Trajenta duo drugs 2.5mg/1000mg Boehringerer treat type 2 diabetes (60 tablets)
Dosage form Box of 60 capsules
Specifications Metformin, linagliptin
Ingredient
Thành phần cho 1 viên
| Composition information | Content |
| Metformin | 1000mg |
| Linagliptin | 2.5mg |
Uses
Indications
Trajenta duo 2.5 mg/500 mg indicated additional treatment for appropriate and motor movement to improve blood sugar control in patients with adult type 2 diabetes should be treated simultaneously with linagliptin and metformin; have not been controlled for blood sugar suitable for single -procedure metformin; Being well controlled by blood sugar when treated simultaneously Linagliptin and Metformin separately.
Trajenta Duo 2.5 mg/500 mg is designated in combination with a sulphonylurea (3 -drug treatment regimen), along with the appropriate diet, and exercise in patients who have not controlled good blood sugar with metformin doses and a sulphonylurea at maximum tolerance.
Pharmacokinatus
Sub -treatment group: Coordination of oral hypoglycemic drugs, ATC code: A10BD11
Linagliptin is an enzyme inhibitor DPP-4 (Dipeptidyl peptidase 4, EC 3.4.14.5), is an enzyme involved in the inactivated hormone of Incretin GLP-1 and GIP (peptide-1 like glucagon, polypeptide stimulating insulin depends on glucose). These hormones are fastened by the DPP-4 enzyme.
Both Incretin hormones are related to the physiological regulation for glucose balance. Incretin is excreted at a low concentration throughout the day and this concentration increases immediately after eating. GLP-1 and Gip increase insulin biosynthesis and glucagon secretion from beta cells in the pancreas when blood sugar is normal and increased.
Moreover, GLP-1 also reduces the excretion of glucagon from alpha cells in the pancreas, leading to reducing the excretion of the liver. Linagliptin connects very effectively with DPP-4 and can be separated, thereby increasing stability and prolonging the activated insertin level. Linagliptin increases the secretion of glucose depends on glucose and reduces the excretion of glucagon secretion, so it generally improves glucose balance. Linagliptin selectively connects with DPP-4 and has selective> 10000 times compared to DPP-8 or DPP-9 activity on In vitro.metformin hydrochloride is a biguanide that has anti -hypertension effects, reducing both plasma sugar levels at a basic level as well as after meals. The drug does not stimulate insulin secretion so it does not cause hypoglycemia. Metformin Hydrochloride can work through 3 mechanisms:
(1) Reduce the production of glucose in the liver due to glucose synthesis and glycogen awards.
(2) In muscle, thanks to increasing sensitivity to insulin, improving the absorption and use of peripheral glucose.
(3) and slow down the absorption of glucose in the intestine.
metformin hydrochloride stimulates intracellular glycogen synthesis due to the impact on glycogen synthase.
metformin hydrochloride increases the transport ability of all glucose transportation through the cell membrane (GLUT) to date.
In humans, metformin hydrochloride also has a favorable effect on lipid metabolism, independent of the effect on blood sugar. This effect is recorded in the dose of treatment in clinical studies with a long and long -term research time: Metformin hydrochloride reduces total cholesterol, LDL cholesterol and triglycerides.
Clinical effect and safety
Linagliptin adds to Metformin treatment
The effect and safety of linagliptin combined with metformin on patients who have not been controlled with blood sugar with single -treatment metformin is evaluated in a short -term regard for a 24 -week regard. Linagliptin in combination with Metformin significantly improved HBA1C (change - 0.64% compared to placebo) from the initial average value HBA1C is 8%.
Linagliptin also shows significantly improving the amount of sugar in the plasma (FPG) with a reduction of 21.1 mg/dl (1.2 mmol/l) and the amount of sugar 2 hours after eating (PPG) decreased by 67.1 mg/dl (3.7 mmol/l) compared to the placebo and the patient rate achieved HBA1C target
In a place of place -shaped redundant design, 24 weeks of initial treatment evaluation, Linagliptin 2.5 mg 2 times daily in combination with Metformin (500 mg or 1000 mg 2 times daily) significantly improves the parameters related to blood sugar compared to single therapy with the results summarized in Table 3 (HBA1C initially an average of 8.65%).
Table 4: Blood sugar parameters in the last examination (24 -week research) of patients with type 2 diabetes have not been well controlled with good blood sugar with diet and exercise using Linagliptin and Metformin simply or coordinated.
-1,2 Patients (n,%) achieve HBA1C The average HBA1C reduction than the original value is generally greater in patients with the higher the initial HBA1C value. The influence on plasma lipids is generally not available. Losing weight when combining linagliptin and metformin is similar to single or placebo Metformin; There is no change compared to the beginning of treatment in patients who only use linagliptin. The ratio of hypoglycemia is similar to treatment groups (placebo 1.4%, linagliptin 5 mg 0%, metformin 2.1%, and 2.5 mg linagliptin with metformin twice daily 1.4%). In addition, this study includes pressing (n = 66) with a more severe hyperglycemia (HBA1C at the beginning of treatment> = 11%) and is opened to open labels twice daily with Linagliptin 2.5 mg and Metformin 1000 mg. In this patient group, the average HBalc value at the beginning was 11.8% and the average FPG was 261.8 mg/dl (14.5 mmol/l). The average reduction of HBA1C compared to the original was 3.74% (n = 48) and 81.2 mg/dl (4.5 mmol/l) for FPG (n = 41) observed in patients who complete clinical tests lasting 24 weeks without rescue treatment. In LOCF analysis, all patients have determined the main evaluation criteria (n = 65) at the last tracking without treatment for rescue, changes compared to the beginning of 3.19% for HBA1C decreased by 73.6% mg/dl (4.1 mmol/l) for FPG. Efficiency and safety of Linagliptin 2.5 mg twice daily compared to 5 mg once a day when used in combination with Metformin in patients who are not controlled well with blood sugar with Metfomin monon treatment, which is assessed in a double blind study, a regard to a 12 -week regard. Linagliptin (2.5 mg twice daily and 5 mg once daily) adds to treatment with metformin significantly improving blood sugar parameters compared to placebo. Linagliptin 5 mg once daily and 2.5 mg twice a day decreases significantly to the equivalent level compared to the placebo (KTC: -0.17; 0.19), down 0.80% (compared to the original 7.98%), and 0.74% (compared to the original 7.96%). The rate of hypoglycemia recorded in patients treated with linagliptin is equivalent to placebo (2.2% with 2.5 mg linagliptin 2 times daily, 0.9% with Linagliptin 5 mg once daily and 2.3% with placebo). Body mass is not significant difference between groups. Linagliptin adds to Metformin and Sulphonylurea combining treatment A 24 -week placebo -control study was conducted to evaluate the effectiveness and safety of Linagliptin 5 mg compared to the placebo, in patients who were not well controlled with Metformin combining sulphonylurea. Linagliptin significantly improves the HBalc (down 0.62% compared to placebo) from the initial average HBA1C value of 8.14%. Linagliptin also shows significant improvement in the proportion of patients achieving HBA1C target linagliptin combined with metformin and insulin A restorative study with a placebo, a 24 -week lasting conducted to evaluate the safety and effectiveness of linagliptin (5 mg once daily) added to treatment with or without metformin insulin. 83% of patients have been using metformin in combination with insulin in this study. Linaglipin combined with metformin along with insulin shows significant improvement in HBALC in this group with average adjustment compared to the initial value decreased by 0.68% (CI: -0.78; -0.57) (HBALC initial average value is 8.28%) compared to placebo when combined with Metformin with Insulin. There is no significant change in body salary compared to the original in both groups. 24 -month data for Linagliptin to add to the treatment mode with Metformin compared to Glimepiride In a study comparing the safety and effectiveness of the addition of Linagliptin 5 mg or Glimepiride (a sulphonylurea) in patients who have not been well controlled with single -blood sugars with single -treatment Metformin, Linagliptin is similar to Glimepiride in reducing HBA1C, with a difference Glimepiride is +0.20%. In this study, the ratio of insulin on insulin, indicating the effectiveness of the synthesis and release of insulin, shows significant improvement of statistical significance when using linagliptin compared to Glimepiride treatment. The rate of hypoglycemia in patients using Linagliptin (7.5%) is significantly lower than the Glimepiride group (36.1%). Patients treated with Linagliptin significantly decreased average weight compared to the original, while patients using Glimepiride gained weight significantly (-1.39 compared to +1.29 kg). Linagliptin is added to treatment in elderly patients Typ 2 diabetes (age ≥ 70) The effectiveness and safety of Linagliptin in elderly patients with Type 2 diabetes (age ≥ 70) have been assessed in a double blind study compared to a place of 24 -week placebo. When being researched, the patient is being treated with Metformin and/or sulphonylurea and/or insulin. The dose of the available diabetes medications is kept stable in the first 12 weeks, then the dose is then allowed. Linagliptin significantly improves HBA1C, down 0.64% (KTC 95% -0.81, -0.48; P Linagliptin also significantly improved blood sugar at hunger (FPG) decreased by 20.7 mg/dl (1.1 mmol/l) (KTC 95% -30.2, -11.2; p In a gross analysis in elderly patients (age ≥ 70) diabetes type 2 (n = 183) has been treating Metformin and Insulin background, linagliptin combined with metformin along with insulin significantly improves HBA1C parameters with average adjustment compared to the original value decreased by 0.81 (CI: -1,01, -0,61) (HBALC average value of 8.13%) Use a placebo combined with metformin with insulin. There is no clinical significance in terms of clinical significance in the rate of hypoglycemia in patients> 70 years old (37.2 in Linagliptin group combined with metformin along with insulin compared to 39.8% in the placebo group combined with metformin with insulin). Starting treatment with combination of linagliptin and metformin in patients has just been diagnosed with significant hyperglycemia and has not used drugs The effectiveness and safety of the beginning of treatment with a combination of Linagliptin 5 mg once a day and Metformin twice a day (adjusted for the first 6 weeks to 1500 mg or 2000 mg/day) compared to Linagliptin 5 mg once daily has been studied in a 24-week test in patients who have been diagnosed with TYP 2 diabetes with significant hyperglycemia and no drugs. After 24 weeks, both monochromatic linagliptin treatment and starting in combination with Linagliptin and Metformin significantly reduced HBALC levels, respectively, 2% and 2.8% compared to the original HBA1C value of 9.9% and 9.8%. The treatment difference decreased by 0.8% (95% CI -1.1 to -0.5) showed that the beginning of combined treatment was superior to the single treatment (P cardiovascular risk In a synthetic and salvation analysis, cardiovascular events are independent from 19 clinical studies on 9459 patients with diabetes type 2, treatment with linagliptin does not accompanied with an increase in cardiovascular risk. Biological equivalent studies conducted on healthy volunteers show that the tablet combined with Trajenta Duo (Linagliptin/Metformin Hydrochloride) Biological equivalent to Linagliptin and Metformin Hydrochloride in a separate tablet form. Use Trajenta Duo 2.5/1000 mg along with food that does not change the general concentration of linagliptin. The AUC of Metformin does not change, however, the peak concentration of Metformin in serum decreases 18% when used with food. The time until the peak concentration of the Metformin in the serum is delayed for 2 hours when used the same food. These changes are less clinically important. The following stated things reflect the characteristics of each individual active ingredient in Trajenta Duo. linagliptin pharmacokinetics have been described in healthy people and patients with Typ 2 diabetes. Linagliptin concentration of Linagliptin decreases in two stages with a long half-life (Linagliptin's excretion half-life is over 100 hours), which is almost completely related to the saturated state, closely linked by Linagliptin with DPP-4 and does not contribute to the accumulation of the drug. Half -life accumulated effect of linagliptin, determined after taking multiple dose of 5 mg Linagliptin, approximately 12 hours. After using a single dose per day, plasma concentration in the stable state of Linagliptin 5 mg achieved after the third dose. AUC in Linagliptin plasma increased by about 33% after taking 5 mg doses at a stable state compared to the first dose. The variable coefficient in each patient and between patients for AUC of Linagliptin is small (equivalent to 12.6% and 28.5%). AUC in the plasma of Linagliptin increases below the proportional level. The pharmacokinetics of Linagliptin are generally equivalent to healthy subjects and in patients with diabetes Typ 2. absorption Absolutely bioavailability of Linagliptin is about 30%. Drinking Linagliptin along with a fat -rich meal that does not affect pharmacokinetics, Linagliptin can be used or not with food. In vitro studies show that Linagliptin is a substrate of P-Glycoprotein and CYP3A4. Rintonavir, a powerful inhibitor P-Glycoprotein and CYP3A4, increases the concentration of drugs (AUC) 2 times and used many times simultaneously Linagliptin with Rifampicin, a strong induction for P-GP and CYP3A, leading to a decrease of about 40% of the AUC level of Linagliptin in a stable state, maybe due to Linagliptin's bioavailability by Linagliptin, by Linaglipin P-Glycoprotein. Distribution Due to tissue bonds, the average appointed distribution volume is in a stable state after using a single -dose of 5mg of Linagliptin's intravenous lines in healthy people at about 1110 liters, showing that Linagliptin is widely distributed to tissues. Linagliptin's plasma protein bonds depend on concentrations, reduced from about 99% at a concentration of 1 nmol/l to 75-89% at a concentration of> 30 nmol/, reflecting saturation associated with DPP-4 when increased Linagliptin levels. At high concentrations, when DPP-4 is completely saturated, 70-80% Linagliptin is linked to other plasma proteins other than DPP-4, so 30-20% in non-binding form in plasma. Metabolism After taking a dose [14C] Linagliptin oral 10 mg, about 5% of radioactive substances are excreted into the urine. Metabolism plays a secondary role in the elimination process of linagliptin. A main metabolites with relative concentrations of 13.3% of Linagliptin dose in a stable state are detected as non-pharmacological activity and thus not contributing to the active inhibition of plasma DPP-4 plasma inhibitors of Linagliptin. Elimination After giving healthy people oral orally [14C] Linagliptin, about 85%of the doses of radioactive activity are eliminated by fertilizer (80%) or urine (5%) within 4 days of medication. The renal clearing in a stable state is about 70 ml/min. Special patient group kidney failure An open, multi -dose label study conducted to evaluate the pharmacokinetics of Linagliptin (dose of 5mg) in patients with chronic renal impairment at different degrees compared to healthy evidence. Research includes patients with renal function, which are classified based on creatinine clearance (50 to Creatinine clearance is calculated by the measurement of creatinine clearance in urine 24 hours or estimated from serum creatinine based on cockcroft-gault formula: CrCl = [140 - Age (year)] x Weight (kg) {x 0.85 for female patients}/[72 x Creatinine serum (mg/dl)]. In a stable state, the level of linagliptin in patients with mild renal failure is the same as a healthy person. In the case of average renal failure, there is a moderate increase in concentration to about 1.7 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 prediction of Linagliptin AUC in a stable state of patients with end -stage kidney disease ESRD shows the concentration of drugs similar to medium or severe kidney failures. In addition, Linagliptin is less likely to be removed to the point of significance in treating dialysis or peritoneal fertilizer. Therefore, it is not necessary to adjust the dose of linagliptin 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. Hepatic failure Body mass index (BMI) No need to adjust the dose based on BMI. According to a pharmacokinetic analysis on the population of research from phase I and phase II, the body mass index does not affect clinical significance to the pharmacokinetics of Linagliptin. Gender There is no need to adjust the dose based on gender. According to a pharmacokinetic analysis on the population research 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 research from phase I and phase II data, the age of no clinical impact 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 been conducted in the linagliptin pharmacokinetics in patients with children. Race There is no need to adjust the dose based on racial factors. The race does not have a significant effect on the concentration of Linagliptin in plasma based on a synthetic analysis from existing pharmacokinetic data, including white skin, Spanish, African -American, Asia. In addition, the pharmacokinetic characteristics of Linagliptin are recorded as in the specialized I -stage studies in healthy Japanese, Chinese and white volunteers and white -American diabetes patients. metformin absorption After taking 1 oral metformin dose, TMAX is achieved after 2.5 hours. Absolute bioavailability of Metformin Hydrochloride 500 mg or 850 mg 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. Pharmacoderminium absorption of Metformin Hydrochloride is 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 taking the dose of 850 mg, 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 to red blood cells. The peak concentration in the blood is lower than the peak plasma concentration and appears at the same time. Many possibilities are a secondary distribution compartment. The average allocation (VD) is in the range of 63 - 276 l. Metabolism metformin hydrochloride eliminates urine in a constant form. No metabolites in humans. Elimination 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 semi -waste time also lasts, resulting in an increase in plasma metformin hydrochloride levels. Special patient group Children Research on single dose: After using single dose Metformin 500 mg, pharmacokinetics in pediatric patients similar to 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 pediatric patients, the peak concentration of the drug in plasma (CMAX) and the concentration of systemic drugs (ACO-) decreased by 33% and 40% compared to adult patients with diabetes repeated dose of 500 mg, 2 times daily for 14 days. 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. changes compared to the initial value (modified average) pharmacokinetic pharmacokinetics
than the control group.
Before taking Trajenta duo drugs 2.5mg/1000mg Boehringerer treat type 2 diabetes (60 tablets)
How to use
Trajenta duo tablets for oral film.
Dosage
recommended dose is 2.5/500 mg, 2.5/850 mg or 2.5/1000 mg twice daily.
Select the dose based on the current treatment, effectiveness and intake of the drug on each patient. The maximum daily dose recommended by Trajenta Duo is 5 mg Linagliptin and 2000 mg metformin.
Should use Trajenta Duo with meals, with a slow dosage to reduce side effects on the gastrointestinal tract related to Metformin.
The recent patient has not been treated with Metformin
For patients who have not been treated with Metformin recently, the starting dose is recommended to be 2.5mg of linagliptin/500mg metformin hydrochloride 2 times daily.
Patients who have not been well controlled at maximum dose Metformin single therapy
For patients who have not been well controlled with single -sugar meture, the normal starting dose of Trajenta Duo should provide 2.5 mg linagliptin 2 times daily (total dose of 5 mg daily) and metformin with the dose in use.
Patients transferred from combination of Linagliptin and Metformin separately
For patients who transferred from Linagliptin and Metformin combinations to the form of a fixed combination, should start Trajenta Duo at the dose of Linagliptin and Metformin the patient is using.
Patients who have not been well controlled with blood sugar with a combination treatment regime include metformin and a sulphonylurea at maximum tolerance.
Should use the dose of Trajenta Duo contains 2.5 mg of linagliptin 2 times daily (total daily dose 5mg) and a metformin dose similar to the dose of the patient in use. When combining Trajenta Duo with a sulphonylurea, the sulphonylurea may be needed lower due to the risk of hypoglycemia (see special and cautious warnings).
Corresponding to different metformin doses, Trajenta Duo has the content of 2.5 mg of Linagliptin plus 500 mg of metformin hydrochloride, 850 mg of metformin hydrochloride or 1000 mg of metformin hydrochloride.
kidney failure
Chỉ có thể sử dụng Trajenta Duo cho bệnh nhân suy thận trung bình, giai đoạn 3a (độ thanh thải creatinin [CrCl] 45-59 mL/phút hoặc độ lọc cầu thận ước tính [eGFR] 45-59 mL/phút/1,73m3) nếu như không có các yếu tố có thể làm tăng nguy cơ tăng nhiễm toan acid lactic và dùng theo liều hiệu chỉnh như sau: Liều tối đa được khuyến cáo của metformin ở những bệnh nhân này là 500 mg 2 Time every day.
Must closely monitor kidney function:
If CrCl or EGFR are below 45-59 ml/min and 45-59 ml/min/1.73m, must stop using Trajenta Duo immediately).
liver failure
Trajenta duo contraindicated in patients with liver failure due to drugs containing metformin ingredients.
Note: The above dose is for reference only. Specific dosage depends on the condition and level of progression of the disease. For a suitable dose, you need to consult a doctor or medical specialist.
Elderly
Due to the renal and elderly metformin, the elderly tends to impaired the kidney function, so monitoring the kidney function is often in the elderly patients treated with Trajenta Duo.
children and teenagers
Do not recommend the use of Trajenta Duo for children under 18 years of age due to lack of data on effectiveness and safety of drugs.
What to do when using overdose?
What to do when forgetting 1 dose? However, if the time to relax with the next dose is too short, skip the dose and continue the calendar of the drug. Do not use double dose to compensate for missed dose.
Side Effects
The safety of Linagliptin 2.5mg twice daily (or biological equivalent dose with 5mg 01 times per day) in combination with Metformin is assessed over 3500 patients with diabetes Typ 2.
In control of a placebo, more than 1,300 patients are treated at a dose of 2.5mg Linagliptin twice daily (or biological equivalent 5mg linagliptin once daily) in combination with metformin in ≥ 12/24 weeks.
In gross analysis of placebo -control tests, the proportion of all adverse events in patients with placebo and Metformin is similar to the ratio in Linagliptin 2.5mg and Metformin (50.6% and 47.8%)
The rate of stopping drug use due to adverse events in groups of placebo combined with Metformin is similar to the Linagliptin and Metformin combination treatment group (2.6% and 2.3%).
Due to the effects of the initial available treatment on adverse events (for example, hypoglycemia), adverse events are analyzed and presented based on the corresponding treatment regime, added to Metformin treatment and added to Metformin treatment in combination sulphonylurea.
Business control studies include 4 studies in which Linagliptin is added to Metformin treatment and 1 study in which Linagliptin is added to Metformin + Sulphonylurea treatment.
Table 1: The adverse reactions are reported in patients using Linagliptin + Metformin in combination (analysis of placebo -control studies).
Disadvantage reaction listed by
treatment regime
Medra PT (version 13.1)
Rhinitis - Throat*
immune system disorders Hypersensitivity*
Ho*
Reduce appetite **
Diarrhea **
Nausea **
Pancreatitis*
vomit **
*Adultery effects are also reported in patients using single therapy linagliptin.
** Adultery effects are also reported in patients using single Metformin therapy
In the place of placeborn in control, the relevant adverse reaction is reported the most to Linagliptin + Metformin is diarrhea (0.9%) at a similar low proportion in the Metformin + placebo group (1.2%).
Harmful reactions are reported when combining linagliptin and metformin with Su:
When Linagliptin and Metformin are combined with a sulphonylurea, hypoglycemia is the most common adverse event (22.9% in Linagliptin plus Metformin plus sulphonylurea compared to 14.8% in the placebo group) and is considered to be an additional adverse reaction. No hypoglycemic hypoglycemia has been ranked seriously.
Adultery reactions when combining linagliptin and metformin with insulin
When Linagliptin and Metformin are used in combination with insulin, the most common adverse event is reported as hypoglycemia, but appears at the same ratio when the placebo and metformin are combined with insulin (Linagliptin in combination with Metformin and Insulin is 29.5% compared to 30.9% in the placebo group with Metformin and Insulin) with a serious low -ratio. 0.9%).
Additional information about each individual ingredient
The previous adultery effects with each individual drug may be the potential adverse effect of Trajenta Duo even when not observed in clinical trials with this product.
All of the adverse effects are reported in patients using the monochromatic linagliptin that has been recorded to Trajenta Duo and includes adverse reactions listed in Table 1 above.
Metformin's adverse reactions have not been recorded in Table 2 below.
Table 2: The adverse reactions are reported in patients using single therapy Metformin.
Medra PT (version 13.1) Lactic acidic acidosis Intense disorders
abdominal pain
Examining liver function test
Hepatitis Ban Ban
urticaria
2 gastrointestinal disorders such as abdominal pain (see Table 2) and nausea, vomiting, diarrhea, reducing cravings (see Table 1) occur most often in the stage of arising and recovery in most cases. To prevent these disorders, Metformin Hydrochloride should be used 2 times daily during or after meals if used for monomers.
Table 3: The adverse reactions are reported in patients with Linagliptin 5mg for additional insulin*
linagliptin + insulin
Nasomitis
immune system disorders Hypersensitivity ho
pancreatitis
Constipation
The adverse effects determined from the after -sales report
The following adverse effects have been reported from after -sales experience when using linagliptin:
Soc
Side effects
immune system disorders Evaluation
urticaria
Rashes
Oral ulcer
Warnings
Before using the drug you need to read the instructions carefully and refer to the information below.
Contraindicated
Trajenta duo drugs 2.5mg/1000mg contraindicated in the following cases:
Precautions when using
General warning
Do not use Trajenta duo for patients with diabetes type 1 or patient 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 may be difficult to identify in the elderly, and in patients taking β-adreneric 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 whenever there is a significant reduction in reproduction 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 acidic acidosis, the metformin level in plasma is usually> 5 µg/ml.
The rate of lactic acidic acidosis in patients using Metformin is about 0.03 cases/1000 patients-(with approximately 0.015 deaths/1000 patients). Of the more than 20,000 patients-Metformin used in clinical trials, no reports are related to lactic acid acidic acidosis.
The reported cases appear mainly in patients with diabetes with significant kidney 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 a lot of 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, at risk of increased lactic acidic acidosis.
The risk of lactic acidic acidosis increases along with the degree of kidney failure and the age of patients. Therefore, the risk of lactic acidic acidosis can be 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.
Do not start the metformin treatment in any patient unless tested to clear the creatinine shows no impaired renal function. In addition, Metformin should be stopped when there is any sign of hypoxemia, dehydration, or infection. Due to the decline in liver function, it can seriously affect lactate elimination, so avoid using metformin in patients with clinical evidence or tests showing 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, temporarily use Metformin before participating in the testing test and any surgery necessary to limit food and fluid. Using Topiramat, an anhydrase carbon inhibitor in the treatment of epilepsy and prevention of migraines 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 and immediately report symptoms.
If any, 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. Stomach disorders appear in patients using long -term metformin with stable doses that can 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 plasma lactate concentration at the upper limit of normal levels is lower than 5 mmol/l in metformin -taking patients that do not necessarily indicate lactic acidic acidosis and may be caused by other mechanisms, such as poor diabetic control 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 recommends dialysis to remove Metformin storage and adjust metabolic acidosis. Such control often leads to reduction in symptoms quickly and recover.
pancreatitis
There have been after -sales reports of acute pancreatitis, including inflammation, but death in patients using linagliptin. Read carefully about the possible signs and symptoms of pancreatitis. If suspected of pancreatitis, immediately stop using Trajenta Duo and start appropriate treatment. It is unknown whether the patient has a history of pancreatitis will increase or not the risk of pancreatitis 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). The reactions include hypersensitivity shock, angioedema, and peeling. Signs of reactions that appear in the first 3 months after the beginning of treatment with Linagliptin, with a few reports appeared 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 concentration may be due to the intervention in the absorption of vitamin B12 from the internal factor combination of B12, however, it is very rare with anemia or neurological manifestation due to short time of use ( The risk may be more related to long -term patients with Metformin, and there have been after -sales adverse reports on hematological and nervous reactions. Reduce the concentration of vitamin B12 quickly reversed when stopping using metformin or supplementing with vitamin B12. It is recommended to control annual periodic hematology parameters in patients who use Trajenta Duo and any abnormalities should be considered and processed.
Some cases (for patients who lack or not fully absorb vitamin B12 or calcium) seem to seem to be easy to vitamin B12 levels below normal, in these patients, regular control of serum vitamin B12 in the period of 2-3 years is beneficial.
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 any cause (for example, acute congestion, acute myocardial infarction, and other conditions are characterized by hypoxemia) is associated with lactic acidic acidosis and can also cause hyper urea hyperurize 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, serum creatinine levels should be determined before the beginning of treatment and periodic treatment:
Contraindicated Trajenta duo for patients with CrCl
Thereal impairment of kidney function in the elderly common and asymptomatic, need to be careful in case the kidney function may be impaired, for example, when dehydrated or when starting treatment 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
Heart failure is 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).
Using 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 EGFR patients 60 ml/min/1.73 m2 must stop Metformin before or during the survey and do not re-use at least 48 hours later, only use the effect of kidney function. interactive part).In patients with average 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 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.
Using 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.
In humans, metformin has excreted into 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. It is not observed that Linagliptin's adverse effects on fertility in non -clinical studies use the highest dose of 240 mg/kg/day (> 900 times of human use).
affects the ability to drive and operate machinery
There has been no research on the effect of the drug on the ability to drive and operate machinery.
Drug interaction
Overview
Linagliptin multi -dose combination (10mg once a day) and Metformin (850mg 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
Assessment of In vitro interaction:
Linagliptin is a inhibitor based on weak to medium and weak competition inhibitors for CYP ISOENZYM CYP3A4, but does not inhibit other CYP Iozymes. 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 record significant interaction clinically requires adjusting dose.
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 using 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.
sulphonylirros:
Pharmacokinetics in a stable state when taking 5mg of Linagliptin dose is not changed when used with a single dose of 1.75mg Glibenclamide (Glyburide) and multiple doses of oral 5 mg Linagliptin.
However, there are 14% off in both AUC and CMAX values of Glibenclamide, which is not a significant clinical. Because glibenclamide is metabolized mainly by CYP2C9, these data also supports that 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 10 mg linagliptin (on the treatment threshold) with daily doses of 45 mg of pioglitazone - a substrate of CYP2C8 and CYP3A4 with no clinical influence on the pharmacokinetics of both linagliptin and pioglitazone or 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 assess the effects of Ritonavir, a strong inhibitor P-Glycoprotein and CYP3A4, on the dynamic pharmacokinetics of Linagliptin. The simultaneous use of a single dose of 5 mg linagliptin and oral multiple doses of 200 mg Ritonavir increases the AUC and CMAX of Linagliptin about 2 and 3 times respectively.
Simulation of Linagliptin levels in plasma in a stable state when available and no ritonavir shows an increase in the concentration of drugs that are not accompanied by accumulation. 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 assess the effects of rifampicin, a powerful P-Glycoprotein and CYP3A4 induction, strong linagliptin pharmacokinetics when used at 5 mg.
Soonered Linagliptin with Rifampicin at the same time leads to a decrease in 39.6% and 43.8% AUC and CMAX respectively in the stable state of Linagliptin and a decrease of about 30% of the DPP-4 inhibitor in the 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:
Simultaneously using daily doses of 5 mg 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 multiple doses of 5 mg Linagliptin does not change the pharmacokinetics of the isomers S (-) or R (+) Warfarin, a CYP2C9 substrate, which shows that Linagliptin is not CYP2C inhibitor.
simvastatin:
On a healthy volunteer, daily dosage of 10 mg linagliptin (on the treatment threshold) has a minimum effect on pharmacokinetics in the stable state of Simvastatin, a sensitive CYP3A4 substrate. After simultaneous use of 10 mg of Linagliptin with 40 mg of simvastatin per day for 6 days, Simvastatin's plasma AUC increased by 34% and CMAX in plasma increased by 10%. Therefore, Linagliptin is considered a weak inhibitor of metabolism through CYP3A4 intermediaries and does not need to adjust the dose of substrate transformed by CYP3A4 when used simultaneously.
Oral contraceptive pills:
Simultaneously used with 5 mg 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 inaglpun at a rich fat meal that does not cause clinical significance for pharmacokinetics, Linagliptin can be used or not with food.
metformin
The risk of lactic acidic acidosis increases 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 section). Alcohol and alcohol should be avoided.
Cation original drugs are excreted mainly through the renal tubules (for example, cimetidine) can interact with metformin due to competition to be transported by the renal tubules. A study conducted on 7 healthy volunteers showed that the 400 mg cimetidine twice a day increased the body concentration 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 CARBONDRASS:
Topiramate or other Anhydrase carbon inhibitors (e.g. Zonisamide, acetazolamide or dichlorphenamide) regularly cause serum loss of bicarbonate 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-rays, iodine contrast drugs that use intravenous tract can cause renal failure, leading to metformin accumulation and the risk of lactic acidic acidosis.
In patients with EGFR> 60 ml/min/1.73m, must stop metformin 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 average renal impairment (EGFR between 45 and 60 ml/min/1.73 m), Metformin must be stopped 48 hours before the survey and not using the drug within 48 hours later, only after reassessing the kidney function and the results are not worse.
Storage
Leave a cool place, avoid light, temperature below 30⁰C.
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