Kombogliz Prolong
Kombogliz Prolong: instructions for use and reviews
- 1. Release form and composition
- 2. Pharmacological properties
- 3. Indications for use
- 4. Contraindications
- 5. Method of application and dosage
- 6. Side effects
- 7. Overdose
- 8. Special instructions
- 9. Application during pregnancy and lactation
- 10. Use in childhood
- 11. In case of impaired renal function
- 12. For violations of liver function
- 13. Use in the elderly
- 14. Drug interactions
- 15. Analogs
- 16. Terms and conditions of storage
- 17. Terms of dispensing from pharmacies
- 18. Reviews
- 19. Price in pharmacies
Latin name: Kombiglyce Prolong
ATX code: A10BD07
Active ingredient: metformin (Metformin) + saxagliptin (Saxagliptin)
Producer: AstraZeneca Pharmaceuticals, LP (AstraZeneca Pharmaceutical, LP) (USA)
Description and photo updated: 30.11.2018
Prices in pharmacies: from 1416 rubles.
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Combogliz Prolong is a combined oral hypoglycemic drug.
Release form and composition
Dosage form - modified release film-coated tablets (in a cardboard box 4 blisters of 7 tablets and instructions for use of Komboglyza Prolong, additionally for tablets of 1000 + 2.5 mg - 8 blisters of 7 tablets):
- dosage 1000 mg + 2.5 mg: capsule-shaped, biconvex, film shell from pale to light yellow; in blue ink on one side the inscription "2.5 / 1000", on the other side - "4222";
- dosage of 500 mg + 5 mg: capsule-shaped, biconvex, film shell from light brown to brown; in blue ink “5/500” on one side and “4221” on the other;
- dosage 1000 mg + 5 mg: capsule-shaped, biconvex, pink film shell; in blue ink, 5/1000 is written on one side and 4223 on the other.
Active ingredients in 1 tablet:
- metformin hydrochloride - 1000 mg + saxagliptin - 2.5 mg;
- metformin hydrochloride - 500 mg + saxagliptin - 5 mg;
- metformin hydrochloride - 1000 mg + saxagliptin - 5 mg.
Composition for one modified release film-coated tablet (1000 mg + 2.5 mg / 500 mg + 5 mg / 1000 mg + 5 mg):
- tablet core: metformin hydrochloride mixed with 0.5% magnesium stearate - 1005 / 502.5 / 1005 mg; carmellose sodium - 50/50/50 mg; hypromellose 2208 - 393/358/393 mg; hypromellose 2910 - 0/10/0 mg; magnesium stearate - 2/1/2 mg; microcrystalline cellulose - 0/102/0 mg;
- the first layer of the shell coating (protective): Opadry II white (% m / m) - 130.5 / 99 / 130.5 mg (partially hydrolyzed polyvinyl alcohol - 40%; titanium dioxide - 25%; macrogol 3350 - 20.2%; talc - 14.8%); 1M hydrochloric acid solution - up to pH 2 ± 0.3;
- the second layer of the shell coating (active): saxagliptin - 2.5 / 5/5 mg; Opadry II white - 20/20/20 mg; 1M hydrochloric acid solution - up to pH 2 ± 0.3;
- lettering ink: Opacode ink blue (% m / m) - 0.03 / 0.03 / 0.03 mg (indigo carmine aluminum varnish - 16%; shellac ~ 45% in ethanol - 55.4%; butanol -15 %; propylene glycol - 10.5%; isopropanol - 3%; 28% ammonium hydroxide solution - 0.1%).
Third (colored) shell coating layer:
- 1000 + 2.5 mg: Opadry II yellow (% m / m) - 48 mg (partially hydrolyzed polyvinyl alcohol - 40%; titanium dioxide - 24.25%; macrogol 3350 - 20.2%; talc - 14.8%; yellow dye iron oxide - 0.75%), 1M hydrochloric acid solution - to pH 2 ± 0.3;
- 1000 + 5 mg: Opadry II yellowish brown (% m / m) - 33 mg (partially hydrolyzed polyvinyl alcohol - 40%; macrogol 3350 - 20.2%; titanium dioxide - 19.58%; talc - 14.8%; yellow dye iron oxide - 5%; red dye iron oxide - 0.42%); 1M hydrochloric acid solution - up to pH 2 ± 0.3;
- 500 + 5 mg: Opadry II pink (% m / m) - 48 mg (partially hydrolyzed polyvinyl alcohol - 40%; titanium dioxide - 24.25%; macrogol 3350 - 20.2%; talc - 14.8%; red dye iron oxide - 0.75%); 1M hydrochloric acid solution to pH 2 ± 0.3.
Pharmacological properties
Pharmacodynamics
Kombogliz Prolong combines two hypoglycemic agents with a mutually complementary mechanism of action aimed at improving glycemic control in patients with T2DM (type 2 diabetes mellitus): saxagliptin, which is a DPP-4 inhibitor (dipeptidylpeptidase 4), and metformin, which belongs to the class biguanides.
Saxagliptin
In response to food intake, the small intestine releases incretin hormones into the bloodstream, such as GLP-1 (glucagon-like peptide-1) and GIP (glucose-dependent insulinotropic polypeptide).
The incretin hormones promote the release of insulin from the beta cells of the pancreas, which depends on the blood glucose concentration, but they are inactivated within a few minutes by the DPP-4 enzyme. GLP-1 also acts to decrease the secretion of glucagon in alpha cells of the pancreas, which leads to a decrease in glucose production in the liver. The concentration of GLP-1 in patients with T2DM is reduced, but the insulin response to GLP-1 is preserved. Saxagliptin, as a competitive inhibitor of DPP-4, reduces the inactivation of incretin hormones, thereby increasing their concentration in the bloodstream, and leads to a decrease in glucose concentration both on an empty stomach and after meals.
Metformin
Metformin is a hypoglycemic drug that improves glucose tolerance in patients with T2DM (by lowering basal and postprandial glucose concentrations).
The clinical efficacy of metformin is to reduce the production of glucose by the liver, weaken the absorption of glucose in the intestine, and increase the sensitivity to insulin (peripheral absorption and utilization of glucose increases).
Metformin, unlike sulfonylureas, does not cause hyperinsulinemia and hypoglycemia in patients with T2DM or in healthy people (with the exception of special situations). Insulin secretion does not change during metformin therapy, although there may be a decrease in fasting insulin concentration and in response to food intake during the day.
Pharmacokinetics
Bioequivalence and the effect of food on the combination of active substances Komboglyza Prolong were characterized when the patients followed a low-calorie diet, which provided 324 kcal with the food composition and contained: proteins - 11.1%; fats - 10.5%; carbohydrates - 78.4%. Under these nutritional conditions, in healthy subjects, according to the results of studies, bioequivalence of the pharmacokinetics of the combination of metformin + saxagliptin tablets and individual tablets of modified release of saxagliptin and metformin in similar doses was revealed.
Saxagliptin
The pharmacokinetic processes of saxagliptin and its active metabolite (5-hydroxysaxagliptin) are similar in patients with T2DM and in healthy volunteers. The C max (maximum concentration of the substance) and AUC (area under the concentration-time curve) of saxagliptin and its active metabolite in plasma increase proportionally in the dose range of 2.5–400 mg. After a single oral administration of 5 mg of saxagliptin to healthy volunteers, the average AUC values of the substance and its main metabolite are 78 and 214 ng × h / ml, respectively, and the values of C max in plasma are 24 and 47 ng / ml. The average variability of C max and AUC of saxagliptin and its active metabolite is less than 25%.
The development of a noticeable cumulation of saxagliptin or its active metabolite with repeated use once a day at any dosage is not observed. Also, no dependence of their clearance on dose and time was found when applied for 14 days once a day in the dose range of 2.5-400 mg.
After oral administration, at least 75% of the accepted dose of saxagliptin is absorbed. Food intake has no significant effect on the pharmacokinetics of a substance in healthy volunteers. Saxagliptin does not have an effect on the Cmax value of saxagliptin from eating food with a high fat content, while there is an increase in AUC by 27% in comparison with fasting. T max (time to reach maximum concentration) for saxagliptin increases by about 0.5 hours when taken with food compared to when taken on an empty stomach. However, these changes have no clinical significance.
After taking a dose of 5 mg once a day, the average T max of saxagliptin is 2 hours, for its active metabolite - 4 hours. The use of the substance with food with a high fat content, in comparison with fasting, increases the T max and AUC of saxagliptin by about 20 minutes and by 27%, respectively. Saxagliptin can be used with or without food. Food does not significantly affect its pharmacokinetics when used as part of a combination of metformin + saxagliptin tablets.
Saxagliptin and its main metabolite bind to serum proteins insignificantly, therefore, it can be assumed that the distribution of the substance during modifications of the protein composition of the blood serum, which are observed in patients with renal / hepatic insufficiency, will not undergo significant changes.
Saxagliptin metabolism occurs mainly with the participation of cytochrome P 450 3A4 / 5 (CYP3A4 / 5) isoenzymes, while the formation of an active main metabolite occurs, its inhibitory effect on DPP-4 is twice weaker than that of saxagliptin.
Saxagliptin is excreted through the intestines and kidneys. After a single dose of 50 mg of labeled 14C-saxagliptin by the kidneys, it is excreted as unchanged saxagliptin - 24%, as the main metabolite - 36%. The total radioactivity found in urine corresponds to 75% of the dose. Average renal clearance of the substance ~ 230 ml / min, average value of glomerular filtration ~ 120 ml / min. Renal clearance for the major metabolite is comparable to the mean glomerular filtration rate. Approximately 22% of total radioactivity is detected in feces.
Metformin
With max metformin after a single oral administration, on average, it is achieved in 7 hours (in the range of 4-8 hours). With max and AUC, modified release substances increase disproportionately to the dosage in the dose range of 500–2000 mg. When taking doses of 500, 1000, 1500 and 2000 mg once a day C max in blood plasma is 0.6; 1.1; 1.4 and 1.8 μg / ml, respectively. Despite the fact that the degree of absorption (as measured by AUC) of metformin from modified release tablets increases by approximately 50% when taken simultaneously with food, food intake has an effect on C max and T maxdoes not. Foods characterized by both low and high fat content have the same effect on the pharmacokinetic parameters of modified release metformin.
The distribution of modified release metformin has not been studied, but its apparent V d (volume of distribution) after a single oral administration of immediate release metformin tablets at a dose of 850 mg averages 654 ± 358 L. The substance binds to plasma proteins to a small extent.
Most likely, the penetration of metformin into erythrocytes is determined by time. Since it binds slightly to plasma proteins, it is thus less likely to interact with drugs that bind well to plasma proteins, including sulfonamides, salicylates, probenecid, and chloramphenicol.
According to studies with a single intravenous administration of metformin to healthy volunteers, the substance is excreted by the kidneys unchanged, is not metabolized in the liver (no metabolites have been identified in humans) and is not excreted through the intestines.
The renal clearance of metformin is approximately 3.5 times that of creatinine, hence tubular secretion is the main route of elimination for metformin. Approximately 90% of the absorbed substance after oral administration is excreted in the first 24 hours by the kidneys, while T 1/2 (half-life) from plasma is approximately 6.2 hours. T 1/2 in the blood is about 17.6 hours, therefore, erythrocyte mass may be part of the distribution.
Special clinical situations
It is not recommended to use Combogliz Prolong in case of renal failure and impaired liver function.
In patients 65–80 years of age, no clinically significant differences in the parameters of the pharmacokinetics of saxagliptin were found in comparison with patients of a younger age (18–40 years); therefore, dose adjustment in elderly patients is not required. However, it must be borne in mind that in this category of patients, a decrease in renal function is more likely. At any age, Combogliz Prolong should not be prescribed until normal renal function is confirmed.
Patients over 80 years old are contraindicated to take the drug, except in cases where normal renal function is confirmed by measurements of creatinine clearance.
The pharmacokinetics of the active substances of Comboglyse Prolong have not been studied in children.
Indications for use
Combogliz Prolong tablets are prescribed for the treatment of type 2 diabetes mellitus with the aim of improving glycemic control in combination with diet and exercise.
Contraindications
Absolute:
- type 1 diabetes mellitus (use not studied);
- simultaneous use with insulin (use has not been studied);
- hepatic dysfunction;
- impaired renal function (serum creatinine: men ≥ 1.5 mg / dl, women ≥ 1.4 mg / dl, or decreased creatinine clearance), including those associated with septicemia, acute myocardial infarction, acute cardiovascular failure (shock);
- diseases in the acute course, in which there is a risk of impaired renal function: fever, dehydration (against the background of vomiting, diarrhea), severe infectious diseases, hypoxia (bronchopulmonary diseases, sepsis, shock, kidney infections);
- metabolic acidosis in acute or chronic course, including diabetic ketoacidosis with / without coma;
- acute and chronic diseases with clinically pronounced manifestations that can cause the development of tissue hypoxia (including acute myocardial infarction, respiratory and heart failure);
- trauma and serious surgical operations (in cases where insulin therapy is indicated);
- acute ethanol poisoning, chronic alcoholism;
- lactic acidosis (including a burdened history);
- congenital galactose intolerance, glucose-galactose malabsorption and lactase deficiency;
- X-ray or radioisotope studies using iodine-containing contrast media (including a period of 48 hours before and after their implementation);
- adherence to a low-calorie diet (<1000 kcal per day);
- serious hypersensitivity reactions (angioedema or anaphylaxis) to DPP-4 inhibitors;
- pregnancy, lactation;
- age up to 18 years;
- individual intolerance to the components of the drug.
Relative (Combogliz Prolong tablets are used under medical supervision):
- a burdened history of pancreatitis (the relationship between taking Combogliz Prolong and an increased risk of developing pancreatitis has not been established);
- burdened history of heart failure;
- a history of moderate to severe renal failure;
- age over 60 years against the background of heavy physical work (associated with an increased risk of lactic acidosis).
Kombogliz Prolong, instructions for use: method and dosage
Kombogliz Prolong is taken orally, once a day with dinner. The tablets should be swallowed whole without crushing, chewing or breaking.
The dose is selected individually.
As a rule, during therapy with a drug containing saxagliptin and metformin, the daily dose of saxagliptin is 5 mg.
The initial dose of modified release metformin is 500 mg once a day, if necessary, it can be increased to 2000 mg. This can be achieved by taking two tablets of 2.5 mg + 1000 mg taken once a day. The dose of metformin should be increased gradually to minimize the risk of side effects from the digestive system.
The maximum daily dose is: saxagliptin - 5 mg, modified release metformin - 2000 mg.
Special studies of the efficacy and safety of Comboglyse Prolong in patients who have previously received other hypoglycemic agents have not been conducted. T2DM therapy should be adjusted with caution and under control of blood glucose concentration.
The daily dose of saxagliptin when used simultaneously with potent inhibitors of CYP3A4 / 5 isoenzymes (including itraconazole, indinavir, ritonavir, atazanavir, ketoconazole, clarithromycin, nefazodone, nelfinavir, telithromycin and saquinavir in one dose) should be 2.5 mg.
The inactive components that make up Komboglyza Prolong can be excreted through the intestines in the form of a moist soft mass that can maintain the shape of a tablet.
In the elderly, therapy should be carried out with caution, which is associated with a high probability of decreased renal function. Any dose adjustment of metformin should be made after careful assessment of renal function.
Side effects
Side effects associated with the use of saxagliptin in monotherapy and in combination therapy noted in studies of glycemic control
When using 5 mg saxagliptin, ≥ 5% of patients most often developed the following disorders (regardless of the investigator's assessment of the causal relationship): infections of the upper respiratory and urinary tract, headache. Against the background of the use of saxagliptin in a daily dose of 2.5 mg, the only disorder with a frequency of development ≥ 5% was headache. ≥ 2% of patients taking 2.5 and 5 mg of saxagliptin developed sinusitis, abdominal pain, vomiting, and gastroenteritis.
The undesirable effect of saxagliptin on bone tissue has not been established.
In the course of clinical observations, the development of thrombocytopenia was recorded, which corresponds to the diagnosis of idiopathic thrombocytopenic purpura. The causal relationship of this violation with the intake of saxagliptin has not been established.
Side effects associated with the combined use of saxagliptin and metformin in the treatment of T2DM in patients who have not previously received therapy
When using saxagliptin 5 mg and metformin 500-2000 mg, ≥ 5% of patients most often developed the following disorders (regardless of the investigator's assessment of the causal relationship): headache, nasopharyngitis.
In patients who received saxagliptin in addition to metformin therapy or as an initial combination therapy, diarrhea was the only digestive disorder that developed in ≥ 5% of patients.
Hypoglycemia
Information on hypoglycemia as a side effect is compiled from reports of hypoglycemia; concomitant measurement of glucose concentration was not required.
The incidence of hypoglycemia with the use of 2.5 and 5 mg saxagliptin and placebo (respectively):
- monotherapy: 4; 5.6 and 4.1%;
- combination therapy with metformin: 7.8; 5.8 and 5%.
In previously untreated patients, the incidence of hypoglycemia was 3.4% with the use of 5 mg of saxagliptin in combination with metformin, with metformin alone - in 4% of patients.
Hypersensitivity reactions
The incidence of hypersensitivity reactions (such as facial edema and urticaria) with the use of 2.5 and 5 mg of saxagliptin and placebo (respectively) was 1.5; 1.5 and 0.4%.
In patients treated with saxagliptin, according to the researchers, none of these phenomena required hospitalization and were not life-threatening.
Adverse reactions with metformin monotherapy
Vomiting, nausea, and diarrhea were the most common adverse events reported in> 5% of patients treated with modified-release metformin and more frequently than in the placebo group.
Saxagliptin Adverse Reactions Recorded in the SAVOR Study
The proportion of patients who developed severe hypoglycemia during treatment (hypoglycemia requiring the help of third parties) was higher in the saxagliptin group compared to the placebo group.
The increased risk of hypoglycemia in general, as well as severe hypoglycemia in the saxagliptin group, was mainly observed in patients receiving sulfonylureas, but not in patients receiving metformin or insulin as basic therapy.
In total, an increased risk of hypoglycemia, as well as severe hypoglycemia, is observed mainly in patients with a baseline glycated hemoglobin (HbAlc) value of less than 7%.
Post-marketing use
During post-marketing observation, the development of the following adverse reactions was recorded: acute pancreatitis, hypersensitivity reactions (including anaphylaxis, angioedema, rash and urticaria) and arthralgia. It is not reliably possible to assess the frequency of development of these phenomena.
Against the background of the use of saxagliptin, there is a dose-dependent average decrease in the absolute number of lymphocytes. In most cases, with repeated use of saxagliptin, a relapse was not observed, although in some patients, the number of lymphocytes decreased again with resumption of saxagliptin therapy, which led to the discontinuation of the drug. A decrease in the number of lymphocytes is not accompanied by clinical manifestations. The reasons for this disorder are unknown. If a prolonged or unusual infection develops, the lymphocyte count should be measured. The effect of saxagliptin on lymphocyte counts in patients with abnormal lymphocytes (including human immunodeficiency virus) is unknown.
In clinical trials of metformin, approximately 7% of patients showed a decrease in the serum concentration of vitamin B 12 (previously normal) to subnormal values, not accompanied by clinical manifestations. At the same time, such a decrease in the development of anemia is very rarely accompanied, after the abolition of metformin or additional intake of vitamin B 12, it is quickly restored.
Overdose
Saxagliptin overdose:
- symptoms: against the background of long-term therapy with saxagliptin in doses up to 80 times higher than recommended, no symptoms of intoxication have been described;
- therapy: symptomatic; the substance and its main metabolite are excreted from the body using hemodialysis at a rate of up to 23% of the dose in 4 hours.
Metformin overdose:
- symptoms: there is information about cases of metformin overdose, including taking more than 50,000 mg, in which hypoglycemia developed in approximately 10% of cases, but its causal relationship with metformin was not established, lactic acidosis occurred in 32% of cases;
- therapy: removal of metformin is carried out during dialysis, while the clearance reaches 170 ml / min.
special instructions
Lactic acidosis is a rare, serious metabolic complication. Its development can be noted due to the accumulation of metformin during the use of Kombogliz Prolong. With the development of lactic acidosis associated with the therapy, the plasma concentration of metformin in the blood is higher than 5 μg / ml.
Against the background of diabetes mellitus, lactic acidosis develops more often in patients with severe renal insufficiency, including those associated with congenital kidney disease and insufficient renal perfusion, especially when taking several drugs.
In patients with heart failure, in particular, against the background of unstable angina pectoris or acute heart failure and the risk of hypoperfusion and hypoxemia, there is a high likelihood of lactic acidosis. The risk increases in proportion to the patient's age and the degree of renal failure.
Patients taking metformin should have regular monitoring of renal function. Metformin should be used at the lowest effective dose. Elderly patients require monitoring of renal function. Patients over 80 years of age with renal dysfunction should not be prescribed the drug, since they have an increased risk of developing lactic acidosis. Immediate withdrawal of the drug is required if conditions occur that are accompanied by hypoxemia, sepsis or dehydration. Since the ability to excrete lactate can be significantly limited against the background of liver failure, patients with laboratory or clinical signs of liver disease should not be prescribed metformin.
Early lactic acidosis may be subtle and may be accompanied by nonspecific symptoms, including malaise, myalgia, respiratory distress, increased drowsiness, discomfort, and abdominal pain. Hypotension, hypothermia, and resistant bradyarrhythmia may occur. When these symptoms appear, metformin should be discontinued. Monitoring of the following indicators is required: serum electrolytes, ketone bodies, blood glucose; if indicated, blood pH, lactate concentration and blood metformin concentration.
Gastrointestinal symptoms that develop late in metformin use may be associated with lactic acidosis or another disease. In cases where the plasma concentration of lactate in venous blood on an empty stomach exceeds the upper limit of the norm, but does not reach 5 mmol / l, it is possible to assume the impending development of lactic acidosis. However, these conditions can be associated with other causes, for example, uncompensated diabetes mellitus, obesity, excessive physical activity.
All patients with diabetes mellitus and metabolic acidosis without signs of ketoacidosis (ketonemia, ketonuria) should be screened for lactic acidosis.
Treatment of lactic acidosis is carried out in a hospital setting. If a disease is detected in a patient taking metformin, it is necessary to immediately discontinue therapy and immediately carry out general supportive measures, in particular dialysis in order to correct acidosis and eliminate cumulated metformin.
Against the background of alcohol intake, the risk of lactic acidosis increases, so during therapy it is recommended to limit its use.
It is necessary to check kidney function before taking Combogliz Prolong and at least once a year thereafter. If impaired renal function is suspected, it should be assessed more frequently. If signs of renal failure appear, the drug is discontinued.
Before any surgical procedure (with the exception of small procedures that are not associated with restriction of food and fluid intake), the use of Kombogliz Prolong should be temporarily canceled. Resumption of therapy is allowed after normal renal function is confirmed and the patient is able to take medications by mouth.
In patients with type 2 diabetes who were previously well controlled on therapy with Comboglizom Prolong, and who have abnormal laboratory parameters or develop diseases (especially with an unclear diagnosis), an assessment of signs of lactic acidosis or ketoacidosis should be performed. With the development of any form of acidosis, Combogliz Prolong is replaced with another hypoglycemic drug.
Since hypoglycemia may develop with the use of insulin and sulfonylurea derivatives, the dose of saxagliptin during combination therapy may be adjusted to reduce the likelihood of this disorder.
In patients who take only metformin on a regular basis, hypoglycemia does not develop, but it can occur due to insufficient intake of carbohydrates, the concomitant use of other hypoglycemic drugs (sulfonylurea and insulin derivatives) or alcohol, and also be associated with the fact that active physical the load is not compensated by carbohydrate intake.
Weakened, elderly or malnourished patients and patients with pituitary or adrenal insufficiency or alcohol intoxication are most sensitive to hypoglycemic effects. Difficulty in the diagnosis of hypoglycemia can be observed in elderly patients and patients taking β-blockers.
Caution is required in the combined use of Comboglyse Prolong with drugs that can affect renal function, cause significant hemodynamic changes or lead to a violation of the distribution of metformin.
With cardiovascular collapse (shock) of any origin, acute heart failure, acute myocardial infarction and other conditions accompanied by lactic acidosis and hypoxia, prerenal azotemia may develop. When these violations appear, Kombogliz Prolong is immediately canceled.
Surgery, fever, infection, trauma can cause changes in blood glucose concentration, which could previously be controlled with Komboglyza Prolong. In this case, the patient, after temporary discontinuation of therapy, may be transferred to the use of insulin. After improving the general condition of the patient and stabilizing the concentration of glucose in the blood, the drug can be taken again.
With the development of serious hypersensitivity reactions, Combogliz Prolong is canceled. At the same time, other possible causes of this disorder should be analyzed and alternative therapy for diabetes mellitus should be prescribed.
During post-marketing surveillance, cases of acute pancreatitis, characterized by intense prolonged abdominal pain, have been reported. In case of suspicion of the development of pancreatitis, the reception of Kombogliz Prolong should be canceled.
In the SAVOR studies, the saxagliptin group showed an increase in the frequency of hospitalization for heart failure compared with the placebo group (the relationship with the intake of Kombogliz Prolong has not been established). Caution should be exercised when prescribing therapy to patients with risk factors for the development of heart failure, including heart failure or moderate to severe renal failure in history. Patients should be aware of the characteristic symptoms of heart failure and, if they appear, immediately report them to the doctor.
In post-marketing reports, there are indications of the development of joint pain, including severe pain, against the background of the use of DPP-4 inhibitors. After discontinuation of the drug, relief of symptoms is usually noted, in some cases, when the use of the same or another DPP-4 inhibitor is resumed, a relapse is observed. After starting to use the drug, the onset of symptoms can be rapid or occur during prolonged therapy. The feasibility of continuing to take Comboglyse Prolong in patients with severe joint pain is assessed individually.
Influence on the ability to drive vehicles and complex mechanisms
Studies to study the effect of Komboglyza Prolong on the ability to drive vehicles have not been conducted. Patients should take into account that saxagliptin can lead to the development of headaches that interfere with concentration and reduce the speed of motor reactions.
Application during pregnancy and lactation
Kombogliz Prolong is not prescribed during pregnancy / lactation.
Pediatric use
Studies of the safety and efficacy of Kombogliza Prolong in patients under the age of 18 have not been conducted, therefore, it is contraindicated to prescribe the drug to this group of patients.
With impaired renal function
Contraindications to the use of Kombogliz Prolong on the part of renal function:
- impaired renal function (serum creatinine: men ≥ 1.5 mg / dl, women ≥ 1.4 mg / dl, or decreased creatinine clearance), including those associated with septicemia, acute myocardial infarction, acute cardiovascular failure (shock);
- diseases in acute course, in which there is a risk of impaired renal function.
For violations of liver function
In patients with clinical and laboratory signs of impaired hepatic function, Combogliz Prolong is contraindicated due to the possible development of lactic acidosis.
Use in the elderly
Combogliz Prolong for patients over the age of 60 against the background of heavy physical work is prescribed under medical supervision, which is associated with an increased risk of lactic acidosis.
Drug interactions
Saxagliptin metabolism is mediated mainly by the cytochrome P 450 ZA4 / 5 (CYP3A4 / 5) isoenzyme system. During the research, it was found that saxagliptin and its main metabolite isoenzymes CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1 and ZA4 do not inhibit and CYP1A2, 2B6, 2C9, and ZA4 isoenzymes do not induce. Therefore, the effect of the substance on the metabolic clearance of drugs, in the biotransformation of which these isozymes are involved, is not expected. Saxagliptin is not a significant inhibitor or inducer of glycoprotein-P (P-gp).
Some drugs increase hyperglycemia (sympathomimetics, phenytoin, glucocorticosteroids, thiazide and other diuretics, phenothiazines, preparations of iodine-containing thyroid hormones, oral contraceptives, estrogens, nicotinic acid, isoniazid, slow calcium channel blockers). Against the background of the use of Combogliz Prolong, when prescribing / canceling such drugs, careful monitoring of the concentration of glucose in the blood should be carried out. Metformin binds to plasma proteins to a small extent, therefore it is considered unlikely that it will interact with substances that bind highly to plasma proteins, including salicylates, sulfonamides, probenecid and chloramphenicol (in contrast to sulfonylurea derivatives, which bind to high degree with serum proteins).
Rifampicin significantly reduces the exposure of saxagliptin without changing the AUC value of its active metabolite (5-hydroxy-saxagliptin). Rifampicin has no effect on the inhibition of DPP-4 in blood plasma during the 24-hour interval of therapy.
Diltiazem, when combined, enhances the therapeutic effect of saxagliptin. An increase in the plasma concentration of saxagliptin in the blood is expected with the following drugs: amprenavir, aprepitant, erythromycin, fluconazole, fosamprenavir, grapefruit juice and verapamil; however, dosage adjustments for saxagliptin are not recommended.
Ketoconazole significantly increases the plasma concentration of saxagliptin in plasma. A similar change is expected with other potent inhibitors of CYP3A4 / 5 isoenzymes (including itraconazole, nelfinavir, ritonavir, indinavir, atazanavir, clarithromycin, nefazodone, telithromycin and saquinavir). When combined with a potent inhibitor of CYP3A4 / 5 isoenzymes, the dose of saxagliptin should be reduced to a minimum (2.5 mg).
Cationic drugs (including quinine, triamterene, ranitidine, amiloride, procainamide, morphine, digoxin, quinidine, vancomycin, or trimethoprim) that are excreted by glomerular filtration by the kidneys can theoretically interact with metformin, with competition for shared renal tubular transport systems …
When conducting studies of drug interaction of cimetidine and metformin with a single / repeated dose of the drug in healthy volunteers, the development of interaction was observed. At the same time, there is an increase in C max and AUC of metformin in plasma and whole blood by 60 and 40%, respectively. With a single dose of the drug, changes in the T 1/2 value were not observed. Metformin has no effect on the pharmacokinetic parameters of cimetidine. It is recommended to conduct careful monitoring of the patient's condition and, if necessary, adjust the dose in patients who use cationic drugs excreted using the proximal renal tubule system.
Furosemide increases the C max of metformin in plasma and blood, and AUC in the blood by 22 and 15%, respectively; no significant change in the renal clearance of metformin is observed. With max and AUC of furosemide when combined with metformin decreases by 31 and 12%, respectively. At the same time, there is a decrease in T 1/2 by 32% without a significant change in the renal clearance of furosemide. There are no data on the development of the interaction of furosemide and metformin with long-term combined use.
Nifedipine, according to studies with healthy volunteers, increases C max in plasma, and AUC of metformin by 20 and 9%, respectively, and also increases its excretion by the kidneys. The T 1/2 and T max values remain unchanged. The absorption of metformin in combination with nifedipine increases. Metformin has practically no effect on the pharmacokinetics of nifedipine.
Special pharmacokinetic studies of the interaction of Comboglyse Prolong have not been carried out, although such studies were carried out with its active substances.
The effect of other drugs on saxagliptin:
- glibenclamide, simvastatin, famotidine: С max of saxagliptin increases, the AUC value remains unchanged;
- diltiazem (prolonged dosage form), ketoconazole: C max and AUC of saxagliptin significantly increase, while the same indicators for its active metabolite decrease;
- rifampicin: C max and AUC of saxagliptin decrease, while the C max of the active metabolite increases, and AUC does not change significantly;
- aluminum hydroxide + magnesium hydroxide + simethicone: C max of saxagliptin decreases, the AUC value remains unchanged.
Analogs
The analogues of Kombogliz Prolong are Velmetia, Yanumet, Yanumet Long, Glukovans, Glibomet, Gluconorm, Galvus Met, etc.
Terms and conditions of storage
Store at temperatures up to 30 ° C. Keep out of the reach of children.
The shelf life is 3 years.
Terms of dispensing from pharmacies
Dispensed by prescription.
Reviews about Komboglize Prolong
Patients leave mostly positive reviews about Komboglize Prolong. They note significant improvements in blood sugar control. Indicate that the drug can be successfully used in old age.
The main disadvantage is the high cost of the tablets.
Price for Kombogliz Prolong in pharmacies
The approximate price for Kombogliz Prolong is:
- 1000 mg + 2.5 mg (56 tablets) - 3685 rubles;
- 1000 mg + 5 mg (28 tablets) - 3597 rubles.
Kombogliz Prolong: prices in online pharmacies
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Drug name Price Pharmacy |
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Combogliz Prolong 1000 mg + 5 mg modified release film-coated tablets 28 pcs. 1416 RUB Buy |
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Combogliz Prolong 1000 mg + 2.5 mg modified release film-coated tablets 56 pcs. 2816 RUB Buy |
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Combogliz prolong tablets p.o. with mod. release 1000mg + 5mg 28 pcs. 3423 RUB Buy |
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Combogliz prolong tablets p.o. with mod. release 1000mg + 2.5mg 56 pcs. 3423 RUB Buy |
Maria Kulkes Medical journalist About the author
Education: First Moscow State Medical University named after I. M. Sechenov, specialty "General Medicine".
Information about the drug is generalized, provided for informational purposes only and does not replace the official instructions. Self-medication is hazardous to health!
