TRULICITY 3mg / 0.5ml injectible solution medication leaflet

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

Trulicity 0.75 mg solution for injection in pre-filled pen

Each pre-filled pen contains 0.75 mg of dulaglutide* in 0.5 ml solution.

Trulicity 1.5 mg solution for injection in pre-filled pen

Each pre-filled pen contains 1.5 mg of dulaglutide* in 0.5 ml solution.

Trulicity 3 mg solution for injection in pre-filled pen

Each pre-filled pen contains 3 mg of dulaglutide* in 0.5 ml solution.

Trulicity 4.5 mg solution for injection in pre-filled pen

Each pre-filled pen contains 4.5 mg of dulaglutide* in 0.5 ml solution.

*produced in CHO cells by recombinant DNA technology.

For the full list of excipients, see section 6.1.

Solution for injection.

Clear, colourless solution.

Type 2 Diabetes Mellitus

Trulicity is indicated for the treatment of patients 10 years and above with insufficiently controlledtype 2 diabetes mellitus as an adjunct to diet and exercise

* as monotherapy when metformin is considered inappropriate due to intolerance orcontraindications

* in addition to other medicinal products for the treatment of diabetes.

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.

The recommended dose is 0.75 mg once weekly.

Add-on therapy

The recommended dose is 1.5 mg once weekly.

If needed,

* the 1.5 mg dose can be increased after at least 4 weeks to 3 mg once weekly.

* the 3 mg dose can be increased after at least 4 weeks to 4.5 mg once weekly.

The maximum dose is 4.5 mg once weekly.

Paediatrics

The starting dose for paediatric patients 10 years and above is 0.75 mg once weekly.

If needed, the dose can be increased to 1.5 mg once weekly after at least 4 weeks. The maximum doseis 1.5 mg once weekly.

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

The use of Trulicity does not require blood glucose self-monitoring. Blood glucose self-monitoring isnecessary to adjust the dose of sulphonylurea or insulin, particularly when Trulicity therapy is startedand insulin is reduced. A stepwise approach to insulin dose reduction is recommended.

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 (72 hours) remain before the next scheduled dose,the missed dose should be skipped and the next dose should be administered on the regularlyscheduled day. In each case, patients can then resume their regular once weekly dosing schedule.

Special population

No dose adjustment is required based on age (see section 5.2).

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

There is very limited experience in patients with end stage renal disease (< 15 ml/min/1.73m2),therefore Trulicity cannot be recommended in this population (see sections 5.1 and 5.2).

No dose adjustment is required in patients with hepatic impairment.

The safety and efficacy of dulaglutide in children aged less than 10 years have not been establishedand no data are available (see sections 5.1 and 5.2).

Trulicity is to be injected subcutaneously in the abdomen, thigh or upper arm. It should not beadministered intravenously or intramuscularly.

The dose can be administered at any time of day, with or without meals.

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

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

In order to improve the traceability of biological medicinal products, the name and the batch numberof the administered medicinal product should be clearly recorded.

Type 1 diabetes mellitus or diabetic ketoacidosis

Dulaglutide should not be used in patients with type 1 diabetes mellitus or for the treatment ofdiabetic ketoacidosis. Dulaglutide is not a substitute for insulin.

Diabetic ketoacidosis has been reported in insulin-dependent patients after rapid discontinuation ordose reduction of insulin (see section 4.2).

Severe gastrointestinal disease

Dulaglutide has not been studied in patients with severe gastrointestinal disease, including severegastroparesis, and is therefore not recommended in these patients. Events related to impaired gastricemptying, including severe gastroparesis, have been reported. Monitor and consider dose modificationor discontinuation in patients who develop severe gastrointestinal symptoms while on treatment.

Aspiration in association with general anaesthesia or deep sedation

Cases of pulmonary aspiration have been reported in patients receiving GLP-1 receptor agonistsundergoing general anaesthesia or deep sedation. Therefore, the increased risk of residual gastriccontent due to delayed gastric emptying (see section 4.8) should be considered prior to performingprocedures with general anaesthesia or deep sedation.

Dehydration, sometimes leading to acute renal failure or worsening renal impairment, has beenreported in patients treated with dulaglutide, especially at the initiation of treatment. Many of thereported 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 ofdehydration, particularly in relation to gastrointestinal adverse reactions and take precautions to avoidfluid depletion.

Use of GLP-1 receptor agonists has been associated with a risk of developing acute pancreatitis. Inclinical trials, acute pancreatitis has been reported in association with dulaglutide (see section 4.8).

Patients should be informed of the characteristic symptoms of acute pancreatitis. If pancreatitis issuspected, dulaglutide should be discontinued. If pancreatitis is confirmed, dulaglutide should not berestarted. In the absence of other signs and symptoms of acute pancreatitis, elevations in pancreaticenzymes alone are not predictive of acute pancreatitis (see section 4.8).

Patients receiving dulaglutide in combination with sulphonylurea or insulin may have an increasedrisk of hypoglycaemia. The risk of hypoglycaemia may be lowered by a reduction in the dose ofsulphonylurea or insulin (see sections 4.2 and 4.8).

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially‘sodium- free’.

Dulaglutide delays gastric emptying and has the potential to impact the rate of absorption ofconcomitantly administered oral medicinal products. In the clinical pharmacology studies describedbelow, dulaglutide doses up to 1.5 mg did not affect the absorption of the orally administeredmedicinal products tested to any clinically relevant degree. For the 4.5 mg dose, absence of majorclinically relevant interactions was predicted by physiologically-based pharmacokinetic (PBPK)modelling simulations.

For patients receiving dulaglutide in combination with oral medicinal products with rapidgastrointestinal absorption or prolonged release, there is a potential for altered medicinal productexposure, particularly at the time of dulaglutide treatment initiation.

Sitagliptin

Sitagliptin exposure was unaffected when coadministered with a single 1.5 mg dose of dulaglutide.

Following coadministration with 2 consecutive 1.5 mg doses of dulaglutide, sitagliptin AUC(0-τ) and

Cmax decreased by approximately 7.4 % and 23.1 %, respectively. Sitagliptin tmax increasedapproximately 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 (1.5 mg)coadministration with sitagliptin increased dulaglutide exposure and Cmax by approximately 38 % and27 %, respectively, and median tmax increased approximately 24 hours. Therefore, dulaglutide doeshave 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.

Following a first dose of 1 and 3 mg dulaglutide, paracetamol Cmax was reduced by 36 % and 50 %,respectively, and the median tmax occurred later (3 and 4 hours, respectively). After coadministrationwith up to 3 mg of dulaglutide at steady state, there were no statistically significant differences on

AUC(0-12), Cmax or tmax of paracetamol. No dose adjustment of paracetamol is necessary whenadministered with dulaglutide.

Coadministration of 1.5 mg of dulaglutide with atorvastatin decreased Cmax and AUC(0-∞) up to 70 %and 21 %, respectively, for atorvastatin and its major metabolite o-hydroxyatorvastatin. The mean t1/2of atorvastatin and o-hydroxyatorvastatin were increased by 17 % and 41 %, respectively, followingdulaglutide administration. These observations are not clinically relevant. No dose adjustment ofatorvastatin is necessary when administered with dulaglutide.

After coadministration of steady state digoxin with 2 consecutive 1.5 mg doses of dulaglutide, overallexposure (AUCτ) and tmax of digoxin were unchanged; and Cmax decreased by up to 22 %. This changeis not expected to have clinical consequences. No dose adjustment is required for digoxin whenadministered with dulaglutide.

Anti-hypertensives

Coadministration of multiple dulaglutide 1.5 mg doses with steady state lisinopril caused no clinicallyrelevant changes in the AUC or Cmax of lisinopril. Statistically significant delays in lisinopril tmax ofapproximately 1 hour were observed on Days 3 and 24 of the study. When a single 1.5 mg dose ofdulaglutide and metoprolol were coadministered, the AUC and Cmax of metoprolol increased by19 %and 32 %, respectively. While metoprolol tmax was delayed by 1 hour, this change was not statisticallysignificant. These changes were not clinically relevant; therefore, no dose adjustment of lisinopril ormetoprolol is necessary when administered with dulaglutide.

Following dulaglutide (1.5 mg) coadministration, S- and R-warfarin exposure and R-warfarin Cmaxwere unaffected, and S-warfarin Cmax decreased by 22 %. AUCINR increased by 2 %, which is unlikelyto be clinically significant, and there was no effect on maximum international normalised ratioresponse (INRmax). The time of international normalised ratio response (tINRmax) was delayed by6 hours, consistent with delays in tmax of approximately 4 and 6 hours for S- and R-warfarin,respectively. These changes are not clinically relevant. No dose adjustment for warfarin is necessarywhen given together with dulaglutide.

Coadministration of dulaglutide (1.5 mg) with an oral contraceptive (norgestimate 0.18 mg/ethinylestradiol 0.025 mg) did not affect the overall exposure to norelgestromin and ethinyl estradiol.

Statistically significant reductions in Cmax of 26 % and 13 % and delays in tmax of 2 and 0.30 hourswere observed for norelgestromin and ethinyl estradiol, respectively. These observations are notclinically relevant. No dose adjustment for oral contraceptives is required when given together withdulaglutide.

Following coadministration of multiple 1.5 mg doses of dulaglutide with steady state metformin(immediate release formula [IR]), metformin AUCτ increased up to 15 % and Cmax decreased up to12 %, respectively, with no changes in tmax. These changes are consistent with the gastric emptyingdelay of dulaglutide and within the pharmacokinetic variability of metformin and thus are notclinically relevant. No dose adjustment for metformin IR is recommended when given withdulaglutide.

There are no or limited amount of data from the use of dulaglutide in pregnant women. Studies inanimals have shown reproductive toxicity (see section 5.3). Therefore, the use of dulaglutide is notrecommended during pregnancy.

It is unknown whether dulaglutide is excreted in human milk. A risk to newborns/infants cannot beexcluded. Dulaglutide should not be used during breast-feeding.

The effect of dulaglutide on fertility in humans is unknown. In the rat, there was no direct effect onmating or fertility following treatment with dulaglutide (see section 5.3).

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

In the completed phase 2 and phase 3 studies to support the initial registration of dulaglutide 0.75 mgand 1.5 mg, 4,006 patients were exposed to dulaglutide alone or in combination with other glucoselowering medicinal products. The most frequently reported adverse reactions in clinical trials weregastrointestinal, including nausea, vomiting and diarrhoea. In general, these reactions were mild ormoderate in severity and transient in nature. Results from the long-term cardiovascular outcome studywith 4,949 patients randomised to dulaglutide and followed for a median of 5.4 years were consistentwith these findings.

The following adverse reactions have been identified based on evaluation of the full duration of thephase 2 and phase 3 clinical studies, the long-term cardiovascular outcome study and post-marketingreports. The adverse reactions are listed in Table 1 as MedDRA preferred term by system organ classand 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 beestimated from available data). Within each incidence grouping, adverse reactions are presented inorder of decreasing frequency. Frequencies for events have been calculated based on their incidencein the phase 2 and phase 3 registration studies.

Table 1. The frequency of adverse reactions of dulaglutide

System organ Very common Common Uncommon Rare Notclass known

Immune system Hypersensitivity Anaphylacticdisorders reaction#

Metabolism Hypoglycaemia* Hypoglycaemia* Dehydrationand nutrition (when used in (when used asdisorders combination monotherapy orwith insulin, in combinationglimepiride, with metforminmetformin† or plusmetformin plus pioglitazone)glimepiride)

Gastrointestinal Nausea, Decreased Acute Non-disorders diarrhoea, appetite, pancreatitis, mechanicalvomiting†, dyspepsia, delayed intestinalabdominal pain† constipation, gastric obstructionflatulence, emptyingabdominaldistention,gastroesophagealreflux disease,eructation

Hepatobiliary Cholelithiasis,disorders cholecystitis

Skin and Angioedema#subcutaneoustissue disorders

General Fatigue Injection sitedisorders and reactions$administrationsite conditions

Investigations Sinustachycardia, firstdegreeatrioventricularblock (AVB)# From post-marketing reports.

* Documented, symptomatic hypoglycaemia with blood glucose ≤ 3.9 mmol/L† For dulaglutide 0.75 mg, adverse reaction met frequency for next lower incidence grouping.$ The frequency seen in a paediatric study was common; 3.9 % (2 patients) in the dulaglutide 0.75 mggroup, 3.8 % (2 patients) in the dulaglutide 1.5 mg group and 2 % (1 patient) in the placebo group. Allevents were mild to moderate in severity.

When dulaglutide 0.75 mg and 1.5 mg were used as monotherapy or in combination with metforminalone or metformin and pioglitazone, the incidences of documented symptomatic hypoglycaemia were5.9 % to 10.9 % and the rates were 0.14 to 0.62 events/patient/year, and no episodes of severehypoglycaemia 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 and metformin were 39.0 % and 40.3 %and the rates were 1.67 and 1.67 events/patient/year. The severe hypoglycaemia event incidenceswere 0 % and 0.7 %, and rates were 0.00 and 0.01 events/patient/year for each dose, respectively. Theincidence of documented symptomatic hypoglycaemia when dulaglutide 1.5 mg was used withsulphonylurea alone was 11.3 % and the rate was 0.90 events/patient/year, and there were no episodesof severe hypoglycaemia.

The incidence of documented symptomatic hypoglycaemia when dulaglutide 1.5 mg was used incombination with insulin glargine was 35.3 % and the rate was 3.38 events/patient/year. The severehypoglycaemia 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 withprandial insulin were 85.3 % and 80.0 % and rates were 35.66 and 31.06 events/patient/year. Thesevere hypoglycaemia event incidences were 2.4 % and 3.4 %, and rates were 0.05 and0.06 events/patient/year.

In a phase 3 study through to week 52, when dulaglutide 1.5 mg, 3 mg and 4.5 mg were used incombination with metformin, the incidences of documented symptomatic hypoglycaemia were 3.1 %,2.4 % and 3.1 %, respectively, and rates were 0.07, 0.05 and 0.07 events/patient/year; one episode ofsevere hypoglycaemia was reported with dulaglutide 1.5 mg and 4.5 mg, respectively.

Cumulative reporting of gastrointestinal events up to 104 weeks with dulaglutide 0.75 mg and 1.5 mg,respectively, included nausea (12.9 % and 21.2 %), diarrhoea (10.7 % and 13.7 %) and vomiting(6.9 % and 11.5 %). These were typically mild or moderate in severity and were reported to peakduring the first 2 weeks of treatment and rapidly declined over the next 4 weeks, after which the rateremained relatively constant.

In a phase 3 study with 1.5 mg, 3 mg and 4.5 mg dulaglutide doses respectively, cumulative reportingof gastrointestinal events through to 52 weeks included nausea (14.2 %, 16.1 % and 17.3 %),diarrhoea (7.7 %, 12.0 % and 11.6 %) and vomiting (6.4 %, 9.1 % and 10.1 %). In clinicalpharmacology studies conducted in patients with type 2 diabetes mellitus up to 6 weeks, the majorityof gastrointestinal events were reported during the first 2-3 days after the initial dose and declinedwith subsequent doses.

The incidence of acute pancreatitis in phase 2 and 3 registration studies was 0.07 % for dulaglutidecompared to 0.14 % for placebo and 0.19 % for comparators with or without additional backgroundantidiabetic therapy. Acute pancreatitis and pancreatitis have also been reported in the post-marketingsetting.

Pancreatic enzymes

Dulaglutide is associated with mean increases from baseline in pancreatic enzymes (lipase and/orpancreatic amylase) of 11 % to 21 % (see section 4.4). In the absence of other signs and symptoms ofacute pancreatitis, elevations in pancreatic enzymes alone are not predictive of acute pancreatitis.

Small mean increases in heart rate of 2 to 4 beats per minute (bpm) and a 1.3 % and 1.4 % incidenceof sinus tachycardia, with a concomitant increase from baseline ≥ 15 bpm, were observed withdulaglutide 0.75 mg and 1.5 mg, respectively.

In a phase 3 study with 1.5 mg, 3 mg and 4.5 mg dulaglutide doses, the incidence of sinustachycardia, with a concomitant increase from baseline ≥ 15 bpm, was 2.6 %, 1.9 % and 2.6 %respectively. Mean increases in heart rate of 1 - 4 beats per minute (bpm) were observed.

First degree AV block/PR interval prolongation

Small mean increases from baseline in PR interval of 2 to 3 msec and a 1.5 % and 2.4 % incidence offirst-degree AV block were observed with dulaglutide 0.75 mg and 1.5 mg, respectively.

In a phase 3 study with 1.5 mg, 3 mg and 4.5 mg dulaglutide doses, the incidence of first-degree AVblock was 1.2 %, 3.8 % and 1.7 % respectively. Mean increases from baseline in PR interval of3 - 5 msec were observed.

In registration studies, treatment with dulaglutide was associated with a 1.6 % incidence of treatmentemergent dulaglutide anti-drug antibodies, indicating that the structural modifications in the GLP-1and modified IgG4 parts of the dulaglutide molecule, together with high homology with native GLP-1and native IgG4, minimise the risk of immune response against dulaglutide. Patients with dulaglutideanti-drug antibodies generally had low titres, and although the number of patients developingdulaglutide anti-drug antibodies was low, examination of the phase 3 data revealed no clear impact ofdulaglutide anti-drug antibodies on changes in HbA1c. None of the patients with systemichypersensitivity developed dulaglutide anti-drug antibodies.

In the phase 2 and phase 3 registration studies, systemic hypersensitivity events (e.g., urticaria,edema) were reported in 0.5 % of patients receiving dulaglutide. Cases of anaphylactic reaction havebeen rarely reported with marketed use of dulaglutide.

Injection site adverse events were reported in 1.9 % of patients receiving dulaglutide. Potentiallyimmune-mediated injection site adverse events (e.g., rash, erythema) were reported in 0.7 % ofpatients and were usually mild.

In studies of 26 weeks duration, the incidence of discontinuation due to adverse events was 2.6 %(0.75 mg) and 6.1 % (1.5 mg) for dulaglutide versus 3.7 % for placebo. Through the full studyduration (up to 104 weeks), the incidence of discontinuation due to adverse events was 5.1 %(0.75 mg) and 8.4 % (1.5 mg) for dulaglutide. The most frequent adverse reactions leading todiscontinuation for 0.75 mg and 1.5 mg dulaglutide, respectively, were nausea (1.0 %, 1.9 %),diarrhoea (0.5 %, 0.6 %), and vomiting (0.4 %, 0.6 %), and were generally reported within the first4 - 6 weeks.

In a phase 3 study with 1.5 mg, 3 mg and 4.5 mg dulaglutide doses, the incidence of discontinuationdue to adverse events through 52 weeks was 6.0 % (1.5 mg), 7.0 % (3 mg) and 8.5 % (4.5 mg). Themost frequent adverse reactions leading to discontinuation for dulaglutide 1.5 mg, 3 mg and 4.5 mg,respectively, were nausea (1.3 %, 1.3 %, 1.5 %), diarrhoea (0.2 %, 1.0 %, 1.0 %), and vomiting(0.0 %, 0.8 %, 1.3 %).

Dulaglutide doses of 3 mg and 4.5 mg

The safety profile in patients treated with dulaglutide 3 mg and 4.5 mg once weekly is consistent withthat described above for dulaglutide doses of 0.75 mg and 1.5 mg once weekly.

The safety profile in paediatric patients aged 10 years and above treated with dulaglutide 0.75 mg and1.5 mg once-weekly is comparable with that described above for adult patients.

The immunogenicity profile in paediatric patients treated with dulaglutide is consistent with thatdescribed above for adult patients. In the paediatric study, 2.1 % and 4.0 % of patients treated withplacebo and dulaglutide respectively developed treatment emergent dulaglutide anti-drug antibodies.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Effects of overdose with dulaglutide in clinical studies have included gastrointestinal disorders andhypoglycaemia. In the event of overdose, appropriate supportive treatment should be initiatedaccording to the patient’s clinical signs and symptoms.

Pharmacotherapeutic group: Drugs used in diabetes, blood glucose lowering drugs, excl. insulins,

ATC code: A10BJ05

Dulaglutide is a long-acting glucagon-like peptide 1 (GLP-1) receptor agonist. The molecule consistsof 2 identical disulfide-linked chains, each containing a modified human GLP-1 analogue sequencecovalently linked to a modified human immunoglobulin G4 (IgG4) heavy chain fragment (Fc) by asmall peptide linker. The GLP-1 analog portion of dulaglutide is approximately 90 % homologous tonative human GLP-1 (7-37). Native GLP-1 has a half-life of 1.5 - 2 minutes due to degradation by

DPP-4 and renal clearance. In contrast to native GLP-1, dulaglutide is resistant to degradation by

DPP-4, and has a large size that slows absorption and reduces renal clearance. These engineeringfeatures result in a soluble formulation and a prolonged half-life of 4.7 days, which makes it suitablefor once-weekly subcutaneous administration. In addition, the dulaglutide molecule was engineered toprevent the Fcγ receptor-dependent immune response and to reduce its immunogenic potential.

Dulaglutide exhibits several antihyperglycaemic actions of GLP-1. In the presence of elevated glucoseconcentrations, dulaglutide increases intracellular cyclic AMP (cAMP) in pancreatic beta cells leadingto insulin release. Dulaglutide suppresses glucagon secretion which is known to be inappropriatelyelevated in patients with type 2 diabetes. Lower glucagon concentrations lead to decreased hepaticglucose output. Dulaglutide also slows gastric emptying.

Dulaglutide improves glycaemic control through the sustained effects of lowering fasting, pre-mealand postprandial glucose concentrations in patients with type 2 diabetes starting after the firstdulaglutide administration and is sustained throughout the once weekly dosing interval.

A pharmacodynamic study with dulaglutide demonstrated, in patients with type 2 diabetes, arestoration of first phase insulin secretion to a level that exceeded levels observed in healthy subjectson placebo and improved second phase insulin secretion in response to an intravenous bolus ofglucose. In the same study, a single 1.5 mg dose of dulaglutide appeared to increase maximal insulinsecretion from the β-cells, and to enhance β-cell function in subjects with type 2 diabetes mellitus ascompared with placebo.

Consistent with the pharmacokinetic profile, dulaglutide has a pharmacodynamic profile suitable foronce weekly administration (see section 5.2).

The safety and efficacy of dulaglutide were evaluated in ten randomised, controlled, phase 3 trialsinvolving 8,035 patients with type 2 diabetes. Of these, 1,644 were ≥ 65 years of which 174 were≥ 75 years. These studies included 5,650 dulaglutide treated patients, of whom 1,558 were treatedwith Trulicity 0.75 mg weekly, 2,862 were treated with Trulicity 1.5 mg weekly, 616 were treatedwith Trulicity 3 mg weekly and 614 were treated with Trulicity 4.5 mg weekly. In all studies,dulaglutide produced clinically significant improvements in glycaemic control as measured byglycosylated haemoglobin A1c (HbA1c).

Dulaglutide was studied in a 52-week active controlled monotherapy study in comparison tometformin. Trulicity 1.5 mg and 0.75 mg were superior to metformin (1500 - 2000 mg/day) in thereduction in HbA1c and a significantly greater proportion of patients reached an HbA1c target of< 7.0 % and ≤ 6.5 % with Trulicity 1.5 mg and Trulicity 0.75 mg compared to metformin at 26 weeks.

Table 2. Results of a 52-week active controlled monotherapy study with two doses of dulaglutide incomparison to metformin

Baseline Mean Patients at target Change in Change in

HbA1c change in HbA1c FBG body weight

HbA1c(%) (%) < 7.0 % ≤ 6.5 % (mmol/L) (kg)(%)a (%)b26 weeks

Dulaglutide 1.5 mgonce weekly 7.63 -0.78†† 61.5# 46.0## -1.61 -2.29(n = 269)

Dulaglutide 0.75 mgonce weekly 7.58 -0.71†† 62.6# 40.0# -1.46 -1.36#(n = 270)

Metformin1500 - 2000 mg/day 7.60 -0.56 53.6 29.8 -1.34 -2.22(n = 268)52 weeks

Dulaglutide 1.5 mgonce weekly 7.63 -0.70†† 60.0# 42.3## -1.56# -1.93(n = 269)

Dulaglutide 0.75 mgonce weekly 7.58 -0.55† 53.2 34.7 -1.00 -1.09#(n = 270)

Metformin1500 - 2000 mg/day 7.60 -0.51 48.3 28.3 -1.15 -2.20(n = 268)† multiplicity adjusted 1-sided p-value < 0.025, for noninferiority; †† multiplicity adjusted 1-sidedp-value < 0.025, for superiority of dulaglutide to metformin, assessed for HbA1c only# p < 0.05, ## p < 0.001 dulaglutide treatment group compared to metformina HbA1c value of 7.0 % (DCCT) corresponds to 53.0 mmol/mol (IFCC) (average blood glucose:

8.6 mmol/L)b HbA1c value of 6.5 % (DCCT) corresponds to 47.5 mmol/mol (IFCC) (average blood glucose:

7.8 mmol/L)

FBG = fasting blood glucose; DCCT = Diabetes Control and Complications Trial; IFCC =

International Federation of Clinical Chemistry and Laboratory Medicine

The rate of documented symptomatic hypoglycaemia with dulaglutide 1.5 mg and 0.75 mg, andmetformin were 0.62, 0.15, and 0.09 episodes/patient/year, respectively. No cases of severehypoglycaemia were observed.

Combination therapy with metformin

The safety and efficacy of dulaglutide was investigated in a placebo and active controlled (sitagliptin100 mg daily) study of 104 weeks duration, all in combination with metformin. Treatment with

Trulicity 1.5 mg and 0.75 mg resulted in a superior reduction in HbA1c compared to sitagliptin at52 weeks, accompanied by a significantly greater proportion of patients achieving HbA1c targets of< 7.0 % and ≤ 6.5 %. These effects were sustained to the end of the study (104 weeks).

Table 3. Results of a 104-week placebo and active controlled study with two doses of dulaglutide incomparison to sitagliptin

Baseline Mean Patients at target Change in Change in

HbA1c change in HbA1c FBG body

HbA1c weight(%) (%) < 7.0 % ≤ 6.5 % (mmol/L) (kg)(%)a (%)b26 weeks

Dulaglutide 1.5 mgonce weekly 8.12 -1.22‡‡,## 60.9**,## 46.7**,## -2.38**,## -3.18**,##(n = 304)

Dulaglutide 0.75 mgonce weekly 8.19 -1.01‡‡,## 55.2**,## 31.0**,## -1.97**,## -2.63**,##(n = 302)

Placebo (n = 177) 8.10 0.03 21.0 12.5 -0.49 -1.47

Sitagliptin100 mg once daily 8.09 -0.61 37.8 21.8 -0.97 -1.46(n = 315)52 weeks

Dulaglutide 1.5 mgonce weekly 8.12 -1.10†† 57.6## 41.7## -2.38## -3.03##(n = 304)

Dulaglutide 0.75 mgonce weekly 8.19 -0.87†† 48.8## 29.0## -1.63## -2.60##(n = 302)

Sitagliptin 100 mgonce daily (n = 315) 8.09 -0.39 33.0 19.2 -0.90 -1.53104 weeks

Dulaglutide 1.5 mgonce weekly 8.12 -0.99†† 54.3## 39.1## -1.99## -2.88##(n = 304)

Dulaglutide 0.75 mgonce weekly 8.19 -0.71†† 44.8## 24.2## -1.39## -2.39(n = 302)

Sitagliptin 100 mgonce daily (n = 315) 8.09 -0.32 31.1 14.1 -0.47 -1.75†† multiplicity adjusted 1-sided p-value < 0.025, for superiority of dulaglutide compared to sitagliptin,assessed only for HbA1c at 52 and 104 weeks‡‡ multiplicity adjusted 1-sided p-value < 0.001 for superiority of dulaglutide compared to placebo,assessed for HbA1c only

** p < 0.001 dulaglutide treatment group compared to placebo## p < 0.001 dulaglutide treatment group compared to sitagliptina HbA1c value of 7.0 % (DCCT) corresponds to 53.0 mmol/mol (IFCC) (average blood glucose:

8.6 mmol/L)b HbA1c value of 6.5 % (DCCT) corresponds to 47.5 mmol/mol (IFCC) (average blood glucose:

7.8 mmol/L)

The rates of documented symptomatic hypoglycaemia with dulaglutide 1.5 mg and 0.75 mg, andsitagliptin were 0.19, 0.18, and 0.17 episodes/patient/year, respectively. No cases of severehypoglycaemia with dulaglutide were observed.

The safety and efficacy of dulaglutide was also investigated in an active controlled study (liraglutide1.8 mg daily) of 26 weeks duration, both in combination with metformin. Treatment with Trulicity1.5 mg resulted in similar lowering of HbA1c and patients achieving HbA1c targets of < 7.0 % and≤ 6.5 % compared to liraglutide.

Table 4. Results of a 26-week active controlled study of one dose of dulaglutide in comparison toliraglutide

Baseline Mean Patients at target Change in Change in

HbA1c change HbA1c FBG bodyin weight

HbA1c(%) (%) < 7.0 % ≤ 6.5 % (mmol/L) (kg)(%)a (%)b26 weeks

Dulaglutide 1.5 mgonce weekly 8.06 -1.42‡ 68.3 54.6 -1.93 -2.90#(n = 299)

Liraglutide+ 1.8 mg -1.36daily (n = 300) 8.05 67.9 50.9 -1.90 -3.61‡ 1-sided p-value p < 0.001, for noninferiority of dulaglutide compared to liraglutide, assessed onlyfor HbA1c.

# p < 0.05 dulaglutide treatment group compared to liraglutide.+ Patients randomised to liraglutide were initiated at a dose of 0.6 mg/day. After Week 1, patientswere up-titrated to 1.2 mg/day and then at Week 2 to 1.8 mg/day.a HbA1c value of 7.0 % (DCCT) corresponds to 53.0 mmol/mol (IFCC) (average blood glucose:

8.6 mmol/L)b HbA1c value of 6.5 % (DCCT) corresponds to 47.5 mmol/mol (IFCC) (average blood glucose:

7.8 mmol/L)

The rate of documented symptomatic hypoglycaemia with dulaglutide 1.5 mg was0.12 episodes/patient/year and with liraglutide was 0.29 episodes/patient/year. No cases of severehypoglycaemia were observed.

Combination therapy with metformin and sulphonylurea

In an active controlled study of 78 weeks duration, dulaglutide was compared to insulin glargine, bothon a background of metformin and a sulphonylurea. At 52 weeks, Trulicity 1.5 mg demonstratedsuperior lowering in HbA1c to insulin glargine which was maintained at 78 weeks; whereas loweringin HbA1c with Trulicity 0.75 mg was non-inferior to insulin glargine. With Trulicity 1.5 mg asignificantly higher percentage of patients reached a target HbA1c of < 7.0 % or ≤ 6.5 % at 52 and78 weeks compared to insulin glargine.

Table 5. Results of a 78-week active controlled study with two doses of dulaglutide in comparison toinsulin glargine

Baseline Mean Patients at target Change in Change in

HbA1c change HbA1c FBG bodyin weight

HbA1c(%) (%) < 7.0 % ≤ 6.5 % (mmol/L) (kg)(%)a (%)b52 weeks

Dulaglutide 1.5 mgonce weekly 8.18 -1.08†† 53.2## 27.0## -1.50 -1.87##(n = 273)

Dulaglutide 0.75 mgonce weekly 8.13 -0.76† 37.1 22.5# -0.87## -1.33##(n = 272)

Insulin glargine+once daily (n = 262) 8.10 -0.63 30.9 13.5 -1.76 1.4478 weeks

Dulaglutide 1.5 mgonce weekly 8.18 -0.90†† 49.0## 28.1## -1.10# -1.96##(n = 273)

Dulaglutide 0.75 mgonce weekly 8.13 -0.62† 34.1 22.1 -0.58## -1.54##(n = 272)

Insulin glargine+once daily (n = 262) 8.10 -0.59 30.5 16.6 -1.58 1.28† multiplicity adjusted 1-sided p-value < 0.025, for noninferiority; †† multiplicity adjusted 1-sidedp-value < 0.025, for superiority of dulaglutide to insulin glargine, assessed for HbA1c only# p < 0.05, ## p < 0.001 dulaglutide treatment group compared to insulin glargine+ Insulin glargine doses were adjusted utilising an algorithm with a fasting plasma glucose target of< 5.6 mmol/La HbA1c value of 7.0 % (DCCT) corresponds to 53.0 mmol/mol (IFCC) (average blood glucose:

8.6 mmol/L)b HbA1c value of 6.5 % (DCCT) corresponds to 47.5 mmol/mol (IFCC) (average blood glucose:

7.8 mmol/L)

The rates of documented symptomatic hypoglycaemia with dulaglutide 1.5 mg and 0.75 mg, andinsulin glargine were 1.67, 1.67, and 3.02 episodes/patient/year, respectively. Two cases of severehypoglycaemia were observed with dulaglutide 1.5 mg and two cases of severe hypoglycaemia wereobserved with insulin glargine.

Combination therapy with sulphonylurea

The safety and efficacy of dulaglutide as add-on to a sulphonylurea was investigated in a placebocontrolled study of 24 weeks duration. Treatment with Trulicity 1.5 mg in combination withglimepiride resulted in a statistically significant reduction in HbA1c compared to placebo withglimepiride at 24 weeks. With Trulicity 1.5 mg, a significantly higher percentage of patients reached atarget 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

Baseline Mean Patients at target Change in Change in

HbA1c change HbA1c FBG bodyin weight

HbA1c(%) (%) < 7.0 % ≤ 6.5 % (mmol/L) (kg)(%)a (%)b24 weeks

Dulaglutide 1.5 mgonce weekly 8.39 -1.38‡‡ 55.3‡‡ 40.0** -1.70‡‡ -0.91(n = 239)

Placebo (n = 60) 8.39 -0.11 18.9 9.4 0.16 -0.24‡‡ 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 placeboa HbA1c value of 7.0 % (DCCT) corresponds to 53.0 mmol/mol (IFCC) (average blood glucose:

8.6 mmol/L)b HbA1c value of 6.5 % (DCCT) corresponds to 47.5 mmol/mol (IFCC) (average blood glucose:

7.8 mmol/L)

The rates of documented symptomatic hypoglycaemia with dulaglutide 1.5 mg and placebo were 0.90and 0.04 episodes/patient/year, respectively. No cases of severe hypoglycaemia were observed fordulaglutide or placebo.

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 controlledstudy 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 higherpercentage of patients reached a target HbA1c of < 7.0 % and ≤ 6.5 % at 24 weeks compared toplacebo.

Table 7. Results of a 24-week placebo controlled study of dulaglutide as add-on to SGLT2i therapy

Baseline Mean Patients at target Change in Change in

HbA1c change HbA1c FBG bodyin weight

HbA1c(%) (%) < 7. 0%^ ≤ 6.5 % (mmol/L) (kg)(%)a (%)b24 weeks

Dulaglutide 0.75 mgonce weekly 8.05 -1.19‡‡ 58.8‡‡ 38.9** -1.44 -2.6(n = 141)

Dulaglutide 1.5 mgonce weekly 8.04 -1.33‡‡ 67.4‡‡ 50.8** -1.77 -3.1(n = 142)

Placebo (n = 140) 8.05 -0.51 31.2 14.6 -0.29 -2.3‡‡ 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^ Patients who withdrew from randomised treatment before 24 weeks were considered as not meetingthe targeta HbA1c value of 7.0 % (DCCT) corresponds to 53.0 mmol/mol (IFCC) (average blood glucose:8.6 mmol/L)b HbA1c value of 6.5 % (DCCT) corresponds to 47.5 mmol/mol (IFCC) (average blood glucose:7.8 mmol/L)

The rates of documented symptomatic hypoglycaemia with dulaglutide 0.75 mg, dulaglutide 1.5 mg,and placebo were 0.15, 0.16 and 0.12 episodes/patient/year, respectively. One patient reported severehypoglycaemia with dulaglutide 0.75 mg in combination with SGLT2i therapy and none withdulaglutide 1.5 mg or placebo.

Combination therapy with metformin and pioglitazone

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

Table 8. Results of a 52-week active controlled study with two doses of dulaglutide in comparison toexenatide

Baseline Mean Patients at target Change in Change in

HbA1c change in HbA1c FBG body

HbA1c weight(%) (%) < 7.0 % ≤ 6.5 % (mmol/L) (kg)(%)a (%)b26 weeks

Dulaglutide 1.5 mgonce weekly 8.10 -1.51‡‡,†† 78.2**,## 62.7**,## -2.36**,## -1.30**(n = 279)

Dulaglutide 0.75 mgonce weekly 8.05 -1.30‡‡/†† 65.8**/## 53.2**/## -1.90**/## 0.20 */##(n = 280)

Placebo (n = 141) 8.06 -0.46 42.9 24.4 -0.26 1.24

Exenatide+10 mcg twice daily 8.07 -0.99 52.3 38.0 -1.35 -1.07(n = 276)52 weeks

Dulaglutide 1.5 mgonce weekly 8.10 -1.36†† 70.8## 57.2## -2.04## -1.10(n = 279)

Dulaglutide 0.75 mgonce weekly 8.05 -1.07†† 59.1# 48.3## -1.58# 0.44#(n = 280)

Exenatide+10 mcg twice daily 8.07 -0.80 49.2 34.6 -1.03 -0.80(n = 276)†† multiplicity adjusted 1-sided p-value < 0.025, for superiority of dulaglutide to exenatide, assessedfor 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 thereaftera HbA1c value of 7.0 % (DCCT) corresponds to 53.0 mmol/mol (IFCC) (average blood glucose:

8.6 mmol/L)b HbA1c value of 6.5 % (DCCT) corresponds to 47.5 mmol/mol (IFCC) (average blood glucose:7.8 mmol/L)

The rates of documented symptomatic hypoglycaemia with dulaglutide 1.5 mg and 0.75 mg, andexenatide twice daily were 0.19, 0.14, and 0.75 episodes/patient/year, respectively. No cases of severehypoglycaemia were observed for dulaglutide and two cases of severe hypoglycaemia were observedwith 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 titratedbasal insulin glargine (88 % with and 12 % without metformin) to evaluate the effect on glycaemiccontrol and safety. To optimise the insulin glargine dose, both groups were titrated to a target fastingserum glucose of < 5.6 mmol/L. The mean baseline dose of insulin glargine was 37 units/day forpatients receiving placebo and 41 units/day for patients receiving Trulicity 1.5 mg. The initial insulinglargine doses in patients with HbA1c < 8.0 % were reduced by 20 %. At the end of the 28-weektreatment 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 astatistically significant reduction in HbA1c compared to placebo and a significantly greaterpercentage of patients achieving HbA1c targets of < 7.0 % and ≤ 6.5 % (Table 9).

Table 9. Results of a 28-week study of dulaglutide compared to placebo as add-on to titrated insulinglargine

Baseline Mean Patients at target Change in Change in

HbA1c change in HbA1c FBG body

HbA1c weight(%) (%) < 7.0 % ≤ 6.5 % (mmol/L) (kg)(%)a (%)b28 weeks

Dulaglutide 1.5 mgonce weekly and ‡‡insulin glargine 8.41 -1.44 66.7‡‡ 50.0** -2.48‡‡ -1.91‡‡(n = 150)

Placebo onceweekly and insulin 8.32 -0.67 33.3 16.7 -1.55 0.50glargine (n = 150)‡‡ p < 0.001 for superiority of dulaglutide compared to placebo, overall type I error controlled

** p < 0.001 dulaglutide treatment group compared to placeboa HbA1c value of 7.0 % (DCCT) corresponds to 53.0 mmol/mol (IFCC) (average blood glucose:

8.6 mmol/L)b HbA1c value of 6.5 % (DCCT) corresponds to 47.5 mmol/mol (IFCC) (average blood glucose:

7.8 mmol/L)

The rates of documented symptomatic hypoglycaemia with dulaglutide 1.5 mg and insulin glarginewere 3.38 episodes/patient/year compared to placebo and insulin glargine 4.38 episodes/patient/year.

One patient reported severe hypoglycaemia with dulaglutide 1.5 mg in combination with insulinglargine 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 theirprestudy insulin regimen and were randomised to dulaglutide once weekly or insulin glargine oncedaily, both in combination with prandial insulin lispro three times daily, with or without metformin.

At 26 weeks, both Trulicity 1.5 mg and 0.75 mg were superior to insulin glargine in lowering of

HbA1c and this effect was sustained at 52 weeks. A greater percentage of patients achieved HbA1ctargets of < 7.0 % or ≤ 6.5 % at 26 weeks and < 7.0 % at 52 weeks than with insulin glargine.

Table 10. Results of a 52-week active controlled study with two doses of dulaglutide in comparison toinsulin glargine

Baseline Mean Patients at target Change in Change in

HbA1c change in HbA1c FBG body

HbA1c weight(%) (%) < 7.0 % ≤ 6.5 % (mmol/L) (kg)(%)a (%)b26 weeks

Dulaglutide 1.5 mgonce weekly 8.46 -1.64†† 67.6# 48.0# -0.27## -0.87##(n = 295)

Dulaglutide 0.75 mgonce weekly 8.40 -1.59†† 69.0# 43.0 0.22## 0.18##(n = 293)

Insulin glargine+once daily (n = 296) 8.53 -1.41 56.8 37.5 -1.58 2.3352 weeks

Dulaglutide 1.5 mgonce weekly 8.46 -1.48†† 58.5# 36.7 0.08## -0.35##(n = 295)

Dulaglutide 0.75 mgonce weekly 8.40 -1.42†† 56.3 34.7 0.41## 0.86##(n = 293)

Insulin glargine+once daily (n = 296) 8.53 -1.23 49.3 30.4 -1.01 2.89†† multiplicity adjusted 1-sided p-value < 0.025, for superiority of dulaglutide to insulin glargine,assessed for HbA1c only# p < 0.05, ## p < 0.001 dulaglutide treatment group compared to insulin glargine+ Insulin glargine doses were adjusted utilizing an algorithm with a fasting plasma glucose target of< 5.6 mmol/La HbA1c value of 7.0 % (DCCT) corresponds to 53.0 mmol/mol (IFCC) (average blood glucose:

8.6 mmol/L)b HbA1c value of 6.5 % (DCCT) corresponds to 47.5 mmol/mol (IFCC) (average blood glucose:

7.8 mmol/L)

The rates of documented symptomatic hypoglycaemia with dulaglutide 1.5 mg and 0.75 mg, andinsulin glargine were 31.06, 35.66, and 40.95 episodes/patient/year, respectively. Ten patientsreported severe hypoglycaemia with dulaglutide 1.5 mg, seven with dulaglutide 0.75 mg, and fifteenwith insulin glargine.

Fasting blood glucose

Treatment with dulaglutide resulted in significant reductions from baseline in fasting blood glucose.

The majority of the effect on fasting blood glucose concentrations occurred by 2 weeks. Theimprovement in fasting glucose was sustained through the longest study duration of 104 weeks.

Postprandial glucose

Treatment with dulaglutide resulted in significant reductions in mean post prandial glucose frombaseline (changes from baseline to primary time point -1.95 mmol/L to -4.23 mmol/L).

Beta-cell function

Clinical studies with dulaglutide have indicated enhanced beta-cell function as measured byhomeostasis model assessment (HOMA2-%B). The durability of effect on beta-cell function wasmaintained through the longest study duration of 104 weeks.

Trulicity 1.5 mg was associated with sustained weight reduction over the duration of studies (frombaseline to final time point -0.35 kg to -2.90 kg). Changes in body weight with Trulicity 0.75 mgranged from 0.86 kg to -2.63 kg. Reduction in body weight was observed in patients treated withdulaglutide irrespective of nausea, though the reduction was numerically larger in the group withnausea.

Dulaglutide significantly improved total treatment satisfaction compared to exenatide twice daily. Inaddition, there was significantly lower perceived frequency of hyperglycaemia and hypoglycaemiacompared to exenatide twice daily.

The effect of dulaglutide on blood pressure as assessed by Ambulatory Blood Pressure Monitoringwas evaluated in a study of 755 patients with type 2 diabetes. Treatment with dulaglutide providedreductions 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 weredemonstrated at the final 26 week time point of the study.

Cardiovascular Evaluation

Meta-analysis of phase 2 and 3 studies

In a meta-analysis of phase 2 and 3 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). Theresults 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 clinicaltrial. 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 notadministered 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 was7.2 %. 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 adversecardiovascular 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 componentcontributed to the reduction of MACE, as shown in Figure 2.

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

Figure 2. Forest plot of analyses of individual cardiovascular event types, all cause death, andconsistency 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 treatmentdifference -0.51 % [-0.57; -0.45]; p < 0.001). There were significantly fewer patients in the Trulicitygroup who received an additional glycaemic intervention compared to placebo (Trulicity: 2,086[42.2 %]; placebo: 2,825 [57.0 %]; p < 0.001).

Combination of dulaglutide 4.5 mg, 3 mg and 1.5 mg therapy with metformin

The safety and efficacy of dulaglutide 3 mg and 4.5 mg once weekly compared to dulaglutide 1.5 mgonce weekly as add-on to metformin were investigated in a 52 weeks study. At 36 weeks, both

Trulicity 3 mg and 4.5 mg were superior to Trulicity 1.5 mg in lowering of HbA1c and body weight.

A greater percentage of patients achieved HbA1c targets of < 7.0 % or ≤ 6.5 % at 36 weeks with

Trulicity 3 mg and Trulicity 4.5 mg. The proportions of patients that achieved ≥ 5 % body weightreduction from baseline were 31 %, 40 % and 49 % for Trulicity 1.5 mg, 3 mg and 4.5 mgrespectively. These effects were sustained through 52 weeks.

Table 11. Results of an active controlled study comparing three doses of dulaglutide

Baseline Mean Patients at target Change Change

HbA1c change in HbA1c in FBG in body

HbA1c weight(%) (%) < 7.0 % ≤ 6.5 % (mmol/L) (kg)(%)a (%)b36 weeks

Dulaglutide 1.5 mgonce weekly 8.64 -1.53 57.0 38.1 -2.45 -3.1(n = 612)

Dulaglutide 3 mgonce weekly 8.63 -1.71# 64.7# 48.4‡‡ -2.66 -4.0#(n = 616)

Dulaglutide 4.5 mgonce weekly 8.64 -1.87## 71.5# 51.7‡‡ -2.90# -4.7##(n = 614)52 weeks

Dulaglutide 1.5 mgonce weekly 8.64 -1.52 58.6 40.4 -2.39 -3.5(n = 612)

Dulaglutide 3 mgonce weekly 8.63 -1.71‡ 65.4‡ 49.2‡ -2.70‡ -4.3‡(n = 616)

Dulaglutide 4.5 mgonce weekly 8.64 -1.83‡‡ 71.7‡‡ 51.3‡‡ -2.92‡‡ -5.0‡‡(n = 614)# p < 0.05, ## p < 0.001 for superiority compared to dulaglutide 1.5 mg, adjusted p-values with overalltype I error controlled‡ p < 0.05, ‡‡ p < 0.001 compared to dulaglutide 1.5 mga HbA1c value of 7.0 % (DCCT) corresponds to 53.0 mmol/mol (IFCC) (average blood glucose:

8.6 mmol/L)b HbA1c value of 6.5 % (DCCT) corresponds to 47.5 mmol/mol (IFCC) (average blood glucose:

7.8 mmol/L)

Results target the on-treatment effect (analysis is based on mixed models for repeated measurementsor longitudinal logistic regression).

Figure 3. Mean change in HbA1c (%) and body weight (kg) from baseline to week 52

The rates of documented symptomatic hypoglycaemia with dulaglutide 1.5 mg, 3 mg and 4.5 mg were0.07, 0.05 and 0.07 episodes/patient/year respectively. One patient reported severe hypoglycaemiawith dulaglutide 1.5 mg, no patient with dulaglutide 3 mg, and one patient with dulaglutide 4.5 mg.

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-onto prandial insulin lispro to evaluate the effect on glycaemic control and safety of patients withmoderate to severe chronic kidney disease (eGFR [by CKD-EPI] < 60 and ≥ 15 mL/min/1.73 m2).

Patients discontinued their pre-study insulin regimen at randomisation. At baseline, overall meaneGFR 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 HbA1ctargets of < 8.0 % at 26 and 52 weeks with both dulaglutide doses as well as insulin glargine.

Table 12. Results of a 52-week active controlled study with two doses of dulaglutide in comparison toinsulin glargine (in patients with moderate to severe chronic kidney disease)

Baseline Mean Patients at Change in Change in

HbA1c change in target FBG body weight

HbA1c HbA1c(%) (%) < 8.0 % (%)a (mmol/L) (kg)26 weeks

Dulaglutide 1.5 mgonce weekly 8.60 -1.19† 78.3 1.28## -2.81##(n = 192)

Dulaglutide 0.75 mgonce weekly 8.58 -1.12† 72.6 0.98## -2.02##(n = 190)

Insulin glargine+once daily (n = 194) 8.56 -1.13 75.3 -1.06 1.1152 weeks

Dulaglutide 1.5 mgonce weekly 8.60 -1.10† 69.1 1.57## -2.66##(n = 192)

Dulaglutide 0.75 mgonce weekly 8.58 -1.10† 69.5 1.15## -1.71##(n = 190)

Insulin glargine+once daily (n = 194) 8.56 -1.00 70.3 -0.35 1.57† 1-sided p-value < 0.025, for non-inferiority of dulaglutide to insulin glargine## p < 0.001 dulaglutide treatment group compared to insulin glargine+ Insulin glargine doses were adjusted utilizing an algorithm with a fasting plasma glucose target of≤ 8.3 mmol/La HbA1c value of 8.0 % (DCCT) corresponds to 63.9 mmol/mol (IFCC) (average blood glucose:

10.1 mmol/L)

The rates of documented symptomatic hypoglycaemia with dulaglutide 1.5 mg and dulaglutide0.75 mg, and insulin glargine were 4.44, pct. 4.34, and 9.62 episodes/patient/year, respectively. Nopatients reported cases of severe hypoglycaemia with dulaglutide 1.5 mg, six with dulaglutide0.75 mg, and seventeen with insulin glargine. The safety profile of dulaglutide in patients with renalimpairment was similar to that observed in other studies with dulaglutide.

Use in the paediatric population

The safety and efficacy of dulaglutide 0.75 mg and 1.5 mg once weekly in children and adolescentsaged 10 years and above were compared to placebo added to diet and exercise alone, with or withoutmetformin and/or basal insulin. The double-blind placebo-controlled period lasted for 26 weeks, afterwhich patients assigned to placebo started 26 weeks of open-label treatment with dulaglutide 0.75 mgonce weekly and patients assigned to dulaglutide continued open-label dulaglutide at their assigneddose. At 26 weeks, dulaglutide was superior to placebo treatment in lowering HbA1c.

Table 13. Glycemic results in paediatric patients aged 10 years and above with type 2 diabetes, withinadequate glycemic control despite diet and exercise (with or without metformin and/or basal insulin)

Baseline Mean Patients at target Mean Mean

HbA1c change HbA1c change in change inin FBG body mass

HbA1c index(%) (%) < 7.0 % ≤ 6.5 % (mmol/L) (kg/m2)(%)a (%)b26 weeks

Dulaglutide pooledc(n = 103) 8.0 -0.8## 51.5## 41.8‡‡ -1.1## -0.1

Dulaglutide 0.75 mg ## ## ‡‡once weekly (n = 51) 7.9 -0.6 54.9 43.1 -0.7# -0.2

Dulaglutide 1.5 mg ## ## ‡‡ ##once weekly (n = 52) 8.2 -0.9 48.1 40.4 -1.4 -0.1

Placebo once weekly(n = 51) 8.1 0.6 13.7 9.8 1.0 0.052 weeksd

Dulaglutide pooledc(n = 103) 8.0 -0.4 59.5 45.2 -0.63 0.1

Dulaglutide 0.75 mgonce weekly (n = 51) 7.9 -0.2 65.0 55.0 -0.21 0.0

Dulaglutide 1.5 mgonce weekly (n = 52) 8.2 -0.6 54.6 36.4 -0.95 0.1

Placebo/dulaglutide0.75 mg once 8.1 -0.1 50.0 29.4 0.24 -0.2weeklye (n = 51)# p < 0.05, ## p < 0.001 for superiority compared to placebo, adjusted p-values with overall type Ierror controlled.

‡ p < 0.05, ‡‡ p < 0.001 for superiority compared to placebo.a HbA1c value of 7.0 % (DCCT) corresponds to 53.0 mmol/mol (IFCC) (average blood glucose:

8.6 mmol/L)b HbA1c value of 6.5 % (DCCT) corresponds to 47.5 mmol/mol (IFCC) (average blood glucose:

7.8 mmol/L)c Combined results for Trulicity 0.75 mg and 1.5 mg. The comparison of the two doses together andindividually with placebo was prespecified with overall type I error controlled.d Efficacy estimates at the primary endpoint (26 weeks) are based on the treatment regimenestimand while estimates at the end of the open label extension (52 weeks) are based on theefficacy estimand.

e Patients assigned to placebo for the initial 26 week double-blind period started treatment withdulaglutide 0.75 mg once weekly for the follow-on 26 week open-label period.

Following subcutaneous administration to patients with type 2 diabetes, dulaglutide reaches peakplasma concentrations in 48 hours. The mean peak (Cmax) and total (AUC) exposures wereapproximately 114 ng/ml and 14,000 ngh/ml, respectively, after multiple subcutaneous 1.5 mg dosesof dulaglutide in patients with type 2 diabetes. Steady-state plasma concentrations were achievedbetween 2 to 4 weeks of once-weekly administration of dulaglutide (1.5 mg). Exposures aftersubcutaneous administration of single dulaglutide (1.5 mg) doses in the abdomen, thigh, or upper armwere comparable. The mean absolute bioavailability of dulaglutide following single-dosesubcutaneous administration of single 1.5 mg and 0.75 mg doses was 47 % and 65 %, respectively.

Absolute bioavailabilities for 3 mg and 4.5 mg doses were estimated to be similar to 1.5 mg althoughthey have not been specifically studied. Over the dose range 0.75 mg to 4.5 mg, the increase indulaglutide concentration is approximately proportional.

The apparent population mean central volume of distribution was 3.09 L and the apparent populationmean peripheral volume of distribution was 5.98 L.

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

Apparent population mean clearance of dulaglutide was 0.142 L/h. and the elimination half-life wasapproximately 5 days.

Age had no clinically relevant effect on the pharmacokinetic and pharmacodynamic properties ofdulaglutide.

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

Body weight or body mass index

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

The pharmacokinetics of dulaglutide were evaluated in a clinical pharmacology study and weregenerally 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 weekclinical 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 and1.5 mg once weekly was similar to that demonstrated in previous clinical studies. This clinical studydid not include patients with end stage renal disease.

The pharmacokinetics of dulaglutide were evaluated in a clinical pharmacology study, where subjectswith hepatic impairment had statistically significant decreases in dulaglutide exposure of up to 30 %to 33 % for mean Cmax and AUC, respectively, compared to healthy controls. There was a generalincrease in tmax of dulaglutide with increased hepatic impairment. However, no trend in dulaglutideexposure was observed relative to the degree of hepatic impairment. These effects were notconsidered to be clinically relevant.

A population pharmacokinetic analysis was conducted for dulaglutide 0.75 mg and 1.5 mg using datafrom 128 paediatric patients (10 to < 18 years of age) with type 2 diabetes. The AUC in paediatricpatients was approximately 37 % lower than that in adult patients. However, this difference was notdetermined to be clinically meaningful.

Non-clinical data reveal no special hazards for humans based on conventional studies of safetypharmacology or repeat-dose toxicity.

In a 6 month carcinogenicity study in transgenic mice, there was no tumorigenic response. In a 2 yearcarcinogenicity study in rats, at ≥ 3 times the human clinical exposure following 4.5 mg dulaglutideper week, dulaglutide caused statistically significant, dose-related increases in the incidence of thyroid

C-cell tumours (adenomas and carcinomas combined). The clinical relevance of these findings iscurrently unknown.

During the fertility studies, a reduction in the number of corpora lutea and prolonged oestrous cyclewere observed at dose levels that were associated with decreased food intake and body weight gain inmaternal animals; however, no effects on indices of fertility and conception or embryonicdevelopment were observed. In reproductive toxicology studies, skeletal effects and a reduction infoetal growth were observed in the rat and rabbit at exposures of dulaglutide 5- to 18-fold higher thanthose proposed clinically, but no foetal malformations were observed. Treatment of rats throughoutpregnancy and lactation produced memory deficits in female offspring at exposures that were 7-foldhigher than those proposed clinically. Dulaglutide dosing of male and female juvenile rats did notproduce memory deficits at 38-fold the highest human exposure.

Sodium citrate

Citric acid

Mannitol

Polysorbate 80

Water for injections

In the absence of compatibility studies this medicinal product must not be mixed with other medicinalproducts.

2 years

Store in a refrigerator (2 ºC - 8 ºC).

Do not freeze.

Store in original package in order to protect from light.

In-use

Trulicity may be stored unrefrigerated for up to 14 days at a temperature not above 30 ºC.

Glass syringe (type I) encased in a disposable pen.

Each pre-filled pen contains 0.5 ml of solution.

Packs of 2 and 4 pre-filled pens and multipack of 12 (3 packs of 4) pre-filled pens. Not all pack sizesmay be marketed.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

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.

Eli Lilly Nederland B.V., Papendorpseweg 83, 3528 BJ Utrecht, The Netherlands.

EU/1/14/956/001

EU/1/14/956/002

EU/1/14/956/003

EU/1/14/956/006

EU/1/14/956/007

EU/1/14/956/008

EU/1/14/956/011

EU/1/14/956/012

EU/1/14/956/013

EU/1/14/956/014

EU/1/14/956/015

EU/1/14/956/016

Date of first authorisation: 21 November 2014

Date of latest renewal: 23 August 2019

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu