Side Effects of Januvia (sitagliptin)

Januvia (sitagliptin) is a DPP-4 inhibitor used in combination with exercise and diet to improve blood glucose levels in individuals with type 2 diabetes.

Following a meal, incretin hormones such as glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are released from the intestine, and their levels increase in the blood.

• GLP-1 and GIP reduce blood glucose by increasing the production and release of insulin from the pancreas.
• GLP-1 also reduces blood glucose by reducing the secretion by the pancreas of the hormone, glucagon, a hormone that increases the production of glucose by the liver and raises the blood level of glucose.
• The net effect of increased release of GLP-1 and GIP is to reduce blood glucose levels. Januvia inhibits the enzyme, DPP-4, that destroys GLP-1 and GIP and increases the levels and activity of both hormones.
• As a result, blood glucose levels fall. Januvia should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.

Common side effects of Januvia include:

• upper respiratory tract infection,
• headache,
• abdominal pain,
• nausea, and
• diarrhea.

Serious side effects of Januvia include:

• acute pancreatitis,
• acute renal failure,
• increased risk of low blood sugar (hypoglycemia), and
• serious allergic and hypersensitivity reactions. 

Drug interactions of Januvia include digoxin, because Januvia may slightly increase the concentration of digoxin in the body.

The occurrence of low blood glucose increases when Januvia is combined with a sulfonylurea (for example, glyburide [Micronase, Diabeta, Glynase, Prestab]) or insulin.

There are no adequate studies of Januvia in pregnant women. It is unknown if Januvia passes into breast milk. Consult your doctor before breastfeeding.

WARNING

• There have been postmarketing reports of acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis. If pancreatitis is suspected, promptly discontinue sitagliptin.
• There have been postmarketing reports of acute renal failure, sometimes requiring dialysis. Dosage adjustment is recommended in patients with moderate or severe renal insufficiency and in patients with ESRD. Assessment of renal function is recommended prior to initiating sitagliptin and periodically thereafter.
• There is an increased risk of hypoglycemia when sitagliptin is added to an insulin secretagogue (e.g., sulfonylurea) or insulin therapy. Consider lowering the dose of the sulfonylurea or insulin to reduce the risk of hypoglycemia.
• There have been postmarketing reports of serious allergic and hypersensitivity reactions in patients treated with sitagliptin such as anaphylaxis, angioedema, and exfoliative skin conditions including Stevens-Johnson syndrome. In such cases, promptly stop sitagliptin, assess for other potential causes, institute appropriate monitoring and treatment, and initiate alternative treatment for diabetes.
• There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with sitagliptin or any other anti-diabetic drug.

Common side effects

The most common side effects of sitagliptin are:

• upper respiratory tract infection and
• headache.

Other important side effects of sitagliptin include:

• abdominal pain,
• nausea and
• diarrhea.

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.
• In controlled clinical studies as both monotherapy and combination therapy with metformin, pioglitazone, or rosiglitazone and metformin, the overall incidence of adverse reactions, hypoglycemia, and discontinuation of therapy due to clinical adverse reactions with Januvia were similar to placebo.
• In combination with glimepiride, with or without metformin, the overall incidence of clinical adverse reactions with Januvia was higher than with placebo, in part related to a higher incidence of hypoglycemia (see Table 3); the incidence of discontinuation due to clinical adverse reactions was similar to placebo.
• Two placebo-controlled monotherapy studies, one of 18-and one of 24-week duration, included patients treated with Januvia 100 mg daily, Januvia 200 mg daily, and placebo. Five placebo-controlled add-on combination therapy studies were also conducted: one with metformin; one with pioglitazone; one with metformin and rosiglitazone; one with glimepiride (with or without metformin); and one with insulin (with or without metformin).
• In these trials, patients with inadequate glycemic control on a stable dose of the background therapy were randomized to add-on therapy with Januvia 100 mg daily or placebo.
• The adverse reactions, excluding hypoglycemia, reported regardless of investigator assessment of causality in ≥5% of patients treated with Januvia 100 mg daily and more commonly than in patients treated with placebo, are shown in Table 1 for the clinical trials of at least 18 weeks duration. Incidences of hypoglycemia are shown in Table 3.

Table 1: Placebo-Controlled Clinical Studies of Januvia Monotherapy or Add-on Combination Therapy with Pioglitazone, Metformin + Rosiglitazone, or Glimepiride +/-Metformin: Adverse Reactions (Excluding Hypoglycemia) Reported in ≥5% of Patients and More Commonly than in Patients Given Placebo, Regardless of Investigator Assessment of Causality*

• In the 24-week study of patients receiving Januvia as add-on combination therapy with metformin, there were no adverse reactions reported regardless of investigator assessment of causality in ≥5% of patients and more commonly than in patients given placebo.
• In the 24-week study of patients receiving Januvia as add-on therapy to insulin (with or without metformin), there were no adverse reactions reported regardless of investigator assessment of causality in ≥5% of patients and more commonly than in patients given placebo, except for hypoglycemia (see Table 3).
• In the study of Januvia as add-on combination therapy with metformin and rosiglitazone (Table 1), through Week 54 the adverse reactions reported regardless of investigator assessment of causality in ≥5% of patients treated with Januvia and more commonly than in patients treated with placebo were: upper respiratory tract infection (Januvia, 15.5%; placebo, 6.2%), nasopharyngitis (11.0%, 9.3%), peripheral edema (8.3%, 5.2%), and headache (5.5%, 4.1%).
• In a pooled analysis of the two monotherapy studies, the add-on to metformin study, and the add-on to pioglitazone study, the incidence of selected gastrointestinal adverse reactions in patients treated with Januvia was as follows: abdominal pain (Januvia 100 mg, 2.3%; placebo, 2.1%), nausea (1.4%, 0.6%), and diarrhea (3.0%, 2.3%).
• In an additional, 24-week, placebo-controlled factorial study of initial therapy with sitagliptin in combination with metformin, the adverse reactions reported (regardless of investigator assessment of causality) in ≥5% of patients are shown in Table 2.

Table 2: Initial Therapy with Combination of Sitagliptin and Metformin: Adverse Reactions Reported (Regardless of Investigator Assessment of Causality) in ≥5% of Patients Receiving Combination Therapy (and Greater than in Patients Receiving Metformin alone, Sitagliptin alone, and Placebo)*

• In a 24-week study of initial therapy with Januvia in combination with pioglitazone, there were no adverse reactions reported (regardless of investigator assessment of causality) in ≥5% of patients and more commonly than in patients given pioglitazone alone.
• No clinically meaningful changes in vital signs or in ECG (including in QTc interval) were observed in patients treated with Januvia.
• In a pooled analysis of 19 double-blind clinical trials that included data from 10,246 patients randomized to receive sitagliptin 100 mg/day (N=5429) or corresponding (active or placebo) control (N=4817), the incidence of acute pancreatitis was 0.1 per 100 patient-years in each group (4 patients with an event in 4708 patient-years for sitagliptin and 4 patients with an event in 3942 patient-years for control).

Hypoglycemia

• In the above studies (N=9), adverse reactions of hypoglycemia were based on all reports of symptomatic hypoglycemia.
• A concurrent blood glucose measurement was not required although most (74%) reports of hypoglycemia were accompanied by a blood glucose measurement ≤70 mg/dL.
• When Januvia was coadministered with a sulfonylurea or with insulin, the percentage of patients with at least one adverse reaction of hypoglycemia was higher than in the corresponding placebo group (Table 3).

Table 3: Incidence and Rate of Hypoglycemia* in Placebo-Controlled Clinical Studies when Januvia was used as Add-On Therapy to Glimepiride (with or without Metformin) or Insulin (with or without Metformin), Regardless of Investigator Assessment of Causality

• In a pooled analysis of the two monotherapy studies, the add-on to metformin study, and the add-on to pioglitazone study, the overall incidence of adverse reactions of hypoglycemia was 1.2% in patients treated with Januvia 100 mg and 0.9% in patients treated with placebo.
• In the study of Januvia as add-on combination therapy with metformin and rosiglitazone, the overall incidence of hypoglycemia was 2.2% in patients given add-on Januvia and 0.0% in patients given add-on placebo through Week 18. Through Week 54, the overall incidence of hypoglycemia was 3.9% in patients given add-on Januvia and 1.0% in patients given add-on placebo.
• In the 24-week, placebo-controlled factorial study of initial therapy with Januvia in combination with metformin, the incidence of hypoglycemia was 0.6% in patients given placebo, 0.6% in patients given Januvia alone, 0.8% in patients given metformin alone, and 1.6% in patients given Januvia in combination with metformin.
• In the study of Januvia as initial therapy with pioglitazone, one patient taking Januvia experienced a severe episode of hypoglycemia. There were no severe hypoglycemia episodes reported in other studies except in the study involving coadministration with insulin.
• In an additional, 30-week placebo-controlled, study of patients with type 2 diabetes inadequately controlled with metformin comparing the maintenance of sitagliptin 100 mg versus withdrawal of sitagliptin when initiating basal insulin therapy, the event rate and incidence of documented symptomatic hypoglycemia (blood glucose measurement ≤70 mg/dL) did not differ between the sitagliptin and placebo groups.

Laboratory Tests

• Across clinical studies, the incidence of laboratory adverse reactions was similar in patients treated with Januvia 100 mg compared to patients treated with placebo.
• A small increase in white blood cell count (WBC) was observed due to an increase in neutrophils. This increase in WBC (of approximately 200 cells/microL vs placebo, in four pooled placebo-controlled clinical studies, with a mean baseline WBC count of approximately 6600 cells/microL) is not considered to be clinically relevant.
• In a 12-week study of 91 patients with chronic renal insufficiency, 37 patients with moderate renal insufficiency were randomized to Januvia 50 mg daily, while 14 patients with the same magnitude of renal impairment were randomized to placebo. Mean (SE) increases in serum creatinine were observed in patients treated with Januvia [0.12 mg/dL (0.04)] and in patients treated with placebo [0.07 mg/dL (0.07)].
• The clinical significance of this added increase in serum creatinine relative to placebo is not known.

Postmarketing Experience

• Additional adverse reactions have been identified during postapproval use of Januvia as monotherapy and/or in combination with other antihyperglycemic agents.
• 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.
• Hypersensitivity reactions including
  • anaphylaxis,
  • angioedema,
  • rash,
  • urticaria,
  • cutaneous vasculitis, and
  • exfoliative skin conditions including
    • Stevens-Johnson syndrome;
    • hepatic enzyme elevations;
    • acute pancreatitis, including fatal and non-fatal hemorrhagic and necrotizing pancreatitis;
    • worsening renal function, including acute renal failure (sometimes requiring dialysis);
    • severe and disabling arthralgia;
    • bullous pemphigoid;
    • constipation;
    • vomiting;
    • headache;
    • myalgia;
    • pain in extremity;
    • back pain;
    • pruritus;
    • mouth ulceration;
    • stomatitis;
    • rhabdomyolysis.

Digoxin

• There was a slight increase in the area under the curve (AUC, 11%) and mean peak drug concentration (Cmax, 18%) of digoxin with the coadministration of 100 mg sitagliptin for 10 days.
• Patients receiving digoxin should be monitored appropriately.
• No dosage adjustment of digoxin or Januvia is recommended.

Insulin Secretagogues Or Insulin

• Coadministration of Januvia 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.