Side Effects of Janumet (metformin and sitagliptin)

Janumet (metformin and sitagliptin) is a combination of drugs used to reduce blood glucose (sugar) levels in individuals with type 2 diabetes.

Insulin is a hormone produced by the pancreas. It limits blood glucose levels by reducing the amount of glucose released by the liver into the blood and by increasing the removal of glucose from blood by muscle and fat tissues.

Type 2 diabetes results when there is reduced sensitivity of muscle and fat to the effects of insulin. When the diabetes progresses, the pancreas produces less insulin. Both defects result in increased levels of glucose in the blood. Metformin is an oral medication that lowers blood glucose by increasing the sensitivity of liver, muscle, fat, and other tissues to the effects of insulin.

Increasing the sensitivity of tissues to insulin causes more glucose to be removed from blood and thereby reduces the level of glucose in the blood. In scientific studies, metformin reduced the complications of diabetes such as

• heart disease,
• blindness and
• kidney disease.

Sitagliptin reduces blood glucose levels in patients 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 glucagon, a hormone that increases the production of glucose by the liver and raises the level of glucose in the blood.

The net effect of increased release of GLP-1 and GIP is to reduce blood glucose levels. In addition, sitagliptin inhibits the enzyme, dipeptidyl peptidase-4 (DPP-4) that destroys GLP-1 and GIP and thereby increases the levels and activity of both hormones and thereby the release of insulin. As a result, blood glucose levels fall.

Common side effects of Janumet include

• stomach upset,
• nausea,
• vomiting,
• constipation,
• diarrhea,
• headache,
• weakness,
• back pain,
• joint or muscle pain,
• metallic taste in the mouth,
• vitamin B12 deficiency, and
• cold symptoms such as
  • runny or stuffy nose,
  • sneezing, and
  • sore throat.

Serious side effects of Janumet include

• lactic acidosis. Symptoms include
  • weakness,
  • trouble breathing,
  • abnormal heartbeats,
  • unusual muscle pain,
  • stomach discomfort,
  • lightheadedness, and
  • feeling cold.

Drug interactions of Janumet include cimetidine, because it decreases the elimination of metformin from the body, which can increase the amount of metformin in the blood by 40%, which may increase the frequency of side effects from metformin.

There are no adequate studies of Janumet or the individual components in pregnant women. Most experts agree insulin is the appropriate treatment for diabetes during pregnancy.

It is unknown if sitagliptin is secreted in human breast milk. However, metformin is excreted into breast milk and can therefore be transferred to the nursing infant. Consult your doctor before breastfeeding.

WARNING

Lactic acidosis is a serious side effect of metformin that occurs in one out of every 30,000 patients and is fatal in 50% of cases. The symptoms of lactic acidosis are

• weakness,
• trouble breathing,
• abnormal heartbeats,
• unusual muscle pain,
• stomach discomfort,
• light-headedness and
• feeling cold.

Patients at risk for lactic acidosis include those with

• reduced function of the kidneys or liver,
• congestive heart failure,
• severe acute illnesses, and
• dehydration.

Janumet should be discontinued immediately if lactic acidosis is suspected.

Common Side Effects

• There have been postmarketing reports of acute pancreatitis,  including fatal and non-fatal hemorrhagic or necrotizing pancreatitis. If pancreatitis is suspected, promptly discontinue Janumet.
• Heart failure has been observed with two other members of the DPP-4 inhibitor class. Consider risks and benefits of Janumet in patients who have known risk factors for heart failure. Monitor patients for signs and symptoms.
• There have been postmarketing reports of acute renal failure,
• sometimes requiring dialysis. Before initiating Janumet and at
• least annually thereafter, assess renal function.
• Vitamin B12 deficiency: Metformin may lower Vitamin B12 levels. Measure hematologic parameters annually. When used with an insulin secretagogue (e.g., sulfonylurea) or with insulin, a lower dose of the insulin secretagogue or insulin may be required to reduce the risk of hypoglycemia.
• There have been postmarketing reports of serious allergic and hypersensitivity reactions in patients treated with sitagliptin (one of the components of Janumet), such as anaphylaxis, angioedema, and exfoliative skin conditions including Stevens-Johnson syndrome. In such cases, promptly stop Janumet, assess for other potential causes, institute appropriate monitoring and treatment, and initiate alternative treatment for diabetes.
• Severe and disabling arthralgia has been reported in patients taking DPP-4 inhibitors. Consider as a possible cause for severe joint pain and discontinue drug if appropriate.
• There have been postmarketing reports of bullous pemphigoid requiring hospitalization in patients taking DPP-4 inhibitors. Tell patients to report development of blisters or erosions. If bullous pemphigoid is suspected, discontinue Janumet.

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.

Sitagliptin And Metformin Immediate-Release Coadministration In Patients With Type 2 Diabetes Inadequately Controlled On Diet and Exercise

Table 1 summarizes the most common (≥5% of patients) adverse reactions reported (regardless of investigator assessment of causality) in a 24-week placebo-controlled factorial study in which sitagliptin and metformin immediate-release were coadministered to patients with type 2 diabetes inadequately controlled on diet and exercise.

Table 1: Sitagliptin and Metformin Immediate-Release Coadministered to Patients with Type 2 Diabetes Inadequately Controlled on Diet and Exercise: Adverse Reactions Reported (Regardless of Investigator Assessment of Causality) in ≥5% of Patients Receiving Combination Therapy (and Greater than in Patients Receiving Placebo)*

Sitagliptin Add-on Therapy In Patients With Type 2 Diabetes Inadequately Controlled On Metformin Immediate-Release Alone

In a 24-week placebo-controlled trial of sitagliptin 100 mg administered once daily added to a twice daily metformin immediate-release regimen, there were no adverse reactions reported regardless of investigator assessment of causality in ≥5% of patients and more commonly than in patients given placebo. Discontinuation of therapy due to clinical adverse reactions was similar to the placebo treatment group (sitagliptin and metformin immediate-release, 1.9%; placebo and metformin immediate-release, 2.5%).

Gastrointestinal Adverse Reactions

The incidences of pre-selected gastrointestinal adverse experiences in patients treated with sitagliptin and metformin immediate-release were similar to those reported for patients treated with metformin immediate-release alone. See Table 2.

Table 2: Pre-selected Gastrointestinal Adverse Reactions (Regardless of Investigator Assessment of Causality) Reported in Patients with Type 2 Diabetes Receiving Sitagliptin and Metformin Immediate-Release

Sitagliptin In Combination With Metformin Immediate-Release And Glimepiride

• In a 24-week placebo-controlled study of sitagliptin 100 mg as add-on therapy in patients with type 2 diabetes inadequately controlled on metformin immediate-release and glimepiride (sitagliptin, N=116; placebo, N=113), the adverse reactions reported regardless of investigator assessment of causality in ≥5% of patients treated with sitagliptin and more commonly than in patients treated with placebo were:
  • hypoglycemia (Table 3) and
  • headache (6.9%, 2.7%).

Sitagliptin In Combination With Metformin Immediate-Release And Rosiglitazone

• In a placebo-controlled study of sitagliptin 100 mg as add-on therapy in patients with type 2 diabetes inadequately controlled on metformin immediate-release and rosiglitazone (sitagliptin, N=181; placebo, N=97), the adverse reactions reported regardless of investigator assessment of causality through Week 18 in ≥5% of patients treated with sitagliptin and more commonly than in patients treated with placebo were:
  • upper respiratory tract infection (sitagliptin, 5.5%; placebo, 5.2%) and
  • nasopharyngitis (6.1%, 4.1%).
• Through Week 54, the adverse reactions reported regardless of investigator assessment of causality in ≥5% of patients treated with sitagliptin and more commonly than in patients treated with placebo were:
  • upper respiratory tract infection (sitagliptin, 15.5%; placebo, 6.2%),
  • nasopharyngitis (11.0%, 9.3%),
  • peripheral edema (8.3%, 5.2%), and
  • headache (5.5%, 4.1%).

Sitagliptin In Combination With Metformin Immediate-Release And Insulin

• In a 24-week placebo-controlled study of sitagliptin 100 mg as add-on therapy in patients with type 2 diabetes inadequately controlled on metformin immediate-release and insulin (sitagliptin, N=229; placebo, N=233), the only adverse reaction reported regardless of investigator assessment of causality in ≥5% of patients treated with sitagliptin and more commonly than in patients treated with placebo was hypoglycemia (Table 3).

Hypoglycemia

• In all (N=5) studies, adverse reactions of hypoglycemia were based on all reports of symptomatic hypoglycemia; a concurrent glucose measurement was not required although most (77%) reports of hypoglycemia were accompanied by a blood glucose measurement ≤70 mg/dL.
• When the combination of sitagliptin and metformin immediate-release was coadministered with a sulfonylurea or with insulin, the percentage of patients reporting at least one adverse reaction of hypoglycemia was higher than that observed with placebo and metformin immediate-release coadministered with a sulfonylurea or with insulin (Table 3).

Table 3: Incidence and Rate of Hypoglycemia* (Regardless of Investigator Assessment of Causality) in Placebo-Controlled Clinical Studies of Sitagliptin in Combination with Metformin Immediate-Release Coadministered with Glimepiride or Insulin

• The overall incidence of reported adverse reactions of hypoglycemia in patients with type 2 diabetes inadequately controlled on diet and exercise was
  • 0.6% in patients given placebo,
  • 0.6% in patients given sitagliptin alone,
  • 0.8% in patients given metformin immediate-release alone, and
  • 1.6% in patients given sitagliptin in combination with metformin immediate-release.
• In patients with type 2 diabetes inadequately controlled on metformin immediate-release alone, the overall incidence of adverse reactions of hypoglycemia was
  • 1.3% in patients given add-on sitagliptin and
  • 2.1% in patients given add-on placebo.
• In the study of sitagliptin and add-on combination therapy with metformin immediate-release and rosiglitazone, the overall incidence of hypoglycemia was   
  • 2.2% in patients given add-on sitagliptin 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 sitagliptin and
  • 1.0% in patients given add-on placebo.

Vital Signs And Electrocardiograms

• With the combination of sitagliptin and metformin immediate-release, no clinically meaningful changes in vital signs or in electrocardiogram parameters (including the QTc interval) were observed.

Pancreatitis

• 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).

Sitagliptin

• The most common adverse experience in sitagliptin monotherapy reported regardless of investigator  assessment of causality in ≥5% of patients and more commonly than in patients given placebo was nasopharyngitis.

Metformin Extended-Release

• 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

Sitagliptin

• The incidence of laboratory adverse reactions was similar in patients treated with sitagliptin and metformin immediate-release (7.6%) compared to patients treated with placebo and metformin (8.7%).
• In most but not all studies, a small increase in white blood cell count (approximately 200 cells/microL difference in WBC vs. placebo; mean baseline WBC approximately 6600 cells/microL) was observed due to a small increase in neutrophils.
• This change in laboratory parameters is not considered to be clinically relevant.

Metformin Hydrochloride

• In controlled clinical trials of metformin of 29 weeks duration, a decrease to subnormal levels of previously normal serum Vitamin B12 levels, without clinical manifestations, was observed in approximately 7% of patients. Such decrease, possibly due to interference with B12 absorption from the B12-intrinsic factor complex, is, however, very rarely associated with anemia and appears to be rapidly reversible with discontinuation of metformin or Vitamin B12 supplementation.

Postmarketing Experience

Additional adverse reactions have been identified during postapproval use of sitagliptin with metformin, sitagliptin, 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.

Hypersensitivity reactions including

• anaphylaxis,
• angioedema,
• rash,
• urticaria,
• cutaneous vasculitis, and
• exfoliative skin conditions including Stevens-Johnson syndrome;
•  upper respiratory tract infection;
• hepatic enzyme elevations;
• acute pancreatitis, including fatal and nonfatal 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;
• cholestatic, hepatocellular, and mixed hepatocellular liver injury.

Carbonic Anhydrase Inhibitors

• Topiramate or other carbonic anhydrase inhibitors (e.g., zonisamide, acetazolamide or dichlorphenamide) frequently cause a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis.
• Concomitant use of these drugs with Janumet XR may increase the risk of lactic acidosis. Consider more frequent monitoring of these patients.

Drugs That Reduce Metformin Clearance

• Concomitant use of drugs that interfere with common renal tubular transport systems involved in the renal elimination of metformin, including organic cationic transporter-2 [OCT2] / multidrug and toxin extrusion [MATE] inhibitors such as
  • ranolazine,
  • vandetanib,
  • dolutegravir, and
  • cimetidine) could increase systemic exposure to metformin and may increase the risk for lactic acidosis. Consider the benefits and risks of concomitant use.

Alcohol

• Alcohol is known to potentiate the effect of metformin on lactate metabolism.
• Warn patients against excessive alcohol intake while receiving Janumet XR.

Insulin Secretagogues Or Insulin

• Coadministration of Janumet XR 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.
• Use Of Metformin With Other Drugs
• Certain drugs tend to produce hyperglycemia and may lead to loss of glycemic control.
• These drugs include the thiazides and other
  • diuretics,
  • corticosteroids,
  • phenothiazines,
  • thyroid products,
  • estrogens,
  • oral contraceptives,
  • phenytoin,
  • nicotinic acid,
  • sympathomimetics,
  • calcium channel blocking drugs, and
  • isoniazid.
• When such drugs are administered to a patient receiving Janumet XR the patient should be closely observed to maintain adequate glycemic control.