FDA label f5fcf510-02ce-41fd-83da-698eb57eef24

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 JUVISYNC. ( 5.1 ) Skeletal muscle effects (e.g., myopathy and rhabdomyolysis): Risks increase with higher doses and concomitant use of certain medicines. Predisposing factors include advanced age (≥65), female gender, uncontrolled hypothyroidism, and renal impairment. ( 4 , 5.2 , 8.5 ) Patients should be advised to report promptly any unexplained and/or persistent muscle pain, tenderness, or weakness. JUVISYNC therapy should be discontinued immediately if myopathy is diagnosed or suspected. See Drug Interaction table. (5.2) Liver enzyme abnormalities: Persistent elevations in hepatic transaminase can occur. Check liver enzyme tests before initiating therapy and as clinically indicated thereafter. ( 5.3 ) There have been postmarketing reports of acute renal failure, sometimes requiring dialysis, in patients treated with sitagliptin. Assessment of renal function is recommended prior to initiation of JUVISYNC and periodically thereafter. ( 5.4 , 6.2 ) There is an increased risk of hypoglycemia when JUVISYNC 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 , 5.5 ) There have been postmarketing reports of serious allergic and hypersensitivity reactions in patients treated with sitagliptin such as anaphylaxis, angioedema, and exfoliative skin conditions including Stevens-Johnson syndrome. In such cases, promptly stop JUVISYNC, assess for other potential causes, institute appropriate monitoring and treatment, and initiate alternative treatment. ( 5.6 , 6.2 ) 5.1 Pancreatitis There have been postmarketing reports of acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis, in patients taking sitagliptin. After initiation of JUVISYNC, patients should be observed carefully for signs and symptoms of pancreatitis. If pancreatitis is suspected, JUVISYNC 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 JUVISYNC. [See also Adverse Reactions (6.2) .] 5.2 Myopathy/Rhabdomyolysis Simvastatin occasionally causes myopathy manifested as muscle pain, tenderness or weakness with creatine kinase (CK) above ten times the upper limit of normal (ULN). Myopathy sometimes takes the form of rhabdomyolysis with or without acute renal failure secondary to myoglobinuria, and rare fatalities have occurred. The risk of myopathy is increased by high levels of statin activity in plasma. Predisposing factors for myopathy include advanced age (≥65 years), female gender, uncontrolled hypothyroidism, and renal impairment. The risk of myopathy, including rhabdomyolysis, is dose related. In a clinical trial database in which 41,413 patients were treated with simvastatin, 24,747 (approximately 60%) of whom were enrolled in studies with a median follow-up of at least 4 years, the incidence of myopathy was approximately 0.03% and 0.08% at 20 and 40 mg/day, respectively. The incidence of myopathy with 80 mg (0.61%) was disproportionately higher than that observed at the lower doses. In these trials, patients were carefully monitored and some interacting medicinal products were excluded. In a clinical trial in which 12,064 patients with a history of myocardial infarction were treated with simvastatin (mean follow-up 6.7 years), the incidence of myopathy (defined as unexplained muscle weakness or pain with a serum creatine kinase [CK] >10 times upper limit of normal [ULN]) in patients on 20 mg/day was approximately 0.02%; in patients treated with 80 mg/day, the incidence was 0.9%. The incidence of rhabdomyolysis (defined as myopathy with a CK >40 times ULN) in patients on 20 mg/day was 0%; in patients on 80 mg/day, the incidence was approximately 0.4%. The incidence of myopathy, including rhabdomyolysis, was highest during the first year and then notably decreased during the subsequent years of treatment. In this trial, patients were carefully monitored and some interacting medicinal products were excluded. There have been rare reports of immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, associated with statin use. IMNM is characterized by: proximal muscle weakness and elevated serum creatine kinase, which persist despite discontinuation of statin treatment; muscle biopsy showing necrotizing myopathy without significant inflammation; improvement with immunosuppressive agents. All patients starting therapy with JUVISYNC, or whose dose of JUVISYNC is being increased, should be advised of the risk of myopathy, including rhabdomyolysis, and told to report promptly any unexplained muscle pain, tenderness or weakness particularly if accompanied by malaise or fever or if muscle signs and symptoms persist after discontinuing JUVISYNC. JUVISYNC therapy should be discontinued immediately if myopathy is diagnosed or suspected. In most cases, muscle symptoms and CK increases resolved when treatment was promptly discontinued. Periodic CK determinations may be considered in patients starting therapy with JUVISYNC or whose dose is being increased, but there is no assurance that such monitoring will prevent myopathy. Many of the patients who have developed rhabdomyolysis on therapy with simvastatin have had complicated medical histories, including renal impairment usually as a consequence of long-standing diabetes mellitus. Such patients merit closer monitoring. JUVISYNC therapy should be discontinued if markedly elevated CPK levels occur or myopathy is diagnosed or suspected. JUVISYNC therapy should also be temporarily withheld in any patient experiencing an acute or serious condition predisposing to the development of renal failure secondary to rhabdomyolysis, e.g., sepsis; hypotension; major surgery; trauma; severe metabolic, endocrine, or electrolyte disorders; or uncontrolled epilepsy. Drug Interactions The risk of myopathy and rhabdomyolysis is increased by high levels of statin activity in plasma. Simvastatin is metabolized by the cytochrome P450 isoform 3A4. Certain drugs which inhibit this metabolic pathway can raise the plasma levels of simvastatin and may increase the risk of myopathy. These include itraconazole, ketoconazole, posaconazole, and voriconazole, the macrolide antibiotics erythromycin and clarithromycin, the ketolide antibiotic telithromycin, HIV protease inhibitors, boceprevir, telaprevir, the antidepressant nefazodone, cobicistat-containing products, and grapefruit juice [see Clinical Pharmacology (12.3) ] . Combination of these drugs with JUVISYNC is contraindicated. If short-term treatment with strong CYP3A4 inhibitors is unavoidable, therapy with JUVISYNC must be suspended during the course of treatment. [See Contraindications (4) ; Drug Interactions (7.1) .] The combined use of JUVISYNC with gemfibrozil, cyclosporine, or danazol is contraindicated [see Contraindications (4) ; Drug Interactions (7.1 , 7.2) ]. Caution should be used when prescribing other fibrates with JUVISYNC, as these agents can cause myopathy when given alone and the risk is increased when they are coadministered [see Drug Interactions (7.2) ] . Cases of myopathy, including rhabdomyolysis, have been reported with simvastatin coadministered with colchicine, and caution should be exercised when prescribing JUVISYNC with colchicine [see Drug Interactions (7.7) ] . The benefits of the combined use of JUVISYNC with the following drugs should be carefully weighed against the potential risks of combinations: amiodarone, dronedarone, verapamil, diltiazem, amlodipine, ranolazine and lipid-lowering drugs other than gemfibrozil (other fibrates, ≥1 g/day of niacin, or, for patients with HoFH, lomitapide), [see Drug Interactions (7.2 , 7.3 , 7.4) ; Table 6 in Clinical Pharmacology (12.3) ] [also see Dosage and Administration, Patients with Homozygous Familial Hypercholesterolemia (2.5) ] . Cases of myopathy, including rhabdomyolysis, have been observed with simvastatin coadministered with lipid-modifying doses (≥1 g/day niacin) of niacin-containing products. In an ongoing, double-blind, randomized cardiovascular outcomes trial, an independent safety monitoring committee identified that the incidence of myopathy is higher in Chinese compared with non-Chinese patients taking simvastatin 40 mg coadministered with lipid-modifying doses of a niacin-containing product. Caution should be used when treating Chinese patients with JUVISYNC 100 mg/40 mg or 50 mg/40 mg per day coadministered with lipid-modifying doses of niacin-containing products. It is unknown if the risk for myopathy with coadministration of JUVISYNC with lipid-modifying doses of niacin-containing products observed in Chinese patients applies to other Asian patients [see Drug Interactions (7.4) ] . Prescribing recommendations for interacting agents are summarized in Table 1 [see also Dosage and Administration (2.4 , 2.5) ; Drug Interactions (7.1 , 7.2 , 7.3) ; Clinical Pharmacology (12.3) ] . Table 1: Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis Interacting Agents Prescribing Recommendations Strong CYP3A4 Inhibitors, e.g.: Itraconazole Ketoconazole Posaconazole Voriconazole Erythromycin Clarithromycin Telithromycin HIV protease inhibitors Boceprevir Telaprevir Nefazodone Cobicistat-containing products Gemfibrozil Cyclosporine Danazol Contraindicated with JUVISYNC Verapamil Diltiazem Dronedarone Do not exceed 10 mg simvastatin (100 mg/10 mg or 50 mg/10 mg JUVISYNC) daily Amiodarone Amlodipine Ranolazine Do not exceed 20 mg simvastatin (100 mg/20 mg or 50 mg/20 mg JUVISYNC) daily Lomitapide For patients with HoFH, do not exceed 20 mg simvastatin (100 mg/20 mg or 50 mg/20 mg JUVISYNC) daily For patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 40 mg simvastatin when taking lomitapide. Grapefruit juice Avoid grapefruit juice 5.3 Liver Dysfunction Persistent increases (to more than 3× the ULN) in serum transaminases have occurred in approximately 1% of patients who received simvastatin in clinical studies . When drug treatment was interrupted or discontinued in these patients, the transaminase levels usually fell slowly to pretreatment levels. The increases were not associated with jaundice or other clinical signs or symptoms. There was no evidence of hypersensitivity. In the Scandinavian Simvastatin Survival Study (4S) [see Clinical Studies (14.2) ] , the number of patients with more than one transaminase elevation to >3× ULN, over the course of the study, was not significantly different between the simvastatin and placebo groups (14 [0.7%] vs. 12 [0.6%]). Elevated transaminases resulted in the discontinuation of 8 patients from therapy in the simvastatin group (n=2221) and 5 in the placebo group (n=2223). Of the 1986 simvastatin treated patients in 4S with normal liver function tests (LFTs) at baseline, 8 (0.4%) developed consecutive LFT elevations to >3× ULN and/or were discontinued due to transaminase elevations during the 5.4 years (median follow-up) of the study. Among these 8 patients, 5 initially developed these abnormalities within the first year. All of the patients in this study received a starting dose of 20 mg of simvastatin; 37% were titrated to 40 mg. In 2 controlled clinical studies in 1105 patients, the 12-month incidence of persistent hepatic transaminase elevation without regard to drug relationship was 0.9% and 2.1% at the 40 and 80 mg dose, respectively. No patients developed persistent liver function abnormalities following the initial 6 months of treatment at a given dose. It is recommended that liver function tests be performed before the initiation of treatment, and thereafter when clinically indicated. There have been rare postmarketing reports of fatal and non-fatal hepatic failure in patients taking statins, including simvastatin. If serious liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during treatment with JUVISYNC, promptly interrupt therapy. If an alternate etiology is not found do not restart JUVISYNC. Note that ALT may emanate from muscle, therefore ALT rising with CK may indicate myopathy [see Warnings and Precautions (5.2) ]. The drug should be used with caution in patients who consume substantial quantities of alcohol and/or have a past history of liver disease. Active liver diseases or unexplained transaminase elevations are contraindications to the use of JUVISYNC. As with other lipid-lowering agents, moderate (less than 3× ULN) elevations of serum transaminases have been reported following therapy with simvastatin. These changes appeared soon after initiation of therapy with simvastatin, were often transient, were not accompanied by any symptoms and did not require interruption of treatment. [See also Adverse Reactions (6.1) .] 5.4 Renal Impairment Assessment of renal function is recommended prior to initiating JUVISYNC and periodically thereafter. JUVISYNC is not recommended for use in patients with severe renal impairment or ESRD because doses of JUVISYNC appropriate for patients with severe renal impairment or ESRD are not available in this combination product. [See Dosage and Administration (2.2) ; Clinical Pharmacology (12.3) .] A dosage adjustment is recommended in patients with moderate renal impairment. [See Dosage and Administration (2.2) ; Clinical Pharmacology (12.3) .] Caution should be used to ensure that the correct dose of JUVISYNC is prescribed for patients with moderate renal impairment (creatinine clearance ≥30 to <50 mL/min). There have been postmarketing reports of worsening renal function, including acute renal failure, sometimes requiring dialysis, in patients treated with sitagliptin. A subset of these reports involved patients with renal impairment, some of whom were prescribed inappropriate doses of sitagliptin. A return to baseline levels of renal impairment has been observed with supportive treatment and discontinuation of potentially causative agents. Sitagliptin has not been found to be nephrotoxic in preclinical studies at clinically relevant doses, or in clinical trials. 5.5 Use with Medications Known to Cause Hypoglycemia 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 (6.1) .] Therefore, a lower dose of sulfonylurea or insulin may be required to reduce the risk of hypoglycemia. [See Dosage and Administration (2.3) .] 5.6 Hypersensitivity Reactions [See also Adverse Reactions (6.2) .] There have been postmarketing reports of serious hypersensitivity reactions in patients treated with sitagliptin. 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 JUVISYNC, assess for other potential causes for the event, and institute alternative treatment. 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 JUVISYNC. 5.7 Endocrine Function Increases in A1C and fasting serum glucose levels have been reported with HMG-CoA reductase inhibitors, including simvastatin.

<table width="80%" ID="table1"> <caption>Table 1: Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis</caption> <col width="50%" align="left" valign="top"/> <col width="50%" align="left" valign="top"/> <thead> <tr> <th styleCode="Lrule Rrule">Interacting Agents</th> <th styleCode="Rrule">Prescribing Recommendations</th> </tr> </thead> <tbody> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> <content styleCode="xmChange">Strong CYP3A4 Inhibitors, e.g.: Itraconazole Ketoconazole Posaconazole Voriconazole Erythromycin Clarithromycin Telithromycin HIV protease inhibitors Boceprevir Telaprevir Nefazodone Cobicistat-containing products Gemfibrozil Cyclosporine Danazol</content> </td> <td styleCode="Rrule">Contraindicated with JUVISYNC</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Verapamil Diltiazem Dronedarone</td> <td styleCode="Rrule">Do not exceed 10 mg simvastatin (100 mg/10 mg or 50 mg/10 mg JUVISYNC) daily</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Amiodarone Amlodipine Ranolazine</td> <td styleCode="Rrule">Do not exceed 20 mg simvastatin (100 mg/20 mg or 50 mg/20 mg JUVISYNC) daily</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> <content styleCode="xmChange">Lomitapide</content> </td> <td styleCode="Rrule">For patients with HoFH, do not exceed 20 mg simvastatin (100 mg/20 mg or 50 mg/20 mg JUVISYNC) daily<footnote>For patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 40 mg simvastatin when taking lomitapide.</footnote> </td> </tr> <tr> <td styleCode="Lrule Rrule"> <content styleCode="xmChange">Grapefruit juice</content> </td> <td styleCode="Rrule"> Avoid grapefruit juice </td> </tr> </tbody> </table>

6 ADVERSE REACTIONS Most common adverse reactions (incidence ≥5%) with simvastatin are: upper respiratory infection, headache, abdominal pain, constipation, and nausea. Adverse reactions reported in ≥5% of patients treated with sitagliptin 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 sitagliptin 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 JUVISYNC 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 a pooled subgroup analysis of 19 controlled clinical studies of sitagliptin involving 1582 patients whose background therapy included simvastatin, incidences of adverse reactions for patients treated with sitagliptin and simvastatin (n=827) were similar to those for patients treated with control therapy (placebo or active comparator) and simvastatin (n=755). Among these patients, 3.3% of the sitagliptin-treated group and 4.2% of controls discontinued due to adverse reactions. Sitagliptin 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 sitagliptin were similar to placebo. In combination with glimepiride, with or without metformin, the overall incidence of clinical adverse reactions with sitagliptin was higher than with placebo, in part related to a higher incidence of hypoglycemia (see Table 4 ); 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 sitagliptin 100 mg daily, sitagliptin 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 sitagliptin 100 mg daily or placebo. The adverse reactions, excluding hypoglycemia, reported regardless of investigator assessment of causality in ≥5% of patients treated with sitagliptin 100 mg daily and more commonly than in patients treated with placebo, are shown in Table 2 for the clinical trials of at least 18 weeks duration. Incidences of hypoglycemia are shown in Table 4 . Table 2: Placebo-Controlled Clinical Studies of Sitagliptin 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) Sitagliptin 100 mg Placebo N = 443 N = 363 Nasopharyngitis 23 (5.2) 12 (3.3) Combination with Pioglitazone (24 weeks) Sitagliptin 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) Sitagliptin 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) Sitagliptin 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 sitagliptin 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 sitagliptin 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 4 ). In the study of sitagliptin as add-on combination therapy with metformin and rosiglitazone ( Table 2 ), 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%). 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 sitagliptin was as follows: abdominal pain (sitagliptin 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 3 . Table 3: 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 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 sitagliptin 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 sitagliptin. 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 the sitagliptin clinical trial program, 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 sitagliptin 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 4 ). Table 4: 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 Sitagliptin 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) Sitagliptin 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) Sitagliptin 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 sitagliptin 100 mg and 0.9% in patients treated with placebo. In the study of sitagliptin as 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. In the 24-week, placebo-controlled factorial study of initial therapy with sitagliptin in combination with metformin, the incidence of hypoglycemia 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 the study of sitagliptin as initial therapy with pioglitazone, one patient taking sitagliptin experienced a severe episode of hypoglycemia. There were no severe hypoglycemia episodes reported in other studies except in the study involving coadministration with insulin. Simvastatin In the pre-marketing controlled clinical studies and their open-label extensions (2423 patients with median duration of follow-up of approximately 18 months), 1.4% of patients were discontinued due to adverse reactions. The most common adverse reactions that led to treatment discontinuation were: gastrointestinal disorders (0.5%), myalgia (0.1%), and arthralgia (0.1%). The most commonly reported adverse reactions (incidence ≥5%) in simvastatin controlled clinical trials were: upper respiratory infections (9.0%), headache (7.4%), abdominal pain (7.3%), constipation (6.6%), and nausea (5.4%). Scandinavian Simvastatin Survival Study In 4S involving 4444 patients (age range 35-71 years, 19% women, 100% Caucasians) treated with 20-40 mg/day of simvastatin (n=2221) or placebo (n=2223) over a median of 5.4 years, adverse reactions reported in ≥2% of patients and at a rate greater than placebo are shown in Table 5 . Table 5: Adverse Reactions Reported Regardless of Causality by ≥2% of Patients Treated with Simvastatin and Greater than Placebo in 4S Simvastatin (N = 2221) % Placebo (N = 2223) % Body as a Whole Edema/swelling Abdominal pain 2.7 5.9 2.3 5.8 Cardiovascular System Disorders Atrial fibrillation 5.7 5.1 Digestive System Disorders Constipation Gastritis 2.2 4.9 1.6 3.9 Endocrine Disorders Diabetes mellitus 4.2 3.6 Musculoskeletal Disorders Myalgia 3.7 3.2 Nervous System/ Psychiatric Disorders Headache Insomnia Vertigo 2.5 4.0 4.5 2.1 3.8 4.2 Respiratory System Disorders Bronchitis Sinusitis 6.6 2.3 6.3 1.8 Skin / Skin Appendage Disorders Eczema 4.5 3.0 Urogenital System Disorders Infection, urinary tract 3.2 3.1 Heart Protection Study In the Heart Protection Study (HPS), involving 20,536 patients (age range 40-80 years, 25% women, 97% Caucasians, 3% other races) treated with simvastatin 40 mg/day (n=10,269) or placebo (n=10,267) over a mean of 5 years, only serious adverse reactions and discontinuations due to any adverse reactions were recorded. Discontinuation rates due to adverse reactions were 4.8% in patients treated with simvastatin compared with 5.1% in patients treated with placebo. The incidence of myopathy/rhabdomyolysis was <0.1% in patients treated with simvastatin. Other Clinical Studies In a clinical trial in which 12,064 patients with a history of myocardial infarction were treated with simvastatin (mean follow-up 6.7 years), the incidence of myopathy (defined as unexplained muscle weakness or pain with a serum creatine kinase [CK] >10 times upper limit of normal [ULN]) in patients on 20 mg/day was approximately 0.02%; in patients treated with 80 mg/day, the incidence was 0.9%. The incidence of rhabdomyolysis (defined as myopathy with a CK >40 times ULN) in patients on 20 mg/day was 0%; in patients on 80 mg/day, the incidence was approximately 0.4%. The incidence of myopathy, including rhabdomyolysis, was highest during the first year and then notably decreased during the subsequent years of treatment. In this trial, patients were carefully monitored and some interacting medicinal products were excluded. Other adverse reactions reported in clinical trials were: diarrhea, rash, dyspepsia, flatulence, and asthenia. Laboratory Tests Sitagliptin Across clinical studies, the incidence of laboratory adverse reactions was similar in patients treated with sitagliptin 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 impairment, 37 patients with moderate renal impairment were randomized to sitagliptin 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 sitagliptin [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. Simvastatin Marked persistent increases of hepatic transaminases have been noted [see Warnings and Precautions (5.3) ] . Elevated alkaline phosphatase and γ-glutamyl transpeptidase have also been reported. About 5% of patients had elevations of CK levels of 3 or more times the normal value on one or more occasions. This was attributable to the noncardiac fraction of CK. [See Warnings and Precautions (5.2) .] 6.2 Postmarketing Experience Additional adverse reactions have been identified during postapproval use of sitagliptin (as monotherapy and/or in combination with other antihyperglycemic agents) or simvastatin. 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. Anemia; depression; headache; dizziness; paresthesia; peripheral neuropathy; interstitial lung disease; pancreatitis; acute pancreatitis, including fatal and non-fatal hemorrhagic and necrotizing pancreatitis [see Indications and Usage (1.3) ; Warnings and Precautions (5.1) ] ; constipation; vomiting; hepatitis/jaundice; fatal and non-fatal hepatic failure; hepatic enzyme elevations; pruritus; alopecia; a variety of skin changes (e.g., nodules, discoloration, dryness of skin/mucous membranes, changes to hair/nails); muscle cramps; myalgia; rhabdomyolysis; arthralgia; pain in extremity; back pain; worsening renal function, including acute renal failure (sometimes requiring dialysis); erectile dysfunction. There have been rare reports of immune-mediated necrotizing myopathy associated with statin use [see Warnings and Precautions (5.2) ] . There have been rare postmarketing reports of cognitive impairment (e.g., memory loss, forgetfulness, amnesia, memory impairment, confusion) associated with statin use. These cognitive issues have been reported for all statins. The reports are generally nonserious, and reversible upon statin discontinuation, with variable times to symptom onset (1 day to years) and symptom resolution (median of 3 weeks). Hypersensitivity reactions including anaphylaxis, angioedema, rash, urticaria, cutaneous vasculitis, and exfoliative skin conditions including Stevens-Johnson syndrome have been reported with sitagliptin [see Warnings and Precautions (5.6) ] . An apparent hypersensitivity syndrome has been reported rarely with simvastatin which has included some of the following features: anaphylaxis, angioedema, lupus erythematous-like syndrome, polymyalgia rheumatica, dermatomyositis, vasculitis, purpura, thrombocytopenia, leukopenia, hemolytic anemia, positive ANA, ESR increase, eosinophilia, arthritis, arthralgia, urticaria, asthenia, photosensitivity, fever, chills, flushing, malaise, dyspnea, toxic epidermal necrolysis, erythema multiforme, including Stevens-Johnson syndrome.

<table width="100%" ID="table2"> <caption>Table 2: Placebo-Controlled Clinical Studies of Sitagliptin 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>Intent-to-treat population</footnote> </caption> <col width="40%" align="left" valign="top"/> <col width="30%" align="center" valign="top"/> <col width="30%" align="center" valign="top"/> <thead> <tr> <th styleCode="Lrule Rrule"/> <th styleCode="Rrule" colspan="2">Number of Patients (%)</th> </tr> </thead> <tbody> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> <content styleCode="bold">Monotherapy </content>(18 or 24 weeks)</td> <td styleCode="Rrule"> <content styleCode="bold">Sitagliptin 100 mg</content> </td> <td styleCode="Rrule"> <content styleCode="bold">Placebo</content> </td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"/> <td styleCode="Rrule">N = 443</td> <td styleCode="Rrule">N = 363</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Nasopharyngitis</td> <td styleCode="Rrule">23 (5.2)</td> <td styleCode="Rrule">12 (3.3)</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> <content styleCode="bold">Combination with Pioglitazone</content> (24 weeks)</td> <td styleCode="Rrule"> <content styleCode="bold">Sitagliptin 100 mg + Pioglitazone </content> </td> <td styleCode="Rrule"> <content styleCode="bold">Placebo + Pioglitazone</content> </td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"/> <td styleCode="Rrule">N = 175</td> <td styleCode="Rrule">N = 178</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Upper Respiratory Tract Infection</td> <td styleCode="Rrule">11 (6.3)</td> <td styleCode="Rrule">6 (3.4)</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Headache</td> <td styleCode="Rrule">9 (5.1)</td> <td styleCode="Rrule">7 (3.9)</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> <content styleCode="bold">Combination with Metformin + Rosiglitazone</content> (18 weeks)</td> <td styleCode="Rrule"> <content styleCode="bold">Sitagliptin 100 mg + Metformin + Rosiglitazone</content> </td> <td styleCode="Rrule"> <content styleCode="bold">Placebo + Metformin + Rosiglitazone</content> </td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"/> <td styleCode="Rrule">N = 181</td> <td styleCode="Rrule">N = 97</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Upper Respiratory Tract Infection</td> <td styleCode="Rrule">10 (5.5)</td> <td styleCode="Rrule">5 (5.2)</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Nasopharyngitis</td> <td styleCode="Rrule">11 (6.1)</td> <td styleCode="Rrule">4 (4.1)</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> <content styleCode="bold">Combination with Glimepiride (+/- Metformin)</content> (24 weeks)</td> <td styleCode="Rrule"> <content styleCode="bold">Sitagliptin 100 mg + Glimepiride (+/- Metformin)</content> </td> <td styleCode="Rrule"> <content styleCode="bold">Placebo + Glimepiride (+/- Metformin)</content> </td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"/> <td styleCode="Rrule">N = 222</td> <td styleCode="Rrule">N = 219</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Nasopharyngitis</td> <td styleCode="Rrule">14 (6.3)</td> <td styleCode="Rrule">10 (4.6)</td> </tr> <tr> <td styleCode="Lrule Rrule"> Headache</td> <td styleCode="Rrule">13 (5.9)</td> <td styleCode="Rrule">5 (2.3)</td> </tr> </tbody> </table>

<table width="100%" ID="table3"> <caption>Table 3: 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>Intent-to-treat population.</footnote> </caption> <col width="23%" align="left" valign="top"/> <col width="12%" align="center" valign="top"/> <col width="17%" align="center" valign="top"/> <col width="24%" align="center" valign="top"/> <col width="24%" align="center" valign="top"/> <thead> <tr styleCode="Botrule"> <th styleCode="Lrule Rrule"/> <th styleCode="Rrule" colspan="4">Number of Patients (%)</th> </tr> <tr> <th styleCode="Lrule Rrule"/> <th styleCode="Rrule"> Placebo</th> <th styleCode="Rrule">Sitagliptin 100 mg QD</th> <th styleCode="Rrule"> Metformin 500 or 1000 mg bid<footnote ID="t3fn2">Data pooled for the patients given the lower and higher doses of metformin. </footnote> </th> <th styleCode="Rrule">Sitagliptin 50 mg bid + Metformin 500 or 1000 mg bid<footnoteRef IDREF="t3fn2"/> </th> </tr> </thead> <tbody> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"/> <td styleCode="Rrule">N = 176</td> <td styleCode="Rrule">N = 179</td> <td styleCode="Rrule">N = 364<footnoteRef IDREF="t3fn2"/> </td> <td styleCode="Rrule">N = 372<footnoteRef IDREF="t3fn2"/> </td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Upper Respiratory Infection</td> <td styleCode="Rrule">9 (5.1)</td> <td styleCode="Rrule">8 (4.5)</td> <td styleCode="Rrule">19 (5.2)</td> <td styleCode="Rrule">23 (6.2)</td> </tr> <tr> <td styleCode="Lrule Rrule">Headache</td> <td styleCode="Rrule">5 (2.8)</td> <td styleCode="Rrule">2 (1.1)</td> <td styleCode="Rrule">14 (3.8)</td> <td styleCode="Rrule">22 (5.9)</td> </tr> </tbody> </table>

<table width="90%" ID="table4"> <caption>Table 4: Incidence and Rate of Hypoglycemia<footnote ID="t4fn1">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 Sitagliptin 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%" align="left" valign="top"/> <col width="33%" align="center" valign="top"/> <col width="33%" align="center" valign="top"/> <tbody> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> <content styleCode="bold">Add-On to Glimepiride (+/- Metformin)</content> (24 weeks)</td> <td styleCode="Rrule"> <content styleCode="bold">Sitagliptin 100 mg + Glimepiride (+/- Metformin)</content> </td> <td styleCode="Rrule"> <content styleCode="bold">Placebo + Glimepiride (+/- Metformin)</content> </td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"/> <td styleCode="Rrule">N = 222</td> <td styleCode="Rrule">N = 219</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Overall (%)</td> <td styleCode="Rrule">27 (12.2)</td> <td styleCode="Rrule">4 (1.8)</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Rate (episodes/patient-year)<footnote ID="t4fn2">Based on total number of events (i.e., a single patient may have had multiple events).</footnote> </td> <td styleCode="Rrule">0.59</td> <td styleCode="Rrule">0.24</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Severe (%)<footnote ID="t4fn3">Severe events of hypoglycemia were defined as those events requiring medical assistance or exhibiting depressed level/loss of consciousness or seizure.</footnote> </td> <td styleCode="Rrule">0 (0.0)</td> <td styleCode="Rrule">0 (0.0)</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> <content styleCode="bold">Add-On to Insulin (+/- Metformin)</content> (24 weeks)</td> <td styleCode="Rrule"> <content styleCode="bold">Sitagliptin 100 mg + Insulin (+/- Metformin)</content> </td> <td styleCode="Rrule"> <content styleCode="bold">Placebo + Insulin (+/- Metformin)</content> </td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"/> <td styleCode="Rrule">N = 322</td> <td styleCode="Rrule">N = 319</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Overall (%)</td> <td styleCode="Rrule">50 (15.5)</td> <td styleCode="Rrule">25 (7.8)</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Rate (episodes/patient-year)<footnoteRef IDREF="t4fn2"/> </td> <td styleCode="Rrule">1.06</td> <td styleCode="Rrule">0.51</td> </tr> <tr> <td styleCode="Lrule Rrule"> Severe (%)<footnoteRef IDREF="t4fn3"/> </td> <td styleCode="Rrule">2 (0.6)</td> <td styleCode="Rrule">1 (0.3)</td> </tr> </tbody> </table>