Trulicity (Page 2 of 7)

5.4 Hypersensitivity Reactions

There have been postmarketing reports of serious hypersensitivity reactions including anaphylactic reactions and angioedema in patients treated with TRULICITY [see Adverse Reactions (6.3)]. If a hypersensitivity reaction occurs, discontinue TRULICITY; treat promptly per standard of care, and monitor until signs and symptoms resolve. Do not use in patients with a previous hypersensitivity reaction to TRULICITY [see Contraindications (4)].

Anaphylaxis and angioedema have been reported with other GLP-1 receptor agonists. Use caution in a patient with a history of angioedema or anaphylaxis with another GLP-1 receptor agonist because it is unknown whether such patients will be predisposed to anaphylaxis with TRULICITY.

5.5 Acute Kidney Injury

In patients treated with GLP-1 receptor agonists, including TRULICITY, there have been postmarketing reports of acute renal failure and worsening of chronic renal failure, which may sometimes require hemodialysis. Some of these events were reported in patients without known underlying renal disease. A majority of reported events occurred in patients who had experienced nausea, vomiting, diarrhea, or dehydration. Because these reactions may worsen renal function, use caution when initiating or escalating doses of TRULICITY in patients with renal impairment. Monitor renal function in patients with renal impairment reporting severe adverse gastrointestinal reactions [see Use in Specific Populations (8.6)].

5.6 Severe Gastrointestinal Disease

Use of TRULICITY may be associated with gastrointestinal adverse reactions, sometimes severe [see Adverse Reactions (6.1)]. TRULICITY has not been studied in patients with severe gastrointestinal disease, including severe gastroparesis, and is therefore not recommended in these patients.

5.7 Diabetic Retinopathy Complications in Patients with a History of Diabetic Retinopathy

In a cardiovascular outcomes trial with a median follow up of 5.4 years involving patients with type 2 diabetes with established cardiovascular disease or multiple cardiovascular risk factors, diabetic retinopathy complications occurred in patients treated with TRULICITY 1.5 mg (1.9%) and placebo (1.5%). These events were prospectively ascertained as a secondary composite endpoint. The proportion of patients with diabetic retinopathy complications was larger among patients with a history of diabetic retinopathy at baseline (TRULICITY 8.5%, placebo 6.2%) than among patients without a known history of diabetic retinopathy (TRULICITY 1%, placebo 1%).

Rapid improvement in glucose control has been associated with a temporary worsening of diabetic retinopathy. Patients with a history of diabetic retinopathy should be monitored for progression of diabetic retinopathy.

6 ADVERSE REACTIONS

The following serious reactions are described below or elsewhere in the prescribing information:

  • Risk of Thyroid C-cell Tumors [see Warnings and Precautions (5.1)]
  • Pancreatitis [see Warnings and Precautions (5.2)]
  • Hypoglycemia with Concomitant Use of Insulin Secretagogues or Insulin [see Warnings and Precautions (5.3)]
  • Hypersensitivity Reactions [see Warnings and Precautions (5.4)]
  • Acute Kidney Injury [see Warnings and Precautions (5.5)]
  • Severe Gastrointestinal Disease [see Warnings and Precautions (5.6)]
  • Diabetic Retinopathy Complications in Patients with a History of Diabetic Retinopathy [see Warnings and Precautions (5.7)]

6.1 Clinical Studies Experience

Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.

Pool of Placebo-controlled Trials for TRULICITY 0.75 mg and 1.5 mg Doses

The data in Table 1 are derived from a pool of placebo-controlled trials and include 1670 patients exposed to TRULICITY with a mean duration of exposure of 23.8 weeks [see Clinical Studies (14)]. The mean age of patients was 56 years, 1% were 75 years or older and 53% were male. The population was 69% White, 7% Black or African American, 13% Asian; 30% were of Hispanic or Latino ethnicity. At baseline, the population had diabetes for an average of 8 years, a mean HbA1c of 8.0%, and 2.5% of the population reported retinopathy. Baseline estimated renal function was normal or mildly impaired (eGFR ≥60 mL/min/1.73 m2) in 96%.

Table 1 shows adverse reactions, excluding hypoglycemia, occurring in ≥5% of TRULICITY treated patients and more commonly than placebo in a pool of placebo-controlled trials.

Table 1: Adverse Reactions in Pool of Placebo-Controlled Trials Occurring in ≥5% of TRULICITY-Treated Patients

a Includes diarrhea, fecal volume increased, frequent bowel movements.

b Includes retching, vomiting, vomiting projectile.

c Includes abdominal discomfort, abdominal pain, abdominal pain lower, abdominal pain upper, abdominal tenderness, gastrointestinal pain.

d Includes fatigue, asthenia, malaise.

Note: Percentages reflect the number of patients that reported at least 1 treatment-emergent occurrence of the adverse reaction.

Adverse Reaction Placebo (N=568) % TRULICITY 0.75 mg (N=836) % TRULICITY 1.5 mg (N=834) %
Nausea 5.3 12.4 21.1
Diarrheaa 6.7 8.9 12.6
Vomitingb 2.3 6.0 12.7
Abdominal Painc 4.9 6.5 9.4
Decreased Appetite 1.6 4.9 8.6
Dyspepsia 2.3 4.1 5.8
Fatigued 2.6 4.2 5.6

Gastrointestinal Adverse Reactions

In the pool of placebo-controlled trials, gastrointestinal adverse reactions occurred more frequently among patients receiving TRULICITY than placebo (placebo 21.3%, 0.75 mg 31.6%, 1.5 mg 41.0%). More patients receiving TRULICITY 0.75 mg (1.3%) and TRULICITY 1.5 mg (3.5%) discontinued treatment due to gastrointestinal adverse reactions than patients receiving placebo (0.2%). Investigators graded the severity of gastrointestinal adverse reactions occurring on 0.75 mg and 1.5 mg of TRULICITY as “mild” in 58% and 48% of cases, respectively, “moderate” in 35% and 42% of cases, respectively, or “severe” in 7% and 11% of cases, respectively.

The following adverse reactions were reported more frequently in TRULICITY-treated patients than placebo (frequencies listed, respectively, as: placebo; 0.75 mg; 1.5 mg): constipation (0.7%, 3.9%, 3.7%), flatulence (1.4%, 1.4%, 3.4%), abdominal distension (0.7%, 2.9%, 2.3%), gastroesophageal reflux disease (0.5%, 1.7%, 2.0%), and eructation (0.2%, 0.6%, 1.6%).

TRULICITY 3 mg and 4.5 mg Doses

Table 2 shows adverse reactions occurring ≥5% in any of the treatment groups through 36 weeks in a clinical trial with 1842 patients treated with Trulicity 1.5 mg, 3 mg, or 4.5 mg once weekly as an add-on to metformin. The adverse reaction profile is consistent with previous clinical trials.

Table 2: Adverse Reactions Occurring in ≥5% of Patients Receiving TRULICITY 1.5 mg, 3 mg, or 4.5 mg in a Clinical Trial through 36 Weeksa

a Percentages reflect the number of patients that reported at least 1 treatment-emergent occurrence of the adverse reaction.

Adverse Reaction TRULICITY 1.5 mg (N=612) % TRULICITY 3 mg (N=616) % TRULICITY 4.5 mg (N=614) %
Nausea 13.4 15.6 16.4
Diarrhea 7.0 11.4 10.7
Vomiting 5.6 8.3 9.3
Dyspepsia 2.8 5.0 2.6

Other Adverse Reactions

Hypoglycemia

Table 3 summarizes the incidence of hypoglycemia in the placebo-controlled clinical studies: episodes with a glucose level <54 mg/dL with or without symptoms, and severe hypoglycemia, defined as an episode requiring the assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions.

Table 3: Incidence (%) of Hypoglycemia in Placebo-Controlled Trials
Placebo TRULICITY 0.75 mg TRULICITY 1.5 mg
Add-on to Metformin
(26 weeks) N=177 N=302 N=304
Hypoglycemia with a glucose level <54 mg/dL 0 0.3 0.7
Severe hypoglycemia 0 0 0
Add-on to Metformin + Pioglitazone
(26 weeks) N=141 N=280 N=279
Hypoglycemia with a glucose level <54 mg/dL 1.4 2.1 0
Severe hypoglycemia 0 0 0
Add-on to Glimepiride
(24 weeks) N=60 N=239
Hypoglycemia with a glucose level <54 mg/dL 0 3.3
Severe hypoglycemia 0 0
In Combination with Insulin Glargine ± Metformin
(28 weeks) N=150 N=150
Hypoglycemia with a glucose level <54 mg/dL 9.3 14.7
Severe hypoglycemia 0 0.7
Add-on to SGLT2i ± Metformin
(24 weeks) N=140 N=141 N=142
Hypoglycemia with a glucose level <54 mg/dL 0.7 0.7 0.7
Severe hypoglycemia 0 0.7 0

Hypoglycemia was more frequent when TRULICITY was used in combination with a sulfonylurea or insulin than when used with non-secretagogues. In a 78-week clinical trial, hypoglycemia (glucose level <54 mg/dL) occurred in 20% and 21% of patients when TRULICITY 0.75 mg and 1.5 mg, respectively, were co-administered with a sulfonylurea. Severe hypoglycemia occurred in 0% and 0.7% of patients when TRULICITY 0.75 mg and 1.5 mg, respectively, were co-administered with a sulfonylurea. In a 52-week clinical trial, hypoglycemia (glucose level <54 mg/dL) occurred in 77% and 69% of patients when TRULICITY 0.75 mg and 1.5 mg, respectively, were co-administered with prandial insulin. Severe hypoglycemia occurred in 2.7% and 3.4% of patients when TRULICITY 0.75 mg and 1.5 mg, respectively, were co-administered with prandial insulin. Refer to Table 3 for the incidence of hypoglycemia in patients treated in combination with basal insulin glargine.

In the clinical trial with patients on TRULICITY 1.5 mg, TRULICITY 3 mg, or TRULICITY 4.5 mg once weekly, as add-on to metformin, incidences of hypoglycemia (glucose level <54 mg/dL) through 36 weeks were 1.1%, 0.3%, and 1.1%, respectively, and incidences of severe hypoglycemia were 0.2%, 0%, and 0.2%, respectively.

Cholelithiasis and Cholecystitis

In a cardiovascular outcomes trial with a median follow up of 5.4 years, cholelithiasis occurred at a rate of 0.62/100 patient-years in TRULICITY-treated patients and 0.56/100 patient-years in placebo-treated patients after adjusting for prior cholecystectomy. Serious events of acute cholecystitis were reported in 0.5% and 0.3% of patients on TRULICITY and placebo respectively.

Heart Rate Increase and Tachycardia-Related Adverse Reactions

TRULICITY 0.75 mg and 1.5 mg resulted in a mean increase in heart rate (HR) of 2-4 beats per minute (bpm).

Adverse reactions of sinus tachycardia were reported more frequently in patients exposed to TRULICITY. Sinus tachycardia was reported in 3.0%, 2.8%, and 5.6% of patients treated with placebo, TRULICITY 0.75 mg and TRULICITY 1.5 mg, respectively. Persistence of sinus tachycardia (reported at more than 2 visits) was reported in 0.2%, 0.4% and 1.6% of patients treated with placebo, TRULICITY 0.75 mg and TRULICITY 1.5 mg, respectively. Episodes of sinus tachycardia, associated with a concomitant increase from baseline in heart rate of ≥15 beats per minute, were reported in 0.7%, 1.3% and 2.2% of patients treated with placebo, TRULICITY 0.75 mg and TRULICITY 1.5 mg, respectively.

Hypersensitivity

Systemic hypersensitivity adverse reactions, sometimes severe (e.g., severe urticaria, systemic rash, facial edema, lip swelling), occurred in 0.5% of patients on TRULICITY in clinical studies.

Injection-site Reactions

In the placebo-controlled studies, injection-site reactions (e.g., injection-site rash, erythema) were reported in 0.5% of TRULICITY-treated patients and in 0.0% of placebo-treated patients.

PR Interval Prolongation and Adverse Reactions of First-Degree Atrioventricular (AV) Block

A mean increase from baseline in PR interval of 2-3 milliseconds was observed in TRULICITY-treated patients in contrast to a mean decrease of 0.9 milliseconds in placebo-treated patients. The adverse reaction of first-degree AV block occurred more frequently in patients treated with TRULICITY than placebo (0.9%, 1.7% and 2.3% for placebo, TRULICITY 0.75 mg and TRULICITY 1.5 mg, respectively). On electrocardiograms, a PR interval increase to at least 220 milliseconds was observed in 0.7%, 2.5% and 3.2% of patients treated with placebo, TRULICITY 0.75 mg and TRULICITY 1.5 mg, respectively.

Amylase and Lipase Increase

Patients exposed to TRULICITY had mean increases from baseline in lipase and/or pancreatic amylase of 14% to 20%, while placebo-treated patients had mean increases of up to 3%.

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