Janumet XR is indicated as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus inadequately controlled on metformin or sitagliptin alone or in patients already being treated with the combination of sitagliptin and metformin.

 

 

Janumet XR is also indicated in combination with a sulfonylurea (i.e., triple combination therapy) as an adjunct to diet and exercise in patients with type 2 diabetes mellitus inadequately controlled with any two of the three agents: metformin, sitagliptin, or a sulfonylurea.

 

If the blood glucose level is insufficiently controlled by diet and exercise and insulin- in combination with insulin.

The dosage of antihyperglycemic therapy with Janumet XR 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.

 

Janumet XR should be given once daily with a meal preferably in the evening.

The dose should be escalated gradually to reduce the gastrointestinal (GI) side effects due to metformin.

To preserve the modified-release properties, the tablets must not be split, broken, crushed, or chewed before swallowing.

The plasma concentrations of metformin are enhanced by administration of Janumet XR with food. There have been reports of incompletely dissolved Janumet XR tablets being eliminated in the feces. It is not known whether this material seen in feces contains active drug. Therefore, glycemic control should be carefully assessed in patients reporting repeatedly seeing remainders of tablets in feces.

Any change in therapy of type 2 diabetes should be undertaken with care and appropriate monitoring because of potential changes in glycaemic control. The same also applies when switching from metformin tablets without extended release to extended-release metformin, e.g., Janumet XR.

 

Dosing Recommendations:

The starting dose of Janumet XR should be based on the patient’s current regimen.

 

Janumet XR should be given once daily with a meal preferably in the evening. Janumet XR tablets are available in the following strengths:

 

50 mg sitagliptin/500 mg extended-release metformin hydrochloride

50 mg sitagliptin/1000 mg extended-release metformin hydrochloride

100 mg sitagliptin/1000 mg extended-release metformin hydrochloride

 

For patients using the 50 mg sitagliptin/500 mg metformin hydrochloride extended-release tablet or the 50 mg sitagliptin/1000 mg metformin hydrochloride extended-release tablet, two tablets should be taken together once daily. The 100 mg sitagliptin/1000 mg metformin hydrochloride extended-release tablet should be taken as a single tablet once daily.

 

For patients inadequately controlled on metformin monotherapy:

For patients inadequately controlled on metformin alone, the recommended total daily starting dose of Janumet XR is 100 mg sitagliptin and the previously prescribed dose of metformin.

 

For patients inadequately controlled on sitagliptin monotherapy:

For patients inadequately controlled on sitagliptin alone, the recommended total daily starting dose of Janumet XR is 100 mg sitagliptin and 1000 mg metformin hydrochloride. The metformin dose can be titrated as needed to achieve glycemic control. Gradual dose escalation to reduce the gastrointestinal (GI) side effects associated with metformin should be considered. Patients taking sitagliptin monotherapy dose-adjusted for renal impairment should not be switched to Janumet XR (see CONTRAINDICATIONS).

 

For patients switching from coadministration of sitagliptin and metformin:

For patients switching from coadministration of sitagliptin and metformin, Janumet XR may be initiated at the dose of sitagliptin and metformin already being taken.

 

For patients inadequately controlled on dual combination therapy with any two of the following three antihyperglycemic agents: sitagliptin, metformin or a sulfonylurea:

The usual starting dose of Janumet XR should provide 100 mg total daily dose of sitagliptin. In determining the starting dose of the metformin component, the patient’s level of glycemic control and current dose (if any) of metformin should be considered. Gradual dose escalation to reduce the gastrointestinal (GI) side effects associated with metformin should be considered. Patients currently on or initiating a sulfonylurea may require lower sulfonylurea doses to reduce the risk of sulfonylurea-induced hypoglycemia (see PRECAUTIONS).

 

For patients inadequately controlled on dual combination therapy with any two of the following three antihyperglycemic agents: sitagliptin, metformin or insulin:

The usual starting dose of Janumet XR should provide 100 mg total daily dose of sitagliptin. In determining the starting dose of the metformin component, the patient’s level of glycemic control and current dose (if any) of metformin should be considered. Gradual dose escalation to reduce the gastrointestinal (GI) side effects associated with metformin should be considered. Patients currently on or initiating insulin therapy may require lower doses of insulin to reduce the risk of hypoglycemia (see PRECAUTIONS).

 

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

 

Special populations

 

Recommendations for use in renal impairment:

Assess renal function prior to initiation of Janumet XR and periodically thereafter.

 

Janumet XR is contraindicated in patients with an estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m². Discontinue Janumet XR if the patient’s eGFR later falls below 30 mL/min/1.73 m² (see CONTRAINDICATIONS and SPECIAL WARNINGS AND PRECAUTIONS FOR USE).

 

Initiation of Janumet XR in patients with an eGFR ≥ 30 mL/min/1.73 m² and < 45 mL/min/1.73 m² is not recommended. In patients taking Janumet XR whose eGFR later falls below 45 mL/min/1.73 m², assess the benefit and risk of continuing therapy and limit dose of the sitagliptin component to 50 mg once day.

 

Use in children and adolescents

Safety and effectiveness of Janumet XR in children and adolescent patients have not been established.

 

Use in the elderly

As metformin and sitagliptin are substantially excreted by the kidney, Janumet XR 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 SPECIAL WARNINGS AND PRECAUTIONS FOR USE, Metformin hydrochloride, Lactic acidosis).

 

Janumet XR is contraindicated in patients with: 1. Severe renal impairment (eGFR < 30 mL/min/1.73 m2) (see SPECIAL WARNINGS AND PRECAUTIONS FOR USE, Metformin hydrochloride, Renal Impairment). 2. Acute diseases that might lead to a renal impairment, e.g. cardiovascular compromise (including myocardial infarction), sepsis, dehydration (diarrhea, repeated vomiting), severe infections, for example of the urinary tract, high fever. 3. Known hypersensitivity to sitagliptin phosphate, metformin hydrochloride or any other component of Janumet XR (see SPECIAL WARNINGS AND PRECAUTIONS FOR USE, Sitagliptin phosphate, Hypersensitivity Reactions and SIDE EFFECTS, Postmarketing Experience). 4. Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma. 5. Intravascular application of iodine-containing contrast agents for radiological investigations may lead to kidney failure and in consequence may cause accumulation of metformin and lactic acidosis. Treatment with metformin must be stopped 48 hours before any such investigation, if creatinine clearance is <60 ml/min or eGFR is <60 ml/min/1.73 m2. Therapy with metformin may only be continued if renal function has been checked 48 hours after the investigation involving a contrast agent and there has been no further deterioration (see SPECIAL WARNINGS AND PRECAUTIONS FOR USE). Janumet XR should be temporarily discontinued in patients being administered intravascular administration of iodinated contrast materials, because the use of such products may result in acute alteration of renal function (see SPECIAL WARNINGS AND PRECAUTIONS FOR USE; Metformin hydrochloride).

 

Janumet XR

 

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

 

Pancreatitis

There have been reports of acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis (see SIDE EFFECTS), in patients taking sitagliptin. Patients should be informed of the characteristic symptom of acute pancreatitis: persistent, severe abdominal pain. Resolution of pancreatitis has been observed after discontinuation of sitagliptin.  If pancreatitis is suspected, Janumet XR, and other potentially suspect medicinal products should be discontinued.

 

Monitoring of Renal Function: Metformin and sitagliptin are known to be substantially excreted by the kidney. Before initiation of therapy with Janumet XR renal function should be assessed as the risk of metformin accumulation and lactic acidosis increases with increasing impairment of renal function. Janumet XR is contraindicated in patients with severe renal impairment (eGFR < 30 mL/min/1.73 m²).

 

Renal function should be re-assessed under treatment with Janumet XR at regular intervals, at least:

• annually in patients with normal renal function;
• at least every 3 – 6 months in patients with an eGFR of ≥45 – 59 ml/min/1.73 m², as well as in elderly patients;
• at least every 3 months in patients with an eGFR of ≥30 – 44 ml/min/1.73 m².

Janumet XR should be discontinued immediately, if eGFR falls below 30 ml/min/1.73 m².

 

Use with Medications Known to Cause Hypoglycemia: It is known that antidiabetic medication of the sulfonylurea type or insulins can cause hypoglycemia. Therefore, a reduction of the sulfonylurea or insulin dose, respectively may be necessary when taking these substances in combination with Janumet XR.

 

 

 

Sitagliptin phosphate

 

Myopathy / Rhabdomyolysis

Myopathies have been reported in connection with the use of Janumet, which manifest in the form of muscle pain, weakness or tenderness together with highly increased creatine kinase (CK, to ten times the upper limit of the norm). Myopathy can sometimes occur in the form of rhabdomyolysis with or without acute renal failure due to myoglobinuria, and deaths have rarely occurred.

 

Physicians should prescribe Janumet with caution in patients with predisposing factors for rhabdomyolysis. A creatine kinase level should be determined before starting treatment in the following situations:

-       Impairment of kidney function

-       Non-controlled hypothyroidism

-       Personal or family history of hereditary muscle disorders

-       History of muscle toxicity with a statin or fibrate

-       Alcohol addiction

-       Elderly persons (≥ 65 years): the necessity of such measurement should be considered in the presence of other predisposing factors for rhabdomyolysis

-       Female gender: the necessity of such measurement should be considered in the presence of other predisposing factors for rhabdomyolysis

 

In these situations, the risk of treatment should be considered in relation to the possible benefits.

Use with Medications Known to Cause Hypoglycemia: In clinical trials of sitagliptin as monotherapy and as part of combination therapy with agents not known to cause hypoglycemia (i.e., metformin or PPARγ agonists (thiazolidinedione)), rates of hypoglycemia reported with sitagliptin were similar to rates in patients taking placebo.

 

Hypersensitivity Reactions:

There have been postmarketing reports of serious hypersensitivity reactions in patients treated with sitagliptin, one of the components of Janumet XR. 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 even occurring after the first dose. Because these reactions are reported from a population of uncertain size, it is not possible to reliably estimate their frequency. If a hypersensitivity reaction is suspected, discontinue Janumet XR. (See CONTRAINDICATIONS and Side Effects, Postmarketing Experience.)

 

Bullous Pemphigoid:

Postmarketing cases of bullous pemphigoid requiring hospitalization have been reported with DPP-4 inhibitor use. In reported cases, patients typically recovered under topical or systemic immunosuppressive treatment and following discontinuation of the DPP-4 inhibitor. Tell patients to contact their doctor upon development of blisters or erosions of the skin while under treatment with Janumet XR. If bullous pemphigoid is suspected, Janumet XR should be discontinued and referral to a dermatologist should be considered for diagnosis and appropriate treatment.

 

Metformin hydrochloride

 

Lactic Acidosis: Lactic acidosis is a rare, but serious, metabolic complication that can occur due to metformin accumulation during treatment with Janumet XR (sitagliptin phosphate/metformin HCl extended-release); when it occurs, it is fatal in approximately 50% of cases. Lactic acidosis may also occur in association with a number of pathophysiologic conditions, including diabetes mellitus, and whenever there is significant tissue hypoperfusion and hypoxemia. Lactic acidosis is characterized by elevated blood lactate levels (>5 mmol/L), decreased blood pH, electrolyte disturbances with an increased anion gap, and an increased lactate/pyruvate ratio. When metformin is implicated as the cause of lactic acidosis, metformin plasma levels >5 µg/mL are generally found.

 

The reported incidence of lactic acidosis in patients receiving metformin hydrochloride is very low (approximately 0.03 cases/1’000 patient-years, with approximately 0.015 fatal cases/1’000 patient-years). In more than 20’000 patient-years exposure to metformin in clinical trials, there were no reports of lactic acidosis. Reported cases have occurred primarily in diabetic patients with severe impairment of renal function or chronic renal failure. Patients with congestive heart failure requiring pharmacologic management, in particular those with unstable or acute congestive heart failure with hypoperfusion and hypoxemia, are at increased risk of lactic acidosis. The risk of lactic acidosis increases with the degree of renal insufficiency and the patient's age. The risk of lactic acidosis may, therefore, be significantly decreased by regular monitoring of renal function in patients taking metformin and by use of the minimum effective dose of metformin. In particular, treatment of the elderly should be accompanied by careful monitoring of renal function (see Use in the elderly, Metformin hydrochloride). In addition, metformin should be promptly withheld in the presence of any condition associated with hypoxemia, dehydration, or sepsis. Because impaired hepatic function may significantly limit the ability to clear lactate, metformin should generally be avoided in patients with clinical or laboratory evidence of hepatic disease.

Patients should be cautioned against excessive alcohol intake, either acute or chronic, when taking metformin, since alcohol potentiates the effects of metformin hydrochloride on lactate metabolism. In addition, metformin should be temporarily discontinued prior to any intravascular radiocontrast application and for any surgical procedure.

 

The onset of lactic acidosis often is subtle, and accompanied primarily by nonspecific symptoms such as malaise, myalgias, respiratory distress, increasing somnolence, and nonspecific abdominal distress. There may be associated hypothermia, hypotension, and resistant bradyarrhythmias with more marked acidosis. The patient and the patient's physician must be aware of the possible importance of such symptoms and the patient should be instructed to notify the physician immediately if they occur. Metformin should be withdrawn and the patient should be hospitalized. Serum electrolytes, ketones, blood glucose, and blood pH, lactate levels, and even blood metformin levels may be useful.

 

Levels of fasting venous plasma lactate above the upper limit of normal but less than 5 mmol/L in patients taking metformin do not necessarily indicate impending lactic acidosis and may be explainable by other mechanisms, such as poorly controlled diabetes or obesity, vigorous physical activity, or technical problems in sample handling.

 

Lactic acidosis should be suspected in any diabetic patient with metabolic acidosis lacking evidence of ketoacidosis (ketonuria and ketonemia).

 

Lactic acidosis is a medical emergency that must be treated in a hospital setting. In a patient with lactic acidosis who is taking metformin, the drug should be discontinued immediately and general supportive measures promptly instituted. Because metformin hydrochloride and lactate are dialyzable (with a clearance of up to 170 mL/min under good hemodynamic conditions), prompt hemodialysis is recommended. Such management often results in prompt reversal of symptoms and recovery (see CONTRAINDICATIONS).

 

Once a patient is stabilized on any dose level of metformin, gastrointestinal symptoms, which are common during initiation of therapy, are unlikely to be drug related. Later occurrence of gastrointestinal symptoms could be due to lactic acidosis or other serious disease.

 

Hypoglycemia: Hypoglycemia does not occur in patients receiving metformin as monotherapy under usual circumstances of use, but could occur in exceptions for example when caloric intake is deficient, with strenuous exercise, or during concomitant use with alcohol or other glucose-lowering agents (such as sulfonylureas and insulin).

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.

 

Use of concomitant medications that may affect renal function or metformin disposition: Concomitant medication(s) that may affect renal function or result in significant hemodynamic change or may interfere with the disposition of metformin, such as cationic drugs that are eliminated by renal tubular secretion (see DRUG INTERACTIONS, Metformin hydrochloride), should be used with caution.

 

 

Application of iodine-containing contrast agents

Intravascular application of iodine-containing contrast agents for radiological investigations may lead to renal failure. As this can cause accumulation of metformin and lactic acidosis, treatment with metformin must be stopped timely (about 2 days) before any such investigation in patients with an eGFR of <60 ml/min/1.73 m². Therapy with metformin may only be resumed if renal function has not deteriorated 2 days after the investigation involving a contrast agent.

Hypoxic states: 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 XR therapy, the drug should be promptly discontinued.

 

Surgical procedures: Use of Janumet XR should be temporarily suspended for any surgical procedure (except minor procedures not associated with restricted intake of food and fluids) and should only be restarted when the patient's oral intake has resumed and renal function has been evaluated as acceptable (see DOSAGE AND ADMINISTRATION).

 

Alcohol intake: 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 XR.

 

Sodium: This medicinal product contains less than 1 mmol sodium (23 mg) per tablet and is considered to be essentially ‘sodium-free’.

 

Impaired hepatic function: Since impaired hepatic function has been associated with some cases of lactic acidosis, Janumet XR should generally be avoided in patients with clinical or laboratory evidence of hepatic disease.

 

Vitamin B₁₂ levels: 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 the reduction of the B₁₂ absorption, 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 XR and any apparent abnormalities should be appropriately investigated and managed.

 

Certain individuals (those with inadequate Vitamin B₁₂ or calcium intake or absorption) appear to be predisposed to developing subnormal Vitamin B₁₂ levels. In these patients, routine serum Vitamin B₁₂ measurements at two- to three-year intervals may be useful.

 

Change in clinical status of patients with previously controlled type 2 diabetes: A patient with type 2 diabetes previously well controlled on Janumet XR who develops laboratory abnormalities or clinical illness (especially vague and poorly defined illness) should be evaluated promptly for evidence of ketoacidosis or lactic acidosis. Evaluation should include serum electrolytes and ketones, blood glucose and, if indicated, blood pH, lactate, pyruvate, and metformin levels. If a metabolic acidosis is suspected – irrespective of its genesis - Janumet XR must be stopped immediately and the patient be hospitalized.

 

Loss of control of blood glucose: 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 XR and temporarily administer insulin. Janumet XR may be reinstituted after the acute episode is resolved.

 

 

Use in children and adolescents

Safety and effectiveness of Janumet XR and one of its components, sitagliptin in children and adolescent patients under 18 years have not been established.

 

Use in the elderly

Janumet XR

 

As metformin and sitagliptin are substantially excreted by the kidney, Janumet XR 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 SPECIAL WARNINGS AND PRECAUTIONS FOR USE, Metformin hydrochloride, Lactic acidosis).

 

Sitagliptin phosphate

 

In clinical studies, the safety and effectiveness of sitagliptin in the elderly (³65 years,) were comparable to those seen in younger patients (<65 years).

 

Metformin hydrochloride

 

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.

 

Generally, Janumet t XR should be taken together with the evening meal. By administration together with food the gastrointestinal side effects of metformin can partially be reduced. In addition it has to be anticipated that the bioavailability of extended-release metformin is reduced when administered on an empty stomach. This could make diabetic control more difficult. It has to be considered that the bioavailability of metformin without extended release is reduced by concomitant food administration - in contrast to extended-release metformin.

Sitagliptin and metformin

Coadministration of multiple doses of sitagliptin (50 mg b.i.d.) and metformin (1000 mg b.i.d.) did not meaningfully alter the pharmacokinetics of either sitagliptin or metformin in patients with type 2 diabetes.

 

Pharmacokinetic drug interaction studies with Janumet XR have not been performed; however, such studies have been conducted with the individual components of Janumet XR, sitagliptin and metformin.

 

Sitagliptin phosphate

 

In drug interaction studies, sitagliptin did not have clinically meaningful effects on the pharmacokinetics of the following: metformin, rosiglitazone, glyburide, simvastatin, warfarin, and oral contraceptives. Based on these data, sitagliptin does not inhibit CYP isozymes CYP3A4, 2C8, or 2C9. Based on in vitro data, sitagliptin is also not expected to inhibit CYP2D6, 1A2, 2C19 or 2B6 or to induce CYP3A4.

 

Population pharmacokinetic analyses have been conducted in patients with type 2 diabetes. Concomitant medications did not have a clinically meaningful effect on sitagliptin pharmacokinetics. Medications assessed were those that are commonly administered to patients with type 2 diabetes.

 

There was a slight increase in the area under the curve (AUC, 11%) and mean peak drug concentration (C_max, 18%) of digoxin with the coadministration of sitagliptin. These increases are not considered to be clinically meaningful. Patients receiving digoxin should be monitored appropriately.

The AUC and C_max of sitagliptin were increased approximately 29% and 68%, respectively, in subjects with coadministration of a single 100-mg oral dose of sitagliptin and a single 600‑mg oral dose of cyclosporine, a potent probe inhibitor of p-glycoprotein. The observed changes in sitagliptin pharmacokinetics are not considered to be clinically meaningful.

 

 

Metformin hydrochloride

 

Glyburide: In a single-dose interaction study in type 2 diabetes patients, coadministration 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.

 

Furosemide: A single-dose, metformin-furosemide drug interaction study in healthy subjects demonstrated that pharmacokinetic parameters of both compounds were affected by coadministration. 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 coadministered chronically.

 

Nifedipine: A single-dose, metformin-nifedipine drug interaction study in normal healthy volunteers demonstrated that coadministration 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.

 

Concomitant use of drugs that interfere with the renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transporter-2 [OCT2] / multidrug and toxin extrusion [MATE] inhibitors such as ranolazine, vandetanib, dolutegravir, and cimetidine) could increase systemic exposure of metformin and may increase the risk for lactic acidosis. In interaction studies with both single and multiple dose of metformin in combination with cimetidine in healthy subjects peak metformin plasma and whole blood concentrations increased by 60% and the plasma and whole blood metformin AUC increased by 40%. Therefore, consider the benefits and risks of concomitant use of these substances with metformin.

 

Other: 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.

 

In healthy volunteers, the pharmacokinetics of metformin and propranolol, and metformin and ibuprofen were not affected when coadministered 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.

 

Fertility

Animal data do not suggest an effect of treatment with sitagliptin on male and female fertility. Human data are lacking.

 

Pregnancy

There are no adequate and well-controlled studies in pregnant women with Janumet XR or its individual components; therefore, the safety of Janumet  XR in pregnant women is not known. Janumet  XR, like other oral antihyperglycemic agents, is not recommended for use in pregnancy.

 

Lactation

No studies in lactating animals have been conducted with the combined components of Janumet  XR. 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 is excreted in human milk. Therefore, Janumet  XR should not be used by a woman who is nursing.

 

No studies of the effects of Janumet  XR on the ability to drive and use machines have been performed. However, Janumet  XR is not expected to affect the ability to drive and use machines.

Summary of the safety profile

There were no clinical studies conducted with Janumet  XR tablets. However, bioequivalence was shown between Janumet  XR and sitagliptin coadministered with extended-release metformin (see PHARMACOKINETICS).

In placebo-controlled clinical trials, in patients with type 2 diabetes mellitus, the combination of sitagliptin and metformin without extended release was generally well tolerated. The overall incidence of side effects reported in patients receiving the combination of sitagliptin and metformin was similar to that reported in patients receiving the combination of placebo and metformin.

 

The frequencies are defined as: common ³1/100, <1/10; uncommon ³1/1000, <1/100; rare ³1/10000, <1/1000; very rare <1/10000.

 

Combination Therapy with Sitagliptin and Metformin

 

In a 24-week placebo-controlled study, patients inadequately controlled with diet and exercise alone received sitagliptin 50 mg twice daily in combination with metformin at 500 or 1000 mg twice daily. The drug-related adverse reactions reported in ³1% of patients receiving combination therapy (and greater than in patients receiving placebo) are shown as follows:

 

Metabolism and nutrition disorders

Common: hypoglycemia

 

Nervous system disorders

Common: headache

 

Gastrointestinal disorders

Common: diarrhea, nausea, dyspepsia, flatulence, vomiting

 

 

In a 24-week placebo-controlled study of sitagliptin added to ongoing metformin therapy, 464 patients on metformin were treated with sitagliptin 100 mg once daily and 237 patients were given placebo with metformin. The drug-related adverse reaction reported that occurred with an incidence of ³1% and higher than placebo in patients receiving sitagliptin and metformin is as follows:

 

Gastrointestinal disorders

Common: nausea

 

 

Hypoglycemia and Gastrointestinal Adverse Experiences

 

In the placebo-controlled studies of combination therapy with sitagliptin and metformin, the incidence of hypoglycemia (regardless of investigator assessment of causality) reported in patients treated with the combination of sitagliptin and metformin was similar to that reported for patients treated with metformin and placebo. The incidences of gastrointestinal adverse experiences in patients treated with the combination of sitagliptin and metformin were similar to those reported for patients treated with metformin alone. See Table 1.

 

Table 1 Hypoglycemia and Pre-specified Gastrointestinal Intestinal Adverse Experiences (Regardless of Investigator Assessment of Causality) Reported in Patients Receiving Combination Therapy
	Number of Patients (%)
	Study of Sitagliptin and Metformin in patients inadequately controlled on diet and exercise alone				Study of Sitagliptin as Add-on to Metformin
	Placebo	Sitagliptin 100 mg q.d.	Metformin 500 or 1000 mg b.i.d. ††	Sitagliptin 50 mg b.i.d. + Metformin 500 or 1000 mg b.i.d. ††	Placebo and Metformin ³1500 mg daily	Sitagliptin 100 mg q.d. and Metformin ³1500 mg daily
	N = 176	N = 179	N = 364	N = 372	N= 237	N= 464
Hypoglycemia	1 (0.6)	1 (0.6)	3 (0.8)	6 (1.6)	5 (2.1)	6 (1.3)
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 (2.1)	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)

^† Abdominal discomfort was included in the analysis of abdominal pain in the study of patients inadequately controlled on diet and exercise alone

^†† Data pooled for the patients given the lower and higher doses of metformin.

 

In all studies all adverse experiences of hypoglycemia were considered, including those not documented by a glucose measurement.

 

Sitagliptin in Combination with Metformin and a Sulfonylurea

 

In a 24-week placebo-controlled study of sitagliptin 100 mg daily added to ongoing combination treatment with glimepiride ≥4 mg daily and metformin ≥1500 mg daily, the drug-related adverse reactions reported in ³1% of patients treated with sitagliptin (N=116) and more commonly than in patients treated with placebo (N=113) are shown as follows:

 

Metabolism and nutrition disorders

Common: hypoglycemia

 

Gastrointestinal disorders

Common: constipation

 

No clinically meaningful changes in vital signs or in ECG (including in QTc interval) were observed with sitagliptin plus metformin treatment.

 

 

Sitagliptin in Combination with Metformin and Insulin

 

In a 24‑week placebo-controlled study of sitagliptin 100 mg added to ongoing combination treatment with metformin ≥1500 mg daily and stable-dose insulin, the only adverse reaction reported in ³1% of patients treated with sitagliptin (N=229) and more commonly than in patients treated with placebo (N=233) was hypoglycemia (sitagliptin, 15.3%; placebo, 8.2%). These frequencies include all adverse events independently from the investigator assessment for causality. Especially for the rates of hypoglycemia it should be considered that all patients receiving either sitagliptin or placebo were also treated with insulin and partially with metformin. In another 24-week study of patients receiving sitagliptin as add-on therapy while undergoing insulin intensification (with or without metformin), the adverse reactions reported in ³1% in patients treated with sitagliptin and metformin (N=285) and more commonly than in patients treated with placebo and metformin (N=283) were: constipation (sitagliptin and metformin, 1.4%; placebo and metformin, 1.1%), diarrhea (4.9%, 2.5%), vomiting (3.2%, 1.1%), peripheral edema (2.1%, 1.4%), pyrexia (1.1%, 0.4%), bronchitis (1.4%, 1.1%), cellulitis (1.4%, 1.1%), pharyngitis (1.8%, 1.1%), upper respiratory tract infection (4.2%, 1.4%), decreased creatinine clearance (1.1%, 0.0%), musculoskeletal pain (1.4%, 1.1%), myalgia (1.1%, 0.7%), nephrolithiasis (1.1%, 0.4%), and cough (2.8%, 1.8%). These frequencies include all adverse events independently from the investigator assessment for causality. Additionally, the incidence of hypoglycemia was 24.9% for patients treated with sitagliptin, metformin, and insulin and 37.8% for patients treated with placebo, metformin and insulin.

 

 

Established Adverse Reactions with Sitagliptin

There were no drug-related adverse reactions reported that occurred with an incidence of ³1% in patients receiving sitagliptin.

 

Established Adverse Reactions with Metformin

Blood and the lymphatic system disorders

rare cases of leucopenia, thrombopenia and hemolytic anemia

Very rare: decreased vitamin B12 levels

 

Metabolism and nutrition disorders

Very rare: lactacidosis (incidence 3cases/100'000 patient years, see Precautions)

 

Nervous system disorders

Common: mettalic taste (3%)

 

Gastrointestinal disorders

Common: Gastrointestinal disorders like vomiting, nausea, diarrhea, abdominal pain, loss of appetite. These symptooms occur at the beginning of the therape and disappear spontaneously.

 

Hepato-biliary disorders

Single cases: abnormal liver function tests, e.g. increased transaminases and hepatitis (reversible after discontinuation of therapy)

 

Skin and subcutaneous tissue disorders

Very rare: skin reactions like erythema, pruritus, urticaria.

 

TECOS Cardiovascular Safety Study

 

The Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS) included 7,332 patients treated with sitagliptin, 100 mg daily (or 50 mg daily if the baseline estimated glomerular filtration rate (eGFR) was ≥30 and <50 mL/min/1.73 m²), and 7,339 patients treated with placebo in the intention-to-treat population. Both treatments were added to usual care. The study population included a total of 2,004 patients ≥75 years of age (970 treated with sitagliptin and 1,034 treated with placebo). The overall incidence of serious adverse events in patients receiving sitagliptin was similar to that in patients receiving placebo. Assessment of pre-specified diabetes-related complications revealed similar incidences between groups including infections (18.4% of the sitagliptin-treated patients and 17.7% of the placebo-treated patients) and renal failure (1.4% of sitagliptin-treated patients and 1.5% of placebo-treated patients). The adverse event profile in patients ≥75 years of age was generally similar to the overall population.

 

Among patients who were using insulin and/or a sulfonylurea at baseline, the incidence of severe hypoglycemia was 2.7% in sitagliptin-treated patients and 2.5% in placebo-treated patients; among patients who were not using insulin and/or a sulfonylurea at baseline, the incidence of severe hypoglycemia was 1.0% in sitagliptin-treated patients and 0.7% in placebo-treated patients. The incidence of pancreatitis, confirmed by an adjudication committee, was 0.3% in sitagliptin-treated patients and 0.2% in placebo-treated patients. The incidence of malignancies, confirmed by an adjudication committee, was 3.7% in sitagliptin‑treated patients and 4.0% in placebo-treated patients.

 

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). (See also TECOS Cardiovascular Safety Study and Warnings and Precautions FOR USE, Pancreatitis).

 

Postmarketing Experience:

 

Additional adverse reactions have been identified during postmarketing use of Janumet  XR or sitagliptin, one of the components of Janumet  XR. These reactions have been reported when Janumet  XR 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 CONTRAINDICATIONS and SPECIAL WARNINGS AND PRECAUTIONS FOR USE, Sitagliptin phosphate, Hypersensitivity Reactions); acute pancreatitis including fatal and non-fatal hemorrhagic and necrotizing pancreatitis (see SPECIAL WARNINGS AND PRECAUTIONS FOR USE); worsening renal function, including acute renal failure (sometimes requiring dialysis); rhabdomyolysis; bullous pemphigoid (see SPECIAL WARNINGS AND PRECAUTIONS FOR USE, Bullous Pemphigoid); upper respiratory tract infection; nasopharyngitis; constipation; vomiting; headache; arthralgia; myalgia; pain in extremity; back pain; pruritus.

 

 

Laboratory test findings

Sitagliptin phosphate

 

 The incidence of laboratory adverse experiences was similar in patients treated with sitagliptin and metformin compared to patients treated with placebo and metformin. Across clinical 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 observation was seen in most but not all studies. 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 PRECAUTIONS, Metformin hydrochloride).

 

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is very important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions online .

 

 

To report any side effect(s):

·       Saudi Arabia:

The National Pharmacovigilance Centre (NPC):

SFDA Call Center: 19999

E-mail: npc.drug@sfda.gov.sa

Website: https://ade.sfda.gov.sa

 

·       Other GCC States:

Please contact the relevant competent authority.

 

 

Sitagliptin phosphate

 

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. There is no experience with doses above 800 mg in clinical studies. 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 periods up to 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.

 

Metformin hydrochloride

 

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 PRECAUTIONS, Metformin hydrochloride). 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.

 

 

Pharmacotherapeutic group: Drugs used in diabetes, Combinations of oral blood glucose lowering drugs, ATC code: A10BD07

Janumet XR combines two antihyperglycaemic medicinal products with complementary mechanisms of action to improve glycaemic control in patients with type 2 diabetes: sitagliptin phosphate, a dipeptidyl peptidase 4 (DPP-4) inhibitor, and metformin hydrochloride, a member of the biguanide class.

 

 

Sitagliptin

Mechanism of action

Sitagliptin phosphate is a member of a class of oral anti-hyperglycemic agents called dipeptidyl peptidase 4 (DPP-4) inhibitors, which improve glycemic control in patients with type 2 diabetes by enhancing the levels of active incretin hormones. Incretin hormones, including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are released by the intestine throughout the day, and levels are increased in response to a meal. The incretins are part of an endogenous system involved in the physiologic regulation of glucose homeostasis. When blood glucose concentrations are normal or elevated, GLP-1 and GIP increase insulin synthesis and release from pancreatic beta cells by intracellular signaling pathways involving cyclic AMP. Treatment with GLP-1 or with DPP-4 inhibitors in animal models of type 2 diabetes has been demonstrated to improve beta cell responsiveness to glucose and stimulate insulin biosynthesis and release. With higher insulin levels, tissue glucose uptake is enhanced. In addition, GLP-1 lowers glucagon secretion from pancreatic alpha cells. Decreased glucagon concentrations, along with higher insulin levels, lead to reduced hepatic glucose production, resulting in a decrease in blood glucose levels. The effects of GLP-1 and GIP are glucose-dependent such that when blood glucose concentrations are low, stimulation of insulin release and suppression of glucagon secretion by the incretin hormones GLP-1 are not observed. For both GLP-1 and GIP, stimulation of insulin release is enhanced as glucose rises above normal concentrations. Further, GLP-1 and GIP does not impair the normal glucagon response to hypoglycemia. The activity of GLP-1 and GIP is limited by the DPP-4 enzyme, which rapidly hydrolyzes the incretin hormones to produce inactive products. Sitagliptin prevents the hydrolysis of incretin hormones by DPP-4, thereby increasing plasma concentrations of the active forms of GLP-1 and GIP. By enhancing active incretin levels, sitagliptin increases insulin release and decreases glucagon levels in a glucose-dependent manner. In patients with type 2 diabetes with hyperglycemia, these changes in insulin and glucagon levels lead to lower hemoglobin A_1c (HbA_1c) and lower fasting and postprandial glucose concentrations. The glucose-dependant mechanism of sitagliptin is distinct from the mechanism of sulfonylureas, which increases insulin secretion even when glucose levels are low and can lead to hypoglycemia in patients with type 2 diabetes and in normal subjects. Sitagliptin is a potent and highly selective inhibitor of the enzyme DPP-4 and does not inhibit the closely-related enzymes DPP-8 or DPP-9 at therapeutic concentrations.

.

Metformin hydrochloride

Mechanism of action

 

Metformin is an antihyperglycemic agent which improves glucose tolerance in patients with type 2 diabetes, lowering both basal and postprandial plasma glucose. Its pharmacologic mechanisms of action are different from other classes of oral antihyperglycemic agents. Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. Unlike sulfonylureas, metformin does not produce hypoglycemia in either patients with type 2 diabetes or normal subjects (except in special circumstances, see PRECAUTIONS, Metformin hydrochloride) and does not cause hyperinsulinemia. With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin response may actually decrease.

 

 

Clinical Efficacy

Clinical Studies

There were no clinical studies conducted with Janumet XR on efficacy and safety. Clinical studies of the coadministration of sitagliptin and metformin without extended release demonstrated significant improvements in glycemic control in patients with type 2 diabetes. The bioequivalence between Janumet XR tablets and coadministered sitagliptin and extended-release metformin tablets was demonstrated for all tablet strengths.

In a comparative study, once daily administration of extended-release metformin had efficacy similar to the commonly prescribed twice daily administration of the metformin formulation without extended release in all measures of glycemic control.

 

Sitagliptin and Metformin without extended release in Patients with Type 2 Diabetes

 

A total of 1091 patients with type 2 diabetes and inadequate glycemic control on diet and exercise participated in a 24-week, randomized, double-blind, placebo-controlled study designed to assess the safety and efficacy of therapy with the combination of sitagliptin and metformin.

 

In patients with inadequate glycemic control on diet and exercise alone the combination of sitagliptin and metformin provided significant improvements in HbA_1c, FPG, and 2-hour PPG compared to placebo, to metformin alone, and to sitagliptin alone (p<0.001; Table 2, Figure 1). An improvement in FPG, with near maximal FPG reduction, was achieved by the 3-week time point (the first time point assessed after initiation of therapy) and sustained throughout the 24-week study. Mean reductions from baseline in HbA_1c compared with placebo were generally greater for patients with higher baseline HbA_1c values.

The improvement in HbA_1c was generally consistent across subgroups defined by gender, age, race, or baseline BMI. Measures of beta cell function, HOMA-β and the proinsulin to insulin ratio also showed greater improvement with the coadministration of sitagliptin and metformin compared with either monotherapy alone. Lipid effects were generally neutral.  Mean reductions from baseline HbA_1c for the sub-group of patients not on an antihyperglycemic agent at study entry were: sitagliptin 100 mg once daily (N=88), -1.06 %; metformin 500 mg bid (N=90), -1.09 %; metformin 1000 mg bid (N=87), -1.24 %; sitagliptin 50 mg bid with metformin 500 mg bid (N=100), -1.59 %; and sitagliptin 50 mg bid with metformin 1000mg bid (N=86), -1.94%; and for patients receiving placebo (N=83), -0.17 %.

 

Figure 1: Mean Change from Baseline for HbA_1c over 24 Weeks with Sitagliptin and Metformin, Alone and in Combination as Initial Therapy in Patients with Type 2 Diabetes†

^†All Patients Treated Population Least squares means adjusted for prior antihyperglycemic therapy and baseline value.

 

 

Table 2

Glycemic Parameters and Body Weight at Final Visit after 24-Weeks^†

 

 

^† All Patients Treated Population (an intention-to-treat analysis).

^‡ Least squares means adjusted for prior antihyperglycemic therapy status and baseline value.

^§ p<0.001 compared to placebo.

^% All Patients as Treated (APaT) population, excluding data following glycemic rescue therapy.

^¶ p=0.005 compared to placebo.

^# Not statistically significant (p³0.05) compared to placebo.

 

In addition, this study included patients (N=117) with more severe hyperglycemia (HbA_1c >11% or blood glucose >15.56 mmol/L) who were treated with sitagliptin at 50 mg and metformin at 1000 mg twice daily. There was no placebo control for these patients. In this group of patients, the baseline HbA_1c value was on average 11.15%, FPG was 17.4 mmol/L, and 2-hour PPG was 24.5 mmol/L. At 24 weeks, decreases from baseline of ‑2.94 % for HbA_1c, ‑7.04 mmol/L for FPG, and ‑11.55 mmol/L for 2-hour PPG were observed. In this cohort, an increase in body weight of 1.3 kg was observed at 24 weeks.

 

Sitagliptin Add-on Therapy in Patients Inadequately Controlled on Metformin Alone:

 

The combination of sitagliptin and metformin without extended release has been evaluated for safety and efficacy in two double-blind, placebo-controlled clinical studies in patients with type 2 diabetes mellitus. In both studies, patients with inadequate glycemic control on stable doses of metformin ≥1500 mg were randomized to receive either sitagliptin 100 mg per day or placebo in addition to ongoing treatment with metformin.

 

In one study, 701 patients received 100 mg of sitagliptin or placebo once daily for 24 weeks. The addition of sitagliptin to ongoing metformin treatment without extended release provided significant improvements compared with the addition of placebo to ongoing metformin treatment in HbA_1c (-0.65%), FPG (-1.41 mmol/L), and 2-hour PPG (-2.81 mmol/L) (see Figure 2 and Table 3). This improvement in HbA_1c compared to placebo was not affected by baseline HbA_1c value, prior antihyperglycemic therapy, gender, age, baseline BMI, length of time since diagnosis of diabetes, presence of metabolic syndrome, or standard indices of insulin resistance (HOMA-IR) or insulin secretion (HOMA-β).

 

Figure 2: Mean Change from Baseline for HbA_1c over 24 Weeks with Sitagliptin 100-mg Total Daily Dose and Metformin or Placebo and Metformin in Patients with Type 2 Diabetes^{† ‡}

 

^† Patients with inadequate glycemic control on metformin monotherapy.

^‡ All Patients Treated Population Least squares means adjusted for prior antihyperglycemic therapy and baseline value.

 

 

Table 3: Glycemic Parameters and Body Weight at Final Visit (24-Week Study)

Sitagliptin as Add-on Therapy in Patients with Inadequate Glycemic Control on Metformin ^†

 

 

 

^† All Patients Treated Population (an intention-to-treat analysis).

^‡ Least squares means adjusted for prior antihyperglycemic therapy and baseline value.

^§ p<0.001 compared to placebo + metformin.

^% All Patients as Treated (APaT) population, excluding data following glycemic rescue therapy.

^¶ Not statistically significant (p³0.05) compared to placebo + metformin.

 

 

 

 

Figure 3: 24-hour Plasma Glucose Profile after 4-Week Treatment with

Sitagliptin 50-mg BID and Metformin or

Placebo and Metformin in Patients with Type 2 Diabetes^†

 

^†Patients with inadequate glycemic control on metformin monotherapy.

 

Sitagliptin Add-on Therapy in Patients Inadequately Controlled on the Combination of Metformin without extended release and Glimepiride:

 

A total of 441 patients with type 2 diabetes participated in a 24-week, randomized, double-blind, placebo-controlled study designed to assess the efficacy of sitagliptin 100 mg once daily compared to placebo in combination with glimepiride (alone or in combination with metformin). In this study, 220 patients were on the combination of glimepiride (≥ 4 mg per day) and metformin (≥ 1500 mg per day)

The combination of sitagliptin, glimepiride, and metformin provided significant reduction from baseline in HbA_1c (-0.89%) and FPG (-1.15 mmol/L) compared to placebo (see Table 4). Mean reductions from baseline in HbA_1c compared with placebo were generally greater for patients with higher baseline HbA_1c values.

 

 

Table 4

Glycemic* Parameters and Body Weight at Final Visit (24-Week Study)

for Sitagliptin as Add-on Combination Therapy with Glimepiride and Metformin^†

 

 

 

 

*Primary and secondary glycemic parameters measured included HbA_1c and fasting glucose

^† All Patients Treated Population (an intention-to-treat analysis).

^‡ Least squares means adjusted for prior antihyperglycemic therapy status and baseline value.

^§ p<0.001 compared to placebo.

^% All Patients as Treated (APaT) population, excluding data following glycemic rescue therapy.

^††p=0.007 compared to placebo.

 

Sitagliptin Add-on Therapy in Patients Inadequately Controlled on the Combination of Metformin without extended release and Insulin:

A total of 641 patients with type 2 diabetes participated in a 24‑week, randomized, double-blind, placebo-controlled study designed to assess the efficacy of sitagliptin 100 mg once daily in combination with a stable dose of insulin. Approximately 75% of patients were also taking metformin. Patients on pre-mixed, long-acting or intermediate acting insulin (with or without metformin) were randomized to the addition of either 100 mg of sitagliptin or placebo. Glycemic endpoints measured included HbA_1c, fasting glucose and 2-hour postprandial glucose (PPG).

 

The combination of sitagliptin, metformin and insulin provided significant improvements in HbA_1c, fasting glucose and 2-hour PPG compared to placebo (Table 5). The improvement in HbA_1c compared to placebo was generally consistent across subgroups defined by gender, age, race, baseline BMI, length of time since diagnosis of diabetes, presence of metabolic syndrome, or standard indices of insulin resistance (HOMA‑IR) or insulin secretion (HOMA‑β). There was no meaningful change from baseline in body weight in either group.

Table 5

Glycemic Parameters and Body Weight at Final Visit (24‑Week Study)

for Sitagliptin as Add-on Combination Therapy with Metformin and a Stable Dose of Insulin^†

 

 

^† All Patients Treated Population (an intention-to-treat analysis).

^‡ Least squares mean adjusted for insulin use at Visit 1 (premixed vs. non-pre-mixed [intermediate- or long-acting]), and baseline value.

^§ Treatment by insulin stratum interaction was not significant (p > 0.10).

^% p<0.001 compared to placebo.

^¶ All Patients as Treated (APaT) population, excluding data following glycemic rescue therapy.

^# Not statistically significant (p³0.05) compared to placebo.

 

In another 24-week, randomized, double-blind, placebo-controlled study designed to assess the insulin-sparing efficacy of sitagliptin as add-on combination therapy, 660 patients with inadequate glycemic control on insulin glargine with or without metformin (≥1500 mg per day) were randomized to the addition of either 100 mg of sitagliptin (N=330) or placebo (N=330), administered once daily while undergoing intensification of insulin therapy. Among patients taking metformin, baseline HbA_1c was 8.70% and baseline insulin dose was 37 IU/day. Patients were instructed to titrate their insulin glargine dose based on fingerstick fasting glucose values. Secondary study-endpoints included HbA_1c and FPG.

 

Among patients taking metformin, at Week 24, the increase in daily insulin dose was smaller in patients treated with sitagliptin (19 IU/day, N=285) than in patients treated with placebo (24 IU/day, N=283). This difference was statistically significant (p=0.007).

Regarding secondary study-endpoints there was a reduction in HbA_1c for patients treated with sitagliptin, metformin, and insulin of -1.35% compared to -0.90% for patients treated with placebo, metformin, and insulin, a difference of -0.45% [95% CI: -0.62, -0.29]. The reduction in FPG for patients treated with sitagliptin, metformin, and insulin was -3.0 mmol/L compared to -2.4 mmol/L for patients treated with placebo, metformin, and insulin, a difference of -0.7 mmol/L [95% CI: -1.0, -0.3].

 

Glipizide-Controlled Study in Combination with Metformin without extended release

 

Long-term maintenance of effect was evaluated in a 52-week, double-blind, glipizide-controlled trial in patients with type 2 diabetes and inadequate glycemic control on metformin monotherapy at ≥1500 mg/day. In this study, patients were randomized to the addition of either sitagliptin 100 mg daily (N = 588) or glipizide (N = 584) for 52 weeks. Patients receiving glipizide were given an initial dosage of 5 mg/day and then electively titrated by the investigator to a target FPG of <110 mg/dL, without significant hypoglycemia, over the next 18 weeks. A maximum dosage of 20 mg/day was allowed to optimize glycemic control. Thereafter, the glipizide dose was to have been kept constant. The mean dose of glipizide after the titration period was 10.3 mg.

 

Both treatments resulted in a statistically significant improvement in glycemic control from baseline. After 52 weeks, the reduction from baseline in HbA_1c was 0.67% for sitagliptin 100 mg daily and 0.67% for glipizide, confirming comparable efficacy of the two agents. The reduction in FPG was 0.56 mmol/L for sitagliptin and 0.42 mmol/L for glipizide. In a post-hoc analysis, patients with higher baseline HbA_1c (≥9%) in both groups had greater reductions from baseline in HbA_1c (sitagliptin, -1.68%; glipizide, -1.76%). In this study, the proinsulin to insulin ratio, a marker of efficiency of insulin synthesis and release, improved with sitagliptin and deteriorated with glipizide treatment. The incidence of hypoglycemia in the sitagliptin group (4.9%) was significantly lower than that in the glipizide group (32.0%). Patients treated with sitagliptin exhibited a significant mean decrease from baseline in body weight compared to a significant weight gain in patients administered glipizide (-1.5 kg vs. +1.1 kg).

 

Metformin hydrochloride

 

The prospective randomized (UKPDS) study has established the long-term benefit of intensive blood glucose control in type 2 diabetes. Analysis of the results for overweight patients treated with metformin after failure of diet alone showed:

- a significant reduction of the absolute risk of any diabetes-related complication in the metformin group (29.8 events/1000 patient-years) versus diet alone (43.3 events/1000 patient-years), p=0.0023, and versus the combined sulphonylurea and insulin monotherapy groups (40.1 events/1000 patient-years), p=0.0034.

- a significant reduction of the absolute risk of diabetes-related mortality: metformin 7.5 events/1000 patient-years, diet alone 12.7 events/1000 patient-years, p=0.017.

- a significant reduction of the absolute risk of overall mortality: metformin 13.5 events/1000 patient-years versus diet alone 20.6 events/1000 patient-years (p=0.011), and versus the combined sulphonylurea and insulin monotherapy groups 18.9 events/1000 patient-years (p=0.021).

- a significant reduction in the absolute risk of myocardial infarction: metformin 11 events/1000 patient-years, diet alone 18 events/1000 patient-years (p=0.01).

 

TECOS Cardiovascular Safety Study

 

The Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS) was a randomized study in 14,671 patients in the intention-to-treat population with an HbA1c of ≥6.5 to 8.0% with established CV disease who received sitagliptin (7,332) 100 mg daily (or 50 mg daily if the baseline eGFR was ≥30 and <50 mL/min/1.73 m²) or placebo (7,339) added to usual care targeting regional standards for HbA1c and CV risk factors. Patients with an eGFR <30 mL/min/1.73 m² were not to be enrolled in the study. The study included 2,004 patients who were ≥75 years of age and 3,324 patients who had renal impairment (eGFR <60 mL/min/1.73 m²).

 

 Patients in the sitagliptin group received fewer antihyperglycemic agents than did those in the placebo group (hazard ratio 0.72; 95% CI, 0.68 to 0.77; p£0.001) and, among patients not on insulin at study entry, were less likely to start chronic insulin therapy (hazard ratio 0.70; 95% CI, 0.63 to 0.79; p<0.001).

The primary cardiovascular endpoint was a composite of the first occurrence of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for unstable angina. Secondary cardiovascular endpoints included the first occurrence of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke; first occurrence of the individual components of the primary composite; all-cause mortality; and hospital admissions for congestive heart failure.

 

After a median follow up of 3 years, sitagliptin, when added to usual care, did not increase the risk of major adverse cardiovascular events or the risk of hospitalization for heart failure in patients with type 2 diabetes (Table 6).

 

Table 6

Rates of Composite Cardiovascular Outcomes and Key Secondary Outcomes

 

* Incidence rate per 100 patient-years is calculated as 100 × (total number of patients with ≥1 event during eligible exposure period per total patient-years of follow-up).

^† Based on a Cox model stratified by region. For composite endpoints, the p-values correspond to a test of non-inferiority seeking to show that the hazard ratio is less than 1.3. For all other endpoints, the p-values correspond to a test of differences in hazard rates.

^‡ The analysis of hospitalization for heart failure was adjusted for a history of heart failure at baseline.

The results of a study in healthy subjects demonstrated that the Janumet XR (sitagliptin/metformin HCl extended-release) 50 mg/500 mg and 100 mg/1000 mg tablets, and coadministration of corresponding doses of sitagliptin (JANUVIA^™) and metformin hydrochloride extended-release as individual tablets are bioequivalent.

 

Bioequivalence between two Janumet XR 50 mg/500 mg tablets and one Janumet XR 100 mg/1000 mg tablet was also demonstrated.

 

In a crossover study in healthy subjects, the AUC and C_max for sitagliptin and AUC for metformin after administration of a single Janumet XR 50 mg/500 mg tablet probe formulation and administration of a single Janumet (sitagliptin phosphate/metformin HCl without extended release) 50 mg/500 mg tablet were similar. After administration of a single Janumet XR 50 mg/500 mg tablet probe formulation, the mean C_max value for metformin was 30% lower and the median T_max value occurred 4 hours later compared with corresponding values after administration of a single Janumet 50 mg/500 mg tablet, which is consistent with the expected modified-release characteristics for metformin associated with the Janumet XR formulation.

 

After administration of two Janumet XR 50 mg/1000 mg tablets once daily with the evening meal for 7 days in healthy adult subjects, steady-state for sitagliptin and metformin was reached by Day 4 and 5, respectively. The median Tmax values for sitagliptin and metformin at steady state were approximately 3 and 8 hours postdose, respectively. The median Tmax values for sitagliptin and metformin after administration of a single tablet of Janumet were 3 and 3.5 hours postdose, respectively.

 

Pharmacokinetic data that characterize distribution, metabolism and elimination of metformin and sitagliptin were obtained from studies with administration of the individual components of metformin without extended release and sitagliptin, and they are applicable to Janumet XR.

 

Absorption

Janumet XR

After administration of Janumet XR tablets with a high-fat breakfast, the AUC for sitagliptin was not altered. The mean C_max was decreased by 17%, although the median T_max was unchanged relative to the fasted state. After administration of Janumet XR with a high-fat breakfast, the AUC for metformin increased 62%, the C_max for metformin decreased by 9%, and the median T_max for metformin occurred 2 hours later relative to the fasted state.

Sitagliptin phosphate

The absolute bioavailability of sitagliptin is approximately 87%. Coadministration of a high-fat meal with sitagliptin phosphate had no effect on the pharmacokinetics of sitagliptin.

 

Distribution

Sitagliptin phosphate

 

The mean volume of distribution at steady state following a single 100-mg intravenous dose of sitagliptin to healthy subjects is approximately 198 liters. The fraction of sitagliptin reversibly bound to plasma proteins is low (38%).

 

Metformin hydrochloride

 

Distribution studies with extended-release metformin have not been conducted. The apparent volume of distribution (V/F) of metformin following single oral doses of metformin hydrochloride tablets 850 mg without extended release averaged 654 ± 358 L. Metformin is negligibly bound to plasma proteins, in contrast to sulfonylureas, which are more than 90% protein bound. Metformin partitions into erythrocytes, most likely as a function of time. At usual clinical doses and dosing schedules of metformin hydrochloride tablets, steady state plasma concentrations of metformin are reached within 24-48 hours and are generally <1 mcg/mL. During controlled clinical trials of metformin, maximum metformin plasma levels did not exceed 5 mcg/mL, even at maximum doses.

 

Metabolism

Sitagliptin phosphate

 

Sitagliptin is primarily eliminated unchanged in urine, and metabolism is a minor pathway. Approximately 79% of sitagliptin is excreted unchanged in the urine.

 

Following a [¹⁴C]sitagliptin oral dose, approximately 16% of the radioactivity was excreted as metabolites of sitagliptin. Six metabolites were detected at trace levels and are not expected to contribute to the plasma DPP‑4 inhibitory activity of sitagliptin. In vitro studies indicated that the primary enzyme responsible for the limited metabolism of sitagliptin was CYP3A4, with contribution from CYP2C8.

 

Metformin hydrochloride

 

Intravenous single-dose studies in normal subjects demonstrate that metformin is excreted unchanged in the urine and does not undergo hepatic metabolism (no metabolites have been identified in humans) nor biliary excretion.

 

Elimination

Sitagliptin phosphate

 

Following administration of an oral [¹⁴C]sitagliptin dose to healthy subjects, approximately 100% of the administered radioactivity was eliminated in feces (13%) or urine (87%) within one week of dosing. The apparent terminal t_1/2 following a 100-mg oral dose of sitagliptin was approximately 12.4 hours and renal clearance was approximately 350 mL/min.

 

Elimination of sitagliptin occurs primarily via renal excretion and involves active tubular secretion. Sitagliptin is a substrate for human organic anion transporter-3 (hOAT-3), which may be involved in the renal elimination of sitagliptin. The clinical relevance of hOAT-3 in sitagliptin transport has not been established. Sitagliptin is also a substrate of p-glycoprotein, which may also be involved in mediating the renal elimination of sitagliptin. However, cyclosporine, a p-glycoprotein inhibitor, did not reduce the renal clearance of sitagliptin.

 

Metformin hydrochloride

 

Renal clearance is approximately 3.5 times greater than creatinine clearance, which indicates that tubular secretion is the major route of metformin elimination. Following oral administration of metformin without extended release, approximately 90% of the absorbed drug is eliminated via the renal route within the first 24 hours, with a plasma elimination half-life of approximately 6.2 hours. In blood, the elimination half-life is approximately 17.6 hours, suggesting that the erythrocyte mass may be a compartment of distribution.

 

 

Renal Impairment

 

Sitagliptin phosphate

 

An approximately 2-fold increase in the plasma AUC of sitagliptin was observed in patients with moderate renal impairment with eGFR of 30 to <45 mL/min/1.73 m², and an approximately 4-fold increase was observed in patients with severe renal impairment (eGFR < 30 mL/min/1.73 m²) including patients with end-stage renal disease (ESRD) on hemodialysis, as compared to subjects with normal renal function.

 

Metformin hydrochloride

 

In patients with decreased renal function, the plasma and blood half-life of metformin without extended release is prolonged and the renal clearance is decreased (see CONTRAINDICATIONS and SPECIAL WARNINGS AND PRECAUTIONS FOR USE).

 

Hepatic Impairment

 

Sitagliptin phosphate

 

In patients with moderate hepatic impairment (Child-Pugh score 7 to 9), mean AUC and C_max of sitagliptin increased approximately 21% and 13%, respectively, compared to healthy matched controls following administration of a single 100‑mg dose of sitagliptin phosphate. These differences are not considered to be clinically meaningful.

 

There is no clinical experience in patients with severe hepatic impairment (Child-Pugh score >9). However, because sitagliptin is primarily renally eliminated, severe hepatic impairment is not expected to affect the pharmacokinetics of sitagliptin.

 

Metformin hydrochloride

 

No pharmacokinetic studies of metformin have been conducted in patients with hepatic impairment.

 

Use in the elderly

Sitagliptin phosphate

 

Age did not have a clinically meaningful impact on the pharmacokinetics of sitagliptin based on a population pharmacokinetic analysis of Phase I and Phase II data. Elderly subjects (65 to 80 years) had approximately 19% higher plasma concentrations of sitagliptin compared to younger subjects.

 

Metformin hydrochloride

 

Limited data from controlled pharmacokinetic studies of metformin without extended release in healthy elderly subjects suggest that total plasma clearance of metformin is decreased, the half life is prolonged, and C_max is increased, compared to healthy young subjects. From these data, it appears that the change in metformin pharmacokinetics with aging is primarily accounted for by a change in renal function (see GLUCOPHAGE[1] prescribing information: CLINICAL PHARMACOLOGY, Special Populations, Geriatrics).

 

 

Use in children and adolescents

No studies on safety and efficacy with Janumet XR have been performed in children and adolescent patients.

 

Gender

Sitagliptin phosphate

 

Gender had no clinically meaningful effect on the pharmacokinetics of sitagliptin based on a composite analysis of Phase I pharmacokinetic data and on a population pharmacokinetic analysis of Phase I and Phase II data.

 

Metformin hydrochloride

 

Metformin pharmacokinetic parameters did not differ significantly between healthy subjects and patients with type 2 diabetes when analyzed according to gender. Similarly, in controlled clinical studies in patients with type 2 diabetes, the antihyperglycemic effect of metformin was comparable in males and females.

 

Race

 

Sitagliptin phosphate

 

Race had no clinically meaningful effect on the pharmacokinetics of sitagliptin based on a composite analysis of Phase I pharmacokinetic data and on a population pharmacokinetic analysis of Phase I and Phase II data, including subjects of white, Hispanic, black, Asian, and other racial groups.

 

Metformin hydrochloride

 

No studies of metformin pharmacokinetic parameters according to race have been performed. In controlled clinical studies of metformin in patients with type 2 diabetes, the antihyperglycemic effect was comparable in whites (n=249), blacks (n= 51), and Hispanics (n=24).

 

Body Mass Index (BMI)

 

Sitagliptin phosphate

 

Body mass index (BMI) had no clinically meaningful effect on the pharmacokinetics of sitagliptin based on a composite analysis of Phase I pharmacokinetic data and on a population pharmacokinetic analysis of Phase I and Phase II data.

 

 

[1] GLUCOPHAGE® is a registered trademark of Merck Sante S.A.S, an associate of Merck KGaA of Darmstadt, Germany.

Sitagliptin and Metformin

 

Preclinical toxicokinetic and oral toxicity studies with coadministered sitagliptin and metformin without extended release have been conducted in dogs.

 

In a sixteen-week oral toxicity study, female dogs were administered 20 mg/kg/day of metformin, alone or in combination with 2, 10, or 50 mg/kg/day of sitagliptin. Transient ataxia and/or tremors were observed in the high-dose combination-treatment group. These signs were considered to be an effect of sitagliptin because they were seen in previous dog studies with sitagliptin alone at 50 mg/kg/day. The no-effect level for treatment-related changes in this study was 10 mg/kg/day of sitagliptin plus 20 mg/kg/day of metformin, which provided systemic exposure to sitagliptin of approximately 6 times that in patients treated with 100 mg/day of sitagliptin and systemic exposure to metformin of approximately 2.5 times that in patients treated with 2000 mg/day of metformin.

 

No animal studies have been conducted with the combined products in Janumet XR to evaluate carcinogenesis, mutagenesis, impairment of fertility or effects on reproduction. The following data are findings in studies performed with sitagliptin or metformin individually.

 

 

Sitagliptin

Effects in non-clinical studies with rats were observed only at exposures considered sufficiently in excess of the maximum human exposure, indicating little relevance to human use. Sitagliptin has not been demonstrated to be genotoxic or mutagenic in preclinical safety studies.

 

In a series of repeated-dose toxicity studies in dogs, doses of 2, 10, and 50 mg/kg/day were tested for up to 53 weeks. No effects were found after 53 weeks of treatment at a dose of 10 mg/kg/day, or approximately 6 times the human exposure at the recommended adult human dose of 100 mg/day. In dogs treated with 50 mg/kg/day of sitagliptin (approximately 26 times the human dose), transient treatment-related physical signs, including open-mouth breathing, salivation, white foamy emesis, ataxia, trembling, decreased activity, and/or hunched posture were observed. In addition, very slight to slight skeletal muscle degeneration was observed histologically in the 14- and 27-week toxicity studies at the 50‑mg/kg/day dose. However, no skeletal muscle degeneration was found in the 53-week toxicity study, indicating the lack of reproducibility or progression of this change with increased duration of treatment.

The systemic exposure at the NOEL in the 53 week study (10 mg/kg/day) was 5 times higher as in the 27 week study (2 mg/kg/day).

 

Additional 3 month oral toxicity studies were conducted in rhesus and cynomolugus monkeys.  The 3 month study in the rhesus was conducted to evaluate the potential for sitagliptin to cause skin lesions or kidney toxicity, with evaluations limited to skin and kidney.  Monkeys were administered up to 100 mg/kg/day of sitagliptin (28-fold over the systemic exposure following the 100 mg/day clinical dose).  There were no treatment-related antemortem or postmortem findings.

 

In the 3 month oral toxicity study in cynomologus monkeys, routine complete evaluations were conducted.  Animals were administered doses up to 100 mg/kg/day of sitagliptin (27-fold over the systemic exposure following a 100 mg/day clinical dose).  There were no treatment-related antemortem or postmortem findings.

 

Sitagliptin was not carcinogenic in mice when administered orally for 2 years at a maximum-tolerated dose of 500 mg/kg/day. A two-year carcinogenicity study was conducted in male and female rats given oral doses of sitagliptin of 50, 150, and 500 mg/kg/day. There was an increased incidence of hepatic adenomas and carcinomas in the high-dose males and hepatic carcinomas in the high-dose females. This dose in rats results in approximately 58 times the human exposure based on the recommended daily adult human dose of 100 mg/day. This dose level was associated with hepatotoxicity in rats. The no-observed effect level for induction of hepatic neoplasia was 150 mg/kg/day, approximately 19-fold the human exposure at the 100‑mg recommended dose. Since hepatotoxicity has been shown to correlate with induction of hepatic neoplasia in rats, this increased incidence of hepatic tumors in rats was likely secondary to chronic hepatic toxicity at this high dose. The clinical significance of these findings for humans is unknown.

 

No adverse effects upon fertility were observed in male and female rats given sitagliptin orally at doses up to 1000 mg/kg daily (up to approximately 100 times the human exposure based on the recommended daily adult human dose of 100 mg/day) prior to and throughout mating.

 

Reproductive toxicity studies showed a slight treatment-related increased incidence of fetal rib malformations (absent, hypoplastic and wavy ribs) in the offspring of rats at oral doses of 1000 mg/kg/day. The no-observed effect level for developmental effects was 250 mg/kg/day (32 times the human exposure based on the recommended daily adult human dose of 100 mg/day). Sitagliptin is secreted in the milk of lactating rats.

No studies were conducted with sitagliptin, metformin and a sulfonylurea.

 

Metformin hydrochloride

 

Preclinical data for metformin reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction.

 

Propyl gallate, polyethylene glycol, the color indigotine (E132), sodium stearyl fumarate, povidone (K29/32), purified water, hydroxypropylcellulose, hypromellose, colloidal silicon dioxide, macrogol 3350, kaolin, titanium dioxide (E171) and carnauba wax. Janumet XR 50 mg/500 mg tablets contain in addition microcrystalline cellulose.

Janumet XR 50 mg/1000 mg tablets contain in addition yellow iron oxide (E172).

Not applicable.

2 years.

 

Store below 30°C.

 

Janumet XR 50mg/500mg is supplied in bottles of 56 & 28 film-coated tablets

Janumet XR 50mg/1000mg is supplied in bottles of 56 & 28 film-coated tablets.

Janumet XR 100mg/1000mg is supplied in bottles of 28 & 14 film-coated tablets.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.