Teduglutide is a recombinant glucagon-like peptide-2 (GLP-2) analog. It is used to treat adult and pediatric patients 1 year and older with intestinal failure secondary to short bowel syndrome (SBS) who are dependent on parenteral nutrition. Teduglutide improves bowel function by enhancing absorption of nutrients and fluids, and decreases dependence on parenteral nutrition. Endogenous GLP-2, a gastrointestinal, trophic hormone, is involved in the repair and regeneration of intestinal cells. However, endogenous GLP-2 is rapidly degraded by dipeptidyl peptidase-4 (DDP-4) resulting in a half-life of only 7 minutes. Teduglutide is created in E. coli, and differs from human GLP-2 by the substitution of glycine for alanine at position 2; as a result, teduglutide is resistant to DDP-4 degradation, thereby increasing the half-life and allowing for once-daily subcutaneous administration. Due to a potential increased risk of developing cancer, polyps, and intestinal obstruction, teduglutide is only available through a restricted distribution system (GATTEX REMS Program) for certified prescribers and pharmacies to ensure compliance with the required colonoscopy monitoring prior to and during treatment at the required intervals.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Injectable Administration
-Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
-Missed dose: If a dose is missed, administer it as soon as possible on the same day. Do not administer 2 doses on the same day.
Subcutaneous Administration
Reconstitution
-A 10 mg/mL sterile solution is obtained after reconstitution.
-Slowly inject the 0.5 mL of preservative-free Sterile Water for Injection provided in the prefilled syringe into the vial containing teduglutide.
-Allow the vial containing teduglutide 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.
-If undissolved powder is observed, gently roll the vial again until all material is dissolved.
-If the product remains undissolved after the second attempt, do not use.
-A maximum of 0.38 mL of the reconstituted solution, containing 3.8 mg of teduglutide, can be withdrawn from the vial for dosing.
-Teduglutide does not contain any preservatives and is a clear, colorless to a light straw-colored solution. If there is any discoloration or particulates, discard the solution.
-Storage: Teduglutide is for single-use only; use within 3 hours after reconstitution. Discard any unused portion.
Subcutaneous Injection
-Calculate the approximate teduglutide dose, withdraw into a syringe, and administer as a subcutaneous injection.
-Appropriate sites include the thighs, upper arms, and the quadrants of the abdomen.
-Missed dose: If a dose is missed, administer it as soon as possible on the same day. Do not administer 2 doses on the same day.
-Alternate administration sites with each injection.
Teduglutide was studied in 2 randomized, placebo-controlled, multicenter clinical trials involving 136 adult patients and in 2 clinical studies involving 41 pediatric patients aged 1 year to less than 17 years. Overall, the safety profile of teduglutide in pediatric patients was similar to that in adults.
Teduglutide use may be associated with accelerated neoplastic growth, colorectal polyps, and small bowel neoplasia; patients should be screened regularly for new primary malignancy or malignancy risk factors. In adult patients, colonoscopy with polyp removal must be performed before treatment. Repeat colonoscopy is recommended at 1 year of use; subsequent colonoscopies may be performed as needed but should be performed at least every 5 years. In pediatric patients, perform fecal occult blood testing prior to initiating treatment and annually while receiving teduglutide; if there is unexplained blood in the stool with initial testing, perform colonoscopy/sigmoidoscopy. Perform colonoscopy/sigmoidoscopy after 1 year of treatment, every 5 years thereafter while on continuous teduglutide treatment, or if new or unexplained gastrointestinal bleeding occurs. If malignancy occurs, discontinue the drug; benefits and risks of treatment should be carefully considered in patients who develop a non-GI malignancy. In adult clinical studies with teduglutide 0.05 mg/kg/day, 3 patients were diagnosed with a new primary malignancy. All patients were male. One had a history of abdominal radiation for Hodgkin's disease 2 decades before receiving teduglutide and a prior liver lesion on CT scan and was diagnosed with metastatic adenocarcinoma of unconfirmed origin after 11 months of exposure to teduglutide. Two subjects with extensive smoking histories were diagnosed with lung cancers (squamous and non-small cell) after 12 months and 3 months of teduglutide exposure, respectively. Additionally, 14 subjects were diagnosed with polyps of the GI tract after initiation of study treatment. In the short bowel syndrome controlled trials, 1/109 (1%) of subjects on teduglutide 0.05 mg/kg/day and 1/59 (2%) of subjects on placebo 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 teduglutide 0.1 and 0.05 mg/kg/day dose groups, respectively), 2 hyperplastic polyps (onset 6 months in teduglutide 0.1 mg/kg/day dose group and 24 months in the 0.05 mg/kg/day dose group), 4 colorectal tubular adenomas (onset between 24 and 29 months in teduglutide 0.05 mg/kg/day dose group), 1 serrated adenoma (onset at 24 months in teduglutide 0.05 mg/kg/day dose group), 1 colorectal polyp biopsy not done (onset at 24 months in teduglutide 0.05 mg/kg/day dose group), 1 rectal inflammatory polyp (onset at 10 months in the teduglutide 0.05 mg/kg/day dose group), and 1 small duodenal polyp (onset at 3 months in teduglutide 0.05 mg/kg/day dose group). In pediatric patients, one case of cecal polyp was reported, but was not biopsied and was not seen on repeat colonoscopy.
In adult clinical studies with teduglutide, gastrointestinal blockage (GI obstruction) was reported in 12 subjects. Patients experienced 1 or more episodes of intestinal obstruction/stenosis. Six cases of GI obstruction occurred in the placebo-controlled trials and all 6 patients were receiving teduglutide: 3/77 (4%) on teduglutide 0.05 mg/kg/day and 3/32 (9%) on teduglutide 0.1 mg/kg/day (twice the recommended dose). 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 receiving teduglutide 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 a 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. Small intestinal stenosis was reported in less than 5% of patients treated with teduglutide. In pediatric clinical studies, obstruction was reported in 1 patient; teduglutide was temporarily withheld and the obstruction resolved without further intervention. If a patient develops intestinal obstruction, temporarily discontinue teduglutide therapy pending clinical evaluation and management.
In adult studies with teduglutide, gallbladder, biliary, and pancreatic disease were reported. In placebo-controlled studies, 3 patients were diagnosed with cholecystitis, all of whom had a prior history of gallbladder disease and were in the teduglutide 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; 3 subjects had new-onset cholelithiasis, and 1 patient experienced cholestasis secondary to an obstructed biliary stent. Additionally, 1 subject in the placebo-controlled studies who was receiving teduglutide 0.05 mg/kg/day had a pancreatic pseudocyst diagnosed after 4 months of teduglutide therapy. In the extension studies, 1 subject was diagnosed with chronic pancreatitis; and 1 subject was diagnosed with acute pancreatitis. Colonic stenosis and pancreatic duct stenosis were reported in less than 5% of patients treated with teduglutide. During postmarketing, cholecystitis, cholangitis, and cholelithiasis have been reported. To identify the onset or worsening of the biliary tract or pancreatic disease, bilirubin, alkaline phosphatase, lipase, and amylase should be assessed before therapy and every 6 months after that. If abnormalities are seen, further clinical evaluation is recommended (including imaging of the pancreas, gallbladder, and biliary tract), and reassess the need for continued teduglutide treatment.
Fluid overload was reported in 12% of overall adult patients receiving teduglutide vs. 7% of patients receiving placebo in 2 randomized, placebo-controlled, 24-week, double-blind clinical studies. Peripheral edema accounted for 10% of adult subjects receiving teduglutide 0.05 mg/kg/day vs. 3% of subjects taking placebo who experienced fluid overload. Generalized edema was reported in 1% of adult patients in the teduglutide group vs. 0% with placebo. Fluid retention and jugular vein distension were other types of fluid overload reported. There were 2 cases (3%) of congestive heart failure (CHF) in adult patients receiving teduglutide; 1 case 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 or cardiac dysfunction.
As with all therapeutic proteins, antibody formation to teduglutide may occur. Based on integrated data from 2 adult trials (a 6-month randomized placebo-controlled trial, followed by a 24-month open-label trial), the development of anti-teduglutide antibodies in patients who received 0.05 mg/kg teduglutide subcutaneously once daily was 3% (2/60) at Month 3, 17% (13/77) at Month 6, 24% (16/67) at Month 12, 33% (11/33) at Month 24, and 48% (14/29) at Month 30. Anti-teduglutide antibodies were cross-reactive to native glucagon-like peptide-2 (GLP-2) in 5 of the 6 patients (83%) who had anti-teduglutide antibodies and were tested for cross-reactivity. In the same 2 trials, a total of 36 patients were tested for neutralizing antibodies: 1 patient developed borderline positive neutralizing antibody responses at month 24 of the extension trial. During a clinical trial in pediatric patients, the development of anti-teduglutide antibodies in patients who received 0.05 mg/kg teduglutide subcutaneously once daily for 24 weeks was 19% (5/26) at Month 6 and was similar to the rate of antibody formation in adult patients (17%). Of the 5 pediatric patients who developed antibodies to teduglutide at Month 6, 2 patients had neutralizing antibodies. The rate of anti-teduglutide antibody formation at Month 12 was higher in pediatric patients (54%) compared to that of adults (24%). Of the 14 pediatric patients who developed antibodies to teduglutide at Month 12, 1 patient had neutralizing antibodies. The antibody formation has not been associated with clinically relevant safety findings, reduced efficacy of the drug, or changed the pharmacokinetics of teduglutide.
Gastrointestinal (GI) adverse effects have been reported in adult patients receiving teduglutide. GI adverse reactions occurring in patients during the 2 pivotal clinical studies with a rate of at least 5% in the teduglutide group (n = 77) and at an incidence greater than with placebo were: abdominal pain (30%), nausea (23%), abdominal distension (20%), vomiting (12%), flatulence (9%), and decreased appetite (7%). In subjects with a stoma, GI stoma complication was reported in 13/31 (42%) subjects receiving teduglutide and 3/22 (14%) of subjects receiving placebo.
Injection site reaction was among the most commonly reported adverse reactions in adult patients treated with teduglutide and was reported in 13% of patients compared to 12% placebo. Hypersensitivity reactions have also been reported in 10% subjects on teduglutide and 7% of subjects on placebo. Hypersensitivity reactions included erythema, rash, allergic dermatitis, pruritus, maculopapular rash, urticaria or drug eruption, eyelid edema (blepharedema), and flushing.
Adverse reactions occurring in adult patients participating in 2 pivotal clinical studies with a rate of at least 5% in the teduglutide group (n = 77) and an incidence greater than with placebo were: upper respiratory tract infection (21%), influenza (7%), cough (5%), skin hemorrhage (5%), and sleep disturbances (5%). Dyspnea was reported in less than 5% of patients treated with teduglutide.
In patients at increased risk for neoplastic disease, consider use of teduglutide only if the benefits outweigh the risks. Based on the pharmacologic activity and findings in animals, teduglutide has the potential to cause hyperplastic changes including new primary malignancy. In patients with active gastrointestinal malignancy (GI tract, hepatobiliary, pancreatic), teduglutide should be discontinued. In patients with active non-gastrointestinal malignancy, the decision to continue teduglutide should be made based on risk-benefit considerations. During clinical trials, colorectal polyps were identified. Therefore, colonoscopy of the entire colon with removal of polyps should be done in adult patients within 6 months prior to starting treatment with teduglutide. A follow-up colonoscopy (or alternate imaging) is recommended at the end of 1 year of teduglutide use, with subsequent colonoscopies every 5 years or more often as needed. If a polyp is found, adherence to current polyp follow-up guidelines is recommended. In pediatric patients, perform fecal occult blood testing prior to initiating treatment and annually while receiving teduglutide. If there is unexplained blood in the stool with initial testing, perform colonoscopy/sigmoidoscopy. A follow-up colonoscopy (or alternate imaging) is recommended at the end of 1 year of teduglutide use, every 5 years thereafter while on continuous teduglutide treatment, or if new or unexplained gastrointestinal bleeding occurs. If a patient is diagnosed with colorectal cancer, discontinue therapy with teduglutide. Patients should also be monitored clinically for small bowel neoplasia; if a benign neoplasm is found, it should be removed. In case of small bowel cancer, discontinue therapy with teduglutide.
In clinical trials, GI obstruction has been reported. In patients who develop intestinal or stomal obstruction, temporarily discontinue teduglutide while the patient is clinically managed. Teduglutide may be restarted when the obstructive presentation resolves, if clinically indicated.
Cholecystitis, cholangitis, and cholelithiasis, have been reported in clinical studies. In order to identify the onset or worsening of gallbladder disease or biliary tract disease, patients should undergo laboratory assessment of bilirubin and alkaline phosphatase within 6 months prior to starting teduglutide and at least every 6 months while on teduglutide. If clinically meaningful changes are evident, further evaluation including imaging of the gallbladder and/or biliary tract is recommended; the need for continued teduglutide treatment should be reassessed.
Pancreatitis has been reported in clinical studies. In order to identify the onset or worsening of pancreatic disease, patients should undergo laboratory assessment of lipase and amylase within 6 months prior to starting teduglutide and at least every 6 months while on teduglutide. If clinically meaningful changes are evident, further evaluation such as imaging of the pancreas is recommended; the need for continued teduglutide treatment should be reconsidered.
Teduglutide should be used cautiously in patients with cardiac disease and congestive heart failure. Fluid overload and congestive heart failure have been reported in clinical trials, as a result of enhanced fluid absorption associated with teduglutide. Fluid overload may lead to electrolyte imbalance. If fluid overload occurs, adjust parenteral support and reassess teduglutide treatment If significant cardiac deterioration develops while on teduglutide, reconsider the need for continued teduglutide treatment. In addition, discontinuation of treatment with teduglutide in any patient may result in fluid and electrolyte imbalance. Therefore, monitor patients' fluid and electrolyte status carefully.
In patients with moderate and severe renal impairment (creatinine clearance less than 60 mL/minute) and end-stage renal disease (renal failure), dose reduction of teduglutide is recommended.
Available data from case reports with teduglutide use during human pregnancy have not identified a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Pregnant women with short bowel syndrome are at risk for malnutrition, which is associated with adverse maternal and fetal outcomes. Severe malnutrition in pregnant women is associated with preterm delivery, low birth weight, intrauterine growth restriction, congenital malformations, and perinatal mortality. In animal reproduction studies, no effects on embryo-fetal development or impaired fertility were observed with the subcutaneous administration of teduglutide to pregnant rats and rabbits during organogenesis at exposures up to 686 and 657 times, respectively, the clinical exposure at the recommended daily human dose (RDHD), based on AUC. In a pre- and postnatal development study in rats (gestation day 7 to lactation day 20), teduglutide did not show any significant adverse effects on pre- and postnatal development at doses up to 25 mg/kg twice daily (50 mg/kg/day) (about 343 times the RDHD of 0.05 mg/kg, based on body surface area).
Because of the potential for serious adverse reactions in a breastfed infant, including tumorigenicity, advise lactating patients that breast-feeding is not recommended while they are receiving teduglutide. There is no information regarding the presence of teduglutide in human milk, the effects on the breastfed infant, or the effects of the drug on milk production. Systemic exposure of teduglutide to a breastfed infant is expected to be low. Teduglutide is present in the milk of lactating rats. The maximum concentration of teduglutide in the rat milk corresponded to 0.9% and 2.9% of the plasma concentration at 1.5 and 4 hours after dosing, respectively. However, these data may not be reflective of human use due to differences in lactation physiology.
For the treatment of short bowel syndrome in persons who are dependent on parenteral support:
Subcutaneous dosage:
Adults: 0.05 mg/kg/dose subcutaneously once daily.
Children and Adolescents: 0.05 mg/kg/dose subcutaneously once daily.
Therapeutic Drug Monitoring:
-Colonoscopy Schedule in Adults: Perform a colonoscopy with polyp removal within 6 months prior to starting teduglutide. Repeat colonoscopy at 1 year of use. If no polyp is found, perform subsequent colonoscopies no less frequently than every 5 years. If a polyp is found, adhere to current polyp follow-up guidelines.
-Colonoscopy Schedule in Pediatric Patients: Perform fecal occult blood testing prior to initiating treatment and annually while receiving teduglutide. If there is unexplained blood in the stool with initial testing, perform colonoscopy/sigmoidoscopy. Perform colonoscopy/sigmoidoscopy after 1 year of treatment, every 5 years thereafter while on continuous teduglutide treatment, or if new or unexplained gastrointestinal bleeding occurs.
-Laboratory testing is recommended every 6 months.
Maximum Dosage Limits:
-Adults
0.05 mg/kg/day subcutaneously.
-Geriatric
0.05 mg/kg/day subcutaneously.
-Adolescents
0.05 mg/kg/day subcutaneously.
-Children
0.05 mg/kg/day subcutaneously.
-Infants
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
Mild and moderate hepatic impairment (Child-Pugh grade A and B): No dosage adjustment is recommended.
Severe hepatic impairment (Child-Pugh grade C): Teduglutide has not been studied.
Patients with Renal Impairment Dosing
eGFR 60 mL/minute/1.73 m2 or more: No dosage adjustment is necessary.
eGFR less than 60 mL/minute/1.73 m2: 0.025 mg/kg/dose subcutaneously once daily.
*non-FDA-approved indication
Alprazolam: (Moderate) Altered mental status has been observed in patients taking teduglutide and benzodiazepines in the adult clinical studies for teduglutide. Careful monitoring and possible dose adjustment of the benzodiazepine agent may be required. Teduglutide has direct effects on the gut that may increase benzodiazepine exposure by improving oral absorption.
Benzodiazepines: (Moderate) Altered mental status has been observed in patients taking teduglutide and benzodiazepines in the adult clinical studies for teduglutide. Careful monitoring and possible dose adjustment of the benzodiazepine agent may be required. Teduglutide has direct effects on the gut that may increase benzodiazepine exposure by improving oral absorption.
Carbamazepine: (Moderate) Teduglutide may increase absorption of carbamazepine because of it's pharmacodynamic effect of improving intestinal absorption. Careful monitoring and possible dose adjustment of cabamazepine is recommended.
Chlordiazepoxide: (Moderate) Altered mental status has been observed in patients taking teduglutide and benzodiazepines in the adult clinical studies for teduglutide. Careful monitoring and possible dose adjustment of the benzodiazepine agent may be required. Teduglutide has direct effects on the gut that may increase benzodiazepine exposure by improving oral absorption.
Chlordiazepoxide; Amitriptyline: (Moderate) Altered mental status has been observed in patients taking teduglutide and benzodiazepines in the adult clinical studies for teduglutide. Careful monitoring and possible dose adjustment of the benzodiazepine agent may be required. Teduglutide has direct effects on the gut that may increase benzodiazepine exposure by improving oral absorption.
Chlordiazepoxide; Clidinium: (Moderate) Altered mental status has been observed in patients taking teduglutide and benzodiazepines in the adult clinical studies for teduglutide. Careful monitoring and possible dose adjustment of the benzodiazepine agent may be required. Teduglutide has direct effects on the gut that may increase benzodiazepine exposure by improving oral absorption.
Clobazam: (Moderate) Altered mental status has been observed in patients taking teduglutide and benzodiazepines in the adult clinical studies for teduglutide. Careful monitoring and possible dose adjustment of the benzodiazepine agent may be required. Teduglutide has direct effects on the gut that may increase benzodiazepine exposure by improving oral absorption.
Clonazepam: (Moderate) Altered mental status has been observed in patients taking teduglutide and benzodiazepines in the adult clinical studies for teduglutide. Careful monitoring and possible dose adjustment of the benzodiazepine agent may be required. Teduglutide has direct effects on the gut that may increase benzodiazepine exposure by improving oral absorption.
Clorazepate: (Moderate) Altered mental status has been observed in patients taking teduglutide and benzodiazepines in the adult clinical studies for teduglutide. Careful monitoring and possible dose adjustment of the benzodiazepine agent may be required. Teduglutide has direct effects on the gut that may increase benzodiazepine exposure by improving oral absorption.
Cyclosporine: (Moderate) Teduglutide may increase absorption of cyclosporine because of it's pharmacodynamic effect of improving intestinal absorption. Careful monitoring and possible dose adjustment of cyclosporine is recommended.
Dextromethorphan; Quinidine: (Moderate) Teduglutide may increase absorption of quinidine because of it's pharmacodynamic effect of improving intestinal absorption. Careful monitoring and possible dose adjustment of quinidine is recommended.
Diazepam: (Moderate) Altered mental status has been observed in patients taking teduglutide and benzodiazepines in the adult clinical studies for teduglutide. Careful monitoring and possible dose adjustment of the benzodiazepine agent may be required. Teduglutide has direct effects on the gut that may increase benzodiazepine exposure by improving oral absorption.
Digoxin: (Moderate) Teduglutide may increase absorption of digoxin because of it's pharmacodynamic effect of improving intestinal absorption. Careful monitoring and possible dose adjustment of digoxin is recommended.
Disopyramide: (Moderate) Teduglutide may increase absorption of disopyramide because of it's pharmacodynamic effect of improving intestinal absorption. Careful monitoring and possible dose adjustment of disopyramide is recommended.
Estazolam: (Moderate) Altered mental status has been observed in patients taking teduglutide and benzodiazepines in the adult clinical studies for teduglutide. Careful monitoring and possible dose adjustment of the benzodiazepine agent may be required. Teduglutide has direct effects on the gut that may increase benzodiazepine exposure by improving oral absorption.
Ethosuximide: (Moderate) Teduglutide may increase absorption of ethosuximide because of it's pharmacodynamic effect of improving intestinal absorption. Careful monitoring and possible dose adjustment of ethosuximide is recommended.
Flecainide: (Moderate) Teduglutide may increase absorption of flecainide because of it's pharmacodynamic effect of improving intestinal absorption. Careful monitoring and possible dose adjustment of flecainide is recommended.
Flurazepam: (Moderate) Altered mental status has been observed in patients taking teduglutide and benzodiazepines in the adult clinical studies for teduglutide. Careful monitoring and possible dose adjustment of the benzodiazepine agent may be required. Teduglutide has direct effects on the gut that may increase benzodiazepine exposure by improving oral absorption.
Levothyroxine: (Moderate) Monitor thyroid status and for symptoms of increased thyroid effect. Based upon the pharmacodynamic effect of teduglutide, there is a potential for increased absorption of concomitant oral medications, which should be considered if these drugs require titration or have a narrow therapeutic index, such as orally administered thyroid hormones.
Levothyroxine; Liothyronine (Porcine): (Moderate) Monitor thyroid status and for symptoms of increased thyroid effect. Based upon the pharmacodynamic effect of teduglutide, there is a potential for increased absorption of concomitant oral medications, which should be considered if these drugs require titration or have a narrow therapeutic index, such as orally administered thyroid hormones.
Levothyroxine; Liothyronine (Synthetic): (Moderate) Monitor thyroid status and for symptoms of increased thyroid effect. Based upon the pharmacodynamic effect of teduglutide, there is a potential for increased absorption of concomitant oral medications, which should be considered if these drugs require titration or have a narrow therapeutic index, such as orally administered thyroid hormones.
Liothyronine: (Moderate) Monitor thyroid status and for symptoms of increased thyroid effect. Based upon the pharmacodynamic effect of teduglutide, there is a potential for increased absorption of concomitant oral medications, which should be considered if these drugs require titration or have a narrow therapeutic index, such as orally administered thyroid hormones.
Lithium: (Moderate) Teduglutide may increase absorption of lithium because of it's pharmacodynamic effect of improving intestinal absorption. Careful monitoring and possible dose adjustment of lithium is recommended.
Lorazepam: (Moderate) Altered mental status has been observed in patients taking teduglutide and benzodiazepines in the adult clinical studies for teduglutide. Careful monitoring and possible dose adjustment of the benzodiazepine agent may be required. Teduglutide has direct effects on the gut that may increase benzodiazepine exposure by improving oral absorption.
Midazolam: (Moderate) Altered mental status has been observed in patients taking teduglutide and benzodiazepines in the adult clinical studies for teduglutide. Careful monitoring and possible dose adjustment of the benzodiazepine agent may be required. Teduglutide has direct effects on the gut that may increase benzodiazepine exposure by improving oral absorption.
Nanoparticle Albumin-Bound Sirolimus: (Moderate) Teduglutide may increase absorption of sirolimus because of it's pharmacodynamic effect of improving intestinal absorption. Careful monitoring and possible dose adjustment of sirolimus is recommended.
Oxazepam: (Moderate) Altered mental status has been observed in patients taking teduglutide and benzodiazepines in the adult clinical studies for teduglutide. Careful monitoring and possible dose adjustment of the benzodiazepine agent may be required. Teduglutide has direct effects on the gut that may increase benzodiazepine exposure by improving oral absorption.
Phenytoin: (Moderate) Teduglutide may increase absorption of phenytoin because of it's pharmacodynamic effect of improving intestinal absorption. Careful monitoring and possible dose adjustment of phenytoin is recommended.
Procainamide: (Moderate) Teduglutide may increase absorption of procainamide because of it's pharmacodynamic effect of improving intestinal absorption. Careful monitoring and possible dose adjustment of procainamide is recommended.
Quazepam: (Moderate) Altered mental status has been observed in patients taking teduglutide and benzodiazepines in the adult clinical studies for teduglutide. Careful monitoring and possible dose adjustment of the benzodiazepine agent may be required. Teduglutide has direct effects on the gut that may increase benzodiazepine exposure by improving oral absorption.
Quinidine: (Moderate) Teduglutide may increase absorption of quinidine because of it's pharmacodynamic effect of improving intestinal absorption. Careful monitoring and possible dose adjustment of quinidine is recommended.
Remimazolam: (Moderate) Altered mental status has been observed in patients taking teduglutide and benzodiazepines in the adult clinical studies for teduglutide. Careful monitoring and possible dose adjustment of the benzodiazepine agent may be required. Teduglutide has direct effects on the gut that may increase benzodiazepine exposure by improving oral absorption.
Sirolimus: (Moderate) Teduglutide may increase absorption of sirolimus because of it's pharmacodynamic effect of improving intestinal absorption. Careful monitoring and possible dose adjustment of sirolimus is recommended.
Tacrolimus: (Moderate) Teduglutide may increase absorption of tacrolimus because of it's pharmacodynamic effect of improving intestinal absorption. Careful monitoring and possible dose adjustment of tacrolimus is recommended.
Temazepam: (Moderate) Altered mental status has been observed in patients taking teduglutide and benzodiazepines in the adult clinical studies for teduglutide. Careful monitoring and possible dose adjustment of the benzodiazepine agent may be required. Teduglutide has direct effects on the gut that may increase benzodiazepine exposure by improving oral absorption.
Theophylline, Aminophylline: (Moderate) Teduglutide may increase the oral absorption of theophylline because of teduglutide's effect of improving intestinal absorption. Careful monitoring and possible dose adjustment of theophylline or aminophylline is recommended.
Thyroid hormones: (Moderate) Monitor thyroid status and for symptoms of increased thyroid effect. Based upon the pharmacodynamic effect of teduglutide, there is a potential for increased absorption of concomitant oral medications, which should be considered if these drugs require titration or have a narrow therapeutic index, such as orally administered thyroid hormones.
Triazolam: (Moderate) Altered mental status has been observed in patients taking teduglutide and benzodiazepines in the adult clinical studies for teduglutide. Careful monitoring and possible dose adjustment of the benzodiazepine agent may be required. Teduglutide has direct effects on the gut that may increase benzodiazepine exposure by improving oral absorption.
Valproic Acid, Divalproex Sodium: (Moderate) Teduglutide may increase absorption of valproic acid, divalproex sodium because of it's pharmacodynamic effect of improving intestinal absorption. Careful monitoring and possible dose adjustment of valproic acid is recommended.
Warfarin: (Moderate) Although an interaction is possible, these drugs may be used together. Teduglutide may increase the actions of warfarin. Your prescriber will monitor your therapy closely. Report any unusual effects to your prescriber.
Teduglutide is an analog of naturally occurring human glucagon-like peptide-2 (GLP-2), a peptide secreted by L-cells of the distal intestine in response to a meal. GLP-2 is known to increase intestinal and portal blood flow, inhibit gastric acid secretion, and decrease gastric motility. GLP-2 appears to induce its effects most readily in the small bowel; however high doses may elicit changes in the colon as well. GLP-2 induces proliferation of the small bowel mucosa by stimulating crypt compartment cell proliferation and inhibiting apoptosis of enterocytes. Small bowel villus height and diameter are also increased; these trophic actions increase the surface area of the small intestine allowing for increased absorption of nutrients. 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, nitric oxide and keratinocyte growth factor (KGF).
Teduglutide is given via subcutaneous administration. In healthy subjects, teduglutide has a volume of distribution (103 mL/kg) similar to blood volume. Although the metabolic pathway of teduglutide has not been studied in humans, teduglutide is expected to be degraded into small peptides and amino acids via catabolic pathways, similar to the catabolism of endogenous GLP-2. The plasma clearance of teduglutide in healthy subjects was approximately 123 mL/hour/kg, which is similar to the GFR suggesting that teduglutide is primarily cleared by the kidney. The mean terminal half-life of teduglutide is approximately 2 hours in healthy subjects and 1.3 hours in patients with short bowel syndrome (SBS).
In a dose-ranging study of 17 adults with SBS, the ability of teduglutide to improve intestinal absorption was assessed using daily subcutaneous doses of 0.03, 0.10, 0.15 mg/kg (n = 2 to 3 per dose group) over 21 days. All doses studied, except 0.03 mg/kg once daily, resulted in enhanced gastrointestinal fluid (wet weight) absorption of approximately 750 to 1,000 mL/day, and increased villus height and crypt depth of the intestinal mucosa.
-Route-Specific Pharmacokinetics
Subcutaneous Route
In healthy subjects, subcutaneous administration of teduglutide had an absolute bioavailability of 88% and reached maximum plasma concentrations at 3 to 5 hours after administration. After a 0.05 mg/kg subcutaneous dose in patients with SBS, the median peak concentration (Cmax) was 36 ng/mL and the median area under the curve (AUC) was 0.15 mcg x hour/mL. No accumulation of teduglutide was observed after repeated subcutaneous administrations. The Cmax and AUC of teduglutide was dose proportional over the dose range of 0.05 to 0.4 mg/kg.
-Special Populations
Hepatic Impairment
Patients with moderate hepatic impairment had lower teduglutide Cmax and AUC compared to healthy matched control subjects after a single 20 mg subcutaneous dose. Subjects with severe hepatic impairment were not studied.
Renal Impairment
In subjects with moderate to severe renal impairment or end stage renal disease (ESRD), after a 10 mg subcutaneous dose of teduglutide, Cmax and AUC increased with the degree of renal impairment. In subjects with ESRD, teduglutide exposure increased by a factor of 2.1 (Cmax) and 2.6 (AUC) compared to healthy subjects.
Pediatrics
In pediatric patients, similar teduglutide Cmax was seen across all age groups. Lower AUC was seen in pediatric patients 1 to 17 years of age as compared with adults and increased with increasing age. For pediatric patients 1 to 11 years (n = 37) the mean Cmax was 33.5 +/- 11.5 ng/mL, AUCss was 128 +/- 56.7 ng x hour/mL, CL/F was 7.45 +/- 2.1 L/hour, and t1/2 was 0.7 +/- 0.2 hours. For pediatric patients 12 to 17 years (n = 3) the mean Cmax was 29.7 +/- 8.4 ng/mL, AUCss was 154 +/- 17.6 ng x hour/mL, CL/F was 13 +/- 2.3 L/hour, and t1/2 was 1 +/- 0.01 hours.
Geriatric
No pharmacokinetic differences 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 Differences
Gender did not affect the pharmacokinetics of teduglutide.