This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions.

NAME OF THE MEDICINAL PRODUCT

QUALITATIVE AND QUANTITATIVE COMPOSITION

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 a concentration of 10 mg/ml.

PHARMACEUTICAL FORM

Powder and solvent for solution for injection. The powder is white and the solvent is clear and colourless.

CLINICAL PARTICULARS

Posology and method of administration

Treatment should be initiated under the supervision of a medical professional with experience in the treatment of Short Bowel Syndrome (SBS). Treatment should not be initiated until it is reasonable to assume that no further intestinal adaptation will occur. Optimisation and stabilisation of intravenous fluid and nutrition support should be performed before initiation of treatment. Treatment effect should be evaluated after 6 months. The assessment by the physician should consider individual treatment objectives and patient preferences. Treatment should be stopped if no overall improvement of the patient condition is achieved. Efficacy and safety in responding patients should be closely monitored on an ongoing basis according to clinical treatment guidelines.

The recommended dose of teduglutide is 0.05 mg/kg body weight once daily. A table with the injection volume per body weight is provided in section 6.6. Due to the heterogeneity of the SBS population, a carefully monitored down-titration of the daily dose may be considered for some patients to optimise tolerability of the treatment. If a dose is missed, that dose should be taken as soon as possible on that day.

No dose adjustment is necessary for patients with mild renal impairment. In patients with moderate and severe renal impairment (creatinine clearance less than 50 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 a study conducted in Child-Pugh grade B subjects. Revestive has not been studied in patients with severe hepatic impairment (see sections 4.4 and 5.2).

Revestive should not be used in children below 18 years old because of safety concerns (vulnerability to fluid overload) (see section 5.1).

The reconstituted solution should be administered by subcutaneous injection once daily, alternating sites between 1 of the 4 quadrants of the abdomen. In case the injection into the abdomen is hampered by pain, scarring or hardening of the tissue, the thigh can also be used. Revestive should not be administered intravenously or intramuscularly. For instructions on reconstitution of the medicinal product before administration, see section 6.6.

Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1, or trace residues of tetracycline. Active or suspected malignancy. Patients with a history of malignancies in the gastrointestinal tract including the hepatobiliary system within the last five years.

Special warnings and precautions for use

A colonoscopy with removal of polyps should be performed at the time of starting treatment with Revestive. Subsequent colonoscopies are recommended at a minimum of five year intervals. An individual assessment whether increased frequency of surveillance is necessary should be performed based on the patient characteristics (e.g. age, underlying disease). See also section 5.1. If a polyp is found, adherence to current polyp follow-up guidelines is recommended. In case of malignancy, Revestive therapy should be discontinued (see section 4.3).

In the rat carcinogenicity study, benign tumours were found in the small bowel and the extrahepatic bile ducts. These observations were not confirmed in clinical studies of more than one year duration. If a neoplasia is detected, it should be removed. In case of malignancy, Revestive therapy should be discontinued (see sections 4.3 and 5.3).

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

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

SBS patients are to be kept under close surveillance according to clinical treatment guidelines. This usually includes the monitoring of short bowel function, gallbladder and bile ducts, and pancreas for signs and symptoms, and, if indicated, additional laboratory investigations and appropriate imaging techniques.

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

Due to increased fluid absorption, patients with cardiovascular disease, such as cardiac insufficiency and hypertension, should be monitored with regard to fluid overload, especially during initiation of therapy. Patients should be advised to contact their physician in case of sudden weight gain, swollen ankles and/or dyspnoea. In general, fluid overload can be prevented by appropriate and timely assessment of parenteral nutrition needs. This assessment should be conducted more frequently within the first months of treatment. In case of a significant deterioration of the cardiovascular disease, the need for continued Revestive treatment should be reassessed.

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

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 with malignancies 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 in subjects 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 managed carefully.

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 to tetracycline.

Interaction with other medicinal products and other forms of interaction

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

Fertility, pregnancy and lactation

There are no data from the use of Revestive in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3). As a precautionary measure, 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 concentration in milk was less than 3% of the maternal plasma concentration following a single subcutaneous injection of 25 mg/kg. A risk to the breastfed newborn/infant cannot be excluded. As a precautionary measure it is preferable to avoid the use of Revestive during breastfeeding.

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

Effects on ability to drive and use machines

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

Undesirable effects

Summary of the safety profile

Adverse reactions were retrieved from two placebo-controlled clinical studies with Revestive in 109 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 Revestive experienced adverse reactions (versus 36% of the patients given placebo). The most commonly reported adverse reactions were abdominal pain and distension (49%), respiratory tract infections (28%), nausea (27%), injection site reactions (21%), headache (17%), vomiting (14%) and oedema peripheral (10%). Approximately 38% of the treated patients with a stoma experienced gastrointestinal stoma complications. The majority of these reactions were mild or moderate.

Tabulated list of adverse reactions

Adverse reactions are listed below by MedDRA system organ class and by frequency. Frequencies are defined 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 available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Frequency System Organ Class	Very common	Common	Uncommon
Infections and infestations	Respiratory tract infection	Influenza
Metabolism and nutrition disorders		Decreased appetite
Psychiatric disorders		Anxiety Sleep disorder
Nervous system disorders	Headache	Paraesthesia
Cardiac disorders		Cardiac failure congestive
Vascular disorders		Flushing	Syncope
Respiratory, thoracic and mediastinal disorders		Dyspnoea Cough
Gastrointestinal disorders	Abdominal pain and distension Vomiting Nausea Gastrointestinal stoma complication *	Pancreatitis Intestinal obstruction
Hepatobiliary disorders		Cholestasis and cholecystitis
Skin and subcutaneous tissue disorders		Dermatitis allergic
Musculoskeletal and connective tissue disorders		Arthralgia
Renal and urinary disorders		Renal colic Costovertebral angle tenderness
General disorders and administration site conditions	Oedema peripheral Injection site reaction	Chest pain Night sweats
Investigations		C-reactive protein increased

Gastrointestinal stoma complication (swelling of the stoma and associated complications) is considered to be rather a sign of efficacy than an adverse reaction.

Description of selected adverse reactions

Immunogenicity

Consistent with the potentially immunogenic properties of medicinal products containing peptides, administration of Revestive may potentially trigger the development of antibodies. In phase 3 studies with SBS patients who received Revestive for up to one year, 30% of patients developed anti-teduglutide antibodies and 40% of patients developed antibodies against E.coli protein (residual host cell protein from the manufacture). The antibody formation has not been associated with clinically relevant safety findings, reduced efficacy or changed pharmacokinetics of Revestive.

Injection site reactions

Injection site reactions occurred in 21% of patients treated with teduglutide. The reactions appeared to be dose dependent and occurred with the same frequency in patients given the recommended dose of 0.05 mg/kg/day teduglutide and in patients given placebo (injection site reactions were experienced by 12% of the placebo-treated patients, by 12% of the patients who received 0.05 mg/kg/day teduglutide and by 41% of the patients who received 0.10 mg/kg/day teduglutide). The reactions included injection site erythema, injection site haematoma and injection site pain (see also section 5.3).

C-reactive protein

Modest increases of C-reactive protein of approximately 25 mg/l have been observed within the first seven days of Revestive treatment, which decreased continuously under ongoing daily injections. After 24 weeks of Revestive treatment, patients showed small overall increase in C-reactive protein of approximately 1.5 mg/l on average. These changes were neither associated with any changes in other laboratory parameters nor with any reported clinical symptoms.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

Overdose

The maximum dose of teduglutide studied during clinical development was 86 mg/day for 8 days. No unexpected 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.

PHARMACOLOGICAL PROPERTIES

Pharmacodynamic properties

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

The naturally occurring human glucagon-like peptide-2 (GLP-2) is a peptide secreted by L cells of the intestine which is known to increase intestinal and portal blood flow, inhibit gastric acid secretion, and decrease 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 of the 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 by glycine at the second position of the N-terminus. The single amino acid substitution relative to naturally occurring GLP-2 results in resistance to in vivo degradation by the enzyme dipeptidyl peptidase-IV (DPP-IV), resulting in an extended half-life. Teduglutide increases villus height and crypt depth of the intestinal epithelium. Based on the concerns derived from pre-clinical studies (see section 5.3) and the proposed mechanism of action with the trophic effects on intestinal mucosa, there appears to be a risk for the promotion of small intestinal and/or colonic neoplasia. The clinical studies conducted could neither exclude nor confirm such an increased risk. Several cases of benign colonic polyps occurred during the course of the trials, however, the frequency was not increased compared to placebo-treated patients. In addition to the need for a colonoscopy with removal of polyps by the time of the initiation of the treatment (see section 4.4. ), every patient should be assessed for the need of an enhanced surveillance schedule based on the patient characteristics (e.g. age and underlying disease, previous occurrence of polyps etc. ).

Revestive was studied in 17 patients with SBS allocated to five treatment groups using doses of 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 of approximately 750-1000 ml/day with improvements in the absorption of macronutrients and electrolytes; decreased stomal or faecal fluid and macronutrients excretion, and enhanced key structural and functional adaptations in the intestinal mucosa. Structural adaptations were transient in nature 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 required parenteral nutrition, 43 patients were randomised to a 0.05 mg/kg/day dose of teduglutide and 43 patients to placebo for up to 24 weeks. The proportion of teduglutide treated subjects achieving a 20% to 100% reduction of parenteral nutrition at Week 20 and 24 was statistically significantly different from placebo (27 out of 43 subjects, 62.8% versus 13 out of 43 patients, 30.2%, p=0.002). Treatment with teduglutide resulted in a 4.4 l/week reduction in parenteral nutrition requirements (from a pre-treatment baseline of 12.9 litres) versus 2.3 l/week (from a pre-treatment baseline of 13.2 litres) for placebo at 24 weeks. Twenty-one patients treated with teduglutide (48.8%) versus 9 on placebo (20.9%) achieved at least a one day reduction in parenteral nutrition administration (p=0.008). Ninety-seven percent of patients (37 out of 39 patients treated with teduglutide) that completed the placebo-controlled study entered a follow-up study where all patients received 0.05 mg/kg of teduglutide daily for up to an additional two years. In total 88 patients participated in this follow-up study, thereof 39 treated with placebo and 12 enrolled, but not randomised, in the previous study. At an interim assessment after six months of the follow-up study, continued reductions in parenteral nutrition have been achieved. Three subjects were completely weaned off parenteral nutrition at the time of the interim report. In another phase 3 double-blind, placebo-controlled study in patients with SBS, who required parenteral nutrition, patients received a 0.05 mg/kg/day dose (n = 35), a 0.10 mg/kg/day dose (n = 32) of teduglutide or placebo (n = 16) for up to 24 weeks. The primary efficacy analysis of the study results showed no statistically significant difference between the group on teduglutide 0.10 mg/kg/day and the placebo group, while the proportion of subjects 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 versus placebo (46% versus 6.3%, p<0.01). Treatment with Revestive resulted in a 2.5 l/week reduction in parenteral nutrition requirements (from a pre-treatment baseline of 9.6 litres) versus 0.9 l/week (from a pre-treatment baseline of 10.7 litres) for placebo at 24 weeks. Revestive treatment induced expansion of the absorptive epithelium by significantly increasing villus height in the small intestine. Sixty-five patients entered a follow-up SBS study for up to an additional 28 weeks of treatment. Patients on Revestive 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 Week 20 and 24 in the initial study, 75% sustained this response on Revestive after up to one year of continuous treatment. The mean reduction of weekly parenteral nutrition volume was 4.9 l/week (52% reduction from baseline) after one year of continuous teduglutide treatment. Two patients on the recommended teduglutide dose were able to be totally 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 4.2 for information on paediatric use).

Pharmacokinetic properties

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

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

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

Teduglutide has a terminal elimination half-life of approximately two hours. Following intravenous administration teduglutide plasma clearance was approximately 127 ml/hr/kg which is equivalent to the glomerular filtration rate (GFR). Renal elimination was confirmed in a study investigating pharmacokinetics in subjects with renal impairment. No accumulation of teduglutide was observed following repeated subcutaneous administrations.

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

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

In a phase 1 study the effect of hepatic impairment on the pharmacokinetics of teduglutide following subcutaneous administration of 20 mg teduglutide was investigated. The maximum exposure and the overall 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 following subcutaneous administration of 10 mg teduglutide was investigated. With progressive renal impairment up to and including end stage renal disease the primary pharmacokinetic parameters of teduglutide increased up to a factor of 2.6 (AUCinf) and 2.1 (Cmax) compared to healthy subjects.

Preclinical safety data

Hyperplasia in the gall bladder, hepatic biliary ducts, and pancreatic ducts were observed in subchronic and chronic toxicology studies. These observations were potentially associated with the expected intended pharmacology of teduglutide and were to a varying degree reversible within an 8-13 week recovery period following chronic administration.

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

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 duct epithelium in males exposed to teduglutide plasma levels approximately 32- and 155-fold higher than obtained in patients administered the recommended daily dose (incidence of 1 out of 44 and 4 out of 48, respectively). Adenomas of the jejunal mucosa were observed in 1 out of 50 males and 5 out of 50 males exposed to teduglutide plasma levels approximately 10- and 155-fold higher than obtained in patients administered the recommended daily dose. In addition, a jejunal adenocarcinoma was observed in a male rat administered the lowest dose tested (animal:human plasma exposure margin of approximately 10-fold).

Reproductive and developmental toxicity studies evaluating teduglutide have been carried out in rats and rabbits at doses of 0, 2, 10 and 50 mg/kg/day subcutaneously. Teduglutide was not associated with effects on reproductive performance, in utero or developmental parameters measured in studies to investigate fertility, embryo-fetal development and pre- and post-natal development. Pharmacokinetic data demonstrated that the teduglutide exposure of fetal rabbits and suckling rat pups was very low.

PHARMACEUTICAL PARTICULARS

List of excipients

L-histidine Mannitol Sodium phosphate monohydrate Disodium phosphate heptahydrate Sodium hydroxide (pH adjustment) Hydrochloric acid (pH adjustment)

Incompatibilities

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

Shelf life

3 years. After reconstitution, from a microbiological point of view, the solution should be used immediately. However, chemical and physical stability has been demonstrated for 3 hours at 25degC.

Special precautions for storage

Do not freeze. For storage conditions after reconstitution of the medicinal product, see section 6.3.

Nature and contents of container

5 mg teduglutide powder in vial (glass) with rubber stopper (bromobutyl). 0.5 ml of solvent in pre-filled syringe (glass) and plungers (plastic) for assembly with the pre-filled syringe. Pack size of 28 vials of powder, 28 pre-filled syringes and 6 plungers.

Special precautions for disposal and other handling

Determination of the number of vials needed for administration of one dose must be based on the individual patient's weight and the recommended dose of 0.05 mg/kg/day (see injection volumes in the table below). The physician should at each visit weigh the patient, determine the daily dose to be administered until next visit and inform the patient accordingly. A table with the injection volume per body weight is provided below:

The pre-filled syringe must be assembled with the plunger and 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-down once. Once a clear colourless solution is formed in the vial, the solution should be sucked up into a 1 ml injection syringe with scale intervals of 0.02 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 solution sucked up into the injection syringe containing the solution from the first vial. Any volume exceeding the 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 not possible, on the thigh (see section 4.2 Method of administration) using a thin needle for subcutaneous injection. 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 local requirements. All needles and syringes should be disposed of in a sharps disposal container.

MARKETING AUTHORISATION HOLDER

NPS Pharma Holdings Limited Grand Canal House 1 Grand Canal Street Upper Dublin 4 Ireland Tel. : +800 6774 4357

MARKETING AUTHORISATION NUMBER(S)

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

DATE OF REVISION OF THE TEXT

Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu.

ANNEX II

MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND MANUFACTURER RESPONSIBLE FOR BATCH RELEASE

CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE

OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION

MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE(S) AND MANUFACTURER RESPONSIBLE FOR BATCH RELEASE

Boehringer Ingelheim RCV GmbH & Co KG Dr. Boehringer-Gasse 5-11 A-1121 Vienna Austria

Nycomed Danmark ApS Langebjerg 1 DK-4000 Roskilde Denmark Almac Pharma Services Seagoe Industrial Estate Craigavon County Armagh BT63 5UA United Kingdom The printed package leaflet of the medicinal product must state the name and address of the manufacturer responsible for the release of the concerned batch.

Body weight	Volume to be injected
38-41 kg	0.20 ml
42-45 kg	0.22 ml
46-49 kg	0.24 ml
50-53 kg	0.26 ml
54-57 kg	0.28 ml
58-61 kg	0.30 ml
62-65 kg	0.32 ml
66-69 kg	0.34 ml
70-73 kg	0.36 ml
74-77 kg	0.38 ml
78-81 kg	0.40 ml
82-85 kg	0.42 ml
86-89 kg	0.44 ml
90-93 kg	0.46 ml

ANNEX I

SUMMARY OF PRODUCT CHARACTERISTICS