PALYNZIQ Solution for injection Ref.[113789] Active ingredients: Pegvaliase

Traceability

In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.

Hypersensitivity reactions

Hypersensitivity reactions cover a group of terms that comprises acute systemic hypersensitivity reactions, other systemic hypersensitivity reactions such as angioedema and serum sickness which may have an acute or chronic presentation, and local hypersensitivity reactions such as injection site reactions or other skin reactions. Hypersensitivity reactions including anaphylaxis 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). The risk of a hypersensitivity reaction is 2.6-fold higher in induction/titration phase compared to the maintenance phase.

Management of hypersensitivity reactions should be based on the severity of the reaction; in clinical trials, this has included dose adjustment, treatment interruption or discontinuation, additional antihistamines, antipyretics, corticosteroids, adrenaline, and/or oxygen (see sections 4.2, Method of administration and 4.8).

Acute systemic hypersensitivity reactions (Type III)

The underlying mechanism for acute systemic hypersensitivity reactions observed in clinical trials was non-IgE mediated Type III (immune-complex mediated) hypersensitivity (see sections 4.3 and 4.8). Manifestations of acute systemic hypersensitivity reactions 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). Acute systemic hypersensitivity reactions were 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. Four out of 16 (1%, 4/285) patients experienced a total of 5 episodes of acute systemic hypersensitivity reactions that were considered severe. The risk of an acute systemic hypersensitivity reaction occurring is 6-fold higher in induction/titration phase compared to maintenance phase.

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 an 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 emergency use of the adrenaline injection device, and the requirement to seek immediate medical care. The risks associated with adrenaline use should be reconsidered when prescribing Palynziq. Refer to the adrenaline product information for complete information. For 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).

Due to the potential for acute systemic hypersensitivity reactions, 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).

Other systemic hypersensitivity reactions

For other severe systemic hypersensitivity reactions (e.g. anaphylaxis, severe angioedema, severe serum sickness), patients should seek immediate medical care and Palynziq should be permanently discontinued (see section 4.3).

Re-administering following an acute systemic hypersensitivity reaction

The prescribing physician should consider the risks and benefits of re-administering the medicinal product following resolution of the first mild to moderate acute systemic hypersensitivity reaction. Upon re-administration, the first dose must be administered with premedication under the supervision of a healthcare professional with the ability to manage acute systemic hypersensitivity reactions. The 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 54 months. The majority of patients (67%) reached a response by 18 months of total treatment. An additional 8% 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, 46% of the patients developed hypophenylalaninaemia (blood phenylalanine levels below 30 micromol/l on two consecutive measurements). The risk of hypophenylalaninaemia occurring is 2.1-fold higher in the maintenance phase compared to the induction/titration phase (see section 4.8).

Monitoring of blood phenylalanine level is recommended once a month. In case of hypophenylalaninaemia, 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 medicinal product contains less than 1 mmol sodium (23 mg) per pre-filled syringe, that is to say essentially ‘sodium-free’.

No interaction studies have been performed.

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).

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.

Summary of the safety profile

In clinical trials, the majority of patients experienced injection site reactions (93%), arthralgia (86%), 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 from clinical trials in patients treated with Palynziq.

Frequencies are defined as: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1 000 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.

Table 2. Adverse reactions in patients treated with Palynziq:

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, dizziness, dyspnoea, rash, serum sickness, and urticaria.
³ Refer to Special Warnings and Precautions.
⁴ The frequency of anaphylaxis in the post-marketing setting cannot be determined.
⁵ Abdominal pain reflects the following terms: abdominal pain, abdominal pain upper and abdominal discomfort.
⁶ Complement factor C3/C4 decrease is defined by changing from normal or high baseline complement value to low post-baseline complement value.
⁷ 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

Arthralgia and other joint related signs and symptoms

In clinical trials, 86% of 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. The risk of arthralgia occurring is 3.1-fold higher in induction/titration phase compared to maintenance phase.

Severe arthralgia (severe pain limiting self-care activities of daily living) was experienced in 5% of patients. Arthralgia episodes were managed with concomitant medicinal products (e.g. nonsteroidal anti-inflammatory drugs, glucocorticoids, and/or antipyretic), dose reduction, treatment interruption, or treatment withdrawal, and 97% of arthralgia episodes resolved by the time of study completion.

Persistent arthralgia (lasting at least 6 months) occurred in 7% of patients. Dose was not changed for 96% of episodes and all persistent arthralgia episodes resolved without sequelae.

Injection site reactions

Injection site reactions were reported in 93% of 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. The risk of injection site reactions occurring is 5.2-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 10 days, and 99% of injection site reactions resolved by the time of study completion.

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, 47% of patients treated with Palynziq experienced cutaneous reactions (not limited to the injection site) lasting at least 14 days. 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, rash, erythema, and urticaria. Other reactions reported included skin exfoliation, generalised rash, erythematous rash, maculo-papular rash, and pruritic rash. The mean (SD) duration of these reactions was 63 (76) days, and 86% of these reactions resolved by the time of study completion.

Immunogenicity

All patients treated with Palynziq developed a sustained total anti-pegvaliase antibody (TAb) response with nearly all patients becoming positive by Week 4. Mean TAb titres were sustained through long-term treatment (greater than 3 years after treatment initiation). Anti-phenylalanine ammonia lyase (PAL) IgM was detected in nearly all treated patients by 2 months after treatment initiation, with incidence and mean titres gradually declining over time. Anti-PAL IgG was detected in nearly all patients by 4 months and mean titres were relatively stable through long-term treatment. Pegvaliase induced anti-PEG IgM and IgG responses were detected in nearly all patients, with mean titres peaking at 1 to 3 months after treatment initiation and returning to baseline levels in most patients by 6 to 9 months after treatment initiation. Neutralising antibodies (NAb) capable of inhibiting PAL enzyme activity were detected in a majority of patients by 1 year after treatment initiation and mean titres were relatively stable 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 levels returned towards baseline. Presence of antibody titres was 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.

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.