Trulicity 1,5 mg Solution for Injection

TRULICITY is indicated as an adjunct to diet and exercise to improve glycaemic control in adults with type 2 diabetes mellitus:

• as monotherapy
• in combination with other glucose-lowering medicines

TRULICITY is indicated to reduce the risk of major adverse cardiovascular events (cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke) in adults with type 2 diabetes mellitus who have established cardiovascular disease or multiple cardiovascular risk factors.

General

TRULICITY should be administered once weekly. The dose can be administered at any time of the day, with or without meals, and can be injected subcutaneously in the abdomen, thigh or upper arm. TRULICITY should not be administered intravenously or intramuscularly. TRULICITY is for single use in one patient only. Discard the pen once the injection is completed.

Use in Adults (u2265 18 years)

The recommended dose of TRULICITY is 1,5 mg per week. Administer TRULICITY once weekly, at any time of day, independently of meals.

Use in the Elderly (u2265 65 years)

No dose adjustment is required based on age.

Use in Children and adolescents

The safety and effectiveness of TRULICITY have not been established in children and adolescents under 18 years of age.

Use in Renal Impairment

No dose adjustment is required in patients with mild (creatinine clearance 60 to < 90 mL/min), moderate (creatinine clearance 30 to < 60 mL/min) or severe (creatinine clearance < 30 mL/min to u2265 15 mL/min not requiring dialysis) renal impairment. There is limited experience in patients with end-stage renal disease (creatinine clearance < 15 mL/min requiring dialysis treatment), therefore TRULICITY cannot be recommended in this population (see 4.4 Special warnings and precautions for use and 5.1 Pharmacodynamic Properties).

Use in Hepatic Impairment

No dose adjustment is required based on hepatic impairment.

Missed dose

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 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.

Changing Weekly Dosage Schedule

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

TRULICITY is contraindicated in patients with:

• hypersensitivity to dulaglutide or to any of the excipients in TRULICITY (see section 6.1)
• a personal or family history of medullary thyroid carcinoma (MTC) or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2) (see section 4.4)
• pancreatitis
• Type 1 Diabetes Mellitus
• diabetic ketoacidosis
• severe gastrointestinal disease including severe gastroparesis

TRULICITY should not be used in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis. TRULICITY 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 and 4.3).

Risk of Thyroid C-cell Tumours: In male and female rats, dulaglutide causes a dose-related and treatment-duration-dependent increase in the incidence of thyroid C-cell tumours (adenomas and carcinomas) after lifetime exposure (see section 5.3 PRECLINICAL SAFETY DATA). Glucagon-like peptide-1 (GLP-1) receptor agonists have induced thyroid C-cell adenomas and carcinomas in mice and rats at clinically relevant exposures. It is unknown whether TRULICITY will cause thyroid C-cell tumours, including medullary thyroid carcinoma (MTC), in humans, as the human relevance of dulaglutide-induced rodent thyroid C-cell tumours has not been determined. One case of MTC was reported in a patient treated with TRULICITY in the phase 3 clinical studies. This patient had pretreatment calcitonin levels approximately 8 times the upper limit of normal (ULN). An additional case of C-cell hyperplasia with elevated calcitonin levels following treatment was reported in the long-term cardiovascular outcomes study (REWIND). Cases of MTC in patients treated with liraglutide, another GLP-1 receptor agonist, have been reported in the post-marketing period; the data in these reports are insufficient to establish or exclude a causal relationship between MTC and GLP-1 receptor agonist use in humans. TRULICITY is contraindicated in patients with a personal or family history of MTC or in patients with MEN 2. Counsel patients regarding the potential risk for MTC with the use of TRULICITY and inform them of symptoms of thyroid tumours (e.g. a mass in the neck, dysphagia, dyspnea, persistent hoarseness).

Routine monitoring of serum calcitonin or using thyroid ultrasound is of uncertain value for early detection of MTC in patients treated with TRULICITY. Such monitoring may increase the risk of unnecessary procedures, due to the low test specificity for serum calcitonin and a high background incidence of thyroid disease. Significantly elevated serum calcitonin values may indicate MTC and patients with MTC usually have calcitonin values >50 ng/L. If serum calcitonin is measured and found to be elevated, the patient should be further evaluated. Patients with thyroid nodules noted on physical examination or neck imaging should also be further evaluated.

Dehydration: Dehydration, sometimes leading to acute renal failure or worsening renal impairment, has been reported in patients treated with TRULICITY, 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 TRULICITY should be advised of the potential risk of dehydration, particularly in relation to gastrointestinal side effects and take precautions to avoid fluid depletion.

Severe gastrointestinal disease: TRULICITY 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.

Acute pancreatitis: Increased incidence of pancreatitis has been reported with use of TRULICITY. Patients should be informed of the characteristic symptoms of acute pancreatitis: persistent, severe abdominal pain. If pancreatitis is suspected, TRULICITY and other potentially suspect medicines should be discontinued until evaluation is complete. If the diagnosis of pancreatitis is confirmed, TRULICITY should be permanently discontinued. 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: Hypoglycaemia occurred commonly with TRULICITY when used as monotherapy and in combination with metformin plus pioglitazone and very commonly when TRULICITY was taken in combination with other hypoglycaemic medicines.

TRULICITY causes a delay in gastric emptying, and thereby has the potential to impact the absorption of concomitantly administered oral medications. In clinical pharmacology studies, TRULICITY did not affect the absorption of the orally administered medications tested to any clinically relevant degree (e.g. warfarin, metformin, lisinopril, metoprolol, digoxin, paracetamol, norelgestromin, ethinyloestradiol, sitagliptin, atorvastatin). No dosage adjustments of concomitant medications are required. As elimination of TRULICITY is presumed to be by proteolytic degradation into its amino acid components and is not anticipated to be eliminated intact in the urine or metabolised by cytochrome P450 enzymes, pharmacokinetic interactions with medicines primarily renally eliminated or metabolised by cytochrome P450 enzymes are not expected.

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

Breastfeeding: It is unknown whether TRULICITY is excreted in human milk. A risk to newborns/infants cannot be excluded. TRULICITY should not be used during breastfeeding.

Fertility: The effect of TRULICITY on fertility in humans is unknown. In the rat, there was no direct effect on mating or fertility following treatment with TRULICITY (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).

Summary of safety profile: In the completed phase II and phase III initial registration studies, 4 006 patients were exposed to TRULICITY alone or in combination with other glucose lowering medicines. 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 outcomes study with 4 949 patients randomised to TRULICITY and followed for a median of 5,4 years were consistent with these findings.

Tabulated list of adverse reactions: The following adverse reactions have been identified based on evaluation of the full duration of the phase II and phase III clinical studies, the long-term cardiovascular outcomes 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: u2265 1/10; common: u2265 1/100 to < 1/10; uncommon: u2265 1/1 000 to < 1/100; rare: u2265 1/10 000 to < 1/1 000; very rare: < 1/10 000 and not known: cannot be estimated from available data). Within each incidence grouping, adverse reactions are presented in order of decreasing frequency. Frequencies for events have been calculated based on their incidence in the phase II and phase III registration studies.

Table 1: The frequency of adverse reactions of TRULICITY

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

# From post-marketing reports.

* Documented, symptomatic hypoglycaemia with blood glucose u2264 3,9 mmol/L

Description of selected adverse reactions

Hypoglycaemia: When TRULICITY 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 TRULICITY 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 TRULICITY 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 TRULICITY 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 of documented symptomatic hypoglycaemia when TRULICITY 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.

Gastrointestinal adverse reactions: Cumulative reporting of gastrointestinal events up to 104 weeks with TRULICITY 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 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 II and III clinical studies was 0,07% for TRULICITY 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: TRULICITY 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 u2265 15 bpm, were observed with TRULICITY 0,75 mg and 1,5 mg, respectively.

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 TRULICITY 0,75 mg and 1,5 mg, respectively.

Immunogenicity: In clinical studies, treatment with TRULICITY was associated with a 1,6 % incidence of treatment emergent TRULICITY 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 TRULICITY. Patients with dulaglutide antibodies generally had low titres, and although the number of patients developing dulaglutide antibodies was low, examination of the phase III data revealed no clear impact of dulaglutide antibodies on changes in HbA1c. None of the patients with systemic hypersensitivity developed dulaglutide antibodies.

Hypersensitivity: In the phase II and phase III clinical studies, systemic hypersensitivity events (e.g., urticaria, oedema) were reported in 0,5 % of patients receiving TRULICITY. Cases of anaphylactic reaction have been rarely reported with marketed use of TRULICITY.

Injection site reactions: Injection site adverse events were reported in 1,9 % of patients receiving TRULICITY. 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 TRULICITY 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 TRULICITY. The most frequent adverse reactions leading to discontinuation for 0,75 mg and 1,5 mg TRULICITY, 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 of suspected adverse reactions: Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Healthcare providers are requested to report any suspected adverse reactions to SAHPRA via the Med Safety APP (Medsafety X SAHPRA) and eReporting platform (who-umc.org) found on SAHPRA website. Alternately, report suspected adverse events to the company at [email protected]

Effects of overdose with TRULICITY in clinical studies have included gastrointestinal disorders and hypoglycaemia. In the event of overdose, appropriate supportive treatment should be initiated according to the patientu2019s clinical signs and symptoms.