ADVERSE REACTIONS
Clinical Trial Experience
Because clinical trials are conducted under more controlled conditions, the observed adverse reaction rates may not predict the rates observed in patients in clinical practice. The data described below reflect exposure of 39 Pompe disease patients to 20 or 40 mg/kg of MYOZYME administered every other week in 2 separate clinical trials for periods ranging from 1 to 106 weeks (mean 61 weeks). Patients were ages 1 month to 3.5 years at first treatment. The population was nearly evenly distributed in gender (18 females and 21 males).
The most serious adverse reactions reported with MYOZYME
were anaphylactic reactions, acute cardiorespiratory failure,
and cardiac arrest.
Anaphylactic reactions have been reported during and
within 3 hours after MYOZYME infusion
[see
Boxed Warning
and
Warnings and Precautions
].
Acute cardiorespiratory failure has been observed in a few infantile-onset Pompe disease patients with underlying cardiac hypertrophy, possibly associated with fluid overload with intravenous administration of alglucosidase alfa
[see
Boxed Warning
and Warnings and Precautions
and Instructions for Use].
The most common serious treatment-emergent adverse reactions occurring in >10% of patients observed in clinical studies with MYOZYME were pneumonia, respiratory failure, respiratory distress, catheter-related infection, respiratory syncytial virus infection, gastroenteritis and fever.
The most common adverse reactions requiring intervention in clinical trials
were infusion reactions
[see
Warnings and Precautions
].
Twenty of 39 patients (51%) treated with MYOZYME in clinical studies developed infusion reactions. Infusion reactions, defined as an adverse reaction occurring during the infusion or within 2 hours after completion of the infusion, that occurred in more than 1 patient in clinical studies and the expanded access program include rash, flushing, urticaria, fever, cough, tachycardia, decreased oxygen saturations, vomiting, tachypnea, agitation, increased blood pressure, cyanosis, hypertension, irritability, pallor, pruritus, retching, rigors, tremor, hypotension, bronchospasm, erythema, face edema, feeling hot, headache, hyperhidrosis, increased lacrimation, livedo reticularis, nausea, periorbital edema, restlessness, and wheezing.
The most common treatment-emergent adverse reactions occurring in ≥ 20% of patients were fever, diarrhea, rash, vomiting, cough, pneumonia, otitis media, upper respiratory tract infection, gastroenteritis and decreased oxygen saturation.
Table 2 enumerates treatment-emergent
adverse reactions that occurred in
at least 20% of patients treated with MYOZYME in
clinical trials described above. Reported frequencies
of adverse events have been classified by MedDRA terms.
Table 2. Summary of Adverse Reactions by System Organ Class and Preferred Term
Occurring in at Least 20% of Patients Treated with
MYOZYME® in Clinical Trials
|
System Organ
Class
Preferred Term
|
Number of Patients
(N=39)
n
(%)
|
Number of Adverse
Events
n
|
|
Any Adverse Events
=
|
39
|
1859
|
|
General disorders
and administration site conditions
|
38 (97)
|
|
| Pyrexia |
36 (92) |
169 |
|
Respiratory,
thoracic and mediastinal disorders
|
38 (97)
|
|
| Cough |
18 (46) |
69 |
|
Respiratory
distress
|
13 (33) |
18 |
|
Respiratory
failure
|
12 (31) |
24 |
| Rhinorrhea |
11 (28) |
16 |
| Tachypnea |
9 (23) |
15 |
|
Infections and
infestations
|
37 (95)
|
|
| Pneumonia |
18 (46) |
43 |
|
Otitis
media
|
17 (44) |
35 |
|
Upper
respiratory tract infection
|
17 (44) |
39 |
| Gastroenteritis |
16 (41) |
17 |
| Pharyngitis |
14 (36) |
26 |
|
Ear
infection
|
13 (33) |
23 |
|
Oral
candidiasis
|
12 (31) |
20 |
|
Catheter-related
infection
|
11 (28) |
15 |
| Bronchiolitis |
9 (23) |
10 |
| Nasopharyngitis |
9 (23) |
25 |
|
Gastrointestinal
disorders
|
32 (82)
|
|
| Diarrhea |
24 (62) |
62 |
| Vomiting |
19 (49) |
62 |
|
Gastroesophageal
reflux disease
|
10 (26) |
13 |
| Constipation |
9 (23) |
14 |
|
Skin and
subcutaneous tissue disorders
|
32 (82)
|
|
| Rash |
21 (54) |
72 |
|
Diaper
dermatitis
|
14 (36) |
34 |
| Urticaria |
8 (21) |
25 |
|
Investigations
|
28 (72)
|
|
|
Oxygen
saturation decreased
|
16 (41) |
44 |
|
Cardiac
disorders
|
24 (62)
|
|
| Tachycardia |
9 (23) |
31 |
| Bradycardia |
8 (21) |
18 |
|
Injury, poisoning
and procedural complications
|
22 (56)
|
|
|
Post
procedural pain
|
10 (26) |
20 |
|
Blood and
lymphatic system disorders
|
17 (44)
|
|
| Anemia |
12 (31) |
23 |
|
Vascular
disorders
|
14 (36)
|
|
| Flushing |
8 (21) |
15 |
Five additional juvenile-onset Pompe disease patients
were evaluated in a single-center, open-label, non-randomized,
uncontrolled clinical trial. Patients were ages 5 to
15 years, ambulatory (able to walk at least 10 meters in 6
minutes), and not receiving invasive ventilatory support at
study entry. All 5 patients received treatment with 20
mg/kg MYOZYME for 26 weeks. The most common
treatment-emergent adverse reactions
observed with MYOZYME treatment in this study were headache (4.1%), pharyngitis (9.1%), upper abdominal pain (15.2%), malaise (6.1%) and rhinitis (6.1%).
Immunogenicity
As with all therapeutic proteins, there is potential for immunogenicity. The majority of patients (34 of 38; 89%) in the
two clinical trials tested positive for IgG antibodies to
alglucosidase alfa. The data reflect the percentage of
patients whose test results were considered positive for
antibodies to alglucosidase alfa using an enzyme-linked
immunosorbent assay (ELISA) and radioimmunoprecipitation (RIP)
assay for alglucosidase alfa-specific IgG antibodies.
Most patients who develop antibodies do so within the first 3
months of exposure. There is evidence to suggest that
patients developing sustained titers ≥12,800
of anti-alglucosidase alfa antibodies may have a poorer clinical
response to treatment, or may lose motor function as antibody
titers increase. Treated patients who experience a
decrease in motor function should be tested for neutralization
of enzyme uptake or activity. Five patients with
antibody titers ≥12,800 at Week 12 had an
average increase in clearance of 50% from Week 1 to Week
12
[see
Clinical Pharmacology
]
.
Some patients who developed IgG antibodies to alglucosidase alfa in clinical studies or in the postmarketing setting were evaluated for the presence of inhibitory antibodies and tested positive for inhibition of enzyme activity and/or uptake in
in vitro
assays.
The effect of antibody development on the long-term efficacy of MYOZYME is not fully understood. However, CRIM negative infants have shown poorer clinical response in the presence of high sustained IgG antibody titers and positive inhibitory antibodies.
Infusion reactions were reported in 20 of 39 patients
(51%) treated with MYOZYME in clinical studies and
appear to be more common in antibody-positive patients: 8 of 15
patients with high antibody titers experienced infusion
reactions whereas none of 3 antibody-negative patients
experienced infusion reactions
[see
Warnings and Precautions
].
Patients who develop IgE antibodies to alglucosidase alfa appear to be at a higher risk for the occurrence of anaphylaxis and severe allergic reactions
[
see
Warnings and Precautions
].
Therefore, these patients should be monitored more closely during administration of MYOZYME.
Postmarketing Experience
The following adverse reactions have been identified during post approval use of MYOZYME. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
In postmarketing experience with MYOZYME, severe and
serious infusion reactions have been reported, some of which
were life-threatening, including anaphylactic shock
[see
Boxed Warning
and
Warnings and Precautions
].
Acute cardiorespiratory failure, possibly
associated with fluid overload, has been reported in
infantile-onset Pompe disease patients with pre-existing
hypertrophic cardiomyopathy
[see
Boxed Warning
and
Warning and Precautions
].
In addition to the infusion reactions
reported in clinical trials and expanded access programs, the
following infusion reactions have been reported in patients
during postmarketing use of MYOZYME: cardiac arrest, respiratory arrest, apnea, stridor, pharyngeal edema, peripheral edema, chest pain, chest discomfort, muscle
spasm, fatigue and conjunctivitis
[see
Warnings and Precautions
and
]
. Systemic and cutaneous immune mediated
reactions, including ulcerative and necrotizing skin lesions
have been reported
[see
Warnings and Precautions
].
|
