Leaflet REVESTIVE 5mg powder+solvent for injection

Revestive 5 mg powder and solvent for solution for injection

One vial of powder contains 5 mg of teduglutide*.

After reconstitution, each vial contains 5 mg teduglutide in 0.5 ml of solution, corresponding to aconcentration of 10 mg/ml.

*A glucagon-like peptide-2 (GLP-2) analogue produced in Escherichia coli cells by recombinant

DNA technology.

For the full list of excipients, see section 6.1.

Powder and solvent for solution for injection.

The powder is white and the solvent is clear and colourless.

Revestive is indicated for the treatment of patients 4 months corrected gestational age and above with

Short Bowel Syndrome (SBS). Patients should be stable following a period of intestinal adaptationafter surgery.

Treatment should be initiated under the supervision of a medical professional with experience in thetreatment of SBS.

Treatment should not be initiated until it is reasonable to assume that a patient is stable following aperiod of intestinal adaptation. Optimisation and stabilisation of intravenous fluid and nutritionsupport should be performed before initiation of treatment.

Clinical assessment by the physician should consider individual treatment objectives and patientpreferences. Treatment should be stopped if no overall improvement of the patient condition isachieved. Efficacy and safety in all patients should be closely monitored on an ongoing basisaccording to clinical treatment guidelines.

The recommended dose of Revestive is 0.05 mg/kg body weight once daily. The injection volume perbody weight is provided below in Table 1. Due to the heterogeneity of the SBS population, a carefullymonitored down-titration of the daily dose may be considered for some patients to optimise tolerabilityof the treatment. If a dose is missed, that dose should be injected as soon as possible on that day.

Treatment effect should be evaluated after 6 months. Limited data from clinical studies have shownthat some patients may take longer to respond to treatment (i.e., those who still have presence ofcolon-in-continuity or distal/terminal ileum); if no overall improvement is achieved after 12 months,the need for continued treatment should be reconsidered.

Continued treatment is recommended for patients who have weaned off parenteral nutrition.

Table 1: Injection volume per body weight for adults5 mg strength

Body weight Volume to be injected38-41 kg 0.20 ml42-45 kg 0.22 ml46-49 kg 0.24 ml50-53 kg 0.26 ml54-57 kg 0.28 ml58-61 kg 0.30 ml62-65 kg 0.32 ml66-69 kg 0.34 ml70-73 kg 0.36 ml74-77 kg 0.38 ml78-81 kg 0.40 ml82-85 kg 0.42 ml86-89 kg 0.44 ml90-93 kg 0.46 ml

Paediatric population (≥ 1 year)

Treatment should be initiated under the supervision of a medical professional with experience in thetreatment of paediatric SBS.

The recommended dose of Revestive in children and adolescents (aged 1 to 17 years) is the same asfor adults (0.05 mg/kg body weight once daily). The injection volume per body weight when using the5 mg strength vial is provided in Table 2 below. A 1.25 mg strength vial is also available for paediatricuse (patients with a body weight < 20 kg).

If a dose is missed, that dose should be injected as soon as possible on that day. A treatment period of6 months is recommended after which treatment effect should be evaluated. In children below the ageof two years, treatment should be evaluated after 12 weeks. There are no data available in paediatricpatients after 6 months (see section 5.1).

Table 2: Injection volume per body weight for paediatric population (≥ 1 year)5 mg strength

Body weight Volume to be injected10-11 kg 0.05 ml12-13 kg 0.06 ml14-17 kg 0.08 ml18-21 kg 0.10 ml5 mg strength

Body weight Volume to be injected22-25 kg 0.12 ml26-29 kg 0.14 ml30-33 kg 0.16 ml34-37 kg 0.18 ml38-41 kg 0.20 ml42-45 kg 0.22 ml46-49 kg 0.24 ml≥ 50 kg See Table 1 under “Adults” section.

Paediatric population (aged 4 months to less than 12 months)

For paediatric patients aged 4 months to less than 12 months, Revestive 1.25 mg vial should be used.

Refer to the Summary of Product Characteristics of Revestive 1.25 mg powder and solvent forsolution for injection for dosing information.

No dose adjustment is necessary in patients above the age of 65 years.

No dose adjustment is necessary for adult or paediatric patients with mild renal impairment. In adult orpaediatric patients with moderate and severe renal impairment (creatinine clearance less than50 ml/min), and end-stage renal disease, the daily dose should be reduced by 50% (see section 5.2).

No dose adjustment is necessary for patients with mild and moderate hepatic impairment based on astudy conducted in Child-Pugh grade B subjects. Revestive has not been studied in patients withsevere hepatic impairment (see sections 4.4 and 5.2).

Paediatric population (< 4 months)

There are currently no available data in children below 4 months corrected gestational age.

The reconstituted solution should be administered by subcutaneous injection once daily, alternatingsites between 1 of the 4 quadrants of the abdomen. In case the injection into the abdomen is hamperedby pain, scarring or hardening of the tissue, the thigh can also be used. Revestive should not beadministered intravenously or intramuscularly.

For instructions on reconstitution of the medicinal product before administration, see section 6.6.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1, or traceresidues of tetracycline.

Active or suspected malignancy.

Patients with a history of malignancies in the gastrointestinal tract, including the hepatobiliary systemand pancreas within the last five years.

It is strongly recommended that every time Revestive is administered to a patient, the name and lotnumber of the product are recorded in order to maintain a link between the patient and the lot of theproduct.

Colo-rectal polyps

A colonoscopy with removal of polyps should be performed at the time of starting treatment with

Revestive. Once yearly follow-up colonoscopies (or alternate imaging) are recommended during thefirst 2 years of Revestive treatment. Subsequent colonoscopies are recommended at a minimum offive year intervals. An individual assessment whether increased frequency of surveillance is necessaryshould be performed based on the patient characteristics (e.g., age, underlying disease). See alsosection 5.1. If a polyp is found, adherence to current polyp follow-up guidelines is recommended. Incase of malignancy, Revestive therapy must be discontinued (see section 4.3).

Gastrointestinal neoplasia including hepatobiliary tract

In the rat carcinogenicity study, benign tumours were found in the small bowel and the extrahepaticbile ducts. Development of small intestinal polyps has also been observed in human SBS patientswithin several months after start of teduglutide treatment. Because of this, upper gastro-intestinalendoscopy or other imaging is recommended before and during the treatment with teduglutide. If aneoplasia is detected, it should be removed. In case of malignancy, teduglutide treatment must bediscontinued (see sections 4.3 and 5.3).

Gallbladder and bile ducts

Cases of cholecystitis, cholangitis, and cholelithiasis have been reported in clinical studies. In case ofgallbladder or bile duct-related symptoms, the need for continued Revestive treatment should bereassessed.

Pancreatic diseases

Pancreatic adverse events such as chronic and acute pancreatitis, pancreatic duct stenosis, pancreasinfection and increased blood amylase and lipase have been reported in clinical studies. In case ofpancreatic adverse events, the need for continued Revestive treatment should be reassessed.

Monitoring of small bowel, gallbladder and bile ducts, and pancreas

SBS patients are to be kept under close surveillance according to clinical treatment guidelines. Thisusually includes the monitoring of small bowel function, gallbladder and bile ducts, and pancreas forsigns and symptoms, and, if indicated, additional laboratory investigations and appropriate imagingtechniques.

Intestinal obstruction

Cases of intestinal obstruction have been reported in clinical studies. In case of recurrent intestinalobstructions, the need for continued Revestive treatment should be reassessed.

Fluid overload and Electrolyte Balance

To avoid fluid overload or dehydration, careful adjustment of parenteral support is required in patientstaking Revestive. Electrolyte balance and fluid status should be carefully monitored throughouttreatment, especially during initial therapeutic response and discontinuation of Revestive treatment

Fluid overload

Fluid overload has been observed in clinical trials. Fluid overload adverse events occurred mostfrequently during the first 4 weeks of therapy and decreased over time.

Due to increased fluid absorption, patients with cardiovascular disease, such as cardiac insufficiencyand hypertension, should be monitored with regard to fluid overload, especially during initiation oftherapy. Patients should be advised to contact their physician in case of sudden weight gain, faceswelling, swollen ankles and/or dyspnoea. In general, fluid overload can be prevented by appropriateand timely assessment of parenteral nutrition needs. This assessment should be conducted morefrequently within the first months of treatment.

Congestive heart failure has been observed in clinical trials. In case of a significant deterioration of thecardiovascular disease, the need for continued treatment with Revestive should be reassessed.

Patients with SBS are susceptible to dehydration that may lead to acute renal failure.

In patients receiving Revestive, parenteral support should be reduced carefully and should not bediscontinued abruptly. The patient’s fluid status should be evaluated following parenteral supportreduction and corresponding adjustment performed, as needed.

Patients receiving oral concomitant medicinal products requiring titration or with a narrow therapeuticindex should be monitored closely due to potential increased absorption (see section 4.5).

Special clinical conditions

Revestive has not been studied in patients with severe, clinically unstable concomitant diseases, (e.g.,cardiovascular, respiratory, renal, infectious, endocrine, hepatic, or CNS), or in patients withmalignancies within the last five years (see section 4.3). Caution should be exercised when prescribing

Revestive.

Revestive has not been studied in patients with severe hepatic impairment. The data from use insubjects with moderate hepatic impairment do not suggest a need for restricted use.

Due to the risk of dehydration, discontinuation of treatment with Revestive should be managedcarefully.

See also general precautions for adults under this section.

Colo-rectal polyps/Neoplasia

Prior to initiating treatment with Revestive, faecal occult blood testing should be done for all childrenand adolescents. Colonoscopy/sigmoidoscopy is required if there is evidence of unexplained blood inthe stool. Subsequent faecal occult blood testing should be done annually in children and adolescentswhile they are receiving Revestive.

Colonoscopy/sigmoidoscopy is recommended for all children and adolescents after one year oftreatment, every 5 years thereafter while on continuous treatment with Revestive, and if they have newor unexplained gastrointestinal bleeding.

Revestive contains less than 1 mmol sodium (23 mg) per dose. This means that it is essentially‘sodium-free’.

Caution is needed when administering Revestive to persons with a known hypersensitivity totetracycline (see section 4.3).

No clinical pharmacokinetic drug-drug interaction studies have been performed. An in vitro studyindicates that teduglutide does not inhibit cytochrome P450 drug metabolising enzymes. Based uponthe pharmacodynamic effect of teduglutide, there is a potential for increased absorption ofconcomitant medicinal products (see section 4.4).

There are no data from the use of Revestive in pregnant women. Animal studies do not indicate director indirect harmful effects with respect to reproductive toxicity (see section 5.3). As a precautionarymeasure, it is preferable to avoid the use of Revestive during pregnancy.

It is unknown whether teduglutide is excreted in human milk. In rats, mean teduglutide concentrationin milk was less than 3% of the maternal plasma concentration following a single subcutaneousinjection of 25 mg/kg. A risk to the breast-fed newborn/infant cannot be excluded. As a precautionarymeasure it is preferable to avoid the use of Revestive during breast-feeding.

There are no data on the effects of teduglutide on human fertility. Animal data do not indicate anyimpairment of fertility.

Revestive has minor influence on the ability to drive and use machines. However, cases of syncopehave been reported in clinical studies (see section 4.8). Such events might impact the ability to driveand use machines.

Adverse reactions were retrieved from 2 placebo-controlled clinical studies with teduglutide in109 patients with SBS treated with doses of 0.05 mg/kg/day and 0.10 mg/kg/day for up to 24 weeks.

Approximately 52% of the patients treated with teduglutide experienced adverse reactions (versus36% of the patients given placebo). The most commonly reported adverse reactions were abdominalpain and distension (45%), respiratory tract infections (28%) (including nasopharyngitis, influenza,upper respiratory tract infection, and lower respiratory tract infection), nausea (26%), injection sitereactions (26%), headache (16%), and vomiting (14%). Approximately 38% of the treated patientswith a stoma experienced gastrointestinal stoma complications. The majority of these reactions weremild or moderate.

No new safety signals have been identified in patients exposed to 0.05 mg/kg/day of teduglutide for upto 30 months in a long-term open-label extension study.

Adverse reactions are listed below by MedDRA system organ class and by frequency. Frequencies aredefined as very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1 000 to < 1/100);rare (≥ 1/10 000 to < 1/1 000); very rare (< 1/10 000); not known (cannot be estimated from availabledata). Within each frequency grouping, adverse reactions are presented in order of decreasingseriousness.

All adverse reactions identified in post-marketing experience are italicised.

Frequency Very common Common Uncommon Not known

System organclass

Infections and Respiratory tract Influenza-like illnessinfestations infection*

Immune system Hypersensitivitydisorders

Metabolism and Decreased appetitenutrition disorders Fluid overload

Psychiatric Anxietydisorders Insomnia

Nervous system Headachedisorders

Cardiac disorders Congestive heartfailure

Vascular disorders Syncope

Respiratory, Coughthoracic and Dyspnoeamediastinaldisorders

Gastrointestinal Abdominal Colorectal polyp Small intestinal Gastric polypdisorders distension Colonic stenosis polyp‡

Abdominal pain Flatulence

Nausea Intestinal

Vomiting obstruction

Pancreatic ductstenosis

Pancreatitis†

Small intestinalstenosis

Hepatobiliary Cholecystitisdisorders Cholecystitis acute

General disorders Injection site Oedema peripheral Fluid retentionand administration reaction§site conditions

Injury, poisoning Gastrointestinaland procedural stoma complicationcomplications

*Includes the following preferred terms: Nasopharyngitis, Influenza, Upper respiratory tract infection, and Lowerrespiratory tract infection.†Includes the following preferred terms: Pancreatitis, Pancreatitis acute, and Pancreatitis chronic.‡Locations include duodenum, jejunum, and ileum.§Includes the following preferred terms: Injection site haematoma, Injection site erythema, Injection site pain,

Injection site swelling and Injection site haemorrhage.

Consistent with the potentially immunogenic properties of medicinal products containing peptides,administration of Revestive may potentially trigger the development of antibodies. Based onintegrated data from two trials in adults with SBS (a 6-month randomised placebo-controlled trial,followed by a 24-month open-label trial), the development of anti-teduglutide antibodies in subjectswho received subcutaneous administration of 0.05 mg/kg teduglutide once daily was 3% (2/60) at

Month 3, 17% (13/77) at Month 6, 24% (16/67) at Month 12, 33% (11/33) at Month 24, and48% (14/29) at Month 30. In phase 3 studies with SBS patients who received teduglutide for ≥ 2 years,28% of patients developed antibodies against E. coli protein (residual host cell protein from themanufacture). The antibody formation has not been associated with clinically relevant safety findings,reduced efficacy or changed pharmacokinetics of Revestive.

Injection site reactions occurred in 26% of SBS patients treated with teduglutide, compared to 5% ofpatients in the placebo arm. The reactions included injection site haematoma, injection site erythema,injection site pain, injection site swelling and injection site haemorrhage (see also section 5.3). Themajority of reactions were moderate in severity and no occurrences led to drug discontinuation.

C-reactive protein

Modest increases of C-reactive protein of approximately 25 mg/l have been observed within the firstseven days of teduglutide treatment, which decreased continuously under ongoing daily injections.

After 24 weeks of teduglutide treatment, patients showed small overall increase in C-reactive proteinof approximately 1.5 mg/l on average. These changes were neither associated with any changes inother laboratory parameters nor with any reported clinical symptoms. There were no clinically relevantmean increases of C-reactive protein from baseline following long-term treatment with teduglutide forup to 30 months.

In two completed clinical trials, there were 87 paediatric subjects (aged 1 to 17 years) enrolled andexposed to teduglutide for a duration of up to 6 months. No subject discontinued the studies due to anadverse event. Overall, the safety profile of teduglutide (including type and frequency of adversereactions, and immunogenicity) in children and adolescents (ages 1-17 years) was similar to that inadults.

In three completed clinical studies in paediatric subjects (aged 4 to < 12 months corrected gestationalage), the safety profile reported in these studies was consistent with the safety profile seen in theprevious paediatric studies and no new safety issues were identified.

Limited long-term safety data is available for the paediatric population. No data are available forchildren under 4 months of age.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

The maximum dose of teduglutide studied during clinical development was 86 mg/day for 8 days. Nounexpected systemic adverse reactions were seen (see section 4.8).

In the event of an overdose, the patient should be carefully monitored by the medical professional.

Pharmacotherapeutic group: Other alimentary tract and metabolism products, various alimentary tractand metabolism products, ATC code: A16AX08.

The naturally occurring human glucagon-like peptide-2 (GLP-2) is a peptide secreted by L cells of theintestine which is known to increase intestinal and portal blood flow, inhibit gastric acid secretion, anddecrease intestinal motility. Teduglutide is an analogue of GLP-2. In several nonclinical studies,teduglutide has been shown to preserve mucosal integrity by promoting repair and normal growth ofthe intestine through an increase of villus height and crypt depth.

Similar to GLP-2, teduglutide is 33 amino acids in length with an amino acid substitution of alanine byglycine at the second position of the N-terminus. The single amino acid substitution relative tonaturally occurring GLP-2 results in resistance to in vivo degradation by the enzyme dipeptidylpeptidase-IV (DPP-IV), resulting in an extended half-life. Teduglutide increases villus height andcrypt depth of the intestinal epithelium.

Based on the findings derived from pre-clinical studies (see sections 4.4 and 5.3) and the proposedmechanism of action with the trophic effects on intestinal mucosa, there appears to be a risk for thepromotion of small intestinal and/or colonic neoplasia. The clinical studies conducted could neitherexclude nor confirm such an increased risk. Several cases of benign colorectal polyps occurred duringthe course of the trials, however, the frequency was not increased compared to placebo-treatedpatients. In addition to the need for a colonoscopy with removal of polyps by the time of the initiationof the treatment (see section 4.4.), every patient should be assessed for the need of an enhancedsurveillance schedule based on the patient characteristics (e.g., age and underlying disease, previousoccurrence of polyps etc.).

Paediatric population 4 months to less than 12 months of age

The efficacy data presented are derived from 1 controlled and 1 un-controlled core studies for a 28-week duration, and 2 extension studies for up to 9 cycles (24 weeks per cycle) of teduglutidetreatment. These studies included infants 4 months to < 12 months corrected gestational age:

10 infants (2 infants aged 4 to < 6 months, 8 aged 6 to < 12 months) in the controlled study (5 inteduglutide treatment arm and 5 in standard of care arm), 2 infants in the un-controlled study (bothtreated). From the core controlled study, 6 of the 10 infants completed the study, and continued in theextension study (5 treated and 1 non-treated). From the core uncontrolled study, 2 infants completedthe study and continued in the second extension study (both treated). The infants in these studies weretreated with teduglutide 0.05 mg/kg/day. Despite the limited sample size in the core and extensionstudies, clinically meaningful numerical reductions in the requirement for parenteral support wereobserved.

The controlled core study

Complete weaning

No subject achieved enteral autonomy, i.e., complete weaning off PS during either core or extensionstudies.

Reduction in parenteral nutrition volume

In the controlled core study, based on subject diary data, 3 (60.0%) subjects enrolled in the TED armand 1 (20.0%) subject in the SOC arm experienced at least 20% reduction in PS volume at end oftreatment (EOT) from baseline (2 subjects in the SOC arm had missing data). In the TED arm, themean change in PS volume at EOT from baseline was -21.5±28.91 ml/kg/day (-24.8%). In the SOCarm, the mean change in PS volume at EOT from baseline was -9.5±7.50 ml/kg/day (-16.8%).

Reduction in parenteral nutrition calories

In the controlled core study, based on subject diary data, the mean percentage change in PS caloricintake at EOT from baseline was -27.0±29.47% for subjects in the TED arm and -13.7±21.87% in the

SOC arm.

Reduction in infusion time

In the controlled core study, in the TED arm, the change in diary PS infusion time at EOT frombaseline was -3.1±3.31 hours/day (-28.9%) and -1.9±2.01 days/week (-28.5%). In the SOC arm, thechange in diary PS infusion time at EOT from baseline was -0.3±0.63 hours/day (-1.9%) and nochange was observed on the days per week of PS infusion time.

The un-controlled core study

Complete weaning

No infant subjects reached complete weaning.

Reduction in parenteral nutrition volume

Among the 2 infants included in and completed the study, a ≥ 20% reduction in PS volume wasrecorded in 1 infant during the teduglutide treatment. The mean change in PS volume at EOT frombaseline was -26.2±13.61 ml/kg/day (-26.7%).

Reduction in parenteral nutrition calories

In infants, the mean change in PS caloric intake at EOT from baselinewas -13.8±3.17 kcal/kg/day (-25.7%).

Reduction in infusion time

There was no change in daily PS usage hours in the 2 infants during the study.

Paediatric population between 1 and 17 years of age

The efficacy data presented are derived from 2 controlled studies in paediatric patients up to 24 weeksduration. These studies included 101 patients in the following age groups: 5 patients 1-2 years,56 patients 2 to < 6 years, 32 patients 6 to < 12 years, 7 patients 12 to < 17 years, and 1 patient 17 to< 18 years. Despite the limited sample size, which did not allow meaningful statistical comparisons,clinically meaningful, numerical reductions in the requirement for parenteral support were observedacross all age groups.

Teduglutide was studied in a 12-week, open-label, clinical study in 42 paediatric subjects aged 1 yearthrough 14 years with SBS who were dependent on parenteral nutrition. The objectives of the studywere to evaluate safety, tolerability, and efficacy of teduglutide compared to standard of care. Three(3) doses of teduglutide, 0.0125 mg/kg/day (n=8), 0.025 mg/kg/day (n=14), and 0.05 mg/kg/day(n=15), were investigated for 12 weeks. Five (5) subjects were enrolled in a standard of care cohort.

Complete weaning

Three subjects (3/15, 20%) on the recommended teduglutide dose were weaned off parenteral nutritionby Week 12. After a 4-week washout period, two of these patients had reinitiated parenteral nutritionsupport.

Reduction in parenteral nutrition volume

The mean change in parenteral nutrition volume from baseline at Week 12 in the ITT population,based on physician-prescribed data, was -2.57 (±3.56) l/week, correlating to a -39.11% (±40.79) meandecrease, compared to 0.43 (±0.75) l/week, correlating to a 7.38% (±12.76) increase in the standard ofcare cohort. At Week 16 (4 weeks following the end of treatment) parenteral nutrition volumereductions were still evident but less than observed at Week 12 when subjects were still on teduglutide(mean decrease of -31.80% (±39.26) compared to a 3.92% (±16.62) increase in the standard of caregroup).

Reduction in parenteral nutrition calories

At Week 12, there was a -35.11% (±53.04) mean change from baseline in parenteral nutrition calorieconsumption in the ITT population based on physician-prescribed data. The corresponding change inthe standard of care cohort was 4.31% (±5.36). At Week 16, the parenteral nutrition caloriesconsumption continued to decrease with percentage mean changes from baseline of -39.15% (±39.08)compared to -0.87% (±9.25) for the standard of care cohort.

Increases in enteral nutrition volume and enteral calories

Based on prescribed data, the mean percentage change from baseline at Week 12 in enteral volume, inthe ITT population, was 25.82% (±41.59) compared to 53.65% (±57.01) in the standard of care cohort.

The corresponding increase in enteral calories was 58.80% (±64.20), compared to 57.02% (±55.25) inthe standard of care cohort.

Reduction in infusion time

The mean decrease from baseline at Week 12 in the number of days/week on parenteral nutrition, inthe ITT population based on physician-prescribed data, was -1.36 (±2.37) days/week corresponding toa percentage decrease of -24.49% (±42.46). There was no change from baseline in the standard of carecohort. Four subjects (26.7%) on the recommended teduglutide dose achieved at least a three-dayreduction in parenteral nutrition needs.

At Week 12, based on subject diary data, subjects showed mean percentage reductions of35.55% (±35.23) hours per day compared to baseline, which corresponded to reductions in thehours/day of parenteral nutrition usage of -4.18 (±4.08), while subjects in the standard of care cohortshowed minimal change in this parameter at the same time point.

An additional 24-week, randomised, double-blind, multicentre study was conducted in 59 paediatricsubjects aged 1 year through 17 years who were dependent on parenteral support. The objective was toevaluate safety/tolerability, pharmacokinetics and efficacy of teduglutide. Two doses of teduglutidewere studied: 0.025 mg/kg/day (n=24) and 0.05 mg/kg/day (n=26); 9 subjects were enrolled in astandard of care (SOC) arm. Randomisation was stratified by age across dose groups. Results belowcorrespond to the ITT population at the recommended dose of 0.05 mg/kg/day.

Complete weaning

Three (3) paediatric subjects in the 0.05 mg/kg group achieved the additional endpoint of enteralautonomy by week 24.

Reduction in parenteral nutrition volume

Based on subject diary data, 18 (69.2%) subjects in the 0.05 mg/kg/day group achieved the primaryendpoint of ≥ 20% reduction in PN/IV volume at end of treatment, compared to baseline; in the SOCarm, 1 (11.1%) subject achieved this endpoint.

The mean change in parenteral nutrition volume from baseline at Week 24, based on subject diarydata, was -23.30 (±17.50) ml/kg/day, corresponding to -41.57% (±28.90); the mean change in the SOCarm was -6.03 (±4.5) ml/kg/day (corresponding to a -10.21% [±13.59]).

Reduction in infusion time

At week 24, there was a decrease in the infusion time of -3.03 (±3.84) hours/day in the 0.05 mg/kg/dayarm, corresponding to a percentage change of -26.09% (±36.14). The change from baseline in the SOCcohort was -0.21 (±0.69) hours/day (-1.75% [±5.89]).

The mean decrease from baseline at Week 24 in the number of days/week on parenteral nutrition,based on subject diary data, was -1.34 (±2.24) days/week corresponding to a percentage decreaseof -21.33% (±34.09). There was no reduction in PN/IV infusion days per week in the SOC arm.

Teduglutide was studied in 17 patients with SBS allocated to five treatment groups using dosesof 0.03, 0.10 or 0.15 mg/kg teduglutide once daily, or 0.05 or 0.075 mg/kg bid in a 21-day open-label,multicenter, dose-ranging study. Treatment resulted in enhanced gastrointestinal fluid absorption ofapproximately 750-1 000 ml/day with improvements in the absorption of macronutrients andelectrolytes, decreased stomal or faecal fluid and macronutrients excretion, and enhanced keystructural and functional adaptations in the intestinal mucosa. Structural adaptations were transient innature and returned to baseline levels within three weeks of discontinuing the treatment.

In the pivotal phase 3 double-blind, placebo-controlled study in patients with SBS, who requiredparenteral nutrition, 43 patients were randomised to a 0.05 mg/kg/day dose of teduglutide and43 patients to placebo for up to 24 weeks.

The proportion of teduglutide-treated subjects achieving a 20% to 100% reduction of parenteralnutrition at Week 20 and 24 was statistically significantly different from placebo (27 out of43 subjects, 62.8% versus 13 out of 43 patients, 30.2%, p=0.002). Treatment with teduglutide resultedin a 4.4 l/week reduction in parenteral nutrition requirements (from a pre-treatment baseline of12.9 litres) versus 2.3 l/week (from a pre-treatment baseline of 13.2 litres) for placebo at 24 weeks.

Twenty-one (21) patients treated with teduglutide (48.8%) versus 9 on placebo (20.9%) achieved atleast a one day reduction in parenteral nutrition administration (p=0.008).

Ninety-seven percent (97%) of patients (37 out of 39 patients treated with teduglutide) that completedthe placebo-controlled study entered a long-term extension study where all patients received0.05 mg/kg of teduglutide daily for up to an additional 2 years. In total 88 patients participated in thisextension study, thereof 39 treated with placebo and 12 enrolled, but not randomised, in the previousstudy; 65 of 88 patients completed the extension study. There continued to be evidence of increasedresponse to treatment for up 2.5 years in all groups exposed to teduglutide in terms of parenteralnutrition volume reduction, gaining additional days off parenteral nutrition per week, and achievingweaning of parenteral support.

Thirty (30) of the 43 teduglutide-treated patients from the pivotal study who entered the extensionstudy completed a total of 30 months of treatment. Of these, 28 patients (93%) achieved a 20% orgreater reduction of parenteral support. Of responders in the pivotal study who completed theextension study, 21 out of 22 (96%) sustained their response to teduglutide after an additional 2 yearsof continuous treatment.

The mean reduction in parenteral nutrition (n=30) was 7.55 l/week (a 65.6% reduction from baseline).

Ten (10) subjects were weaned off their parenteral support while on teduglutide treatment for30 months. Subjects were maintained on teduglutide even if no longer requiring parenteral nutrition.

These 10 subjects had required parenteral nutrition support for 1.2 to 15.5 years, and prior to treatmentwith teduglutide had required between 3.5 l/week and 13.4 l/week of parenteral nutrition support. Atthe end of study, 21 (70%), 18 (60%) and 18 (60%) of the 30 completers achieved a reduction of 1, 2,or 3 days per week in parenteral support, respectively.

Of the 39 placebo subjects, 29 completed 24 months of treatment with teduglutide. The meanreduction in parenteral nutrition was 3.11 l/week (an additional 28.3% reduction). Sixteen (16, 55.2%)of the 29 completers achieved a 20% or greater reduction of parenteral nutrition. At the end of study,14 (48.3%), 7 (24.1%) and 5 (17.2%) patients achieved a reduction of 1, 2, or 3 days per week inparenteral nutrition, respectively. Two (2) subjects were weaned off their parenteral support while onteduglutide.

Of the 12 subjects not randomised in the pivotal study, 6 completed 24 months of treatment withteduglutide. The mean reduction in parenteral nutrition was 4.0 l/week (39.4% reduction from baseline- the start of the extension study) and 4 of the 6 completers (66.7%) achieved a 20% or greaterreduction in parenteral support. At the end of study, 3 (50%), 2 (33%) and 2 (33%) achieved areduction of 1, 2, or 3 days per week in parenteral nutrition, respectively. One subject was weaned offtheir parenteral support while on teduglutide.

In another phase 3 double-blind, placebo-controlled study in patients with SBS, who requiredparenteral nutrition, patients received a 0.05 mg/kg/day dose (n=35), a 0.10 mg/kg/day dose (n=32) ofteduglutide or placebo (n=16) for up to 24 weeks.

The primary efficacy analysis of the study results showed no statistically significant differencebetween the group on teduglutide 0.10 mg/kg/day and the placebo group, while the proportion ofsubjects receiving the recommended teduglutide dose of 0.05 mg/kg/day achieving at least a 20%reduction of parenteral nutrition at Week 20 and 24 was statistically significantly different versusplacebo (46% versus 6.3%, p< 0.01). Treatment with teduglutide resulted in a 2.5 l/week reduction inparenteral nutrition requirements (from a pre-treatment baseline of 9.6 litres) versus 0.9 l/week (from apre-treatment baseline of 10.7 litres) for placebo at 24 weeks.

Teduglutide treatment induced expansion of the absorptive epithelium by significantly increasingvillus height in the small intestine.

Sixty-five (65) patients entered a follow-up SBS study for up to an additional 28 weeks of treatment.

Patients on teduglutide maintained their previous dose assignment throughout the extension phase,while placebo patients were randomised to active treatment, either 0.05 or 0.10 mg/kg/day.

Of the patients who achieved at least a 20% reduction of parenteral nutrition at Weeks 20 and 24 in theinitial study, 75% sustained this response on teduglutide after up to 1 year of continuous treatment.

The mean reduction of weekly parenteral nutrition volume was 4.9 l/week (52% reduction frombaseline) after one year of continuous teduglutide treatment.

Two (2) patients on the recommended teduglutide dose were weaned off parenteral nutrition by

Week 24. One additional patient in the follow-up study was weaned off parenteral nutrition.

The European Medicines Agency has deferred the obligation to submit the results of studies with

Revestive in one or more subsets of the paediatric population in the treatment of SBS (see section 4.2for information on paediatric use).

Teduglutide was rapidly absorbed from subcutaneous injection sites with maximum plasma levelsoccurring approximately 3-5 hours after dose administration at all dose levels. The absolutebioavailability of subcutaneous teduglutide is high (88%). No accumulation of teduglutide wasobserved following repeated subcutaneous administration.

Following subcutaneous administration, teduglutide has an apparent volume of distribution of 26 litresin patients with SBS.

The metabolism of teduglutide is not fully known. Since teduglutide is a peptide it is likely that itfollows the principal mechanism for peptide metabolism.

Teduglutide has a terminal elimination half-life of approximately 2 hours. Following intravenousadministration teduglutide plasma clearance was approximately 127 ml/hr/kg which is equivalent tothe glomerular filtration rate (GFR). Renal elimination was confirmed in a study investigatingpharmacokinetics in subjects with renal impairment. No accumulation of teduglutide was observedfollowing repeated subcutaneous administrations.

Dose linearity

The rate and extent of absorption of teduglutide is dose-proportional at single and repeatedsubcutaneous doses up to 20 mg.

Pharmacokinetics in subpopulations

Following subcutaneous administration, similar Cmax of teduglutide driving the efficacy responses,across age groups (4 months corrected by gestational age to 17 years) was demonstrated by populationpharmacokinetics modelling based on PK samples collected in the population following SC0.05 mg/kg daily dose. However, lower exposure (AUC) and shorter half-life were seen in paediatricpatients 4 months to 17 years of age, as compared with adults. The pharmacokinetic profile ofteduglutide in this paediatric population, as evaluated by clearance and volume of distribution, wasdifferent from that observed in adults after correcting for body weights. Specifically, clearancedecreases with increasing age from 4 months to adults. No data are available for paediatric patientswith moderate to severe renal impairment and end-stage renal disease (ESRD).

No clinically relevant gender differences were observed in clinical studies.

In a phase 1 study no difference in pharmacokinetics of teduglutide could be detected between healthysubjects younger than 65 years versus older than 65 years. Experience in subjects 75 years and aboveis limited.

In a phase 1 study the effect of hepatic impairment on the pharmacokinetics of teduglutide followingsubcutaneous administration of 20 mg teduglutide was investigated. The maximum exposure and theoverall extent of exposure to teduglutide following single 20 mg subcutaneous doses were lower(10-15%) in subjects with moderate hepatic impairment relative to those in healthy matched controls.

In a phase 1 study, the effect of renal impairment on the pharmacokinetics of teduglutide followingsubcutaneous administration of 10 mg teduglutide was investigated. With progressive renalimpairment up to and including end-stage renal disease the primary pharmacokinetic parameters ofteduglutide increased up to a factor of 2.6 (AUCinf) and 2.1 (Cmax) compared to healthy subjects.

Hyperplasia in the gall bladder, hepatic biliary ducts, and pancreatic ducts were observed insubchronic and chronic toxicology studies. These observations were potentially associated with theexpected intended pharmacology of teduglutide and were to a varying degree reversible within an8-13 week recovery period following chronic administration.

In pre-clinical studies, severe granulomatous inflammations were found associated with the injectionsites.

Carcinogenicity/mutagenicity

Teduglutide was negative when tested in the standard battery of tests for genotoxicity.

In a rat carcinogenicity study, treatment related benign neoplasms included tumours of the bile ductepithelium in males exposed to teduglutide plasma levels approximately 32- and 155-fold higher thanobtained in patients administered the recommended daily dose (incidence of 1 out of 44 and 4 outof 48, respectively). Adenomas of the jejunal mucosa were observed in 1 out of 50 males and 5 out of50 males exposed to teduglutide plasma levels approximately 10- and 155-fold higher than obtained inpatients administered the recommended daily dose. In addition, a jejunal adenocarcinoma wasobserved in a male rat administered the lowest dose tested (animal:human plasma exposure margin ofapproximately 10-fold).

Reproductive and developmental toxicity studies evaluating teduglutide have been carried out in ratsand rabbits at doses of 0, 2, 10 and 50 mg/kg/day subcutaneously. Teduglutide was not associated witheffects on reproductive performance, in utero or developmental parameters measured in studies toinvestigate fertility, embryo-foetal development and pre- and post-natal development.

Pharmacokinetic data demonstrated that the teduglutide exposure of foetal rabbits and suckling ratpups was very low.

L-histidine

Mannitol

Sodium phosphate monohydrate

Disodium phosphate heptahydrate

Sodium hydroxide (pH adjustment)

Hydrochloric acid (pH adjustment)

Water for injections

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinalproducts.

Unopened vials4 years.

Reconstituted product

Chemical and physical stability has been demonstrated for 3 hours at 25 °C.

From a microbiological point of view, unless the method of reconstitution precludes the risk ofmicrobial contamination, the solution should be used immediately.

If not used immediately, in-use storage times and conditions are the responsibility of the user andwould normally not be longer than 24 hours at 2 to 8 °C, unless reconstitution has taken place incontrolled and validated aseptic conditions.

Store below 25 °C.

Do not freeze.

For storage conditions after reconstitution of the medicinal product, see section 6.3.

Powder3 ml vial (glass) with rubber stopper (bromobutyl) containing 5 mg teduglutide.

Pre-filled syringe (glass) with plungers (bromobutyl) containing 0.5 ml of solvent.

Pack sizes of 1 vial of powder with 1 pre-filled syringe or 28 vials of powder with 28 pre-filledsyringes.

Not all pack sizes may be marketed.

Determination of the number of vials needed for administration of one dose must be based on theindividual patient’s weight and the recommended dose of 0.05 mg/kg/day. The physician should ateach visit weigh the patient, determine the daily dose to be administered until next visit and inform thepatient accordingly.

Tables with the injection volumes based on the recommended dose per body weight for both adultsand paediatric patients are provided in section 4.2.

The pre-filled syringe must be assembled with a reconstitution needle.

The powder in the vial must then be dissolved by adding all the solvent from the pre-filled syringe.

The vial should not be shaken, but can be rolled between the palms and gently turned upside-downonce. Once a clear colourless solution is formed in the vial, the solution should be sucked up into a1 ml injection syringe (or 0.5 ml or smaller injection syringe for paediatric use) with scale intervals of0.02 ml or smaller (not included in the pack).

If two vials are needed, the procedure for the second vial must be repeated and the additional solutionsucked up into the injection syringe containing the solution from the first vial. Any volume exceedingthe prescribed dose in ml must be expelled and discarded.

The solution must be injected subcutaneously into a cleaned area on the abdomen, or if this is notpossible, on the thigh (see section 4.2 Method of administration) using a thin needle for subcutaneousinjection.

Detailed instructions on the preparation and injection of Revestive are provided in the package leaflet.

The solution must not be used if it is cloudy or contains particulate matter.

For single use only.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

All needles and syringes should be disposed of in a sharps disposal container.

Takeda Pharmaceuticals International AG Ireland Branch

Block 2 Miesian Plaza50 - 58 Baggot Street Lower

Dublin 2, D02 HW68

IrelandmedinfoEMEA@takeda.com

EU/1/12/787/001

EU/1/12/787/002

Date of first authorisation: 30 August 2012

Date of latest renewal: 23 June 2017

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.