CLASSES

Glucagon-like Peptide-2 (GLP-2) Analogs

DEA CLASS

Rx

DESCRIPTION

Recombinant glucagon-like peptide-2 (GLP-2) analog; given subcutaneously once daily
Used in adult and pediatric patients 1 year and older with short bowel syndrome (SBS) who are dependent on parenteral nutrition
Potential increased risk of developing cancer, polyps, and intestinal obstruction; perform colonoscopy before prescribing

COMMON BRAND NAMES

Gattex

HOW SUPPLIED

Gattex Subcutaneous Inj Pwd F/Sol: 5mg

DOSAGE & INDICATIONS

MAXIMUM DOSAGE

0.05 mg/kg/day subcutaneously.

0.05 mg/kg/day subcutaneously.

0.05 mg/kg/day subcutaneously.

0.05 mg/kg/day subcutaneously.

Safety and efficacy have not been established.

DOSING CONSIDERATIONS

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.

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.

ADMINISTRATION

For subcutaneous use only. Not for intravenous or intramuscular administration.
Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.

STORAGE

Gattex:
- Discard product if it contains particulate matter, is cloudy, or discolored
- Discard unused portion. Do not store for later use.
- Do not freeze
- Do not freeze reconstituted product
- Prior to dispensing, store in refrigerator (36 to 46 degrees F)
- Reconstituted product should be used within 3 hours
- Store unreconstituted product at or below 77 degrees F

CONTRAINDICATIONS / PRECAUTIONS

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).[52779]

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.[52779]

ADVERSE REACTIONS

cholecystitis / Delayed / 1.0-10.0
GI obstruction / Delayed / 0-5.0
heart failure / Delayed / 3.0-3.0
new primary malignancy / Delayed / Incidence not known
pancreatitis / Delayed / Incidence not known

antibody formation / Delayed / 0-48.0
peripheral edema / Delayed / 10.0-10.0
dyspnea / Early / 0-5.0
edema / Delayed / 1.0-1.0
fluid retention / Delayed / 1.0-1.0
cholestasis / Delayed / Incidence not known
cholangitis / Delayed / Incidence not known
cholelithiasis / Delayed / Incidence not known
erythema / Early / Incidence not known

abdominal pain / Early / 30.0-30.0
nausea / Early / 23.0-23.0
infection / Delayed / 21.0-21.0
injection site reaction / Rapid / 13.0-13.0
vomiting / Early / 12.0-12.0
rash / Early / 0-10.0
flatulence / Early / 9.0-9.0
influenza / Delayed / 7.0-7.0
cough / Delayed / 5.0-5.0
urticaria / Rapid / Incidence not known
flushing / Rapid / Incidence not known
blepharedema / Early / Incidence not known
pruritus / Rapid / Incidence not known
maculopapular rash / Early / Incidence not known

DRUG INTERACTIONS

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.
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.

PREGNANCY AND LACTATION

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).[52779]

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.[52779]

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 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).

PHARMACOKINETICS

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.