clinical trial in which 12,064 patients with a history of myocardial infarction were treated with simvastatin (mean follow-up 6.7 years), the incidence of myopathy (defined as unexplained muscle weakness or pain with a serum creatine kinase [CK] >10 times upper limit of normal [ULN]) in patients on 20 mg/day was approximately 0.02%; in patients treated with 80 mg/day, the incidence was 0.9%. The incidence of rhabdomyolysis (defined as myopathy with a CK >40 times ULN) in patients on 20 mg/day was 0%; in patients on 80 mg/day, the incidence was approximately 0.4%. The incidence of myopathy, including rhabdomyolysis, was highest during the first year and then notably decreased during the subsequent years of treatment. In this trial, patients were carefully monitored and some interacting medicinal products were excluded.
Other adverse reactions reported in clinical trials were: diarrhea, rash, dyspepsia, flatulence, and asthenia.
Laboratory Tests
Sitagliptin
Across clinical studies, the incidence of laboratory adverse reactions was similar in patients treated with sitagliptin 100 mg compared to patients treated with placebo. A small increase in white blood cell count (WBC) was observed due to an increase in neutrophils. This increase in WBC (of approximately 200 cells/microL vs placebo, in four pooled placebo-controlled clinical studies, with a mean baseline WBC count of approximately 6600 cells/microL) is not considered to be clinically relevant. In a 12-week study of 91 patients with chronic renal impairment, 37 patients with moderate renal impairment were randomized to sitagliptin 50 mg daily, while 14 patients with the same magnitude of renal impairment were randomized to placebo. Mean (SE) increases in serum creatinine were observed in patients treated with sitagliptin [0.12 mg/dL (0.04)] and in patients treated with placebo [0.07 mg/dL (0.07)]. The clinical significance of this added increase in serum creatinine relative to placebo is not known.
Simvastatin
Marked persistent increases of hepatic transaminases have been noted [see Warnings and Precautions (5.3)]. Elevated alkaline phosphatase and γ-glutamyl transpeptidase have also been reported. About 5% of patients had elevations of CK levels of 3 or more times the normal value on one or more occasions. This was attributable to the noncardiac fraction of CK. [See Warnings and Precautions (5.2).]
6.2 Postmarketing Experience
Additional adverse reactions have been identified during postapproval use of sitagliptin (as monotherapy and/or in combination with other antihyperglycemic agents) or simvastatin. Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Anemia; depression; headache; dizziness; paresthesia; peripheral neuropathy; interstitial lung disease; pancreatitis; acute pancreatitis, including fatal and non-fatal hemorrhagic and necrotizing pancreatitis [see Indications and Usage (1.3); Warnings and Precautions (5.1)]; constipation; vomiting; hepatitis/jaundice; fatal and non-fatal hepatic failure; hepatic enzyme elevations; pruritus; alopecia; a variety of skin changes (e.g., nodules, discoloration, dryness of skin/mucous membranes, changes to hair/nails); muscle cramps; myalgia; rhabdomyolysis; arthralgia; pain in extremity; back pain; worsening renal function, including acut |
