Janumet

A study was conducted to assess the effect of cyclosporine, a potent inhibitor of p-glycoprotein, on the pharmacokinetics of sitagliptin. Coadministration of a single 100-mg oral dose of sitagliptin and a single 600 mg oral dose of cyclosporine increased the AUC and C_max of sitagliptin by approximately 29% and 68%, respectively. These modest changes in sitagliptin pharmacokinetics were not considered to be clinically meaningful. The renal clearance of sitagliptin was also not meaningfully altered. Therefore, meaningful interactions would not be expected with other p-glycoprotein inhibitors. No dosage adjustment for JANUMET is recommended when co-administered with cyclosporine or other p-glycoprotein inhibitors (e.g., ketoconazole).

Co-administration with sitagliptin did not meaningfully alter the steady-state pharmacokinetics of norethindrone or ethinyl estradiol.

In clinical studies, as described below, sitagliptin did not meaningfully alter the pharmacokinetics of metformin, glyburide, simvastatin, rosiglitazone, warfarin, or oral contraceptives, providing in vivo evidence of a low propensity for causing drug interactions with substrates of CYP3A4, CYP2C8, CYP2C9, and organic cationic transporter (OCT).

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 C_max 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.

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, estrogen plus progestogen, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blocking drugs, isoniazid and beta-2-agonists. ACE-inhibitors may decrease the blood glucose levels. When such drugs are administered to a patient receiving JANUMET the patient should be closely observed to maintain adequate glycemic control.

Elimination rate of the anticoagulant phenprocoumon has been reported to be increased by 20% when used concurrently with metformin. Therefore, patients receiving phenprocoumon or other antivitamin K anticoagulants should be monitored carefully when both types of drugs are used simultaneously. In such cases, an important increase of prothrombin time may occur upon cessation of JANUMET therapy, with an increased risk of hemorrhage.

Multiple daily doses of sitagliptin did not meaningfully alter the pharmacokinetics, as assessed by measurement of S(−) or R(+) warfarin enantiomers, or pharmacodynamics (as assessed by measurement of prothrombin INR) of a single dose of warfarin. Since S(−) warfarin is primarily metabolized by CYP2C9, these data also support the conclusion that sitagliptin is not a CYP2C9 inhibitor.

Sitagliptin had a minimal effect on the pharmacokinetics of digoxin. Following administration of 0.25 mg digoxin concomitantly with 100 mg of sitagliptin daily for 10 days, the plasma AUC of digoxin was increased by 11%, and the plasma C_max by 18%. These increases are not considered likely to be clinically meaningful. No dosage adjustment of digoxin or JANUMET is recommended.

Single-dose pharmacokinetics of rosiglitazone were not meaningfully altered in subjects receiving multiple daily doses of sitagliptin. Therefore, sitagliptin is not an inhibitor of CYP2C8-mediated metabolism. Clinically meaningful interactions with pioglitazone are not expected because pioglitazone predominantly undergoes CYP2C8- or CYP3A4-mediated metabolism. The effect of thiazolidinediones on the pharmacokinetics of sitagliptin was not assessed.

There are no known interactions with food.

No studies of the effects of JANUMET on the ability to drive and use machines have been performed. JANUMET is not expected to affect the ability to drive and use machines under usual circumstances. However, patients should be warned about driving a vehicle or operating machinery under conditions where a risk of hypoglycemia is present (see Warnings and Precautions, Endocrine and Metabolism, Metformin ).

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.

Intravascular contrast studies with iodinated materials can lead to acute alteration of renal function and have been associated with lactic acidosis in patients receiving metformin (see Contraindications and Warnings and Precautions).

Single-dose pharmacokinetics of simvastatin, a CYP3A4 substrate, were not meaningfully altered in subjects receiving multiple daily doses of sitagliptin. Therefore, sitagliptin is not an inhibitor of CYP3A4-mediated metabolism.

Interactions with herbal products have not been established.

Single-dose pharmacokinetics of glyburide, a CYP2C9 substrate, were not meaningfully altered in subjects receiving multiple doses of sitagliptin. Clinically meaningful interactions would not be expected with other sulfonylureas (e.g., glipizide, tolbutamide, and glimepiride) which, like glyburide, are primarily eliminated by CYP2C9. The effect of sulfonylureas on the pharmacokinetics of sitagliptin was not assessed.

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 C_max by 22% and blood AUC by 15%, without any significant change in metformin renal clearance. When administered with metformin, the C_max 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 C_max and AUC by 20% and 9%, respectively, and increased the amount excreted in the urine. T_max and half-life were unaffected. Nifedipine appears to enhance the absorption of metformin. Metformin had minimal effects on nifedipine.

Patients should be cautioned against excessive alcohol intake, either acute or chronic, when taking JANUMET, since alcohol intake potentiates the effect of metformin on lactate metabolism (see Contraindications).

As metformin and sitagliptin are excreted by the kidney, JANUMET should be used with caution as age increases. Monitoring of renal function is necessary to aid in prevention of metformin-associated lactic acidosis, particularly in the elderly (see Warnings and Precautions, Endocrine and Metabolism, Lactic Acidosis and Action and Clinical Pharmacology, Special Populations and Conditions, Geriatrics).

JANUMET should not be used in patients with renal failure or renal dysfunction e.g., serum creatinine levels ≥136 μmol/L [males], ≥124 μmol/L [females] or abnormal creatinine clearance (see Contraindications and Warnings and Precautions).

Over a period of time, patients may become progressively less responsive to therapy with oral hypoglycemic agents because of deterioration of their diabetic state. Patients should therefore be monitored with regular clinical and laboratory evaluations, including blood glucose and glycosylated hemoglobin (AlC) determinations, to determine the minimum effective dosage and to detect primary failure or secondary failure (see Warnings and Precautions).

In patients in whom the maximum dose fails to lower the blood glucose adequately, therapeutic alternatives should be considered.

The dosage of antihyperglycemic therapy with JANUMET should be individualized on the basis of the patient’s current regimen, effectiveness, and tolerability while not exceeding the maximum recommended daily dose of 100 mg sitagliptin and 2000 mg metformin.

JANUMET should generally be given twice daily with meals, with gradual dose escalation, to reduce the gastrointestinal (GI) side effects due to metformin.

Use of JANUMET in patients with severe hepatic insufficiency is not recommended (see Contraindications and Warnings and Precautions).

The starting dose of JANUMET should be based on the patient’s current regimen. JANUMET should be given twice daily with meals. The following doses are available:

50 mg sitagliptin/500 mg metformin hydrochloride;

50 mg sitagliptin/850 mg metformin hydrochloride;

50 mg sitagliptin/1000 mg metformin hydrochloride.

No studies have been performed specifically examining the safety and efficacy of JANUMET in patients previously treated with other oral antihyperglycemic agents and switched to JANUMET. Any change in therapy of type 2 diabetes should be undertaken with care and appropriate monitoring as changes in glycemic control can occur.

There are no data available on the use of JANUMET in patients younger than 18 years of age. Therefore, use of JANUMET in pediatric patients is not recommended.

If a dose of JANUMET is missed, it should be taken as soon as the patient remembers. If he/she does not remember until it is time for the next dose, the missed dose should be skipped and returned to the regular schedule. Two doses of JANUMET should not be taken at the same time.

dysmenorrhea, erectile dysfunction.

The following additional adverse reactions have been identified during post-marketing use of JANUMET or sitagliptin, one of the components of JANUMET. 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 include anaphylaxis, angioedema, rash, urticaria, cutaneous vasculitis and exfoliative skin conditions, including Stevens-Johnson syndrome (see Contraindications and Warnings and Precautions, Hypersensitivity Reactions); pancreatitis.

The incidence of laboratory adverse experiences was similar in patients treated with sitagliptin 100 mg compared to patients treated with placebo. In most clinical studies, a slight decrease in alkaline phosphatase and small increases in uric acid and white blood cell count (due to an increase in neutrophils) were observed. In active comparator studies versus a sulfonylurea agent (glipizide) similar changes were seen in alkaline phosphatase and uric acid.

decreased appetite, hypoglycemia.

very rare (<1/10 000 and isolated reports). The incidence of rash/dermatitis in controlled clinical trials was comparable to placebo for metformin monotherapy and to sulfonylurea for metformin/sulfonylurea therapy. Reports of skin reactions such as erythema, pruritus, and urticaria are very rare.

face edema, malaise, peripheral edema, pain.

bundle branch block.

very rare (<1/10 000 and isolated reports) (see Warnings and Precautions and Overdosage).

common (≥1/100). During initiation of metformin therapy complaints of taste disturbance are common, i.e. metallic taste.

cough.

migraine, neuropathy peripheral, parosmia, somnolence.

exanthem, rash, urticaria.

muscle tightness.

gastric ulcer helicobacter, helicobacter gastritis, upper respiratory tract infection.

During controlled clinical trials of 29 weeks duration, approximately 9% of patients on metformin monotherapy and 6% of patients on metformin/sulfonylurea therapy developed asymptomatic subnormal serum vitamin B₁₂ levels; serum folic acid levels did not decrease significantly. However, only five cases of megaloblastic anemia have been reported with metformin administration (none during U.S. clinical studies) and no increased incidence of neuropathy has been observed (see Warnings and Precautions, Endocrine and Metabolism).

Decrease of vitamin B₁₂ absorption with decrease of serum levels during long-term use of metformin is rare (≥1/10 000 and <1/1000). Consideration of such aetiology is recommended if a patient presents with megaloblastic anemia.

hepatic steatosis.

orthostatic hypotension.

Nausea was the only drug-related adverse reaction reported by the investigator that occurred with an incidence ≥1% in patients receiving sitagliptin (1.1%) and greater than in patients receiving placebo (0.4%).

very common (>1/10). Gastrointestinal symptoms (diarrhea, nausea, vomiting, abdominal bloating, flatulence, and anorexia) are the most common reactions to metformin and are approximately 30% more frequent in patients on metformin monotherapy than in placebo-treated patients, particularly during initiation of metformin therapy. These symptoms are generally transient and resolve spontaneously during continued treatment. Occasionally, temporary dose reduction may be useful.

Because gastrointestinal symptoms during therapy initiation appear to be dose-related, they may be decreased by gradual dose escalation and by having patients take metformin (metformin HCl) with meals (see Dosage and Administration).

Because significant diarrhea and/or vomiting can cause dehydration and prerenal azotemia, metformin should be temporarily discontinued, under such circumstances.

For patients who have been stabilized on metformin, nonspecific gastrointestinal symptoms should not be attributed to therapy unless intercurrent illness or lactic acidosis have been excluded.

blood glucose decreased.

abdominal discomfort, abdominal pain upper, diarrhea, dyspepsia, flatulence, reflux esophagitis disease, retching.

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).

very rare (<1/10 000 and isolated reports). Liver function tests abnormalities or hepatitis resolving upon metformin discontinuation has been documented in isolated reports.

Safety and effectiveness of JANUMET in pediatric patients have not been established. Therefore, JANUMET should not be used in this population.

Because sitagliptin and metformin are substantially excreted by the kidney and because aging can be associated with reduced renal function, JANUMET should be used with caution as age increases. Care should be taken in dose selection and should be based on careful and regular monitoring of renal function (see Warnings and Precautions, Special Populations, Geriatrics (≥65 years of age)).

During controlled clinical trials in healthy subjects, single doses of up to 800 mg sitagliptin were generally well tolerated. Minimal increases in QTc, not considered to be clinically relevant, were observed in one study at a dose of 800 mg sitagliptin (see Action and Clinical Pharmacology, Pharmacodynamics). There is no experience with doses above 800 mg in humans. In phase I multiple-dose studies, there were no dose-related clinical adverse reactions observed with sitagliptin with doses of up to 600 mg per day for 10 days and 400 mg per day for periods of up to 28 days.

In the event of an overdose, it is reasonable to employ the usual supportive measures, e.g., remove unabsorbed material from the gastrointestinal tract, employ clinical monitoring (including obtaining an electrocardiogram), and institute supportive therapy if required.

Sitagliptin is modestly dialyzable. In clinical studies, approximately 13.5% of the dose was removed over a 3- to 4-hour hemodialysis session. Prolonged hemodialysis may be considered if clinically appropriate. It is not known if sitagliptin is dialyzable by peritoneal dialysis.

Available information concerning treatment of a massive overdosage of metformin hydrochloride is very limited. It would be expected that adverse reactions of a more intense character including epigastric discomfort, nausea and vomiting followed by diarrhea, drowsiness, weakness, dizziness, malaise and headache might be seen. Should those symptoms persist, lactic acidosis should be excluded. The drug should be discontinued and proper supportive therapy instituted.

Overdose of metformin hydrochloride has occurred, including ingestion of amounts greater than 50 grams. Hypoglycemia was reported in approximately 10% of cases, but no causal association with metformin hydrochloride has been established. Lactic acidosis has been reported in approximately 32% of metformin overdose cases (see Warnings and Precautions, Endocrine and Metabolism, Lactic Acidosis). Metformin is dialyzable with a clearance of up to 170 mL/min under good hemodynamic conditions. Therefore, hemodialysis may be useful for removal of accumulated drug from patients in whom metformin overdosage is suspected.

Each red, capsule-shaped, film-coated tablet with “577” debossed on one side, contains: sitagliptin phosphate monohydrate 64.25 mg and metformin hydrochloride equivalent to sitagliptin 50 mg as free base and metformin hydrochloride 1000 mg. Nonmedicinal ingredients: microcrystalline cellulose, polyvinylpyrrolidone, sodium lauryl sulfate and sodium stearyl fumarate; film coating: black iron oxide, polyvinyl alcohol, polyethylene glycol, red iron oxide, talc and titanium dioxide. Bottles of 60.

Each light pink, capsule-shaped, film-coated tablet with “575” debossed on one side, contains: sitagliptin phosphate monohydrate 64.25 mg and metformin hydrochloride equivalent to sitagliptin 50 mg as free base and metformin hydrochloride 500 mg. Nonmedicinal ingredients: microcrystalline cellulose, polyvinylpyrrolidone, sodium lauryl sulfate and sodium stearyl fumarate; film coating: black iron oxide, polyvinyl alcohol, polyethylene glycol, red iron oxide, talc and titanium dioxide. Bottles of 60.

Each pink, capsule-shaped, film-coated tablet with “515” debossed on one side, contains: sitagliptin phosphate monohydrate 64.25 mg and metformin hydrochloride equivalent to sitagliptin 50 mg as free base and metformin hydrochloride 850 mg. Nonmedicinal ingredients: microcrystalline cellulose, polyvinylpyrrolidone, sodium lauryl sulfate and sodium stearyl fumarate; film coating: black iron oxide, polyvinyl alcohol, polyethylene glycol, red iron oxide, talc and titanium dioxide. Bottles of 60.

When a patient stabilized on any diabetic regimen is exposed to stress such as fever, trauma, infection, or surgery, a temporary loss of glycemic control may occur. At such times, it may be necessary to withhold JANUMET and temporarily administer insulin. JANUMET may be reinstituted after the acute episode is resolved.

The effectiveness of oral antidiabetic drugs in lowering blood glucose to a targeted level decreases in many patients over a period of time. This phenomenon, which may be due to progression of the underlying disease or to diminished responsiveness to the drug, is known as secondary failure, to distinguish it from primary failure in which the drug is ineffective during initial therapy.

Should secondary failure occur with JANUMET, therapeutic alternatives should be considered.

In clinical studies, no overall differences in safety or effectiveness were observed between subjects 65 years and over and younger subjects. While this and other reported clinical experience have not identified differences in responses between the geriatric and younger patients, greater sensitivity of some older individuals cannot be ruled out.

Alcohol is known to potentiate the effect of metformin on lactate metabolism. Patients, therefore, should be warned against excessive alcohol intake, acute or chronic, while receiving JANUMET.

There are no adequate and well-controlled studies in pregnant women with JANUMET or its individual components; therefore, the safety of JANUMET in pregnant women is not known. JANUMET is not recommended for use in pregnancy.

Because recent information suggests that abnormal blood glucose levels during pregnancy are associated with a higher incidence of congenital abnormalities, there is a consensus among experts that insulin be used during pregnancy to maintain blood glucose levels as close to normal as possible.

Cardiovascular collapse (shock) from whatever cause, acute congestive heart failure, acute myocardial infarction and other conditions characterized by hypoxemia have been associated with lactic acidosis and may also cause prerenal azotemia. When such events occur in patients on JANUMET therapy, the drug should be promptly discontinued.

Careful selection of patients is important. It is imperative that there be rigid attention to diet and careful adjustment of dosage. Regular thorough follow-up examinations are necessary.

If vomiting occurs, withdraw drug temporarily, exclude lactic acidosis, then resume dosage cautiously (see Adverse Reactions).

Particular attention should be paid to short range and long range complications which are peculiar to diabetes. Periodic cardiovascular, ophthalmic, hematological, hepatic and renal assessments are advisable.

Use of JANUMET must be considered as treatment in addition to proper dietary regimen and not as a substitute for diet.

Care should be taken to ensure that JANUMET is not given when a contraindication exists.

If during JANUMET therapy the patient develops acute intercurrent disease such as: clinically significant hepatic dysfunction, cardiovascular collapse, congestive heart failure, acute myocardial infarction, or other conditions complicated by hypoxemia, the drug should be discontinued.

Impairment of vitamin B₁₂ absorption has been reported in some patients. Therefore, measurements of serum vitamin B₁₂ are advisable at least every one to two years in patients on long-term treatment with JANUMET.

A decrease to subnormal levels of previously normal serum Vitamin B₁₂ levels, without clinical manifestations, is observed in approximately 7% of patients receiving metformin in controlled clinical trials of 29 weeks duration. 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. Measurement of hematologic parameters on an annual basis is advised in patients on JANUMET and any apparent abnormalities should be appropriately investigated and managed (see Warnings and Precautions, Monitoring and Laboratory Tests). Certain individuals (those with inadequate Vitamin B₁₂ or calcium intake or absorption) appear to be predisposed to developing subnormal Vitamin B₁₂ levels.

Because sitagliptin and metformin are substantially excreted by the kidney and because aging can be associated with reduced renal function, JANUMET should be used with caution as age increases. Care should be taken in dose selection and should be based on careful and regular monitoring of renal function (see Warnings and Precautions, Renal; Dosage and Administration, Geriatrics).

JANUMET should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.

There have been post-marketing reports of serious hypersensitivity reactions in patients treated with sitagliptin, one of the components of JANUMET. These reactions include anaphylaxis, angioedema, and exfoliative skin conditions including Stevens-Johnson syndrome. Onset of these reactions occurred within the first 3 months after initiation of treatment with sitagliptin, with some reports occurring after the first dose. If a hypersensitivity reaction is suspected, discontinue JANUMET, assess for other potential causes for the event, and institute alternative treatment for diabetes (see Contraindications and Adverse Reactions, Post-Market Adverse Drug Reactions).

Response to all diabetic therapies should be monitored by periodic measurements of blood glucose and HbA_1c levels, with a goal of decreasing these levels towards the normal range. HbA_1c is especially useful for evaluating long-term glycemic control.

Initial and periodic monitoring of hematologic parameters (e.g., hemoglobin/hematocrit and red blood cell indices) and renal function (serum creatinine) should be performed, at least on an annual basis. While megaloblastic anemia has rarely been seen with metformin therapy, if this is suspected, Vitamine B₁₂ deficiency should be excluded.

A limited number of patients with congestive heart failure participated in clinical studies of sitagliptin. In studies of sitagliptin in combination with metformin, patients with congestive heart failure requiring pharmacological therapy or NYHA Class III or IV congestive heart failure were excluded. Patients with Classes I and II were included in small number. Use in this population is not recommended.

Safety and effectiveness of JANUMET in pediatric patients have not been established. Therefore, JANUMET should not be used in this population.

Metformin and sitagliptin are known to be substantially excreted by the kidney. The risk of metformin accumulation and lactic acidosis increases with the degree of impairment of renal function. Thus, patients with serum creatinine levels above the upper limit of normal for their age should not receive JANUMET. In patients with advanced age, JANUMET should be carefully titrated to establish the minimum dose for adequate glycemic effect, because aging can be associated with reduced renal function. In elderly patients, particularly those ≥80 years of age, renal function should be monitored regularly.

Before initiation of therapy with JANUMET and at least annually thereafter, renal function should be assessed and verified as normal. In patients in whom development of renal dysfunction is anticipated, renal function should be assessed more frequently and JANUMET discontinued if evidence of renal impairment is present.

Hypoglycemia does not occur in patients receiving metformin alone under usual circumstances of use, but could occur when caloric intake is deficient, when strenuous exercise is not compensated by caloric supplementation, or during concomitant use with other glucose-lowering agents (such as sulfonylureas and insulin) or ethanol. Elderly, debilitated, or malnourished patients, and those with adrenal or pituitary insufficiency or alcohol intoxication are particularly susceptible to hypoglycemic effects. Hypoglycemia may be difficult to recognize in the elderly, and in people who are taking β-adrenergic blocking drugs.

The patients should be warned about driving a vehicle or operating machinery under these conditions where risk of hypoglycemia is present.

No studies in lactating animals have been conducted with the combined components of JANUMET. In studies performed with the individual components, both sitagliptin and metformin are secreted in the milk of lactating rats. It is not known whether sitagliptin and/or metformin are excreted in human milk. Therefore, JANUMET should not be used by a woman who is nursing.

Controlled clinical studies of metformin did not include sufficient numbers of elderly patients to determine whether they respond differently from younger patients, although other reported clinical experience has not identified differences in responses between the elderly and younger patients. Metformin is known to be substantially excreted by the kidney and because the risk of serious adverse reactions to the drug is greater in patients with impaired renal function, metformin should only be used in patients with normal renal function (see Contraindications). Because aging is associated with reduced renal function, metformin should be used with caution as age increases. Care should be taken in dose selection and should be based on careful and regular monitoring of renal function.

In a randomized, placebo-controlled crossover study, 79 healthy subjects were administered a single oral dose of sitagliptin 100 mg, sitagliptin 800 mg (8 times the recommended dose), and placebo. At the recommended dose of 100 mg, there was no effect on the QTc interval obtained at the peak plasma concentration, or at any other time during the study. Following the 800-mg dose, the maximum increase in the placebo-corrected mean change in QTc from baseline at 3 hours postdose was 8.0 msec. This small increase was not considered to be clinically significant. At the 800-mg dose, peak sitagliptin plasma concentrations were approximately 11-time higher than the peak concentrations following a 100-mg dose.

In patients with type 2 diabetes administered sitagliptin 100 mg (N=81) or sitagliptin 200 mg (N=63) daily, there were no meaningful changes in QTc interval based on ECG data obtained at the time of expected peak plasma concentration.

An approximately 2-fold increase in the plasma AUC of sitagliptin was observed in patients with moderate renal insufficiency, and an approximately 4-fold increase was observed in patients with severe renal insufficiency and in patients with ESRD on hemodialysis, as compared to normal healthy control subjects.

No dosage adjustment is necessary based on gender.

No studies with JANUMET have been performed in pediatric patients.

24-Hour Plasma Glucose Profile After 4-Week Treatment with Sitagliptin 50 mg BID with Metformin or Placebo with Metformin

No dosage adjustment is necessary based on race.

When administered in the fed state (following a standard high-fat breakfast), the metformin component of JANUMET was bioequivalent to metformin taken together with sitagliptin as individual tablets.

JANUMET should not be used in patients with renal insufficiency (see Contraindications).

In a two-day study in healthy subjects, sitagliptin alone increased active GLP-1 concentrations, whereas metformin alone increased active and total GLP-1 concentrations to similar extents. Co-administration of sitagliptin and metformin has an additive effect on active GLP-1 concentrations. Sitagliptin, but not metformin, increased active GIP concentrations. It is unclear what these findings mean for changes in glycemic control in patient with type 2 diabetes.

In studies with healthy subjects, sitagliptin did not lower blood glucose or cause hypoglycemia, suggesting that the insulinotropic and glucagon suppressive actions of the drug are glucose dependent.

In patients with decreased renal function (based on measured creatinine clearance (<60 mL/min), the plasma and blood half-lifes of metformin are prolonged and the renal clearance is decreased in proportion to the decrease in creatinine clearance.