Juvisync

Name: Juvisync

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Side Effects of Juvisync

Serious side effects have happened in people taking Juvisync.

See "Drug Precautions".
myopathy (muscle weakness) and rhabdomyolysis (muscle breakdown). Tell your doctor right away if you have unexplained muscle pain, tenderness, or weakness while you take Juvisync.
- Muscle problems, including muscle breakdown, can be serious in some people and on rare occasions may cause kidney damage that can lead to death.
- The risk of muscle breakdown is greater at higher doses of Juvisync.
- The risk of muscle breakdown is greater in people 65 years of age and older, females, and people with kidney or thyroid problems.
liver problems. Your doctor should do blood tests to check your liver before you start taking Juvisync and if you have any symptoms of liver problems while you take Juvisync. Call your doctor right away if you have the following symptoms of liver problems:
- feel tired or weak
- loss of appetite
- upper belly pain
- dark urine
- yellowing of your skin or the whites of your eyes
kidney problems, sometimes requiring dialysis
low blood sugar (hypoglycemia). If you take Juvisync with another medicine that can cause low blood sugar, such as a sulfonylurea or insulin, your risk of getting low blood sugar is higher. The dose of your sulfonylurea medicine or insulin may need to be lowered while you use Juvisync. Signs and symptoms of low blood sugar may include:

headache
drowsiness
weakness
dizziness
confusion
irritability
hunger
fast heart beat
sweating
feeling jittery

Serious allergic reactions. If you have any symptoms of a serious allergic reaction, stop taking Juvisync and call your doctor right away. Your doctor may give you a medicine for your allergic reaction and prescribe a different medicine for your diabetes.

The most common side effects of Juvisync include:

upper respiratory infection
stuffy or runny nose and sore throat
headache
stomach pain
constipation
nausea

Juvisync may cause other side effects, including:

swelling of the hands or legs. Swelling of the hands or legs can happen if you take Juvisync in combination with rosiglitazone (Avandia). Rosiglitazone is another type of diabetes medicine.
joint pain
muscle pain
alterations in some laboratory blood tests
liver problems (sometimes serious)
nausea
dizziness
tingling sensation
depression
trouble sleeping
poor memory
erectile dysfunction
breathing problems including persistent cough and/or shortness of breath or fever.

These are not all the possible side effects of Juvisync. For more information, ask your doctor or pharmacist.

Tell your doctor if you have any side effect that bothers you, is unusual or does not go away.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

Juvisync Usage

Take one Juvisync tablet each day, in the evening, exactly as your doctor tells you.
Take Juvisync tablets whole. Do not break, cut, crush, dissolve, or chew Juvisync tablets before swallowing. If you cannot swallow tablets whole, tell your doctor.
Your doctor may tell you to take Juvisync along with other diabetes medicines. Low blood sugar can happen more often when Juvisync is taken with certain other diabetes medicines.
If you take too much Juvisync, call your doctor or go to the nearest hospital emergency room right away.
When your body is under some types of stress, such as fever, trauma (such as a car accident), infection or surgery, the amount of diabetes medicine that you need may change. Tell your doctor right away if you have any of these conditions and follow your doctor's instructions.
Check your blood sugar as your doctor tells you to.
Stay on your prescribed diet and exercise program while taking Juvisync.
Talk to your doctor about how to prevent, recognize and manage low blood sugar (hypoglycemia), high blood sugar (hyperglycemia), and problems you have because of your diabetes.
Your doctor will monitor your condition with regular blood tests, including your blood sugar levels, hemoglobin A1C, and cholesterol levels, and to check for side effects.
Your doctor will do blood tests to check how well your kidneys are working before and during your treatment with Juvisync.

Juvisync Dosage

Take this medication exactly as prescribed by your doctor. Follow the directions on your prescription label carefully.

The dose your doctor recommends may be based on the following:

how you respond to this medication
other medications you are taking
your renal function

The recommended starting dose/dose range of Juvisync is 100 mg/40 mg per day.

The dose may be reduced based on your renal function.

What happens if i miss a dose (juvisync)?

Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

Uses of Juvisync

It is used to lower blood sugar in patients with high blood sugar (diabetes).
It is used to slow the progress of heart disease.
It is used to lower bad cholesterol and raise good cholesterol (HDL).
It is used to lower triglycerides.

How do I store and/or throw out Juvisync?

Store at room temperature.
Store in a dry place. Do not store in a bathroom.
Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
Check with your pharmacist about how to throw out unused drugs.

Contraindications

Juvisync is contraindicated in the following conditions:

History of a serious hypersensitivity reaction, such as anaphylaxis or angioedema, to any component of this medication. [See Warnings and Precautions (5.6); Adverse Reactions (6.2).]
Concomitant administration of strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, HIV protease inhibitors, boceprevir, telaprevir, erythromycin, clarithromycin, telithromycin, nefazodone, and cobicistat-containing products) [see Warnings and Precautions (5.2)].
Concomitant administration of gemfibrozil, cyclosporine, or danazol [see Warnings and Precautions (5.2)].
Active liver disease, which may include unexplained persistent elevations in hepatic transaminase levels [see Warnings and Precautions (5.3)].
Women who are pregnant or may become pregnant. Serum cholesterol and triglycerides increase during normal pregnancy, and cholesterol or cholesterol derivatives are essential for fetal development. Because HMG-CoA reductase inhibitors (statins) decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol, simvastatin may cause fetal harm when administered to a pregnant woman. Atherosclerosis is a chronic process and the discontinuation of lipid-lowering drugs during pregnancy should have little impact on the outcome of long-term therapy of primary hypercholesterolemia. There are no adequate and well-controlled studies of use with Juvisync during pregnancy; however, in rare reports congenital anomalies were observed following intrauterine exposure to statins. In rat and rabbit animal reproduction studies, simvastatin revealed no evidence of teratogenicity. Juvisync should be administered to women of childbearing age only when such patients are highly unlikely to conceive. If the patient becomes pregnant while taking this drug, Juvisync should be discontinued immediately and the patient should be apprised of the potential hazard to the fetus [see Use in Specific Populations (8.1)].
Nursing mothers. Because statins have the potential for serious adverse reactions in nursing infants, women who require treatment with Juvisync should not breastfeed their infants. A small amount of another drug in the statin class passes into breast milk. It is not known whether simvastatin is excreted into human milk [see Use in Specific Populations (8.3)].

Clinical Studies

Sitagliptin Clinical Studies

There were approximately 5200 patients with type 2 diabetes randomized in nine double-blind, placebo-controlled clinical safety and efficacy studies conducted to evaluate the effects of sitagliptin on glycemic control. In a pooled analysis of seven of these studies, the ethnic/racial distribution was approximately 59% white, 20% Hispanic, 10% Asian, 6% black, and 6% other groups. Patients had an overall mean age of approximately 55 years (range 18 to 87 years). In addition, an active (glipizide)-controlled study of 52 weeks duration was conducted in 1172 patients with type 2 diabetes who had inadequate glycemic control on metformin.

In patients with type 2 diabetes, treatment with sitagliptin produced clinically significant improvements in hemoglobin A1C, fasting plasma glucose (FPG) and 2-hour post-prandial glucose (PPG) compared to placebo.

Monotherapy

A total of 1262 patients with type 2 diabetes participated in two double-blind, placebo-controlled studies, one of 18-week and another of 24-week duration, to evaluate the efficacy and safety of sitagliptin monotherapy. In both monotherapy studies, patients currently on an antihyperglycemic agent discontinued the agent, and underwent a diet, exercise, and drug washout period of about 7 weeks. Patients with inadequate glycemic control (A1C 7% to 10%) after the washout period were randomized after completing a 2-week single-blind placebo run-in period; patients not currently on antihyperglycemic agents (off therapy for at least 8 weeks) with inadequate glycemic control (A1C 7% to 10%) were randomized after completing the 2-week single-blind placebo run-in period. In the 18-week study, 521 patients were randomized to placebo, sitagliptin 100 mg, or sitagliptin 200 mg, and in the 24-week study 741 patients were randomized to placebo, sitagliptin 100 mg, or sitagliptin 200 mg. Patients who failed to meet specific glycemic goals during the studies were treated with metformin rescue, added on to placebo or sitagliptin.

Treatment with sitagliptin at 100 mg daily provided significant improvements in A1C, FPG, and 2-hour PPG compared to placebo (Table 7). In the 18-week study, 9% of patients receiving sitagliptin 100 mg and 17% who received placebo required rescue therapy. In the 24-week study, 9% of patients receiving sitagliptin 100 mg and 21% of patients receiving placebo required rescue therapy. The improvement in A1C compared to placebo was not affected by gender, age, race, prior antihyperglycemic therapy, or baseline BMI. As is typical for trials of agents to treat type 2 diabetes, the mean reduction in A1C with sitagliptin appears to be related to the degree of A1C elevation at baseline. In these 18- and 24-week studies, among patients who were not on an antihyperglycemic agent at study entry, the reductions from baseline in A1C were -0.7% and -0.8%, respectively, for those given sitagliptin, and -0.1% and -0.2%, respectively, for those given placebo. Overall, the 200 mg daily dose did not provide greater glycemic efficacy than the 100 mg daily dose. Body weight did not increase from baseline with sitagliptin therapy in either study, compared to a small reduction in patients given placebo.

Table 7: Glycemic Parameters in 18- and 24-Week Placebo-Controlled Studies of Sitagliptin in Patients with Type 2 Diabetes*

	18-Week Study		24-Week Study
	Sitagliptin 100 mg	Placebo	Sitagliptin 100 mg	Placebo
* Intent-to-treat population using last observation on study prior to metformin rescue therapy. † Least squares means adjusted for prior antihyperglycemic therapy status and baseline value. ‡ p<0.001 compared to placebo. § Data not available.
A1C (%)	N = 193	N = 103	N = 229	N = 244
Baseline (mean)	8.0	8.1	8.0	8.0
Change from baseline (adjusted mean†)	-0.5	0.1	-0.6	0.2
Difference from placebo (adjusted mean†) (95% CI)	-0.6‡ (-0.8, -0.4)		-0.8‡ (-1.0, -0.6)
Patients (%) achieving A1C <7%	69 (36%)	16 (16%)	93 (41%)	41 (17%)
FPG (mg/dL)	N = 201	N = 107	N = 234	N = 247
Baseline (mean)	180	184	170	176
Change from baseline (adjusted mean†)	-13	7	-12	5
Difference from placebo (adjusted mean†) (95% CI)	-20‡ (-31, -9)		-17‡ (-24, -10)
2-hour PPG (mg/dL)	§	§	N = 201	N = 204
Baseline (mean)			257	271
Change from baseline (adjusted mean†)			-49	-2
Difference from placebo (adjusted mean†) (95% CI)			-47‡ (-59, -34)

Add-on Combination Therapy with Metformin

A total of 701 patients with type 2 diabetes participated in a 24-week, randomized, double-blind, placebo-controlled study designed to assess the efficacy of sitagliptin in combination with metformin. Patients already on metformin (N=431) at a dose of at least 1500 mg per day were randomized after completing a 2-week single-blind placebo run-in period. Patients on metformin and another antihyperglycemic agent (N=229) and patients not on any antihyperglycemic agents (off therapy for at least 8 weeks, N=41) were randomized after a run-in period of approximately 10 weeks on metformin (at a dose of at least 1500 mg per day) in monotherapy. Patients with inadequate glycemic control (A1C 7% to 10%) were randomized to the addition of either 100 mg of sitagliptin or placebo, administered once daily. Patients who failed to meet specific glycemic goals during the studies were treated with pioglitazone rescue.

In combination with metformin, sitagliptin provided significant improvements in A1C, FPG, and 2-hour PPG compared to placebo with metformin (Table 8). Rescue glycemic therapy was used in 5% of patients treated with sitagliptin 100 mg and 14% of patients treated with placebo. A similar decrease in body weight was observed for both treatment groups.

Table 8: Glycemic Parameters at Final Visit (24-Week Study) for Sitagliptin in Add-on Combination Therapy with Metformin*

	Sitagliptin 100 mg + Metformin	Placebo + Metformin
* Intent-to-treat population using last observation on study prior to pioglitazone rescue therapy. † Least squares means adjusted for prior antihyperglycemic therapy and baseline value. ‡ p<0.001 compared to placebo + metformin.
A1C (%)	N = 453	N = 224
Baseline (mean)	8.0	8.0
Change from baseline (adjusted mean†)	-0.7	-0.0
Difference from placebo + metformin (adjusted mean†) (95% CI)	-0.7‡ (-0.8, -0.5)
Patients (%) achieving A1C <7%	213 (47%)	41 (18%)
FPG (mg/dL)	N = 454	N = 226
Baseline (mean)	170	174
Change from baseline (adjusted mean†)	-17	9
Difference from placebo + metformin (adjusted mean†) (95% CI)	-25‡ (-31, -20)
2-hour PPG (mg/dL)	N = 387	N = 182
Baseline (mean)	275	272
Change from baseline (adjusted mean†)	-62	-11
Difference from placebo + metformin (adjusted mean†) (95% CI)	-51‡ (-61, -41)

Initial Combination Therapy with Metformin

A total of 1091 patients with type 2 diabetes and inadequate glycemic control on diet and exercise participated in a 24-week, randomized, double-blind, placebo-controlled factorial study designed to assess the efficacy of sitagliptin as initial therapy in combination with metformin. Patients on an antihyperglycemic agent (N=541) discontinued the agent, and underwent a diet, exercise, and drug washout period of up to 12 weeks duration. After the washout period, patients with inadequate glycemic control (A1C 7.5% to 11%) were randomized after completing a 2-week single-blind placebo run-in period. Patients not on antihyperglycemic agents at study entry (N=550) with inadequate glycemic control (A1C 7.5% to 11%) immediately entered the 2-week single-blind placebo run-in period and then were randomized. Approximately equal numbers of patients were randomized to receive initial therapy with placebo, 100 mg of sitagliptin once daily, 500 mg or 1000 mg of metformin twice daily, or 50 mg of sitagliptin twice daily in combination with 500 mg or 1000 mg of metformin twice daily. Patients who failed to meet specific glycemic goals during the study were treated with glyburide (glibenclamide) rescue.

Initial therapy with the combination of sitagliptin and metformin provided significant improvements in A1C, FPG, and 2-hour PPG compared to placebo, to metformin alone, and to sitagliptin alone (Table 9, Figure 1). Mean reductions from baseline in A1C were generally greater for patients with higher baseline A1C values. For patients not on an antihyperglycemic agent at study entry, mean reductions from baseline in A1C were: sitagliptin 100 mg once daily, -1.1%; metformin 500 mg bid, -1.1%; metformin 1000 mg bid, -1.2%; sitagliptin 50 mg bid with metformin 500 mg bid, -1.6%; sitagliptin 50 mg bid with metformin 1000 mg bid, -1.9%; and for patients receiving placebo, -0.2%. The decrease in body weight in the groups given sitagliptin in combination with metformin was similar to that in the groups given metformin alone or placebo.

Table 9: Glycemic Parameters at Final Visit (24-Week Study) for Sitagliptin and Metformin, Alone and in Combination as Initial Therapy*

	Placebo	Sitagliptin 100 mg QD	Metformin 500 mg bid	Metformin 1000 mg bid	Sitagliptin 50 mg bid + Metformin 500 mg bid	Sitagliptin 50 mg bid + Metformin 1000 mg bid
* Intent-to-treat population using last observation on study prior to glyburide (glibenclamide) rescue therapy. † Least squares means adjusted for prior antihyperglycemic therapy status and baseline value. ‡ p<0.001 compared to placebo.
A1C (%)	N = 165	N = 175	N = 178	N = 177	N = 183	N = 178
Baseline (mean)	8.7	8.9	8.9	8.7	8.8	8.8
Change from baseline (adjusted mean†)	0.2	-0.7	-0.8	-1.1	-1.4	-1.9
Difference from placebo (adjusted mean†) (95% CI)		-0.8‡ (-1.1, -0.6)	-1.0‡ (-1.2, -0.8)	-1.3‡ (-1.5, -1.1)	-1.6‡ (-1.8, -1.3)	-2.1‡ (-2.3, -1.8)
Patients (%) achieving A1C <7%	15 (9%)	35 (20%)	41 (23%)	68 (38%)	79 (43%)	118 (66%)
% Patients receiving rescue medication	32	21	17	12	8	2
FPG (mg/dL)	N = 169	N = 178	N = 179	N = 179	N = 183	N = 180
Baseline (mean)	196	201	205	197	204	197
Change from baseline (adjusted mean†)	6	-17	-27	-29	-47	-64
Difference from placebo (adjusted mean†) (95% CI)		-23‡ (-33, -14)	-33‡ (-43, -24)	-35‡ (-45, -26)	-53‡ (-62, -43)	-70‡ (-79, -60)
2-hour PPG (mg/dL)	N = 129	N = 136	N = 141	N = 138	N = 147	N = 152
Baseline (mean)	277	285	293	283	292	287
Change from baseline (adjusted mean†)	0	-52	-53	-78	-93	-117
Difference from placebo (adjusted mean†) (95% CI)		-52‡ (-67, -37)	-54‡ (-69, -39)	-78‡ (-93, -63)	-93‡ (-107, -78)	-117‡ (-131, -102)

* All Patients Treated Population; least squares means adjusted for prior antihyperglycemic therapy and baseline value.

Figure 1: Mean Change from Baseline for A1C (%) over 24 Weeks with Sitagliptin and Metformin, Alone and in Combination as Initial Therapy in Patients with Type 2 Diabetes*

Initial combination therapy or maintenance of combination therapy may not be appropriate for all patients. These management options are left to the discretion of the health care provider.

Active-Controlled Study vs Glipizide in Combination with Metformin

The efficacy of sitagliptin was evaluated in a 52-week, double-blind, glipizide-controlled noninferiority trial in patients with type 2 diabetes. Patients not on treatment or on other antihyperglycemic agents entered a run-in treatment period of up to 12 weeks duration with metformin monotherapy (dose of ≥1500 mg per day) which included washout of medications other than metformin, if applicable. After the run-in period, those with inadequate glycemic control (A1C 6.5% to 10%) were randomized 1:1 to the addition of sitagliptin 100 mg once daily or glipizide for 52 weeks. Patients receiving glipizide were given an initial dosage of 5 mg/day and then electively titrated over the next 18 weeks to a maximum dosage of 20 mg/day as needed to optimize glycemic control. Thereafter, the glipizide dose was to be kept constant, except for down-titration to prevent hypoglycemia. The mean dose of glipizide after the titration period was 10 mg.

After 52 weeks, sitagliptin and glipizide had similar mean reductions from baseline in A1C in the intent-to-treat analysis (Table 10). These results were consistent with the per protocol analysis (Figure 2). A conclusion in favor of the non-inferiority of sitagliptin to glipizide may be limited to patients with baseline A1C comparable to those included in the study (over 70% of patients had baseline A1C <8% and over 90% had A1C <9%).

Table 10: Glycemic Parameters in a 52-Week Study Comparing Sitagliptin to Glipizide as Add-On Therapy in Patients Inadequately Controlled on Metformin (Intent-to-Treat Population)*

	Sitagliptin 100 mg	Glipizide
* The intent-to-treat analysis used the patients' last observation in the study prior to discontinuation. † Least squares means adjusted for prior antihyperglycemic therapy status and baseline A1C value.
A1C (%)	N = 576	N = 559
Baseline (mean)	7.7	7.6
Change from baseline (adjusted mean†)	-0.5	-0.6
FPG (mg/dL)	N = 583	N = 568
Baseline (mean)	166	164
Change from baseline (adjusted mean†)	-8	-8

* The per protocol population (mean baseline A1C of 7.5%) included patients without major protocol violations who had observations at baseline and at Week 52.

Figure 2: Mean Change from Baseline for A1C (%) Over 52 Weeks in a Study Comparing Sitagliptin to Glipizide as Add-On Therapy in Patients Inadequately Controlled on Metformin (Per Protocol Population)*

The incidence of hypoglycemia in the sitagliptin group (4.9%) was significantly (p<0.001) lower than that in the glipizide group (32.0%). Patients treated with sitagliptin exhibited a significant mean decrease from baseline in body weight compared to a significant weight gain in patients administered glipizide (-1.5 kg vs +1.1 kg).

Add-on Combination Therapy with Pioglitazone

A total of 353 patients with type 2 diabetes participated in a 24-week, randomized, double-blind, placebo-controlled study designed to assess the efficacy of sitagliptin in combination with pioglitazone. Patients on any oral antihyperglycemic agent in monotherapy (N=212) or on a PPARγ agent in combination therapy (N=106) or not on an antihyperglycemic agent (off therapy for at least 8 weeks, N=34) were switched to monotherapy with pioglitazone (at a dose of 30-45 mg per day), and completed a run-in period of approximately 12 weeks in duration. After the run-in period on pioglitazone monotherapy, patients with inadequate glycemic control (A1C 7% to 10%) were randomized to the addition of either 100 mg of sitagliptin or placebo, administered once daily. Patients who failed to meet specific glycemic goals during the studies were treated with metformin rescue. Glycemic endpoints measured were A1C and fasting glucose.

In combination with pioglitazone, sitagliptin provided significant improvements in A1C and FPG compared to placebo with pioglitazone (Table 11). Rescue therapy was used in 7% of patients treated with sitagliptin 100 mg and 14% of patients treated with placebo. There was no significant difference between sitagliptin and placebo in body weight change.

Table 11: Glycemic Parameters at Final Visit (24-Week Study) for Sitagliptin in Add-on Combination Therapy with Pioglitazone*

	Sitagliptin 100 mg + Pioglitazone	Placebo + Pioglitazone
* Intent-to-treat population using last observation on study prior to metformin rescue therapy. † Least squares means adjusted for prior antihyperglycemic therapy status and baseline value. ‡ p<0.001 compared to placebo + pioglitazone.
A1C (%)	N = 163	N = 174
Baseline (mean)	8.1	8.0
Change from baseline (adjusted mean†)	-0.9	-0.2
Difference from placebo + pioglitazone (adjusted mean†) (95% CI)	-0.7‡ (-0.9, -0.5)
Patients (%) achieving A1C <7%	74 (45%)	40 (23%)
FPG (mg/dL)	N = 163	N = 174
Baseline (mean)	168	166
Change from baseline (adjusted mean†)	-17	1
Difference from placebo + pioglitazone (adjusted mean†) (95% CI)	-18‡ (-24, -11)

Initial Combination Therapy with Pioglitazone

A total of 520 patients with type 2 diabetes and inadequate glycemic control on diet and exercise participated in a 24-week, randomized, double-blind study designed to assess the efficacy of sitagliptin as initial therapy in combination with pioglitazone. Patients not on antihyperglycemic agents at study entry (<4 weeks cumulative therapy over the past 2 years, and with no treatment over the prior 4 months) with inadequate glycemic control (A1C 8% to 12%) immediately entered the 2-week single-blind placebo run-in period and then were randomized. Approximately equal numbers of patients were randomized to receive initial therapy with 100 mg of sitagliptin in combination with 30 mg of pioglitazone once daily or 30 mg of pioglitazone once daily as monotherapy. There was no glycemic rescue therapy in this study.

Initial therapy with the combination of sitagliptin and pioglitazone provided significant improvements in A1C, FPG, and 2-hour PPG compared to pioglitazone monotherapy (Table 12). The improvement in A1C was generally consistent across subgroups defined by gender, age, race, baseline BMI, baseline A1C, or duration of disease. In this study, patients treated with sitagliptin in combination with pioglitazone had a mean increase in body weight of 1.1 kg compared to pioglitazone alone (3.0 kg vs. 1.9 kg).

Table 12: Glycemic Parameters at Final Visit (24-Week Study) for Sitagliptin in Combination with Pioglitazone as Initial Therapy*

	Sitagliptin 100 mg + Pioglitazone	Pioglitazone
* Intent-to-treat population using last observation on study. † Least squares means adjusted for baseline value. ‡ p<0.001 compared to placebo + pioglitazone.
A1C (%)	N = 251	N = 246
Baseline (mean)	9.5	9.4
Change from baseline (adjusted mean†)	-2.4	-1.5
Difference from pioglitazone (adjusted mean†) (95% CI)	-0.9‡ (-1.1, -0.7)
Patients (%) achieving A1C <7%	151 (60%)	68 (28%)
FPG (mg/dL)	N = 256	N = 253
Baseline (mean)	203	201
Change from baseline (adjusted mean†)	-63	-40
Difference from pioglitazone (adjusted mean†) (95% CI)	-23‡ (-30, -15)
2-hour PPG (mg/dL)	N = 216	N = 211
Baseline (mean)	283	284
Change from baseline (adjusted mean†)	-114	-69
Difference from pioglitazone (adjusted mean†) (95% CI)	-45‡ (-57, -32)

Add-on Combination Therapy with Metformin and Rosiglitazone

A total of 278 patients with type 2 diabetes participated in a 54-week, randomized, double-blind, placebo-controlled study designed to assess the efficacy of sitagliptin in combination with metformin and rosiglitazone. Patients on dual therapy with metformin ≥1500 mg/day and rosiglitazone ≥4 mg/day or with metformin ≥1500 mg/day and pioglitazone ≥30 mg/day (switched to rosiglitazone ≥4 mg/day) entered a dose-stable run-in period of 6 weeks. Patients on other dual therapy were switched to metformin ≥1500 mg/day and rosiglitazone ≥4 mg/day in a dose titration/stabilization run-in period of up to 20 weeks in duration. After the run-in period, patients with inadequate glycemic control (A1C 7.5% to 11%) were randomized 2:1 to the addition of either 100 mg of sitagliptin or placebo, administered once daily. Patients who failed to meet specific glycemic goals during the study were treated with glipizide (or other sulfonylurea) rescue. The primary time point for evaluation of glycemic parameters was Week 18.

In combination with metformin and rosiglitazone, sitagliptin provided significant improvements in A1C, FPG, and 2-hour PPG compared to placebo with metformin and rosiglitazone (Table 13) at Week 18. At Week 54, mean reduction in A1C was -1.0% for patients treated with sitagliptin and -0.3% for patients treated with placebo in an analysis based on the intent-to-treat population. Rescue therapy was used in 18% of patients treated with sitagliptin 100 mg and 40% of patients treated with placebo. There was no significant difference between sitagliptin and placebo in body weight change.

Table 13: Glycemic Parameters at Week 18 for Sitagliptin in Add-on Combination Therapy with Metformin and Rosiglitazone*

	Sitagliptin 100 mg + Metformin + Rosiglitazone	Placebo + Metformin + Rosiglitazone
* Intent-to-treat population using last observation on study prior to glipizide (or other sulfonylurea) rescue therapy. † Least squares means adjusted for prior antihyperglycemic therapy status and baseline value. ‡ p<0.001 compared to placebo + metformin + rosiglitazone.
A1C (%)	N = 176	N = 93
Baseline (mean)	8.8	8.7
Change from baseline (adjusted mean†)	-1.0	-0.4
Difference from placebo + rosiglitazone + metformin (adjusted mean†) (95% CI)	-0.7‡ (-0.9, -0.4)
Patients (%) achieving A1C <7%	39 (22%)	9 (10%)
FPG (mg/dL)	N = 179	N = 94
Baseline (mean)	181	182
Change from baseline (adjusted mean†)	-30	-11
Difference from placebo + rosiglitazone + metformin (adjusted mean†) (95% CI)	-18‡ (-26, -10)
2-hour PPG (mg/dL)	N = 152	N = 80
Baseline (mean)	256	248
Change from baseline (adjusted mean†)	-59	-21
Difference from placebo + rosiglitazone + metformin (adjusted mean†) (95% CI)	-39‡ (-51, -26)

Add-on Combination Therapy with Glimepiride, with or without Metformin

A total of 441 patients with type 2 diabetes participated in a 24-week, randomized, double-blind, placebo-controlled study designed to assess the efficacy of sitagliptin in combination with glimepiride, with or without metformin. Patients entered a run-in treatment period on glimepiride (≥4 mg per day) alone or glimepiride in combination with metformin (≥1500 mg per day). After a dose-titration and dose-stable run-in period of up to 16 weeks and a 2-week placebo run-in period, patients with inadequate glycemic control (A1C 7.5% to 10.5%) were randomized to the addition of either 100 mg of sitagliptin or placebo, administered once daily. Patients who failed to meet specific glycemic goals during the studies were treated with pioglitazone rescue.

In combination with glimepiride, with or without metformin, sitagliptin provided significant improvements in A1C and FPG compared to placebo (Table 14). In the entire study population (patients on sitagliptin in combination with glimepiride and patients on sitagliptin in combination with glimepiride and metformin), a mean reduction from baseline relative to placebo in A1C of -0.7% and in FPG of -20 mg/dL was seen. Rescue therapy was used in 12% of patients treated with sitagliptin 100 mg and 27% of patients treated with placebo. In this study, patients treated with sitagliptin had a mean increase in body weight of 1.1 kg vs. placebo (+0.8 kg vs. -0.4 kg). In addition, there was an increased rate of hypoglycemia. [See Warnings and Precautions (5.5); Adverse Reactions (6.1).]

Table 14: Glycemic Parameters at Final Visit (24-Week Study) for Sitagliptin as Add-On Combination Therapy with Glimepiride, with or without Metformin*

	Sitagliptin 100 mg + Glimepiride	Placebo + Glimepiride	Sitagliptin 100 mg + Glimepiride + Metformin	Placebo + Glimepiride + Metformin
* Intent-to-treat population using last observation on study prior to pioglitazone rescue therapy. † Least squares means adjusted for prior antihyperglycemic therapy status and baseline value. ‡ p<0.001 compared to placebo. § p<0.01 compared to placebo.

A1C (%)	N = 102	N = 103	N = 115	N = 105
Baseline (mean)	8.4	8.5	8.3	8.3
Change from baseline (adjusted mean†)	-0.3	0.3	-0.6	0.3
Difference from placebo (adjusted mean†) (95% CI)	-0.6‡ (-0.8, -0.3)		-0.9‡ (-1.1, -0.7)
Patients (%) achieving A1C <7%	11 (11%)	9 (9%)	26 (23%)	1 (1%)
FPG (mg/dL)	N = 104	N = 104	N = 115	N = 109
Baseline (mean)	183	185	179	179
Change from baseline (adjusted mean†)	-1	18	-8	13
Difference from placebo (adjusted mean†) (95% CI)	-19§ (-32, -7)		-21‡ (-32, -10)

Add-on Combination Therapy with Insulin (with or without Metformin)

A total of 641 patients with type 2 diabetes participated in a 24-week, randomized, double-blind, placebo-controlled study designed to assess the efficacy of sitagliptin as add-on to insulin therapy (with or without metformin). The racial distribution in this study was approximately 70% white, 18% Asian, 7% black, and 5% other groups. Approximately 14% of the patients in this study were Hispanic. Patients entered a 2-week, single-blind run-in treatment period on pre-mixed, long-acting, or intermediate-acting insulin, with or without metformin (≥1500 mg per day). Patients using short-acting insulins were excluded unless the short-acting insulin was administered as part of a pre-mixed insulin. After the run-in period, patients with inadequate glycemic control (A1C 7.5% to 11%) were randomized to the addition of either 100 mg of sitagliptin or placebo, administered once daily. Patients were on a stable dose of insulin prior to enrollment with no changes in insulin dose permitted during the run-in period. Patients who failed to meet specific glycemic goals during the double-blind treatment period were to have uptitration of the background insulin dose as rescue therapy.

The median daily insulin dose at baseline was 42 units in the patients treated with sitagliptin and 45 units in the placebo-treated patients. The median change from baseline in daily dose of insulin was zero for both groups at the end of the study. In combination with insulin (with or without metformin), sitagliptin provided significant improvements in A1C, FPG, and 2-hour PPG compared to placebo (Table 15). Both treatment groups had an adjusted mean increase in body weight of 0.1 kg from baseline to Week 24. There was an increased rate of hypoglycemia in patients treated with sitagliptin. [See Warnings and Precautions (5.5); Adverse Reactions (6.1).]

Table 15: Glycemic Parameters at Final Visit (24-Week Study) for Sitagliptin as Add-on Combination Therapy with Insulin*

	Sitagliptin 100 mg + Insulin (+/- Metformin)	Placebo + Insulin (+/- Metformin)
* Intent-to-treat population using last observation on study prior to rescue therapy. † Least squares means adjusted for metformin use at the screening visit (yes/no), type of insulin used at the screening visit (pre-mixed vs. non-pre-mixed [intermediate- or long-acting]), and baseline value. ‡ Treatment by stratum interaction was not significant (p>0.10) for metformin stratum and for insulin stratum. § p<0.001 compared to placebo.

A1C (%)	N = 305	N = 312
Baseline (mean)	8.7	8.6
Change from baseline (adjusted mean†)	-0.6	-0.1
Difference from placebo (adjusted mean†,‡) (95% CI)	-0.6§ (-0.7, -0.4)
Patients (%) achieving A1C <7%	39 (12.8%)	16 (5.1%)
FPG (mg/dL)	N = 310	N = 313
Baseline (mean)	176	179
Change from baseline (adjusted mean†)	-18	-4
Difference from placebo (adjusted mean†) (95% CI)	-15§ (-23, -7)
2-hour PPG (mg/dL)	N = 240	N = 257
Baseline (mean)	291	292
Change from baseline (adjusted mean†)	-31	5
Difference from placebo (adjusted mean†) (95% CI)	-36§ (-47, -25)

Simvastatin Clinical Studies

Reductions in Risk of CHD Mortality and Cardiovascular Events

In 4S, the effect of therapy with simvastatin on total mortality was assessed in 4444 patients with CHD and baseline total cholesterol 212-309 mg/dL (5.5-8.0 mmol/L). In this multicenter, randomized, double-blind, placebo-controlled study, patients were treated with standard care, including diet, and either simvastatin 20-40 mg/day (n=2221) or placebo (n=2223) for a median duration of 5.4 years. Over the course of the study, treatment with simvastatin led to mean reductions in total-C, LDL-C and TG of 25%, 35%, and 10%, respectively, and a mean increase in HDL-C of 8%. Simvastatin significantly reduced the risk of mortality by 30% (p=0.0003, 182 deaths in the simvastatin group vs 256 deaths in the placebo group). The risk of CHD mortality was significantly reduced by 42% (p=0.00001, 111 vs 189 deaths). There was no statistically significant difference between groups in non-cardiovascular mortality. Simvastatin significantly decreased the risk of having major coronary events (CHD mortality plus hospital-verified and silent non-fatal myocardial infarction [MI]) by 34% (p<0.00001, 431 vs 622 patients with one or more events). The risk of having a hospital-verified non-fatal MI was reduced by 37%. Simvastatin significantly reduced the risk for undergoing myocardial revascularization procedures (coronary artery bypass grafting or percutaneous transluminal coronary angioplasty) by 37% (p<0.00001, 252 vs 383 patients). Simvastatin significantly reduced the risk of fatal plus non-fatal cerebrovascular events (combined stroke and transient ischemic attacks) by 28% (p=0.033, 75 vs 102 patients). Simvastatin reduced the risk of major coronary events to a similar extent across the range of baseline total and LDL cholesterol levels. Because there were only 53 female deaths, the effect of simvastatin on mortality in women could not be adequately assessed. However, simvastatin significantly lessened the risk of having major coronary events by 34% (60 vs 91 women with one or more event). The randomization was stratified by angina alone (21% of each treatment group) or a previous MI. Because there were only 57 deaths among the patients with angina alone at baseline, the effect of simvastatin on mortality in this subgroup could not be adequately assessed. However, trends in reduced coronary mortality, major coronary events and revascularization procedures were consistent between this group and the total study cohort. Additionally, simvastatin resulted in similar decreases in relative risk for total mortality, CHD mortality, and major coronary events in elderly patients (≥65 years), compared with younger patients.

The Heart Protection Study (HPS) was a large, multi-center, placebo-controlled, double-blind study with a mean duration of 5 years conducted in 20,536 patients (10,269 on simvastatin 40 mg and 10,267 on placebo), including 5963 patients with diabetes mellitus (2978 on simvastatin and 2985 on placebo). Patients were allocated to treatment using a covariate adaptive method which took into account the distribution of 10 important baseline characteristics of patients already enrolled and minimized the imbalance of those characteristics across the groups. Patients had a mean age of 64 years (range 40-80 years), were 97% Caucasian and were at high risk of developing a major coronary event because of existing CHD (65%), diabetes (Type 2, 26%; Type 1, 3%), history of stroke or other cerebrovascular disease (16%), peripheral vessel disease (33%), or hypertension in males ≥65 years (6%). At baseline, 3421 patients (17%) had LDL-C levels below 100 mg/dL, of whom 953 (5%) had LDL-C levels below 80 mg/dL; 7068 patients (34%) had levels between 100 and 130 mg/dL; and 10,047 patients (49%) had levels greater than 130 mg/dL.

The HPS results showed that simvastatin 40 mg/day significantly reduced: total and CHD mortality; non-fatal MI, stroke, and revascularization procedures (coronary and non-coronary) (see Table 16).

Table 16: Summary of Heart Protection Study Results

Endpoint	Simvastatin (N=10,269) n (%)*	Placebo (N=10,267) n (%)*	Risk Reduction (%) (95% CI)	p-Value
* n = number of patients with indicated event
Primary
Mortality	1328 (12.9)	1507 (14.7)	13 (6-19)	p=0.0003
CHD mortality	587 (5.7)	707 (6.9)	18 (8-26)	p=0.0005
Secondary
Non-fatal MI	357 (3.5)	574 (5.6)	38 (30-46)	p<0.0001
Stroke	444 (4.3)	585 (5.7)	25 (15-34)	p<0.0001
Tertiary
Coronary revascularization	513 (5)	725 (7.1)	30 (22-38)	p<0.0001
Peripheral and other non-coronary revascularization	450 (4.4)	532 (5.2)	16 (5-26)	p=0.006

Two composite endpoints were defined in order to have sufficient events to assess relative risk reductions across a range of baseline characteristics (see Figure 3). A composite of major coronary events (MCE) was comprised of CHD mortality and non-fatal MI (analyzed by time-to-first event; 898 patients treated with simvastatin had events and 1212 patients on placebo had events). A composite of major vascular events (MVE) was comprised of MCE, stroke and revascularization procedures including coronary, peripheral and other non-coronary procedures (analyzed by time-to-first event; 2033 patients treated with simvastatin had events and 2585 patients on placebo had events). Significant relative risk reductions were observed for both composite endpoints (27% for MCE and 24% for MVE, p<0.0001). Treatment with simvastatin produced significant relative risk reductions for all components of the composite endpoints. The risk reductions produced by simvastatin in both MCE and MVE were evident and consistent regardless of cardiovascular disease related medical history at study entry (i.e., CHD alone; or peripheral vascular disease, cerebrovascular disease, diabetes or treated hypertension, with or without CHD), gender, age, creatinine levels up to the entry limit of 2.3 mg/dL, baseline levels of LDL-C, HDL-C, apolipoprotein B and A-1, baseline concomitant cardiovascular medications (i.e., aspirin, beta blockers, or calcium channel blockers), smoking status, alcohol intake, or obesity. Diabetic patients showed risk reductions for MCE and MVE (27% and 22%, respectively; p<0.0001) due to simvastatin treatment regardless of baseline A1C levels or obesity with the greatest effects seen for diabetic patients without CHD.

Figure 3: The Effects of Treatment with Simvastatin on Major Vascular Events and Major Coronary Events in HPS

N = number of patients in each subgroup. The inverted triangles are point estimates of the relative risk, with their 95% confidence intervals represented as a line. The area of a triangle is proportional to the number of patients with MVE or MCE in the subgroup relative to the number with MVE or MCE, respectively, in the entire study population. The vertical solid line represents a relative risk of one. The vertical dashed line represents the point estimate of relative risk in the entire study population.

Modifications of Lipid Profiles

Primary Hyperlipidemia (Fredrickson type lla and llb)

Simvastatin has been shown to be effective in reducing total-C and LDL-C in heterozygous familial and non-familial forms of hyperlipidemia and in mixed hyperlipidemia. Maximal to near maximal response is generally achieved within 4-6 weeks and maintained during chronic therapy. Simvastatin consistently and significantly decreased total-C, LDL-C, total-C/HDL-C ratio, and LDL-C/HDL-C ratio; simvastatin also decreased TG and increased HDL-C (see Table 17).

Table 17: Mean Response in Patients with Primary Hyperlipidemia and Combined (mixed) Hyperlipidemia (Mean Percent Change from Baseline After 6 to 24 Weeks)

TREATMENT	N	TOTAL-C	LDL-C	HDL-C	TG*
* median percent change † mean baseline LDL-C 244 mg/dL and median baseline TG 168 mg/dL ‡ mean baseline LDL-C 188 mg/dL and median baseline TG 128 mg/dL § mean baseline LDL-C 226 mg/dL and median baseline TG 156 mg/dL ¶ Study also included another treatment arm receiving a different dose of simvastatin; baseline mean LDL-C and median TG values were calculated across all treatment arms in study # mean baseline LDL-C 156 mg/dL and median baseline TG 391 mg/dL.
Lower Dose Comparative Study† (Mean % Change at Week 6)
Simvastatin 5 mg q.p.m.	109	-19	-26	10	-12
Simvastatin 10 mg q.p.m.	110	-23	-30	12	-15
Scandinavian Simvastatin Survival Study‡ (Mean % Change at Week 6)
Placebo	2223	-1	-1	0	-2
Simvastatin 20 mg q.p.m.	2221	-28	-38	8	-19
Upper Dose Comparative Study§,¶ (Mean % Change Averaged at Weeks 18 and 24)
Simvastatin 40 mg q.p.m.	433	-31	-41	9	-18
Multi-Center Combined Hyperlipidemia Study# (Mean % Change at Week 6)
Placebo	125	1	2	3	-4
Simvastatin 40 mg q.p.m.	123	-25	-29	13	-28

Hypertriglyceridemia (Fredrickson type lV)

The results of a subgroup analysis in 74 patients with type lV hyperlipidemia from a 130-patient, double-blind, placebo-controlled, 3-period crossover study are presented in Table 18.

Table 18: Six-Week, Lipid-Lowering Effects of Simvastatin in Type lV Hyperlipidemia Median Percent Change (25th and 75th percentile) from Baseline*

TREATMENT	N	Total-C	LDL-C	HDL-C	TG	VLDL-C	Non-HDL-C
* The median baseline values (mg/dL) for the patients in this study were: total-C = 254, LDL-C = 135, HDL-C = 36, TG = 404, VLDL-C = 83, and non-HDL-C = 215.
Placebo	74	+2 (-7, +7)	+1 (-8, +14)	+3 (-3, +10)	-9 (-25, +13)	-7 (-25, +11)	+1 (-9, +8)
Simvastatin 40 mg/day	74	-25 (-34, -19)	-28 (-40, -17)	+11 (+5, +23)	-29 (-43, -16)	-37 (-54, -23)	-32 (-42, -23)

Dysbetalipoproteinemia (Fredrickson type lll)

The results of a subgroup analysis in 7 patients with type lll hyperlipidemia (dysbetalipoproteinemia) (apo E2/2) (VLDL-C/TG>0.25) from a 130-patient, double-blind, placebo-controlled, 3-period crossover study are presented in Table 19.

Table 19: Six-Week, Lipid-Lowering Effects of Simvastatin in Type lll Hyperlipidemia Median Percent Change (min, max) from Baseline*

TREATMENT	N	Total-C	LDL-C + IDL	HDL-C	TG	VLDL-C + IDL	Non-HDL-C
* The median baseline values (mg/dL) were: total-C = 324, LDL-C = 121, HDL-C = 31, TG = 411, VLDL-C = 170, and non-HDL-C = 291.
Placebo	7	-8 (-24, +34)	-8 (-27, +23)	-2 (-21, +16)	+4 (-22, +90)	-4 (-28, +78)	-8 (-26, -39)
Simvastatin 40 mg/day	7	-50 (-66, -39)	-50 (-60, -31)	+7 (-8, +23)	-41 (-74, -16)	-58 (-90, -37)	-57 (-72, -44)

Homozygous Familial Hypercholesterolemia

In a controlled clinical study, 4 patients, 19-27 years of age, with homozygous familial hypercholesterolemia received simvastatin 40 mg/day in a single dose or in 3 divided doses. Reductions in LDL-C were observed for all patients. The mean LDL-C reduction for the 40 mg dose was 14% (range 8% to 23%, median 12%).

Endocrine Function

In clinical studies, simvastatin did not impair adrenal reserve or significantly reduce basal plasma cortisol concentration. Small reductions from baseline in basal plasma testosterone in men were observed in clinical studies with simvastatin, an effect also observed with other statins and the bile acid sequestrant cholestyramine. There was no effect on plasma gonadotropin levels. In a placebo-controlled, 12-week study there was no significant effect of simvastatin 80 mg on the plasma testosterone response to human chorionic gonadotropin. In another 24-week study, simvastatin 20-40 mg had no detectable effect on spermatogenesis. In 4S, in which 4444 patients were randomized to simvastatin 20-40 mg/day or placebo for a median duration of 5.4 years, the incidence of male sexual adverse events in the two treatment groups was not significantly different. Because of these factors, the small changes in plasma testosterone are unlikely to be clinically significant. The effects, if any, on the pituitary-gonadal axis in pre-menopausal women are unknown.

Important information

Juvisync is a combination medicine for people with type 2 diabetes who also have high cholesterol.

You should not use Juvisync if you have liver disease or severe kidney disease. Do not use if you are in a state of diabetic ketoacidosis (call your doctor for treatment with insulin).

Do not use Juvisync if you are pregnant, and stop taking the medicine if you become pregnant.

Do not use this medicine if you are breast-feeding.

Call your doctor right away if you have unexplained muscle pain, tenderness, or weakness especially if you also have fever, unusual tiredness, and dark colored urine. Also call your doctor if you have severe pain in your upper stomach spreading to your back.

There are many other drugs that should not be used together with Juvisync. Tell your doctor about all other medicines you use. Do not consume grapefruit products while taking this medicine.

Before taking this medicine

You should not use Juvisync if you are allergic to simvastatin or sitagliptin, or if you have:

liver disease;
severe kidney disease;
if you are pregnant or breast-feeding; or
if you are in a state of diabetic ketoacidosis (call your doctor for treatment with insulin).

There are many other drugs that should not be used together with this medicine. Some medicines can cause unwanted or dangerous effects when used with Juvisync. Your doctor may need to change your treatment plan if you use any of the following drugs:

cyclosporine;
danazol;
gemfibrozil;
nefazodone;
certain antibiotics--clarithromycin, erythromycin, or telithromycin;
certain antifungal medications--itraconazole, ketoconazole, posaconazole, or voriconazole;
the hepatitis C medications boceprevir or telaprevir; or
certain HIV/AIDS medications--atazanavir, cobicistat (Stribild, Tybost), indinavir, nelfinavir, ritonavir, saquinavir, or tipranavir.

To make sure Juvisync is safe for you, tell your doctor if you have:

a history of liver or kidney disease;
a history of pancreatitis;
a history of gallstones;
high triglycerides (a type of fat in the blood);
underactive thyroid;
a history of alcoholism, or if you drink large amounts of alcohol; or
if you use a blood thinner such as warfarin (Coumadin, Jantoven).

This medicine can harm an unborn baby or cause birth defects. Do not take Juvisync if you are pregnant. Stop taking the medicine and tell your doctor right away if you become pregnant. Use effective birth control to prevent pregnancy while you are taking Juvisync.

It is not known whether this medication passes into breast milk or if it could harm a nursing baby. Do not breast-feed while you are taking Juvisync.

Do not give this medication to anyone under 18 years old without medical advice.

For the Consumer

Applies to simvastatin / sitagliptin: oral tablet

Along with its needed effects, simvastatin / sitagliptin may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur while taking simvastatin / sitagliptin:

More common

Anxiety
blurred vision
chills
cold sweats
confusion
cool, pale skin
depression
dizziness
fainting
fast or irregular heartbeat
headache
increased hunger
nausea
nightmares
seizures
shakiness
slurred speech
unusual tiredness or weakness

Less common

Bladder pain
bloody or cloudy urine
difficult, burning, or painful urination
dry mouth
flushed, dry skin
frequent urge to urinate
fruit-like breath odor
increased thirst
increased urination
loss of consciousness
lower back or side pain
stomachache
sweating
swelling
troubled breathing
unexplained weight loss
vomiting

Rare

Bloating
constipation
dark-colored urine
fever
indigestion
loss of appetite
muscle cramps or spasms
muscle pain, tenderness, wasting, or weakness
pains in the stomach, side, or abdomen, possibly radiating to the back
yellow eyes or skin

Incidence not known

Agitation
black, tarry stools
bleeding gums
blistering, peeling, or loosening of the skin
burning, crawling, itching, numbness, prickling, "pins and needles", or tingling feelings
chest pain
decreased urine output
diarrhea
difficulty with moving
difficulty with swallowing
feeling of warmth
hives
increased sensitivity of the skin to sunlight
irritability
joint or muscle pain
large, hive-like swelling on the face, eyelids, lips, tongue, throat, hands, legs, feet, or sex organs
lethargy
pinpoint red spots on the skin
rapid weight gain
red, irritated eyes
red, sore, or itching skin
red skin lesions, often with a purple center
redness of the face, neck, arms, and occasionally, upper chest
seizures
severe sunburn
skin rash
sore throat
sores, ulcers, or white spots on the lips or in the mouth
sores, welts, or blisters on the skin
swollen glands
swollen joints
tightness in the chest
unsteadiness or awkwardness
unusual bleeding or bruising
weakness in the arms, hands, legs, or feet

Some side effects of simvastatin / sitagliptin may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them: