FDA label 6e2738ec-80c8-7941-e053-2991aa0a8dd0

5 WARNINGS AND PRECAUTIONS There have been postmarketing reports of acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis. If pancreatitis is suspected, promptly discontinue JANUVIA. ( 5.1 ) There have been postmarketing reports of acute renal failure, sometimes requiring dialysis. Dosage adjustment is recommended in patients with moderate or severe renal insufficiency and in patients with ESRD. Assessment of renal function is recommended prior to initiating JANUVIA and periodically thereafter. ( 2.2 , 5.2 , 6.2 ) There is an increased risk of hypoglycemia when JANUVIA is added to an insulin secretagogue (e.g., sulfonylurea) or insulin therapy. Consider lowering the dose of the sulfonylurea or insulin to reduce the risk of hypoglycemia. ( 2.3 , 5.3 ) There have been postmarketing reports of serious allergic and hypersensitivity reactions in patients treated with JANUVIA such as anaphylaxis, angioedema, and exfoliative skin conditions including Stevens-Johnson syndrome. In such cases, promptly stop JANUVIA, assess for other potential causes, institute appropriate monitoring and treatment, and initiate alternative treatment for diabetes. ( 5.4 , 6.2 ) Severe and disabling arthralgia has been reported in patients taking DPP-4 inhibitors. Consider as a possible cause for severe joint pain and discontinue drug if appropriate. ( 5.5 ) There have been postmarketing reports of bullous pemphigoid requiring hospitalization in patients taking DPP-4 inhibitors. Tell patients to report development of blisters or erosions. If bullous pemphigoid is suspected, discontinue JANUVIA. ( 5.6 ) There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with JANUVIA or any other anti-diabetic drug. ( 5.7 ) 5.1 Pancreatitis There have been postmarketing reports of acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis, in patients taking JANUVIA. After initiation of JANUVIA, patients should be observed carefully for signs and symptoms of pancreatitis. If pancreatitis is suspected, JANUVIA 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 JANUVIA. 5.2 Renal Impairment Assessment of renal function is recommended prior to initiating JANUVIA and periodically thereafter. A dosage adjustment is recommended in patients with moderate or severe renal insufficiency and in patients with ESRD requiring hemodialysis or peritoneal dialysis. [See Dosage and Administration (2.2) ; Clinical Pharmacology (12.3) .] Caution should be used to ensure that the correct dose of JANUVIA is prescribed for patients with moderate (creatinine clearance ≥30 to <50 mL/min) or severe (creatinine clearance <30 mL/min) renal impairment. There have been postmarketing reports of worsening renal function, including acute renal failure, sometimes requiring dialysis. A subset of these reports involved patients with renal insufficiency, some of whom were prescribed inappropriate doses of sitagliptin. A return to baseline levels of renal insufficiency has been observed with supportive treatment and discontinuation of potentially causative agents. Consideration can be given to cautiously reinitiating JANUVIA if another etiology is deemed likely to have precipitated the acute worsening of renal function. JANUVIA has not been found to be nephrotoxic in preclinical studies at clinically relevant doses, or in clinical trials. 5.3 Use with Medications Known to Cause Hypoglycemia When JANUVIA 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 (6.1) .] Therefore, a lower dose of sulfonylurea or insulin may be required to reduce the risk of hypoglycemia. [See Dosage and Administration (2.3) .] 5.4 Hypersensitivity Reactions There have been postmarketing reports of serious hypersensitivity reactions in patients treated with JANUVIA. 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 JANUVIA, with some reports occurring after the first dose. If a hypersensitivity reaction is suspected, discontinue JANUVIA, 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 JANUVIA. 5.5 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. 5.6 Bullous Pemphigoid Postmarketing cases of bullous pemphigoid requiring hospitalization have been reported with DPP-4 inhibitor use. In reported cases, patients typically recovered with topical or systemic immunosuppressive treatment and discontinuation of the DPP-4 inhibitor. Tell patients to report development of blisters or erosions while receiving JANUVIA. If bullous pemphigoid is suspected, JANUVIA should be discontinued and referral to a dermatologist should be considered for diagnosis and appropriate treatment. 5.7 Macrovascular Outcomes There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with JANUVIA or any other anti-diabetic drug.

6 ADVERSE REACTIONS Adverse reactions reported in ≥5% of patients treated with JANUVIA and more commonly than in patients treated with placebo are: upper respiratory tract infection, nasopharyngitis and headache. In the add-on to sulfonylurea and add-on to insulin studies, hypoglycemia was also more commonly reported in patients treated with JANUVIA compared to placebo. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., at 1-877-888-4231 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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. In controlled clinical studies as both monotherapy and combination therapy with metformin, pioglitazone, or rosiglitazone and metformin, the overall incidence of adverse reactions, hypoglycemia, and discontinuation of therapy due to clinical adverse reactions with JANUVIA were similar to placebo. In combination with glimepiride, with or without metformin, the overall incidence of clinical adverse reactions with JANUVIA was higher than with placebo, in part related to a higher incidence of hypoglycemia (see Table 3); the incidence of discontinuation due to clinical adverse reactions was similar to placebo. Two placebo-controlled monotherapy studies, one of 18- and one of 24-week duration, included patients treated with JANUVIA 100 mg daily, JANUVIA 200 mg daily, and placebo. Five placebo-controlled add-on combination therapy studies were also conducted: one with metformin; one with pioglitazone; one with metformin and rosiglitazone; one with glimepiride (with or without metformin); and one with insulin (with or without metformin). In these trials, patients with inadequate glycemic control on a stable dose of the background therapy were randomized to add-on therapy with JANUVIA 100 mg daily or placebo. The adverse reactions, excluding hypoglycemia, reported regardless of investigator assessment of causality in ≥5% of patients treated with JANUVIA 100 mg daily and more commonly than in patients treated with placebo, are shown in Table 1 for the clinical trials of at least 18 weeks duration. Incidences of hypoglycemia are shown in Table 3. Table 1: Placebo-Controlled Clinical Studies of JANUVIA Monotherapy or Add-on Combination Therapy with Pioglitazone, Metformin + Rosiglitazone, or Glimepiride +/- Metformin: Adverse Reactions (Excluding Hypoglycemia) Reported in ≥5% of Patients and More Commonly than in Patients Given Placebo, Regardless of Investigator Assessment of Causality Intent-to-treat population Number of Patients (%) Monotherapy (18 or 24 weeks) JANUVIA 100 mg Placebo N = 443 N = 363 Nasopharyngitis 23 (5.2) 12 (3.3) Combination with Pioglitazone (24 weeks) JANUVIA 100 mg + Pioglitazone Placebo + Pioglitazone N = 175 N = 178 Upper Respiratory Tract Infection 11 (6.3) 6 (3.4) Headache 9 (5.1) 7 (3.9) Combination with Metformin + Rosiglitazone (18 weeks) JANUVIA 100 mg + Metformin + Rosiglitazone Placebo + Metformin + Rosiglitazone N = 181 N = 97 Upper Respiratory Tract Infection 10 (5.5) 5 (5.2) Nasopharyngitis 11 (6.1) 4 (4.1) Combination with Glimepiride (+/- Metformin) (24 weeks) JANUVIA 100 mg + Glimepiride (+/- Metformin) Placebo + Glimepiride (+/- Metformin) N = 222 N = 219 Nasopharyngitis 14 (6.3) 10 (4.6) Headache 13 (5.9) 5 (2.3) In the 24-week study of patients receiving JANUVIA as add-on combination therapy with metformin, there were no adverse reactions reported regardless of investigator assessment of causality in ≥5% of patients and more commonly than in patients given placebo. In the 24-week study of patients receiving JANUVIA as add-on therapy to insulin (with or without metformin), there were no adverse reactions reported regardless of investigator assessment of causality in ≥5% of patients and more commonly than in patients given placebo, except for hypoglycemia (see Table 3). In the study of JANUVIA as add-on combination therapy with metformin and rosiglitazone (Table 1), through Week 54 the adverse reactions reported regardless of investigator assessment of causality in ≥5% of patients treated with JANUVIA and more commonly than in patients treated with placebo were: upper respiratory tract infection (JANUVIA, 15.5%; placebo, 6.2%), nasopharyngitis (11.0%, 9.3%), peripheral edema (8.3%, 5.2%), and headache (5.5%, 4.1%). In a pooled analysis of the two monotherapy studies, the add-on to metformin study, and the add-on to pioglitazone study, the incidence of selected gastrointestinal adverse reactions in patients treated with JANUVIA was as follows: abdominal pain (JANUVIA 100 mg, 2.3%; placebo, 2.1%), nausea (1.4%, 0.6%), and diarrhea (3.0%, 2.3%). In an additional, 24-week, placebo-controlled factorial study of initial therapy with sitagliptin in combination with metformin, the adverse reactions reported (regardless of investigator assessment of causality) in ≥5% of patients are shown in Table 2. Table 2: Initial Therapy with Combination of Sitagliptin and Metformin: Adverse Reactions Reported (Regardless of Investigator Assessment of Causality) in ≥5% of Patients Receiving Combination Therapy (and Greater than in Patients Receiving Metformin alone, Sitagliptin alone, and Placebo) Intent-to-treat population. Number of Patients (%) Placebo Sitagliptin (JANUVIA) 100 mg QD Metformin 500 or 1000 mg bid Data pooled for the patients given the lower and higher doses of metformin. Sitagliptin 50 mg bid + Metformin 500 or 1000 mg bid N = 176 N = 179 N = 364 N = 372 Upper Respiratory Infection 9 (5.1) 8 (4.5) 19 (5.2) 23 (6.2) Headache 5 (2.8) 2 (1.1) 14 (3.8) 22 (5.9) In a 24-week study of initial therapy with JANUVIA in combination with pioglitazone, there were no adverse reactions reported (regardless of investigator assessment of causality) in ≥5% of patients and more commonly than in patients given pioglitazone alone. No clinically meaningful changes in vital signs or in ECG (including in QTc interval) were observed in patients treated with JANUVIA. 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 (5.1) .] Hypoglycemia In all (N=9) studies, adverse reactions of hypoglycemia were based on all reports of symptomatic hypoglycemia. A concurrent blood glucose measurement was not required although most (74%) reports of hypoglycemia were accompanied by a blood glucose measurement ≤70 mg/dL. When JANUVIA was coadministered with a sulfonylurea or with insulin, the percentage of patients with at least one adverse reaction of hypoglycemia was higher than in the corresponding placebo group (Table 3). Table 3: Incidence and Rate of Hypoglycemia Adverse reactions of hypoglycemia were based on all reports of symptomatic hypoglycemia; a concurrent glucose measurement was not required; intent-to-treat population. in Placebo-Controlled Clinical Studies when JANUVIA was used as Add-On Therapy to Glimepiride (with or without Metformin) or Insulin (with or without Metformin), Regardless of Investigator Assessment of Causality Add-On to Glimepiride (+/- Metformin) (24 weeks) JANUVIA 100 mg + Glimepiride (+/- Metformin) Placebo + Glimepiride (+/- Metformin) N = 222 N = 219 Overall (%) 27 (12.2) 4 (1.8) Rate (episodes/patient-year) Based on total number of events (i.e., a single patient may have had multiple events). 0.59 0.24 Severe (%) Severe events of hypoglycemia were defined as those events requiring medical assistance or exhibiting depressed level/loss of consciousness or seizure. 0 (0.0) 0 (0.0) Add-On to Insulin (+/- Metformin) (24 weeks) JANUVIA 100 mg + Insulin (+/- Metformin) Placebo + Insulin (+/- Metformin) N = 322 N = 319 Overall (%) 50 (15.5) 25 (7.8) Rate (episodes/patient-year) 1.06 0.51 Severe (%) 2 (0.6) 1 (0.3) In a pooled analysis of the two monotherapy studies, the add-on to metformin study, and the add-on to pioglitazone study, the overall incidence of adverse reactions of hypoglycemia was 1.2% in patients treated with JANUVIA 100 mg and 0.9% in patients treated with placebo. In the study of JANUVIA as add-on combination therapy with metformin and rosiglitazone, the overall incidence of hypoglycemia was 2.2% in patients given add-on JANUVIA 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 JANUVIA and 1.0% in patients given add-on placebo. In the 24-week, placebo-controlled factorial study of initial therapy with JANUVIA in combination with metformin, the incidence of hypoglycemia was 0.6% in patients given placebo, 0.6% in patients given JANUVIA alone, 0.8% in patients given metformin alone, and 1.6% in patients given JANUVIA in combination with metformin. In the study of JANUVIA as initial therapy with pioglitazone, one patient taking JANUVIA experienced a severe episode of hypoglycemia. There were no severe hypoglycemia episodes reported in other studies except in the study involving coadministration with insulin. Laboratory Tests Across clinical studies, the incidence of laboratory adverse reactions was similar in patients treated with JANUVIA 100 mg compared to patients treated with placebo. A small increase in white blood cell count (WBC) was observed due to an increase in neutrophils. This increase in WBC (of approximately 200 cells/microL vs placebo, in four pooled placebo-controlled clinical studies, with a mean baseline WBC count of approximately 6600 cells/microL) is not considered to be clinically relevant. In a 12-week study of 91 patients with chronic renal insufficiency, 37 patients with moderate renal insufficiency were randomized to JANUVIA 50 mg daily, while 14 patients with the same magnitude of renal impairment were randomized to placebo. Mean (SE) increases in serum creatinine were observed in patients treated with JANUVIA [0.12 mg/dL (0.04)] and in patients treated with placebo [0.07 mg/dL (0.07)]. The clinical significance of this added increase in serum creatinine relative to placebo is not known. 6.2 Postmarketing Experience Additional adverse reactions have been identified during postapproval use of JANUVIA as monotherapy 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 (5.4) ] ; hepatic enzyme elevations; acute pancreatitis, including fatal and non-fatal hemorrhagic and necrotizing pancreatitis [see Indications and Usage (1.2) ; Warnings and Precautions (5.1) ] ; worsening renal function, including acute renal failure (sometimes requiring dialysis) [see Warnings and Precautions (5.2) ] ; severe and disabling arthralgia [see Warnings and Precautions (5.5) ]; bullous pemphigoid [see Warnings and Precautions (5.6) ]; constipation; vomiting; headache; myalgia; pain in extremity; back pain; pruritus.

<table width="700.000" ID="id_c840453c-9062-48e9-ac20-ce47d0b7ca3b"> <caption ID="id_79b8e2a8-0aba-47a0-8ed2-2d7c3b7db1e0">Table 1: Placebo-Controlled Clinical Studies of JANUVIA Monotherapy or Add-on Combination Therapy with Pioglitazone, Metformin + Rosiglitazone, or Glimepiride +/- Metformin: Adverse Reactions (Excluding Hypoglycemia) Reported in &#x2265;5% of Patients and More Commonly than in Patients Given Placebo, Regardless of Investigator Assessment of Causality <footnote ID="id-a6da4ea0-6a43-4eb5-a6a1-9a59ef7588cc">Intent-to-treat population</footnote> </caption> <col width="40.0%"/> <col width="30.0%"/> <col width="30.0%"/> <thead> <tr ID="id_788e70f5-2c37-436d-8f57-eb50f4bb7e14"> <td align="left" styleCode="Botrule" valign="top"/> <td align="center" colspan="2" styleCode="Botrule" valign="top"> <content styleCode="bold">Number of Patients (%)</content> </td> </tr> </thead> <tbody> <tr ID="id_31837cf9-1e15-4f8d-8c54-4a6cc0d22c80"> <td align="left" styleCode="Toprule Botrule" valign="top"> <content styleCode="bold">Monotherapy</content> (18 or 24 weeks) </td> <td align="center" styleCode="Botrule" valign="top"> <content styleCode="bold">JANUVIA 100 mg</content> </td> <td align="center" styleCode="Botrule" valign="top"> <content styleCode="bold">Placebo</content> </td> </tr> <tr ID="id_8131f7df-a70f-40e6-b80a-6927e262f3d7"> <td align="left" valign="top"/> <td align="center" valign="top">N = 443</td> <td align="center" valign="top">N = 363</td> </tr> <tr ID="id_81ed872c-4dae-4490-bf6d-97c87690cd3a"> <td align="left" styleCode="Botrule" valign="top"> Nasopharyngitis</td> <td align="center" styleCode="Botrule" valign="top">23 (5.2)</td> <td align="center" styleCode="Botrule" valign="top">12 (3.3)</td> </tr> <tr ID="id_37f0cd00-3423-4802-b6f1-e6cdc495b5e5"> <td align="left" styleCode="Botrule" valign="top"> <content styleCode="bold">Combination with Pioglitazone </content> (24 weeks) </td> <td align="center" styleCode="Botrule" valign="top"> <paragraph> <content styleCode="bold">JANUVIA 100 mg +</content> </paragraph> <content styleCode="bold">Pioglitazone </content> </td> <td align="center" styleCode="Botrule" valign="top"> <paragraph> <content styleCode="bold">Placebo +</content> </paragraph> <content styleCode="bold">Pioglitazone</content> </td> </tr> <tr ID="id_0d8e91d2-3abb-4a75-9d1a-f14a7fda07e3"> <td align="left" valign="top"/> <td align="center" valign="top">N = 175</td> <td align="center" valign="top">N = 178</td> </tr> <tr ID="id_b3da3a38-eec9-4d1a-9758-3c675e960dc8"> <td align="left" valign="top"> Upper Respiratory Tract Infection</td> <td align="center" valign="top">11 (6.3)</td> <td align="center" valign="top">6 (3.4)</td> </tr> <tr ID="id_79bc1fe7-930d-4595-91a1-be20f3b60d2c"> <td align="left" styleCode="Botrule" valign="top"> Headache</td> <td align="center" styleCode="Botrule" valign="top">9 (5.1)</td> <td align="center" styleCode="Botrule" valign="top">7 (3.9)</td> </tr> <tr ID="id_46334508-a82e-49d2-b61f-46ab263db3c6"> <td align="left" styleCode="Botrule" valign="top"> <content styleCode="bold">Combination with Metformin + Rosiglitazone </content>(18 weeks) </td> <td align="center" styleCode="Botrule" valign="top"> <paragraph> <content styleCode="bold">JANUVIA 100 mg +</content> </paragraph> <content styleCode="bold">Metformin + </content> <content styleCode="bold">Rosiglitazone </content> </td> <td align="center" styleCode="Botrule" valign="top"> <paragraph> <content styleCode="bold">Placebo +</content> </paragraph> <content styleCode="bold">Metformin + Rosiglitazone</content> </td> </tr> <tr ID="id_70876fb8-0281-4010-93e7-ca9db0ffeb5f"> <td align="left" valign="top"/> <td align="center" valign="top">N = 181</td> <td align="center" valign="top">N = 97</td> </tr> <tr ID="id_6df55a08-ef85-4a29-a596-8a17d9d062ae"> <td align="left" valign="top"> Upper Respiratory Tract Infection</td> <td align="center" valign="top">10 (5.5)</td> <td align="center" valign="top">5 (5.2)</td> </tr> <tr ID="id_f5f8d6fb-26f9-4932-a5b8-e59145ad8087"> <td align="left" styleCode="Botrule" valign="top"> Nasopharyngitis</td> <td align="center" styleCode="Botrule" valign="top">11 (6.1)</td> <td align="center" styleCode="Botrule" valign="top">4 (4.1)</td> </tr> <tr ID="id_f688b366-88c8-4a41-9ade-5c0f39162bae"> <td align="left" styleCode="Botrule" valign="top"> <content styleCode="bold">Combination with Glimepiride (+/- Metformin) </content>(24 weeks) </td> <td align="center" styleCode="Botrule" valign="top"> <paragraph> <content styleCode="bold">JANUVIA 100 mg </content> </paragraph> <paragraph> <content styleCode="bold">+ Glimepiride </content> </paragraph> <paragraph> <content styleCode="bold">(+/- Metformin)</content> </paragraph> </td> <td align="center" styleCode="Botrule" valign="top"> <paragraph> <content styleCode="bold">Placebo</content> </paragraph> <paragraph> <content styleCode="bold">+ Glimepiride</content> </paragraph> <paragraph> <content styleCode="bold">(+/- Metformin)</content> </paragraph> </td> </tr> <tr ID="id_751e6186-72ab-4c94-8f9f-55891e719348"> <td align="left" valign="top"/> <td align="center" valign="top">N = 222</td> <td align="center" valign="top">N = 219</td> </tr> <tr ID="id_15d2a260-5f8b-4248-abb9-184f004b43f2"> <td align="left" valign="top"> Nasopharyngitis</td> <td align="center" valign="top">14 (6.3)</td> <td align="center" valign="top">10 (4.6)</td> </tr> <tr ID="id_1c8ab553-12e4-4f12-b40b-c6f4beaeb85d"> <td align="left" styleCode="Botrule" valign="top"> Headache</td> <td align="center" styleCode="Botrule" valign="top">13 (5.9)</td> <td align="center" styleCode="Botrule" valign="top">5 (2.3)</td> </tr> </tbody> </table>

<table width="708.000" ID="id_047b5aa9-db22-4b70-9c05-9cdbde75fea6"> <caption ID="id_5c635d19-d426-4203-8124-9b6250f43eae">Table 2: Initial Therapy with Combination of Sitagliptin and Metformin: Adverse Reactions Reported (Regardless of Investigator Assessment of Causality) in &#x2265;5% of Patients Receiving Combination Therapy (and Greater than in Patients Receiving Metformin alone, Sitagliptin alone, and Placebo) <footnote ID="id-a09cba00-0c5a-4239-a4ba-59f121967f05">Intent-to-treat population.</footnote> </caption> <col width="26.8%"/> <col width="13.6%"/> <col width="16.2%"/> <col width="20.9%"/> <col width="22.5%"/> <thead> <tr ID="id_0aaec772-f08c-4b86-afc7-877176c62c69"> <td align="left" styleCode="Botrule" valign="top"/> <td align="center" colspan="4" styleCode="Botrule" valign="top"> <content styleCode="bold">Number of Patients (%)</content> </td> </tr> </thead> <tbody> <tr ID="id_3473b863-a25c-4d11-a6d0-818331456ae7"> <td align="left" styleCode="Toprule Botrule" valign="top"/> <td align="center" styleCode="Botrule" valign="top"> <paragraph> <content styleCode="bold">Placebo</content> </paragraph> </td> <td align="center" styleCode="Botrule" valign="top"> <paragraph> <content styleCode="bold">Sitagliptin</content> </paragraph> <paragraph> <content styleCode="bold"/> <content styleCode="bold">(JANUVIA) 100 mg QD </content> </paragraph> </td> <td align="center" styleCode="Botrule" valign="top"> <paragraph> <content styleCode="bold">Metformin</content> </paragraph> <paragraph> <content styleCode="bold">500 or 1000 mg bid <footnote ID="id-2ba24461-405e-40d4-93d4-579cf7f5ddb5">Data pooled for the patients given the lower and higher doses of metformin.</footnote> </content> </paragraph> </td> <td align="center" styleCode="Botrule" valign="top"> <paragraph> <content styleCode="bold">Sitagliptin</content> </paragraph> <paragraph> <content styleCode="bold">50 mg bid +</content> </paragraph> <paragraph> <content styleCode="bold">Metformin</content> </paragraph> <paragraph> <content styleCode="bold">500 or 1000 mg bid <footnoteRef IDREF="id-2ba24461-405e-40d4-93d4-579cf7f5ddb5"/> </content> </paragraph> </td> </tr> <tr ID="id_351574b3-d125-4d9b-a1d2-8d8be785691f"> <td align="left" valign="top"/> <td align="center" valign="top">N = 176</td> <td align="center" valign="top">N = 179</td> <td align="center" valign="top">N = 364 <footnoteRef IDREF="id-2ba24461-405e-40d4-93d4-579cf7f5ddb5"/> </td> <td align="center" valign="top">N = 372 <footnoteRef IDREF="id-2ba24461-405e-40d4-93d4-579cf7f5ddb5"/> </td> </tr> <tr ID="id_fcfee006-21f8-4cdd-a792-595b83558aec"> <td align="left" valign="top"> Upper Respiratory Infection</td> <td align="center" valign="top">9 (5.1)</td> <td align="center" valign="top">8 (4.5)</td> <td align="center" valign="top">19 (5.2)</td> <td align="center" valign="top">23 (6.2)</td> </tr> <tr ID="id_f8887dee-6c81-4690-8c87-8c3403788a96"> <td align="left" styleCode="Botrule" valign="top"> Headache</td> <td align="center" styleCode="Botrule" valign="top">5 (2.8)</td> <td align="center" styleCode="Botrule" valign="top">2 (1.1)</td> <td align="center" styleCode="Botrule" valign="top">14 (3.8)</td> <td align="center" styleCode="Botrule" valign="top">22 (5.9)</td> </tr> </tbody> </table>

<table width="681.000" ID="id_6b9f5938-e350-479b-bd16-b19960ba2bf8"> <caption ID="id_a48f2157-0969-4621-ad08-1146f618d099">Table 3: Incidence and Rate of Hypoglycemia <footnote ID="id-e6b39dff-dbe7-42f8-ba89-627750b1ceea">Adverse reactions of hypoglycemia were based on all reports of symptomatic hypoglycemia; a concurrent glucose measurement was not required; intent-to-treat population.</footnote> in Placebo-Controlled Clinical Studies when JANUVIA was used as Add-On Therapy to Glimepiride (with or without Metformin) or Insulin (with or without Metformin), Regardless of Investigator Assessment of Causality </caption> <col width="34.9%"/> <col width="30.8%"/> <col width="34.2%"/> <thead> <tr ID="id_1835c83a-b85c-4e86-873e-187851a45af0"> <td align="left" styleCode="Botrule" valign="top"> <content styleCode="bold">Add-On to Glimepiride (+/- Metformin) </content> (24 weeks) </td> <td align="center" styleCode="Botrule" valign="top"> <paragraph> <content styleCode="bold">JANUVIA 100 mg</content> </paragraph> <paragraph> <content styleCode="bold">+ Glimepiride</content> </paragraph> <content styleCode="bold">(+/- Metformin)</content> </td> <td align="center" styleCode="Botrule" valign="top"> <paragraph> <content styleCode="bold">Placebo</content> </paragraph> <paragraph> <content styleCode="bold">+ Glimepiride</content> </paragraph> <content styleCode="bold">(+/- Metformin)</content> </td> </tr> </thead> <tbody> <tr ID="id_24a0519e-6a67-47fd-907b-6da9158c6d8d"> <td align="left" styleCode="Toprule Botrule" valign="top"/> <td align="center" styleCode="Botrule" valign="top">N = 222</td> <td align="center" styleCode="Botrule" valign="top">N = 219</td> </tr> <tr ID="id_86258215-13b3-4153-8e20-6c4e9fb87e93"> <td align="left" valign="top"> Overall (%)</td> <td align="center" valign="top">27 (12.2)</td> <td align="center" valign="top">4 (1.8)</td> </tr> <tr ID="id_a1a01f3f-fa44-4aee-a22d-19fdc8f4e5d1"> <td align="left" valign="top"> Rate (episodes/patient-year) <footnote ID="id-89d714d7-9813-4858-9eb0-b63955a02eaa">Based on total number of events (i.e., a single patient may have had multiple events).</footnote> </td> <td align="center" valign="top">0.59</td> <td align="center" valign="top">0.24</td> </tr> <tr ID="id_93fd46a4-a7f7-424b-9d2c-23577d25a34d"> <td align="left" styleCode="Botrule" valign="top"> Severe (%) <footnote ID="id-f446e291-98f7-4a1a-97d8-66112da0687b">Severe events of hypoglycemia were defined as those events requiring medical assistance or exhibiting depressed level/loss of consciousness or seizure.</footnote> </td> <td align="center" styleCode="Botrule" valign="top">0 (0.0)</td> <td align="center" styleCode="Botrule" valign="top">0 (0.0)</td> </tr> <tr ID="id_e8c18e49-e95b-4fbd-83dd-a54764dcf554"> <td align="left" styleCode="Botrule" valign="top"> <content styleCode="bold">Add-On to Insulin (+/- Metformin) </content> (24 weeks) </td> <td align="center" styleCode="Botrule" valign="top"> <paragraph> <content styleCode="bold">JANUVIA 100 mg</content> </paragraph> <paragraph> <content styleCode="bold">+ Insulin</content> </paragraph> <content styleCode="bold">(+/- Metformin)</content> </td> <td align="center" styleCode="Botrule" valign="top"> <paragraph> <content styleCode="bold">Placebo</content> </paragraph> <paragraph> <content styleCode="bold">+ Insulin</content> </paragraph> <content styleCode="bold">(+/- Metformin)</content> </td> </tr> <tr ID="id_a383ae25-f882-48f7-8936-359efd4fb722"> <td align="left" styleCode="Botrule" valign="top"/> <td align="center" styleCode="Botrule" valign="top">N = 322</td> <td align="center" styleCode="Botrule" valign="top">N = 319</td> </tr> <tr ID="id_7e51dd23-2df2-4158-83ee-4c5296499e4e"> <td align="left" valign="top"> Overall (%)</td> <td align="center" valign="top">50 (15.5)</td> <td align="center" valign="top">25 (7.8)</td> </tr> <tr ID="id_5c41cf8a-24c7-4bab-a4bc-6a15b18313ab"> <td align="left" valign="top"> Rate (episodes/patient-year) <footnoteRef IDREF="id-89d714d7-9813-4858-9eb0-b63955a02eaa"/> </td> <td align="center" valign="top">1.06</td> <td align="center" valign="top">0.51</td> </tr> <tr ID="id_c5d49352-aa02-42c0-95ce-6d07f4f8f0c1"> <td align="left" styleCode="Botrule" valign="top"> Severe (%) <footnoteRef IDREF="id-f446e291-98f7-4a1a-97d8-66112da0687b"/> </td> <td align="center" styleCode="Botrule" valign="top">2 (0.6)</td> <td align="center" styleCode="Botrule" valign="top">1 (0.3)</td> </tr> </tbody> </table>