Dulaglutide

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

Coadministration of dulaglutide with atorvastatin decreased C_max and AUC_(0-∞) up to 70% and 21%, respectively, for atorvastatin and its major metabolite o-hydroxyatorvastatin. The mean t_½ 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 (AUC_τ) and t_max of digoxin were unchanged; and C_max 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 1.5 mg doses with steady state lisinopril caused no clinically relevant changes in the AUC or C_max of lisinopril. Statistically significant delays in lisinopril t_max 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 C_max of metoprolol increased by 19% and 32%, respectively. While metoprolol t_max 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 coadministration of multiple dose dulaglutide with steady state metformin (immediate release formula [IR]), metformin AUC_τ increased up to 15% and C_max decreased up to 12%, respectively, with no changes in t_max. 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.

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 C_max of 26% and 13% and delays in t_max 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 a first dose of 1 and 3 mg dulaglutide, paracetamol C_max 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), C_max or t_max of paracetamol. No dose adjustment of paracetamol is necessary when administered with dulaglutide.

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 C_max decreased by approximately 7.4% and 23.1%, respectively. Sitagliptin t_max 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 C_max by approximately 38% and 27%, respectively, and median t_max increased approximately 24 hours. Therefore, dulaglutide does have a high degree of protection against DPP-4 inactivation. The increased exposure may enhance the effects of dulaglutide on blood glucose levels.

Following dulaglutide coadministration, S- and R-warfarin exposure and R-warfarin C_max were unaffected, and S-warfarin C_max decreased by 22%. AUC_INR increased by 2%, which is unlikely to be clinically significant, and there was no effect on maximum international normalised ratio response (INR_max). The time of international normalised ratio response (tINR_max) 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.

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.

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 should be considered prior to performing procedures with general anaesthesia or deep sedation.

There are no or limited amount of data from the use of dulaglutide in pregnant women. Studies in animals have shown reproductive toxicity. 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.

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.

Dulaglutide 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.

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 the table below 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.

The frequency of adverse reactions of dulaglutide:

^# 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%. 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.