Source: European Medicines Agency (EU) Revision Year: 2019 Publisher: Eli Lilly Nederland B.V., Papendorpseweg 83, 3528 BJ Utrecht, The Netherlands
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
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, 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.
Use of GLP-1 receptor agonists has been associated with a risk of developing acute pancreatitis. In clinical 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 is suspected, dulaglutide should be discontinued. If 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).
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).
There is limited experience in patients with congestive heart failure.
This medicinal product contains less than 1 mmol sodium (23 mg) per 1.5 mg dose, i.e. essentially ‘sodium-free’.
Dulaglutide delays gastric emptying and has the potential to impact the rate of absorption of concomitantly administered oral medicinal products. 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.
Following a first dose of 1 and 3 mg dulaglutide, paracetamol Cmax was reduced by 36% and 50%, respectively, and the median t max 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.
Coadministration 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 t½ 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.
After coadministration of steady state digoxin with 2 consecutive 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.
Coadministration of multiple dulaglutide 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 dose of dulaglutide and metoprolol were coadministered, the AUC and Cmax of metoprolol increased by 19% 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.
Following dulaglutide 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 t max 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.
Coadministration of dulaglutide 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.
Following coadministration of multiple dose 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.
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). The increased exposure may enhance the effects of dulaglutide on blood glucose levels.
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.
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.
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).
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).
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.
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:
Uncommon: Hypersensitivity
Rare: Anaphylactic reaction#
Very common: Hypoglycaemia* (when used in combination with insulin, glimepiride, metformin† or metformin plus glimepiride)
Common: Hypoglycaemia* (when used as monotherapy or in combination with metformin plus pioglitazone)
Uncommon: Dehydration
Very common: Nausea, diarrhoea, disorders vomiting†, abdominal pain†
Common: Decreased appetite, dyspepsia, constipation, flatulence, abdominal distention, gastroesophageal reflux disease, eructation
Rare: Acute pancreatitis
Not known: Non-mechanical intestinal obstruction
Uncommon: Cholelithiasis, cholecystitis
Rare: Angioedema#
Common: Fatigue
Uncommon: Injection site reactions
Common: Sinus tachycardia, first degree atrioventricular block (AVB)
# 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.
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.
Cumulative reporting of gastrointestinal events up to 104 weeks with dulaglutide 0.75mg 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 clinical pharmacology studies conducted in patients with type 2 diabetes mellitus up to 6 weeks, the majority of gastrointestinal events were reported during the first 2-3 days after the initial dose and declined with subsequent doses.
The incidence of acute pancreatitis in Phase II and III clinical studies was 0.07% for dulaglutide compared to 0.14% for placebo and 0.19% for comparators with or without additional background antidiabetic therapy.
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.
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 0.75mg and 1.5 mg, respectively.
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 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.
In the phase II and phase III clinical 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 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.
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.
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 national reporting system listed in Appendix V.
In the absence of compatibility studies this medicinal product must not be mixed with other medicinal products.
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