POMBILITI Powder for concentrate for solution for infusion Ref.[50960] Active ingredients: Cipaglucosidase alfa

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.

Anaphylaxis and infusion-associated reactions

Serious anaphylaxis and IARs have occurred in some patients during infusion and following infusion with cipaglucosidase alfa, see section 4.8. Premedication with oral antihistamine, antipyretics, and/or corticosteroids may be administered to assist with signs and symptoms related to IARs experienced with prior ERT treatment. Reduction of the infusion rate, temporary interruption of the infusion, symptomatic treatment with oral antihistamine, or antipyretics, and appropriate resuscitation measures should be considered to manage serious IARs. Mild to moderate and transient IARs may be adequately managed by slowing the infusion rate or interrupting the infusion; medical treatment or discontinuation of cipaglucosidase alfa may not be required.

If anaphylaxis or severe allergic reactions occur, infusion should be immediately paused, and appropriate medical treatment should be initiated. The current medical standards for emergency treatment of anaphylactic reactions are to be observed and cardiopulmonary resuscitation equipment should be readily available. The risks and benefits of re-administering cipaglucosidase alfa following anaphylaxis or severe allergic reaction should be carefully considered, and appropriate resuscitation measures made available if the decision is made to readminister the medicinal product. If a patient experiences anaphylaxis or severe allergic reactions in the home setting, and if the patient continues therapy, their next infusions must occur in a clinical setting, equipped to deal with such medical emergencies.

Risk of acute cardiorespiratory failure in susceptible patients

Patients with acute underlying respiratory illness or compromised cardiac and/or respiratory function may be at risk of serious exacerbation of their cardiac or respiratory compromise during infusions. Appropriate medical support and monitoring measures should be readily available during cipaglucosidase alfa infusion.

Immune complex-related reactions

Immune complex-related reactions have been reported with other ERTs in patients who had high IgG antibody titres, including severe cutaneous reactions and nephrotic syndrome. A potential class effect cannot be excluded. Patients should be monitored for clinical signs and symptoms of systemic immune complex-related reactions while receiving cipaglucosidase alfa with miglustat. If immune complex-related reactions occur, discontinuation of the administration of cipaglucosidase alfa should be considered and appropriate medical treatment should be initiated. The risks and benefits of re-administering cipaglucosidase alfa following an immune complex-related reaction should be reconsidered for each individual patient.

Sodium

This medicinal product contains 10.5 mg sodium per vial. This is equivalent to 0.52% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

No interaction studies have been performed related to the use of cipaglucosidase alfa or with cipaglucosidase alfa in combination with miglustat. As cipaglucosidase alfa is a recombinant human protein, it is an unlikely candidate for cytochrome P450 or P-gP mediated interactions with other medicinal products.

Contraception in females

Reliable contraceptive measures must be used by women of childbearing potential during treatment with cipaglucosidase alfa in combination with miglustat, and for 4 weeks after discontinuing treatment, see section 5.3. The medicinal product is not recommended in women of childbearing potential not using reliable contraception.

Pregnancy

There are no clinical data from the use of cipaglucosidase alfa in combination with miglustat in pregnant women. Cipaglucosidase alfa alone has not shown reproductive toxicity. Animal studies with miglustat alone as well as with cipaglucosidase alfa and miglustat have shown reproductive toxicity, see section 5.3. Cipaglucosidase alfa in combination with miglustat therapy is not recommended during pregnancy.

Breast-feeding

It is not known if cipaglucosidase alfa and miglustat are secreted in human breast milk. Available pharmacodynamic/toxicological data in animals have shown secretion/excretion of cipaglucosidase alfa in milk, see section 5.3. A risk to newborns/infants cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from cipaglucosidase alfa in combination with miglustat therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

Fertility

There are no clinical data on the effects of cipaglucosidase alfa on fertility. Preclinical data did not reveal any significant adverse findings with cipaglucosidase alfa, see section 5.3.

Cipaglucosidase alfa has minor influence on the ability to drive and to use machines since dizziness, hypotension, and somnolence have been reported as adverse reactions. Caution is required when driving or using any tools or machines after receiving cipaglucosidase alfa.

Summary of the safety profile

The most commonly reported adverse reactions only attributable to cipaglucosidase alfa were chills (4.0%), dizziness (2.6%), flushing (2.0%), somnolence (2.0%), chest discomfort (1.3%), cough, (1.3%), infusion site swelling (1.3%), and pain (1.3%).

Reported serious adverse reactions only attributable to cipaglucosidase alfa were urticaria (2.0%), anaphylaxis (1.3%), pyrexia (0.7%), presyncope (0.7%), dyspnoea (0.7%), pharyngeal oedema (0.7%), wheezing (0.7%), and hypotension (0.7%).

Tabulated list of adverse reactions

The assessment of adverse reactions was informed by subjects treated with cipaglucosidase alfa in combination with miglustat therapy from the pooled safety analysis of the 3 clinical trials. The total mean duration of exposure was 17.2 months.

Adverse reactions from the clinical trials are listed by MedDRA system organ class in Table 1. The corresponding frequency categories are defined as follows: 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 available data).

Table 1. Summary of adverse reactions from clinical trials with cipaglucosidase alfa-treated subjects:

^* Reported with cipaglucosidase alfa only
^‡ See below “Infusion-associated reactions”.
¹ Anaphylaxis, anaphylactic reaction, and anaphylactoid reaction are grouped under anaphylaxis.
² Rash, rash erythematous, and rash macular are grouped under rash.
³ Urticaria, urticaria rash, and mechanical urticaria are grouped under urticaria.
⁴ Migraine and migraine with aura are grouped under migraine.
⁵ Hypertension and blood pressure increased are grouped under blood pressure increased.
⁶ Tachycardia and sinus tachycardia are grouped under tachycardia.
⁷ Abdominal pain, abdominal pain upper, and abdominal pain lower are grouped under abdominal pain.

Description of selected adverse reactions

Infusion-associated reactions (IARs)

The following IARs were reported in the phase 3 study during the cipaglucosidase alfa infusion or within 2 hours after completion of this infusion: abdominal distension, chills, pyrexia, dizziness, dysgeusia, dyspnoea, pruritus, rash, and flushing.

0.7% of patients experienced a serious adverse reaction of anaphylaxis (characterised by generalised pruritus, dyspnoea, and hypotension) during the phase 3 trial receiving cipaglucosidase alfa and miglustat. 1.3% of patients receiving cipaglucosidase alfa and miglustat discontinued treatment due to IARs (anaphylaxis and chills). Most IARs were mild or moderate in severity and transient in nature.

Immunogenicity

In the phase 3 trial, the percent of ERT-naïve subjects treated with cipaglucosidase alfa with positive specific anti-rhGAA antibodies and detectable titres increased from 0% at baseline to 87.5% at the last study visit; the percent of ERT-experienced subjects with positive specific anti-rhGAA antibodies and detectable titres remained stable for subjects treated with cipaglucosidase alfa (83.1% at baseline to 74.1% at last trial visit).

The majority of ERT-experienced and ERT-naïve subjects treated with cipaglucosidase alfa were positive post-treatment for neutralising antibodies (Nabs). The incidence of enzyme activity inhibition Nabs was similar between subjects treated with either cipaglucosidase alfa or with alglucosidase alfa.

Subjects who had an IAR post-treatment were tested for anti-rhGAA IgE (immunoglobulin E) after the occurrence of the IAR; there was no clear trend in IAR occurrence with the incidence of anti-rhGAA IgE or with total anti-rhGAA antibodies.

Overall, there was no apparent association between immunogenicity and safety, pharmacokinetics, or pharmacodynamic effects. However, patients should be monitored for signs and symptoms of systemic immune complex-related reactions, see section 4.4.

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.