Hylenex recombinant (hyaluronidase human injection) in ...

Hylenex® recombinant (hyaluronidase human injection) in Subcutaneous Fluidhuman injection) in Subcutaneous Fluid

Administration for Achieving Rehydration

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Hylenex® recombinant (hyaluronidase humanHylenex recombinant (hyaluronidase human injection) Indication

H l bi t (h l id h i j ti ) iHylenex recombinant (hyaluronidase human injection) is a tissue modifier indicated as an adjuvant in subcutaneous fluid administration for achieving hydration, g y ,to increase the dispersion and absorption of other injected drugs, and in subcutaneous urography for improving resorption of radiopaque agentsimproving resorption of radiopaque agents.

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Hylenex® recombinant (hyaluronidase humanHylenex recombinant (hyaluronidase human injection) Important Safety Information• Hypersensitivity to hyaluronidase or any other ingredient in the formulation

is a contraindication to the use of this product.• Discontinue Hylenex recombinant (hyaluronidase human injection) if

sensitization occurs.• Hyaluronidase should not be used to enhance the absorption and dispersion• Hyaluronidase should not be used to enhance the absorption and dispersion

of dopamine and/or alpha agonist drugs.• Hyaluronidase should not be injected into or around an infected or acutely

inflamed area because of the danger of spreading a localized infection.• Hyaluronidase should not be used to reduce the swelling of bites or stings.• Hyaluronidase should not be used for intravenous injections because the

enzyme is rapidly inactivated.Furosemide the benzodiazepines and phenytoin have been found to be• Furosemide, the benzodiazepines, and phenytoin have been found to be incompatible with hyaluronidase.

• Anaphylactic-like reactions following retrobulbar block or intravenous injections have occurred, rarely.

• Hyaluronidase should not be applied directly to the cornea.

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Hylenex® recombinant (hyaluronidase human y ( yinjection) Important Safety Information (cont)

The most frequently reported adverse experiences have been local injection site reactions, such as erythema and pain. Hyaluronidase has been reported to enhance the adverse events associated with co-administered drug products.

Patients receiving large doses of salicylates cortisone ACTH estrogens orPatients receiving large doses of salicylates, cortisone, ACTH, estrogens or antihistamines may require larger amounts of hyaluronidase for equivalent dispersing effect, since these drugs apparently render tissues partly resistant to the action of hyaluronidase.

Edema has been reported most frequently in association with subcutaneous fluid administration. The rate and volume of subcutaneous fluid administration should not exceed those employed for intravenous infusion. As with all parenteral fluid p y ptherapy, use the same precautions for restoring fluid and electrolyte balance. Special care must be taken in pediatric patients to avoid overhydration by controlling the rate and total volume of infusion. When solutions devoid of inorganic electrolytes are given subcutaneously hypovolemiainorganic electrolytes are given subcutaneously, hypovolemiamay occur.

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MOA videoMOA video

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BackgroundBackground

S b t (S bQ) d i i t ti f fl id• Subcutaneous (SubQ) administration of fluids was common from 1900 to 1950• IV route first developed in the 50s

• SubQ fluids safe and effective in mild to moderate dehydration1

• IV access may be difficult in dehydrated children and theIV access may be difficult in dehydrated children and the elderly

• Recombinant human hyaluronidase (rHuPH20) is FDA approved in subcutaneous fluid administration forFDA approved in subcutaneous fluid administration for achieving hydration

1. Allen CH, Etzwiler LS, Miller MK, et al. Pediatrics. 2009;124:e858-e867.

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INFUSE (INcreased Flow Utilizing SC-Enabled)INFUSE (INcreased Flow Utilizing SC Enabled)• Adult and Pediatric Hydration

INFUSE L t t d Ri ’ Cli i l St d– INFUSE-Lactated Ringer’s Clinical Study• First clinical study to assess the safety, tolerability, and SC infusion

flow rate of lactated Ringer’s solution with and without Hylenex recombinant. Study conducted from 11/2005-1/2006.

Proof of ConceptADULTS

recombinant. Study conducted from 11/2005 1/2006.– INFUSE-Pediatric Rehydration Study I

• First clinical study to evaluate the safety, effectiveness, and ease of use of SC rehydration using Hylenex recombinant for the Single Arm

Studyrehydration of pediatric patients with mild to moderate dehydration. Study conducted 8/2007-6/2008.

– INFUSE-Pediatric Rehydration Study IIFi t li i l t d t th f t ff ti d

StudyPEDS

• First clinical study to compare the safety, effectiveness, and ease of use of SC rehydration using Hylenex recombinant vs. IV for the rehydration of pediatric patients with mild to moderate dehydration. Study conducted 11/2008-12/2009.

Head-to-Head Study

PEDS

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INFUSE-LR: Study DesignINFUSE LR: Study Design• Objective

– To compare flow rate, tolerability, and safety of gravity-infused p , y, y g ySubQ fluid hydration Hylenex® recombinant in healthy adults

• Methods– Double-blind, 2-stage, placebo-controlled (N = 54)– Stage 1 (N = 5): All received 1 mL Hylenex recombinant SubQ

and saline placebo, followed by 400 mL LR– Stage 2 (N = 49): Multiple doses tested; however, N = 18

i d H l bi t S bQ d li l breceived Hylenex recombinant SubQ and saline placebo, followed by 400 mL LR. N = 16 in efficacy analysis.

• EndpointsP i ti t i f 400 L LR– Primary: time to infuse 400 mL LR

– Secondary included investigator-rated tolerability, subject-rated discomfort, and AEs

LR = lactated Ringer’s.Thomas JR, Yocum RC, Haller MF, et al. J Palliat Med. 2007;10:1312-1320.

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INFUSE-LR: Outcomes

100600

Flow Rate

SD

INFUSE LR: Outcomes

383 119Mod-Severe = 94%

Edema

60

80

400

500

Mod

erat

e or

de

ma

mL/

hr) M

ean 383 119

P < .0001Severe

35%

P = .0004

20

40

100

200

300

Subj

ects

With

Se

vere

Ed

e of

Infu

sion

(m

82 30Severe

0%

Moderate

Moderate59%

00

100

% S

Rat

e

(N = 17)

Moderate12%

(N = 16)Hylenex® Placebo Hylenex® Placebo

• 4-fold greater flow rate and significantly fewer subjects with moderate to severe edemafor Hylenex® recombinant versus placebo

• Subject-rated discomfort lower versus placebo (5.8 10.7 versus 9.6 15.3) on VAS (P 002)

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on VAS (P.002)VAS = visual analog scale, on which 0 = no discomfort and 100 = worst discomfort.Thomas JR, Yocum RC, Haller MF, et al. J Palliat Med. 2007;10:1312-1320.

INFUSE-LR: All AEs Reported in 2 SubjectsUS s epo ted Subjects• AEs localized, mild to moderate; no severe or serious AEs• Overall, subject and investigator preference for Hylenex® recombinant

88% (P 002) d 94% (P 001) ti l

M dDRA S /P f d T

Incidence* %

Hylenex recombinant Placebo

was 88% (P=.002) and 94% (P.001), respectively

MedDRA Soc/Preferred Term (n = 18) (n = 18)

General disorders and administration site conditions

38.9 50.0

Infusion/injection/catheter site pain 27 8 38 9Infusion/injection/catheter site pain 27.8 38.9

Infusion/injection site burning 11.1 5.6

Injection site anesthesia 11.1 5.6

Infusion/catheter site erythema 5 6 0Infusion/catheter site erythema 5.6 0

Infusion site induration 0 11.1

*From the time of initial exposure to study drug through the 28-day follow-up assessment.

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MedDRA = Medical Dictionary for Regulatory Activities System Organ Class Preferred Term list; Thomas JR, Yocum RC, Haller MR, et al. J Palliat Med. 2007;10:1312-1320.

INFUSE-Peds I: Study DesignINFUSE Peds I: Study Design

• Objective– To assess the efficacy, safety, and utility of Hylenex® recombinant-

enabled SubQ rehydration in children with mild to moderate dehydration• Methods

– Phase IV single-arm pilot study– Phase IV, single-arm, pilot study– 51 patients (aged 2 months to 10 years) received 1 mL Hylenex

recombinant SubQ, followed by 1-hour continuous infusion of 20 mL/kg isotonic fluidI f i ti d l t l t t 72 h if d d– Infusion continued electrolytes up to 72 h if needed

• Endpoints– Primary: Proportion of patients successfully rehydrated by SubQ infusion

and discharged without need for alternative rehydrationand discharged without need for alternative rehydration– Secondary included ease of use (eg, time from catheter placement to

start of infusion, number of attempts needed for SubQ catheterization), and AEs

Allen CH, Etzwiler LS, Miller MK, et al. Pediatrics. 2009;124:e859-e868.

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INFUSE-PEDS I: Endpoints of SubQ InfusionsINFUSE PEDS I: Endpoints of SubQ Infusions

• 100% had successful SubQ line placement on the first attempt– Approximately 10% of the catheters dislodged and required reinsertion

• 94.1% (48/51) of patients were clinically rehydrated via SubQ infusion

• Median time to infusion after catheter placement: 2 min (range, 0 to 15)

• Only 1 attempt needed for SubQ access in 90 2% (46/51) of patients• Only 1 attempt needed for SubQ access in 90.2% (46/51) of patients • Investigators rated the SubQ procedure as more effective (92%) and

less difficult (90%) than IV infusion90% f t “ ti fi d” “ ti fi d” ith th d• 90% of parents were “satisfied” or “very satisfied” with the procedure and 94% considered the SubQ procedure to be successful

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INFUSE-PEDS I: Infusion Site Pain on Day 1Number of Patients With Objective Pain

Rating Score* (n = 40)

INFUSE PEDS I: Infusion Site Pain on Day 1

Investigator-assessed 0 1-2 3-4 5-6 7-8 9-10After Hylenex® recombinant (pre-infusion) 4 6 9 10 7 4

After infusion start (max score) 28 7 4 1 0 0

Number of Patients With FACES Pain Score† (n = 6)

S lf d 1 2 3 4 5Self-assessed 1 2 3 4 5After Hylenex® recombinant (pre-infusion) 2 3 0 1 0

After infusion start (max score) 3 1 1 1 0

*Objective Pain Rating Scale used for patients aged 3 y, where 0 (none), 1, or 2 (worst) in face, legs, activity, cry, and consolability (FLACC) and score sums range from 0 to 10.

†FACES Pain Scale used for patients aged 3 to 10 years, where 0 = no hurt, 1= hurts a little bit, 2 = hurts a little more, 3 = hurts even more, 4 = hurts a whole lot, 5 = hurts worst.

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PEDS II: Procedural Infusion Site Pain in Children < 3-years old

789

10

ore

4.7

3456

OPR

S Sc

o

0.5 0.7

012

Baseline Pain during catheter Pain after start of

O

insertion infusion

The Objective Pain Rating Scale (OPRS) was used for children younger than 3 years (N=40).

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The OPRS, also known as FLACC (Face, Legs, Activity, Cry, Consolability), measures pain on a scale from 0 (none) to 10 (most).

PEDS II: Overview (cont)PEDS II: Overview (cont)• Objective

T l t h th H l ® bi t bl d– To evaluate whether Hylenex® recombinant-enabled subcutaneous fluid administration can be given safely and effectively, with volumes similar to those delivered IV, in children with mild to moderate dehydrationwith mild to moderate dehydration

• Methods– Pediatric patients >1 month to 10 years of age with mild to

moderate dehydrationmoderate dehydration– Noninferiority study was powered to test that the mean volume

infused via SubQ was ≥85% of the volume delivered via IV– A sample size of 74 patients per group would provide at leastA sample size of 74 patients per group would provide at least

80% power at the 1-sided 0.025 level of significance for establishing the noninferiority of Hylenex recombinant-enabled subcutaneous fluid administration compared with IV

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INFUSE-Peds II CSR; data on file, Halozyme Therapeutics.

Peds II: Methods – Infusion ProceduresPeds II: Methods Infusion Procedures

• rHFSC SubQ Catheter Placement OptionrHFSC – Access with angiocatheter or butterfly– 150 USP Hylenex® recombinant given

(1 mL)(1 mL)– 20 mL/kg isotonic fluid given over 1 hour– Hydration continued for up to 72 hours

T i l IV C th t Pl t• IV

– Access with angiocatheter20 L/k i t i fl id i 1 h

Typical IV Catheter Placement

– 20 mL/kg isotonic fluid given over 1 hour– Hydration continued for up to 72 hours

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rHFSC = Hylenex® recombinant-enabled subcutaneous fluid administration.

PEDS II: Baseline CharacteristicsPEDS II: Baseline Characteristics

VariablerHFSC(n = 73)

IV(n = 75)

Total(N = 148)

Mean (SD) age, y 2.1 (1.72) 2.4 (2.07) 2.3 (1.91)

Age group, n (%)1 mo to <1 y1 y to <2 y2 y to <3 y3

23 (31.5)20 (27.4)17 (23.3)13 (17 8)

12 (16)28 (37.3)18 (24)

17 (22 7)

35 (23.6)48 (32.4)35 (23.6)30 (20 3)3 y 13 (17.8) 17 (22.7) 30 (20.3)

Sex, n (%)MaleFemale

34 (46.6)39 (53.4)

39 (52)36 (48)

73 (49.3)75 (50.7)

Race, n (%)BlackWhiteOther

25 (34.2)39 (53.4)9 (12.3)

22 (29.3)40 (53.3)13 (17.3)

47 (31.8)79 (53.4)22 (14.9)

Mean (SD) baseline weight, kg 11.8 (4.14) 12.9 (4.68) 12.4 (4.44)

Gorelick Deh dration Score n (%)Gorelick Dehydration Score, n (%)Mild (1-2)Moderate (3-6)

20 (27.4)53 (72.6)

23 (30.7)52 (69.3)

43 (29.1)105 (70.9)


Patient Flowat e t o

EnrolledN = 148

rHFSC IVN 148

Randomizedn = 73

Randomized n = 75

Non = 0

Yesn 59

Yesn = 73

Successful Infusion Device Placement via Randomized

RouteNo

n 16W/dn = 1n = 0 n = 59n = 73 Route n = 16

Successful Infusion Device Placement via

Rescue RouteYes

n = 15

n = 1

Homen = 2

Yesn = 57

Home13

Successful Hydration

Yesn = 68

Non = 5

Non = 2

ED Discharge Destination

Yesn = 15

Home49

Home59

Home1 n = 13

Inpatientn =2

Destination n = 49

Inpatientn = 8

n = 59

Inpatientn = 9

n = 1

Inpatientn = 4

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PEDS-II: 95% SubQ Needle Placement After 1 Stick

IVrHFSC94.5

74.6

60

80

100

%)

5.515.3

8.51.7

0

20

40

Patie

nts

(%

1 2 1 2 3 >3

-21.3-40

-20 1 2 1 2 3 >3

FailureNumber of Attempts By Treatment

rHFSC = Hylenex® recombinant-enabled subcutaneous fluid administration; IV = intravenous.rHFSC: 1 attempt, n = 69, 2 attempts, n = 4, 3 attempts, n = 0; >3 attempts, n = 0IV: 1 attempt, n = 44; 2 attempts, n = 9, 3 attempts, n = 5; >3 attempts, n = 1; failure, n = 16*Overall P<0.01 comparing distributions of rHFSC and IV groups (successes)16 (21.3%) patients in the IV group did not achieve successful access. Additional needle sticks were required to initiate

th


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rescue therapy.

PEDS-II: 100% SubQ Catheterization S 00% SubQ Cat ete at oSuccess Across All Groups

rHFSC (n = 73) IV (n = 75)

100 100 100 100

83

100

8090

100

rHFSC (n 73) IV (n 75)

P<0.001 P<0.01 P=0.08

5871

304050607080

cces

s R

ate

(%)

0102030

1 mo to <1 yr ≥1 to <2 yrs ≥2 to <3 yrs ≥3 yrs

Suc

23/23 7/12 20/20 20/28 17/17 15/18 13/13 17/17

rHFSC = Hylenex® recombinant-enabled subcutaneous fluid administration; IV = intravenous.

Age Group

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PEDS II: Time to Treatment InitiationPEDS II: Time to Treatment Initiation(First Catheterization to Start of Infusion)

IVrHFSC

80

100

%)

56 8

41.1 38.4

15 120

40

60

Patie

nts

(%

16.221.6

56.8

15.15.5

0

20

<3 3 to <6 6 to <10 ≥10

5.416.2

>3 3 to <6 6 to <10 ≥10

rHFSC: Median time = 3.5 minutes; IV: Median time = 11.8 minutes *Overall P<0.0001.

Time (min)

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Peds II: Percent Rehydration SuccessPeds II: Percent Rehydration Success Among All Randomized Patients

93.2

69.380

100

%)

20

40

60

Patie

nts

(%

0

20

SubQ with Hylenex®

recombinantIV

• In patients randomized to receive Hylenex recombinant-facilitated SubQ rehydration who were successfully catheterized, 93.2% (68/73) were successfully rehydrated

• In patients randomized to IV administration, 78.7% (59/75) had successful

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catheter placement; 69.3% (52/75) were successfully rehydrated

Peds II: Percent Successful Rehydration eds e ce t Success u e yd at oAmong Patients With Successful Catheter Placement

93.2 88.1100

40

60

80

ient

s (%

)

0

20

40

Pat

• 93.2% (68/73) of patients in SubQ arm were successfully rehydrated in the ED

% ( / ) f f

SubQ with Hylenex®

recombinantIV

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• 88.1% (52/59) of patients in IV arm were successfully rehydrated in the ED

Peds II: Secondary OutcomesPeds II: Secondary Outcomes

R d i d t HFSC R d i d t IVRandomized to rHFSC (n = 73)

Mean (95% CI)

Randomized to IV (n = 75)

Mean (95% CI) P value*

D h d ti 2 6 2 2Dehydration score improvement†

2.6(2.9, 2.3)

2.2(2.6, 1.8)

0.07

0 3 0 5Weight change from baseline (kg)

0.3(-0.3, 1.0)

0.5(-0.6, 17.7)

0.47


*Null hypothesis tested: rHFSC<IV.†Gorelick 10-item score.

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Peds II: Patients on SubQ Route Had a First-Hour Bolus Flow Rate (20 mL/kg/hour) Similar to IV

19.8 20

18202224

ur)

81012141618

w ra

te (m

L/ho

u

0246

Flow

n = 66 n = 55

SubQ with Hylenex®

recombinantIV

• During the first hour of infusion, the mean flow rate of the infusion was similar for those receiving Hylenex recombinant-facilitated SubQ rehydration compared with those receiving IV-enabled rehydration*

• In successfully rehydrated patients who received hydration therapy for at least 1 hour and in

recombinant

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• In successfully rehydrated patients who received hydration therapy for at least 1 hour and in whom weights were obtained.


INFUSE-PEDS ll: Total Volume Delivered in ED Was Similar Between SubQ and IV

Fluid Volume Infused

165 2400

500Fluid Volume Infused

464.8 mL

365.0 mL30.7

165.2

200

300 Hospital stayED Only

n Vo

lum

e (m

L)

365.0 mL

334.3 299.6100

200

Mea

n (

P=0.0325

0SubQ with Hylenex®

recombinant(n = 73)

IV(n = 75)

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INFUSE-PEDS II: Total Volume Delivered in US S ota o u e e e edED Was Similar Between SubQ and IV (cont)

All Randomized Patients

Randomized to rHFSC(n = 73)

Mean (SD)

Randomized to IV

(n = 75)Mean (SD)

P value*

Total volume (mL) infused at a single infusion site (ED + inpatient)

365.0 (324.57)

455.8 (597.43)

0.51

Total volume (mL)(adjusted by duration)

406.7(233 23)

413.7(232 88) 0.04(adjusted by duration) (233.23) (232.88)

Total volume (mL) (ED only)

334.3(226.40)

299.6 (252.33) 0.03

Note: For those patients who did not have the assigned type of infusion device (IV or SubQ) successfully placed (ie, the 16 IV-assigned patients who did not have successful placement of an IV device), the volume of IV fluid infused was imputed as 0 mL.

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*A P value of <0.05 is required to reject inferiority of rHFSC versus IV.

INFUSE-PEDS ll: Total Volume Delivered in ED Was Similar Between Non-rescued SubQ and IV

600

700Fluid Volume Infused

579.4 mL

30 7

198.6400

500

600

Hospital stayED O lVo

lum

e L)

365 mL

334.3 380.8

30.7

100

200

300 ED Only

Mea

n V

(m

0

100

SubQ with Hylenex®

recombinant( 73)

IV(n = 59)

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(n = 73) (n = 59)

INFUSE-PEDS II: Total Volume Delivered inINFUSE PEDS II: Total Volume Delivered in ED Was Similar Between IV and SubQ (cont)(cont)

Randomized to rHFSC

Randomized to IVNonrescued Patients to rHFSC

(n = 73)Mean (SD)

to IV(n = 59)

Mean (SD)

P value*

Total volume (mL) infused at a single infusion site (ED + inpatient)

365.0 (324.57)

579.4(618.49)

0.8915

T t l l ( L) 334 3 380 8Total volume (mL) (ED only)

334.3(226.40)

380.8(223.08) 0.5469


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* A P value of <0.05 is required to reject inferiority of rHFSC versus IV.

Adverse Events – Infusion Site ReactionsAdverse Events Infusion Site Reactions

Administration Site Conditions

rHFSC(n = 73) a

n (%)

IV(n = 75) a

n (%)Administration Site Conditions n (%) n (%)

Any infusion site reaction 73 (100.0) 63 (84.0)

Erythemab 54 (74.0) 19 (25.3)

Edemac 5 (6.8) 1 (1.3)

Paind 57 (78.1) 59 (78.7)

R h 0 1 (1 3)Rash 0 1 (1.3)

Swellingef 59 (80.8) 16 (21.3)

Extravasation 0 1 (1.3)( )

aFrequency and count based on treatment received.All infusion-site reactions were mild except for the following: bmoderate (rHFSC [n = 4]; IV [n = 1]); cmoderate (rHFSC [n = 2]); dmoderate (rHFSC [n = 11]; IV [n = 9]); severe (rHFSC [n = 1]); emoderate (rHFSC [n = 10]; IV [n = 1]); fSwelling in rHFSC group due to infusion fluid and not inflammatory process.

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moderate (rHFSC [n 10]; IV [n 1]); Swelling in rHFSC group due to infusion fluid and not inflammatory process.


PEDS-II: Safety SummaryPEDS II: Safety Summary

• All patients receiving rHFSC fluid administration (n = 73) i d t l t 1 i f i it AE 63 (84%) fexperienced at least 1 infusion-site AE versus 63 (84%) of

patients in the IV group (P<0.001)• The majority of AEs were considered to be mild to j y

moderate in severity. Seventy-three of 73 (100%) patients in the rHFSC group versus 64 of 75 (85.3%) in the IV group experienced administration-site adverse events orgroup experienced administration site adverse events or general disorders

• SAEs were reported in 8 patients (rHFSC, n = 3 and IV, n = 5) None were determined by the investigator to be= 5). None were determined by the investigator to be related to study treatment.


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PEDS-II: ConclusionsPEDS II: Conclusions• Hylenex® recombinant-enabled SubQ is a safe and effective

alternative to the IV route for mild to moderate dehydration• The primary efficacy outcome measures

– Total (ED plus inpatient hospital stay) mean (SD) volume infused SubQ was 365.0 (SD = 324.57) mL over 3.1 hours versus 455.8 (SD = 597.43) mL over 6 6 hours for IV which was insufficient to reject the hypothesis ofmL over 6.6 hours for IV, which was insufficient to reject the hypothesis of noninferiority

• The difference in the mean duration of infusion resulted from hospital practices and treatment protocolsp p

• When the ED data were analyzed separately, rHFSC and IV hydration were similar – SC: 334.3 mL (SD = 226.40) (P<0.03)– IV: 299.6 mL (SD = 252.33)


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SummarySummary • Hylenex recombinant-enabled subcutaneous delivery of fluids is

clinically proven to be a safe and effective alternative to the IV route in y pmild to moderate dehydration.

• Clinical studies demonstrated a 100% first stick catheter placement success rate.

• The subcutaneous route of administration enabled by Hylenexrecombinant is clinically proven to save time in catheter insertion and fluid infusion.

• The Hylenex recombinant-enabled subcutaneous fluid delivery route is preferred over IV by parents, patients and caregivers.

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HYLENEX recombinant(hyaluronidase human injection)

150 USP units/mL

HYLENEX recombinant(hyaluronidase human injection)150 USP units/mL

HIGHLIGHTS OF PRESCRIBING INFORMATIONThese highlights do not include all the information needed to use HYLENEX recombinant safely and effectively. See full prescribing information for HYLENEX recombinant.

HYLENEX recombinant (hyaluronidase human injection) Initial U.S. Approval: 2005

INDICATIONS AND USAGEHYLENEX recombinant is a tissue permeability modifier indicated as an adjuvant

• in subcutaneous fluid administration for achieving hydration (1.1)• to increase the dispersion and absorption of other injected drugs (1.2)• in subcutaneous urography for improving resorption of radiopaque agents (1.3)

DOSAGE AND ADMINISTRATION• Subcutaneous fluid administration: Inject 150 U HYLENEX recombinant prior to subcutaneous

fluid administration. It will facilitate absorption of 1,000 mL or more of solution. The dosageof subcutaneous fluids administered is dependent upon the age, weight, and clinical conditionof the patient as well as laboratory determinations. The rate and volume of subcutaneous fluidadministration should not exceed those employed for intravenous infusion (2.1)

• Increasing dispersion and absorption of injected drugs: Add 50-300 U (most typically 150 U)HYLENEX recombinant to the injection solution. Consultation of references on physical orchemical incompatibilities recommended (2.2)

• Subcutaneous Urography: Inject 75 U HYLENEX recombinant subcutaneously over eachscapula, followed by injection of the contrast medium at the same sites (2.3)

DOSAGE FORMS AND STRENGTHS150 USP units/mL single dose vials (3)

CONTRAINDICATIONS• Hypersensitivity (4)

WARNINGS AND PRECAUTIONS• Spread of Localized Infection (5.1)• Ocular Damage (5.2)• Enzyme Inactivation with Intravenous Administration (5.3)

ADVERSE REACTIONS• The most frequently reported adverse reactions have been mild local injection site reactions (6)• Allergic and anaphylactic-like reactions have been reported, rarely (6)

To report SUSPECTED ADVERSE REACTIONS, contact Halozyme Therapeutics, Inc. at 1-855-495-3639or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

LBL293-01

DRUG INTERACTIONS• Furosemide, the benzodiazepines and phenytoin are incompatible with hyaluronidase (7.1)• Hyaluronidase should not be used to enhance the dispersion and absorption of dopamine

and/or alpha agonist drugs (7.2)• Local anesthetics: Hyaluronidase hastens onset and shortens duration of effect, increases

incidence of systemic reactions (7.3)• Large doses of salicylates, cortisone, ACTH, estrogens or antihistamines may require larger

amounts of hyaluronidase for equivalent dispersing effect (7.4)USE IN SPECIFIC POPULATIONS

• Pediatric Use: Clinical hydration requirements for children can be achieved throughadministration of subcutaneous fluids facilitated with HYLENEX recombinant. The dosage ofsubcutaneous fluids administered is dependent upon the age, weight, and clinical condition ofthe patient as well as laboratory determinations. For premature infants or during the neonatalperiod, the daily dosage should not exceed 25 mL/kg of body weight, and the rate ofadministration should not be greater than 2 mL per minute. During subcutaneous fluidadministration, special care must be taken in pediatric patients to avoid over hydration bycontrolling the rate and total volume of the infusion (2.1, 8.4, 14).

See 17 for PATIENT COUNSELING INFORMATIONRevised: 08/2011

FULL PRESCRIBING INFORMATION

1. INDICATIONS AND USAGE1.1 Subcutaneous Fluid AdministrationHYLENEX recombinant is indicated as an adjuvant in subcutaneous fluid administration for achieving hydration.1.2 Dispersion and Absorption of Injected DrugsHYLENEX recombinant is indicated as an adjuvant to increase the dispersion and absorption of otherinjected drugs.1.3 Subcutaneous UrographyHYLENEX recombinant is indicated as an adjunct in subcutaneous urography for improving resorption ofradiopaque agents.2. DOSAGE AND ADMINISTRATIONAlways use aseptic precautions. Lightly pinch the skin up into a small mound and insert theneedle/catheter into the subcutaneous space. Inject HYLENEX recombinant through the catheter hub orinjection port closest to the needle/catheter. Begin administration of the injection solution. Solutionshould start in readily.2.1 Subcutaneous Fluid Administration150 U of HYLENEX recombinant injected prior to start of subcutaneous fluid administration will facilitateabsorption of 1,000 mL or more of solution. As with all parenteral fluid therapy, observe effect closely,with the same precautions for restoring fluid and electrolyte balance as in intravenous injections. The dose,the rate of injection, and the type of solution (saline, glucose, Ringer’s, etc.) must be adjusted carefully tothe individual patient. When solutions devoid of inorganic electrolytes are administered subcutaneously,hypovolemia may occur. This may be prevented by using solutions containing adequate amounts ofinorganic electrolytes and/or controlling the volume and speed of administration.

HYLENEX recombinant may be added to small volumes of solution, such as fluid replacement solutions orsolutions of drugs for subcutaneous injection. Subcutaneous fluids should be administered as directed bya physician. The dosage of subcutaneous fluids administered is dependent upon the age, weight, andclinical condition of the patient as well as laboratory determinations. The rate and volume ofsubcutaneous fluid administration should not exceed those employed for intravenous infusion. Forpremature infants or during the neonatal period, the daily dosage should not exceed 25 mL/kg of bodyweight, and the rate of administration should not be greater than 2 mL per minute.2.2 Dispersion and Absorption of Injected DrugsDispersion and absorption of other injected drugs may be enhanced by adding 50-300 U, most typically150 U hyaluronidase, to the injection solution.It is recommended that appropriate references be consulted regarding physical or chemicalincompatibilities before adding HYLENEX recombinant to a solution containing another drug.2.3 Subcutaneous UrographyThe subcutaneous route of administration of urographic contrast media is indicated when intravenousadministration cannot be successfully accomplished, particularly in infants and small children. With thepatient prone, 75 U of HYLENEX recombinant is injected subcutaneously over each scapula, followed byinjection of the contrast medium at the same sites.Parenteral drug products should be inspected visually for particulate matter and discoloration prior toadministration whenever solution and container permit.3. DOSAGE FORMS AND STRENGTHS150 USP units/mL single dose vials4. CONTRAINDICATIONSHYLENEX is contraindicated in patients with known hypersensitivity to hyaluronidase or any of theexcipients in HYLENEX. A preliminary skin test for hypersensitivity to HYLENEX recombinant can beperformed. The skin test is made by an intradermal injection of approximately 0.02 mL (3 Units) of a150 Unit/mL solution. A positive reaction consists of a wheal with pseudopods appearing within 5 minutes and persisting for 20 to 30 minutes and accompanied by localized itching. Transientvasodilation at the site of the test, i.e., erythema, is not a positive reaction.5. WARNINGS AND PRECAUTIONS5.1 Spread of Localized InfectionHyaluronidase should not be injected into or around an infected or acutely inflamed area because of thedanger of spreading a localized infection.Hyaluronidase should not be used to reduce the swelling of bites or stings.5.2 Ocular DamageHyaluronidase should not be applied directly to the cornea. It is not for topical use.5.3 Enzyme Inactivation with Intravenous AdministrationHYLENEX recombinant should not be administered intravenously. Its effects relative to dispersion andabsorption of other drugs are not produced when it is administered intravenously because the enzyme israpidly inactivated.6. ADVERSE REACTIONSThe following adverse reactions have been identified during post-approval use of hyaluronidaseproducts. Because these reactions are reported voluntarily from a population of uncertain size, it is notalways possible to reliably estimate their frequency or establish a causal relationship to drug exposure.The most frequently reported adverse experiences have been mild local injection site reactions such aserythema and pain. Hyaluronidase has been reported to enhance the adverse events associated with co-administered drug products. Edema has been reported most frequently in association withsubcutaneous fluid administration. Allergic reactions (urticaria or angioedema) have been reported inless than 0.1% of patients receiving hyaluronidase. Anaphylactic-like reactions following retrobulbarblock or intravenous injections have occurred, rarely.7. DRUG INTERACTIONS7.1 IncompatibilitiesFurosemide, the benzodiazepines and phenytoin have been found to be incompatible with hyaluronidase.7.2 Drug-Specific PrecautionsHyaluronidase should not be used to enhance the dispersion and absorption of dopamine and/or alphaagonist drugs.When considering the administration of any other drug with hyaluronidase, it is recommended thatappropriate references first be consulted to determine the usual precautions for the use of the otherdrug. 7.3 Local AnestheticsWhen hyaluronidase is added to a local anesthetic agent, it hastens the onset of analgesia and tends toreduce the swelling caused by local infiltration, but the wider spread of the local anesthetic solutionincreases its absorption; this shortens its duration of action and tends to increase the incidence ofsystemic reaction.7.4 Salicylates, Cortisone, ACTH, Estrogens and AntihistaminesPatients receiving large doses of salicylates, cortisone, ACTH, estrogens or antihistamines may requirelarger amounts of hyaluronidase for equivalent dispersing effect, since these drugs apparently rendertissues partly resistant to the action of hyaluronidase.

FULL PRESCRIBING INFORMATION: CONTENTS*

1. INDICATIONS AND USAGE1.1 Subcutaneous Fluid Administration1.2 Dispersion and Absorption of Injected

Drugs1.3 Subcutaneous Urography

2. DOSAGE AND ADMINISTRATION2.1 Subcutaneous Fluid Administration2.2 Dispersion and Absorption of Injected

Drugs2.3 Subcutaneous Urography

3. DOSAGE FORMS AND STRENGTHS4. CONTRAINDICATIONS5. WARNINGS AND PRECAUTIONS

5.1 Spread of Localized Infection5.2 Ocular Damage5.3 Enzyme Inactivation with Intravenous

Administration6. ADVERSE REACTIONS7. DRUG INTERACTIONS

7.1 Incompatibilities7.2 Drug-Specific Precautions7.3 Local Anesthetics7.4 Salicylates, Cortisone, ACTH, Estrogens

and Antihistamines

8. USE IN SPECIFIC POPULATIONS8.1 Pregnancy8.2 Labor and Delivery8.3 Nursing Mothers8.4 Pediatric Use8.5 Geriatric Use

11. DESCRIPTION12. CLINICAL PHARMACOLOGY

12.1 Mechanism of Action12.2 Pharmacodynamics12.3 Pharmacokinetics

13. NONCLINICAL TOXICOLOGY13.1 Carcinogenesis, Mutagenesis,

Impairment of Fertility14. CLINICAL STUDIES16. HOW SUPPLIED/STORAGE AND HANDLING17. PATIENT COUNSELING INFORMATION

17.1 Important Precautions Regarding HYLENEX recombinant

17.2 What Patients Should Know About Adverse Reactions

17.3 Patients Should Inform Their DoctorsIf Taking Other Medications

*Sections or subsections omitted from the fullprescribing information are not listed.

8. USE IN SPECIFIC POPULATIONS8.1 PregnancyPregnancy Category C. Animal reproduction studies have not been conducted with HYLENEX recombinant.It is also not known whether HYLENEX recombinant can cause fetal harm when administered to apregnant woman. HYLENEX recombinant should be given to a pregnant woman only if clearly needed.8.2 Labor and DeliveryAdministration of hyaluronidase during labor was reported to cause no complications: no increase inblood loss or differences in cervical trauma were observed. 8.3 Nursing MothersIt is not known whether hyaluronidase is excreted in human milk. Because many drugs are excreted inhuman milk, caution should be exercised when hyaluronidase is administered to a nursing woman.8.4 Pediatric UseClinical hydration requirements for children can be achieved through administration of subcutaneousfluids facilitated with HYLENEX recombinant.The dosage of subcutaneous fluids administered is dependent upon the age, weight, and clinical conditionof the patient as well as laboratory determinations. The potential for chemical or physicalincompatibilities should be kept in mind [See Drug Interactions (7)].The rate and volume of subcutaneous fluid administration should not exceed those employed forintravenous infusion. For premature infants or during the neonatal period, the daily dosage should notexceed 25 mL/kg of body weight, and the rate of administration should not be greater than 2 mL per minute.During subcutaneous fluid administration, special care must be taken in pediatric patients to avoid overhydration by controlling the rate and total volume of the infusion. [See Dosage and Administration (2.1)].8.5 Geriatric UseNo overall differences in safety or effectiveness have been observed between elderly and younger adult patients.11. DESCRIPTIONHYLENEX recombinant is a purified preparation of the enzyme recombinant human hyaluronidase.HYLENEX recombinant is produced by genetically engineered Chinese Hamster Ovary (CHO) cells containinga DNA plasmid encoding for a soluble fragment of human hyaluronidase (PH20). The purified hyaluronidaseglycoprotein contains 447 amino acids with an approximate molecular weight of 61,000 Daltons.HYLENEX recombinant is supplied as a sterile, clear, colorless, nonpreserved, ready for use solution.Each mL contains 150 USP units of recombinant human hyaluronidase with 8.5 mg sodium chloride, 1.4 mgdibasic sodium phosphate, 1.0 mg albumin human, 0.9 mg edetate disodium, 0.3 mg calcium chloride,and sodium hydroxide added for pH adjustment.HYLENEX recombinant has an approximate pH of 7.0 and an osmolality of 290 to 350 mOsm.12. CLINICAL PHARMACOLOGY12.1 Mechanism of ActionHyaluronidase is a dispersion agent, which modifies the permeability of connective tissue through thehydrolysis of hyaluronic acid, a polysaccharide found in the intercellular ground substance of connectivetissue, and of certain specialized tissues, such as the umbilical cord and vitreous humor. Hyaluronic acid isalso present in the capsules of type A and C hemolytic streptococci. Hyaluronidase hydrolyzes hyaluronicacid by splitting the glucosaminidic bond between C1 of an N-acetylglucosamine moiety and C4 of aglucuronic acid moiety. This temporarily decreases the viscosity of the cellular cement and promotesdispersion of injected fluids or of localized transudates or exudates, thus facilitating their absorption.Hyaluronidase cleaves glycosidic bonds of hyaluronic acid and, to a variable degree, some other acidmucopolysaccharides of the connective tissue. The activity is measured in vitro by monitoring thedecrease in the amount of an insoluble serum albumin-hyaluronic acid complex as the enzyme cleavesthe hyaluronic acid component.12.2 PharmacodynamicsIn the absence of hyaluronidase, material injected subcutaneously disperses very slowly. Hyaluronidasefacilitates dispersion, provided local interstitial pressure is adequate to furnish the necessary mechanicalimpulse. Such an impulse is normally initiated by injected solutions. The rate and extent of dispersionand absorption is proportionate to the amount of hyaluronidase and the volume of solution.The reconstitution of the dermal barrier removed by intradermal injection of hyaluronidase (20, 2, 0.2, 0.02, and0.002 U/mL) to adult humans indicated that at 24 hours the restoration of the barrier is incomplete and inverselyrelated to the dosage of hyaluronidase; at 48 hours, the barrier is completely restored in all treated areas.Results from an experimental study, in humans, on the influence of hyaluronidase in bone repair supportthe conclusion that hyaluronidase alone, in the usual clinical dosage, does not deter bone healing.12.3 PharmacokineticsKnowledge of the mechanisms involved in the disappearance of injected hyaluronidase is limited. It isknown, however, that the components in blood of a number of mammalian species bring about theinactivation of hyaluronidase.Studies have demonstrated that hyaluronidase is antigenic; repeated injections of relatively largeamounts of hyaluronidase preparations may result in the formation of neutralizing antibodies.13. NONCLINICAL TOXICOLOGY13.1 Carcinogenesis, Mutagenesis, Impairment of FertilityLong-term animal studies have not been performed to assess the carcinogenic or mutagenic potential ofhyaluronidase. Hyaluronidase is found in most tissues of the body.

Human studies on the effect of intravaginal hyaluronidase in sterility due to oligospermia indicated thathyaluronidase may have aided conception. Thus, it appears that hyaluronidase may not adversely affectfertility in females.14. CLINICAL STUDIESHYLENEX recombinant facilitated the administration of subcutaneous fluids in pediatric patients withmild to moderate dehydration in an open-label, multicenter, single arm study in fifty-one (51) patients. Asubcutaneous injection of 1 mL (150 U) of HYLENEX recombinant was immediately followed bysubcutaneous infusion of isotonic fluids in either the mid-anterior thigh or the inter-scapular area of theupper back. The safety and flow rate of subcutaneously administered Lactated Ringer’s (LR) solution with andwithout HYLENEX recombinant was evaluated in a prospective, randomized, double-blinded, placebo-controlled, within-subject, single-center study in fifty-four (54) healthy volunteers. The mean HYLENEXrecombinant facilitated infusion rate was 464 mL/hr versus 118 mL/hr for the saline control (p < 0.001,paired t-test). 16. HOW SUPPLIED/STORAGE AND HANDLINGHYLENEX recombinant is supplied sterile as 150 USP units of nonpreserved recombinant humanhyaluronidase per mL in a single-use glass vial.1 mL Single Dose Vial available in a carton of 4 (NDC 18657-102-04) Not Recommended for IV Use.Store unopened in a refrigerator at 2° to 8°C (36° to 46° F).DO NOT FREEZE.17. PATIENT COUNSELING INFORMATION17.1 Important Precautions Regarding HYLENEX recombinantInstruct patient that HYLENEX recombinant is being used to increase the dispersion and absorption offluids or other injected drugs, as appropriate to the intended use.Instruct patient that there may be mild local injection site signs and symptoms, such as redness,swelling, itching, or pain localized to the site of injection.17.2 What Patients Should Know About Adverse ReactionsThe most frequently reported adverse reactions have been mild local injection site reactions such asredness, swelling, itching, or pain.Anaphylactic-like reactions, and allergic reactions, such as hives, have been reported rarely in patientsreceiving hyaluronidases.17.3 Patients Should Inform Their Doctors If Taking Other MedicationsYou may not receive furosemide, the benzodiazepines, phenytoin, dopamine and/or alpha agonists withHYLENEX. These medications have been found to be incompatible with hyaluronidase.If you are taking salicylates (e.g., aspirin), steroids (e.g., cortisone or estrogens), or antihistamines yourdoctor may need to prescribe larger amounts of hyaluronidase for equivalent dispersing effect.

Halozyme and Hylenex are registered trademarks of Halozyme, Inc.U.S Patent No. 7,767,429

Manufactured for and Marketed by: Halozyme Therapeutics, Inc.San Diego, CA 92121

For Product Inquiry 1-855-495-3639

Rev. August 2011 LBL293-013-3531-356

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