Consumer medicine information

Revestive

Teduglutide

BRAND INFORMATION

Brand name

Revestive

Active ingredient

Teduglutide

Schedule

What is in this leaflet

Please read this leaflet before you start using REVESTIVE.

This leaflet answers some common questions about REVESTIVE. It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you using REVESTIVE against the benefits they expect it will have for you.

If you have any concerns about using this medicine, ask your doctor or pharmacist.

Keep this leaflet with the medicine. You may need to read it again.

What REVESTIVE is used for

REVESTIVE is used to treat adults with Short Bowel Syndrome who need additional nutrition or fluids from intravenous feeding (parenteral support). Short Bowel Syndrome is a disorder arising from an inability to absorb food nutrients and fluid across the gastrointestinal tract (gut). It is often caused by surgical removal of all or part of the small intestine.

REVESTIVE contains the active substance teduglutide. It improves the absorption of nutrients and fluid from your remaining gut.

Ask your doctor if you have any questions about why this medicine has been prescribed for you. Your doctor may have prescribed it for another reason.

This medicine is not addictive.

This medicine is available only with a doctor's prescription.

Before you use REVESTIVE

When you must not use it

Do not use REVESTIVE if you have an allergy to:

any medicine containing teduglutide
any of the ingredients listed at the end of this leaflet.

Some of the symptoms of an allergic reaction may include:

shortness of breath
wheezing or difficulty breathing
swelling of the face, lips, tongue or other parts of the body
rash, itching or hives on the skin.

Do not use REVESTIVE if you:

have cancer in the gastrointestinal tract, liver, gallbladder, bile ducts or pancreas
have had cancer in the gastrointestinal tract, including liver, gallbladder, bile ducts or pancreas, within the last five years.

Do not give this medicine to a person below 18 years of age. The benefits and risks in children or adolescents below 18 years of age have not been established.

Do not use this medicine after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering. If it has expired or is damaged, return it to your pharmacist for disposal.

If you are not sure whether you should start using this medicine, talk to your doctor.

Before you start to use it

Tell your doctor if you have allergies to any other medicines, foods, preservatives or dyes.

Tell your doctor if you have or have had any of the following medical conditions:

severely decreased liver function
certain cardiovascular diseases (affecting the heart and/or blood vessels), such as high blood pressure or a weak heart. The symptoms include sudden weight gain, swollen ankles and/or shortness of breath
decreased kidney function
other severe diseases that are not well controlled.

Tell your doctor if you are pregnant or plan to become pregnant or are breast-feeding. Your doctor can discuss with you the risks and benefits involved.

Medical check-ups before and during treatment

Before you start treatment with this medicine, your doctor will need to perform a colonoscopy (a procedure to see inside your colon and rectum) to check for the presence of polyps (small abnormal growths) and remove them. It is recommended that your doctor performs these examinations once a year during the first two years after starting treatment, and then at a minimum of five-year intervals. If polyps are found either before or during your treatment with REVESTIVE, your doctor will decide whether you should continue using this medicine.

REVESTIVE should not be used if a cancer is detected during your colonoscopy.

If you have not told your doctor about any of the above, tell him/her before you start using REVESTIVE.

Taking other medicines

Tell your doctor or pharmacist if you are using any other medicines, including any that you get without a prescription from your pharmacy, supermarket or health food shop.

REVESTIVE may affect how other medicines are absorbed from the gut and therefore how well they work. Your doctor may have to change your dose of other medicines.

Your doctor and pharmacist have more information on medicines to be careful with or avoid while using this medicine.

How to use REVESTIVE

Follow all directions given to you by your doctor or pharmacist carefully. They may differ from the information contained in this leaflet.

If you do not understand the instructions on the box, ask your doctor, pharmacist or nurse for help.

How much to use

The recommended daily dose is 0.05 mg per kg body weight once per day, given under the skin. The dose will be prescribed as mL of solution.

Your doctor will choose the dose that is right for you depending on your body weight. Your doctor will tell you which dose to inject. If you are not sure, ask your doctor, pharmacist or nurse.

How to use it

REVESTIVE is injected under the skin (subcutaneously) once daily.

The injection can be self-administered or given by another person, for example your doctor, his/her assistant or your home nurse.

If you are injecting the medicine yourself, you must receive adequate training by your doctor or nurse. You will find detailed instructions for injections at the end of this leaflet.

How long to use it

Continue using this medicine for as long as your doctor prescribes it for you.

Do not stop using this medicine without consulting your doctor, as a sudden stop can cause changes in your fluid balance.

If you forget to use it

If you forget to inject this medicine (or cannot inject it at your usual time), use it as soon as possible on that day.

Never use more than one injection in the same day.

Do not inject a double dose to make up for the dose that you missed.

If you have trouble remembering to use your medicine, ask your pharmacist or nurse for some hints.

If you use too much (overdose)

Immediately telephone your doctor or the Poisons Information Centre (Australia: 13 11 26; New Zealand: 0800 POISON or 0800 764766) for advice, or go to Accident and Emergency at the nearest hospital, if you think that you or anyone else may have used too much REVESTIVE. Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

While you are using REVESTIVE

Things you must do

If you are about to be started on any new medicine, remind your doctor and pharmacist that you are using REVESTIVE.

Tell any other doctors, dentists, and pharmacists who treat you that you are using this medicine.

If you become pregnant while using this medicine, tell your doctor immediately.

Keep all of your doctor's appointments so that your progress can be checked. It is recommended that your doctor performs examinations to check for the presences of polyps once a year during the first two years after starting treatment, and then at a minimum of five-year intervals. (See 'Medical check-ups before and during treatment' in 'Before you use REVESTIVE' section).

Your doctor will take special care and monitor your small bowel function and monitor for signs and symptoms indicating problems with your gallbladder, bile ducts and pancreas. Your doctor will also monitor your fluid and electrolyte balance to make sure you do not get fluid overload or dehydration.

Things you must not do

Do not use REVESTIVE to treat any other complaints unless your doctor tells you to.

Do not give your medicine to anyone else, even if they have the same condition as you.

Do not stop using your medicine or lower the dosage without checking with your doctor. If you stop using it suddenly, your body may no longer be able to absorb enough fluid and nutrients from your gut, this could lead to dehydration and imbalance of your body's electrolytes. If you need to stop this treatment for any reason, your doctor or healthcare team will advise you and monitor your condition during this period.

Things to be careful of

Be careful driving or operating machinery until you know how REVESTIVE affects you. This medicine may cause you to feel dizzy. If this happens to you, do not drive or use machines until you feel better.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are using REVESTIVE.

Like all medicines, REVESTIVE can cause some side effects. Sometimes they are serious, most of the time they are not. You may need medical attention if you get some of the side effects.

Do not be alarmed by the following lists of side effects. You may not experience any of them.

Ask your doctor or pharmacist to answer any questions you may have.

Tell your doctor or pharmacist if you notice any of the following and they worry you:

cold or flu-like symptoms
decreased appetite
headache
stomach pain
bloated stomach
polyps (small abnormal growths) in your large bowel
flatulence
nausea
vomiting
swelling of stoma (an artificial opening for waste removal)
trouble sleeping
cough
urinary tract infection
reddening, pain or swelling at the site of the injection

The above list includes the more common side effects of your medicine. They are usually mild and short-lived.

Tell your doctor as soon as possible if you notice any of the following:

swelling of hands, face or feet
any infection of the sinuses, throat, airways or lungs (respiratory tract infection)
chest pain
tiredness, shortness of breath, with or without swelling of ankles or legs (congestive heart failure)

The above list includes serious side effects that may require medical attention. Serious side effects are rare.

Contact your doctor or go to the emergency unit immediately if any of the following occurs:

allergic reaction which may result in a rash or more rarely to a sharp drop in blood pressure, difficulty breathing, and hives/itching (anaphylactic reaction)
severe stomach ache, fever (inflammation of the pancreas)
severe stomach ache, vomiting, constipation (blockage of the bowel)
yellowing of the skin and the whites in the eyes, itching, dark urine and light-coloured stools or pain in the upper right side or middle of the stomach area (reduced flow of bile from the gallbladder and/or inflammation of the gallbladder)

Tell your doctor, pharmacist or nurse if you notice anything that is making you feel unwell.

Other side effects not listed above may also occur in some people.

After using REVESTIVE

Storage

Keep your medicine in the pack until it is time to take it. If you take the medicine out of the pack it may not keep well.

Keep the medicine in a cool dry place where the temperature stays below 25°C. Do not freeze it.

After reconstitution, the solution should be used immediately. However, chemical and physical stability has been demonstrated for 3 hours at 25°C.

Do not store REVESTIVE or any other medicine in the bathroom or near a sink. Do not leave it on a window sill or in the car. Heat and dampness can destroy some medicines.

Keep it where children cannot reach it. A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Disposal

If your doctor tells you to stop using this medicine or the expiry date has passed, ask your pharmacist what to do with any medicine that is left over.

Product description

What REVESTIVE looks like

REVESTIVE is a powder and solvent for solution for injection (5 mg powder in vial, 0.5 mL solvent in pre-filled syringe). The powder is white and the solvent is clear and colourless.

One vial of powder contains 5 mg of teduglutide. After reconstitution, each vial contains 5 mg teduglutide in 0.5 mL of solution, corresponding to a concentration of 10 mg/mL.

Each pack contains 28 vials with powder and 28 pre-filled syringes with solvent.

Ingredients

Active ingredient:

REVESTIVE contains teduglutide as the active ingredient.

Other ingredients:

histidine
mannitol
monobasic sodium phosphate monohydrate
dibasic sodium phosphate heptahydrate

The solvent is sterile water for injections.

Sponsor

Shire Australia Pty Limited
Shire is now part of Takeda
Level 39, 225 George Street
Sydney, NSW 2000
Australia
Telephone: 1800 012 612

This leaflet was prepared in April 2020.

Australian Registration Number:
AUST R 274911

REVESTIVE is a registered trademark of Shire-NPS Pharmaceuticals, Inc., a Takeda company.

Instructions for preparing and injecting REVESTIVE

Important information
Read the leaflet carefully before using REVESTIVE.

REVESTIVE is for injection under the skin (subcutaneous injection). Do not inject it into a vein or muscle.

After reconstitution, from a microbiological point of view, the solution should be used immediately. However, chemical and physical stability has been demonstrated for 3 hours at 25°C.

Do not use REVESTIVE if you notice that the solution is cloudy or contains particulate matter.

Dispose of all needles and syringes in a sharps disposal container.

Materials in the REVESTIVE pack:

28 vials with 5 mg teduglutide as a powder
28 pre-filled syringes with solvent

Materials needed but not included in the REVESTIVE pack:

reconstitution needles (size 22G, length 1 ½ " (0.7 x 40 mm))
1 mL injection syringes (with scale intervals of 0.02 mL or smaller)
thin injection needles for subcutaneous injection (for example, size 26G, length 5/8" (0.45 x 16 mm))
alcohol wipes
alcohol swabs
a puncture-proof container for safe disposal of the used syringes and needles

NOTE: Before you start, make sure you have a clean work surface and that you have washed your hands before proceeding.

1. Prepare the pre-filled syringe

Once you have all the materials ready, you need to prepare the prefilled syringe. The following procedure shows how you do this.

1.1 Take the pre-filled syringe containing the solvent and flip off the top part of the white plastic cap on the pre-filled syringe so that it is ready for the reconstitution needle to be attached.

1.2 Attach the reconstitution needle (22G, 1½" (0.7 x 40 mm)) to the prefilled syringe by screwing it on in a clockwise direction.

2. Dissolve the powder

Now you are ready to dissolve the powder with the solvent.

2.1 Remove the green flip-off button from the powder vial, wipe the top with an alcohol wipe and allow it to dry. Do not touch the top of the vial.

2.2 Uncap the reconstitution needle on the pre-filled syringe with solvent without touching the tip of the needle.

2.3 Taking the powder vial, insert the reconstitution needle attached to the pre-filled syringe into the centre of the rubber stopper and gently push the plunger all the way down to inject all the solvent into the vial.

2.4 Leave the reconstitution needle and empty syringe in the vial. Let the vial rest for about 30 seconds.

2.5 Gently roll the vial between your palms for about 15 seconds. Then gently turn the vial upside-down once with the reconstitution needle and empty syringe still in the vial. Do not shake the vial. Shaking the vial may produce foam, which makes it difficult to extract the solution from the vial.

2.6 Let the vial rest for about 2 minutes.

2.7 Observe the vial for any undissolved powder. If any powder remains, repeat steps 2.5 and 2.6.

Do not shake the vial. If there is still some undissolved powder, discard the vial and start the preparation again from the beginning with a new vial.

NOTE: The final solution should be clear. If the solution is cloudy or contains particulate matter, do not inject it.

NOTE: Once prepared, the solution should be used immediately. It should be kept below 25°C and maximum storage time is 3 hours.

3. Prepare the injection syringe

3.1 Remove the reconstitution syringe from the reconstitution needle which is still in the vial and discard the reconstitution syringe.

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

3.3 Turn the vial upside down, slide the tip of the reconstitution needle close to the stopper and allow all the medicine to fill the syringe by pulling the plunger back gently.

NOTE: If your doctor has told you that you need two vials, prepare a second pre-filled syringe with solvent and a second powder vial as shown in the main steps 1 and 2. Withdraw the solution from the second vial into the same injection syringe by repeating step 3.

3.4 Remove the injection syringe from the reconstitution needle leaving the needle in the vial. Discard the vial and reconstitution needle together into the sharps disposal container.

3.5 Take the injection needle (26G, 5/8" (0.45 x 16 mm)), but do not remove the plastic needle cap. Attach the needle to the injection syringe containing the medicine.

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

3.7 Your dose in mL has been calculated by your doctor. Expel any excessive volume from the syringe with the needle cap still on until your dose is reached.

4. Inject the solution

4.1 Find an area on your belly, or if you have pain or hardening of the tissue on your belly, on your thigh where it is easy for you to give the injection.

NOTE: Do not use the same area each day for each injection - rotate sites each day (use upper, lower, and left and right side of your belly) to avoid discomfort. Do not inject into the side if it has a stoma (an artificial opening for waste removal). Avoid areas that are inflamed, swollen, scarred or covered by a mole, birthmark or other lesion.

4.2 Clean the intended site of injection on your skin with an alcohol swab, using a circular motion, working outwards. Allow the area to air-dry.

4.3 Remove the plastic cap from the needle of the prepared injection syringe. Gently grasp the cleaned skin at the injection site with one hand. With the other hand, hold the syringe as you would with a pencil. Bend your wrist back and quickly insert the needle at a 45° angle.

4.4 Pull back the plunger slightly. If you see any blood in the syringe, withdraw the needle and replace the needle on the injection syringe with a clean one of the same size. You can still use the medicine that is already in the syringe. Try to inject in another place in the cleaned skin area.

4.5 Inject the medicine slowly by pushing steadily on the plunger until all the medicine is injected and the syringe is empty.

4.6 Pull the needle straight out of the skin and discard the needle and syringe together into the sharps disposal container. A small amount of bleeding may occur. If necessary, press gently on the injection site with an alcohol swab or 2x2 gauze until any bleeding has stopped.

4.7 Dispose of all needles and syringes in a sharps disposal container.

Published by MIMS June 2020

BRAND INFORMATION

Brand name

Revestive

Active ingredient

Teduglutide

Schedule

1 Name of Medicine

Teduglutide.

2 Qualitative and Quantitative Composition

Revestive contains teduglutide powder and solvent for solution for injection. Each single-use vial contains 5 mg of teduglutide as a white lyophilised powder. The solvent is water for injections. After reconstitution, each vial contains 5 mg teduglutide in 0.5 mL of solution, corresponding to a concentration of 10 mg/mL.
The active ingredient teduglutide (rDNA origin) is a 33 amino acid glucagon-like peptide-2 (GLP-2) analogue manufactured using a strain of Escherichia coli modified by recombinant DNA technology.
See Section 6.7 Physicochemical Properties for the chemical composition and structural formula.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Powder for solution for injection.

4 Clinical Particulars

4.1 Therapeutic Indications

Revestive is indicated for the treatment of adult and paediatric patients 2 years of age and above with Short Bowel Syndrome (SBS) who are dependent on parenteral support.
Patients should be stable for at least 4 weeks on their parenteral support regimen before initiating teduglutide therapy.

4.2 Dose and Method of Administration

Treatment should be initiated under the supervision of a medical professional with experience in the treatment of SBS. Revestive may be self-administered or administered by a caregiver only after training in subcutaneous injection technique by a healthcare professional.

Paediatric (2 years of age and above).

See also general instructions for adults in this section.
Revestive should not be administered to children weighing less than 10 kg. Treatment should be evaluated after 6 months. If no overall improvement is achieved, the need for continued treatment should be re-assessed. There are no data available in paediatric patients after 6 months of continued treatment (see Section 5.1, Clinical trials).

Adult.

Treatment effect should be evaluated on an ongoing basis. Clinical assessment by the physician should consider individual treatment objectives and patient preferences. If no overall improvement is achieved after 12 months for adults, the need for continued treatment should be assessed.
Continued treatment is recommended for patients who have weaned off parenteral nutrition.

Dosage.

The recommended dose of Revestive for both adults and paediatric patients (aged 2 years and above) is 0.05 mg/kg body weight administered by subcutaneous injection once daily.
After reconstitution with the solvent (0.5 mL water for injections), the prepared solution from each vial contains 10 mg/mL of teduglutide.
Special populations.

Elderly.

No dose adjustment is necessary in patients above the age of 65 years.

Hepatic impairment.

No dose adjustment is necessary for patients with mild and moderate hepatic impairment based on a study conducted in Child-Pugh grade B subjects. Teduglutide has not been formally studied in subjects with severe hepatic impairment.

Renal impairment.

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

Administration.

Detailed instructions on the preparation (including assembly of the pre-filled syringe, dissolving the powder, preparing the injection syringe) and injection of Revestive reconstituted solution are provided in the package leaflet.
The reconstituted solution must be injected subcutaneously into a cleaned area on the abdomen, or if this is not possible, on the thigh using a thin needle for subcutaneous injection. Revestive should not be administered intravenously or intramuscularly. If a dose is missed, that dose should be taken as soon as possible on that day. Do not take 2 doses on the same day.
Alternation of sites for subcutaneous injection is recommended. Sites of injection include the thighs, arms, and the quadrants of the abdomen.
Determination of the number of vials needed for administration of one dose must be based on the individual patient's weight and the recommended dose of 0.05 mg/kg/day. The physician should at each visit weigh the patient, determine the daily dose to be administered until next visit and inform the patient accordingly. Injection volume per body weight is provided in Table 1:

The powder in the vial must be dissolved by adding all the solvent from the pre-filled syringe. The vial should not be shaken, but can be rolled between the palms and gently turned upside-down once.
Reconstituted Revestive is a sterile, clear, colourless to light straw-coloured solution, which should be free from particulates. The drug should be completely dissolved before the solution is withdrawn from the vial. Do not shake or freeze the reconstituted solution. The solution should not be used if it is cloudy or contains particulate matter. Revestive does not contain any preservatives and should be used within 3 hours after reconstitution. The product is for single use in one patient only. Discard any residue.
Once the drug is completely dissolved, withdraw the prescribed dose solution into an injection syringe (up to 1 mL with scale intervals of 0.02 mL or smaller for paediatric use).
If two vials are needed, the procedure for the second vial must be repeated and the additional solution drawn up into the injection syringe containing the solution from the first vial. Any volume exceeding the prescribed dose in mL must be expelled and discarded.

4.3 Contraindications

Hypersensitivity to the active ingredient or to any of the excipients.
Active or suspected malignancy.
Patients with a history of malignancies in the gastrointestinal tract including the hepatobiliary system within the last 5 years.

4.4 Special Warnings and Precautions for Use

Colorectal polyps/neoplasia.

Adults.

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

Paediatric.

See also general precautions for adults in this section.
Prior to initiating treatment with Revestive, faecal occult blood testing should be done for all children and adolescents. Colonoscopy/sigmoidoscopy is required if there is unexplained blood in the stool. Subsequent faecal occult blood testing should be done annually in children and adolescents while they are receiving Revestive.
Colonoscopy/sigmoidoscopy is recommended for all children and adolescents after one year of treatment, every 5 years thereafter while on continuous treatment with Revestive, and if they have new or unexplained gastrointestinal bleeding.

Gastrointestinal neoplasia including hepatobiliary tract.

Based on the pharmacologic activity and findings in animals and humans, teduglutide has the potential to cause hyperplastic changes, including neoplasia, in the small bowel and hepatobiliary tract. These observations were not confirmed in clinical studies of more than one year duration.
Patients should be monitored clinically for small bowel and hepatobiliary neoplasia. Upper GI endoscopy or other imaging is recommended before and during the treatment with teduglutide per clinical discretion. If a benign neoplasm is found, it should be removed. In patients with active gastrointestinal malignancy (gastrointestinal tract, hepatobiliary, pancreatic), teduglutide therapy should be discontinued. In patients with active non-gastrointestinal malignancy or who are at increased risk for malignancy, the clinical decision to continue teduglutide should be made based on risk-benefit considerations.

Gallbladder and bile tract disease.

Cholecystitis, cholangitis, and cholelithiasis have been reported in clinical studies. For identification of the onset or worsening of gallbladder/biliary disease, patients should undergo laboratory assessment of bilirubin and alkaline phosphatase prior to starting teduglutide, and while on teduglutide. If clinically meaningful changes are seen, further evaluation including imaging of the gallbladder and/or biliary tract is recommended and the need for continued teduglutide treatment should be reassessed.

Pancreatic diseases.

Pancreatic adverse events such as chronic and acute pancreatitis, pancreatic duct stenosis, pancreas infection and increased blood amylase and lipase have been reported in clinical studies.
For identification of onset or worsening of pancreatic disease, patients should undergo laboratory assessment of lipase and amylase prior to starting teduglutide, and while on teduglutide. If clinically meaningful changes are seen, further evaluation such as imaging of the pancreas is recommended; and the need for continued teduglutide treatment should be reassessed.

Intestinal obstruction.

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

Fluid and electrolyte balance.

To avoid fluid overload or dehydration, careful adjustment of parenteral support is required in patients taking teduglutide. Electrolyte balance and fluid status should be carefully monitored throughout treatment, especially during initial therapeutic response and discontinuation of teduglutide treatment.

Fluid overload.

Fluid overload and congestive heart failure have been observed in clinical trials. Fluid overload adverse events occurred most frequently during the first 4 weeks of therapy and decreased over time. There is a theoretical rationale that, during the initial several weeks of teduglutide treatment, subjects may become volume expanded if their parenteral nutrition and intravenous fluids (PN/IV) volumes are not appropriately down titrated.
Due to increased fluid absorption, patients with and without a history of cardiovascular disease, such as cardiac insufficiency and hypertension, should be monitored with regard to fluid overload, especially during initiation of therapy. Patients should be advised to contact their physician in case of sudden weight gain, face swelling, swollen ankles and/or dyspnoea. In general, fluid overload can be prevented by appropriate and timely assessment and adjustment of parenteral nutrition needs. This assessment should be conducted more frequently within the first months of treatment with close monitoring afterwards. In case of a significant deterioration of cardiovascular disease, the need for continued teduglutide treatment should be reassessed.

Dehydration.

Patients with SBS are susceptible to dehydration that may lead to acute renal failure. Fluid and electrolyte imbalance leading to dehydration and acute renal impairment/failure was similarly observed between patients with SBS receiving teduglutide and patients not receiving teduglutide. In general, dehydration can be prevented by appropriate and timely monitoring for fluid and electrolyte imbalance, and subsequent adjustment of parenteral fluid and electrolytes. This assessment should be conducted more frequently within the first few months after treatment response, at discontinuation of treatment, and during times of dehydration and acute metabolic stress such as intercurrent infection, intestinal obstruction, and during the post-operative period.

Concomitant medication.

Patients receiving oral concomitant medicinal products requiring titration or with a narrow therapeutic index should be monitored closely due to potential increased absorption and may require dose adjustment of these medications while on teduglutide. Examples of such medications include benzodiazepines, opioids, digoxin, anti-hypertensives.

Special clinical conditions.

Revestive has not been studied in patients with severe, clinically unstable concomitant diseases (e.g. cardiovascular, respiratory, renal, infectious, endocrine, hepatic, or CNS), or in patients with malignancies within the last 5 years (also see Section 4.3 Contraindications).

Discontinuation of treatment.

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

Paediatric use.

Revestive should not be used in children under 2 years of age. Data on safety and efficacy of Revestive in children under 2 years of age is limited.

Use in the elderly.

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

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Based upon the pharmacodynamic effects 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.
Clinical interaction studies were not performed. No inhibition or induction of the cytochrome P450 enzyme system (CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4 [10HMDZ and 6βT]) has been observed based on in vitro studies, although the relevance of in vitro studies to an in vivo setting is unknown. Teduglutide treatment is unlikely to result in P-glycoprotein-mediated drug interactions.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

There are no data on the effects of teduglutide on human fertility. There were no effects on fertility in rats administered with teduglutide at subcutaneous doses up to 50 mg/kg/day (about 180 times the recommended human dose of 0.05 mg/kg/day, based on body surface area).
(Category B1)
There are limited data from the use of teduglutide in pregnant women. Available data from case reports with teduglutide use in pregnant women have not identified a drug associated risk of major birth defects, miscarriage, or adverse maternal or foetal outcomes. A risk to the pregnant woman or developing foetus cannot be excluded. A decision should be made whether to initiate or discontinue treatment with teduglutide, taking into account the risk/benefit of therapy.
In animal studies, no adverse effects on embryofoetal development were observed in rats or rabbits given teduglutide during the period of organogenesis at subcutaneous doses up to 50 mg/kg/day (plasma AUC exposure more than 400 times clinical exposure at the recommended human dose of 0.05 mg/kg/day). There were no adverse effects on pre- and postnatal development in rats given teduglutide from early gestation to weaning at subcutaneous doses up to 50 mg/kg/day (about 180 times the recommended human dose of 0.05 mg/kg/day, based on body surface area). Pharmacokinetic data demonstrated that the teduglutide exposure of foetal rabbits and suckling rat pups was low. Because animal reproductive studies are not always predictive of human response, Revestive should be used during pregnancy only if clearly needed.
It is not known whether teduglutide is excreted in human milk. Teduglutide was excreted in the noncolostral milk of lactating rats (highest concentration 2.9% of the plasma concentration) following a single subcutaneous injection of 25 mg/kg (about 90 times the recommended human dose, based on body surface area). Because many drugs are excreted in human milk, because of the potential for serious adverse reactions to nursing infants from teduglutide and because of the potential for tumorigenicity shown for teduglutide in mice and rats, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

4.7 Effects on Ability to Drive and Use Machines

Teduglutide has minor influence on the ability to drive and use machines. However, cases of syncope have been reported in clinical studies. Such events might impact the ability to drive and use machines.

4.8 Adverse Effects (Undesirable Effects)

Adverse events in Revestive-treated patients with SBS participating in 2 randomised, placebo-controlled, 24-week, double-blind clinical studies (Studies CL0600-020 and CL0600-004, involving in total 109 patients treated with Revestive) are listed in Table 2. The most commonly reported adverse events were abdominal pain (28%) and abdominal distension (17%), nausea (26%), injection site reactions (26%), headache (16%), vomiting (14%), urinary tract infection (13%), and nasopharyngitis (13%). Approximately 38% of the treated patients with a stoma experienced gastrointestinal stoma complications. The majority of these events were mild or moderate.
Adverse reactions are listed by MedDRA system organ class and by frequency. Frequencies are defined as very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000). Adverse reactions from post-marketing experience are indicated with #.

Infections and infestations.

Very common: Nasopharyngitis.
Common: Influenza; Influenza-like illness^#.

Immune system disorders.

Not known: Hypersensitivity^#.

Metabolism and nutrition disorders.

Common: Decreased appetite.
Uncommon: Fluid overload.

Psychiatric disorders.

Common: Insomnia.

Nervous system disorders.

Very common: Headache.

Cardiac disorders.

Common: Cardiac failure congestive.

Respiratory, thoracic and mediastinal disorders.

Common: Cough; Dyspnoea.

Gastrointestinal disorders.

Very common: Abdominal distension; Abdominal pain; Flatulence; Nausea; Vomiting.
Common: Colonic polyp; Intestinal obstruction; Pancreatitis*; Small intestinal stenosis.
Uncommon: Small intestinal polyp**; Colonic stenosis; Pancreatic duct stenosis.

Hepatobiliary disorders.

Common: Cholecystitis; Cholecystitis acute.

General disorders and administration site conditions.

Very common: Injection site reaction***; Oedema peripheral.
Not known: Fluid retention^#.

Injury, poisoning and procedural complications.

Very common: Gastrointestinal stoma complication.
* Includes the following preferred terms: Pancreatitis, Pancreatitis acute^#, and Pancreatitis chronic.
** Locations include duodenum, ileum, and jejunum.
*** Includes the following preferred terms: Injection site haematoma, Injection site erythema, Injection site pain, Injection site swelling, Injection site haemorrhage, Injection site induration (unknown), Injection site inflammation (unknown), Injection site pruritus (unknown), Injection site rash (unknown), Injection site urticaria (unknown), and Injection site warmth (unknown).

Immunogenicity.

Based on data from a trial and its extension in adults with SBS (a 6-month randomised placebo-controlled trial, followed by a 24-month open-label extension), the development of anti-teduglutide antibodies in subjects who received subcutaneous administration of 0.05 mg/kg teduglutide 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.
The antibody formation has not been associated with clinically relevant safety findings, reduced efficacy or changed pharmacokinetics of Revestive.
The rate of anti-teduglutide antibody formation in the 24-week paediatric study was 19%, similar to the rate of antibody formation in adult subjects. However, with the longer duration of treatment, the rate of anti-teduglutide formation at Month 12 was higher in paediatric patients with 54% (14/26), compared to that of adults (24%). Of the 14 paediatric patients who had developed antibodies to teduglutide at Month 12, 1 patient had neutralizing antibodies. Among the small number of paediatric patients who developed anti-teduglutide antibodies, no association with adverse events of hypersensitivity or lack of efficacy was observed.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at http://www.tga.gov.au/reporting-problems.

4.9 Overdose

The maximum dose of Revestive studied during clinical development was 80 mg/day for 8 days. No unexpected systemic adverse reactions were seen. In the event of overdose, the patient should be carefully monitored by the medical professional.
For information on the management of overdose, contact the Poison Information Centre on 131126 (Australia), or the National Poisons Centre on 0800 POISON (0800 764766) in New Zealand.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Other alimentary tract and metabolism products, various alimentary tract and metabolism products.
ATC code: A16AX08.

Mechanism of action.

Teduglutide is an analogue of naturally occurring human GLP-2, a peptide secreted by L-cells of the distal intestine. Similar to GLP-2, teduglutide is 33 amino acids in length with an amino acid substitution of alanine by glycine at the second position of the N-terminus. The single amino acid substitution relative to naturally occurring GLP-2 results in resistance to in vivo degradation by the enzyme dipeptidyl peptidase-IV (DPP-IV), resulting in an extended half-life. GLP-2 is known to increase intestinal and portal blood flow, decrease intestinal motility and inhibit gastric acid secretion. Teduglutide binds to the GLP-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 has been shown to preserve mucosal integrity by promoting repair and normal growth of the intestine through an increase of villus height and crypt depth.

Pharmacodynamic effects.

The ability of teduglutide to improve intestinal absorption of fluid and nutrients was studied in 17 adult subjects with Short Bowel Syndrome (SBS) using daily doses of 0.03, 0.10, and 0.15 mg/kg (n = 2-3 per dose group) in a 21-day, open-label, multi-centre, dose-ranging study. All subcutaneous (abdomen) doses studied, except 0.03 mg/kg once daily, decreased stomal output or faecal fluid and macronutrient excretion, resulted in enhanced gastrointestinal fluid (wet weight) absorption of approximately 750-1000 mL/day, and increased villus height and crypt depth of the intestinal mucosa.
At a dose 5 times the maximum recommended dose, teduglutide did not prolong the QTc interval to any clinically relevant extent.

Clinical trials.

Adults with SBS.

The safety and clinical evidence of efficacy of Revestive in adult patients with SBS is derived from 2 randomised placebo-controlled trials and 2 extension trials. In these studies, 173 patients received Revestive at doses of 0.05 mg/kg (n = 134) or 0.10 mg/kg (n = 39) via subcutaneous injection.
Study CL0600-020. The efficacy, safety, and tolerability of Revestive was evaluated in a randomised, double-blind, placebo-controlled, parallel-group, multinational, multi-centre clinical trial in adults with SBS who were dependent on parenteral nutrition/intravenous (PN/IV) support for at least 12 months and required PN at least 3 times per week.
For 8 weeks (or less) prior to randomisation, investigators optimised the PN/IV volume of all subjects. Optimisation was followed by a 4-week to 8-week period of fluid stabilisation. Subjects then were randomised (1:1) to placebo (n = 43) or Revestive 0.05 mg/kg/day (n = 43). Study treatment was administered subcutaneously once daily for 24 weeks. PN/IV volume adjustments (up to 30% decrease) and clinical assessments were made at 2, 4, 8, 12, 16, 20, and 24 weeks.
The primary efficacy endpoint was based on a clinical response, defined as a subject achieving at least 20% reduction in weekly PN/IV volume from baseline (immediately before randomisation) to both weeks 20 and 24.
The mean age of subjects was 50.3 years. Mean duration of PN/IV dependency prior to enrolment was 6.25 years (range 1-25.8 years). The most common reasons for intestinal resection leading to SBS were vascular disease (34.1%, 29/85), Crohn's Disease (21.2%, 18/85), and "other" (21.2%, 18/85). Stoma was present in 44.7% (38/85) of subjects, and the most common type was jejunostomy/ileostomy (81.6%, 31/38). The mean length of remaining small intestine was 77.3 ± 64.4 cm (range: 5 to 343 cm). The colon was not in continuity in 43.5% (37/85) of subjects. At baseline, the mean (± SD) prescribed days per week for PN/IV infusion was 5.73 (± 1.59) days.
The percentages of treatment group responders were compared in the intent-to-treat population of this study which was defined as all randomised patients. Sixty-three percent (27/43) of subjects treated with Revestive versus 30% (13/43) of placebo-treated subjects were considered responders (p = 0.002).
At week 24, the mean reduction in weekly PN/IV volume was 4.4 L for subjects treated with Revestive (from pre-treatment baseline of 12.9 L) versus 2.3 L for placebo-treated subjects (from pre-treatment baseline of 13.2 L/week) (p < 0.001).
The mean changes from baseline in PN/IV volume by visit are shown in Figure 1.

Study CL0600-021. CL0600-021 was a 2-year open-label extension of CL0600-020, in which 88 subjects received Revestive 0.05 mg/kg/day. Ninety-seven percent (76/78) of subjects who completed CL0600-020 elected to enrol in CL0600-021 (37 received Revestive; 39 received placebo). An additional 12 subjects whom entered CL0600-021 had been optimised and stabilised but not randomised in CL0600-020 because of closed enrolment.

24 months exposure.

Of the 39 placebo subjects from CL0600-020 entering CL0600-021, 29 completed 24 months of treatment with Revestive. The mean reduction in PN/IV was 3.11 L/week (an additional 28.3% reduction) from the start of CL0600-021. Sixteen (55.2%) of the 29 completers achieved a 20% or greater reduction in parenteral support. At the end of the study, 14 (48.3%), 7 (24.1%) and 5 (17.2%) subjects achieved a reduction of 1, 2, or 3 days per week in PN/IV support, respectively. Two subjects were weaned off their PN/IV support while on Revestive.
Of the 12 subjects entering CL0600-021 directly, 6 completed 24 months of treatment with Revestive. Similar effects were seen. One of the six subjects was weaned off their PN/IV support while on Revestive.

30 months exposure.

Thirty subjects on Revestive completed a total duration of 30 months (CL0600-020 followed by CL0600-021 treatment). Of these, 28 subjects (93%) achieved a 20% or greater reduction of parenteral support. Of the responders in CL0600-020 who had completed 2 additional years of continuous treatment with Revestive, 96% (21/22) demonstrated durability in the effect of Revestive.
The mean reduction in PN/IV (n = 30) was 7.55 L/week (a 65.6% reduction from baseline). Ten subjects were weaned off their PN/IV support while on treatment with Revestive for 30 months. Subjects were maintained on Revestive even if no longer requiring PN/IV support. These 10 subjects had required PN/IV support for 1.2 to 15.5 years, and prior to Revestive had required between 3.5 L/week and 13.4 L/week of PN/IV support. At 24 months, 21 (70%), 18 (60%) and 18 (60%) of the 30 completers achieved a reduction of 1, 2, or 3 days per week in PN/IV support, respectively.
Study CL0600-004. CL0600-004 was a randomised, double-blind, placebo-controlled, three-arm parallel-group, multinational study in adults with SBS who were dependent on PN/IV support for at least 12 months and required PN at least 3 times per week. After a period of optimisation and stabilisation similar to CL0600-020, subjects were randomised to receive 24 weeks of one of the following treatment regimens: Revestive 0.05 mg/kg/day (n = 35), Revestive 0.10 mg/kg/day dose (n = 33), or placebo (n = 16). The primary efficacy endpoint was a graded categorical score that did not achieve statistical significance for the high dose (0.10 mg/kg/day).
Study CL0600-005. CL0600-005 was a randomised, double-blinded, parallel-group, extension of CL0600-004, in which 65 subjects from CL0600-004 received Revestive for up to an additional 28 weeks of treatment. Of the responders in CL0600-004 who entered CL0600-005, 75% (12/16) demonstrated durability in the effect of Revestive after one year of treatment. In the Revestive 0.05 mg/kg/day dose group, a 20% or greater reduction of parenteral support was achieved in 68% (17/25) of subjects. The mean reduction of weekly PN/IV volume was 4.9 L/week (52% reduction from baseline) after one year of continuous treatment with Revestive. The subjects who had been completely weaned off PN/IV support in CL0600-004 remained off parenteral support through CL0600-005. During CL0600-005, an additional subject from CL0600-005 was weaned off parenteral support.

Paediatric from 1 to 17 years with SBS.

The efficacy data presented are derived from 2 controlled studies in paediatric patients of 24-weeks and 12 weeks duration. These studies included 87 patients treated with teduglutide (41 with 0.05 mg/kg/day) and while 4 subjects aged 1 to < 2 years received teduglutide, only 1 received 0.05 mg/kg/day. 14 other subjects received standard care only (no teduglutide). Otherwise, despite the limited sample size, which did not allow meaningful statistical comparisons, clinically meaningful, numerical reductions in the requirement for parenteral support were observed across all age groups.
TED-C14-006. A 24 week, randomized, double blind, multicentre study was conducted in 59 paediatric subjects aged 1 year through 17 years who were dependent on PS. Subjects chose whether to receive Revestive or standard of care (SOC). Subjects in the Revestive treatment arm were randomized in a double blind manner to 0.025 mg/kg/day (n = 24) or 0.05 mg/kg/day (n = 26), while 9 subjects enrolled in the SOC arm. Results described below correspond to subject diary data in the ITT population at the recommended dose of 0.05 mg/kg SC once daily. See Table 3.

Three subjects (12%) in the 0.05 mg/kg group achieved enteral autonomy by week 24. See Figure 2.

TED-C13-003. Revestive was studied in a 12 week, open label, clinical study in 42 paediatric subjects aged 1 year through 14 years with SBS who were dependent on PS. Three doses of Revestive, 0.0125 mg/kg/day (n = 8), 0.025 mg/kg/day (n = 14), and 0.05 mg/kg/day (n = 15), were investigated for 12 weeks. Five subjects were enrolled in a SOC cohort.
The clinical findings from this study were comparable to that from the study TED C14-006.
The clinical findings from this 12-week study were comparable to that from the 24-week TED-C14-006 study, suggesting the most rapid clinical changes, including PS volume reductions, occurs during the first 12 weeks of teduglutide treatment.

Reduction in infusion time.

Subjects in the SOC cohort showed minimal change in PS hours/day.

Enteral autonomy.

Based on physician prescribed and subject diary data, 1 subject on the recommended dose of Revestive achieved enteral autonomy at the end of treatment.

5.2 Pharmacokinetic Properties

Absorption.

In healthy subjects, teduglutide administered subcutaneously in the thigh/abdomen had an absolute bioavailability of 88% and reached maximum plasma teduglutide concentrations at 3-5 hours after administration. Following a 0.05 mg/kg subcutaneous dose in SBS subjects, the mean peak teduglutide concentration (C_max) was 36.4 nanogram/mL and the mean area under the curve (AUC_0-T) was 235 nanogram.h/mL. No accumulation of teduglutide was observed following repeated subcutaneous administrations.

Distribution.

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

Metabolism.

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

Excretion.

In healthy subjects, teduglutide plasma clearance was approximately 123 mL/h/kg which is similar to the GFR, suggesting that teduglutide is primarily cleared by the kidney.
Teduglutide has a mean terminal half-life (t_1/2) of approximately 1.1 hours in SBS subjects.

Dose linearity.

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

Special populations.

Gender.

No clinically relevant gender differences were observed.

Paediatrics.

Following subcutaneous administration of 0.05 mg/kg daily dose, similar C_max of teduglutide across age groups was demonstrated by population pharmacokinetics modelling (see Table 4). However, lower exposure (AUC) and shorter half-life were seen in paediatric patients 1 to 17 years of age, as compared with adults. The pharmacokinetic profile of teduglutide in this paediatric population, as evaluated by clearance and volume of distribution was different from that observed in adults, after correcting for body weights. Specifically, body weight corrected clearance decreases with increasing age from 1 year old to adults.