Xelevia, 100 mg 28 pcs.

Interaction

In studies on interactions with other drugs, sitagliptin had no clinically significant effect on the pharmacokinetics of the following drugs: metformin, rosiglitazone, glibenclamide, simvastatin, warfarin, oral contraceptives. Based on these data, sitagliptin does not inhibit the CYP3A4, 2C8 or 2C9 isoenzymes. Based on in vitro data, sitagliptin also does not inhibit the CYP2D6, 1A2, 2C19, and 2B6 isoenzymes and does not induce the CYP3A4 isoenzyme.

Special Instructions

Hypoglycemia
According to clinical trials of sitagliptin, the incidence of hypoglycemia during monotherapy or combined therapy with drugs that do not cause hypoglycemia (metformin, pioglitazone) was comparable to the incidence of hypoglycemia in the placebo group. As in the case of other hypoglycemic drugs, hypoglycemia was observed when using sitagliptin in combination with insulin or sulfonylurea derivatives (see section “Side effects”). In order to reduce the risk of sulfon-induced hypoglycemia, the sulfonylurea derivative dose should be reduced (see section “Dosage and administration”).

Use in the elderly
In clinical trials, the efficacy and safety of sitagliptin in elderly patients (≥65 years, 409 patients) were comparable with these parameters in patients younger than 65 years. No dose adjustment based on age is required. Elderly patients are more likely to develop renal failure. Accordingly, as in other age groups, dosage adjustment is required in patients with significant renal insufficiency (see section “Dosage and administration”).

The sitagliptin Cardiovascular Safety Evaluation Study (TECOS)
In the sitagliptin Cardiovascular Safety Evaluation Study (TECOS), patients were taking sitagliptin 100 mg daily (or 50 mg daily if baseline estimated glomerular filtration rate (eGFR) was ≥30 and <50 mL/min/1.73 m2), or placebo, which were added to standard therapy according to current national standards for determining target HbA1C levels and controlling cardiovascular risk factors. At the end of a mean follow-up period of 3 years, in patients with type 2 diabetes mellitus, taking sitagliptin in addition to standard treatment did not increase the risk of serious cardiovascular adverse events (hazard ratio, 0.98; 95% confidence interval, 0.89-1.08; p<0.001 for evidence of no superiority) or risk of hospitalization due to heart failure (risk ratio 1.00; 95% confidence interval, 0.83-1.20; p=0.98 for risk frequency difference), compared with standard treatment without additional sitagliptin administration.

Effect on the ability to drive and operate machinery:
No studies have been performed to study the effect of Xelevia® on the ability to drive and operate machinery. Nevertheless, no negative effect of Xelevia® on the ability to drive vehicles and operate mechanisms is expected.

Contraindications

– Hypersensitivity to any drug component;
– pregnancy, breast-feeding period;
– diabetes mellitus type 1;
– diabetic ketoacidosis;
– children under 18 years old;
– renal insufficiency of medium and severe severity (for this dosage – see section “Dosage method.

With caution:
Renal insufficiency
The main route of excretion of sitagliptin from the body is renal excretion. In order to achieve the same plasma concentrations as in patients with normal renal excretory function, patients with moderate to severe renal failure and patients with terminal CKD requiring hemodialysis or peritoneal dialysis require correction (reduction) of the dose of Xelevia® (see

Pancreatitis
There have been reports of acute pancreatitis, including hemorrhagic or necrotic with or without fatal outcome, in patients taking sitagliptin (see section “Adverse effects”). Patients should be informed about the characteristic symptoms of acute pancreatitis: persistent, severe abdominal pain. Clinical manifestations of pancreatitis disappeared after discontinuation of sitagliptin. In case of suspected pancreatitis, Xelevia® and other potentially dangerous drugs should be discontinued.

Side effects

Sitagliptin is generally well tolerated both in monotherapy and in combination with other hypoglycemic drugs. In clinical trials, the overall incidence of adverse events, as well as the rate of drug withdrawal due to adverse events was similar to that of placebo.

According to 4 placebo-controlled studies (duration 18-24 weeks) of sitagliptin at a daily dose of 100-200 mg as mono- or combined therapy with metformin or pioglitazone, no adverse reactions associated with the study drug, the incidence of which exceeded 1% in the group of patients who took sitagliptin, were observed. The safety profile of the 200 mg daily dose was comparable to that of the 100 mg daily dose.

Analysis of data from the above clinical trials showed that the overall incidence of hypoglycemia in patients taking sitagliptin was similar to that of placebo (sitagliptin 100 mg – 1.2%, sitagliptin 200 mg – 0.9%, placebo – 0.9%). The frequency of gastrointestinal adverse events monitored with sitagliptin in both doses was similar to that with placebo (except for more frequent nausea with sitagliptin at a dose of 200 mg daily): abdominal pain (sitagliptin 100 mg-2.3%, sitagliptin 200 mg-1.3%, placebo-2.1%), nausea (1.4%, 2.9%, 0.6%), vomiting (0.8%, 0.7%, 0.9%), diarrhea (3.0%, 2.6%, 2.3%).
In all studies, adverse reactions in the form of hypoglycemia were recorded based on all reports of clinically significant symptoms of hypoglycemia; parallel measurement of blood glucose concentration was not required.

Starting combination therapy with metformin
In a 24-week placebo-controlled factorial study of starting combination therapy with sitagliptin at a daily dose of 100 mg and metformin at a daily dose of 1000 mg or 2000 mg (sitagliptin 50 mg + metformin 500 mg or 1000 mg x 2 times daily), the following adverse events were observed in the combination treatment group compared with the metformin monotherapy group
drug-related adverse reactions observed with a frequency of ≥1% in the sitagliptin treatment group and more frequently than in the metformin monotherapy group: Diarrhea (sitagliptin + metformin 3.5%, metformin 3.3%), dyspepsia (1.3%, 1.1%), headache (1.3%, 1.1%), flatulence (1.3%, 0.5%), hypoglycemia (1.1%, 0.5%), vomiting (1.1%, 0.3%).

Combination with sulfonylurea derivatives or sulfonylurea derivatives and metformin
In a 24-week placebo-controlled study of combination therapy with sitagliptin (100 mg daily dose) and glimepiride or glimepiride and metformin, the following adverse events were observed in the study drug group compared to the group of patients taking placebo and glimepiride or glimepiride and metformin
drug-related adverse reactions observed with a frequency of ≥1% in the sitagliptin treatment group and more frequently than in the placebo combination therapy group: hypoglycemia (sitagliptin 9.5%, placebo 0.9%).

Starter combination therapy with PPAR-γ agonists
In a 24-week study of starting combination therapy with sitagliptin at a daily dose of 100 mg and pioglitazone at a daily dose of 30 mg, the following adverse events were observed in the combination treatment group compared with pioglitazone monotherapy:
drug-related adverse reactions observed with a frequency of ≥1% in the sitagliptin treatment group and more frequently than in the pioglitazone monotherapy group: asymptomatic decrease in blood glucose concentration (sitagliptin + pioglitazone – 1.1%, pioglitazone – 0.0%), symptomatic hypoglycemia (0.4%, 0.8%).

Combination with PPAR-y agonists and metformin
According to data of a placebo-controlled study during treatment with sitagliptin (daily dose of 100 mg) in combination with rosiglitazone and metformin the following adverse events were observed in the study drug group compared to the group of patients receiving placebo sroglitazone and metformin:
At 18 weeks of follow-up:
drug-related adverse reactions observed with a frequency of ≥1% in the sitagliptin treatment group and more frequently than in the combination therapy with placebo group: Headache (sitagliptin 2.4%, placebo 0.0%), diarrhea (1.8%, 1.1%), nausea (1.2%, 1.1%), hypoglycemia (1.2%, 0.0%), vomiting (1.2%, 0.0%).
At 54 weeks of follow-up:
drug-related adverse reactions observed with a frequency of ≥1% in the sitagliptin treatment group and more frequently than in the combination therapy with placebo group: Headache (sitagliptin 2.4%, placebo 0.0%), hypoglycemia (2.4%, 0.0%), upper respiratory tract infections (1.8%, 0.0%), nausea (1.2%, 1.1%), cough (1.2%, 0.0%), fungal skin infection (1.2%, 0.0%), peripheral edema (1.2%, 0.0%), vomiting (1.2%, 0.0%).

Combination with Insulin
In a 24-week placebo-controlled study of combination therapy with sitagliptin (at a daily dose of 100 mg) and a constant dose of insulin (with or without metformin), the following adverse events were observed in the study drug group compared to the group of patients taking placebo and insulin (with or without metformin)
drug-related adverse reactions observed with a frequency of ≥1% in the sitagliptin treatment group and more frequently than in the insulin treatment group (with or without metformin): Hypoglycemia (sitagliptin + insulin (with or without metformin) 9.6%, placebo + insulin (with or without metformin)-5.3%), influenza (1.2%, 0.3%), headache (1.2%, 0.0%).
In another 24-week study in which patients received sitagliptin as adjunctive therapy to insulin therapy (with or without metformin), there were no adverse reactions associated with taking the drug, with a frequency of >1% in the sitagliptin treatment group (100 mg dose), and more often than in the placebo group.

Pancreatitis
In a pooled analysis of 19 double-blind, randomized clinical trials of sitagliptin at a daily dose of 100 mg or the corresponding control drug (active or placebo), the incidence of unconfirmed acute pancreatitis was 0.1 per 100 patient-years of treatment in each group (see “Caution. Pancreatitis”, as well as “Study to evaluate the cardiovascular safety of sitagliptin (TECOS)” below).
No clinically significant deviations of vital signs or ECG (including QTc interval length) were observed during sitagliptin treatment.

The sitagliptin Cardiovascular Safety Evaluation Study (TECOS)
The sitagliptin Cardiovascular Safety Evaluation Study (TECOS) enrolled 7332 patients who were taking sitagliptin 100 mg daily (or 50 mg daily if baseline estimated glomerular filtration rate (eGFR) was ≥30 and <50 mL/min/1.73 m ), and 7339 placebo-treated patients in the general population. The study drug (sitagliptin or placebo) was added to standard therapy according to current national standards for the selection of target HbA1C levels and the control of cardiovascular risk factors. A total of 2004 patients aged 75 years and older were included in the study (970 took sitagliptin and 1034 took placebo). The overall incidence of serious adverse events in patients taking sitagliptin was similar to that in patients taking placebo. Evaluation of previously designated diabetes-related complications for follow-up revealed comparable rates of adverse events between groups, including infections (18.4% in patients taking sitagliptin and 17.7% in patients taking placebo) and impaired renal function (1.4% in patients taking sitagliptin and 1.5% in patients taking placebo). The adverse event profile in patients aged 75 years and older was generally similar to that in the general population.
In the intention-to-treat patient population, among those initially receiving insulin therapy and/or sulfonylureas, the incidence of severe hypoglycemic episodes was 2.7% in patients taking sitagliptin and 2.5% in patients taking placebo. Among patients not initially receiving insulin and/or sulfonylureas, the incidence of severe hypoglycemic episodes was 1.0% in patients taking sitagliptin and 0.7% in patients taking placebo. The incidence of examination-confirmed pancreatitis was 0.3% in patients taking sitagliptin and 0.2% in patients taking placebo. The incidence of examination-confirmed malignancies was 3.7% in patients taking sitagliptin and 4.0% in patients taking placebo.

Post-registration observations
Additional adverse events were identified during post-registration monitoring of sitagliptin use in monotherapy and/or in combination therapy with other hypoglycemic agents. Since these data were obtained voluntarily from a population of undetermined size, it is not possible to determine the incidence and the causal relationship to therapy of these adverse events. These include:
hypersensitivity reactions, including anaphylaxis, angioneurotic edema, rash, urticaria, cutaneous vasculitis, exfoliative skin disorders, including Stevens-Johnson syndrome; acute pancreatitis, including hemorrhagic and necrotic forms with and without lethal deterioration of renal function, including acute renal failure (sometimes dialysis is required); upper respiratory tract infections; nasopharyngitis; constipation; vomiting; headache; arthralgia; myalgia; limb pain; back pain; itching; pemphigoid.
Changes in laboratory parameters

The frequency of abnormal laboratory parameters in the sitagliptin treatment groups (100 mg daily dose) was comparable to that in the placebo groups. In most, but not all, clinical trials there was a small increase in white blood cell counts (approximately 200/μL compared with placebo, median count at the start of treatment was 6600/μL) due to an increase in neutrophil counts.
Analysis of data from clinical studies of the drug showed a slight increase in uric acid concentration (approximately 0.2 mg/dL compared to placebo, average pre-treatment concentration 5-5.5 mg/dL) in patients receiving sitagliptin at doses of 100 and 200 mg daily. No cases of gout development were reported. There was a slight decrease in total alkaline phosphatase concentration (approximately 5 IU/L compared to placebo, mean pre-treatment concentration 56-62 IU/L), partly related to a small decrease in bone fraction of alkaline phosphatase.

The listed changes in laboratory parameters are not considered clinically significant.

Overdose

During clinical trials in healthy volunteers, a single dose of 800 mg of sitagliptin was generally well tolerated. Minimal QTc interval changes not considered clinically significant were observed in one study of sitagliptin at a dose of 800 mg per day. Doses above 800 mg daily have not been studied in humans.

In phase I clinical trials of multiple doses, no adverse reactions associated with sitagliptin treatment were noted when taking the drug in a daily dose of up to 400 mg for 28 days.
In case of overdose, standard supportive measures should be initiated: removal of unabsorbed drug from the gastrointestinal tract, monitoring of vital signs, including ECG, and administration of supportive therapy, if required.

Sitagliptin is poorly dialyzed. In clinical studies, only 13.5% of the dose was removed from the body during a 3-4 hour dialysis session. Prolonged dialysis may be indicated if clinically necessary. There are no data on the effectiveness of peritoneal dialysis of sitagliptin.

Similarities

Januvia