Dulaglutide

Common name: Dulaglutide Injection

Trade name: Dulaglutide®, TRULICITY®

English name: Dulaglutide Injection

All names: Dulaglutide Injection, TRULICITY®, Dulaglutide Injection

[Indications]

This product is suitable for blood sugar control in adult patients with type 2 diabetes: monotherapy for patients with poor blood sugar control through diet control and exercise alone. Combination therapy: On the basis of diet control and exercise, adult patients with type 2 diabetes who still have poor blood sugar control receive metformin, or sulfonylureas, or metformin combined with sulfonylureas to treat adults with type 2 diabetes.

[Usage and Dosage]

The recommended starting dose of this product is 0.75 mg once a week. To further improve glycemic control, the dose may be increased to 1.5 mg once weekly. The maximum recommended dose is 1.5 mg once weekly. When dulaglutide is added to metformin, the current dose of metformin can be continued. When dulaglutide is added to sulfonylurea therapy, a reduction in the sulfonylurea dose should be considered to reduce the risk of hypoglycemia (see Adverse Reactions and Precautions).

Self-monitoring of blood glucose is not required when using dulaglutide. Blood glucose self-monitoring may be necessary to adjust the sulfonylurea dose. Patients with renal impairment: No dose adjustment is required in patients with mild, moderate, or severe renal impairment (eGFR between 15 and 90 mL/min/1.73 m2). Treatment experience in patients with end-stage renal disease (<15 ml/min/1.73 m2) is very limited and dulaglutide is not recommended for use in this population (see Clinical Trials and Pharmacokinetics).

Patients with hepatic impairment

No dose adjustment is required for patients with hepatic impairment.

Elderly patients

No dosage adjustment is required based on the patient’s age (see [Pharmacokinetics]). However, treatment experience in patients aged ≥75 years is very limited.

Pediatric Population

There is currently no data on the safety and effectiveness of dulaglutide in children under 18 years of age.

[Method of administration]

Dulaglutide is administered by subcutaneous injection, and the site can be the abdomen, thigh or upper arm. Not for intravenous or intramuscular injection. The injection can be given at any time of the day, regardless of whether you have eaten or not. If a dose is missed, it should be administered as soon as possible if it is at least 3 days (72 hours) before the next scheduled dose. If the next scheduled dose is less than 3 days (72 hours) away, the dose should be abandoned and the next scheduled dose should be carried out regularly. In each case, patients can resume their regular weekly dosing regimen. If necessary, the weekly dosing date can be changed as long as it has been more than 3 days (72 hours) since the last dose.

[Adverse Reactions]

Safety Summary

A total of 12,654 patients have been exposed to dulaglutide in completed and ongoing Phase II, Phase III/IIIb and Phase IV clinical studies. The most common adverse reactions in clinical trials were gastrointestinal adverse reactions, including nausea, vomiting, and diarrhea. These adverse reactions are usually mild or moderate and transient.

Adverse Reaction List The following adverse reactions were identified based on evaluation of Phase II, Phase III clinical studies, long-term cardiovascular outcome studies, and postmarketing reports and are listed in Table 1, shown as per MedDRA System organ class/preferred term and in descending order of occurrence (very common: ≥1/10; common: ≥1/100, <1/10; rare: ≥1/1000, <1/100; rare: ≥1/10000, <1/1000; very rare: <1/10000 and unknown: cannot be estimated from available data). Within each incidence group, adverse reactions are listed in descending order of incidence. Frequencies of events were calculated based on their occurrence in phase II and III registration studies.

Table 1: Frequency of adverse reactions of dulaglutide

Description of Selected Adverse Reactions

Hypoglycemia

When dulaglutide 0.75 mg and 1.5 mg was given as monotherapy or with metformin or in combination with metformin and pioglitazone, the incidence of symptomatic hypoglycemia was documented in 5.9% to 10.9%, with a rate of 0.14 to 0.62 events/patient/year. No events of severe hypoglycemia were reported.

The documented incidence of symptomatic hypoglycemia was 39.0% and 40.3% when dulaglutide 0.75 mg and 1.5 mg were combined with a sulfonylurea and metformin, respectively, with rates of 1.67 and 1.67 events/patient/year. The incidence of severe hypoglycemic events was 0% and 0.7%, respectively, with rates of 0.00 and 0.01 events/patient/year.

When dulaglutide 1.5 mg was given in combination with a sulfonylurea, the documented incidence of symptomatic hypoglycemia was 11.3%, a rate of 0.90 events/patient/year, with no episodes of severe hypoglycemia.

When dulaglutide 1.5 mg was given in combination with insulin glargine, the documented incidence of symptomatic hypoglycemia was 35.3%, with a rate of 3.38 events/patient/year. The incidence of severe hypoglycemic events was 0.7%, with a rate of 0.01 events/patient/year.

When dulaglutide 0.75 mg and 1.5 mg were given in combination with prandial insulin, the incidence of documented symptomatic hypoglycemia was 85.3% and 80.0%, respectively, with rates of 35.66 and 31.06 events/patient/year. The incidence of severe hypoglycemic events was 2.4% and 3.4%, with rates of 0.05 and 0.06 events/patient/year.

Gastrointestinal Adverse Reactions

The cumulative 104-week incidence of reported gastrointestinal adverse events with dulaglutide 0.75 mg and 1.5 mg, respectively, included nausea (12.9% and 21.2%), diarrhea (10.7% and 13.7%), and vomiting (6.9% and 11.5%). These events were generally mild or moderate in severity, with rates peaking during the first 2 weeks of treatment, declining rapidly over the next 4 weeks, and remaining relatively stable thereafter.

In a 6-week clinical pharmacology study in patients with type 2 diabetes, most gastrointestinal adverse events were reported on days 2-3 after the first dose and decreased with subsequent doses.

Acute pancreatitis

In phase II and phase III clinical studies, the incidence rates of acute pancreatitis in the dulaglutide group, placebo group and control drug group were 0.07%, 0.14% and 0.19% respectively (with or without other antihyperglycemic treatments).

Treatment with the pancreatic enzyme dulaglutide is associated with an increase in mean pancreatic enzyme (lipase and/or amylase) values ​​from baseline ranging from 11% to 21% (see Precautions). Elevated pancreatic enzyme levels alone do not indicate acute pancreatitis in the absence of other signs and symptoms of acute pancreatitis.

Increased heart rate

With dulaglutide 0.75 mg and 1.5 mg, the average small increase in heart rate was 2 to 4 beats per minute (bpm), and the incidence of sinus tachycardia with an increase from baseline of ≥15 bpm was 1.3% and 1.4%, respectively. First-degree AV block/PR interval prolongation

A small mean increase in the PR interval of 2 to 3 milliseconds (msec) from baseline was observed with dulaglutide 0.75 mg and 1.5 mg, and the incidence of first-degree AV block was 1.5% and 2.4%, respectively.

Immunogenicity

In clinical studies, the incidence of anti-dulaglutide antibodies during dulaglutide treatment was 1.6%, indicating that the structural modification of GLP-1 and the modification of the IgG4 moiety in the dulaglutide molecule as well as the high homology to native GLP-1 and IgG4 resulted in an evaluation of the dulaglutide study data showing that anti-dulaglutide antibodies had no significant impact on changes in glycosylated hemoglobin. No patients who developed anaphylaxis developed antidulaglutide antibodies.

Allergic reaction

In Phase II and III clinical studies, anaphylaxis events (e.g., urticaria, edema) were reported in 0.5% of patients treated with dulaglutide. Rarely reported cases of immediate anaphylaxis have occurred with post-marketing dulaglutide.

Injection site reactions

Injection site adverse events were reported in 1.9% of patients treated with dulaglutide. Potential immune-mediated injection site adverse events (e.g., rash, erythema) were reported in 0.7% of patients and were generally mild.

Discontinuation due to adverse events During the 26-week study period, the incidence of discontinuation due to adverse events was 2.6% (0.75 mg) and 6.1% (1.5 mg) in the dulaglutide group and 3.7% in the placebo group. Over the entire study period (through Week 104), the incidence of discontinuation due to adverse events was 5.1% (0.75 mg) and 8.4% (1.5 mg) in the dulaglutide group. For dulaglutide 0.75 mg and 1.5 mg, the most common adverse reactions leading to discontinuation were nausea (1.0%, 1.9%), diarrhea (0.5%, 0.6%), and vomiting (0.4%, 0.6%), respectively, and were generally reported in the first 4-6 weeks.

[Contraindications]

Patients who are allergic to the active ingredients or any excipients of this product. This product is contraindicated in patients with a personal or family history of medullary thyroid carcinoma (MTC) or multiple endocrine neoplasia syndrome type 2 (MEN 2) (see Precautions).

[Precautions]

Dulaglutide should not be used in patients with type 1 diabetes or in the treatment of diabetic ketoacidosis. Dulaglutide does not replace insulin. Diabetic ketoacidosis has developed in insulin-dependent patients after rapid discontinuation of insulin or dose reduction (see Dosage and Administration).

Dehydration

Dehydration, sometimes leading to acute renal failure or worsening of renal impairment, has been reported in patients receiving dulaglutide, especially during the initiation of treatment. Many reported adverse renal events occur in patients who develop nausea, vomiting, diarrhea, or dehydration. Patients receiving dulaglutide should be informed of the possible risk of dehydration, particularly related to gastrointestinal side effects, and precautions should be taken to avoid fluid depletion.

The use of GLP-1 receptor agonists may be associated with adverse gastrointestinal effects. This should be considered when treating patients with renal impairment, as adverse effects such as nausea, vomiting, and/or diarrhea may cause dehydration, leading to worsening of renal function. Dulaglutide has not been studied in patients with severe gastrointestinal disease, including severe gastroparesis, and its use in this population is not recommended.

Risk of thyroid C-cell tumors

Glucagon-like peptide (GLP-1) receptor agonists have been associated with thyroid C-cell adenomas and adenocarcinomas in mice and rats at clinically relevant exposures. Dulaglutide causes a dose-related and treatment duration-dependent increase in the incidence of thyroid C-cell tumors (adenomas and adenocarcinomas) in male and female rats following lifelong exposure (see Pharmacology and Toxicology). The relevance of dura glycopeptides to human thyroid C-cell neoplasms has not been established. It is unknown whether this product causes thyroid C-cell neoplasms in humans, including medullary thyroid carcinoma (MTC).

One case of MTC was reported in a patient receiving dulaglutide. This patient's pretreatment calcitonin level was approximately 8 times the upper limit of normal (ULN). Postmarketing reports have shown cases of MTC in patients treated with liraglutide, another GLP-1 receptor agonist. The data in these reports are insufficient to establish or exclude a causal relationship between MTC and GLP-1 receptor agonist use in humans.

This product is contraindicated in patients with a personal or family history of MTC or in patients with MEN 2. Inform patients about the potential risk of MTC and symptoms of thyroid tumors (e.g., neck mass, dysphagia, dyspnea, persistent hoarseness).

The value of routine serum calcitonin monitoring or thyroid ultrasound monitoring for early detection of MTC in patients treated with this product is unclear. Such monitoring may increase the risk of unnecessary procedures because of the low specificity of serum calcitonin testing and the 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 undergo further evaluation. Patients with thyroid nodules identified on physical examination or neck imaging should also undergo further evaluation.

Acute Pancreatitis

GLP-1 receptor agonist use is associated with a risk of acute pancreatitis. Acute pancreatitis has been reported in association with dulaglutide in clinical trials (see Adverse Reactions). Patients should be informed and observed that the characteristic symptoms of acute pancreatitis include persistent severe abdominal pain. If pancreatitis is suspected, dulaglutide should be discontinued. If pancreatitis is confirmed, dulaglutide should not be used again. In the absence of other signs and symptoms of acute pancreatitis, elevated pancreatic enzymes alone do not indicate acute pancreatitis (see Adverse Reactions).

Hypoglycemia The combined use of dulaglutide and sulfonylureas may increase the risk of hypoglycemia. The risk of hypoglycemia can be reduced by reducing the dose of sulfonylureas (see Dosage and Administration and Adverse Reactions).

There have been post-marketing reports of serious allergic reactions, including tachyphylaxis and angioedema, in patients receiving dulaglutide (see [Adverse Reactions]). If an allergic reaction occurs, discontinue treatment with dulaglutide; immediately initiate standard treatment and monitor until signs and symptoms subside. Patients with a past allergic reaction to dulaglutide should not use this product (see [Contraindications]).

Other GLP-1 Immediate anaphylactic reactions and angioedema have been reported with agonists. Patients with a history of angioedema or anaphylaxis to another GLP-1 receptor agonist should be used with caution, as it is unknown whether such patients are more likely to develop anaphylactic reactions after treatment with dulaglutide.

Acute kidney injury

Receiving GLP-1. There have been postmarketing reports of acute kidney injury and exacerbation of chronic kidney disease in patients treated with agonists including dulaglutide, which may sometimes require dialysis. Some of these events did not reveal the patient's underlying kidney disease, and most patients experienced nausea, vomiting, diarrhea, or dehydration. Because these reactions can worsen renal function, caution should be used when initiating treatment with or escalating the dose of dulaglutide in patients with renal impairment. Renal function should be monitored in patients with renal impairment who report serious gastrointestinal reactions (see Dosage and Administration).

Others

The sodium content in every 1.5mg of this product is less than 1mmol (23mg), which is basically "sodium-free".

Effects on ability to drive and operate machinery Dulaglutide has no or negligible effects on the ability to drive and operate machinery. When dulaglutide is used in combination with sulfonylureas, patients should be counseled to avoid hypoglycemia while driving and operating machinery. Disposal and Disposal Precautions Any unused pharmaceutical products or waste materials should be disposed of in accordance with local requirements.

Instructions for Use Prefilled pens are for single use only. The instructions for use of the injection pen in the package insert must be followed carefully. Dulaglutide should not be used if particles are present, or if the solution appears turbid and/or discolored. Do not use frozen dulaglutide.

[Storage]

Store in the refrigerator (2ºC-8ºC). Do not freeze. Store in original packaging and protect from light. When in use:

This product can be used at temperatures not exceeding 30ºC Store unrefrigerated at temperatures up to 14 days.