Algucosidase Alfa (4110)
| Ingredients: |
Algucosidase Alfa |
| Indications: |
Pompe disease; Alpha- glucosidase (GAA) deficiency |
| Pregnancy Category: |
B |
| FDA Approved: |
2006- 04- 01 |
| Classes: |
Enzymes, metabolic |
| Brand Names: |
Myozyme
-
US
;
|
| DEA schedules: |
(none)
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BOXED WARNING
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RISK OF HYPERSENSITIVITY REACTIONS
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LIFE- THREATENING ANAPHYLACTIC REACTIONS, INCLUDING ANAPHYLACTIC SHOCK, HAVE BEEN OBSERVED IN PATIENTS DURING ALGLUCOSIDASE
ALFA INFUSION.
BECAUSE OF THE POTENTIAL FOR SEVERE INFUSION REACTIONS, APPROPRIATE MEDICAL SUPPORT MEASURES SHOULD BE READILY AVAILABLE WHEN
ALGLUCOSIDASE ALFA IS ADMINISTERED.
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DESCRIPTION
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Myozyme (alglucosidase alfa) consists of the human enzyme acid α- glucosidase (GAA), encoded by the most predominant of nine
observed haplotypes of this gene. Alglucosidase alfa is produced by recombinant DNA technology in a Chinese hamster ovary
cell line. Alglucosidase alfa degrades glycogen by catalyzing the hydrolysis of α- 1, 4- and α- 1, 6- glycosidic linkages
of lysosomal glycogen.
Alglucosidase alfa is a glycoprotein with a calculated mass of 99, 377 daltons for the polypeptide chain, and a total mass
of approximately 109, 000 daltons, including carbohydrates. Alglucosidase alfa has a specific activity of 3 to 5 U/ mg (one
unit is defined as that amount of activity that results in the hydrolysis of 1 µmole of synthetic substrate per minute under
the specified assay conditions). Myozyme is intended for IV infusion. It is supplied as a sterile, nonpyrogenic, white to
off- white, lyophilized cake or powder for reconstitution with 10.3 ml sterile water for injection. Each 50- mg vial contains
52.5 mg a/ glucosidase alfa, 210 mg mannitol, 0.5 mg polysorbate 80, 9.9 mg sodium phosphate dibasic heptahydrate, 31.2 mg
sodium phosphate monobasic monohydrate.Following reconstitution as directed, each vial contains 10.5 ml reconstituted solution
and a total extractable volume of 10 ml at 5.0 mg/ ml alglucosidase alfa. Myozyme does not contain preservatives; each vial
is for single use only.
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CLINICAL PHARMACOLOGY
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Mechanism of Action
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Pompe disease (glycogen storage disease type II, GSD II, glycogenosis type II, acid maltase deficiency) is an inherited disorder
of glycogen metabolism caused by the absence or marked deficiency of the lysosomal enzyme GAA.
In the infantile- onset form, Pompe disease results in intralysosomal accumulation ofglycogen in various tissues, particularly
cardiac and skeletal muscles, and hepatic tissues, leading to the development of cardiomyopathy, progressive muscle weakness,
and impairment of respiratory function.
In the juvenile- and adult- onset forms, intralysosomal accumulation of glycogen is limited primarily to skeletal muscle,
resulting in progressive muscle weakness. Death in all forms is usually related to respiratory failure.
Alglucosidase alfa provides an exogenous source of GAA. Binding to mannose- 6- phosphate receptors on the cell surface has
been shown to occur via carbohydrate groups on the GAA molecule, after which it is internalized and transported into Iysosomes,
where it undergoes proteolytic cleavage that results in increased enzymatic activity. It then exerts enzymatic activity in
cleaving glycogen.
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Pharmacokinetics
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The pharmacokinetics of alglucosidase alfa were evaluated in 13 patients of age ranging from 1- 7 months with infantile- onset
Pompe disease who received 20 mg/ kg (as an approximate 4- hour infusion) or 40 mg/ kg (as an approximate 6.5- hour infusion)
of alglucosidase alfa every 2 weeks. The measurement of alglucosidase alfa plasma concentration was based on an activity assay
using an artificial substrate. Systemic exposure was approximately dose proportional between the 20 and 40 mg/ kg doses (see TABLE 1 ).
| TABLE 1
Pharmacokinetic Parameters (Mean ± SD) After Single IV Infusion of Alglucosidase Alfa
|
| Pharmacokinetic Parameter |
20 mg/ kg (n=5) |
40 mg/ kg (n=8) |
| Cmax (µg/ ml)
|
162 ± 31 |
276 ± 64 |
| AUC(∞) (µg·h/ ml) |
811 ± 141 |
1781 ± 520 |
| CL (ml/ h/ kg) |
25 ± 4 |
24 ± 7 |
| Vss (ml/ kg) |
96 ± 16 |
119 ± 28 |
| T½ (h)
|
2.3 ± 0.4 |
2.9 ± 0.5 |
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The pharmacokinetics of alglucosidase alfa were also evaluated in a separate trial in 14 patients of age ranging from 6 months
to 3.5 years with Pompe disease who received 20 mg/ kg of alglucosidase alfa as an approximate 4- hour infusion every 2 weeks.
The pharmacokinetic parameters were similar to those observed for the 20 mg/ kg dose group in the trial of patients of age
ranging from 1- 7 months.
Nineteen (19) of 21 patients who received treatment with alglucosidase alfa and had pharmacokinetics and antibody titer data
available at Week 12 developed antibodies to alglucosidase alfa. Five (5) patients with antibody titers ≥12, 800 at Week 12
had an average increase in clearance of 50% (range 5- 90%) from Week 1 to Week 12. The other 14 patients with antibody titers
<12, 800 at Week 12 had similar average clearance values at Week 1 and Week 12.
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CLINICAL STUDIES
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The safety and efficacy of alglucosidase alfa were assessed in 2 separate clinical trials in 39 Pompe disease patients, who
ranged in age from 1 month to 3.5 years at the time of first infusion.
Study 1 was an international, multicenter, open- label, clinical trial of 18 infantile- onset Pompe disease patients. This
study was conducted between 2003 and 2005. Patients were randomized equally to either 20 mg/ kg or 40 mg/ kg alglucosidase
alfa every 2 weeks, with length of treatment ranging from 52- 106 weeks.Enrollment was restricted to patients ages 7 months
or less at first infusion with clinical signs of Pompe disease, with cardiac hypertrophy, and who did not require ventilatory
support at study entry.
Efficacy was assessed by comparing the proportions of alglucosidase alfa- treated patients who died or needed invasive ventilator
support with the mortality experience of an historical cohort of untreated infantile- onset Pompe patients with similar age
and disease severity. In the historical cohort, 61 untreated patients with infantile- onset Pompe disease diagnosed by age
6 months, born between 1982 and 2002, were identified by a retrospective review of medical charts. By the age of 18 months,
only 1 of the 61 historical control patients was alive (98% mortality), indicating the poor outcome of patients who are left
untreated.
Within the first 12 months of treatment, 3 of 18 alglucosidase alfa- treated patients required invasive ventilatory support
(17%, with 95% CI 4- 41 %); there were no deaths. With continued treatment beyond 12 months, 4 additional patients required
invasive ventiatory support, after receiving between 13 and 18 months of alglucosidase alfa treatment; 2 of these 4 patients
died after receiving 14 and 25 months of treatment, and after receiving 11 days and 7.5 months of invasive ventilatory support,
respectively. No other deaths have been reported through a median follow- up of 20 months, and all 16 surviving patients continue
to be followed.Survival without invasive ventilatory support was substantially greater in the alglucosidase alfa- treated
patients in this study than would be expected compared to the poor survival of the historical control patients. No differences
in outcome were observed between patients who received 20 mg/ kg versus 40 mg/ kg.
Other outcome measures in this study included unblinded assessments of motor function by the Alberta Infant Motor Scale (AIMS).
The AIMS is a measure of infant motor performance that assesses motor maturation of the infant through age 18 months and is
validated for comparison to normal, healthy infants. AIMS- assessed gains in motor function occurred in 13 patients. In the
majority of patients, motor function was substantially delayed compared to normal infants of comparable age. The continued
effect of alglucosidase alfa treatment over time on motor function is unknown. Two (2) of 9 patients who had demonstrated
gains in motor function after 12 months of alglucosidase alfa treatment and continued to be followed regressed despite ongoing
treatment.
Changes from baseline to Month 12 in left ventricular mass index (LVMI), an evaluation of bioactivity, were measured by echocardiography.For
the 15 patients with both baseline and Month 12 echocardiograms, all had decreases from baseline in LVMI (mean decrease 118
g/ m2, range 45- 193 g/ m2). The magnitude of the decrease in LVMI did not correlate with the clinical outcome measure of ventilator- free survival.
Study 2 is an ongoing, international, multicenter, nonrandomized, open- label clinical trial that enrolled 21 patients who
were ages 3 months to 3.5 years at first treatment. All patients received 20 mg/ kg alglucosidase alfa every other week for
up to 104 weeks. Five (5) of 21 patients were receiving invasive ventilatory support at the time of first infusion.
The primary outcome measure was the proportion of patients alive at the conclusion of treatment. At the 52- week interim analysis,
16 of 21 patients were alive. Sixteen (16) patients were free of invasive ventilatory support at the time of first infusion:
of these, 4 died, 2 required invasive ventilatory support, and 10 were free of invasive ventilatory support after 52 weeks
of treatment. For the 5 patients who were receiving invasive ventilatory support at baseline, 1 died, and 4 remained on invasive
ventilatory support at Week 52. The status of patients at Week 52 overlapped with that of an untreated historical group of
patients, and no effect of alglucosidase alfa treatment could be determined.
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INDICATIONS AND USAGE
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Alglucosidase alfa is indicated for use in patients with Pompe disease (GAA deficiency). Alglucosidase alfa has been shown
to improve ventilator- free survival in patients with infantile- onset Pompe disease as compared to an untreated historical
control, whereas use of alglucosidase alfa in patients with other forms of Pompe disease has not been adequately studied to
assure safety and efficacy (see CLINICAL STUDIES ).
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CONTRAINDICATIONS
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None known.
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WARNINGS
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RISK OF HYPERSENSITIVITY REACTIONS
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See BOXED WARNING .
Serious hypersensitivity reactions, including anaphylactic reactions, have been reported during alglucosidase alfa infusion.
Some reactions were life- threatening. One patient developed anaphylactic shock during alglucosidase alfa infusion that required
life- support measures (see ADVERSE REACTIONS ).
In clinical trials and expanded access programs with alglucosidase alfa, 38 of 280 (approximately 14%) patients treated with
alglucosidase alfa have developed infusion reactions that involved at least 2 of 3 body systems, cutaneous, respiratory or
cardiovascular systems. These events included: Cardiovascular: hypotension, cyanosis, hypertension, tachycardia, ventricular
extrasystoles, bradycardia, pallor, flushing, noda'i rhythm, peripheral coldness; Respiratory: tachypnea, wheezing/ bronchospasm,
rales, throat tightness, hypoxia, dyspnea, cough, respiratory tract irritation, oxygen saturation decreased; Cutaneous: angioneurotic
edema, urticaria, rash, erythema, periorbital edema, pruritus, hyperhidrosis, cold sweat, livedo reticularis (see ADVERSE REACTIONS ). Of these cases, 8 patients experienced severe or significant hypersensitivity reactions.
If severe hypersensitivity or anaphylactic reactions occur, immediate discontinuation of the administration of alglucosidase
alfa should be considered, and appropriate medical treatment should be initiated. Because of the potential for severe infusion
reactions, appropriate medical support measures should be readily available when alglucosidase alfa is administered.
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RISK OF CARDIAC ARRHYTHMIA AND SUDDEN CARDIAC DEATH DURING GENERAL ANESTHESIA FOR CENTRAL VENOUS CATHETER PLACEMENT
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Cardiac arrhythmia, including ventricular fibrilation, ventricular tachycardia and bradycardia, resulting in cardiac arrest
or death, or requiring cardiac resuscitation or defibrilation have been observed in infantile- onset Pompe disease patients
with cardiac hypertrophy, associated with the use of general anesthesia for the placement of a central venous catheter intended
for alglucosidase alfa infusion.
Caution should be used when administering general anesthesia for the placement of a central venous catheter in infantile-
onset Pompe disease patients with cardiac hypertrophy.
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RISK OF ACUTE CARDIORESPIRATORY FAILURE
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Acute cardiorespiratory failure requiring intubation and inotropic support has been observed after infusion with alglucosidase
alfa in 1 infantile- onset Pompe disease patient with underlying cardiac hypertrophy, possibly associated with fluid overload
with IV administration of alglucosidase alfa. (See DOSAGE AND ADMINISTRATION, Instructions for Use; Reconstitution, Dilution and Administration for information on appropriate infusion volumes.)
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Infusion Reactions
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Infusion reactions occurred in 20 of 39 (51 %) of patients treated with alglucosidase alfa in clinical studies (see ADVERSE REACTIONS ). Some reactions were severe. Severe infusion reactions reported in more than 1 patient in clinical studies and the expanded
access program included pyrexia, decreased oxygen saturation, tachycardia, cyanosis and hypotension. Other infusion reactions
reported in more than 1 patient in clinical studies and the expanded access program included rash, flushing, urticaria, pyrexia,
cough, tachycardia, decreased oxygen saturation, vomiting, tachypnea, agitation, increased blood pressure, cyanosis, hypertension,
irritability, pallor, pruritus, retching, rigors, tremor, hypotension, bronchospasm, erythema, face edema, feeling hot, headache,
hyperhidrosis, lacrimation increased, livedo reticularis, nausea, periorbital edema, restlessness and wheezing. Some patients
were pretreated with antihistamines, antipyretics and/ or steroids. Infusion reactions occurred in some patients after receiving
antipyretics, antihistamines, or steroids. Infusion reactions may occur at any time during, or up to 2 hours after, the infusion
of alglucosidase alfa, 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 reactions.Therefore, these patients should be monitored more closely during
administration of alglucosidase alfa.
If an infusion reaction 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 alglucosidase alfa should be considered, and appropriate medical treatment
should be initiated. Because of the potential for severe infusion reactions, appropriate medical support measures should be
readily available when alglucosidase alfa is administered. Patients who have experienced infusion reactions should be treated
with caution when readministered alglucosidase alfa.
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PRECAUTIONS
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General
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Patients with an acute underlying illness at the time of alglucosidase alfa infusion appear to be at greater risk for infusion
reactions. Careful consideration should be given to the patient's clinical status prior to administration of alglucosidase
alfa.
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Information for the Patient
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Patients and their caregivers should be informed that a registry for patients with Pompe disease has been established in order
to better understand the variability and progression of Pompe disease and to continue to monitor and evaluate treatments.Patients
and their caregivers are encouraged to participate and should be advised that their participation may involve long- term follow-
up.Information regarding the registry program may be found at www.pomperegistry.com or by calling 1- 800- 745- 4447.
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Laboratory Tests
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There are no marketed tests for antibodies against alglucosidase alfa. If testing is warranted, contact your local Genzyme
representative or Genzyme Corporation at 1- 800- 745- 4447.
Results from 2 IV repeated- dose animal toxicology studies using doses of 100 or 200 mg/ kg alglucosidase alfa (about 1.6-
3.2 times the recommended human dose based on body surface area) in Cynomolgus monkeys to evaluate the possibility of liver
accumulation over time showed GAA levels above background in liver tissue several days following the last dose; however, no
concurrent changes in liver enzymes or histopathology were observed. It is suggested that liver enzymes be evaluated prior
to the initiation of alglucosidase alfa treatment and periodically thereafter. Care should be exercised in interpreting these
tests since aspartate aminotransferase and alanine aminotransferase levels may also be raised as a result of the muscle pathology
in patients with Pompe disease.
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Carcinogenesis, Mutagenesis, and Impairment of Fertility
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Long- term studies in animals to evaluate carcinogenic potential or studies to evaluate mutagenic potential have not been
performed with alglucosidase alfa.
Alglucosidase alfa at IV doses up to 40 mg/ kg, administered every other day (about 0.2 times the recommended human bi- weekly
dose based on body surface area) had no effect on fertility and reproductive performance in mice.
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Pregnancy, Teratogenic Effects, Pregnancy Category B
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A reproduction study has been performed in pregnant mice at doses up to 40 mg/ kg/ day (about 0.2 times the recommended human
bi- weekly dose based on body surface area) and has revealed no evidence of impaired fertility or harm to the fetus due to
alglucosidase alfa. There are, however, no adequate and well- controlled studies in pregnant women. Because animal reproduction
studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
Women of childbearing potential are encouraged to enroll in the Pompe patient registry (see PRECAUTIONS, Information for the Patient ).
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Nursing Mothers
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It is not known whether alglucosidase alfa is excreted in human milk. Because many drugs are excreted in human milk, caution
should be exercised when alglucosidase alfa is administered to a nursing woman (See PRECAUTIONS, Information for the Patient regarding a registry program. Nursing women are encouraged to participate in the registry program).
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Pediatric Use
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Pediatric patients aged 1 month to 3.5 years at time of first infusion have been treated with alglucosidase alfa in clinical
trials (see CLINICAL STUDIES ). Other open- label clinical trials of alglucosidase alfa have been performed in older pediatric patients ranging from 2-
16 years at the initiation of treatment uuvenile- onset Pompe disease); however the risks and benefits of alglucosidase alfa
treatment have not been established in the juvenile- onset Pompe disease population.
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Geriatric Use
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Clinical studies did not include any subjects aged 65 years and older. It is not known whether they respond differently than
younger subjects.
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DRUG INTERACTIONS
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No drug interaction studies have been performed.
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ADVERSE REACTIONS
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The most serious adverse reactions reported with alglucosidase alfa were cardiorespiratory failure and anaphylactic reactions.
Cardiorespiratory failure, possibly associated with fluid overload, was reported in one infantile- onset Pompe disease patient,
and pre- existing cardiac hypertrophy likely contributed to the severity of the reaction (see WARNINGS, Risk of Acute Cardiorespiratory Failure ). Anaphylactic reactions have been reported during alglucosidase alfa infusion (see BOXED WARNING, Risk of Hypersensitivity Reactions , and WARNINGS, Risk of Hypersensitivity Reactions ).
The most common serious treatment- emergent adverse events (regardless of relationship) observed in clinical studies with
alglucosidase alfa were pneumonia, respiratory failure, respiratory distress, catheter- related infection, respiratory syncytial
virus infection, gastroenteritis and fever.
The most common treatment- emergent adverse events (regardless of relationship) were fever, diarrhea, rash, vomiting, cough,
pneumonia, otitis media, upper respiratory tract infection, gastroenteritis and decreased oxygen saturation.
The most common adverse reactions requiring intervention were infusion- related reactions (see WARNINGS, Infusion Reactions ). Twenty (20) of 39 patients (51 %) treated with alglucosidase alfa in clinical studies developed infusion reactions during
the infusion or during the 2 hours following infusion.The majority of these reactions were mild to moderate. Infusion reactions
reported in more than 1 patient in clinical studies and the expanded access program included rash, flushing, urticaria, pyrexia,
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, lacrimation increased, livedo reticularis, nausea, periorbital edema, restlessness and wheezing.Most infusion-
related reactions requiring intervention were ameliorated with slowing of the infusion rate, temporarily stopping the infusion,
and/ or administration of antipyretics, antihistamines, or steroids.
The data described below reflect exposure of 39 Pompe disease patients to 20 or 40 mg/ kg of alglucosidase alfa administered
every other week in 2 separate clinical trials for periods ranging from 1- 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).
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.
TABLE 2 enumerates treatment- emergent adverse events (regardless of relationship) that occurred in at least 20% of patients treated
with alglucosidase alfa in clinical trials described above. Reported frequencies of adverse events have been classified by
MedDRA terms.
| TABLE 2
Summary of Adverse Events by System Organ Class and Preferred Term Occurring in at Least 20% of Patients Treated With Alglucosidase
Alfa in Clinical Trials
|
| System Organ Class |
Number of Patients |
Number of |
| |
Preferred Term |
(n=39) |
Adverse Events |
| Adverse Events
|
39 (100%)
|
1859
|
| General Disorders and Administration Site Conditions
|
38 (97%)
|
|
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Pyrexia |
36 (92%) |
169 |
| Respiratory, Thoracic and Mediastinal Disorders
|
38 (97%)
|
|
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Cough |
18 (46%) |
69 |
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Respiratory distress |
13 (33%) |
18 |
| |
Respiratory failure |
12 (31%) |
24 |
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Rhinorrhea |
11 (28%) |
16 |
| |
Tachypnea |
9 (23%) |
15 |
| Infections and Infestations
|
37 (95%)
|
|
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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%)
|
|
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Diarrhea |
24 (62%) |
62 |
| |
Vomiting |
19 (49%) |
62 |
| |
Gastroesophageal reflux disease |
10 (26%) |
13 |
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Constipation |
9 (23%) |
14 |
| Skin and SC Tissue Disorders
|
32 (82%)
|
|
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Rash |
21 (54%) |
72 |
| |
Diaper dematitis |
14 (36%) |
34 |
| |
Urticaria |
8 (21%) |
25 |
| Investigations
|
28 (72%)
|
|
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Oxygen saturation decreased |
16 (41%) |
44 |
| Cardiac Disorders
|
24 (62%)
|
|
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Tachycardia |
9 (23%) |
31 |
| |
Bradycardia |
8 (21%) |
18 |
| Injury, Poisoning and Procedural Complications
|
22 (56%)
|
|
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Post procedural pain |
10 (26%) |
20 |
| Blood and Lymphatic System Disorders
|
17 (44%)
|
|
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Anemia |
12 (31%) |
23 |
| Vascular Disorders
|
14 (36%)
|
|
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Flushing |
8 (21%) |
15 |
|
Five (5) additional juvenile- onset Pompe disease patients were evaluated in a single- center, open- label, nonrandomized,
uncontrolled clinical trial.Patients were ages 5- 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 alglucosidase
alfa for 26 weeks. The most common treatment- emergent adverse events (regardless of causality) observed with alglucosidase
alfa treatment in this study were headache, pharyngitis, upper abdominal pain, malaise and rhinitis.
Immunogenicity
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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 antialglucosidase 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, Pharmacokinetics ).
Infusion reactions were reported in 20 of 39 patients (51 %) treated with alglucosidase alfa 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.
Approximately 40 patients in clinical trials and expanded access programs have undergone testing for alglucosidase alfa- specific
IgE antibodies.Testing was performed for infusion reactions, especially moderate to severe or recurrent reactions, for which
mast- cell activation was suspected. Three (3) of these patients tested positive for alglucosidase alfa specific IgE binding
antibodies, 1 of whom experienced an anaphylactic reaction (see WARNINGS, Risk of Hypersensitivity Reactions ).
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OVERDOSAGE
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There have been no reports of overdose with alglucosidase alfa. In clinical trials, patients received doses up to 40 mg/ kg
of body weight.
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DOSAGE AND ADMINISTRATION
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The recommended dosage regimen of alglucosidase alfa is 20 mg/ kg body weight administered every 2 weeks as an IV infusion.
The total volume of infusion is determined by the patient's body weight and should be administered over approximately 4 hours.
Infusions should be administered in a step- wise manner using an infusion pump. The initial infusion rate should be no more
than 1 mg/ kg/ h.The infusion rate may be increased by 2 mg/ kg/ h every 30 minutes, after patient tolerance to the infusion
rate is established, until a maximum rate of 7 mg/ kg/ h is reached. Vital signs should be obtained at the end of each step.
If the patient is stable, alglucosidase alfa may be administered at the maximum rate of 7 mg/ kg/ h until the infusion is
completed. The infusion rate may be slowed and/ or temporarily stopped in the event of infusion reactions. See TABLE 3 for the rate of infusion at each step, expressed as ml/ h based on the recommended infusion volume by patient weight.
| TABLE 3
Recommended Infusion Volumes and Rates
|
| |
|
Step 1 |
Step 2 |
Step 3 |
Step 4 |
| |
|
1 mg/ kg/ h |
3 mg/ kg/ h |
5 mg/ kg/ h |
7 mg/ kg/ h |
| Patient Weight (kg) |
Total Infusion Volume (ml) |
(ml/ h) |
(ml/ h) |
(ml/ h) |
(ml/ h) |
| 1.25- 10 |
50 |
3 |
8 |
13 |
18 |
| 10.1- 20 |
100 |
5 |
15 |
25 |
35 |
| 20.1- 30 |
150 |
8 |
23 |
38 |
53 |
| 30.1- 35 |
200 |
10 |
30 |
50 |
70 |
| 35.1- 50 |
250 |
13 |
38 |
63 |
88 |
| 50.1- 60 |
300 |
15 |
45 |
75 |
105 |
| 60.1- 100 |
500 |
25 |
75 |
125 |
175 |
| 100.1- 120 |
600 |
30 |
90 |
150 |
210 |
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Instructions for Use
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| |
Alglucosidase alfa does not contain any preservatives. Vials are single- use only. Any unused product should be discarded.
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Reconstitution, Dilution and Administration
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| |
Alglucosidase alfa should be reconstituted, diluted and administered by a health care professional.
Use aseptic technique during preparation. Do not use filer needles during preparation.
Step 1
| • |
Determine the number of vials to be reconstituted based on the individual patient's weight and the recommended dose of 20
mg/ kg.
|
| • |
Patient weight (kg) × dose (mg/ kg) = patient dose (in mg).
|
| • |
Patient dose (in mg) divided by 50 mg/ vial = number of vials to reconstitute. If the number of vials includes a fraction,
round up to the next whole number.
|
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Example: Patient weight (16 kg) × dose (20 mg/ kg) = patient dose (320 mg).
|
| • |
320 mg divided by 50 mg/ vial = 6.4 vials; therefore, 7 vials should be reconstituted.
|
| • |
Remove the required number of vialsfrom the refrigerator and allow them to reach room temperature prior to reconstitution
(approximately 30 minutes).
|
Step 2
| • |
Reconstitute each alglucosidase alfa vial by slowly injecting 10.3 ml of sterile water for injection to the inside wall of
each vial. Each vial will yield 5 mg/ ml. The total extractable dose per vial is 50 mg per 10 ml. Avoid forceful impact of
the water for injection on the powder and avoid foaming. This is done by slow drop- wise addition of the water for injection
down the inside of the vial and not directly onto the lyophilized cake. Tilt and roll each vial gently. Do not invert, swirl,
or shake.
|
Step 3
| • |
The reconstituted alglucosidase alfa solution should be protected from light.
|
Step 4
| • |
Perform an immediate visual inspection on the reconstituted vials for particulate matter and discoloration. If upon immediate
inspection opaque particles are observed or if the solution is discolored do not use. The reconstituted solution may occasionally
contain some alglucosidase alfa particles (typically less than 10 in a vial) in the form of thin white strands or translucent
fibers subsequent to the initial inspection. This may also happen following dilution for infusion. These particles have been
shown to contain alglucosidase alfa and may appear after the initial reconstitution step and increase over time. Studies have
shown that these particles are removed via in- line filration without having a detectable effect on the purity or strength.
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Step 5
| • |
Alglucosidase alfa should be diluted in 0.9% sodium chloride for injection immediately after reconstitution, to a final alglucosidase
alfa concentration of 0.5- 4 mg/ ml. See TABLE 3 for the recommended total infusion volume based on patient weight.
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Step 6
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Slowly withdraw the reconstituted solution from each vial. Avoid foaming in the syringe.
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Step 7
| • |
Remove airspace from the infusion bag to minimize particle formation due to the sensitivity of alglucosidase alfa to air-
liquid interfaces.
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Step 8
| • |
Add the reconstituted alglucosidase alfa solution slowly and directly into the sodium chloride solution. Do not add directly
into airspace that may remain within the infusion bag. Avoid foaming in the infusion bag.
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Step 9
| • |
Gently invert or massage the infusion bag to mix. Do not shake.
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The diluted solution should be filtered through a 0.2 µm, low protein- binding, in- line filter during administration to remove
any visible particles.
Alglucosidase alfa should not be infused in the same IV line with other products.
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HOW SUPPLIED
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Myozyme 50- mg vials are supplied as a sterile, nonpyrogenic, white to off- white lyophilized cake or powder. Myozyme is supplied
in single- use, clear Type I glass 20 ml (cc) vials. The closure consists of a siliconized butyl stopper and an aluminum seal
with a plastic flip- off cap.
Storage
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Store alglucosidase alfa under refrigeration between 2- 8°C (36- 46°F). Do not use alglucosidase alfa after the expiration
date on the vial.
The reconstituted and diluted solution should be administered without delay. If immediate use is not possible, the reconstituted
and diluted solution is stable for up to 24 hours at 2- 8°C (36- 46°F). Storage of the reconstituted solution at room temperature
is not recommended. The reconstituted and diluted alglucosidase alfa solution should be protected from light. DO NOT FREEZE
OR SHAKE.
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PRODUCT IDENTIFICATION
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None Available |
PATIENT DRUG CONSULT HANDOUT
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None Available |
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