Tradjenta Side Effects Center

SIDE EFFECTS

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

• Pancreatitis [see WARNINGS AND PRECAUTIONS]
• Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues [see WARNINGS AND PRECAUTIONS]
• Hypersensitivity Reactions [see WARNINGS AND PRECAUTIONS]
• Severe and Disabling Arthralgia [see WARNINGS AND PRECAUTIONS]
• Bullous Pemphigoid [see WARNINGS AND PRECAUTIONS]
• Heart Failure [see WARNINGS AND PRECAUTIONS]

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.

The safety evaluation of TRADJENTA 5 mg once daily in patients with type 2 diabetes is based on 14 placebo-controlled trials, 1 active-controlled study, and one study in patients with severe renal impairment. In the 14 placebo-controlled studies, a total of 3625 patients were randomized and treated with TRADJENTA 5 mg daily and 2176 with placebo. The mean exposure in patients treated with TRADJENTA across studies was 29.6 weeks. The maximum follow-up was 78 weeks.

TRADJENTA 5 mg once daily was studied as monotherapy in three placebo-controlled trials of 18 and 24 weeks' duration and in five additional placebo-controlled studies lasting ≤18 weeks. The use of TRADJENTA in combination with other antihyperglycemic agents was studied in six placebo-controlled trials: two with metformin (12 and 24 weeks' treatment duration); one with a sulfonylurea (18 weeks' treatment duration); one with metformin and sulfonylurea (24 weeks' treatment duration); one with pioglitazone (24 weeks' treatment duration); and one with insulin (primary endpoint at 24 weeks).

In a pooled dataset of 14 placebo-controlled clinical trials, adverse reactions that occurred in ≥2% of patients receiving TRADJENTA (n = 3625) and more commonly than in patients given placebo (n = 2176), are shown in Table 1.

Table 1 : Adverse Reactions Reported in ≥2% of Patients Treated with TRADJENTA and Greater than Placebo in Placebo-Controlled Clinical Studies of TRADJENTA Monotherapy or Combination Therapy

Adverse Reactions	TRADJENTA 5 mg (%) n = 3625	Placebo (%) n = 2176
Nasopharyngitis	7.0	6.1
Diarrhea	3.3	3.0
Cough	2.1	1.4

Rates for other adverse reactions for TRADJENTA 5 mg vs placebo when TRADJENTA was used in combination with specific antidiabetic agents were: urinary tract infection (3.1% vs 0%) and hypertriglyceridemia (2.4% vs 0%) when TRADJENTA was used as add-on to sulfonylurea; hyperlipidemia (2.7% vs 0.8%) and weight increased (2.3% vs 0.8%) when TRADJENTA was used as add-on to pioglitazone; and constipation (2.1% vs 1%) when TRADJENTA was used as add-on to basal insulin therapy. Other adverse reactions reported in clinical studies with treatment of TRADJENTA were hypersensitivity (e.g., urticaria, angioedema, localized skin exfoliation, or bronchial hyperreactivity) and myalgia.

Following 104 weeks' treatment in a controlled study comparing TRADJENTA with glimepiride in which all patients were also receiving metformin, adverse reactions reported in ≥5% of patients treated with TRADJENTA (n = 776) and more frequently than in patients treated with a sulfonylurea (n = 775) were back pain (9.1% vs 8.4%), arthralgia (8.1% vs 6.1%), upper respiratory tract infection (8.0% vs 7.6%), headache (6.4% vs 5.2%), cough (6.1% vs 4.9%), and pain in extremity (5.3% vs 3.9%).

In the clinical trial program, pancreatitis was reported in 15.2 cases per 10,000 patient year exposure while being treated with TRADJENTA 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.

Hypoglycemia

Table 2 summarizes the incidence of hypoglycemia in placebo-controlled studies of TRADJENTA. The incidence of hypoglycemia increased when TRADJENTA was administered with sulfonylurea or insulin.

Table 2: Incidence (%) of Hypoglycemia in Placebo-Controlled Clinical Studies of TRADJENTA in Patients with Type 2 Diabetes Mellitus

Add-on to Sulfonylurea (18 Weeks)	Placebo (N=84)	TRADJENTA (N=161)
Hypoglycemia with plasma glucose <54 mg/dL (%)	1.2	1.9
Severe* hypoglycemia (%)	0	0
Add-on to Metformin and Sulfonylurea (24 Weeks)	Placebo (N=263)	TRADJENTA (N=792)
Hypoglycemia with plasma glucose <54 mg/dL (%)	5.3	8.1
Severe* hypoglycemia (%)	0.8	0.6
Add-on to Basal Insulin (52 Weeks)	Placebo (N=630)	TRADJENTA (N=631)
Hypoglycemia with plasma glucose <54 mg/dL (%)	21.6	19.8
Severe* hypoglycemia (%)	1.1	1.7
*Hypoglycemia requiring assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions.

In an active-controlled (glimepiride) cardiovascular safety study with TRADJENTA (CAROLINA) with median time on treatment of 5.9 years, the incidence of severe hypoglycemia was 0.3% in the TRADJENTA group (N=3014) and 2.2% in glimepiride group (N=3000).

Use In Renal Impairment

TRADJENTA was compared to placebo as add-on to pre-existing antidiabetic therapy over 52 weeks in 133 patients with severe renal impairment (estimated GFR <30 mL/min). For the initial 12 weeks of the study, background antidiabetic therapy was kept stable and included insulin, sulfonylurea, glinides, and pioglitazone. For the remainder of the trial, dose adjustments in antidiabetic background therapy were allowed. In general, the incidence of adverse events including severe hypoglycemia was similar to those reported in other TRADJENTA trials. The observed incidence of hypoglycemia was higher (TRADJENTA, 63% compared to placebo, 49%) due to an increase in asymptomatic hypoglycemic events especially during the first 12 weeks when background glycemic therapies were kept stable. Ten TRADJENTA-treated patients (15%) and 11 placebo-treated patients (17%) reported at least one episode of confirmed symptomatic hypoglycemia (accompanying finger stick glucose ≤54 mg/dL). During the same time period, severe hypoglycemic events, defined as an event requiring the assistance of another person to actively administer carbohydrate, glucagon or other resuscitative actions, were reported in 3 (4.4%) TRADJENTA-treated patients and 3 (4.6%) placebo-treated patients. Events that were considered life-threatening or required hospitalization were reported in 2 (2.9%) patients on TRADJENTA and 1 (1.5%) patient on placebo.

Renal function as measured by mean eGFR and creatinine clearance did not change over 52 weeks' treatment compared to placebo.

Laboratory Tests

Changes in laboratory findings were similar in patients treated with TRADJENTA 5 mg compared to patients treated with placebo.

Increase In Uric Acid

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

Increase In Lipase

In a placebo-controlled clinical trial with TRADJENTA 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 TRADJENTA 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 TRADJENTA and placebo arms, respectively.

Increase In Amylase

In a cardiovascular safety study comparing TRADJENTA versus glimepiride in patients with type 2 diabetes mellitus, amylase levels above 3 times upper limit of normal were seen in 1.0% compared to 0.5% of patients in the TRADJENTA and glimepiride arms, respectively.

The clinical significance of elevations in lipase and amylase with TRADJENTA is unknown in the absence of potential signs and symptoms of pancreatitis [see WARNINGS AND PRECAUTIONS].

Vital Signs

No clinically meaningful changes in vital signs were observed in patients treated with TRADJENTA.

Postmarketing Experience

Additional adverse reactions have been identified during postapproval use of TRADJENTA. 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 [see INDICATIONS AND USAGE]
• Hypersensitivity reactions including anaphylaxis, angioedema, and exfoliative skin conditions
• Severe and disabling arthralgia
• Bullous pemphigoid
• Rash
• Mouth ulceration, stomatitis
• Rhabdomyolysis

DRUG INTERACTIONS

Inducers Of P-glycoprotein Or CYP3A4 Enzymes

Rifampin decreased linagliptin exposure, suggesting that the efficacy of TRADJENTA may be reduced when administered in combination with a strong P-gp or CYP3A4 inducer. Therefore, use of alternative treatments is strongly recommended when linagliptin is to be administered with a strong P-gp or CYP3A4 inducer [see CLINICAL PHARMACOLOGY].

Insulin Secretagogues Or Insulin

The risk of hypoglycemia is increased when linagliptin is used in combination with an insulin secretagogue (e.g., sulfonylurea) or insulin. Coadministration of TRADJENTA with an insulin secretagogue (e.g., sulfonylurea) or insulin may require lower doses of the insulin secretagogue or insulin to reduce the risk of hypoglycemia [see WARNINGS AND PRECAUTIONS].

Read the entire FDA prescribing information for Tradjenta (Linagliptin)