4.1. Therapeutic indications

Xenpozyme is indicated as an enzyme replacement therapy for the treatment of non-Central Nervous System (CNS) manifestations of Acid Sphingomyelinase Deficiency (ASMD) in paediatric and adult patients with type A/B or type B.

4.2. Posology and method of administration

Xenpozyme treatment should be supervised by a healthcare professional experienced in the management of ASMD or other inherited metabolic disorders. Xenpozyme infusion should be administered by a healthcare professional with access to appropriate medical support to manage potential severe reactions such as serious systemic hypersensitivity reactions.

Posology

The rapid metabolism of accumulated sphingomyelin (SM) by olipudase alfa generates pro‑inflammatory breakdown products, which may induce infusion-associated reactions and/or transient liver enzyme elevations.

Treatment with Xenpozyme must always be initiated via a dose escalation regimen (see below) to minimise the risk of infusion-associated reactions, including acute phase reactions, and increases in liver transaminases. All instructions for dosage and administration (see below), and for preparation and handling (see section 6.6), should be followed to avoid the risk of overdose (see section 4.9). Please note that the dose escalation for paediatric patients differs from the one for adults. In addition to the dose escalation regimen, each dose must be administered using a staggered infusion rate (see Tables 3 and 4).

For missed doses see also below. Home infusion for patients should only be considered after the dose escalation phase.

Xenpozyme dose is based on the actual body weight for patient with a body mass index (BMI) ≤30 or an optimal body weight for patient with a BMI >30 (see section for patients with a BMI >30).

Adults

Dose escalation phase

The recommended starting dose of Xenpozyme is 0.1 mg/kg* for adults (also see missed doses subsection for additional guidance) and subsequently, the dose should be increased according to the dose escalation regimen presented in Table 1:

Table 1: Dose escalation regimen in adults

Adult patients (≥18 years old)

First dose (Day 1/Week 0)

0.1 mg/kg*

Second dose (Week 2)

0.3 mg/kg*

Third dose (Week 4)

0.3 mg/kg*

Fourth dose (Week 6)

0.6 mg/kg*

Fifth dose (Week 8)

0.6 mg/kg*

Sixth dose (Week 10)

1 mg/kg*

Seventh dose (Week 12)

2 mg/kg*

Eighth dose (Week 14)

3 mg/kg* (recommended maintenance dose)

*Actual body weight will be used for patients with a BMI ≤ 30. For patients with a BMI > 30, an optimal body weight will be used as described below.

Maintenance phase

The recommended maintenance dose of Xenpozyme is 3 mg/kg* every 2 weeks.

*Actual body weight will be used for patients with a BMI ≤30. For patients with a BMI> 30, an optimal body weight will be used as described below.

Paediatric population

Dose escalation phase

The recommended starting dose of Xenpozyme is 0.03 mg/kg* for paediatric patients, and the dose should be subsequently increased according to the dose escalation regimen presented in Table 2A:

Table 2A: Dose escalation regimen in paediatric patients

Paediatric patients (0 to <18 years old)

First dose (Day 1/Week 0)

0.03 mg/kg*

Second dose (Week 2)

0.1 mg/kg*

Third dose (Week 4)

0.3 mg/kg*

Fourth dose (Week 6)

0.3 mg/kg*

Fifth dose (Week 8)

0.6 mg/kg*

Sixth dose (Week 10)

0.6 mg/kg*

Seventh dose (Week 12)

1 mg/kg*

Eighth dose (Week 14)

2 mg/kg*

Ninth dose (Week 16)

3 mg/kg* (recommended maintenance dose)

*Actual body weight will be used for patients with a BMI ≤ 30. For patients with a BMI > 30, an optimal body weight will be used as described below.

Maintenance phase

The recommended maintenance dose of Xenpozyme is 3 mg/kg* every 2 weeks.

*Actual body weight will be used for patients with a BMI ≤30. For patients with a BMI >30, an optimal body weight will be used as described below.

Patients with BMI >30

In adult and paediatric patients with a body mass index (BMI) >30, the body weight that is used to calculate the dose of Xenpozyme is estimated via the following method (for dose escalation and maintenance phases).

Body weight (kg) to be used for dose calculation = 30 × (actual height in m)2

Example:

For a patient with:

BMI of 38

body weight of 110 kg

height of 1.7 m.

The dose to be administered will be calculated using a body weight of 30 × 1.72 = 86.7 kg.

Missed doses

A dose is considered missed when not administered within 3 days of the scheduled date. When a dose of Xenpozyme is missed, the next dose should be administered as described below as soon as possible. Thereafter, administrations should be scheduled every 2 weeks from the date of the last administration. The dose escalation regimen for administration of Xenpozyme prevents a rapid release of catabolites, which can result in serious toxicity such as hepatic inflammation/transaminase elevations, serious and life-threatening infusion associated reactions or even death (see section 4.4, 4.8 and 4.9). A patient who has not been largely debulked or has suspected re-accumulation, due to missed doses, should resume treatment at a lower dose.

Table 2B: Xenpozyme dosing recommendations for adult and paediatric patients after one or several missed dose(s).

Consecutive missed doses

Dose escalation phase

Maintenance phase

If 1 infusion is missed*:

The last tolerated dose should be administered, before resuming dose escalation according to the regimen in adults (Table 1) or in paediatric patients (Table 2A).

The maintenance dose should be administered and the treatment schedule adjusted accordingly.

If 2 consecutive infusions are missed*:

1 dose level lower than the last tolerated dose (using a minimal dose of 0.3 mg/kg) should be administered, before resuming dose escalation according to Table 1 or Table 2A.

1 dose below the maintenance dose (i.e. 2 mg/kg) should be administered. Then for subsequent infusions, the maintenance dose (3 mg/kg) every 2 weeks should be administered.

If 3 or more consecutive infusions are missed:

For adult patients who have not completed the dose escalation regimen, re-initiate the dose escalation regimen starting at first escalation dose described in Table 1.

For paediatric patients who have not completed the dose escalation regimen, re-initiate the dose escalation regimen starting at at the first escalation dose described in Table 2A.

For adult patients who have missed maintenance dosing for 3 or more consecutive doses during which sphingomyelin could have reaccumulated, the treating physician is advised to re-initiate the dose escalation regimen starting at the first escalation dose described in Table 1.

For paediatric patients who have missed maintenance dosing for 3 or more consecutive doses during which sphingomyelin could have reaccumulated, the treating physician is advised to re-initiate the dose escalation regimen starting at the first escalation dose described in Table 2A.

* In case the next scheduled infusion after a missed dose is a dose of 0.3 or 0.6 mg/kg, that dose should be administered twice as per Table 1 and Table 2A

Monitoring of transaminase level

Transaminase (alanine aminotransferase [ALT] and aspartate aminotransferase [AST]) levels should be obtained prior to treatment initiation and monitored during any dose escalation phases (see section 4.4). If the pre-infusion transaminase levels are elevated above baseline and >2 times the upper limit of normal (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. If a patient requires a dose adjustment or treatment interruption, treatment re-initiation should follow the dose escalation regimen described in Table 1 and Table 2A for adult and paediatric patients, respectively, and recommendations in case of missed doses (see missed doses section).

Special populations

Elderly patients

No dose adjustment is recommended for patients over the age of 65 (see section 5.2).

Hepatic impairment

No dose adjustment is recommended in patients with hepatic impairment (see section 5.2).

Renal impairment

No dose adjustment is recommended in patients with renal impairment (see section 5.2).

Method of administration

Xenpozyme is for intravenous use only. Infusions should be administered in a stepwise manner preferably using an infusion pump.

For instructions on reconstitution and dilution of the medicinal product before administration, see section 6.6.

After reconstitution and dilution, the solution is administered as an intravenous infusion. The infusion rates must be incrementally increased during the infusion only in the absence of infusion-associated reactions (in case of infusion-associated reactions, see section 4.4.). The infusion rate and duration of infusion (+/- 5 min) for each step of infusion are detailed in Table 3 and Table 4.

When determining the infusion rate in Tables 3 and 4, use the dose level from the dose escalation regimen, found in either Table 1 (adult) or Table 2A (paediatric patients).

Table 3: Infusion rates and duration of infusion in adult patients

Dose* (mg/kg)

Infusion rate

Duration of infusion

Approximate duration of infusion

step 1

step 2

step 3

step 4

0.1

20 mL/hr for 20 min

60 mL/hr for 15 min

NA

NA

35 min

0.3 to 3

3.33 mL/hr for 20 min

10 mL/hr for 20 min

20 mL/hr for 20 min

33.33 mL/hr for 160 min

220 min

hr: hour; min: minute; NA: Not applicable

*Dose level from the dose escalation regimen in Table 1

Table 4: Infusion rates and duration of infusion in paediatric patients

Dose* (mg/kg)

Infusion rate

Duration of infusion

Approximate duration of infusion

step 1

step 2

step 3

step 4

0.03

0.1 mg/kg/hr for the full length of the infusion

NA

NA

NA

18 min

0.1

0.1 mg/kg/hr for 20 min

0.3 mg/kg/hr onwards

NA

NA

35 min

0.3

0.1 mg/kg/hr for 20 min

0.3 mg/kg/hr for 20 min

0.6 mg/kg/hr onwards

NA

60 min

0.6

0.1 mg/kg/hr for 20 min

0.3 mg/kg/hr for 20 min

0.6 mg/kg/hr for 20 min

1 mg/kg/hr onwards

80 min

1

100 min

2

160 min

3

220 min

hr: hour; min: minute; NA: Not applicable

*Dose level from the dose escalation regimen in Table 2A

Signs and symptoms of infusion‑associated reactions (IARs), such as headache, urticaria, pyrexia, nausea and vomiting, and other signs or symptoms of hypersensitivity should be monitored during the infusion. Depending on the symptom severity, the infusion may be slowed, paused or discontinued and appropriate medical treatment initiated as needed.

In case of severe hypersensitivity and/or anaphylactic reaction, treatment with Xenpozyme should be discontinued immediately (see section 4.4).

At the end of infusion (once the syringe or infusion bag is empty), the infusion line should be flushed with sodium chloride 9 mg/mL (0.9%) solution for injection using the same infusion rate as the one used for the last part of the infusion.

Home infusion during maintenance phase

Home infusion under the supervision of a healthcare professional may be considered for patients on maintenance dose and who are tolerating their infusions well. The decision to have patients moved to home infusion should be made after evaluation and recommendation by the prescribing physician.

Appropriate medical support, including personnel trained in emergency measures, should be readily available when Xenpozyme is administered. If anaphylactic or other acute reactions occur, immediately discontinue the Xenpozyme infusion, initiate appropriate medical treatment and seek the attention of a physician. If severe hypersensitivity reactions occur, subsequent infusions should only occur in a setting where resuscitation measures are available. The dose and infusion rates used in the home settings should remain the same as were used in the supervised clinical settings, and should not be changed without supervision of the prescribing physician. In case of missed doses or delayed infusion, the prescribing physician should be contacted as subsequent infusions may occur in a supervised clinical setting.

4.3. Contraindications

Life-threatening hypersensitivity (anaphylactic reaction) to olipudase alfa or to any of the excipients listed in section 6.1 (see section 4.4).

4.4. Special warnings and precautions for use

Traceability

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.

Absence of blood-brain barrier transfer

Xenpozyme is not expected to cross the blood-brain barrier or modulate the CNS manifestations of the disease.

Infusion associated reactions (IARs)

IARs occurred in approximately 60% 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.

Serious adverse reactions, including death, have occurred following overdose during the dose escalation phase (see sections 4.2 and 4.9).

Hypersensitivity/anaphylaxis

Hypersensitivity reactions, including anaphylaxis, have been reported in Xenpozyme-treated patients (see section 4.8). In clinical studies, hypersensitivity reactions occurred in 9 (22.5%) adult and 9 (45%) paediatric patients including one paediatric patient who experienced anaphylaxis.

Management

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 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 patients with severe hypersensitivity, desensitisation procedure to Xenpozyme may be considered (see section 4.8). 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 2A 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.

Immunogenicity

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 transaminases elevation

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.

Sodium content

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.

4.5. Interaction with other medicinal products and other forms of interaction

No drug interaction studies have been performed. Because olipudase alfa is a recombinant human protein, no cytochrome P450 mediated drug-drug interactions are expected.

4.6. Fertility, pregnancy and lactation

Women of childbearing potential

Women of childbearing potential are advised to use effective contraception during treatment and for 14 days after the last dose if Xenpozyme is discontinued.

Pregnancy

There are limited 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 effective contraception, unless the potential benefits to the mother outweigh the potential risks, including those to the foetus.

Breast-feeding

It is unknown whether olipudase alfa is excreted in human milk. Olipudase alfa was detected in the milk of lactating mice (see section 5.3). 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.

Fertility

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).

4.7. Effects on ability to drive and use machines

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).

4.8. Undesirable effects

Summary of the safety profile

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. One adult patient discontinued due to recurrent adverse events of rash.

The most frequently reported adverse drug reactions (ADRs) were headache (31.7%), urticaria (26.7%), pyrexia (25%), nausea (20%), abdominal pain (16.7%), vomiting (16.7%), pruritus (13.3%), myalgia (13.3%), rash (11.7%), abdominal pain upper (10%), erythema (10%), and C-reactive protein increased (11.7%).

Tabulated list of adverse reactions

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, abdominal pain upper

Diarrhoea, abdominal discomfort, gastrointestinal pain

Hepatobiliary disorders

Hepatic pain

Skin and subcutaneous tissue disorders

Urticaria, pruritus, rash, erythema

Angioedema, fixed eruption, rash papular, rash macular, rash maculopapular, rash erythematous, rash pruritic, rash morbilliform, papule, macule

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

Description of selected adverse reactions

Infusion-associated reactions (IARs), including hypersensitivity/anaphylactic reactions

IARs were reported in 57.5% of adult and 65% of paediatric patients. IAR symptoms reported most frequently in adult patients were headache (25%), nausea (17.5%), urticaria (17.5%), myalgia (12.5%), arthralgia (10%), pyrexia (10%), pruritus (10%), vomiting (7.5%), abdominal pain (7.5%), erythema (7.5%) and fatigue (7.5%). IAR symptoms reported most frequently in paediatric patients were pyrexia (40%), urticaria (40%), vomiting (30%), C-reactive protein increased (20%), headache (20%), nausea (20%), erythema (15%), rash (15%), serum ferritin increased (15%), abdominal pain (10%), and pruritus (10%). IARs typically occurred between the time of infusion and 24 hours after infusion end.

Hypersensitivity-related IARs, including anaphylaxis, occurred in 30% patients, 22.5% adult and 45% paediatric patients in clinical studies. The most frequently reported hypersensitivity-related IAR symptoms were urticaria (25%), pruritus (10%), erythema (10%), and rash (8.3%).

Anaphylactic reactions were reported in paediatric patients in the clinical studies and in the post-marketing setting. Anti-olipudase alfa IgE antibodies were detected in some of those patients. Although a tailored desensitisation regimen enabled certain patients to resume long term treatment at the recommended maintenance dose, there are also cases where desensitisation was unsuccessful, and treatment had to be stopped due to anaphylactic reactions before reaching the maintenance dose.

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.

Transaminase elevations

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 46.9% 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.

Immunogenicity

Overall, 19 out of 40 (47.5%) adult patients and 15 out of 20 (75%) paediatric patients treated with Xenpozyme developed treatment-emergent anti-drug antibodies (ADA). The median time to seroconversion from first Xenpozyme infusion was approximately 52 weeks in adults and 12 weeks in paediatric patients. The majority of ADA-positive patients (16 out of 19 adult and 10 out of 15 paediatric patients) had a low ADA response (peak titer ≤400) or reverted to ADA-negative. Three adult ADA-positive patients and 4 paediatric ADA-positive patients developed intermediate ADA responses (peak titer ranged 800-6400). Eight out of the 19 adult ADA-positive patients and 9 out of the 15 paediatric ADA-positive patients had Neutralizing Antibodies (NAb) that inhibited the olipudase alfa activity. Only 2 adult patients and 3 paediatric patients had NAb at more than one timepoint. 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 (70.6% versus 46.2%).

Paediatric population

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.

Long-term use

The median exposure duration was 4.95 years (range: 0.4 to 9.6 years) in adult patients and 6.15 years (range: 4.3 to 8.2 years) in paediatric patients. 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 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 Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

Cases of overdose of Xenpozyme have been reported in paediatric patients during dose escalation. Some of these patients experienced serious adverse reactions within 24 hours of treatment initiation, including death. The main clinical findings included respiratory failure, hypotension, marked elevations in liver function tests, and gastrointestinal bleeding.

There is no known specific antidote for Xenpozyme overdose. In the event of overdose, the infusion should be stopped immediately, and the patient should be monitored closely in a hospital setting for the development of IARs including acute phase reactions. For the management of adverse reactions, see sections 4.4 and 4.8.