TRIJARDY XR SIDE EFFECTS

SIDE EFFECTS

The following important adverse reactions are described below and elsewhere in the labeling:

• Lactic Acidosis
• Pancreatitis
• Heart Failure
• Hypotension
• Ketoacidosis
• Acute Kidney Injury
• Urosepsis and Pyelonephritis
• Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues
• Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene)
• Genital Mycotic Infections
• Hypersensitivity Reactions
• Vitamin B12 Deficiency
• Severe and Disabling Arthralgia
• Bullous Pemphigoid

Clinical Trials Experience

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

Empagliflozin, Linagliptin And Metformin

The safety of concomitantly administered empagliflozin (daily dose 10 mg or 25 mg), linagliptin (daily dose 5 mg) and metformin has been evaluated in a total of 686 patients with type 2 diabetes treated for up to 52 weeks in an active-controlled clinical trial. The most common adverse reactions are shown in Table 1.

Table 1 : Adverse Reactions Reported in ≥5% of Patients Treated with Empagliflozin, Linagliptin, and Metformin in an Active-Controlled Clinical Trial of 52 Weeks

Hypoglycemia

The incidence of hypoglycemia (defined as plasma or capillary glucose of less than 54 mg/dL) was 0.7% in patients receiving empagliflozin 10 mg/linagliptin 5 mg/metformin and 0.7% in patients receiving empagliflozin 25 mg/linagliptin 5 mg/metformin. Events of severe hypoglycemia (requiring assistance regardless of blood glucose) did not occur in this trial.

Empagliflozin

Adverse reactions that occurred in ≥2% of patients receiving empagliflozin and more commonly than in patients given placebo included (10 mg, 25 mg, and placebo): urinary tract infection (9.3%, 7.6%, and 7.6%), female genital mycotic infections (5.4%, 6.4%, and 1.5%), upper respiratory tract infection (3.1%, 4.0%, and 3.8%), increased urination (3.4%, 3.2%, and 1.0%), dyslipidemia (3.9%, 2.9%, and 3.4%), arthralgia (2.4%, 2.3%, and 2.2%), male genital mycotic infections (3.1%, 1.6%, and 0.4%), and nausea (2.3%, 1.1%, and 1.4%).

Thirst (including polydipsia) was reported in 0%, 1.7%, and 1.5% for placebo, empagliflozin 10 mg, and empagliflozin 25 mg, respectively.

Empagliflozin causes an osmotic diuresis, which may lead to intravascular volume contraction and adverse reactions related to volume depletion. Events related to volume depletion (hypotension and syncope) were reported in 3 patients (1.1%) treated with empagliflozin, linagliptin and metformin combination therapy.

Linagliptin

Adverse reactions reported in ≥2% of patients treated with linagliptin 5 mg and more commonly than in patients treated with placebo, included: nasopharyngitis (7.0% and 6.1%), diarrhea (3.3% and 3.0%), and cough (2.1% and 1.4%).

Other adverse reactions reported in clinical studies with treatment of linagliptin monotherapy were hypersensitivity (e.g., urticaria, angioedema, localized skin exfoliation, or bronchial hyperreactivity) and myalgia.

In the clinical trial program, pancreatitis was reported in 15.2 cases per 10,000 patient-year exposure while being treated with linagliptin, compared with 3.7 cases per 10,000 patient-year exposure while being treated with comparator (placebo and active comparator, sulfonylurea). Three additional cases of pancreatitis were reported following the last administered dose of linagliptin.

Metformin

The most common (>5%) established adverse reactions due to initiation of metformin therapy are diarrhea, nausea/vomiting, flatulence, abdominal discomfort, indigestion, asthenia, and headache.

In a 24-week clinical trial in which extended-release metformin or placebo was added to glyburide therapy, the most common (>5% and greater than placebo) adverse reactions in the combined treatment group were hypoglycemia (13.7% vs 4.9%), diarrhea (12.5% vs 5.6%), and nausea (6.7% vs 4.2%).

Laboratory Tests

Empagliflozin

Increases in Serum Creatinine and Decreases in eGFR: Initiation of empagliflozin causes an increase in serum creatinine and decrease in eGFR. Patients with hypovolemia may be more susceptible to these changes.

Increase in Low-Density Lipoprotein Cholesterol (LDL-C): Dose-related increases in low-density lipoprotein cholesterol (LDL-C) were observed in patients treated with empagliflozin. LDL-C increased by 2.3%, 4.6%, and 6.5% in patients treated with placebo, empagliflozin 10 mg, and empagliflozin 25 mg, respectively. The range of mean baseline LDL-C levels was 90.3 to 90.6 mg/dL across treatment groups.

Increase in Hematocrit: Median hematocrit decreased by 1.3% in placebo and increased by 2.8% in empagliflozin 10 mg and 2.8% in empagliflozin 25 mg-treated patients. At the end of treatment, 0.6%, 2.7%, and 3.5% of patients with hematocrits initially within the reference range had values above the upper limit of the reference range with placebo, empagliflozin 10 mg, and empagliflozin 25 mg, respectively.

Linagliptin

Increase in Uric Acid: Changes in laboratory values that occurred more frequently in the linagliptin group and ≥1% more than in the placebo group were increases in uric acid (1.3% in the placebo group, 2.7% in the linagliptin group).

Increase in Lipase: In a placebo-controlled clinical trial with linagliptin in type 2 diabetes mellitus patients with micro-or macroalbuminuria, a mean increase of 30% in lipase concentrations from baseline to 24 weeks was observed in the linagliptin arm, compared to a mean decrease of 2% in the placebo arm. Lipase levels above 3 times upper limit of normal were seen in 8.2% compared to 1.7% patients in the linagliptin and placebo arms, respectively.

Metformin

Decrease in Vitamin B12: In metformin clinical trials of 29-week duration, a decrease to subnormal levels of previously normal serum vitamin B12 levels was observed in approximately 7% of patients.

Postmarketing Experience

Additional adverse reactions have been identified during postapproval use of linagliptin, empagliflozin, or metformin. Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

• Acute Pancreatitis, including Fatal Pancreatitis
• Ketoacidosis
• Urosepsis and Pyelonephritis
• Necrotizing Fasciitis of the Perineum (Fournier’s gangrene)
• Hypersensitivity Reactions including Anaphylaxis, Angioedema, and Exfoliative Skin Conditions
• Severe and Disabling Arthralgia
• Bullous Pemphigoid
• Skin Reactions (e.g., rash, urticaria)
• Mouth Ulceration, Stomatitis
• Cholestatic, hepatocellular, and mixed hepatocellular liver injury
• Rhabdomyolysis

SRC: NLM .