Active ingredients: Sitagliptin
Tesavel 25 mg film-coated tablets
Tesavel package inserts are available for packs:- Tesavel 25 mg film-coated tablets
- Tesavel 50 mg film-coated tablets
- Tesavel 100 mg film-coated tablets
Why is Tesavel used? What is it for?
Tesavel contains the active substance sitagliptin which belongs to a class of medicines called dipeptidyl peptidase-4 (DPP-4) inhibitors which lower blood sugar levels in adult patients with type 2 diabetes mellitus.
This medicine helps to increase the levels of insulin produced after a meal and decreases the amount of sugar produced by the body.
Your doctor has prescribed this medicine to help you lower your blood sugar level, which is too high due to type 2 diabetes. This medicine can be used alone or together with other medicines (insulin, metformin, sulphonylurea or glitazones) which lower blood sugar, which you may already be taking to treat your diabetes along with a diet and exercise program.
What is type 2 diabetes?
Type 2 diabetes is a disease in which the body does not make enough insulin, and the insulin produced by the body does not work as well as it should. The body can also make too much sugar. When this happens, sugar (glucose) builds up in the blood. This can lead to serious medical problems such as heart disease, kidney disease, blindness, and amputations.
Contraindications When Tesavel should not be used
Do not take Tesavel
- if you are allergic to sitagliptin or any of the other ingredients of this medicine.
Precautions for use What you need to know before you take Tesavel
Cases of inflammation of the pancreas (pancreatitis) have been reported in patients treated with Tesavel.
- Tell your doctor if you have or have had:
- a pancreatic disease (such as pancreatitis)
- gallstones, alcohol addiction or very high levels of triglycerides (a form of fat) in the blood. These medical conditions can increase your risk of developing pancreatitis
- type 1 diabetes
- diabetic ketoacidosis (a complication of diabetes with high blood sugar, rapid weight loss, nausea or vomiting)
- any past or present kidney problems - an allergic reaction to Tesavel
This medicine is unlikely to cause low blood sugar (hypoglycaemia) because it does not work when your blood sugar is low. However, when this medicine is taken with a sulphonylurea or with insulin, (hypoglycaemia) can occur. Your doctor may reduce the dose of the sulphonylurea or insulin.
Children and adolescents
Children and adolescents under the age of 18 should not use this medicine. It is not known whether the use of this medicine is safe and effective in children and adolescents under the age of 18 years.
Interactions Which drugs or foods can modify the effect of Tesavel
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines.
In particular, tell your doctor if you are taking digoxin (a medicine used to treat irregular heartbeat and other heart problems). The level of digoxin in your blood may need to be checked if taken with Tesavel.
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. You should not use this medicine during pregnancy.
It is not known if this medicine passes into breast milk. You should not take this medicine if you are breastfeeding or think you will need to breastfeed.
Driving and using machines
This medicine has no or negligible influence on the ability to drive and use machines. However, dizziness and somnolence have been reported, which may affect your ability to drive and use machines.
Taking this medicine with other medicines called sulphonylureas or with insulin may cause hypoglycaemia, which may affect your ability to drive, use machines or work without protective barriers.
Dose, Method and Time of Administration How to use Tesavel: Posology
Always take this medicine exactly as your doctor has told you. If in doubt, consult your doctor or pharmacist.
The usual recommended dose is:
- one 100 mg film-coated tablet
- once a day
- by mouth.
If you have kidney problems, your doctor may prescribe lower doses (such as 25 mg or 50 mg).
You can take this medicine with or without food and drink.
Your doctor may prescribe this medicine alone or together with other medicines that lower your blood sugar level.
Diet and exercise can help your body use blood sugar better. It is important to continue the diet and exercise program recommended by your doctor while taking Tesavel.
If you forget to take Tesavel
If you forget a dose, take it as soon as you remember it. If you don't remember until your next dose is due, skip the missed dose and continue with your normal dose. Do not take a double dose of this medicine.
If you stop taking Tesavel
Keep taking this medicine for as long as your doctor prescribes it so that you can continue to monitor your blood sugar level. You should not stop taking this medicine without first talking to your doctor.
If you have any further questions on the use of this medicine, ask your doctor or pharmacist.
Overdose What to do if you have taken too much Tesavel
If you take more than the prescribed dosage of this medicine, contact your doctor immediately.
Side Effects What are the side effects of Tesavel
Like all medicines, this medicine can cause side effects, although not everybody gets them.
STOP taking Tesavel 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 may extend to the back with or without nausea and vomiting, as these could be signs of inflammation of the pancreas (pancreatitis).
If you have a severe allergic reaction (frequency not known), including rash, hives, blisters on the skin / peeling skin and swelling of the face, lips, tongue and throat which may cause difficulty in breathing or swallowing, stop treatment with this medicine and contact your doctor immediately. Your doctor may prescribe a medicine to treat your allergic reaction and a different medicine for your diabetes.
Some patients have experienced the following side effects after adding sitagliptin to metformin:
Common (may affect up to 1 in 10 people): low blood sugar, nausea, flatulence, vomiting
Uncommon (may affect up to 1 in 100 people): stomach pain, diarrhea, constipation, sleepiness.
Some patients have reported different types of stomach pain when starting sitagliptin and metformin together as part of the combination therapy (frequency is common).
Some patients have experienced the following side effects when taking sitagliptin in combination with a sulphonylurea and metformin:
Very common (may affect more than 1 in 10 people): low blood sugar
Common: constipation
Some patients have experienced the following side effects when taking sitagliptin and pioglitazone:
Common: flatulence, swelling of the hands or legs
Some patients have experienced the following side effects when taking sitagliptin in combination with pioglitazone and metformin:
Common: swelling of the hands or legs
Some patients have experienced the following side effects when taking sitagliptin in combination with insulin (with or without metformin):
Common: flu
Uncommon: dry mouth
Some patients have experienced the following side effects when taking sitagliptin alone in clinical trials, or during post-approval use alone and / or with other diabetes medicines:
Common: low blood sugar, headache, upper respiratory tract infection, runny or stuffy nose and sore throat, osteoarthritis, pain in the arms or legs
Uncommon: dizziness, constipation, itching
Frequency not known: kidney problems (sometimes requiring dialysis), vomiting, joint pain, muscle pain, back pain, interstitial lung disease
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. By reporting side effects you can help. to 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 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.
Other Information
What Tesavel contains
- The active ingredient is sitagliptin. Each film-coated tablet (tablet) contains sitagliptin phosphate monohydrate, equivalent to 25 mg sitagliptin.
- The other ingredients are: in the tablet core: microcrystalline cellulose (E460), anhydrous calcium hydrogen phosphate (E341), croscarmellose sodium (E468), magnesium stearate (E470b), and sodium stearyl fumarate. The tablet coating contains: poly (vinyl alcohol), macrogol 3350, talc (E553b), titanium dioxide (E171), red iron oxide (E172), and yellow iron oxide (E172).
Description of what Tesavel looks like and contents of the pack
Round, pink film-coated tablets with "221" on one side. Opaque blisters (PVC / PE / PVDC and aluminum).
Packs of 14, 28, 30, 56, 84, 90 or 98 film-coated tablets and 50 x 1 film-coated tablets in perforated unit dose blisters.
Not all pack sizes may be marketed.
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
TESAVEL 25 MG TABLETS COATED WITH FILM
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains sitagliptin phosphate monohydrate, equivalent to 25 mg sitagliptin.
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM
Film-coated tablet (tablet).
Round, pink film-coated tablet with "221" on one side.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
For adult patients with type 2 diabetes mellitus, Tesavel is indicated to improve glycemic control:
in monotherapy
• in patients inadequately controlled with diet and exercise alone and for whom metformin is not appropriate due to contraindications or intolerance.
in dual oral therapy in combination with
• metformin when diet and exercise plus metformin alone do not provide adequate glycemic control.
• a sulphonylurea when diet and exercise plus the maximum tolerated dose of a sulphonylurea alone do not provide adequate glycemic control and when metformin is not appropriate due to contraindications or intolerance.
• a peroxisome proliferator-activated receptor (PPARg) agonist (eg, a thiazolidinedione) when use of a PPARg agonist is appropriate and when diet and exercise plus the PPARg agonist alone do not provide adequate control blood sugar.
in triple oral therapy in combination with
• a sulphonylurea and metformin when diet and exercise plus dual therapy with these medicines do not provide adequate glycemic control.
• a PPARg agonist and metformin when use of a PPARg agonist is appropriate and when diet and exercise plus dual therapy with these drugs do not provide adequate glycemic control.
Tesavel is also indicated as add-on therapy to insulin (with or without metformin) when diet and exercise plus a stable dose of insulin do not provide adequate glycemic control.
04.2 Posology and method of administration
Dosage
The dose is 100 mg of sitagliptin once daily. When used in combination with metformin and / or a PPARg agonist, the dose of metformin and / or the PPARg agonist should be maintained and Tesavel should be administered concomitantly.
When Tesavel is used in combination with a sulphonylurea or insulin, a lower dose of the sulphonylurea or insulin may be considered to reduce the risk of hypoglycaemia (see section 4.4).
If a dose of Tesavel is missed, it should be taken as soon as the patient remembers it.
A double dose should not be taken on the same day.
Special populations
Kidney damage
When considering the use of sitagliptin in combination with another anti-diabetic medicinal product, the manner of use in patients with renal impairment should be checked.
For patients with mild renal impairment (creatinine clearance [CrCl] ≥50 ml / min), no dose adjustment is required.
For patients with moderate renal impairment (CrCl ≥30 to
For patients with severe renal impairment (CrCl hemodialysis or peritoneal dialysis, the dose of Tesavel is 25 mg once daily. Treatment can be administered regardless of the timing of dialysis.
Since there is a dosage adjustment based on renal function, evaluation of renal function is recommended prior to initiating therapy with Tesavel and periodically thereafter.
Hepatic impairment
No dose adjustment is necessary for patients with mild to moderate hepatic impairment. Tesavel has not been studied in patients with severe hepatic impairment and caution should be exercised (see section 5.2).
However, since sitagliptin is eliminated primarily via the kidney, severe hepatic impairment is not expected to affect the pharmacokinetics of sitagliptin.
Senior citizens
No dose adjustment is necessary based on age. Limited safety data are available in patients ≥75 years of age and caution should be exercised in these cases.
Pediatric population
The safety and efficacy of sitagliptin in children and adolescents aged less than 18. There are no data available.
Method of administration
Tesavel can be taken with or without food.
04.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1 (see sections 4.4 and 4.8).
04.4 Special warnings and appropriate precautions for use
Generality
Tesavel should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.
Acute pancreatitis
The use of dipeptidyl peptidase 4 (DPP-4) inhibitors has been associated with a risk of developing acute pancreatitis. Patients should be informed of the characteristic symptom of acute pancreatitis: severe, persistent abdominal pain. Resolution of pancreatitis has been observed. after discontinuation of sitagliptin therapy (with or without supportive treatment), but very rare cases of necrotizing or haemorrhagic pancreatitis and / or death have been reported. If pancreatitis is suspected, therapy with Tesavel and other potentially suspect medicinal products should be discontinued; if the diagnosis of acute pancreatitis is confirmed, therapy with Tesavel must not be restarted.Caution should be exercised in patients with a history of pancreatitis.
Hypoglycaemia when used in combination with other antihyperglycemic medicines
In clinical trials of Tesavel as monotherapy and as part of combination therapy with medicinal products not known to cause hypoglycaemia (eg metformin and / or a PPARg agonist), the incidence of hypoglycaemia reported with sitagliptin was similar to the incidence in patients taking placebo. Hypoglycaemia has been observed when sitagliptin was used in combination with insulin or a sulphonylurea. Therefore, a lower dose of sulphonylurea or insulin may be considered to reduce the risk of hypoglycaemia (see section 4.2).
Kidney damage
Sitagliptin is excreted via the kidney. To achieve plasma concentrations of sitagliptin similar to those in patients with normal renal function, lower dosages are recommended in patients with moderate and severe renal impairment, as well as in patients with ESRD requiring hemodialysis or peritoneal dialysis (see sections 4.2 and 5.2).
When considering the use of sitagliptin in combination with another anti-diabetic medicinal product, the manner of use in patients with renal impairment should be checked.
Hypersensitivity reactions
In post-marketing reports, serious hypersensitivity reactions have been reported in patients treated with sitagliptin. These reactions include anaphylaxis, angioedema and exfoliative skin disorders including Stevens-Johnson syndrome. The onset of these reactions occurred within the first 3 months after initiation of treatment, with some reports occurring after the first dose.
If a hypersensitivity reaction is suspected, treatment with Tesavel should be discontinued. Other possible causes of the event should be investigated and alternative treatment for diabetes initiated.
04.5 Interactions with other medicinal products and other forms of interaction
Effects of other medicinal products on sitagliptin
The clinical data described below suggest that the risk of clinically significant interactions with concomitant medicinal products is limited.
Education in vitro indicated that the major enzyme responsible for the limited metabolism of sitagliptin is CYP3A4 with a contribution from CYP2C8. In patients with normal renal function, metabolism, including that of CYP3A4, has a limited role in the clearance of sitagliptin. Metabolism may play a more significant role in the elimination of sitagliptin in the context of severe renal impairment or end stage renal disease (ESRD). For this reason it is possible that potent CYP3A4 inhibitors (eg ketoconazole, itraconazole, ritonavir, clarithromycin) may alter the pharmacokinetics of sitagliptin in patients with severe renal impairment or ESRD The effects of potent CYP3A4 inhibitors in renal impairment have not been established in a clinical study.
Transport studies in vitro showed that sitagliptin is a substrate for p-glycoprotein and organic anion transporter 3 (OAT3). OAT3-mediated transport of sitagliptin was inhibited in vitro probenecid although the risk of clinically relevant interactions is considered limited. Concomitant administration of OAT3 inhibitors has not been evaluated in vivo.
Metformin: Co-administration of multiple doses of metformin 1,000 mg with sitagliptin 50 mg twice daily did not significantly alter the pharmacokinetics of sitagliptin in patients with type 2 diabetes.
Cyclosporine: A study was performed to evaluate the effect of cyclosporin, a potent inhibitor of p-glycoprotein, on the pharmacokinetics of sitagliptin. Coadministration of a single oral dose of 100 mg sitagliptin and a single oral dose of 600 mg cyclosporine has increased the AUC and Cmax of sitagliptin by approximately 29% and 68%, respectively. These changes in sitagliptin pharmacokinetics were not considered clinically relevant. The renal clearance of sitagliptin was not significantly altered. Therefore, no interactions are expected. relevant with other p-glycoprotein inhibitors.
Effects of sitagliptin on other medicinal products
Digoxin: Sitagliptin had a limited effect on plasma digoxin concentrations. Following administration of 0.25 mg digoxin concomitantly with 100 mg daily sitagliptin for 10 days, the plasma AUC of digoxin increased on average by 11%, and the plasma Cmax on average increased by 18%. No dose adjustments of digoxin are recommended. However, digoxin toxicity should be monitored in patients at risk of digoxin toxicity when sitagliptin and digoxin are co-administered.
Data in vitro suggest that sitagliptin does not inhibit or induce CYP450 isoenzymes. In clinical trials sitagliptin did not significantly alter the pharmacokinetics of metformin, glyburide, simvastatin, rosiglitazone, warfarin, or oral contraceptives, providing evidence in vivo a low propensity to cause interactions with substrates of CYP3A4, CYP2C8, CYP2C9, and with the organic cation transporter (OCT). Sitagliptin may be a weak inhibitor of p-glycoprotein in vivo.
04.6 Pregnancy and breastfeeding
Pregnancy
There are no adequate data on the use of sitagliptin in pregnant women. Animal studies have shown reproductive toxicity at high doses (see section 5.3). The potential risk for humans is unknown. Due to lack of human data, Tesavel should not be used during pregnancy.
Feeding time
It is unknown whether sitagliptin is excreted in human milk. Animal studies have shown the excretion of sitagliptin in breast milk. Tesavel should not be used while breastfeeding.
Fertility
Animal data do not suggest an effect of sitagliptin treatment on male and female fertility. There is a lack of human data.
04.7 Effects on ability to drive and use machines
Tesavel has no or negligible influence on the ability to drive and use machines.
However, when driving vehicles or operating machines it should be borne in mind that dizziness and somnolence have been reported.
In addition, when Tesavel is used in combination with a sulphonylurea or with insulin, patients should be made aware of the risk of hypoglycaemia.
04.8 Undesirable effects
Summary of the safety profile
Serious adverse reactions including pancreatitis and hypersensitivity reactions have been reported.
Hypoglycaemia has been reported in association with sulphonylurea (4.7% -13.8%) and insulin (9.6%) (see section 4.4).
Table of adverse reactions
Adverse reactions are listed below (Table 1) by system organ class and frequency. Frequencies are defined as: very common (≥ 1/10); common (≥ 1/100,
Table 1. Frequency of adverse reactions identified from placebo-controlled clinical trials of sitagliptin monotherapy and from post-marketing experience
* Adverse reactions that have been identified in post-marketing surveillance.
† See section 4.4.
Description of selected adverse reactions
In addition to the drug-related adverse experiences described above, adverse experiences reported regardless of causal relationship with the medicinal product and which occurred in at least 5% of cases and most commonly in patients treated with sitagliptin included upper respiratory tract infection and nasopharyngitis. Additional adverse experiences reported regardless of causal relationship with the medicinal product which occurred more commonly in patients treated with sitagliptin (which did not reach the 5% level, but which occurred with an incidence of> 0.5% higher with sitagliptin versus that of the control group) included osteoarthritis and pain in extremities.
Some adverse reactions were observed more frequently in studies of the combination use of sitagliptin with other anti-diabetic medicinal products than in studies of sitagliptin alone. These included hypoglycaemia (frequency very common with the combination of sulphonylurea and metformin), influenza ( common with insulin (with or without metformin)), nausea and vomiting (common with metformin), flatulence (common with metformin or pioglitazone), constipation (common with the combination of sulphonylurea and metformin), peripheral edema (common with pioglitazone or with the combination of pioglitazone and metformin) somnolence and diarrhea (uncommon with metformin) and dry mouth (uncommon with insulin (with or without metformin)).
Reporting of suspected adverse reactions
The reporting of suspected adverse reactions that occur after the authorization of the medicinal product is important, as it allows continuous monitoring of the benefit / risk ratio of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Italian Medicines Agency. , website: http://www.agenziafarmaco.gov.it/it/responsabili.
04.9 Overdose
During controlled clinical trials in healthy subjects, single doses of sitagliptin up to 800 mg were administered. Minimal increases in QTc, not considered clinically relevant, were observed at a sitagliptin dose of 800 mg in one study. There is no experience with doses above 800 mg in clinical studies. No dose-related adverse reactions were observed in multiple-dose Phase I studies with doses of sitagliptin up to 600 mg per day for periods up to 10 days and 400 mg per day for periods up to 28 days.
In the event of an overdose, it is reasonable to use common supportive measures, eg: remove unabsorbed material from the gastrointestinal tract, use clinical monitoring (including electrocardiography), and institute supportive care if required.
The dialyzability of sitagliptin is modest. In clinical studies, approximately 13.5% of the dose was removed during a 3-4 hour hemodialysis session. Prolonged hemodialysis may be considered if deemed clinically appropriate. The dialyzability of sitagliptin with peritoneal dialysis is unknown.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: drugs used in diabetes, dipeptidyl peptidase 4 (DPP-4) inhibitors, ATC code: A10BH01.
Mechanism of action
Tesavel belongs to a class of oral antihyperglycemic medicines called dipeptidyl peptidase 4 (DPP-4) inhibitors. The improvement in glycemic control observed with this medicinal product may be mediated by "increased levels of active incretins. Incretins, hormones that include glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP)," they are released from the intestine during the day, and their level increases in response to meals. Incretins are part of an endogenous system involved in the physiological regulation of glucose homeostasis. When blood glucose is normal or elevated, GLP-1 and GIP increase the synthesis and release of insulin by pancreatic beta cells via intracellular signaling pathways. involving cyclical AMP. Treatment with GLP-1 or DPP-4 inhibitors in animal models of type 2 diabetes has been shown to improve beta cell response to glucose and to stimulate insulin biosynthesis and release. With higher insulin levels, tissue glucose uptake is increased. GLP-1 also decreases the secretion of glucagon by pancreatic alpha cells. Lower glucagon concentrations, together with higher insulin levels, result in reduced hepatic production of glucose, which results in a decrease in blood glucose. The effects of GLP-1 and GIP are glucose dependent so that when blood glucose is low, no stimuli for insulin release and suppression of glucagon secretion are observed. For both GLP-1 and GIP the stimulation of insulin release rises when glucose rises above normal concentrations. Furthermore, GLP-1 does not affect the normal response of glucagon to hypoglycemia. The activity of GLP-1 and GIP is limited by the DPP-4 enzyme which rapidly hydrolyzes incretins to inactive metabolites. Sitagliptin prevents the hydrolysis of incretins by DPP-4, thereby increasing plasma concentrations of the active forms of GLP-1 and GIP. Increasing the levels of active incretins sitagliptin increases insulin release and decreases glucagon levels in a glucose manner. In patients with type 2 diabetes with hyperglycemia, these changes in insulin and glucagon levels lead to decreased hemoglobin A1c (HbA1c) and lower fasting and blood glucose concentrations. post prandium. The glucose-dependent mechanism of sitagliptin is distinct from the mechanism of sulfonylureas, which increase insulin secretion even when glucose levels are low and can lead to hypoglycemia in patients with type 2 diabetes and in normal subjects. Sitagliptin is an inhibitor potent and highly selective of DPP-4 enzyme and does not inhibit the activity of closely related enzymes DPP-8 or DPP-9 at therapeutic concentrations.
In a 2-day study in healthy subjects, sitagliptin alone increased active GLP-1 concentrations, while metformin alone increased active and total GLP-1 concentrations similarly. Co-administration of sitagliptin and metformin had an additive effect on active GLP-1 concentrations. Sitagliptin, but not metformin, increased active GIP concentrations.
Clinical efficacy and safety
Overall, sitagliptin improved glycemic control when given as monotherapy or in combination therapy (see Table 2).
Two studies were conducted to evaluate the efficacy and safety of sitagliptin alone. Treatment with sitagliptin monotherapy at 100 mg once daily resulted in significant improvements in HbA1c, fasting plasma glucose (FPG), and 2-hour postprandial glucose (2-hour PPG), compared with placebo in two studies, one lasting 18 weeks and the other 24 weeks. There was improvement in surrogate markers of beta cell function, including HOMA-? (Homeostasis Model Assessment-?), proinsulin / insulin ratio. and measures of beta cell response to meal tolerance testing with frequent sampling. The incidence of hypoglycemia observed in patients treated with sitagliptin was similar to placebo. Body weight in the two studies did not increase from baseline with sitagliptin therapy compared with a slight decrease seen in placebo-treated patients.
Sitagliptin 100 mg once daily induced significant improvements in glycemic parameters compared to placebo in two 24-week add-on studies of sitagliptin, one in combination with metformin and one in combination with pioglitazone. The change from baseline in body weight was similar for patients treated with sitagliptin compared to placebo. In these studies, there was "a" similar incidence of hypoglycaemia reported for patients treated with sitagliptin or placebo.
A 24-week placebo-controlled study was designed to evaluate the efficacy and safety of sitagliptin (100 mg once daily) added to glimepiride alone or to glimepiride in combination with metformin. The addition of sitagliptin or glimepiride alone or with glimepiride and metformin induced significant improvements in glycemic parameters. Patients treated with sitagliptin had modest gain in body weight compared to those given placebo.
A 26-week placebo-controlled study was designed to evaluate the efficacy and safety of sitagliptin (100 mg once daily) added to the combination of pioglitazone and metformin. The addition of sitagliptin to pioglitazone and metformin resulted in significant improvements in glycemic parameters. The change in body weight from baseline was similar in patients treated with sitagliptin and in those treated with placebo. The incidence of hypoglycemia was also similar in the patients treated with placebo. patients treated with sitagliptin or placebo.
A 24-week placebo-controlled study was designed to evaluate the efficacy and safety of sitagliptin (100 mg once daily) added to insulin (at a stable dose for at least 10 weeks) with or without metformin (at least 1,500 mg). ). In patients taking premixed insulin, the average daily dose was 70.9 U / day. In patients taking non-premixed (intermediate-acting / long-acting) insulin, the average daily dose was 44.3 U / day. The addition of sitagliptin to insulin induced significant improvements in glycemic parameters. There was no significant change in body weight from baseline in either group.
In a 24-week, placebo-controlled, from initiation combination therapy factorial study, sitagliptin 50 mg twice daily in combination with metformin (500 mg or 1,000 mg twice daily) resulted in significant improvements in glycemic parameters compared to with each monotherapy. Weight loss with the combination sitagliptin and metformin was similar to that observed with metformin alone or with placebo; no change from baseline was observed in patients treated with sitagliptin monotherapy. The incidence of hypoglycemia was similar between the treatment groups.
Table 2: HbA1c Results in Placebo-Controlled Monotherapy and Combination Therapy Studies *
* All treated patient population (intention-to-treatment analysis).
† Least squares means adjusted for previous hypoglycemic therapy and baseline value.
‡ p
§HbA1c (%) at 18 weeks.
% HbA1c (%) at 24 weeks.
# HbA1c (%) at 26 weeks.
¶ Least squares means adjusted for metformin use at Visit 1 (yes / no), for insulin use at Visit 1 [premixed versus non-premixed (intermediate-acting or long-acting)] and baseline. treatment per layer (for use of metformin and insulin) were not significant (p> 0.10).
A 24-week active-controlled study (metformin) was designed to evaluate the efficacy and safety of sitagliptin 100 mg once daily (N = 528) compared with metformin (N = 522) in patients who did not have adequate glycemic control with diet and exercise and who were not on antihyperglycemic therapy (without therapy for at least 4 months). The mean dose of metformin was approximately 1,900 mg per day. The reduction in HbA1c from mean baseline values of 7.2% was -0.43% for sitagliptin and -0.57% for metformin (analysis per protocol). The overall incidence of gastrointestinal adverse reactions considered drug related in patients treated with sitagliptin was 2 , 7% compared to 12.6% in metformin-treated patients. The incidence of hypoglycemia was not significantly different between the treatment groups (sitagliptin, 1.3%; metformin, 1.9%). Body weight decreased from baseline in both groups (sitagliptin, -0.6 kg; metformin -1.9 kg).
In a study comparing the efficacy and safety of adding sitagliptin 100 mg once daily or glipizide (a sulphonylurea) in patients with inadequate glycemic control on metformin monotherapy, sitagliptin was similar to glipizide in reducing HbA1c. The mean dose of glipizide used in the comparator group was 10 mg / day with approximately 40% of patients requiring a glipizide dose of ≤ 5 mg / day throughout the study. However, patients in the sitagliptin group experienced more discontinuations due to lack of efficacy than in the glipizide group. Patients treated with sitagliptin showed a significant mean decrease in body weight from baseline compared to a significant weight gain seen in patients receiving glipizide (-1.5 vs +1.1 kg). In this study, the proinsulin / insulin ratio, a marker of insulin synthesis and release efficiency, improved with sitagliptin and worsened with glipizide treatment. The incidence of hypoglycemia in the sitagliptin group (4.9%) it was significantly lower than that in the glipizide group (32.0%).
A 24-week placebo-controlled study involving 660 patients was designed to evaluate the insulin sparing efficacy and safety of sitagliptin (100 mg once daily) added to insulin glargine with or without metformin (at least 1,500 mg) during intensification of insulin therapy. Baseline HbA1c was 8.74% and baseline insulin dose was 37 IU / day. Patients were instructed to titrate the insulin glargine dose based on fasting glucose values measured by fingerstick. At week 24, the increase in daily insulin dose was 19 IU / day in patients treated with sitagliptin and 24 IU / day in patients treated with palcebo. The reduction in HbA1c in patients treated with sitagliptin and insulin (with or without metformin) was -1.31% versus -0.87% in patients treated with placebo and insulin (with or without metformin), a difference of -0.45% [95% CI: -0.60, -0.29]. The incidence of hypoglycemia was 25.2% in patients treated with sitagliptin and insulin (with or without metformin) and 36.8% in patients treated with placebo and insulin (with or without metformin) . The difference was mainly due to a higher percentage of patients in the placebo group who experienced 3 or more episodes of hypoglycemia (9.4 vs. 19.1%). There was no difference in the incidence of severe hypoglycemia.
A study comparing sitagliptin 25 or 50 mg once daily and glipizide 2.5 to 20 mg / day was performed in patients with moderate to severe renal impairment. This study involved 423 patients with chronic renal impairment (estimated glomerular filtration rate
Another study comparing sitagliptin 25 mg once daily and glipizide 2.5 to 20 mg / day was performed in 129 patients with ESRD who were on dialysis. After 54 weeks, the mean reduction in HbA1c from baseline was -0.72% with sitagliptin and -0.87% with glipizide. In this study, the efficacy and safety profile of sitagliptin 25 mg once daily was generally similar to that observed in other monotherapy studies performed in patients with normal renal function. The incidence of hypoglycemia was not significantly different between the treatment groups (sitagliptin, 6.3%; glipizide, 10.8%).
In another study involving 91 patients with type 2 diabetes and chronic renal impairment (creatinine clearance
Pediatric population
The European Medicines Agency has deferred the obligation to submit the results of studies with Tesavel in one or more subsets of the pediatric population in type 2 diabetes mellitus (see section 4.2 for information on pediatric use).
05.2 Pharmacokinetic properties
Absorption
After oral administration of a 100 mg dose to healthy subjects, sitagliptin was rapidly absorbed, with peak plasma concentrations (median Tmax) 1 to 4 hours post-dose, the mean plasma AUC of sitagliptin was 8. 52 mcM • now, Cmax was 950 nM. The absolute bioavailability of sitagliptin is approximately 87%. Since coadministration of a high-fat meal with sitagliptin had no effect on pharmacokinetics, Tesavel can be administered independently of meals.
The plasma AUC of sitagliptin increased in a dose-proportional manner. Dose-proportionality was not established for Cmax and C24h (Cmax increased more than dose-proportionality and C24h increased to a lesser extent. with respect to dose-proportionality).
Distribution
The mean steady-state volume of distribution following a single 100 mg intravenous dose of sitagliptin to healthy subjects is approximately 198 liters. The fraction of sitagliptin bound to plasma proteins in a reversible manner is low (38%).
Biotransformation
Sitagliptin is eliminated unchanged primarily via the urine, and metabolism is a minor metabolic pathway. Approximately 79% of sitagliptin is excreted unchanged in the urine.
Following an oral [14C] sitagliptin dose, approximately 16% of the radioactivity was excreted as metabolites of sitagliptin. Traces of six metabolites of sitagliptin have been found and are not expected to contribute to the plasma DPP-4 inhibitory activity of sitagliptin. in vitro indicated that the enzyme primarily responsible for the limited metabolism of sitagliptin is CYP3A4, with a contribution from CYP2C8.
Data in vitro showed that sitagliptin is not an inhibitor of CYP isozymes CYP3A4, 2C8, 2C9, 2D6, 1A2, 2C19 or 2B6, and is not an inducer of CYP3A4 and CYP1A2.
Elimination
Following oral administration of [14C] sitagliptin to healthy subjects, approximately 100% of the administered radioactivity was eliminated in faeces (13%) or urine (87%) within one week of administration. The apparent terminal t1 / 2 following a 100 mg oral dose of sitagliptin was approximately 12.4 hours. Sitagliptin accumulates only minimally with multiple doses. Renal clearance was approximately 350 mL / min.
Elimination of sitagliptin occurs primarily via renal excretion and involves active tubular secretion. Sitagliptin is a substrate for the human organic anion transporter 3 (hOAT-3) which may be involved in the renal elimination of sitagliptin. The clinical relevance of hOAT-3 in the transport of sitagliptin has not been established. Sitagliptin is also a substrate of p -glycoprotein, which may also be involved in mediating the renal elimination of sitagliptin. However, ciclosporin, a p-glycoprotein inhibitor, did not reduce the renal clearance of sitagliptin. Sitagliptin is not a substrate for OCT2 or OAT1 or PEPT1 / 2 transporters. In vitro, sitagliptin did not inhibit OAT3 (IC50 = 160 mcM) or p-glycoprotein (up to 250 mcM) mediated transport at therapeutically relevant plasma concentrations. In a clinical study sitagliptin had a limited effect on plasma digoxin concentrations indicating that sitagliptin may be a weak inhibitor of p-glycoprotein.
Characteristics of patients
The pharmacokinetics of sitagliptin were generally similar in healthy subjects and in patients with type 2 diabetes.
Kidney damage
& EGRAVE; An open-label single-dose study was conducted to evaluate the pharmacokinetics of a reduced dose of sitagliptin (50 mg) in patients with varying degrees of chronic renal impairment compared to healthy normal control subjects. The study included patients with renal impairment classified by creatinine clearance as mild (50 to
Patients with mild renal impairment had no clinically significant increases in sitagliptin plasma concentrations compared with normal healthy controls. An approximately 2-fold increase in plasma AUC of sitagliptin was observed in patients with moderate renal impairment, and in patients with severe renal impairment and ESDR on hemodialysis an approximately 4-fold increase in plasma AUC was observed compared to healthy control subjects. Sitagliptin was removed to a limited extent by hemodialysis (13.5% over a 3 to 4 hour hemodialysis session starting 4 hours post-dose). To achieve plasma concentrations of sitagliptin similar to those found in patients with normal renal function, lower dosages are recommended in patients with moderate and severe renal impairment, as well as in patients with ESRD requiring dialysis (see section 4.2).
Hepatic impairment
No dose adjustment is required for Tesavel in patients with mild or moderate hepatic impairment (Child-Pugh score ≤ 9). There is no clinical experience in patients with severe hepatic impairment (Child-Pugh score> 9).
However, as sitagliptin is eliminated primarily via the kidney, severe hepatic impairment is not expected to affect the pharmacokinetics of sitagliptin.
Senior citizens
No dose adjustment is required based on age. Age did not have a clinically significant impact on the pharmacokinetics of sitagliptin based on data from a Phase I and Phase II population pharmacokinetic analysis. In the elderly (from 65 to 80 years), approximately 19% higher plasma concentrations of sitagliptin were observed than in young people.
Pediatric population
Studies with Tesavel have not been conducted in pediatric patients.
Other characteristics of patients
No dose adjustment is necessary based on gender, race, or body mass index (BMI). These characteristics did not have a clinically significant effect on sitagliptin pharmacokinetics based on data from a Phase I composite pharmacokinetic analysis and data from a Phase I and Phase II population pharmacokinetic analysis.
05.3 Preclinical safety data
In rodents, renal and hepatic toxicity were observed at systemic exposure values equal to 58 times the human exposure, while the no effect level was found at 19 times the human exposure. Incisor abnormalities were observed in rats at exposure levels equal to 67 times the human clinical exposure; the no-effect level for this event was 58-fold based on a 14-week rat study. The relevance of these data to humans is unknown. Transient physical signs related to treatment have been observed in dogs at exposure levels approximately 23 times the clinical exposure level, some of which suggest neural toxicity, such as open mouth breathing. , salivation, white foamy emesis, ataxia, tremor, decreased activity and / or bent posture. At doses equivalent to approximately 23 times the systemic exposure level in humans, very mild to mild skeletal muscle degeneration was also observed histologically. A no effect level for these events was found at exposure equal to 6 times the clinical exposure level.
Sitagliptin did not demonstrate genotoxicity in preclinical studies. Sitagliptin was not carcinogenic in mice. In rats there was an increase in the incidence of liver adenomas and carcinomas at systemic exposure levels equal to 58 times the human exposure. Since hepatotoxicity was shown to be correlated with the induction of liver cancer in the rat , this increased incidence of liver tumors in the rat is likely secondary to the chronic liver toxicity occurring at these high doses.
Due to the large margin of safety (19 times at this level with no effect), these neoplastic lesions are not considered relevant to the exposure circumstances in humans.
No adverse effects on fertility were observed in male and female rats treated with sitagliptin before and during mating.
In pre- / postnatal development studies conducted in rats sitagliptin showed no adverse effects.
Reproductive toxicity studies showed a slight treatment-related increase in the incidence of fetal rib malformations (absent, hypoplastic, and wavy ribs) in the offspring of rats at systemic exposure levels 29 times higher than human exposure levels. Maternal toxicity was observed in rabbits at exposure levels greater than 29 times the human exposure levels. Due to the wide safety margins, these findings do not suggest the presence of relevant reproductive risks in humans. Sitagliptin is secreted in appreciable quantities in the milk of lactating rats (milk / plasma ratio: 4: 1).
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Core of the tablet:
microcrystalline cellulose (E460)
calcium hydrogen phosphate anhydrous (E341)
croscarmellose sodium (E468)
magnesium stearate (E470b)
sodium stearyl fumarate
Tablet coating:
poly (vinyl alcohol)
macrogol 3350
talc (E553b)
titanium dioxide (E171)
red iron oxide (E172)
yellow 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
Opaque blisters (PVC / PE / PVDC and aluminum). Packs of 14, 28, 30, 56, 84, 90 or 98 film-coated tablets and 50 x 1 film-coated tablets in perforated unit dose blisters.
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
Merck Sharp & Dohme Ltd.
Hertford Road, Hoddesdon
Hertfordshire EN11 9BU
UK
Representative for Italy:
ADDENDA PHARMA S.r.l.
Viale Shakespeare, 47 - 00144 Rome
Dealership for sale: Sigma-Tau Industrie Farmaceutiche Riunite S.p.A.
Via Pontina km 30,400 - 00071 Pomezia (Rome)
08.0 MARKETING AUTHORIZATION NUMBER
EU / 1/07/435/001
EU / 1/07/435/002
EU / 1/07/435/003
EU / 1/07/435/004
EU / 1/07/435/005
EU / 1/07/435/006
EU / 1/07/435/019
EU / 1/07/435/020
038448015
038448027
038448039
038448041
038448054
038448066
038448193
038448205
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
Date of first authorization: 10 January 2008
Date of most recent renewal: 20 September 2012
10.0 DATE OF REVISION OF THE TEXT
25/06/2015
