TRULICITY 0.75mg 1.5mg 3mg 4.5mg solution for injection in pre-filled pen

Changes

Added (underline) deleted (strikethrough)

4.8   Undesirable effects

…..

Description of selected adverse reactions

…..

Acute pancreatitis

The incidence of acute pancreatitis in phase 2 and 3 registration studies was 0.07% for dulaglutide compared to 0.14% for placebo and 0.19% for comparators with or without additional background antidiabetic therapy. Acute pancreatitis and pancreatitis have also been reported in the post-marketing setting.

 10.     DATE OF REVISION OF THE TEXT

11 February 2021 17 June 2021

 TR014TR018

4.       Possible side effects

Other side effects

….

Rare: may affect up to 1 in 1,000 people

• A delay in the emptying of the stomach

….

6.       Contents of the pack and other information

….

For any information about this medicine, please contact the local representative of the Marketing Authorisation Holder

Ireland and United Kingdom (Northern Ireland)

Eli Lilly and Company (Ireland) Limited

Tel: + 353-(0) 1 661 4377

Malta

Charles de Giorgio Ltd.

Tel: + 356 25600 500

This leaflet was last revised in January February 2021

Changes

Added (underline) deleted (strikethrough)

4.       CLINICAL PARTICULARS

4.8   Undesirable effects

….

Table 1. The frequency of adverse reactions of dulaglutide

10.     DATE OF REVISION OF THE TEXT

18 November 2020 11 February 2021

TR13M    LY014

Instructions & images in '1 UNCAP' section have been updated.

The date of revision of the leaflet is updated to January 2021.

Instructions & images in '1 UNCAP' section have been updated.

The date of revision of the leaflet is updated to January 2021.

Instructions & images in '1 UNCAP' section have been updated.

The date of revision of the leaflet is updated to January 2021.

Instructions & images in  '1 UNCAP'  section have been updated.

The date of revision of the leaflet is updated to January 2021.

Summary of the changes             

PIL:  A minor change to section 6 of the PIL -  “The other ingredients are sodium citrate (see section 2 under ‘Trulicity contains sodium citrate’ for further information); citric acid; mannitol; polysorbate 80 and water for injections.” The date of revision of the leaflet is January 2021.

Package leaflet: Information for the patient

Trulicity 0.75 mg solution for injection in pre‑filled pen

Trulicity 1.5 mg solution for injection in pre‑filled pen

Trulicity 3 mg solution for injection in pre‑filled pen

Trulicity 4.5 mg solution for injection in pre‑filled pen

dulaglutide

……………………

2. What you need to know before you use Trulicity

…………………….

Other medicines and Trulicity

Because Trulicity can slow stomach emptying which could affect other medicines, tell your doctor, pharmacist or nurse if you are using, have recently used or might use any other medicine.

Especially tell your doctor:

if you are using other medicines that lower the amount of sugar in your blood, such as insulin or a medicine containing sulphonylurea. Your doctor may want to lower the dose of these other medicines to prevent you from getting low blood sugar levels (hypoglycaemia). Ask your doctor, pharmacist or nurse if you are not sure what your other medicines contain.

if you are using insulin, your doctor will tell you how to reduce the dose of insulin and will recommend you to monitor your blood sugar more frequently, in order to avoid hyperglycaemia (high blood sugar) and diabetic ketoacidosis (a complication of diabetes that occurs when the body is unable to break down glucose because there is not enough insulin).

Pregnancy and breast-feeding

It is not known if dulaglutide could harm your unborn child. Women who could become pregnant should use contraception during treatment with dulagutide. Tell your doctor if you are pregnant, think you may be pregnant or are planning to have a baby, as Trulicity should not be used during pregnancy. Talk to your doctor about the best way to control your blood sugar while you are pregnant.

Breast-feeding

Talk to your doctor if you would like to or are breast-feeding before taking this medicine. Do not use Trulicity if you are breast-feeding. It is not known if dulaglutide passes into human breast milk.

Driving and using machines

Trulicity has no to little effect on the ability to drive or use machines. However, Iif you use Trulicity in combination with a sulphonylurea or insulin, low blood sugar (hypoglycaemia) may occur which may reduce your ability to concentrate. Avoid driving or using machines if you get any signs of low blood sugar. See section 2, ‘Warning and precautions’ for information on increased risk of low blood sugar and section 4 for the warning signs of low blood sugar. Talk to your doctor for further information.Please keep this in mind in all situations where you might put yourself and others at risk (e.g. driving a car or using machines).

Trulicity contains sodium

This medicine contains less than 1 mmol sodium (23 mg) per dose0.75 mg or 1.5 mg, that is to say essentially ‘sodium-free’.

3.  How to use Trulicity

Always use this medicine exactly as your doctor or pharmacist has told you. Check with your doctor or pharmacist if you are not sure how to use this medicine.

When used alone, Your doctor may the recommended a dose isof 0.75 mg once a week for the treatment of your diabetes either due to your individual needs or when Trulicity is used alone.

When used with other medicines for diabetes, your doctor maythe recommended a dose isof 1.5 mg once a week.

If your blood sugar is not controlled well enough, your doctor may increase your dose to 3 mg once a week. 

If further blood sugar control is needed the dose may be increased again to 4.5 mg once a week. 

In certain situations, for example if you are 75 years or older, your doctor may recommend a starting dose of 0.75 mg once a week.

Each pen contains one weekly dose of Trulicity (0.75 mg, or 1.5 mg, 3 mg or 4.5 mg). Each pen delivers only one dose.

………………….

If you use more Trulicity than you should

If you use more Trulicity than you should talk to your doctor immediately. Too much Trulicity of this medicine may make your blood sugar too low (hypoglycaemia) and can make you feel sick or be sick.

………………….

4.  Possible side effects
 

……………….

Other side effects

Very common: may affect more than 1 in 10 people

-  Nausea (fFeeling sick (nausea) – this usually goes away over time

-  Vomiting (bBeing sick (vomiting) – this usually goes away over time

-  Diarrhoea – this usually goes away over time

-  Abdominal (sStomach (abdominal) pain.

These side effects are usually not severe. They are most common when first starting dulaglutide but decrease over time in most patients.

• -  Hypoglycaemia (lLow blood sugar (hypoglycaemia) is very common when dulaglutide is used with medicines that contain metformin, a sulphonylurea and/or insulin. If you are taking a sulphonylurea or insulin, the dose may need to be lowered while you use dulaglutide.
• Symptoms of low blood sugar may include headache, drowsiness, weakness, dizziness, feeling hungry, confusion, irritability, fast heartbeat and sweating. Your doctor should tell you how to treat low blood sugar.

Common: may affect up to 1 in 10 people

• Low blood sugar (Hhypoglycaemia) is common when dulaglutide is used alone, or with both metformin and pioglitazone together, or with a sodium-glucose co-transporter 2 inhibitor (SGLT2i) with or without metformin. For a list of possible symptoms, see above under very common affects.
• Symptoms of low blood sugar may include headache, drowsiness, weakness, dizziness, feeling hungry, confusion, irritability, fast heartbeat and sweating. Your doctor should tell you how to treat low blood sugar.
• Feeling less hungry (decreased appetite)
• Indigestion
• Constipation
• Gas (flatulence)
• Bloating of the stomach
• Reflux or heartburn (also called Ggastroesophageal reflux disease – GERD) - a disease caused by stomach acid coming up into the tube from your stomach to your mouth

• Burping
• Feeling tired
• Increased heart rate
• Slowing of the electrical currents in the heart
   
  ……………..

6.            Contents of the pack and other information

What Trulicity contains

The active substance is dulaglutide.

• Trulicity 0.75 mg: Each pre-filled pen contains 0.75 mg of dulaglutide in 0.5 ml solution.
• Trulicity 1.5 mg: Each pre-filled pen contains 1.5 mg of dulaglutide in 0.5 ml solution.
• Trulicity 3 mg: Each pre-filled pen contains 3 mg of dulaglutide in 0.5 ml solution.
• Trulicity 4.5 mg: Each pre-filled pen contains 4.5 mg of dulaglutide in 0.5 ml solution.
           

The other ingredients are sodium citrate (see section 2 under ‘Trulicity contains sodium citrate’ for further information); citric acid, anhydrous; mannitol; polysorbate 80 and water for injections.

…………….

This leaflet was last revised in October 2020

New leaflet (IFU) for new strength of product.

New leaflet (IFU) for new strength of product.

Minor wording & formatting changes - sections 'About TRULICITY pre-filled pen' and 'Before you get started'.    Last revised date updated.

Minor wording & formatting changes - sections 'About TRULICITY pre-filled pen' and 'Before you get started'.    Last revised date updated.

Package leaflet: Information for the patient

Trulicity 0.75 mg solution for injection in pre‑filled pen

Trulicity 1.5 mg solution for injection in pre‑filled pen

Trulicity 3 mg solution for injection in pre‑filled pen

Trulicity 4.5 mg solution for injection in pre‑filled pen

dulaglutide

……………………

2. What you need to know before you use Trulicity

…………………….

Other medicines and Trulicity

Because Trulicity can slow stomach emptying which could affect other medicines, tell your doctor, pharmacist or nurse if you are using, have recently used or might use any other medicine.

Especially tell your doctor:

if you are using other medicines that lower the amount of sugar in your blood, such as insulin or a medicine containing sulphonylurea. Your doctor may want to lower the dose of these other medicines to prevent you from getting low blood sugar levels (hypoglycaemia). Ask your doctor, pharmacist or nurse if you are not sure what your other medicines contain.

if you are using insulin, your doctor will tell you how to reduce the dose of insulin and will recommend you to monitor your blood sugar more frequently, in order to avoid hyperglycaemia (high blood sugar) and diabetic ketoacidosis (a complication of diabetes that occurs when the body is unable to break down glucose because there is not enough insulin).

Pregnancy and breast-feeding

It is not known if dulaglutide could harm your unborn child. Women who could become pregnant should use contraception during treatment with dulagutide. Tell your doctor if you are pregnant, think you may be pregnant or are planning to have a baby, as Trulicity should not be used during pregnancy. Talk to your doctor about the best way to control your blood sugar while you are pregnant.

Breast-feeding

Talk to your doctor if you would like to or are breast-feeding before taking this medicine. Do not use Trulicity if you are breast-feeding. It is not known if dulaglutide passes into human breast milk.

Driving and using machines

Trulicity has no to little effect on the ability to drive or use machines. However, Iif you use Trulicity in combination with a sulphonylurea or insulin, low blood sugar (hypoglycaemia) may occur which may reduce your ability to concentrate. Avoid driving or using machines if you get any signs of low blood sugar. See section 2, ‘Warning and precautions’ for information on increased risk of low blood sugar and section 4 for the warning signs of low blood sugar. Talk to your doctor for further information.Please keep this in mind in all situations where you might put yourself and others at risk (e.g. driving a car or using machines).

Trulicity contains sodium

This medicine contains less than 1 mmol sodium (23 mg) per dose0.75 mg or 1.5 mg, that is to say essentially ‘sodium-free’.

3.  How to use Trulicity

Always use this medicine exactly as your doctor or pharmacist has told you. Check with your doctor or pharmacist if you are not sure how to use this medicine.

When used alone, Your doctor may the recommended a dose isof 0.75 mg once a week for the treatment of your diabetes either due to your individual needs or when Trulicity is used alone.

When used with other medicines for diabetes, your doctor maythe recommended a dose isof 1.5 mg once a week.

If your blood sugar is not controlled well enough, your doctor may increase your dose to 3 mg once a week. 

If further blood sugar control is needed the dose may be increased again to 4.5 mg once a week. 

In certain situations, for example if you are 75 years or older, your doctor may recommend a starting dose of 0.75 mg once a week.

Each pen contains one weekly dose of Trulicity (0.75 mg, or 1.5 mg, 3 mg or 4.5 mg). Each pen delivers only one dose.

………………….

If you use more Trulicity than you should

If you use more Trulicity than you should talk to your doctor immediately. Too much Trulicity of this medicine may make your blood sugar too low (hypoglycaemia) and can make you feel sick or be sick.

………………….

4.  Possible side effects
 

……………….

Other side effects

Very common: may affect more than 1 in 10 people

-  Nausea (fFeeling sick (nausea) – this usually goes away over time

-  Vomiting (bBeing sick (vomiting) – this usually goes away over time

-  Diarrhoea – this usually goes away over time

-  Abdominal (sStomach (abdominal) pain.

These side effects are usually not severe. They are most common when first starting dulaglutide but decrease over time in most patients.

• -  Hypoglycaemia (lLow blood sugar (hypoglycaemia) is very common when dulaglutide is used with medicines that contain metformin, a sulphonylurea and/or insulin. If you are taking a sulphonylurea or insulin, the dose may need to be lowered while you use dulaglutide.
• Symptoms of low blood sugar may include headache, drowsiness, weakness, dizziness, feeling hungry, confusion, irritability, fast heartbeat and sweating. Your doctor should tell you how to treat low blood sugar.

Common: may affect up to 1 in 10 people

• Low blood sugar (Hhypoglycaemia) is common when dulaglutide is used alone, or with both metformin and pioglitazone together, or with a sodium-glucose co-transporter 2 inhibitor (SGLT2i) with or without metformin. For a list of possible symptoms, see above under very common affects.
• Symptoms of low blood sugar may include headache, drowsiness, weakness, dizziness, feeling hungry, confusion, irritability, fast heartbeat and sweating. Your doctor should tell you how to treat low blood sugar.
• Feeling less hungry (decreased appetite)
• Indigestion
• Constipation
• Gas (flatulence)
• Bloating of the stomach
• Reflux or heartburn (also called Ggastroesophageal reflux disease – GERD) - a disease caused by stomach acid coming up into the tube from your stomach to your mouth

• Burping
• Feeling tired
• Increased heart rate
• Slowing of the electrical currents in the heart
   
  ……………..

6.            Contents of the pack and other information

What Trulicity contains

The active substance is dulaglutide.

• Trulicity 0.75 mg: Each pre-filled pen contains 0.75 mg of dulaglutide in 0.5 ml solution.
• Trulicity 1.5 mg: Each pre-filled pen contains 1.5 mg of dulaglutide in 0.5 ml solution.
• Trulicity 3 mg: Each pre-filled pen contains 3 mg of dulaglutide in 0.5 ml solution.
• Trulicity 4.5 mg: Each pre-filled pen contains 4.5 mg of dulaglutide in 0.5 ml solution.
           

The other ingredients are sodium citrate (see section 2 under ‘Trulicity contains sodium citrate’ for further information); citric acid, anhydrous; mannitol; polysorbate 80 and water for injections.

…………….

This leaflet was last revised in October 2020

Changes to the SmPC include:

-  Introduction of new content relating to the 3mg and 4.5mg pre-filled pens.

-  Removal of content relating to the non-marketed 0.75mg and 1.5mg pre-filled syringes.

-  Amended formatting & content throughout SmPC.

SmPC sections impacted are; 1, 2, 4.2, 4.4, 4.5, 4.8, 5.1, 5.2, 5.3, 6.1, 6.5, 6.6, 8 and 10

Changes

Added (underline) deleted (strikethrough)

1. What Trulicity is and what it is used for

Trulicity contains an active substance called dulaglutide and is used to lower blood sugar (glucose) in adults with type 2 diabetes mellitus and can help prevent heart disease. 

Type 2 diabetes is a condition in which your body does not make enough insulin, and the insulin that

your body produces does not work as well as it should. Your body can also make too much sugar.

When this happens, sugar (glucose) builds up in the blood.

2. What you need to know before you use Trulicity

 Warnings and precautions

Talk to your doctor, pharmacist or nurse before using Trulicity if:

- you are on dialysis as this medicine is not recommended.

- you have type 1 diabetes (the type that usually starts when you are young and your body does not produce any insulin) as this medicine may not be right for you.

Other medicines and Trulicity

Because Trulicity can slow stomach emptying which could affect other medicines, Ttell your doctor, pharmacist or nurse if you are using, have recently used or might use any other medicine.

Trulicity contains sodium citrate

This medicine contains less than 1 mmol sodium (23 mg) per 0.75 mg or 1.5 mg, that is to say essentially ‘sodium-free’.

4. Possible side effects

Severe side effects

Rare: may affect up to 1 in 1,000 people

Severe allergic reactions (anaphylactic reactions, angioedema). have been reported rarely (may affect up to 1 in 1,000 people).

-

You should see a doctor immediately if you experience symptoms such as:

- Rrashes, itching and rapid swelling of the tissues of the neck, face, mouth or throat,

Hhives and difficulties breathing.

- Inflamed pancreas (acute pancreatitis) which could cause severe pain in the stomach and back which does not go away.

You should see a doctor immediately if you experience such symptoms.

Not known: the frequency cannot be estimated from the available data

- Bowel obstruction – a severe form of constipation with additional symptoms such as stomach ache, bloating or vomiting.

You should see a doctor immediately if you experience such symptoms.

- Other side effects

Very common: side effects with this medicine that may affect more than 1 in 10 people are:

- Nausea (feeling sick)

- Vomiting (being sick)

- Diarrhoea

- Abdominal (stomach) pain.

Common: may affect up to 1 in 10 people

- Hypoglycaemia is common (may affect up to 1 in 10 people using this medicine) when dulaglutide is used alone, or with both metformin and pioglitazone together, or with a sodium-glucose co-transporter 2 inhibitor (SGLT2i) with or without metformin.

-

- Symptoms of low blood sugar may include headache, drowsiness, weakness, dizziness, feeling hungry, confusion, irritability, fast heartbeat and sweating. Your doctor should tell you how to treat low blood sugar.

-

Other common side effects:

- Feeling less hungry (decreased appetite)

Uncommon: side effects (may affect up to 1 in 100 people using this medicine):

- Injection site reactions (e.g. rash or redness)

- Whole body aAllergic reactions (hypersensitivity) (e.g. swelling, raised itchy skin rash (hives))

- Dehydration, often associated with nausea, vomiting and/or diarrhoea

- Gallstones

- Inflamed gallbladder

Rare side effects (may affect up to 1 in 1,000 people using this medicine):

- Inflamed pancreas (acute pancreatitis)

The following side effect has been reported but the frequency for it to occur is not known:

- Bowel obstruction - a severe form of constipation with additional symptoms such as stomach ache, bloating or vomiting

6. Contents of the pack and other information

This leaflet was last revised in August October 2019

Changes

Added (underline) deleted (strikethrough)

4.        CLINICAL PARTICULARS

4.1   Therapeutic indications

Type 2 Diabetes Mellitus

Trulicity is indicated in for the treatment of adults with insufficiently controlled type 2 diabetes mellitus as an adjunct to diet and exercise to diet and exercise

Monotherapy

• as monotherapy wWhen diet and exercise alone do not provide adequate glycaemic control in patients for whom the use of metformin is considered inappropriate due to intolerance or contraindications.

Add on therapy

• in addition to other In combination with other glucose lowering medicinal products for the treatment of diabetes. 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).

For study results with respect to combinations, effects on glycaemic control and cardiovascular events, and the populations studied, see sections 4.4, 4.5 and 5.1.

4.2   Posology and method of administration

Posology

Add-on therapy

The recommended dose is 1.5 mg once weekly.

For potentially vulnerable populations, such as patients ≥ 75 years, 0.75 mg once weekly can be considered as a starting dose. 

Elderly

No dose adjustment is required based on age (see section 5.2). However, the therapeutic experience in patients ≥ 75 years is very limited (see section 5.1), and in these patients 0.75mg once weekly can be considered as a starting dose. 

4.4   Special warnings and precautions for use

Populations not studied

There is limited experience in patients with congestive heart failure.

4.5   Interaction with other medicinal products and other forms of interaction

Dulaglutide delays gastric emptying and has the potential to impact the rate of absorption of concomitantly administered oral medicinal products. In the clinical pharmacology studies described below, dulaglutide did not affect the absorption of the orally administered medications tested to any clinically relevant degree. However, for patients receiving oral medicinal products requiring rapid gastrointestinal absorption or prolonged release formulations the potential for altered drug exposure should be considered. Dulaglutide should be used with caution in patients receiving oral medicinal products that require rapid gastrointestinal absorption. For some prolonged release formulations, an increased release due to an extended gastric residence time may slightly increase drug exposure.

Sitagliptin

Sitagliptin exposure was unaffected when coadministered with a single dose of dulaglutide. Following coadministration with 2 consecutive doses of dulaglutide, sitagliptin AUC(0-τ) and Cmax decreased by approximately 7.4 % and 23.1 %, respectively. Sitagliptin tmax increased approximately 0.5 hours following coadministration with dulaglutide compared to sitagliptin alone.

Sitagliptin can produce up to 80 % inhibition of DPP‑4 over a 24‑hour period. Dulaglutide coadministration with sitagliptin increased dulaglutide exposure and Cmax by approximately 38 % and 27 %, respectively, and median tmax increased approximately 24 hours. Therefore, dulaglutide does have a high degree of protection against DPP‑4 inactivation (see section 5.1, Mechanism of action). The increased exposure may enhance the effects of dulaglutide on blood glucose levels.

(The above two paragraphs on Sitagliptin have been relocated within section 4.5).

4.8   Undesirable effects

Summary of safety profile

In the completed phase II and phase III initial registration studies, 4,006 patients were exposed to dulaglutide alone or in combination with other glucose lowering medicinal products. The most frequently reported adverse reactions in clinical trials were gastrointestinal, including nausea, vomiting and diarrhoea. In general these reactions were mild or moderate in severity and transient in nature. Results from the long-term cardiovascular outcome study with 4949 patients randomised to dulaglutide and followed for a median of 5.4 years were consistent with these findings.

Tabulated list of adverse reactions

The following adverse reactions have been identified based on evaluation of the full duration of the phase II and phase III clinical studies, the long-term cardiovascular outcome study and post-marketing reports. The adverse reactions and are listed in Table 1 as MedDRA preferred term by system organ class and in order of decreasing incidence (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 and not known: cannot be estimated from available data). Within each incidence grouping, adverse reactions are presented in order of decreasing frequency. Frequencies for events have been calculated based on their incidence in the phase II and phase III registration studies.

5.        PHARMACOLOGICAL PROPERTIES

5.1   Pharmacodynamic properties

Clinical efficacy and safety

Glycaemic control

The safety and efficacy of dulaglutide were evaluated in eight nine randomised, controlled, phase III trials involving 5,7706,193 patients with type 2 diabetes. Of these, 1,139206 were ≥ 65 years of which 115119 were ≥ 75 years. These studies included 3,525808 dulaglutide‑treated patients, of whom 2,108250 were treated with Trulicity 1.5 mg weekly and 1,417558 were treated with Trulicity 0.75 mg weekly. In all studies, dulaglutide produced clinically significant improvements in glycaemic control as measured by glycosylated haemoglobin A1c (HbA1c).

Cardiovascular Evaluation

Meta-analysis of phase II and III studies

In a meta-analysis of phase II and III registration studies, a total of 51 patients (dulaglutide: 26 [N = 3,885]; all comparators: 25 [N = 2,125]) experienced at least one cardiovascular (CV) event (death due to CV causes, nonfatal MI, nonfatal stroke, or hospitalisation for unstable angina). The results showed that there was no increase in CV risk with dulaglutide compared with control therapies (HR: 0.57; CI: [0.30, 1.10]).

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 0.75 mg dose was not administered in this study). 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 3,114 (31.5 %) patients with established CV disease. The median baseline HbA1c was 7.2 %. The Trulicity treatment arm included patients ≥ 65 years (n = 2,619) and ≥ 75 years (n = 484), and patients with mild (n = 2,435), moderate (n = 1,031) or severe (n = 50) 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. Trulicity was superior in preventing MACE compared to placebo (Figure 1). Each MACE component contributed to the reduction of MACE, as shown in Figure 2

Graph included.

Figure 1. Kaplan-Meier plot of time to first occurrence of the composite outcome: CV death, non-fatal myocardial infarction or non-fatal stroke, in the dulaglutide long-term cardiovascular outcome study

Graph included.

Figure 2: Forest plot of analyses of individual cardiovascular event types, all cause death, and consistency of effect across subgroups for the primary endpoint

A significant and sustained reduction in HbA1c levels 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).

10.           DATE OF REVISION OF THE TEXT

23 August 2019  21 October 2019                                                                                  TR121M

[minor editorial changes and removal of black triangle] 

This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions.

3.       PHARMACEUTICAL FORM

Solution for injection (injection).

4.8   Undesirable effects

Reporting suspected adverse reactions after authorisation 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 via Ireland: HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2, Tel: +353 1 6764971, Fax: +353 1 6762517; website: www.hpra.ie; e-mail: medsafety@hpra.ie, or United Kingdom: Yellow Card Scheme; website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

5.1   Pharmacodynamic properties

Pharmacotherapeutic group: Drugs used in diabetes, blood glucose lowering drugs, excl. insulins, glucagon-like peptide-1 (GLP-1) analogues ATC code: A10BJ05.

9.       DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

…

Date of latest renewal: 23 August 2019

10.     DATE OF REVISION OF THE TEXT

25 February 201923 August 2019

TR1011M

4.2   Posology and method of administration

Posology

Add-on therapy…

The use of Trulicity does not require blood glucose self‑monitoring. Self-monitoring may be necessary to adjust the dose of sulphonylurea or insulin. Blood glucose self-monitoring is necessary to adjust the dose of sulphonylurea or insulin, particularly when Trulicity therapy is started and insulin is reduced. A stepwise approach to insulin dose reduction is recommended.

4.4   Special warnings and precautions for use

Dulaglutide should not be used in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis. Dulaglutide is not a substitute for insulin. Diabetic ketoacidosis has been reported in insulin-dependent patients after rapid discontinuation or dose reduction of insulin (see section 4.2).

Dehydration

Use of GLP‑1 receptor agonists may be associated with gastrointestinal adverse reactions. This should be considered when treating patients with impaired renal function since these events, i.e. nausea, vomiting, and/or diarrhoea, may cause dehydration which could cause a deterioration of renal function. Dehydration, sometimes leading to acute renal failure or worsening renal impairment, has been reported in patients treated with dulaglutide, especially at the initiation of treatment. Many of the reported adverse renal events occurred in patients who had experienced nausea, vomiting, diarrhoea, or dehydration. Patients treated with dulaglutide should be advised of the potential risk of dehydration, particularly in relation to gastrointestinal side-effects and take precautions to avoid fluid depletion. Dulaglutide has not been studied in patients with severe gastrointestinal disease, including severe gastroparesis, and is therefore not recommended in these patients.

4.8            Undesirable effects …

Table 1: The frequency of adverse reactions of dulaglutide - 'Dehydaration' added under 'Uncommon' for 'Metabolism and nutrition disorders'

10.     DATE OF REVISION OF THE TEXT

25 February 201902 July 2018

Cholelithiasis, cholecystitis added as AEs

Date of revision changed from 26 April 2018 to 02 July 2018

• Updated images throughout both IFUs
  • Front page image detailing colour coding of pen specific to each strength
  • Annotated pen image
  • Updated images for steps 1, 2, 3 and disposal step
• Change to FAQ section, referring patient to ‘local Lilly office listed in the Information for the patient’ as opposed to their doctor, pharmacist or nurse.
• Addition of following text to BEFORE YOU GET STARTED section

‘Leave the Base Cap on until you are ready to inject.’

Changes

Added (underline) deleted (strikethrough) summary of changes 

4.         CLINICAL PARTICULARS

4.2   Posology and method of administration

Posology

Monotherapy

The recommended dose is 0.75 mg once weekly.

Add-on therapy

The recommended dose is 1.5 mg once weekly.

For potentially vulnerable populations, such as patients ≥ 75 years, 0.75 mg once weekly can be considered as a starting dose.

When Trulicity is added to existing metformin and/or pioglitazone therapy, the current dose of metformin and/or pioglitazone can be continued. When Trulicity is added to existing metformin and/or sodium-glucose co-transporter 2 inhibitor (SGLT2i) therapy, the current dose of metformin and/or SGLT2i can be continued. When it is added to existing therapy of a sulphonylurea or insulin, a reduction in the dose of sulphonylurea or insulin may be considered to reduce the risk of hypoglycaemia (see sections 4.4 and 4.8).

………. 

5.            PHARMACOLOGICAL PROPERTIES

5.1   Pharmacodynamic properties

………..

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.

Table 7 inserted - Data from AWARD10. Subsequent tables renamed accordingly.

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.

…………..

10.          DATE OF REVISION OF THE TEXT

26 April 2018

            TR7M  TR8M

Changes

Added (underline) deleted (strikethrough)

4.8   Undesirable effects

Table 1: The frequency of adverse reactions of dulaglutide

               ^# From post-marketing reports.

 * Documented, symptomatic hypoglycaemia with blood glucose ≤ 3.9 mmol/L

 †  Dulaglutide 1.5 mg dose only. For dulaglutide 0.75 mg, adverse reaction met frequency for next 

    lower  incidence grouping.

                                                                                                                                             TR6M TR7M

Changes

Added (underline) deleted (strikethrough) Summary of changes

TRULICITY^® (dulaglutide)                            SUMMARY OF PRODUCT CHARACTERISTICS

1.       NAME OF THE MEDICINAL PRODUCT

Trulicity^] 0.75 mg solution for injection in pre‑filled pen.

4.2   Posology and method of administration

Renal impairment

No dosage adjustment is required in patients with mild,  or moderate or severe renal impairment (eGFR < 90 to ≥ 15 mL/min/1.73 m²).

There is very limited experience in patients with severe renal impairment (eGFR [by CKD‑EPI] < 30 ml/min/1.73 m²) or end stage renal disease (< 15 mL/min/1.73 m²), therefore Trulicity is can not be recommended in this population (see sections 5.1 and 5.2).

4.8   Undesirable effects

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation 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 via Ireland: HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2, Tel: +353 1 6764971, Fax: +353 1 6762517; website: www.hpra.ie; e-mail: medsafety@hpra.ie, or United Kingdom: Yellow Card Scheme; website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

5.1   Pharmacodynamic properties

Pharmacotherapeutic group: Drugs used in diabetes, other blood glucose lowering drugs, excl. insulins, glucagon-like peptide-1 (GLP-1) analogues ATC code: A10BX14A10BJ05.

New passage titled ‘special populations’ including use in patients with renal impairment and AWARD7 data (Table 10: Results of a 52 week active controlled study with two doses of dulaglutide in comparison to insulin glargine (in patients with moderate to severe chronic kidney disease))

5.2   Pharmacokinetic properties

Renal impairment

The pharmacokinetics of dulaglutide were evaluated in a clinical pharmacology study and were generally similar between healthy subjects and patients with mild to severe renal impairment (CrCl < 30 mL/min), including end stage renal disease (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 0.75 mg and 1.5 mg once weekly was similar to that demonstrated in previous clinical studies.  In clinical studies, the dulaglutide safety profile in patients with moderate renal impairment was similar to the overall type 2 diabetes population. These This clinical study did not include patients with severe renal impairment or end stage renal disease.

6.6   Special precautions for disposal and other handling

Pre‑filled pen   

Instructions for use

The pre‑filled pen is for single‑use only.

The instructions for using the pen, included with the package leaflet, must be followed carefully.

Trulicity should not be used if particles appear or if the solution is cloudy and/or discoloured.

Trulicity that has been frozen must not be used.

Pre‑filled syringe

Instructions for use

The pre‑filled syringe is for single‑use only.

The instructions for using the syringe, included with the package leaflet, must be followed carefully.

Trulicity should not be used if particles appear or if the solution is cloudy and/or discoloured.

Trulicity that has been frozen must not be used.

10.     DATE OF REVISION OF THE TEXT

16 June 201722 February 2018

^]TRULICITY (dulaglutide) is a trademark of Eli Lilly and Company.                                       TR5M TR6M

Changes (New text bold & underlined.  Text struck-through removed)

4.         CLINICAL PARTICULARS

4.8   Undesirable effects

Summary of safety profile

In the completed phase II and phase III registration studies, 4,006 patients were exposed to dulaglutide alone or in combination with other glucose lowering medicinal products. The most frequently reported adverse reactions in clinical trials were gastrointestinal, including nausea, vomiting and diarrhoea. In general these reactions were mild or moderate in severity and transient in nature.

Tabulated list of adverse reactions

The following adverse reactions have been identified based on evaluation of the full duration of the phase II and phase III clinical studies and post-marketing reports and are listed in Table 1 as MedDRA preferred term by system organ class and in order of decreasing incidence (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 and not known: cannot be estimated from available data). Within each incidence grouping, adverse reactions are presented in order of decreasing frequency.

               Table 1: The frequency of adverse reactions of dulaglutide

^# From post-marketing reports.

 * Documented, symptomatic hypoglycaemia with blood glucose ≤ 3.9 mmol/L

 †  Dulaglutide 1.5 mg dose only. For dulaglutide 0.75 mg, adverse reaction met frequency for next 

    lower  incidence grouping.

…………

Immunogenicity

In clinical studies, treatment with dulaglutide was associated with a 1.6 % incidence of treatment emergent dulaglutide anti‑drug antibodies, indicating that the structural modifications in the GLP‑1 and modified IgG4 parts of the dulaglutide molecule, together with high homology with native GLP‑1 and native IgG4, minimise the risk of immune response against dulaglutide. Patients with dulaglutide anti‑drug antibodies generally had low titres, and although the number of patients developing dulaglutide anti‑drug antibodies was low, examination of the phase III data revealed no clear impact of dulaglutide anti‑drug antibodies on changes in HbA1c. None of the patients with systemic hypersensitivity developed dulaglutide anti‑drug antibodies.

Hypersensitivity

In the phase II and phase III clinical studies, systemic hypersensitivity events (e.g., urticaria, oedema) were reported in 0.5 % of patients receiving dulaglutide. None of the patients with systemic hypersensitivity developed dulaglutide anti‑drug antibodies. Cases of anaphylactic reaction have been rarely reported with marketed use of dulaglutide.

………

10           DATE OF REVISION OF THE TEXT

                13 October 201616 June 2017

Changes (New text bold.  Text struck-through removed)

4.         CLINICAL PARTICULARS

4.2       Posology and method of administration

Posology

……….

Add-on therapy

The recommended dose is 1.5 mg once weekly.

For potentially vulnerable populations, such as patients ≥ 75 years, 0.75 mg once weekly can be considered as a starting dose.

When Trulicity is added to existing metformin and/or pioglitazone therapy, the current dose of metformin and/or pioglitazone can be continued. When it is added to existing therapy of a sulphonylurea or prandial insulin, a reduction in the dose of sulphonylurea or insulin may be considered to reduce the risk of hypoglycaemia (see sections 4.4 and 4.8).

The use of Trulicity does not require blood glucose self‑monitoring. Self‑monitoring may be necessary to adjust the dose of sulphonylurea or prandial insulin.

……..

4.7   Effects on ability to drive and use machines

Trulicity has no or negligible influence on the ability to drive or use machines. When it is used in combination with a sulphonylurea or prandial insulin, patients should be advised to take precautions to avoid hypoglycaemia while driving and using machines (see section 4.4).

4.8   Undesirable effects

Summary of safety profile

In the completed phase II and phase III registration studies conducted, 4,006 patients were exposed to dulaglutide alone or in combination with other glucose lowering medicinal products. The most frequently reported adverse reactions in clinical trials were gastrointestinal, including nausea, vomiting and diarrhoea. In general these reactions were mild or moderate in severity and transient in nature.

Tabulated list of adverse reactions

The following adverse reactions have been identified based on evaluation of the full duration of the phase II and phase III clinical studies and are listed in Table 1 as MedDRA preferred term by system organ class and in order of decreasing incidence (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 and not known: cannot be estimated from available data). Within each incidence grouping, adverse reactions are presented in order of decreasing frequency.

               Table 1: The frequency of adverse reactions of dulaglutide

 * Documented, symptomatic hypoglycaemia andwith blood glucose ≤ to 3.9 mmol/L

 †  Dulaglutide 1.5 mg dose only. For dulaglutide 0.75 mg, adverse reaction met frequency for next 

    lower  incidence grouping.

Description of selected adverse reactions

Hypoglycaemia

When dulaglutide 0.75 mg and 1.5 mg were used as monotherapy or in combination with metformin alone or metformin and pioglitazone, the incidences of documented symptomatic hypoglycaemia were 5.9% to 10.9% and the rates were 0.14 to 0.62 events/patient/year, and no episodes of severe hypoglycaemia were reported.

The incidences of documented symptomatic hypoglycaemia when dulaglutide 0.75 mg and 1.5 mg, respectively, were used in combination with a sulphonylurea (plusand metformin) were 39.0% and 40.3% and the rates were 1.67 and 1.67 events/patient/year. The severe hypoglycaemia event incidences were 0% and 0.7%, and rates were 0.00 and 0.01 events/patient/year for each dose, respectively. The incidence of documented symptomatic hypoglycaemia when dulaglutide 1.5 mg was used with sulphonylurea 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.

The incidences when dulaglutide 0.75 mg and 1.5 mg, respectively, were used in combination with prandial insulin were 85.3% and 80.0% and rates were 35.66 and 31.06 events/patient/year. The severe hypoglycaemia event incidences were 2.4% and 3.4%, and rates were 0.05 and 0.06 events/patient/year.

…………

5.         PHARMACOLOGICAL PROPERTIES

5.1       Pharmacodynamic properties

……….

Clinical efficacy and safety

Glycaemic control

The safety and efficacy of dulaglutide waswere evaluated in sixeight randomised, controlled, phase III trials involving 5,171770 patients with type 2 diabetes. Of these, 9581,139 were ≥ 65 years of which 93115 were ≥ 75 years. These studies included 3,136525 dulaglutide‑treated patients, of whom 1,7192,108 were treated with Trulicity 1.5 mg weekly and 1,417 were treated with Trulicity 0.75 mg weekly. In all studies, dulaglutide produced clinically significant improvements in glycaemic control as measured by glycosylated haemoglobin A1c (HbA1c).

……..

Combination therapy with sulphonylurea

The safety and efficacy of dulaglutide as add-on to a sulphonylurea was investigated in a placebo controlled study of 24 weeks duration. Treatment with Trulicity 1.5mg 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.

Table 6: Results of a 24 week placebo controlled study of dulaglutide as add-on to glimepiride

^‡‡   p < 0.001 for superiority of dulaglutide compared to placebo, with overall type I error controlled

^** p < 0.001 for dulaglutide treatment group 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 therapy with metformin and pioglitazone

In a placebo and active (exenatide twice daily) controlled study, both in combination with metformin and pioglitazone, Trulicity 1.5 mg and 0.75 mg demonstrated superiority for HbA1c reduction in comparison to placebo and exenatide, accompanied by a significantly greater percentage of patients achieving HbA1c targets of < 7.0 % or ≤ 6.5 %.

Table 67: Results of a 52 week active controlled study with two doses of dulaglutide in comparison to exenatide

†† multiplicity adjusted 1‑sided p‑value < 0.025, for superiority of dulaglutide to exenatide, assessed       

     for HbA1c only

‡‡ multiplicity adjusted 1‑sided p‑value < 0.001 for superiority of dulaglutide compared to placebo,

     assessed for HbA1c only

                * p < 0.05, ** p < 0.001 dulaglutide treatment group compared to placebo

                        ^#  p < 0.05, ^##  p < 0.001 dulaglutide treatment group compared to exenatide

                        ⁺ Exenatide dose was 5 mcg twice daily for first 4 weeks and 10 mcg twice daily thereafter

The rates of documented symptomatic hypoglycaemia with Trulicity 1.5 mg and 0.75 mg, and exenatide twice daily were 0.19, 0.14, and 0.75 episodes/patient/year, respectively. No cases of severe hypoglycaemia were observed for dulaglutide and two cases of severe hypoglycaemia were observed with exenatide twice daily.

Combination therapy with titrated basal insulin, with or without metformin

In a 28 week placebo controlled study, Trulicity1.5 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 1.5mg.  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 8).

Table 8: Results of a 28 week study of dulaglutide compared to placebo as add-on to titrated insulin glargine

^‡‡  p < 0.001 for superiority of dulaglutide compared to placebo, overall type I error controlled

** p < 0.001 dulaglutide treatment group compared to placebo

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 therapy with prandial insulin with or without metformin

In this study, patients on 1 or 2 insulin injections per day prior to study entry, discontinued their prestudy insulin regimen and were randomised to dulaglutide once weekly or insulin glargine once daily, both in combination with prandial insulin lispro three times daily, with or without metformin. At 26 weeks, both Trulicity 1.5 mg and 0.75mg were superior to insulin glargine in lowering of HbA1c and this effect was sustained at 52 weeks.  A greater percentage of patients achieved HbA1c targets of < 7.0 % or ≤ 6.5 % at 26 weeks and < 7.0 % at 52 weeks than with insulin glargine.

Table 79: Results of a 52 week active controlled study with two doses of dulaglutide in comparison to insulin glargine

………

5.2   Pharmacokinetic properties

…….

Renal impairment

The pharmacokinetics of dulaglutide were evaluated in a clinical pharmacology study and were generally similar between healthy subjects and patients with mild to severe renal impairment (CrCl < 30 ml/min), including end stage renal disease (requiring dialysis). In clinical studies, the dulaglutide safety profile in patients with moderate renal impairment was similar to the overall T2DMtype 2 diabetes population. These studies did not include patients with severe renal impairment or end stage renal disease.

10           DATE OF REVISION OF THE TEXT

Changes :

(New text bold.  Text struck-through removed)

7.       MARKETING AUTHORISATION HOLDER

 Eli Lilly Nederland B.V., Grootslag 1-5 NL - 3991 RA, HoutenPapendorpseweg 83, 3528 BJ Utrecht, The Netherlands.

10.     DATE OF REVISION OF THE TEXT