Komboglyze XR 5mg/1000mg Astrazeneca tablets support blood sugar control (4 blisters x 7 tablets)

Komboglyze XR 5 mg/1000 mg is also designated to coordinate with insulin (such as 3 -drug combination therapy) to support diet and exercise, to control blood sugar in patients aged 18 or older with type 2 diabetes when insulin and metformin have not controlled blood sugar well.

Komboglyze XR 5 mg/1000 mg is also indicated in combination with 1 sulfonylura (such as a combination therapy of 3 drugs) to support the diet and exercise, to control blood sugar in patients aged 18 and older with type 2 diabetes without good control of blood sugar after maximum dosage of both methormin and sulfonylium.

Pharmacology

saxagliptin

In patients with type 2 diabetes, using saxagliptin will inhibit the enzyme activity DPP-4 for 24 hours. After using oral glucose or after meals, the inhibition of DPP-4 will increase 2-3 times the concentration of GLP-1 hormone and Gip activity in the blood, reduce glucagon levels and increase insulin release from beta cells of the pancreas depending on glucose levels. Increasing insulin levels and reducing glucagon concentrations are associated with reducing glucose concentrations at hunger and reducing glucose after taking glucose or after meals.

ECG physiology

saxagliptin: In a clinical trial with a placebo, random, double blind, diagonal 4, using a control drug is moxifloxacin on 40 healthy subjects, saxagliptin is not related to the extension of QTC or significant heart rate at the dose up to 40 mg/day (8 times the maximum doses of use recommendations).

pharmacokinetics

komboglyze xr

Biological equivalent and the effects of food on Komboglyze XR are described by low energy diet. Low energy diet consists of 324 kcal in a diet containing 11.1% protein, 10.5% fat and 78.4% carbohydrate.

Biological equivalent research results on healthy volunteers show that the tablet combined with Komboglyze XR is equivalent to biological equivalent compared to when drinking in combination with each individual tablet with the corresponding doses of saxagliptin (Onglyza) and Metformin hydrochloride release on the situation of food that has been used for food.

saxagliptin

Pharmacokinetics of saxagliptin and active metabolites, 5-Hydroxy saxagliptin are similar between healthy volunteers and patients with type 2 diabetes.

After taking 5 mg of single doses of Saxagliptin in healthy volunteers, the average AUC value in the plasma of saxagliptin and its active metabolites respectively is 78 ng*hours/ml and 214 ng*hours/ml. The value of cmax in plasma is 24 ng/ml and 47 ng/ml. The average coefficient of interior variation (% CV) on CMAX and AUC of saxagliptin and its active metabolites is less than 25%. There is no saxagliptin accumulation and its active metabolites are recorded when used repeated doses 1 time/day at any dosage.

There is no dependence on dosage and time recorded on the saxagliptin and its active metabolites in 14 days of using saxagliptin 1 time/day in the dose range from 2.5 to 400 mg.

metformin hydrochloride

Metformin release long -lasting cmax reaches median value after 7 hours and ranges from 4 to 8 hours. In a stable state, Metformin has AUC and CMAX lower than the ratio at the extended dose of metformin to use in the dose range from 500 to 2000 mg. After the dose repeats the prolonged release metformin, the metformin does not accumulate in the blood.

metformin is excreted in the form of unchanged urine and is not metabolized through the liver. The peak of the blood in the blood tablets extended Metformin is about 20% lower than the same level of instantaneous release tablets, however, the level of absorption (calculated according to AUC) is similar between prolonged release tablets and instant release tablets.

absorption

saxagliptin

Average time to achieve maximum plasma concentrations (TMAX) after use 5 mg 1 time/day is 2 hours for saxagliptin and 4 hours for active metabolites.

Use at the same time with saxagliptin's increased fat foods about 20 minutes compared to hunger. Saxagliptin's AUC increased by about 27% when used with food compared to hunger. Saxagliptin can be used during or outside meals. Food does not affect the pharmacokinetics of saxagliptin when used in the form of a tablet combined with Komboglyze XR.

metformin hydrochloride

After taking the long -lasting Metformin dose, CMAX reaches the median value after 7 hours and ranges from 4 to 8 hours. Although the absorption level of Metformin (calculated by AUC) in the form of release tablets lasts to about 50% when used with food, food does not affect Metformin's CMAX and TMAX. Both rich and low -fat meals have similar effects on the pharmacokinetics of the long -lasting release.

Metformin's non -affecting food for pharmacokinetics when used in the form of Komboglyze XR combination tablets.

distribution

saxagliptin

In vitro research shows that the cohesion of saxagliptin and its active metabolites with non -significant human serum protein. Therefore, changes in blood protein content in different conditions (such as kidney failure or liver failure) will not affect the distribution of saxagliptin.

metformin hydrochloride

The studies on the distribution of long -lasting metformin have not been conducted, however, the apparent distribution (v/f) of the metformin after taking single dose Metformin instantly releases the average 850 mg of 654 ± 358 L. Unlike sulfonylurea associated with protein more than 90%, Metformin is not significantly connected to plasma protein.

Metformin has a accumulated in red blood cells, which is very likely to work over time. Metformin is negligible with plasma proteins and therefore can be less interactive with high -pitched drugs with protein such as salicylate, sulfonamide, chloramphenicol and probenecid, compared to sulfonylurea, widely associated with serum protein.

transformation

saxagliptin

Metabolism of saxagliptin mainly occurs through the cytochrome P450 3A4/5 (CYP3A4/5). The active metabolite of saxagliptin also has the effect of inhibiting DPP-4 and is active in ½ and compared to saxagliptin. Therefore, strong CYP3A4/5 inhibitors and touch will change the pharmacokinetics of saxagliptin and its active metabolites.

metformin hydrochloride

Single veins of venous therapy in healthy volunteers shows that metformin is excreted without a constant urine and does not metabolize through the liver (no metabolic is found in humans) or excreted through bile.

Metabolism of metabolism of long -lasting release tablets has not been done.

Elimination

saxagliptin

Saxagliptin is eliminated through both lines: kidney and liver. After taking a single dose of 14C-Saxagliptin 50 mg, the intact saxagliptin, the active metabolic form and the sum of the radioactive active compounds are excreted in the urine with a rate of 24%, 36% and 75% of the dose of use. The average retention of the kidneys of saxagliptin (~ 230 ml/min) is higher than the average estimated glomerular filtration (EGFR) (~ 120 ml/min), showing active excretory mechanisms in the kidneys.

About 22% of the radioactive substance is present in the feces, proving that there is a part of the saxagliptin excreted through the bile and/or a part that is not absorbed through the gastrointestinal tract. After taking a single -dose of Saxagliptin 5 mg on healthy objects, the average selling time (t ½) of saxagliptin and metabolites is active in the corresponding plasma of 2.5 hours and 3.1 hours respectively.

metformin hydrochloride

The renal clearance is about 3.5 times higher than the creatinine clearance, which shows the excretion in the renal tubules is the Metformin main elimination line. After drinking, about 90% of the absorption drug is excreted through the kidneys within the first 24 hours, with a semi -discharged time in plasma about 6.2 hours. In the blood, the sale time is about 17.6 hours, showing that red blood cells can be a drug distribution compartment.

Table 6: Metformin's impact on the concentration and contact time of the drug shared

Too hypersensitivity to metformin hydrochloride. - Acute or chronic metabolic acidosis, including diabetic ceto-acid infection. Patients infected with diabetes should be treated with insulin.

History of serious hypersensitivity reactions with Komboglyze XR or Saxagliptin such as anaphylactic reaction, angioedema or flaking skin condition.

Be cautious when using

Lactic acid infection

Lactic acid infection is a rare but very serious metabolic complication, which may occur due to metformin accumulation during treatment with Komboglyze XR when occurring, the mortality rate is approximately 50%. Lactic acid infection can occur with a number of pathological conditions, including diabetes and whenever there is a decrease in perfusion in tissue and severe deficiency of oxygen. Lactic acid contamination is characterized by increased lactate concentration in the blood (> 5 mmol/l), reducing blood pH, electrolyte disorders with an increase in anion space (anion gap), increasing lactate/pyruvate ratio. When metformin is considered as the cause of lactic acid infection, the metformin concentration is often seen in plasma> 5 µg/ml.

Lactic acid infections in patients using metformin hydrochloride are recorded very low (approximately 0.03 cases/1000 patients - year, with about 0.015 deaths/1000 patients - five). Of the more than 20,000 patients - the year of using metformin in clinical studies, there is no lactic acid contamination report. The reports occur mainly in diabetes patients with significant kidney failure, including kidney tissue and renal disease due to reduced renal perfusion, common in patients with simultaneous problems of medical/surgery and simultaneous use of many types of drugs, in patients with congestive heart failure need to use drugs, especially patients with acute congestive or non -stable blood infection with reduced risk of irrigation and oxygen.

The risk of lactic acid infection increases with the level of kidney dysfunction and age of the patient. Therefore, the risk of lactic acid infection can be significantly reduced by regular monitoring of kidney function in patients using metformin and by using the lowest Metformin doses effectively. Especially the treatment in the elderly should be accompanied by careful monitoring of kidney function. Metformin should not be used for initial treatment in patients ≥ 80 years old except for the test of creatinine clearance showing that the kidney function does not decline, lactic acid infection is easy to appear on these objects. Moreover, Metformin should be stopped immediately when the presence of any symptoms is associated with oxygen deficiency, dehydration or blood infection.

Due to impaired liver function may limit the ability to eliminate lactate, often avoiding metformin in patients with subclinical or clinical evidence of liver disease. Patients should be warned to limit alcohol use while treatment with metformin because alcohol increases the effects of metformin hydrochloride on lactate metabolism. In addition, Metformin should be temporarily stopped before the X-ray has an iodine contrast injection and any surgery. [See the note and caution].

The onset of lactic acid infection is often difficult to detect and only accompanied by nausical symptoms such as discomfort, muscle pain, respiratory failure, drowsiness and nausical symptoms of abdominal pain. Heat lower body, hypotension, and slow -resistant heart rate is accompanied by more obvious acidosis. Patients and treatment doctors must be alert about the importance of such symptoms and should guide the patient to notify the doctor as soon as the symptoms appear [see the note and cautious].

Should stop using metformin until the cause is clearly defined. Measure electrolytes in blood walls, ceton, blood glucose and if indicated, measure blood pH, lactate concentration and even blood metformin levels can be helpful in assessing the condition. When the patient has stabilized at a certain level of metformin, the symptoms on the stomach - intestines, which are common at the beginning of the therapy, is most likely not related to the drug. Symptoms on the stomach - bowel appear later may be due to lactic acid infection or other serious diseases.

In patients with metformin, lactate concentration in venous plasma when hungry is at the upper limit of normal levels but lower than 5 mmol/l, not necessarily forecasting to occur lactic acid infection and can be explained by other metabolic mechanisms, such as poor control of diabetes or obesity, excessive physical activity or technical problems in the testing of tests.

Suspected lactic acid infection in any patient with diabetes with metabolic acidosis but lacks evidence of ceto-acid infection (ureter and blood ceton).

Lactic acid infection is a medical emergency and must be treated at the hospital. For patients infected with lactic acid that is taking Metformin, it is advisable to stop using the drug immediately and timely general support treatment. Because metformin hydrochloride can be fertilized (the clearance can be up to 170 ml/mm in good hemodynamic conditions), it is recommended to promptly dialysis to overcome acidic infection and remove the accumulated metformin. Such management often helps to reverse symptoms and recover in time [see the contraindications and attention and caution].

Pancreatitis

Acute pancreatitis in patients using saxagliptin has been recorded after the drug circulates on the market. After starting to use Komboglyze XR, patients should be carefully monitored with signs and symptoms of pancreatitis. If there is a suspected pancreatitis, Komboglyze XR should be suspected and take appropriate treatment.

It is not clear whether patients with a history of pancreatitis when using Komboglyze XR increases the risk of pancreatitis.

In the study of Saxagliptin's cardiac for diabetic - thrombosis in myocardial infarction (SAVOR), the rate of pancreatitis events determined after adjustment is 0.3% in both groups using saxagliptin and placebo in the intended population (ITT). [See unwanted effects]

Review kidney function

metformin is excreted mainly through the kidneys, the risk of metformin accumulation and lactic acid infection increases with the degree of impaired renal function. Therefore, contraindicated use of Komboglyze XR in patients with renal failure [see the contraindications section].

Before starting to use Komboglyze XR, and at least each year later, it is advisable to evaluate and confirm the kidney function is normal, in patients who are expected to have renal function progression (for example, the elderly) should assess the kidney function more often and stop using Komboglyze XR if there is evidence of kidney failure.

Evaluation of liver function

There are several cases of lactic acid infections in patients with hepatic impairment using metformin. Therefore, it is not recommended to use Komboglyze XR for patients with liver failure.

Vitamin B12 concentration

In Metformin's control clinical studies conducted for 29 weeks, a decrease below the normal level of vitamin B12 in the previous normal serum, without clinical manifestations in about 7% of patients. This reduction may be due to the intervention to the ability to absorb vitamin B12 from the intrinsic complex of vitamin B12, however, it is rarely related to anemia and will quickly admire when stopping metformin or supplementing with vitamin B12. Patients who use Komboglyze XR are recommended to check the annual hematological parameters, and if any abnormalities manifest should be surveyed and properly treated [see the adverse reaction].

The normal level of vitamin B12 is tended to be seen in some individuals (such as people with vitamin B12 or by taking calcium or by absorbent). In these patients, the quantitative concentration of B12 of serum usually in every 2-3 years can be very helpful.

Alcohol (alcohol)

Alcohol may enhance the effects of metformin on lactate metabolism. Patients should be warned to restrict alcohol while taking Komboglyze XR.

Surgery

Should temporarily stop using Komboglyze XR when performing any surgery (except for minor surgery not to restrict the use of food and drinks), and should not start using the drug until the patient's back and kidney function are considered normal.

Changes on clinical conditions of patients with type 2 diabetes were previously controlled

On patients with type 2 diabetes, the previous one has been well controlled by Komboglyze XR, with abnormal testing or deteriorating clinical conditions (especially vague and unknown pathological conditions) should be evaluated in time to find evidence of CETO-acid acidosis or lactic acid infection. Evaluation indicators include electrolytes and serum kerosen, blood glucose, and if indicated, perform blood pH, lactate, pyruvat, and blood metformin levels. If any acidosis occurs, Komboglyze XR immediately discontinue and take appropriate management measures.

Hypoglycemia when using Saxagliptin at the same time with sulfonylurea or insulin

When using saxagliptin in combination with sulfonylurea or with insulin, are drugs that cause hypoglycemia, frequency of hypoglycemia that is diagnosed higher when using placebo in combination with sulfonylurea or with insulin. [See the unwanted effect]. Therefore, low doses of insulin or insulin stimulants should be used to minimize the risk of lowering glucose in the blood when used in combination with Komboglyze XR. [See the dosage and usage]

metformin hydrochloride

Hypoglycemia does not occur in patients using single metformin under normal conditions, but may occur when the amount of calories put into the body is deficient or when exercise severe physical strength but not offset by adding the corresponding calorie, or when used simultaneously with drugs that reduce blood glucose (such as sulfonylurea and insulin), or alcohol or alcohol, or alcohol or alcohol, or alcohol or alcohol, or alcohol, or alcohol, or dice The adrenal impairment or pituitary insertion or alcohol poisoning is particularly sensitive to hypoglycemic effects. Hypoglycemia can be difficult to identify in older patients and patients taking the sympathetic receptor inhibitors.

Concentrated use with drugs affect kidney function or metformin distribution

Timeless use of these drugs can affect kidney function or significantly change hemodynamics, or may interfere with metformin distribution, such as cationic drugs that are eliminated through the excretion of the renal tubules [see the drug interaction section]. Therefore should be used carefully when used simultaneously with these drugs.

X-rays with injections of contrast substances containing iodine

X-rays with iodine-containing contrast substances can lead to renal functional transformation and are associated with lacid acid infections in patients using metformin. Therefore, in patients who are expected to perform X-rays, they should stop using temporary komboglyze before or at the time of implementation and in the next 48 hours after implementation, only use the drug again after the kidney function is reassused and confirmed as normal.

Oxygen deficiency

Cardiovascular collapse (shock), acute congestive heart failure, acute myocardial infarction and other diseases are characterized by oxygen deficiency, associated with lactic acid infection and can cause blood urea before the kidneys. When these events appear in patients being treated with Komboglyze XR, should stop taking the drug immediately.

Hypersensitivity reaction

There have been reports that record serious hypersensitivity reactions in patients using saxagliptin after the drug circulates on the market. These reactions include anaphylactic reaction, angioed, and flaky skin condition. These reactions occur within the first 3 months of treatment with saxagliptin, some cases occurred after the first dose. If the hypersensitivity reaction is suspected, the Komboglyze XR is suspected, assessing the hidden causes of the event, and looking for an alternative treatment for diabetes. [See unwanted effects]

Use cautiously for patients with a history of angioedema with other dipeptidyl peptidase-4 (DPP4) inhibitors because they still know if these patients may have angioed with Komboglyze XR or not.

heart failure

In the Savor study, the percentage of hospitalized patients due to heart failure in patients using saxagliptin increased compared to placebo, although the causal relationship has not been established. Be careful when using Komboglyze XR for patients with risk factors for hospitalization due to heart failure such as a history of heart failure or medium to severe renal failure. Patients should know typical heart failure symptoms and should be reported as soon as they have these symptoms. [View Clinical Research section]

joint pain

joint pain, there may be severe cases, which have been recorded in the DPP4 inhibitors after the drug circulated on the market. Symptoms after stopping the drug and in some patients, symptoms recur when they return to the medication or other DPP4 inhibitors. Symptoms may start rapidly after starting medication or after longer treatment. If severe joint pain occurs, it is advisable to assess the continued treatment of each patient. [See unwanted effects]

Large vascular complications

There is no clinical research showing evidence conclusions about reducing the risk of large blood vessel complications when taking Komboglyze XR or any other diabetes treatment.

In random Savor clinical research, placebo, there is no link between the use of saxagliptin and increasing the risk of the main cardiovascular events. [See unwanted effects]

The ability to drive and operate machinery

No research on the impact of Komboglyze XR or Saxagliptin on the ability to drive and operate machinery.

Saxagliptin or Metformin may not be significantly affected by driving and operating machinery. It should be noted that dizziness has been recorded in studies with saxagliptin.

Pregnancy

Pregnant women - Group B

There are no full -up of control studies about the use of Komboglyze XR or the individual ingredients of the drug in pregnant women. Because animal reproduction studies cannot always be used to predict the response occurs in humans, Komboglyze XR should not be used as well as other diabetes treatments while pregnant unless really necessary.

Use a combination of Saxagliptin and Metformin for mice and rabbits that are pregnant during the establishment of the agency, not detect the death of embryos or teratogen when surveying at the dosage that the whole body concentration is achieved (AUC) in the mice up to 100 and 10 times the maximum doses recommended in humans (MRHD; Saxagliptin 5 MG and Metformin 2000 MG); The whole body concentration achieved in rabbits up to 249 and 1.1 times the maximum dose recommended in humans.

In mice, the progression of secondary toxic toxicity is limited to the ratio of the curve; The pregnancy toxicity is limited to a weight reduction rate from 11% to 17% in the research process and related to food reduction in pregnancy. On the rabbit, a subdivision of mother rabbits (12 children of 30 children), poorly tolerated drugs, resulting in death, dying or miscarriage. However, among the mother rabbits of the assessment, pregnancy toxicity is limited to the level of body weight decrease from 21 to 29 of pregnancy. And the toxicity of progress in these litters is limited to fetal weight reduction 7% and a slow low proportion of the fetal nail.

The period of breastfeeding

There has been no research on nursing animals using the combined form of Komboglyze XR. In studies performed on each drug ingredient, both saxagliptin and metformin are excreted in milk in breastfeeding mice. No saxagliptin or metformin has not been determined whether or not to excrete in breast milk or not. Due to a lot of excreted drugs in breast milk, caution should be used when using Komboglyze XR in breastfeeding women.

Drug interaction

Strong enzyme inhibitors CYP3A4/5

saxagliptin

Ketoconazole significantly increases the level of saxagliptin in the body. Similarly, the increase in the concentration of saxagliptin in plasma also occurs when using strongly strong inhibitors CYP3A4/5 (such as Atazanavir, Clarithromycin , indinavir, iTraconazole , Nefazodone, Nelfinavir, Ritonavir Saquinavir and telithromycin).

Cationic ionic drugs

metformin hydrochloride