NAGLAZYME galsulfase Infusion Site Training

1
NAGLAZYME (galsulfase) Infusion Site Training
2
Agenda

• MPS VI Clinical Overview
• NAGLAZYME (galsulfase) Overview
• Dosage and Administration of NAGLAZYME

3
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 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 NAGLAZYME infusions 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
NAGLAZYME infusion should be given when treating
patients who present with an acute febrile or
respiratory illness.
4
Maroteaux-Lamy Syndrome (MPS VI) Clinical
Overview
5
Maroteaux-Lamy Syndrome (MPS VI)

• 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

6
GAG Accumulation in Lysosomes
Biochemical Basis of MPS

• 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

7
Classification of MPS Disorders

• 11 known enzyme deficiencies cause 7 main MPS
  types

DS dermatan sulfate, HS heparan sulfate, CS
chondroitin sulfate, KS keratan sulfate, HA
Hyaluronan
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

9
MPS VI Clinical Manifestations Summary

• Abdomen
• Hepatosplenomegaly
• Umbilical and inguinal hernias
• Bones Joints
• Joint stiffness and contractures
• Skeletal abnormalities (dysostosis multiplex)
• Hip dysplasia
• Brain Nerves
• Spinal cord compression
• Hydrocephalus
• Carpal tunnel syndrome
• Not associated with primary mental delay

• Appearance/General
• Coarse facial features
• Macrocephaly
• Short Stature
• Reduced endurance
• Eyes, Ears, Nose Throat
• Impaired vision
• Corneal Clouding
• Glaucoma
• Optic nerve disease
• Impaired hearing
• Recurrent otitis media
• Recurrent sinusitis

• Mouth Teeth
• Enlarged tongue
• Small, wide spaced teeth
• Airway Respiration
• Obstructive airway disease
• Restrictive airway disease
• Sleep apnea
• Recurrent pulmonary infections
• Heart
• Valvular disease
• Cardiomyopathy
• Cardiac arrhythmia
• Systemic and pulmonary hypertension

10
Spectrum of Clinical Presentation
Age of onset, spectrum of symptom severity and
rate of disease progression varies dramatically
between and within MPS disorders
Photos (right) courtesy of The National MPS
Society Inc.
Slowly Advancing
Rapidly Advancing
Disease Progression

• Later onset of symptoms
• Debilitating symptoms occur later
• Survival into adulthood
• Not a mild disease

• Early onset of symptoms
• Severe debilitation during first decade
• Early death

11
Disease Progression Rapidly Advancing

• Rapidly advancing disease is apparent at an early
  age.
• At 1 year of age
• facial coarsening is not yet marked
• macrocephaly, skeletal abnormalities, fixed
  flexion of fingers, enlarged abdomen
  (hepatomegaly) and umbilical hernia are evident

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 clinical
  features.

13
Clinical Manifestations
14
Coarse Facial Features

• Typical coarse facial features of MPS VI include
• Broad nose
• Flat nasal bridge
• Prominent eyes
• Enlarged tongue and lips

• Prominent forehead
• Macrocephaly
• Coarse hair/hirsutism

• Findings may be subtle in early or slowly
  advancing disease

Photos courtesy of The National MPS Society Inc.
15
Stature Clinical Features

• Height varies with the severity and rate of
  disease progression
• Typical height in rapidly advancing form of MPS
  VI is about 3 feet
• Typical height in slowly advancing form of MPS VI
  is about 5 feet
• Hunched posture with hip and knee flexion is
  pronounced in rapidly advancing disease

16
Eyes Clinical Features

• Corneal clouding
• Glaucoma
• Retinal changes
• Optic nerve atrophy/compression
• Blindness

17
ENT Mouth Clinical Features

• Recurrent otitis media
• Recurrent sinusitis
• Hearing loss
• Enlarged tongue
• Broad gum ridges
• Delayed eruption of dentition
• Dental cysts
• Poorly formed teeth

18
Airways and Respiration Clinical Features

• Obstructive airway disease
  
• Enlarged tonsils adenoids
• Narrow trachea
• Restrictive airway disease
• Noisy breathing / snoring

• Excessive and thickened secretions
• Recurrent pulmonary infections
• Reduced pulmonary function
• Sleep apnea

19
Heart Clinical Features

• Valvular disease (mitral and/or aortic)
• Cardiomyopathy
• Coronary artery disease
• Cardiac arrhythmia
• Systemic and pulmonary hypertension
• Congestive heart failure

20
Abdomen Clinical Features

• 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

• Clinical Features
• Bone and joint abnormalities
• Short, thickened fingers
• Fixed flexion abnormality of hands
• Trigger finger abnormality
• Loss of dexterity

22
Bones and Joints Clinical Features

• Constellation of characteristic skeletal
  abnormalities (dysostosis multiplex)

• Cranial hyperostosis and J shaped sella
• Vertebral beaking with subluxation and
  kyphoscoliosis
• Genu valgum
• Hip dysplasia

• Joint pain, stiffness and contractures

Photos and radiographs courtesy of Dr. P Maroteau
23
Brain and Nerves Clinical Features

• Communicating hydrocephalus
• Cervical spinal cord compression
• Carpal tunnel syndrome
• MPS VI is not associated with primary mental
  delay/regression

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

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.

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

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

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

31
NAGLAZYME Improved Endurance 12-minute walk test
By week 24, the group treated with NAGLAZYME
showed a 10925 m improvement from baseline
(Plt0.001) compared with 2523 m (P0.28) in the
placebo group.3
Fitted values
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 (p0.025).
32
NAGLAZYME Improved Endurance 3-minute stair
climb
By week 24, the group treated with NAGLAZYME
showed a 7.43.3 stairs/min improvement in
stair-climbing rate (Plt0.001) compared with
2.63.1 stairs/min (P0.22) in the placebo
group.3
Fitted values.1
Patients in the NAGLAZYME group experienced an
increase of 5,7 /- 2.9 stairs/min (model
derived group mean adjusted for baseline)
relative to the placebo group after 24 weeks of
treatment in the double-blind study (p0.053).
33
NAGLAZYME Reduced Urinary Glycosaminoglycans

The group treated with NAGLAZYME experienced a
75 reduction in mean urinary GAG levels by week
24

• 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

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

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

36
NAGLAZYME Infusion-Associated Reactions (IARs)

• 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

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

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
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 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 NAGLAZYME infusions 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
NAGLAZYME infusion should be given when treating
patients who present with an acute febrile or
respiratory illness.
41
NAGLAZYME Overview
Please follow your institutions protocols and
prescribing physicians orders for administration

• 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)

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 (µm)
  filter
• Additional supplies per the institution protocol

43
NAGLAZYME Dose Preparation
44
Dose Preparation

• 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

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

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

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

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

49
Dose Preparation

• Label the infusion bag per your institutions
  policy. Do not mix NAGLAZYME with other medicinal
  products

NAGLAZYME does not contain any preservatives ther
efore, after dilution with saline in the infusion
bag, any unused product or waste material should
be discarded and disposed of in accordance with
local requirements.
50
NAGLAZYME Administration
The following slides are suggested practice for
the administration of Naglazyme
(galsulfase) Refer to the package insert, the
prescribing physicians orders and your
institutions policies and procedures for
additional information and guidance.
Full Prescribing Information
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

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

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

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)

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

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

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

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

• Fever
• Chills/Rigors
• Headache
• Rash
• Urticaria

• Nausea and vomiting
• Elevated blood pressure
• Retrosternal pain
• Abdominal pain

• Angioneurotic edema
• Hypotension
• Dyspnea
• Respiratory distress
• Apnea

• Mild symptoms may progress rapidly if untreated
• Monitor patients throughout infusion, especially
  after rate increases
• Stop infusion promptly if IAR occurs

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
  ofre-administering NAGLAZYME following a severe
  hypersensitivity or anaphylactic reaction

Note Caution should be exercised if epinephrine
use is being considered in patients with MPS VI
due to increased prevalence of coronary artery
disease.
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

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

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

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)

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

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

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

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
  866-906-6100Email bpps_at_bmrn.com

• Additional information and support resources
• Information on MPS VI
• BioMarin MPS VI website www.mpsvi.com
• The National MPS Society www.mpssociety.org
• NAGLAZYME information
• NAGLAZYME website www.naglazyme.com