Trajena Duo Boehringer Ingelheim supports the treatment of diabetes (14 tablets)
Dosage form Box of 14 tablets
Specifications Metformin, linagliptin
Ingredient
| Composition information | Content |
| Metformin | 1000mg |
| Linagliptin | 2.5mg |
Uses
Indication
Trajenta duo drugs 2.5mg/1000mg is indications for treatment in the following cases:
Additional treatment for appropriate and moving diet in order to improve blood sugar control in patients with adult type 2 diabetes should be treated simultaneously with Linagliptin and Metformin, patients who have not been controlled appropriate blood sugar for monon treatment Metformin or patients undergoing blood sugar well when treated simultaneously with Linagliptin and Metformin separately.
Determine coordination with a sulphonylurea (ie 3 -drug treatment regimen), along with a suitable diet and exercise in patients who have not been well controlled with metformin doses and a sulphonylurea at maximum tolerance.
Pharmacology
Sub -treatment group: Combining 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 DPP4 and has a selective personality> 10000 times compared to the DPP-8 or DPP-9 activity on In vitro.
metformin hydrochloride is a biguanide that has anti -hyperglycemic effects, reduces the plasma sugar levels at a basic level as well as after an insulin -stimulating drug, so it does not cause hypoglycemia.
metformin hydrochloride can work through 3 mechanisms:
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 in 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 trials
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 significant improvement in the amount of sugar in hunger (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's achievement rate of HBA1C target
In a place of fatalate design with placebo, 24 weeks of evaluation on the beginning of treatment, Linagliptin 2.5mg 2 times a day in combination with Metformin (500 mg or 1000mg 2 times daily) significantly improves the parameters related to blood sugar compared to single therapy with the results summarized in the table below (HBA1C initially is 8.65%).
Table: Blood glucose parameters in the last examination (24 -week research) by patients with diabetes Typ 2 have not been well controlled with good blood sugar with diet and exercise using linagliptin and metformin or coordination
Parent Linagliptin 5mg 1 time every day*
Metformin
500mg
2 times
Every day
Linagliptin
2.5mg
2 times
every day*
+
metformin
500mg
2 times
Every day
Metformin
1000mg
2 times
Every day
Linagliptin
2.5mg
2 times
every day*
+ metformin
1000mg
2 times
Every day
HBA1C (%)
The number of patients n = 65
n = 135
ni 141
n = 137
n = 138
n = 140
Initial value (average)
8.7
8.7
8.7
8.7
8.5
8.7
0.1
-0.5
-0.6
-1,2
-1,1
-1.6
-0.6
( -0.9; -0.3)
-0,8
( -1,0; -0.5)
-1.3
( -1,6; -1,1)
-1,2
( -1,5; -0,9)
-1,7
(-2,0; -1,4)
14 (10,4)
27 (19,1)
42 (30,7)
43 (31,2)
76 (54,3)
29,2
11,1
13.5
7.3
8.0
4.3
The number of patients n = 61 n = 134
ri = 136
n = 135
n = 132
n = 136
Initial value (average)
203
195
191
199
191
196
10
-9
-16
-33
-32
-49
-19
( -31; -6)
-26
( -38; -14)
-43
( -56; -31)
-42
( -55; -30)
-60
( -72; -47)
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 only using linagliptin.
The rate of hypoglycemia is similar to treatment groups (placebo 1.4%, linagliptin 5mg 0%, 2.1%, and 2.5mg linagliptin with metformin twice daily 1.4%).
In addition, this study includes patients (n = 66) with a more severe hyperglycemia (HBA1C at the beginning of treatment>/= 11%) and being treated with an open label twice daily with Linagliptin 2.5mg and Metformin 1000mg. In this patient group, the average HBA1C 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 2.5mg twice daily compared to 5 mg once a day when used in combination with Metformin in patients who are not controlled with good blood sugar with single -treatment Metformin, which is assessed in a double blind study, regarded for 12 weeks. Linagliptin (2.5mg twice daily and 5 mg once daily) adds to treatment with metformin significantly improving blood sugar parameters compared to placebo. Linagliptin 5mg once a day and 2.5mg 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 Linagliptin 2.5mg 2 times daily, 0.9% with linagliptin 5mg 1 time daily and 2.3% with placebo). Body mass is not significant difference between groups.
Linagliptin adds to Metformin and Sulfonyleas 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 HBA1C (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. Linagliptin combined with metformin along with insulin shows significant improvement in HBA1C in this group with average adjustment compared to the initial value decreased by 0.68% (Cl: -0.78; -0.57) (HBA1C initial average value is 8.28%) compared to placebo when combined with Metformin with insulin.
There is no significant change in body weight compared to the original in both groups.
24 -month data for Linagliptin to add to the treatment regime with Metformin comparison with Glimepiride in a study comparing the safety and effectiveness of adding Linagliptin 5mg or Glimepiride (a sulphonylurea) in patients who have not been well -controlled with good blood sugar with single -therapy Metformin, Linagliptin is similar to GLIMEPRIDE in the HBA1C, other than HBA1C, similar HBA1C average treatment from the beginning to the 104th week for linagliptin compared to 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 adds to treatment in elderly patients Typ 2 (age> 70)
The effectiveness and safety of Linagliptin in elderly patients with Type 2 diabetes (age> 70) were assessed in a double 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
However, on the background of Sulphonylurea treatment with or not with Metformin, the proportion of patients with hypoglycemia is reported in a group of patients treated with Linagliptin higher (24 out of 82 patients, 29.3%) compared to placebo (7 out of 42 patients, 16.7%). There is no difference between groups using Linagliptin and placebo for serious hypoglycemia events. -0.61) (The initial average HBA1C value is 8.13%) compared to the placebo group combined with metformin along with insulin. There is no clinical significant difference in terms of the rate of hypoglycemia events 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 drug use.
The effectiveness and safety of the beginning of treatment with a combination of Linagliptin 5 mg once a day and Metformin twice each dysentery (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 test that lasts 24 Tuan in patients who have been diagnosed with a significant blood sugar diabetes with significant blood sugar (HBA1C initially. 8.5-12.0%). After 24 weeks, both monochromatic linagliptin treatment and starting in combination with Linagliptin and Metformin significantly reduced HBA1C, 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% CL -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, the cardiovascular events are independent from 19 clinical studies on 9459 patients with type 2 diabetes, treated with Linagliptin does not accompanied with an increase in cardiovascular risk. The main criterion, including a combination of appearance or time until the appearance of cardiovascular death, myocardial infarction does not cause death, non -fatal stroke or hospitalized due to unstable angina, is not significant lower when using linagliptin compared to the group of control, active and placebo [Harm ratio 0.78 (trust range 95% 0.55; 1.12)]. The total has 60 main events in the Linagliptin group and 62 main events in the control groups.
Cardiovascular events are observed with a similar ratio between the group using linagliptin and placebo [Harm ratio 1.09 (KTC 95% 0.68; 1.75)]. In the restraint studies with placebo, the total number of 43 main events (1.03%) in the Linagliptin group and 29 main events (1.35%) in the placebo group.
Dynamic pharmacokinetics
Biological equivalent studies conducted on healthy volunteers show that the tablet combined with Trajenta Duo (Linagliptin/Metformin Hydrochloride) is biological equivalent with Linagliptin and Metformin Hydrochloride.
Use Trajenta Duo 2.5/1000mg 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 pharmacokinetic characteristics of each individual active ingredient in Trajenta Duo.
linagliptin
Linagliptin's pharmacokinetics have been described in healthy people and patients with type 2 diabetes. After taking 5mg orally in patients who are healthy volunteers, Linagliptin is quickly absorbed with peak plasma concentrations (TMAX) appears 1.5 hours after use.
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 5mg Linagliptin, approximately 12 hours. After using a single dose per day, plasma concentration in the stable state of Linagliptin 5mg achieved after the third dose.
AUC in Linagliptin plasma increased by about 33% after taking 5mg doses in 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 without clinical effects on pharmacokinetics, Linagliptin can be used or not with food. In vitro studies show that Linagliptin is a substrate of p-Glycoprotein and CYP3A4. Ritonavir, a powerful inhibitor P-Glycoprotein and CYP3A4 increases the drug concentration (AUC) 2 times and used many times the Linagliptin period with Rifampicin, a strong induction for P-GP and CYP3A leading to a decrease of about 40% of the AUC concentration of Linagliptin in a stable state, perhaps due to increased use of Linagliptin by the inhibition 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 concentration, reduced from about 99% at 1 nmol/l to 75 - 89% at a concentration of> 30 nmol/l, reflecting saturation associated with DPP -4 when increased Linagliptin concentration. At high concentrations, when the 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 10mg, about 5% of radioactive substances are excreted into the urine. Metabolism plays a secondary role in the elimination of linagliptin. A main metabolites with relatively 13.3% of Linagliptin dose in stable state are detected as non-pharmacological activity and therefore does not contribute to the activity 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 taking the drug. The renal removal in a stable state is about 70 ml/min.
Special patient group
kidney failure
A open -dose and 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. The study includes patients with renal function that is classified based on mild creatinine clearance (50 to Creatinine clearance is calculated by measuring the deterioration of creatinine in urine 24 hours or estimated from serum creatinine based on the formula of cockcroft-gault:
CRCI = [140 - Age (year)] x Weight (kg) {x 0.85 for female patients}/[72 x Creatinin 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 medium renal failure, there is a moderate increase in concentration to about 1.7 times compared to the control group. The concentration in patients with type 2 diabetes with severe renal impairment increases about 1.4 times compared to patients with type 2 diabetes with normal kidney function. The AUC prediction of Linagliptin in a stable state of patients with end -stage kidney disease ESRD shows 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, 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
The average AUC and CMAX AUC of Linagliptin in patients with medium mild and severe hepatic liver failure (according to Child-Pugh classification) are similar to that in the control group of healthy pairing after using 5mg of Linagliptin. It is not necessary to adjust the linagliptin dose for patients with mild, medium or severe liver 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. 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 at 20 - 30%. After oral use, Metformin Hydrochloride is absorbed incomplete and saturated. The phase pharmacokinetics of the absorption of metformin hydrochloride are thought to be uncertain, at the dose and dose mode of the metformin hydrochloride, plasma concentration in stable state achieved within 24 to 48 hours and usually lower than 1 microgram/ml. In control clinical trials, the maximum concentration of the plasma metformin hydrochloride (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 850mg, the peak concentration 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 the bridge room. 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 - 276L.
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 eliminates 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 is also prolonged, resulting in increased plasma metformin hydrochloride levels.
Special patient group
Children
Research on single dose: After using single dose Metformin 500mg, 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 daily for 7 days in patients with children, the peak of the drug in plasma (CMAX) and the concentration of systemic drugs (ACO-T) decreased by 33% and 40% compared to adult patients with diabetes repeated with a dose of 500mg, 2 times daily for 14 days. The dosage of the drug is adjusted based on the level of blood sugar, 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.
Before taking Trajena Duo Boehringer Ingelheim supports the treatment of diabetes (14 tablets)
How to use
Drugs for oral film tablets.
Dosage
Dosage recommended by Trajenta Duo
The recommended dose is 2.5/500mg, 2.5/850mg or 2.5/1000mg twice daily.Should choose the dose based on the current treatment regime, effectiveness and intake of the drug on each patient.
The maximum daily dose recommended by Trajenta Duo is 5mg of linagliptin and 2000mg 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 of Metformin monotherapy
For patients who have not been well controlled with single -sugar metformin, the normal starting dose of Trajenta Duo should provide 2.5mg linagliptin 2 times daily (total dose of 5mg per day) and metformin with the dose in use.
Patients transferred from Linagliptin and Metformin in combination with individual forms
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 2.5mg 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 lower doses of sulphonylurea may be needed due to the risk of hypoglycemia
Corresponding to different metformin doses, Trajenta Duo has the content of 2.5mg of Linagliptin plus 500mg of metformin hydrochloride, 850mg metformin hydrochloride or 1000mg metformin hydrochloride.
Metformin recommended dose
The starting dose for patients who are not using Metformin is 500mg, once a day, orally. If the patient does not have a harmful reaction to the gastrointestinal tract and need to increase the dose, an additional 500mg can be used after each treatment period from 1 to 2 weeks. The dose of Metformin should be considered for adjustment on each specific patient based on the effectiveness and tolerance of the patient and not exceeding the maximum dose recommended as 2000 mg/day.
Recommendation of using drugs in patients with renal failure
Review kidney function before starting treatment with Metformin and periodic assessment.
Contraindicated Metformin in patients with EGFR is less than 30 ml/min/1.73 m2.
It is not recommended to start treatment with Metformin in patients with EGFR in the range of 30 - 45ml/min/1.73 m2.
In patients using Metformin and having EGFR drops below 45 ml/min/1.73 m2, assessing the risk of benefits when continuing treatment.
Stop using metformin if the patient has EGFR drop below 30 ml/min/1.73 m2.
Stop using metformin when performing an image diagnostic test using contrast drug containing IOD.
In patients with EGFR in the range of 30 - 60 ml/min/1.73 m2, in patients with a history of liver, alcoholic or heart failure, or on patients who will use iodine contrast drugs through artery, stop metformin before or at the time of diagnostic testing tests using iodine containing iodine. Reassess the EGFR after a 48 -hour projection, reuse Metformin if the kidney function is stable.
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.What to do when overdose?
Symptoms
In control clinical trials conducted on healthy volunteers, single dose up to 600mg of linagliptin (equivalent to 120 recommended dose) is well tolerated.
Inexperienced in dosage use more than 600mg in humans.
Hypoglycemia does not occur with metformin hydrochloride dose up to 85 g despite lactic acidic acidosis. High doses of metformin hydrochloride or associated risk factors can lead to lactic acidic acidosis. Lactic acidic acidosis is a medical emergency and must be treated at the hospital.
Treatment
In case of overdose, it is advisable to take common supportive treatments, for example: removal of unprocessed removal from the digestive tract, clinical monitoring and the necessary treatment. The most effective measure to eliminate lactate and metformin hydrochloride is dialysis.
In an emergency, call the 115 emergency center immediately or go to the nearest local health station.
What to do when you forget 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 daily) in combination with Metformin is assessed over 6800 patients with diabetes Typ 2. week.
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 the Linagliptin group 2.5mg and Metformin (54.3% and 49.0%).
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 (3.8% and 2.9%).
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 7 studies in which Linagliptin is added to Metformin treatment and 1 study in which Linagliptin is added to Metformin + Sulphonylurea treatment.
Table: The adverse reactions are reported in patients using Linagliptin +Metformin (analysis of the place of fat control studies)
Disadvantage reaction listed according to the treatment regime
Medra PT (version 18.0)
Rhinitis - Throat*
immune system disorders
Hypersensitivity*
Ho*
Reduce appetite **
Diarrhea **
Nausea **
Pancreatitis*
vomit **
itching **
subclinical Increase lipase2
The adverse effects that were previously reported with each individual ingredient of the drug may be the potential adverse effect of Trajenta Duo even when not observed in clinical trials with this product.
All the adverse effects are reported in patients using the monochromatic linagliptin that has been recorded to Trajenta Duo and includes adverse reactions listed in the table above.
Metformin's adverse reactions have not been recorded in the table below.
Table: The adverse reactions are reported in patients using Metformin single therapy
nervous system disorders
Skin disorders and subcutaneous skin tissue
Hong Ban
urticaria
2 gastrointestinal disorders such as abdominal pain and nausea, vomiting, diarrhea, reducing cravings that occur most often during 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.
Additional adverse reactions are reported when linagliptin and metformin are in combination with insulin.
When combining linagliptin and metformin with insulin, there has been a must -have adverse reaction of constipation.
The adverse effects determined from after -sales report.
The following adverse effects have been reported from after -sales experience when using linagliptin:
Soc
Side effects
immune system disorders
eagowns
urticaria
Rashes
Pemphigoid puffer
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:
Patients who have a history of hypersensitivity to metformin/linagliptin or any excipients of the drug.
Patients with acute or chronic metabolic acidosis, including diabetes cetonic acidosis.
Diabetes coma.
Acute conditions are at risk of kidney function such as dehydration, severe infections, shock, use of intravenous iodine contrast drugs.
The disease can cause tissue deficiency (especially acute diseases or worsening the worsening of chronic diseases) such as: recent heart failure, respiratory failure, recent myocardial infarction, shock.
Hepatic failure
Trajenta duo contraindicated in patients with liver failure due to drugs containing metformin ingredients.
Elderly
Due to the renal and elderly metformin, the elderly tends to impaired the kidney function, so the kidney function should be monitored regularly in 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.
Caution when using
General warning
Do not use Trajenta duo for patients with diabetes type 1 or patient with diabetes.
Use 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.
Higher hypoglycemia ratio when using linagliptin combined 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 who are taking P-commenergic inhibitors.
Lactic acidosis
After -sales surveillance process has recorded lactic acidosis related to metformin, including death, body temperature, hypotension, prolonged slow arrhythmia. The onset of lactic acidic acidosis related to Metformin is often not easy to detect, accompanied by typical symptoms such as discomfort, muscle pain, respiratory failure, drowsiness and abdominal pain. Lactic acidic acidosis associated with metformin is characterized by increased lactate concentration in the blood (> 5mmol/l), reducing blood pH, anion space (without evidence of keto urine or blood keto), increasing lactate/pyruvate ratio and plasma metformin levels in general increases> 5 PG/mL. The risk factor of lactic acidic acidosis is related to Metformin, including renal failure, simultaneous use with certain drugs (for example, anhydrase carbon inhibitors such as Topiramate), aged 65 and older, performing screens using contrast drugs, surgery and performing other procedures, reducing inhaled oxygen (e.g., acute congestical heart failure), drinking alcohol and drinking alcohol and drinking.
Measures to minimize the risk and management of lactic acidic acidosis related to metformin in a group of high -risk patients are presented in detail in the drug manual.
If there is suspicion of lactic acidosis related to Metformin, Metformin should stop using Metformin, quickly take patients to the hospital and take treatment measures. In patients who have been treated with metformin, have been diagnosed with lactic acidosis or suspected lactic acidic acidosis, quickly recommend filtering to regulate acidosis and remove the accumulated Metformin part (metformin hydrochloride can be separated with 170 mL/minute in good dynamics). Dialysis can reverse symptoms and recovery.
Instructions for patients and family members about acidic symptoms and if these symptoms occur, it is necessary to stop trajenta duo and report these symptoms to the doctor.
For each factor that increases the risk of lactic acidosis related to metformin, recommendations to minimize the risk and handle lactic acidosis related to metformin, specifically as follows:
kidney failure
Lactic acidosis related to Metformin during after -sales drug monitoring occurs mainly in patients with severe renal failure. The risk of cumulative metformin and lactic acidosis is related to metformin increases with the severity of renal failure because metformin is excreted mainly through the kidneys. Clinical recommendations based on patient kidney function include:
Drug interaction
multi -dose combination of Linagliptin (10mg 01 times per 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 an inhibitor based on the mechanism from-yard to medium and weak competitive inhibitors.
For CYP Isoenzyme CYP3A4, but do not inhibit other CYP enzymes. The drug is not an induction substance for CYP iszymes.
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 cation (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.
Sulphonylirros: Dynamic pharmacokinetics in a stable state when using 5mg of Linagliptin dose is not changed when used with a single dose of 1.75mg Glibenclamide (Glyburide) and many doses of oral 5mg linagliptin. However, there are 14% reduction in both AUC and CMAX values of Glibenclamide, which is not 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 without 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 influence of ritonavir, a strong 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 plasma linagliptin levels in a stable state when available and no ritonavir shows an increase in the concentration of drugs that do not accompany 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 evaluate the effects of rifampicin, a powerful induction P-Glycoprotein and CYP3A4, on Linagliptin's dynamic pharmacokinetics 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 0.25mg Digoxin in healthy volunteers does not affect the pharmacokinetics of Digoxin. Therefore, on Vivo, Linagliptin is not a transportation inhibitor through P-Glycoprotein intermediaries.
warfarin: Daily dosage 5mg Linagliptin does not change the pharmacokinetics of isomers S (-) or R (+) Warfarin, a CYP2C9 substrate, this shows that Linagliptin is not CYP2C9 inhibitor.
Simvastatin: On a healthy volunteer, daily dosage use 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 10mg of Linagliptin with 40 mg 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 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
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) may interact with metformin due to competition to be transported by the renal tubules. A study that was elaborated on 7 healthy volunteers showed that cimetidin 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.
Injecting of the internal contrast drug in patients who are being treated for metformin can lead to impaired renal function and cause lactic acidosis. Stop using Metformin before or at the time of performing screens using iodine -containing contrast drugs in patients with EGFR in the range of 30 - 60 ml/min/1.73 m2, patients with a history of liver failure, alcoholism, heart failure or patients will use optical bumper containing iodine in artery lines. Reassess EGFR 48H after screening and reuse Metformin if the kidney function is stable.
Storage
Leave a cool place, avoid light, temperature below 30⁰C.
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