Special Warning : אזהרת שימוש

5     WARNINGS AND PRECAUTIONS
5.1 Lactic Acidosis
Metformin hydrochloride
Lactic acidosis is a rare, but serious, metabolic complication that can occur due to metformin accumulation during treatment with JANUET; 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 g/mL are generally found.
The reported incidence of lactic acidosis in patients receiving metformin hydrochloride is very low (approximately 0.03 cases/1000 patient-years, with approximately 0.015 fatal cases/1000 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 significant renal impairment, including both intrinsic renal disease and renal hypoperfusion, often in the setting of multiple concomitant medical/surgical problems and multiple concomitant medications. Patients with congestive heart failure requiring pharmacologic management, in particular those with unstable or acute congestive heart failure who are at risk of hypoperfusion and hypoxemia, are at increased risk of lactic acidosis. The risk of lactic acidosis increases with the degree of renal dysfunction 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. 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 study and for any surgical procedure [see Warnings and Precautions (5.4, 5.6, 5.7, 5.11)].
The onset of lactic acidosis often is subtle, and accompanied only 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 [see Warnings and Precautions (5.12)]. Metformin should be withdrawn until the situation is clarified. Serum electrolytes, ketones, blood glucose, and if indicated, blood pH, lactate levels, and even blood metformin levels may be useful. 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.
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 [see Warnings and Precautions (5.8, 5.13)].
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 is dialyzable (with a clearance of up to 170 mL/min under good hemodynamic conditions), prompt hemodialysis is recommended to correct the acidosis and remove the accumulated metformin. Such management often results in prompt reversal of symptoms and recovery [see Contraindications (4); Warnings and Precautions (5.6, 5.7, 5.10, 5.11, 5.12)].
5.2 Pancreatitis
There have been postmarketing reports of acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis, in patients taking JANUET. After initiation of JANUET, patients should be observed carefully for signs and symptoms of pancreatitis. If pancreatitis is suspected, JANUET should promptly be discontinued and appropriate management should be initiated. It is unknown whether patients with a history of pancreatitis are at increased risk for the development of pancreatitis while using JANUET.
5.3 Impaired Hepatic Function
Since impaired hepatic function has been associated with some cases of lactic acidosis, JANUET should generally be avoided in patients with clinical or laboratory evidence of hepatic disease.
5.4 Assessment of Renal Function
Metformin and sitagliptin are known to be substantially excreted by the kidney.
Metformin hydrochloride
The risk of metformin accumulation and lactic acidosis increases with the degree of impairment of renal function. Therefore, JANUET is contraindicated in patients with renal impairment.
Before initiation of JANUET and at least annually thereafter, renal function should be assessed and verified as normal. In patients in whom development of renal dysfunction is anticipated (e.g., elderly), renal function should be assessed more frequently and JANUET discontinued if evidence of renal impairment is present.
Sitagliptin
There have been postmarketing reports of worsening renal function, including acute renal failure, sometimes requiring dialysis. Before initiation of therapy with JANUET and at least annually thereafter, renal function should be assessed and verified as normal. In patients in whom development of renal dysfunction is anticipated, particularly in elderly patients, renal function should be assessed more frequently and JANUET discontinued if evidence of renal impairment is present.
5.5 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 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 JANUET and any apparent abnormalities should be appropriately investigated and managed. [See Adverse Reactions (6.1).] 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.
5.6 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 JANUET.
5.7 Surgical Procedures
Use of JANUET should be temporarily suspended for any surgical procedure (except minor procedures not associated with restricted intake of food and fluids) and should not be restarted until the patient's oral intake has resumed and renal function has been evaluated as normal.
5.8 Change in Clinical Status of Patients with Previously Controlled Type 2 Diabetes A patient with type 2 diabetes previously well controlled on JANUET 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 acidosis of either form occurs, JANUET must be stopped immediately and other appropriate corrective measures initiated.
5.9 Use with Medications Known to Cause Hypoglycemia
Sitagliptin
When sitagliptin was used in combination with a sulfonylurea or with insulin, medications known to cause hypoglycemia, the incidence of hypoglycemia was increased over that of placebo used in combination with a sulfonylurea or with insulin [see Adverse Reactions (6)]. Therefore, patients also receiving an insulin secretagogue (e.g., sulfonylurea) or insulin may require a lower dose of the insulin secretagogue or insulin to reduce the risk of hypoglycemia [see Dosage and Administration (2.1)].
Metformin hydrochloride
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.
5.10 Concomitant Medications Affecting 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 (7.2)], should be used with caution.
5.11 Radiologic Studies with Intravascular Iodinated Contrast Materials Intravascular contrast studies with iodinated materials (for example, intravenous urogram, intravenous cholangiography, angiography, and computed tomography (CT) scans with intravascular contrast materials) can lead to acute alteration of renal function and have been associated with lactic acidosis in patients receiving metformin [see Contraindications (4)]. Therefore, in patients in whom any such study is planned, JANUET should be temporarily discontinued at the time of or prior to the procedure, and withheld for 48 hours subsequent to the procedure and reinstituted only after renal function has been re- evaluated and found to be normal.
5.12 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 JANUET therapy, the drug should be promptly discontinued.
5.13 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 JANUET and temporarily administer insulin. JANUET may be reinstituted after the acute episode is resolved.
5.14 Hypersensitivity Reactions
There have been postmarketing reports of serious hypersensitivity reactions in patients treated with sitagliptin, one of the components of JANUET. 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 JANUET, assess for other potential causes for the event, and institute alternative treatment for diabetes. [See Adverse Reactions (6.2).] Angioedema has also been reported with other dipeptidyl peptidase-4 (DPP-4) inhibitors. Use caution in a patient with a history of angioedema with another DPP-4 inhibitor because it is unknown whether such patients will be predisposed to angioedema with JANUET.
5.15 Severe and Disabling Arthralgia
There have been postmarketing reports of severe and disabling arthralgia in patients taking DPP-4 inhibitors. The time to onset of symptoms following initiation of drug therapy varied from one day to years.
Patients experienced relief of symptoms upon discontinuation of the medication. A subset of patients experienced a recurrence of symptoms when restarting the same drug or a different DPP-4 inhibitor.
Consider DPP-4 inhibitors as a possible cause for severe joint pain and discontinue drug if appropriate.
5.16 Macrovascular Outcomes
There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with JANUET or any other anti-diabetic drug.

6       ADVERSE REACTIONS
6.1    Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Sitagliptin and Metformin Coadministration in Patients with Type 2 Diabetes Inadequately Controlled on Diet and Exercise
Table 1 summarizes the most common (5% of patients) adverse reactions reported (regardless of investigator assessment of causality) in a 24-week placebo-controlled factorial study in which sitagliptin and metformin were coadministered to patients with type 2 diabetes inadequately controlled on diet and exercise.

Table 1: Sitagliptin and Metformin Coadministered to Patients with Type 2 Diabetes Inadequately Controlled on Diet and Exercise:
Adverse Reactions Reported (Regardless of Investigator Assessment of Causality) in  5% of Patients Receiving Combination Therapy (and Greater than in Patients Receiving Placebo)* 
Number of Patients (%)
Sitagliptin
Placebo        Sitagliptin         Metformin 500 mg/        50 mg twice daily + 100 mg once          Metformin 1000 mg         Metformin 500 mg/
† daily               twice daily         Metformin 1000 mg twice
† daily
†                       †
N = 176         N = 179                 N = 364                 N = 372 Diarrhea                 7 (4.0)         5 (2.8)                 28 (7.7)                28 (7.5) Upper Respiratory        9 (5.1)         8 (4.5)                 19 (5.2)                23 (6.2) Tract Infection
Headache                   5 (2.8)         2 (1.1)                14 (3.8)                22 (5.9) *
Intent-to-treat population.
†
Data pooled for the patients given the lower and higher doses of metformin.

Sitagliptin Add-on Therapy in Patients with Type 2 Diabetes Inadequately Controlled on Metformin Alone In a 24-week placebo-controlled trial of sitagliptin 100 mg administered once daily added to a twice daily metformin regimen, there were no adverse reactions reported regardless of investigator assessment of causality in ≥5% of patients and more commonly than in patients given placebo. Discontinuation of therapy due to clinical adverse reactions was similar to the placebo treatment group (sitagliptin and metformin, 1.9%; placebo and metformin, 2.5%).
Gastrointestinal Adverse Reactions
The incidences of pre-selected gastrointestinal adverse experiences in patients treated with sitagliptin and metformin were similar to those reported for patients treated with metformin alone. See Table 2.
Table 2: Pre-selected Gastrointestinal Adverse Reactions (Regardless of Investigator Assessment of Causality) Reported in Patients with Type 2 Diabetes Receiving Sitagliptin and Metformin 
Number of Patients (%)
Study of Sitagliptin and Metformin in Patients Inadequately Controlled              Study of Sitagliptin Add-on in on Diet and Exercise                                     Patients Inadequately Controlled on Metformin Alone
Sitagliptin 50 mg twice                       Sitagliptin 100 mg
Placebo and
Placebo     Sitagliptin   Metformin 500 mg/                   daily +                                once daily and Metformin
100 mg       Metformin 1000 mg            Metformin 500 mg/                               Metformin 1500 mg once daily        twice daily*             Metformin 1000 mg                             1500 mg daily daily twice daily*
N = 176      N = 179             N = 364                     N = 372                   N = 237          N = 464 Diarrhea            7 (4.0)       5 (2.8)           28 (7.7)                  28 (7.5)                   6 (2.5)         11 (2.4) Nausea              2 (1.1)       2 (1.1)           20 (5.5)                  18 (4.8)                   2 (0.8)          6 (1.3) Vomiting            1 (0.6)       0 (0.0)           2 (0.5)                   8 (2.2)                    2 (0.8)          5 (1.1) Abdominal           4 (2.3)       6 (3.4)           14 (3.8)                  11 (3.0)                   9 (3.8)         10 (2.2) ††
Pain
*
Data pooled for the patients given the lower and higher doses of metformin.
†
Abdominal discomfort was included in the analysis of abdominal pain in the study of initial therapy.

Sitagliptin in Combination with Metformin and Glimepiride
In a 24-week placebo-controlled study of sitagliptin 100 mg as add-on therapy in patients with type 2 diabetes inadequately controlled on metformin and glimepiride (sitagliptin, N=116; placebo, N=113), the adverse reactions reported regardless of investigator assessment of causality in 5% of patients treated with sitagliptin and more commonly than in patients treated with placebo were: hypoglycemia (Table 3) and headache (6.9%, 2.7%).
Sitagliptin in Combination with Metformin and Rosiglitazone
In a placebo-controlled study of sitagliptin 100 mg as add-on therapy in patients with type 2 diabetes inadequately controlled on metformin and rosiglitazone (sitagliptin, N=181; placebo, N=97), the adverse reactions reported regardless of investigator assessment of causality through Week 18 in 5% of patients treated with sitagliptin and more commonly than in patients treated with placebo were: upper respiratory tract infection (sitagliptin, 5.5%; placebo, 5.2%) and nasopharyngitis (6.1%, 4.1%). Through Week 54, the adverse reactions reported regardless of investigator assessment of causality in 5% of patients treated with sitagliptin and more commonly than in patients treated with placebo were: upper respiratory tract infection (sitagliptin, 15.5%; placebo, 6.2%), nasopharyngitis (11.0%, 9.3%), peripheral edema (8.3%, 5.2%), and headache (5.5%, 4.1%).
Sitagliptin in Combination with Metformin and Insulin
In a 24-week placebo-controlled study of sitagliptin 100 mg as add-on therapy in patients with type 2 diabetes inadequately controlled on metformin and insulin (sitagliptin, N=229; placebo, N=233), the only adverse reaction reported regardless of investigator assessment of causality in 5% of patients treated with sitagliptin and more commonly than in patients treated with placebo was hypoglycemia (Table 3).
Hypoglycemia
In all (N=5) studies, adverse reactions of hypoglycemia were based on all reports of symptomatic hypoglycemia; a concurrent glucose measurement was not required although most (77%) reports of hypoglycemia were accompanied by a blood glucose measurement ≤70 mg/dL. When the combination of sitagliptin and metformin was coadministered with a sulfonylurea or with insulin, the percentage of patients reporting at least one adverse reaction of hypoglycemia was higher than that observed with placebo and metformin coadministered with a sulfonylurea or with insulin (Table 3).
Table 3
*
Incidence and Rate of Hypoglycemia (Regardless of Investigator Assessment of Causality) in Placebo-Controlled Clinical Studies of Sitagliptin in Combination with Metformin Coadministered with Glimepiride or Insulin
Sitagliptin 100 mg                            Placebo
Add-On to Glimepiride +                               + Metformin                              + Metformin Metformin (24 weeks)                               + Glimepiride                            + Glimepiride N = 116                                  N = 113
Overall (%)                                           19 (16.4)                                 1 (0.9) †
Rate (episodes/patient-year)                            0.82                                     0.02 ‡
Severe (%)                                             0 (0.0)                                  0 (0.0) Sitagliptin 100 mg                        Placebo
Add-On to Insulin                                         + Metformin                         + Metformin + Metformin (24 weeks)                                    + Insulin                           + Insulin N = 229                             N = 233
Overall (%)                                              35 (15.3)                            19 (8.2) †
Rate (episodes/patient-year)                                0.98                                0.61 ‡
Severe (%)                                                1 (0.4)                              1 (0.4) *
Adverse reactions of hypoglycemia were based on all reports of symptomatic hypoglycemia; a concurrent glucose measurement was not required: Intent to treat population.
†
Based on total number of events (i.e., a single patient may have had multiple events).
‡
Severe events of hypoglycemia were defined as those events requiring medical assistance or exhibiting depressed level/loss of consciousness or seizure.

The overall incidence of reported adverse reactions of hypoglycemia in patients with type 2 diabetes inadequately controlled on diet and exercise was 0.6% in patients given placebo, 0.6% in patients given sitagliptin alone, 0.8% in patients given metformin alone, and 1.6% in patients given sitagliptin in combination with metformin. In patients with type 2 diabetes inadequately controlled on metformin alone, the overall incidence of adverse reactions of hypoglycemia was 1.3% in patients given add-on sitagliptin and 2.1% in patients given add-on placebo.
In the study of sitagliptin and add-on combination therapy with metformin and rosiglitazone, the overall incidence of hypoglycemia was 2.2% in patients given add-on sitagliptin and 0.0% in patients given add- on placebo through Week 18. Through Week 54, the overall incidence of hypoglycemia was 3.9% in patients given add-on sitagliptin and 1.0% in patients given add-on placebo.
Vital Signs and Electrocardiograms
With the combination of sitagliptin and metformin, no clinically meaningful changes in vital signs or in ECG (including in QTc interval) were observed.
Pancreatitis
In a pooled analysis of 19 double-blind clinical trials that included data from 10,246 patients randomized to receive sitagliptin 100 mg/day (N=5429) or corresponding (active or placebo) control (N=4817), the incidence of acute pancreatitis was 0.1 per 100 patient-years in each group (4 patients with an event in 4708 patient-years for sitagliptin and 4 patients with an event in 3942 patient-years for control) [See Warnings and Precautions (5.2).]
Sitagliptin
The most common adverse experience in sitagliptin monotherapy reported regardless of investigator assessment of causality in ≥5% of patients and more commonly than in patients given placebo was nasopharyngitis.
Metformin hydrochloride
The most common (>5%) established adverse reactions due to initiation of metformin therapy are diarrhea, nausea/vomiting, flatulence, abdominal discomfort, indigestion, asthenia, and headache.
Laboratory Tests
Sitagliptin
The incidence of laboratory adverse reactions was similar in patients treated with sitagliptin and metformin (7.6%) compared to patients treated with placebo and metformin (8.7%). In most but not all studies, a small increase in white blood cell count (approximately 200 cells/microL difference in WBC vs placebo; mean baseline WBC approximately 6600 cells/microL) was observed due to a small increase in neutrophils. This change in laboratory parameters is not considered to be clinically relevant.
Metformin hydrochloride
In controlled clinical trials of metformin of 29 weeks duration, a decrease to subnormal levels of previously normal serum Vitamin B12 levels, without clinical manifestations, was observed in approximately 7% of patients. Such decrease, possibly due to interference with B12 absorption from the B12-intrinsic factor complex, is, however, very rarely associated with anemia and appears to be rapidly reversible with discontinuation of metformin or Vitamin B12 supplementation. [See Warnings and Precautions (5.5).]
6.2 Postmarketing Experience
Additional adverse reactions have been identified during postapproval use of JANUET or sitagliptin, one of the components of JANUET. These reactions have been reported when JANUET or sitagliptin have been used alone and/or in combination with other antihyperglycemic agents. Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Hypersensitivity reactions including anaphylaxis, angioedema, rash, urticaria, cutaneous vasculitis, and exfoliative skin conditions including Stevens-Johnson syndrome [see Warnings and Precautions (5.14)]; upper respiratory tract infection; hepatic enzyme elevations; acute pancreatitis, including fatal and non- fatal hemorrhagic and necrotizing pancreatitis [see Indications and Usage (1); Warnings and Precautions (5.2)]; worsening renal function, including acute renal failure (sometimes requiring dialysis) [see Warnings and Precautions (5.4)]; severe and disabling arthralgia [see Warnings and Precautions (5.15)]; constipation; vomiting; headache; myalgia; pain in extremity; back pain; pruritus.

Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form
(http://forms.gov.il/globaldata/getsequence/getsequence.aspx?formType=AdversEffectMedic@moh.healt h.gov.il ) or by email (adr@MOH.HEALTH.GOV.IL ).

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