sitagliptin and simvastatin
Dosage Form: tablet, film coated
FULL PRESCRIBING INFORMATION
Indications and Usage for Juvisync
Juvisync™ (sitagliptin and simvastatin) is indicated in patients for whom treatment with both sitagliptin and simvastatin is appropriate.
Sitagliptin
Sitagliptin is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. [See Clinical Studies (14.1).]
Simvastatin
Therapy with lipid-altering agents should be only one component of multiple risk factor intervention in individuals at significantly increased risk for atherosclerotic vascular disease due to hypercholesterolemia. Drug therapy is indicated as an adjunct to diet when the response to a diet restricted in saturated fat and cholesterol and other nonpharmacologic measures alone has been inadequate. In patients with coronary heart disease (CHD) or at high risk of CHD, simvastatin can be started simultaneously with diet.
Reductions in Risk of CHD Mortality and Cardiovascular Events
In patients at high risk of coronary events because of existing coronary heart disease, diabetes, peripheral vessel disease, history of stroke or other cerebrovascular disease, simvastatin is indicated to:
- Reduce the risk of total mortality by reducing CHD deaths.
- Reduce the risk of non-fatal myocardial infarction and stroke.
- Reduce the need for coronary and non-coronary revascularization procedures.
Hyperlipidemia
Simvastatin is indicated to:
- Reduce elevated total cholesterol (total-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (Apo B), and triglycerides (TG), and to increase high-density lipoprotein cholesterol (HDL-C) in patients with primary hyperlipidemia (Fredrickson type IIa, heterozygous familial and nonfamilial) or mixed dyslipidemia (Fredrickson type IIb).
- Reduce elevated TG in patients with hypertriglyceridemia (Fredrickson type lV hyperlipidemia).
- Reduce elevated TG and VLDL-C in patients with primary dysbetalipoproteinemia (Fredrickson type lll hyperlipidemia).
- Reduce total-C and LDL-C in patients with homozygous familial hypercholesterolemia as an adjunct to other lipid-lowering treatments (e.g., LDL apheresis) or if such treatments are unavailable.
Important Limitations of Use
Juvisync should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis, as it would not be effective in these settings.
Juvisync has not been studied in patients with a history of pancreatitis. It is unknown whether patients with a history of pancreatitis are at increased risk for the development of pancreatitis while using Juvisync. [See Warnings and Precautions (5.1).]
Juvisync has not been studied in conditions where the major abnormality is elevation of chylomicrons (i.e., hyperlipidemia Fredrickson types I and V).
Because doses of Juvisync appropriate for patients with moderate or severe renal impairment (CrCl <50 mL/min, approximately corresponding to serum creatinine levels of >1.7 mg/dL in men and >1.5 mg/dL in women) or end-stage renal disease (ESRD) are not available in this combination product, Juvisync is not recommended in patients with moderate or severe renal impairment or ESRD.
Juvisync Dosage and Administration
Recommended Dosing
The dosages for therapy with Juvisync are 100 mg/10 mg, 100 mg/20 mg, and 100 mg/40 mg (sitagliptin/simvastatin) once daily. Juvisync should be taken as a single daily dose in the evening. Juvisync should be swallowed whole. The tablets must not be split, crushed, or chewed before swallowing.
The recommended starting dose is 100 mg/40 mg per day. For patients already taking simvastatin (10, 20, or 40 mg daily) with or without sitagliptin 100 mg daily, Juvisync may be initiated at the dose of 100 mg sitagliptin and the dose of simvastatin already being taken.
After initiation or titration of Juvisync, lipid levels may be analyzed after 4 or more weeks and dosage adjusted, if needed.
Patients with Renal Impairment
Juvisync is not recommended in patients with moderate or severe renal impairment or ESRD. Juvisync can be used in patients with normal renal function or mild renal impairment (creatinine clearance [CrCl] ≥50 mL/min, approximately corresponding to serum creatinine levels of ≤1.7 mg/dL in men and ≤1.5 mg/dL in women). Because simvastatin does not undergo significant renal excretion, modification of the dose of the simvastatin component should not be necessary in patients with mild renal impairment.
Assessment of renal function is recommended prior to initiation of Juvisync and periodically thereafter. Creatinine clearance can be estimated from serum creatinine using the Cockcroft-Gault formula. [See Warnings and Precautions (5.4); Clinical Pharmacology (12.3).] There have been postmarketing reports of worsening renal function in patients with renal impairment treated with sitagliptin, some of whom were prescribed inappropriate doses of sitagliptin.
Concomitant Use with an Insulin Secretagogue (e.g., Sulfonylurea) or with Insulin
When Juvisync is used in combination with an insulin secretagogue (e.g., sulfonylurea) or with insulin, a lower dose of the insulin secretagogue or insulin may be required to reduce the risk of hypoglycemia. [See Warnings and Precautions (5.5).]
Coadministration with Other Drugs
Patients taking Verapamil, or Diltiazem
- The dose of Juvisync should not exceed 100 mg/10 mg per day [see Warnings and Precautions (5.2); Drug Interactions (7.3); Clinical Pharmacology (12.3)].
Patients taking Amiodarone, Amlodipine or Ranolazine
- The dose of Juvisync should not exceed 100 mg/20 mg per day [see Warnings and Precautions (5.2); Drug Interactions (7.3); Clinical Pharmacology (12.3)].
Patients with Homozygous Familial Hypercholesterolemia
The recommended dosage is 100 mg/40 mg per day in the evening. Juvisync should be used as an adjunct to other lipid-lowering treatments (e.g., LDL apheresis) in these patients or if such treatments are unavailable.
Chinese Patients Taking Lipid-Modifying Doses (≥1 g/day Niacin) of Niacin-Containing Products
Because of an increased risk for myopathy in Chinese patients taking simvastatin 40 mg coadministered with lipid-modifying doses (≥1 g/day niacin) of niacin-containing products, caution should be used when treating Chinese patients with Juvisync 100 mg/40 mg per day coadministered with lipid-modifying doses of niacin-containing products. The cause of the increased risk of myopathy is not known. It is also 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 Warnings and Precautions (5.2).]
Dosage Forms and Strengths
- Juvisync 100 mg/10 mg tablets are pink-beige, bi-convex round, film-coated tablets, coded with the Merck logo and "753" on one side and plain on the other.
- Juvisync 100 mg/20 mg tablets are pink-beige, bi-convex modified capsule-shaped, film-coated tablets, coded with the Merck logo and "757" on one side and plain on the other.
- Juvisync 100 mg/40 mg tablets are orange-beige, bi-convex modified capsule-shaped, film-coated tablets, coded with the Merck logo and "773" on one side and plain on the other.
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, HIV protease inhibitors, erythromycin, clarithromycin, telithromycin and nefazodone) [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)].
Warnings and Precautions
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).]
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.
All patients starting therapy with Juvisync, or whose dose of simvastatin 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. 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 of simvastatin is being increased. 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, and posaconazole, the macrolide antibiotics erythromycin and clarithromycin, the ketolide antibiotic telithromycin, HIV protease inhibitors, the antidepressant nefazodone, and large quantities of grapefruit juice (>1 quart daily). Combination of these drugs with Juvisync is contraindicated. If treatment with itraconazole, ketoconazole, posaconazole, erythromycin, clarithromycin or telithromycin is unavoidable, therapy with Juvisync must be suspended during the course of treatment. [See Contraindications (4); Drug Interactions (7.1).] In vitro studies have demonstrated a potential for voriconazole to inhibit the metabolism of simvastatin. Adjustment of the Juvisync dose may be needed to reduce the risk of myopathy, including rhabdomyolysis, if voriconazole must be used concomitantly with Juvisync. [See 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, verapamil, diltiazem, amlodipine, ranolazine and lipid-lowering drugs other than gemfibrozil (other fibrates or ≥1 g/day of niacin), [see Drug Interactions (7.2, 7.3, 7.4); Table 6 in Clinical Pharmacology (12.3)].
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 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); Drug Interactions (7.1, 7.2, 7.3); Clinical Pharmacology (12.3)].
| Interacting Agents | Prescribing Recommendations |
|---|---|
| Itraconazole Ketoconazole Posaconazole Erythromycin Clarithromycin Telithromycin HIV protease inhibitors Nefazodone Gemfibrozil Cyclosporine Danazol | Contraindicated with Juvisync |
| Verapamil Diltiazem | Do not exceed 100 mg/10 mg Juvisync daily |
| Amiodarone Amlodipine Ranolazine | Do not exceed 100 mg/20 mg Juvisync daily |
| Grapefruit juice | Avoid large quantities of grapefruit juice (>1 quart daily) |
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).]
Renal Impairment
Assessment of renal function is recommended prior to initiating Juvisync and periodically thereafter. Juvisync is not recommended for use in patients with moderate or severe renal impairment or ESRD because doses of Juvisync appropriate for patients with moderate or severe renal impairment or ESRD are not available in this combination product. [See Dosage and Administration (2.2); Clinical Pharmacology (12.3).]
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.
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).]
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.
Endocrine Function
Increases in A1C and fasting serum glucose levels have been reported with HMG-CoA reductase inhibitors, including simvastatin.
Adverse Reactions
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.
| 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.
| Number of Patients (%) | ||||
|---|---|---|---|---|
Placebo | Sitagliptin 100 mg QD | Metformin 500 or 1000 mg bid † | 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).
| ||
| 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)† | 0.59 | 0.24 |
| Severe (%)‡ | 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.
| 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).]
Postmarketing Experience
Additional adverse reactions have been identified during postapproval use of sitagliptin (as monotherapy and/or in combination with other antihypergly
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