4.1. Therapeutic indications

Pombiliti (cipaglucosidase alfa) is a long-term enzyme replacement therapy used in combination with the enzyme stabiliser miglustat for the treatment of adults with late-onset Pompe disease (acid α‑glucosidase [GAA] deficiency).

4.2. Posology and method of administration

Treatment should be supervised by a physician experienced in the management of patients with Pompe disease or other inherited metabolic or neuromuscular diseases.

Cipaglucosidase alfa must be used in combination with miglustat 65 mg hard capsules. Because of this, the summary of product characteristics (SmPC) for miglustat 65 mg hard capsules should be consulted before taking cipaglucosidase alfa concerning number of capsules (based on body weight), dose time, and fasting.

Posology

The recommended dose of cipaglucosidase alfa is 20 mg/kg of body weight every other week. The cipaglucosidase alfa infusion should start 1 hour after taking miglustat capsules. In the event of infusion delay, the start of infusion should not exceed 3 hours from taking miglustat.

Figure 1. Dose timeline

✶The cipaglucosidase alfa infusion should start 1 hour after taking miglustat capsules. In the event of infusion delay, the start of infusion should not exceed 3 hours from taking miglustat.

Patient response to treatment should be routinely evaluated based on a comprehensive evaluation of all clinical manifestations of the disease. In case of an insufficient response or intolerable safety risks, discontinuation of cipaglucosidase alfa in combination with miglustat treatment should be considered, see section 4.4. Both medicinal products should either be continued or discontinued.

Switching patients from another enzyme replacement therapy (ERT)

If the patient is switching from another ERT to cipaglucosidase alfa in combination with miglustat therapy, the patient can be started with cipaglucosidase alfa‑miglustat therapy at the next scheduled dosing time (i.e. approximately 2 weeks after the last ERT administration).

Patients who have switched from another ERT to cipaglucosidase alfa in combination with miglustat therapy should be advised to continue with any premedications used with the previous ERT therapy to minimise infusion-associated reactions (IARs). Depending on tolerability, premedication may be modified, see section 4.4.

Missed dose

If the cipaglucosidase alfa infusion cannot be started within 3 hours of oral administration of miglustat, reschedule treatment of cipaglucosidase alfa and miglustat at least 24 hours after taking miglustat. If cipaglucosidase alfa and miglustat are both missed, treatment should occur as soon as possible.

Special populations

Renal and hepatic impairment

The safety and efficacy of cipaglucosidase alfa in combination with miglustat therapy have not been evaluated in patients with renal and/or hepatic impairment. When administering every other week, increased plasma miglustat exposure as a result of moderate or severe renal or hepatic impairment is not expected to appreciably impact cipaglucosidase alfa exposures and is not anticipated to affect efficacy and safety of cipaglucosidase alfa in a clinically meaningful manner. No dose adjustment is required in patients with renal impairment. The safety and efficacy of cipaglucosidase alfa in patients with hepatic impairment have not been evaluated and no specific dose regimen can be recommended for these patients.

Elderly

There is limited experience with the use of cipaglucosidase alfa in combination with miglustat therapy in patients above the age of 65 years old. There is no dose adjustment required in elderly patients, see section 5.2.

Paediatric population

The safety and efficacy of cipaglucosidase alfa in combination with miglustat therapy in paediatric patients less than 18 years old have not yet been established. No data are available.

Method of administration

Cipaglucosidase alfa is to be administered by intravenous infusion.

Infusion of the 20 mg/kg dose is normally administered over the course of 4 hours if tolerated. Infusion should be administered in a stepwise manner. An initial cipaglucosidase alfa infusion rate of 1 mg/kg/hr is recommended. This infusion rate may be gradually increased by 2 mg/kg/hr approximately every 30 minutes if there are no signs of IARs until a maximum infusion rate of 7 mg/kg/hr is reached. The rate of infusion should be guided by the patient's previous experience during infusion. The infusion rate may be slowed or temporarily stopped in the event of mild to moderate IARs. In the event of severe allergic, anaphylaxis, serious or severe IARs, the administration should immediately be discontinued, and appropriate medical treatment should be initiated, see sections 4.3 and 4.4.

Home infusion

Infusion of cipaglucosidase alfa at home may be considered for patients who are tolerating their infusions well and have no history of moderate or severe IARs for a few months. The decision to have a patient move to home infusion should be made after evaluation and upon recommendation by the treating physician. A patient's underlying co-morbidities and ability to adhere to the home infusion requirements need to be taken into account when evaluating the patient for eligibility to receive home infusion. The following criteria should be considered:

• The patient must have no ongoing concurrent condition that, in the opinion of the physician, may affect patient's ability to tolerate the infusion.

• The patient is considered medically stable. A comprehensive evaluation must be completed before the initiation of home infusion.

• The patient must have received cipaglucosidase alfa infusions supervised by a physician with expertise in management of Pompe patients for a few months that could be in a hospital or in another appropriate setting of outpatient care. Documentation of a pattern of well-tolerated infusions is a prerequisite for the initiation of home infusion.

• The patient must be willing and able to comply with home infusion procedures.

• Home infusion infrastructure, resources, and procedures, including training, must be established and available to the healthcare professional. The healthcare professional should be always available during the home infusion and for a specified time after infusion, depending on patient's tolerance prior to starting home infusion.

If the patient experiences adverse reactions during the home infusion, the infusion process should be stopped immediately, and appropriate medical treatment should be initiated, see section 4.4. Subsequent infusions may need to occur in a hospital or in an appropriate setting of outpatient care until no such adverse reaction is present. Dose and infusion rate must not be changed without consulting the responsible physician.

The reconstituted product prior to dilution appears as a clear to opalescent colourless to slightly yellow solution. For instructions on reconstitution and dilution of the medicinal product before administration, see section 6.6.

4.3. Contraindications

• Life‑threatening hypersensitivity to the active substance, or to any of the excipients listed in section 6.1, when rechallenge was unsuccessful, see sections 4.4 and 4.8.

• Contraindication to miglustat.

4.4. Special warnings and precautions for use

Cipaglucosidase alfa must be used in combination with miglustat 65 mg hard capsules. Because of this, the summary of product characteristics (SmPC) for miglustat 65 mg hard capsules should be consulted in relation to its safety profile before taking 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.

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

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.

4.6. Fertility, pregnancy and lactation

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. Animal studies with cipaglucosidase alfa in combination with miglustat as well as with miglustat alone 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 of miglustat and 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 alone or in combination with miglustat on fertility.

In female rats, increase in preimplantation loss was noted in cipaglucosidase alfa in combination with miglustat and with miglustat alone, see section 5.3.

In male rats, no effect on spermatogenesis was observed following exposure of cipaglucosidase alfa in combination with miglustat or cipaglucosidase alfa alone, see section 5.3.

4.7. Effects on ability to drive and use machines

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.

4.8. Undesirable effects

Summary of the safety profile

The most commonly reported adverse reactions only attributable to cipaglucosidase alfa were 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 pharyngeal oedema (0.7%), presyncope (0.7%), pyrexia (0.7%), chills (0.7%), dyspnoea (0.7%), and wheezing (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 28.0 months.

Adverse reactions 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 (≥ 1/1000 to < 1/100), rare (≥ 1/10 000 to < 1/1000), very rare (< 1/10 000), and not known (cannot be estimated from available data).

Table 1: Summary of adverse reactions of cipaglucosidase alfa‑treated patients

System organ class (SOC)

Frequency

Adverse reaction (preferred term)

Immune system disorders

Common

Anaphylactic reaction‡1

Uncommon

Hypersensitivity

Nervous system disorders

Very common

Headache

Common

Dizziness*, tremor, somnolence*, dysgeusia, paraesthesia

Uncommon

Balance disorder, burning sensation*, migraine4, presyncope*

Cardiac disorders

Common

Tachycardia6

Vascular disorders

Common

Flushing*, hypotension

Uncommon

Pallor

Respiratory, thoracic and mediastinal disorders

Common

Dyspnoea, cough*

Uncommon

Asthma, oropharyngeal discomfort*, pharyngeal oedema*, wheezing*

Gastrointestinal disorders

Common

Diarrhoea, nausea, abdominal pain7, flatulence, abdominal distension, vomiting

Uncommon

Dyspepsia*, oesophageal pain*, oesophageal spasm, oral discomfort*, oral pain, swollen tongue*

Skin and subcutaneous tissue disorder

Common

Urticaria3, rash2, pruritus, hyperhidrosis

Uncommon

Skin discolouration, skin oedema*

Musculoskeletal and connective tissue disorders

Common

Muscle spasms, myalgia, arthralgia, muscular weakness

Uncommon

Flank pain, muscle fatigue, musculoskeletal stiffness

General disorders and administration site conditions

Common

Fatigue, pyrexia, chills, chest discomfort*, infusion site swelling*, pain*, peripheral swelling

Uncommon

Asthenia, facial pain, infusion site pain*, malaise*, non‑cardiac chest pain, swelling face*

Investigations

Common

Blood pressure increased5

Uncommon

Body temperature fluctuation*, lymphocyte count decreased

Injury, poisoning and procedural complications

Uncommon

Skin abrasion*

* Reported with cipaglucosidase alfa only

‡ See below “Infusion-associated reactions”.

1 Anaphylaxis, anaphylactic reaction, and anaphylactoid reaction are grouped under anaphylactic reaction.

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:

Yellow Card Scheme

Website: at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

No doses of cipaglucosidase alfa in excess of 20 mg/kg body weight have been studied and no experience with accidental overdose have been observed to inform management of overdose. For management of adverse reactions, see sections 4.4 and 4.8.