Gattestive^® (Lyophilisate) Instructions for Use

Marketing Authorization Holder

Takeda Pharmaceuticals International AG Ireland Branch (Ireland)

Manufactured By

Patheon Italia, S.P.A. (Italy)

Labeled By

ALMAC PHARMA SERVICES, Limited (United Kingdom)

Solvent Manufacturer

VETTER PHARMA-FERTIGUNG, GmbH & Co.KG (Germany)

Quality Control Release

TAKEDA PHARMACEUTICALS INTERNATIONAL AG IRELAND BRANCH (Ireland)

ATC Code

A16AX08 (Teduglutide)

Active Substance

Teduglutide (Rec.INN registered by WHO)

Dosage Form

Gattestive®

Lyophilisate for the preparation of solution for subcutaneous administration 5 mg: vial 28 pcs. in a set with solvent

Dosage Form, Packaging, and Composition

Lyophilisate for the preparation of solution for subcutaneous administration in the form of a white powder or a compacted white porous mass (whole or crumbled); solvent – a transparent colorless liquid; reconstituted solution – a clear or slightly opalescent, colorless solution.

Excipients: L-histidine – 3.88 mg, mannitol – 15 mg, sodium dihydrogen phosphate monohydrate – 0.645 mg, sodium hydrogen phosphate heptahydrate – 3.435 mg, 1H hydrochloric acid solution (for pH adjustment) – q.s. to pH 7.4, 1M sodium hydroxide solution (for pH adjustment) – q.s. to pH 7.4.

1 pre-filled syringe with solvent contains water for injections – 0.5 ml.

Vials made of borosilicate glass (type I) with a volume of 3 ml (28) in a set with solvent (syringe volume 1.5 ml, amount of solvent – 0.5 ml, 28 pcs.) – cardboard packs.

To control the first opening of the pack, two special stickers are provided.

Clinical-Pharmacological Group

Glucagon-like peptide-2 (GLP-2) analog used for short bowel syndrome (SBS)

Pharmacotherapeutic Group

Drugs for the treatment of gastrointestinal diseases and metabolic disorders

Pharmacological Action

Teduglutide is an analog of glucagon-like peptide-2 (GLP-2) produced in Escherichia coli cells using recombinant DNA technology.

Mechanism of action

Natural human GLP-2, secreted by L cells of the intestine, enhances intestinal and portal blood flow, suppresses the secretion of hydrochloric acid in the stomach, and reduces intestinal peristalsis. Preclinical studies have shown that Teduglutide preserves the integrity of the mucosa by stimulating the restoration and normal growth of the intestine by increasing the size of the intestinal villi and the depth of the crypts.

Pharmacodynamics

Like GLP-2, Teduglutide is a polypeptide chain of 33 amino acids in which alanine is replaced by glycine at the second position of the N-terminus. The replacement of a single amino acid compared to naturally produced GLP-2 results in resistance to in vivo degradation by the enzyme dipeptidyl peptidase-4 (DPP-4), which prolongs the half-life of teduglutide. Teduglutide increases the size of the villi and the depth of the intestinal epithelial crypts.

According to preclinical data (see section “Special Instructions”) and the proposed mechanism of action, along with trophic effects on the intestinal mucosa, there is a risk of stimulating the growth of neoplasms of the small and/or large intestine. Conducted clinical studies could neither exclude nor confirm the presence of this increased risk. During clinical trials, several cases of benign colorectal polyp formation were noted, but their frequency did not increase compared to patients receiving placebo. In addition to the need for colonoscopy to remove polyps by the start of therapy (see section “Special Instructions”), each patient should be continuously monitored taking into account their characteristics (e.g., age, underlying disease, history of polyps).

Pharmacokinetics

Absorption

Teduglutide is rapidly absorbed from the site of subcutaneous injection; C_max in plasma is reached approximately 3-5 hours after administration of the drug at all doses. The absolute bioavailability of teduglutide for subcutaneous administration is high (88%). No accumulation of teduglutide was observed after repeated subcutaneous administration.

The rate and extent of absorption of teduglutide are proportional to the dose after single and repeated subcutaneous administration in doses up to 20 mg.

Distribution

After subcutaneous administration, the apparent V_d of teduglutide is 26 L in patients with short bowel syndrome.

Metabolism

The metabolism of teduglutide has not been fully studied. Since Teduglutide is a peptide, its metabolism is likely to correspond to the main mechanism of peptide metabolism.

Elimination

The terminal T_1/2 of teduglutide is approximately 2 hours. After intravenous administration, the plasma clearance of teduglutide was approximately 127 ml/h/kg, which is equivalent to the glomerular filtration rate. During the pharmacokinetic study of the drug, the elimination of teduglutide by the kidneys was confirmed in patients with renal failure.

Pharmacokinetics in special patient groups

Children. After subcutaneous administration of teduglutide, similar C_max values were demonstrated in all age groups using population pharmacokinetic modeling. However, lower exposure (AUC) and shorter T_1/2 were noted in patients aged 1 year to 17 years compared to adult patients. The pharmacokinetic profile of teduglutide in this population of children (according to clearance and V_d values) differed from that in adult patients after correction for body weight. In particular, clearance decreases with increasing age from 1 year and as they grow older. There are no data in pediatric patients with moderate or severe renal impairment, or end-stage renal disease.

Gender. In clinical studies, no significant differences depending on patient gender were observed.

Elderly patients. In phase 1 clinical studies, no differences in the pharmacokinetic parameters of teduglutide were identified in healthy volunteers under 65 years of age compared to volunteers over 65 years of age. Experience with teduglutide in volunteers aged 75 years and older is limited.

Impaired liver function. Phase 1 clinical studies evaluated the effect of hepatic impairment on the pharmacokinetic parameters of teduglutide after its subcutaneous administration at a dose of 20 mg. The maximum exposure and total exposure of teduglutide after a single subcutaneous administration of a 20 mg dose were lower (10-15%) in volunteers with moderate hepatic impairment than in healthy volunteers.

Impaired renal function. Phase 1 clinical studies evaluated the effect of renal impairment on the pharmacokinetic parameters of teduglutide after its subcutaneous administration at a dose of 10 mg. As renal impairment progressed to the terminal stage, the main pharmacokinetic parameters of teduglutide increased by 2.6 (AUC_inf) and 2.1 (C_max) times compared to the values in healthy volunteers.

Indications

• For the treatment of patients aged 1 year and older with short bowel syndrome (SBS). Patients should be in a stable condition after a period of intestinal adaptation following surgery.

ICD codes

Dosage Regimen

The drug Gattestive^® is intended for subcutaneous administration only.

The drug solution should be administered subcutaneously once daily, daily, alternating injection sites in the four quadrants of the abdominal wall. If administration of the drug into the abdomen is complicated by pain, scarring, or tissue induration, the thigh area can be used for injection.

Do not administer Gattestive^® intravenously or intramuscularly.

Treatment should be initiated under the supervision of a physician experienced in the treatment of patients with SBS.

Therapy should not be initiated until the patient has reached a stable condition after a period of intestinal adaptation. Before starting therapy, intravenous fluid and parenteral nutrition should be optimized and stabilized.

Based on the assessment of the patient’s clinical condition, the physician should determine individual therapy goals and patient preferences. Therapy should be discontinued if an overall improvement in the patient’s condition is not achieved. The efficacy and safety of therapy in all patients should be continuously monitored in accordance with clinical guidelines.

Dosage regimen

Adult patients

The recommended dose of Gattestive^® is 0.05 mg/kg body weight once daily. Table 1 below indicates the volume of the drug solution to be administered based on the patient’s body weight. Due to the heterogeneity of the SBS patient population, some patients may require a carefully controlled reduction in the daily dose of the drug to improve treatment tolerance.

If a dose of the drug is missed, it should be administered as soon as possible on the same day.

The efficacy of therapy should be assessed after 6 months of treatment. Limited clinical trial data have shown that some patients may respond to therapy after a longer period of time (i.e., those who still have a colon or distal/terminal ileum); if overall improvement is not achieved after 12 months of therapy, the need to continue treatment should be re-evaluated.

Continuation of therapy is also recommended for patients who have discontinued parenteral nutrition.

Table 1

Children (≥1 year)

Therapy should be initiated by a physician experienced in the treatment of SBS in children.

The recommended dose of Gattestive^® in children and adolescents (aged 1 to 17 years) is the same as in adult patients (0.05 mg/kg body weight once daily). Table 2 below indicates the recommended volume of the drug based on the child’s body weight.

If a dose of the drug is missed, it should be administered as soon as possible on the same day.

The recommended treatment period is 6 months, after which the efficacy of therapy should be assessed. In children under 2 years of age, it is recommended to assess the efficacy of therapy after 12 weeks of therapy. There are no data on the use of the drug for more than 6 months in children.

Table 2

The volume of the injection syringe for use in children should be 0.5 ml or less, with a graduation of 0.01 ml.

Elderly patients

No dose adjustment of the drug is required in patients over 65 years of age.

Patients with renal impairment

No dose adjustment is required in adult patients or children with mild renal impairment. The daily dose of the drug should be reduced by 50% in adult patients or children with moderate and severe renal impairment (with CC less than 50 ml/min) and end-stage renal disease (see section “Pharmacokinetics”).

Patients with hepatic impairment

No dose adjustment is required in adult patients or children with mild or moderate hepatic impairment, considering the results of clinical studies of teduglutide in patients with Child-Pugh class B hepatic impairment. Clinical studies in patients with severe hepatic impairment have not been conducted (see sections “Pharmacokinetics” and “Special Instructions”).

Children

The safety and efficacy of Gattestive^® in children under 1 year of age have not been established, no data available.

Instructions for the preparation of the Gattestive^® drug solution

The number of vials required for the administration of a single dose of the drug should be determined based on the patient’s body weight and the recommended dose of 0.05 mg/kg/day.

During each visit, the physician should weigh the patient, determine the daily dose to be administered until the next visit, and instruct the patient accordingly.

Tables with recommended injection volumes of the drug solution based on the recommended dose per kg of body weight for both children and adults are presented above in this section.

If 2 vials of the drug are required, it is necessary to repeat the powder dissolution procedure for the second vial, and then draw the additional volume of the drug solution from the second vial into the syringe already containing the solution from the first vial. The volume of the solution remaining after the administration of the prescribed dose of the drug must be discarded and disposed of.

For single use only.

Instructions for the preparation and administration of Gattestive^®

The Gattestive^® package contains

• 1 or 28 vials with 5 mg of teduglutide in powder form (lyophilisate);
• 1 or 28 pre-filled syringes with solvent.

Necessary materials not included in the package

• Needles for drug solution preparation (size 22G, 1¹/₂^"; 0.7 × 40 mm);
• 0.5 or 1 ml injection syringes (with scale intervals of 0.02 ml and less). For children, a 0.5 ml syringe or smaller (with scale intervals of 0.01 ml and less) should be used for injections;
• Thin needles for subcutaneous injections (e.g., size 26G, 5/8 (0.45 × 16 mm) or smaller needles for children if required);
• Alcohol wipes;
• Alcohol swabs;
• A tightly closed container for the safe disposal of used syringes and needles.

Note: Before starting the procedure, make sure you have a clean work surface and wash your hands.

1. Assembly of the pre-filled syringe

After preparing all necessary materials, assemble the pre-filled syringe as follows

1.1. Take the pre-filled syringe with solvent and flip off the top part of the plastic cap so that it is ready to attach the needle for drug solution preparation.

1.2. Attach the needle for drug solution (22G 1¹/₂^"; 0.7 × 40 mm) to the pre-filled syringe by screwing it on clockwise.

2. Drug dissolution

2.1. Remove the flip-off plastic disc from the powder vial, wipe the top of the vial with an alcohol wipe and let it dry. Do not touch the top of the vial.

2.2. Remove the cap from the needle on the assembled, pre-filled syringe with solvent, without touching the tip of the needle.

2.3. Pierce the center of the rubber stopper of the powder vial with the needle of the pre-filled syringe and gently press the syringe plunger, injecting all the solvent into the vial.

2.4. Leave the needle with the empty syringe attached to the vial for about 30 seconds.

2.5. Gently roll the vial between your palms for 15 seconds. Then gently invert the vial once, without removing the needle and empty syringe from the vial.

Note: Do not shake the vial. Shaking the vial may cause foam formation, which makes it difficult to withdraw the drug solution from the vial.

2.6. Leave the vial with the attached empty syringe for 2 minutes.

2.7. Check the vial for undissolved powder. If powder remains, repeat steps 2.5 and 2.6. Do not shake the vial. If undissolved powder still remains in the vial, discard the vial and begin preparing the drug solution with a new powder vial.

Note: The prepared solution should be clear or slightly opalescent and colorless. If the solution is cloudy or contains foreign particles, it should not be used.

Note: After preparation, the solution should be administered immediately. The prepared solution, if not administered immediately after reconstitution, should be stored at a temperature below 25°C (77°F) for no more than 3 hours.

3. Preparation of the injection syringe

3.1. Remove the empty powder dissolution syringe from the drug solution vial, leaving the needle in the vial, and discard the syringe.

3.2. Take the injection syringe and attach it to the needle that is still in the vial.

3.3. Turn the vial upside down, bring the needle tip closer to the stopper and draw the entire drug solution into the syringe by gently pulling the plunger.

Note: If the physician has determined that 2 vials of the drug are to be administered, prepare a second pre-filled syringe with solvent and a second powder vial as described in steps 1 and 2. Draw the solution from the second vial into the same injection syringe by repeating step 3.

3.4. Disconnect the injection syringe from the needle, leaving it in the vial. Discard the vial with the needle in a sharps disposal container.

3.5. Take the needle for subcutaneous injection, but do not remove the plastic cap from it. Attach the needle to the injection syringe containing the drug solution.

3.6. Check the solution in the syringe for air bubbles. If air bubbles are present, gently tap the syringe until they rise to the top. Then gently push the plunger to expel the air.

3.7. The dose/volume of the drug solution should be calculated by the attending physician. Remove the excess volume of the drug solution from the syringe without removing the needle cap until the required dose of the drug remains in the syringe.

4. Injection Administration

4.1. Identify an area on the abdomen or on the thigh if injections in the abdomen are painful or if there are indurations (see figure).

Note: Do not use the same site for injections every day – rotate sites (use the upper, lower, left, and right quadrants of the abdomen) to avoid discomfort. Avoid injecting the drug solution into inflamed, swollen areas, areas with scars or moles, birthmarks, or other skin lesions.

4.2. Wipe the intended skin area with an alcohol swab using a circular motion. Allow it to dry.

4.3. Remove the plastic cap from the injection syringe needle. Gently grasp the cleansed skin at the injection site with one hand. Hold the syringe like a pencil with the other hand. Pull the wrist back and quickly insert the needle at a 45° angle.

4.4. Pull back the plunger slightly. If blood appears in the syringe, remove the needle and replace it with a clean needle of the same size. The drug already in the syringe can still be used. Try injecting into a different site on the prepared skin area.

4.5. Inject the drug slowly, continuously pressing the plunger until the entire drug solution is injected and the syringe is empty.

4.6. Pull the needle out of the skin, discard the needle and syringe in a sharps disposal container. Slight bleeding may occur. If needed, gently press the injection site with a cotton ball or gauze pad until bleeding stops.

Adverse Reactions

Safety Profile Overview

The most frequent adverse reactions (ARs) reported in clinical studies of teduglutide were: abdominal pain, abdominal distension, respiratory tract infections (including nasopharyngitis, influenza, upper and lower respiratory tract infections), nausea, injection site reactions, headache, and vomiting. Approximately 38% of stoma patients receiving teduglutide therapy developed stoma complications. Most ARs were mild or moderate in severity.

No new safety signals were identified in patients treated with Teduglutide at a dose of 0.05 mg/kg/day for up to 30 months during an extended, open-label study.

List of ARs in Table Form

The ARs listed below are organized by system organ class with frequency of occurrence according to WHO recommendations: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); frequency not known (cannot be estimated from the available data). All ARs reported during the post-marketing period are highlighted in italics.

* Includes the following preferred terms: nasopharyngitis, influenza, upper respiratory tract infections, and lower respiratory tract infections.

⁺ Includes the following preferred terms: pancreatitis, acute pancreatitis, and chronic pancreatitis.

^◊ Includes the following preferred terms: injection site haematoma, injection site erythema, injection site pain, injection site swelling, and injection site haemorrhage.

Description of Selected Adverse Reactions

Immunogenicity

Consistent with the potentially immunogenic properties of peptide-containing drugs, administration of Gattestive^® may induce antibody formation. Based on pooled data from 2 clinical studies in adult patients with SBS (a 6-month randomized, placebo-controlled clinical study followed by a 24-month open-label clinical study) who received subcutaneous injections of teduglutide at a dose of 0.05 mg/kg once daily, antibodies to teduglutide were detected in 3% (2/60) of patients at 3 months, 17% (13/77) at 6 months, 24% (16/67) at 12 months, 33% (11/33) at 24 months, and 48% (14/29) at 30 months of treatment. In Phase 3 clinical studies, 28% of SBS patients treated with Teduglutide for ≥2 years had antibodies to E. coli protein (residual proteins from the production strain). Antibody production was not associated with clinically significant safety findings, reduced efficacy, or altered pharmacokinetics of teduglutide.

Injection Site Reactions

Injection site reactions occurred in 26% of SBS patients treated with teduglutide compared to 5% of patients in the placebo group. Reactions included injection site haematoma, erythema, pain, swelling, and haemorrhage (see also section “Special Precautions”). Most reactions were moderate in severity and did not lead to drug discontinuation.

C-reactive Protein

During the first 7 days of teduglutide therapy, a moderate increase in C-reactive protein concentration to approximately 25 mg/L was observed, which continuously decreased with continued daily drug administration. After 24 weeks of teduglutide use, patients showed a small overall increase in C-reactive protein concentration, averaging 1.5 mg/L. These changes were not accompanied by changes in other laboratory parameters or clinical symptoms. No clinically significant mean increase in C-reactive protein from baseline was observed after extended teduglutide therapy for up to 30 months.

Children

In 2 completed clinical studies, 87 children (aged 1 to 17 years) received Teduglutide for periods of up to 6 months. No patient discontinued the study prematurely due to an adverse event. Overall, the safety profile of teduglutide (including the type and frequency of ARs, as well as immunogenicity) in children and adolescents (aged 1-17 years) was similar to that in adult patients.

Long-term safety data are not yet available for the pediatric population. Data are also lacking for children under 1 year of age.

Contraindications

• Hypersensitivity to teduglutide and/or any excipient in the drug;
• Diagnosed or suspected malignancy;
• Patients with a history (within the last 5 years) of malignant neoplasms of the gastrointestinal tract, including the hepatobiliary system and pancreas;
• Children under 1 year of age (due to lack of clinical data on efficacy and safety).

Caution

Caution should be exercised when prescribing Gattestive^® to patients with cardiovascular diseases, such as cardiovascular failure or hypertension (see section “Special Precautions”); patients taking concomitant medications requiring dose titration or having a narrow therapeutic index (see sections “Special Precautions” and “Drug Interactions”); patients with severe, clinically unstable comorbidities (e.g., heart and vascular, lung, kidney, liver, CNS, or endocrine system diseases, as well as infectious diseases) due to insufficient clinical data.

Use in Pregnancy and Lactation

Pregnancy

There are no data on the use of Gattestive^® in pregnant women. Studies in animals have not shown direct or indirect reproductive toxicity of Gattestive^® (see section “Special Precautions”). As a precaution, it is recommended to avoid the use of Gattestive^® in pregnant women.

Breastfeeding Period

Data on the excretion of teduglutide in breast milk are not available. In rats, the mean concentration of teduglutide in milk was less than 3% of their plasma concentration after a single subcutaneous administration of the drug at a dose of 25 mg/kg. A risk to breastfed newborns/infants cannot be excluded. As a precaution, it is recommended to avoid the use of Gattestive^® in women during breastfeeding.

Fertility

There are no data on the effect of teduglutide on human fertility. Results from animal studies did not reveal impairment of fertility.

Use in Hepatic Impairment

The drug should be prescribed with caution to patients with severe, clinically unstable concomitant liver diseases.

Use in Renal Impairment

The drug should be prescribed with caution to patients with severe, clinically unstable concomitant kidney diseases.

Pediatric Use

Contraindicated for use in children under 1 year of age.

Geriatric Use

No dose adjustment of the drug is required for patients over 65 years of age.

Special Precautions

Each administration of Gattestive^® to a patient should be recorded, noting the patient’s full name and the drug batch number, to maintain a link between the patient and the administered drug.

Adult Patients

Colorectal Polyps

Before starting therapy with Gattestive^®, a colonoscopy with polyp removal should be performed. During the first 2 years of therapy with Gattestive^®, an annual colonoscopy (or an alternative imaging method) is recommended. Thereafter, colonoscopy is recommended at least once every 5 years. The need for increased frequency of monitoring is determined based on individual patient assessment (e.g., age, underlying disease). If a polyp is detected, current polyp surveillance guidelines should be followed. If a malignant tumor develops, therapy with Gattestive^® should be discontinued.

Gastrointestinal Neoplasia, Including Liver and Bile Ducts

In a carcinogenicity study in rats, benign tumors were found in the small intestine and extrahepatic bile ducts. These findings were not confirmed in clinical studies lasting more than one year. If neoplasia is detected, it should be removed. If a malignant tumor develops, therapy with Gattestive^® should be discontinued.

Gallbladder and Bile Ducts

Cases of cholecystitis, cholangitis, and cholelithiasis have been reported during clinical studies. If symptoms of gallbladder or bile duct disease appear, the need to continue therapy with Gattestive^® should be re-evaluated.

Pancreatic Diseases

Adverse events related to the pancreas, such as chronic and acute pancreatitis, pancreatic duct stenosis, pancreatic infection, and increased blood amylase and lipase activity, have been reported during clinical studies. If adverse pancreatic reactions develop, the need to continue therapy with Gattestive^® should be re-evaluated.

Monitoring of Small Intestine, Gallbladder and Bile Ducts, Pancreas

In accordance with therapy guidelines, patients with SBS should be carefully monitored. This typically involves monitoring for signs and symptoms of impaired small intestine, gallbladder and bile duct, and pancreatic function, and, if necessary, performing additional laboratory tests and appropriate imaging methods.

Intestinal Obstruction

Cases of intestinal obstruction have been recorded in clinical studies. In case of recurrent intestinal obstruction, the need to continue therapy with Gattestive^® should be re-evaluated.

Hypervolaemia and Electrolyte Balance

To avoid hypervolaemia or dehydration in patients receiving Gattestive^® therapy, careful adjustment of parenteral support is required. Electrolyte and fluid balance should be carefully monitored throughout treatment, especially during the initial therapeutic response and treatment discontinuation.

Hypervolaemia. Cases of hypervolaemia were observed in clinical studies. Hypervolaemia most frequently developed within the first 4 weeks of therapy and decreased over time.

Due to increased fluid absorption, patients with cardiovascular diseases, such as heart failure and hypertension, should be monitored for the development of hypervolaemia, especially at the start of therapy. Patients should report sudden weight gain, swelling of the face and ankles, and/or shortness of breath to their doctor. In general, hypervolaemia can be prevented by timely appropriate assessment of the need for parenteral nutrition. This assessment should be performed more frequently in the first months of therapy.

Cases of chronic heart failure have been reported in clinical studies. In case of significant worsening of cardiovascular disease, the need to continue therapy with Gattestive^® should be re-evaluated.

Dehydration. Patients with SBS are prone to dehydration, which can lead to acute renal failure.

Patients receiving Gattestive^® should carefully reduce parenteral nutrition and not discontinue it abruptly. After reducing parenteral nutrition, the patient’s fluid volume should be assessed and, if necessary, appropriate correction should be made.

Concomitant Therapy

Close monitoring is required for patients receiving concomitant therapy with oral medications requiring dose titration or with a narrow therapeutic index, due to possible increased absorption.

Special Clinical Conditions

Gattestive^® has not been studied in patients with severe, clinically unstable comorbidities (e.g., cardiovascular, respiratory, renal, endocrine, hepatic, CNS diseases, or infectious diseases). Caution should be exercised when prescribing Gattestive^® to these patients.

Gattestive^® has not been studied in patients with malignancies within the last 5 years.

Hepatic Impairment

Studies of Gattestive^® in patients with severe hepatic impairment have not been conducted. Based on available data, no restrictions on the use of the drug are required in patients with moderate hepatic impairment.

Discontinuation of Therapy

Due to the risk of dehydration, therapy with Gattestive^® should be discontinued cautiously.

Children

See also the general precautions specified for adult patients in this section.

Colorectal Polyps/Neoplasia

Before starting Gattestive^®, all children and adolescents should undergo a fecal occult blood test. If blood of unclear etiology is present in the stool, colonoscopy/sigmoidoscopy should be performed. Subsequent fecal occult blood tests should be performed annually in all children and adolescents while using Gattestive^®.

Colonoscopy/sigmoidoscopy is recommended for all children and adolescents after 1 year of treatment, and then at least once every 5 years as Gattestive^® therapy continues, as well as in case of new or unexplained gastrointestinal bleeding.

Preclinical Safety Data

In subchronic and chronic toxicity studies, hyperplasia of the gallbladder, bile ducts, and pancreatic ducts was noted. These observations were potentially associated with the expected pharmacological properties of teduglutide and were reversible to varying degrees within 8-13 weeks after long-term use.

Carcinogenicity/Mutagenicity. The results of a standard battery of genotoxicity tests for teduglutide were negative. In a carcinogenicity study in rats, therapy-related benign tumors included bile duct epithelial tumors in males where plasma concentrations of teduglutide were approximately 32 and 155 times higher than in patients receiving the drug daily at the recommended dose (incidence: 1 out of 44 and 4 out of 48, respectively). Adenoma of the jejunal mucosa was observed in 1 out of 50 males and 5 out of 50 males where plasma concentrations of teduglutide were approximately 10 and 155 times higher than in patients receiving the drug daily at the recommended dose. Additionally, jejunal adenocarcinoma was noted in one male rat receiving the lowest tested dose (the animal:human plasma exposure ratio was approximately 10-fold).

Reproductive and Developmental Toxicity. Studies on the reproductive and developmental toxicity of teduglutide were conducted in rats and rabbits administered the drug at doses of 0; 2; 10; and 50 mg/kg/day. Teduglutide had no effect on reproductive function or fetal development parameters determined in fertility, embryo-fetal development, and pre- and postnatal development studies. Pharmacokinetic data from these studies indicated that teduglutide exposure in rabbit fetuses and rat pups was very low.

Injection Site Reactions

Preclinical studies revealed foci of pronounced granulomatous inflammation at injection sites.

Excipients

Gattestive^® contains less than 1 mmol sodium (23 mg) per vial, which is essentially ‘sodium-free’.

Effect on the Ability to Drive Vehicles and Mechanisms

Therapy with Gattestive^® has a minor influence on the ability to drive and use machines. However, cases of syncope were observed in clinical studies of the drug (see the “Adverse Reactions” section). These adverse reactions may affect the ability to drive vehicles and operate machinery.

Overdose

The maximum dose of teduglutide studied during the drug’s clinical development program was 86 mg/day for 8 days. No unexpected systemic adverse reactions were observed (see the “Adverse Reactions” section).

In case of overdose, the physician should carefully monitor the patient’s condition.

Drug Interactions

Drug interaction studies with teduglutide have not been conducted. Results of in vitro studies showed that Teduglutide does not inhibit cytochrome P450 isoenzymes involved in drug metabolism. Considering the pharmacodynamic effect of teduglutide, there is a possibility of increased absorption of concomitantly administered medicinal products (see the “Special Precautions” section).

Storage Conditions

The drug should be stored out of the reach of children at a temperature not exceeding 25°C (77°F); do not freeze.

Shelf Life

The shelf life of the lyophilisate is 4 years, the solvent is 4 years. Do not use after the expiration date stated on the packaging.

Dispensing Status

The drug is dispensed by prescription.

Note Information for healthcare professionals. Before use, consult your attending physician.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.