ANNEX I
`
`SUMMARY OF PRODUCT CHARACTERISTICS
`
`1
`
`Page 1
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`NPS EX. 2057
`CFAD v. NPS
`IPR2015-01093
`
`

`
`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.
`
`1.
`
`NAME OF THE MEDICINAL PRODUCT
`
`Revestive 5 mg powder and solvent for solution for injection
`
`2.
`
`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.
`
`* 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.
`
`3.
`
`PHARMACEUTICAL FORM
`
`Powder and solvent for solution for injection.
`The powder is white and the solvent is clear and colourless.
`
`4.
`
`CLINICAL PARTICULARS
`
`4.1 Therapeutic indications
`
`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.
`
`4.2
`
`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 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 evaluated 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.
`
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`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.
`
`4.3 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.
`
`4.4
`
`Special warnings and precautions for use
`
`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).
`
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`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.
`
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`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.
`
`4.5
`
`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).
`
`4.6
`
`Fertility, pregnancy and lactation
`
`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.
`
`4.7 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.
`
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`4.8
`
`Undesirable effects
`
`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.
`
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`Frequency
`
`Very common
`
`Common
`
`Uncommon
`
`System Organ Class
`Infections and infestations Respiratory tract
`infection
`
`Metabolism and nutrition
`disorders
`Psychiatric disorders
`
`Nervous system disorders Headache
`Cardiac disorders
`
`Vascular disorders
`Respiratory, thoracic and
`mediastinal disorders
`Gastrointestinal disorders Abdominal pain and
`distension
`Vomiting
`Nausea
`Gastrointestinal stoma
`complication*
`
`Hepatobiliary disorders
`
`Skin and subcutaneous
`tissue disorders
`Musculoskeletal and
`connective tissue disorders
`Renal and urinary
`disorders
`
`General disorders and
`administration site
`conditions
`Investigations
`
`Oedema peripheral
`Injection site reaction
`
`Syncope
`
`Influenza
`
`Decreased appetite
`
`Anxiety
`Sleep disorder
`Paraesthesia
`Cardiac failure
`congestive
`Flushing
`Dyspnoea
`Cough
`Pancreatitis
`Intestinal obstruction
`
`Cholestasis and
`cholecystitis
`Dermatitis allergic
`
`Arthralgia
`
`Renal colic
`Costovertebral angle
`tenderness
`Chest pain
`Night sweats
`
`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 ≥ 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
`
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`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 the national reporting system
`listed in Appendix V.
`
`4.9 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.
`
`5.
`
`PHARMACOLOGICAL PROPERTIES
`
`5.1 Pharmacodynamic properties
`
`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.).
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`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.
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`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).
`
`5.2
`
`Pharmacokinetic properties
`
`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.
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`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 (AUCinf) and 2.1 (Cmax) compared to healthy subjects.
`
`5.3
`
`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.
`
`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 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.
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`6.
`
`PHARMACEUTICAL PARTICULARS
`
`6.1 List of excipients
`
`Powder
`L-histidine
`Mannitol
`Sodium phosphate monohydrate
`Disodium phosphate heptahydrate
`Sodium hydroxide (pH adjustment)
`Hydrochloric acid (pH adjustment)
`
`Solvent
`Water for injections
`
`6.2
`
`Incompatibilities
`
`In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal
`products.
`
`6.3
`
`Shelf life
`
`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.
`
`6.4
`
`Special precautions for storage
`
`Store below 25°C.
`
`Do not freeze.
`
`For storage conditions after reconstitution of the medicinal product, see section 6.3.
`
`6.5
`
`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.
`
`6.6
`
`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.
`
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`A table with the injection volume per body weight is provided below:
`
`Body weight
`38-41 kg
`42-45 kg
`46-49 kg
`50-53 kg
`54-57 kg
`58-61 kg
`62-65 kg
`66-69 kg
`70-73 kg
`74-77 kg
`78-81 kg
`82-85 kg
`86-89 kg
`90-93 kg
`
`Volume to be injected
`0.20 ml
`0.22 ml
`0.24 ml
`0.26 ml
`0.28 ml
`0.30 ml
`0.32 ml
`0.34 ml
`0.36 ml
`0.38 ml
`0.40 ml
`0.42 ml
`0.44 ml
`0.46 ml
`
`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.
`
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`7. MARKETING AUTHORISATION HOLDER
`
`NPS Pharma Holdings Limited
`5 Riverwalk
`Citywest Business Campus
`Dublin 24
`Ireland
`Tel.: +800 6774 4357
`
`8. MARKETING AUTHORISATION NUMBER(S)
`
`EU/1/12/787/001
`
`9.
`
`DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
`
`Date of first authorisation: 30 August 2012
`
`10. 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.
`
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`
`ANNEX II
`
`A.
`
`B.
`
`C.
`
`D.
`
`MANUFACTURER(S) OF THE BIOLOGICAL ACTIVE
`SUBSTANCE(S) AND MANUFACTURER(S) RESPONSIBLE
`FOR BATCH RELEASE
`
`CONDITIONS OR RESTRICTIONS REGARDING SUPPLY
`AND USE
`
`OTHER CONDITIONS AND REQUIREMENTS OF THE
`MARKETING AUTHORISATION
`
`CONDITIONS OR RESTRICTIONS WITH REGARDS TO
`THE SAFE AND EFFECTIVE USE OF THE MEDICINAL
`PRODUCT
`
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`
`A. MANUFACTURER(S) OF THE BIOLOGICAL ACTIVE SUBSTANCE(S) AND
`MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE
`
`Name and address of the manufacturer of the biological active substance
`
`Boehringer Ingelheim RCV GmbH & Co KG
`Dr. Boehringer-Gasse 5-11
`A-1121 Vienna
`Austria
`
`Name and address of the manufacturer responsible for batch release
`
`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.
`
`B.
`
`