4.1. Therapeutic indications

Myozyme is indicated for long-term enzyme replacement therapy (ERT) in patients with a confirmed diagnosis of Pompe disease (acid α-glucosidase deficiency).

Myozyme is indicated in adults and paediatric patients of all ages.

4.2. Posology and method of administration

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

Posology

The recommended dose regimen of alglucosidase alfa is 20 mg/kg of body weight administered once every 2 weeks.

Patient response to treatment should be routinely evaluated based on a comprehensive evaluation of all clinical manifestations of the disease.

Paediatric and older people

There is no evidence for special considerations when Myozyme is administered to paediatric patients of all ages or older people.

Patients with renal and hepatic impairment

The safety and efficacy of Myozyme in patients with renal or hepatic impairment have not been evaluated and no specific dose regimen can be recommended for these patients.

Method of administration

Myozyme should be administered as an intravenous infusion.

Infusions should be administered incrementally. It is recommended that the infusion begin at an initial rate of 1 mg/kg/h and be gradually increased by 2 mg/kg/h every 30 minutes if there are no signs of infusion associated reactions (IARs) until a maximum rate of 7 mg/kg/h is reached. IARs are described in section 4.8.

Home infusion

Infusion of Myozyme 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.

Home infusion infrastructure, resources, and procedures, including training, must be established and available to the healthcare professional. Home infusion should be supervised by a healthcare professional who should be always available during the home infusion and for a specified time after infusion.

Dose and infusion rate should remain constant while at home, and not be changed without supervision of a healthcare professional.

Appropriate information should be given by the treating physician and/or nurse to the patient and/or caregiver prior to initiation of 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.

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

4.3. Contraindications

Life threatening hypersensitivity (anaphylactic reaction) 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).

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 product should be clearly recorded.

Hypersensitivity/Anaphylactic reactions

Serious and life-threatening anaphylactic reactions, including anaphylactic shock, have been reported in infantile- and late-onset patients during Myozyme infusions (see section 4.8). Because of the potential for severe infusion associated reactions, appropriate medical support measures, including cardiopulmonary resuscitation equipment, should be readily available when Myozyme is administered. If severe hypersensitivity or anaphylactic reactions occur, immediate discontinuation of Myozyme infusion should be considered and appropriate medical treatment should be initiated. The current medical standards for emergency treatment of anaphylactic reactions are to be observed.

Infusion Associated Reactions

Approximately half of the patients treated with Myozyme in infantile-onset clinical studies and 28% of the patients treated with Myozyme in a late-onset clinical study developed infusion associated reactions (IARs). IARs are defined as any related adverse event occurring during the infusion or during the hours following infusion. Some reactions were severe (see section 4.8). A tendency was observed in infantile patients treated with a higher dose (40 mg/kg) to experience more symptoms when developing IARs. Infantile onset patients who develop high IgG antibody titres appear to be at higher risk for developing more frequent IARs. However, IARs occurred regardless of antibody titres. Patients with an acute illness (e.g. pneumonia, sepsis) at the time of Myozyme infusion appear to be at greater risk for IARs. Careful consideration should be given to the patient's clinical status prior to administration of Myozyme. Patients should be closely monitored and all cases of IARs, delayed reactions and possible immunological reactions should be reported to the marketing authorisation holder.

Patients who have experienced IARs (and in particular anaphylactic reactions) should be treated with caution when re-administering Myozyme (see sections 4.3 and 4.8). Mild and transient effects may not require medical treatment or discontinuation of the infusion. Reduction of the infusion rate, temporary interruption of the infusion, or pre-treatment, generally with oral antihistamine and/or antipyretics and/or corticosteroids, has effectively managed most reactions. IARs may occur at any time during the infusion of Myozyme or generally up to 2 hours after, and are more likely with higher infusion rates.

Patients with advanced Pompe disease may have compromised cardiac and respiratory function, which may predispose them to a higher risk of severe complications from infusion associated reactions. Therefore, these patients should be monitored more closely during administration of Myozyme.

Immunogenicity

The effect of IgG antibody formation on safety and efficacy has been evaluated in clinical trials and post-marketing experience. In clinical studies, the majority of patients developed IgG antibodies to alglucosidase alfa and seroconversion typically occurred within 3 months of treatment. Thus, development of IgG antibodies is expected to occur in most patients treated with Myozyme. Overall, a correlation was not observed between the onset of IARs and the time of IgG antibody formation. IARs can occur across all levels of antibody titres, however a trend was observed for more frequent IARs with higher titres of IgG antibody. The clinical impact on efficacy is multifactorial, however the development of high and sustained IgG antibody titres is a contributing factor.

With regard to IOPD, a tendency was observed for patients treated with a higher dose (40 mg/kg) to develop higher titres of IgG antibodies. Furthermore, Cross Reactive Immunologic Material (CRIM) status has been shown to be associated with immunogenicity and patients' responses to enzyme replacement therapies. Negative CRIM status, indicating no endogenous enzyme is detected, is a risk factor to develop high and sustained IgG antibody titres. This risk is higher among CRIM negative patients versus CRIM-positive patients and is a contributing factor to a poor outcome. However, high and sustained IgG antibody titres has also occurred in a limited number of CRIM-positive patients, generally with very low endogenous enzyme.

With respect to LOPD patients, the majority showed either stabilizing or decreasing antibody titres over time. The development of high and sustained IgG antibody titres is infrequent in LOPD patients. Thus, the impact of IgG antibodies is more limited for LOPD patients.

IgG antibody titres should be monitored based on clinical phenotype. Baseline serum sample collection prior to the first infusion is strongly encouraged. For IOPD patients, regular monitoring during first year of treatment (example: every 3 months) is suggested and subsequent monitoring depending on clinical outcomes and antibody titres level. For LOPD patients, antibody development should be assessed within 6 months and subsequent monitoring as clinically warranted based on safety and efficacy considerations.

Patients who experience hypersensitivity reactions may also be tested for IgE antibodies to alglucosidase alfa and other mediators of anaphylaxis. Patients who develop IgE antibodies to alglucosidase alfa appear to be at a higher risk for the occurrence of IARs when Myozyme is re-administered (see section 4.8). Therefore, these patients should be monitored more closely during administration of Myozyme. Some IgE positive patients were successfully rechallenged with Myozyme using a slower infusion rate at lower initial doses and have continued to receive Myozyme under close clinical supervision.

Immune-mediated reactions

Severe cutaneous reactions, possibly immune mediated, have been reported with alglucosidase alfa, including ulcerative and necrotizing skin lesions (see section 4.8). Nephrotic syndrome was observed in a few patients with Pompe disease treated with alglucosidase alfa and who had high IgG antibody titres (≥ 102,400) (see section 4.8). In these patients renal biopsy showed immune complex deposition. Patients improved following treatment interruption. It is therefore recommended to perform periodic urinalysis among patients with high IgG antibody titres.

Patients should be monitored for signs and symptoms of systemic immune-mediated reactions involving skin and other organs while receiving alglucosidase alfa. If immune-mediated reactions occur, discontinuation of the administration of alglucosidase alfa should be considered and appropriate medical treatment initiated. The risks and benefits of re-administering alglucosidase alfa following an immune-mediated reaction should be considered. Some patients have been successfully rechallenged and continued to receive alglucosidase alfa under close clinical supervision.

Immunomodulation

Immunogenicity data from clinical trials and published literature in CRIM-negative infantile-onset patients (IOPD) suggests that the administration of immune tolerance induction (ITI) regimen given to alglucosidase alfa naive patients (prophylactic ITI) may be effective in preventing or reducing the development of High Sustained Antibody Titre (HSAT) against alglucosidase alfa. Data from a small number of patients with HSAT, with or without inhibitory activity, showed limited ITI treatment effect. Better treatment responses were observed in younger patients with less advanced disease who received prophylactic ITI before development of HSAT, which suggests that early initiation of ITI can result in improved clinical outcomes. ITI regimens may need to be tailored to individual patient needs (see section 5.1).

Patients with Pompe disease are at increased risk of respiratory infections due to the progressive effects of the disease on the respiratory muscles. Patients with Pompe disease treated with immunosuppressive agents maybe at further increased risk of developing severe infections and vigilance is recommended. Fatal and life-threatening respiratory infections have been observed in some of these patients.

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

No interactions studies have been performed. Because it is a recombinant human protein, alglucosidase alfa is an unlikely candidate for cytochrome P450 mediated drug-drug interactions.

4.6. Fertility, pregnancy and lactation

Pregnancy

There is limited data from the use of alglucosidase alfa in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). Myozyme should not be used during pregnancy unless the clinical condition of the woman requires treatment with alglucosidase alfa.

Breast-feeding

Limited data suggest that alglucosidase alfa is excreted in breast milk in very low concentrations. No clinical effect is expected in a breastfed infant due to low breast milk transfer and poor bioavailability. Breast-feeding during treatment with Myozyme may therefore be considered. As a precautionary measure, breast-feeding interruption for the first 24 hours after treatment may be considered.

Fertility

There is too limited clinical data on the effects of alglucosidase alfa on fertility to evaluate its impact. Preclinical data did not reveal any significant adverse findings (see section 5.3).

4.7. Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been performed. Because dizziness, somnolence, tremor and hypotension have been reported as an infusion associated reaction, this may affect the ability to drive and use machines on the day of the infusion.

4.8. Undesirable effects

Summary of the safety profile

Infantile-onset Pompe disease

In clinical trials, 39 infantile-onset patients were treated with Myozyme for more than three years (168 weeks with a median of 121 weeks; see section 5.1). Adverse reactions reported in at least 2 patients are listed in Table 1 by System Organ Class. Adverse reactions were mostly mild to moderate in intensity and almost all occurred during the infusion or during the 2 hours following the infusion (infusion associated reactions, IARs). Serious infusion reactions including urticaria, rales, tachycardia, decreased oxygen saturation, bronchospasm, tachypnoea, periorbital oedema and hypertension have been reported.

Late-onset Pompe disease

In a placebo-controlled study lasting 78 weeks, 90 patients with late-onset Pompe disease, aged 10 to 70 years, were treated with Myozyme or placebo randomized in a 2:1 ratio (see section 5.1). Overall, the numbers of patients experiencing adverse reactions and serious adverse reactions were comparable between the two groups. The most common adverse reactions observed were IARs. Slightly more patients in the Myozyme group than in the placebo group experienced IARs (28% versus 23%). The majority of these reactions were non-serious, mild to moderate in intensity and resolved spontaneously. Adverse reactions reported in at least 2 patients are listed in Table 1. Serious adverse reactions reported in 4 patients treated with Myozyme were: angioedema, chest discomfort, throat tightness, non-cardiac chest pain and supraventricular tachycardia. Reactions in 2 of these patients were IgE-mediated hypersensitivity reactions.

Tabulated list of adverse reactions

Table 1: Adverse reactions (reported in at least 2 patients) and adverse reactions reported in post-marketing setting, expanded access programs and non-controlled clinical trials, 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). Due to the small patient population, an adverse reaction reported in 2 patients is classified as common. Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

System Organ Class

Frequency

Adverse reaction

(Preferred Term Level)

Additional adverse reactions4

Infantile-onset Pompe disease1

Late-onset Pompe disease2

Infantile- and Late-onset Pompe disease

Immune system disorders

common

Hypersensitivity

Psychiatric disorders

common

Agitation

not known

Agitation

Restlessness

Nervous system disorders

common

Tremor

Dizziness

Paraesthesia

Headache3

not known

Tremor

Headache

Somnolence

Syncope

Burning sensation

Eye disorders

not known

Conjunctivitis

Cardiac disorders

very common

Tachycardia

common

Cyanosis

not known

Cardiac arrest

Bradycardia

TachycardiaCyanosis

Palpitations

Vascular disorders

very common

Flushing

common

Hypertension

Pallor

Flushing

not known

Hypertension

Hypotension

Vasoconstriction

Pallor

Respiratory, thoracic and mediastinal disorders

very common

Tachypnoea

Cough

common

Throat tightness

not known

Respiratory arrest

Apnoea

Respiratory distress

Asthma

Bronchospasm

Wheezing

Pharyngeal oedema

Dyspnoea

Tachypnoea

Throat tightness

Throat irritation

Stridor

Cough

Hypoxia

Gastrointestinal disorders

very common

Vomiting

common

Retching

Nausea

Diarrhoea

Vomiting

Nausea3

not known

Abdominal pain

Retching

Dyspepsia

Dysphagia

Skin and subcutaneous tissue disorders

very common

Urticaria

Rash

common

Erythema

Rash maculopapular

Rash macular

Rash papular

Pruritus

Urticaria

Rash papular

Pruritus

Hyperhidrosis

not known

Periorbital oedema

Livedo reticularis

Lacrimation increased

Rash

ErythemaHyperhidrosis

Palmar erythema

Transient skin discolouration

Blister

Musculoskeletal and connective tissue disorders

common

Muscle spasms

Muscle twitching

Myalgia

not known

Arthralgia

Renal and urinary disorders

not known

Nephrotic syndrome

Proteinuria

General disorders and administration site conditions

very common

Pyrexia

common

Irritability

Chills

Pyrexia

Chest discomfort

Peripheral oedema

Local swelling

Fatigue3

Feeling hot

not known

Chest pain

Face oedema

Feeling hot

Pyrexia

Chills

Chest discomfort

Irritability

Peripheral coldness

Asthenia

Malaise

Feeling cold

Infusion site pain

Infusion site reaction

Infusion site swelling

Infusion site induration

Infusion site extravasation

Infusion site erythema

Infusion site urticaria

Infusion site pruritus

Investigations

very common

Oxygen saturation decreased

common

Heart rate increased

Blood pressure increased

Body temperature increased

Blood pressure increased

not known

Oxygen saturation decreased

Heart rate increased

Blood pressure decreased

1 Reactions reported in 39 infantile-onset patients in 2 clinical trials.

2 Reactions reported in 60 late-onset patients in a placebo-controlled clinical trial.

3 Reactions reported more frequently in the placebo group than in the Myozyme group in late-onset patients.

4 Additional adverse reactions from post-marketing, expanded access programs and non-controlled clinical trials.

Description of selected adverse reactions

A small number of patients (<1%) in clinical trials and in the commercial setting developed anaphylactic shock and/or cardiac arrest during Myozyme infusion that required life-support measures. Reactions generally occurred shortly after initiation of the infusion. Patients presented with a constellation of signs and symptoms, primarily respiratory, cardiovascular, oedematous and/or cutaneous in nature (see section 4.4).

Recurrent reactions consisting of flu-like illness or a combination of events such as fever, chills, myalgia, arthralgia, pain, or fatigue occurring post-infusion and lasting usually for a few days, have been observed in some patients treated with alglucosidase alfa. The majority of patients were successfully re-challenged with alglucosidase alfa using lower doses and/or pre-treatment with anti-inflammatory drugs and/or corticosteroids and have continued to receive treatment under close clinical supervision.

Patients with moderate to severe or recurrent IARs have been evaluated for alglucosidase alfa specific IgE antibodies; some patients tested positive including some who experienced an anaphylactic reaction.

Nephrotic syndrome as well as severe cutaneous reactions, possibly immune mediated, have been reported with alglucosidase alfa including ulcerative and necrotizing skin lesions (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 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

In clinical studies doses up to 40 mg/kg body weight were used. IARs are more likely to occur with higher dose or infusion rates than recommended (see section 4.4).

Symptoms and signs

IARs have been reported, which included:

• cyanosis, tachycardia, palpitations

• hypoxia, dyspnoea, cough

• dizziness, headache, dysgeusia

• hypertension, flushing

• tongue oedema, vomiting, diarrhoea, nausea

• chest pain, chest discomfort, throat tightness, pyrexia, chills, feeling cold, infusion site erythema,

• myalgia

• erythema

Management

In the event of overdose, the infusion rate should be reduced, or the infusion temporarily interrupted. There is no known specific antidote for alglucosidase alfa overdose. The patient should be monitored for any signs or symptoms of adverse reactions and, if required, administered appropriate symptomatic treatment immediately.