4.1. Therapeutic indications

Type 2 Diabetes Mellitus

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

• as monotherapy when metformin is considered inappropriate due to intolerance or contraindications

• 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.

4.2. Posology and method of administration

Posology

Adults

Monotherapy

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 dose is 1.5 mg once weekly.

Combination therapy

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).

The use of Trulicity does not require blood glucose self‑monitoring. 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.

Missed doses

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 regularly scheduled day. In each case, patients can then resume their regular once weekly dosing schedule.

Special population

Elderly

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

Renal impairment

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).

Hepatic impairment

No dose adjustment is required in patients with hepatic impairment.

Paediatric population

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

Method of administration

Trulicity is to be injected subcutaneously in the abdomen, thigh or upper arm. It should not be administered 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 was administered 3 or more days (72 hours) before.

4.3. Contraindications

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

4.4. Special warnings and precautions for use

Traceability

In order to improve the traceability of biological medicinal products, the name and the batch number of 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 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).

Severe gastrointestinal disease

Dulaglutide has not been studied in patients with severe gastrointestinal disease, including severe gastroparesis, and is therefore not recommended in these patients. Events related to impaired gastric emptying, including severe gastroparesis, have been reported. Monitor and consider dose modification or 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 agonists undergoing general anaesthesia or deep sedation. Therefore, the increased risk of residual gastric content due to delayed gastric emptying (see section 4.8) should be considered prior to performing procedures with general anaesthesia or deep sedation.

Dehydration

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 adverse reactions and take precautions to avoid fluid depletion.

Acute pancreatitis

Dulaglutide has not been studied in patients with a history of pancreatitis, and should be used with caution in these patients.

Use of GLP‑1 receptor agonists has been associated with a risk of developing acute pancreatitis. This includes post-marketing reports of necrotising pancreatitis and reports with a fatal outcome.

In clinical trials, acute pancreatitis has been reported in association with dulaglutide (see section 4.8). Patients should be informed of the symptoms of acute pancreatitis, including persistent, severe abdominal pain. Patients should be advised to seek immediate medical attention if they occur. If pancreatitis is suspected, dulaglutide should be discontinued. If the diagnosis of pancreatitis is confirmed, dulaglutide should not be restarted.

In the absence of other signs and symptoms of acute pancreatitis, elevations in pancreatic enzymes alone are not predictive of acute pancreatitis (see section 4.8).

Hypoglycaemia

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

Sodium content

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

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 doses up to 1.5 mg did not affect the absorption of the orally administered medicinal products tested to any clinically relevant degree. For the 4.5 mg dose, absence of major clinically relevant interactions was predicted by physiologically-based pharmacokinetic (PBPK) modelling simulations.

For patients receiving dulaglutide in combination with oral medicinal products with rapid gastrointestinal absorption or prolonged release, there is a potential for altered medicinal product exposure, 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 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 (1.5 mg) 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.

Paracetamol

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 coadministration with 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 when administered with dulaglutide.

Atorvastatin

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 t1/2 of atorvastatin and o‑hydroxyatorvastatin were increased by 17 % and 41 %, respectively, following dulaglutide administration. These observations are not clinically relevant. No dose adjustment of atorvastatin is necessary when administered with dulaglutide.

Digoxin

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

Anti‑hypertensives

Coadministration of multiple dulaglutide 1.5 mg doses with steady state lisinopril caused no clinically relevant changes in the AUC or Cmax of lisinopril. Statistically significant delays in lisinopril tmax of approximately 1 hour were observed on Days 3 and 24 of the study. When a single 1.5 mg dose of dulaglutide 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 statistically significant. These changes were not clinically relevant; therefore, no dose adjustment of lisinopril or metoprolol is necessary when administered with dulaglutide.

Warfarin

Following dulaglutide (1.5 mg) coadministration, S‑ and R‑warfarin exposure and R‑warfarin Cmax were unaffected, and S‑warfarin Cmax decreased by 22 %. AUCINR increased by 2 %, which is unlikely to be clinically significant, and there was no effect on maximum international normalised ratio response (INRmax). The time of international normalised ratio response (tINRmax) was delayed by 6 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 necessary when given together with dulaglutide.

Oral contraceptives

Coadministration of dulaglutide (1.5 mg) with an oral contraceptive (norgestimate 0.18 mg/ethinyl estradiol 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 hours were observed for norelgestromin and ethinyl estradiol, respectively. These observations are not clinically relevant. No dose adjustment for oral contraceptives is required when given together with dulaglutide.

Metformin

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 to 12 %, respectively, with no changes in tmax. These changes are consistent with the gastric emptying delay of dulaglutide and within the pharmacokinetic variability of metformin and thus are not clinically relevant. No dose adjustment for metformin IR is recommended when given with dulaglutide.

4.6. Fertility, pregnancy and lactation

Pregnancy

There are no or limited amount of data from the use of dulaglutide in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). Therefore, the use of dulaglutide is not recommended during pregnancy.

Breast‑feeding

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

Fertility

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

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 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 2 and phase 3 studies to support the initial registration of dulaglutide 0.75 mg and 1.5 mg, 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 4,949 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 2 and phase 3 clinical studies, the long-term cardiovascular outcome study and post-marketing reports. The adverse reactions are listed in Table 1 as MedDRA preferred term 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 2 and phase 3 registration studies.

Table 1. The frequency of adverse reactions of dulaglutide

System organ class

Very common

Common

Uncommon

Rare

Not known

Immune system disorders

Hypersensitivity

Anaphylactic reaction#

Metabolism and nutrition disorders

Hypoglycaemia* (when used in combination with insulin, glimepiride, metformin† or metformin plus glimepiride)

Hypoglycaemia* (when used as monotherapy or in combination with metformin plus pioglitazone)

Dehydration

Nervous system disorders

Dysgeusia

Gastrointestinal disorders

Nausea, diarrhoea, vomiting†, abdominal pain†

Decreased appetite, dyspepsia, constipation, flatulence, abdominal distention, gastroesophageal reflux disease, eructation

Acute pancreatitis, delayed gastric emptying

Non-mechanical intestinal obstruction

Hepatobiliary disorders

Cholelithiasis, cholecystitis

Skin and subcutaneous tissue disorders

Angioedema#

General disorders and administration site conditions

Fatigue

Injection site reactions$

Investigations

Sinus tachycardia, first degree atrioventricular block (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 mg group, 3.8 % (2 patients) in the dulaglutide 1.5 mg group and 2 % (1 patient) in the placebo group. All events were mild to moderate in severity.

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 and 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.

In a phase 3 study through to week 52, when dulaglutide 1.5 mg, 3 mg and 4.5 mg were used in combination 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 of severe hypoglycaemia was reported with dulaglutide 1.5 mg and 4.5 mg, respectively.

Gastrointestinal adverse reactions

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 peak during the first 2 weeks of treatment and rapidly declined over the next 4 weeks, after which the rate remained relatively constant.

In a phase 3 study with 1.5 mg, 3 mg and 4.5 mg dulaglutide doses respectively, cumulative reporting of 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 clinical pharmacology studies conducted in patients with type 2 diabetes mellitus up to 6 weeks, the majority of gastrointestinal events were reported during the first 2-3 days after the initial dose and declined with subsequent doses.

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.

Pancreatic enzymes

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

Heart rate increase

Small mean increases in heart rate of 2 to 4 beats per minute (bpm) and a 1.3 % and 1.4 % incidence of sinus tachycardia, with a concomitant increase from baseline ≥ 15 bpm, 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 sinus tachycardia, 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 of first-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 AV block was 1.2 %, 3.8 % and 1.7 % respectively. Mean increases from baseline in PR interval of 3 – 5 msec were observed.

Immunogenicity

In registration 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 3 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 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 have been rarely reported with marketed use of dulaglutide.

Injection site reactions

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

Discontinuation due to an adverse event

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 study duration (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 to discontinuation 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 first 4 ‑ 6 weeks.

In a phase 3 study with 1.5 mg, 3 mg and 4.5 mg dulaglutide doses, the incidence of discontinuation due to adverse events through 52 weeks was 6.0 % (1.5 mg), 7.0 % (3 mg) and 8.5 % (4.5 mg). The most 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 with that described above for dulaglutide doses of 0.75 mg and 1.5 mg once weekly.

Paediatric population

The safety profile in paediatric patients aged 10 years and above treated with dulaglutide 0.75 mg and 1.5 mg once-weekly is comparable with that described above for adult patients.

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

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 the Yellow Card Scheme, Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

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