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Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
In 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.
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
|Monotherapy (18 or 24 weeks)||Number of Patients (%)|
|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)|
|* Intent-to-treat population|
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 W eek 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)*
|Number of Patients (%)|
N = 176
|Sitagliptin 100 mg QD
N = 179
|Metformin 500 or 1000 mg bid†
N = 364†
|Sitagliptin 50 mg bid + Metformin 500 or 1000 mg bid†
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)|
|* Intent-to-treat population.
† Data pooled for the patients given the lower and higher doses of metformin.
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] 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* 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)|
|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)|
|Severe (%)‡||2 (0.6)||1 (0.3)|
|* Adverse reactions of hypoglycemia were based on all
reports of symptomatic hypoglycemia; a concurrent glucose measurement was not
required; intent-to-treat population.
† Based on total number of events (i.e., a single patient may have had multiple events).
‡ Severe events of hypoglycemia were defined as those events requiring medical assistance or exhibiting depressed level/loss of consciousness or seizure.
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.
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
(N = 2221) %
(N = 2223) %
|Body as a Whole|
|Cardiovascular System Disorders|
|Digestive System Disorders|
|Nervous System/ Psychiatric Disorders|
|Respiratory System Disorders|
|Skin / Skin Appendage Disorders|
|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.
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.
Marked persistent increases of hepatic transaminases have been noted [see WARNINGS AND PRECAUTIONS]. 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]
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; WARNINGS AND PRECAUTIONS]; 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].
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].
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.
Read the Juvisync (sitagliptin and simvastatin) Side Effects Center for a complete guide to possible side effects
[See CLINICAL PHARMACOLOGY]
Strong CYP3A4 Inhibitors, Cyclosporine, Or Danazol
Strong CYP3A4 inhibitors: Simvastatin, like several other inhibitors of HMG-CoA reductase, is a substrate of CYP3A4. Simvastatin is metabolized by CYP3A4 but has no CYP3A4 inhibitory activity; therefore it is not expected to affect the plasma concentrations of other drugs metabolized by CYP3A4.
Elevated plasma levels of HMG-CoA reductase inhibitory activity increase the risk of myopathy and rhabdomyolysis, particularly with higher doses of simvastatin. [See WARNINGS AND PRECAUTIONS; CLINICAL PHARMACOLOGY] Concomitant use of drugs labeled as having a strong inhibitory effect on CYP3A4 is contraindicated [see CONTRAINDICATIONS]. If treatment with itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin or telithromycin is unavoidable, therapy with JUVISYNC must be suspended during the course of treatment. If JUVISYNC is suspended during treatment with any of these agents, consideration should be given to the use of sitagliptin to maintain glycemic control until JUVISYNC can be reinstated.
Cyclosporine or Danazol: The risk of myopathy, including rhabdomyolysis, is increased by concomitant administration of cyclosporine or danazol. Therefore, concomitant use of these drugs is contraindicated [see CONTRAINDICATIONS; WARNINGS AND PRECAUTIONS; CLINICAL PHARMACOLOGY].
Lipid-Lowering Drugs That Can Cause Myopathy When Given Alone
Other fibrates: Caution should be used when prescribing with JUVISYNC [see WARNINGS AND PRECAUTIONS].
Amiodarone, Dronedarone, Ranolazine, Or Calcium Channel Blockers
The risk of myopathy, including rhabdomyolysis, is increased by concomitant administration of amiodarone, dronedarone, ranolazine, or calcium channel blockers such as verapamil, diltiazem, or amlodipine [see DOSAGE AND ADMINISTRATION; WARNINGS AND PRECAUTIONS; Table 6 in CLINICAL PHARMACOLOGY].
Cases of myopathy, including rhabdomyolysis, have been observed with simvastatin coadministered with lipid-modifying doses ( ≥ 1 g/day niacin) of niacin-containing products. In particular, caution should be used when treating Chinese patients with JUVISYNC 100 mg/40 mg or 50 mg/40 mg coadministered with lipid-modifying doses of niacin-containing products. [See WARNINGS AND PRECAUTIONS; CLINICAL PHARMACOLOGY]
No dosage adjustment of digoxin or JUVISYNC is recommended. Patients receiving digoxin should be monitored.
In two clinical studies, one in normal volunteers and the other in hypercholesterolemic patients, simvastatin 20-40 mg/day modestly potentiated the effect of coumarin anticoagulants: the prothrombin time, reported as International Normalized Ratio (INR), increased from a baseline of 1.7 to 1.8 and from 2.6 to 3.4 in the volunteer and patient studies, respectively. With other statins, clinically evident bleeding and/or increased prothrombin time has been reported in a few patients taking coumarin anticoagulants concomitantly. In such patients, prothrombin time should be determined before starting JUVISYNC and frequently enough during early therapy to ensure that no significant alteration of prothrombin time occurs. Once a stable prothrombin time has been documented, prothrombin times can be monitored at the intervals usually recommended for patients on coumarin anticoagulants. If the dose of JUVISYNC is changed or JUVISYNC is discontinued, the same procedure should be repeated. Simvastatin therapy has not been associated with bleeding or with changes in prothrombin time in patients not taking anticoagulants.
Cases of myopathy, including rhabdomyolysis, have been reported with simvastatin coadministered with colchicine, and caution should be exercised when prescribing JUVISYNC with colchicine.
Read the Juvisync Drug Interactions Center for a complete guide to possible interactions
Last reviewed on RxList: 3/11/2014
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