Please see Important Safety Information on page 7 and click here for full Prescribing Information.

1

Weaning PS/IV in adults: An overview of the weaning protocol from STEPS and STEPS2

For adults with Short Bowel Syndrome (SBS) dependent on parenteral support/intravenous (PS/IV) support who are taking GATTEX®

IndicationGATTEX® (teduglutide) for injection is indicated for the treatment of adults and pediatric patients 1 year of age and older with Short Bowel Syndrome (SBS) who are dependent on parenteral support.

Important Safety InformationWarnings and PrecautionsGATTEX has been associated with acceleration of neoplastic growth, intestinal obstruction, biliary and pancreatic disease, fluid imbalance and fluid overload, and increased absorption of concomitant oral medication.

“ Attempts should be made, when appropriate, to wean patients who have sufficient absorptive capacity [off PS/IV support]”

— The 2002 official recommendations of the American Gastroenterological Association (AGA) on Short Bowel Syndrome1

2Please see Important Safety Information on page 7 and click here for full Prescribing Information.

• 54% of patients on GATTEX (21/39) achieved at least a one day per week reduction in PS/IV support vs 23% on placebo (9/39) in the 6-month study (STEPS)2,3,c

c After randomization of the intent-to-treat population (n=86), 1 patient was randomized in error, 4 patients in the GATTEX arm and 3 patients in the placebo arm discontinued treatment, leaving 78 evaluable patients.

GATTEX helped patients achieve complete independence from PS/IV support2

• No patients were completely independent of the need for PS/IV support at 6 months in STEPS3

GATTEX® significantly reduced weekly PS/IV support volume (STEPS)2

More than twice as many patients taking GATTEX had a clinical response in 6 months (STEPS)2

• 63% (27/43) for GATTEX vs 30% (13/43) for placebo compared to baseline (P=0.002)

• STEPS (Study 1 in Prescribing Information) – STEPS was a 6-month, randomized, double-blind, placebo-controlled, multicenter clinical trial of

adult SBS patients dependent on PS/IV support ≥3 times/week for ≥12 months2

– The primary efficacy endpoint was based on a clinical response defined as a ≥20% reduction in weekly PS/IV support volume from baseline (immediately before randomization) to both Weeks 20 and 242

GATTEX showed a long-term clinical response (STEPS2)2

• a Of the 39 placebo patients who entered STEPS2, 29 completed 24 months of treatment with GATTEX2

• b 30 GATTEX patients completed a total duration of 30 months (STEPS followed by STEPS2)2

• STEPS2 (Study 2 in Prescribing Information) – 97% (76/78) of patients who completed STEPS elected

to enroll in STEPS2 (n=37, GATTEX; n=39, placebo). STEPS2 was a 24-month, open-label extension study. All patients (n=88), including 12 who were never in STEPS, received GATTEX in STEPS2. Clinical response was defined as a ≥20% reduction in weekly PS/IV support volume from baseline2

Important Safety Information Warnings and PrecautionsAcceleration of neoplastic growth Colorectal polyps were identified during clinical trials. There is a risk for acceleration of neoplastic growth. In adults, within 6 months prior to starting treatment with GATTEX, colonoscopy of the entire colon with removal of polyps should be performed and follow-up colonoscopy (or alternate imaging) is recommended at the end of 1 year of GATTEX. Subsequent colonoscopies should be performed every 5 years or more often as needed.

≥1 day off perweek vs baseline

≥3 days off perweek vs baseline

Per

cent

age

of

Pat

ient

s (%

)

0

20

40

60

80

100 70%

(21/30)(18/30)

60%

Placebo/GATTEX(24-month

GATTEX exposure)a

Per

cent

age

of

Pat

ient

s (%

)0

20

40

60

80

100

55%

(16/29)a

GATTEX exposure)b

GATTEX/GATTEX(30-month

93%

(28/30)b

Patients in STEPS2 With ≥20% Reduction in PS/IV Support Volume2

n=30.

Reduction in Day(s) on PS/IV Support Following 30 Months of GATTEX (STEPS2)2

≥1 day off perweek vs baseline

≥3 days off perweek vs baseline

Per

cent

age

of

Pat

ient

s (%

)

0

20

40

60

80

100 70%

(21/30)(18/30)

60%

Placebo/GATTEX(24-month

GATTEX exposure)a

Per

cent

age

of

Pat

ient

s (%

)

0

20

40

60

80

100

55%

(16/29)a

GATTEX exposure)b

GATTEX/GATTEX(30-month

93%

(28/30)b

33% of patients (10/30) were completely independent of the need for PS/IV support while on GATTEX treatment for 30 months2

GATTEX increased the day(s) off of PS/IV support from baseline2

3Please see Important Safety Information on page 7 and click here for full Prescribing Information.

The patients’ PS/IV support was optimized and stabilized prior to randomization3

OptimizationPatients were assessed at planned intervals (Weeks 2, 4, 6, and 8, ±3 days) for hydration and nutrition.3

• 48-hour oral fluid intake and urine output were measured immediately before each visit – Measurements included 1-day on and 1-day off PS/IV support, unless the PS/IV support was infused daily

• Blood and urine samples were collected at each visit to evaluate hydration and nutrition – A targeted urine output of 1.0 to 2.0 L/d was used to determine if patients required optimization or could

enter the stabilization period

• PS/IV support was adjusted in targeted increments of ≥10% of the volume at the previous visit

StabilizationDuring the stabilization period, oral fluid intake and urine volume could not deviate ±25% from the optimized levels. PS/IV support was determined to be stable when3:

• Actual PS/IV support usage matched the prescribed PS/IV support

• 48-hour oral fluid intake and urine output volumes were within ±25% of baseline

• Urine output volume of 2-4 L/48 hours

No further PS/IV adjustments permitted during stabilization period.3

• Patients entered STEPS once they had their PS/IV fluid optimized and stabilized2

• Patients who failed to remain stable for ≥4 consecutive weeks immediately before randomization underwent repeat optimization. If patients failed to stabilize after 2 attempts, they did not proceed into the study3

Important Safety Information Warnings and Precautions (continued)Acceleration of neoplastic growth (continued)In children and adolescents, perform fecal occult blood testing prior to initiating treatment with GATTEX. Colonoscopy/sigmoidoscopy is required if there is unexplained blood in the stool. Perform subsequent fecal occult blood testing annually in children and adolescents while they are receiving GATTEX. Colonoscopy/sigmoidoscopy is recommended for all children and adolescents after 1 year of treatment, every 5 years thereafter while on continuous treatment with GATTEX, and if they have new or unexplained gastrointestinal bleeding.

In case of intestinal malignancy (GI tract, hepatobiliary, pancreatic), discontinue GATTEX. The clinical decision to continue GATTEX in patients with non-gastrointestinal malignancy should be made based on benefit-risk considerations.

Patient flow during STEPS and through STEPS2

0-8 weeks 4-8 weeks

24 monthsSTEPS2

6 monthsSTEPS

PS/IV Fluid Optimization

PS/IV Fluid Stabilization

GATTEX® 0.05 mg/kg/d n=432,d

Placebo n=432,d

GATTEX 0.05 mg/kg/d n=88 n=37, GATTEX in

STEPS; n=39, Placebo in STEPS; n=12, not enrolled in STEPS

dPatients in the intent-to-treat population2

4Please see Important Safety Information on page 7 and click here for full Prescribing Information.

Weaning protocol for STEPS and STEPS23,4

48-hour urine output

PS/IV support increased by

≥10% or to the previous level

PS/IV support maintained

PS/IV support reduced by ≥10% up to a clinically

appropriate amount (30% maximum)

<1.0 L/d or target, based on stabilized

urine output

STEPS/STEPS2 study continuation until next clinical assessment*

≥1.0 L/d but less than baselinee

If well-tolerated, PS/IV support volume

was maintained

<10% increase vs baseline

If not well-tolerated, PS/IV support was resumed

at the previously well-tolerated level

≥10% increase vs baseline

If dehydrated or inadequately nourished, PS/IV

support increased; if not, PS/IV support

was maintained

Interim safety evaluation done 1 week later: • Repeat 48-hour urine collection• Clinical evaluation – Clinical signs and symptoms of dehydration – Weight changes – Review of recorded oral fluid intake – Blood samples (hematocrit, creatinine,

blood urea nitrogen) – Urine sodium

Important Safety Information Warnings and Precautions (continued)Intestinal obstructionIntestinal obstruction has been reported in clinical trials and postmarketing. In patients who develop intestinal or stomal obstruction, GATTEX should be temporarily discontinued pending further clinical evaluation and management.

Biliary and pancreatic diseaseCholecystitis, cholangitis, cholelithiasis, and pancreatitis have been reported in clinical trials and postmarketing. Laboratory assessment (bilirubin, alkaline phosphatase, lipase, amylase) should be obtained within 6 months prior to starting GATTEX. Subsequent laboratory tests should be done every 6 months or more often as needed. If clinically meaningful changes are seen, further evaluation is recommended including imaging, and continued treatment with GATTEX should be reassessed.

e Baseline urine output is the urine volume obtained during the stabilization period before initiating treatment

5Please see Important Safety Information on page 7 and click here for full Prescribing Information.

Clinical assessments* for PS/IV volume adjustments were performedIn STEPS, initial patient evaluation occurred as early as 2 weeks after stabilization3

• PS/IV support volume adjustments (up to 30% decrease) and clinical assessments were made at Weeks 2, 4, 8, 12, 20, and 24

In the long-term (24-month) study STEPS2, PS/IV volume adjustments (up to 30% decrease) and clinical assessments were conducted less frequently4

• Week 2, Month 1, Month 2, Month 3, and every 3 months thereafter

Important Safety Information Warnings and Precautions (continued)Fluid imbalance and fluid overloadFluid overload and congestive heart failure have been observed in clinical trials. If fluid overload occurs, especially in patients with underlying cardiovascular disease, parenteral support should be adjusted and GATTEX treatment reassessed. If significant cardiac deterioration develops while on GATTEX, continued GATTEX treatment should be reassessed.

Discontinuation of treatment with GATTEX may also result in fluid and electrolyte imbalance. Fluid and electrolyte status should be monitored in patients who discontinue treatment with GATTEX.

6Please see Important Safety Information on page 7 and click here for full Prescribing Information.

Physicians’ clinical judgment and patients’ personal preference drove approaches to weaningWith the goal of reducing PS/IV support volume in mind, decisions addressed whether to3:

• Stop a day of PS/IV support

• Reduce the percentage volume for the days that PS/IV support was administered

• Change the proportion of the PS/IV constituents

• Completely wean off PS/IV support, if possible

Hypothetical weaning exampleCalculations based on the Weaning Protocol on page 4.

Baseline urine volume=1.2 L/d

Increase PS/IV support by ≥10% or to previous level

Maintain PS/IV support

Reduce PS/IV support 10% to 30% from baseline

Increase or maintain PS/IV support volume

based on nutritional and hydration status

Urine volume at current visit

If 0-.999 L/d

If ≥1.32 L/d increase vs baseline

If 1.0-1.199 L/d but less than baseline

If 1.2-1.319 L/d increase vs baseline

Important Safety Information Warnings and Precautions (continued)Increased absorption of concomitant oral medicationIn clinical trials, one patient receiving prazepam concomitantly with GATTEX experienced dramatic deterioration in mental status progressing to coma during first week of GATTEX therapy. Patients receiving concomitant oral drugs requiring titration or with a narrow therapeutic index should be monitored for adverse reactions due to potential increased absorption of the concomitant drug. The concomitant drug may require a reduction in dosage.

7

IndicationGATTEX® (teduglutide) for injection is indicated for the treatment of adults and pediatric patients 1 year of age and older with Short Bowel Syndrome (SBS) who are dependent on parenteral support.

Important Safety Information Warnings and PrecautionsAcceleration of neoplastic growthColorectal polyps were identified during clinical trials. There is a risk for acceleration of neoplastic growth. In adults, within 6 months prior to starting treatment with GATTEX, colonoscopy of the entire colon with removal of polyps should be performed and follow-up colonoscopy (or alternate imaging) is recommended at the end of 1 year of GATTEX. Subsequent colonoscopies should be performed every 5 years or more often as needed.

In children and adolescents, perform fecal occult blood testing prior to initiating treatment with GATTEX. Colonoscopy/sigmoidoscopy is required if there is unexplained blood in the stool. Perform subsequent fecal occult blood testing annually in children and adolescents while they are receiving GATTEX. Colonoscopy/sigmoidoscopy is recommended for all children and adolescents after 1 year of treatment, every 5 years thereafter while on continuous treatment with GATTEX, and if they have new or unexplained gastrointestinal bleeding.

In case of intestinal malignancy (GI tract, hepatobiliary, pancreatic), discontinue GATTEX. The clinical decision to continue GATTEX in patients with non-gastrointestinal malignancy should be made based on benefit-risk considerations.

Intestinal obstructionIntestinal obstruction has been reported in clinical trials and postmarketing. In patients who develop intestinal or stomal obstruction, GATTEX should be temporarily discontinued pending further clinical evaluation and management.

Biliary and pancreatic diseaseCholecystitis, cholangitis, cholelithiasis, and pancreatitis have been reported in clinical trials and postmarketing. Laboratory assessment (bilirubin, alkaline phosphatase, lipase, amylase) should be obtained within 6 months prior to starting GATTEX. Subsequent laboratory tests should be done every 6 months or more often as needed. If clinically meaningful changes are seen, further evaluation is recommended including imaging, and continued treatment with GATTEX should be reassessed.

Fluid imbalance and fluid overloadFluid overload and congestive heart failure have been observed in clinical trials. If fluid overload occurs, especially in patients with underlying cardiovascular disease, parenteral support should be adjusted and GATTEX treatment reassessed. If significant cardiac deterioration develops while on GATTEX, continued GATTEX treatment should be reassessed.

Discontinuation of treatment with GATTEX may also result in fluid and electrolyte imbalance. Fluid and electrolyte status should be monitored in patients who discontinue treatment with GATTEX.

Increased absorption of concomitant oral medicationIn clinical trials, one patient receiving prazepam concomitantly with GATTEX experienced dramatic deterioration in mental status progressing to coma during first week of GATTEX therapy. Patients receiving concomitant oral drugs requiring titration or with a narrow therapeutic index should be monitored for adverse reactions due to potential increased absorption of the concomitant drug. The concomitant drug may require a reduction in dosage.

Adverse ReactionsThe most common adverse reactions (≥ 10%) with GATTEX are abdominal pain, nausea, upper respiratory tract infection, abdominal distension, injection site reaction, vomiting, fluid overload, and hypersensitivity.

Use in Specific PopulationsBreastfeeding is not recommended during treatment with GATTEX.

Please click here for full Prescribing Information.

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Considerations for weaning PS/IV support from STEPS and STEPS2 studies• During the 6-month trial3

– Clinical evaluations for PS/IV volume adjustments were made at Weeks 2, 4, 8, 12, 20 and 24

– Additional safety evaluations were performed 1 week after each PS/IV support adjustment

• Patients tracked their PS/IV support volumes, oral fluid intake, urinary output, and shared with the physician3

– Patients were asked to keep intake as constant as possible while taking GATTEX®

• Patients discussed individual preferences for weaning3

– Skipping a day vs reducing the volume of PS/IV support

• Full communication occurred across the multidisciplinary team

– Prescribers of GATTEX® and of PS/IV support

– Other healthcare providers who may need to adjust oral medications

– Home infusion companies

– The patient and caregiver

Important Safety Information (continued) Adverse Reactions The most common adverse reactions (≥ 10%) with GATTEX are abdominal pain, nausea, upper respiratory tract infection, abdominal distension, injection site reaction, vomiting, fluid overload, and hypersensitivity.

Use in Specific PopulationsBreastfeeding is not recommended during treatment with GATTEX.

Please click here for full Prescribing Information.

GATTEX is a registered trademark of Shire-NPS Pharmaceuticals, Inc., a Takeda company. TAKEDA and the TAKEDA logo are trademarks or registered trademarks of Takeda Pharmaceutical Company Limited. Copyright © 2019 Takeda Pharmaceutical Company Limited. All rights reserved.S48873 06/19

For more information about getting patients started on GATTEX®, contact your GATTEX® representative or

call Takeda at 1-866-888-0660.

References: 1. American Gastroenterological Association. American Gastroenterological Association medical position statement: short bowel syndrome and intestinal transplantation. Gastroenterology. 2003;124(4):1105-1110. 2. GATTEX (teduglutide) for injection [package insert]. Lexington, MA: Shire-NPS Pharmaceuticals, Inc; 2019. 3. Jeppesen PB, Pertkiewicz M, Messing B, et al. Teduglutide reduces need for parenteral support among patients with short bowel syndrome with intestinal failure. Gastroenterology. 2012;143(6):1473-1481. 4. Schwartz LK, O’Keefe SJ, Fujioka K, et al. Long-term teduglutide for the treatment of patients with intestinal failure associated with short bowel syndrome. Clin Transl Gastroenterol. 2016;7:e142.