Revestive: Indications, Dosage, Precautions, Adverse Effects
Россия
  • Россия
  • Украина

Revestive - Product Information

Manufacture: Shire, Inc.
Country: Canada
Condition: Short Bowel Syndrome
Class: Miscellaneous GI agents
Form: Subcutaneous (SC), Powder
Ingredients: teduglutide, dibasic sodium phosphate heptahydrate, L-histidine, mannitol, monobasic sodium phosphate monohydrate, sterile water for injection.

5 mg powder and 0.5 mL solvent for solution for injection

Summary Product Information

Route of AdministrationDosage Form /
Strength
Clinically Relevant Nonmedicinal Ingredients
Subcutaneous injectionPowder for solution /
5mg/vial
none
For a complete listing see Dosage Forms, Composition and Packaging section.

Indications and Clinical Use

REVESTIVE (teduglutide) is indicated for the treatment of adult patients with Short Bowel Syndrome (SBS) who are dependent on parenteral support.

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

Treatment effect should be evaluated on an ongoing basis. Clinical assessment by the physician should consider individual treatment objectives and patient preferences. If no overall improvement is achieved after 12 months, the need for continued treatment should be assessed.

Treatment should not be initiated until the 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. For safety monitoring, patients should undergo initial laboratory assessments (see Warnings and Precautions, Gallbladder and Biliary Tract Disease and Pancreatic Diseases) prior to starting treatment with REVESTIVE.

Geriatrics (> 65 Years of Age)

No clinically significant differences in safety and efficacy were observed between subjects younger than 65 years and those older than 65 years. Experience in subjects 75 years and older is limited.

Pediatrics (< 18 Years of Age)

Safety and efficacy in pediatric patients have not been established.

Pregnant Women

There are no data from the use of REVESTIVE on pregnant women (see Warnings and Precautions, Special Populations – Pregnant Women)

Nursing Women

There are no data from the use of REVESTIVE on nursing women (see Warnings and Precautions, Special Populations – Nursing Women)

Contraindications

REVESTIVE is contraindicated in patients who:

  • are hypersensitive to this drug or to any ingredient in the formulation or component of the container. For a complete listing, see the Dosage Forms, Composition and Packaging section of the product monograph;
  • have active gastrointestinal (GI) malignancy (GI tract, hepatobiliary, pancreatic);
  • have a history of malignancies in the gastrointestinal tract including the hepatobiliary system within the last 5 years.

Warnings and Precautions

General

Concomitant Medication

Based upon the pharmacodynamic effect of REVESTIVE, patients receiving oral concomitant medicinal products requiring titration or with a narrow therapeutic index should be monitored closely due to potential increased absorption. Patients may require dose adjustment of these medications while on REVESTIVE. Examples of such medications include but are not limited to benzodiazepines, opioids, digoxin, anti-hypertensives.

Discontinuation of Treatment

Discontinuation of treatment with REVESTIVE may result in fluid and electrolyte imbalance leading to potential dehydration. Therefore, patients` fluid and electrolyte status should be carefully monitored.

Cardiovascular

Fluid overload and congestive heart failure have been observed in clinical trials. Due to increased fluid absorption, patients with and without a history of 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 and adjustment of parenteral nutrition needs. This assessment should be conducted more frequently within the first months of treatment with close monitoring afterwards. In case of a significant deterioration of cardiovascular disease, the need for continued REVESTIVE treatment should be assessed.

Heart Rate Increase

An increase in heart rate was reported with REVESTIVE in a clinical trial in healthy volunteers undergoing serial ECG monitoring (see Action and Clinical Pharmacology, Pharmacodynamics – Cardiac Eletrophysiology). Because of limited clinical experience in patients who have cardiac conditions that might be worsened by an increase in heart rate, such as ischemic heart disease or tachyarrhythmias, caution should be observed in these patients. (see Drug Interactions, Drug-Drug Interactions – Drugs that Increase Heart Rate).

Gastrointestinal

Gastrointestinal Neoplasia Including Hepatobiliary Tract

Based on the pharmacologic activity and findings in animals, REVESTIVE has the potential to cause hyperplastic changes including neoplasia in the small bowel and hepatobiliary tract. These observations were not confirmed in clinical studies of more than one year duration.

Patients should be monitored clinically for small bowel and hepatobiliary neoplasia. If a benign neoplasm is found, it should be removed. In patients with active gastrointestinal malignancy (GI tract, hepatobiliary, pancreatic), REVESTIVE therapy should be discontinued. In patients with active non-gastrointestinal malignancy or who are at increased risk for malignancy, the clinical decision to continue REVESTIVE should be made based on risk-benefit considerations.

Colorectal Polyps

Colorectal polyps were identified during the clinical trials. Colonoscopy of the entire colon with removal of polyps should be done within 6 months prior to starting treatment with REVESTIVE. A follow-up colonoscopy (or alternate imaging) is recommended between 1 to 2 years after initiating REVESTIVE. Subsequent colonoscopies should be done every 5 years or more often as needed in high risk individuals. If a polyp is found, adherence to current polyp follow-up guidelines is recommended. In case of diagnosis of colorectal cancer, REVESTIVE therapy should be discontinued.

Intestinal Obstruction

Intestinal obstruction has been reported in clinical trials. In patients who develop intestinal or stomal obstruction, REVESTIVE should be temporarily discontinued while the patient is clinically managed. REVESTIVE may be restarted when the obstructive presentation resolves, if clinically indicated.

Hepatic/Biliary/Pancreatic

Gallbladder and Biliary Tract Disease

Cholecystitis, cholangitis, and cholelithiasis have been reported in clinical studies.

For identification of the onset or worsening of gallbladder/biliary disease, patients should undergo laboratory assessment of bilirubin and alkaline phosphatase prior to starting REVESTIVE, and while on REVESTIVE. If clinically meaningful changes are seen, further evaluation including imaging of the gallbladder and/or biliary tract is recommended; and 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.

For identification of onset or worsening of pancreatic disease, patients should undergo laboratory assessment of lipase and amylase prior to starting REVESTIVE, and while on REVESTIVE. If clinically meaningful changes are seen, further evaluation such as imaging of the pancreas is recommended, and the need for continued REVESTIVE treatment should be reassessed.

Special Populations

Pregnant Women

There are no data from the use of REVESTIVE in pregnant women.

In animal studies, no effects on embryo-fetal development were observed in pregnant rats given subcutaneous teduglutide at doses up to 50 mg/kg/day (about 1000 times the recommended daily human dose of 0.05 mg/kg) or pregnant rabbits given subcutaneous doses up to 50 mg/kg/day (about 1000 times the recommended daily human dose of 0.05 mg/kg). A pre- and postnatal development study in rats showed no evidence of any adverse effect on pre- and postnatal development at subcutaneous doses up to 50 mg/kg/day (about 1000 times the recommended daily human dose of 0.05 mg/kg).

Because animal reproductive studies are not always predictive of human response, REVESTIVE should be used during pregnancy only if clearly needed.

Nursing Women

It is not known whether teduglutide is present in human milk.

Teduglutide is excreted in the milk of lactating rats, and the highest concentration measured in milk was 2.9% of the plasma concentration following a single subcutaneous injection of 25 mg/kg (500 times the recommended daily human dose of 0.05 mg/kg).

Because of the potential for serious adverse reactions to nursing infants from REVESTIVE and because of the potential for tumorigenicity shown for teduglutide in mice and rats, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatrics (<18 years of age)

The safety and efficacy of REVESTIVE in pediatric patients have not been established.

Geriatrics (>65 years of age)

Of the 595 subjects treated with REVESTIVE in clinical trials, 43 subjects were 65 years or older, whereas 6 subjects were 75 years of age or older. No clinically significant differences were observed between subjects younger than 65 years and those older than 65 years.

Renal Insufficiency

In patients with moderate or severe renal impairment, or end-stage renal disease the dose should be reduced by 50% (see Dosage and Administration, Dosing Considerations – Patients with Renal Impairment; Action and Clinical Pharmacology, Pharmacokinetics – Renal Insufficiency).

Adverse Reactions

Adverse Drug Reaction Overview

Across all clinical studies, 595 subjects were exposed to at least one dose of REVESTIVE (249 patient-years of exposure; mean duration of exposure was 22 weeks). Of the 595 subjects, 173 subjects were treated in Phase 3 SBS studies (134/173 [77%] at the dose of 0.05 mg/kg/day and 39/173 [23%] at the dose of 0.10 mg/kg/day).

The most commonly reported (≥ 10%) adverse reactions in patients treated with REVESTIVE across all clinical studies (n=595) were: abdominal pain (31.3%), injection site reactions (21.8%), nausea (18.8%), headaches (16.3%), abdominal distension (14.8%), and upper respiratory tract infection (11.9%).

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

The rates of adverse reactions in patients with SBS participating in 2 randomized, placebo-controlled, 24-week, double-blind clinical studies (Studies CL0600-020 and CL0600-004) are summarized in Table 1. Only those reactions with a rate of at least 5% in the REVESTIVE group and occurring greater than in the placebo group are summarized. The majority of these reactions were mild or moderate. Of subjects receiving REVESTIVE at the recommended dose of 0.05 mg/kg/day, 88.3% (n=68/77) experienced an adverse reaction, as compared to 83.1% (n=49/59) for placebo. Many of these adverse reactions have been reported in association with the underlying disease and/or parenteral nutrition.

Table 1: Adverse reactions in ≥5% of REVESTIVE-treated SBS subjects and more frequent than placebo: CL0600-020 and CL0600-004
Adverse ReactionREVESTIVE
0.05 mg/kg/day
(N=77)
n (%)
Placebo
(N=59)
n (%)
Gastrointestinal Disorders
Abdominal Pain29 (38)16 (27)
Nausea19 (25)12 (20)
Abdominal Distension15 (20)1 (2)
Vomiting9 (12)6 (10)
Flatulence7 (9)4 (7)
Appetite Disorders5 (7)2 (3)
Infections and Infestations
Upper Respiratory Tract Infection20 (26)8 (14)
Psychiatric Disorders
Sleep Disturbances4 (5)0
Respiratory, Thoracic and Mediastinal Disorders
Cough4 (5)0
Skin and Subcutaneous Tissue Disorders
Hypersensitivity6 (8)3 (5)
Skin Hemorrhage4 (5)1 (2)
Vascular Disorders
Fluid Overload9 (12)4 (7)
Subjects with Stoma
Gastrointestinal Stoma Complication13 (42)a3 (14)a

aPercentage based on 53 subjects with a stoma (n=22 placebo; n=31 REVESTIVE 0.05 mg/kg/day)

No new safety signals have been identified in patients exposed to 0.05 mg/kg/day of REVESTIVE for up to 42 months in long-term open-label extension studies.

Adverse Reactions of Special Interest

Malignancy

Three subjects were diagnosed with malignancy in the clinical studies, all of whom were male and had received REVESTIVE 0.05 mg/kg/day in CL0600-021. One subject had a history of abdominal radiation for Hodgkin`s disease two decades prior to receiving REVESTIVE and a prior liver lesion on CT scan, and was diagnosed with metastatic adenocarcinoma of unconfirmed origin after 11 months of exposure to REVESTIVE. Two subjects had extensive smoking histories, and were diagnosed with lung cancers (squamous and non-small cell) after 12 months and 3 months of REVESTIVE exposure, respectively.

Colorectal Polyps

In the clinical studies, 14 subjects were diagnosed with polyps of the GI tract after initiation of study treatment. In the SBS placebo-controlled studies, 1/59 (1.7%) of subjects on placebo and 1/109 (0.9%) of subjects on REVESTIVE 0.05 mg/kg/day were diagnosed with intestinal polyps (inflammatory stomal and hyperplastic sigmoidal after 3 and 5 months, respectively). The remaining 12 polyp cases occurred in the extension studies – 2 colorectal villous adenomas (onset at 6 and 7 months in REVESTIVE 0.10 and 0.05 mg/kg/day dose groups, respectively), 2 hyperplastic polyp (onset 6 months in REVESTIVE 0.10 mg/kg/day dose group and 24 months in REVESTIVE 0.05 mg/kg/day dose group), 4 colorectal tubular adenomas (onset between 24 and 36 months in REVESTIVE 0.05 mg/kg/day dose group), 1 serrated adenoma (onset at 24 months in REVESTIVE 0.05 mg/kg/day dose group), 1 colorectal polyp biopsy not done (onset at 24 months in REVESTIVE 0.05 mg/kg/day dose group), 1 rectal inflammatory polyp (onset at 10 months in the REVESTIVE 0.05 mg/kg/day dose group, and 1 small duodenal polyp (onset at 3 months in REVESTIVE 0.05 mg/kg/day dose group).

Gastrointestinal Obstruction

Overall, 12 subjects experienced one or more episodes of intestinal obstruction/stenosis: 6 in SBS placebo-controlled studies and 6 in the extension studies. The 6 subjects in the placebo-controlled trials were all on REVESTIVE: 3/77 (3.9%) on REVESTIVE 0.05 mg/kg/day and 3/32 (9.4%) on REVESTIVE 0.10 mg/kg/day. No cases of intestinal obstruction occurred in the placebo group. Onsets ranged from 1 day to 6 months. In the extension studies, 6 additional subjects (all on REVESTIVE 0.05 mg/kg/day) were diagnosed with intestinal obstruction/stenosis with onsets ranging from 6 days to 19 months. Two of the 6 subjects from the placebo-controlled trials experienced recurrence of obstruction in the extension studies. Of all 8 subjects with an episode of intestinal obstruction/stenosis in these extension studies, 2 subjects required endoscopic dilation and 1 required surgical intervention.

Gallbladder, Biliary and Pancreatic Disease

For gallbladder and biliary disease in the placebo-controlled studies, 3 subjects were diagnosed with cholecystitis, all of whom had a prior history of gallbladder disease and were in the REVESTIVE 0.05 mg/kg/day dose group. No cases were reported in the placebo group. One of these 3 cases had gallbladder perforation and underwent cholecystectomy the next day. The remaining 2 cases underwent elective cholecystectomy at a later date. In the extension studies, 4 subjects had an episode of acute cholecystitis; 4 subjects had new-onset cholelithiasis; and 1 subject experienced cholestasis secondary to an obstructed biliary stent. For pancreatic disease in the placebo-controlled studies, 1 subject (REVESTIVE 0.05 mg/kg/day dose group) had a pancreatic pseudocyst diagnosed after 4 months of REVESTIVE. In the extension studies, 1 subject was diagnosed with chronic pancreatitis; and 1 subject was diagnosed with acute pancreatitis.

Fluid Overload

In the placebo-controlled trials, fluid overload was reported in 4/59 (6.8%) of subjects on placebo and 9/77 (11.7%) subjects on REVESTIVE 0.05 mg/kg/day. Of the 9 cases in the REVESTIVE group, there were 2 cases of congestive heart failure (CHF), 1 of whom was reported as a serious adverse event and the other as non-serious. The serious case had onset at 6 months, and was possibly associated with previously undiagnosed hypothyroidism and/or cardiac dysfunction.

Concomitant Oral Medication

REVESTIVE can increase the absorption of concomitant oral medications such as benzodiazepines and psychotropic agents. One subject in the placebo controlled trials in the REVESTIVE 0.05 mg/kg/day group (on prazepam) experienced dramatic deterioration in mental status progressing to coma during her first week of REVESTIVE therapy. She was admitted to the Intensive Care Unit where her benzodiazepine level was >300 mcg/L. REVESTIVE and prazepam were discontinued, and the coma resolved 5 days later.

Immunogenicity

Based on data from 2 trials in adults with SBS (a 6-month randomized placebo-controlled trial, followed by a 24-month open-label trial), the incidence of anti-teduglutide antibodies was 3% (2/60) at Month 3, 18% (13/74) at Month 6, 25% (18/71) at Month 12, 31% (10/32) at Month 24 and 48% (14/29) at Month 30 in subjects who received subcutaneous administration of 0.05 mg/kg REVESTIVE once daily. The anti-teduglutide antibodies were cross-reactive to native glucagon-like peptide (GLP-2) in 5 of the 6 subjects (83%) who had anti-teduglutide antibodies. Anti-teduglutide antibodies appear to have no impact on short term (up to 2.5 years) efficacy and safety although the long-term impact is unknown.

In the same two trials, a total of 36 subjects were tested for neutralizing antibodies: 9 of these subjects had no neutralizing antibodies, and the remaining 27 subjects had no detectable neutralizing antibodies although, the presence of teduglutide at low levels in these study samples could have resulted in false negatives (no neutralizing antibody detected although present).

Injection Site Reactions

In the placebo-controlled trials CL0600-020 and CL0600-004, 12% of patients in each of the placebo and REVESTIVE 0.05 mg/kg/day treatment groups experienced an injection site reaction. The majority of reactions were moderate in severity and no occurrences led to drug discontinuation.

Abnormal Hematologic and Clinical Chemistry Findings

No clinically meaningful changes from baseline were seen for any of the hematology analytes, and no clinically meaningful shifts occurred.

Abnormal clinical chemistry is a common manifestation of SBS and a significant proportion of subjects in the SBS placebo-controlled trials had abnormal chemistry at baseline. The most common markedly abnormal clinical chemistry analyte post-baseline in REVESTIVE 0.05 mg/kg/day patients vs. placebo was C-Reactive Protein (CRP) ≥ 21mg/L, (25% vs. 8.6%). Higher changes from baseline in CRP values were found in REVESTIVE-treated subjects (1.74g/m3) vs. placebo-treated subjects (−1.15 g/m3) at Week 24. For the remainder of the analytes, the change from baseline was similar or greater in placebo-treated subjects.

Post-Market Adverse Drug Reactions

The following adverse reactions have been identified during post-approval use of REVESTIVE. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Cardiac disorders: Cardiac arrest, cardiac failure

Nervous system disorders: Cerebral hemorrhage

Drug Interactions

Overview

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 oral medications, such as benzodiazepines , opioids, digoxin and anti-hypertensives, which should be considered if these drugs require titration or have a narrow therapeutic index.

Among the patients on benzodiazepines, one patient in the 0.05 mg/kg/day REVESTIVE group in Study CL0600-004 was taking prazepam and experienced dramatic deterioration in mental status progressing to coma during the first week of REVESTIVE therapy. The patient was admitted to the ICU where the benzodiazepine level was >300 mcg/L; REVESTIVE and prazepam were discontinued, and the coma resolved 5 days later.

Drug-Drug Interactions

No clinical drug-drug interaction studies have been performed.

Drugs that Increase Heart Rate

REVESTIVE caused an increase in heart rate in a clinical trial in healthy volunteers (see Warnings and Precautions, Cardiovascular – Heart Rate Increase; Action and Clinical Pharmacology, Pharmacodynamics – Cardiac Eletrophysiology). The impact on heart rate of co-administration of REVESTIVE with other drugs that increase heart rate, such as sympathomimetic drugs, has not been evaluated in drug-drug interaction studies. As a result, caution should be observed with co-administration of REVESTIVE with these drugs.

Drug-Food Interactions

Interactions with food have not been established.

Drug-Herb Interactions

Interactions with herbal products have not been established.

Drug-Laboratory Interactions

Interactions with laboratory tests have not been established.

Dosage and Administration

Dosing Considerations

Patients with Renal Impairment

Reduce the dose by 50% in patients with moderate and severe renal impairment (creatinine clearance less than 50 mL/min), and end-stage renal disease. No dose adjustment is necessary for patients with mild renal impairment.

Patients with Hepatic Impairment

No dosage 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 subjects with severe hepatic impairment.

Recommended Dose and Dosage Adjustment

The recommended daily dose of REVESTIVE is 0.05 mg/kg body weight administered by subcutaneous injection once daily. Alternation of sites for subcutaneous injection is recommended, and can include the thighs, arms, and the 4 quadrants of the abdomen. REVESTIVE should not be administered intravenously or intramuscularly.

Missed Dose

If a dose is missed, that dose should be taken as soon as possible on that day. Do not take 2 doses on the same day.

Administration

Each single-use vial of REVESTIVE contains 5 mg of teduglutide as a white lyophilized powder for solution for subcutaneous injection. At the time of administration the lyophilized powder is reconstituted with 0.5 mL of Sterile Water for Injection, which is provided in a pre-filled syringe. A 10 mg/mL sterile solution is obtained after reconstitution (see Reconstitution below).

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.

Table 2: REVESTIVE Injection Volume Per Body Weight
Body weight (kg)Volume to be injected (mL)
38-410.20
42-450.22
46-490.24
50-530.26
54-570.28
58-610.30
62-650.32
66-690.34
70-730.36
74-770.38
78-810.40
82-850.42
86-890.44
90-930.46

The prepared solution must be injected subcutaneously into a cleaned area on the abdomen, arm, or thigh using a thin needle for subcutaneous injection.

Detailed instructions on the preparation and injection of REVESTIVE are provided in the Patient Medication Information.

Reconstitution

Reconstitute each vial of REVESTIVE by slowly injecting the 0.5 mL of preservative-free Sterile Water for Injection provided in the pre-filled syringe. Allow the vial containing REVESTIVE and water to stand for approximately 30 seconds and then gently roll the vial between your palms for about 15 seconds. Do not shake the vial. Allow the mixed contents to stand for about 2 minutes. Inspect the vial for any undissolved powder.

If undissolved powder is observed, gently roll the vial again until all material is dissolved. Do not shake the vial. The solution should be clear and colorless to light straw colored and free from visible particles. Do not use if the product remains undissolved or is discolored.

Once the drug is completely dissolved, withdraw the prescribed dose of solution into an injection syringe (up to 1 mL with scale intervals of 0.02 mL or lower) equipped with a thin needle (not included in the pack).

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

Reconstitution
Vial
Strength
Volume of Diluent to
be Added to Vial
Approximate
Available Volume
Nominal Concentration per mL
5 mg0.5 mL Sterile Water for Injection0.38 mL10 mg/mL (up to 3.8 mg teduglutide can be withdrawn)

Vials of REVESTIVE and pre-filled syringes of Sterile Water for Injection do not contain any preservatives and are for single-use only. After reconstitution, from a microbiological point of view, the solution should be used immediately. However, chemical and physical stability have been demonstrated for up to 3 hours below 25°C after reconstitution. Any unused product or waste material should be disposed of in accordance with local requirements.

In the absence of compatibility studies, REVESTIVE should not be mixed with other medicinal products.

Overdosage

The maximum dose of REVESTIVE studied during clinical development was 80 mg/day for 8 days. No unexpected systemic adverse reactions were seen. In the event of overdose, the patient should be carefully monitored by the medical professional.

For management of a suspected drug overdose, contact your regional Poison Control Centre.

Action and Clinical Pharmacology

Mechanism of Action

Teduglutide is an analog of naturally occurring human glucagon-like peptide-2 (GLP-2), a peptide secreted by L-cells of the distal intestine. 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 binds to the glucagon-like peptide-2 receptors located in intestinal subpopulations of enteroendocrine cells, subepithelial myofibroblasts and enteric neurons of the submucosal and myenteric plexus. Activation of these receptors results in the local release of multiple mediators including insulin-like growth factor (IGF)-1, vasoactive intestinal polypeptide (VIP), nitric oxide and keratinocyte growth factor (KGF). GLP-2 is mainly responsible for the maintenance and expansion of the gastrointestinal mucosal surface area through the regulation of proliferation and apoptosis of the intestinal epithelium. GLP-2 also promotes energy absorption through a number of mechanisms including enhanced capacity for carbohydrate, amino acid, and lipid absorption, increased activity and expression of brush border digestive enzymes, and increased mucosal nutrient transport. Exogenous GLP-2 increases intestinal and portal blood flow, decreases gastrointestinal motility and inhibits gastric acid secretion. 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.

Pharmacodynamics

The ability of REVESTIVE to improve intestinal absorption of fluids and nutrients was studied in 17 adult subjects with Short Bowel Syndrome using daily doses of 0.03, 0.10, 0.15 mg/kg (n=2-3 per dose group) in a 21-day, open-label, multi-center, dose-ranging study. All subcutaneous (abdomen) doses studied, except 0.03 mg/kg once daily, decreased stomal output or fecal fluid and macronutrient excretion, resulted in enhanced gastrointestinal fluid (wet weight) absorption of approximately 750-1000 mL/day, and increased villus height and crypt depth of the intestinal mucosa.

Cardiac Electrophysiology

A randomised, double-blind, placebo- and active-controlled, four period crossover study was performed to investigate the electrocardiographic effects of single subcutaneous doses of REVESTIVE 5 mg and 20 mg in healthy subjects (N=70).

REVESTIVE was associated with increases in heart rate. Following single dose treatment with REVESTIVE 5 mg, statistically significant positive mean differences from placebo were observed from 1 to 16 h post-dosing, inclusive, with a maximum mean difference from placebo of 9.3 bpm (90% CI 8.0, 10.6) at 1 h post-dosing. Following treatment with a supra-therapeutic 20 mg dose, statistically significant positive mean differences from placebo were observed from 1 to 24 h post-dosing, inclusive, with a maximum mean difference from placebo of 9.8 bpm (90% CI 8.0, 11.5) at 6 h post-dosing (see Warnings and Precautions, Cardiovascular – Heart Rate Increase; Drug Interactions, Drug-Drug Interactions – Drugs that Increase Heart Rate).

There was no evidence of a treatment-related effect of REVESTIVE on the QTcF interval, the QRS duration, or the PRc interval.

Pharmacokinetics

Table 3: Summary of REVESTIVE Pharmacokinetic Parameters in Patients with SBS
Cmax
(ng/mL)
t½
(h)
AUC
(ng·hr/mL)
Clearance
(L/h)
Volume of
distribution
(L)
Single dose
mean
(0.05 mg/kg)
38.41.524713.127.2

Cmax and AUC are measured under steady state conditions

The Cmax and AUC of teduglutide was dose proportional over the dose range of 0.05 to 0.4 mg/kg teduglutide.

Absorption

In healthy subjects, REVESTIVE when administered subcutaneously in the thigh/abdomen had an absolute bioavailability of 88% and reached maximum plasma teduglutide concentrations at 3-5 hours after administration. Following a 0.05 mg/kg subcutaneous dose in SBS subjects, the median peak teduglutide concentration (Cmax) was 36 ng/mL and the median area under the curve (AUC0-inf) was 0.15 μg·hr/mL. No accumulation of teduglutide was observed following repeated subcutaneous administrations.

Distribution

In healthy subjects, teduglutide had a volume of distribution of 103mL/kg, similar to blood volume.

Metabolism

The metabolic pathway of teduglutide was not investigated in humans. However, teduglutide is expected to be degraded into small peptides and amino acids via catabolic pathways, similar to the catabolism of endogenous GLP-2.

Excretion

In healthy subjects, teduglutide plasma clearance was approximately 123 mL/hr/kg which is similar to the GFR suggesting that teduglutide is primarily cleared by the kidney. Teduglutide has a mean terminal half-life (t½) of approximately 2 hours in healthy subjects and 1.3 hours in SBS subjects.

Special Populations and Conditions

Pediatrics: There are no pharmacokinetic (PK) data in children.

Geriatrics: No differences in PK were observed between healthy subjects younger than 65 years and those older than 65 years. Experience in subjects 75 years and older is limited.

Gender: No clinically relevant gender differences were observed.

Hepatic Insufficiency: Subjects with moderate hepatic impairment had lower teduglutide Cmax and AUC (10 ~15%) compared to healthy matched control subjects after a single subcutaneous dose of 20 mg REVESTIVE. Teduglutide PK was not assessed in subjects with severe hepatic impairment.

Renal Insufficiency: In subjects with moderate to severe renal impairment or end stage renal disease (ESRD), teduglutide Cmax and AUC0-inf increased with the degree of renal impairment following a single subcutaneous administration of 10 mg teduglutide. Teduglutide exposure increased by a factor of 2.1 (Cmax) and 2.6 (AUC0-inf) in ESRD subjects compared to healthy subjects.

Storage and Stability

Prior to dispensing, store refrigerated (2-8°C). Do not freeze.

Dispensing Instructions: Dispense with a 90-day ❝use by❞ dating and specify: ❝Store below 25°C. Do not freeze.❞ Provide the Patient Medication Information to each patient. Do not dispense within 90 days of the expiration date stated on the carton.

Keep in a safe place out of the reach and sight of children.

Reconstituted solution: Store below 25°C. Do not freeze. The product should be used within 3 hours after reconstitution.

Dosage Forms, Composition and Packaging

REVESTIVE is intended for subcutaneous injection and is supplied as a sterile, white lyophilized powder for reconstitution that should be reconstituted with Sterile Water for Injection. The REVESTIVE pack is supplied with the following :

  • 5 mg teduglutide powder in glass vial with rubber stopper (bromobutyl)
  • 0.5 mL of diluent sterile Water for Injection in pre-filled syringe (glass) assembled with plungers (plastic)
  • Pack size of 28 vials of powder and 28 pre-filled syringes

Each single-use vial of REVESTIVE contains 5 mg of teduglutide and the following nonmedicinal ingredients : dibasic sodium phosphate heptahydrate, L-histidine, mannitol, monobasic sodium phosphate monohydrate. No preservatives are present.

Other materials needed for administration but not included in the pack are:

  • Reconstitution needles (size 22G, length 1½" [0.7 x 40 mm])
  • 1 mL injection syringes (with scale intervals of 0.02 mL or smaller)
  • Thin injection needles for subcutaneous injection (e.g. size 26G, length 5/8" [0.45 x 16 mm])
  • Alcohol swabs
  • A puncture-proof container for safe disposal of the used syringes and needles