Consumer medicine information

Trulicity

Dulaglutide

BRAND INFORMATION

Brand name

Trulicity

Active ingredient

Dulaglutide

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Trulicity.

SUMMARY CMI

TRULICITY®

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

1. Why am I using TRULICITY?

TRULICITY contains the active ingredient dulaglutide (rch). In adults with Type 2 diabetes, TRULICITY is used to improve blood sugar control and reduce the risk of major adverse cardiovascular events in patients with multiple risk for, or existing cardiovascular disease. For more information, see Section 1. Why am I using TRULICITY? in the full CMI.

2. What should I know before I use TRULICITY?

Do not use if you have ever had an allergic reaction to TRULICITY or any of the ingredients listed at the end of the CMI.

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding. For more information, see Section 2. What should I know before I use TRULICITY?.

3. What if I am taking other medicines?

Some medicines may interfere with TRULICITY and affect how it works. A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I use TRULICITY?

  • The recommended starting dose of TRULICITY is 1.5 mg once weekly.
  • TRULICITY should be used once weekly at any time of the day, with or without meals.
  • More instructions can be found in Section 4. How do I use TRULICITY? in the full CMI.

5. What should I know while using TRULICITY?

Things you should do
  • Remind any doctor, dentist, pharmacist or diabetes nurse educator you visit that you are using TRULICITY.
  • Always carry glucose or sugary foods with you. Tell your doctor if you experience low blood sugar.
Things you should not do
  • Do not stop using this medicine suddenly and without consulting your Doctor/Healthcare provider.
  • Do not use this medicine if you think it has been frozen or exposed to excessive heat.
Driving or using machines
  • Be careful before you drive or use machines or tools until you know how TRULICITY affects you.
Drinking alcohol
  • Tell your doctor if you drink alcohol. Alcohol may mask the symptoms of low blood sugar (hypoglycaemia), or make it worse.
Looking after your medicine
  • Keep TRULICITY pens in a fridge between 2°C - 8°C. Do not freeze.
  • Keep TRULICITY pens in the original pack until ready to use.

For more information, see Section 5. What should I know while using TRULICITY? in the full CMI.

6. Are there any side effects?

Nausea, diarrhoea, abdominal (stomach) pain and vomiting were very commonly reported in patients using TRULICITY. These side effects are usually not severe and are most common when first starting TRULICITY but decrease over time in most patients.

Serious side effects may include severe low blood sugar, dehydration, gallbladder complaints, and sudden inflammation of the pancreas (severe abdominal pain is the predominant symptom.).

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.



FULL CMI

TRULICITY® (TRU-li-si-tee) Single dose Pre-filled Pen (autoinjector)

Active ingredient(s): dulaglutide (rch)

Consumer Medicine Information (CMI)

This leaflet provides important information about using TRULICITY. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using TRULICITY.

Where to find information in this leaflet:

1. Why am I using TRULICITY?
2. What should I know before I use TRULICITY?
3. What if I am taking other medicines?
4. How do I use TRULICITY?
5. What should I know while using TRULICITY?
6. Are there any side effects?
7. Product details

1. Why am I using TRULICITY?

TRULICITY contains the active ingredient dulaglutide (rch). TRULICITY is a type of medicine called 'GLP-1 receptor agonists', which are used to help treat diabetes.

Diabetes is a condition in which your pancreas does not produce enough insulin to control your blood sugar level. TRULICITY helps your body to produce more insulin when your blood sugar level is high.

In adults with Type 2 diabetes, TRULICITY is used to improve blood sugar control and reduce the risk of major adverse cardiovascular events in patients with or without existing cardiovascular disease.

TRULICITY may be used alone or with other medicines to control your blood sugar levels. Your doctor may want you to use one or more other medicines in addition to TRULICITY, such as metformin, sulfonylurea, thiazolidinedione (TZD) or insulin.

TRULICITY has not been studied in children.

2. What should I know before I use TRULICITY?

Warnings

Do not use TRULICITY if:

  • you are allergic to dulaglutide, or any of the ingredients listed at the end of this leaflet. Check the ingredients in section 7. Product Details to make sure you can use this medicine. Signs of an allergic reaction include redness, swelling and itching at the injection site, rash, shortness of breath, fast pulse or sweating.
  • if the packaging is torn or shows signs of tampering.
  • if you are experiencing low blood sugar (hypoglycaemia). (See additional information in section 5. What Should I know while using TRULICITY?)
  • if the product appears cloudy, discoloured, contains particles, or has been frozen or exposed to excessive heat.
  • if the expiry date on the pack has passed

If you are not sure whether you should start using TRULICITY, talk to your doctor, pharmacist or diabetes nurse educator.

Check with your doctor if you:

  • have any other medical conditions, especially pancreatitis (an inflamed pancreas causing severe stomach and back pain which does not go away), any condition affecting your digestive system or end stage kidney disease.
  • If you have type 1 diabetes or diabetic ketoacidosis (often caused by very high blood sugar levels).
  • if you have had an allergic reaction to any medicine which you have used previously to treat your current condition.
  • if you are also taking a sulfonylurea (such as glimepiride or glibenclamide) or an insulin. Your doctor may tell you to test your blood sugar to decide if the dose of the sulfonylurea or insulin needs to be changed.
  • take any medicines for any other condition

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

Check with your doctor if you are pregnant or intend to become pregnant.

Talk to your doctor if you are breastfeeding or intend to breastfeed.

Use of this medicine during pregnancy and breast-feeding has not been studied. It is not known whether taking TRULICITY may harm your unborn child, or if TRULICITY is excreted in significant amounts in breast milk.

3. What if I am taking other medicines?

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

Some medicines may interfere with TRULICITY and affect how it works.

When TRULICITY is used with a medicine that contains sulfonylurea or insulin, low blood sugar (hypoglycaemia) can occur. The dose of your sulfonylurea or insulin may need to be reduced while you use TRULICITY.

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect TRULICITY.

4. How do I use TRULICITY?

Follow all directions given to you by your doctor, pharmacist or diabetes nurse educator carefully.

These may differ from the information contained in this leaflet.

How much to use

  • The recommended dose of TRULICITY is 1.5 mg once weekly.

The dose is the amount contained in one single use pen.

Follow the instructions provided. Do not stop TRULICITY just because you feel better. It is important that you do not stop using TRULICITY unless your doctor tells you to do so.

When to use TRULICITY

  • TRULICITY should be used once weekly, at any time of the day, with or without meals.
  • You should take your TRULICITY on the same day each week if you can. To help you remember, you may wish to tick the day of the week when you take your first dose of TRULICITY on the box that your medicine comes in, or on a calendar.

How to use TRULICITY Pre-filled Pen (autoinjector)

  • Read the instructions for use for the pen carefully before using TRULICITY.
  • Inject TRULICITY under the skin of your stomach or upper leg.
  • You should inject the whole contents of the single use pen each week.
  • If the injection is given by someone else, it may be injected into your upper arm.

If you want to do so, you can use the same area of your body each week. But be sure to choose a different injection site within that area.

If you forget to use TRULICITY

TRULICITY should be used regularly on the same day each week. If you miss your dose on the usual day, and if there are at least 3 days before your next dose is due, then take your TRULICITY dose as soon as possible.

Take your next dose on your regular scheduled day.

If there are less than 3 days before your next dose is due, skip the dose you missed and take your next dose when you are meant to.

Do not take a double dose to make up for a forgotten dose.

  • You can also change the day of the week when you take TRULICITY if needed, as long as it has been at least 3 days since your last dose of TRULICITY.
  • If you have trouble remembering to use your medicine, ask your doctor, pharmacist, or diabetes nurse educator for some hints.

If you use too much TRULICITY

If you think that you have used too much TRULICITY, talk to your doctor immediately.

Too much TRULICITY can make you feel sick or be sick.

You should immediately:

  • phone the Poisons Information Centre
    (by calling (Australia) 13 11 26 (New Zealand) 0800 764 766), or
  • contact your doctor, or
  • go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

5. What should I know while using TRULICITY?

Things you should do

While you are using TRULICITY, tell your doctor or pharmacist before you start any new medicine.

Remind any doctor, dentist, pharmacist or diabetes nurse educator you visit that you are using TRULICITY.

Tell your doctor, pharmacist or diabetes nurse educator if you are travelling.

  • Ask your doctor for a letter explaining why you are taking injecting devices with you. Each country you visit will need to see this letter so you should take several copies.
  • You may not be able to get TRULICITY in the country you are visiting. Your doctor, pharmacist or diabetes nurse educator can provide you with some helpful information.

If you become pregnant while using TRULICITY tell your doctor.

Always carry something to show you have diabetes.

Always carry glucose or sugary foods with you.

Call your doctor straight away if you:

  • Experience low blood sugar (hypoglycaemia).
  • When TRULICITY is used with a medicine that contains sulfonylurea or insulin, low blood sugar (hypoglycaemia) can occur. The dose of your sulfonylurea or insulin may need to be reduced while you use TRULICITY.

Things you should not do

  • Do not stop using this medicine suddenly and without consulting your Doctor/Healthcare provider.
  • Do not use the medicine if you think it has been frozen or exposed to excessive heat. It may not work as well.
  • Do not give your TRULICITY to anyone else, even if they have the same condition as you. Your doctor has prescribed TRULICITY only for you.

Hypoglycaemia (low blood sugar)

  • It is important you know and can recognise the symptoms of hypoglycaemia (low blood sugar).

Symptoms of mild to moderate low blood sugar (hypoglycaemia) can include:

  • sweating
  • hunger, headache
  • tremor, unsteady movement
  • light-headedness
  • drowsiness, dizziness
  • depressive mood, anxiety
  • irritability, personality change
  • abnormal behaviour
  • inability to concentrate
  • sleep disturbance
  • blurred vision
  • increased heart rate or irregular heartbeat
  • tingling in the hands/feet/lips or tongue
  • slurred speech.

Tell your doctor if you have trouble recognising the symptoms of hypoglycaemia.

Recognising these mild to moderate hypoglycaemic symptoms early may allow you to take the necessary steps to avoid more serious hypoglycaemia.

Symptoms of severe hypoglycaemia can include:

  • disorientation
  • seizures
  • unconsciousness.

If you experience symptoms of low blood sugar, eat some sugary food or drink, such as jelly beans, orange juice or glucose tablets.

If you do not feel better after eating/drinking some sugary food or drink, contact your doctor or go to the Emergency Department at your nearest hospital

Tell your relatives, friends, close workmates or carers that you have Type 2 diabetes. It is important that they know and can recognise the signs and symptoms of hypoglycaemia.

Make sure they know to give you some sugary food or fruit juice for mild to moderate symptoms of hypoglycaemia.

If you lose consciousness, make sure they know:

  • to turn you on your side and get medical help immediately
  • not to give you anything to eat or drink.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how TRULICITY affects you.

If you use TRULICITY in combination with sulfonylureas or insulin, low blood sugar (hypoglycaemia) can occur. Low blood sugar (hypoglycaemia) may reduce your ability to concentrate.

Drinking alcohol

Tell your doctor if you drink alcohol.

Alcohol may mask the symptoms of low blood sugar (hypoglycaemia), or make it worse.

Looking after your medicine

  • Keep TRULICITY pens in a fridge between 2°C - 8°C.
  • When refrigeration is not possible, you can keep your pen at room temperature (below 30°C) for up to a total of 14 days.
  • Do not allow the pen to freeze. Do not use it if it has been frozen.
  • Keep TRULICITY in the original package in order to protect it from light.
  • Do not use a pen after the expiry date (month, year) stamped on the label.

Follow the instructions in the carton on how to take care of your medicine properly.

Keep it where young children cannot reach it.

When to discard your medicine

If your doctor tells you to stop using TRULICITY.

Empty pens should be disposed of in a sharps container or similar puncture proof container composed of hard plastic or glass.

Ask your doctor, pharmacist, or diabetes nurse educator where you can dispose of the container once it is full.

You can also refer to the instructions for use for the pen for additional information on storage and handling of this medicine.

Getting rid of any unwanted medicine

If you no longer need to use this medicine or it is out of date, take it to any pharmacy for safe disposal.

Do not use this medicine after the expiry date.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Less serious side effects

Less serious side effectsWhat to do
Stomach complaints:
  • Feeling sick (nausea)
  • Diarrhoea
  • vomiting
  • Abdominal (stomach) pain (also refer to Serious Side Effects)
  • Heartburn, indigestion
  • Constipation
  • Increased burping, belching or farting (flatulence)
  • Bloating
  • Indigestion (reflux)
  • Decreased appetite
  • Difficulty swallowing
General disorders and Injection site related:
  • Tiredness, loss of energy and strength
  • Redness, swelling or itching at the injection site
Speak to your doctor if you have any of these less serious side effects and they persist or worry you.

Serious side effects

Serious side effectsWhat to do
Metabolism and nutrition related:
  • Symptoms of dehydration (such as dry mouth, decreased frequency of urination and concentrated urine, headache, muscle weakness, dizziness or light headedness.)
  • Symptoms of severe low blood sugar (disorientation, seizures, fits or convulsions, loss of consciousness)
Stomach complaints:
  • Symptoms of acute pancreatitis (severe pain in the stomach and back which does not go away, vomiting, diarrhoea)
Gallbladder complaints:
  • Gallstones or an inflamed gallbladder (symptoms may include pain in your upper stomach (abdomen), fever, yellowing of skin or eyes (jaundice), clay-coloured stools)
Severe allergic reactions:
You should see a doctor immediately if you experience symptoms of an allergic reaction such as;
  • rashes
  • itching and rapid swelling of the tissues of the neck, face, mouth, or throat
  • hives, and
  • difficulty breathing
Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

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

What TRULICITY contains

Active ingredient
(main ingredient)		dulaglutide (rch)
Other ingredients
(inactive ingredients)		sodium citrate dihydrate
citric acid
mannitol
polysorbate 80
Water for Injections

Do not take this medicine if you are allergic to any of these ingredients.

What TRULICITY looks like

TRULICITY is a clear colourless solution available as a single use pre-filled pen (autoinjector).

TRULICITY is available:

Australia:

TRULICITY 1.5 mg/0.5 mL Pre-filled Pen (Autoinjector). AUST R 217965

New Zealand:

TRULICITY 1.5 mg/0.5 mL Pre-filled Pen (Autoinjector). TT50-10823

Who distributes TRULICITY

Australia:

Eli Lilly Australia Pty Ltd
Level 9, 60 Margaret Street
SYDNEY NSW 2000

New Zealand:

Eli Lilly and Company (NZ) Limited
PO Box 109 197
Newmarket Auckland 1149

Further Information

You can get more information about diabetes from:

Diabetes Australia

Diabetes New Zealand

If you have any questions about TRULICITY, contact Lilly at 1800 454 559 (Australia), or 0800 500 056 (New Zealand) or your healthcare professional for assistance.

To check for CMI updates and obtain the latest version, visit:

This leaflet was prepared May 2023 (ANZ vA3.0).

Published by MIMS June 2023

BRAND INFORMATION

Brand name

Trulicity

Active ingredient

Dulaglutide

Schedule

S4

 

1 Name of Medicine

Dulaglutide (rch).

2 Qualitative and Quantitative Composition

Trulicity contains dulaglutide (rch) 1.5 mg per 0.5 mL solution.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Solution for injection.
Trulicity is a clear, colourless, essentially free from particles, sterile and non-pyrogenic solution for subcutaneous administration.

4 Clinical Particulars

4.1 Therapeutic Indications

Type 2 diabetes mellitus: glycaemic control.

Trulicity is indicated as an adjunct to diet and exercise to improve glycaemic control in adults with type 2 diabetes mellitus: as monotherapy; in combination with other glucose-lowering medicinal products including insulin, when these, together with diet and exercise, do not provide adequate glycaemic control (see Section 5.1 for data with respect to different combinations).

Type 2 diabetes mellitus: reduction in risk of major adverse cardiovascular events.

Trulicity is indicated as an adjunct to standard of care therapy to reduce the risk of major adverse cardiovascular events in adults with type 2 diabetes mellitus who have: established cardiovascular disease or; multiple cardiovascular risk factors.

4.2 Dose and Method of Administration

General.

Trulicity should be administered once weekly. The dose can be administered at any time of the day, with or without meals, and can be injected subcutaneously in the abdomen, thigh or upper arm. Trulicity should not be administered intravenously or intramuscularly. Trulicity is for single use in one patient only. Discard the pen once the injection is completed.

Use in adults (≥ 18 years).

The recommended dose of Trulicity is 1.5 mg per week. Administer Trulicity once weekly, at any time of day, independently of meals.

Use in the elderly (≥ 65 years).

No dose adjustment is required based on age.

Use in children and adolescents.

The safety and effectiveness of Trulicity have not been established in children and adolescents under 18 years of age.

Use in renal impairment.

No dose adjustment is required in patients with mild (creatinine clearance 60 to < 90 mL/min), moderate (creatinine clearance 30 to < 60 mL/min) or severe (creatinine clearance < 30 mL/min to ≥ 15 mL/min not requiring dialysis) renal impairment.
There is limited experience in patients with end-stage renal disease (creatinine clearance < 15 mL/min requiring dialysis treatment), therefore Trulicity can not be recommended in this population (see Section 4.4 Special Warnings and Precautions for Use; Section 5.1 Pharmacodynamic Properties).

Use in hepatic impairment.

No dose adjustment is required based on hepatic impairment.

Missed dose.

If a dose is missed, it should be administered as soon as possible if there are at least 3 days (72 hours) until the next scheduled dose. If less than 3 days remain before the next scheduled dose, the missed dose should be skipped and the next dose should be administered on the regularly scheduled day. In each case, patients can then resume their regular once weekly dosing schedule.

Changing weekly dosage schedule.

The day of weekly administration can be changed, if necessary, as long as the last dose was administered 3 or more days (72 hours or more) before.

4.3 Contraindications

Trulicity is contraindicated in patients with known hypersensitivity to dulaglutide or any of the excipients in the product.

4.4 Special Warnings and Precautions for Use

Trulicity should not be used in patients with Type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis.

Use in patients with severe gastrointestinal disease.

Use of GLP-1 receptor agonists may be associated with gastrointestinal adverse reactions which include nausea, vomiting and diarrhoea (see Section 4.8 Adverse Effects (Undesirable Effects)). These events may lead to dehydration, which could cause a deterioration in renal function including acute renal failure. Dulaglutide has not been studied in patients with severe gastrointestinal disease, including severe gastroparesis, and is therefore not recommended in these patients.

Acute pancreatitis.

Pancreatitis has been reported with use of GLP-1 receptor agonists, including dulaglutide. Patients should be informed of the symptoms of acute pancreatitis. If acute pancreatitis is suspected Trulicity should be discontinued until evaluation is complete. In the absence of other signs and symptoms of acute pancreatitis, elevations in pancreatic enzymes alone are not predictive of acute pancreatitis (see Section 4.8 Adverse Effects (Undesirable Effects)). If the diagnosis of acute pancreatitis is confirmed, Trulicity should be permanently discontinued.

Risk of hypoglycaemia.

Patients receiving Trulicity in combination with sulfonylurea or insulin may have an increased risk of hypoglycaemia. The risk of hypoglycaemia may be lowered by a reduction in the dose of sulfonylurea or insulin.

Use in patients with congestive heart failure.

There is limited therapeutic experience in patients with congestive heart failure.

Use in hepatic impairment.

No dose adjustment is required based on hepatic impairment.

Use in renal impairment.

There is limited therapeutic experience in patients with end stage renal disease (< 15 mL/min requiring dialysis treatment), therefore Trulicity can not be recommended in this population. (See Section 4.2 Dose and Method of Administration; Section 5.1 Pharmacodynamic Properties).

Use in the elderly.

No dose adjustment is required based on age.

Paediatric use.

The safety and effectiveness of dulaglutide have not been established in patients under 18 years of age.

Effects on laboratory tests.

No information on the effect of dulaglutide on laboratory tests is available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Dulaglutide causes a delay in gastric emptying, and thereby has the potential to impact the absorption of concomitantly administered oral medications. In clinical pharmacology studies, dulaglutide did not affect the absorption of the orally administered medications tested to any clinically relevant degree (e.g. warfarin, metformin, lisinopril, metoprolol, digoxin, paracetamol, norelgestromin, ethinyloestradiol, sitagliptin, atorvastatin). No dosage adjustments of concomitant medications are required.
As elimination of dulaglutide is presumed to be by proteolytic degradation into its amino acid components and is not anticipated to be eliminated intact in the urine or metabolised by cytochrome P450 enzymes, pharmacokinetic interactions with drugs primarily renally eliminated or metabolised by cytochrome P450 enzymes are not expected.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

No adverse effects on fertility were observed in male and female rats given subcutaneous doses of dulaglutide at ≤ 16.3 mg/kg every 3 days, yielding exposure to dulaglutide (based on plasma AUC) ≥ 30 times higher than that in patients at the maximum recommended human dose.
(Category B3)
There are no adequate and well controlled studies of dulaglutide in pregnant women. Administer Trulicity to pregnant women only if the potential benefit justifies the potential risk to the foetus.
High doses of dulaglutide (11 to 44 times the human clinical exposure following once weekly administration of 1.5 mg dulaglutide) during the period of organogenesis to pregnant rats and rabbits caused increased post-implantation loss, reduced foetal growth, and skeletal and visceral abnormalities (including malformations in rabbits). These findings were observed in association with maternal effects (decreased maternal food intake and decreased weight gain) and are not considered likely to reflect direct embryofoetal toxicity or teratogenicity. Memory deficits were observed in the female offspring of rats treated throughout pregnancy and lactation at 1.63 mg/kg every 3 days (yielding 16 times the human clinical exposure). No adverse effects on embryofoetal development were seen in rats and rabbits at subcutaneous doses of 0.49 mg/kg and ≤ 0.12 mg/kg, respectively, given every 3 days (yielding exposures approximately 4 times higher than that in patients at the maximum recommended human dose).
 It is not known whether dulaglutide is excreted in human milk. Administer Trulicity to nursing women only if the potential benefit to the mother justifies the potential risk to the infant. In rats, treatment with dulaglutide throughout pregnancy and lactation at 1.63 mg/kg every 3 days delayed postnatal growth and development and produced memory deficits in the offspring. No adverse effects on postnatal development were observed in rats with subcutaneous dosing at 0.49 mg/kg every 3 days (yielding 4.5 times the exposure in patients at the maximum recommended human dose).

4.7 Effects on Ability to Drive and Use Machines

No studies on the effects on ability to drive or use machinery have been performed. When Trulicity is used in combination with a sulfonylurea or insulin, patients should be advised to take precautions to avoid hypoglycaemia while driving or using machinery.

4.8 Adverse Effects (Undesirable Effects)

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 www.tga.gov.au/reporting-problems.

Clinical trial data.

In the completed phase 2 and 3 initial registration studies 4,006 individuals received at least one dose of dulaglutide for a total of 3,531 patient years, 703 received placebo for 284 patient years and 1,541 received active comparator for 1,722 patient years. The 1.5 mg dose of dulaglutide was received by 1,762 individuals for 1,689 patient years. In studies of 26-week duration, 69.9% of patients who received dulaglutide 1.5 mg reported one or more treatment emergent adverse event compared to 66.0% of patients who received placebo.
The safety profile from the long-term cardiovascular outcome study with 4949 patients randomised to dulaglutide and followed for a median of 5.4 years was consistent with the initial phase 2 and phase 3 registration studies.
The following related adverse reactions have been identified based on evaluation of the full duration of phase 2 and phase 3 clinical studies, the long-term cardiovascular outcome study and post-marketing reports. The adverse reactions are listed in Table 1 as MedDRA preferred term in order of decreasing incidence. Frequencies of adverse reactions have been calculated based on their incidence in the phase 2 and phase 3 registration studies.
Gastrointestinal disorders. Gastrointestinal events (nausea, vomiting and diarrhoea) reported were typically mild or moderate in severity. The onset of nausea, vomiting and diarrhoea was observed to peak during the first two weeks of treatment and rapidly decline over the next four weeks, after which they remained relatively constant.
In clinical pharmacology studies conducted in patients with type 2 diabetes mellitus up to 6 weeks, the majority of gastrointestinal events were reported during the first 2-3 days after the initial dose and declined with subsequent doses.
The following adverse reactions were reported more frequently in Trulicity-treated patients than placebo (frequencies listed, respectively, as: placebo; 1.5 mg): constipation (0.7%, 3.7%), flatulence (1.4%, 3.4%), abdominal distension (0.7%, 2.3%), gastroesophageal reflux disease (0.5%, 2.0%), and eructation (0.2%, 1.6%).
Cholecystitis. In glycaemic control studies with patients receiving dulaglutide 1.5 mg, the incidence of cholecystitis was 0.1% (uncommon).
General disorders and administration site conditions. Potentially immune-mediated injection site adverse events (e.g. rash, erythema) have been reported in 0.7% of patients receiving dulaglutide and have usually been mild.

Immunogenicity.

In clinical studies treatment with dulaglutide at any dose was associated with a 1.6% incidence of treatment emergent dulaglutide anti-drug antibodies.

Hypersensitivity.

Systemic hypersensitivity events (e.g. urticaria, angiooedema) have been reported in 0.3% of patients receiving dulaglutide 1.5 mg once weekly, compared to 0.7% in placebo. Systemic hypersensitivity events were reported in 0.5% of patients receiving dulaglutide at any dose. In the 1.6% of dulaglutide-treated patients with treatment emergent anti-drug antibodies, there were no systemic hypersensitivity adverse events reported.
Cardiac arrhythmia. In the long-term cardiovascular outcome trial, a higher proportion of patients experienced serious adverse events of atrial fibrillation in the dulaglutide group (93 patients [1.9%]) compared to the placebo group (63 patients [1.3%]); p = 0.015.
Investigations. Dulaglutide is associated with a small mean increase in heart rate of 2 to 4 beats per minute and a 1.4% incidence of sinus tachycardia with a concomitant increase from baseline of ≥ 15 beats per minute.
Dulaglutide is associated with small mean increases from baseline in PR interval of 2 to 3 msec and a 2.4% incidence of first-degree atrioventricular block.
Dulaglutide is associated with mean increases from baseline in pancreatic enzymes (pancreatic amylase and/or lipase) of 14% to 20% (see Section 4.4 Special Warnings and Precautions for Use).
Discontinuation due to an adverse event. In studies of 26-week duration the incidence of discontinuation due to adverse events was 6.1% for Trulicity 1.5 mg versus 3.7% for placebo, which was not statistically different. Through the full study duration (up to 104 weeks) the incidence of discontinuation due to adverse events was 8.4% for dulaglutide 1.5 mg. The most frequent adverse events leading to discontinuation were nausea (1.9%), diarrhoea (0.6%) and vomiting (0.6%), and were generally reported within the first 4-6 weeks.
In the long-term cardiovascular outcome study (median follow-up 5.4 years), a higher proportion of patients in the dulaglutide group permanently discontinued study drug due to an adverse event (dulaglutide: 451 [9.1%]; placebo: 310 [6.3%]; p < 0.001). Gastrointestinal events were the most common reason for study drug discontinuation (dulaglutide: 201 [4.1%]; placebo: 54 [1.1%]). The most frequent adverse events leading to discontinuation of study drug in the dulaglutide group were nausea (1.3%), diarrhoea (0.7%) and vomiting (0.6%).
Metabolic and nutrition disorders. See Table 2.

Combination with insulin secretagogues and/or insulin.

Documented symptomatic hypoglycaemia was reported very commonly when Trulicity was administered concomitantly with metformin plus glimepiride and when Trulicity was administered concomitantly with prandial insulin. When dulaglutide was used in combination with metformin and a sulfonylurea or with prandial insulin the rates of hypoglycaemia were 1.67 events/patient/year and 31.06 events/patient/year, respectively. The rates of severe hypoglycaemia events were 0.01 events/patient/year and 0.06 events/patient/year, respectively.
The incidence of documented symptomatic hypoglycaemia when dulaglutide 1.5 mg was used with sulfonylurea alone was 11.3% and the rate was 0.90 events/patient/year, and there were no episodes of severe hypoglycaemia.
The incidence of documented symptomatic hypoglycaemia when dulaglutide 1.5 mg was used in combination with insulin glargine was 35.3% and the rate was 3.38 events/patient/year. The severe hypoglycaemia event incidence was 0.7% and the rate was 0.01 events/patient/year.

Combination with non-secretagogues.

Documented symptomatic hypoglycaemia was reported very commonly when Trulicity was administered concomitantly with metformin and was reported commonly when Trulicity was administered concomitantly with metformin and pioglitazone. When dulaglutide was used in combination with a non-secretagogue, the rates of hypoglycaemia were 0.19 to 0.26 events/patient/year, and no episodes of severe hypoglycaemia were reported.

Monotherapy.

Documented symptomatic hypoglycaemia was reported commonly when Trulicity was administered as monotherapy. The rate of hypoglycaemia was 0.62 events/patient/year and no episodes of severe hypoglycaemia were reported.

Postmarketing data.

The following adverse drug reaction is based on post marketing spontaneous reports.

Immune system disorders.

Anaphylactic reactions: Rare (≥ 0.01%, < 0.1%).

4.9 Overdose

Effects of overdose in dulaglutide studies have included gastrointestinal disorders and hypoglycaemia. In the event of overdose, appropriate supportive treatments should be initiated according to the patient's clinical signs and symptoms.
For information on the management of overdose, contact the Poison Information Centre on 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Dulaglutide improves glycaemic control through the sustained effects of lowering fasting, pre-meal and postprandial glucose concentrations in patients with type 2 diabetes starting after the first dulaglutide administration and is sustained throughout the once weekly dosing interval.
A pharmacodynamic study with Trulicity demonstrated, in patients with type 2 diabetes, a restoration of first phase insulin secretion to a level that exceeded levels observed in healthy subjects on placebo, and improved second phase insulin secretion in response to an intravenous bolus of glucose, as shown in Figure 1. In the same study, a single 1.5 mg dose of Trulicity appeared to increase maximal insulin secretion from the β cells, and to enhance β cell function in subjects with type 2 diabetes mellitus as compared with placebo.
Consistent with the pharmacokinetic profile, dulaglutide has a pharmacodynamic profile suitable for once weekly administration (see Section 5.2 Pharmacokinetic Properties).

Mechanism of action.

Dulaglutide is a long acting GLP-1 receptor agonist. Native GLP-1 has a half-life of 1.5 - 2 minutes due to degradation by dipeptidyl peptidase-4 (DPP-4) and renal clearance. In contrast to native GLP-1, dulaglutide is relatively resistant to degradation by DPP-4, and has a large size that slows absorption and reduces renal clearance. These engineering features result in a soluble formulation and a prolonged half-life of 4.7 days, which makes it suitable for once-weekly subcutaneous administration. In addition, the dulaglutide molecule was engineered to prevent the Fcγ-receptor dependent immune response and to reduce its immunogenic potential.
Dulaglutide exhibits several anti-hyperglycaemic actions of GLP-1. In the presence of elevated glucose concentrations, dulaglutide increases intracellular cyclic AMP in pancreatic beta cells leading to insulin release. Dulaglutide suppresses glucagon secretion which is known to be inappropriately elevated in patients with type 2 diabetes. Lower glucagon concentrations lead to decreased hepatic glucose output. Dulaglutide also slows gastric emptying.

Clinical trials.

The efficacy of Trulicity has been established in eight pivotal phase 3 studies involving 5,770 patients with type 2 diabetes mellitus. These studies were designed to assess safety and efficacy in patients across different stages of the type 2 diabetes mellitus treatment continuum from monotherapy, combination with one or two oral antidiabetic medications, to combination with insulin. These studies included 3,525 patients treated with Trulicity, of whom 2,108 were treated with Trulicity 1.5 mg once weekly. In all studies, Trulicity produced clinically significant improvements in glycaemic control as measured by glycosylated haemoglobin A1c (HbA1c). Superiority of dulaglutide to comparators for HbA1c change from baseline was consistently demonstrated. Treatment with dulaglutide was associated with modest weight loss.
Table 3 provides a summary for five initial registration studies of Trulicity as monotherapy, add on to metformin, add on to metformin and TZD, add on to metformin and sulfonylurea, and add on to insulin lispro ± metformin. Change in HbA1c (%) was the primary endpoint, other important secondary outcomes included change in fasting blood glucose (FBG), percentage of patients achieving a target HbA1c < 7.0%, and change in body weight at the primary and final study time points. The type 2 diabetes mellitus population was well represented by patients participating in the five phase 3 studies of dulaglutide, with approximately 51% being male and a mean baseline age of 56.2 years. Of the 4,572 patients included in the five studies, 847 (18.5%) were aged ≥ 65 years, of whom 86 were aged ≥ 75 years (1.9%). Across the five studies at baseline, the mean duration of diabetes ranged from 2.6 to 12.7 years, mean baseline HbA1c ranged from 7.6% to 8.5% and mean body mass index ranged from 31.2 kg/m2 to 33.3 kg/m2.
Tables 4, 6 and 7 provide a summary for studies of Trulicity as add-on to titrated basal insulin, add-on to SGLT2 inhibitor therapy, and add-on to glimepiride, respectively.
Tables 5 and 8 provide a summary for studies of Trulicity compared to liraglutide, both in combination with metformin, and in comparison to insulin glargine in patients with moderate to severe chronic kidney disease, respectively.
Monotherapy. Study GBDC was a 52-week phase 3, randomised, parallel-arm, double-blind, double-dummy, active-comparator trial to assess the safety and efficacy of 2 doses of once weekly dulaglutide (1.5 mg and 0.75 mg) as monotherapy in patients with early type 2 diabetes mellitus. In this study, patients discontinued their prior oral antidiabetic medication and were then randomised to Trulicity once weekly or metformin following a two week lead in period. Trulicity 1.5 mg was superior to metformin (1500-2000 mg/day) in the reduction in HbA1c from baseline (mean baseline 7.6%) and a significantly greater proportion of patients reached an HbA1c target of < 7.0% (p < 0.05) and ≤ 6.5% (p < 0.001) with Trulicity compared to metformin at 26 weeks. These effects were sustained for up to 52 weeks of treatment. The rate of documented symptomatic hypoglycaemia with Trulicity 1.5 mg alone was 0.62 episodes/patient/year and with metformin was 0.09 episodes/patient/year. No cases of severe hypoglycaemia were observed.
Combination therapy with titrated basal insulin, with or without metformin. In a 28 week placebo controlled study, Trulicity 1.5 mg was compared to placebo as add-on to titrated basal insulin glargine (88% with and 12% without metformin) to evaluate the effect on glycaemic control and safety. To optimise the insulin glargine dose, both groups were titrated to a target fasting serum glucose of < 5.6 mmol/L. The mean baseline dose of insulin glargine was 37 units/day for patients receiving placebo and 41 units/day for patients receiving Trulicity 1.5 mg. The initial insulin glargine doses in patients with HbA1c < 8.0% were reduced by 20%. At the end of the 28 week treatment period the dose was 65 units/day and 51 units/day, for patients receiving placebo and Trulicity 1.5 mg, respectively. At 28 weeks, treatment with once weekly Trulicity 1.5 mg resulted in a statistically significant reduction in HbA1c compared to placebo and a significantly greater percentage of patients achieving HbA1c targets of < 7.0% and ≤ 6.5% (Table 4).
The rates of documented symptomatic hypoglycaemia with Trulicity 1.5 mg and insulin glargine were 3.38 episodes/patient/year compared to placebo and insulin glargine 4.38 episodes/patient/year. One patient reported severe hypoglycaemia with Trulicity 1.5 mg in combination with insulin glargine and none with placebo.
Combination with oral antidiabetic medications.

Combination with metformin.

Study GBCF was a 104-week, adaptive, phase 2/3, placebo-controlled, safety, and efficacy study of once weekly dulaglutide compared to sitagliptin in patients on metformin. In the initial dose-finding portion of the study, 7 doses of dulaglutide (0.25 mg, 0.5 mg, 0.75 mg, 1.0 mg, 1.5 mg, 2.0 mg, and 3.0 mg), sitagliptin, and placebo were assessed. An optimal or maximum utility dose was to be selected based on the use of a pre-defined clinical utility index combining efficacy (HbA1c and weight) and safety (diastolic blood pressure and heart rate) measures. At the completion of the dose-finding portion, the dulaglutide 1.5 mg dose was selected as the optimal dose. The dulaglutide 0.75 mg dose was additionally selected to move forward as a contingency dose. Following completion of the dose-finding stage, evaluation of the safety and efficacy of these 2 doses and comparator arms continued in Study GBCF. Treatment with Trulicity 1.5 mg resulted in a superior reduction in HbA1c compared to placebo (at 26 weeks). Trulicity was also superior to sitagliptin for reduction in HbA1c at 52 weeks accompanied by a significantly (p < 0.001) greater proportion of patients achieving HbA1c targets of < 7.0% and ≤ 6.5%. Treatment with Trulicity also resulted in significantly (p < 0.001) greater reductions in fasting plasma glucose and body weight than observed for sitagliptin. These effects were sustained to the end of the study (104 weeks). The rate of documented symptomatic hypoglycaemia with Trulicity 1.5 mg was 0.19 episodes/patient/year and with sitagliptin was 0.17 episodes/patient/year. No cases of severe hypoglycaemia with Trulicity were observed.
The safety and efficacy of Trulicity was also investigated in an active controlled study (liraglutide 1.8 mg daily) of 26 weeks duration, both in combination with metformin. Treatment with dulaglutide 1.5 mg resulted in similar lowering of HbA1c compared to liraglutide.
The rate of documented symptomatic hypoglycaemia with dulaglutide 1.5 mg was 0.12 episodes/patient/year and with liraglutide was 0.29 episodes/patient/year. No cases of severe hypoglycaemia were observed. The most frequent adverse events were gastrointestinal, including nausea, diarrhoea, dyspepsia, and vomiting, and were similar between the groups .

Combination with metformin and thiazolidinedione.

Study GBDA was a 52-week, phase 3, randomized, parallel-arm, placebo-controlled, open-label to active-comparator (exenatide twice daily) trial. It was double-blind with respect to dulaglutide 1.5 mg, dulaglutide 0.75 mg, and placebo treatment assignment to 26 weeks. For those patients randomized to placebo who were then switched to dulaglutide after 26 weeks, it was also double-blind with respect to the dulaglutide dose assignment (1.5 mg or 0.75 mg) to 52 weeks. This study was designed to assess the safety and efficacy of dulaglutide 1.5 mg and dulaglutide 0.75 mg in patients who were on stable doses of metformin and pioglitazone. In this study, Trulicity 1.5 mg demonstrated a significant improvement in HbA1c change compared to placebo at 26 weeks. Trulicity also demonstrated superiority for HbA1c reduction in comparison to exenatide at 26 weeks and at 52 weeks. This was accompanied by significantly (p < 0.001) greater reductions in fasting serum glucose and a greater percentage of patients achieving HbA1c targets of < 7.0% or ≤ 6.5% at 26 and 52 weeks. Weight loss with Trulicity was comparable to exenatide. The rate of documented symptomatic hypoglycaemia with Trulicity 1.5 mg was 0.19 episodes/patient/year and with exenatide twice daily was 0.75 episodes/patient/year (p = 0.006 by paired stepwise comparison). No cases of severe hypoglycaemia were observed for Trulicity and two cases of severe hypoglycaemia were observed with exenatide twice daily.

Combination therapy with SGLT2 inhibitor with or without metformin.

The safety and efficacy of dulaglutide as add-on to sodium-glucose co-transporter 2 inhibitor (SGLT2i) therapy (96% with and 4% without metformin) were investigated in a placebo controlled study of 24 weeks duration. Treatment with Trulicity 0.75 mg or Trulicity 1.5 mg in combination with SGLT2i therapy resulted in a statistically significant reduction in HbA1c compared to placebo with SGLT2i therapy at 24 weeks. With both Trulicity 0.75 mg and 1.5 mg, a significantly higher percentage of patients reached a target HbA1c of < 7.0% and ≤ 6.5% at 24 weeks compared to placebo.
The rates of documented symptomatic hypoglycaemia with Trulicity 0.75 mg, Trulicity 1.5 mg, and placebo were 0.15, 0.16 and 0.12 episodes/patient/year, respectively. One patient reported severe hypoglycaemia with Trulicity 0.75 mg in combination with SGLT2i therapy and none with Trulicity 1.5 mg or placebo.

Combination with metformin and sulfonylurea.

Study GBDB was a 78-week phase 3, randomised, parallel-arm, open-label (double-blind with respect to dulaglutide dose assignment), active comparator (insulin glargine) trial to assess the safety and efficacy of 2 doses of once weekly dulaglutide (1.5 mg and 0.75 mg) in patients who were on stable doses of metformin and glimepiride. At 52 weeks, Trulicity 1.5 mg demonstrated superior lowering in HbA1c to insulin glargine which was maintained at 78 weeks. This was accompanied by a significantly (p < 0.001) higher percentage of subjects reaching a target HbA1c of < 7.0% or ≤ 6.5% at primary (52 weeks) and final (78 weeks) time points. Subjects treated with Trulicity lost a mean of 1.87 kg in comparison to a gain of 1.44 kg in the insulin glargine arm (p < 0.001) in the first 52 weeks and this effect was sustained to 78 weeks. The rate of documented symptomatic hypoglycaemia with Trulicity 1.5 mg was 1.67 episodes/patient/year and with insulin glargine was 3.03 episodes/patient/year (p = 0.012). Two cases of severe hypoglycaemia were observed with Trulicity and two cases of severe hypoglycaemia were observed with insulin glargine.

Combination therapy with sulfonylurea.

The safety and efficacy of dulaglutide as add-on to a sulfonylurea was investigated in a placebo controlled study of 24 weeks duration. Treatment with Trulicity 1.5 mg in combination with glimepiride resulted in a statistically significant reduction in HbA1c compared to placebo with glimepiride at 24 weeks. With Trulicity 1.5 mg, a significantly higher percentage of patients reached a target HbA1c of < 7.0% and ≤ 6.5% at 24 weeks compared to placebo.
The rates of documented symptomatic hypoglycaemia with Trulicity 1.5 mg and placebo were 0.90 and 0.04 episodes/patient/year, respectively. No cases of severe hypoglycaemia were observed for Trulicity or placebo.
Combination with prandial insulin. Study GBDD was a 52-week phase 3, randomized, parallel-arm, open-label (double-blind with respect to dulaglutide dose assignment), active comparator (insulin glargine) trial to assess the safety and efficacy of 2 doses of once weekly dulaglutide (1.5 mg and 0.75 mg), both in combination with insulin lispro, with or without metformin, in patients previously treated with a stable, conventional insulin regimen for at least 3 months. In this study, patients on 1 or 2 insulin injections per day prior to study entry, discontinued their pre-study insulin regimen and were randomised to Trulicity once weekly or insulin glargine once daily, both in combination with prandial insulin lispro three times daily, with or without metformin. At 26 weeks, Trulicity 1.5 mg was superior to insulin glargine in lowering of HbA1c and this effect was sustained at 52 weeks. This was accompanied by a significant (p < 0.001) weight loss in comparison to insulin glargine, where weight gain was observed over the course of the study. A greater percentage of patients also achieved HbA1c targets of < 7.0% or ≤ 6.5% at 26 weeks (p < 0.05) and < 7.0% at 52 weeks (p < 0.05) when treated with Trulicity than with insulin glargine. The rate of documented symptomatic hypoglycaemia with Trulicity 1.5 mg was 31.06 episodes/patient/year and with insulin glargine was 40.95 episodes/patient/year. Ten patients reported severe hypoglycaemia with Trulicity and fifteen with insulin glargine.

Use in patients with renal impairment.

In a 52 week study, Trulicity 1.5 mg and 0.75 mg were compared to titrated insulin glargine as add-on to prandial insulin lispro to evaluate the effect on glycaemic control and safety of patients with moderate to severe chronic kidney disease (eGFR [by CKD-EPI] < 60 and ≥ 15 mL/min/1.73 m2). Patients discontinued their prestudy insulin regimen at randomisation. At baseline, overall mean eGFR was 38 mL/min/1.73 m2, 30% of patients had eGFR < 30 mL/min/1.73 m2.
At 26 weeks, both Trulicity 1.5 mg and 0.75 mg were non-inferior to insulin glargine in lowering of HbA1c and this effect was sustained at 52 weeks. A similar percentage of patients achieved HbA1c targets of < 8.0% at 26 and 52 weeks with both dulaglutide doses as well as insulin glargine.
The rates of documented symptomatic hypoglycaemia with Trulicity 1.5 mg and Trulicity 0.75 mg, and insulin glargine were 4.44, 4.34, and 9.62 episodes/patient/year, respectively. No patients reported cases of severe hypoglycaemia with Trulicity 1.5 mg, six with Trulicity 0.75 mg, and seventeen with insulin glargine. The safety profile of Trulicity in patients with renal impairment was similar to that observed in other studies with Trulicity.
Fasting blood glucose. Treatment with Trulicity 1.5 mg resulted in significant reductions from baseline in fasting blood glucose (least-square mean changes from baseline to primary time point -0.27 mmol/L to -2.38 mmol/L). The majority of the effect on fasting blood glucose concentrations occurred by 2 weeks. The improvement in fasting glucose was sustained through the longest study duration of 104 weeks.
Postprandial glucose. Treatment with Trulicity 1.5 mg resulted in significant reductions in self-monitored mean post prandial glucose from baseline (least-square mean changes from baseline to primary time point -1.95 mmol/L to -4.23 mmol/L).
Beta cell function. Clinical studies with Trulicity 1.5 mg have indicated enhanced beta-cell function as measured by homeostasis model assessment (HOMA2-%B). The durability of effect on beta-cell function was maintained through the longest study duration of 104 weeks.
Body weight. Trulicity 1.5 mg was associated with sustained weight reduction over the duration of studies (least square mean change from baseline to final time point -0.35 kg to -2.88 kg). This was significant (p < 0.001) in comparison to sitagliptin and insulin glargine and comparable to exenatide twice daily and metformin. Reduction in body weight was observed in patients treated with Trulicity irrespective of nausea, though the reduction was numerically larger in the group with nausea.
Patient reported outcomes. Trulicity 1.5 mg significantly improved (p < 0.05) total treatment satisfaction as measured by the diabetes treatment satisfaction questionnaire (DTSQs) compared to exenatide twice daily. In addition, there was significantly (p < 0.05) lower perceived frequency of hyperglycaemia and hypoglycaemia compared to exenatide twice daily.
Blood pressure. The effect of Trulicity 1.5 mg on blood pressure as assessed by ambulatory blood pressure monitoring was evaluated in a study of 755 patients with type 2 diabetes. Treatment with Trulicity provided reductions in systolic blood pressure (SBP) (-2.8 mmHg difference compared to placebo) at 16 weeks. There was no difference in diastolic blood pressure (DBP). Similar results for SBP and DBP were demonstrated at the final 26 week time point of the study.
Immunogenicity. Across four phase 2 and five phase 3 clinical studies, 64 (1.6%) Trulicity treated patients developed anti-drug antibodies (ADAs) to the active ingredient in Trulicity (i.e. dulaglutide). Of the 64 dulaglutide-treated patients that developed dulaglutide ADAs, 34 patients (0.9% of the overall population) had dulaglutide-neutralising antibodies, and 36 patients (0.9% of the overall population) developed antibodies against native GLP-1.
Patients with dulaglutide ADAs generally had low titres and although the number of patients developing dulaglutide ADAs was low, examination of the phase III data revealed no clear impact of dulaglutide ADAs on changes in HbA1c.
The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralising antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, the incidence of antibodies to dulaglutide cannot be directly compared with the incidence of antibodies of other products.
Hypersensitivity. In the phase 2 and phase 3 clinical studies, systemic hypersensitivity events (e.g. urticaria, angiooedema) have been reported in 0.5% of patients receiving dulaglutide at any dose for any duration. None of the patients with systemic hypersensitivity developed dulaglutide anti-drug antibodies.
Cardiovascular outcome study. The Trulicity long-term cardiovascular outcome study was a placebo-controlled, double-blind clinical trial. Type 2 diabetes patients were randomly allocated to either Trulicity 1.5 mg (4,949) or placebo (4,952) both in addition to standards of care for type 2 diabetes. The median study follow-up time was 5.4 years.
The mean age was 66.2 years, the mean BMI was 32.3 kg/m2, and 46.3% of patients were female. There were 6,221 (62.8%) patients with multiple cardiovascular (CV) risk factors but without established CV disease, and 3,114 (31.5%) patients with established CV disease. The median baseline HbA1c was 7.2%. The majority of patients had a baseline HbA1c ranging from 6.0%-8.9% (10th-90th percentile). The mean duration of diabetes was 10.5 years. The Trulicity treatment arm included patients ≥ 65 years (n = 2,619; 52.9%) and ≥ 75 years (n = 484; 9.7%), and patients with mild (n = 2,435; 50.2%), moderate (n = 1,031; 21.3%) or severe (n = 50; 1.1%) renal impairment.
The primary endpoint was the time from randomisation to first occurrence of any major adverse cardiovascular events (MACE): CV death, non-fatal myocardial infarction, or non-fatal stroke. Primary outcome status or vital status at the end of study was available for 99.7% of participants randomised to Trulicity and placebo. Trulicity was superior in preventing MACE compared to placebo (see Figure 2). Trulicity-treated patients had a lower rate of MACE as compared to placebo [HR: 0.88; 95% CI (0.79, 0.99)]. Each MACE component contributed to the reduction of MACE, as shown in Figure 3. The efficacy of Trulicity on MACE was consistent across major demographic and disease subgroups, including prior cardiovascular disease status, baseline HbA1c, gender, duration of diabetes, age, and eGFR.
A significant and sustained reduction in HbA1c from baseline to month 60 was observed with Trulicity vs placebo, in addition to standard of care (-0.29% vs 0.22%; estimated treatment difference -0.51% [-0.57; -0.45]; p < 0.001). There were significantly fewer patients in the Trulicity group who received an additional glycaemic intervention compared to placebo (Trulicity: 2,086 [42.2%]; placebo: 2,825 [57.0%]; p < 0.001).
QTc interval. Dulaglutide did not prolong QTc interval at supratherapeutic doses of 4 mg and 7 mg as assessed in a thorough QTc study.

5.2 Pharmacokinetic Properties

Absorption.

Following subcutaneous administration to patients with type 2 diabetes, dulaglutide reaches peak plasma concentrations in 48 hours. The mean peak (Cmax) and total (AUC) exposures were approximately 114 nanogram/mL and 14,000 nanogram.h/mL, respectively after multiple subcutaneous 1.5 mg doses of dulaglutide in patients with type 2 diabetes. Steady state plasma concentrations were achieved after 2 to 4 weeks of once-weekly administration of dulaglutide 1.5 mg. Exposures after subcutaneous administration of single 1.5 mg dulaglutide doses in the abdomen, thigh or upper arm were comparable. The mean absolute bioavailability of dulaglutide following a single dose subcutaneous administration of one 1.5 mg dose was approximately 47%.

Distribution.

The mean volume of distribution after subcutaneous administration of dulaglutide 1.5 mg to steady state in patients with type 2 diabetes mellitus was approximately 17.4 L.

Metabolism.

Dulaglutide is presumed to be degraded into its component amino acids by general protein catabolism pathways.

Elimination.

The mean apparent clearance of dulaglutide in humans at steady state was 0.107 L/h with an elimination half-life of 4.7 days.

Special populations.

No dose adjustment is needed based on age, gender, race, ethnicity, body weight, or renal or hepatic impairment.

Elderly.

Age had no clinically relevant effect on the pharmacokinetics or pharmacodynamics of dulaglutide.

Gender and race.

Gender and race had no clinically meaningful effect on the pharmacokinetics of dulaglutide.

Renal impairment.

The pharmacokinetics of dulaglutide were evaluated in subjects with varying degrees of renal impairment, and were generally similar between healthy subjects and patients with mild (creatinine clearance 60 to < 90 mL/min) to severe renal impairment (creatinine clearance < 30 mL/min not requiring dialysis), including end stage renal disease (creatinine clearance < 15 mL/min requiring dialysis treatment) requiring dialysis. Additionally, in a 52-week clinical study in patients with type 2 diabetes and moderate to severe renal impairment (eGFR [by CKD-EPI] < 60 and ≥ 15 mL/min/1.73 m2), the pharmacokinetic profile of Trulicity 1.5 mg once weekly was similar to that demonstrated in previous clinical studies. This clinical study did not include patients with end stage renal disease.

Hepatic impairment.

The pharmacokinetics of dulaglutide were evaluated in subjects with varying degrees of hepatic impairment. Subjects with hepatic impairment had statistically significant decreases in dulaglutide exposure of up to 30% and 33% for mean Cmax and AUC, respectively, compared to healthy controls. There was a general increase in tmax of dulaglutide with increased hepatic impairment, however no trend in dulaglutide exposure was observed relative to the degree of hepatic impairment. These effects were not considered clinically relevant.

Body weight or body mass index.

Pharmacokinetic analyses have demonstrated a statistically significant inverse relationship between body weight or body mass index (BMI) and dulaglutide exposure, although there was no clinically relevant impact of weight or BMI on glycaemic control.

5.3 Preclinical Safety Data

Genotoxicity.

The genotoxic potential of dulaglutide has not been assessed. As a large molecular weight protein, dulaglutide is not expected to interact with DNA or other chromosomal material.

Carcinogenicity.

In a 93-week carcinogenicity study in rats, dulaglutide caused statistically significant, dose-related increases in the incidence of thyroid C-cell tumours (adenomas and carcinomas combined) with subcutaneous administration at ≥ 0.5 mg/kg twice weekly, yielding ≥ 7 times the human clinical exposure following once weekly administration of 1.5 mg dulaglutide. Exposure (plasma AUC) at the no observable effect level for carcinogenicity in the rat (0.05 mg/kg) was subclinical. The human relevance of these findings is unknown. There was no tumourigenic response in a 6-month carcinogenicity study in transgenic mice with subcutaneous doses ≤ 3 mg/kg twice weekly, yielding exposures up to 5 times higher than that in patients at the maximum recommended human dose.

6 Pharmaceutical Particulars

6.1 List of Excipients

Trulicity contains the excipients sodium citrate dihydrate, citric acid, mannitol, polysorbate 80 and water for injections.

6.2 Incompatibilities

Incompatibilities were not identified as part of the registration of this medicine (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Trulicity ready-to-use pre-filled pens should be stored at 2°C-8°C. Refrigerate. Do not freeze. Trulicity may be stored unrefrigerated for up to 14 days at temperatures up to 30°C. Protect from light.

6.5 Nature and Contents of Container

Trulicity is available as a single dose, ready-to-use pre-filled pen (autoinjector). The product is contained in a 1 mL-long, type 1 borosilicate glass, syringe with a bromobutyl plunger. The syringe has a 29G thin wall ½" staked needle.
Trulicity is available in pack sizes of 2 or 4 ready-to-use pre-filled pens.
Not all pack sizes may be marketed.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Chemical structure.

Dulaglutide (rch) consists of 2 identical disulfide-linked chains, each containing a modified human glucagon-like peptide 1 (GLP-1) analogue sequence covalently linked to a modified human immunoglobulin G4 (IgG4) heavy chain fragment (Fc) by a small peptide linker. The GLP-1 analogue portion of dulaglutide is approximately 90% homologous to native human GLP-1 (7-37).
The GLP-1 analogue, linker region, and IgG4 Fc CH2 and CH3 domains are depicted above. The 12 Cys residues that are involved in the inter-chain and intra-chain disulfide bonding are also shown. The hexagonal symbol represents the N-linked glycosylation at Asn126 in each polypeptide chain.
The molecular weight of dulaglutide with the predominant form of N-linked glycosylation is 62,561 Da.

CAS number.

923950-08-7.

7 Medicine Schedule (Poisons Standard)

S4 - Prescription Medicine.

Summary Table of Changes