
pegvaliase 
 
 
2.  STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each pre-filled syringe contains 20 mg pegvaliase in 1 ml solution. 
 
 
3.  LIST OF EXCIPIENTS 
 
Excipients: trometamol, trometamol hydrochloride, sodium chloride, trans-cinnamic acid, water for 
injections. See leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Solution for injection 
 
1 pre-filled syringe 
10 pre-filled syringes 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
For single use only. 
Read the package leaflet before use. 
Subcutaneous use 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator. Do not freeze. 
 

33 



Can be stored outside the refrigerator (below 25°C) for a single period up to 30 days. 
 
Date removed from refrigeration: _____/_____/______ 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
BioMarin International Limited 
Shanbally, Ringaskiddy 
County Cork 
Ireland 
P43 R298 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/19/1362/003 1 x 20 mg pre-filled syringe 
EU/1/19/1362/004 10 x 20 mg pre-filled syringes 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Palynziq 20 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC: 
SN: 
NN: 
 
 

34 



MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
2.5 MG TRAY COVER 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Palynziq 2.5 mg solution for injection in pre-filled syringe 
pegvaliase 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
BioMarin International Limited 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 
 
Subcutaneous use 
 
Date removed from refrigeration: _____/_____/______ 
 
Peel here 
 
 

35 



MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
10 MG TRAY COVER 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Palynziq 10 mg solution for injection in pre-filled syringe 
pegvaliase 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
BioMarin International Limited 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 
 
Subcutaneous use 
 
Date removed from refrigeration: _____/_____/______ 
 
Peel here 
 
 

36 



MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
20 MG TRAY COVER 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Palynziq 20 mg solution for injection in pre-filled syringe 
pegvaliase 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
BioMarin International Limited 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 
 
Subcutaneous use 
 
Date removed from refrigeration: _____/_____/______ 
 
Peel here 
 
 

37 



MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
2.5 MG PRE-FILLED SYRINGE 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Palynziq 2.5 mg injection 
pegvaliase 
SC 
 
 
2. METHOD OF ADMINISTRATION 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
0.5 ml 
 
 
6. OTHER 
 
 

38 



MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
10 MG PRE-FILLED SYRINGE 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Palynziq 10 mg injection 
pegvaliase 
SC 
 
 
2. METHOD OF ADMINISTRATION 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
0.5 ml 
 
 
6. OTHER 
 
 

39 



MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
20 MG PRE-FILLED SYRINGE 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Palynziq 20 mg injection 
pegvaliase 
SC 
 
 
2. METHOD OF ADMINISTRATION 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
1 ml 
 
 
6. OTHER 
 
 

40 



 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 

41 



Package leaflet: Information for the user 
 

Palynziq 2.5 mg solution for injection in pre-filled syringe 
Palynziq 10 mg solution for injection in pre-filled syringe 
Palynziq 20 mg solution for injection in pre-filled syringe 

pegvaliase 
 
▼This medicine is subject to additional monitoring. This will allow quick identification of new safety 
information. You can help by reporting any side effects you may get. See the end of section 4 for how 
to report side effects. 
 
Read all of this leaflet carefully before you start using this medicine because it contains 
important information for you. 
- Keep this leaflet. You may need to read it again. 
- If you have any further questions, ask your doctor, pharmacist or nurse. 
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours. 
- If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible 

side effects not listed in this leaflet. See section 4. 
 
What is in this leaflet 
 
1. What Palynziq is and what it is used for  
2. What you need to know before you use Palynziq 
3. How to use Palynziq 
4. Possible side effects 
5. How to store Palynziq 
6. Contents of the pack and other information 
 
 
1. What Palynziq is and what it is used for 
 
Palynziq contains the active substance pegvaliase, an enzyme that can break down a substance called 
phenylalanine in the body. Palynziq is a treatment for patients aged 16 years and older with 
phenylketonuria (PKU), a rare inherited disorder that causes phenylalanine from proteins in food to 
build up in the body. People who have PKU have high levels of phenylalanine and this can lead to 
serious health problems. Palynziq reduces the levels of phenylalanine in the blood of patients who 
have PKU whose blood phenylalanine levels cannot be kept below 600 micromol/l by other means 
such as by diet.  
 
 
2. What you need to know before you use Palynziq 
 
Do not use Palynziq 
 
- if you have a severe allergy to pegvaliase or any other ingredients of this medicine, or another 

medicine that contains polyethylene glycol (PEG) (listed in section 6). 
 
Warnings and precautions 
 
Talk to your doctor, pharmacist, or nurse before using Palynziq. 
 
Allergic reactions  
You may have allergic reactions when being treated with Palynziq. Your doctor will tell you how to 
manage your allergic reactions based on the severity of the reaction, and will prescribe you additional 
medicines to manage the reaction. 
 

42 



Before using Palynziq, tell your doctor if you cannot use or do not want to use an adrenaline injection 
device to treat a severe allergic reaction to Palynziq. 
 
Palynziq can cause severe allergic reactions that may be life-threatening and these can happen any 
time after a Palynziq injection.  
 
 Stop injecting Palynziq if any of the following symptoms occur.  

 
- Swelling of the face, eyes, lips, mouth, throat, tongue, hands and/or feet 
- Trouble breathing or wheezing 
- Throat tightness or choking feeling 
- Trouble swallowing or speaking 
- Feeling dizzy or fainting 
- Losing control of urine or stools 
- Rapid heartbeat 
- Hives (like an itchy, bumpy skin rash) that spreads quickly  
- Flushing 
- Severe stomach cramps or pain, vomiting, or diarrhoea 

 
 Use adrenaline injection device as instructed by your doctor and seek urgent medical 

assistance.  
 

Your doctor will prescribe an adrenaline injection device to use for a severe allergic reaction. Your 
doctor will train you and someone helping you on when and how to use adrenaline. Keep the 
adrenaline injection device with you at all times.  
 
For at least the first 6 months of treatment, someone must be with you when you are self-injecting 
Palynziq. This person must stay with you for at least 1 hour after your injection to watch you for signs 
and symptoms of a severe allergic reaction and, if needed, give you an injection of adrenaline and call 
for emergency medical help. 
 
If you have a severe allergic reaction, do not continue to use Palynziq until you have talked with the 
doctor who prescribes you Palynziq. Tell your doctor that you had a severe allergic reaction. Your 
doctor will tell you if you can continue Palynziq treatment. 
 
Time needed to lower your blood phenylalanine levels 
Your doctor will start you on Palynziq at a low dose and will increase your dose slowly. It will take 
time to find the dose that works best to lower your blood phenylalanine levels. Most people respond 
within 18 months, but it can sometimes take up to 30 months. 
 
Injection of other medicines that contain PEG while using Palynziq  
Palynziq includes an ingredient called polyethylene glycol (PEG). If you inject Palynziq with another 
injectable medicine that contains PEG, such as PEGylated medroxyprogesterone acetate, you may 
have an allergic reaction. Tell your doctor or pharmacist if you are injecting, have recently injected or 
might inject any other medicines. 
 
Blood phenylalanine levels that are too low 
You may have blood phenylalanine levels that are too low when using Palynziq. Your doctor will 
check your blood phenylalanine levels monthly. If your blood phenylalanine levels are too low, your 
doctor may ask you to change your diet and/or will lower your dose of Palynziq. Your doctor will 
check your blood phenylalanine levels every 2 weeks until your blood phenylalanine levels return to 
normal. 
 
Children and adolescents 
It is not known if Palynziq is safe and effective in children and adolescents less than 16 years of age 
with PKU and therefore should not be used in people aged less than 16 years. 
 

43 



Other medicines and Palynziq 
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other 
medicines.  
 
Pregnancy, breast-feeding and fertility 
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask 
your doctor for advice before using this medicine. 
 
Palynziq is not recommended during pregnancy unless your condition requires treatment with 
Palynziq and other ways of controlling your blood phenylalanine levels do not work. If your 
phenylalanine levels are too high or too low during pregnancy, this may harm you or your baby. You 
and your doctor will decide the best way for you to manage your blood phenylalanine levels. It is very 
important to keep your phenylalanine levels under control before and during pregnancy. 
 
It is not known if Palynziq passes into breast milk or if it will affect your baby. Talk to your healthcare 
provider about the best way to feed your baby if you use Palynziq. 
 
It is not known if Palynziq has an effect on fertility. Animal studies suggest that women may have 
difficulty becoming pregnant if their phenylalanine levels are abnormally low. 
 
Driving and using machines 
Palynziq can affect your ability to drive and use machines if you have a severe allergic reaction. 
 
Palynziq contains sodium  
This medicine contains less than 1 mmol sodium (23 mg) per pre-filled syringe, that is to say 
essentially ‘sodium-free’. 
 
 
3. How to use Palynziq 
 
Always use this medicine exactly as your doctor has told you. Check with your doctor if you are not 
sure. 
 
Palynziq is given as an injection under the skin (subcutaneous injection). 
 
Dose 

 
 You will start Palynziq at the lowest dose. You will use the 2.5 mg syringe once a week for at 

least the first 4 weeks. The 2.5 mg syringe has a white plunger.  
 Your doctor will then slowly increase your dose and/or how often you inject Palynziq. Your 

doctor will tell you how long to stay at each dose. Slowly increasing your dose over time allows 
your body to adjust to this medicine.  

 The goal is to reach a daily dose that lowers your blood phenylalanine levels to within the target 
range of 120 to 600 micromol/l and does not cause too many side effects. Patients usually need 
a daily dose of 20 mg, 40 mg, or 60 mg to reach their target blood phenylalanine level. 

 

44 



Example of steps to reach your blood phenylalanine goal 
 

Palynziq dose and how often to take it Syringe colour 
 

2.5 mg once a week 
2.5 mg two times a week 

White plunger 

10 mg once a week 
10 mg twice a week 
10 mg four times a week 
10 mg daily 

Green plunger 
 

20 mg daily 
40 mg daily 
(2 injections of 20 mg pre-filled syringe)1 
60 mg daily 
(3 injections of 20 mg pre-filled syringe)1 

Blue plunger 
 

1 If you need more than one injection to receive your daily dose, 
all injections should be done at the same time of day and 
injection sites should be at least 5 centimetres away from each 
other. Do not divide your daily dose throughout the day. 

 
 Your doctor will continue to check your blood phenylalanine levels during treatment and may 

adjust your dose of Palynziq or ask you to change your diet. 
 Your doctor will need to check your blood phenylalanine monthly to see if this medicine is 

working for you.  
 
Starting Palynziq 
 
 Your healthcare provider will give you the Palynziq injection until you (or a caregiver) can do it 

yourself.  
 Your doctor will prescribe medicines for you to take before your Palynziq injection, such as 

paracetamol, fexofenadine, and/or ranitidine. These medicines help to reduce the symptoms of 
an allergic reaction. 

 A healthcare provider will monitor you for at least 1 hour after you get Palynziq for signs and 
symptoms of an allergic reaction. 

 Your doctor will also prescribe adrenaline injection device to use for any severe allergic 
reactions. Your healthcare provider will also tell you which signs and symptoms to look out for 
and what to do if you have a severe allergic reaction. 

 Your doctor will show you how and when to use the adrenaline injection device. Keep it with 
you at all times.  

 
Continuing Palynziq 
 
 This medicine comes in pre-filled syringes with 3 different strengths (2.5 mg-white plunger, 

10 mg-green plunger, or 20 mg-blue plunger). You may need more than one pre-filled syringe 
for your prescribed dose. Your healthcare provider will tell you which syringe, or a combination 
of syringes, to use and will show you (or a caregiver) how to inject Palynziq.  

 The “Instructions for Use” (section 7 of this leaflet) shows you: 
o how to prepare and inject Palynziq and 
o how to throw away Palynziq syringes properly after you use them 

 Your doctor will tell you how long to continue taking medicines such as paracetamol, 
fexofenadine, and/or ranitidine before you take Palynziq. 

 For at least the first 6 months of Palynziq treatment, you must have someone with you when 
you self-inject Palynziq, and for at least 1 hour after your injection to watch for signs and 
symptoms of a severe allergic reaction and, if needed, give you an injection of adrenaline and 
call for emergency medical help.  
o Your doctor will train them on the signs and symptoms of a severe allergic reaction and 

how to give an injection of adrenaline. 

45 



o Your doctor will tell you if you need an observer for longer than 6 months.  
 Do not change your protein intake unless your doctor tells you to. 
 
If you use more Palynziq than you should 
If you use more Palynziq than you should, tell your doctor. See section 4 for details on what to do 
based on your symptoms.  
 
If you forget to use Palynziq 
If you miss a dose, take your next dose at the regular time. Do not take two doses of Palynziq to make 
up for a missed dose. 
 
If you stop taking Palynziq 
If you stop taking Palynziq treatment, your blood phenylalanine levels are likely to increase. Talk to 
your doctor before stopping Palynziq treatment. 
 
If you have any further questions on the use of this medicine, ask your doctor. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. 
 
Allergic reactions occur very commonly (may affect more than 1 in 10 people) and range in severity. 
Symptoms of allergic reaction can include skin rash, itching, swelling of head or face, itchy or runny 
eyes, cough, and wheezing. Your doctor will tell you how to manage any allergic reactions based on 
their severity, and will prescribe you additional medicines to manage the reaction. Some of these 
allergic reactions can be more serious, as described below, and will require immediate attention.  
 
Serious side effects include: 
 
- Sudden severe allergic reactions: (Common – may affect up to 1 in 10 people). Stop injecting 

Palynziq if you notice any serious sudden signs of allergy or combination of signs listed below. 
o Swelling of the face, eyes, lips, mouth, throat, tongue, hands and/or feet 
o Trouble breathing or wheezing 
o Throat tightness or a choking feeling 
o Trouble swallowing or speaking 
o Feeling dizzy or fainting 
o Losing control of urine or stools 
o Rapid heartbeat 
o Hives (like an itchy, bumpy skin rash) that spreads quickly  
o Flushing 
o Severe stomach cramps or pain, vomiting, or diarrhoea 

 
Use adrenaline injection device as instructed by your doctor and seek urgent medical 
assistance. Your doctor will prescribe an adrenaline injection device to use for a severe allergic 
reaction. Your doctor will train and instruct you and someone helping you on when and how to 
use adrenaline. Keep the adrenaline injection device with you at all times. 

 
Contact your doctor immediately if you have the following: 
- A type of allergic reaction called serum sickness which includes a combination of fever (high 

temperature), rash, muscle and joint aches (Common – may affect up to 1 in 10 people) 
 
Other side effects 
 
Very common: may affect more than 1 in 10 people 
- skin redness, swelling, bruising, tenderness, or pain where you injected Palynziq 
- joint pain 

46 



- decrease in complement factors C3 and C4 proteins (which are parts of your immune system) in 
blood test 

- allergic reaction 
- too low levels of phenylalanine in blood tests 
- headache 
- skin rash 
- stomach pain 
- feeling sick, also called nausea 
- vomiting 
- hives (raised itchy rash on the skin) 
- itchiness 
- thinning or loss of hair 
- cough 
- increase in c-reactive protein (CRP) in blood test (CRP is a protein that indicates that you have 

inflammation) 
- swollen glands in the neck, armpit or groin 
- skin redness 
- muscle pain 

 
Common: may affect up to 1 in 10 people 
- joint stiffness 
- joint swelling 
- muscle stiffness 
- skin rash with small bumps 
- blistering or peeling of the outer layer of the skin 
 
Reporting of side effects 
If you get any side effects, talk to your doctor, pharmacist, or nurse. This includes any possible side 
effects not listed in this leaflet. You can also report side effects directly via the national reporting 
system listed in Appendix V. By reporting side effects, you can help provide more information on the 
safety of this medicine. 
 
 
5. How to store Palynziq 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date which is stated on the syringe label, tray cover, and 
carton after “EXP”. The expiry date refers to the last day of that month. 
 
Store in a refrigerator (2°C – 8°C). Do not freeze. 
 
If needed, you may store Palynziq in its sealed tray outside the refrigerator (below 25°C) for up to a 
single period of 30 days away from sources of heat. Record the date removed from refrigeration on the 
unopened product tray. Once stored outside of refrigeration, the product must not be returned to the 
refrigerator. 
 
Do not use this medicine if the pre-filled syringe is damaged or you notice the solution is discoloured, 
cloudy, or if you can see particles. 
 
Use safe disposal procedures for syringes. Do not throw away any medicines via wastewater or 
household waste. Ask your pharmacist how to throw away medicines you no longer use. These 
measures will help protect the environment. 
 
 

47 

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6. Contents of the pack and other information 
 
What Palynziq contains  
- The active substance is pegvaliase. 

Each 2.5 mg pre-filled syringe contains 2.5 mg pegvaliase in 0.5 ml solution. 
Each 10 mg pre-filled syringe contains 10 mg pegvaliase in 0.5 ml solution. 
Each 20 mg pre-filled syringe contains 20 mg pegvaliase in 1 ml solution. 

- The other ingredients are trometamol, trometamol hydrochloride, sodium chloride (see section 2 
for further information), trans-cinnamic acid, water for injections. 

 
What Palynziq looks like and contents of the pack 
Palynziq solution for injection (injection) is a clear to slightly opalescent, colourless to pale yellow 
solution. The pre-filled syringe includes an automatic needle guard. 
 
Pre-filled syringe 2.5 mg (white plunger): 
Each 2.5 mg carton contains 1 pre-filled syringe. 
 
Pre-filled syringe 10 mg (green plunger): 
Each 10 mg carton contains 1 pre-filled syringe. 
 
Pre-filled syringe 20 mg (blue plunger): 
Each 20 mg carton contains 1 or 10 pre-filled syringes.  
 
Not all pack sizes may be marketed. 
 
Marketing Authorisation Holder and Manufacturer 
BioMarin International Limited 
Shanbally, Ringaskiddy  
County Cork  
Ireland 
P43 R298 
 
This leaflet was last revised in MM/YYYY. 
 
Other sources of information 
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu. There are also links to other websites about rare diseases and treatments. 
 
 
7. Instructions for use  
 
BEFORE YOU START 
 
Read this Instructions for use before you start using the Palynziq pre-filled syringe and each time you 
get a new prescription. There may be new information. Also, talk to your healthcare provider about 
your medical condition or your treatment. 
 
Follow these instructions carefully while you are using Palynziq. If your healthcare provider decides 
that you or your caregiver can give your injections of Palynziq at home, your healthcare provider will 
show you or your caregiver how to inject Palynziq before you inject it for the first time. Do not inject 
Palynziq until your healthcare provider has shown you or your caregiver how to inject Palynziq. 
 
Talk to your healthcare provider if you have any questions about how to inject Palynziq the right way. 
 
Do not share your pre-filled syringes with anyone else.  
 

48 

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For storage instructions, refer to section 5 “How to store Palynziq” of this leaflet.  
 

Important things to know about using your Palynziq pre-filled syringe: 
 

 Use each Palynziq pre-filled syringe once only. Do not use a Palynziq syringe more than 
once. 

 Never pull back on the plunger. 
 Do not remove the needle cap until you are ready to inject.  

 
Figure A below shows what the pre-filled syringe looks like before use. 
 

Figure A 

 
 
Select the correct Palynziq pre-filled syringe(s) for your dose: 
When you receive your Palynziq pre-filled syringe(s), check that the name “Palynziq” appears on the 
carton(s). 

 Palynziq pre-filled syringes come in 3 different strengths: 2.5 mg, 10 mg, and 20 mg. 
 You may need more than one pre-filled syringe for your prescribed dose. Your healthcare 

provider will tell you which syringe, or combination of syringes, to use. Ask your 
healthcare provider if you have any questions. 

 Before you inject Palynziq, check each carton and syringe to make sure you have the 
right pre-filled syringe for your prescribed dose. 

 
Figure B 

 
 
PREPARING FOR INJECTION 
 
Step 1: Collect supplies: 
Gather your supplies for the injection and place them on a clean flat surface. Take out the required 
number of cartons needed for your dose from the refrigerator. 
 

49 



Supplies you will need for your Palynziq Injection: 
 Palynziq pre-filled syringe(s) in sealed tray(s). Each tray contains 1 syringe. 
 gauze pad or cotton ball 
 1 alcohol pad 
 1 bandage 
 1 sharps disposal or puncture resistant container 

 
Step 2: Remove Palynziq tray(s) from carton and check expiry date: 
- Take out the cartons needed for your dose from the refrigerator. Check the expiry date on the 

carton. If the expiry date has passed, do not use the pre-filled syringe in that carton. 
- Open each carton and take out the sealed tray you need for your dose. 
- Place each sealed tray on a clean, flat surface out of reach of children and pets. 
- Put the carton with any remaining trays back in the refrigerator. If a refrigerator is not available, 

see section 5 “How to store Palynziq” in this leaflet. 
 
Step 3: Allow Palynziq tray(s) to sit at room temperature for 30 minutes before opening: 
Let the sealed tray(s) sit at room temperature for at least 30 minutes. Injecting cold Palynziq can be 
uncomfortable. 
- Do not warm up the pre-filled syringe in any other way. Do not use a microwave and do not 

place in hot water. 
 
Step 4: Remove syringe from tray: 
Peel the cover from the tray. Hold the middle of the 
pre-filled syringe body and take out the pre-filled 
syringe from the tray (see Figure C). 

 Do not use the pre-filled syringe if it 
looks damaged or used. Use a new 
pre-filled syringe for your injection. 

 Do not remove the needle cap from your 
pre-filled syringe. 

 Do not shake or roll the syringe in your 
hands. 

 

Figure C 

 

 
Step 5: Check syringe strength and check for particles: 
 
Check the syringe label to make sure you have the 
correct strength for your prescribed dose. Look at the 
liquid through the viewing window (see Figure D). 
The liquid should look clear and colourless to pale 
yellow. It is normal to see an air bubble. 

 Do not flick or try to push the bubble out. 
 Do not use the pre-filled syringe if the 

liquid is cloudy, discoloured, or has 
lumps or particles in it. Use a new 
pre-filled syringe for your injection. 

 

Figure D 

 

50 



INJECTING PALYNZIQ  
 
Step 6: Choose your injection site. 
 
The recommended injection sites are: 

 Front middle of the thighs. 
 Lower part of the abdomen except for the 

5 centimetre area around the belly button 
(navel). 

 
If a caregiver is giving the injection, the top of the 
buttocks and the back of the upper arms may also be 
used (see Figure E).  
 
Note: 

 Do not inject into moles, scars, 
birthmarks, bruises, rashes, or areas 
where the skin is hard, tender, red, 
damaged, burned, inflamed, or tattooed.  

 If you need more than 1 injection for your 
daily dose, the injection sites should be at 
least 5 centimetres away from each other 
(see Figures E and F). 

 Each day, change (rotate) your injection 
sites. Choose an injection site that is at 
least 5 centimetres away from the 
injection site(s) you used the day before. 
It can be on the same part of the body or a 
different part of the body (see Figures E 
and F). 

 

Figure E 

 
 

Figure F 
Inject at least 5 cm apart 

 

Step 7: Wash your hands well with soap and water 
(see Figure G). 
 
 
 
 
 
 
 
 

Figure G 

 

Step 8: Clean the chosen site with an alcohol pad. Let 
the skin air dry for at least 10 seconds before injecting 
(see Figure H). 

 Do not touch the cleaned injection site. 
 Do not remove the needle cap until you 

are ready to inject Palynziq. 
 Before injecting, check to make sure the 

needle is not damaged or bent. 
 

Figure H 

 

 
 

51 



Inject Palynziq  
 
Step 9: Hold the body of the pre-filled syringe with one hand 
with the needle facing away from you (see Figure I). 

 Do not use the pre-filled syringe if it has been 
dropped. Use a new pre-filled syringe for your 
injection. 

 
 
 
 
 
 
 
 

Figure I 

 

Step 10: Pull the needle cap straight off the needle 
(see Figure J). 
 

 Do not twist the needle cap during removal.  
 Do not hold the pre-filled syringe by the plunger 

or plunger head while taking the needle cap off. 
 
You may see a drop of liquid on the tip of the needle. This is 
normal. Do not wipe it away. Throw the needle cap away in a 
sharps disposal or puncture-resistant container. 
 
 
 
 
 
 

Figure J 

 

Step 11: Hold the body of the pre-filled syringe in 1 hand 
between your thumb and index finger. Use your other hand to 
pinch up the skin around the injection site. Hold the skin 
firmly (see Figure K). 
 

 Do not touch the plunger head while inserting 
the needle into the skin. 

 
 
 

Figure K 

 
 
 
Step 12: Use a quick motion to fully insert the needle into the 
pinched skin at a 45 to 90 degree angle (see Figure L).  
 
Release the pinch of skin. Use that hand to hold the bottom of 
the syringe steady. Place the thumb of your other hand on the 
plunger head (see Figure L). 
 
 

 
Figure L 

52 



Step 13: Use your thumb to push in the plunger slowly and 
steadily as far as it will go to inject all the medicine 
(see Figure M). More pressure may be needed to inject all the 
medicine for the 10 mg and 20 mg strengths. 
 
 
 
 
 
 
 
 
 

Figure M 

 

Step 14: Slowly move your thumb up to release the plunger 
allowing the needle to automatically be covered by the syringe 
body (see Figure N). 
 
 
 

Figure N 

 
Treat injection site 
 
Step 15: Treat injection site (if needed). 
 
If you see drops of blood at the injection site, press a sterile 
cotton ball or gauze over the injection site and hold for about 
10 seconds. You may cover the injection site with an adhesive 
bandage if needed. 
 

 

If more than one syringe is needed: 
 
Step 16: If your health care provider tells you to use more 
than one syringe for your dose, repeat Steps 4 to 15 listed 
above for each syringe that you use. 
 

 Note: Do not inject multiple injections in the 
same spot. The injection sites should be at least 
5 centimetres away from each other. See Step 6 
for choosing an injection site. 

 If multiple syringes are needed for a single dose, 
you should inject at the same time of day. Doses 
should not be divided over the course of the day 

 
 

 
 

If your dose requires more 
than one syringe, repeat 

Steps 4 to 15 immediately for 
each syringe you use. 

 
AFTER THE INJECTION 
 
Dispose of the used syringes 
Put your used needles and syringes in a sharps disposal or puncture-resistant container right away after 
use. Check with your doctor, pharmacist or nurse about the right way to throw away the container. Use 
safe disposal procedures for syringes.  
 

53 


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER(S) OF THE BIOLOGICAL ACTIVE SUBSTANCE(S) AND MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET