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 a concentration 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 adult patients with Short Bowel Syndrome. Patients should be stable following a period of intestinal adaptation after surgery.

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 a patient is stable following a period of intestinal adaptation. Optimisation and stabilisation of intravenous fluid and nutrition support should be performed before initiation of treatment.

Treatment effect should be eva luated after 6 months. Clinical 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 all patients should be closely monitored on an ongoing basis according to clinical treatment guidelines. Continued treatment is recommended for patients who have weaned off parenteral nutrition.

Posology

Adults

The recommended dose of Revestive 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.

Special populations

Elderly

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

Renal impairment

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).

Hepatic impairment

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).

Paediatric population

The safety and efficacy of Revestive in children below 18 years old has not been established (see section 5.1).

Method of administration

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.

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.

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 the first 2 years of Revestive treatment. 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).

Gastrointestinal neoplasia including hepatobiliary tract

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 treatment should be discontinued (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 of gallbladder or bile duct-related symptoms, the need for continued Revestive treatment should be reassessed.

Pancreatic diseases

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.

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

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.

Intestinal obstruction

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.

Cardiovascular

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.

Concomitant medication

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).

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 with malignancies within the last five years (see section 4.3). Caution should be exercised when prescribing Revestive.

Hepatic impairment

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.

Discontinuation of treatment

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

Excipients

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.

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).

Pregnancy

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.

Breast-feeding

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.

Fertility

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

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.

Summary of the safety profile

Adverse reactions were retrieved from 2 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.

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

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.

* 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 ≥ 2 years, 39% of patients developed anti-teduglutide antibodies and 21% 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 SBS patients treated with Revestive. The reactions appeared to be dose dependent and occurred with similar frequency in patients given the recommended dose of 0.05 mg/kg/day Revestive and in patients given placebo (injection site reactions were experienced by 12% of the placebo-treated patients, by 13% of the patients who received 0.05 mg/kg/day Revestive and by 41% of the patients who received 0.10 mg/kg/day Revestive). 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. There were no clinically relevant mean increases of C-reactive protein from baseline following long-term treatment with Revestive for up to 30 months.

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

Ireland

HPRA Pharmacovigilance

Earlsfort Terrace

IRL - Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6762517

Website: www.hpra.ie

e-mail: medsafety@hpra.ie

United Kingdom

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard

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.

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

Mechanism of action

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.

Pharmacodynamic effects

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.).

Clinical efficacy

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 Revestive and 43 patients to placebo for up to 24 weeks.

The proportion of Revestive-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 Revestive 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 Revestive (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 long-term extension study where all patients received 0.05 mg/kg of Revestive daily for up to an additional 2 years. In total 88 patients participated in this extension study, thereof 39 treated with placebo and 12 enrolled, but not randomised, in the previous study; 65 of 88 patients completed the extension study. There continued to be evidence of increased response to treatment for up 2.5 years in all groups exposed to Revestive in terms of parenteral nutrition volume reduction, gaining additional days off parenteral nutrition per week, and achieving weaning of parenteral support.

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

The mean reduction in parenteral nutrition (n=30) was 7.55 l/week (a 65.6% reduction from baseline). Ten subjects were weaned off their parenteral support while on Revestive treatment for 30 months. Subjects were maintained on Revestive 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 treatment with Revestive had required between 3.5 l/week and 13.4 l/week of parenteral nutrition support. At the 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 Revestive. The mean reduction in parenteral nutrition was 3.11 l/week (an additional 28.3% reduction). Sixteen (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 in parenteral nutrition, respectively. Two subjects were weaned off their parenteral support while on Revestive.

Of the 12 subjects not randomised in the pivotal study, 6 completed 24 months of treatment with Revestive. 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 greater reduction in parenteral support. At the end of study, 3 (50%), 2 (33%) and 2 (33%) achieved a reduction of 1, 2, or 3 days per week in parenteral nutrition, respectively. One subject was weaned off their parenteral support while on Revestive.

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 Weeks 20 and 24 in the initial study, 75% sustained this response on Revestive after up to 1 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 weaned off parenteral nutrition by Week 24. One additional patient in the follow-up study was weaned off parenteral nutrition.

Paediatric population

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).

Absorption

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.

Distribution

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

Biotransformation

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.

Elimination

Teduglutide has a terminal elimination half-life of approximately 2 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.

Dose linearity

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

Pharmacokinetics in subpopulations

Gender

No clinically relevant gender differences were observed in clinical studies.

Elderly

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.

Hepatic impairment

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.

Renal impairment

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 (AUC_inf) and 2.1 (C_max) compared to healthy subjects.

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.

Injection site reactions

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

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 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

Reproductive and developmental toxicity studies eva luating 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.

Powder

L-histidine

Mannitol

Sodium phosphate monohydrate

Disodium phosphate heptahydrate

Sodium hydroxide (pH adjustment)

Hydrochloric acid (pH adjustment)

Solvent

Water for injections

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

4 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 25°C.

Store below 25°C.

Do not freeze.

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

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.

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.

NPS Pharma Holdings Limited

5 Riverwalk

Citywest Business Campus

Dublin 24

Ireland

Tel.: +800 6774 4357

EU/1/12/787/001

Date of first authorisation: 30 August 2012

08/2015

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