Metformin, saxagliptin

Pharmacological properties

saxagliptin. in patients with type II diabetes mellitus, the use of saxagliptin inhibits the activity of the enzyme dipeptidyl peptidase 4 (dpp-4) for a period of 24 hours after oral glucose loading or food intake, the suppression of dpp-4 led to an increase in circulating levels of active glucagon-like peptide-1 (hpp-1 ) and glucose-dependent insulinotropic polypeptide (gip) by 2–3 times, a decrease in glucagon concentration and an increase in glucose-dependent insulin secretion by pancreatic beta cells. an increase in insulin levels and a decrease in glucagon levels were associated with a lower fasting glucose concentration and a decreased glucose concentration after an oral glucose load or a meal. treatment with saxagliptin at a dose of 5 mg and sustained release metformin once daily in the evening, during meals, for 4 weeks led to a significant decrease in the total glucose concentration during the interval between doses of 24 hours compared with placebo plus slow release metformin . a significant decrease in glucose concentration was observed 2 hours after eating and a two-day average fasting glucose level.

Electrophysiology of the heart. Saxagliptin. The use of saxagliptin was not associated with a clinically significant prolongation of the Q – Tc interval or an increase in heart rate at a dose of up to 40 mg / day (8 times higher than the maximum recommended dose in humans).

Pharmacokinetics The drug Kombiglyze XR is bioequivalent to the simultaneous use of appropriate doses of saxagliptin (Onglyza) and metformin hydrochloride in the form of separate tablets.

Saxagliptin. The pharmacokinetics of saxagliptin and its active metabolite 5-hydroxysaxagliptin was similar in healthy volunteers and in people with type II diabetes mellitus. In the case of repeated administration of any dose 1 time per day, neither saxagliptin nor its active metabolite, which could be determined, were accumulated. The clearance of saxagliptin and its active metabolite was independent of the dose and time of administration within 14 days of taking saxagliptin 1 time per day in a dose of 2.5 to 400 mg.

Metformin hydrochloride. Median of achievement period C_max metformin sustained release is 7 hours. The degree of absorption of metformin from a metformin sustained-release tablet is increased by almost 50% when taken with food. After repeated administration of metformin, sustained release metformin does not accumulate in blood plasma. Metformin is excreted unchanged in the urine, but is not metabolized in the liver.

Suction. Saxagliptin. The median time to maximum concentration (Tmax) after taking 5 mg once a day was 2 hours for saxagliptin and 4 hours for its active metabolite. Saxagliptin can be used with or without food.

Metformin hydrochloride. After a single oral administration of sustained release metformin, the median of reaching C_max equal to 7 hours and has a range of 4 to 8 hours.

Metformin absorption rate (measured by AUC) from sustained release metformin tablets increases by almost 50% when taken with food, food exposure to C_max and T_max metformin was not observed. Foods with both high and low fat have the same effect on the pharmacokinetics of slow release metformin.

Distribution. Saxagliptin. The binding of saxagliptin and its active metabolite to plasma proteins in vitro is insignificant, therefore, a change in the level of protein in the blood in various diseases (for example, with impaired renal or liver function) should not affect the distribution of saxagliptin.

Metformin hydrochloride. Studies of the distribution of metformin sustained release have not been conducted. Metformin slightly binds to plasma proteins, in contrast to sulfonylurea, the degree of binding to proteins of which is 90%.Metformin penetrates red blood cells and it is very likely that this process intensifies with time.

Metabolism. Saxagliptin. Saxagliptin metabolism is mediated mainly by cytochrome P450 3A4 / 5 (CYP 3A4 / 5). The main metabolite of saxagliptin is also a DPP-4 inhibitor, the action force is almost 2 times less than that of saxagliptin. So, potent inhibitors and inducers of CYP 3A4 / 5 affect the pharmacokinetics of saxagliptin and its active metabolite.

Metformin hydrochloride. Metformin sustained release tablet metabolism studies have not been conducted.

Saxagliptin. Saxagliptin is secreted by both the kidneys and the liver. After a single oral administration of saxagliptin in a dose of 5 mg by healthy volunteers, the average final T_½ from blood plasma, saxagliptin and its active metabolite is 2.5 and 3.1 hours, respectively.

Metformin hydrochloride. The main route of excretion of metformin is tubular secretion. After oral administration, approximately 90% of the absorbed substance is excreted by the kidneys during the first 24 hours, with T_½ from blood plasma is about 6.2 hours. T_½ from the blood is approximately 17.6 hours

Individual patient groups

Impaired renal function. Comboglyz XR should not be used in patients with impaired renal function.

Saxagliptin. Dose adjustment is not required for patients with mild renal impairment.

Metformin hydrochloride. In patients with impaired renal function (based on measured creatinine clearance) T_½ metformin from blood plasma and blood lengthens, and renal clearance decreases in proportion to a decrease in creatinine clearance.

Impaired liver function

Saxagliptin. Patients with impaired liver function dose adjustment is not required.

Metformin hydrochloride. Studies of the pharmacokinetics of metformin in patients with impaired liver function have not been conducted. Since impaired liver function is associated with several cases of lactic acidosis, the administration of Combogliz XR should be avoided in patients with clinical or laboratory signs of liver disease.

Body mass index

Saxagliptin. It is not recommended to adjust the dose based on body mass index.

Floor

Saxagliptin. It is not recommended to adjust the dose depending on gender.

Metformin hydrochloride. In studies in patients with type II diabetes, the hypoglycemic effect of metformin was comparable in women and men.

Elderly patients

Saxagliptin. It is not recommended to adjust the dose based on age only.

Metformin hydrochloride. Comboglyz XR is not prescribed for patients over 80 years of age, unless an analysis of creatinine clearance confirms the absence of a decrease in renal function.

Pediatric patients

Saxagliptin. Studies of the pharmacokinetics of saxagliptin in pediatric patients have not been conducted.

Metformin hydrochloride. After a single oral administration of metformin at a dose of 500 mg (in tablet form) with food, the geometric mean C_max and Metformin AUC differed by 5% in children with type II diabetes (12–16 years old) and healthy adults matched by sex and body weight (aged 20–45 years). Renal function was normal in all categories of patients.

Racial and Ethnicity

Saxagliptin. No dose adjustment is required depending on race.

Metformin hydrochloride. Studies of pharmacokinetic parameters of metformin depending on race have not been conducted.

Indications

Combination xr is indicated as an adjunct to diet and exercise to improve glycemic control in adult patients with type II diabetes mellitus, if treatment with saxagliptin and metformin is appropriate.

Application

Recommended Dosage

The dosage of the drug Kombiglyze XR is prescribed individually, depending on the current treatment regimen of the patient, effectiveness and tolerability.As a rule, the Combogliz XR preparation should be used once a day, in the evening, during meals, gradually increasing the dose to reduce the severity of side effects from the gastrointestinal tract associated with the use of metformin.

The following release forms are available:

• XR comboglyza, film-coated tablets, 5 mg / 500 mg;
• XR comboglyza, film-coated tablets, 5 mg / 1000 mg;
• XR comboglyza, film-coated tablets, 2.5 mg / 1000 mg each.

The recommended initial dose of Comboglyz XR for patients with a need for 5 mg of saxagliptin who are not currently taking metformin is 5 mg of saxagliptin / 500 mg of sustained release metformin 1 time per day with a gradual increase in dose and should not exceed the maximum recommended dose of saxagliptin 5 mg sustained release metformin 2000 mg

In patients taking metformin, the dose of Comboglyz XR should ensure that metformin is taken at the same dose as the patient is already taking, or at the nearest appropriate therapeutic dose.

After switching from immediate release metformin to sustained release metformin, careful glycemic control and appropriate dose adjustment are necessary.

Patients with a daily requirement of 2.5 mg of saxagliptin in combination with sustained release metformin can take Combogliz XR 2.5 mg / 1000 mg. Patients with a daily requirement of 2.5 mg of saxagliptin who have not previously taken metformin or who require a dose of metformin greater than 1000 mg should take the components of the combination as separate preparations.

Any changes in the treatment of type II diabetes mellitus should be implemented carefully, with constant monitoring of the level of glycemia.

As a rule, Combogliz XR tablets should be swallowed whole; they cannot be broken, cannot be cut and cannot be chewed. Sometimes the inactive ingredients of Combogliz XR are excreted in the feces in the form of a soft hydrated mass, which may resemble the original tablet in appearance.

Dose adjustment while using powerful CYP 3A4 / 5 inhibitors

The maximum recommended dose of saxagliptin is 2.5 mg once a day under the conditions of the simultaneous use of potent inhibitors of cytochrome P450 3A4 / 5 (CYP 3A4 / 5) (e.g. ketoconazole, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, ritonavir telithromycin). In such cases, the dose of Comboglyz XR should be limited to a dosage of 2.5 mg / 1000 mg 1 time per day (see INTERACTIONS and Pharmacokinetics).

Individual patient groups

Impaired liver function. This medicine should not be used in patients with impaired liver function.

Elderly patients (≥65 years old). Since metformin and saxagliptin are excreted by the kidneys, this medicine should be used with caution in elderly patients. Monitoring renal function is necessary to prevent the development of metformin-associated lactic acidosis, especially in elderly patients.

Children. The safety and effectiveness of the use of the drug Kombiglyze XR in pediatric patients have not been established.

Contraindications

Comboglyz xr is contraindicated in patients with severe impaired renal function (estimated glomerular filtration rate (rskf) below 30 ml / min / 1.73 m2).

Comboglyz XR is not indicated for the treatment of type I diabetes mellitus or diabetic ketoacidosis due to the lack of efficacy in such conditions.

The use of this drug has not been studied in combination with insulin.

This medicine should not be prescribed to patients with known hypersensitivity to saxagliptin or metformin hydrochloride.The history of a severe hypersensitivity reaction, such as anaphylaxis, anaphylactic shock, anaphylactic reactions, angioedema, or exfoliative skin diseases, to any DPP-4 inhibitor.

Acute or chronic metabolic acidosis, including lactic acidosis, diabetic ketoacidosis with or without coma.

Diabetic coma.

In diabetic ketoacidosis, insulin should be used.

Acute conditions that may affect kidney function, such as:

• dehydration,
• severe infection;
• shock.

An acute or chronic disease that can lead to tissue hypoxia, such as:

• heart or lung failure;
• recent myocardial infarction;
• shock;
• impaired liver function;
• acute alcohol intoxication, alcoholism;
• lactation period.

It is necessary to temporarily stop the use of the drug Combogliz XR in patients undergoing x-ray studies, including intravascular injection of iodine-containing contrast agents, since the use of such drugs can lead to acute impairment of renal function.

Side effects

The following serious adverse reactions are described:

• pancreatitis (see SPECIAL INSTRUCTIONS);
• heart failure (see SPECIAL INSTRUCTIONS);
• hypoglycemia with the simultaneous use of sulfonylurea or insulin (see SPECIAL INSTRUCTIONS);
• hypersensitivity reactions (see SPECIAL INSTRUCTIONS);
• severe and disabling arthralgia (see SPECIAL INSTRUCTIONS);
• bullous pemphigoid (see SPECIAL INSTRUCTIONS).

Clinical research experience. Since clinical trials are conducted under conditions that vary significantly, the frequency of adverse reactions in clinical trials of a medicinal product cannot be directly compared with the frequency of adverse reactions in clinical trials of another medicinal product, and this frequency may not correspond to what will be observed in practice.

Adverse Reactions Observed in Efficacy Studies

Metformin hydrochloride. In placebo-controlled studies of metformin slow-release monotherapy, diarrhea and nausea / vomiting were observed in 5% of patients taking metformin, and more often than in patients taking placebo (9.6 and 2.6% for diarrhea and 6.5 and 1, 5% for nausea / vomiting). Diarrhea necessitated the withdrawal of the study drug in only 0.6% of patients taking sustained release metformin.

Saxagliptin. The data presented in table. 1, were obtained from 5 placebo-controlled clinical trials in which 882 patients were taking saxagliptin, the average duration of treatment with saxagliptin was 21 weeks. The average age of the patients was 55 years old, 1.4% were over 75 years old, 48.4% were males, 67.5% of the subjects were Caucasian, 4.6% were Negroid (including African Americans), 17 , 4% were patients of the Mongoloid race, and 10.5 and 9.8% were of Spanish or Latin American ethnic origin. At baseline, study participants had diabetes mellitus for an average of 5.2 years and an average HbA1c of 8.2%. The initial calculated indicator of renal function corresponded to a normal or mild degree of impairment (eGFR ≥60 ml / min / 1.73 m²) in 91% of patients.

In the table. 1 shows frequent adverse reactions, with the exception of hypoglycemia, which have been associated with saxagliptin. These adverse reactions were observed more often in the saxagliptin treatment group than in the placebo group, and were recorded in at least 5% of patients taking saxagliptin.

Table 1. Adverse reactions in placebo-controlled studies * observed in ≥5% of patients taking saxagliptin 5 mg, and more often than in patients taking placebo

Adverse reactions	Number (%) of Patients
	Saxagliptin 5 mg N = 882	Placebo N = 799
Upper respiratory tract infection	7,7	7,6
Urinary tract infection	6,8	6,1
Headache	6,5	5,9

* Among 5 placebo-controlled studies, 2 were studies of monotherapy, 1 was a study of additional combination therapy with one of the following drugs: metformin, thiazolidinedione or glyburide. In the table. 1 shows data for a 24-week period, regardless of the drugs used in emergency cases associated with changes in blood glucose levels.

In patients taking saxagliptin at a dose of 2.5 mg, headache (6.5%) was the only adverse reaction that was observed with a frequency of ≥5% and more often than in patients taking placebo.

In a complementary therapy study with TZD (thiazolidinedione), the incidence of peripheral edema was higher in the 5 mg saxagliptin group compared with placebo (8.1 and 4.3%, respectively). The frequency of peripheral edema in the 2.5 mg saxagliptin treatment group was 3.1%. In none of the patients did peripheral edema cause the need to cancel the study drug. The frequency of peripheral edema in the groups of saxagliptin 2.5 mg and saxagliptin 5 mg compared with placebo was 3.6 and 2% compared with 3% under monotherapy, 2.1 and 2.1% compared with 2.2% in conditions of additional therapy for metformin and 2.4 and 1.2% - compared with 2.2% in conditions of additional therapy for glyburide.

The frequency of fractures was 1.0 and 0.6 per 100 patient-years, respectively, for saxagliptin (analysis of the combined data for doses of 2.5 mg, 5 mg and 10 mg) and placebo. A dosage of 10 mg saxagliptin is not an approved dose. An increase over time in the frequency of fractures in patients taking saxagliptin was not observed. There was no causal connection of fractures with the use of the drug; undesirable effects of saxagliptin on bone tissue have not been proven in preclinical studies.

There are no data on the relationship of idiopathic thrombocytopenic purpura with saxagliptin.

The study treatment was canceled due to adverse reactions in 2.2; 3.3 and 1.8% of patients taking saxagliptin 2.5 mg, saxagliptin 5 mg and placebo, respectively. The most common adverse reactions (noted in at least 2 patients taking saxagliptin 2.5 mg, or at least 2 patients taking saxagliptin 5 mg) associated with early withdrawal of therapy were lymphopenia (0.1 and 0.5% compared to 0%, respectively), a rash (0.2 and 0.3% compared to 0.3%), an increase in blood creatinine (0.3 and 0% compared to 0%) and increase in blood CPK level (0.1 and 0.2% compared to 0%).

Adverse reactions with the simultaneous use of insul