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Agenda. MPS VI Clinical OverviewNAGLAZYME (galsulfase) OverviewDosage and Administration of NAGLAZYME. NAGLAZYME Indication. NAGLAZYME is indicated for patients with Mucopolysaccharidosis VI (MPS VI). NAGLAZYME has been shown to improve walking and stair-climbing capacity. Important Safety Inf
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1. NAGLAZYME (galsulfase) Infusion Site Training BM/VI/116/121806BM/VI/116/121806
2. Agenda MPS VI Clinical Overview
NAGLAZYME (galsulfase) Overview
Dosage and Administration of NAGLAZYME
3. Included here is Important Safety Information for NAGLAZYME (galsulfase). Please see NAGLAZYME (galsulfase for injection) full prescribing information. BioMarin Pharmaceutical Inc.
Included here is Important Safety Information for NAGLAZYME (galsulfase). Please see NAGLAZYME (galsulfase for injection) full prescribing information. BioMarin Pharmaceutical Inc.
4. Maroteaux-Lamy Syndrome (MPS VI) Clinical Overview
5. One of more than 40 known lysosomal storage disorders (LSD)
Estimated incidence from available studies: 1/340,000 live births
Autosomal recessive inheritance pattern
Deficient enzyme in MPS VI is Arylsulfatase B (ASB)
ASB deficiency results in multisystemic accumulation of GAG and causes widespread, progressive pathology
Maroteaux-Lamy Syndrome (MPS VI) Maroteaux-Lamy syndrome is also known as mucopolysaccharidosis VI, or MPS VI. MPS VI is caused by a deficiency of the enzyme arylsulfatase B which is involved in the catabolism of the glycosaminoglycan (GAG) dermatan sulfate.
If arylsulfatase B is deficient, degradation of dermatan sulfate (DS) is blocked and therefore DS accumulates in the lysosomes of the cells, eventually leading to organ damage primarily affecting soft tissue and skeleton.1
Individually MPS VI is a rare disease but combined, the LSDs together affect approximately 1:5,000 live birthsrepresenting a significant medical need7
The estimated global incidence for MPS VI of 1 per 340,000 births reflects a combined analysis of multiple studies. Individual estimates of MPS VI incidence range from 1 per 238,000 (Northern Portugal) to 1 per 1,298,000 (British Columbia)1-5 No data is available for MPS VI in most countries. The distribution of MPS VI appears to be panethnic, with reported cases of Asian, Australian indigenous, South American indigenous, and European descent, but with enriched subpopulations in certain geographic areas.
Estimated global prevalence is 1100 individuals.6
MPS VI is likely to be under diagnosed due to the broad clinical spectrum including slowly advancing disease and misdiagnosed according to the presenting symptomsfor example, arthritis.
REFERENCES
1. Neufeld EF, Muenzer J. The mucopolysaccharidoses. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic and Molecular Bases of Inherited Disease. Vol 3. 8th ed. New York: McGraw-Hill; 2001:34213452. 2. Pinto R, Caseiro C, Lemos M, et al. Prevalence of lysosomal storage disorders in Portugal. Eur J Hum Genet. 2004;12:8792. 3. Meikle PJ, Hopwood JJ, Clague AE, Carey WF. Prevalence of lysosomal storage disorders. JAMA. 1999;281:249254. 4. Poorthuis BJ, Wevers RA, Klejer WJ, et al. The frequency of lysosomal storage disorders in the Netherlands. Hum Genet. 1999;105:151-156. 5. Nelson J. Incidence of the mucopolysaccharidoses in Northern Ireland. Hum Genet. 1997;101:355-358. 6. Lowry RB, Applegarth DA, Toone JR, et al. An update on the frequency of mucopolysaccharide syndromes in British Columbia. Hum Genet.1990;85:389-390. 7. Swiedler SJ, Beck M, Bajbouj M, et al. Threshold effect of urinary glycosaminoglycans and the walk test as indicators of disease progression in a survey of subjects with mucopolysaccharidosis VI (Maroteaux-Lamy syndrome). Am J Med Genet A. 2005;134:144150. 8. Fisher A, Fox J. Newborn screening for lysosomal storage disorders [fact sheet]. National MPS Society, Inc. 2004. Available at: http://www.mpssociety.org/lib-factsheet.html. Accessed December 17, 2004.
Maroteaux-Lamy syndrome is also known as mucopolysaccharidosis VI, or MPS VI. MPS VI is caused by a deficiency of the enzyme arylsulfatase B which is involved in the catabolism of the glycosaminoglycan (GAG) dermatan sulfate.
If arylsulfatase B is deficient, degradation of dermatan sulfate (DS) is blocked and therefore DS accumulates in the lysosomes of the cells, eventually leading to organ damage primarily affecting soft tissue and skeleton.1
Individually MPS VI is a rare disease but combined, the LSDs together affect approximately 1:5,000 live birthsrepresenting a significant medical need7
The estimated global incidence for MPS VI of 1 per 340,000 births reflects a combined analysis of multiple studies. Individual estimates of MPS VI incidence range from 1 per 238,000 (Northern Portugal) to 1 per 1,298,000 (British Columbia)1-5 No data is available for MPS VI in most countries. The distribution of MPS VI appears to be panethnic, with reported cases of Asian, Australian indigenous, South American indigenous, and European descent, but with enriched subpopulations in certain geographic areas.
Estimated global prevalence is 1100 individuals.6
MPS VI is likely to be under diagnosed due to the broad clinical spectrum including slowly advancing disease and misdiagnosed according to the presenting symptomsfor example, arthritis.
REFERENCES
1. Neufeld EF, Muenzer J. The mucopolysaccharidoses. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic and Molecular Bases of Inherited Disease. Vol 3. 8th ed. New York: McGraw-Hill; 2001:34213452. 2. Pinto R, Caseiro C, Lemos M, et al. Prevalence of lysosomal storage disorders in Portugal. Eur J Hum Genet. 2004;12:8792. 3. Meikle PJ, Hopwood JJ, Clague AE, Carey WF. Prevalence of lysosomal storage disorders. JAMA. 1999;281:249254. 4. Poorthuis BJ, Wevers RA, Klejer WJ, et al. The frequency of lysosomal storage disorders in the Netherlands. Hum Genet. 1999;105:151-156. 5. Nelson J. Incidence of the mucopolysaccharidoses in Northern Ireland. Hum Genet. 1997;101:355-358. 6. Lowry RB, Applegarth DA, Toone JR, et al. An update on the frequency of mucopolysaccharide syndromes in British Columbia. Hum Genet.1990;85:389-390. 7. Swiedler SJ, Beck M, Bajbouj M, et al. Threshold effect of urinary glycosaminoglycans and the walk test as indicators of disease progression in a survey of subjects with mucopolysaccharidosis VI (Maroteaux-Lamy syndrome). Am J Med Genet A. 2005;134:144150. 8. Fisher A, Fox J. Newborn screening for lysosomal storage disorders [fact sheet]. National MPS Society, Inc. 2004. Available at: http://www.mpssociety.org/lib-factsheet.html. Accessed December 17, 2004.
6. GAG Accumulation in Lysosomes Lysosomal degradation of a substrate (GAG) is blocked due to enzyme deficiency
Undegraded GAG accumulates within lysosomes
Progressive GAG storage leads to enlargement of the lysosome, eventually causing cellular dysfunction An inherited deficiency in one of the many lysosomal enzymes results in a lysosomal storage disorder (LSD). The complex material (or substrate) that is normally broken down by the missing enzyme instead accumulates and is stored inside the lysosomes.
As shown in the photographs on this slide, progressive accumulation of the undegraded substrate causes lysosomes to become engorged; this effect is plainly visible in the photograph on the right.
Over time, lysosomal storage results in cell dysfunction and death, giving rise to a range of progressive, multisystemic pathologies.1
REFERENCES
1. Whitley CB. The mucopolysaccharidoses. In: Beighton P (ed). McKusicks Heritable Disorders of Connective Tissue. 5th ed. St Louis, Missouri: Mosby, 1993, 367-499.
An inherited deficiency in one of the many lysosomal enzymes results in a lysosomal storage disorder (LSD). The complex material (or substrate) that is normally broken down by the missing enzyme instead accumulates and is stored inside the lysosomes.
As shown in the photographs on this slide, progressive accumulation of the undegraded substrate causes lysosomes to become engorged; this effect is plainly visible in the photograph on the right.
Over time, lysosomal storage results in cell dysfunction and death, giving rise to a range of progressive, multisystemic pathologies.1
REFERENCES
1. Whitley CB. The mucopolysaccharidoses. In: Beighton P (ed). McKusicks Heritable Disorders of Connective Tissue. 5th ed. St Louis, Missouri: Mosby, 1993, 367-499.
7. Classification of MPS Disorders There are 7 different types of MPS, two with subtypes. Each type and subtype is associated with an deficiency in a particular GAG-degrading enzyme and the accumulation of specific GAG(s). MPS III & MPS IV have subtypes caused by a different enzyme deficiency.1
The MPS diseases are designated by type (roman numeral) but are also known by common/historical names-usually the name of the physician who first described the disorder-assigned before the genetic and biochemical basis of the disorder was understood. Scheie Syndrome was originally designated as MPS type V but later was found to be caused by the same enzyme defect as type I-Hurler. Types V and VIII designations are no longer used.
REFERENCES
1. Neufeld EF, Muenzer J. The mucopolysaccharidoses. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic and Molecular Bases of Inherited Disease. Vol 3. 8th ed. New York: McGraw-Hill; 2001:34213452.
There are 7 different types of MPS, two with subtypes. Each type and subtype is associated with an deficiency in a particular GAG-degrading enzyme and the accumulation of specific GAG(s). MPS III & MPS IV have subtypes caused by a different enzyme deficiency.1
The MPS diseases are designated by type (roman numeral) but are also known by common/historical names-usually the name of the physician who first described the disorder-assigned before the genetic and biochemical basis of the disorder was understood. Scheie Syndrome was originally designated as MPS type V but later was found to be caused by the same enzyme defect as type I-Hurler. Types V and VIII designations are no longer used.
REFERENCES
1. Neufeld EF, Muenzer J. The mucopolysaccharidoses. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic and Molecular Bases of Inherited Disease. Vol 3. 8th ed. New York: McGraw-Hill; 2001:34213452.
8. Significance of Glycosaminoglycans Glycosaminoglycans (GAGs) are polysaccharide chains
Previously known as mucopolysaccharides
As in all LSDs, the disease spectrum is primarily due to the distribution and turnover of the affected substrate
GAGs are a major component of connective tissue
Widely distributed throughout the body
Basic substance of skin, cartilage, bone
A component of lubricating fluid in joints
Regulate multiple processes, including cell-cell adhesion
As in all LSDs, the disease spectrum is primarily due to the distribution and turnover of the affected substrate. Glycosaminoglycans (GAG) are structural polysaccharides (sugar chains) formerly called mucopolysaccharides. Recycling and remodeling of GAG is a fundamental process and disruption of this process leads to progressive GAG accumulation and cell dysfunction.
In MPS disorders, the affected substrate, GAG, is a major component of connective tissue and so is widely distributed throughout the body therefore the accumulation of GAG results in pathology in a wide range of organ systems, including nervous, ocular, auditory, oropharyngeal, respiratory, cardiovascular, and musculoskeletal systems.1
REFERENCES
1. Whitley CB. The mucopolysaccharidoses. In: Beighton P (ed). McKusicks Heritable Disorders of Connective Tissue. 5th ed. St Louis, Missouri: Mosby, 1993, 367-499.
As in all LSDs, the disease spectrum is primarily due to the distribution and turnover of the affected substrate. Glycosaminoglycans (GAG) are structural polysaccharides (sugar chains) formerly called mucopolysaccharides. Recycling and remodeling of GAG is a fundamental process and disruption of this process leads to progressive GAG accumulation and cell dysfunction.
In MPS disorders, the affected substrate, GAG, is a major component of connective tissue and so is widely distributed throughout the body therefore the accumulation of GAG results in pathology in a wide range of organ systems, including nervous, ocular, auditory, oropharyngeal, respiratory, cardiovascular, and musculoskeletal systems.1
REFERENCES
1. Whitley CB. The mucopolysaccharidoses. In: Beighton P (ed). McKusicks Heritable Disorders of Connective Tissue. 5th ed. St Louis, Missouri: Mosby, 1993, 367-499.
9. MPS VI Clinical Manifestations Summary The clinical manifestations of MPS VI are highly variable, as are initial clinical presentations. A cluster of suggestive features is significant; the absence of a particular feature does not rule out MPS.1
MPS VI patients may present with marked disease early in life or with only subtle findings and slow progression of the disease over years. 1
REFERENCES
1. Wilcox WR. Lysosomal storage disorders: the need for better pediatric recognition and comprehensive care. J Pediatr. 2004;144(5 Suppl):S3S14. Review.
The clinical manifestations of MPS VI are highly variable, as are initial clinical presentations. A cluster of suggestive features is significant; the absence of a particular feature does not rule out MPS.1
MPS VI patients may present with marked disease early in life or with only subtle findings and slow progression of the disease over years. 1
REFERENCES
1. Wilcox WR. Lysosomal storage disorders: the need for better pediatric recognition and comprehensive care. J Pediatr. 2004;144(5 Suppl):S3S14. Review.
10. Spectrum of Clinical Presentation All of the MPS disorders have a wide spectrum of severity. Prognosis, age of clinical presentation, extent of organ involvement, and rate of disease progression varies among individuals with the same MPS type. Less severe/slowly advancing clinical phenotypes can occur due to mutations that allow a small amount of residual enzyme activity as well as other genetic or environmental factors.1-2
It is important to remember that despite the wide range of rates of disease progression and symptom severity, MPS disorders are progressive. Patients who present with what seem to be mild symptoms should not be regarded as having mild disease, but rather as being in the early stages of a process that generally leads to progressive multisystemic manifestations and progressive disability. 3
As illustrated by these photographs, the spectrum of severity and rate of disease progression varies widely in patients with MPS VI. Four patients, aged 9-12 years, demonstrate the wide spectrum of disease severity and rates of disease progression
Despite differences in rate of disease progression, all MPS VI individuals eventually develop serious clinical manifestations.1
REFERENCES
1. Neufeld EF, Muenzer J. The mucopolysaccharidoses. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic and Molecular Bases of Inherited Disease. Vol 3. 8th ed. New York: McGraw-Hill; 2001:34213452. 2. Wilcox WR. Lysosomal storage disorders: the need for better pediatric recognition and comprehensive care. J Pediatr. 2004;144(5 Suppl):S3S14. Review. 3. Swiedler SJ, Beck M, Bajbouj M, et al. Threshold effect of urinary glycosaminoglycans and the walk test as indicators of disease progression in a survey of subjects with mucopolysaccharidosis VI (Maroteaux-Lamy syndrome). Am J Med Genet A. 2005;134:144150.
2. Swiedler SJ, Beck M, Bajbouj M, et al. Threshold effect of urinary glycosaminoglycans and the walk test as indicators of disease progression in a survey of subjects with mucopolysaccharidosis VI (Maroteaux-Lamy syndrome). Am J Med Genet A. 2005;134:144150.
Photos (right) courtesy of The National MPS Society Inc.
All of the MPS disorders have a wide spectrum of severity. Prognosis, age of clinical presentation, extent of organ involvement, and rate of disease progression varies among individuals with the same MPS type. Less severe/slowly advancing clinical phenotypes can occur due to mutations that allow a small amount of residual enzyme activity as well as other genetic or environmental factors.1-2
It is important to remember that despite the wide range of rates of disease progression and symptom severity, MPS disorders are progressive. Patients who present with what seem to be mild symptoms should not be regarded as having mild disease, but rather as being in the early stages of a process that generally leads to progressive multisystemic manifestations and progressive disability. 3
As illustrated by these photographs, the spectrum of severity and rate of disease progression varies widely in patients with MPS VI. Four patients, aged 9-12 years, demonstrate the wide spectrum of disease severity and rates of disease progression
Despite differences in rate of disease progression, all MPS VI individuals eventually develop serious clinical manifestations.1
REFERENCES
1. Neufeld EF, Muenzer J. The mucopolysaccharidoses. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic and Molecular Bases of Inherited Disease. Vol 3. 8th ed. New York: McGraw-Hill; 2001:34213452. 2. Wilcox WR. Lysosomal storage disorders: the need for better pediatric recognition and comprehensive care. J Pediatr. 2004;144(5 Suppl):S3S14. Review. 3. Swiedler SJ, Beck M, Bajbouj M, et al. Threshold effect of urinary glycosaminoglycans and the walk test as indicators of disease progression in a survey of subjects with mucopolysaccharidosis VI (Maroteaux-Lamy syndrome). Am J Med Genet A. 2005;134:144150.
2. Swiedler SJ, Beck M, Bajbouj M, et al. Threshold effect of urinary glycosaminoglycans and the walk test as indicators of disease progression in a survey of subjects with mucopolysaccharidosis VI (Maroteaux-Lamy syndrome). Am J Med Genet A. 2005;134:144150.
Photos (right) courtesy of The National MPS Society Inc.
11. Disease Progression: Rapidly Advancing As illustrated by the series of photographs, this individual with rapidly advancing MPS VI exhibits early and progressive development of coarse facial features, macrocephaly, abdominal protrusion, umbilical hernia, and skeletal/joint abnormalities.
Photos courtesy of The National MPS Society Inc.
As illustrated by the series of photographs, this individual with rapidly advancing MPS VI exhibits early and progressive development of coarse facial features, macrocephaly, abdominal protrusion, umbilical hernia, and skeletal/joint abnormalities.
Photos courtesy of The National MPS Society Inc.
12. Disease Progression: Slowly Advancing Unlike the preceding individual with rapidly advancing MPS VI, this male with slowly advancing disease does not exhibit obvious physical features of MPS VI.
Photos courtesy of The National MPS Society Inc.
Unlike the preceding individual with rapidly advancing MPS VI, this male with slowly advancing disease does not exhibit obvious physical features of MPS VI.
Photos courtesy of The National MPS Society Inc.
13. Clinical Manifestations
14. Coarse Facial Features Typical coarse facial features of MPS VI include broad nose and flat nasal bridge, prominent eyes, enlarged tongue and lips, along with macrocephaly, and shortened neck.
An individual with rapidly advancing MPS VI exhibits marked coarsening of facial features (left). A male with more slowly advancing disease exhibits very subtle facial coarsening (right).
It is important to point out that individuals with MPS VI often have a normal appearance at birth, and that this normalor relatively normalappearance persists for a variable period of time following birth, depending on the rate of disease progression.1
REFERENCES
1. Neufeld EF, Muenzer J. The mucopolysaccharidoses. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic and Molecular Bases of Inherited Disease. Vol 3. 8th ed. New York: McGraw-Hill; 2001:34213452.
Typical coarse facial features of MPS VI include broad nose and flat nasal bridge, prominent eyes, enlarged tongue and lips, along with macrocephaly, and shortened neck.
An individual with rapidly advancing MPS VI exhibits marked coarsening of facial features (left). A male with more slowly advancing disease exhibits very subtle facial coarsening (right).
It is important to point out that individuals with MPS VI often have a normal appearance at birth, and that this normalor relatively normalappearance persists for a variable period of time following birth, depending on the rate of disease progression.1
REFERENCES
1. Neufeld EF, Muenzer J. The mucopolysaccharidoses. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic and Molecular Bases of Inherited Disease. Vol 3. 8th ed. New York: McGraw-Hill; 2001:34213452.
15. Stature Clinical Features A male with rapidly advancing MPS VI (left) exhibits extreme short stature. Flexed-knee stance results in part from joint stiffening and contracturesparticularly in the knees, and hips. Protruding abdomen results, in part, from organomegaly. Also note the coarse facies and shortened neck.
A younger individual with slowly advancing disease does not exhibit such obvious features (right).
Height varies with the severity and rate of disease progression, and may vary substantially from patient to patient. Individuals with the rapidly advancing form of MPS VI may not grow beyond 3 feet, while patients with the slowly advancing form may grow to about 5 feet.1
REFERENCES
1. Kakkis ED and Neufeld EF. The mucopolysaccharidoses. In: Principles of Child Neurology. B. Berg (ed). 1st ed. New York, New York: McGraw-Hill Inc; 1996; 1141-1166
Photo (right) courtesy of The National MPS Society Inc.
A male with rapidly advancing MPS VI (left) exhibits extreme short stature. Flexed-knee stance results in part from joint stiffening and contracturesparticularly in the knees, and hips. Protruding abdomen results, in part, from organomegaly. Also note the coarse facies and shortened neck.
A younger individual with slowly advancing disease does not exhibit such obvious features (right).
Height varies with the severity and rate of disease progression, and may vary substantially from patient to patient. Individuals with the rapidly advancing form of MPS VI may not grow beyond 3 feet, while patients with the slowly advancing form may grow to about 5 feet.1
REFERENCES
1. Kakkis ED and Neufeld EF. The mucopolysaccharidoses. In: Principles of Child Neurology. B. Berg (ed). 1st ed. New York, New York: McGraw-Hill Inc; 1996; 1141-1166
Photo (right) courtesy of The National MPS Society Inc.
16. Eyes Clinical Features Corneal clouding results from ocular GAG accumulation. Obvious corneal clouding is typically preceded by the appearance of corneal opacities, which are visible with slit lamp exam.
Corneal clouding is a major cause of vision loss in patients with MPS VI. Vision loss may also be caused by retinal changes, optic nerve damage, or glaucoma. Some individuals with MPS VI have undergone corneal transplants, which usually improve vision, however, over time, GAG accumulation recurs.1-2
REFERENCES
1. Neufeld EF, Muenzer J. The mucopolysaccharidoses. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic and Molecular Bases of Inherited Disease. Vol 3. 8th ed. New York: McGraw-Hill; 2001:34213452. 2. Kakkis ED and Neufeld EF. The mucopolysaccharidoses. In: Principles of Child Neurology. B. Berg (ed). 1st ed. New York, New York: McGraw-Hill Inc; 1996; 1141-1166
Corneal clouding results from ocular GAG accumulation. Obvious corneal clouding is typically preceded by the appearance of corneal opacities, which are visible with slit lamp exam.
Corneal clouding is a major cause of vision loss in patients with MPS VI. Vision loss may also be caused by retinal changes, optic nerve damage, or glaucoma. Some individuals with MPS VI have undergone corneal transplants, which usually improve vision, however, over time, GAG accumulation recurs.1-2
REFERENCES
1. Neufeld EF, Muenzer J. The mucopolysaccharidoses. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic and Molecular Bases of Inherited Disease. Vol 3. 8th ed. New York: McGraw-Hill; 2001:34213452. 2. Kakkis ED and Neufeld EF. The mucopolysaccharidoses. In: Principles of Child Neurology. B. Berg (ed). 1st ed. New York, New York: McGraw-Hill Inc; 1996; 1141-1166
17. Recurrent otitis media
Recurrent sinusitis
Hearing loss
Enlarged tongue
Broad gum ridges
Delayed eruption of dentition
Dental cysts
Poorly formed teeth Recurrent otitis media and middle ear effusion, an accumulation of thickened fluid, is common in MPS VI patients. Excess secretion of mucus and poor mucociliary clearance in MPS VI patients increases the risk of bacterial otitis media secondary to viral respiratory infections and blockage of the eustachian tube resulting in negative pressure behind the eardrum can cause effusion in the middle ear.
Many MPS VI patients experience conductive, sensorineural, or mixed hearing loss. Regular otological and auditory examinations are recommended. Middle ear effusion and bony abnormalities can lead to conductive hearing loss, whereas sensorineural deafness usually is caused by damage to hair cells in the inner ear. Recurrent otitis media may exacerbate hearing loss.
Characteristic oral features in MPS VI patients include enlarged tongue, tonsils and adenoids; broad gum ridges; delayed eruption of dentition; and poorly formed teeth. Due to abnormal formation of teeth in MPS VI patients, abscesses are common. Furthermore, MPS VI patients with cardiac co-morbidities, especially valvular abnormalities, are at increased risk of bacterial endocarditis from abscesses, dental procedures, and surgery.1-2
To minimize risks of infective endocarditis in MPS VI patients, good oral hygiene, prevention of caries, immediate treatment of abscesses, and use of prophylactic antibiotics before and after dental treatment are essential.
Delayed eruption of dentition is treated with surgical exposure, orthodontic traction, or surgical extraction.3
Photo courtesy of The National MPS Society Inc.
REFERENCES
1. Kakkis E, Neufeld E, The Mucopolysccharidoses, 1996; Part 4/Major Categories of Disease, 1141-1166. 2. Kakkis ED and Neufeld EF. The mucopolysaccharidoses. In: Principles of Child Neurology. B. Berg (ed). 1st ed. New York, New York: McGraw-Hill Inc; 1996; 1141-1166. 3. Smith KS, Hallett, KB, Hall RK, Wardrop RW, Firth N. Mucopolysccharidosis: MPS VI and associated delayed tooth eruption; Int. J. Oral Maxillofac Surg 1995; 24: 1976-180.
Recurrent otitis media and middle ear effusion, an accumulation of thickened fluid, is common in MPS VI patients. Excess secretion of mucus and poor mucociliary clearance in MPS VI patients increases the risk of bacterial otitis media secondary to viral respiratory infections and blockage of the eustachian tube resulting in negative pressure behind the eardrum can cause effusion in the middle ear.
Many MPS VI patients experience conductive, sensorineural, or mixed hearing loss. Regular otological and auditory examinations are recommended. Middle ear effusion and bony abnormalities can lead to conductive hearing loss, whereas sensorineural deafness usually is caused by damage to hair cells in the inner ear. Recurrent otitis media may exacerbate hearing loss.
Characteristic oral features in MPS VI patients include enlarged tongue, tonsils and adenoids; broad gum ridges; delayed eruption of dentition; and poorly formed teeth. Due to abnormal formation of teeth in MPS VI patients, abscesses are common. Furthermore, MPS VI patients with cardiac co-morbidities, especially valvular abnormalities, are at increased risk of bacterial endocarditis from abscesses, dental procedures, and surgery.1-2
To minimize risks of infective endocarditis in MPS VI patients, good oral hygiene, prevention of caries, immediate treatment of abscesses, and use of prophylactic antibiotics before and after dental treatment are essential.
Delayed eruption of dentition is treated with surgical exposure, orthodontic traction, or surgical extraction.3
Photo courtesy of The National MPS Society Inc.
REFERENCES
1. Kakkis E, Neufeld E, The Mucopolysccharidoses, 1996; Part 4/Major Categories of Disease, 1141-1166. 2. Kakkis ED and Neufeld EF. The mucopolysaccharidoses. In: Principles of Child Neurology. B. Berg (ed). 1st ed. New York, New York: McGraw-Hill Inc; 1996; 1141-1166. 3. Smith KS, Hallett, KB, Hall RK, Wardrop RW, Firth N. Mucopolysccharidosis: MPS VI and associated delayed tooth eruption; Int. J. Oral Maxillofac Surg 1995; 24: 1976-180.
18. Airways and Respiration Clinical Features Many patients with MPS VI develop obstruction in the upper airways, especially due to thickened tongue, short neck, enlarged tonsils and adenoids, narrowing of the trachea, and redundant tissue of the nasopharynx. As a result, labored or loud breathing and snoring are common, and in some patients progressive obstruction leads to sleep apnea and associated cor pulmonale. Recurrent sinopulmonary infections are common in individuals with MPS VI. Factors contributing to these infections include obstructive airway disease, restricted respiration due to skeletal abnormality and organomegaly, and excessive and thickened secretions. 1-3
Pulmonary function tests reveal abnormally low forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1), and peak expiratory flow (PEF).4
REFERENCES
1. Bredenkamp et al. 1992, Otolaryngologic Manifestations of the Muccopolysachharidosis; Ann Otel Rhinol Laryngol 101:1992; 472 to 477. 2. Kakkis ED and Neufeld EF. The mucopolysaccharidoses. In: Principles of Child Neurology. B. Berg (ed). 1st ed. New York, New York: McGraw-Hill Inc; 1996; 1141-1166 3. Neufeld EF, Muenzer J. The mucopolysaccharidoses. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic and Molecular Bases of Inherited Disease. Vol 3. 8th ed. New York, NY:McGraw-Hill; 2001:34213452. 4. Swiedler SJ, Beck M, Bajbouj M, et al. Threshold effect of urinary glycosaminoglycans and the walk test as indicators of disease progression in a survey of subjects with mucopolysaccharidosis VI (Maroteaux-Lamy syndrome). Am J Med Genet A. 2005;134:144150.
Many patients with MPS VI develop obstruction in the upper airways, especially due to thickened tongue, short neck, enlarged tonsils and adenoids, narrowing of the trachea, and redundant tissue of the nasopharynx. As a result, labored or loud breathing and snoring are common, and in some patients progressive obstruction leads to sleep apnea and associated cor pulmonale. Recurrent sinopulmonary infections are common in individuals with MPS VI. Factors contributing to these infections include obstructive airway disease, restricted respiration due to skeletal abnormality and organomegaly, and excessive and thickened secretions. 1-3
Pulmonary function tests reveal abnormally low forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1), and peak expiratory flow (PEF).4
REFERENCES
1. Bredenkamp et al. 1992, Otolaryngologic Manifestations of the Muccopolysachharidosis; Ann Otel Rhinol Laryngol 101:1992; 472 to 477. 2. Kakkis ED and Neufeld EF. The mucopolysaccharidoses. In: Principles of Child Neurology. B. Berg (ed). 1st ed. New York, New York: McGraw-Hill Inc; 1996; 1141-1166 3. Neufeld EF, Muenzer J. The mucopolysaccharidoses. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic and Molecular Bases of Inherited Disease. Vol 3. 8th ed. New York, NY:McGraw-Hill; 2001:34213452. 4. Swiedler SJ, Beck M, Bajbouj M, et al. Threshold effect of urinary glycosaminoglycans and the walk test as indicators of disease progression in a survey of subjects with mucopolysaccharidosis VI (Maroteaux-Lamy syndrome). Am J Med Genet A. 2005;134:144150.
19. Heart Clinical Features Cardiac involvement is a significant cause of mortality in patients with MPS disorders, including MPS VI. Thickening and calcification of the aortic and mitral valves lead to valvular dysfunction. In a recent survey study, almost all (96%) of the 68 diagnosed MPS VI patients evaluated by echocardiography for evidence of abnormalities in mitral, aortic, pulmonary, and tricuspid valves demonstrated valvular abnormalities, including evidence of stenosis and/or regurgitation of the cardiac valves.1
Cardiac hypertrophy, pulmonary hypertension, and narrowing of coronary arteries also occur, leading eventually to congestive heart failure.2 Patients 5 years of age and younger have sometimes presented with cardiomyopathy or endocardial fibroelastosis.3-4 In addition, narrowing of the abdominal aorta, the visceral arteries, and the renal arteries may promote systemic hypertension.
REFERENCES
1. Swiedler SJ, Beck M, Bajbouj M, et al. Threshold effect of urinary glycosaminoglycans and the walk test as indicators of disease progression in a survey of subjects with mucopolysaccharidosis VI (Maroteaux-Lamy syndrome). Am J Med Genet A. 2005;134:144150. 2. Neufeld EF, Muenzer J. The mucopolysaccharidoses. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic and Molecular Bases of Inherited Disease. Vol 3. 8th ed. New York, NY:McGraw-Hill; 2001:34213452. 3. Miller G, Partridge A. Mucopolysaccharidosis type VI presenting in infancy with endocardial fibroelastosis and heart failure.Pediatr Cardiol. 1983;4:6162. 4. Hayflick S, Rowe S, Kavanaugh-McHugh A, et al. Acute infantile cardiomyopathy as a presenting feature of mucopolysaccharidosis VI. J Pediatrics. 1992;120:269.
Photo courtesy of The National MPS Society Inc
Cardiac involvement is a significant cause of mortality in patients with MPS disorders, including MPS VI. Thickening and calcification of the aortic and mitral valves lead to valvular dysfunction. In a recent survey study, almost all (96%) of the 68 diagnosed MPS VI patients evaluated by echocardiography for evidence of abnormalities in mitral, aortic, pulmonary, and tricuspid valves demonstrated valvular abnormalities, including evidence of stenosis and/or regurgitation of the cardiac valves.1
Cardiac hypertrophy, pulmonary hypertension, and narrowing of coronary arteries also occur, leading eventually to congestive heart failure.2 Patients 5 years of age and younger have sometimes presented with cardiomyopathy or endocardial fibroelastosis.3-4 In addition, narrowing of the abdominal aorta, the visceral arteries, and the renal arteries may promote systemic hypertension.
REFERENCES
1. Swiedler SJ, Beck M, Bajbouj M, et al. Threshold effect of urinary glycosaminoglycans and the walk test as indicators of disease progression in a survey of subjects with mucopolysaccharidosis VI (Maroteaux-Lamy syndrome). Am J Med Genet A. 2005;134:144150. 2. Neufeld EF, Muenzer J. The mucopolysaccharidoses. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic and Molecular Bases of Inherited Disease. Vol 3. 8th ed. New York, NY:McGraw-Hill; 2001:34213452. 3. Miller G, Partridge A. Mucopolysaccharidosis type VI presenting in infancy with endocardial fibroelastosis and heart failure.Pediatr Cardiol. 1983;4:6162. 4. Hayflick S, Rowe S, Kavanaugh-McHugh A, et al. Acute infantile cardiomyopathy as a presenting feature of mucopolysaccharidosis VI. J Pediatrics. 1992;120:269.
Photo courtesy of The National MPS Society Inc
20. Hepatomegaly may be apparent, usually by age 6
May interfere with respiration and appetite
Splenomegaly may be present
Umbilical or inguinal hernia
21. Hands Clinical Features Flexion contractures of the fingers and underlying boney abnormality leads to the characteristic claw hand deformity in MPS. 1
REFERENCES
1. Spranger JW, Koch F, McKusick VA, Natzschka, J, et al. Mucopolysaccharidosis VI (Maroteaux-Lamys disease). Helvet Paediatr Acta. 1970; 25(4):337-363.
Flexion contractures of the fingers and underlying boney abnormality leads to the characteristic claw hand deformity in MPS. 1
REFERENCES
1. Spranger JW, Koch F, McKusick VA, Natzschka, J, et al. Mucopolysaccharidosis VI (Maroteaux-Lamys disease). Helvet Paediatr Acta. 1970; 25(4):337-363.
22. Bones and Joints Clinical Features An MPS VI patient exhibits flexed-knee stance with genu valgum (knock-knee). Femoral radiographs of the same patient reveal: irregular ossification of the femoral head, fragmentation of the capital epiphyses, elongated, constricted femoral necks, and epiphyseal dysplasia of the proximal femur
Cranial and spinal radiographs of the same individual with MPS VI reveal: macrocephaly & J-shaped sella, dolichocephaly (elongated skull) and odontoid hypoplasia. Spinal film reveals: gibbus (hump), vertebral anomalies including anterior beaking, and lumbar lordosis (arching of lumbar spine). Such spinal deformities, as well as scoliosis, are commona result of hypoplastic vertebrae and subsequent instability.1
Chest (not shown) typically shows irregular clavicles with broad ends, and oar-shaped ribs
REFERENCE
Maroteaux P, Leveque B, Marie J, Lamy M. [A new dysostosis with urinary elimination of chondroitin sulfate B]. PresseMed. 1963;71:18491852. French.
Photos and radiographs courtesy of Dr P Maroteaux
An MPS VI patient exhibits flexed-knee stance with genu valgum (knock-knee). Femoral radiographs of the same patient reveal: irregular ossification of the femoral head, fragmentation of the capital epiphyses, elongated, constricted femoral necks, and epiphyseal dysplasia of the proximal femur
Cranial and spinal radiographs of the same individual with MPS VI reveal: macrocephaly & J-shaped sella, dolichocephaly (elongated skull) and odontoid hypoplasia. Spinal film reveals: gibbus (hump), vertebral anomalies including anterior beaking, and lumbar lordosis (arching of lumbar spine). Such spinal deformities, as well as scoliosis, are commona result of hypoplastic vertebrae and subsequent instability.1
Chest (not shown) typically shows irregular clavicles with broad ends, and oar-shaped ribs
REFERENCE
Maroteaux P, Leveque B, Marie J, Lamy M. [A new dysostosis with urinary elimination of chondroitin sulfate B]. PresseMed. 1963;71:18491852. French.
Photos and radiographs courtesy of Dr P Maroteaux
23. Brain and Nerves Clinical Features Unlike some other MPS disorders, particularly MPS I Hurler syndrome, mental development is generally normal in MPS VI. Impaired hearing or vision may, however, contribute to poor school performance, in some cases creating the superficial appearance of cognitive deficit.1
Communicating hydrocephalus may present with drowsiness, headache, or behavioral changes. Untreated hydrocephalus can accelerate the occurrence of blindness. Cervical spinal cord compression caused by meningeal thickening and a stenotic spinal canal has been described in MPS VI. This may cause myelopathy and subsequent paralysis.1-2
Peripheral nerve entrapment, including carpal tunnel syndrome, is common in MPS VI but usually has an atypical presentation and therefore is under-diagnosed. MPS VI patients experiencing carpal tunnel syndrome usually lack some typical symptoms, such as pain, tingling, or loss of feeling in the fingertips, and instead present with atrophy of the thenar muscle, difficulty with fine motor tasks, and weakness of hand grasp.3
REFERENCES
1. Neufeld EF, Muenzer J. The mucopolysaccharidoses. In: Scriver CR, Beaudet AL,Sly WS, Valle D, eds. The Metabolic and Molecular Bases of Inherited Disease. Vol 3. 8th ed. New York, NY: McGraw-Hill; 2001:34213452. 2. Vougioukas VI, Berlis A, Kopp MV, et al. Neurosurgical interventions in children with Maroteaux-Lamy syndrome. Case report and review of the literature. Pediatr Neurosurg.2001;35:3538. Review 3. Wraith JE and Alani SM. Carpal tunnel syndrome in the mucopolysaccharidoses and related disorders. Arch Dis Childhood. 1990: 65:962-963.
Unlike some other MPS disorders, particularly MPS I Hurler syndrome, mental development is generally normal in MPS VI. Impaired hearing or vision may, however, contribute to poor school performance, in some cases creating the superficial appearance of cognitive deficit.1
Communicating hydrocephalus may present with drowsiness, headache, or behavioral changes. Untreated hydrocephalus can accelerate the occurrence of blindness. Cervical spinal cord compression caused by meningeal thickening and a stenotic spinal canal has been described in MPS VI. This may cause myelopathy and subsequent paralysis.1-2
Peripheral nerve entrapment, including carpal tunnel syndrome, is common in MPS VI but usually has an atypical presentation and therefore is under-diagnosed. MPS VI patients experiencing carpal tunnel syndrome usually lack some typical symptoms, such as pain, tingling, or loss of feeling in the fingertips, and instead present with atrophy of the thenar muscle, difficulty with fine motor tasks, and weakness of hand grasp.3
REFERENCES
1. Neufeld EF, Muenzer J. The mucopolysaccharidoses. In: Scriver CR, Beaudet AL,Sly WS, Valle D, eds. The Metabolic and Molecular Bases of Inherited Disease. Vol 3. 8th ed. New York, NY: McGraw-Hill; 2001:34213452. 2. Vougioukas VI, Berlis A, Kopp MV, et al. Neurosurgical interventions in children with Maroteaux-Lamy syndrome. Case report and review of the literature. Pediatr Neurosurg.2001;35:3538. Review 3. Wraith JE and Alani SM. Carpal tunnel syndrome in the mucopolysaccharidoses and related disorders. Arch Dis Childhood. 1990: 65:962-963.
24. Impact on Life Span MPS VI is progressive.
All patients eventually experience significant disability and may experience shortened life span
Wide range of actual life span:
Rapidly advancing 1st to 2nd decade
Slowly advancing 5th to 6th decade
Major causes of mortality:
Cardiac complications
Pulmonary complications
Complications associated with surgery and general anesthesia Proactive medical management and ongoing evaluation are crucial to minimizing the risk of life-threatening acute complications and maximizing the life span of these patients. 1
Complications arising from cardiac disease, pulmonary disease, or general anesthesia account for a significant proportion of mortality in patients with MPS VI.2
REFERENCES
Sweidler SJ, Beck M, Bajbouj M, et al. Threshold effect of urniary glycosaminoglycans and the walk test as indicators of disease progression in a survey of subjects with Mucopolysaccharidosis VI (Maroteaux-Lamy syndrome). Am J Med Genet A. 2005; 134:144-150.
Wilcox WR. Lysosomal storage disorders: the need for better pediatric recognition and comprehensive care. JPediatr. 2004;144(5 Suppl):S3S14. 2. Neufeld EF, Muenzer J. The mucopolysaccharidoses. In: Scriver CR, Beaudet AL,Sly WS, Valle D, eds. The Metabolic and Molecular Bases of Inherited Disease. Vol 3. 8th ed. New York, NY: McGraw-Hill; 2001:34213452.
Proactive medical management and ongoing evaluation are crucial to minimizing the risk of life-threatening acute complications and maximizing the life span of these patients. 1
Complications arising from cardiac disease, pulmonary disease, or general anesthesia account for a significant proportion of mortality in patients with MPS VI.2
REFERENCES
Sweidler SJ, Beck M, Bajbouj M, et al. Threshold effect of urniary glycosaminoglycans and the walk test as indicators of disease progression in a survey of subjects with Mucopolysaccharidosis VI (Maroteaux-Lamy syndrome). Am J Med Genet A. 2005; 134:144-150.
Wilcox WR. Lysosomal storage disorders: the need for better pediatric recognition and comprehensive care. JPediatr. 2004;144(5 Suppl):S3S14. 2. Neufeld EF, Muenzer J. The mucopolysaccharidoses. In: Scriver CR, Beaudet AL,Sly WS, Valle D, eds. The Metabolic and Molecular Bases of Inherited Disease. Vol 3. 8th ed. New York, NY: McGraw-Hill; 2001:34213452.
25. NAGLAZYME (galsulfase): the first and only enzyme replacement therapy (ERT) for Maroteaux-Lamy syndrome (MPS VI)
26. NAGLAZYME for MPS VI NAGLAZYME is indicated for patients with mucopolysaccharidosis VI (MPS VI). NAGLAZYME has been shown to improve walking and stair-climbing capacity.
Important safety information
The most common adverse events observed in clinical trials in patients treated with NAGLAZYME were headache, fever, arthralgia, vomiting, upper respiratory infections, abdominal pain, diarrhea, ear pain, cough, and otitis media. Severe reactions included angioneurotic edema, hypotension, dyspnea, bronchospasm, respiratory distress, apnea, and urticaria. The most common symptoms of infusion reactions included fever, chills/rigors, headache, rash, and mild to moderate urticaria. Nausea, vomiting, elevated blood pressure, retrosternal pain, abdominal pain, malaise, and joint pain were also reported. No patients discontinued infusions of NAGLAZYME for adverse events and all patients who completed the double-blind portion of the trial continued to receive weekly infusions of NAGLAZYME. Nearly all patients developed antibodies as a result of treatment, but the level of the immune response did not correlate with the severity of adverse events. Because antihistamine use may increase the risk of apneic episodes, evaluation of airway patency should be considered prior to the initiation of treatment. Consideration to delay infusion of NAGLAZYME should be given when treating patients who present with an acute febrile or respiratory illness. Included here is Important Safety Information for NAGLAZYME (galsulfase). Please see NAGLAZYME (galsulfase for injection) full prescribing information. BioMarin Pharmaceutical Inc.
Included here is Important Safety Information for NAGLAZYME (galsulfase). Please see NAGLAZYME (galsulfase for injection) full prescribing information. BioMarin Pharmaceutical Inc.
27. Treatment for MPS VI Supportive, symptom-based management
Previously, this was the only treatment available for most MPS patients
Can improve quality of life
Does not reduce GAG storage
Enzyme replacement therapy (ERT) is disease-specific therapy designed to treat the underlying pathology
Owing to a lack of available disease specific therapies, the medical management of MPS disorders has traditionally been symptom-based, aimed at ameliorating some of the more dangerous and debilitating manifestations of MPS as they arise.1
Proactive evaluation and symptom-based management can play an important role in maintaining the patients quality of lifeand in some cases can prevent the occurrence of irreversible and severely disabling sequelae, such as blindness secondary to hydrocephalus or tetraparesis secondary to spinal cord compression, but cannot halt disease progression. Other examples of symptom-based management include: VP shunt for hydrocephalus; Corneal transplant for corneal clouding; CPAP or BiPAP for sleep apnea; Physical therapy & pain medication for stiff, painful joints. 1-2
Disease specific therapy targets the underlying pathology of the disease to replace the deficient enzyme and reverse the GAG accumulation that causes so many deleterious effects. 2
REFERENCES 1. Neufeld EF, Muenzer J. The mucopolysaccharidoses. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic and Molecular Bases of Inherited Disease. Vol 3. 8th ed. New York, NY: McGraw-Hill; 2001:34213452. 2. Muenzer J., Fisher A., Advances in the Treatment of Mucopolysaccharidosis Type 1, New England Medical Journal, May 6, 2004; 350;19, 1932-1934.
Owing to a lack of available disease specific therapies, the medical management of MPS disorders has traditionally been symptom-based, aimed at ameliorating some of the more dangerous and debilitating manifestations of MPS as they arise.1
Proactive evaluation and symptom-based management can play an important role in maintaining the patients quality of lifeand in some cases can prevent the occurrence of irreversible and severely disabling sequelae, such as blindness secondary to hydrocephalus or tetraparesis secondary to spinal cord compression, but cannot halt disease progression. Other examples of symptom-based management include: VP shunt for hydrocephalus; Corneal transplant for corneal clouding; CPAP or BiPAP for sleep apnea; Physical therapy & pain medication for stiff, painful joints. 1-2
Disease specific therapy targets the underlying pathology of the disease to replace the deficient enzyme and reverse the GAG accumulation that causes so many deleterious effects. 2
REFERENCES1. Neufeld EF, Muenzer J. The mucopolysaccharidoses. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic and Molecular Bases of Inherited Disease. Vol 3. 8th ed. New York, NY: McGraw-Hill; 2001:34213452. 2. Muenzer J., Fisher A., Advances in the Treatment of Mucopolysaccharidosis Type 1, New England Medical Journal, May 6, 2004; 350;19, 1932-1934.
28. Enzyme Replacement Therapy (ERT) Provides recombinant version of the deficient enzyme via regular IV infusion
Corrects lysosomal storage in a number of tissues
ERT is currently approved for 6 LSDs: MPS I, MPS II, MPS VI, Gaucher disease, Fabry disease, and Pompe disease
Enzyme replacement therapy (ERT) directly addresses the underlying biochemical defect that leads to substrate storage, and subsequently, to progressive, multisystemic pathologies.
In ERT, a recombinant version of the deficient enzyme is administered as an IV infusion. Animal model studies have demonstrated that the enzyme can be taken up by tissues and reduce lysosomal storage.1
The concept of ERT has been successfully demonstrated in 4 lysosomal storage disorders: Gaucher disease, Fabry disease, and MPS types I and VI. Patients receiving ERT for these lysosomal storage disorders have experienced significant clinical benefits. 2-7
REFERENCES
1. Byers S, Crawley AC, Brumfield LK, Nuttall JD, and Hopwood JJ. Enzyme replacement therapy in a feline model of MPS VI: Modification of enzyme structure and dose frequency. Pediatr Res 2000; 47:743749. 2. Cerezyme (imiglucerase forinjection) full prescribing information. Genzyme Corporation. 3. Aldurazyme (laronidase solution for intravenous infusion only) full prescribing information. BioMarin/Genzyme LLC. 4. ElapraseTM (idursulfse solution for intravenous infusion) full prescribing information. Shire Human Genetic Therapies. 5. Fabrazyme (agalsidase beta for intravenous infusion) full prescribing information. Genzyme Corporation. 6. MyozymeTM (solution for intravenous infusion only) full prescribing information. Genzyme Corporation. 7. NAGLAZYME (galsulfase solution for intravenous infusion only) full prescribing information. BioMarin Pharmaceutical Inc.
Enzyme replacement therapy (ERT) directly addresses the underlying biochemical defect that leads to substrate storage, and subsequently, to progressive, multisystemic pathologies.
In ERT, a recombinant version of the deficient enzyme is administered as an IV infusion. Animal model studies have demonstrated that the enzyme can be taken up by tissues and reduce lysosomal storage.1
The concept of ERT has been successfully demonstrated in 4 lysosomal storage disorders: Gaucher disease, Fabry disease, and MPS types I and VI. Patients receiving ERT for these lysosomal storage disorders have experienced significant clinical benefits. 2-7
REFERENCES
1. Byers S, Crawley AC, Brumfield LK, Nuttall JD, and Hopwood JJ. Enzyme replacement therapy in a feline model of MPS VI: Modification of enzyme structure and dose frequency. Pediatr Res 2000; 47:743749. 2. Cerezyme (imiglucerase forinjection) full prescribing information. Genzyme Corporation. 3. Aldurazyme (laronidase solution for intravenous infusion only) full prescribing information. BioMarin/Genzyme LLC. 4. ElapraseTM (idursulfse solution for intravenous infusion) full prescribing information. Shire Human Genetic Therapies. 5. Fabrazyme (agalsidase beta for intravenous infusion) full prescribing information. Genzyme Corporation. 6. MyozymeTM (solution for intravenous infusion only) full prescribing information. Genzyme Corporation. 7. NAGLAZYME (galsulfase solution for intravenous infusion only) full prescribing information. BioMarin Pharmaceutical Inc.
29. NAGLAZYME improved symptoms in 24 weeks
30. NAGLAZYME: Clinical Studies A total of 56 MPS VI patients were enrolled in three clinical studies
Primary endpoint variable: 12-minute walk test
Statistically and clinically significant improvement in endurance was seen in Phase 3 double-blind study after 24 weeks
NAGLAZYME reduced urinary GAG level
Placebo patients switched to active drug at week 24
Greater improvement in endurance after switching to NAGLAZYME
Urinary GAG level decreased after receiving NAGLAZYME
Supported by open-label extension NAGLAZYME (galsulfase for injection) full prescribing information. BioMarin Pharmaceutical Inc.
Reference: 1. Harmatz P, Giugliani R, Schwartz I, et al. Enzyme replacement therapy for mucopolysaccharidosis VI: a phase 3, randomized, double-blind, placebo-controlled, multinational study of recombinant human N-acetylgalactosamine 4-sulfatase (rhASB) and follow-on open-label extension study. J Pediatr. April 2006.
NAGLAZYME (galsulfase for injection) full prescribing information. BioMarin Pharmaceutical Inc.
Reference: 1. Harmatz P, Giugliani R, Schwartz I, et al. Enzyme replacement therapy for mucopolysaccharidosis VI: a phase 3, randomized, double-blind, placebo-controlled, multinational study of recombinant human N-acetylgalactosamine 4-sulfatase (rhASB) and follow-on open-label extension study. J Pediatr. April 2006.
31. NAGLAZYME Improved Endurance: 12-minute walk test Patients in the NAGLAZYME group experienced a 92 m +/- 40m (model derived group mean) increase in mean distance walked at 12 minutes relative to the placebo group after 24 weeks of treatment in the double-blind study. This improvement was statistically significant (p=0.025).
In the open-label extension study, the placebo patients now receiving NAGLAZYME experienced a 66 +/- 133m mean improvement relative to initiation of the extension study, while those that had continued receiving NAGLAZYME improved by an additional 36 m.
By week 48, patients in the drug group had been taking NAGLAZYME for 48 weeks; patients in the placebo group had only been taking NAGLAZYME for the 24-week open-label extension period.2
One patient in the placebo group left the study for reasons unrelated to treatment. Patients receiving placebo were switched to NAGLAZYME in the trial extension period.2
One patient failed to complete the assessment.2
|| Model-derived group mean difference in the change from baseline between NAGLAZYME and placebo groups.
REFERENCES:
1. NAGLAZYME (galsulfase for injection) full prescribing information. BioMarin Pharmaceutical Inc. 2. Data on File, BioMarin Pharmaceutical Inc. 3. Harmatz P, Giugliani R, Schwartz I, et al. Enzyme replacement therapy for mucopolysaccharidosis VI: a phase 3, randomized, double-blind, placebo-controlled, multinational study of recombinant human N-acetylgalactosamine 4-sulfatase (rhASB) and follow-on open-label extension study. J Pediatr. April 2006.
Patients in the NAGLAZYME group experienced a 92 m +/- 40m (model derived group mean) increase in mean distance walked at 12 minutes relative to the placebo group after 24 weeks of treatment in the double-blind study. This improvement was statistically significant (p=0.025).
In the open-label extension study, the placebo patients now receiving NAGLAZYME experienced a 66 +/- 133m mean improvement relative to initiation of the extension study, while those that had continued receiving NAGLAZYME improved by an additional 36 m.
By week 48, patients in the drug group had been taking NAGLAZYME for 48 weeks; patients in the placebo group had only been taking NAGLAZYME for the 24-week open-label extension period.2
One patient in the placebo group left the study for reasons unrelated to treatment. Patients receiving placebo were switched to NAGLAZYME in the trial extension period.2
One patient failed to complete the assessment.2
|| Model-derived group mean difference in the change from baseline between NAGLAZYME and placebo groups.
REFERENCES:
1. NAGLAZYME (galsulfase for injection) full prescribing information. BioMarin Pharmaceutical Inc. 2. Data on File, BioMarin Pharmaceutical Inc. 3. Harmatz P, Giugliani R, Schwartz I, et al. Enzyme replacement therapy for mucopolysaccharidosis VI: a phase 3, randomized, double-blind, placebo-controlled, multinational study of recombinant human N-acetylgalactosamine 4-sulfatase (rhASB) and follow-on open-label extension study. J Pediatr. April 2006.
32. NAGLAZYME Improved Endurance: 3-minute stair climb In the analysis, the rate of stairs climbed per minute was used.
The placebo group showed a nearly constant rate of climb over time (mean SD: 31 18 stairs per minute at baseline and 33 20 at Week 24).
The rate in the NAGLAZYME group was 19 13 stairs per minute at baseline; it increased to 27 17 stairs per minute at Week 24. In the longitudinal analysis, the difference between the mean change in the rates for the NAGLAZYME and placebo patients was 5.7 3 stairs/min and approached statistical significance (p = 0.053) (model derived group mean)
By week 48, patients in the drug group had been taking NAGLAZYME for 48 weeks; patients in the placebo group had only been taking NAGLAZYME for the 24-week open-label extension period.2
One patient in the placebo group left the study for reasons unrelated to treatment. Patients receiving placebo were switched to NAGLAZYME in the trial extension period.2
One patient failed to complete the assessment.2
||model-derived group mean difference in the change from baseline between NAGLAZYME and placebo groups.
REFERENCES:
1. NAGLAZYME (galsulfase for injection) full prescribing information. BioMarin Pharmaceutical Inc. 2. Data on File, BioMarin Pharmaceutical Inc. 3. Harmatz P, Giugliani R, Schwartz I, et al. Enzyme replacement therapy for mucopolysaccharidosis VI: a phase 3, randomized, double-blind, placebo-controlled, multinational study of recombinant human N-acetylgalactosamine 4-sulfatase (rhASB) and follow-on open-label extension study. J Pediatr. April 2006.
In the analysis, the rate of stairs climbed per minute was used.
The placebo group showed a nearly constant rate of climb over time (mean SD: 31 18 stairs per minute at baseline and 33 20 at Week 24).
The rate in the NAGLAZYME group was 19 13 stairs per minute at baseline; it increased to 27 17 stairs per minute at Week 24. In the longitudinal analysis, the difference between the mean change in the rates for the NAGLAZYME and placebo patients was 5.7 3 stairs/min and approached statistical significance (p = 0.053) (model derived group mean)
By week 48, patients in the drug group had been taking NAGLAZYME for 48 weeks; patients in the placebo group had only been taking NAGLAZYME for the 24-week open-label extension period.2
One patient in the placebo group left the study for reasons unrelated to treatment. Patients receiving placebo were switched to NAGLAZYME in the trial extension period.2
One patient failed to complete the assessment.2
||model-derived group mean difference in the change from baseline between NAGLAZYME and placebo groups.
REFERENCES:
1. NAGLAZYME (galsulfase for injection) full prescribing information. BioMarin Pharmaceutical Inc. 2. Data on File, BioMarin Pharmaceutical Inc. 3. Harmatz P, Giugliani R, Schwartz I, et al. Enzyme replacement therapy for mucopolysaccharidosis VI: a phase 3, randomized, double-blind, placebo-controlled, multinational study of recombinant human N-acetylgalactosamine 4-sulfatase (rhASB) and follow-on open-label extension study. J Pediatr. April 2006.
33. NAGLAZYME Reduced Urinary Glycosaminoglycans Urinary GAG levels decreased in patients treated with NAGLAZYME compared to patients treated with with placebo
No subject in the group receiving NAGLAZYME reached the normal range for urinary GAG levels during the 24-week blinded study
Seventeen of 19 NAGLAZYME patients and no placebo patients had a > 50% percent reduction in urinary GAG levels between baseline and Week 24 (p < 0.001). The NAGLAZYME patients had a decrease from a mean ( SD) of 346 128 g/mg creatinine at baseline to 85 35 g/mg creatinine at Week 24.
Both groups showed a rapid reduction in urinary GAG levels after initiation of NAGLAZYME treatment. The combined estimated mean change SE after 24 weeks of treatment with NAGLAZYME was 242 18 mg/mg creatinine (p < 0.001). Overall, 94 percent of the patients showed at least a 50 percent reduction in urinary GAG after 24 weeks of treatment with NAGLAZYME.
*One patient in the placebo group left the study for reasons unrelated to treatment. Patients receiving placebo were switched to NAGLAZYME in the trial extension period.2
One patient failed to complete the assessment.2
REFERENCES:
1. NAGLAZYME (galsulfase for injection) full prescribing information. BioMarin Pharmaceutical Inc. 2. Data on File, BioMarin Pharmaceutical Inc. 3. Harmatz P, Giugliani R, Schwartz I, et al. Enzyme replacement therapy for mucopolysaccharidosis VI: a phase 3, randomized, double-blind, placebo-controlled, multinational study of recombinant human N-acetylgalactosamine 4-sulfatase (rhASB) and follow-on open-label extension study. J Pediatr. April 2006.
Seventeen of 19 NAGLAZYME patients and no placebo patients had a > 50% percent reduction in urinary GAG levels between baseline and Week 24 (p < 0.001). The NAGLAZYME patients had a decrease from a mean ( SD) of 346 128 g/mg creatinine at baseline to 85 35 g/mg creatinine at Week 24.
Both groups showed a rapid reduction in urinary GAG levels after initiation of NAGLAZYME treatment. The combined estimated mean change SE after 24 weeks of treatment with NAGLAZYME was 242 18 mg/mg creatinine (p < 0.001). Overall, 94 percent of the patients showed at least a 50 percent reduction in urinary GAG after 24 weeks of treatment with NAGLAZYME.
*One patient in the placebo group left the study for reasons unrelated to treatment. Patients receiving placebo were switched to NAGLAZYME in the trial extension period.2
One patient failed to complete the assessment.2
REFERENCES:
1. NAGLAZYME (galsulfase for injection) full prescribing information. BioMarin Pharmaceutical Inc. 2. Data on File, BioMarin Pharmaceutical Inc. 3. Harmatz P, Giugliani R, Schwartz I, et al. Enzyme replacement therapy for mucopolysaccharidosis VI: a phase 3, randomized, double-blind, placebo-controlled, multinational study of recombinant human N-acetylgalactosamine 4-sulfatase (rhASB) and follow-on open-label extension study. J Pediatr. April 2006.
34. NAGLAZYME: Safety Profile The most common adverse reactions observed across all clinical studies included:
headache, fever, arthralgia, vomiting, upper respiratory infections, abdominal pain, diarrhea, ear pain, cough, and otitis media
The most common adverse reactions requiring interventions were infusion-associated reactions (IARs)
No study patients discontinued due to IARs REFERENCES:
1. NAGLAZYME (galsulfase for injection) full prescribing information. BioMarin Pharmaceutical Inc. REFERENCES:
1. NAGLAZYME (galsulfase for injection) full prescribing information. BioMarin Pharmaceutical Inc.
35. NAGLAZYME: Infusion-Associated Reactions (IARs) IARs occurred in 30 of 55 patients across all three studies
Initial reactions occurred as late as week 55
The most common symptoms of infusion reactions included:
Fever, chills/rigors, headache, rash, and mild to moderate urticaria
Nausea, vomiting, elevated blood pressure, retrosternal pain, abdominal pain, malaise, and joint pain were also reported
Severe symptoms included:
Angioedema, hypotension, dyspnea, bronchospasm, respiratory distress, apnea, and urticaria
The most frequent serious adverse events related to the use of NAGLAZYME occurred during infusions and included:
urticaria of the face and neck, bronchospasm, respiratory distress, and apnea There was one SAE during infusion, apnea, which occurred in one Phase 3 patient receiving NAGLAZYME that raised an important safety consideration in the management of MPS VI patients. This patient had a significantly compromised airway at study entry as well as a history of sleep apnea. After receiving his dose of pretreatment antihistamine at Week 18, he fell asleep during the infusion and was unable to be aroused. This subsequently resulted in an apparent respiratory arrest requiring intubation and then a tracheostomy to restore ventilation.
There were no specific signs of an anaphylactoid reaction such as a rash, facial swelling, or angioedema. Nor did this patient experience any reactions during previous or subsequent study drug infusions. It may be difficult to distinguish between NAGLAZYME treatmentrelated effects and the effects of ancillary treatments such as the antihistamine administered pretreatment in this patient. Regardless of the exact cause of the event, this case indicates that patients with highly compromised upper airways warrant close monitoring during infusion, and caution should be exercised when administering prophylactic antihistamines to these patients.
REFERENCES:
1. NAGLAZYME (galsulfase for injection) full prescribing information. BioMarin Pharmaceutical Inc. 2. Data on File, BioMarin Pharmaceutical Inc.
There was one SAE during infusion, apnea, which occurred in one Phase 3 patient receiving NAGLAZYME that raised an important safety consideration in the management of MPS VI patients. This patient had a significantly compromised airway at study entry as well as a history of sleep apnea. After receiving his dose of pretreatment antihistamine at Week 18, he fell asleep during the infusion and was unable to be aroused. This subsequently resulted in an apparent respiratory arrest requiring intubation and then a tracheostomy to restore ventilation.
There were no specific signs of an anaphylactoid reaction such as a rash, facial swelling, or angioedema. Nor did this patient experience any reactions during previous or subsequent study drug infusions. It may be difficult to distinguish between NAGLAZYME treatmentrelated effects and the effects of ancillary treatments such as the antihistamine administered pretreatment in this patient. Regardless of the exact cause of the event, this case indicates that patients with highly compromised upper airways warrant close monitoring during infusion, and caution should be exercised when administering prophylactic antihistamines to these patients.
REFERENCES:
1. NAGLAZYME (galsulfase for injection) full prescribing information. BioMarin Pharmaceutical Inc. 2. Data on File, BioMarin Pharmaceutical Inc.
36. Because of the potential for IARs, patients should receive antihistamines with or without antipyretics prior to infusion
In 13 of the 30 patients treated with NAGLAZYME, IARs were recurrent despite these measures
Symptoms typically abated with slowing or interruption of infusion and additional antihistamines, antipyretics, and occasionally corticosteroids
Evaluation of airway patency should be considered prior to initiation of treatment due to the increased risk of sleep apnea
NAGLAZYME: Infusion-Associated Reactions (IARs) REFERENCES:
1. NAGLAZYME (galsulfase for injection) full prescribing information. BioMarin Pharmaceutical Inc. 2. Data on File, BioMarin Pharmaceutical Inc.REFERENCES:
1. NAGLAZYME (galsulfase for injection) full prescribing information. BioMarin Pharmaceutical Inc. 2. Data on File, BioMarin Pharmaceutical Inc.
37. NAGLAZYME: Immunogenicity 98% (53 of 54) of patients treated with NAGLAZYME developed anti-galsulfase IgG antibodies
No observed association with IARs
No observed association between antibody development and urine GAG levels
No correlation with the severity of adverse events
No factors were identified that predisposed patients to IARs
Initial evidence of antibody development appeared following 48 weeks of treatment NAGLAZYME (galsulfase for injection) full prescribing information. BioMarin Pharmaceutical Inc.
NAGLAZYME (galsulfase for injection) full prescribing information. BioMarin Pharmaceutical Inc.
38. Participate in the MPS VI Clinical Surveillance Program (CSP) The MPS VI CSP is an ongoing observational database following the medical history and treatment outcomes of individuals with MPS VI.
Objectives
Advance MPS VI treatment and research
Provide a comprehensive MPS VI resource for physicians
Optimize patient care
Provide easy participation for both physician and patient
No experimental treatments or assessments are involved in this program
All MPS VI patients and physicians are encouraged to participate.
39. NAGLAZYME Dosing and Administration Guidelines These following steps are recommended for dosing and administration of NAGLAZYME. Please follow your institutions protocols and prescribing physicians orders for administration
40. Included here is Important Safety Information for NAGLAZYME (galsulfase). Please see NAGLAZYME (galsulfase for injection) full prescribing information. BioMarin Pharmaceutical Inc.
Included here is Important Safety Information for NAGLAZYME (galsulfase). Please see NAGLAZYME (galsulfase for injection) full prescribing information. BioMarin Pharmaceutical Inc.
41. IV Infusion
Must be diluted in 0.9% sodium chloride
Dosing Regimen
1 mg per kilogram of patient weight diluted in normal saline
Once weekly I.V. infusion over no less than 4 hours
Life-long therapy
How Supplied:
NAGLAZYME is supplied as a sterile, nonpyrogenic, colorless to pale yellow, clear to slightly opalescent solution
Each 5-mL single-use vial provides 5 mg of galsulfase (expressed as protein content)
The recommended dosage regimen of NAGLAZYME is 1 mg/kg of actual body weight administered once weekly as an intravenous infusion, delivered over 4 hours followed by an observation period as specified by the physician.
REFERENCES:
1. NAGLAZYME (galsulfase for injection) full prescribing information. BioMarin Pharmaceutical Inc. The recommended dosage regimen of NAGLAZYME is 1 mg/kg of actual body weight administered once weekly as an intravenous infusion, delivered over 4 hours followed by an observation period as specified by the physician.
REFERENCES:
1. NAGLAZYME (galsulfase for injection) full prescribing information. BioMarin Pharmaceutical Inc.
42. NAGLAZYME Dilution Supplies NAGLAZYME 5-mL single-use vials
0.9% Sodium Chloride Injection, USP infusion bag (100-mL or 250-mL)
Syringes for dilution
18-gauge needles without filtering devices for dilution
PVC straight IV tubing (no Volutrol or Buretrol)
In-line, low protein-binding 0.2-micrometer (m) filter
Additional supplies per the institution protocol
The following items are recommended for the preparation and administration of NAGLAZYME:
NAGLAZYME 5 mg in single-use 5.0-mL glass vials
0.9% Sodium Chloride Injection, USP infusion bag (100 mL or 250 mL)
Syringes for dilution-10cc syringe is recommended as larger syringe draws drug up with more force
18 gauge needles (without filtering devices)
PVC infusion set equipped with an in-line, low protein-binding 0.2-micrometer (m) filter
Additional supplies as per the institutions IV infusion protocol
The following items are recommended for the preparation and administration of NAGLAZYME:
NAGLAZYME 5 mg in single-use 5.0-mL glass vials
0.9% Sodium Chloride Injection, USP infusion bag (100 mL or 250 mL)
Syringes for dilution-10cc syringe is recommended as larger syringe draws drug up with more force
18 gauge needles (without filtering devices)
PVC infusion set equipped with an in-line, low protein-binding 0.2-micrometer (m) filter
Additional supplies as per the institutions IV infusion protocol
43. NAGLAZYME Dose Preparation
44. Determine the number of vials needed using the 2-step formula below.
Remove the required number of vials from the refrigerator and allow them to reach room temperature. Do not allow vials to remain at room temperature longer than 24 hours prior to dilution. Do not heat or microwave vials
Step 1: Patients weight (kg) x 1 mL/kg of NAGLAZYME = total mL NAGLAZYME
Step 2: Total mL NAGLAZYME 5 mL per vial = total vials needed
Round to the nearest whole vial Dose Preparation Determine the number of vials to be diluted based on the individual patients weight and the recommended dose of 1 mg/kg of body weight. Round to the nearest whole vial.
The patients weight (kg) multiplied by 1 mL/kg NAGLAZYME equals the total mL of drug.
The total mL of NAGLAZYME divided by 5 mL per vial equals the total number of vials.
Round to the nearest whole vial
REFERENCES:
1. NAGLAZYME (galsulfase for injection) full prescribing information. BioMarin Pharmaceutical Inc.
Determine the number of vials to be diluted based on the individual patients weight and the recommended dose of 1 mg/kg of body weight. Round to the nearest whole vial.
The patients weight (kg) multiplied by 1 mL/kg NAGLAZYME equals the total mL of drug.
The total mL of NAGLAZYME divided by 5 mL per vial equals the total number of vials.
Round to the nearest whole vial
REFERENCES:
1. NAGLAZYME (galsulfase for injection) full prescribing information. BioMarin Pharmaceutical Inc.
45. Dose Preparation Before withdrawing NAGLAZYME from the vial, visually inspect each vial for particulate matter and discoloration
The NAGLAZYME solution should be clear to slightly opalescent and colorless to pale yellow. A few translucent particles may be present
Do not use if the solution is discolored, cloudy, or if there is particulate matter in the solution
Do not freeze or shake vial Before withdrawing the NAGLAZYME from the vial, visually inspect each vial for particulate matter and discoloration. The NAGLAZYME solution should be clear to slightly opalescent and colorless to pale yellow. A few translucent particles may be present. Do not use if the solution is discolored, cloudy, or if there is particulate matter in the solution.
REFERENCES:
1. NAGLAZYME (galsulfase for injection) full prescribing information. BioMarin Pharmaceutical Inc.
Before withdrawing the NAGLAZYME from the vial, visually inspect each vial for particulate matter and discoloration. The NAGLAZYME solution should be clear to slightly opalescent and colorless to pale yellow. A few translucent particles may be present. Do not use if the solution is discolored, cloudy, or if there is particulate matter in the solution.
REFERENCES:
1. NAGLAZYME (galsulfase for injection) full prescribing information. BioMarin Pharmaceutical Inc.
46. Dose Preparation Determine total infusion volume
All MPS VI study patients, including those with weights as low as 14 kg, were infused using 250-mL total volume
Consider using 100-mL infusion bag for patients who are:
20 kg and under
Susceptible to fluid overload due to pulmonary disease cardiac valvular disease, or congestive heart failure
All MPS VI study patients, including those with weights as low as 14 kg, were infused using 250 ml total volume.
Prescribing physician should consider using a smaller total volume (100 mL) for patients who are:
20 kg or less
Patients who are susceptible to fluid volume overload (for example, patients with pulmonary disease, heart valve disease, congestive heart failure)
All MPS VI study patients, including those with weights as low as 14 kg, were infused using 250 ml total volume.
Prescribing physician should consider using a smaller total volume (100 mL) for patients who are:
20 kg or less
Patients who are susceptible to fluid volume overload (for example, patients with pulmonary disease, heart valve disease, congestive heart failure)
47. Dose Preparation For a 250-mL infusion bag
Withdraw and discard a volume of the 0.9% Sodium Chloride USP bag, equal to the volume of NAGLAZYME to be added
For a 100-mL infusion bag
Withdrawing and discarding of dose volume is not necessary. Add dose volume directly to the infusion bag
Using an 18-gauge non-filter needle, slowly withdraw the calculated dose of NAGLAZYME from the appropriate number of vials, using caution to avoid excessive agitation, bubbles, and foaming
Slowly add the NAGLAZYME to the 0.9% Sodium Chloride bag; angle needle tip to slowly add drug directly into fluid For a 250 mL infusion bag , withdraw and discard a volume of the 0.9% Sodium Chloride Injection, USP from the infusion bag, equal to the volume of NAGLAZYME dose.
For a 100 mL infusion bag, withdrawing and discarding of dose volume is not necessary.
Slowly withdraw the calculated volume of NAGLAZYME from the appropriate number of vials using caution to avoid excessive agitation, bubbles or foaming. Do not use a filter needle, as this may cause agitation.
Slowly add the NAGLAZYME to the 0.9% Sodium Chloride bag; angle needle tip to inject drug into fluid (not air pocket) to avoid bubbles
Agitation may denature NAGLAZYME, rendering it biologically inactive.
Agitation of protein may cause microaggregation which may increase immunogenicity.
For a 250 mL infusion bag , withdraw and discard a volume of the 0.9% Sodium Chloride Injection, USP from the infusion bag, equal to the volume of NAGLAZYME dose.
For a 100 mL infusion bag, withdrawing and discarding of dose volume is not necessary.
Slowly withdraw the calculated volume of NAGLAZYME from the appropriate number of vials using caution to avoid excessive agitation, bubbles or foaming. Do not use a filter needle, as this may cause agitation.
Slowly add the NAGLAZYME to the 0.9% Sodium Chloride bag; angle needle tip to inject drug into fluid (not air pocket) to avoid bubbles
Agitation may denature NAGLAZYME, rendering it biologically inactive.
Agitation of protein may cause microaggregation which may increase immunogenicity.
48. Dose Preparation Gently rotate the infusion bag to mixdo not shake
Agitation may denature NAGLAZYME, rendering it biologically inactive
Use care to avoid agitation of the solutions
Do not use a filter needle
Do not shake the solution
Do not use a pneumatic tube delivery system
Do not use Volutrol or Buretrol straight IV tubing
Avoid generating bubbles or foam
Slowly add the NAGLAZYME to the 0.9% Sodium Chloride Injection, USP using care to avoid agitation of the solutions. Do not use a filter needle.
Gently rotate the infusion bag to ensure proper distribution of NAGLAZYME. Do not shake the solution.
Do not use a pneumatic tube delivery system.
Use straight tubing -no Volutrol or Buretrol -as the action of filling the chamber generates bubbles and foam.
Slowly add the NAGLAZYME to the 0.9% Sodium Chloride Injection, USP using care to avoid agitation of the solutions. Do not use a filter needle.
Gently rotate the infusion bag to ensure proper distribution of NAGLAZYME. Do not shake the solution.
Do not use a pneumatic tube delivery system.
Use straight tubing -no Volutrol or Buretrol -as the action of filling the chamber generates bubbles and foam.
49. Dose Preparation Label the infusion bag per your institutions policy. Do not mix NAGLAZYME with other medicinal products
50. NAGLAZYME Administration NAGLAZYME (galsulfase for injection) full prescribing information. BioMarin Pharmaceutical Inc.
NAGLAZYME (galsulfase for injection) full prescribing information. BioMarin Pharmaceutical Inc.
51. NAGLAZYME Administration Recommended equipment
IV infusion pump
Wall suction (or portable suction machine)
Oxygen set up
Pulse oximeter
Emergency medication such as diphenhydramine, systemic corticosteroids, and epinephrine An IV pump is required for infusion of NAGLAZYME. A double pump is recommended if available only to facilitate transition to plain saline in case of a reaction.
Other equipment is recommended to have on hand in case of a reaction.
An IV pump is required for infusion of NAGLAZYME. A double pump is recommended if available only to facilitate transition to plain saline in case of a reaction.
Other equipment is recommended to have on hand in case of a reaction.
52. NAGLAZYME Administration Explain the procedure to the patient and/or parent
Obtain vital signs prior to infusion, including blood pressure, pulse, respiration, temperature, pulse oximetry level
Assess patient respiratory function and review recent health history with patient and/or parent
Consider delaying infusions in patients who present with an acute febrile or respiratory illness
Explain the procedure to the patient.
Assess Patient Status Prior To Each Infusion
Obtain vital signs and review recent health history with patient and/or parent prior to each infusion to determine if there are any changes in his or her baseline health status and respiratory function, such as fever, flu or cold symptoms. Intercurrent illness with fever and respiratory symptoms can confound the interpretation of infusion related reactions if symptoms occur during infusion. It is advisable to postpone infusions in patients who present with acute febrile or respiratory illness on infusion day.
Note to Pharmacy: To avoid wasting drug, NAGLAZYME should not be mixed for infusion until the infusion site staff has determined that the infusion will be conducted as planned and that IV access has been obtained.
Explain the procedure to the patient.
Assess Patient Status Prior To Each Infusion
Obtain vital signs and review recent health history with patient and/or parent prior to each infusion to determine if there are any changes in his or her baseline health status and respiratory function, such as fever, flu or cold symptoms. Intercurrent illness with fever and respiratory symptoms can confound the interpretation of infusion related reactions if symptoms occur during infusion. It is advisable to postpone infusions in patients who present with acute febrile or respiratory illness on infusion day.
Note to Pharmacy: To avoid wasting drug, NAGLAZYME should not be mixed for infusion until the infusion site staff has determined that the infusion will be conducted as planned and that IV access has been obtained.
53. NAGLAZYME Administration Premedication
Pretreatment with antihistamines, with or without antipyretics, approximately 30 minutes to one hour prior to start of infusion is recommended
Despite premedication, 13 of 30 patients had recurrent infusion reactions
Pain control for IV insertion/required time varies
Examples:
EMLA Cream 1 hour prior to IV
LMX 4 30 minutes prior to IV
Numby Stuff/Iontocaine 10 minutes prior to IV
Ethyl Chloride spray immediately prior to IV
Premedication with an antihistamine approximately 30 minutes to one hour prior to start of infusion is recommended (Diphenhydramine or an equivalent including non-sedating antihistamine).
It is recommend that a patient does not go home unattended after receiving diphenhydramine or an equivalent that may cause drowsiness.
Changes in skin in MPS patients can make IV insertion difficult. Venipuncture is a painful procedure and a cause of considerable anticipatory anxiety in children. Pain control & reduction of anxiety with IV access should be addressed at the initiation of therapy. Treatment is weekly and lifelong and compliance is critically important, therefore, steps to minimize pain with IV insertion are very important.
Topical anesthetic is recommended. There are several choices which require different times for maximum effectiveness.
Premedication with an antihistamine approximately 30 minutes to one hour prior to start of infusion is recommended (Diphenhydramine or an equivalent including non-sedating antihistamine).
It is recommend that a patient does not go home unattended after receiving diphenhydramine or an equivalent that may cause drowsiness.
Changes in skin in MPS patients can make IV insertion difficult. Venipuncture is a painful procedure and a cause of considerable anticipatory anxiety in children. Pain control & reduction of anxiety with IV access should be addressed at the initiation of therapy. Treatment is weekly and lifelong and compliance is critically important, therefore, steps to minimize pain with IV insertion are very important.
Topical anesthetic is recommended. There are several choices which require different times for maximum effectiveness.
54. NAGLAZYME Administration Obtain IV access
Draw blood work if needed and flush line with normal saline
Consider using plain 0.9% Sodium Chloride Injection, USP (no drug added) as primary line at the rate specified by physician
To keep vein open prior to starting NAGLAZYME infusion
For immediate use in case of an infusion-associated reaction (IAR)
Obtain IV access. Antecubital, wrist, or hand veins may be used for access. Central access is also an option. Draw required blood work and flush line with normal saline.
Use normal saline as the primary infusion line at a rate specified by the physician, in order to keep vein open prior to NAGLAZYME infusion start and for immediate use in case of an infusion associated reaction (IAR).
Obtain IV access. Antecubital, wrist, or hand veins may be used for access. Central access is also an option. Draw required blood work and flush line with normal saline.
Use normal saline as the primary infusion line at a rate specified by the physician, in order to keep vein open prior to NAGLAZYME infusion start and for immediate use in case of an infusion associated reaction (IAR).
55. NAGLAZYME Administration Prime IV tubing with NAGLAZYME solution
Attach 0.2 micron in-line filter to the end of the tubing and prime the filter
Prime tubing and filter SLOWLY to prevent foaming
Be sure the drug administration tubing and filter are primed with drug solution (not plain saline) to ensure that the correct volume is delivered in the first hour of infusion
If using plain saline as a primary line, connect NAGLAZYME tubing at port closest to patient Set up the administration set: connect IV tubing (no Volutrol or Buretrol) with the NAGLAZYME infusion bag, connect the 0.2 micron filter to the NAGLAZYME tubing set. Prime the tubing and filter set with NAGLAZYME solution. Prime slowly to avoid foaming.
Be sure that the tubing has been primed with diluted NAGLAZYME solution (not plain saline) in order for the correct volume to be delivered in the first (slow rate) hour.
A double IV infusion pump is recommended, if available, to facilitate switching from drug to plain normal saline in case of an IAR. If a double pump is not available, use a single pump for the drug solution.
Connect the NAGLAZYME solution and filter line to the lowest additive port on the patients primary administration set-the port closest to the patient.
Set up the administration set: connect IV tubing (no Volutrol or Buretrol) with the NAGLAZYME infusion bag, connect the 0.2 micron filter to the NAGLAZYME tubing set. Prime the tubing and filter set with NAGLAZYME solution. Prime slowly to avoid foaming.
Be sure that the tubing has been primed with diluted NAGLAZYME solution (not plain saline) in order for the correct volume to be delivered in the first (slow rate) hour.
A double IV infusion pump is recommended, if available, to facilitate switching from drug to plain normal saline in case of an IAR. If a double pump is not available, use a single pump for the drug solution.
Connect the NAGLAZYME solution and filter line to the lowest additive port on the patients primary administration set-the port closest to the patient.
56. NAGLAZYME Administration Infuse the total volume of NAGLAZYME solution over no less than 4 hours
2.5% of the total NAGLAZYME solution volume in the 1st hour
97.5% of the total volume over the next 3 hours
Infusion rate examples:
Infusion rate for 250-mL total volume
6 mL/hr for the first hour. If infusion is well tolerated, infusion rate can be increased to 81 mL/hr for the remaining 3 hours
Infusion rate for 120-mL total volume
3 mL/hr for the first hour. If infusion is well tolerated, infusion rate can be increased to 39 mL/hr for the remaining 3 hours
Use IV infusion pump for Naglazyme administration
The total time is no less than 4 hours plus additional time for the small amount of overfill in standard IV bags plus small amount of plain saline used to flush the tubing at infusion completion.
Patients and families often ask if the infusion can be administered in a shorter amount of time. It is not advisable to increase the rate of administration over the recommended rate. Patient and parent education helps them to understand that the safety and efficacy of NAGLAZYME was established in the clinical studies when administered over the specified period of time.
Note: The safety and efficacy of NAGLAZYME has been established in clinical studies when administered over the specified period of time. It is not advisable to administer NAGLAZYME at a faster rate than recommended.
The total time is no less than 4 hours plus additional time for the small amount of overfill in standard IV bags plus small amount of plain saline used to flush the tubing at infusion completion.
Patients and families often ask if the infusion can be administered in a shorter amount of time. It is not advisable to increase the rate of administration over the recommended rate. Patient and parent education helps them to understand that the safety and efficacy of NAGLAZYME was established in the clinical studies when administered over the specified period of time.
Note: The safety and efficacy of NAGLAZYME has been established in clinical studies when administered over the specified period of time. It is not advisable to administer NAGLAZYME at a faster rate than recommended.
57. NAGLAZYME Administration Monitor Vital Signs
Prior to infusion
Every hour during the infusion
At infusion completion
Prior to discharge
When monitoring vital signs, look for signs of infusion-associated reactions such as:
Increase/decrease in heart rate
Increase/decrease in respiratory rate
Decrease in oxygen saturation (pulse oximetry)
Increase/decrease in temperature
When monitoring vital signs, look for:
Increase/decrease in heart rate; may or may not be associated with observable increased anxiety
Increase/decrease in respiratory rate
Decrease in oxygen saturation (pulse oximetry)
Increase/decrease in temperature
Note: these may be signs of an infusion-associated reaction.
When monitoring vital signs, look for:
Increase/decrease in heart rate; may or may not be associated with observable increased anxiety
Increase/decrease in respiratory rate
Decrease in oxygen saturation (pulse oximetry)
Increase/decrease in temperature
Note: these may be signs of an infusion-associated reaction.
58. NAGLAZYME Administration When the infusion is complete, run plain normal saline to clear residual NAGLAZYME solution from tubing
Obtain post-infusion vital signs
Observe patient for a post-infusion period as specified by the treating physician
Discard and dispose of infusion-related materials in accordance with your institutional policies
59. Management of Infusion- Associated Reactions
60. Infusion-Associated Reactions (IARs) Examples of IAR symptoms: REFERENCES:
1. NAGLAZYME (galsulfase for injection) full prescribing information. BioMarin Pharmaceutical Inc.
REFERENCES:
1. NAGLAZYME (galsulfase for injection) full prescribing information. BioMarin Pharmaceutical Inc.
61. Management of Infusion-Associated Reactions Stop the infusion
Assess and appropriately manage patients symptoms
Consider administration of additional antihistamines, antipyretics, possibly systemic corticosteroids
If symptoms subside, consider restarting infusion at a slower rate (e.g. half the rate at which the IAR occurred)
Subsequent infusions may be managed with a slower rate additional prophylactic antihistamines, antipyretics, and possibly prophylactic corticosteroids
The physician should evaluate risks and benefits of re-administering NAGLAZYME following a severe hypersensitivity or anaphylactic reaction Infusion reactions occurred in 30 out of 55 patients treated with NAGLAZYME. Reactions began as late as Week 55 of study drug treatment, and occurred during multiple infusions, though not always in consecutive weeks. The most common symptoms included fever, chills/rigors, headache, rash, and mild to moderate urticaria. Subsequent infusions were managed with a slower rate of drug administration (infusions of up to 20 hours have been completed), treatment with additional prophylactic antihistamines, and, infrequently, in the event of a more severe reaction, treatment with prophylactic steroids. Despite these measures, recurrent 13 of the 30 patients had additional infusion reactions.
Infusion reactions occurred in 30 out of 55 patients treated with NAGLAZYME. Reactions began as late as Week 55 of study drug treatment, and occurred during multiple infusions, though not always in consecutive weeks. The most common symptoms included fever, chills/rigors, headache, rash, and mild to moderate urticaria. Subsequent infusions were managed with a slower rate of drug administration (infusions of up to 20 hours have been completed), treatment with additional prophylactic antihistamines, and, infrequently, in the event of a more severe reaction, treatment with prophylactic steroids. Despite these measures, recurrent 13 of the 30 patients had additional infusion reactions.
62. Infusion-Associated Reactions An infusion-associated reaction may not occur until multiple infusions have been given
First IARs occurred as late as 55 weeks in the clinical studies of NAGLAZYME
Therefore, it is important that:
A physician be available
The patient is monitored closely for IAR signs and symptoms
Emergency procedures be in place in the event a severe infusion reaction occurs
Patients and/or parents are educated and encouraged to promptly report IAR symptoms
This is especially important for parents of younger patients who may not be able to self report IAR symptoms
Educate patients and parents of signs and symptoms to report promptly. Parents are often at the bedside throughout the infusion and are the first to notice any unusual behavior in younger children who may not be able to verbalize any discomfort.
Educate patients and parents of signs and symptoms to report promptly. Parents are often at the bedside throughout the infusion and are the first to notice any unusual behavior in younger children who may not be able to verbalize any discomfort.
63. NAGLAZYME Storage Store NAGLAZYME vials under refrigeration at 2?C to 8?C ( 36?F to 46?F)
DO NOT FREEZE OR SHAKE
DO NOT USE AFTER EXPIRATION DATE ON VIAL
NAGLAZYME contains no preservatives and should be used immediately following preparation
Prepared NAGLAZYME may be refrigerated at 2?C to 8?C (36?F to 46?F) for no longer than 48 hours between the time of preparation to completion of administration The diluted solution should be used immediately. If immediate use is not possible, the diluted solution should be stored refrigerated at 2?C to 8?C (36?F46?F). The in-use storage should not be longer than 48 hours from the time of preparation to completion of administration. Room temperature storage of diluted solution is not recommended.
NAGLAZYME does not contain any preservatives; therefore, after dilution with saline in the infusion bags, any unused product or waste material should be disposed of in accordance with local requirements.
NAGLAZYME must not be mixed with other medicinal products in the same infusion.
Compatibility of NAGLAZYME in solution with other products has not been evaluated.
Do not use after expiration date on vial.
REFERENCES:
1. NAGLAZYME (galsulfase for injection) full prescribing information. BioMarin Pharmaceutical Inc.
The diluted solution should be used immediately. If immediate use is not possible, the diluted solution should be stored refrigerated at 2?C to 8?C (36?F46?F). The in-use storage should not be longer than 48 hours from the time of preparation to completion of administration. Room temperature storage of diluted solution is not recommended.
NAGLAZYME does not contain any preservatives; therefore, after dilution with saline in the infusion bags, any unused product or waste material should be disposed of in accordance with local requirements.
NAGLAZYME must not be mixed with other medicinal products in the same infusion.
Compatibility of NAGLAZYME in solution with other products has not been evaluated.
Do not use after expiration date on vial.
REFERENCES:
1. NAGLAZYME (galsulfase for injection) full prescribing information. BioMarin Pharmaceutical Inc.
64. Pertinent Patient Issues and Support Resources
65. Patient Issues: Special Safety Considerations for Patients with Airway Obstruction Patients with highly compromised upper airway disease warrant close monitoring during infusions
Sleep apnea is common in MPS VI patients and antihistamine pretreatment may increase the risk of apneic episodes
Caution should be exercised when administering prophylactic antihistamines as patients may have airway difficulty during deep sleep
Use of CPAP or BiPAP during infusion should be considered in patients with sleep apnea who are using positive airway pressure machines
Evaluation of airway patency should be considered prior to initiation of treatment due to the increased risk of sleep apnea
Patients with highly compromised upper airway disease warrant close monitoring during infusions. Caution should be exercised when administering prophylactic antihistamines as patients may have airway difficulty during deep sleep. Use of CPAP or BiPAP during infusion should be considered in patients with sleep apnea who are using positive airway pressure machines at home.
Patients with highly compromised upper airway disease warrant close monitoring during infusions. Caution should be exercised when administering prophylactic antihistamines as patients may have airway difficulty during deep sleep. Use of CPAP or BiPAP during infusion should be considered in patients with sleep apnea who are using positive airway pressure machines at home.
66. Patient Issues: IV Access and Pain Control Venipuncture is a painful procedure and a cause of considerable anticipatory anxiety in children
Pain control & reduction of anxiety with IV access should be addressed at the initiation of therapy
Topical anesthetics
Warm limb
Advise patient and parents of the importance of good hydration
Child life specialist consultation prior to first infusion and ongoing
Repetitive intravenous infusions may eventually make IV access difficult
Long-term options for physician consideration:
Surgically implanted access devices (Port-A-Cath) are common in enzyme replacement therapy (ERT) patients
Peripherally inserted central catheters (PICC lines)
Venipuncture is a painful procedure and a cause of considerable anticipatory anxiety in children. IV insertion in MPS patients can be especially difficult due to changes in the skin.
Pain control with IV insertion is extremely important in this population. Treatment is weekly and lifelong and compliance is critically important, therefore, steps to minimize pain with IV insertion are very important. The most successful ERT sites use these recommended steps to minimize discomfort and facilitate IV insertion.
Topical anesthetic is recommended. There are several choices which require different times for maximum effectiveness.
Warming the limb aids in venous dilation, making the vein easier to see and feel. Good hydration has a similar effect in making IV insertion easier.
Due to the complexity of this therapy, and the many medical procedures involved in the management of MPS patients, the involvement of a child life expert (if available at your institution) may prove to be very helpful.
Port-A-Cath devices have been used successfully in ERT patients over a long period of time.
Venipuncture is a painful procedure and a cause of considerable anticipatory anxiety in children. IV insertion in MPS patients can be especially difficult due to changes in the skin.
Pain control with IV insertion is extremely important in this population. Treatment is weekly and lifelong and compliance is critically important, therefore, steps to minimize pain with IV insertion are very important. The most successful ERT sites use these recommended steps to minimize discomfort and facilitate IV insertion.
Topical anesthetic is recommended. There are several choices which require different times for maximum effectiveness.
Warming the limb aids in venous dilation, making the vein easier to see and feel. Good hydration has a similar effect in making IV insertion easier.
Due to the complexity of this therapy, and the many medical procedures involved in the management of MPS patients, the involvement of a child life expert (if available at your institution) may prove to be very helpful.
Port-A-Cath devices have been used successfully in ERT patients over a long period of time.
67. Patient Issues: Compliance In order for the patient to benefit from treatment, regular ERT is necessary
If therapy stops, GAG builds up and symptoms may return
Patients and families may have unrealistic expectations about treatment options
It is important to help patients and families understand that results vary and some improvements occur over a long period of time. Efficacy of ERT for MPS VI seen in the clinical trial was measured over a 6-month period
The infusion site staff plays a critical role in encouraging treatment compliance.
Patients and families may have unrealistic expectations. It is important to help patients and families understand that results do vary and some improvements occur over a long period of time. Efficacy of ERT for MPS VI seen in the clinical study was measured over a 6 month period.
Even with disease-specific therapy, MPS VI patients will also likely require on-going symptom-based treatments due to the complexity of this disease.
The infusion site staff plays a critical role in encouraging treatment compliance.
Patients and families may have unrealistic expectations. It is important to help patients and families understand that results do vary and some improvements occur over a long period of time. Efficacy of ERT for MPS VI seen in the clinical study was measured over a 6 month period.
Even with disease-specific therapy, MPS VI patients will also likely require on-going symptom-based treatments due to the complexity of this disease.
68. Patient Issues: Compliance Proactively address issues that may affect compliance
in the long term
MPS VI patients may have difficulty making infusion appointments due to work and school obligations, or frequent illness or hospitalization
Be as flexible as possible in scheduling or rescheduling appointments
Painful IV insertion can be a cause for anxiety which could reduce compliance
Consider the use of topical anesthetics to reduce the pain of IV insertion
Transportation and other problems may arise
Utilize social services or call your BioMarin Clinical Sales Specialist for advice Patients and families are generally very anxious to initiate ERT when it becomes available but over time the demands of everyday life may interfere with compliance. Steps should be taken to reduce conflicting demands whenever possible. Issues with school and work schedules require some flexibility in rescheduling ERT appointments as do the frequent illnesses and hospitalizations experienced by this population. Pain with IV insertion should be addressed from the first infusion to avoid the cycle of pain and extreme anxiety that can occur and make the weekly therapy a very unpleasant experience.
Long infusions can cause children to become fussy and age-appropriate games, books, videos, video games make the day much more enjoyable.
Patients and families are generally very anxious to initiate ERT when it becomes available but over time the demands of everyday life may interfere with compliance. Steps should be taken to reduce conflicting demands whenever possible. Issues with school and work schedules require some flexibility in rescheduling ERT appointments as do the frequent illnesses and hospitalizations experienced by this population. Pain with IV insertion should be addressed from the first infusion to avoid the cycle of pain and extreme anxiety that can occur and make the weekly therapy a very unpleasant experience.
Long infusions can cause children to become fussy and age-appropriate games, books, videos, video games make the day much more enjoyable.
69. Patient Education and Support Educate patients and their families regarding their treatment options
Allow the patients and their families to verbalize concerns regarding placement of indwelling catheter
Encourage families to speak with others who have had experience with MPS VI and ERT
Caring for patients with chronic conditions is different than caring for patients with acute conditions
Many patients/families are well informed about MPS VI
It is essential to include the patient/family in decision making Patients and families who deal with chronic disease are generally quite knowledgeable about the condition but be aware of individual educational needs.
Many families are in touch with other MPS families. If a family contact is needed let your MSL know.
Patients and families who deal with chronic disease often feel a need to have some control over daily disease management issues; try to involve the patient and family in decision-making whenever possible.
Patients and families who deal with chronic disease are generally quite knowledgeable about the condition but be aware of individual educational needs.
Many families are in touch with other MPS families. If a family contact is needed let your MSL know.
Patients and families who deal with chronic disease often feel a need to have some control over daily disease management issues; try to involve the patient and family in decision-making whenever possible.
70. BioMarin Patient and Physician Support (BPPS) BPPS patient advocates provide individualized support to help guide each physician and patient through the treatment process.
Contact BPPS to obtain information and support related to:
Medical insurance programs
The Clinical Surveillance Program
Reporting infusion-associated reactions
Please contact BPPS: Toll free: 866-906-6100 Email: bpps@bmrn.com
