Source: European Medicines Agency (EU) Revision Year: 2022 Publisher: Genzyme Europe B.V., Paasheuvelweg 25, 1105 BP Amsterdam, The Netherlands
Life-threatening hypersensitivity (anaphylactic reaction) to olipudase alfa or to any of the excipients listed in section 6.1 (see section 4.4).
In order to improve the traceability of biological medicinal products, the name and the batch number of the administered medicinal product should be clearly recorded.
Xenpozyme is not expected to cross the blood-brain barrier or modulate the CNS manifestations of the disease.
IARs occurred in approximately 58% of patients treated with Xenpozyme in clinical studies. These IARs included hypersensitivity reactions and acute phase reactions (see section 4.8). The most frequent IARs were headache, urticaria, pyrexia, nausea and vomiting (see section 4.8). IARs typically occurred between the time of infusion and up to 24 hours after infusion completion.
Hypersensitivity reactions, including anaphylaxis, have been reported in Xenpozyme-treated patients (see section 4.8). In clinical studies, hypersensitivity reactions occurred in 7 (17.5%) adult and 9 (45%) paediatric patients including one paediatric patient who experienced anaphylaxis.
Patients should be observed closely during and for an appropriate period of time after the infusion, based on clinical judgement. Patients must be informed of the potential symptoms of hypersensitivity/anaphylaxis and instructed to seek immediate medical care should symptoms occur. IARs management should be based on the severity of signs and symptoms and may include temporarily interrupting the Xenpozyme infusion, lowering the infusion rate, and/or appropriate medical treatment.
If severe hypersensitivity or anaphylaxis occurs, Xenpozyme should be discontinued immediately, and appropriate medical treatment should be initiated. The patient who experienced anaphylaxis in the clinical study underwent a tailored desensitization regimen that enabled the patient to resume long term treatment with Xenpozyme at the recommended maintenance dose. The prescriber should evaluate the risks and benefits of Xenpozyme re-administration following anaphylaxis or severe hypersensitivity reaction. If considering re-administration of Xenpozyme following anaphylaxis, the prescribing physician should contact the local Sanofi representative for advice on re-administration. In such patients, extreme caution should be exercised, with appropriate resuscitation measures available, when Xenpozyme is readministered.
If mild or moderate IARs occur, the infusion rate may be slowed or temporarily stopped, the duration of each step for an individual infusion increased, and/or the Xenpozyme dose reduced. If a patient requires a dose reduction, re-escalation should follow dose escalation described in Table 1 and Table 2 for adult and paediatric patients, respectively (see section 4.2).
Patients may be pre-treated with antihistamines, antipyretics, and/or glucocorticoids to prevent or reduce allergic reactions.
Treatment-emergent antidrug antibodies (ADA) were reported in adult and paediatric patients during the clinical trials (see section 4.8). IARs and hypersensitivity reactions may occur independent of the development of ADA. The majority of IARs and hypersensitivity reactions were mild or moderate and were managed with standard clinical practices.
IgE ADA testing may be considered for patients who experienced a severe hypersensitivity reaction to olipudase alfa. While in clinical studies, no loss of efficacy was reported, IgG ADA testing may be considered in case of loss of response to therapy.
Transient transaminase elevations (ALT or AST) within 24 to 48 hours after infusions were reported during the dose escalation phase with Xenpozyme in clinical studies (see section 4.8). At the time of the next scheduled infusion, these elevated transaminase levels generally returned to the levels observed prior to the Xenpozyme infusion.
Transaminases (ALT and AST) levels should be obtained within 1 month prior to Xenpozyme treatment initiation (see section 4.2). During dose escalation or upon resuming treatment following missed doses, transaminases levels should be obtained within 72 hours prior to the next scheduled Xenpozyme infusion. If either the baseline or a pre-infusion transaminase level is >2 times the ULN during dose escalation, then additional transaminase levels should be obtained within 72 hours after the end of the infusion. If the pre-infusion transaminase levels are elevated above baseline and >2 times the ULN, the Xenpozyme dose can be adjusted (prior dose repeated or reduced) or treatment can be temporarily withheld in accordance with the degree of transaminase elevation (see section 4.2). Upon reaching the recommended maintenance dose, transaminase testing can be performed as part of routine clinical management of ASMD.
This medicinal product contains 3.02 mg sodium per vial, equivalent to 0.15% of the WHO recommended maximum daily intake of 2 g sodium for an adult or an adolescent, and ≤0. 38% of the maximum acceptable daily intake of sodium for children below 16 years of age.
No drug interaction studies have been performed. Because olipudase alfa is a recombinant human protein, no cytochrome P450 mediated drug-drug interactions are expected.
There are no data from the use of olipudase alfa in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). Xenpozyme is not recommended during pregnancy and in women of childbearing potential not using contraception, unless the potential benefits to the mother outweigh the potential risks, including those to the foetus.
It is unknown whether olipudase alfa is excreted in human milk. There is insufficient information on the excretion of olipudase alfa in animal milk. A risk to the newborns/infants cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue Xenpozyme therapy taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman.
No human data are available on the effects of olipudase alfa on male and female fertility. Animal data do not indicate direct or indirect harmful effects with respect to fertility (see section 5.3).
Because hypotension has been reported in clinical studies, Xenpozyme may have minor influence on the ability to drive and use machines (see section 4.8).
Serious adverse reactions reported in patients treated with Xenpozyme were an event of extrasystoles in the context of a history of cardiomyopathy in 1 (2.5%) adult patient, and anaphylactic reaction, urticaria, rash, hypersensitivity, and alanine aminotransferase level increase, each in 1 (5%) paediatric patient. The incidence of serious hypersensitivity-related IARs were higher in paediatric patients compared to adults
The most frequently reported adverse drug reactions (ADRs) were headache (31.7%), pyrexia (25%), urticaria (21.7%), nausea (20%), vomiting (16.7%), abdominal pain (15%), myalgia (11.7%), pruritus (10%) and C-reactive protein increased (10%).
The pooled safety analysis from 4 clinical studies (a tolerability study in adult patients, ASCEND, ASCEND-Peds, and an extension study in adult and paediatric patients) included a total of 60 patients (40 adult and 20 paediatric patients) treated with Xenpozyme at doses up to 3 mg/kg every 2 weeks.
Adverse reactions reported in the pooled safety analysis of clinical studies are listed in Table 5 per System Organ Class, presented by frequency categories: 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).
Table 5. Adverse drug reactions in patients treated with Xenpozyme in pooled analysis of clinical studies:
| System Organ Class | Frequency | |
|---|---|---|
| Very common | Common | |
| Immune system disorders | Anaphylaxis and hypersensitivity | |
| Nervous system disorders | Headache | |
| Eye disorders | Ocular hyperaemia, ocular discomfort, eye pruritus | |
| Cardiac disorders | Palpitations, tachycardia | |
| Vascular disorders | Hypotension, hot flush, flushing | |
| Respiratory, thoracic, and mediastinal disorders | Pharyngeal oedema, pharyngeal swelling, throat tightness, wheezing, larynx irritation, dyspnoea, throat irritation | |
| Gastrointestinal disorders | Nausea, abdominal pain, vomiting | Diarrhoea, abdominal pain upper, abdominal discomfort, gastrointestinal pain |
| Hepatobiliary disorders | Hepatic pain | |
| Skin and subcutaneous tissue disorders | Urticaria, pruritus | Angioedema, fixed eruption, rash, rash papular, rash macular, rash maculopapular, rash erythematous, rash pruritic, rash morbilliform, papule, macule, erythema |
| Musculoskeletal and connective tissue disorders | Myalgia | Bone pain, arthralgia, back pain |
| General disorders and administration site conditions | Pyrexia | Pain, chills, catheter site pain, catheter site related reaction, catheter site pruritus, catheter site swelling, fatigue, asthenia |
| Investigations | C-reactive protein increased | Alanine aminotransferase increased, aspartate aminotransferase increased, serum ferritin increased, C-reactive protein abnormal, body temperature increased |
IARs were reported in 55% of adult and 65% of paediatric patients. IAR symptoms reported most frequently in adult patients were headache (22.5%), nausea (15%), urticaria (12.5%), arthralgia (10%), myalgia (10%), pyrexia (10%), pruritus (7.5%), vomiting (7.5%), and abdominal pain (7.5%). IAR symptoms reported most frequently in paediatric patients were pyrexia (40%), urticaria (35%), vomiting (30%), headache (20%), nausea (20%), and rash (15%). IARs typically occurred between the time of infusion and 24 hours after infusion end.
Hypersensitivity-related IARs, including anaphylaxis, occurred in 26.7% patients, 17.5% adult and 45% paediatric patients in clinical studies. The most frequently reported hypersensitivity-related IAR symptoms were urticaria (20%), pruritus (6.7%), erythema (6.7%), and rash (5%).
One paediatric patient in the clinical studies incurred a severe anaphylactic reaction. Also, independent of the clinical study program, a 16-month-old patient with ASMD type A treated with Xenpozyme experienced 2 anaphylactic reactions. Anti-olipudase alfa IgE antibodies were detected in both patients.
In 2 adults and 3 paediatric patients, IAR symptoms were associated with changes in laboratory parameters (e.g C-reactive protein, ferritin value) indicative of acute phase reaction.
Transient transaminase (ALT or AST) elevations within 24 to 48 hours after an infusion occurred in some patients treated with Xenpozyme during the dose escalation phase in the clinical studies. These elevations generally returned to the previous pre-infusion transaminase levels by the next scheduled infusion.
Overall, after 52 weeks of treatment with Xenpozyme, mean ALT decreased 45.9% and mean AST decreased 40.2%, compared to baseline. In adult patients, all 16 patients with an elevated baseline ALT had an ALT within the normal range and 10 of 12 patients with an elevated baseline AST had an AST within the normal range.
Overall, 16 out of 40 (40%) adult patients and 13 out of 20 (65%) paediatric patients treated with Xenpozyme developed treatment-emergent antidrug antibodies (ADA). The median time to seroconversion from first Xenpozyme infusion was approximately 33 weeks in adults and 10 weeks in paediatric patients. The majority of ADA-positive patients (11 out of 16 adult and 8 out of 13 paediatric patients) had a low ADA response (≤400) or reverted to ADA-negative. Four out of the 16 adult ADA-positive patients and 5 out of the 13 paediatric ADA-positive patients had Neutralizing Antibodies (NAb) that inhibited the olipudase alfa activity. Six patients developed NAbs at a single time point and 3 patients had an intermittent response. One paediatric patient had a treatment boosted ADA response. One paediatric patient experienced an anaphylactic reaction and developed IgE ADA, and IgG ADA with a peak titer of 1600.
No effect of ADA was observed on pharmacokinetics and efficacy of Xenpozyme in adult and paediatric populations. There was a higher percentage of patients with treatment-emergent IARs (including hypersensitivity reactions) in patients who developed treatment-emergent ADA versus those who did not (75.9% versus 41.9%).
Except for a higher incidence of hypersensitivity-related IARs in paediatric patients compared to adults, the safety profile of Xenpozyme in paediatric and adult patients was similar.
Overall, the pattern of adverse events observed in adult and paediatric patients in longer term use was consistent with that observed during the first year of treatment.
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.
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