Trajenta duo 2.5mg/850mg Boehringer Ingelheim control blood sugar in type 2 diabetes (60 tablets)

concentration in patients with type 2 diabetes with severe renal failure increases by 1.4 times compared to patients with diabetes Type 2 with normal kidney function. The AUC prediction of Linagliptin is in a stable state of patients with end -stage kidney disease ESRD showing the concentration of drugs similar to patients with medium or severe renal failure.

In addition, Linagliptin is less likely to be removed to the point of significance in treating dialysis or peritoneal fertilizer. Therefore, there is no need to adjust the linagliptin dose in patients with renal impairment at any level.

In addition, mild kidney failure does not affect the pharmacokinetics of Linagliptin in patients with diabetes type 2 according to the pharmacokinetic analysis evaluation on the research population.

Liver failure

Average AUC and CMAX, of Linagliptin in patients with medium mild hepatic and severe liver failure (according to Child-Pugh classification) similar to the control group of healthy pairing after using 5mg of Linagliptin. It is not necessary to adjust the linagliptin dose for patients with mild, moderate or severe liver failure.

Body mass index (BMI)

No need to adjust the dose based on BMI. According to a pharmacokinetic analysis on the research population from phase I and phase II, the body mass index does not affect clinical significance to the pharmacokinetics of Linagliptin.

Sex

There is no need to adjust the dose based on gender. According to a pharmacokinetic analysis on the research population from phase I and phase II data, gender does not affect clinical significance to pharmacokinetics of Linagliptin.

Elderly

There is no need to adjust the dose based on age, due to a pharmacokinetic analysis on the population studied from phase I and phase II data, the age does not impact, clinically significance to the pharmacokinetics of Linagliptin. Elderly subjects (65 to 80 years old) have plasma linagliptin levels no different from young people.

Children

The studies have not yet been conducted to determine the dynamics of Linagliptin in patients who are children.

Race

There is no need to adjust the dose based on racial factors. The race does not have a significant impact on the concentration of Linagliptin in plasma based on a synthetic analysis from existing pharmacokinetic data, including patients with white skin corner, Spanish, African -American, Asia. In addition, the pharmacokinetic characteristics of Linagliptin are recorded as in the specialized studies I specially in healthy Japanese, Chinese and white volunteers and whites and patients with 2 African -American diabetes.

metformin

absorption

After taking 1 oral metformin dose, TMAX is achieved after 2.5 hours. The absolute bioavailability of Metformin Hydrochloride 500mg or 850mg tablets in healthy volunteers is about 50 - 60%. After an oral dose, the non -absorbing drug is found in the feces of 20 - 30%.

After oral use, Metformin Hydrochloride is absorbed in incomplete and saturated. Pharmacokinetic pharmacokinetics of metformin hydrochloride are thought to be non -linear.

At the dose and dose mode of the metformin hydrochloride, the plasma drug concentration in a stable state is reached within 24 to 48 hours and usually lower than 1 microgram/ml. In control clinical trials, the maximum concentration of Metformin hydrochloride in plasma (CMAX) does not exceed 5 micrograms/ml even at the maximum dose.

Food reduces the level and slows significantly the absorption process of Metformin Hydrochloride. After using the dose of 850mg, the peak of the drug in plasma has decreased by 40%, AUC (area under the curve) decreased by 25% and the time until reaching the peak concentration in plasma lasted another 35 minutes. The clinical significance of this decrease is unknown.

distribution

drugs are negligible with plasma proteins. Metformin Hydrochloride is distributed into red blood cells. The peak concentration in the blood is lower than the peak concentration in plasma and appears at the same time. Many possibilities are a secondary distribution compartment. The average distribution volume (VD) is in the range of 63 - 276 L.

transformation

metformin hydrochloride eliminates urine in a constant form. No metabolites are detected in humans.

excretion

The renal waste of the metformin hydrochloride> 400 ml/min shows that metformin hydrochloride is eliminated by glomerular filtration and excreted through the renal tubules. After an oral dose, the apparent sale time is about 6.5 hours.

When kidney function decreases, the removal of drugs through the kidneys decreases proportional to creatinine clearance, so the selling time also lasts, resulting in an increase in plasma metformin hydrochloride levels in plasma.

Special patient group

Children

Single dose research: After using a single dose of Metformin 500 mg, pharmacokinetics in pediatric patients are similar to in healthy adults.

Research on multi -dose use: data is limited to a study. After repeating the dose of 500mg, 2 times a day for 7 days in the pediatric patient, the peak concentration of the drug in plasma (cmax) and the concentration of systemic drugs (AUC0-T Because the dose of the drug is adjusted based on blood sugar levels, this finding is less clinical significance.

kidney failure

Data on patients with average renal failure is rare and not reliable enough to estimate the system exposure to Metformin in this group of patients compared to patients with normal renal function. Therefore, when adjusting the dose should consider the clinical effect/ drug tolerance (see the dose and how to use).

Be cautious when using

need to be very careful when taking the drug for patients in the following cases:

General warning

Do not use Trajenta Duo for patients with diabetes type 1 or patients with diabetes.

Used with known drugs that cause hypoglycemia

linagliptin

Insulin and insulin secretion stimulants are known to cause hypoglycemia. In a clinical study, the use of linagliptin combined with an insulin secretion (eg sulfonylurea) accompanied with a higher rate of hypoglycemia than a placebo group. The rate of hypoglycemia is higher when using linagliptin in combination with insulin in patients with severe renal impairment. Therefore, to reduce the risk of hypoglycemia when used in conjunction with Trajenta Duo, may request a lower dose than insulin or insulin secretion.

metformin

Hypoglycemia does not appear in patients using single Metformin when used in normal cases, but may appear when the calories are insufficient, when exercising too much without adequate calories, or when used simultaneously with other hypoglycemic drugs (eg su and insulin) or ethanol or ethanol. Elderly, depressed, or malnutrition patients, and patients with pituitary or adrenal impairment or alcohol poisoning are especially sensitive to hypoglycemic effects. Hypoglycemia can be difficult to identify in the elderly, and in patients taking adrenergic inhibitors.

Lactic acidic acidosis

Lactic acidic acidosis is a serious metabolic complication that can appear due to metformin accumulation during treatment with Trajenta Duo and death in about 50% of cases. Lactic acidic acidosis may appear along with a number of pathophysiological conditions, including diabetes, and caught periodically when there is a significant reduction in perfusion to tissue and reducing blood oxygen. Lactic acidic acidosis has the characteristics of increased blood lactate levels (> 5 mmol/l), reducing blood pH, electrolyte disorders due to an increase in anion space, and increasing lactate/pyruvate ratio. When metformin is considered to be the cause of lactic acid acidosis, the plasma metformin level is> 5ug/ml.

The rate of lactic acidic acidosis in patients using metformin is about 0.03 cases/1000 patients - five, (with approximately 0.015 deaths/1000 patients - year). In more than 20,000 patients - the year using metformin in clinical trials, no reports are related to lactic acid acidic acidosis. Cases that have reported mainly in patients with diabetes with significant renal failure, including kidney disease and reduced renal perfusion, often in cases where there are many medical/surgical problems simultaneously and at the same time taking many drugs. Patients with congestive heart failure need to control drugs, especially when accompanied by reduced perfusion and hypoxemia due to unstable or acute heart failure, risk of increased lactic acidic acidosis. The risk of lactic acidic acidosis increases with the level of renal failure and the age of patients. Therefore, the risk of lactic acidic acidosis is significantly reduced by regular control of kidney function in patients using metformin. In particular, treatment in elderly patients should go along with strict control of kidney function. Metformin treatment should not be started in the caught patient unless checking for creatinine clearance shows no impaired renal function. In addition, Metformin should be stopped when there is any sign of reducing blood oxygen, tears, or infection. Due to the decline in liver function, it can seriously affect lactate elimination, so avoid using metformin in patients with clinical or testing tables that show liver failure. Patients should be cautious when drinking a lot of alcohol while using Metformin, because alcohol can affect the metabolism of metformin. In addition, Metformin should be temporarily used before participating in the testing test of the internal circuit and the surgery is necessary to limit food and fluid. Using Topiramat: A Anhydrase carbon dice in the treatment of epilepsy and migraine prevention can cause metabolic acidosis depends on the dose and can worsen the risk of metformin causing lactic acidic acidosis.

Lactic acidic acidosis is often difficult to see, and accompanied by nonspecific symptoms such as discomfort, muscle pain, respiratory failure, increased drowsiness, and nonspecific abdomen. A more severe acidosis comes with signs such as reducing body temperature, lowering blood pressure, and anti -treatment heart rate. Patients should be instructed to identify foxes immediately. If so, you should stop using Trajenta Duo until the lactic acidic acidosis is completely gone. Stomach disorders are a common report when starting treatment with Metformin and is observed with lower frequency in patients who have used long -term metformin with stable doses. Gastric disorders appear in patients using Metformin Castle with stable doses that may be caused by lactic acidic acidosis or other serious pathology.

To eliminate lactic acidic acidosis, serum electrolyte, ketone, blood sugar, pH, lactate and metformin levels may be helpful. Venous lactate concentration at hunger is higher than the upper limit of normal levels but lower than 5 mmol/l in patients using Metformin does not necessarily indicate lactic acidic acidosis and may be due to other mechanisms, such as underbearing or obesity, excessive physical activity, or technical problems during blood tests.

Suspected lactic acidic acidosis in any patient with diabetes metabolic lack of evidence of keton acid infection (urinary tract and blood keton). Lactic acidic acidosis is an emergency medical condition so it must be treated in the hospital. Should stop using immediately and immediately transferred to replacement support measures in patients with lactic acidic acidosis which is using Metformin. Metformin can be separated (cleared up to 170 ml/minute in good hemodynamics) and recommended dialysis to remove metformin storage and calibration of metabolic acidosis.Such control often leads to rapid and recovery reduction.

Pancreatitis

There have been after -sales reports of acute pancreatitis, including fatal pancreatitis in patients using linagliptin. Read carefully about the possible signs and symptoms of Tuy inflammation. If pancreatitis rest, immediately stop using Trajenta Duo and start appropriate treatment. It is unknown whether the patient has a history of pancreatitis, which increases or does not risk inflammation while using Trajenta Duo.

Hypersensitivity reaction

There have been after -sales reports on serious hypersensitivity reactions in patients using Linagliptin (a component of Trajenta Duo), reactions that include hypersensitivity shock, angioedema, and peeling. The oil starts the reactions that appear in the first 3 months after the beginning of treatment with Linagliptin, with a few reports that appear after the first dose. If a serious hypersensitivity reaction is suspected, stop using Trajenta Duo, assess other abilities that can cause events, and use another measure to treat diabetes.

Evaluation has been reported with other Dipeptidyl peptidase-4 (DPP-4) inhibitors. Use cautiously in patients with a history of angioedema due to the previous use of DPP-4 inhibitors because they do not know whether these patients may have angioed angels when treated with Trajenta Duo.

Vitamin B12 concentration

In a 29 -week control clinical study with Metformin, it was observed that approximately 7% of patients treated with Metformin fell below normal levels of vitamin B12 and no clinical manifestations. Reducing this vitamin B12 level may be due to the intervention in the absorption of vitamin B12 from the complex of internal factors of B12, however, it is very rare with anemia or neurological manifestations due to short use time (

Use alcohol

Wine is known to increase the effects of metformin on lactate metabolism. Therefore, patients should be warned not to drink excessive alcohol while using Trajenta Duo.

Lack of oxygen

Cardiovascular collapse (shock) due to the cause of the arrest (for example, acute congestion, acute myocardial infarction, and other conditions are characterized by hypoxemia) associated with lactic acidic acidosis and can also cause hyper urea hyperurgery before the kidneys. The drug should be discontinued as soon as these events occur in patients who are being treated for Trajenta Duo.

Kidney function

Because metformin hydrochloride is eliminated through the kidney, the serum creatinine level should be determined before the beginning of treatment and periodic treatment:

Contraindicated Trajenta duo for patients with CrCl

A decrease in kidney function in the elderly is common and asymptomatic. It is necessary to be special in case the renal function may be impaired, for example, when dehydrated or when it is started to treat with anti -hypertension drugs, diuretics and when starting treatment with nonsteroidal anti -inflammatory drugs.

In the above cases, kidney function should be checked before starting treatment with metformin.

Heart function

Patients with heart failure are at higher risk of oxygen and renal failure. In patients with stable chronic heart failure, Trajenta Duo can be used on the regular monitoring of heart and kidney function.

Contraindicated Trajenta Duo for patients with acute heart failure and heart failure is unstable because the drug contains metformin (see the contraindication section).

Use iodine contrast drugs

The use of intravenous iodine contrast drugs in X-rays can lead to renal failure, so it can lead to metformin accumulation and increase the risk of lactic acidic acidosis.

In patients with EGFR> 60 ml/minute 1.73m2 to stop metformin before or during the survey and do not use it at least for at least 48 hours after that, only use after re -evaluation of the kidney function and the result is not worse (see the interaction).

In patients with medium renal impairment (EGFR between 45 and 60 ml/min/1.73 m2), Metformin must be stopped 48 hours before using iodine contrast drugs and do not re -use at least 48 hours later, only use after re -evaluation of the kidney function and the results are not worse (see the interaction).

Surgery

Metformin hydrochloride must be stopped 48 hours before surgery under the program with systemic anesthesia, spinal anesthesia or external epidural. It is possible to reuse the drug after 48 hours from the surgery or after the patient is raised again by oral and only when the kidney function is determined to be normal.

The effect of drugs on driving and operating machinery

There has been no research on the effect of the drug on driving and operating machinery.

Use drugs for women during pregnancy and lactation

pregnancy

There is no appropriate and strict research conducted in pregnant women using Trajenta Duo or its individual active ingredients. The non -clinical studies on reproduction conducted on mice using trajenta duo drugs do not show the teratogenic effect of simultaneous use of Linagliptin and Metformin.

Linagliptin use data on pregnant women is limited. Non -clinical studies do not show direct or indirect harmful effects in terms of reproductive toxicity.

Metformin data on pregnant women is limited. Metformin does not cause teratogenic rats at a dose of 200 mg/kg/day - 4 times the dose of human use. The teratogenic effect has been recorded in mice with higher dose metformin (500 and 1000 mg/kg/day - 11 and 23 times the dose of human use).

To be cautious, better to avoid using Trajenta Duo during pregnancy.

When a patient plans to get pregnant and during pregnancy, you should not treat diabetes with Trajenta Duo but should use insulin to maintain blood sugar level as close as normal as possible to reduce the risk of fetal deformities related to abnormalities.

breastfeeding

There are no animal studies in the period of milk secretion used in combination with metformin and linagliptin. Clinical studies conducted on each active active ingredient show that both Metformin and Linagliptin are excreted in breastfeeding mice. In humans, Metformin has excreted breast milk. It is still unclear whether Linagliptin is excreted in breast milk or not. Do not use Trajenta Duo in breastfeeding women.

fertility

There has been no research on the influence of Trajenta Duo on the fertility of the person conducted. Not observing any adverse effects of Linagliptin on fertility in non -clinical studies used to high school 240 mg/kg/day (900 times the dose of human use).

Drug interaction

Overview

Linagliptin multi -dose combination (10mg 01 times per day) and Metformin (850 mg 2 times daily) on healthy volunteers does not significantly affect the pharmacokinetics of Linagliptin and Metformin.

Studies on pharmacokinetic interaction of Trajenta Duo have not been conducted; However, these studies have been conducted with individual active ingredients of Trajenta Duo, Linagliptin and Metformin.

linagliptin

Interrogen interaction assessment

Linagliptin is a inhibitor based on weak to medium and weak competition inhibitors for CYP ISOENZE CYP3A4 but does not inhibit other ISOZYM CYP. The drug is not an induction substance for the CYP iszym.

Linagliptin is a p-glycoprotein substrate and inhibits Digoxin transportation through P-Glycoprotein intermediaries with low activity. Based on these results and studies on Vivo, Linagliptin, which is considered to be less likely to interact with other P-GP substrates.

Interaction assessment in vivo

Clinical data shown below shows the risk of clinical interactions due to the use of drugs and low. Do not recognize the clinical interaction that requires dose adjustment.

Linagliptin has no clinical impact related to the pharmacokinetics of Metformin, Glibenclamide, Simvastatin, Pioglitazone, Warfarin, Digoxin or oral contraceptives, which provides in vivo evidence that the trend is less likely to cause drug interactions with the substrates of CYP3A4, CYP2C9, CYP2C8, P-G-G-G-G-G-G-G-G-G-G-G-G-G-G-G-G-G-G-G-G-G-G-G-G-G-G-G-G-G-G-G-G-G-G-GOP2C, P-CYP2C, P-CYP2C Organic Cationic Transporter (OCT).

Metformin: In healthy volunteers, simultaneously use Metformin 850mg doses three times a day with a dose on the treatment threshold of 10 mg of Linagliptin once daily does not change the clinical significance of linagliptin or metformin. Therefore, Linagliptin is not an inhibitor through the ocean.

SulphonylueS: Dynamic pharmacokinetics in a stable state when using 5mg of Linagliptin dose is not changed when used with a single dose of 1.75mg of Glibenclamid (Glyburide) and Linagliptin 5 mg of oral dose. However, there are 14% reduction in both AUC and CMAX values ​​of glibenclamide is not clinically significant. Because glibenclamide is specialized mainly by CYP2C9, these data linagliptin is not a CYP2C9 inhibitor. Clinical interactions that are hard to occur with other sulphonylurea (eg Ghlipizide, Tolbutamide and Glimepiride) are excreted mainly by CYP2C9 similar to glibenclamide.

Thiazolidinedione: Use simultaneously daily doses of 10mg Linagliptin (on the treatment threshold) with daily doses of 45 mg of pioglitazone - a substrate of CYP2C8 and CYP3A4 without clinical influence on the dynamics of both Linagliptin and Pioglitazone or the active metabolites of Pioglitazone A metabolic inhibitor through intermediaries CYP2C8 in vivo and support the conclusion that the inhibition of CYP3A4 In Vivo of Linagliptin is negligible.

Ritonavir: A study was conducted to evaluate the influence of ritonavir, a powerful inhibitor P-Glycoprotein and CYP3A4, on the pharmacokinetics of Linagliptin. The simultaneous use of a single dose of 5mg Linagliptin and the oral multiple doses of 200mg Ritonavir increases the AUC and CMAX of Linagliptin about 2 and 3 times respectively. The simulation of Linagliptin concentration in plasma in a stable state when available and no ritonavir shows an increase in drug concentration

accompanied by accumulated increase. Linagliptin pharmacokinetic changes are not considered clinical significance. Therefore, clinical interactions are thought to be difficult to occur with P-Glycoprotein/CYP3A4 inhibitors and do not need to adjust the dose.

Rifampicin: A study was conducted to evaluate the influence of rifampicin, a cold. Strongly strong P-Glycoprotein and CYP3A4, on the dynamic of Linagliptin when used at the dose of 5mg. Simultaneous use of Linagliptin doses with rifampicin leads to a decrease of 39.6% and 43.8% AUC and CMAX respectively, in the stable state of linagliptin and reduce about 30% of the DPP-4 inhibitor in bottom concentration. Therefore, combination of Linagliptin and strong P-GP induction substances is thought to be clinically effective although the full efficiency may not be achieved.

Digoxin: Simultaneous daily use of 5mg Linagliptin with multiple doses of 0.25 mg of digoxin in healthy volunteers does not affect the pharmacokinetics of digoxin. Therefore, on Vivo, Linagliptin is not a shipping inhibitor through P-Glycoprotein.

warfarin: Daily dosage 5mg Linagliptin does not change the dynamics of isomers S (-) or R (+) Warfarin, a CYP2C9 substrate, this shows that Linagliptin is not CYP2C9 inhibitor.

Simvastatin: On a healthy volunteer, daily use of 10 mg linagliptin (on the treatment threshold) has a minimum impact on the dynamics in the stable state of Simvastatin, a sensitive CYP3A4 substrate. After simultaneous use of 10 mg Linagliptin with 40 mg Simvastatin per day for 6 days, Simvastatin's plasma AUC increased by 34% and and CMAX in plasma increased by 10%, so Linagliptin is considered a weak inhibitor of metabolism through CYP3A4 intermediaries and does not need to adjust the dose of the substrate transformed by CYP3A4 when used simultaneously.

Oral contraceptive pills: simultaneously used with 5mg of Linagliptin does not change the pharmacokinetics in the stable state of levonorgestrel or ethinylelestradiol.

Absolutely bioavailability of Linagliptin is about 30%. Due to the simultaneous use of Linagliptin at a fat -rich meal that does not cause clinical effects on pharmacokinetics, Linagliptin can be used or not with food.

metformin

Increased risk of lactic acidic acidosis in acute alcoholic poisoning patients (especially in the case of fasting, malnutrition or liver failure due to the active ingredient Metformin of Trajenta Duo (see the special and cautious warning).

Cation original drugs are excreted mainly through the renal tubules (for example, cimetidine) may interact with metformin due to competition to be transported by the renal tubules. A study conducted on 7 healthy volunteers showed that cimetidine dose 400mg 2 times daily increases the body level level of Metformin (AUC) by 50% and CMAX 81%. Therefore, it is advisable to consider monitoring the blood sugar closely, adjust the dose in the recommended dose and change the treatment of diabetes when used simultaneously with cation removal drugs through the renal tubules.

ANHYDRASE CARBANDRASE ACCESSS

Topiramate or other Anhydrase carbonic inhibitors (eg zonisamide, acetazolamide or dichlorphenamide) often cause serum bicarbonate loss and cause hypertension metabolism, without changing anion space. Concomitant use of these drugs can cause metabolic acidosis. Be careful to use these drugs in patients treated with Trajenta Duo because it can increase the risk of lactic acidic acidosis.

In X-ray surveys, iodine contrast drugs that use intravenous sugar can cause renal failure, leading to metformin accumulation and the risk of lactic acidic acidosis. In patients with EGFR> 60ml/min/1.73m2, Metformin must stop before using iodine contrast drugs and do not use at least 48 hours later, only use after re -evaluation of kidney function and the results are not worse. In patients with medium renal impairment (EGFR between 45 and 60 ml/minute 1.73 m2), Metformin must be stopped 48 hours before the survey and do not use the drug within 48 hours afterwards, only used after re -evaluation of the kidney function and the result is not worse.