Myozyme 50 Mg Solution

MYOZYME is indicated for long-term use as an enzyme replacement therapy for the treatment of patients with a confirmed diagnosis of Pompe disease (acid alpha-glucosidase deficiency).

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

Posology

The recommended dosage regimen of MYOZYME is 20 mg/kg of body weight administered once every 2 weeks as an intravenous infusion. Patient response to treatment should be routinely evaluated based on a comprehensive evaluation of all clinical manifestations of the disease.

Special populations

Paediatric patients: The safety and efficacy of MYOZYME have been evaluated in patients with ages ranging from infancy through adulthood.

Elderly patients: Clinical studies completed to date did not include a sufficient number of subjects aged 65 years and older in order to evaluate the safety and efficacy of MYOZYME in this population.

Renal or hepatic insufficiency: The safety and efficacy of MYOZYME in patients with renal or hepatic insufficiency have not been evaluated and no specific dosage 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. Vital signs should be obtained at each step, prior to increasing the infusion rate. The infusion rate may be slowed and/or temporarily stopped in the event of infusion reactions. For instructions on reconstitution and dilution of MYOZYME before administration, see section 6.6.

Hypersensitivity to alglucosidase alfa or to any of the excipients listed in section 6.1.

Hypersensitivity/anaphylactic reactions: Serious hypersensitivity reactions, including life-threatening anaphylactic reactions, have been observed in Pompe patients during MYOZYME infusion, some of which were IgE-mediated. A small number of patients developed anaphylactic shock and/or cardiac arrest during MYOZYME infusion that required life-support measures. Reactions included bronchospasm, wheezing, respiratory arrest, respiratory distress, apnoea, stridor, dyspnoea, decreased oxygen saturation, cardiac arrest, hypotension, bradycardia, tachycardia, cyanosis, vasoconstriction, flushing, chest pain, chest discomfort, throat tightness, angioedema, pharyngeal oedema, face oedema, peripheral oedema, urticaria and rash.

If severe hypersensitivity or anaphylactic reactions occur, immediate discontinuation of the administration of MYOZYME is essential and appropriate medical treatment should be initiated. Because of the potential for severe infusion reactions, appropriate medical support measures, including cardiopulmonary resuscitation equipment especially for patients with cardiac hypertrophy and patients with significantly compromised respiratory function, should be readily available when MYOZYME is administered.

Infusion-associated reactions (IARs): Infusion-associated reactions (IARs) occurred in approximately 50 % of patients treated with MYOZYME in two infantile-onset clinical studies for 52 weeks. In a randomised, double-blind, placebo-controlled trial of patients with late-onset Pompe disease, 28 % of patients in the alglucosidase alfa treatment group experienced IARs. IARs occur at any time during, and within a few hours after the infusion of MYOZYME, and are more likely with higher infusion rates. The majority of reactions were assessed as mild to moderate; some reactions were severe. Some patients were pretreated with antihistamines, antipyretics and/or corticosteroids. IARs may occur in patients after receiving pretreatment with antipyretics, antihistamines or corticosteroids. If an IAR occurs, regardless of pretreatment, decreasing the infusion rate, temporarily stopping the infusion, and/or administration of antihistamines and/or antipyretics may ameliorate the symptoms. If severe infusion reactions occur, immediate discontinuation of the administration of MYOZYME should be considered, and appropriate medical support measures, including cardiopulmonary resuscitation equipment, should be available. Patients who have experienced IARs should be treated with caution when re-administered MYOZYME. 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 reactions. Therefore, these patients should be monitored more closely when administering MYOZYME.

General: Patients with an acute underlying illness at the time of MYOZYME infusion appear to be at greater risk for IARs. Careful consideration should be given to the patientu2019s clinical status prior to administration of MYOZYME.

Immunogenicity: In clinical studies, the majority of patients developed IgG antibodies to MYOZYME, typically within 3 months of treatment. Infantile-onset patients treated with higher doses of MYOZYME tended to develop a more robust antibody response and experienced more IARs. It is recommended that patients be monitored for IgG antibody formation periodically. The effect of antibody development on the long-term efficacy of MYOZYME is not fully understood. There is an observation that some patients who develop high and sustained IgG antibody titres, including cross-reactive immunologic material (CRIM)-negative patients (i.e. patients in whom no endogenous GAA protein was detected by Western blot analysis and/or predicted based on the genotype), may experience reduced clinical treatment efficacy with MYOZYME. The cause of a poor clinical response in some of these patients is thought to be multi-factorial (see Immunomodulation below). Some IgG-positive infantile-onset and late-onset patients in clinical trials who were retrospectively evaluated for the presence of inhibitory antibodies tested positive for inhibition of enzyme activity and/or uptake in in vitro assays. However, the clinical relevance of this in vitro inhibition is unclear. Patients treated with higher doses of MYOZYME tended to develop a more severe antibody response and IARs. A small number (3 of 36) of IgG-positive infantile-onset patients in clinical trials who were retrospectively evaluated for the presence of inhibitory antibodies tested positive for inhibition of enzyme activity and/or uptake in in vitro assays.

It is recommended that patients be monitored for IgG antibody formation every 3 months. The effect of antibody development on the long-term efficacy of MYOZYME is not understood. Some patients, including those who possess 2 null mutations, may develop high and sustained anti-alglucosidase alfa antibody titres. A small number of patients tested positive for alglucosidase alfa-specific IgE antibodies, some of whom experienced anaphylactic reactions. Testing was typically performed for IARs, especially moderate to severe or recurrent reactions. Some patients have been successfully rechallenged using slower rates and/or lower infusion doses and continued to receive treatment with MYOZYME under close clinical supervision.

Immunomodulation: Immunogenicity data from clinical trials and published literature in CRIM-negative infantile-onset patients (IOPD) suggest that the administration of immune tolerance induction (ITI) regimen given to MYOZYME naive patients (prophylactic ITI) may be effective in preventing or reducing the development of high sustained antibody titre (HSAT) against MYOZYME. Data from a small number of patients previously treated with HSAT, with or without inhibitory activity, showed limited 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.

Pompe patients are at increased risk of respiratory infections due to the progressive effects of the disease on the respiratory muscles. Pompe patients treated with immunosuppressive medicines may be 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.

Cardiac dysrhythmia and sudden death during general anaesthesia for central venous catheter placement: Caution should be used when administering general anaesthesia for the placement of a central venous catheter or for other surgical procedures in infantile-onset Pompe disease patients with cardiac hypertrophy. Cardiac dysrhythmia, including ventricular fibrillation, ventricular tachycardia and bradycardia, resulting in cardiac arrest or death, or requiring cardiac resuscitation or defibrillation have been associated with the use of general anaesthesia in infantile-onset Pompe disease patients with cardiac hypertrophy treated with MYOZYME.

Acute cardiorespiratory failure: Acute cardiorespiratory failure requiring intubation and inotropic support has been observed after infusion with MYOZYME in a few infantile-onset patients with underlying cardiac hypertrophy, possibly associated with fluid overload with intravenous administration of MYOZYME. See section 6.6.

No interaction studies have been conducted with MYOZYME.

Pregnancy

The limited amount of data from post-marketing reports and published case reports with the use of alglucosidase alfa in pregnant women have not identified a MYOZYME-associated risk of miscarriage, or adverse maternal or fetal outcomes. There have been reports of diaphragmatic hernia, atrial septal defect and truncus arteriosus persistent in post-marketing experience, however the relationship of MYOZYME to these events is unknown. The estimated background risk of major birth defects and miscarriage in the indicated population is unknown. The continuation of treatment for Pompe disease during pregnancy should be individualised to the pregnant woman. Untreated Pompe disease may result in worsening disease symptoms in pregnant women.

Lactation

Alglucosidase alfa may be excreted in breast milk. However, there are no risks identified with use in the breastfed infant. The developmental and health benefits of breastfeeding should be considered along with the motheru2019s clinical need for MYOZYME and any potential adverse effects on the breastfed child from MYOZYME or from the underlying maternal condition. A lactating woman may consider interrupting breastfeeding, pumping and discarding breast milk during MYOZYME administration and for 24 hours thereafter in order to minimise exposure to a breastfed infant.

Fertility

The limited amount of data from clinical studies, post-marketing reports and published case reports with the use of alglucosidase alfa in male and female patients have not identified a MYOZYME-associated risk on fertility and reproductive performance. Preclinical data did not show any effect on mating and fertility.

No studies on the ability to drive and handle machines have been conducted with MYOZYME. Because dizziness, somnolence, tremor and hypotension have been reported as infusion-associated reactions, these may affect the ability to drive and use machines on the day of the infusion.

The following CIOMS frequency rating is used, when applicable: very common u2265 10 %; common u2265 1 % and < 10 %; uncommon u2265 0,1 % and < 1 %; rare u2265 0,01 % and < 0,1 %; very rare < 0,01 %; not known (cannot be estimated from available data).

Infantile-onset experience

The most common adverse reactions were infusion-associated reactions (IARs). IARs occurred in approximately 50 % of patients treated with MYOZYME in two infantile-onset clinical studies for 52 weeks. The majority of these reactions were mild to moderate. IARs which were reported in more than 1 patient in clinical studies and the expanded access programme, included rash, flushing, urticaria, pyrexia, cough, tachycardia, decreased oxygen saturation, vomiting, tachypnoea, agitation, increased blood pressure, cyanosis, hypertension, irritability, pallor, pruritus, retching, rigors, tremor, hypotension, bronchospasm, erythema, face oedema, feeling hot, headache, hyperhidrosis, increased lacrimation, livedo reticularis, nausea, periorbital oedema, restlessness and wheezing. Severe infusion reactions reported in more than 1 patient included pyrexia, decreased oxygen saturation, tachycardia, cyanosis and hypotension. Most infusion-associated reactions requiring intervention were ameliorated with slowing of the infusion rate, temporarily stopping the infusion, and/or administration of antipyretics, antihistamines, or steroids. See section 4.4 u2013 Infusion-associated reactions (IARs), for details on the management of severe IARs.

Late-onset experience

The most common adverse reactions observed in a randomised, double-blind, placebo-controlled study of 90 patients with late-onset Pompe disease (aged 10 to 70 years) were infusion reactions. Patients were treated with 20 mg/kg MYOZYME or placebo (randomised in a 2:1 ratio) once every two weeks for 78 weeks. Infusion reactions occurred in approximately 28 % of patients treated with MYOZYME, compared to 23 % of placebo-treated patients. The majority of these reactions was mild to moderate and resolved spontaneously. Infusion reactions which were reported in u2265 5 % of MYOZYME-treated patients included headache, nausea, dizziness, urticaria, rash, chest discomfort, anaphylaxis, vomiting, hyperhidrosis, flushing and increased blood pressure.

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 anaphylactic reactions. Adverse reactions reported in at least 2 patients (3 %) treated with MYOZYME are listed in Table 1 below.

Table 1: Summary of treatment emergent adverse events considered related to treatment occurring in at least 3 % of MYOZYME treated patients by treatment group

System organ class Preferred term MYOZYME treated patients Placebo patients Number of patients 1 n (%) Number of patients 1 n (%) Immune system disorders Hypersensitivity 2 (3,3) 0 Nervous system disorders Headache Dizziness Paraesthesia 5 (8,3) 4 (6,7) 2 (3,3) 6 (20,0) 2 (6,7) 1 (3,3) Vascular disorders Flushing 3 (5,0) 0 Respiratory, thoracic and mediastinal disorders Throat tightness 2 (3,3) 0 Gastrointestinal disorders Nausea 5 (8,3) 3 (10,0) Vomiting 3 (5,0) 2 (3,3) Skin and subcutaneous tissue disorders Urticaria Hyperhidrosis Pruritus Papular rash 5 (8,3) 5 (8,3) 2 (3,3) 2 (3,3) 0 0 0 0 Musculoskeletal and connective tissue disorders Muscle twitching Myalgia Muscle spasms 4 (6,7) 4 (5,0) 2 (3,3) 1 (3,3) 1 (3,3) 1 (3,3) General disorders and administration site conditions Fatigue Chest discomfort Local swelling Pyrexia Peripheral oedema Feeling hot 3 (5,0) 4 (6.7) 2 (3,3) 2 (3,3) 2 (3,3) 2 (3,3) 4 (13,3) 1 (3,3) 1 (3,3) 1 (3,3) 0 0 Investigations Blood pressure increased 3 (5,0) 0 u00b9 Percentages are based on the total number of patients treated in the study group. A patient experiencing more than 1 adverse event within a preferred term is counted once within that preferred term.

Symptoms

In clinical trials, patients have received doses up to 40,0 mg/kg body weight. IARs are more likely to occur with higher doses or infusion rates, than recommended. See section 4.4 u2013 Infusion-associated reactions (IARs).

Treatment

See section 4.4 u2013 Infusion-associated reactions (IARs).