Active ingredients: Linagliptin
Trajenta 5 mg film-coated tablets
Indications Why is Trajenta used? What is it for?
Trajenta contains the active substance linagliptin, which belongs to a class of medicines called 'oral antidiabetics'. Oral antidiabetics are used to treat high blood sugar levels.
These medicines work by helping the body to lower the blood sugar level. Trajenta is used in 'type 2 diabetes' in adults, if the disease cannot be adequately controlled with an oral antidiabetic medicine (metformin or sulfonylurea) or with only diet and exercise. Trajenta can be used together with other antidiabetic medicines (insulin, metformin or sulfonylureas eg glimepiride, glipizide).
It is important that you continue to follow the advice you receive from your doctor or nurse regarding diet and exercise.
Contraindications When Trajenta should not be used
Do not take Trajenta
- if you are allergic to linagliptin or any of the other ingredients of this medicine (listed in section 6).
Precautions for use What you need to know before you take Trajenta
Talk to your doctor, pharmacist or nurse before taking Trajenta if:
- have type 1 diabetes (the body does not produce insulin) or diabetic ketoacidosis (a complication of diabetes with high blood sugar, rapid weight loss, nausea or vomiting). Trajenta must not be used to treat these conditions.
- you are taking an anti-diabetic medicine known as 'sulphonylurea' (eg glimepiride, glipizide), your doctor may decide to reduce the dose of sulphonylurea if you take it together with Trajenta, in order to avoid too low blood sugar levels.
- have had allergic reactions to any other medicines you take to control the amount of sugar in your blood.
- have pancreatic disease or have had one in the past.
If you experience symptoms of acute pancreatitis, such as persistent and severe abdominal pain, you should see a doctor.
The skin lesions characteristic of diabetes are a common complication of this disease. You are advised to follow the recommendations given to you by your doctor or nurse for skin and foot care.
Children and adolescents
Trajenta is not recommended for children and adolescents under the age of 18.
Senior citizens
Experience in patients over 80 years of age is limited
Interactions Which drugs or foods can change the effect of Trajenta
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines.
In particular, you should tell your doctor if you are taking medicines containing any of the following active ingredients:
- Carbamazepine, phenobarbital or phenytoin. These can be used to control seizures or chronic pain.
- Rifampicin. This is an antibiotic used to treat infections such as tuberculosis.
Warnings It is important to know that:
Pregnancy and breastfeeding
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine. It is preferable to avoid taking Trajenta if you are pregnant. It is not known whether Trajenta is dangerous to the fetus.
It is not known if Trajenta passes into human breast milk.
Driving and using machines
Trajenta has no known influence on the ability to drive and use machines.
Taking Trajenta in combination with medicines called sulphonylureas and / or insulin can cause too low blood sugar (hypoglycaemia), which can affect your ability to drive and use machines or to work without protective barriers.
Dose, Method and Time of Administration How to use Trajenta: Posology
Always take this medicine exactly as your doctor has told you. If in doubt, consult your doctor or pharmacist.
The recommended dose of Trajenta is one 5 mg tablet once a day.
You can take Trajenta regardless of food.
Your doctor may prescribe Trajenta in combination with another oral antidiabetic medicine. Remember to take all medicines as prescribed by your doctor so that you get the best results for your health.
Overdose What to do if you have taken too much Trajenta
If you take more Trajenta than you should
If you take more Trajenta than you should, consult your doctor immediately.
If you forget to take Trajenta
- If you forget to take a dose of Trajenta, take it as soon as you remember. However, if it is almost time for your next dose, skip the missed dose.
- Do not take a double dose to make up for a forgotten dose. Never take two doses on the same day.
If you stop using Trajenta
Do not stop using Trajenta without consulting your doctor first. Your blood sugar levels may rise when you stop taking Trajenta.
If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse.
Side Effects What are the side effects of Trajenta
Like all medicines, this medicine can cause side effects, although not everybody gets them.
Some symptoms need immediate medical attention
You should stop taking Trajenta and see your doctor immediately if you experience the following symptoms of low blood sugar: shaking, sweating, anxiety, blurred vision, tingling lips, paleness, mood change or confusion (hypoglycaemia). Hypoglycaemia (frequency: very common, may affect more than 1 in 10 people) is a known side effect of the combination of Trajenta with metformin and sulphonylurea.
Some patients have experienced allergic reactions (hypersensitivity; frequency not known), which can be serious and can include wheezing and shortness of breath (bronchial hyperreactivity; frequency not known). Some patients have experienced rash (frequency uncommon), hives (frequency rare) and swelling of the face, lips, tongue and throat which may cause difficulty in breathing or swallowing (angioedema; frequency rare). If you experience any of the signs of the disease mentioned above, stop taking Trajenta and contact your doctor immediately. Your doctor may prescribe a medicine to treat the allergic reaction and a different medicine for diabetes.
Some patients experienced inflammation of the pancreas (pancreatitis; frequency not known, cannot be estimated from the available data).
STOP taking Trajenta and contact a doctor immediately if you notice any of the following serious side effects:
- Severe and persistent pain in the abdomen (stomach area), which can affect the back, as well as nausea and vomiting, as these could be signs of an inflamed pancreas (pancreatitis).
Some patients have experienced the following side effects when taking Trajenta alone:
- Uncommon (may affect up to 1 in 100 people): inflammation of the nose or throat (nasopharyngitis), cough, increased plasma levels of the enzyme amylase.
- Not known (frequency cannot be estimated from the available data): allergic reactions (hypersensitivity).
Some patients have experienced the following side effects when taking Trajenta and metformin:
- Uncommon: inflammation of the nose or throat (nasopharyngitis), allergic reactions (hypersensitivity), cough.
Some patients have experienced the following side effects when taking Trajenta and insulin:
- Uncommon: inflammation of the nose or throat (nasopharyngitis), cough, pancreatitis, constipation, increased plasma levels of the enzyme amylase.
- Not known: allergic reactions (hypersensitivity).
Some patients have experienced the following side effects when taking Trajenta, metformin and a sulphonylurea:
- Not known: inflammation of the nose or throat (nasopharyngitis), allergic reactions (hypersensitivity), cough, increased plasma levels of the enzyme amylase.
Other side effects of Trajenta include:
- Not known: blistering of the skin (bullous pemphigoid).
Reporting of side effects
If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. side effects you can help provide more information on the safety of this medicine.
Expiry and Retention
Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date which is stated on the blister and carton after EXP. The expiry date refers to the last day of that month.
This medicine does not require any special storage conditions.
Do not use Trajenta if you notice that the pack is damaged or shows signs of tampering.
Do not throw any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.
What Trajenta contains
- The active substance is linagliptin.Each coated tablet (tablet) contains 5 mg of linagliptin
- The other ingredients are Tablet core: Mannitol, pregelatinised starch, maize starch, copovidone, magnesium stearate Film-coating: Hypromellose, titanium dioxide (E171), talc, macrogol, red iron oxide (E172)
Description of what Trajenta looks like and contents of the pack
- Trajenta 5 mg tablets are 8 mm diameter, light red, round film-coated tablets with "D5" debossed on one side and the Boehringer Ingelheim logo debossed on the other.
- Trajenta is available in aluminum / aluminum perforated unit dose blisters. The packs contain 10 x 1, 14 x 1, 28 x 1, 30 x 1, 56 x 1, 60 x 1, 84 x 1, 90 x 1, 98 x 1, 100 x 1 and 120 x 1 tablets.
Not all pack sizes may be marketed in your country.
Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.
01.0 NAME OF THE MEDICINAL PRODUCT
TRAJENTA 5 MG TABLETS COATED WITH FILM
▼ Medicinal product subject to additional monitoring. This will allow the rapid identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for information on how to report adverse reactions.
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 5 mg of linagliptin.
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM
Film-coated tablet (tablet).
Round, 8 mm diameter, light red, film-coated tablet debossed with "D5" on one side and the Boehringer Ingelheim logo debossed on the other.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
Trajenta is indicated in the treatment of type 2 diabetes mellitus to improve blood glucose control in adults:
as monotherapy
• in patients inadequately controlled with diet and exercise alone and for whom metformin is inappropriate due to intolerance or contraindicated due to renal insufficiency.
as a combination therapy
• in combination with metformin, when diet and exercise, together with metformin alone, do not provide adequate glycemic control.
• in combination with a sulphonylurea and metformin, when diet and exercise, together with a combination therapy of these two medicines, do not provide adequate glycemic control.
• in combination with insulin, with or without metformin, when this monotherapy regimen, together with diet and exercise, does not provide adequate glycemic control.
04.2 Posology and method of administration
Dosage
The linagliptin dose is 5 mg once daily. When linagliptin is added to metformin, the metformin dose should be maintained and linagliptin should be administered concomitantly. When linagliptin is used in combination with a sulfonylurea or insulin, a lower dose of sulfonylurea or insulin may be considered to reduce the risk of hypoglycaemia (see section 4.4).
Special populations
Patients with renal insufficiency
No dose adjustment of Trajenta is necessary in patients with renal insufficiency.
Patients with hepatic insufficiency
Pharmacokinetic studies suggest that no dose adjustment is necessary in patients with hepatic insufficiency, but clinical experience in these patients is lacking.
Senior citizens
No dose adjustment is necessary based on age.
However, clinical experience in patients> 80 years of age is limited and caution should be used in treating this population.
Pediatric population
The safety and efficacy of linagliptin in children and adolescents have not yet been established.
No data are available.
Method of administration
Trajenta can be taken with or without meals at any time of the day. If a dose is missed, it should be taken as soon as the patient remembers it. A double dose should not be taken on the same day.
04.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
04.4 Special warnings and appropriate precautions for use
General
Trajenta should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.
Hypoglycemia
Linagliptin monotherapy showed a comparable "incidence of hypoglycaemia to placebo. In clinical trials with linagliptin as part of a combination therapy with medicinal products not known to cause hypoglycaemia (metformin), the rates of hypoglycaemia reported with linaglitpin were similar to those reported in patients taking placebo.
When linagliptin was added to a sulphonylurea (metformin as background therapy), the incidence of hypoglycaemia was increased compared to that of placebo (see section 4.8).
Sulfonylureas and insulin are known to cause hypoglycaemia. Therefore, caution is advised when linagliptin is used in combination with a sulfonylurea and / or insulin. A dose reduction of sulfonylurea or insulin may be considered (see section 4.2).
Pancreatitis
Adverse reactions of acute pancreatitis have been spontaneously reported during post-marketing experience with linagliptin. Patients should be informed of the characteristic symptom of acute pancreatitis: severe, persistent abdominal pain. pancreatitis. If pancreatitis is suspected, treatment with Trajenta should be discontinued.
04.5 Interactions with other medicinal products and other forms of interaction
Evaluation of interactions in vitro
Linagliptin is a weak competitor and a weak to moderate inhibitor, mechanism-based inhibition, of the CYP3A4 isoenzyme, but does not inhibit other CYP isoenzymes. It is not an inducer of CYP isoenzymes.
Linagliptin is a substrate of P-glycoprotein and inhibits Pglycoprotein-mediated transport of digoxin
with low power. Based on these results and interaction studies in vivo, linagliptin is considered unlikely to cause interactions with other P-gp substrates.
Evaluation of interactions in vivo
Effects of other medicinal products on linagliptin
The clinical data described below suggest that the risk of clinically significant interactions resulting from co-administration of medicinal products is low.
Metformin: Co-administration of 850 mg metformin in multiple doses three times daily with 10 mg linagliptin once daily did not significantly alter the pharmacokinetics of linagliptin in healthy volunteers.
Sulfonylureas: the steady-state pharmacokinetics of linagliptin 5 mg were not affected by concomitant administration of a single 1.75 mg dose of glibenclamide (glyburide).
Ritonavir: Co-administration of a single 5 mg oral dose of linagliptin and multiple 200 mg oral doses of ritonavir, a potent inhibitor of P-glycoprotein and CYP3A4, increased linagliptin AUC and Cmax by approximately two and threefold. Unbound drug concentrations, which are usually less than 1% at the therapeutic dose of linagliptin, were increased 4 to 5-fold after co-administration with ritonavir. Simulations of steady-state plasma concentrations of linagliptin with and without ritonavir indicated that increased exposure is not associated with increased accumulation. These changes in linagliptin pharmacokinetics are not considered clinically relevant. Therefore no interactions are expected. clinically relevant with other inhibitors of P-glycoprotein and CYP3A4.
Rifampicin: multiple co-administration of linagliptin 5 mg with rifampicin, a potent inducer of P-glycoprotein and CYP3A4, resulted in a 39.6% and 43.8% decrease in linagliptin AUC and Cmax, respectively. steady state and approximately 30% decrease in DPP-4 inhibition downstream. Therefore, the full efficacy of linagliptin in combination with strong P-gp inducers may not be achieved, particularly if these are administered long-term. Co-administration with other potent inducers of P-glycoprotein and CYP3A4, such as carbamazepine, phenobarbital and phenytoin, has not been studied.
Effects of linagliptin on other medicinal products
As described below, linagliptin had no clinically relevant effect on the pharmacokinetics of metformin, glyburide, simvastatin, warfarin, digoxin, or oral contraceptives in clinical trials, providing evidence in vivo a low propensity to cause interactions with medicinal products substrates of CYP3A4, CYP2C9, CYP2C8, P-glycoprotein and organic cation transporter (OCT).
Metformin: Co-administration of multiple daily doses of 10 mg linagliptin with 850 mg of the OCT substrate metformin had no relevant effect on the pharmacokinetics of metformin in healthy volunteers. Therefore, linagliptin is not an inhibitor of OCT mediated transport. .
Sulfonylureas: Co-administration of multiple oral 5 mg doses of linagliptin and a single oral dose of 1.75 mg glibenclamide (glyburide) resulted in a clinically insignificant 14% decrease in both glibenclamide AUC and Cmax. Since glibenclamide is primarily metabolised by CYP2C9, these data also support the conclusion that linagliptin is not a CYP2C9 inhibitor. Clinically significant interactions are not expected with other sulfonylureas (e.g. glipizide, tolbutamide and glimepiride) which, like glibenclamide, they are mainly eliminated by CYP2C9.
Digoxin: Co-administration of multiple doses of 5 mg of linagliptin with multiple doses of 0.25 mg of digoxin had no effect on the pharmacokinetics of digoxin in healthy volunteers. Therefore linagliptin is not a transport inhibitor in vivo mediated by P-glycoprotein.
Warfarin: Multiple daily doses of 5 mg linagliptin did not alter the pharmacokinetics of the two S (-) or R (+) enantiomers of CYP2C9 substrate warfarin when administered as a single dose.
Simvastatin: Multiple daily doses of linagliptin in healthy volunteers had minimal effect on the steady-state pharmacokinetics of the CYP3A4 substrate simvastatin. Following daily administration of a higher than therapeutic dose of 10 mg linagliptin in combination with 40 mg simvastatin for 6 days, the plasma AUC of simvastatin was increased by 34% and the plasma Cmax by 10%.
Oral contraceptives: co-administration with linagliptin 5 mg did not alter the steady-state pharmacokinetics of levonorgestrel or ethinylestradiol.
04.6 Pregnancy and breastfeeding
Pregnancy
The use of linagliptin in pregnant women has not been studied. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3). As a precautionary measure it is preferable to avoid the use of Trajenta during pregnancy.
Feeding time
Available pharmacokinetic data in animals have shown excretion of linagliptin / metabolites in milk.A risk to the breastfed baby cannot be excluded. A decision on whether to discontinue breast-feeding or to discontinue / avoid Trajenta therapy must be made taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.
Fertility
No studies on the effect of Trajenta on human fertility have been conducted. Animal studies do not indicate direct or indirect harmful effects on fertility (see section 5.3).
04.7 Effects on ability to drive and use machines
Trajenta has no or negligible influence on the ability to drive or use machines.
However, patients should be warned of the risk of hypoglycaemia especially when combined with sulfonylurea and / or insulin.
04.8 Undesirable effects
Summary of the safety profile
The safety of Trajenta was evaluated in a total of 6,602 patients with type 2 diabetes mellitus; of these, 5,955 patients received the target dose of 5 mg.
In the placebo-controlled studies, 6,666 patients were included and 4,302 patients were treated with the therapeutic dose of 5 mg of linagliptin. 3,964 patients were exposed to linagliptin 5 mg once daily for ≥ 12 weeks.
In the pooled analysis of placebo-controlled studies, the overall incidence of adverse events in patients treated with placebo was similar to that in patients treated with linagliptin 5 mg (63.1% versus 60.3%).
Discontinuation of therapy due to adverse events was greater in patients given placebo than in those given linagliptin 5 mg (4.4% versus 3.3%).
The most frequently reported adverse reaction was hypoglycaemia, which was observed in 14.6% of patients treated with the triple combination therapy, linagliptin plus metformin plus sulfonylurea, compared with 7.6% in patients treated with placebo.
In the placebo-controlled studies, 6.2% of patients experienced "hypoglycaemia" as an adverse reaction to linagliptin. Of these, 5.1% were mild, 1.0% moderate, and 0.1% were classified as severe. Cases of pancreatitis were reported more frequently in patients randomized to linagliptin (5 events in 4,302 patients treated with linagliptin versus 1 event in 2,364 placebo-treated patients).
Table of adverse reactions
Due to the impact of background therapy on adverse reactions (eg hypoglycaemia), adverse reactions were analyzed and shown according to the respective treatment regimens (monotherapy, in addition to metformin, in addition to metformin and sulphonylurea and in addition to insulin).
Placebo-controlled studies included studies in which linagliptin was administered as
• short-term monotherapy up to 4 weeks
• monotherapy with a duration of ≥ 12 weeks
• in addition to metformin
• in addition to metformin + sulphonylurea
• in addition to insulin with or without metformin
Adverse reactions, classified by system organ class and MedDRA terminology, reported in patients administered linagliptin 5 mg in double-blind studies, as monotherapy or as add-on therapy, are presented in the table below according to to the therapeutic regimen (see table 1).
Adverse reactions are listed by absolute frequency. Frequencies are defined as very common (≥1 / 10), common (≥1 / 100,
Table 1 Adverse reactions reported in patients given linagliptin 5 mg daily as monotherapy or add-on therapies (frequencies established by pooled analysis of placebo-controlled studies) in clinical trial setting and post-marketing experience
* Based on post-marketing experience
Reporting of suspected adverse reactions
Reporting of suspected adverse reactions occurring after authorization of the medicinal product is important as it allows continuous monitoring of the benefit / risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system.
04.9 Overdose
Symptoms
During controlled clinical trials in healthy volunteers, single doses of up to 600 mg of linagliptin (equivalent to 120 times the recommended dose) were generally well tolerated. There is no experience with doses above 600 mg in humans.
Therapy
In the event of an overdose, it is reasonable to use the usual supportive measures, for example removing unabsorbed material from the gastrointestinal tract, resorting to clinical monitoring and, if necessary, instituting clinical measures.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: Medicines used in diabetes, dipeptidyl peptidase 4 (DPP-4) inhibitors, ATC code: A10BH05.
Mechanism of action
Linagliptin is an inhibitor of the enzyme DPP-4 (Dipeptidyl peptidase 4, EC 3.4.14.5), an enzyme involved in the inactivation of the incretin hormones GLP-1 and GIP (glucagon-like peptide-1, glucose-dependent insulinotropic polypeptide). These hormones are rapidly degraded by the DPP-4 enzyme. Both incretins are involved in the physiological regulation of glucose homeostasis. Incretins are secreted at a low baseline level throughout the day and levels rise immediately after food. GLP-1 and GIP increase insulin biosynthesis and its secretion from pancreatic beta cells in the presence of normal and elevated levels of insulin. blood glucose. Furthermore GLP-1 also reduces the secretion of glucagon from pancreatic alpha cells, which leads to a reduction in hepatic glucose production. Linagliptin binds very effectively to DPP-4 in a reversible manner and thus leads to a sustained increase and prolongation of active incretin levels. Linagliptin glucose-dependently increases insulin secretion and decreases glucagon secretion, thus resulting in an overall improvement in glucose homeostasis. Linagliptin selectively binds to DPP-4 and manifests in vitro selectivity> 10,000 times that of DPP-8 or DPP-9.
Clinical efficacy and safety
Eight randomized controlled phase III studies were conducted involving 5,239 patients with type 2 diabetes, of which 3,319 were treated with linagliptin to evaluate its efficacy and safety. These studies included 929 patients of age or age. Over 65 years taking linagliptin. 1,238 patients with mild renal impairment and 143 patients with moderate renal impairment also took linagliptin. Linagliptin taken once daily produced clinically meaningful improvements in glycemic control, with no clinically relevant change in body weight. Similar reductions in glycosylated hemoglobin A1c (HbA1c) were found across subgroups, including those related to gender, age, renal impairment and body mass index (BMI). A higher baseline HbA1c level was associated with a greater reduction in HbA1c. In the pooled studies, there was a significant difference in HbA1c reduction between Asian (0.8%) and Caucasian (0.5%) patients.
Linagliptin as monotherapy in patients who cannot be treated with metformin
The efficacy and safety of linagliptin as monotherapy were evaluated in a 24-week double-blind placebo-controlled study. Treatment with linagliptin 5 mg once daily resulted in a significant improvement in HbA1c (change in -0.69% versus placebo), in patients with baseline HbA1c of approximately 8%. Linagliptin also showed significant improvements in fasting glucose (FPG) and 2-hour post-meal glucose (PPG) compared with to placebo. The incidence of hypoglycaemia observed in patients treated with linagliptin was similar to that of patients treated with placebo.
The efficacy and safety of linagliptin monotherapy were also evaluated in an 18-week double-blind placebo-controlled study in patients for whom metformia therapy is inappropriate, due to intolerance or contraindicated to cause of kidney failure. Linagliptin produced significant improvements in HbA1c (-0.57% change from placebo), from a mean baseline HbA1c of 8.09%. Linagliptin also showed significant improvements in fasting glucose (FPG) compared to placebo. The incidence of hypoglycaemia observed in linagliptin-treated patients was similar to that in placebo-treated patients.
Linagliptin in add-on combination therapy with metformin
The efficacy and safety of linagliptin in combination with metformin were evaluated in a 24-week double-blind placebo-controlled study. Linagliptin produced significant improvements in HbA1c (-0.64% change compared to placebo). , from a mean baseline HbA1c of 8%. Linagliptin also showed significant improvements in fasting plasma glucose (FPG) and 2-hour post-meal glucose (PPG) compared to placebo. The incidence of hypoglycemia observed in linagliptin-treated patients was similar to that in placebo-treated patients.
Linagliptin in add-on combination therapy with metformin and sulfonylurea
A 24-week placebo-controlled study was conducted to evaluate the efficacy and safety of linagliptin 5 mg versus placebo in patients who were insufficiently controlled on a combination of metformin and sulfonylurea. Linagliptin produced significant improvements in HbA1c (-0.62% change from placebo), from a mean baseline HbA1c of 8.14%. Linagliptin also showed significant improvements in fasting blood glucose (FPG) and 2-hour postprandial (PPG) in patients, compared to placebo.
Linagliptin in combination therapy with insulin
The efficacy and safety of linagliptin 5 mg in combination with insulin alone or in combination with metformin and / or pioglitazone were evaluated in a 24-week double-blind placebo-controlled study. Linagliptin produced significant improvements in blood pressure. HbA1c (-0.65% change from placebo), from a mean baseline HbA1c of 8.3%. Linagliptin also resulted in significant improvements in fasting glucose (FPG) and a higher proportion of patients achieved a HbA1c target body weight between groups. Effects on plasma lipids were negligible. The incidence of hypoglycaemia observed in linagliptin-treated patients was similar to that in placebo-treated patients (linagliptin 22.2%; placebo 21.2% ).
24-month data on linagliptin in combination therapy with metformin versus glimepiride
In a study comparing the efficacy and safety of adding 5 mg linagliptin or glimepiride (mean dose 3 mg) to metformin alone, in patients with insufficient glycemic control, the mean reduction in HbA1c was - 0.16% with linagliptin (mean baseline HbA1c 7.69%) and -0.36% with glimepiride (mean baseline HbA1c 7.69%), with a mean treatment difference of 0.20% ( 97.5% CI: 0.09; 0.299). The incidence of hypoglycemia in the linagliptin group (7.5%) was significantly lower than that in the glimepiride group (36.1%). Linagliptin-treated patients showed a significant mean decrease in body weight from baseline. compared to significant weight gain in patients who received glimepiride (-1.39 versus +1.29 kg).
Linagliptin in combination therapy in patients with severe renal impairment, 12-week placebo-controlled data (stable background therapy) and placebo-controlled 40-week extension (variable background therapy)
The efficacy and safety of linagliptin were also evaluated in type 2 diabetic patients with severe renal impairment in a 12-week, double-blind, placebo-controlled study during which background hypoglycemic therapies were kept stable Most patients (80.5%) received insulin as background therapy, alone or in combination with other oral antidiabetic agents such as sulfonylurea, glinide and pioglitazone.
This was followed by an additional 40-week follow-up period of treatment during which dose adjustments of antidiabetic medicinal products were allowed.
Linagliptin produced significant improvements in HbA1c (change of -0.59% compared to placebo after 12 weeks), from a mean baseline HbA1c of 8.2%. The observed difference in HbA1c compared to placebo was -0 , 72% after 52 weeks.
There were no significant differences in body weight between the groups. The incidence of hypoglycaemia observed in linagliptin-treated patients was higher than in placebo-treated patients, due to an increase in asymptomatic hypoglycemia. There was no difference between groups in the incidence of severe hypoglycemia.
Linagliptin in combination therapy in the elderly (≥ 70 years old) with type 2 diabetes
The efficacy and safety of linagliptin in elderly (≥ 70 years old) with type 2 diabetes was evaluated in a 24-week double-blind study. Patients received metformin and / or sulfonylurea and / or insulin as background therapy. Doses of background antidiabetic medicinal products were maintained stable during the first 12 weeks, after which dose adjustments were allowed. Linagliptin produced significant improvements in HbA1c (-0.64% change compared to placebo after 24 weeks) from a mean baseline HbA1c of 7.8%. Linagliptin also produced significant improvements in fasting plasma glucose (FPG) compared to placebo. Body weight trends were not significantly different. between groups.
Cardiovascular risk
In an independently judged prospective meta-analysis of cardiovascular events from 19 clinical trials (ranging in duration from 18 weeks to 24 months), involving 9,459 patients with type 2 diabetes, linagliptin treatment was not associated. to an increased cardiovascular risk. The primary endpoint, consisting of: occurrence of event or time to first event of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, or hospitalization for unstable angina, was not significantly lower for linagliptin than in the treated comparator group. with a combination of active substance and placebo [hazard ratio 0.78 (95% confidence interval 0.55; 1.12)]. A total of 60 primary events occurred in the linagliptin group and 62 in the comparator groups. To date, there is no evidence of an increased cardiovascular risk, but the number of events in clinical trials precludes definitive conclusions. However, cardiovascular events were similar between linagliptin and placebo (1.03% with linagliptin versus 1.35% with placebo).
Pediatric population
The European Medicines Agency has deferred the obligation to submit the results of studies with linagliptin in one or more subsets of the pediatric population in Type 2 diabetes (see section 4.2 for information on pediatric use).
05.2 "Pharmacokinetic properties
The pharmacokinetics of linagliptin were extensively characterized in healthy subjects and in patients with type 2 diabetes. After oral administration of a 5 mg dose to healthy patients or volunteers, linagliptin was rapidly absorbed, with maximum plasma concentrations (median Tmax) occurring. 1.5 hours after taking the dose.
Plasma concentrations of linagliptin decrease in a triphasic manner with a long terminal half-life (terminal half-life for linagliptin greater than 100 hours), which is mostly related to the close saturable binding of linagliptin to DPP-4 and which does not contribute to drug accumulation. .
The effective half-life for linagliptin accumulation, determined following oral administration of multiple 5 mg linagliptin doses, is approximately 12 hours. After a once daily administration of 5 mg linagliptin, steady-state plasma concentrations are reached by the third dose. The plasma AUC of linagliptin increased approximately 33% following steady-state doses of 5 mg compared to the first dose. The intra-individual and inter-individual linagliptin AUC coefficients of variation were low (12.6%, respectively. and 28.5%).Since the binding of linagliptin to DPP-4 is concentration-dependent, the pharmacokinetics of linagliptin based on total exposure are non-linear; in fact, the total plasma AUC of linagliptin was increased less than dose proportionality, while the "AUC of unbound drug increases almost dose proportionally. Linagliptin pharmacokinetics were generally similar in healthy subjects and in patients with type 2 diabetes.
Absorption
The absolute bioavailability of linagliptin is approximately 30%. Co-administration of a high-fat meal with linaglitpin prolonged the time to reach Cmax by 2 hours and reduced Cmax by 15%, but no effect on AUC0-72h was observed. no clinically relevant change in Cmax and Tmax is expected; therefore linagliptin can be administered with or without food.
Distribution
As a result of tissue binding, the mean apparent volume of distribution at steady state following a single 5 mg intravenous dose of linagliptin in healthy subjects is approximately 1,110 liters, indicating that linagliptin is extensively distributed to tissues. Plasma protein binding of linagliptin is concentration dependent and decreases from approximately 99% at 1 nmol / L to 75-89% at ≥ 30 nmol / L, reflecting saturation of DPP-4 binding with increased of linagliptin concentration At high concentrations, where DPP-4 is completely saturated, 70-80% of linagliptin was bound to plasma proteins other than DPP-4, therefore 30-20% was in free plasma.
Biotransformation
Following a 10 mg oral dose of [14C] linagliptin, approximately 5% of the radioactivity was eliminated in the urine. Metabolism plays a subordinate role in the elimination of linagliptin. A major metabolite was detected with a 13.3% relative exposure of linagliptin at steady state, which was pharmacologically inactive and therefore does not contribute to the inhibitory activity of linagliptin on the Plasma DPP-4.
Elimination
Following an oral dose of [14C] linagliptin to healthy subjects, approximately 85% of the administered radioactivity was eliminated in faeces (80%) or urine (5%) within 4 days of administration. Steady-state renal clearance was about 70 ml / min.
Special populations
Kidney failure
An open-label multiple dose study was conducted to evaluate the pharmacokinetics of linagliptin (5 mg dose) in patients with varying degrees of chronic renal failure compared to healthy control subjects. The study included patients with renal impairment classified on the basis of creatinine clearance as mild (50 to hemodialysis. In addition, patients with T2DM and severe renal impairment (creatinine clearance was assessed by 24-hour urinary creatinine clearance measurements or was estimated from serum creatinine based on the Cockcroft-Gault formula:
CrCl = (140 - age) x weight / 72 x serum creatinine [x 0.85 for female patients], where age is expressed in years, weight in kg and serum creatinine in mg / dl.
At steady state, linagliptin exposure in patients with mild renal impairment was similar to that in healthy subjects. In moderate renal impairment, a moderate 1.7-fold increase in exposure was observed compared to control. L " exposure in T2DM patients with severe renal insufficiency was increased approximately 1.4-fold compared to T2DM patients with normal renal function. Predictions for steady-state linagliptin AUC in patients with ESRD indicated exposure similar to that in patients with moderate or severe renal impairment. Furthermore, linagliptin is not expected to be therapeutically significantly eliminated by hemodialysis or peritoneal dialysis. Therefore, no dosage adjustment of linagliptin is required in patients with any degree of renal impairment.
Hepatic insufficiency
In non-diabetic patients with mild, moderate and severe (Child-Pugh classification) hepatic impairment, the mean AUC and Cmax of linagliptin were similar to those of their healthy controls following administration of multiple doses of 5 mg of linagliptin No dosage adjustment of linagliptin is proposed in diabetic patients with mild, moderate and severe hepatic impairment.
Body mass index (BMI)
No dosage adjustment is necessary based on BMI. In a population pharmacokinetic analysis of phase I and phase II data, body mass index had no clinically relevant effect on linagliptin pharmacokinetics. Clinical studies prior to marketing authorization were conducted with BMI values up to 40 kg / m2.
Sex
No dosage adjustment is necessary based on gender. In a population pharmacokinetic analysis of phase I and phase II data, gender had no clinically relevant effect on linagliptin pharmacokinetics.
Senior citizens
No dosage adjustment is required based on age up to 80 years as age had no clinically relevant impact on linagliptin pharmacokinetics in a population pharmacokinetic analysis of phase I and phase II data. elderly subjects (65-80 years, the oldest patient was 78 years old) had plasma concentrations of linagliptin comparable to those of younger subjects.
Pediatric population
Studies to characterize the pharmacokinetics of linagliptin in pediatric patients have not yet been performed.
Race
No dose adjustment is necessary based on race. In a composite analysis of available pharmacokinetic data, including patients of Caucasian, Hispanic, African and Asian descent, race had no apparent effect on plasma linagliptin concentrations. In addition, the pharmacokinetic characteristics of linagliptin were similar in clinical studies. phase I dedicated in Japanese, Chinese and Caucasian healthy volunteers.
05.3 Preclinical safety data
Liver, kidney and gastrointestinal tract are major target organs of toxicity in mice and rats at repeated doses of linagliptin 300 times higher than human exposure.
In rats, effects on reproductive organs, thyroid and lymphatic organs were observed at levels greater than 1,500 times the human exposure. In dogs, strong pseudo-allergic reactions were observed at medium doses, which secondary to cardiovascular changes, considered specific. The liver, kidneys, stomach, reproductive organs, thymus, spleen and lymph nodes were target organs for toxicity in Cynomolgus monkeys at levels greater than 450 times the human exposure. At levels in excess of 100 times human exposure, the main result in these monkeys was stomach irritation.
Linagliptin and its major metabolites show no genotoxic potential.
2-year oral carcinogenicity studies in rats and mice showed no evidence of carcinogenicity in male rats or mice. Only in female mice there was a significantly higher incidence of malignant lymphoma at the highest dose (> 200 times the human exposure), but it is not considered relevant to humans (explanation: incidence not related to treatment, but due to the high variability of the incidence of this event). Based on these studies there is no concern for human carcinogenicity.
The NOAEL for fertility, early embryonic development and teratogenicity in rats was set at> 900 times the human exposure. The NOAEL for maternal, embryo-fetal and offspring toxicity in rats was 49 times the human exposure. No teratogenic effects were observed in rabbits at> 1,000 times the human exposure. A NOAEL of 78 times the human exposure was derived for embryo-fetal toxicity in rabbits, and for maternal toxicity the NOAEL was 2.1 times human exposure.
Therefore, linagliptin is considered unlikely to affect reproduction at therapeutic exposures in humans.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Core of the tablet
Mannitol
Pregelatinised starch (from maize)
Cornstarch
Copovidone
Magnesium stearate
Coating film
Hypromellose
Titanium dioxide (E171)
Talc
Macrogol
Red iron oxide (E172)
06.2 Incompatibility
Not relevant.
06.3 Period of validity
3 years
06.4 Special precautions for storage
This medicine does not require any special storage conditions.
06.5 Nature of the immediate packaging and contents of the package
Aluminum / aluminum perforated unit dose blisters, in cartons containing 10 x 1, 14 x 1, 28 x 1, 30 x 1, 56 x 1, 60 x 1, 84 x 1, 90 x 1, 98 x 1, 100 x 1 and 120 x 1 film-coated tablets.
Not all pack sizes may be marketed.
06.6 Instructions for use and handling
Unused medicine and waste derived from this medicine must be disposed of in accordance with local regulations.
07.0 MARKETING AUTHORIZATION HOLDER
Boehringer Ingelheim International GmbH
Binger Str. 173
D-55216 Ingelheim am Rhein
Germany
08.0 MARKETING AUTHORIZATION NUMBER
EU / 1/11/707/001 (10 tablets)
041401011
EU / 1/11/707/002 (14 tablets)
041401023
EU / 1/11/707/003 (28 tablets)
041401035
EU / 1/11/707/004 (30 tablets)
041401047
EU / 1/11/707/005 (56 tablets)
041401050
EU / 1/11/707/006 (60 tablets)
041401062
EU / 1/11/707/007 (84 tablets)
041401074
EU / 1/11/707/008 (90 tablets)
041401086
EU / 1/11/707/009 (98 tablets)
041401098
EU / 1/11/707/010 (100 tablets)
041401100
EU / 1/11/707/011 (120 tablets)
041401112
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
Date of first authorization: 24 August 2011
10.0 DATE OF REVISION OF THE TEXT
D.CCE September 2014
