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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 Co-administration 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 were co-administered to patients with type 2 diabetes inadequately controlled on diet and exercise.
Table 1: Sitagliptin and Metformin Co-administered 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
|Number of Patients (%)|
N = 176
|Sitagliptin 100 mg QD
N = 179
|Metformin 500 mg/ Metformin 1000 mg bid ††
N = 364††
|Sitagliptin 50 mg bid + Metformin 500 mg/ Metformin 1000 mg bid ††
N = 372††
|Diarrhea||7 (4.0)||5 (2.8)||28 (7.7)||28 (7.5)|
|Upper Respiratory Tract Infection||9 (5.1)||8 (4.5)||19 (5.2)||23 (6.2)|
|Headache||5 (2.8)||2 (1.1)||14 (3.8)||22 (5.9)|
|† Intent-to-treat population.
†† Data pooled for the patients given the lower and higher doses of metformin.
Sitagliptin Add-on Therapy in Patients with Type 2 Diabetes Inadequately Controlled on Metformin Alone
In a 24-week placebo-controlled trial of sitagliptin 100 mg administered once daily added to a twice daily metformin 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, 1.9%; placebo and metformin, 2.5%).
Gastrointestinal Adverse Reactions
The incidences of pre-selected gastrointestinal adverse experiences in patients treated with sitagliptin and metformin were similar to those reported for patients treated with metformin 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
|Number of Patients (%)|
|Study of Sitagliptin and Metformin in Patients Inadequately Controlled on Diet and Exercise||Study of Sitagliptin Add-on in Patients Inadequately Controlled on Metformin Alone|
N = 176
|Sitagliptin 100 mg QD
N = 179
|Metformin 500 mg/ Metformin 1000 mg bid †
N = 364
|Sitagliptin 50 mg bid + Metformin 500 mg/ Metformin 1000 mg bid †
N = 372
|Placebo and Metformin ≥ 1500 mg daily
N = 237
|Sitagliptin 100 mg QD and Metformin ≥ 1500 mg daily
N = 464
|Diarrhea||7 (4.0)||5 (2.8)||28 (7.7)||28 (7.5)||6 (2.5)||11 (2.4)|
|Nausea||2 (1.1)||2 (1.1)||20 (5.5)||18 (4.8)||2 (0.8)||6 (1.3)|
|Vomiting||1 (0.6)||0 (0.0)||2 (0.5)||8 (2.2)||2 (0.8)||5 (1.1)|
|Abdominal Pain††||4 (2.3)||6 (3.4)||14 (3.8)||11 (3.0)||9 (3.8)||10 (2.2)|
|† Data pooled for the patients given the
lower and higher doses of metformin.
†† Abdominal discomfort was included in the analysis of abdominal pain in the study of initial therapy.
Sitagliptin in Combination with Metformin 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 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 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 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 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 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).
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 was co-administered 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 co-administered 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 Co-administered with Glimepiride or
|Add-On to Glimepiride + Metformin (24 weeks)||Sitagliptin 100 mg + Metformin + Glimepiride||Placebo + Metformin + Glimepiride|
|N = 116||N = 113|
|Overall (%)||19 (16.4)||1 (0.9)|
|Severe (%)§||0 (0.0)||0 (0.0)|
|Add-On to Insulin + Metformin (24 weeks)||Sitagliptin 100 mg + Metformin + Insulin||Placebo + Metformin + Insulin|
|N = 229||N = 233|
|Overall (%)||35 (15.3)||19 (8.2)|
|Severe (%)§||1 (0.4)||1 (0.4)|
|† Adverse reactions of hypoglycemia were based on all reports of
symptomatic hypoglycemia; a concurrent glucose measurement was not required:
‡ Based on total number of events (i.e., a single patient may have had multiple events).
§ Severe events of hypoglycemia were defined as those events requiring medical assistance or exhibiting depressed level/loss of consciousness or seizure.
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 alone, and 1.6% in patients given sitagliptin in combination with metformin. In patients with type 2 diabetes inadequately controlled on metformin 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 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.
With the combination of sitagliptin and metformin, no clinically meaningful changes in vital signs or in ECG (including in QTc interval) were observed.
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) [See WARNINGS AND PRECAUTIONS.]
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.
The incidence of laboratory adverse reactions was similar in patients treated with sitagliptin and metformin (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. [See WARNINGS AND PRECAUTIONS]
Additional adverse reactions have been identified during postapproval use of JANUMET or sitagliptin, one of the components of JANUMET. These reactions have been reported when JANUMET or sitagliptin have been used alone 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 [see WARNINGS AND PRECAUTIONS]; upper respiratory tract infection; hepatic enzyme elevations; acute pancreatitis, including fatal and non-fatal hemorrhagic and necrotizing pancreatitis [see INDICATIONS AND USAGE; WARNINGS AND PRECAUTIONS]; worsening renal function, including acute renal failure (sometimes requiring dialysis) [see WARNINGS AND PRECAUTIONS]; constipation; vomiting; headache; arthralgia; myalgia; pain in extremity; back pain.
Read the Janumet (sitagliptin metformin hcl) Side Effects Center for a complete guide to possible side effects
Cationic drugs (e.g., amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim, or vancomycin) that are eliminated by renal tubular secretion theoretically have the potential for interaction with metformin by competing for common renal tubular transport systems. Such interaction between metformin and oral cimetidine has been observed in normal healthy volunteers in both single- and multiple-dose metformin-cimetidine drug interaction studies, with a 60% increase in peak metformin plasma and whole blood concentrations and a 40% increase in plasma and whole blood metformin AUC. There was no change in elimination half-life in the single-dose study. Metformin had no effect on cimetidine pharmacokinetics. Although such interactions remain theoretical (except for cimetidine), careful patient monitoring and dose adjustment of JANUMET and/or the interfering drug is recommended in patients who are taking cationic medications that are excreted via the proximal renal tubular secretory system.
There was a slight increase in the area under the curve (AUC, 11%) and mean peak drug concentration (Cmax, 18%) of digoxin with the co-administration of 100 mg sitagliptin for 10 days. These increases are not considered likely to be clinically meaningful. Digoxin, as a cationic drug, has the potential to compete with metformin for common renal tubular transport systems, thus affecting the serum concentrations of either digoxin, metformin or both. Patients receiving digoxin should be monitored appropriately. No dosage adjustment of digoxin or JANUMET is recommended.
In a single-dose interaction study in type 2 diabetes patients, co-administration of metformin and glyburide did not result in any changes in either metformin pharmacokinetics or pharmacodynamics. Decreases in glyburide AUC and Cmax were observed, but were highly variable. The single-dose nature of this study and the lack of correlation between glyburide blood levels and pharmacodynamic effects make the clinical significance of this interaction uncertain.
A single-dose, metformin-furosemide drug interaction study in healthy subjects demonstrated that pharmacokinetic parameters of both compounds were affected by co-administration. Furosemide increased the metformin plasma and blood Cmax by 22% and blood AUC by 15%, without any significant change in metformin renal clearance. When administered with metformin, the Cmax and AUC of furosemide were 31% and 12% smaller, respectively, than when administered alone, and the terminal half-life was decreased by 32%, without any significant change in furosemide renal clearance. No information is available about the interaction of metformin and furosemide when co-administered chronically.
A single-dose, metformin-nifedipine drug interaction study in normal healthy volunteers demonstrated that co-administration of nifedipine increased plasma metformin Cmax and AUC by 20% and 9%, respectively, and increased the amount excreted in the urine. Tmax and half-life were unaffected. Nifedipine appears to enhance the absorption of metformin. Metformin had minimal effects on nifedipine.
The 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 the patient should be closely observed to maintain adequate glycemic control.
In healthy volunteers, the pharmacokinetics of metformin and propranolol, and metformin and ibuprofen were not affected when co-administered in single-dose interaction studies.
Metformin is negligibly bound to plasma proteins and is, therefore, less likely to interact with highly protein-bound drugs such as salicylates, sulfonamides, chloramphenicol, and probenecid, as compared to the sulfonylureas, which are extensively bound to serum proteins.
Read the Janumet Drug Interactions Center for a complete guide to possible interactions
Last reviewed on RxList: 11/8/2012
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